Progesterone Therapy for Symptomatic Perimenopause
Jerilynn C. Prior MD, FRCPC, Professor of Medicine, Scientific Director, Centre for
Menstrual Cycle and Ovulation Research (CeMCOR), UBC
www.cemcor.ubc.ca
Learning Objectives:
1. Perimenopause, although characterized as a time of dropping estradiol,
involves chaotic estrogen levels that average >20% higher and
intermittently are extremely high and ovulatory disturbances with
decreasing progesterone levels.
2. Perimenopause begins and is most symptomatic when cycles remain
regular.
3. Perimenopause is highly symptomatic for more than 20% of women—
symptoms typically include heavy menstrual flow, night sweats, infertility,
breast tenderness and sleep disturbances.
4. Progesterone, because it normally counterbalances estradiol’s actions, is
effective treatment for heavy flow, probably for night sweats, infertility
and breast tenderness and definitely decreases anxiety and improves
sleep.
Perspective and evidence
There are few systematic or randomized controlled trial (RCT) data on therapies for
symptomatic perimenopause (as differentiated from treatments for menopausal
women—those one year or more beyond their final menstruation). Therefore I will rely
for treatment suggestions on first principles about perimenopausal biology and
endocrinology (1), my 40-year experience in patient care, my extensive research
experience and my 20-year effort to help BC’s most symptomatic perimenopausal
women.
Perimenopause endocrinology and diagnosis
Ample evidence from multiple studies now shows that, despite fewer remaining ovarian
follicles, estradiol (E2) levels increase (2) and become highly erratic (3) while ovulation
becomes inconsistent in perimenopause (4) and progesterone levels decrease within
ovulatory cycles (5). This appears to occur because of disturbed aging-related ovarianpituitary-hypothalamic feedback relationships (1;6). From a meta-analysis, phasespecific menstruating perimenopausal E2 levels are 20-30% higher than in
premenopausal women (1).
There are several implications of this new knowledge about perimenopausal
endocrinology—we stop using the term “menopausal symptoms” which conflates
perimenopause and menopause; we avoid E2 treatment until one year past flow; we
consider P4 to be potentially effective therapy.
Making the diagnosis of perimenopause is currently problematic despite consensus
guidelines (7) because symptomatic women are often regularly menstruating and have
normal FSH levels (2). Like in rheumatology, making a diagnosis with a constellation of
1
typical experience changes allows perimenopause to be diagnosed in regularly
menstruating midlife women whose hormones and experiences have already changed
(8):
Diagnosis of the start of perimenopause in women with regular
cycles—any 3 of the following:
1.
2.
3.
4.
5.
6.
7.
8.
9.
New onset heavy and/or longer menstrual flow
Shorter menstrual cycles lengths ≤ 25 days
New, sore, swollen and/or lumpy breasts
New or increased menstrual cramps
New mid-sleep wakening
Onset of night sweats especially around flow
New or markedly increased migraine headaches
New or increased premenstrual mood swings
Notable weight gain without changes in exercise or food intake (8)
Therefore, I understand perimenopause as a life phase distinct from (post)menopause,
and one that lasts over a decade for a portion of women, beginning with increases in E2
and decreases in P4 levels in regularly menstruating women (4).
Current definitions of perimenopause are in flux—from the Stages of Reproductive
Aging Workshop (STRAW) schema (7), to Phases of Perimenopause (1;4), to the current
Re-Stage Collaboration refinements of the STRAW criteria (9;10). As shown in Figure 1,
perimenopause begins in women with regular flow and extends for one year after the
last menstrual flow when menopause (or postmenopause) is diagnosed. The onset of
the Early Menopause Transition (Early MT) is with cycles that vary by plus or minus six
days (9) and of the Late MT by 60 days without menstruation (or one skipped period).
Given the lack of predictive accuracy of increased FSH levels for menopause (11), they
should not be used, although in the future Anti-Mullerian Hormone levels may be proven
predictive.
