PATIENTeNEWS
JUNE
2016
Bringing the science of nutrition and wellness to patients.
TABLE OF CONTENTS Click on title to be taken to the article.
Supporting Gastrointestinal Health During Cancer Chemotherapy and Radiation
ProThera®, Inc. provides this monthly
Patient eNews as an information service
distributed without charge.
External Signs of Internal Health Problems and Nutrient Deficiencies Part 2: What Hair,
Skin, and Nails Reveal About Your Health
Natural Support for One of Men’s Most Distressing Problems
DID YOU KNOW?
Supporting Gastrointestinal Health During Cancer
Chemotherapy and Radiation
By Stephen F. Olmstead, MD
Gastrointestinal (GI) symptoms are exceedingly common during
cancer chemotherapy and radiation.1 The incidence varies by type
and location of tumor, radiation dose and field, and chemotherapy
regimen. Certain chemotherapy agents such as cisplatin can
directly cause nausea and vomiting.2 However, most GI symptoms
result from the direct cell-damaging effects of chemotherapy and
radiation on the tissue lining the GI tract known as the epithelium,
resulting in mucositis.1,3
The incidence of diarrhea from chemotherapy ranges from 50%
to 80% of patients and depends on the chemotherapy regimen.4
Severe diarrhea requiring hospitalization occurs in 1% to 3% of
people receiving chemotherapy for non-Hodgkin’s lymphoma and
breast cancer. In contrast, 20% of patients receiving a combination
of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI)
for colorectal cancer develop severe diarrhea.5 The incidence of
diarrhea following abdominal or pelvic radiation is around 50%,
higher if radiation is combined with chemotherapy.4
Diarrhea may lead to dehydration and metabolic disturbances.
Mucositis is also associated with bleeding, increased gut
permeability, and a greater risk of bacteremia (invasion of bacteria
into the bloodstream) and sepsis.
HOW CHEMOTHERAPY AND RADIATION AFFECT THE GUT
MICROBIOTA
All available preclinical evidence indicates that cancer chemotherapy and radiation rapidly and profoundly alter the normal gut
microbiota, the population of organisms—both beneficial and
harmful—that reside in the GI tract. Healthful commensals such
as Bifidobacterium and Lactobacillus are reduced while numbers
of potential pathogens such as Clostridium, Enterococcus, and
Escherichia are increased. These are precisely the pathogens
commonly encountered in patients undergoing cancer treatment.6
Altered gut microbiota, called dysbiosis, almost certainly contributes
to mucositis through disruption of gut barrier function and activation
of proinflammatory pathways.1
EVIDENCE IN HUMANS
Remarkably, only a few studies have evaluated the effect of cancer
chemotherapy and radiation on the microbiota of humans. In a
study involving nine children with acute myeloid leukemia treated
with standard chemotherapy and prophylactic antibiotics, fecal
bacterial populations were mapped.7 Cancer chemotherapy and
prophylactic antibiotics reduced the total number of bacteria by
100-fold compared to healthy controls. There was a 10,000-fold
drop in the number of anaerobic bacteria including Bacteroides,
Bifidobacterium, Clostridium cluster XIVa, and Faecalibacterium
prausnitzii. Following chemotherapy, Clostridium XIVa and
F. prausnitzii numbers recovered, but both Bacteroides and
Bifidobacterium were still 10- to 300-fold lower compared with
the healthy controls. Chemotherapy and antimicrobials were also
associated with higher numbers of Enterococcus and Streptococcus.
In a study involving 17 ambulatory patients with different cancers
receiving various chemotherapy protocols with and without
antibiotics, researchers assessed fecal microbial profiles.8 Cancer
patients had a lower total number of fecal bacteria at baseline
compared to healthy controls. Chemotherapy reduced total
microbial abundance, increased numbers of Bacteroides and
Clostridium cluster IV, and decreased Bifidobacterium species
and Clostridium cluster XIVa. Uncommon species not detected
at baseline such as Eggerthella, Megasphaera, Parvimonas,
Anaerostipes, Anaerococcus, Methylobacterium, Holdemania,
Turicibacter, Akkermansia, Sutterella, Sphingomonas, Anaerotruncus,
Coprococcus, and Dorea appeared in the feces following
chemotherapy. These alterations to the gut microecology are of
uncertain significance.
