Bio-Identical Hormone Therapy
Customized to Meet the Needs of Each Woman & Man
2245 Eastern Ave. • Baltimore, MD 21231
Phone 410.675.6046
Toll Free 855.859.2517
Fax 410.563.1147
www.pattersonparkpharmacy.com
[email protected]
2245 Eastern Ave. • Bal more, MD 21231
Phone 410.675.6046
Toll Free 855.859.2517
Fax 410.563.1147
www.pa ersonparkpharmacy.com
contact@pa ersonparkpharmacy.com
results.compounded
Table of Contents
Bio‐Iden cal Hormones ‐ an Introduc on
2
Bio‐Iden cal HRT for Women
5
Andropause and Testosterone Replacement for Men
11
Thyroid Hormone Replacement Therapy for Women and Men
14
Adrenal Dysfunc on
14
Suppor ng Abstracts and Reviews
15
This booklet contains numerous ideas to s mulate discussions regarding bio‐iden cal hormone replacement
therapy. We welcome the opportunity to work together with other health care professionals and their
pa ents to customize medica ons which meet each individual’s specific needs.
Your ques ons are always welcome!
©Storey Marke ng, All rights reserved.
1
What are Bio‐Iden cal Hormones?
Bio‐iden cal hormones have the same chemical structure as hormones that are made by the human body. The term “bio‐iden cal” does not indicate the
source of the hormone, but rather indicates that the chemical structure of the replacement hormone is iden cal to that of the hormone naturally found
in the human body. In order for a replacement hormone to fully replicate the func on of hormones which were originally naturally produced and present
in the human body, the chemical structure must exactly match the original. Bio‐iden cal hormones are able to follow normal metabolic pathways so
that essen al ac ve metabolites are formed in response to hormone replacement therapy.
Note that all other steroid
hormones are made from
pregnenolone and DHEA.
Researchers have long held that there are significant differences between hormones that are natural to humans (bio‐iden cal) and synthe c (including
horse) prepara ons. Side chains are added to a natural substance to create a synthe c product that can be patented by a manufacturer. A patented drug
can be profitable to mass produce, and therefore a drug company can afford to fund research as to the medica on’s use and effec veness. However, bio
‐iden cal substances can not be patented, so scien fic studies are less numerous on these natural hormones, as medical research is frequently funded by
drug companies. Structural differences that exist between human, synthe c, and animal hormones may be responsible for side effects that are
experienced when non‐bio‐iden cal hormones are used for replacement therapy.
The difference in chemical structure is obvious...
Progesterone USP
(bio‐iden cal, human)
Medroxyprogesterone
Acetate (synthe c)
Examples of bio‐iden cal hormones include estrone (E1), estradiol (E2), estriol (E3), progesterone, testosterone,
dehydroepiandrosterone (DHEA), and pregnenolone.
To summarize,
SYNTHETIC = SUBSTITUTION
BIO‐IDENTICAL = REPLACEMENT
Synthe c hormones are not found in humans, and are not iden cal in structure or func on to the
bio‐iden cal hormones they are intended to replace.
Bio‐iden cal Hormone Replacement Therapy: Clarifying Confusing Reports
Bio‐iden cal hormones have become a hot topic in the media, and recent reports are s mula ng discussions in women’s groups and among healthcare
professionals. Unfortunately, many commentaries erroneously report the drugs which were used in various studies, failing to differen ate manufactured
products from compounded hormones.
2
©Storey Marke ng, All rights reserved.
Misconcep ons of the meaning of the term “bio‐iden cal” are obvious when cri cs such as the physician who authored a November 2005 ACOG
Commi ee Opinion on bio‐iden cal hormones, indicate that “adver sing seeks to convince poten al users that the alterna ve treatment more closely
mimics the hormones in a woman's body because they are derived from plants” or that “horse urine is as natural as wild yam.” It is the structure of the
hormone, not its origin, that ul mately determines how it will be u lized and metabolized and the benefits and side effects that will be produced. While
concentrated urine from dehydrated pregnant mares contains estrogens, a major por on is equilin, an estrogen that is never produced naturally in
humans and does not follow normal human metabolic pathways. On the other hand, plant‐derived hormones have a chemical structure that is iden cal
to that of human hormones. The basis for the use of bio‐iden cal estrogens, progesterone, and androgens is physiologic. A similar analogy could be
made with insulin. For many years, only pork and beef insulin were available to treat humans, but recombinant DNA technology now allows for mass
produc on of insulin that is structurally iden cal to human insulin, and pa ents with diabetes have benefited tremendously.
In response to a prescrip on from a licensed prac oner, compounding pharmacists prepare customized dosage forms containing the prescribed
hormones in the precise dose for administra on by the most appropriate route for a specific pa ent, using FDA‐approved pharmaceu cal grade
chemicals with cer ficates of analysis to verify purity. These bulk chemicals originate from the same sources that supply pharmaceu cal manufacturers.
It is a misconcep on that pharmacists extract hormones from soy and other plant materials. Compounding pharmacies are regulated by the 50 state
boards of pharmacy and the U.S. Pharmacopeia. In Canada, the provincial Colleges of Pharmacy have jurisdic on over compounding prac ces.
Un l July 2002, hormone replacement therapy (HRT) was the standard for trea ng menopausal symptoms, and approximately 42% of women aged 50‐
74 years were taking HRT. Recent concerns stem from the results of the Heart and Estrogen/proges n Replacement Study (HERS) and Women's Health
Ini a ve (WHI) clinical trials. The Women’s Health Ini a ve (WHI) study was designed to iden fy the poten al risks and benefits of HRT, but evaluated
only NON‐bio‐iden cal synthe c hormones. For women taking conjugated equine estrogen (CEE) alone, the WHI reported a slightly increased risk of
stroke. For women taking the CEE+proges n (medroxyprogesterone acetate) combina on, researchers found an increased risk of heart disease, breast
cancer, stroke, blood clots, and demen a. Benefits of HRT noted in the WHI study include a decreased risk of osteoporosis‐related hip fractures and
colorectal cancer. The WHI's study popula on consisted of older postmenopausal women. Par cipants were an average age of 63 at the start of the trial.
A more complete analysis of data from the WHI suggests that there is a reduced risk of heart disease if women begin estrogen early in their
postmenopausal years. The data analysis revealed par cipants age 50 to 59 who took estrogen experienced fewer heart a acks and deaths from
coronary artery disease than study par cipants who took a placebo.
Following publica on of WHI results, sales of all commercial hormone therapy products plummeted and hormone therapy exposure declined to 28% of
women aged 50‐74 years. The greatest reduc on in hormone use was among the oral estrogen and oral estrogen/proges n prepara ons, and the
market and demand for customized hormones has grown in the light of media a en on. Sales of bio‐iden cal hormones have soared, while sales of
Wyeth's products declined from approximately $1 billion in 2002 to $850 million by 2004.
O en, nega ve publicity or a empts to restrict the availability of bio‐iden cal hormones originate with pharmaceu cal manufacturers who have a
significant interest in protec ng their market share. For example, in October, 2005, Wyeth filed a ci zen’s pe on with the FDA asking the agency to
take ac on against pharmacies that compound bio‐iden cal hormones. Many women, doctors, and pharmacists viewed the complaint as a classic case of
Big Pharma throwing its weight around against small businesses and seeking to remove an important element of choice for suffering pa ents. Over
50,000 pa ents, physicians and pharmacists filed comments on the FDA Docket in opposi on to Wyeth's posi on.
Medical evidence does indicate that therapeu c benefits and side effects vary based on whether a hormone is administered orally or transdermally,
and that “bio‐iden cal hormones” may offer therapeu c advantages over non‐bio‐iden cal synthe c hormones. The Postmenopausal Estrogen/
Proges n Interven ons (PEPI) trial, a 3‐year mul center, randomized, double‐blind, placebo‐controlled study of 875 healthy postmenopausal women,
confirmed that synthe c proges ns such as medroxyprogesterone acetate par ally negate the beneficial effects on cholesterol levels that result from
taking estrogen, while progesterone maintains the benefits of estrogen on lipid and cholesterol profiles and minimizes the side effects associated with
MPA. Addi onal studies report that progesterone may enhance the beneficial effect of estrogen on exercise‐induced myocardial ischemia in
postmenopausal women (in contrast to MPA). On the other hand, clinical trials have reported that the risk of breast cancer is increased by long‐term
exposure to conjugated equine estrogens, and further increases when synthe c MPA is added to the regimen.
Progesterone was not inves gated in the WHI study, which studied the progesterone analogue or “proges n” medroxyprogesterone acetate (MPA).
MPA and progesterone both protect the uterus from the prolifera ve effects of estrogen, but their benefit and side effect profiles are quite different.
Unfortunately, the terms “progesterone” and “proges n” are incorrectly used interchangeably, not only in the lay press but also by reputable medical
journals and professionals, resul ng in confusion.
In November 2005, the American Society for Reproduc ve Medicine (ASRM) convened a mul disciplinary group of healthcare providers to discuss the
efficacy and risks of hormone therapy for symptoma c women. The recognized experts made presenta ons focused on hormones as an op on for
trea ng vasomotor symptoms, vulvovaginal problems, mood/depression, and changes in sleep and sexual func on associated with the onset of
menopause. The group concluded that “healthy symptoma c women should be offered the op on of hormone therapy for menopausal symptoms.
Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may
provide an overall improvement in quality of life. Hormone therapy should be individualized for symptoma c women. This involves tailoring the regimen
and dose to individual needs.”
Today’s women are seeking a be er quality of life. In a survey of a na onally representa ve sample of 1,009 women aged 40 and older, 83% said they
would prefer to use bio‐iden cal hormones. Sharonne Hayes, M.D., cardiologist and director of the Women's Heart Clinic at Mayo Clinic, Rochester, MN,
tells pa ents: "The absolute risk to an individual woman taking hormone therapy is quite low and may be acceptable to you depending on your
symptoms." For some women, the benefits of therapy outweigh the poten al risks.
A decision about HRT is best made taking a broad, long term view of health goals, symptoms, and lifestyle. Smoking cessa on, weight management,
and exercise should be employed to reduce risk factors (such as high cholesterol and blood pressure) for heart a ack or stroke.
The decision to use any form of HRT should only be made following a thorough medical examina on and evalua on of baseline hormone levels, and
women receiving HRT should be regularly monitored to allow prac oners to use the lowest dose of hormones that will provide therapeu c benefit,
thereby minimizing the risk of side effects.
©Storey Marke ng, All rights reserved.
3
JAMA July 17, 2002; 288:321‐333
J Natl Cancer Inst 1997 Aug 6;89(15):1110‐6
Curr Opin Oncol 2001 Sep;13(5):384‐9
J Am Coll Cardiology 36(7), December 2000: 2154‐9
J Am Coll Cardiology March 1, 1997: 671‐5
h p://www.medscape.com/viewar cle/516138
Business Week Online, April 13, 2006
Chem Res Toxicol 1998, (11) 94 ‐101
Steroids 2000 Oct‐Nov;65(10‐11):659‐64
JAMA Jan. 18, 1995, 273(3): 199‐208
Nature Medicine 3(3): 324‐7
h p://www.medscape.com/viewar cle/537095 posted 08/17/2006
h p://www.usatoday.com/news/health/2005‐11‐06‐bioiden cal‐hormones_x.htm
h p://www.mayoclinic.com/health/hormone‐therapy/WO00046 May 5, 2006
The Evolu on of Bio‐Iden cal HRT
Our knowledge of steroid metabolism has improved drama cally in the last 50 years, yet unfortunately, many women s ll receive much the same
therapy as was prescribed 25 years ago when synthe c proges ns were added to conjugated estrogen therapy once it was realized that unopposed
estrogen caused uterine cancer. We now know that proges ns cause other serious nega ve effects, such as increased risk of breast cancer and
cardiovascular disease; synthe c proges ns are not an acceptable subs tute for bio‐iden cal “natural” progesterone; and oral administra on of
hormones may be subop mal as transdermal delivery has significant advantages.
Orally ingested hormones are significantly processed in the gut lumen before going directly to the liver via the portal vein (“first‐pass metabolism”)
where hormones are extensively metabolized prior to entering the systemic circula on. However, endogenous hormones which are produced by an
endocrine gland (e.g., estradiol from the ovaries) are more likely to reach receptors on target ssues prior to being metabolized. For example, much of
the estradiol produced endogenously does not reach the liver un l a er it has passed through and exerted an effect upon other ssues such as breast,
brain and bone. The same is basically true of hormones applied transdermally to non‐abdominal skin.
When administered orally, hormones reach the liver in a much more direct, concentrated way than endogenous hormones, resul ng in changes in the
hepa c synthesis of various proteins, such as clo ng factors, sex hormone‐binding globulin and thyroid‐binding globulin. The net effects can vary with
dose in a given individual, from person to person with the same dose, and also with me in the same individual as the liver adapts to the stress of oral
estrogen.
The effects of oral inges on of estrogens are unpredictable; the liver may be overburdened; unwanted pa erns of metabolites may be produced; and
the impact on cardiovascular func on may vary. In general, adverse side effects secondary to oral estrogens may indicate that the liver is under stress
and that a dose reduc on or change to a different route of administra on should be considered.
To more closely simulate endogenous estrogen produc on, estrogens can be administered transdermally as divided dose creams, which also avoids the
problem of skin irrita on from patch adhesive. Transdermally administered estradiol does not exert adverse effects on parameters that affect
cardiovascular health; does not nega vely affect clo ng parameters,1,2,3 has resulted in a decrease in the number of hypertensive women with le
ventricular hypertrophy (a er 18 months, compared to placebo);4 and decreases triglycerides.5
Many human and animal studies have indicated that estradiol exerts posi ve effects on parameters influencing cardiac disease, including vasodila on,
reduc on of vascular prolifera ve and inflammatory responses, and decreased sympathe c ac vity. However, the Women’s Health Ini a ve (WHI) trial
indicated that oral conjugated estrogens and oral medroxyprogesterone acetate increased cardiac risk. “This apparent paradox is resolved by realizing
that there are many studies that indicate that medroxyprogesterone acetate is detrimental to cardiovascular func on.”
The choice and ra o of estrogens used for hormone replacement therapy is crucial. Like estradiol, estriol is an estrogen that is naturally present in the
body. One of the unique aspects of estriol is that it is an end metabolite that is not systemically back‐converted to estrone or estradiol to any
appreciable extent, nor is estriol subject to conversion to poten ally carcinogenic catecholestrogen metabolites. In North America, estriol is typically
dosed at 2 mg/day either orally or transdermally, whereas doses of 0.5 mg daily or every other day are common in other countries where estriol has
been studied more extensively. Due to the poten al for accumula on, conserva ve dosing is encouraged.
“One rarely considered aspect of the use of progesterone versus proges ns is the synergy between estradiol and progesterone; each is required for the
op mal expression of the other’s receptors. Progesterone turns on estradiol receptor expression and has also been shown to elevate serum estradiol
levels. Nahoul demonstrated that vaginal administra on of progesterone resulted in an eleva on of serum estradiol, which was similar in magnitude and
dura on to the oral administra on of 0.5 mg of estradiol.6 Therefore, concurrent use of progesterone with estrogen (estradiol or estrone) should allow
for lower dosing of estrogen.”
Up to 43% of menopausal women experience a reduc on in sexual func oning and a decreased sense of well being due to reduc on in normal
testosterone levels, despite estrogen replacement. A er surgically‐induced menopause (hysterectomy), testosterone levels can drop by as much as 50%.
Compounding pharmacies can formulate testosterone in doses and dosage forms that are appropriate for women.
Gillson and Zava conclude “there is a lot of evidence suppor ng BHRT [Bio‐iden cal Hormone Replacement Therapy], but no big trials… Regarding BHRT
and conven onal HRT (conjugated estrogens/proges n), each prac oner has to consider all of the evidence and decide whether the small trials that
show benefits outweigh the large trials that conclusively demonstrate harm, since there is no longer any clear standard of care.”8
HRT should op mize func on and prevent morbidity due to aging, without causing harm.
A study done at Beth Israel Deaconess Medical Centre and Harvard Medical School reported that postmenopausal women who choose hormone
replacement therapy (HRT) o en discon nue this therapy within one year, most frequently due to side effects such as bloa ng and breast swelling/
tenderness.7 At the Research Triangle Ins tute in North Carolina, researchers concluded that clinicians may influence HRT con nua on rates through
ini al drug choice or modifica ons in drug type or regimen over the course of therapy.9 If hormone‐related problems could be solved without using
replacement hormones that produce intolerable side effects, it would be reasonable to expect long‐term compliance to increase.
When a physiologic balance is restored using bio‐iden cal hormones such as estriol, estradiol, progesterone, testosterone, and cor sol, many symptoms
4
©Storey Marke ng, All rights reserved.
a ributed to hormone decline can be eliminated. Based on results of laboratory tests, symptoms, and response to therapy, doses of individual bio‐
iden cal hormones can be adjusted and administered in the most appropriate dosage form to meet each woman’s specific needs, while minimizing the
risk of side effects.
1
2
3
4
N Engl J Med. 1997;336:683‐690
Arterioscler Thromb Vasc Biol. 1997;17:3071‐3078
5
Climacteric. 2001;4:228‐234
7
J Womens Health Gend Based Med. 2001 May;10(4):343‐50
9
Menopause. 2001 Sep‐Oct;8(5):377‐83
Thromb Haemost. 2001;85:619‐625
Am J Hypertens. 1999;12:1000‐1008
6
J Steroid Biochem. 1985;23:1065‐1070
8
Int’l J of Pharmaceu cal Compounding, 7(4), July/August 2003 and 7(5), Sept/Oct 2003
Bio‐Iden cal HRT for Women
Hormone related symptoms or problems occur throughout the feminine life cycle.
 Dysmenorrhea (cramps)
 Premenstrual Syndrome (PMS)
 Infer lity/Endometriosis
 Irregular menstrual periods
 Fibrocys c breasts
 Premenopausal symptoms
 Weight gain
 Mood swings
 Reduced libido
 Vaginal thinning/Dryness
 Painful intercourse
 Hot flashes
 Night sweats
 Depression
 Poor concentra on/Memory lapses
 Insomnia/Disturbed sleep
 Heart disease/Arteriosclerosis
 Osteoporosis
Goals of Bio‐Iden cal HRT
 Alleviate the symptoms caused by the natural decrease in produc on of hormones by the body
 Restore the protec ve benefits which were originally provided by naturally occurring hormones
 Re‐establish a hormonal balance
The three types of hormones typically prescribed for bio‐iden cal hormone replacement therapy (HRT) are estrogens, progesterone, and androgens.
The precise components of each woman’s therapy need to be determined a er physical examina on, medical history, and laboratory tes ng are
considered. Close monitoring is essen al to ensure that appropriate dosage adjustments are made.
Estrogens:
 estrone (E1), estradiol (E2), and estriol (E3) are o en prescribed in combina on to re‐establish a normal physiologic balance.
 relieve menopausal symptoms, including vaginal thinning and dryness.
 may increase HDL “good” cholesterol and decrease LDL “bad” cholesterol.
 help to decrease blood pressure and reduce plaque forma on on the arterial walls.
 reduce the risk of colorectal cancer.
 may improve mood, energy levels, and sleep pa erns.
 may reduce the risk of developing or the severity of type 2 diabetes.
 may improve memory and cogni ve func on.
 reduce bone loss.
The term “estrogen” actually refers to a group of related hormones, each with a unique profile of ac vity. Under normal circumstances, a woman’s
circula ng estrogen levels fluctuate based on her menstrual cycle. For Hormone Replacement Therapy, these hormones are o en prescribed in
combina on to re‐establish a normal physiologic balance. The three main estrogens produced in female humans are:
 Estrone ‐E1‐ (10‐20% of circula ng estrogens) is the primary estrogen produced a er menopause
 Estradiol ‐E2‐ (10‐30% of circula ng estrogens) is the most potent and major secretory product of the ovary, and the predominant estrogen
produced before menopause. Estradiol is the primary estrogen of ovarian origin and the major form of estrogen in pre‐menopausal women.
 Estriol ‐E3‐ (60‐80% of circula ng estrogens) is thought to be protec ve against breast cancer. Estriol causes li le or no buildup of the endometrium
(uterine lining), and is very effec ve in allevia ng vaginal and urinary symptoms in postmenopausal women. Estriol has been shown to be clinically
effec ve for the treatment of menopausal symptoms as well as postmenopausal problems including vaginal atrophy, dryness, vaginal infec ons,
painful intercourse, and various condi ons of the urinary tract. Estriol is produced in very large amounts during pregnancy and may be protec ve
against breast cancer. High levels of estriol are found in vegetarians and Asian women, who have a much lower incidence of breast cancer.
©Storey Marke ng, All rights reserved.
5
In an a empt to develop an inexpensive form of estrogen, Willard Allen extracted an estrogenic product from the urine of a pregnant mare in the 1950s.
It was cheap and easy to obtain, and also had fewer side effects than some of the previous hormones extracted from animals. Given the lack of any
compe on and backed by a massive adver sing campaign, this “pregnant mare’s urine” quickly gained a dominance in the market that has been
maintained to the present me. Approximately 75% of “conjugated equine estrogens” is estrone, a hormone that is also produced by human females, but
as a much lower percentage of total estrogen. However, horses also excrete more than ten other forms of estrogen into their urine. These hormones are
not bio‐iden cal ‐ or biologically equivalent ‐ to the other two main types of estrogen ‐ estriol and estradiol ‐ that occur naturally in women. Drs.
Whitehead and Campbell, two leading menopause researchers in England, did studies of the potencies of the different types of estrogens and the effects
of the various horse estrogens on different target organs in the body. They showed that conjugated equine estrogens are about three mes more potent
than bio‐iden cal estrogens in s mula ng the liver of a woman to produce renin, a substrate used to make angiotensin, which causes increased blood
pressure. None of the serious concerns raised by this research have been addressed by further studies in North America. It is also important to note that
all of the studies indica ng that estrogen replacement therapy leads to an increased risk of breast cancer were done using conjugated estrogens, the
metabolites of which may have carcinogenic poten al.
Structural differences in the estrogen molecules may account for some of the unpleasant side effects experienced by many women who take horse
estrogens for HRT. Women report that natural bio‐iden cal hormones are be er tolerated.
Since women are living longer, on average 20‐40 years a er the end of the reproduc ve years, osteoporosis and heart disease may become more of a
reality, not just a risk. One in two American women is at risk of fracture due to osteoporosis, and one in three women a er the age of 65 develops heart
disease. Risk factors include, but are not limited to, a decline in estrogen and progesterone levels, diet, gene cs, and level of ac vity.
Heart disease is the most common cause of death in women in nearly all industrialized countries. It is believed that this is because the protec ve effect of
naturally‐occurring estrogens is lost in post‐menopausal women, raising their cardiovascular risk to that of men. Estrogens appear to be cardioprotec ve,
increasing HDL “good” cholesterol and decreasing LDL “bad” cholesterol. Estrogen has a relaxing factor in the smooth muscle cells which regulate the
body’s blood flow. This allows the arterial walls to remain flexible. The hormone also has the ability to inac vate nitric oxide (a substance present in the
human body) which may help to decrease blood pressure and reduce plaque forma on on the arterial walls.
Colorectal cancer is the fourth most common cancer and the second cause of cancer deaths, a er lung cancer. Approximately half of the pa ents
diagnosed with colorectal cancer are women. An analysis of 18 studies involving thousands of women concluded that the risk of developing colorectal
cancer is reduced by 34% in current estrogen users. A longer dura on of current use did not appear to offer greater protec on. The protec ve effect
appears to wane once estrogen therapy is stopped, and disappeared five years a er estrogen therapy was discon nued. When making a decision
regarding use of estrogen replacement therapy in postmenopausal women, a reduced risk of colorectal cancer should be considered as an addi onal
benefit.
Upon ini a on of bio‐iden cal hormone replacement therapy, many women experience a significant improvement in energy levels, sleep pa erns,
memory and libido. Dr. E.L. Klaiber found that estrogen therapy is effec ve in improving mood in women who have not responded to more tradi onal
an depressants.
A study in the Journal of the American Medical Associa on found that post‐menopausal women who take estrogen replacement therapy (ERT) have
increased brain func on and memory retrieval pa erns. The ac vity that was observed is similar to that seen in the brains of younger women. While
women were receiving ERT, magne c resonance imaging (MRI) of their brains was obtained as they performed verbal and nonverbal memory tasks. The
parts of the brain where increased ac vity was observed are associated with types of memory func on that are required many mes each day, such as
recalling telephone numbers.
Reports suggest that ERT may reduce the risk of developing type 2 diabetes or may reduce the severity of the disease. A study of over 14,000 women of
various ethnic backgrounds found that hyperglycemia was more o en controlled by diet alone (no hypoglycemic medica on) in women using ERT versus
non‐users. A survey of 418 postmenopausal women suggested that women who had never used ERT were nearly five mes more likely to develop type 2
diabetes. Another report discussed the effect of ERT on the beta cells of the pancreas ‐ where insulin is made. The beta cells appear to func on more
effec vely in pa ents receiving ERT. It is quite important that diabe c pa ents receiving ERT have lipids monitored rou nely, as ERT may raise plasma
triglycerides.
Oral versus Transdermal Estrogen: Contras ng Effects on C‐Reac ve Protein
C‐reac ve protein (CRP) is one of the main independent predictors of cardiovascular events. Oral post‐menopausal estrogen replacement therapy (ERT)
increases CRP levels by a first‐pass hepa c effect. These elevated levels of CRP may be responsible for the early increased cardiovascular risk that has
been reported shortly a er women begin oral combined hormone replacement therapy (HRT) using NON bio‐iden cal synthe c hormones. However,
transdermal 17beta‐estradiol has shown no significant effect on CRP in either short‐term or long‐term use.
The incidence of ischemic heart disease shows a sharp rise a er menopause. However, the effects of HRT on cardiovascular disease are s ll controversial.
Kawano et al. compared the effects of HRT on endothelial func on, cellular an oxidant system and inflamma on between oral and transdermal
administra on in mild hypercholesterolemic postmenopausal women. Transdermal bio‐iden cal estradiol replacement was administrated to 12 pa ents
for 12 weeks, and oral conjugated equine estrogen was administrated to 12 pa ents for 12 weeks. The vasodila on of the brachial artery increased with
HRT, and thioredoxin levels (a marker of the cytoprotec ve an oxidant system) decreased with HRT. CRP levels increased with oral HRT while
transdermal HRT did not elicit any changes. Both oral and transdermal HRT improved endothelial func on and decreased oxida ve stress through
affec ng the cellular redox state.
6
©Storey Marke ng, All rights reserved.
Abbas et al. of the University of Texas, found that synthe c oral conjugated estrogens significantly increased levels of serum amyloid A (SAA), HDL, and
HDL‐SAA, whereas transdermal estradiol reduced both SAA and HDL‐SAA but had no effect on HDL in the same women. They concluded that the effect
was due to first‐pass hepa c mechanism on oral estrogens.
At the University of Connec cut Health Center, a randomized, double‐blind, placebo‐controlled study evaluated the effect of 3 doses (0.25 mg/day, 0.5
mg/day, and 1 mg/day) of micronized 17beta‐estradiol (E2) on CRP, interleukin‐6, and lipids, compared with placebo, in healthy older women
par cipa ng in an osteoporosis study, and found that a er 12 weeks of treatment, CRP decreased 59% in the 0.25 mg/day E2 group and increased 65%
in the 1 mg/day E2 group, compared with placebo. The CRP level con nued to be elevated 12 weeks a er treatment was discon nued in the 1 mg/day
E2 group. HDL and HDL2 cholesterol increased and LDL cholesterol decreased at 12 weeks in the 1 mg/day E2 group, with a significant dose‐response
effect. Therefore, low‐dose E2 decreased CRP, but did not affect lipid parameters, whereas the highest dose increased CRP and had a beneficial effect on
lipid parameters. This study indicates that estradiol dose should be considered when risk:benefit ra os are evaluated for individual women before ERT is
ini ated.
A Finnish study reported that oral but not transdermal estradiol combined with cyclic NETA (synthe c proges n) increased hs‐CRP levels. A placebo‐
controlled study of 27 healthy postmenopausal women showed that 12 weeks of oral but not transdermal estradiol (unopposed by proges n) was
associated with an increase in CRP.
In another placebo‐controlled study in healthy women using oral conjugated equine estrogens and transdermal estradiol (both with oral sequen al
medroxyprogesterone acetate), only oral treatment with NON‐bio‐iden cal hormones increased CRP during 6 and 12 months of therapy.
No published studies describe the effects on CRP produced by bio‐iden cal estriol or a balanced ra o of bio‐iden cal hormones. In conclusion, our
review underscores the importance of customized HRT, using the hormones and route of administra on that are most appropriate for each pa ent,
while considering medical history and treatment goals.
Arterioscler Thromb Vasc Biol. 2004 Oct;24(10):e164‐7
Maturitas. 2003 Dec 10;46(4):245‐53
Thromb Haemost. 2003 Jul;90(1):124‐31
Thromb Haemost. 2001 Apr;85(4):619‐25
Int J Clin Pharmacol Ther. 2003 Aug;41(8):346‐53
Hum Reprod. 2003 Apr;18(4):866‐70
Am J Cardiol. 2003 Jul 15;92(2):212‐4
Progesterone:
 is commonly prescribed for perimenopausal women to counteract “estrogen dominance.”
 alone, or combined with estrogen, may improve Bone Mineral Density.
 minimizes the risk of endometrial cancer in women who are receiving estrogen.
 is preferred by women who had previously taken synthe c proges ns, according to one Mayo Clinic study.
 may enhance the beneficial effect of estrogen on lipid and cholesterol profiles and exercise‐induced myocardial ischemia in postmenopausal
women (in contrast to medroxyprogesterone acetate).