2
Figure 1—New proposed Timelines and Definitions of Women’s Reproductive
Midlife Transition (in press, J. C. Prior & C. L. Hitchcock, Jan. 2011, Frontiers in
Bioscience)
Symptomatic Perimenopause
Women differ quite dramatically in whether or not they are troubled by the changes they
experience in perimenopause. It is currently unknown why some women are miserable
and other women sail through. It is likely that socioeconomic status, past life experiences
and polymorphisms related to steroid metabolism and excretion all play roles. For
example, that Asian women experience fewer hot flushes may not be because of eating
more soy, or being in a culture that values older women, but rather because Asian
women metabolize cortisol and other steroids more rapidly than Caucasians (12) and
thus may not be exposed to as high E2 levels.
The estimate that 20% of perimenopausal women are highly symptomatic, is just an
educated guess (13). This kind of information is still needed—it is best obtained from
population-based samples (such as the Melbourne Midlife Women’s Health Study,
MMWHS) that can also be linked with health care administrative databases. It may be
that the proportion of cycles in which women experience Luteal Out of Phase Events
(LOOP) (as illustrated in Figure 2) determines whether or not they are symptomatic.
Hale estimates that a third of cycles, throughout the menopausal transition, have LOOP
characteristics (11).
Figure 2—Example a Luteal Out of Phase event cycle. The midcycle E2 peak is
followed by a second or even third peak that is yet higher. The last E2 peak and
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another rise in progesterone occurs after flow starts in the following cycle
(shaded) (3).
Menstrual flooding or heavy or long flow
Because perimenopause and menopause were all called ‘menopause’ in the past, and
menopause was understood to mean low estrogen levels, most of the available studies
(especially those using the Kupperman or Green Indices for monitoring) did not consider
heavy flow to be related to perimenopause. Therefore we have little data on its withinperimenopause time course. Kaufert, an anthropologist and therefore more open to
recording women’s experiences, found that “flooding menstruation” was most prevalent
around the time when periods first became irregular (Early MT) (14). The Study of
Women Across the Nation (SWAN), the NIH-funded USA study, documented that longer
episodes of bleeding were associated with anovulation (failure to release an egg and
thus in cycles without progesterone). SWAN hormone data also noted that anovulation
was more prevalent in cycles shorter than 21 days or longer than 36 days. However,
heavy flow was most common in ovulatory cycles and was related to obesity (15).
Breast tenderness (also called mastalgia) The best prospective data on the withinwoman breast sensitivity changes of perimenopause over time are from the MMWHS,
although breast tenderness (like heavy flow) was not initially in the questionnaires.
These data showed that breast tenderness decreased over time and certainly had
become less by the time menstrual periods were being skipped (Late MT) (16). RCT
data on E2 or P4 or both together topically applied to one breast that was scheduled for
an open biopsy of a benign mass showed that E2 increased proliferation and P4
decreased it, whether progesterone was give alone or with estrogen (17;18). Given that
proliferation is likely related to breast tenderness (also accounting for the breast
tenderness teenagers and pregnant women may experience) and the histological results
of those two previously mentioned RCTs, it is likely that perimenopausal higher E2 and
lower P4 levels promote breast cell proliferation and tenderness. These hormonal
perimenopausal changes likely also promote the breast enlargement and increased
nodularity some women report, as well as potentially the documented increased
diagnosis of breast cancer that occurs in midlife women.
Dysmenorrhea or Menstrual Cramps The life course of menstrual cramps is an increase
during adolescence, improvement after childbirth or miscarriage or abortion, and
worsening into the late 30s and the 40s. Women appear most likely to experience
increased cramps early in perimenopause. Although the cause for perimenopausal
cramps is not clear, they may increase, based on monkey studies, because the higher
4
E2 and lower progesterone (P4) levels cause greater production of prostaglandins in the
uterine muscle and endometrium.
Mid-sleep Wakening and Sleep Disturbances Sleep trouble begins early in
perimenopause although it has not been clearly tracked in prospective studies. Typically
women describe the experience of jolting awake after a few hours of deep sleep.