Fecal microbiology was assessed in eight people with
non-Hodgkin’s lymphoma treated with the chemotherapeutic
agents carmustine, etoposide, aracytine, and melphalan.9 No
antibiotics were used. Following chemotherapy, there was a
reduction in overall bacterial diversity with decreased evenness
and richness. At the phylum level there was a significant decrease
in Firmicutes and an increase in Bacteroidetes. Bacteroides and
Escherichia species increased while Bifidobacterium, Blautia,
Faecalibacterium, and Roseburia species decreased.
Scientists assessed fecal microbial populations in 26 people undergoing chemotherapy for different cancers.10 Patients who suffered
from chemotherapy-induced diarrhea had reduced numbers of
Bacteroides, Bifidobacterium, Enterococcus, and Lactobacillus
species and an increase in E. coli and Staphylococcus species.
Continued on page 2
1
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Two clinical studies have assessed the effect of radiation on the gut
microbiota. In a study of 10 patients receiving pelvic radiation for
abdominal tumors, those without diarrhea maintained a gut microbiota similar to healthy controls.11 However, in people developing
diarrhea after radiation, there was an increase in the Actinobacteria
phylum and Bacillus genus and a decrease in Clostridium. In a second
study involving nine women with gynecological cancer, radiation
decreased populations in the phylum Firmicutes and increased
numbers in the phylum Fusobacteria. At the family level, Eubacteriaceae genera were significantly reduced, while Fusobacteriaceae and
Streptococcaceae genera were significantly increased.
PROBIOTICS TO RELIEVE MUCOSITIS AND DIARRHEA CAUSED
BY CHEMOTHERAPY AND RADIATION
Only a few clinical studies have addressed the ability of probiotics
to prevent and treat cancer chemotherapy and radiation mucositis.
One study assessed the impact of Lactobacillus rhamnosus GG
on diarrhea in 157 patients with colorectal cancer receiving two
different dosing regimens of 5-FU and leucovorin.12 Approximately
one-third of the patients also received radiation. Researchers randomized the subjects in a 2:1 ratio to receive either probiotics or
placebo. Patients receiving probiotics were significantly less likely
to develop severe diarrhea, to be hospitalized for gut toxicity, and to
have a reduction in chemotherapy dose due to bowel toxicity. No
adverse effects from the Lactobacillus were encountered.
In a separate study, 24 women receiving pelvic radiation for
gynecological cancers were randomized to receive fermented milk
containing 2 billion colony forming units (CFU) of Lactobacillus
acidophilus and lactulose daily or dietary counseling alone.13
Probiotics significantly reduced the incidence of diarrhea and usage
of antidiarrheal medications. Subjects receiving probiotics reported
more flatulence, probably due to the lactulose.
A large prospective, double-blind, placebo-controlled, randomized
trial evaluated the role of a high-dose, multispecies probiotic in
the prevention of radiation-induced diarrhea in 490 patients with
colorectal or cervical cancer.14 The probiotics consisted of four
Lactobacillus species, three Bifidobacterium species, and Streptococcus thermophilus in the amount of 450 billion CFU three times
daily. Patients receiving the high-dose, multispecies probiotic were
significantly less likely to develop diarrhea compared to the placebo
group. Of those who developed diarrhea, significantly fewer
experienced severe diarrhea in the probiotic group. Probiotic users
also had significantly fewer daily bowel movements and an increased
mean time to use of the antidiarrheal medication, loperamide.
Despite some reporting errors in this study, clear benefits for
probiotic use were observed.