Progesterone is a term that is incorrectly used interchangeably to describe both natural bio‐iden cal progesterone and synthe c subs tutes.
Synthe c proges ns (also called progestogens or progesta onal agents) are analogues of bio‐iden cal progesterone, and have been developed because
they are longer‐las ng, more potent, and patentable. Medroxyprogesterone acetate, the most commonly used synthe c proges n, was shown in a large
study to cause significant lowering of HDL “good” cholesterol, thereby decreasing the cardioprotec ve benefit of estrogen therapy. Bio‐iden cal
progesterone has never been shown to have any serious side effects. However, proges ns can have significant and serious side effects at typical doses,
including migraine headache, weight gain, mood swings, depression, irritability, acne, menstrual irregulari es, and fluid reten on. These side effects are
a frequent cause for discon nua on of HRT. Only about 20% of women who start synthe c HRT remain on it two years later.
Vasomotor flushing is the most bothersome complaint of menopause, and is the most common reason women seek HRT and remain compliant. For over
40 years, estrogens have been the mainstay of treatment of hot flashes, but a recent study showed transdermal progesterone cream to be effec ve as
well.
Women who have had postpartum depression once have about a 68% chance of having it again a er another pregnancy, but trials using prophylac c
progesterone have shown that it is possible to reduce this recurrence rate to 7%.
A study conducted at three pres gious loca ons, including the Yale University School of Medicine, concluded that natural progesterone, but not
medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise‐induced myocardial ischemia in postmenopausal women.
Miyagawa et al. of Oregon Health Sciences University and USC School of Medicine compared synthe c medroxyprogesterone acetate (MPA) with natural
progesterone as the proges n in HRT and studied the corresponding effect on coronary artery vasospasm in ovariectomized primates. MPA was shown
in primate studies to constrict coronary arteries, causing vasospasm and myocardial infarc on, while natural progesterone dilated coronary arteries.
Progesterone plus estradiol protected against vasospasm, but MPA plus estradiol did not. Studies have also demonstrated arterial plaque forma on
in ovariectomized primates. However, the group treated with bio‐iden cal estrogen had 50% less plaque forma on than the control group. In the past,
the choice of MPA over progesterone has been based on familiarity and convenience. Based on these results, formula ons of natural bio‐iden cal
progesterone would appear to offer the wiser alterna ve.
The Postmenopausal Estrogen/Proges n Interven ons (PEPI) Trial, a 3‐year mul center, randomized, double‐blind, placebo‐controlled study of 875
healthy postmenopausal women, confirmed that synthe c proges ns par ally negate the beneficial effects on cholesterol levels that result from taking
©Storey Marke ng, All rights reserved.
7
estrogen. Natural progesterone, on the other hand, maintains all the benefits of estrogen on cholesterol without any of the side effects associated
with synthe c proges ns, such as medroxyprogesterone acetate.
Progesterone is commonly prescribed for perimenopausal women to counteract “estrogen dominance.” Perimenopause is the me between the onset
of changes in hormonal secre ons and menopause, and is characterized by fluctua ng hormones. Estrogen dominance occurs when a woman produces
smaller amounts of progesterone than normal rela ve to estrogen levels.
The benefits of progesterone are not limited to preven on of endometrial cancer in women who are receiving estrogen replacement. Progesterone
therapy is not only needed by women who have an “intact uterus”, but is also valuable for women who have had a hysterectomy. Progesterone
builds bone density, promotes glucose u liza on, and improves sleep pa erns and libido.
The role of natural progesterone as a bone‐building hormone has received considerable a en on. Many individuals associate osteoporosis with low
estrogen levels. However, significant bone loss occurs during the 10 to 15 years before menopause when estrogen levels are s ll normal. Jerilynn Prior,
M.D., of the University of Bri sh Columbia, has presented evidence that progesterone can s mulate new bone forma on in women with
osteoporosis. Dr. Prior measured estrogen and progesterone levels in female marathon runners who had osteoporosis. Although their estrogen levels
were s ll high, they had stopped ovula ng (common in female athletes) and progesterone levels had fallen, triggering the onset of osteoporosis. This can
indicate a role for progesterone use, alone or combined with estrogen which reduces bone loss, in improving Bone Mineral Density.
Progesterone vs. Proges ns
Progesterone is a term that is o en used incorrectly to describe both “natural” bio‐iden cal progesterone and synthe c proges ns (also called
progestogens). Proges ns are deriva ves which were developed prior to the availability of micronized progesterone to provide an oral prepara on that
could be patented, and therefore profitable to manufacture. Progesterone and proges ns exert an an prolifera ve effect on uterine endometrium in
women who are receiving estrogen replacement. However, progesterone therapy is also valuable for women who have had a hysterectomy, as there are
progesterone receptors throughout the body. Studies at Wake Forest University School of Medicine have concluded that bio‐iden cal progesterone
protects against vasospasm.1 In contrast, synthe c proges ns par ally negate the beneficial effects on cholesterol levels that result from taking
estrogen2, increase the progression of coronary artery atherosclerosis and the poten al for development of clots and atherosclero c plaques, promote
insulin resistance and consequent hyperglycemia, and can significantly lower high density lipoproteins.3,4
Mayo Clinic researchers surveyed 176 women taking bio‐iden cal micronized progesterone who had previously taken synthe c proges ns. A er one to
six months, the women reported an overall 34% increase in sa sfac on on progesterone compared to their previous HRT, repor ng these improvements:
50% in hot flashes, 42% in depression, and 47% in anxiety. Micronized progesterone also more effec vely controlled breakthrough bleeding.5
Despite its efficacy, oral progesterone has several poten al drawbacks. Since commercially‐available progesterone capsules contain peanut oil, it poses a
problem for individuals who are allergic to peanuts. Compounding pharmacies can prepare capsules that are free of peanut oil; however, oral
progesterone is not well tolerated by some women, with side effects that include nausea, breast swelling, dizziness, drowsiness, and depression. Oral
progesterone also undergoes a substan al amount of first‐pass gut and liver metabolism, and metabolites such as allopregnanolone and
deoxycor costerone may be responsible for the side effects.6
Transdermal progesterone cream has been widely used over the past 20 years as an alterna ve to oral progesterone and proges ns. Progesterone cream
(20 mg/day) given to postmenopausal women for 1 year (without estrogen replacement therapy) relieved vasomotor symptoms in 83% of women, versus
19% of women given placebo.7 Progesterone is necessary to prime estradiol receptors and may elevate endogenous estradiol levels; therefore, provision
of progesterone alone is able to affect symptoms such as vasomotor complaints thought to be related primarily to low estrogen levels. When
progesterone is properly concentrated in an appropriate base, various studies have shown that transdermal delivery can produce serum total
progesterone levels of 1 to 3 ng/mL that are adequate to protect against endometrial prolifera on.
Gillson and Zava recommend that women who have not undergone a hysterectomy and use progesterone and estrogen(s) should be monitored with
ultrasound and/or endometrial biopsy as indicated to evaluate the status of the endometrium. Oral proges ns exert a much stronger suppressant effect
on the endometrium, which reduces concerns about endometrial prolifera on, but unfortunately the protec on is achieved at the expense of side effects
including increased risk of cancer and cardiovascular and thromboembolic disease; and induc on of an atrophic ssue state, with increased risk of
breakthrough bleeding.8
1
2
3
4
J Reprod Med 2000 Mar;45(3 Suppl):245‐58
Nature Medicine, 3(3): 324‐7
5
Mayo Clinic Women’s Healthsource Aug 1999
7
Obstet Gynecol 1999 Aug;94(2):225‐8
JAMA, Jan. 18, 1995, 273(3): 199‐208
J Am Coll Cardio March 1, 1997: 671‐5
6
Br J Obstet Gynaecol 1984;91:1111‐1119
8
Int’l J of Pharm Comp. 7(5), Sept/Oct 2003
Influence of Route of Administra on on Progesterone Metabolism
Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography‐mass spectrometry, respec vely,
a er inges on of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that
induced a hypno c state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of
progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a
peak between 2 and 6 hours a er oral progesterone administra on. Significant quan es of five compounds (progesterone, 5 alpha‐pregnan‐3 alpha‐ol‐
20‐one, 5 beta‐pregnan‐3 alpha‐ol‐20‐one, 5 beta‐pregnan‐3 alpha,20 beta‐diol, and 5 beta‐pregnan‐3 alpha‐ol‐11,20‐dione) that have been reported to
possess anesthe c quali es were iden fied. The seda ve and hypno c effects of oral administra on of progesterone may be mediated through those
compounds.
8
©Storey Marke ng, All rights reserved.
A separate crossover study found that while inducing similar progesterone levels, the ra o of 5 alpha‐ and 5 beta‐pregnanolone/progesterone plasma
concentra ons drama cally increased a er oral as opposed to vaginal administra on. Therefore, “specific benefit may be expected from oral
administra on on mood and sleep disturbances in postmenopausal women or in women suffering from premenstrual symptoms of anxiety, while vaginal
administra on may induce more predictable endometrial secretory changes without detectable influence on the central nervous system.”
Am J Obstet Gynecol 1988 Nov;159(5):1203‐9
Maturitas 1995 Apr;21(3):251‐7
Bio‐iden cal progesterone can be administered as a micronized powder in an oral capsule, a lozenge or troche, transdermal cream or gel, vaginal or
rectal suppository, or intramuscular injec on. All of these dosage forms are available by prescrip on through our compounding pharmacy. There are a
number of commercial progesterone creams available over the counter (without a prescrip on); however, these products vary considerably as to their
actual progesterone content.
Androgens, such as testosterone and DHEA:
 enhance libido
 enhance bone building (increase calcium reten on)
 provide cardiovascular protec on (lower cholesterol)
 improve energy level and mental alertness
Androgens are hormones that are important to the integrity of skin, muscle, and bone in both males and females, and have an important role in
maintaining libido. DHEA (dehydroepiandrosterone) is an androgen precursor from which the body can derive testosterone. A er menopause, a woman’s
ovaries con nue to produce androgens; however, the majority of the androgens produced in the female body, even before menopause, come from
peripheral conversion of DHEA. As the body ages, produc on of DHEA declines so that by the me a woman goes through menopause, the produc on of
DHEA is o en inadequate.
Recently, a en on has turned to the addi on of the androgens to a woman’s HRT regimen in order to alleviate recalcitrant menopausal symptoms and
further protect against osteoporosis, loss of immune func on, obesity, and diabetes. Declines in serum testosterone are associated with hysterectomy,
menopause, and age‐related gender‐independent decreases in DHEA and DHEA‐sulfate. Addi onally, ERT may cause rela ve ovarian and adrenal
androgen deficiency, crea ng a ra onale for concurrent physiologic androgen replacement.
The diagnosis of female androgen insufficiency syndrome (FAIS) is made on the basis of clinical signs and symptoms and low levels of bioavailable
testosterone. Clinical symptoms of FAIS may include decreased libido and sexual pleasure; a diminished sense of well being; dysphoric mood and loss of
mo va on; and persistent unexplained fa gue. Signs include bone loss, decreased muscle mass and strength, and adipose ssue redistribu on. Although
FAIS remains formally undefined, there is evidence of poten ally therapeu c effects of androgen replacement on overall well being, mood, sexual
func on and bone health in women with low testosterone levels.
The androgens found in women in descending order of their concentra ons include dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone
(DHEA), androstenedione, testosterone (T), and dihydrotestosterone (DHT). Both the ovaries and adrenal glands produce androgens, and levels are at
least par ally regulated by pituitary hormones. Precursor hormones are also converted peripherally. Because androgens affect many organs including the
musculoskeletal and central nervous systems, androgen replacement therapy can have numerous beneficial effects. There is a need for formula ons of
testosterone therapy specifically designed for use in women, along with clear guidelines regarding op mal therapeu c doses and long‐term safety data.
In women, serum androgen levels decline about 50% between the ages of 20 and 40 years, due to the gradual reduc on in adrenal androgen produc on
and the loss of cyclical ovarian androgen. Unlike estrogen levels, testosterone levels do not change significantly at menopause, but decrease at a gradual
rate throughout a woman’s life me. Only 1% to 2% of total circula ng testosterone is free and biologically ac ve. The rest is bound by sex hormone‐
binding globulin (SHBG) and albumin. Women with pituitary or adrenal insufficiency or premature ovarian failure, or those who have a surgically induced
menopause also have reduced androgen produc on. Various drugs ‐ such as cor costeroids, thyroid hormone, and oral estrogens—may decrease
circula ng androgen levels. Increasing levels of estradiol increase SHBG and decrease testosterone levels, exacerba ng testosterone deficiency
syndromes. Condi ons that have been associated with androgen insufficiency include anorexia nervosa, rheumatoid arthri s, SLE, or HIV infec on.
Estrogen therapy in menopausal women improves vasomotor symptoms, vaginal dryness and general well being, but has li le or no benefit for low libido.
However, in women suffering from dyspareunia secondary to atrophic vagini s, estrogen replacement may improve libido secondary to relieving vaginal
symptoms. Testosterone has vasomotor effects, enhancing vaginal blood flow and lubrica on.
Androgen therapy should be combined with estrogen therapy since estrogen up‐regulates androgen receptors, thus facilita ng androgen expression;
estrogen may also modulate the adverse effects of androgens. The op mal replacement dose of estrogen that should be given with androgen treatment
is difficult to predetermine. This may depend on the amount of endogenous estrogen produced in a given individual and will differ between surgically and
naturally menopausal women, as the ovaries con nue to be an important source of androgen a er menopause. Also, in older and obese postmenopausal
women, there is an increased peripheral aroma za on of androgen to estrogen.
Androgens also play an important role in bone physiology. Aroma za on of androgens within bone to estrogen is important for maintenance of bone
mineraliza on. In postmenopausal women, androgen levels are posi vely correlated with bone mineral density (BMD), and low bioavailable testosterone
is associated with vertebral osteoporosis.
©Storey Marke ng, All rights reserved.
9
It is essen al that women have adequate estrogen levels prior to androgen replacement in order to avoid the unwanted side effects of unopposed
androgens. Therefore, a woman must be premenopausal with a regular menstrual cycle, or postmenopausal and receiving estrogen, prior to
commencing T therapy. If circula ng levels of free T are kept within the normal physiological range, masculinizing effects are very unlikely.
Contraindica on to testosterone therapy include pregnancy and lacta on, androgen‐dependent neoplasia, severe acne, hirsu sm, androgenic alopecia,
and a history of polycys c ovary syndrome.
The safety and efficacy of testosterone therapy depend on the dose and type of androgen used in the formula on, dura on of treatment, and route of
administra on, all of which significantly affect the blood levels that are a ained. In general, injectable testosterone is not recommended because of the
associated peaks and valleys and poten al for steroid accumula on. Currently available commercial prepara ons of oral micronized testosterone are
poorly absorbed. Hepa c side effects of androgen therapy in women are predominantly associated with the use of high doses of oral methyltestosterone
(MT) and other 17‐alkylated deriva ves. Oral androgens decrease HDL cholesterol concentra ons significantly, whereas transdermal or implanted
androgens appear to be lipid neutral. However, testosterone implants o en result in supraphysiological dosing in women, increasing the risk of adverse
effects. Transdermal testosterone formula ons have become well accepted in the treatment of testosterone deficiency in men and are currently being
developed in appropriate strengths for women. Both oral and parenteral administra on of androgens appear to have extremely different effects on
markers of cardiovascular risk.
Hormones sold over‐the‐counter (OTC) as dietary supplements vary widely in actual content from the strength stated on the label. Because the
pharmacokine cs and pharmacodynamics of both estrogen and androgens vary with their formula on, women should only use hormones from a trusted
source. Our compounding pharmacy prepares hormones in prescrip on strength exactly as ordered, using an analy cal balance to measure each drug.
Women who choose to receive androgen therapy should be aware that data on safety and efficacy are limited, and that the success of therapy will
depend not only on the prepara on, but the knowledge and experience of the health care team. Quo ng Morris Notelovitz, MD, Ph.D., MB BCh, FRCOG,
“the skill and art of medical prac ce is to know when and how to apply validated scien fic observa ons to the needs of the individual pa ent.”
References:
Hum Reprod Update. 2004 Sep‐Oct;10(5):421‐32. Epub 2004 Aug 05
Fer l Steril. 2001 Jul;76(1):32‐7
Menopause. 2004 Sep‐Oct;11(5):505‐7
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S14‐8
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S8‐13
The ar cles from Mayo Clinic Proceedings are available online. Go to h p://www.mayo.edu/proceedings/ , click on “Back Issues” and then “April 2004 Supplement”
Breast Cancer Incidence in Postmenopausal Women May Be Reduced By Testosterone
There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. Dimitrakakis et al. of the
Developmental Endocrinology Branch, Na onal Ins tutes of Health, had previously shown that ovarian androgens normally protect mammary epithelial
cells from excessive estrogenic s mula on, and therefore hypothesized that the addi on of testosterone to usual (i.e., non‐bio‐iden cal) hormone
therapy might protect women from breast cancer. A retrospec ve, observa onal study followed 508 postmenopausal women in South Australia
receiving testosterone (implant, average 100mg every 5 months) in addi on to “usual” hormone therapy, comprised of estrogen (conjugated estrogens
or estrone) or estrogen plus proges n (medroxyprogesterone acetate or norethisterone). Breast cancer status was ascertained by mammography at the
ini a on of testosterone treatment and biannually therea er. The average age at the start of follow‐up was 56.4 years, and the mean dura on of follow‐
up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported
in the medical literature and to age‐specific local popula on rates. There were seven cases of invasive breast cancer in this popula on of testosterone
users, for an incidence of 238 per 100,000 woman‐years. The rate for estrogen/proges n and testosterone users was 293 per 100,000 woman‐years‐‐
substan ally less than women receiving estrogen/proges n in the Women's Health Ini a ve study (380 per 100,000 woman‐years) or in the "Million
Women" Study (521 per 100,000 woman‐years). The breast cancer rate in these testosterone users was closest to that reported for hormone therapy
“never‐users” in the la er study (283 per 100,000 woman‐years), and their age‐standardized rate was the same as for the general popula on in South
Australia. These observa ons suggest that the addi on of testosterone to conven onal hormone therapy for postmenopausal women does not increase
and may indeed reduce the hormone therapy‐associated breast cancer risk‐thereby returning the incidence to the normal rates observed in the general,
untreated popula on.
Menopause. 2004 Sep‐Oct;11(5):531‐5.
Disorders of desire (libido), arousal, orgasm, and sexual pain affect up to 43% of women, par cularly those who are menopausal. A er surgically‐
induced menopause, testosterone levels can drop by as much as 50%. Many of these women experience a reduc on in sexual func oning and a
decreased sense of well being, despite estrogen replacement. Long‐term safety of testosterone use in women has not been determined, and women
who opt to try testosterone should have periodic checks of lipids, liver func on, hemoglobin, and hematocrit. Commercially available synthe c estrogen/
methyltestosterone combina ons contain about twice the amount of testosterone that most women need, and testosterone patches for men deliver
approximately 10 to 20 mes the amount needed for women. Topical testosterone gels manufactured for men contain alcohol, so applica on to
sensi ve areas could be irrita ng.
Dr. Judith Reichman notes that although the FDA has not approved a testosterone patch for women, it is s ll possible to prescribe androgen therapy for
testosterone‐deficient women. She adds “Testosterone can be formulated [by a compounding pharmacy] in the form of a cream, ointment, capsule,
sublingual drops or lozenge placed under the tongue. Dosages should be kept to an absolute minimum. Too much testosterone can cause oily skin,
acne, growth of body hair and, in large doses, deepening of the voice or even enlargement of the clitoris.”
h p://www.msnbc.msn.com/id/6707662/
10
©Storey Marke ng, All rights reserved.
Andropause
Knowledge and a tudes regarding the existence of and treatments for andropause ‐ the “male menopause” ‐ have recently undergone a revolu onary
change. Andropause may consist of a variety of signs and symptoms, including:
 weakness
 fa gue
 reduced libido
 osteoporosis
 heart disease
 atherosclerosis
 irritability
 insomnia
Hypogonadism is a clinical condi on in which low levels of serum testosterone are found in associa on with specific signs and symptoms, including
diminished libido and sense of vitality, erec le dysfunc on, depression, anemia, reduced muscle mass and bone density, increased fat mass, frailty,
osteopenia, and osteoporosis. When hypogonadism occurs in an older man, the condi on is o en called andropause, or Androgen Deficiency of the
Aging Male (ADAM). Epidemiological studies associate increased morbidity and mortality with low testosterone states in aging males.
Increasing lifespan has resulted in a steady rise in the propor on of older men. The number of men in the United States ≥ 65 years of age is projected to
increase from 14.5 million in 2000 to 31.3 million in 2030. Some men may actually go through a rather sudden change in testosterone levels that might
correlate with the hormonal changes that women experience at menopause. However, most men have a more slow and subtle hormonal decline,
experiencing the same symptoms over a period of me. On the average, a man’s testosterone levels begin to decline at a rate of 1% per year a er age
40. Approximately 5% of men 40 to 50 years of age, 30% of men 60‐70 years of age, and 70% of men 70‐80 years of age have low free or bioavailable
testosterone levels.
Testosterone levels decline for a variety of reasons:
 Testosterone‐producing Leydig cells begin to die off.
 SHBG (Sex Hormone Binding Globulin) increases with age, binding more hormone and decreasing the amount of bioavailable testosterone (the
por on that can be used by the body).
 There is more estradiol but less LH (luteinizing hormone) reaching the testes, so less testosterone is produced.
Clinical symptoms of androgen deficiency should be verified by laboratory studies. Total serum testosterone levels quan fy testosterone that is both
bound and unbound (free). Blood or saliva tes ng is necessary to determine an individual’s testosterone levels and to establish the need for testosterone
replacement therapy. Testosterone replacement therapy is only recommended for men whose testosterone levels are low. Screening for parameters
related to poten al risks of androgen therapy should be performed prior to the ini a on of treatment. Evalua on should include a history of or poten al
for sleep apnea, arrhythmias, significant symptoms of benign prosta c hypertrophy (BPH) or personal or family history of prostate carcinoma, a physical
exam and laboratory tes ng including PSA.
When ordering serum testosterone levels, clinicians should be aware that the results can be influenced by obesity, serum albumin, serum sex‐hormone
binding globulin (SHBG), interac ng drugs and diurnal varia ons. Because serum levels of SHBG increase with age and obesity, the decline in levels of
non‐SHBG‐bound testosterone (bioavailable testosterone) is o en much greater than the decline in total testosterone levels. Testosterone (T) that is
bound to SHBG is not necessarily ac ve, so although total serum T may appear normal, the amount of ac ve T may be low. Therefore, it is important to
measure free or “Bioavailable Testosterone” (BT), which represents testosterone that is physiologically ac ve.
T
V .B
T
Bioavailable Testosterone = Free + Albumin‐Bound
Hypogonadism is defined as bioavailable testosterone less than 60 ng/dl. Concentra ons of total and free testosterone decrease in aging men, with a
larger decline in available free testosterone in ssues. A man may be considered hypogonadal at any age if total testosterone is less than 200 ng/dl. If
only Total Testosterone is studied, about 5% of men are hypogonadal. Because serum levels of SHBG increase with aging, the decline in levels of non‐
SHBG‐bound testosterone (bioavailable testosterone) is o en much greater than the decline in total testosterone levels. Basaria and Dobs of Johns
Hopkins University recommend that elderly men with symptoms of hypogonadism and a total testosterone level <300ng/dl should be started on
hormone replacement. When hormones are replaced or restored back to physiologic levels considered normal for younger males, men may experience
a drama c reversal of many of the changes caused by aging.
The diagnosis of hypogonadism is made based on the presence of signs or symptoms and confirmed by laboratory tes ng, which should include:
 Total testosterone
 Bioavailable testosterone (Free plus Albumin Bound)
 Estradiol
 Cholesterol
©Storey Marke ng, All rights reserved.
11
Goals of Testosterone Replacement Therapy in Adult Hypogonadal Men (≥50 years)
Improvement in psychological well‐being and mood
Improvement in erec le dysfunc on
Improvement in libido
Increased muscle mass
Increased strength and stature
Preserva on of bone mass
Possible decrease in cardiovascular risk
Natural Testosterone Replacement is Central to the Treatment of All Facets of Andropause.
The term “testosterone” is o en used generically when referring to numerous synthe c deriva ves, as well as natural bio‐iden cal testosterone. The
confusion surrounding testosterone transcends the lay person; it is responsible for conflic ng data in the medical literature about the benefits and risks
of testosterone therapy. Studies must be reviewed carefully to determine the form of testosterone that was used. Natural testosterone must not be
confused with synthe c deriva ves or “anabolic steroids,” which when used by athletes and body builders have caused disastrous effects, even resul ng
in heart problems and cancer. For example, administra on of synthe c non‐aroma zable androgens, like stanozolol or methyltestosterone, causes
profound decreases in HDL‐C (“good cholesterol”) and significant increases in LDL‐C (“bad cholesterol”). Yet, hormone replacement with aroma zable
androgens, such as testosterone, results in lower total cholesterol and LDL cholesterol levels while having li le to no impact on serum HDL cholesterol
levels.
Informa on from the medical literature indicates that testosterone therapy may reduce the risk of:
Osteoporosis ‐ According to the Na onal Osteoporosis Founda on, approximately 2 million men in the U.S. have osteoporosis, and another 3 million are
at risk. Osteoporosis‐related fractures occur in 12% of all men older than 50. Twenty‐five percent of all hip fractures occur in men, and 33% of these
pa ents die within one year of fracture. Gradual loss of testosterone is one of the major causes of osteoporosis in elderly men. In one study, 59% of men
with hip fracture had low testosterone, compared with 18% of controls. Fracture occurs at a later age in men than women because men’s bones are
denser at baseline. Androgens are important to the a ainment of peak bone mass and in bone mass maintenance in adult men. Testosterone receptors
are present in osteoblasts, and testosterone is an important factor in bone and calcium metabolism. Several studies have reported beneficial effects of
testosterone therapy on bone in older men, showing an increase in BMD (bone mineral density) and slowing of bone degenera on.
Cardiovascular disease ‐ Risk is decreased with higher serum total testosterone levels, according to most reports. A number of studies have
demonstrated that testosterone minimizes several important risk factors for heart a ack, including:
 reducing cholesterol and triglycerides
 reducing blood glucose levels
 decreasing visceral fat mass
 normalizing blood clo ng
The degree of atherosclero c disease, as measured by the mean percent coronary artery occlusion, increased significantly with declining levels of free
testosterone. Visceral fat accumula on is connected with increased vascular risk, and studies have shown that androgen administra on can decrease this
fat accumula on. The use of anabolic steroids including methyltestosterone, but not natural testosterone, has been associated with serious heart
disease.
Frailty ‐ The age‐related testosterone decline appears to place the older man at risk for developing frailty. In fact, low bioavailable testosterone levels
have been found to predict frailty in inner‐city African‐American males. In addi on to the physical aspects (i.e. generalized weakness, impaired mobility
and balance, and poor endurance), it is clear that frailty can also be related to a decline in cogni ve func on.
Alzheimer’s Disease ‐Two interven onal studies have supported the concept that testosterone can improve cogni ve func on in older men. Testosterone
may play an integral role in the age‐related cogni ve impairment that occurs in males and low testosterone levels may play a permissive role in the
pathogenesis of Alzheimer's disease.
Gandy et al. measured plasma levels of testosterone, 17 ß‐estradiol, and amyloid‐pep de (which is the main neurotoxic component of cerebral amyloid
found in Alzheimer’s Disease) in 6 men aged 44 to 83 years who underwent hormonal suppressive therapy for adenocarcinoma of the prostate. Samples
were obtained 1 week prior to the first treatment and on weeks 4, 12, and 24. Plasma levels of testosterone and 17 ß‐estradiol declined precipitously and
then stabilized at low detectable levels during the first 2 months of therapy in all 6 pa ents. Plasma amyloid‐pep de concentra ons increased in a
parallel manner by about 2‐fold and then stabilized for at least 6 months. These data support the hypothesis that levels of circula ng amyloid‐pep de
may be under the control of gonadal hormones and suggest that androgen replacement therapy might prevent or delay AD in postandropausal men.
J Clin Epidemiol 44:671‐684 ‐ The Journals of Gerontology Series A 56:M263‐M265 (2001) ‐ J Cog Neurosci 12:407‐414
Behav Neurosci 108:325‐332 ‐ Proc Natl Acad Sci USA 2000;97:1202‐1205
Depression ‐ Standardized measurements of depression are higher when levels of bioavailable testosterone are low; perhaps because an associated
decrease in sexual func on results in depression, irritability, and mood swings. In the Rancho Bernardo Study which examined the associa on between
levels of sex hormones and depressed mood in 856 men ages 50‐89, bioavailable testosterone levels were 17% lower for depressed men. The results
suggested that testosterone treatment might improve depressed mood in older men who have lower levels of bioavailable testosterone.