Although trouble falling asleep may be associated with some increased anxiety in
perimenopause, and early morning wakening with depression, the mid-sleep wakening is
most typical. Sleep disturbances, based on the MMWHS data, tend to increase in later
perimenopause and often extend into menopause (16). Although these may be related
to night sweats, many women with insomnia have no day of nighttime vasomotor
symptoms.
Hot Flushes and Night Sweats (Vasomotor symptoms, VMS)
Note that, although VMS are reported to have a prevalence of about 11% in
“premenopausal” women, it is likely that these are women with regular cycles whom I
would designate as being in early perimenopause (19)(Figure 1). The peculiar thing
about the onset of VMS is that they usually start as night sweats that commonly occur
around or just preceding menstrual flow (19). They typically then progress to occur
during both day and night before becoming most intense in the Late MT and the last
year of perimenopause.
According to the MMWHS, night sweats/hot flushes increased the closer to menopause a
woman became (16). Interestingly, an earlier report of increased premenstrual
symptoms predicted those women who were most likely to experience subsequent night
sweats (20). Also, in our study of women with regular cycles and night sweats, typically
they also had marked increases in premenstrual breast tenderness (19) (possibly due to
LOOP events). VMS are increased by economic, social and other stressors as well as by
cigarette smoking and obesity (21). VMS are decreased by various strategies that
decrease the stress response (such as the regular practice of paced yoga-type
breathing, mindfulness meditation, the relaxation response or meditation), by stopping
smoking, and decreasing weight (if appropriate, respectively) and by regular exercise.
CeMCOR is currently performing an observational prospective pilot study on cyclic night
sweats in early perimenopause to determine their patterns, hormonal associations and
whether or not they relate to other experiences. CeMCOR also just received Canadian
Institutes for Health Research funding to do a randomized double-blind trial of oral
micronized progesterone (OMP, Prometrium) for perimenopausal VMS.
New or increased migraine headaches These typically start in very early perimenopause
and can occur either at midcycle or, more typically, right around flow. Women who
experienced pubertal migraines are most likely to have them recur in Perimenopause
although women without previous migraines may also begin to experience them. In
women without classical migraines, likely because of the stress hormone amplifying
effects of high E2 levels (22), ordinary tension or “stress-type” headaches are also more
prevalent in perimenopause.
Increased premenstrual symptoms Classically premenstrual symptoms are understood to
include breast tenderness, bloating, inappropriate (usually increased) appetite and
dysphoric mood symptoms that occur during the week prior to flow. These probably
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increase very early in perimenopause—the typical population in the local “PMS Clinic”
averages age 35-45. Although depression and anxiety have not been shown to be
caused by perimenopause, some women will notice that these feelings have increased.
Previous depression and increased current stress make premenstrual symptoms worse
while regular exercise tends to decrease the risk for perimenopausal depression (23).
Weight gain without exercise or food changes Perimenopause is a time when women
normally gain weight based on population-based Canadian Multicentre Osteoporosis
Study (CaMOS) data. During the 45-54 year decade, the gender difference in BMI
change is huge—men gain 0.5 BMI while women gain 1.4 BMI units (24). Weight gain,
however, appears related to protection against excess bone loss based on the major
bone loss that occurred in those randomized to a weight loss versus maintenance
programme in perimenopause (25).
Although weight gain is common, there is less good evidence that perimenopause is a
time during which insulin resistance increases, as most clearly documented by a gain in
waist circumference in Caucasians to over 88 cm. However, clinical data suggest that
the decade of the 40s is when the diagnosis of the Metabolic Syndrome (obesity, insulin
resistance or diabetes, abnormal lipids and high blood pressure) is first made.
*
*
*
With this background on the symptoms and experience changes of Perimenopause, we
will now discuss how progesterone treatment may assist with each. If a progestin or
progestogen therapy is mentioned instead of OMP, the agent will be specifically named
and the appropriate dose provided.