A placebo-controlled, multicenter study evaluated a liquid yogurt
containing Lactobacillus casei for the prevention of diarrhea in 85
women with cervical or endometrial cancer being treated with
pelvic radiation.15 There was no meaningful difference between
patients receiving probiotic and those receiving placebo in diarrhea
and loperamide use. The lack of benefit may have been related to
dosing the probiotics in yogurt.
Another large trial of probiotics for the prevention of radiationinduced diarrhea evaluated a combination of L. acidophilus and
B. bifidum administered to a group of 246 patients receiving pelvic
radiation for a variety of different pelvic tumors.17 Subjects were
divided into three groups respectively receiving “high dose” probiotics at 20 billion CFU/day, “standard dose” probiotics at 2.6 billion
CFU/day, or placebo. The investigators evaluated the time to first
appearance of moderate and severe diarrhea.
There was no difference between the time to diarrhea in any of
the study groups. However, by day 60, significantly fewer patients
receiving the “standard dose” of probiotics experienced moderate
and severe diarrhea than did the placebo group. “Standard dose”
probiotics significantly reduced the incidence of severe diarrhea in
patients undergoing surgery in addition to radiation. Important confounding factors were the inclusion of very different pelvic cancers
such as cervical, endometrial, prostate, rectal, and other tumors as
well as the wide variety in treatment protocols including different
doses and frequencies of radiation, different portals, different chemotherapy protocols, and concomitant surgeries.
In one other study, 206 patients who developed mild to moderate
diarrhea within four weeks of completing pelvic radiation were
randomized to receive 1.5 billion CFU of L. rhamnosus or placebo
three times per day for up to a week.18 Fewer patients receiving
probiotics required medication to control diarrhea, but the difference did not attain statistical significance. An unvalidated survey
indicated patients in the probiotic group experienced less diarrhea
and improved stool consistency.
SUPPORTING GI HEALTH DURING CANCER TREATMENT
Cancer chemotherapy and radiation are associated with a high
incidence of gastrointestinal disturbances. In addition to toxicity to
epithelial cells, chemotherapy and radiation profoundly alter the
gut microbiota, devastating Bifidobacterium, Lactobacillus, and
other healthful microbial populations while facilitating the emergence of pathogens. It is highly likely gut dysbiosis contributes to
the development of mucositis. Clinical studies, although limited,
suggest probiotics may offer support during cancer chemotherapy
and radiation.
REFERENCES:
1. Touchefeu Y, et al. Aliment Pharmacol Ther. 2014;40:409-21.
2. Chopra D, et al. Indian J Med Paediatr Oncol. 2016;37:42-6.
3. Ciorba MA, et al. Curr Opin Support Palliat Care. 2015;9:157-62.
4. Benson AB 3rd, et al. J Clin Oncol. 2004;22:2918-26.
5. Falcone A, et al. J Clin Oncol. 2007;25:1670-6.
6. Montassier E, et al. Eur J Clin Microbiol Infect Dis. 2013;32:841-50.
7. van Vliet MJ, et al. Clin Infect Dis. 2009;49:262-70.
8. Zwielehner J, et al. PLoS ONE 2011;6:e28654.
9. Montassier E, et al. Microb Ecol. 2014;67:690-9.
10. Stringer AM, et al. Support Care Cancer. 2013;21:1843-52.
11. Manichanh C, et al. Am J Gastroenterol. 2008;103:1754-61.
12. Osterlund P, et al. Br J Cancer. 2007;97:1028-34.
13. Salminen E, et al. Clin Radiol. 1988;39:435-7.
14. Delia P, et al. World J Gastroenterol. 2007;13:912-5.
15. Giralt J, et al. Int J Radiat Oncol Biol Phys. 2008;71:1213-9.
16. Chitapanarux I, et al. Radiat Oncol. 2010;5:31.
17. Demers M, et al. Clin Nutr. 2014;33:761-7.
18. Urbancsek H, et al. Eur J Gastroenterol Hepatol. 2001;13:391-6.
In contrast, in a similar clinical setting involving 63 women with
cervical cancer being treated with radiation and weekly cisplatin, a
combination of 4 billion CFU of L. acidophilus and Bifidobacterium
bifidum was compared to placebo in a double-blind trial.16 Significantly fewer patients taking probiotics developed severe diarrhea
than control subjects. Patients receiving probiotics reported a lower
frequency of liquid stool and significantly less loperamide use.