Symptoms of testosterone deficiency are o en a ributed to other problems, denied by the pa ent, and unrecognized by the physician. Testosterone
12
©Storey Marke ng, All rights reserved.
is necessary for spontaneous erec ons, normal libido, and ejacula on. The Massachuse s Male Aging Study reported that hypogonadism is the sole
cause of erec le dysfunc on (ED, formerly termed impotence) in 10% of cases. Unfortunately, many of these men and their physicians will not be
aware of the cause and the op on of treatment using natural testosterone, as ED is o en s ll erroneously considered a psychological problem. They
may instead resort to other forms of therapy with the poten al for side effects, rather than experience the many benefits of natural hormone
replacement.
What is the Op mal Form of Testosterone for Replacement Therapy?
Testosterone USP is natural bio‐iden cal testosterone that has been approved by the United States Pharmacopoeia and is available as a bulk chemical.
Upon a prescrip on order, compounding pharmacists can use Testosterone USP to prepare numerous dosage forms. The informa on that follows
should be considered as prescriber, pa ent, and pharmacist work together to meet the specific needs of each pa ent.
A healthy adult male secretes 8‐15mg/day of testosterone. This “physiologic dose” should be considered when prescribing replacement therapy. High
serum levels of testosterone can result in a greater conversion to estradiol (and side‐effects resul ng from abnormally high estradiol levels), because
the body can not effec vely store excess testosterone. This may be a reason to administer testosterone on a daily basis, rather than using depot
injec ons. An addi onal advantage of transdermal testosterone replacement is that it delivers testosterone at a controlled rate into the systemic
circula on.
Testosterone is converted into dihydrotestosterone (DHT) by 5a‐reductase or into estradiol by aromatase. Significant obesity can result in high serum
estrogen levels, as estrogen stores are greater in fat. Aromatase ac vity is higher in overweight individuals, resul ng in increased conversion of
testosterone to estradiol. There is good reason to believe that what is important to a man’s health is not necessarily the absolute amount of each
hormone but rather the testosterone to estradiol ra o. Maintaining a proper body weight may produce a more desirable hormonal balance. It may be
possible to maintain sufficient testosterone levels if the conversion to estradiol and dihydrotestosterone can be slowed by inhibi ng the enzymes
aromatase and 5‐alpha reductase. Supplementa on with vitamin C may reduce aromatase ac vity and decrease estradiol produc on.
There are many issues related to the appropriate use of testosterone and related therapies, and considera ons in andropause treatment should
include:
 the role of dihydrotestosterone (DHT) and its rela onship with benign prosta c hypertrophy (BPH), levels of DHT, and even DHT supplementa on.
 the use of 5‐alpha reductase inhibitors and aromatase inhibitors to modify the amount of the metabolites DHT and estradiol that are produced
when testosterone is broken down by the body.
 DHEA (dehydroepiandrosterone) and its role as an “an ‐aging” supplement and in the treatment of symptoms of andropause.
Testosterone replacement therapy (TRT) is well tolerated, and long term TRT appears to be a safe and effec ve means of trea ng hypogonadal elderly
males, provided that frequent follow‐up blood tests and examina ons are performed. Studies on TRT have not shown any increased incidence of stroke,
angina, or myocardial infarc on, and effects on the clo ng system are probably neutral. Testosterone also may have beneficial vasodilatory proper es.
English et al. concluded that low‐dose supplemental testosterone treatment in men with chronic stable angina reduces exercise‐induced myocardial
ischemia.
The general consensus (supported by at least 16 studies) is that TRT does not cause obstruc ve BPH. Tan and Salazar of Baylor College of Medicine and
University of Texas note that current evidence suggests no causal rela onship between prostate cancer and physiological dosing of testosterone,
especially with careful selec on and monitoring of pa ents. However, guidelines recommend that TRT should not be ini ated in older men with PSA
serum levels above the normal range. Due to the poten al of testosterone to cause erythrocytosis, therapy is contraindicated in men with a hematocrit
> 52%. During TRT, hemoglobin should be followed and appropriate measures should be taken if marked erythrocytosis occurs. Side effects of
testosterone therapy can include emo onal lability, leg swelling, skin reac ons, acne, alopecia, gynecomas a, and infer lity (which is usually reversible
with cessa on of T therapy).
In the past, oral testosterone, par cularly the 17‐alkylated deriva ves, caused hepatotoxicity due to high first‐pass metabolism. Due to the increasing
recogni on of hypogonadism in aging males and the introduc on of newer, bioavailable topical prepara ons, testosterone prescrip ons have increased
500% in the past 10 years. TRT has relieved symptoms and improved the quality of life for many men. Testosterone is well‐absorbed from transdermal
creams, gels, and lo ons which avoid first pass metabolism. A sa sfactory response can be achieved with BID dosing. Compounded prepara ons can be
very advantageous because the exact amount of medica on needed by a par cular pa ent can be applied as a single dose. There is no need to shave
the scrotum to apply one or more patches, and there is no skin irrita on from patch adhesive. Tar and Salazar report that hepatotoxicity has not been
reported following T administra on using transdermal gels in physiologic doses.
The only absolute contraindica on to androgen replacement therapy is the presence of prostate or breast cancer. Although it is known that the
clinical course of prostate cancer is accelerated by testosterone, its incidence is not increased by testosterone administra on. There is no clear evidence
that testosterone replacement accelerates the development of BPH.
Annu Rev Med. 2005;56:117‐37
J Clin Endocrinol Metab. 2005 Mar;90(3):1502‐10. Epub 2004 Nov 30
Maturitas 2003;45:15‐27
Atherosclerosis 1996; 125:1‐13
Drugs & Aging 1999 Aug;15(2):131‐42
J Clin Endocrinol Metab. 1999 Feb;84(2):573‐7
Expert Opin Drug Saf. 2004 Nov;3(6):599‐606
J Clin Endocrinol Metab. 2004; 89(2):503‐510
J Clin Endocrinol Metab. 1997 Nov;82(11):3793‐6
N Engl J Med. 2004 Jan 29;350(5):482‐92
Circula on 2000;16:1906‐1911
©Storey Marke ng, All rights reserved.
13
Healthy Lifestyle
A healthy lifestyle has been shown to be associated with higher hormone levels, and higher hormone levels seem to induce a more ac ve, healthier
lifestyle, according to andropause expert Eugene Shippen, M.D. When hormone levels decline, we become less ac ve and gain weight. As we gain
weight, hormones are stored in fat and become unavailable to meet the body’s demands. Lack of exercise, excessive alcohol use, and many diseases can
reduce bioavailable hormone levels. For op mal results, it is vital that hormone replacement therapy be combined with adequate exercise, proper
nutri on, and appropriate use of natural supplements.
Thyroid Hormone Replacement Therapy for Men and Women
Symptoms of hypothyroidism (low levels of thyroid hormone) include fa gue, cold and heat intolerance, hypotension, fluid reten on, dry skin and/or
hair, cons pa on, headaches, low sexual desire, infer lity, irregular menstrual periods, aching muscles and joints, depression, anxiety, slowed
metabolism and decreased heart rate, memory impairment, enlarged tongue, deep voice, swollen neck, PMS, weight gain, hypoglycemia, and high
cholesterol and triglycerides. Yet, more than half of all people with thyroid disease are unaware of their condi on.
Although both T4 (thyroxine, an inac ve form that is converted to T3 in other areas of the body) and T3 (triiodothyronine, the ac ve form) are secreted
by the normal thyroid gland, many hypothyroid pa ents are treated only with levothyroxine (synthe c T4). Some hypothyroid pa ents remain
symptoma c, and T3 may also be required for op mal thyroid replacement therapy. However, the only commercially available form of T3 is synthe c
liothyronine sodium in an immediate release formula on which is rapidly absorbed, and may result in higher than normal T3 concentra ons throughout
the body causing serious side effects, including heart palpita ons. Research indicates there is a need for sustained‐release T3 prepara ons in order to
avoid adverse effects.
A randomized, double‐blind, crossover study found inclusion of T3 in thyroid hormone replacement improved cogni ve performance, mood, physical
status, and neuropsychological func on in hypothyroid pa ents. Two‐thirds of pa ents preferred T4 plus T3, and tended to be less depressed than a er
treatment with T4 alone. Pa ents and their physicians may wish to consider the use of sustained‐release T3 in the treatment of hypothyroidism,
par cularly when the response to levothyroxine (T4) has not been complete.
J Endocrinol Invest. 2002 Feb; 25(2):106‐9
N Engl J Med 1999 Feb 11; 340(6):424‐9
Adrenal Dysfunc on
The adrenal glands secrete hormones such as cor sol, estrogen, and testosterone that are essen al to health and vitality and significantly affect total
body func on. A er mid‐life, the adrenal glands gradually become the major endogenous source of sex hormones in both men and women. Intense or
prolonged physical or emo onal stress commonly associated with modern lifestyles or chronic illness can lead to Adrenal Fa gue, which is an important
contribu ng factor in health condi ons ranging from allergies to obesity.
An ‐inflammatory and an ‐oxidant adrenal hormones like cor sol help to minimize allergic and nega ve reac ons, such as cancer and autoimmune
disorders. These hormones closely affect the u liza on of carbohydrates and fats, the conversion of fats and proteins into energy, and cardiovascular
and gastrointes nal func on. Proper adrenal support is essen al to complete the hormonal pathway to op mal health, and includes proper nutri on,
ge ng plenty of sleep, regular moderate exercise, stress management, slowing down to regain a proper perspec ve on life, and replacement of deficient
hormones.
14
©Storey Marke ng, All rights reserved.
Abstracts and Reviews
Postgrad Med. 2009 Jan;121(1):73‐85.
PDF Full Text available online: h p://www.postgradmed.com/index.php?art=pgm_01_2009?ar cle=1949. Accessed May 2, 2009.
The bioiden cal hormone debate: are bioiden cal hormones (estradiol, estriol, and progesterone) safer or more
efficacious than commonly used synthe c versions in hormone replacement therapy?
Holtorf K.
Holtorf Medical Group, Inc., Torrance, CA 90505, USA. [email protected]
BACKGROUND: The use of bioiden cal hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked
intense debate. Of special concern is their rela ve safety compared with tradi onal synthe c and animal‐derived versions, such as conjugated equine
estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthe c proges ns. Proponents for bioiden cal hormones claim that they are safer
than comparable synthe c and nonhuman versions of HRT. Yet according to the US Food and Drug Administra on and The Endocrine Society, there is
li le or no evidence to support claims that bioiden cal hormones are safer or more effec ve. OBJECTIVE: This paper aimed to evaluate the evidence
comparing bioiden cal hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioiden cal versions of HRT for clinical
efficacy, physiologic ac ons on breast ssue, and risks for breast cancer and cardiovascular disease. METHODS: Published papers were iden fied from
PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioiden cal hormones, synthe c hormones, and
HRT. Papers that compared the effects of bioiden cal and synthe c hormones, including clinical outcomes and in vitro results, were selected. RESULTS:
Pa ents report greater sa sfac on with HRTs that contain progesterone compared with those that contain a synthe c proges n. Bioiden cal hormones
have some dis nctly different, poten ally opposite, physiological effects compared with their synthe c counterparts, which have different chemical
structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the
increased risk associated with synthe c proges ns. Estriol has some unique physiological effects, which differen ate it from estradiol, estrone, and CEE.
Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthe c proges ns have
a variety of nega ve cardiovascular effects, which may be avoided with progesterone. CONCLUSION: Physiological data and clinical outcomes
demonstrate that bioiden cal hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more
efficacious than their synthe c and animal‐derived counterparts. Un l evidence is found to the contrary, bioiden cal hormones remain the preferred
method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.
PMID: 19179815
Endocrine. 2004 Aug;24(3):211‐6
Postmenopausal hormone therapy and breast cancer: a clinician's message for pa ents.
Speroff L.
Obstetrics and Gynecology, Oregon Health & Science University, Portland, Oregon, USA. speroffl@ohsu.edu
The Women's Health Ini a ve agrees with some but not all case‐control and cohort studies that current use of postmenopausal estrogen‐proges n
therapy is associated with a small increase in the risk of breast cancer. It is not known whether this is because of new tumor growth or an effect of
hormonal therapy on preexis ng tumors. Many studies indicate that women who develop breast cancer while using postmenopausal hormone therapy
have a reduced risk of dying from breast cancer; this is consistent with an effect on preexis ng tumors so that tumors appear at a less virulent and
aggressive stage.
PMID: 15542887
Int J Fer l Womens Med. 2004 Nov‐Dec;49(6):252‐67
A clinician's review of the WHI‐related literature
Speroff L.
Department of Obstetrics and Gynecology, Oregon Health Sciences University Portland, Oregon 97239, USA.
When the monitoring board of the Women's Health Ini a ve (WHI) canceled the estrogen‐proges n arm of the study in July 2002, the effect was
immediate and drama c, as several million postmenopausal women with the full agreement of their physicians ceased taking combined hormone
therapy. Soon therea er the manufacturers of conjugated equine estrogens felt compelled to publicize a dras c restric on of the indica ons for their
product. Li le no ce, except in the medical literature, was given to the con nua on of the other treatment arms of the WHI, nor did the rather small
(however significant) increases in risk of cardiovascular disease and breast cancer resul ng from combined therapy receive widespread serious analysis.
In this ar cle, special a en on is given to the popula on sampling involved in se ng up the WHI, arm by arm, with full discussion of how these
samplings compare with those in other studies‐‐HERS, ERA, WEST, etc. All studies are scru nized in terms of treatment regimens, follow‐up, confounding
factors, par cularly sta ns and aspirin, and high drop‐out rates in order to discover possible reasons for the results in the WHI for primary and secondary
preven on of cardiovascular disease in the combined‐therapy arm and slightly disappoin ng results for breast cancer. Each of the two main sec ons of
the ar cle, Cardiovascular Disease and Breast Cancer, concludes with a detailed summa on of points derived from the o en contras ng results of the
various studies, which can be used in counseling pa ents.
PMID: 15751264
©Storey Marke ng, All rights reserved.
15
JAMA. 2007 Apr 4;297
Erratum in: JAMA. 2008 Mar 26;299(12):1426. The correc on has been made to the results sec on below.
Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause.
Rossouw JE, Pren ce RL, Manson JE, Wu L, Barad D, Barnabei VM, Ko M, LaCroix AZ, Margolis KL, Stefanick ML.
Women's Health Ini a ve Branch, Na onal Heart, Lung, and Blood Ins tute, Bethesda, Md 20892, USA.
CONTEXT: The ming of ini a on of hormone therapy may influence its effect on cardiovascular disease. OBJECTIVE: To explore whether the effects of
hormone therapy on risk of cardiovascular disease vary by age or years since menopause began. DESIGN, SETTING, AND PARTICIPANTS: Secondary
analysis of the Women's Health Ini a ve (WHI) randomized controlled trials of hormone therapy in which 10,739 postmenopausal women who had
undergone a hysterectomy were randomized to conjugated equine estrogens (CEE) or placebo and 16,608 postmenopausal women who had not had a
hysterectomy were randomized to CEE plus medroxyprogesterone acetate (CEE + MPA) or placebo. Women aged 50 to 79 years were recruited to the
study from 40 US clinical centers between September 1993 and October 1998. MAIN OUTCOME MEASURES: Sta s cal test for trend of the effect of
hormone therapy on coronary heart disease (CHD) and stroke across categories of age and years since menopause in the combined trials. RESULTS: In
the combined trials, there were 396 cases of CHD and 327 cases of stroke in the hormone therapy group vs 370 [corrected] cases of CHD and 239 cases
of stroke in the placebo group. For women with less than 10 years since menopause began, the hazard ra o (HR) for CHD was 0.76 (95% confidence
interval [CI], 0.50‐1.16); 10 to 19 years, 1.10 (95% CI, 0.84‐1.45); and 20 or more years, 1.28 (95% CI, 1.03‐1.58) (P for trend = .02). The es mated
absolute excess risk for CHD for women within 10 years of menopause was ‐6 per 10,000 person‐years; for women 10 to 19 years since menopause
began, 4 per 10,000 person‐years; and for women 20 or more years from menopause onset, 17 per 10,000 person‐years. For the age group of 50 to 59
years, the HR for CHD was 0.93 (95% CI, 0.65‐1.33) and the absolute excess risk was ‐2 per 10,000 person‐years; 60 to 69 years, 0.98 (95% CI, 0.79‐1.21)
and ‐1 per 10,000 person‐years; and 70 to 79 years, 1.26 (95% CI, 1.00‐1.59) and 19 per 10,000 person‐years (P for trend = .16). Hormone therapy
increased the risk of stroke (HR, 1.32; 95% CI, 1.12‐1.56). Risk did not vary significantly by age or me since menopause. There was a nonsignificant
tendency for the effects of hormone therapy on total mortality to be more favorable in younger than older women (HR of 0.70 for 50‐59 years; 1.05 for
60‐69 years, and 1.14 for 70‐79 years; P for trend = .06). CONCLUSIONS: Women who ini ated hormone therapy closer to menopause tended to have
reduced CHD risk compared with the increase in CHD risk among women more distant from menopause, but this trend test did not meet our criterion for
sta s cal significance. A similar nonsignificant trend was observed for total mortality but the risk of stroke was elevated regardless of years since
menopause. These data should be considered in regard to the short‐term treatment of menopausal symptoms.
PMID: 17405972
Climacteric. 2006 Apr;9(2):108‐18
Comment in: Climacteric. 2006 Apr;9(2):73‐4.
The long‐term impact of 2‐3 years of hormone replacement therapy on cardiovascular mortality and
atherosclerosis in healthy women.
Alexandersen P, Tanko LB, Bagger YZ, Qin G, Chris ansen C.
Center for Clinical and Basic Research, Ballerup, Denmark.
OBJECTIVE: The effect of hormone replacement therapy (HRT) on cardiovascular risk is intensely debated. The aim of this study was to inves gate the
long‐term effects of HRT given for a few years on all‐cause and cardiovascular mortality and the severity of atherosclerosis. METHODS: This analysis was
based on a cohort of 1,458 postmenopausal women (55.8 +/‐ 6.1 years old) who previously par cipated in a number of randomized, placebo‐controlled,
clinical trials assessing the efficacy of 2‐3 years of therapy with various estrogen plus proges n combina ons for preven ng bone loss. Women were
followed on average for 9.8 years and came for a follow‐up visit. Outcome variables were all‐cause and cardiovascular mortality and the severity of
atherosclerosis, as es mated by semi‐quan ta ve scoring of vascular calcifica on in the lumbar aorta on lateral radiographs. RESULTS: A total of 174
women died during the observa on period. All‐cause mortality was decreased by 30% in the HRT+ group compared with the HRT‐ group (hazard ra o
(HR) 0.70; 95% confidence interval (CI) 0.50‐0.97) a er adjus ng for age, body mass index and smoking. Under the same condi ons, similar results
characterized mortality from cardiovascular disease (n = 61 deaths; 35.1% of all deaths) and coronary heart disease (n = 39 deaths; 22.4% of all deaths),
which were decreased by 46% and 53%, respec vely. Furthermore, the mean severity score of aor c calcifica on at follow‐up was significantly lower in
hormone‐treated compared to non‐treated women (p < 0.0001). CONCLUSION: Women who receive 2‐3 years of HRT a er menopause do not have
increased all‐cause mortality, and results of the present study suggest rela ve cardiovascular benefits compared to those who had not used hormones.
PMID: 16698657
Altern Med Rev. 2006 Sept;11(3):208‐223
Complete ar cle is available FREE at h p://www.thorne.com/altmedrev/.fulltext/11/3/208.pdf
A comprehensive review of the safety and efficacy of bioiden cal hormones for the management of menopause
and related health risks
Moskowitz D.
1993 Graduate, Na onal College of Naturopathic Medicine, President, Wellness Designed, LLC, advisor, Women in Balance (www.womeninbalance.org)
Correspondence address: 2407 NE 17th Ave, Portland, OR 97212
16
©Storey Marke ng, All rights reserved.
Numerous forms of estrogens and proges ns are u lized for the treatment of menopausal complaints and associated condi ons that occur temporally.
Although known to be different with respect to molecular structure, receptor affinity, metabolism, and other physiological traits, most have been treated
as if they were clinically iden cal. The majority of these hormone prepara ons, commonly referred to as hormone replacement therapy (HRT), should
perhaps be more aptly referred to as hormone subs tu on therapy, as most of the therapies u lized do not exactly match those produced in the body.
Research indicates these synthe c hormones vary clinically in safety and efficacy. As such, women and their physicians have, in increasing numbers, been
op ng for the use of bioiden cal hormones; i.e., those that match the structure and func on of hormones produced in the body. With greater u liza on
and research surrounding bioiden cal hormones, the differences can now begin to be fully assessed and appreciated. This ar cle reviews the dispari es
between synthe c and bioiden cal estrogens and proges ns/progesterone with respect to safety and efficacy; special a en on is devoted to clinical
outcomes in the breast, endometrium, bone, cardiovascular system, and brain. The studies reviewed suggest bioiden cal progesterone does not have a
nega ve effect on blood lipids or vasculature as do many synthe c proges ns, and may carry less risk with respect to breast cancer incidence. Studies of
both bioiden cal estrogens and progesterone suggest a reduced risk of blood clots compared to non‐bioiden cal prepara ons. Bioiden cal hormone
prepara ons have demonstrated effec veness in addressing menopausal symptoms. The author advocates for con nued research on bioiden cal
hormones and concludes there is currently sufficient evidence to support their preferred use over that of their synthe c cousins.
PMID: 17217322
Menopause. 2006 May‐Jun;13(3):442‐50
Efficacy of a new, oral estradiol acetate formula on for relief of menopause symptoms
Speroff L, Haney AF, Gilbert RD, Ellman H;
Estradiol Acetate Inves gator Group. Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland, OR, USA.
OBJECTIVE: To determine the efficacy of three doses of a new, oral formula on of estradiol acetate (EA) for allevia on of vasomotor and urogenital
symptoms in postmenopausal women. DESIGN: Two separate 12‐week studies were undertaken in postmenopausal women with moderate to severe
vasomotor symptoms. In the first study, women were randomly assigned to EA 0.9 mg/day, EA 1.8 mg/day, or placebo (study 1; N = 293), and in the
second study to oral EA 0.45 mg/day or placebo (study 2; N = 259). Women recorded the frequency and severity of vasomotor symptoms daily and
urogenital symptoms weekly on diary cards. Inves gators assessed signs of vaginal atrophy. RESULTS: Frequency of moderate to severe vasomotor
symptoms decreased significantly versus placebo, star ng at week 2 in the EA 1.8‐mg group (P = 0.005), week 3 in the EA 0.9‐mg group (P = 0.003), and
week 6 in the EA 0.45‐mg group (P < 0.05). At week 12, mean percent reduc on from baseline in vasomotor‐symptom frequency was 91%, 78%, and
61%, respec vely. Vasomotor‐symptom severity decreased significantly versus placebo, star ng at weeks 2 and 3 with EA 1.8 mg and 0.9 mg,
respec vely, and at week 5 with EA 0.45 mg. Vaginal pH and matura on index improved significantly in all EA groups versus placebo, and some signs and
symptoms of vaginal atrophy improved at the EA 0.9‐ and 1.8‐mg doses. Side effects were mild to moderate and consistent with estrogen therapy.
CONCLUSIONS: Oral EA at all doses was well tolerated and significantly reduced the frequency and severity of postmenopause symptoms versus placebo.
PMID: 16735941
Maturitas. 2005 May 16;51(1):4‐7
Comment in: Maturitas. 2005 May 16;51(1):1‐3.
Prac cal guidelines for postmenopausal hormone therapy.
Speroff L, Kenemans P, Burger HG.
Oregon Health & Science University, Portland, OR 97239, USA.
The fourth Amsterdam Menopause Symposium (2‐4 October 2004) was dedicated to prac cal recommenda ons to guide clinicians a er the confusion,
concerns, and controversies generated by study results over the previous several years. Those recommenda ons are summarized in this deliberately
concise and user‐friendly document, always recognizing that each clinician must help women with their decision‐making according to individual needs,
desires, and understanding of benefits and risks.
PMID: 15883102
Maturitas 2001 Dec 14;40(3):195‐201
Hormone replacement therapy: the benefits in tailoring the regimen and dose.
Gambacciani M, Genazzani AR.
Department of Reproduc ve Medicine and Child Development, Division of Obstetrics and Gynecology 'Piero Fiore ', University of Pisa, Via Roma 67,
56100, Pisa, Italy
Despite the clear benefits of long‐term hormone replacement therapy (HRT), the majority of pa ents tend to undergo short‐term treatment. The cyclical
bleedings induced by the sequen al progestogen administra on are o en unacceptable namely in the elderly postmenopausal women. At the standard
doses HRT prepara ons can also induce annoying hormone‐related side effects, both in sequen al and con nuous combined regimens. Lower HRT
schedules are reported to be highly effec ve in the relief of climacteric symptoms, inducing minimal endometrial s mula on with high rates of
amenorrhea. Con nuous administra on of low doses of proges ns is safe for endometrium protec on and minimizes proges n‐related side effects.
Indeed, it has been demonstrated that low dose HRT can prevent the increase in bone turnover and the consequent bone loss in postmenopausal
©Storey Marke ng, All rights reserved.
17
women. The choice of lower HRT dosages can also be useful for the number of poten al disadvantages of standard HRT doses, mainly for long‐term
treatments Low dose regimens should be considered as a star ng dose to minimize the occurrence of side effects, improving compliance and, therefore,
HRT effects on the preven on of long‐term consequences of estrogen depriva on.
Hot Flashes: the Value of Individualized Hormone Replacement Therapy
“Menopause‐related hot flashes are usually treated with a standardized dose of estrogen. This general approach to the most prevalent menopausal
symptom is predicated on the belief that all menopausal women will respond to a uniform dose of estrogen, irrespec ve of the type or route of
administra on.” Morris Notelovitz, MD, Ph.D., MB BCh, FRCOG
However, many perimenopausal menstrua ng women (with adequate endogenous estrogen levels) have estrogen responsive hot flashes during their
luteal and menstrual phases, and 20% of naturally and 10% of surgically menopausal women (all of whom are estrogen deficient) never experience hot
flashes. “Furthermore, the subjec vity of the sensa on of heat and accompanying symptoms such as swea ng, palpita ons, anxiety and irritability is
extremely variable, as is the dura on of this o en debilita ng symptom. Hot flashes can persist for up to 15 years a er menopause in about 20% of
women. Given the heterogeneity in clinical presenta on and response to various doses of estrogen therapy, it is clinically prudent to regard hot flashes
as a symptom of a mul factorial syndrome that involves estrogen deficiency as one of many other relevant vasoac ve and endocrine factors. The role of
androgens is central to this concept and the need for individualizing therapy.”
Hot flashes o en correlate more closely with fluctua ng estrogen concentra ons than with absolute hormone values. Persistent hot flashes in women
receiving “adequate” estrogen therapy are o en indica ve of reduced bioavailability of estrogen due to excess binding with sex hormone binding
globulin (SHBG).
In most symptoma c women, hot flashes cease within 5 years of onset. A recent study showed that high androgen levels are a significant predictor of
early ameliora on and cessa on of hot flashes. These women have rela vely low FSH and luteinizing hormone levels and rela vely high estradiol levels.
This outcome is a ributed to the peripheral aroma za on of androgens to estrogen.
Androgen therapy can be used to relieve vasomotor symptoms in women whose hot flashes are refractory to adequate estrogen replacement. Estrogen
and androgen receptors are present in the areas of the central nervous system relevant to hot flashes. Androgens are a chemical precursor to the
synthesis of estrogen and to the bioavailability of free estrogen in peripheral ssues. In addi on, androgens have direct central nervous system effects
that modulate other endocrine factors associated with hot flashes.
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S8‐13
Cephalalgia 2000;20(3):164‐9
Risks and benefits of hormone replacement therapy
B de Lignières & E A MacGregor
Menopause, the permanent cessa on of menstrua on, is due to ovarian failure, which may lead to oestrogen deficiency diseases, par cularly
osteoporosis, cardiovascular disease and cerebrovascular disease. Mortality and morbidity caused by these condi ons can be modified by using hormone
replacement therapy, but the benefits of this therapy must be weighed against the increased risk of breast cancer and the symptoma c side‐effects the
treatment may cause. The combina on of transdermal oestrogen and natural progesterone offers the most favourable risk‐to‐benefit profile.
Chem Res Toxicol 1998, (11) 94 ‐101
Metabolites of Synthe c Conjugated Estrogens are Linked to Development of Breast Carcinoma
In addi on to containing estrone in a dispropor onately high ra o to that found in humans and 17 ß‐estradiol in a lower ra o, conjugated estrogens also
contain a number of estrogens that are natural to horses, but not to humans, including unsaturated horse estrogens such as equilenin. Chen et al. of the
University of Illinois synthesized the catechol metabolite of equilenin, 4‐hydroxyequilenin (4‐OHEN) and found that the semiquinone radical of 4‐OHEN
reacted with 2’‐deoxynucleosides genera ng highly unusual adducts with DNA. “Our data suggest that several different types of DNA lesions could be
expected including apurinic sites and bulky stable adducts, in addi on to the published oxidized damage to DNA caused by 4‐OHEN. If similar adducts are
formed in vivo which are not repaired efficiently, muta ons could result leading to ini a on of the carcinogenic process in the endometrium or breast.