Progesterone Therapy for Symptomatic Perimenopause
In general, in Early Perimenopause and until after the first skipped period (Early MT),
progesterone is used as a cyclic therapy to supplement or “replace” the luteal phase
(See Figure 3). The exception to this rule is the women with heavy flow (for whom
cyclic therapy is likely to be insufficient) or for those with migraine headaches (who may
experience a rebound increase in headaches with OMP withdrawal). For women with
heavy flow or a history of migraine headaches, daily progesterone therapy is
recommended.
Also, in general, oral micronized progesterone (OMP, Prometrium® or compounded
progesterone in olive oil) is used in a dose of 300 mg at bedtime. This dose keeps the
P4 level above the lower limit of the luteal phase range for 24 hours (26), since it should
only be taken right before sleep because of its causes drowsiness (27). Finally, until RCT
data are available, use of OMP should be undertaken in an “experiment of one” manner
in which at least one cycle of baseline data are obtained using the Daily Perimenopause
Diary© (19)(free under “tools” on www.cemcor.ubc.ca) and the record is kept during
a several-month trial of therapy before the pre- and treatment phases are compared.
Figure 3 shows the typical way in which cyclic progesterone therapy is given.
For a full patient handout see “Cyclic Progesterone Therapy”
www.cemcor.ubc.ca
6
As described earlier, each of the common experience changes of Perimenopause is
described and what is known about progesterone and other therapies are provided.
Menstrual flooding or heavy or long flow
Non-steroidal anti-inflammatory drugs (NSAIDs), that block prostaglandin production in
the endometrium, are effective in decreasing flow by 25-50% based on RCT data (RCT)
(28). Normal doses of 200 mg ibuprofen every 4-8 hours are effective. NSAID therapy
should always be used for heavy menstrual flow (in a woman of any age) and be the
first line of treatment. Other important measures are to ensure adequate fluid volume if
a woman with heavy flow is feeling faint or has a rapid increase in heart rate with sitting
or standing, and assessing for and treating the potential blood-loss (iron deficiency)
anemia.
Oral contraceptives (OC) that contain the low dose of 20µ Ethinyl Estradiol have been
tested in one RCT for menorrhagia in Perimenopause (29). The results showed that
during the first three cycles, OC treatment caused midcycle spotting (metrorrhagia) but
no improvement in heavy flow; however, heavy flow improved during cycles four
through 6 of this RCT (29).
In anovulatory cycles, cyclic oral micronized progesterone may be effective for heavy
flow, but long-cycle (days 6-27) or daily OMP therapy is commonly needed for heavy
flow in ovulatory cycles (30). My experience is that daily therapy with 300 mg OMP, plus
NSAID, is usually needed for at least three months before flow is sufficiently controlled
that the therapy can change to a cyclic OMP schedule (Figure 3). However, a few
women with benign problems (a polyp, or adenomyosis) may require quite high doses of
progesterone/progestin (medroxyprogesterone 20 mg twice a day). If a woman would
prefer not to use the levonorgestrel impregnated IUD (Mirena), I recommend OMP 100300 mg/vagina (or MPA 10-20 mg in the morning) plus 300-600 mg of OMP at bedtime
daily for six months or longer. In my experience, heavy flow is eventually adequately
controlled.
It is usually wise to do an endometrial biopsy after a 3-month trial of full dose OMP and
NSAID treatment has not adequately controlled bleeding. Also, any woman with heavy
flow who plans on a holiday, and especially if she plans on being out of the country,
should carry with her the needed NSAID and OMP to cover her for the duration of her
trip.
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Breast tenderness
The first strategies to deal with breast tenderness are to decrease caffeine, begin an
exercise programme and gradually (a pound a week at most) lose weight (for those who
are users of caffeine or overweight). However, often in perimenopause these strategies
are insufficient. Because breast tenderness tends to be cyclic and worse before flow
(19), cyclic oral micronized progesterone may be effective (although unproven) therapy.
In France where progesterone and progestins are commonly used for breast tenderness
in perimenopause, there was no increased risk for breast cancer with their
perimenopausal use, but breast cancer risk did significantly increase the longer
progesterone/progestins were taken (31). This observational E3N study, however, did
not differentiate between OMP and progestins. OMP, in contrast to all progestins, was
not associated with postmenopausal increased breast cancer when given with
exogenous estrogen (32).