2
External Signs of Internal Health Problems and Nutrient
Deficiencies Part 2: What Hair, Skin, and Nails Reveal
About Your Health
By Chris D. Meletis, ND and Kimberly Wilkes
[This is the second of a two-part series discussing external signs of disease and nutrient deficiencies. This article addresses the hair, skin, and
nails. Last month, we discussed how the eyes and ears offer clues to overall health.]
The condition of the skin, hair, and fingernails is a reflection of inner
health. Using makeup, shampoos, conditioners, and nail polish to
cover up flaws do not get at the root of the problem as effectively
as correcting nutrient deficiencies and addressing underlying
health issues. For example, accelerated skin aging can occur due
to high blood sugar and cortisol levels, as we will discuss in greater
detail later.
In addition, certain nutrient deficiencies have been found in subjects
with hair loss, and the fingernails can serve as a warning sign that
you may be suffering from specific health problems. In this article,
we will discuss the physical manifestations of diseases and nutrient
deficiencies as seen in the hair, skin, and nails.
FACTORS ASSOCIATED WITH HAIR LOSS
Many types of hair loss, or alopecia, involve nutrient imbalances
or underlying health problems. Alopecia areata is an autoimmune
disorder that results in hair loss on the scalp and elsewhere on the
body due to destruction of hair follicles by white blood cells known
as lymphocytes. The first onset occurs before the age of 20 in
60% of patients with the disorder.1 Although alopecia areata has a
genetic component, the occurrence, duration, and worsening of the
condition is also associated with stress and having experienced a
traumatic situation.2
Researchers determined that compared to healthy siblings, children
or adolescents who suffered from alopecia areata underwent more
stressful life experiences and over 24 hours excreted higher amounts
of urinary catecholamines (hormones secreted during stress including norepinephrine and epinephrine).3 Other researchers conducted
a case-control study of 52 adults with alopecia areata and 52 ageand sex-matched controls.4 Their results indicate that although
anxiety and depression were not associated with alopecia areata,
stressful life events may predispose individuals to the disease or
worsen its symptoms.
Another consideration in alopecia areata is low zinc levels. Scientists have determined that patients with alopecia areata have lower
serum zinc concentrations.5 In one study, lower zinc levels were
associated with increased duration and severity of the disease as
well as the extent to which it was resistant to treatment.
Cadmium toxicity may be an under-recognized cause of another
type of hair loss known as telogen effluvium, a condition in which
an excessive number of hair follicles enter a resting state, leading
to hair loss. Researchers measured lead, cadmium, iron, and zinc
blood levels in 40 women with telogen effluvium and 30 healthy
controls.6 Although iron, zinc, and lead levels were not significantly
different between the two groups, blood cadmium concentrations
were markedly higher in subjects with this type of hair loss. Furthermore, telogen effluvium and female pattern hair loss have been
linked with low levels of serum ferritin (iron) and vitamin D.7
Researchers have associated a third form of hair loss, androgenic
alopecia, or male pattern baldness, with cigarette smoking and
increased stress.8,9 Smoking is thought to promote androgenic
alopecia by increasing oxidative stress, as indicated by a mouse
study in which cigarette smoke-induced alopecia was reversed by
administering the antioxidant N-acetyl-L-cysteine.10 Smoking may
also damage cellular DNA in hair follicles and suppress the enzyme
aromatase resulting in lowered estrogen levels.11
SKIN AGING
A number of factors can speed up the aging of skin and addressing
these factors in advance has the potential to slow skin aging. An
individual’s perceived age, as measured by the appearance of facial
skin, takes into account skin wrinkling, lip height, pigmented spots,
and the nasolabial fold (commonly called “laugh lines”). The higher
the perceived age, the higher the risk of morbidity and mortality.12
Furthermore, a higher perceived age is significantly associated with
physical and cognitive decline and the length of telomeres, the ends
of chromosomes that shorten with age.12
Blood levels of glucose and cortisol can play a role in how old your
facial skin appears. Scientists measured perceived age and skin
wrinkling grade in blood samples from 579 nonfasted patients and
219 patients after fasting.13 The perceived age in participants with
the lowest glucose levels was significantly less compared to subjects
with the highest glucose levels. High fasting cortisol also tended to
be correlated with a greater perceived age.