Finally, it should be noted that equilenin or 17ß‐dehydroequilenin are the major urinary and biliary metabolites of equilin [another horse estrogen which
comprises an es mated 6 to 15% of the conjugated estrogen dose], and it is quite possible that 4‐OHEN‐semiquinone radicals are formed from these
estrogens as well. The implica on of these adducts to the biological effects of Premarin[®] is not known; however, given the direct link between long‐term
estrogen replacement therapy and the enhanced risk of breast cancer, the poten al for forma on of redox‐ac ve/electrophilic metabolites from all of
the estrogens in estrogen replacement formula ons needs to be explored.”
18
©Storey Marke ng, All rights reserved.
Chem Res Toxicol 1998 Sep;11(9):1105‐11
The equine estrogen metabolite 4‐hydroxyequilenin causes DNA single‐strand breaks and oxida on of DNA
bases in vitro.
Chen Y, Shen L, Zhang F, Lau SS, van Breemen RB, Nikolic D, Bolton JL
Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, The University of Illinois at Chicago, IL, USA.
Premarin (Wyeth‐Ayerst) is the estrogen replacement treatment of choice and con nues to be one of the most widely dispensed prescrip ons in North
America. In addi on to endogenous estrogens, Premarin contains unsaturated equine estrogens, including equilenin [1,3,5(10),6,8‐estrapentaen‐3‐ol‐17‐
one]. In previous work, we showed that the equilenin metabolite 4‐hydroxyequilenin (4‐OHEN) can be autoxidized to 4‐OHEN‐o‐quinone which readily
entered into a redox couple with the semiquinone radical catalyzed by NAD(P)H, P450 reductase, or quinone reductase, resul ng in genera on of
reac ve oxygen species [Shen, L., Pisha, E., Huang, Z., Pezzuto, J. M., Krol, E., Alam, Z., van Breemen, R. B., and Bolton, J. L. (1997) Carcinogenesis 18,
1093‐1101]. As oxida ve damage to DNA by reac ve oxygen species generated by redox ac ve compounds has been proposed to lead to tumor
forma on, we inves gated whether 4‐OHEN could cause DNA damage. We treated lambda phage DNA with 4‐OHEN and found that extensive single‐
strad breaks could be obtained with increasing concentra ons of 4‐OHEN as well as increasing incuba on mes. If scavengers of reac ve oxygen species
are included in the incuba ons, DNA could be completely protected from 4‐OHEN‐mediated damage. In contrast, NADH and CuCl2 enhanced the ability
of 4‐OHEN to cause DNA single‐strand breaks presumably due to redox cycling between 4‐OHEN and the semiquinone radical genera ng hydrogen
peroxide and ul mately copper peroxide complexes. We also confirmed that 4‐OHEN could oxidize DNA bases since hydrolysis of 4‐OHEN‐treated calf
thymus DNA and HPLC separa on with electrospray MS detec on revealed oxidized deoxynucleosides, including 8‐oxodeoxyguanosine and 8‐
oxodeoxyadenosine. Our data suggest that DNA single‐strand breaks and oxida on of DNA bases by 4‐OHEN could contribute to the carcinogenic
mechanism(s) of equine estrogens.
JAMA 1995 Jan 18;273(3):199‐208
Effects of estrogen or estrogen/proges n regimens on heart disease risk factors in postmenopausal women. The
Postmenopausal Estrogen/Proges n Interven ons (PEPI) Trial. The Wri ng Group for the PEPI Trial.
OBJECTIVE‐‐To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/proges n regimens on selected heart
disease risk factors in healthy postmenopausal women. DESIGN‐‐A 3‐year, mul center, randomized, double‐blind, placebo‐controlled trial.
PARTICIPANTS‐‐A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindica on to hormone therapy.
INTERVENTION‐‐Par cipants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625
mg/d; (3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecu ve MPA, 2.5 mg/d;
or (5) CEE, 0.625 mg/d plus cyclic micronized progesterone (MP), 200 mg/d for 12 d/mo. PRIMARY ENDPOINTS‐‐Four endpoints were chosen to
represent four biological systems related to the risk of cardiovascular disease: (1) high‐density lipoprotein cholesterol (HDL‐C), (2) systolic blood
pressure, (3) serum insulin, and (4) fibrinogen. ANALYSIS‐‐Analyses presented are by inten on to treat. P values for primary endpoints are adjusted for
mul ple comparisons; 95% confidence intervals around es mated effects were calculated without this adjustment. RESULTS‐‐Mean changes in HDL‐C
segregated treatment regimens into three sta s cally dis nct groups: (1) placebo (decrease of 0.03 mmol/L [1.2 mg/dL]); (2) MPA regimens (increases of
0.03 to 0.04 mmol/L [1.2 to 1.6 mg/dL]); and (3) CEE with cyclic MP (increase of 0.11 mmol/L [4.1 mg/dL]) and CEE alone (increase of 0.14 mmol/L [5.6
mg/dL]). Ac ve treatments decreased mean low‐density lipoprotein cholesterol (0.37 to 0.46 mmol/L [14.5 to 17.7 mg/dL]) and increased mean
triglyceride (0.13 to 0.15 mmol/L [11.4 to 13.7 mg/dL]) compared with placebo. Placebo was associated with a significantly greater increase in mean
fibrinogen than any ac ve treatment (0.10 g/L compared with ‐0.02 to 0.06 g/L); differences among ac ve treatments were not significant. Systolic blood
pressure inreased and postchallenge insulin levels decreased during the trial, but neither varied significantly by treatment assignment. Compared with
other ac ve treatments, unopposed estrogen was associated with a significantly increased risk of adenomatous or atypical hyperplasia (34% vs 1%) and
of hysterectomy (6% vs 1%). No other adverse effect differed by treatment assignment or hysterectomy status. CONCLUSIONS‐‐Estrogen alone or in
combina on with a proges n improves lipoproteins and lowers fibrinogen levels without detectable effects on postchallenge insulin or blood pressure.
Unopposed estrogen is the op mal regimen for eleva on of HDL‐C, but the high rate of endometrial hyperplasia restricts use to women without a
uterus. In women with a uterus, CEE with cyclic MP has the most favorable effect on HDL‐C and no excess risk of endometrial hyperplasia.
Altern Med Rev 1998 Apr;3(2):101‐13
Estriol: safety and efficacy.
Head KA.
Thorne Research, Inc., Dover, ID 83825, USA. [email protected]
While conven onal hormone replacement therapy provides certain benefits, it is not without significant risks. Estriol has been found to provide some of
the protec on without the risks associated with stronger estrogens. Depending upon the situa on, estriol may exert either agonis c or antagonis c
effects on estrogen. Estriol appears to be effec ve at controlling symptoms of menopause, including hot flashes, insomnia, vaginal dryness, and frequent
urinary tract infec ons. Results of research on its bone‐density‐maintaining effects have been contradictory, with the most promising results coming
from Japanese studies. Estriol's effect on cardiac risk factors has also been somewhat equivocal; however, unlike conven onal estrogen prescrip ons, it
does not seem to contribute to hypertension. Although estriol appears to be much safer than estrone or estradiol, its con nuous use in high doses may
have a s mulatory effect on both breast and endometrial ssue.
©Storey Marke ng, All rights reserved.
19
Maturitas 2001 Sep 28;39(3):253‐7
Short term oral estriol treatment restores normal premenopausal vaginal flora to elderly women.
Yoshimura T, Okamura H.
Department of Obstetrics and Gynecology, Kumamoto University School of Medicine, Honjo 1‐1‐1, 860‐8556, Kumamoto, Japan.
OBJECTIVE: Estriol is an estrogen with considerably weaker s mulatory effects on endometrial prolifera on than estradiol. A study was conducted to
determine the effects of oral estriol on vaginal flora and endometrial thickness. METHODS: Fi y‐nine postmenopausal women (50‐75 years of age),
complaining of pruritus or vaginal discharge, par cipated in the study. Vaginal flora and endometrial thickness were evaluated before treatment and
a er receiving oral estriol (2 mg/day) for 14 days. RESULTS: Prior to treatment, lactobacilli were found in vaginal cultures from only six of the 59 study
par cipants, whereas a er treatment, the vaginal flora of 27 women showed a presence of lactobacilli (P<0.0001). Endometrial thickness exceeded 5 mm
in only five cases. No side effects were reported. CONCLUSION: Estriol, which has li le effect on the endometrium, has the poten al to be highly useful
for the treatment of atrophic vagini s.
Vaginal Estriol to Alleviate Symptoms of Urogenital Atrophy and Recurrent UTI
Recurrent urinary tract infec ons are a problem for many postmenopausal women. Estrogen replacement restores atrophic mucosa, lowers vaginal pH,
and may prevent urinary tract infec ons. Ninety‐three postmenopausal women with a history of recurrent urinary tract infec ons par cipated in a
randomized, double‐blind, placebo‐controlled trial of a topically applied intravaginal estriol cream. The incidence of urinary tract infec on in the group
given estriol was significantly reduced as compared with that in the group given placebo (0.5 vs. 5.9 episodes per pa ent‐year). Lactobacilli were absent
in all vaginal cultures before treatment and reappeared a er one month in 22 of 36 estriol‐treated women (61%) but in none of the 24 placebo
recipients. With estriol, the mean vaginal pH declined from 5.5 to 3.8.
To assess the efficacy and safety of intravaginal estriol administra on on urinary incon nence, urogenital atrophy, and recurrent urinary tract infec ons
in postmenopausal women, 88 postmenopausal women with urogenital aging symptoms were enrolled in this prospec ve, randomized, placebo‐
controlled study. Women in the treatment group received intravaginal estriol 1 mg once daily for 2 weeks and then 2 mg once weekly for a total of 6
months as maintenance therapy. A er therapy, the symptoms and signs of urogenital atrophy significantly improved in the treatment group. Physicians
observed significant improvements of colposcopic findings, and there were sta s cally significant increases in mean maximum urethral pressure, and in
mean urethral closure pressure as well as in the abdominal pressure transmission ra o to the proximal urethra.
At Copenhagen University, Denmark, 251 postmenopausal women, with a mean age of 66 years, repor ng at least one bothersome lower urinary tract
symptom were treated with either an estradiol‐releasing ring for 24 weeks; or estriol pessaries 0.5 mg every second day for 24 weeks. The two
treatments were equally efficacious in allevia ng urinary urgency (51% vs 56%), urge incon nence (58% vs 58%), stress incon nence (53% vs 59%) and
nocturia (51% vs 54%). The prac cing gynecologists concluded that vaginally administered estradiol and estriol are equally efficacious in allevia ng lower
urinary tract symptoms which appear a er menopause.
Younger women taking oral contracep ves can suffer from similar symptoms. Thirty women (mean age 22.7 years) with a longstanding history of
recurrent urinary tract infec ons received vaginal estrogen therapy consis ng of 1mg estriol (E3) daily for two weeks and twice a week for two addi onal
weeks. In the follow‐up period of 11 months a er treatment, 24/30 pa ents reported no symptoms of cys s and used no addi onal medica on.
Normal bladder epithelium in control cystoscopy a er estriol therapy was seen in all pa ents. Responsiveness to local estriol may correspond to
improved cystoscopic findings as a consequence of increased bladder perfusion.
N Engl J Med. 1993 Sep 9;329(11):753‐6
Menopause. 2004 Jan‐Feb;11(1):49‐56
Eur Urol. 2005 Feb;47(2):243‐9
BJOG. 2000 Aug;107(8):1029‐34
Minerva Ginecol 1991 Apr;43(4):177‐9
[Presenile and senile vulvovagini s. Topical hormonal treatment with estriol] [Ar
cle in Italian]
Sonni R, Bondi G, Travaglini S.
Clinica Ginecologica ed Ostetrica, Universita degli Studi G. D'Annunzio, Chie .
A popula on of 39 women (average age 64.5 years) suffering from presenile or senile vulvovagini s was subjected to topical treatment with oestriol‐
based vaginal cream (daily applica ons of 0.50 mg of oestriol corresponding to 4 g of cream for 14 days and three mes a week in the three following
weeks). The results of treatment were assessed on the basis of the clear‐cut improvement in symptomatology and the noteworthy increase in the index
and volume of matura on of the vaginal epithelium. The effec veness of topical treatment of postmenopausal vulvovagini s with oestriol in the absence
of unwanted side‐effects is confirmed.
20
©Storey Marke ng, All rights reserved.
J Reprod Med 2000 Mar;45(3 Suppl):245‐58
Ra onale for hormone replacement therapy in atherosclerosis preven on.
Wagner JD
Compara ve Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston‐Salem, NC
Progestogens are clearly useful to balance the prolifera ve effects of estrogens on the endometrium; however, some progestogens have been shown to
a enuate the cardiovascular benefits of estrogen, and this has been the subject of considerable debate. Accumula ng evidence confirms the
deleterious effects of medroxyprogesterone acetate on estrogen's cardioprotec ve effects and provides new and compelling evidence that not all
progestogens are alike in this regard. Maintaining estrogen's cardioprotec ve effects is strongly dependent upon the type of progestogen and route and
method of administra on. Numerous periclinical studies conducted on nonhuman primates and other models have demonstrated that certain
progestogens, such as micronized progesterone, can be administered concurrently with estrogen replacement therapy, providing protec on against
endometrial hyperplasia without significantly affec ng the beneficial effects of estrogen on lipid profiles, atherosclerosis and vascular reac vity.
J Clin Endocrinol Metab 2002;87:1062‐1067
Estrogen status correlates with the calcium content of coronary atherosclero c plaques in women.
Chris an RC, Harrington S, Edwards WD, Oberg AL, Fitzpatrick LA.
Division of Endocrinology, Metabolism, and Nutri on, Department of Internal Medicine, Mayo Clinic and Mayo Founda on, Rochester, Minnesota
55905, USA.
BACKGROUND: Coronary artery calcium, a radiographic marker for atherosclerosis and a predictor of coronary heart disease (CHD), is less extensive in
women than in men of the same age. The role of estrogen in the pathogenesis of coronary artery calcifica on is unknown. We examined the associa on
of estrogen status with extent of calcifica on and atherosclero c plaque in coronary arteries of deceased women. METHODS: Coronary arteries were
obtained at autopsy from 56 white women age 18‐‐98 yr, 46 postmenopausal and 10 premenopausal. Exclusion criteria included pa ents with coronary
stents, coronary artery bypass surgery, and medical‐legal cases. Medical records were reviewed for demographics, CHD risk factors, menstrual status,
and use of estrogen replacement therapy. Contact microradiography of coronary arteries assessed true calcium content and atherosclero c plaque area
was analyzed histologically. RESULTS: The coronary arteries from estrogen‐treated postmenopausal women had lower mean coronary calcium content
(P = 0.002), mean plaque area (P < 0.0001), and calcium‐to‐plaque area ra o (P = 0.004) than those from untreated menopausal women. Estrogen
status, age, diabetes, and hypertension predicted calcium and plaque area by univariate analysis. A er controlling for these CHD risk factors, estrogen
status remained an independent predictor of both calcium (P = 0.014) and plaque area (P = 0.001) in all women. Mean calcium area (P < 0.05) but not
plaque area (P = 0.44) was significantly greater in women treated with estrogen replacement therapy than in premenopausal women. Coronary calcium
(P < 0.007) and plaque area (P < 0.03) varied significantly with age in untreated postmenopausal women, but not in the estrogen‐treated or
premenopausal women (P = 0.33). CONCLUSIONS: Estrogen status is associated with coronary calcium and plaque area independent of age and CHD risk
factors. Estrogen may modulate the calcium content of atherosclero c plaques, as well as plaque area and may slow the progression of atheroscerosis
in women.
Estrogen Slows Atherosclerosis Progression in Postmenopausal Women (review of the previous ar cle)
NEW YORK (Reuters Health) Mar 14, 2002 ‐ Autopsy results demonstrate that postmenopausal women who received estrogen replacement therapy had
lower levels of coronary calcium and plaque compare with similar women who did not receive supplemental estrogen.
Dr. Lorraine A. Fitzpatrick and colleagues from the Mayo Clinic, Rochester, Minnesota, evaluated coronary arteries from 56 white women, 18 to 98 years
of age. Forty‐six of the arteries were from postmenopausal women and 10 were from premenopausal women, according to the report in the March
issue of the Journal of Clinical Endocrinology and Metabolism. Analysis revealed that postmenopausal women who had received supplemental estrogen
had lower mean coronary calcium content (p = 0.002), mean plaque area (p < 0.0001) and calcium‐to‐plaque area ra o (p = 0.004) compared with
postmenopausal women who had not had estrogen supplementa on. When Dr. Fitzpatrick's team controlled for risk factors for coronary heart disease,
they found that for all women estrogen was an independent predictor of calcium (p = 0.014) and plaque area (p = 0.001). Compared with
premenopausal women, postmenopausal women treated with supplemental estrogen had significantly greater mean calcium area (p < 0.05) but not
plaque area (p = 0.44), the researchers found. Among postmenopausal women, there were significant varia ons between those who took estrogen
replacement therapy and those who did not, in both coronary calcium (p < 0.007) and plaque area (p < 0.03).
However, the differences in these measures between postmenopausal women treated with supplemental estrogen and premenopausal women was not
significant (p = 0.33), Dr. Fitzpatrick's group notes. "Our data indicates a strong nega ve associa on between estrogen status in women and both
coronary calcium and plaque," Dr. Fitzpatrick said in a statement. "This finding suggests that estrogen may slow the progress of coronary calcifica on
and plaque forma on." Dr. Fitzpatrick added that "this research helps us be er understand the role that hormone replacement therapy plays in
women's bodies and, especially on their heart. Larger, prospec ve clinical trials of longer dura on are now needed to further understand the role of
estrogen in the preven on of coronary artery disease."
©Storey Marke ng, All rights reserved.
21
Am J Epidemiol 2002 Feb 15;155(4):339‐345
Endogenous Estrogen Exposure and Cardiovascular Mortality Risk in Postmenopausal Women.
de Kleijn MJ, van Der Schouw YT, Verbeek AL, Peeters PH, Banga JD, van Der Graaf Y.
Julius Center for General Prac ce and Pa ent Oriented Research, University Medical Center Utrecht, Utrecht, the Netherlands. Department of
Epidemiology, Faculty of Medicine, University of Nijmegen, Nijmegen, the Netherlands. Department of Internal Medicine, University Medical Center
Utrecht, Utrecht, the Netherlands.
In this study, the authors inves gated whether combined informa on on reproduc ve factors has addi ve value to the single reproduc ve factor age at
menopause for assessing endogenous estrogen exposure and cardiovascular mortality risk in postmenopausal women. They conducted a popula on‐
based cohort study that included 9,450 postmenopausal women from Nijmegen, the Netherlands, who were aged 35‐‐65 years at enrollment in 1975,
with a median follow‐up of 20.5 years. A Cox propor onal hazards model and Receiver Opera ng Curves were used to analyze the data. Women aged 52
years or more at menopause had an 18% reduc on in cardiovascular mortality (hazard ra o = 0.82, 95% confidence interval (CI): 0.69, 0.98) compared
with those aged 44 years or less. Women with more than 18 years of exposure to endogenous estrogen had a sta s callysignificant 20% reduc on in
cardiovascular mortality (hazard ra o = 0.80, 95 percent CI: 0.67, 0.96) compared with those who had 13 years of exposure or less. The area under the
curve of the Receiver Opera ng Curves for the two models was iden cal (area under the curve = 0.67, 95 percent CI: 0.66, 0.68). This study shows that
age at menopause is related to cardiovascular disease mortality and that a newly developed composite measure of endogenous estrogen exposure does
not add to the predic ve value of age at menopause for cardiovascular mortality.
Natural Estrogen Seems to Protect
February 15, 2002—Health Scout News
By Cole e Bouchez
A woman's natural estrogen supply seems to reduce her risk of dying from heart disease, even though the latest studies show the synthe c version of the
hormone won't do the job.
Repor ng in the American Journal of Epidemiology, researchers from University Medical Center, Utrecht, the Netherlands, found the older a woman is
when she begins menopause, the less likely she is to die from cardiovascular disease. The reason, they theorize, is she holds onto her natural estrogen
supply longer.
Natural estrogen is made in both fat cells and the ovaries. Because menopause is a me when ovarian func on declines, the authors suggest the
protec ve supply is likely to be ovarian in origin. New York City cardiologist Dr. Dan Fisher says that while the findings are far from defini ve, they are
tantalizing. "Perhaps it's showing us that we should not give up on estrogen as a possible way to protect women from heart disease, even though the
latest studies indicate that, so far, we have not been able to duplicate that protec on with the use of synthe c hormone therapy," says Fisher.
Last July, the American Heart Associa on issued an advisory sugges ng there wasn't sufficient evidence to warrant the use of hormone replacement
therapy (HRT) strictly for the preven on of cardiovascular disease. Then, the recent release of informa on from the largest study ever of HRT found the
therapy may actually increase the risk of cardiovascular disease and death in women. However, results of the Dutch research show estrogen does appear
to have protec ve effects ‐‐ as long as it's made naturally in the body. The study included 9,450 post‐menopausal women from the same area of the
Netherlands. When the study began ‐ in 1975 ‐ the ages of the women ranged from 35 to 65. The researchers followed the women for slightly more than
20 years, and documented the rate of heart disease and death from heart disease for each woman in the study. What they found: Those women who
were 52 or older when they entered menopause saw an 18 percent decrease in cardiovascular disease, when compared to women aged 44 or younger.
More specifically, women who experienced 20 or more years of exposure to natural estrogen had what authors called "a sta s cally significant 20
percent reduc on in cardiovascular mortality, when compared to women who had just 13 years of exposure or less." The study authors conclude that age
at menopause is directly linked to cardiovascular disease and mortality ‐‐ and that extended estrogen produc on is the key.
Fisher, however, ques ons whether it's estrogen alone that should get all the credit. "It's possible that there is some unknown factor that is linked to
natural estrogen produc on in the body ‐‐ something else going on that we have yet to iden fy that could account for the difference in the rate of heart
disease in these women," Fisher says.
For New York gynecologist Dr. Andrei Rebarber, the other factor noted by the researchers ‐‐ the age of the women at menopause ‐‐ may hold the real
clue to understanding the findings. "It could be that whatever factor is causing a woman to go into menopause at a younger age may be the real reason
behind her increased risk of heart disease and death from heart disease," he says. "And that factor may not necessarily be estrogen produc on." On the
other hand, Rebarber suggests that if estrogen is the protec ve element, that protec on may be more dose‐related than thought. "Perhaps we may find
that HRT is able to protect women from heart disease, but that we need to pay more a en on to subtle es in dosing. Perhaps the dose that offers
protec on may be different for each woman," Rebarber says.
Ul mately, the study points up the need for more research to further understand all the factors that place a woman at increased risk for heart disease, he
says. "Maybe its true value is in highligh ng how much we s ll need to learn about women and cardiovascular disease, and the need for more research,"
Fisher says.
What To Do: To learn more about women and heart disease, visit the American Heart Associa on or The Na onal Coali on for Women With Heart
Disease. Read the latest American Heart Associa on advisory about HRT and heart disease.
22
©Storey Marke ng, All rights reserved.
Menopause 2001 Sep‐Oct;8(5):347‐52
Comparison of transdermal and oral estrogen‐proges n replacement therapy: effects on cardiovascular risk
factors.
Chen FP, Lee N, Soong YK, Huang KE.
Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan, Republic of China.
OBJECTIVE: To determine the effects of oral and transdermal hormone replacement therapy on lipid profile and hemosta c factors in postmenopausal
women. DESIGN: Twenty subjects were treated with oral E2 valerate (2 mg) combined with cyproterone acetate (1 mg) (group I) and 21 with
transdermal E2 (1.5 mg) plus oral medroxyprogesterone acetate (5 mg) (group II). The effects on lipid profile and hemosta c parameters were evaluated
at baseline and a er 3, 6, and 12 months of treatment. RESULTS: Group I showed a stronger increase of high‐density lipoprotein (HDL) cholesterol levels
(2‐8%) and stronger reduc on of atherogenic indices (total cholesterol/HDL cholesterol and low‐density lipoprotein/HDL cholesterol) than group II.
Group II showed a more pronounced reduc on of triglyceride (21‐31%) and factor VII (6‐10%) levels than group I. Both groups showed reduced
concentra ons of total cholesterol, low‐density lipoprotein cholesterol, ssue plasminogen ac vator, plasminogen ac vator inhibitor‐1, an thrombin III,
and protein S, whereas protein C was increased a er 12 months of treatment. CONCLUSIONS: The cardioprotec ve effects of hormone replacement
therapy are demonstrated by favorable effects on lipid profile and fibrinoly c ac vity. Oral hormone replacement therapy showed a more prominent
effect on lipoprotein metabolism than did transdermal administra on, but transdermal medica on had a stronger effect on triglyceride and coagula on
factors. However, it needs to be considered that there is an increased risk of venous thrombo c events in the first year of treatment.
Maturitas 1996 May;24(1‐2):43‐50
Transdermal estrogen replacement therapy: beneficial effects on hemosta c risk factors for cardiovascular
disease.
Lindoff C, Peterson F, Lecander I, Mar nsson G, Astedt B.
Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden.
OBJECTIVES: To assess the effect of estrogen replacement therapy on hemosta c risk factors for cardiovascular disease (CVD) in postmenopausal women
during 2 years of treatment. METHODS: In an open prospec ve study, pa ents (n = 42) were inves gated before and during 2 years of treatment, and
compared to an untreated postmenopausal control group (n = 18) followed during the same period, healthy premenopausal women (n = 20) being
included as a reference group for premenopausal values. The pa ents underwent treatment with transdermal 17 beta‐estradiol (E2) (50 micrograms/24
h), oral medroxyprogesterone acetate (5 mg/day) being added for 12 days every second month. RESULTS: A er 2 years of treatment there was a
significant increase in t‐PA an gen (P = 0.01) and a significant decrease in F VII an gen (P = 0.01). PAI‐1 an gen concentra ons decreased slightly.
Fibrinogen concentra ons were already significantly decreased at 3‐month follow‐up (P = 0.01), and were s ll low a er 2 years. By contrast, at 2 year
follow‐up the postmenopausal control group manifested significant increases in F VII and PAI‐1 an gen and slight increases in fibrinogen, which resulted
in significant differences between pa ents and controls. Regression analysis showed the increase in the serum estradiol concentra ons to be inversely
correlated to the decreases in the plasma concen‐tra ons of F VII an gen (r = ‐0.34, P = 0.001) and fibrinogen (r = ‐0.35, P = 0.001). There were no
changes in AT III or protein C in any group. CONCLUSIONS: The increase in serum estradiol concentra ons due to replacement therapy did not adversely
affect the studied components of the fibrinoly c and protein C defense system against thrombosis, and resulted in beneficial decreases in F VII an gen
and fibrinogen. These findings may help to explain the beneficial effects of estrogen replacement therapy in terms of protec on from cardiovascular
disease.
Arch Neurol. 2003 Oct;60(10):1379‐84
Increased risk of stroke in hypertensive women using hormone therapy: analyses based on the Danish Nurse
Study.
Lokkegaard E, Jovanovic Z, Heitmann BL, Keiding N, O esen B, Hundrup YA, Obel EB, Pedersen AT.
Department of Obstetrics and Gynecology, Hvidovre Hospital, Copenhagen, Denmark.
BACKGROUND: Recent randomized clinical trials suggest an increased risk of stroke with hormone therapy (HT), whereas observa onal studies have
suggested mixed results. Differences in design, defini ons of HT exposure, and stroke outcome may explain these discrepancies. Li le a en on has been
paid to iden fying subgroups of women who are par cularly sensi ve to HT. OBJECTIVES: To inves gate the risk of various stroke outcomes among
women using HT based primarily on estradiol‐17beta (unopposed or combined with norethisterone acetate) and to assess the poten al modifying effect
by presence of risk factors for stroke. DESIGN: Prospec ve cohort study. SETTING: In 1993, the Danish Nurse Study was established, and ques onnaires
on lifestyle and HT use were sent to all Danish nurses older than 44 years, of whom 19,898 (85.8%) replied. PARTICIPANTS: Postmenopausal women (n =
13,122) free of previous major cardiovascular and cerebrovascular disease and cancer. MAIN OUTCOME MEASURE: Ischemic or hemorrhagic troke (n =
144) iden fied in the na onal registries of hospital discharges and cause of deaths in the total follow‐up through December 31, 1998. RESULTS: In 1993,
28.0% of the 13 122 were current HT users, 14.3% were past users, and 57.7% were never users. Overall, HT exposure was not consistently associated
with stroke. However, subdivision based on the presence of hypertension showed a significantly increased risk of stroke among hypertensive women.
©Storey Marke ng, All rights reserved.
23
Compared with hypertensive never HT users, an increased risk of total stroke was found with current use (hazard ra o, 2.35; 95% confidence interval,
1.16‐4.74) and especially with current use of estrogen‐proges n (hazard ra o, 3.00; 95% confidence interval, 1.33‐6.76). Normotensive women had no
increased risk of stroke with HT. CONCLUSIONS: We found an increased risk of stroke among hypertensive but not normotensive women using HT. The
present study suggests that HT should be avoided in hypertensive women.
PMID: 14568807
J Neurosci. 2003 Dec 10;23(36):11420‐6
Estradiol a enuates programmed cell death a er stroke‐like injury.