Dysmenorrhea or Menstrual Cramps
If NSAID therapy taken in high doses before cramps become intense (see “Painful
Periods www.cemcor.ubc.ca) is not sufficient for effective treatment, daily or cyclic OMP
therapy often allows relief. Progesterone helps cramps by a mechanism that may be
related to decreased endometrial or myometrial prostaglandin production. In women with
severe cramps related to endometriosis, daily high dose vaginal and/or oral P4 is often
effective in my experience. It is certainly worth a try—first principles suggest that the hot
flush and bone loss side effects of hypothalamic suppression with GnRH
agonist/antagonist therapy will not occur with OMP therapy.
Mid-sleep Wakening and Sleep Disturbances
Oral micronized progesterone has been shown to be effective for sleep in RCTs in men
and in menopausal women when given in a dose of 300 mg at bedtime (27). No matter
what the hormonal or psychosocial factors are in sleep disturbance, OMP 300 mg
usually assists. OMP (but not transdermal P4) increases sleep consistency and early
night rapid eye movement sleep through conversion to its metabolites that interact with
the GABA system in the brain (33). It has the clinical advantage that overdose mortality
is not possible because, unlike all other sleeping medications or pain/sedative
medications, OMP increases rather than suppresses respiration. Furthermore, careful
crossover RCT psychometric testing in the morning during the run-in and after 21 days
on each of active and placebo therapies showed no within-woman differences from
placebo (27). However, a clinician should warn a sleep-deprived woman to plan on
sleeping in after the first few nights of OMP therapy—there is natural catch-up sleep that
may otherwise be misunderstood as a daytime drowsiness side effect of OMP. Likewise,
OMP should always be taken just before lying down to sleep because otherwise it will
cause a strange dizzy feeling.
Hot Flushes and Night Sweats (Vasomotor symptoms, VMS)
Perimenopausal women have more prevalent and more severe VMS than do
menopausal women (occurring for 79% of women with 9% being more frequent than
50/week of moderate-severe intensity) (34). Despite this fact, conventional wisdom says
that “estrogen deficiency” causes hot flushes. The RCT of low dose birth control pills by
Casper and colleagues did not show a significant improvement in VMS compared with
placebo (29), despite the facts that OC are commonly prescribed for that purpose in
Perimenopause. Also, estrogen is the gold standard therapy for VMS in menopausal
women (35).
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RCT evidence that OMP is effective for perimenopausal VMS is currently lacking.
However, CeMCOR just completed an RCT in 127 women showing that daily OMP (300
mg at bedtime) is highly effective for VMS in treatment-seeking healthy early
menopausal women (36). Also, CeMCOR has just obtained a Canadian Institutes of
Health Research grant to perform an RCT of OMP for hot flushes in perimenopause.
Despite lack of RCT data, there are extensive clinical data suggesting that cyclic OMP
300 mg at bedtime is effective for the cyclic night sweats in very early perimenopause
and daily OMP is effective when cycles become irregular. During Early MT, VMS may
consistently occur for weeks at a time (although they may also be absent again for
weeks on end). However, there are abundant clinical data suggesting that OMP is
effective in perimenopause—some of it is illustrated by stories in Estrogen’s Storm
Season (13).
New or increased migraine headaches
Progesterone therapy for migraine headaches in perimenopause is, yet again, a topic on
which there are no RCT data. However, daily OMP appears to be an effective strategy
for some women with migraines, especially when it is added to their usual acute
treatments. OMP may act similarly to beta blockers or tricyclic antidepressants to
decrease the frequency and severity of migraine attacks, perhaps through its sleep
enhancing or anti-inflammatory, anti-oxidant and other positive brain effects (37).