Glucose is involved in skin aging through its ability to enhance the
production of advanced glycation end-products (AGEs), harmful
compounds linked to diabetes and heart disease that are formed
when sugars interact with amino acids. Elevated glucose causes
premature aging in skin cells14,15 and is believed to inhibit the ability
of skin cells to repair and recover from stress.13
Changes in fat tissue and other facial structures can result from
chronic high cortisol levels, such as occurs in Cushing syndrome.13
Men’s perception of facial attractiveness in young females is
associated with blood cortisol concentrations in the women even in
the absence of wrinkling. The higher the blood cortisol levels of the
women (an indication of being under stress), the less attractive the
men perceived them to be.16
Increased roughness and reduced hydration seen in the skin of aging
people can also be an indicator of declining levels of hyaluronic
acid (HA), an important structural component of skin. Studies show
HA can improve skin condition in the elderly17,18 and that there are
age-related alterations in HA’s ability to assist with wound healing.19
SKIN DISEASES MAY SIGNAL AN IMPORTANT DEFICIENCY
Seborrheic dermatitis is a condition involving red patches on the
skin (erythema) and flaking/scaling in locations where there is high
sebaceous gland activity, including the scalp, face, and trunk. Up to
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5% of individuals in the United States are affected.20 Researchers
investigated the effect of a topical HA sodium salt gel 0.2% in 13
subjects ages 18 to 75 with facial seborrheic dermatitis.20 Visual
grading assessments revealed the HA gel improved the physician
global assessment by 65.5% from baseline to week four and reduced
scaling by 76.9%, erythema by 64.3%, and pruritus (itching) by 50%.
By week eight, the physician global assessment had improved in
92.3% of the participants.
Another study by the same researchers investigated the effect of HA
sodium salt cream 0.2% in 14 patients ages 18 to 75 with the chronic
skin disorder, rosacea.21 Flushing, erythema, enlarged capillaries,
edema, papules, and pustules are common manifestations of rosacea.
In this prospective, observational study, visual grading assessments
revealed the HA cream enhanced the clinician global assessment by
47.5% from baseline to week four. Papules were reduced by 47%,
erythema by 51.7%, burning or stinging by 65%, and dryness by
78.8%. At week eight, compared to baseline, there was an
improvement in 78.5% of participants.
SKIN DISORDERS AND A COMMON GENETIC MUTATION
Certain skin disorders may indicate the presence of a mutation in
methylenetetrahydrofolate reductase (MTHFR), an enzyme required
to convert folate to its active form, L-5-methyltetrahydrofolate
(L-5-MTHF).
Skin cancer is associated with mutations in MTHFR.24,25 There is a
high concentration of L-5-MTHF in the epidermis, indicating this form
of folate may have a role to play in skin health, such as protecting
against ultraviolet-induced damage.26 Patients with psoriasis or
rheumatoid arthritis should also be tested for MTHFR mutations,
as should leukemia patients who experience toxic side effects after
treatment with methotrexate as adverse effects occur more often
in patients with mutations of this enzyme.27,28 In addition, MTHFR
mutations are associated with the development of varicose veins.29
If you test positive for the MTHFR mutation, your doctor may
recommend you supplement with L-5-MTHF, which the body uses
more effectively than folic acid.