Rau SW, Dubal DB, Bo ner M, Gerhold LM, Wise PM.
Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA.
Estradiol is a known neurotrophic and neuroprotec ve factor. Our previous work demonstrated that replacement with physiological concentra ons of
estradiol protects the cortex against middle cerebral artery occlusion (MCAO)‐induced cell death. The cerebral cortex exhibits caspase‐dependent
programmed cell death (PCD) in many models of focal cerebral ischemia. We hypothesized that estradiol a enuates PCD during stroke injury. The
current study explored the temporospa al pa ern of markers of PCD, their rela onship to the evolu on of injury, and their modula on by estradiol. Rats
were ovariectomized and treated with either estradiol or vehicle. One week later, rats underwent MCAO, and brains were collected at 1, 4, 8, 16, and 24
hr. We assessed the temporospa al evolu on of infarc on volume, DNA fragmenta on, and levels of spectrin cleavage products in ischemic cortex.
Estradiol led to a delay and a enua on of injury‐mediated DNA fragmenta on as early as 8 hr a er MCAO. Estradiol also drama call reduced the level of
the 120 kDa caspase‐mediated spectrin breakdown product (SBDP120) at 4 hr but not at 8 or 16 hr. The SBDP150, produced by caspase and calpain,
showed peak levels at 16 hr but was not altered by estradiol. These results strongly suggest that estradiol protects the ischemic cortex by a enua ng
PCD, thereby reducing caspase ac vity, DNA fragmenta on, and subsequently, overall cell death. These studies deepen our understanding of the
mechanisms underlying estrogen‐mediated neuroprotec on.
PMID: 14673006
Endocrinology 2001 Mar 1;142(3):969‐973
Minireview: Neuroprotec ve Effects of Estrogen‐New Insights into Mechanisms of Ac on.
Wise PM, Dubal DB, Wilson ME, Rau SW, Bo ner M
Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536.
An accumula ng body of evidence clearly establishes that estradiol is a potent neuroprotec ve and neurotrophic factor in the adult: it influences
memory and cogni on, decreases the risk and delays the onset of neurological diseases such as Alzheimer's disease, and a enuates the extent of cell
death that results from brain injuries such as cerebrovascular stroke and neurotrauma. Thus, estradiol appears to act at two levels: 1) it decreases the
risk of disease or injury; and/or 2) it decreases the extent of injury incurred by suppressing the neurotoxic s mulus itself or increasing the resilience of
the brain to a given injury. During the past century, the average life span of women has increased drama cally, whereas the me of the menopause has
remained essen ally constant. Thus, more women will live a larger frac on of their lives in a postmenopausal, hypoestrogenic state than ever before.
Clearly, it is cri cal for us understand the circumstances under which estradiol exerts protec ve ac ons and he cellular and molecular mechanisms that
underlie these novel, nonreproduc ve ac ons.
"Our analysis strongly suggests estrogen replacement therapy can help reduce the risk of colorectal cancer, which is the second leading cause of cancer
deaths in the United States a er lung cancer," said Stampfer, professor of Epidemiology and Nutri on at the Harvard School of Public Health.
While researchers are not certain how estrogen affects the colon, it is possible that estrogen affects the produc on of bile acids that aid diges on in the
colon and seem to be important for colorectal cancer. Addi onally, estrogen interacts with estrogen‐specific receptors that line the colon and could
suppress the growth of abnormal cells.
Both Drs. Burt and Stampfer agree that further studies are needed to determine why estrogen may protect postmenopausal women against colorectal
cancer, and to shed light on how physicians might prevent the disease in the future.
The American Gastroenterological Associa on recommends colorectal cancer screening for all women over the age of 50, unless there is a family history
of colon cancer, which may make screening at an earlier age necessary. In addi on, women should talk with their physicians about how a healthy
lifestyle and proper diet may reduce their risk for this disease.
24
©Storey Marke ng, All rights reserved.
J Neuroendocrinol. 2007 Jan;19(1):1‐6
Oestrogen, cogni on and the maturing female brain
Craig MC, Murphy DG.
Department of Psychological Medicine, Ins tute of Psychiatry, London, UK.
Many women complain of memory and other cogni ve difficul es at mes that are associated with changes in ovarian steroid levels. However, the
biological mechanisms through which ovarian steroids exert these effects remains poorly understood. Furthermore, the effect of hormone therapy,
especially oestrogen therapy, on cogni on and brain func on in healthy women, and its role in the preven on of Alzheimer's disease, remains
controversial. Here, we review the evidence that, in healthy women, ovarian steroids/oestrogen affects brain regions crucial to higher cogni ve func on
at the macroscopic, microscopic, func onal and neurotransmi er levels.
PMID: 17184480
Hum Reprod Update. 2006 Nov 29; [Epub ahead of print]
Estrogen, cogni on and female ageing
Genazzani AR, Pluchino N, Luisi S, Luisi M.
Department of Reproduc ve Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa.
Star ng from fetal life, estrogens are crucial in determining central gender dimorphism, and an estrogen‐induced synap c plas city is well evident
during puberty and seasonal changes as well as during the ovarian cycle. Estrogens act on the central nervous system (CNS) both through genomic
mechanisms, modula ng synthesis, release and metabolism of neurotransmi ers, neuropep des and neurosteroids, and through non‐genomic
mechanisms, influencing electrical excitability, synap c func on and morphological features. Therefore, estrogen's neuroac ve effects are mul faceted
and encompass a system that ranges from the chemical to the biochemical to the genomic mechanisms, protec ng against a wide range of neurotoxic
insults. Clinical evidences show that, during the climacteric period, estrogen withdrawal in the limbic system gives rise to modifica ons in mood,
behaviour and cogni on and that estrogen administra on is able to improve mood and cogni ve efficiency in post‐menopause. Many biological
mechanisms support the hypothesis that estrogens might protect against Alzheimer's disease (AD) by influencing neurotransmission, increasing cerebral
blood flow, modula ng growth proteins associated with axonal elonga on and blun ng the neurotoxic effects of beta‐amyloid. On the contrary, clinical
studies of estrogen replacement therapy (ERT) and cogni ve func on have reported controversial results, indica ng a lack of efficacy of estrogens on
cogni on in post‐menopausal women aged >/=65 years. These findings suggest the presence of a cri cal period for HRT‐related neuroprotec on and
underlie the poten al importance of early ini a on of therapy for cogni ve benefit. In this review, we shall first describe the mul ple effects of steroids
in the nervous system, which may be significant in the ageing process. A cri cal update of HRT use in women and a discussion of possible prospec ves
for steroid use are subsequently proposed.
PMID: 17135285
BMC Neurosci. 2006 Nov 3;7:74 (Full text ar cle free online)
Estrogen protects neuronal cells from amyloid beta‐induced apoptosis via regula on of mitochondrial proteins
and func on.
Nilsen J, Chen S, Irwin RW, Iwamoto S, Brinton RD.
Department of Pharmacology and Pharmaceu cal Sciences, School of Pharmacy, University of Southern California, Los Angeles, California 90033, USA.
BACKGROUND: Neurodegenera on in Alzheimer's disease is associated with increased apoptosis and parallels increased levels of amyloid beta, which
can induce neuronal apoptosis. Estrogen exposure prior to neurotoxic insult of hippocampal neurons promotes neuronal defence and survival against
neurodegenera ve insults including amyloid beta. Although all underlying molecular mechanisms of amyloid beta neurotoxicity remain undetermined,
mitochondrial dysfunc on, including altered calcium homeostasis and Bcl‐2 expression, are involved in neurodegenera ve vulnerability. RESULTS: In this
study, we inves gated the mechanism of 17beta‐estradiol‐induced preven on of amyloid beta‐induced apoptosis of rat hippocampal neuronal cultures.
Estradiol treatment prior to amyloid beta exposure significantly reduced the number of apopto c neurons and the associated rise in res ng intracellular
calcium levels. Amyloid beta exposure provoked down regula on of a key an apopto c protein, Bcl‐2, and resulted in mitochondrial transloca on of
Bax, a protein known to promote cell death, and subsequent release of cytochrome c. E2 pretreatment inhibited the amyloid beta‐induced decrease in
Bcl‐2 expression, transloca on of Bax to the mitochondria and subsequent release of cytochrome c. Further implica ng the mitochondria as a target of
estradiol ac on, in vivo estradiol treatment enhanced the respiratory func on of whole brain mitochondria. In addi on, estradiol pretreatment
protected isolated mitochondria against calcium‐induced loss of respiratory func on. CONCLUSION: Therefore, we propose that estradiol pretreatment
protects against amyloid beta neurotoxicity by limi ng mitochondrial dysfunc on via ac va on of an apopto c mechanisms.
PMID: 17083736
©Storey Marke ng, All rights reserved.
25
Lancet 1996 Aug 17;348(9025):429‐32
Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease.
Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R
Gertrude H Serglevsky Center, Columbia University, New York, NY 10032, USA.
BACKGROUND: Oestrogen use by postmenopausal women has many health benefits, but findings on the effect of oestrogen in Alzheimer's disease are
conflic ng. Oestrogen promotes the growth and survival of cholinergic neurons and could decrease cerebral amyloid deposi on, both of which may
delay the onset or prevent Alzheimer's disease. To inves gate whether use of oestrogen during the postmenopausal period affects the risk of Alzheimer's
disease, we studied 1124 elderly women who were ini ally free of Alzheimer's disease, Parkinson's disease, and stroke, and who were taking part in a
longitudinal study of aging and health in a New York City community. METHODS: Rela ve risks and age‐at‐onset distribu ons were calculated from
simple and adjusted Cox propor onal hazards models. Standard annual clinical assessments and criterion‐based diagnoses were used in follow‐up (range
1‐5 years). FINDINGS: Overall, 156 (12.5%) women reported taking oestrogen a er onset of menopause. The age at onset of Alzheimer's disease was
significantly later in women who had taken oestrogen than in those who did not and the rela ve risk of the disease was significantly reduced (9/156
[5.8%] oestrogen users vs 158/968 [16.3%] nonusers; 0.40 [95% Cl 0.22‐0.85], p < 0.01), even a er adjustment for differences in educa on, ethnic origin,
and apolipoprotein‐E genotype. Women who had used oestrogen for longer than 1 year had a greater reduc on in risk; none of 23 women who were
taking oestrogen at study enrollment has developed Alzheimer's disease. INTERPRETATION: Oestrogen use in postmenopausal women may delay the onset
and decrease the risk of Alzheimer's disease. Prospec ve studies are needed to establish the dose and dura on of oestrogen required to provide this
benefit and to assess its safety in elderly postmenopausal women.
Ophthalmic Epidemiol. 2005 Feb;12(1):37‐45
Hormone replacement therapy, reproduc ve factors, and age‐related macular degenera on: the Salisbury Eye
Evalua on Project
Freeman EE, Munoz B, Bressler SB, West SK.
Dana Center for Preven ve Ophthalmology, Wilmer Eye Ins tute, Johns Hopkins Hospital, Bal more, MD 21287
PURPOSE: To evaluate a poten al rela onship between hormone replacement therapy (HRT), reproduc ve factors and age‐related macular
degenera on (AMD). METHODS: 1,458 female par cipants (age 65‐84) from the Salisbury Eye Evalua on study were available for this cross‐sec onal
analysis. AMD outcomes were iden fied by reading center assessment of fundus photographs. RESULTS: Women who currently used HRT had a lower
adjusted odds of large drusen (> 125 microm). Use of HRT was not sta s cally significantly associated with the prevalence of early AMD or advanced
AMD, although the odds ra os were all much less than 1. Women who had had an increased number of births had a greater prevalence of large drusen
(test of linear trend, p = 0.03). CONCLUSIONS: Current use of HRT was associated with a lower odds of large drusen, which may be predic ve of advanced
AMD. No sta s cally significant correla ons were found between HRT or reproduc ve factors and early or advanced AMD.
PMID: 15848919
Arch Ophthalmol. 2006 Jul;124(7):988‐92
Hormone therapy and age‐related macular degeneration: the Women's Health Initiative Sight Exam Study
Haan MN, Klein R, Klein BE, Deng Y, Blythe LK, Seddon JM, Musch DC, Kuller LH, Hyman LG, Wallace RB.
Department of Epidemiology, University of Michigan, 611 Church Street, Ann Arbor, MI 48104
OBJECTIVE: To determine the effec veness of treatment with conjugated equine estrogens (CEE) or with CEE combined with proges n (CEE + P) on age‐
related macular degenera on (AMD). METHODS: In an ancillary study to the Women's Health Ini a ve clinical trial of hormone therapy, 4262 women 65
years and older underwent fundus photography for the determina on of AMD. Par cipants were recruited from April 2000 to June 2002 at 21 clinical
sites an average of 5 years a er randomiza on. Par cipants were randomized to treatment with CEE, CEE + P, or placebo. Par cipants had been treated
for an average of 5 years at the ophthalmic evalua on for AMD. RESULTS: The overall prevalence of any AMD was 21.0%. No associa on was found
between CEE + P and early‐stage AMD. The CEE + P was associated with a reduced risk of so drusen a er adjustment for covariates and with a reduced
risk of neovascular AMD. CONCLUSIONS: Treatment with CEE alone or CEE + P does not affect early‐ or late‐stage AMD. Treatment with CEE + P may
reduce the risk of so drusen or neovascular AMD.
PMID: 16832022
Maturitas 2001 Oct 31;40(1):75‐83
Effects of hormonal replacement therapy in postmenopausal hypertensive pa ents.
Affinito P, Palomba S, Bonifacio M, Fontana D, Izzo R, Trimarco B, Nappi C.
Clinical Department of Gynecology, Obstetrics, and Human Reproduc on, Facolta di Medicina e Chirurgia, University of Naples Federico II, Via Pansini 5,
80131 Naples, Italy.
26
©Storey Marke ng, All rights reserved.
OBJECTIVE: To evaluate the effect of hormonal replacement therapy (HRT) on blood pressure (BP) in postmenopausal hypertensive women. METHODS:
Sixty women affected by hypertension were enrolled and randomized in two groups of treatment: transdermal con nuous HRT in a sequen al regimen
(group A) and placebo (group P). At baseline, a er 3 and 6 months of treatment, the BP with standard sphygmomanometer and with 24‐h ambulatory
recording method was evaluated in two periods (from day 10 through day 16 of the cycle and from day 20 through day 27 of the cycle). At the same
me, we also evaluated total cholesterol, LDL‐c, HDL‐c, triglycerides, and fibrinogen levels. RESULTS: A er 3 and 6 months of treatment, no significant
varia ons of systolic and diastolic BP measured with standard sphygmomanometer were detected in both groups. On the contrary, in group A in
comparison with basal values and group P, and without difference between the two phases of treatment, the 24‐h recording showed a significant
(P<0.05) decrease in BP. No significant varia ons were detected in group P versus baseline. In par cular, we observed in group A at 3 months of
treatment a significant (P<0.05) decrease only in day me BP in comparison with basal values and group P, without difference between the two phases of
treatment. Indeed, the decrease in day me BP was significant (P<0.05) for both systolic and diastolic BP. At 3 and 6 months a significant (P<0.05)
decrease in total cholesterol, LDL‐c and fibrinogen levels was detected in group A versus baseline and group P. HDL‐c and triglyceride concentra ons
showed no significant varia ons. CONCLUSIONS: The transdermal HRT induces a significant reduc on of BP values and a favorable metabolic ac on in
postmenopausal hypertensive pa ents.
Hypertension 1999 May;33(5):1190‐4
Estradiol with or without progesterone and ambulatory blood pressure in postmenopausal women.
Seely EW, Walsh BW, Gerhard MD, Williams GH.
Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachuse s, USA.
The purpose of this study was to determine whether transdermal estradiol and intravaginal progesterone given in doses to mimic the premenopausal
state would lower blood pressure (BP) in postmenopausal women. Fi een healthy postmenopausal women were studied in each of 3 condi ons: on
placebo, a er 8 weeks of transdermal estradiol 0.2 mg twice per week, and again 2 weeks a er addi on of intravaginal progesterone 300 mg/d. Women
were studied at each point a er 2 days of 100 mmol/d sodium intake. Twenty‐four‐hour ambulatory BP monitoring was performed, and blood was
assayed for estradiol, progesterone, and hormones of the renin‐angiotensin‐aldosterone system (RAAS). ANOVA with pairwise comparisons was used for
analysis. Urinary sodium excre on was similar at each me point. Levels of estrogen and progesterone similar to those in premenopausal women were
achieved. On estradiol, nocturnal systolic BP (110+/‐3 mm Hg), diastolic BP (63+/‐2 mm Hg), and mean BP (77+/‐2 mm Hg) fell significantly (P<0.02)
compared with placebo systolic BP (116+/‐2 mm Hg), diastolic BP (68+/‐2 mm Hg), and mean BP (82+/‐2 mm Hg). Day me BP followed the same trend
but was significantly lower only for mean BP. There was no ac va on of the RAAS. The addi on of progesterone resulted in no further fall in BP but a
significant ac va on of the RAAS. Thus, contrary to what is o en assumed, administra on of estradiol with or without progesterone not only did not
raise BP but rather substan ally lowered BP. This BP‐lowering effect may be responsible for the lower incidence of hypertension in premenopausal than
in postmenopausal women.
Funct Neurol 2000;15 Suppl 3:143‐53
Migraine associated with menstrua on.
MacGregor A.
City of London Migraine Clinic and St Bartholomew's Hospital, London, UK.
Many women report increased frequency of migraine in associa on with menstrua on. The term 'menstrual' migraine is o en used despite lack of an
agreed defini on. The Interna onal Headache Society has classified most headaches but not 'menstrual' migraine. A proposed defini on is based on the
finding that the prevalence of migraine increases on day 1 +/‐ 2 of the menstrual cycle. A acks occurring at this me of the cycle are typically without
aura. Effec ve acute therapy is the mainstay of management for menstrual and non‐menstrual a acks although there is some evidence that a acks
linked to menstrua on are less responsive to treatment compared with migraine at other mes of the cycle. If several a acks occur throughout the
cycle, standard prophylac c agents should be used. Women with exclusive 'menstrual' migraine may benefit from perimenstrual prophylaxis but this
should only be ins gated once the associa on between migraine and menstrua on has been confirmed with prospec ve records kept or a minimum of
three cycles. NSAIDs are the treatment of choice in reducing migraine associated with menorrhagia and/or dysmenorrhea, otherwise perimenstrual
oestrogen supplements using percutaneous or transdermal oestrogens are recommended. Combined oral contracep ves are useful for women requiring
contracep on although there is a tendency for a acks to occur during the pill‐free interval. If these are contraindicated, depot progestogen is an
alterna ve as it also inhibits ovula on and can improve migraine, provided amenorrhea is achieved. Oral progestogen‐only contracep on has li le place
in the management of 'menstrual' migraine as it does not inhibit ovula on and is o en associated with a disrupted menstrual cycle. Some women
consul ng with menstrual migraine are menopausal and may be considering hormone replacement therapy. Studies suggest that non‐oral routes of
delivery of oestrogen, which provide stable levels, are more likely to improve migraine than oral oestrogens, which produce variable day‐to‐day levels.
Too low a dose of oestrogen is ineffec ve at controlling symptoms but too high a dose, par cularly if coupled with surges of endogenous oestrogen, can
trigger migraine aura. Once the route and dose has been op mized, con nuous oestrogens can control migraine as well as menopausal symptoms.
Addi onal progestogen, necessary for unhysterectomised women, can exacerbate migraine. To minimize this, progesterone deriva ves or non‐oral
routes of delivery are recommended, with con nuous regimens used where possible.
©Storey Marke ng, All rights reserved.
27
Fer l Steril. 2006 Dec;86(6):1669‐75. Epub 2006 Oct 30
A comparison of oral and transdermal short‐term estrogen therapy in postmenopausal women with metabolic
syndrome
Chu MC, Cosper P, Nakhuda GS, Lobo RA.
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York, NY
OBJECTIVE: To determine whether it would be preferable to prescribe oral or transdermal estrogen to symptoma c postmenopausal women with
metabolic syndrome (MBS). DESIGN: Prospec ve, randomized study. SETTING: Academic medical center. PATIENT(S): Fi y obese postmenopausal
women with MBS. INTERVENTION(S): Women were randomized to receive either oral E(2) (oE(2), 1 mg/d) or transdermal E(2) (tE(2), 0.05 mg/d) for 3
months. Fas ng blood was obtained before and a er treatment for glucose, insulin, lipid profiles, the adipocytokines (adiponec n, lep n, and resis n),
and a gastric pep de (ghrelin). In addi on, a 75‐g 2‐hour oral glucose‐tolerance and intravenous insulin‐tolerance tests were performed before and a er
E(2)... CONCLUSION(S): This short‐term study suggests that oral E(2) may worsen insulin resistance (IR) and adipocytokine parameters, worsening
cardiovascular risk. Transdermal E(2) had minimal effects on IR and resulted in higher adiponec n. Although these data may not reflect altera ons that
occur with estrogen therapy in more metabolically normal postmenopausal women or with longer term therapy, the findings suggest that transdermal E
(2) may be a preferable treatment for obese women with MBS. Long‐term studies are needed to make any recommenda ons.
PMID: 17074346
Drugs Aging 2000 Dec;17(6):453‐61
Glycaemic control and hormone replacement therapy: implica ons of the Postmenopausal Estrogen/
Progestogen Interven on (PEPI) study.
Fineberg SE.
Indiana University School of Medicine, Department of Medicine, Indianapolis 46202, USA.
Despite evidence that supports the beneficial effects of postmenopausal hormone replacement therapy (HRT), concerns remain about its possible
adverse effects. However, entry into the postmenopausal state is associated with many characteris cs of the insulin resistance syndrome, including
increased cardiovascular morbidity and mortality, accre on of generalized and visceral adiposity and insulin resistance. Studies carried out in
postmenopausal women have revealed that an increase in visceral obesity is associated with an increase in androgenicity that, in turn, is associated with
type 2 (non‐insulin‐dependent) diabetes mellitus. Short term studies of HRT containing conjugated estrogens (CEE) and medroxyprogesterone (MPA)
have shown preven on of the accre on of visceral fat. However, longer term studies using other techniques suggest that these effects may be
evanescent. A few trials suggest that oral estrogen therapy reduces postmenopausal insulin resistance, as suggested by reduc ons in fas ng insulin and
glucose levels and an increase in glucose metabolism rates, whereas most studies do not show an adverse effect upon carbohydrate metabolism.
MPA may decrease these beneficial effects. Transdermal estrogen is essen ally neutral with regard to insulin sensi vity and oral estradiol (17beta‐
estradiol) may also be neutral or enhance sensi vity. Different progestogens vary in their effects upon carbohydrate metabolism. The
Postmenopausal Estrogen/Progestogen Interven on (PEPI) study was a prospec ve, 3‐year, randomized trial in 875 women that compared placebo,
unopposed CEE, CEE plus con nuous MPA, CEE plus cyclical MPA, and CEE plus cyclical micronized progesterone. Fas ng insulin and glucose levels
decreased significantly by 16.1% and 0.122 mmol/L, respec vely, in all drug treatment groups. However, a er a 75g glucose load, glucose levels at 2
hours increased by 0.33 mmol/L in the ac ve treatment groups without a corresponding increase in insulin levels. No beneficial effects on waist/hip ra o
could be demonstrated. Data from the PEPI trial also suggested that the maximum benefit regarding carbohydrate metabolism was achieved in pa ents
who were the most hyperglycemic and hyperinsulinaemic at the start of therapy. It can be concluded, therefore, that HRT has few, if any, harmful effects
on carbohydrate metabolism and that it may be of benefit in women in modifying the long term complica ons of the postmenopausal state.
Diabetes Care 2001 Jul;24(7):1144‐50
Hormone replacement therapy is associated with be er glycemic control in women with type 2 diabetes: The
Northern California Kaiser Permanente Diabetes Registry.
Ferrara A, Karter AJ, Ackerson LM, Liu JY, Selby JV; The Northern California Kaiser Permanente Diabetes Registry.
Division of Research, Kaiser Permanente, Oakland, California 94611, USA.
OBJECTIVE: In women with diabetes, the changes that accompany menopause may further diminish glycemic control. Li le is known about how
hormone replacement therapy (HRT) affects glucose metabolism in diabetes. The aim of this study was to examine whether HbA(1c) levels varied by
current HRT among women with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a cohort of 15,435 women with type 2 diabetes who were
members of a health maintenance organiza on, HbA(1c) and HRT were assessed by reviewing records in the health plan's computerized laboratory and
pharmacy systems. Sociodemographic and clinical informa on were collected by survey. RESULTS: The mean age was 64.7 years (SD +/‐ 8.7). The study
cohort comprised 55% non‐Hispanic whites, 14% non‐Hispanic blacks, 12% Hispanics, 11% Asians, 4% "other" ethnic groups, and 4% with missing
ethnicity data. Current HRT was observed in 25% of women. HbA(1c) levels were significantly lower in women currently using HRT than in women not
using HRT (age‐adjusted mean +/ SE: 7.9 +/‐ 0.03 vs. 8.5 +/‐ 0.02, respec vely, P = 0.0001). No differences in HbA(1c) level were observed between
women using unopposed estrogens and women using opposed estrogens. In a Generalized Es ma ng Equa on model, which took into account pa ent
clustering within physician and adjusted for age, ethnicity, educa on, obesity, hypoglycemic therapy, diabetes dura on, self‐monitoring of blood
glucose, and exercise, HRT remained significantly and independently associated with decreased HbA(1c) levels (P = 0.0001). CONCLUSIONS: HRT was
independently associated with decreased HbA(1c) level. Clinical trials will be necessary to understand whether HRT may improve glycemic control in
women with diabetes.
28
©Storey Marke ng, All rights reserved.
J Clin Endocrinol Metab 1995 Jun;80(6):1783‐8
A comparison of the effects of oral and transdermal estrogen replacement on insulin sensi vity in
postmenopausal women.
O'Sullivan AJ, Ho KK.
Garvan Ins tute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
Previous studies have shown that oral, but not transdermal, administra on of estrogen s mulates GH secre on in postmenopausal women. Because GH
impairs insulin ac on, the impact of estrogen replacement therapy on carbohydrate metabolism may be influenced by the route of administra on. The
aim of this study was to prospec vely compare the effects of oral and transdermal estrogen replacement on glucose tolerance and insulin sensi vity in
postmenopausal women. In an open label, randomized, cross‐over study, nine postmenopausal women were randomized to transdermal estrogen
patches (Estraderm‐TTS 100) or oral conjugated estrogen (Premarin, 1.25 mg) daily for 12 weeks and then crossed over to receive the alterna ve
treatment for a further 12 weeks. An oral glucose tolerance test and hyperinsulinemic euglycemic clamp (HEC) were performed before treatment and at
the end of 10 weeks of treatment. Oral and transdermal estrogen both significantly reduced LH to the same degree. Mean GH did not significantly
change with transdermal estrogen, but rose significantly during oral estrogen therapy. Peak and mean glucose and insulin levels during the oral glucose
tolerance test were not altered by estrogen therapy and were not significantly different between treatments. Mean glucose and insulin levels were
maintained at an iden cal level during the HEC performed at pretreatment and during estrogen therapy. The mean glucose infusion rate required to
maintain euglycemia during the HEC (mean +/‐ SEM, pretreatment, 40.4 +/‐ 4.8 mumol/kg.min) was unaltered by oral (39.8 +/‐ 4.6 mumol/kg.min) or
transdermal estrogen treatment (42.1 +/‐ 4.2 mumol/kg.min). However, during the transdermal estrogen phase (60 +/‐ 10 mumol/L), the mean
nonesterified free fa y acid concentra on was suppressed to a significantly lower level during the HEC than during the oral estrogen phase (120 +/‐ 20
mumol/L; P < 0.05). We conclude that compared to the oral route, transdermal estrogen therapy is associated with a slight, but significant,
improvement of insulin ac on on lipid metabolism. However, in the short term, the route of estrogen replacement therapy does not have a major
impact on glucose metabolism in postmenopausal women.
Am J Obstet Gynecol 1999 Jun;180(6 Pt 1):1504‐11
Percutaneous absorp on of progesterone in postmenopausal women treated with transdermal estrogen.
Burry KA, Pa on PE, Hermsmeyer K.
Department of Obstetrics, Oregon Health Sciences University, Portland, USA.
OBJECTIVE: The objec ve of this study was to evaluate the serum levels of progesterone resul ng from the applica on of a progesterone cream to the
skin. STUDY DESIGN: Six postmenopausal women were evaluated at a university clinic over a 4‐week period. RESULTS: Transdermal estradiol 0.05 mg
was applied 2 days before the first applica on of progesterone (30 mg/d) and was con nued throughout the study. Patches were changed twice a week.
Progesterone cream was applied once a day for 2 weeks. On day 15 and for the next 2 weeks, the progesterone cream was applied twice daily (60 mg/
d). Serum 17beta‐estradiol and progesterone were measured at 9 different mes over a 24‐hour period on day 1 and at weekly intervals for the 4‐week
dura on of the study. Serum 17beta‐estradiol concentra ons varied among women, with mean concentra ons of 40 to 64 pg/mL observed. Consistency
in 17beta‐estradiol concentra ons was found within individual persons throughout the study. Serum progesterone concentra ons also varied among
women, with mean concentra ons ranging from 1.6 to 3.3 ng/mL. A er 2 weeks of percutaneous dosing, progesterone concentra ons were sustained
for at least 8 hours and were consistent within a given person. An appropriate increase in progesterone concentra on occurred a er 4 weeks compared
with 2 weeks of applica on. Individually, a 0.53 correla on, significant at P <.0001, was seen between the absorp on of 17beta‐estradiol and
progesterone. CONCLUSION: Significant increases in serum concentra ons of progesterone were observed in all of the women studied. The
percutaneous absorp on of progesterone correlates strongly with the absorp on of transdermal 17beta‐estradiol. There is variance in absorp on of
progesterone just as with 17beta‐estradiol, and the 2 measures are closely correlated. The percutaneous applica on of progesterone cream appears to
be a safe and effec ve route of administra on.