Increased premenstrual symptoms
The primary approach to premenstrual fluid, breast tenderness, appetite and mood
symptoms occurring and increasing before flow is to provide social and emotional
support, and reassurance that perimenopause ends and she will enter a less
symptomatic menopausal world. In addition, women’s own record-keeping with the
Daily Perimenopause Diary© may itself be therapeutic in providing insight and the ability
to predict difficult times. In addition, gradually increasing exercise intensity and distance
will likely help with symptoms (as they do in premenopausal women (38)) but they may
not because the feedback disturbances of perimenopause prevent suppression of
hypothalamic gonadal stimulation (1).
There is one early, well performed crossover trial showing that cyclic OMP (300 mg at
bedtime) is effective for premenstrual symptoms (39). It should be used for women with
regular cycles and in the cyclic OMP schedule in Figure 3. In addition, women need to
be provided with lifestyle advice and emotional support.
Weight gain without exercise or food changes
Although there are no direct data that OMP therapy (either cyclically or daily) will
improve the weight gain and insulin resistance of perimenopause, several lines of
evidence suggest that it may. In a prospective observational study in which women
collected 3-day diet diaries in the early follicular phase and premenstrually, all of the
weight-stable young women who ovulated in the cycle ate about 300 calories more than
in the follicular phase--those women who were anovulatory in that cycle showed no
caloric intake difference from the follicular phase (40). This is because about 300
calories a day are required to raise the core temperature the mean of 0.2 degrees as
progesterone and medroxyprogesterone do. Also, in a 1-year comparative RCT of
medroxyprogesterone (MPA, 10 mg/d) with conjugated equine estrogen (CEE, 0.6
9
mg/d), those just-surgical menopausal women on MPA gained significantly less weight
and BMI, and tended to gain less truncal fat than did women on CEE (41).
Therefore, OMP therapy may be rationally used along with a diet rich in whole grains,
vegetables and fruit and an exercise programme as a strategy to assist the
perimenopausal woman in preventing excess weight gain and development of metabolic
syndrome. Those whose waist circumference has become over 88 cm, especially if they
have a family history of diabetes mellitus, I would also treat with metformin (500 mg
with the two meals a day when they are most hungry).
Infertility related to ovulatory disturbances
Yet again there are clinical data but trial evidence that cyclic OMP will be helpful for
treatment of ovulatory disturbance-related infertility. Since short luteal phase cycles
become common (4) and luteal insufficiency is progressive (5) in perimenopause, for
those women who have kept the Daily Perimenopause Diary© and documented
ovulation by the validated quantitative basal temperature method (42;43) may be
assisted to fertility by cyclic OMP therapy. There is a chapter in Estrogen’s Storm
Season(13) describing its use for someone with high cycle day-3 FSH and estradiol
levels who had repeated short luteal phase cycles. The important difference from the
diagram in Figure 3 when OMP is used for fertility is that it should only be started when
the stretchy cervical mucus has begun to wane (indicating that it is well past the
midcycle estradiol peak) or after a urine LH test has become positive, in order to avoid
potentially suppressing the LH peak. The other difference is that it should be continued
until flow starts (which would usually indicate that she has not become pregnant). If
other testing indicates that a pregnancy occurred but underwent early miscarriage, then
in subsequent cycles, OMP could be continued in a dose of 300 mg at bedtime plus 200300 mg vaginally at bedtime until the 12th week should she become pregnant. Based on
clinical evidence that spontaneous fertility is possible in women in their 40s despite what
are currently considered clear evidences of infertility (44), cyclic OMP is at least worth a
try.
In Summary
The above information represents my personal effort to integrate biological, hormonal
and clinical data intermixed with sparse RCT information all of which suggest that it is
hormonally appropriate and clinically safe to use cyclic or daily oral micronized
progesterone for treatment of symptomatic women in perimenopause. The evidence for
OMP’s effectiveness is strongest for heavy flow, sleep disturbances and VMS—these tend
to be the most troublesome problems for which perimenopausal women seek health
care provider assistance.
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Revised from a handout originally presented on Thursday September 30th 2010 at the Canadian
Fertility and Andrology Society conference 2010 (Vancouver).
14