OTHER FACTORS TO CONSIDER IN PSORIASIS
Psoriasis is associated with metabolic syndrome (a cluster of risk
factors for diabetes and heart disease), and may be an independent
risk factor for cardiovascular disease. Scientists assessed whether
psoriasis is an independent risk factor for heart attacks, stroke, or
ischemic heart disease in a study using data from the US National
Health and Nutrition Examination Survey (NHANES).30 Of 520
psoriasis cases, 108 (20.8%) had metabolic syndrome. The
participants with psoriasis were significantly more likely to develop
heart attacks and ischemic heart disease, but not strokes, after
adjusting for primary cardiovascular risk factors.
The mechanism behind which psoriasis may contribute to cardiovascular conditions is thought to involve chronic inflammation.31
Psoriasis patients are also more likely to consume greater amounts
of simple carbohydrates, total fat, omega-6 polyunsaturated fatty
acids (PUFAs), and cholesterol, and less protein, complex carbohydrates, monounsaturated fatty acids, omega-3 PUFAs, and fiber.32
This dietary pattern has been linked to cardiovascular disease and
may further explain the association between the two conditions.
Patients with psoriasis should be counseled to alter their diets and
supplement with nutrients and natural agents such as berberine
that protect the heart and help ameliorate the signs and laboratory
abnormalities associated with metabolic syndrome.33
Psoriasis may also predispose affected individuals to allergies. Skin
damage that occurs in psoriasis may result in increased exposure
to allergens. Researchers observed that psoriasis patients have a
more pronounced concentration of total immunoglobulin E (IgE),
antibodies involved in allergic reactions, compared to patients
without psoriasis.34 Furthermore, there are higher levels of IgE
specific to potato and carrot in psoriasis patients.34 Because cross
reactions occur between birch and motherwort pollens and potato
or carrot allergens, this may indicate a predisposition among
psoriasis patients for certain types of seasonal allergies.
Finally, some studies have observed a deficiency of vitamin D in
persons with psoriasis compared to healthy controls.35,36 One study
found that 57.8% of psoriasis subjects were vitamin D deficient (less
than 20 ng/mL) compared to only 29.7% of healthy controls.36 In
winter, the difference was even more pronounced with 80.9% of
psoriasis patients suffering from vitamin D deficiency compared to
30.3% of healthy controls.
CAN FINGERNAILS PREDICT DISEASE?
Fingernails can serve as a clinical reflection of various systemic diseases. Yellow nail syndrome is characterized by slow-growing nails
that have a thickened and yellowish appearance and become more
convex on the sides of the nail plates. The lunula—the white half
moon on your nails—also disappears. This syndrome is associated
with chronic bronchiectasis (destruction of lung architecture with
irreversible widening of airways, especially the smaller airways, due
to chronic lung inflammation) or sinusitis and excess fluid build up
around the lung (pleural effusions).37 Thiol drugs used in rheumatoid
arthritis patients can also cause yellow nail syndrome.38
Yellowing of nails may occur as a result of protein leakage from
enhanced microvascular permeability (“leaky” blood vessels).39
This is supported by the fact that diseases related to microvascular
permeability such as hypoalbuminemia, pleural effusion, and
lymphedema are associated with yellow nail syndrome.39
Nail “clubbing” is characterized by thickened soft tissue underneath
the nail plate at the lower edge of the nail near the lunula. Clubbing
can be detected by looking for the “Schamroth sign,” the elimination
of the diamond-shaped space that is normally formed when the
fingernails of the left and right hands are pressed up against each
other.40
Clubbing may be a sign of tumors in the lungs and pleura, the
membrane enclosing the lungs.40 It is also associated with lung
diseases such as bronchiectasis, lung abscess, empyema, pulmonary
fibrosis, and cystic fibrosis.40 Other conditions associated with
clubbing include arteriovenous malformations, fistulas, celiac
disease, cirrhosis, inflammatory bowel disease, congenital heart
disease, and endocarditis.40
Onycholysis is another nail disorder that can provide clues to
systemic health. Onycholysis is characterized by a separation of
the nail plate from the nail bed. The affected area turns white.