Arterioscler Thromb Vasc Biol 1997 Nov;17(11):3071‐8
Effects of oral and transdermal estrogen/progesterone regimens on blood coagula on and fibrinolysis in
postmenopausal women. A randomized controlled trial.
Scarabin PY, Alhenc‐Gelas M, Plu‐Bureau G, Taisne P, Agher R, Aiach M.
INSERM‐Cardiovascular Epidemiology Unit U258, Hopital Broussais, Paris, France.
Postmenopausal hormone replacement therapy is associated with a reduc on in the incidence of coronary heart disease. However, inconclusive results
have been reported with respect to the risk of stroke, and recent studies consistently showed an increased risk of venous thromboembolism in
postmenopausal women using oral estrogen. There are surprisingly few interven onal studies to assess the true effects of estrogen‐proges n regimens
on blood coagula on and fibrinolysis, and the impact of the route of estrogen administra on on hemostasis has not been well documented. Therefore,
we inves gated the effects of oral and transdermal estradiol/progesterone replacement therapy on hemosta c variables. Forty‐five healthy
postmenopausal women, aged 45 to 64 years, were assigned randomly to one of the three following groups: cyclic oral or transdermal estradiol, both
combined with progesterone, or no hormonal treatment. Hemosta c variables were assayed at baseline and a er a 6‐month period. Pairwise
differences in the mean change between the three groups were compared using nonparametric tests. Oral but not transdermal estradiol regimen
significantly increased the mean value of prothrombin ac va on pep de (F1 + 2) and decreased mean an thrombin ac vity compared with no
treatment. Differences in fragment F1 + 2 levels between ac ve treatments were significant. The oral estrogen group was associated with a significant
©Storey Marke ng, All rights reserved.
29
decrease in both mean ssue‐type plasminogen (t‐PA) concentra on and plasminogen ac vator inhibitor (PAI‐1) ac vity and a significant rise in global
fibrinoly c capacity (GFC) compared with the two other groups. A transdermal estrogen regimen had no significant effect on PAI‐1, t‐PA, and GFC levels.
There were no significant changes in mean values of fibrinogen, factor VII, von Willebrand factor, protein C, fibrin D‐dimer, and plasminogen between
and within the three groups. We conclude that oral estrogen/progesterone replacement therapy may result in coagula on ac va on and increased
fibrinoly c poten al, whereas opposed transdermal estrogen appears without any substan al effects on hemostasis. Whereas these results may
account for an increased risk of venous thromboembolism in users of oral postmenopausal estrogen, they emphasize the poten al importance of the
route of estrogen administra on in prescribing hormone replacement therapy to postmenopausal women, especially to those at high risk of thrombo c
disease.
Br J Obstet Gynaecol 1997 Nov;104 Suppl 16:19‐25
Transdermal oestradiol gel in the treatment of the climacterium: a comparison with oral therapy.
Hirvonen E, Lamberg‐Allardt C, Lankinen KS, Geurts P, Wilen‐Rosenqvist G.
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Finland.
OBJECTIVE: To compare two doses of a transdermal oestradiol gel (Divigel/Sandrena) plus oral sequen al medroxyprogesterone acetate (MPA) with oral
oestradiol valerate plus oral sequen al MPA (Divina/Dilena). DESIGN: Two year, randomised, open‐label, compara ve study. SETTING: Menopausal
outpa ent clinic in Helsinki. SUBJECTS: Postmenopausal women with climacteric complaints or already using HRT. INTERVENTIONS: (1) One gram gel
containing 1 mg oestradiol for 3 months plus 20 mg oral MPA during the last 14 days; (2) 2 g gel containing 2 mg oestradiol for 21 days plus 10 mg oral
MPA during the last 14 days; (3) 2 mg oestradiol valerate tablets for 3 weeks plus 10 mg oral MPA during the last 10 days. In all groups, each treatment
period was followed by a 7‐day medica on‐free interval. MAIN OUTCOME MEASURES: Climacteric complaints, bleeding control, bone mineral density,
biomarkers of bone metabolism, lipid profile, tolerability and safety. RESULTS: With each prepara on, climacteric complaints were significantly reduced
and good bleeding control was obtained. In addi on, maintenance of bone mineral density as well as a reduc on of bone turnover was achieved in all
groups. Lipid parameters showed no unfavourable changes. Con nua on rates were similar in all groups with overall 74% of pa ents comple ng the
first year, whereas 94% of pa ents who elected to con nue completed the second year. Tolerability of the gel was good: only 1.7% of pa ents
discon nued treatment due to skin irrita on. CONCLUSIONS: Transdermal oestradiol gel and oral oestradiol valerate tablets, used in combina on with
oral sequen al MPA, are effec ve regimens of HRT in postmenopausal women. Transdermal oestradiol gel is an efficient, well‐tolerated form of HRT.
Br J Obstet Gynaecol 1997 Nov;104 Suppl 16
Transdermal estrogen therapy in postmenopausal women: gel vs. patch
An open, randomized, controlled, parallel‐group trial of 12 months dura on compared an estradiol 1.0mg gel applied daily with an estradiol patch
delivering 50 micrograms estradiol/24 hours in one hundred twenty postmenopausal women. In addi on, 25 women without HRT served as a reference
group for bone mineral density measurements. The effect of treatment on clinical symptoms, the endometrium, total body bone mineral density and
lipid metabolism ‐ as well as the tolerability of the treatments with special emphasis on skin irrita on and compliance ‐ were evaluated by Hirvonen et
al. Both treatment regimens were found to be equally safe and effec ve in allevia ng climacteric symptoms and preserving bone mineral density. A
trend towards heavier bleeding was detected in pa ents treated with the estradiol delivering patch. A sta s cally nonsignificant decrease of total
cholesterol and triglyceride concentra ons but no change in high‐density lipoprotein cholesterol concentra on was observed in both groups. The
acceptability of the treatment was higher in the gel group (96.4%) than in the patch group (90.7%). Only two (3.3%) women using the gel complained of
skin irrita on whereas 28 pa ents (46.7%) using the patch reported this adverse effect. The conclusion: both the gel and patch are equally effec ve in
hormone replacement therapy but the gel prepara on is less irrita ng to the skin. In comparison with oral therapy, transdermal estradiol gel is an
efficient, well‐tolerated form of HRT.
Maturitas 2001 Jul 25;39(1):43‐55
The influence of hormone replacement therapy on skin aging: a pilot study.
Sator PG, Schmidt JB, Sator MO, Huber JC, Honigsmann H.
Department of Special and Environmental Dermatology, University of Vienna, General Hospital, Vienna, Austria.
OBJECTIVES: We studied the effect of hormonal treatment on skin aging in menopausal women. METHODS: Twenty‐four pa ents (45‐68 years; mean
age, 54.9 years) without hormone treatment for at least 6 months were included. Pa ents were assigned to three therapy groups: 1, oestrogen only
(Estraderm TTS 50) (n=6); 2, transdermal oestrogen and progesterone (Estraderm TTS 50 and 0.4 mg progesterone vaginal suppository) (n=7); and 3,
oral oestrogen and progesterone (2 mg Progynova and 0.4 mg progesterone vaginal suppository) (n=8). One group without therapy was included as a
control group (n=3). Treatment was con nued for 6 months. Three pa ents, one from group 2 and two from group 3, discon nued therapy before the
study endpoint. The following skin parameters were measured at monthly intervals during treatment: skin surface lipids, epidermal skin hydra on, skin
elas city and skin thickness. Concomitant clinical evalua on included a subjec ve clinical evalua on form, a pa ent ques onnaire and laboratory tests
for oestradiol, progesterone and follicle s mula ng hormone. RESULTS: Mean levels of epidermal skin moisture, elas city and skin thickness were
improved at the end of treatment based on both subjec ve and objec ve evalua on in pa ents with hormone replacement therapy (HRT). Skin surface
30
©Storey Marke ng, All rights reserved.
lipids were increased during combined HRT, which may reflect s mulatory effects of the progestagen component on sebaceous gland ac vity, while
oestrogen alone has a sebum‐suppressive ac on. In the HRT groups, the ques onnaire for climacteric complaints demonstrated significant
improvements, while laboratory tests showed increases in oestradiol and progesterone and decreases in FSH. CONCLUSIONS: HRT with the men oned
regimes significantly improved parameters of skin aging.
Int J Dermatol 1996 Sep;35(9):669‐74
Treatment of aging skin with topical estrogens
The coincidence of climacteric symptoms and the beginning of skin aging suggests that estrogen deficiency may be a common and important factor in
the perimenopausal woman. O en hormones have been considered important in endogenous aging of the skin, but their role has not been clearly
defined. Therefore, Schmidt et al. inves gated whether topical treatment of the skin with estrogen could reverse some of the changes in the aging skin.
The effects of 0.01% estradiol and 0.3% estriol compounds were compared in 59 preclimacteric women with skin aging symptoms. Monthly
determina ons of estradiol (E2), follicle‐s mula ng hormone (FSH), and prolac n (PRL) were done and the monthly clinical monitoring was
supplemented by measurements of skin hydra on by corneometry and profilometry. In 10 pa ents, skin biopsies were taken for immunohistochemical
determina on of collagen types I and III. A er treatment for 6 months, elas city and firmness of the skin had markedly improved and the wrinkle depth
and pore sizes had decreased by 61 to 100% in both groups. Furthermore, skin moisture had increased and the measurement of wrinkles revealed
significant, or even highly significant, decreases of wrinkle depth in the estradiol and the estriol groups, respec vely. With regard to hormone levels,
only those of PRL had increased significantly and no systemic hormonal side effects were noted.
J Womens Health Gend Based Med 2000 May;9(4):381‐7
Comparison of regimens containing oral micronized progesterone or medroxyprogesterone acetate on quality
of life in postmenopausal women: a cross‐sec onal survey.
Fitzpatrick LA, Pace C, Wiita B.
Mayo Clinic and Mayo Founda on, Rochester, Minnesota 55905, USA.
A cross‐sec onal survey was conducted to examine quality of life (QOL) related to physiological, soma c, and vasomotor effects of changing
progestogen treatment from medroxyprogesterone acetate (MPA) to micronized progesterone in postmenopausal women. Eligible women (n = 176)
were currently using hormone replacement therapy (HRT) containing micronized progesterone for 1‐6 months and had previously received HRT
containing MPA. QOL was assessed via telephone interview using the Greene Climacteric Scale and the Women's Health Ques onnaire. When compared
with the MPA‐containing regimen, women using micronized progesterone‐containing HRT experienced significant improvement in vasomotor
symptoms, soma c complaints, and anxiety and depressive symptoms. Women reported improved percep ons of their pa erns of vaginal bleeding and
control of menopausal symptoms while on the micronized progesterone‐containing regimen. Approximately 80% of women reported overall sa sfac on
with the micronized progesterone‐containing regimen. A micronized progesterone‐containing HRT regimen offers the poten al for improved QOL as
measured by improvement of menopause‐associated symptoms.
Fer l Steril 1999 Sep;72(3):389‐97
Micronized progesterone: clinical indica ons and comparison with current treatments.
Fitzpatrick LA, Good A.
Department of Internal Medicine, Mayo Clinic and Mayo Founda on, Rochester, Minnesota 55905, USA.
OBJECTIVE: To integrate and evaluate the pharmacokine c, endocrine, and clinical effects of micronized progesterone formula ons. DESIGN: Published
ar cles concerning the pharmacokine cs of orally administered progesterone and the poten al clinical uses of oral micronized progesterone were
reviewed. Results concerning their use for secondary amenorrhea, premenopausal bleeding disorders, luteal phase dysfunc on, termina on of
premature labor, hormone replacement therapy, and premenopausal syndrome are summarized. Cri cal issues to be resolved through ongoing
preclinical and clinical research are highlighted. RESULT(S): Because of the enhanced bioavailability of oral micronized progesterone, the compound may
be useful for a variety of therapeu c indica ons. Oral micronized progesterone is available in France, and a formula on recently has been approved in
the United States for the treatment of secondary amenorrhea and postmenopausal hormone replacement therapy. A large body of evidence, including
the Postmenopausal Estrogen/Proges n Interven ons study, suggests that the use of a combina on of estrogen and oral micronized progesterone is
op mal for long‐term hormone replacement therapy. There also are data indica ng that oral micronized progesterone could be of poten al use for the
treatment of premenopausal bleeding disorders, luteal phase disorders, and premature labor. CONCLUSION(S): Oral micronized progesterone has
widespread clinical poten al, par cularly for the treatment of secondary amenorrhea and dysfunc onal premenopausal bleeding, and as a component
of postmenopausal hormone replacement therapy.
©Storey Marke ng, All rights reserved.
31
J Am Coll Cardiol 2000 Dec;36(7):2154‐9
Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on
exercise‐induced myocardial ischemia in postmenopausal women.
Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P.
Department of Cardiology, Ospedale San Raffaele, Rome, Italy.
OBJECTIVES: We sought to compare the effects of estrogen/transvaginal progesterone gel with estrogen/medroxyprogesterone acetate (MPA) on
exercise‐induced myocardial ischemia in postmenopausal women with coronary artery disease or previous myocardial infarc on, or both.
BACKGROUND: Estrogen therapy beneficially affects exercise‐induced myocardial ischemia in postmenopausal women; however, women with an intact
uterus also take proges n to protect against uterine malignancies. The effects of combina on estrogen/proges n therapy on myocardial ischemia are
unknown. METHODS: Eighteen postmenopausal women (mean +/‐ SD age 59+/‐7 years) were given 17‐beta‐estradiol in single‐blinded manner for four
weeks (1 mg/day for three weeks then 2 mg/day for one week). Estradiol (2 mg/day) was then con nued, and the pa ents were randomized (double‐
blind) for 12 days to either transvaginal progesterone gel (90 mg on alternate days) and oral MPA placebo (10 mg/day), or vice versa. A er another two
weeks on estradiol alone, the pa ents crossed over to proges n treatment and repeated the protocol on the opposite treatment. Pa ents underwent
treadmill exercise tes ng a er each estradiol phase and at day 10 of each proges n phase. RESULTS: Exercise me to myocardial ischemia increased
a er the first estrogen phase as compared with baseline (mean difference with 95% confidence interval [CI]: 72 s [34 to 110], p = 0.001), and was
increased by combina on estradiol/progesterone therapy as compared with estradiol/MPA therapy (92 s [35 to 149], p = 0.001)). Two pa ents (11%)
were withdrawn while taking estradiol/MPA owing to unstable angina. CONCLUSIONS: Combina on estrogen/transvaginal progesterone gel increases
exercise me to myocardial ischemia, as compared with estrogen/MPA. These results imply that the choice of proges n in women at higher
cardiovascular risk requires careful considera on.
Nat Med 1997 Mar;3(3):324‐7
Medroxyprogesterone interferes with ovarian steroid protec on against coronary vasospasm.
Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K.
Oregon Regional Primate Research Center, Oregon 97006, USA.
Cardiovascular disease, the major cause of death in post‐menopausal women, can be reduced by replacement of ovarian steroid hormones. To compare
medroxyprogesterone with progesterone as the proges n in hormone replacement therapy from the standpoint of coronary artery vasospasm, we
treated ovariectomized rhesus monkeys with physiological levels of estradiol‐17 beta in combina on with medroxyprogesterone or progesterone for
four weeks. Coronary vasospasm in response to pathophysiological s mula on without injury showed that progesterone plus estradiol protected but
medroxyprogesterone plus estradiol failed to protect, allowing vasospasm. We conclude that medroxyprogesterone in contrast to progesterone
increases the risk of coronary vasospasm.
J Reprod Med 1999 Feb;44(2 Suppl):180‐4
Progestogens and cardiovascular disease. A cri cal review.
Clarkson TB.
Compara ve Medicine Clinical Research Center, Wake Forest University School of Medicine, Winston‐Salem, NC
Although progesta onal hormones are clearly beneficial in preven ng estrogen‐induced endometrial hyperplasia and cancer, their effect on other areas
is far less clear. Of par cular interest is the a enua ng effect medroxyprogesterone acetate (MPA) has on the cardiovascular benefits of
postmenopausal estrogen treatment. MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery
atherosclerosis, accelerates low‐density lipoprotein uptake in plaque, increases the thrombogenic poten al of atherosclero c plaques and promotes
insulin resistance and its consequent hyperglycemia. These effects may be largely limited to MPA and not shared with other progestogens.
Arterioscler Thromb Vasc Biol 1997 Jan;17(1):217‐21
Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery
atherosclerosis.
Adams MR, Register TC, Golden DL, Wagner JD, Williams JK.
Compara ve Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston‐Salem, NC
Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis,
the effects of combined (estrogen plus proges n) hormone‐replacement therapy are uncertain. Some observa onal data indicate that users of
combined hormone replacement consis ng of con nuously administered oral conjugated equine estrogens (CEE) and oral sequen ally administered (7
to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduc on in risk similar to that of users of CEE alone. However, the effects of
combined, con nuously administered CEE plus MPA (a prescribing pa ern that has gained favor) on the risk of coronary heart disease or atherosclerosis
are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or
32
©Storey Marke ng, All rights reserved.
in combina on, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fe atherogenic
diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% rela ve to
untreated (estrogen‐deficient) controls (P < .004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of
untreated controls. Although treatment had marked effects on plasma lipoprotein pa erns, sta s cal adjustment for varia on in plasma lipoproteins
did not alter the between‐group rela onships in atherosclero c plaque size, sugges ng that these factors do not explain substan ally the
atheroprotec ve effect of estrogen or the MPA‐associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits
the ini a on and progression of coronary artery atherosclerosis and that con nuously administered oral MPA antagonizes this atheroprotec ve effect.
Steroids 2000 Oct‐Nov;65(10‐11):659‐64
Proges ns and menopause: epidemiological studies of risks of endometrial and breast cancer.
Pike MC, Ross RK.
USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, MS #44, Los Angeles, CA
90033‐0800, USA.
Estrogen replacement therapy (ERT) increases a woman's risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT
increases a woman's risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer
risk, proges ns have been added to ERT (estrogen‐proges n replacement therapy; EPRT) for between 5 and 15 days (usually 7 or 10 days) per month in
a sequen al fashion (sequen al EPRT; SEPRT) or with each dose of ERT (con nuous‐combined EPRT; CEPRT). We conducted two large case‐control
studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. As expected CEPRT
was not associated with any increased risk of endometrial cancer. SEPRT with the proges n being given for 10 days per month also did not increase
endometrial cancer risk. SEPRT with the proges n being given for 7 days per month did increase endometrial cancer risk with only a rela vely slight
rduc on in risk compared to ERT effec vely propor onal to the reduc on in the number of days of unopposed estrogen. The sharp contrast between
the effects of 7 days and 10 days of proges n in SEPRT suggests that the extent of endometrial sloughing or of 'terminal' differen a on at the
comple on of the proges n phase may play a cri cal role in determining endometrial cancer risk. This may provide an explana on of why endometrial
cancer risk increases so sharply with age in young women even in countries where obesity‐associated anovula on is very uncommon; extended periods
of unopposed estrogen is not an explana on but less than 10 days of an 'adequate' progesterone level may be. EPRT significantly increased the risk of
breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 212‐fold greater than the
effect of ERT, which we had previously predicted on theore cal grounds. This effect could also be predicted from the results on mammoraphic densi es
seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densi es to
a much greater extent than ERT. Proges ns need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner
that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administra on. The vaginal route
will provide adequate endometrial proges n levels with low blood levels so that the effects of the proges n on the breast should be small; with the
direct endometrial route the blood proges n levels are even lower, and the effects of the proges n on the breast will be effec vely zero. If this is
unacceptable to a woman, then giving proges ns by mouth (or transdermally) for 10 days every 3 to 4 months should provide sa sfactory protec on of
the endometrium when used with standard‐dose conjugated estrogen (CE). This regimen has much less effecton the breast than monthly SEPRT or
CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that
this approach may be sa sfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed.
Obstet Gynecol 1999 Aug;94(2):225‐8
Transdermal progesterone cream for vasomotor symptoms and postmenopausal bone loss.
Leone HB, Longo S, Anas JN.
Department of Obstetric and Gynecology, St. Luke's Hospital, Bethlehem, Pennsylvania 18015, USA.
OBJECTIVE: To determine effec veness of transdermal progesterone cream for controlling vasomotor symptoms and preven ng postmenopausal bone
loss. METHODS: We randomly assigned 102 healthy women within 5 years of menopause to transdermal progesterone cream or placebo. Study subjects
and inves gators were masked un l data analysis was completed. An ini al evalua on included complete history, physical examina on, bone mineral
density determina on, and serum studies (TSH, FSH, lipid profile, and chemistry profile). Subjects were instructed to apply a quarter teaspoon of cream
(containing 20 mg progesterone or placebo) to the skin daily. Each woman received daily mul vitamins and 1200 mg of calcium and were seen every 4
months for review of symptoms. Bone scans and serum chemistries were repeated a er 1 year. RESULTS: Thirty of the 43 (69%) in the treatment group
and 26 of the 47 (55%) in the placebo group complained ini ally of vasomotor symptoms. Improvement or resolu on of vasomotor symptoms, as
determined by review of weekly symptom diaries, was noted in 25 of 30 (83%) treatment subjects and five of 26 (19%) placebo subjects (P < .001).
However, the number of women who showed gain in bone mineral density exceeding 1.2% did not differ (alpha = .05, power of 80%). CONCLUSION:
Although we found no protec ve effect on bone density a er 1 year, we did see a significant improvement in vasomotor symptoms in the treated
group.
©Storey Marke ng, All rights reserved.
33
Endocr Rev 1990 May;11(2):386‐98
Progesterone as a bone‐trophic hormone.
Prior JC.
Division of Endocrinology and Metabolism, University of Bri sh Columbia, Vancouver, Canada.
Experimental, epidemiological, and clinical data indicate that progesterone is ac ve in bone metabolism. Progesterone appears to act directly on bone
by engaging an osteoblast receptor or indirectly through compe on for a glucocor coid osteoblast receptor. Progesterone seems to promote bone
forma on and/or increase bone turnover. It is possible, through estrogen‐s mulated increased progesterone binding to the osteoblast receptor, that
progesterone plays a role in the coupling of bone resorp on with bone forma on. A model of the interdependent ac ons of progesterone and estrogen
on appropriately‐"ready" cells in each bone mul cellular unit can be ed into the integrated secre ons of these hormones within the ovulatory cycle.
Figure 5 is an illustra on of this concept. It shows the phases of the bone remodeling cycle in parallel with temporal changes in gonadal steroids across a
stylized ovulatory cycle. Increasing estrogen produc on before ovula on may reverse the resorp on occurring in a "sensi ve" bone mul cellular unit
while gonadal steroid levels are low at the me of menstrual flow. The bone remodeling unit would then be ready to begin a phase of forma on as
progesterone levels peaked in the midluteal phase. From this perspec ve, the normal ovulatory cycle looks like a natural bone‐ac va ng, coherence
cycle. Cri cal analysis of the reviewed data indicate that progesterone meets the necessary criteria to play a causal role in mineral metabolism. This
review provides the preliminary basis for further molecular, gene c, experimental, and clinical inves ga on of the role(s) of progesterone in bone
remodeling. Much further data are needed about the interrela onships between gonadal steroids and the "life cycle" of bone. Feldman et al., however,
may have been prophe c when he commented; "If this an ‐glucocor coid effect of progesterone also holds true in bone, then postmenopausal
osteoporosis may be, in part, a progesterone deficiency disease."
JAMA. 2002 Jul 17;288(3):321‐33
Risks and benefits of estrogen plus proges n in healthy postmenopausal women: principal results From the
Women's Health Ini a ve randomized controlled trial.
Rossouw JE, Anderson GL, Pren ce RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM,
Ockene J; Wri ng Group for the Women's Health Ini a ve Inves gators.
Division of Women's Health Ini a ve, Na onal Heart, Lung, and Blood Ins tute, 6705 Rockledge Dr, One Rockledge Ctr, Suite 300, Bethesda, MD 20817,
USA.
CONTEXT: Despite decades of accumulated observa onal evidence, the balance of risks and benefits for hormone use in healthy postmenopausal
women remains uncertain. OBJECTIVE: To assess the major health benefits and risks of the most commonly used combined hormone prepara on in the
United States. DESIGN: Estrogen plus proges n component of the Women's Health Ini a ve, a randomized controlled primary preven on trial (planned
dura on, 8.5 years) in which 16608 postmenopausal women aged 50‐79 years with an intact uterus at baseline were recruited by 40 US clinical centers
in 1993‐1998. INTERVENTIONS: Par cipants received conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, in 1
tablet (n = 8506) or placebo (n = 8102). MAIN OUTCOMES MEASURES: The primary outcome was coronary heart disease (CHD) (nonfatal myocardial
infarc on and CHD death), with invasive breast cancer as the primary adverse outcome. A global index summarizing the balance of risks and benefits
included the primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, and death due to other
causes. RESULTS: On May 31, 2002, a er a mean of 5.2 years of follow‐up, the data and safety monitoring board recommended stopping the trial of
estrogen plus proges n vs placebo because the test sta s c for invasive breast cancer exceeded the stopping boundary for this adverse effect and the
global index sta s c supported risks exceeding benefits. This report includes data on the major clinical outcomes through April 30, 2002. Es mated
hazard ra os (HRs) (nominal 95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02‐1.63) with 286 cases; breast cancer, 1.26 (1.00‐1.59) with
290 cases; stroke, 1.41 (1.07‐1.85) with 212 cases; PE, 2.13 (1.39‐3.25) with 101 cases; colorectal cancer, 0.63 (0.43‐0.92) with 112 cases; endometrial
cancer, 0.83 (0.47‐1.47) with 47 cases; hip fracture, 0.66 (0.45‐0.98) with 106 cases; and death due to other causes, 0.92 (0.74‐1.14) wit 331 cases.
Corresponding HRs (nominal 95% CIs) for composite outcomes were 1.22 (1.09‐1.36) for total cardiovascular disease (arterial and venous disease), 1.03
(0.90‐1.17) for total cancer, 0.76 (0.69‐0.85) for combined fractures, 0.98 (0.82‐1.18) for total mortality, and 1.15 (1.03‐1.28) for the global index.
Absolute excess risks per 10 000 person‐years a ributable to estrogen plus proges n were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more
invasive breast cancers, while absolute risk reduc ons per 10 000 person‐years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute
excess risk of events included in the global index was 19 per 10 000 person‐years. CONCLUSIONS: Overall health risks exceeded benefits from use of
combined estrogen plus proges n for an average 5.2‐year follow‐up among healthy postmenopausal US women. All‐cause mortality was not affected
during the trial. The risk‐benefit profile found in this trial is not consistent with the requirements for a viable interven on for primary preven on of
chronic diseases, and the results indicate that this regimen should not be ini ated or con nued for primary preven on of CHD.
Lancet 2002 Sep 21;360(9337):942‐4
Evidence from randomised trials on the long‐term effects of hormone replacement therapy.
Beral V, Banks E, Reeves G.
Cancer Research UK Epidemiology Unit, Gibson Building, Radcliffe Infirmary, Oxford OX2 6HE, UK.
CONTEXT: Over the past few decades hormone replacement therapy (HRT) has been used increasingly by post‐menopausal women in western countries.
The need for objec ve data on long‐term effects prompted the se ng up of randomised trials to compare cancer and cardiovascular disease endpoints
in HRT users and non‐users. With the early termina on of part of the Women's Health Ini a ve trial (JAMA 2002; 288: 321‐33), it is mely to review the
34
©Storey Marke ng, All rights reserved.
evidence from such studies. STARTING POINT: Four randomised trials including over 20000 women followed up for 4.9 years, on average, have now
reported on the effect of HRT for major, poten ally fatal, condi ons. Overall, HRT users had a significantly increased incidence of breast cancer, stroke,
and pulmonary embolism; a significantly reduced incidence of colorectal cancer and fractured neck of femur; but no significant change in endometrial
cancer or coronary heart disease.There was no significant varia on across the trials in the results for any condi on. Three trials had recruited women
with previous cardiovascular disease and the fourth, the Women's Health Ini a ve, had recruited healthy women.Combined oestrogen/progestagen
HRT was used in three trials and oestrogen alone in one. Use of HRT over a 5‐year period by healthy postmenopausal women in western countries is
es mated to cause an extra breast cancer,stroke, or pulmonary embolus in about 6 per 1000 users aged 50‐59 and 12 per 1000 aged 60‐69. Over the
same period, the es mated reduc on in incidence of colorectal cancer or fractured neck of femur is 1.7 per 1000 users aged 50‐59 and 5.5 per 1000
aged 60‐69. The increased incidence of any one of these condi ons is greater than any reduc on, the es mated net excess over 5 years being 1 per 230
users aged 50‐59, and 1 per 150 aged 60‐69. WHERE NEXT: Substan al new data should soon be available from randomised trials of oestrogen‐alone
HRT versus placebo, whereas few addi onal trial data on combined HRT are expected for about a decade. Exis ng randomised trials are too small to
describe reliably the effect of HRT on important but rarer condi ons, such as ovarian cancer, or on cause‐specific mortality. Nor will they provide
informa on about other types of oestrogen or progestagen. Answers to such ques ons will require judicious analysis and interpreta on of data from
observa onal studies.
JAMA 2003 May 28;289(20):2663‐72
Effect of estrogen plus proges n on global cogni ve func on in postmenopausal women: the Women's Health
Ini a ve Memory Study: a randomized controlled trial.
Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey
M, Bowen D; WHIMS Inves gators.
Department of Psychiatry and Behavioral Medicine, Wake Forest University School of Medicine, Winston‐Salem, NC 27157
CONTEXT: Observa onal studies have suggested that postmenopausal hormone treatment may improve cogni ve func on, but data from randomized
clinical trials have been sparse and inconclusive. The Women's Health Ini a ve Memory Study (WHIMS) is an ancillary study of the Women's Health
Ini a ve (WHI) hormone therapy trials. On July 8, 2002, the estrogen plus proges n therapy in the WHI trial was discon nued because of certain
increased health risks for women. OBJECTIVE: To determine whether estrogen plus proges n therapy protects global cogni ve func on in older
postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double‐blind, placebo‐controlled clinical trial, WHIMS is an ancillary
study of geographically diverse, community‐dwelling women aged 65 years or older from 39 of 40 clinical centers within the WHI estrogen plus
proges n trial that started in June 1995. Of 4894 eligible postmenopausal women aged 65 years or older and free of probable demen a at baseline,
4532 (92.6%) were enrolled in the estrogen plus proges n component of WHIMS. A total of 4381 par cipants (96.7%) provided at least 1 valid cogni ve
func on score between June 1995 and July 8, 2002. INTERVENTIONS: Par cipants received either 1 daily tablet containing 0.625 mg of conjugated
equine estrogen with 2.5 mg of medroxyprogesterone acetate (n = 2145) or matching placebo (n = 2236). MAIN OUTCOME MEASURE: Global cogni ve
func on measured annually with the Modified Mini‐Mental State Examina on. RESULTS: The Modified Mini‐Mental State Examina on mean total
scores in both groups increased slightly over me (mean follow‐up of 4.2 years). Women in the estrogen plus proges n group had smaller average
increases in total scores compared with women receiving placebo (P =.03), but these differences were not clinically important. Removing women by
censoring them a er adjudicated demen a, mild cogni ve impairment, or stroke, and nonadherence to study protocol, did not alter the findings. Prior
hormone therapy use and dura on of prior use did not affect the interpreta on of the results, nor did ming of prior hormone therapy ini a on with
respect to the final menstrual period. More women in the estrogen plus proges n group had a substan al and clinically important decline (> or =2 SDs)
in Modified Mini‐Mental State Examina on total score (6.7%) compared with the placebo group (4.8%) (P =.008). CONCLUSIONS: Among
postmenopausal women aged 65 years or older, estrogen plus proges n did not improve cogni ve func on when compared with placebo. While most
women receiving estrogen plus proges n did not experience clinically relevant adverse effects on cogni on compared with placebo, a small increased
risk of clinically meaningful cogni ve decline occurred in the estrogen plus proges n group.
JAMA 2003 May 28;289(20):2651‐62
Estrogen plus proges n and the incidence of demen a and mild cogni ve impairment in postmenopausal
women: the Women's Health Ini a ve Memory Study: a randomized controlled trial.
Shumaker SA, Legault C, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil‐Smoller S,
Wactawski‐Wende J; WHIMS Inves gators.
Department of Public Health Sciences, Wake Forest University Health Sciences, Winston‐Salem, NC 27104, USA.
CONTEXT: Postmenopausal women have a greater risk than men of developing Alzheimer disease, but studies of the effects of estrogen therapy on
Alzheimer disease have been inconsistent. On July 8, 2002, the study drugs, estrogen plus proges n, in the Women's Health Ini a ve (WHI) trial were
discon nued because of certain increased health risks in women receiving combined hormone therapy. OBJECTIVE: To evaluate the effect of estrogen
plus proges n on the incidence of demen a and mild cogni ve impairment compared with placebo. DESIGN, SETTING, AND PARTICIPANTS: The
Women's Health Ini a ve Memory Study (WHIMS), a randomized, double‐blind, placebo‐controlled clinical trial, began enrolling par cipants from the
Women's Health Ini a ve (WHI) estrogen plus proges n trial in May 1996. Of the 4894 eligible par cipants of the WHI study, 4532 (92.6%)
postmenopausal women free of probable demen a, aged 65 years or older, and recruited from 39 of 40 WHI clinical centers were enrolled in the
WHIMS. INTERVENTION: Par cipants received either 1 daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone
acetate (n = 2229), or a matching placebo (n = 2303). MAIN OUTCOME MEASURES: Incidence of probable demen a (primary outcome) and mild
cogni ve impairment (secondary outcome) were iden fied through a structured clinical assessment. RESULTS: The mean (SD) me between the date of
©Storey Marke ng, All rights reserved.
35
randomiza on into WHI and the last Modified Mini‐Mental State Examina on (3MSE) for all WHIMS par cipants was 4.05 (1.19) years. Overall, 61
women were diagnosed with probable demen a, 40 (66%) in the estrogen plus proges n group compared with 21 (34%) in the placebo group. The
hazard ra o (HR) for probable demen a was 2.05 (95% confidence interval [CI], 1.21‐3.48; 45 vs 22 per 10 000 person‐years; P =.01). This increased risk
would result in an addi onal 23 cases of demen a per 10 000 women per year. Alzheimer disease was the most common classifica on of demen a in
both study groups. Treatment effects on mild cogni ve impairment did not differ between groups (HR, 1.07; 95% CI, 0.74‐1.55; 63 vs 59 cases per 10 000
person‐years; P =.72). CONCLUSIONS: Estrogen plus proges n therapy increased the risk for probable demen a in postmenopausal women aged 65
years or older. In addi on, estrogen plus proges n therapy did not prevent mild cogni ve impairment in these women. These findings, coupled with
previously reported WHI data, support the conclusion that the risks of estrogen plus proges n outweigh the benefits.
JAMA 2003 May 28;289(20):2673‐84
Effect of estrogen plus proges n on stroke in postmenopausal women: the Women's Health Ini a ve: a
randomized trial.
Wassertheil‐Smoller S, Hendrix SL, Limacher M, Heiss G, Kooperberg C, Baird A, Kotchen T, Curb JD, Black H, Rossouw JE, Aragaki A, Safford M, Stein
E, Laowa ana S, Mysiw WJ; WHI Inves gators.
Department of Epidemiology and Social Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
CONTEXT: The Women's Health Ini a ve (WHI) trial of estrogen plus proges n was stopped early because of adverse effects, including an increased risk
of stroke in the estrogen plus proges n group. OBJECTIVE: To assess the effect of estrogen plus proges n on ischemic and hemorrhagic stroke and in
subgroups, and to determine whether the effect of estrogen plus proges n was modified by baseline levels of blood biomarkers. DESIGN: Mul center
double‐blind, placebo‐controlled, randomized clinical trial involving 16 608 women aged 50 through 79 years with an average follow‐up of 5.6 years.
Baseline levels of blood‐based markers of inflamma on, thrombosis, and lipid levels were measured in the first 140 centrally confirmed stroke cases and
513 controls. INTERVENTIONS: Par cipants received 0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate (n =
8506) or placebo (n = 8102). MAIN OUTCOME MEASURES: Overall strokes and stroke subtype and severity were centrally adjudicated by stoke
neurologists. RESULTS: One hundred fi y‐one pa ents (1.8%) in the estrogen plus proges n and 107 (1.3%) in the placebo groups had strokes. Overall
79.8% of strokes were ischemic. For combined ischemic and hemorrhagic strokes, the inten on‐to‐treat hazard ra o (HR) for estrogen plus proges n vs
placebo was 1.31 (95% confidence interval [CI], 1.02‐1.68); with adjustment for adherence, the HR was 1.50 (95% CI, 1.08‐2.08). The HR for ischemic
stroke was 1.44 (95% CI, 1.09‐1.90) and for hemorrhagic stroke, 0.82 (95% CI, 0.43‐1.56). Point es mates of the HRs indicate that excess risk of all stroke
was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular
disease, use of hormones, sta ns, or aspirin. Other risk factors for stroke, including smoking, blood pressure, diabetes, lower use of vitamin C
supplements, blood‐based biomarkers of inflamma on, higher white blood cell count, and higher hematocrit levels did not modify the effect of estrogen
plus proges n on stroke risk. CONCLUSIONS: Estrogen plus proges n increases the risk of ischemic stroke in generally healthy postmenopausal women.
Excess risk for all strokes a ributed to estrogen plus proges n appeared to be present in all subgroups of women examined.
Obstet Gynecol. 2004 Mar;103(3):440‐6
Rapid loss of hip fracture protec on a er estrogen cessa on: evidence from the Na onal Osteoporosis Risk
Assessment.
Yates J, Barre ‐Connor E, Barlas S, Chen YT, Miller PD, Siris ES.
Merck and Company, Inc., Upper Gwynedd, Pennsylvania, USA
OBJECTIVE: Since the findings from the Women's Health Ini a ve became available in July 2002, millions of women have discon nued postmenopausal
hormone therapy (HT). The objec ve of this study was to evaluate the associa on between HT cessa on and hip fracture risk. METHODS: Women who
par cipated in the Na onal Osteoporosis Risk Assessment and completed the 12‐month follow‐up survey were studied. All par cipants were aged at
least 50 years, were postmenopausal, and had no previous diagnosis of osteoporosis. Baseline and 12‐month follow‐up ques onnaires assessed use of
HT and incident fractures. Of the 140,584 women in this study, 269 reported an incident hip fracture. A logis c regression model was used to assess
associa on between HT use and incident hip fracture, controlling for poten al confounders. RESULTS: Consistent with the Women's Health Ini a ve,
women in Na onal Osteoporosis Risk Assessment who were currently on HT had a 40% lower incidence of hip fractures compared with those who nver
used HT. Women who stopped using HT more than 5 years earlier had similar hip fracture risk to never users, as expected. However, surprisingly,
women who had discon nued HT within the previous 5 years had an increased hip fracture odds ra o of 1.65 (95% confidence interval 1.05, 2.59)
rela ve to never users of HT. CONCLUSION: Postmenopausal women who have discon nued HT within the past 5 years have a risk for hip fracture that is
at least as high as that in women who have never used HT.
36
©Storey Marke ng, All rights reserved.
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S8‐13
Hot flashes and androgens: a biological ra onale for clinical prac ce.
Notelovitz M.
Adult Women's Health & Medicine, Boca Raton, Fla, USA
Hot flashes are the most prevalent symptom of menopause. Although the e ology of hot flashes has yet to be determined, it is increasingly apparent that
the physiology of the underlying vasomotor instability is mul factorial. Estrogen and androgen receptors are present in the areas of the central nervous
system relevant to hot flashes. Androgens are central to the synthesis of estrogen and to the bioavailability of free estrogen in peripheral ssues. In
addi on, androgens have direct central nervous system effects that modulate other endocrine factors associated with hot flashes. The pharmacodynamic
differences of testosterone and methyltestosterone are briefly reviewed in the context of choice for individualized clinical use.
Maturitas. 2002 Jan 30;41(1):69‐77
Androgens and estrogens in rela on to hot flushes during the menopausal transi on.
Overlie I, Moen MH, Holte A, Finset A.
Department of Behavioural Sciences in Medicine, University of Oslo, P.O. Box 1111, Blindern, N‐0317 Oslo, Norway.
In this paper, the associa on of hormones to vasomotor complaints during the menopausal transi on is discussed. Fi y‐seven regularly menstrua ng
women without history of hormone replacement therapy (HRT) were selected for a longitudinal, prospec ve study around the menopausal transi on.
The mean age at the start of the study was 51.3 (+/‐2.0) years. At intervals of 12 months all women went through a semi‐structured interview and filled in
ques onnaires. Venous blood samples were collected every 12‐month for analyses of estradiol (E2), testosterone, androstendione,
dehydroepiandrosterone‐sulphate (DHEA‐S), follicle s mula ng hormone (FSH), thyrotropin (TSH), and luteinizing hormone (LH). Vasomotor complaints
were tested using ques ons about hot flushes and bouts of swea ng in terms of occurrence, frequency and degree of distress. Forty‐six percent of the
subjects reported hot flushes and bouts of swea ng before menopause, increasing to 67% during the first year a er menopause and 49% in the second
year postmenopause. Low levels of estradiol and high levels of FSH were associated with vasomotor complaints before menopause. During menopause
high levels of TSH were related to vasomotor complaints. The first year a er menopause, women, who at this point achieved hot flushes, were
characterised by high levels of E2, but declining and low levels of FSH, but increasing. Postmenopausal, high levels of testosterone and DHEA‐S seemed to
protect against vasomotor symptoms. Our most important finding was, that among women who achieved hot flushes at the first assessment
postmenopause, the high androgen levels was a significant predictor of recovery from hot flushes at the last assessment, 1 year later.
Menopause. 2003 Sep‐Oct;10(5):390‐8
Comment in: Menopause. 2003 Sep‐Oct;10(5):383‐4.
Transdermal testosterone therapy improves well‐being, mood, and sexual func on in premenopausal women.
Goldstat R, Brigan E, Tran J, Wolfe R, Davis SR.
Jean Hailes Founda on Research Unit, Clayton, Victoria, Australia.
OBJECTIVE: Circula ng testosterone in women declines during the late reproduc ve years such that otherwise healthy women in their 40s have
approximately half the testosterone level as women in their 20s. Despite this, research showing the benefits of androgen replacement has been limited
to the postmenopausal years. In view of the known premenopausal physiological decline in testosterone, we have evaluated the efficacy of transdermal
testosterone therapy on mood, well‐being, and sexual func on in eugonadal, premenopausal women presen ng with low libido. DESIGN: Premenopausal
women with low libido par cipated in a randomized, placebo‐controlled, crossover, efficacy study of testosterone cream (10 mg/day) with two double‐
blind, 12‐week, treatment periods separated by a single‐blind, 4‐week, washout period. RESULTS: Thirty‐four women completed the study per protocol,
with 31 women (mean age 39.7 +/‐ 4.2 years; serum testosterone 1.07 + 0.50 nmol/L) providing complete data. Testosterone therapy resulted in
sta s cally significant improvements in the composite scores of the Psychological General Well‐Being Index [+12.9 (95% CI, +4.6 to +21.2), P = 0.003] and
the Sabbatsberg Sexual Self‐Ra ng Scale [+15.7 (95% CI, +6.5 to +25.0), P = 0.001] compared with placebo. A mean decrease in the Beck Depression
Inventory score approached significance [‐2.8 (95% CI, ‐5.7 to +0.1), P = 0.06]. Mean total testosterone levels during treatment were at the high end of
the normal range, and estradiol was unchanged. No adverse effects were reported. CONCLUSIONS: Testosterone therapy improves well‐being, mood, and
sexual func on in premenopausal women with low libido and low testosterone. As a substan al number of women experience diminished sexual interest
and well‐being during their late reproduc ve years, further research is warranted to evaluate the benefits and safety of longer‐term interven on.
PMID: 14501599
©Storey Marke ng, All rights reserved.
37
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S3‐7
Formula ons and use of androgens in women.
Chu MC, Lobo RA.
Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, 622 W 168th St, PH 16‐77, New York, NY 10032, USA.
The physiology of normal androgen produc on in women has been poorly understood. Defining an androgen insufficiency state in women, in the
absence of adrenal suppression and/or bilateral oophorectomy, has been difficult. Nevertheless, beneficial effects of androgen on many organ systems,
including bone and the brain, are well documented. This review discusses the defini on of androgen insufficiency, an cipated effects of androgen
treatment on several factors of health, and treatment op ons for women with androgen insufficiency.
PMID: 15065631
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S19‐24
The role of androgens in female sexual dysfunc on.
Shifren JL.
Menopause Program, Vincent Memorial Obstetrics and Gynecology Service, Massachuse s General Hospital and Harvard Medical School, Boston, Mass
02114, USA.
There are many treatment op ons for female sexual dysfunc on (FSD), with the op mal therapy depending on the e ology of the problem. The cause of
sexual dysfunc on is mul factorial and may include psychological problems such as depression or anxiety disorders, conflict within the rela onship,
partner performance and technique, issues rela ng to prior abuse, medical illness, medica ons, fa gue, stress, or gynecological problems that make
sexual ac vity uncomfortable. The role of low androgen concentra ons in FSD is gaining increasing a en on. Available therapeu c op ons include
adjus ng medica ons, counseling, trea ng depression or anxiety, reducing stress and fa gue, sex therapy, devices, estrogen therapy for genitourinary
atrophy, and possibly vasoac ve substances. Although no androgen therapies are currently approved by the Food and Drug Administra on for FSD, they
are being used in clinical prac ce, and early clinical trial results suggest that they may be both effec ve and safe in the treatment of FSD, specifically low
libido. Androgen therapy should be considered primarily in women who have a physiological reason for reduced androgen concentra ons, including
aging, hypopituitarism, oophorectomy, or adrenal insufficiency. Products in use include oral methyltestosterone and dehydroepiandrosterone, topical
testosterone ointment, and testosterone implants and injec ons. Products available for men, including skin patches and gels, are currently being studied
at doses appropriate for women. Possible risks include hirsu sm, acne, liver dysfunc on, lowering of the voice, adverse lipid changes, viriliza on of a
female fetus, and, as androgens are aroma zed to estrogens, poten ally the risks of estrogen therapy.
Int J Fer l Womens Med. 2002 Mar‐Apr;47(2):77‐86
Testosterone deficiency in women: e ologies, diagnosis, and emerging treatments.
Mazer NA.
Department of Medical Affairs, Watson Laboratories, Inc., Salt Lake City, Utah 84108, USA.
Healthy young women produce approximately 300 microg of testosterone per day, of which about half is derived from the ovaries and half from the
adrenal glands. In women, as in men, testosterone is thought to influence pubertal development, sexual func on, bone density, muscle mass,
erythropoiesis, energy, cogni ve func on and mood. Testosterone deficiency in women may result from a variety of condi ons, including oophorectomy,
adrenalectomy, adrenal disease, pituitary disease, HIV infec on, premature ovarian failure, Turner's syndrome, and the use of high‐dose cor costeroids
and some estrogen prepara ons. Simple aging and natural menopause may also contribute to testosterone deficiency in some women. A consensus view
of the diagnosis of female androgen deficiency syndrome (FADS) is currently being developed, and is summarized in this ar cle, as are current
approaches for trea ng testosterone deficiency in women. Recent clinical trials involving an experimental testosterone transdermal patch for women are
highlighted. The impact of conven onal ERT/HRT on testosterone levels in naturally menopausal women is discussed, with the differences between oral
and transdermal routes of estrogen delivery being emphasized.
PMID: 11991434
N Engl J Med. 2000 Sep 7;343(10):682‐8
Comment in: Curr Psychiatry Rep. 2001 Jun;3(3):179‐80, N Engl J Med. 2000 Sep 7;343(10):730‐1.
Transdermal testosterone treatment in women with impaired sexual func on a er oophorectomy.
Shifren JL, Braunstein GD, Simon JA, Casson PR, Buster JE, Redmond GP, Burki RE, Ginsburg ES, Rosen RC, Leiblum SR, Caramelli KE, Mazer NA.
Department of Obstetrics and Gynecology, Massachuse s General Hospital, Boston 02114, USA.
BACKGROUND: The ovaries provide approximately half the circula ng testosterone in premenopausal women. A er bilateral oophorectomy, many
women report impaired sexual func oning despite estrogen replacement. We evaluated the effects of transdermal testosterone in women who had
impaired sexual func on a er surgically induced menopause. METHODS: Seventy‐five women, 31 to 56 years old, who had undergone oophorectomy
and hysterectomy received conjugated equine estrogens (at least 0.625 mg per day orally) and, in random order, placebo, 150 microg of testosterone,
and 300 microg of testosterone per day transdermally for 12 weeks each. Outcome measures included scores on the Brief Index of Sexual Func oning for
Women, the Psychological General Well‐Being Index, and a sexual‐func on diary completed over the telephone. RESULTS: The mean (+/‐SD) serum free
38
©Storey Marke ng, All rights reserved.
testosterone concentra on increased from 1.2+/‐0.8 pg per milliliter (4.2+/‐2.8 pmol per liter) during placebo treatment to 3.9+/‐2.4 pg per milliliter
(13.5+/‐8.3 pmol per liter) and 5.9+/‐4.8 pg per milliliter (20.5+/‐16.6 pmol per liter) during treatment with 150 and 300 microg of testosterone per day,
respec vely (normal range, 1.3 to 6.8 pg per milliliter [4.5 to 23.6 pmol per liter]). Despite an appreciable placebo response, the higher testosterone dose
resulted in further increases in scores for frequency of sexual ac vity and pleasure‐orgasm in the Brief index of Sexual Func oning for Women (P=0.03
for both comparisons with placebo). At the higher dose the percentages of women who had sexual fantasies, masturbated, or engaged in sexual
intercourse at least once a week increased two to three mes from base line. The posi ve‐well‐being, depressed‐mood, and composite scores of the
Psychological General Well‐Being Index also improved at the higher dose (P=0.04, P=0.03, and P=0.04, respec vely, for the comparison with placebo),
but the scores on the telephone‐based diary did not increase significantly. CONCLUSIONS: In women who have undergone oophorectomy and
hysterectomy, transdermal testosterone improves sexual func on and psychological well‐being.
PMID: 10974131
Endocr Res. 2000 Nov;26(4):505‐11
DHEA replacement in women with adrenal insufficiency‐‐pharmacokine cs, bioconversion and clinical effects on
well‐being, sexuality and cogni on.
Arlt W, Callies F, Allolio B.
Department of Internal Medicine, University of Wurzburg, Germany.
Standard replacement for adrenal insufficiency (AI) consists of glucocor coids and mineralocor coids while DHEA deficiency is rou nely ignored. Thus, AI
represents the ideal pathophysiological model of isolated DHEA deficiency. We inves gated the effects of DHEA replacement in 24 women with primary
and secondary AI employing a double blind, placebo‐controlled, randomized crossover design. A DHEA dose of 50 mg/d was chosen based on preceding
single‐dose pharmacokine cs and bioconversion studies. Each pa ent received four months of treatment with DHEA and four months placebo, with a
one‐month washout period. Measurements included serum steroid hormones, somatotropic parameters and psychometric assessment of well‐being,
mood, cogni on and sexuality. Treatment with DHEA raised the ini ally low serum concentra ons of DHEA, DHEAS, androstenedione, and testosterone
into the normal range. DHEA induced a slight increase in serum IGF‐I, but only in pa ents with primary AI, sugges ng a growth hormone‐mediated effect.
DHEA treatment significantly improved overall wellbeing as well as scores for depression, anxiety, and their physical correlates. Furthermore, DHEA
significantly increased both sexual interest and the level of sa sfac on with sex. DHEA replacement had no influence on the cogni ve performance,
which was already on a high level at baseline. In conclusion, DHEA replacement improves well‐being and sexuality in women with adrenal insufficiency. If
this is due to a direct effect of DHEA on the brain, an indirect effect via increased androgen synthesis, or both, remains to be elucidated. Long‐term
studies in pa ents of both sexes are needed to further define the role of DHEA in standard replacement for adrenal insufficiency.
PMID: 11196420
Mayo Clin Proc. 2004 Apr;79(4 Suppl):S14‐8
Poten al anabolic effects of androgens on bone.
Kearns AE, Khosla S.
Division of Endocrinology, Diabetes, Metabolism, and Nutri on, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905
Sex steroid hormones are essen al to normal skeletal growth and maintenance throughout life in both men and women. The importance of estrogens to
bone health in women becomes obvious at menopause when estrogen deficiency occurs and results in accelerated bone loss. A er menopause,
estrogen deficiency results in dras c changes in the androgen‐estrogen ra o. Thus, the rela ve importance of androgens a er menopause may increase.
Androgens also appear to be important for bone health in pre‐menopausal women. Evidence from human, animal, and laboratory studies is leading to a
be er understanding of the effects of androgens on bone in women.
PMID: 15065633
N Engl J Med 1999 Feb 11;340(6):424‐9
Effects of Thyroxine as Compared with Thyroxine plus Triiodothyronine in Pa ents with Hypothyroidism
Robertas Buneviius, M.D., Ph.D., Gintautas Kaanaviius, M.D., Ph.D., Rimas alinkeviius, M.D., and Arthur J. Prange, M.D.
Background Pa ents with hypothyroidism are usually treated with thyroxine (levothyroxine) only, although both thyroxine and triiodothyronine are
secreted by the normal thyroid gland. Whether thyroid secre on of triiodothyronine is physiologically important is unknown. Methods We compared the
effects of thyroxine alone with those of thyroxine plus triiodothyronine (liothyronine) in 33 pa ents with hypothyroidism. Each pa ent was studied for
two five‐week periods. During one period, the pa ent received his or her usual dose of thyroxine. During the other, the pa ent received a regimen in
which 50 µg of the usual dose of thyroxine was replaced by 12.5 µg of triiodothyronine. The order in which each pa ent received the two treatments was
randomized. Biochemical, physiologic, and psychological tests were performed at the end of each treatment period. Results The pa ents had lower serum
free and total thyroxine concentra ons and higher serum total triiodothyronine concentra ons a er treatment with thyroxine plus triiodothyronine than
a er thyroxine alone, whereas the serum thyrotropin concentra ons were similar a er both treatments. Among 17 scores on tests of cogni ve
©Storey Marke ng, All rights reserved.
39
performance and assessments of mood, 6 were be er or closer to normal a er treatment with thyroxine plus triiodothyronine. Similarly, among 15 visual
‐analogue scales used to indicate mood and physical status, the results for 10 were significantly be er a er treatment with thyroxine plus
triiodothyronine. The pulse rate and serum sex hormone–binding globulin concentra ons were slightly higher a er treatment with thyroxine plus
triiodothyronine, but blood pressure, serum lipid concentra ons, and the results of neurophysiologic tests were similar a er the two treatments.
Conclusions In pa ents with hypothyroidism, par al subs tu on of triiodothyronine for thyroxine may improve mood and neuropsychological func on;
this finding suggests a specific effect of the triiodothyronine normally secreted by the thyroid gland.
J Endocrinol Invest. 2002 Feb;25(2):106‐9
Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentra ons.
Woeber KA.
Department of Medicine, University of California, San Francisco/Mount Zion, San Francisco 94143‐1640, USA.
Although the normal thyroid gland secretes both levothyroxine (L‐T4) and levotriiodothyronine (L‐T3), normaliza on of serum TSH with L‐T4‐replacement
therapy alone in hypothyroidism is generally believed to result in a normal serum L‐T3 and to reflect a euthyroid state. However several recent studies
suggest that this may not be the case. Accordingly, the rela onship between serum free L‐T4 and free L‐T3 was examined in 20 normal individuals (group
A) and in 53 pa ents with chronic autoimmune thyroidi s, 18 with normal TSH on no L‐T4‐replacement (group B), and 35 with normal TSH on L‐T4‐
replacement therapy for hypothyroidism (group C). Data were analyzed by applying a one‐way analysis of variance with correc on for mul ple
comparisons. Serum TSH values were very similar among the 3 groups. In groups A and B, mean serum free T4 and free T3 were very similar. In group C,
the mean free T4 (16+/‐2 pmol/l) was significantly higher than the values in groups A (14+/‐1) and B (14+/‐2) (p<0.001) and the mean free T3 lower
(4.0+/‐0.5 pmol/l vs 4.2+/‐0.5, NS and 4.4+/‐0.5, p<0.02). Consequently, the mean molar ra o of free T4 to free T3 was significantly higher in group C
than the ra os in groups A and B (p<0.0001), despite very similar TSH values. These findings indicate that in hypothyroid pa ents L‐T4‐replacement, that
is sufficient to maintain a normal serum TSH, is accompanied by a serum free T4 that is higher than that in untreated euthyroid pa ents or normal
individuals and may not result in an appropriately normal serum free T3 concentra on.
Hormone Replacement for Men
Cancer. 2006 Dec 20;109(3):536‐541 [Epub ahead of print]
Testosterone replacement for hypogonadism a er treatment of early prostate cancer with brachytherapy
Sarosdy MF.
South Texas Urology and Urologic Oncology, San Antonio, Texas.
BACKGROUND.: Controversy and a notable paucity of published clinical data best characterize the current knowledge of testosterone‐replacement
therapy (TRT) for hypogonadism a er treatment for early, localized prostate cancer. The objec ve of this study was to assess the risk of biochemical
failure with TRT a er treatment of early prostate cancer with permanent transperineal brachytherapy with or without external beam therapy in pa ents
with low serum levels of testosterone and clinical symptoms of hypogonadism. METHODS.: Pa ents who underwent prostate brachytherapy from 1996
to 2004 and received subsequent TRT for symptoma c hypogonadism were reviewed to detail cancer characteris cs and treatment as well as pre‐ and
post‐TRT serum testosterone and prostate‐specific an gen (PSA) values. RESULTS.: Thirty‐one men received TRT a er prostate brachytherapy for 0.5 to
8.5 years (median, 4.5 years), with a follow‐up that ranged from 1.5 years to 9.0 years (median, 5.0 years) postbrachytherapy. TRT was started from 0.5
years to 4.5 years (median, 2.0 years) a er brachytherapy. Serum total testosterone levels ranged from 30 ng/dL to 255 ng/dL (median, 188 ng/dL)
before TRT and rose to 365 ng/dL to 1373 ng/dL (median, 498 ng/dL) on TRT. Transient rises in PSA were observed in 1 pa ent. The most recent PSA level
was <0.1 ng/mL in 23 pa ents (74.2%), <0.5 ng/mL in 30 pa ents (96.7%), and <1 ng/mL in 31 pa ents (100%). No pa ents stopped TRT because of
cancer recurrence or documented cancer progression. CONCLUSIONS.: For pa ents with low serum testosterone levels and symptoms of hypogonadism,
TRT may be used with cau on and close follow‐up a er prostate brachytherapy.
PMID: 17183557
Aging Male. 2006 Dec;9(4):201‐6
Testosterone and erec le physiology
Guay AT.
Center for Sexual Func on/Endocrinology, Lahey Clinic Northshore, Peabody, MA, USA.
The role of testosterone deficiency in sexual dysfunc on is an important aspect of aging, because it affects such a large propor on of men over 50 years
old. A number of age‐related factors can cause sexual dysfunc on (in par cular erec le dysfunc on) and testosterone deficiency, such as chronic illness
and mul ple medica ons, and the causa ve link between hypogonadism and erec le dysfunc on is s ll debated. However, studies in castrated animals
have proven that addi on of testosterone, and its conversion to dihydrotestosterone, can restore erec le func on. It appears that testosterone achieves
this by peripheral mechanisms (endothelial dependent and independent) and central mechanisms. Testosterone replacement therapy is therefore
effec ve for erec le dysfunc on in men with hypogonadism, with success rates of 35‐40%. Testosterone supplementa on is also important in men who
40
©Storey Marke ng, All rights reserved.
fail on phosphodiesterase type‐5 inhibitors, because a minimum plasma concentra on of testosterone is required for the successful restora on of
erec le func on with these agents. Testosterone gels are now the preferred formula on for testosterone supplementa on and they can be highly
beneficial in a propor on of men with erec le dysfunc on.
PMID: 17178555
Int J Clin Pract. 2006 Sep;60(9):1087‐92
The evolving role of testosterone in the treatment of erec le dysfunc on
Shabsigh R, Rajfer J, Aversa A, Traish AM, Yassin A, Kalinchenko SY, Buvat J.
Department of Urology, Columbia University, New York, NY 10032, USA. [email protected]
Hypogonadism may play a significant role in the pathophysiology of erec le dysfunc on (ED). A threshold level of testosterone may be necessary for
normal erec le func on. Testosterone replacement therapy is indicated in hypogonadal pa ents and is beneficial in pa ents with ED and
hypogonadism. Monotherapy with testosterone for ED is of limited effec veness and may be most promising in young pa ents with hypogonadism and
without vascular risk factors for ED. A number of laboratory and human studies have shown the combina on of testosterone and other ED treatments,
such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in pa ents with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There
is increasing evidence that combina on therapy is effec ve in trea ng the symptoms of ED in pa ents for whom treatment failed with testosterone or
PDE5 inhibitors alone. Testosterone replacement therapy has poten ally evolved from a monotherapy for ED in cases of low testosterone, to a
combina on therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in
popula ons at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.
PMID: 16939550
J Sex Med. 2005 Nov;2(6):785‐92
Testosterone therapy in erec le dysfunc on and hypogonadism
Shabsigh R.
Department of Urology, Columbia University, New York, NY 10032, USA. [email protected]
INTRODUCTION: Laboratory experiments indicate that the nitric oxide erec le pathway is testosterone‐dependent. Castra on induces erec le
dysfunc on (ED) and reduc on in nitric oxide synthase and in phosphodiesterase type 5 (PDE5) in the erec le ssue. Furthermore, castra on causes
apoptosis adversely affec ng smooth muscle content and penile hemodynamics leading to veno‐occlusive dysfunc on. Testosterone therapy reverses
these structural, biochemical, and physiological changes. In humans, testosterone therapy improves erec le func on in men with hypogonadism.
However, the efficacy of testosterone monotherapy may not be adequate because of the mul factorial nature of the pathophysiology of ED. METHODS:
Preliminary data from a number of studies have been reviewed. RESULTS: There are emerging evidence‐based benefits to using the combina on of
testoterone and PDE5 inhibitors. A recently published mul center, randomized, placebo‐controlled study evaluated the safety and efficacy of
testosterone gel 1% plus sildenafil vs. placebo gel plus sildenafil, in producing an erec le response in hypogonadal men who had failed prior sildenafil
alone for ED. Screening yielded a prevalence of hypogonadism in ED pa ents who failed prior sildenafil. Following randomiza on, the double‐blinded
treatment phase was 12 weeks. Testosterone therapy with testosterone gel significantly improved erec le func on in response to sildenafil. In addi on,
it significantly improved orgasmic func on and pa ent sa sfac on. CONCLUSION: It is important to screen all men with ED for hypogonadism, especially
those with a history of inadequate response to prior PDE5 inhibitors. The combina on of testosterone plus PDE5 inhibitors may be considered for the
treatment of ED in men with low to low‐normal testosterone levels, who had inadequate response to prior treatment with PDE5 inhibitors alone.
PMID: 16422803
Rev Urol. 2003;5 Suppl 1:S34‐40 (Free full text ar cle available online)
New advances in the treatment of hypogonadism in the aging male
Steidle CP.
The signs and symptoms of low testosterone in the aging male include erec le dysfunc on, decreased libido, mood disturbances such as depression,
loss of muscle mass, osteoporosis, and increase in body fat. Many of these signs and symptoms were previously believed to be part of the normal aging
process, and only recently has treatment of low testosterone in the aging male been shown to provide long‐term physical and mental improvement. In
the past, oral and injectable testosterone delivery methods had disadvantages that limited their use, but the introduc on of transdermal testosterone
patches has allowed testosterone to be delivered into the circula on in a consistent fashion. Long‐term use of these patches over the last 3 to 10 years
has been effec ve in maintaining sexual func on and bone and muscle mass, and from short‐term studies it does not appear that testosterone
treatment puts men at risk for the development of prostate cancer. A new topical gel forma on (Tes m) has been designed to provide consistent
transdermal absorp on of testosterone over 24 hours a er a single dose.
PMID: 16985942
©Storey Marke ng, All rights reserved.
41
J Clin Endocrinol Metab. 2006 Oct;91(10):3908‐15. Epub 2006 Jul 18
Associa on of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men
Fink HA, Ewing SK, Ensrud KE, Barre ‐Connor E, Taylor BC, Cauley JA, Orwoll ES.
Geriatric Research Educa on and Clinical Center, Veterans Affairs Medical Center, Minneapolis, MN
CONTEXT: The clinical value of measuring testosterone and estradiol in older men with osteoporosis and of measuring bone mineral density (BMD) in
older men with testosterone or estradiol deficiency is uncertain. OBJECTIVE: The objec ve of the study was to examine the associa on of testosterone
and estradiol deficiency with osteoporosis and rapid bone loss in older men. DESIGN: This study was a cross‐sec onal and longitudinal analysis. Se ng:
The study was conducted at six U.S. centers of the Osteoporo c Fractures in Men study. PARTICIPANTS: The study popula on consisted of 2447
community‐dwelling men aged 65 yr or older. MAIN OUTCOME MEASURES: Total testosterone deficiency was defined as less than 200 ng/dl. Total
estradiol deficiency was defined as less than 10 pg/ml. Osteoporosis was defined as femoral neck or total hip BMD T‐score of ‐2.5 or less. Rapid bone loss
was defined as 3%/yr or more. RESULTS: Prevalence of osteoporosis in men with deficient and normal total testosterone was 12.3 and 6.0% (P = 0.003)
and 15.4 and 2.8% (P < 0.0001) in those with deficient and normal total estradiol. Among osteoporo c men and those with normal BMD, prevalence of
total testosterone deficiency was 6.9 and 3.2% (P = 0.01), and prevalence of total estradiol deficiency was 9.2 and 2.4% (P = 0.0001). Incidence of rapid
hip bone loss in men with deficient and normal total testosterone was 22.5 and 8.6% (p = 0.007) and in those with deficient and normal total estradiol
was 14.3 and 6.3% (p = 0.08). CONCLUSIONS: Older men with total testosterone or estradiol deficiency were more likely to be osteoporo c. Those with
osteoporosis were more likely to be total testosterone or estradiol deficient. Rapid hip bone loss was more likely in men with total testosterone
deficiency. BMD tes ng of older men with sex steroid deficiency may be clinically warranted.
PMID: 16849417
Aging Male. 2006 Dec;9(4):195‐9
Testosterone and the brain
Zitzmann M.
Ins tute of Reproduc ve Medicine, University of Munster, Munster, Germany.
Gender differences in spa al recogni on, and age‐related declines in cogni on and mood, point towards testosterone as an important modulator of
cerebral func ons. Testosterone appears to ac vate a distributed cor cal network, the ventral processing stream, during spa al cogni on tasks, and
addi on of testosterone improves spa al cogni on in younger and older hypogonadal men. In addi on, reduced testosterone is associated with
depressive disorders. The rela onship between depression and testosterone appears to partly depend upon the androgen receptor genotype of the
pa ent, and in appropriate pa ents with low testosterone levels, testosterone subs tu on can increase posi ve mood and decrease nega ve mood. The
much publicized link between testosterone and aggression is probably only of importance in athletes who supplement their testosterone levels to
excessively high levels, whereas in hypogonadal men, testosterone supplementa on only enhances the posi ve aspects of aggression such as vigour and
energy. Current data suggest that testosterone supplementa on in hypogonadal men of all ages will enhance many aspects of mood and cogni on.
PMID: 17178554
J Clin Endocrinol Metab 2000 Aug;85(8):2670‐7
Effects of testosterone replacement in hypogonadal men.
Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewa A, Santanna J, Loh L, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE, Strom BL.
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Treatment of hypogonadal men with testosterone has been shown to ameliorate the effects of testosterone deficiency on bone, muscle, erythropoiesis,
and the prostate. Most previous studies, however, have employed somewhat pharmacological doses of testosterone esters, which could result in
exaggerated effects, and/or have been of rela vely short dura on or employed previously treated men, which could result in dampened effects. The goal
of this study was to determine the magnitude and me course of the effects of physiological testosterone replacement for 3 yr on bone density, muscle
mass and strength, erythropoiesis, prostate volume, energy, sexual func on, and lipids in previously untreated hypogonadal men. We selected 18 men
who were hypogonadal (mean serum testosterone +/‐ SD, 78 +/‐ 77 ng/dL; 2.7 +/‐ 2.7 nmol/L) due to organic disease and had never previously been
treated for hypogonadism. We treated them with testosterone transdermally for 3 yr. Sixteen men completed 12 months of the protocol, and 14men
completed 36 months. The mean serum testosterone concentra on reached the normal range by 3 months of treatment and remained there for the
dura on of treatment. Bone mineral density of the lumbar spine (L2‐L4) increased by 7.7 +/‐ 7.6% (P < 0.001), and that of the femoral trochanter
increased by 4.0 +/‐ 5.4% (P = 0.02); both reached maximum values by 24 months. Fat‐free mass increased 3.1 kg (P = 0.004), and fat‐free mass of the
arms and legs individually increased, principally within the first 6 months. The decrease in fat mass was not sta s cally significant. Strength of knee
flexion and extension did not change. Hematocrit increased drama cally, from mildly anemic (38.0 +/‐ 3.0%) to midnormal (43.1 +/‐ 4.0%; P = 0.002)
within 3 months, and remained at that level for the dura on of treatment. Prostate volume also increased drama cally, from subnormal (12.0 +/‐ 6.0
mL) before treatment to normal (22.4 +/‐ 8.4 mL; P = 0.004), principally during the first 6 months. Self‐reported sense of energy (49+/‐ 19% to 66 +/‐
24%; P = 0.01) and sexual func on (24 +/‐ 20% to 66 +/‐ 24%; P < 0.001) also increased, principally within the first 3 months. Lipids did not change. We
conclude from this study that replacing testosterone in hypogonadal men increases bone mineral density of the spine and hip, fat‐free mass, prostate
volume, erythropoiesis, energy, and sexual func on. The full effect of testosterone on bone mineral density took 24 months, but the full effects on the
other ssues took only 3‐6 months. These results provide the basis for monitoring the magnitude and the me course of the effects of testosterone
replacement in hypogonadal men.
42
©Storey Marke ng, All rights reserved.
Am J Med 2001 May;110(7):563‐72
Hypogonadism and androgen replacement therapy in elderly men.
Basaria S, Dobs AS.
Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine, Bal more, Maryland, USA.
The decrease in testosterone levels with age is both central (pituitary) and peripheral (tes cular) origin. Because serum levels of sex‐hormone‐binding
globulin increase with aging, the decrease in free testosterone is of even greater magnitude. Recent long‐term studies of testosterone therapy in
hypogonadal elderly men have shown beneficial effects on bone density, body composi on, and muscle strength without any substan al adverse effects
on lipids and the prostate. Total testosterone level is the test of choice for ini al screening of elderly men who present with signs and symptoms of
hypogonadism. If the level is below 300 ng/dL, replacement therapy should be ini ated. If the level is normal in a symptoma c pa ent, free or
bioavailable testosterone should bedetermined. The pros and cons of testosterone therapy should be discussed in depth with every pa ent, and
decisions should be made on an individual basis. This review summarizes the trials of testosterone replacement therapy in elderly men an outlines a
diagnos c approach to these pa ents.
Drugs Aging 1999 Aug;15(2):131‐42
Risks versus benefits of testosterone therapy in elderly men.
Basaria S, Dobs AS.
Division of Endocrinology and Metabolism, Johns Hopkins University, Bal more, Maryland 21287, USA.
'Andropause', like menopause, has received significant a en on in recent years. It results in a variety of symptoms experienced by the elderly. Many of
these symptoms are nonspecific and vague. For this reason, many authors have ques oned the value of androgen replacement in this popula on. Also in
dispute is the normal cutoff level for testosterone beyond which therapy should be ini ated, and whether to measure free or total testosterone.
Testosterone levels decline with age, with the lowest level seen in men older than 70 years. This age‐related decline in testosterone levels is both central
(pituitary) and peripheral (testes) in origin. With aging, there is also a loss of circadian rhythm of testosterone secre on and a rise in sex hormone binding
globulin (SHBG) levels. Total testosterone level is the best screening test for pa ents with suspected hypogonadism. If the total testosterone
concentra on is low, free testosterone levels should be obtained. Prostate cancer remains an absolute contraindica on to androgen therapy.
Testosterone replacement results in an improvement in muscle strength and bone mineral density. Similar effects are observed on the haematopoie c
system. Data on cogni on and lipoprotein profiles are conflic ng. Androgen therapy can result in polycythemia and sleep apnoea. These adverse effects
can be deleterious in men with compromised cardiac reserve. We recommend that elderly men with symptoms of hypogonadism and a total
testosterone level <300 ng/dl should be started on testosterone replacement. This review discusses the pros and cons of testosterone replacement in
hypogonadal elderly men and a empts to answer some of the unanswered ques ons. Furthermore, emphasis is made on the regular follow‐up of these
pa ents to prevent the development of therapy‐related complica ons.
J Clin Endocrinol Metab 2001 Nov;86(11):5108‐17
Clinical review 138: Anabolic‐androgenic steroid therapy in the treatment of chronic diseases.
Basaria S, Wahlstrom JT, Dobs AS.
The Johns Hopkins University School of Medicine, Bal more, Maryland 21287, USA.
The purpose of this study was to review the preclinical and clinical literature relevant to the efficacy and safety of anabolic androgen steroid therapy for
pallia ve treatment of severe weight loss associated with chronic diseases. Data sources were published literature iden fied from the Medline database
from January 1966 to December 2000, bibliographic references, and textbooks. Reports from preclinical and clinical trials were selected. Study designs
and results were extracted from trial reports. Sta s cal evalua on or meta‐analysis of combined results was not a empted. Androgenic anabolic steroids
(AAS) are widely prescribed for the treatment of male hypogonadism; however, they may play a significant role in the treatment of other condi ons as
well, such as cachexia associated with human immunodeficiency virus, cancer, burns, renal and hepa c failure, and anemia associated with leukemia or
kidney failure. A review of the anabolic effects of androgens and their efficacy in the treatment of these condi ons is provided. In addi on, the numerous
and some mes serious side effects that have been known to occur with androgen use are reviewed. Although the threat of various side effects is present,
AAS therapy appears to have a favorable anabolic effect on pa ents with chronic diseases and muscle catabolism. We recommend that AAS can be used
for the treatment of pa ents with acquired immunodeficiency syndrome was ng and in severely catabolic pa ents with severe burns. Preliminary data in
renal failure‐associated was ng are also posi ve. Advantages and disadvantages should be weighed carefully when comparing AAS therapy to other
weight‐gaining measures. Although a conserva ve approach to the use of AAS in pa ents with chronic diseases is s ll recommended, the u lity of AAS
therapy in the a enua on of severe weight loss associated with disease states such as cancer, postopera ve recovery, and was ng due to pulmonary
and hepa c disease should be more thoroughly inves gated.
©Storey Marke ng, All rights reserved.
43
Diabetes Care 2000 Apr;23(4):490‐4
Testosterone, sex hormone‐binding globulin, and the development of type 2 diabetes in middle‐aged men:
prospec ve results from the Massachuse s male aging study.
Stellato RK, Feldman HA, Hamdy O, Horton ES, McKinlay JB.
New England Research Ins tutes, Watertown, Massachuse s, USA.
OBJECTIVE: The objec ve was to examine prospec vely the associa on between low testosterone and sex hormone‐binding globulin (SHBG) levels and
the subsequent development of type 2 diabetes in men. RESEARCH DESIGN AND METHODS: Analyses were conducted on the cohort of the
Massachuse s Male Aging Study, a popula on‐based random sample of men aged 40‐70. Of the 1,709 men enrolled in 1987‐1989 (T1), 1,156 were
followed up 7‐10 years later (T2). Testosterone and SHBG levels at T1 were used to predict new cases of diabetes between T1 and T2. RESULTS: A er
controlling for poten al confounders, diabetes at follow‐up was predicted jointly and independently by lower baseline levels of free testosterone and
SHBG. The odds ra o for future diabetes was 1.58 for a decrease of 1SD in free testosterone (4 ng/dl) and 1.89 for a 1SD decrease in SHBG (16 nmol/l),
both significant at P < 0.02. CONCLUSIONS: Our prospec ve findings are consistent with previous, mainly cross‐sec onal reports, sugges ng that low
levels of testosterone and SHBG play some role in the development of insulin resistance and subsequent type 2 diabetes.
Am J Psychiatry 1998 Oct;155(10):1310‐8
Age‐associated testosterone decline in men: clinical issues for psychiatry.
Sternbach H.
Department of Psychiatry, UCLA‐Neuropsychiatric Ins tute, Los Angeles, USA.
OBJECTIVE: The author summarizes current knowledge about the diagnosis and treatment of testosterone decline in healthy aging men and the
associated clinical issues for psychiatry. METHOD: A MEDLINE search was conducted in which the search terms "male climacteric," "male menopause,"
"andropause," "viropause," "low‐testosterone syndrome," and "testosterone replacement therapy" were used. Literature published before 1966 was
iden fied by reviewing the reference lists of later publica ons. RESULTS: Manifesta ons of testosterone deficiency have included depression, anxiety,
irritability, insomnia, weakness, diminished libido, impotence, poor memory, reduced muscle and bone mass, and diminished sexual body hair. Although
testosterone levels decline with age, there is great interindividual variability, and the connec on between serum testosterone levels and clinical
psychiatric signs and symptoms is not clear‐cut, since other hormonal changes are implicated as well. Testosterone replacement therapy may offer
hpogonadal men benefit, but long‐term studies on its efficacy and safety are lacking. Comprehensive biopsychosocial assessment should be a rou ne
part of the evalua on of complaints of low‐testosterone syndrome in men. CONCLUSIONS: Testosterone decline/deficiency is not a state strictly
analogous to female menopause and may exhibit considerable overlap with primary and other secondary psychiatric disorders.
Med Hypotheses 1999 Jan;52(1):49‐51
The hypogonadal‐obesity cycle: role of aromatase in modula ng the testosterone‐estradiol shunt‐‐a major
factor in the genesis of morbid obesity.
Cohen PG.
Massive obesity in males is associated with decreased total and free testosterone levels as well as elevated estradiol levels. The decrease in testosterone
occurs without the compensatory increases in gonadotropin and a progressive hypogonadotropic hypogonadal cycle develops. During the hypogonadal
state, there is a preferen al deposi on of abdominal adipose ssue. With the increasing fa y‐ ssue accumula on, there is an increase of aromatase
ac vity that is associated with a greater conversion of testosterone to estradiol (testosterone‐estradiol shunt). This results in further depression of
testosterone concentra ons and leads to the increased preferen al deposi on of abdominal fat that, in turn, leads to a progressive hypogonadal state.
Testalactone, an aromatase inhibitor, interrupts this cycle and repairs the depressed testosterone concentra ons and decreases estradiol levels. This
increases the testosterone levels and reverses the preferen al deposi on of abdominal fat, while increasing muscle protein and fat‐free mass.
J Clin Endocrinol Metab 1999 Feb;84(2):573‐7
Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study.
Barre ‐Connor E, Von Muhlen DG, Kritz‐Silverstein D.
Department of Family and Preven ve Medicine, School of Medicine, University of California, San Diego, La Jolla 92093‐0607
A cross‐sec onal popula on‐based study examined the associa on between endogenous sex hormones and depressed mood in community‐dwelling
older men. Par cipants included 856 men, ages 50‐89 yr, who a ended a clinic visit between 1984‐87. Total and bioavailable testosterone, total and
bioavailable estradiol, and dihydrotestosterone levels were measured by radioimmunoassay in an endocrinology research laboratory. Depressed mood
44
©Storey Marke ng, All rights reserved.
was assessed with the Beck Depression Inventory (BDI). Levels of bioavailable testosterone and bioavailable estradiol decreased with age, but total
testosterone, dihydrotestosterone, and total estradiol did not. BDI scores increased with age. Low bioavailable testosterone levels and high BDI scores
were associated with weight loss and lack of physical ac vity, but not with cigare e smoking or alcohol intake. By linear regression or quar le analysis
the BDI score was significantly and inversely associated with bioavailable testosterone (both Ps = 0.007), independent of age, weight change, and
physical ac vity; similar associa ons were seen for dihydrotestosterone (P = 0.048 and P = 0.09, respec vely). Bioavailable testosterone levels were 17%
lower for the 25 men with categorically defined depression than levels observed in all other men (P = 0.01). Neither total nor bioavailable estradiol was
associated with depressed mood. These results suggest that testosterone treatment might improve depressed mood in older men who have low levels of
bioavailable testosterone. A clinical trial is necessary to test this hypothesis.
J Clin Endocrinol Metab 2000 Dec;85(12):4500‐10
Long‐term pharmacokine cs of transdermal testosterone gel in hypogonadal men.
Swerdloff RS, Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Longstreth J, Berman N.
Divisions of Endocrinology, Departments of Medicine/Pediatrics, Harbor‐University of California‐Los Angeles Medical Center, Torrance, CA
Transdermal delivery of testosterone (T) represents an effec ve alterna ve to injectable androgens. Transdermal T patches normalize serum T levels and
reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin
irrita on and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the
pharmacokine c profiles a er 1, 30, 90, and 180 days of daily applica on of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/
day, respec vely) and a permea on‐enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel
formula on when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9‐14% of the T applied was bioavailable.
A er 90 days of T gel treatment, the dose was trated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplica on serum T levels were outside
the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch applica on. Our previous study
showed that steady state T levels were achieved 48‐72 h a er first applica on of the gel. The pharmacokine c parameters for serum total and free T
were very similar on days 30, 90, and 180 in all treatment groups. A er repeated daily applica on of the T formula ons for 180 days, the average serum
T level over the 24‐h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4‐ and 1.9‐fold higher than the C(avg) in the 50 mg T gel and T
patch groups, respec vely). Mean serum steady state T levels remained stable over the 180 days of T gel applica on. Upward dose adjustment from T
gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the
normal range for most pa ents. Serum free T levels paralleled those of serum total T, and the percent fee T was not changed with transdermal T
prepara ons. The serum dihydrotestosterone C(avg) rose 1.3‐fold above baseline a er T patch applica on, but was more significantly increased by 3.6‐
and 4.6‐fold with T gel 50 and 100 mg/day, respec vely, resul ng in a small, but significant, increase in the serum dihydrotestosterone/T ra os in the
two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed propor onately with serum T in all study groups; serum sex
hormone‐binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel applica on
can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in
dosing with li le skin irrita on and a low discon nua on rate.
Urology 2000 May;55(5):755‐8
Serum dehydroepiandrosterone sulfate concentra ons in men with erec le dysfunc on.
Reiter WJ, Pycha A, Schatzl G, Klingler HC, Mark I, Auterith A, Marberger M.
Department of Urology, University of Vienna, Vienna, Austria.
OBJECTIVES: In 1994, the Massachuse s Male Aging Study presented the finding of an inverse correla on of the serum levels of dehydroepiandrosterone
sulfate (DHEAS) and the incidence of erec le dysfunc on (ED). Prompted by the posi ve results of a pilot study on the treatment of ED with
dehydroepiandrosterone (DHEA), we performed a detailed inves ga on on the serum DHEAS levels in men with ED according to age category.
METHODS: Inclusion criteria included a history of ED for more than 6 months, a body mass index less than 30, and a state of good general health. Serum
DHEAS concentra ons were determined in 309 pa ents with ED and 133 healthy volunteers. All par cipants were carefully screened to assess medical
factors known or suspected to alter endocrine func on. Ques ons 3 and 4 of the Interna onal Index of Erec le Func on were used to evaluate erec le
func on. RESULTS: The mean serum levels of DHEAS in pa ents with ED were lower than in healthy volunteers un l 60 years of age. The shape o the
curve of the pa ents with ED indicated a quadra c decrease of DHEAS with age in contrast to a more linear decrease of DHEAS with age in the control
group. CONCLUSIONS: Our results suggest that un l the age of 60 years, the mean serum level of DHEAS is lower in pa ents with ED than in healthy
volunteers.
©Storey Marke ng, All rights reserved.
45
Arthri s Res. 2001;3(3):183‐8. Epub 2001 Feb 21
Hyposecre on of the adrenal androgen dehydroepiandrosterone sulfate and its rela on to clinical variables in
inflammatory arthri s.
Dessein PH, Joffe BI, Stanwix AE, Moomal Z.
Department of Rheumatology, Johannesburg Hospital, University of the Witwatersrand, Johannesburg, South Africa.
Hypothalamic‐pituitary‐adrenal underac vity has been reported in rheumatoid arthri s (RA). This phenomenon has implica ons with regard to the
pathogenesis and treatment of the disease. The present study was designed to evaluate the secre on of the adrenal androgen dehydroepiandrosterone
sulfate (DHEAS) and its rela on to clinical variables in RA, spondyloarthropathy (Spa), and undifferen ated inflammatory arthri s (UIA). Eighty‐seven
pa ents (38 with RA, 29 with Spa, and 20 with UIA) were studied, of whom 54 were women. Only 12 pa ents (14%) had taken glucocor coids previously.
Age‐matched, healthy women (134) and men (149) served as controls. Fas ng blood samples were taken for determina on of the erythrocyte
sedimenta on rate (ESR), serum DHEAS and insulin, and plasma glucose. Insulin resistance was es mated by the homeostasis‐model assessment
(HOMAIR). DHEAS concentra ons were significantly decreased in both women and men with inflammatory arthri s (IA) (P < 0.001). In 24 pa ents (28%),
DHEAS levels were below the lower extreme ranges found for controls. Mul ple intergroup comparisons revealed similarly decreased concentra ons in
each disease subset in both women and men. A er the ESR, previous glucocor coid usage, current treatment with nonsteroidal an ‐inflammatory drugs,
dura on of disease and HOMAIR were controlled for, the differences in DHEAS levels between pa ents and controls were markedly a enuated in
women (P = 0.050) and were no longer present in men (P = 0.133). We concluded that low DHEAS concentra ons are commonly encountered in IA and,
in women, this may not be fully explainable by disease‐related parameters. The role of hypoadrenalism in the pathophysiology of IA deserves further
elucida on. DHEA replacement may be indicated in many pa ents with IA, even in those not taking glucocor coids.
PMID: 11299059
Our compounding professionals work together with pa ents and prac oners to provide customized bio‐iden cal
hormone replacement therapy in the most appropriate strength and dosage form to meet each man or woman’s specific
needs. Hormone replacement therapy should be ini ated carefully a er a complete medical and family history have been
reviewed. Every person is unique and will respond to therapy in his or her own way; therefore the selec on of hormone(s),
dose, dosage form, and route of administra on should be specific to each pa ent. Close monitoring and medica on
adjustments are important to minimize the risk of side effects.
46
©Storey Marke ng, All rights reserved.