Common causes of onycholysis include periungual warts and
localized trauma.40
Psoriasis can occur together with onycholysis, usually when
onycholysis affects the outermost portion of the nail.40 In cases
where there is no obvious cause of onycholysis, hyperthyroidism
should be ruled out as this condition is common in hyperthyroid
patients and is known as “Plummer’s nails.”49 Brown discoloration
of the nail plate is also a sign of hyperthyroidism.40
Continued on page 5
4
Continued from page 4
A classic sign of endocarditis is thin red or brown lines known as
splinter hemorrhages under the nail plate.41 Splinter hemorrhages
result from the leakage of capillaries and are more likely to be
caused by endocarditis when they appear on the section of nail
plate close to the lunula rather than on the outermost portion of
the nail.41
Splinter hemorrhages should not be considered a definitive or
specific marker of endocarditis because they are observed in only
about 15% of patients with the disorder.41 Researchers noted splinter
hemorrhages in 22 of 40 healthy females without endocarditis
and in 14 of 24 healthy males.42 Endocarditis as a cause of splinter
hemorrhages is more likely when they exist together with fever,
retinal hemorrhages known as Roth’s spots, red sores on the hands
and feet known as Osler’s nodes, painless lesions called Janeway’s
lesions on the palms of the hands or soles of the feet, or a heart
murmur.40 Other causes of splinter hemorrhages include localized
trauma, fungal infections, and psoriasis.40
A white discoloration of the nail plate that causes the lunula to
disappear is associated with cirrhosis. Known as Terry’s nails, this
condition appeared in 82% of cirrhotic patients in one study.43
However, in another study, 25% of patients hospitalized for a
number of diseases including cirrhosis, chronic congestive heart
failure, and type 2 diabetes mellitus had Terry’s nails.44 In this
study, older patients were more likely to have the condition, while
younger patients with Terry’s nails experienced an elevated risk of
systemic disease.
OUTER CLUES OF INNER PROBLEMS
The hair, skin, and nails can serve as tools to detect systemic disease
and factors predisposing to poor health. Abnormalities in these
external features can also be a sign of nutrient deficiencies. Alopecia,
psoriasis, skin cancer, and rosacea are all associated with specific
comorbidities and/or nutrient deficiencies. Furthermore, certain
skin disorders may be an indication that you should be tested for
MTHFR mutations.
REFERENCES:
1. MacLean KJ, Tidman MJ. Practitioner. 2013;257:29-32.
2. Kuty-Pachecka M. Psychiatr Pol. 2015;49:955-64.
3. Díaz-Atienza F, Gurpegui M. J Psychosom Res. 2011;71:102-7.
4. Güleç AT, et al. Int J Dermatol. 2004;43:352-6.
5. Abdel Fattah NS, et al. Int J Dermatol. 2016;55:24-9.
6. Abdel Aziz AM, et al. Int J Trichology. 2015;7:100-6.
7. Rasheed H, et al. Skin Pharmacol Physiol. 2013;26:101-7.
8. Su LH, Chen TH. Arch Dermatol. 2007;143:1401-6.
9. Gatherwright J, et al. Plast Reconstr Surg. 2013;131:794e-801e.
10. D’Agostini F, et al. Toxicol Lett. 2000;114:117-23.
11. Trüeb RM. Dermatology. 2003;206:189-91.
12. Christensen K, et al. BMJ. 2009;339:b5262.
13. van Drielen K, et al. Age (Dordr). 2015;37:9771.
14. Blazer S, et al. Biochem Biophys Res Commun. 2002;296:93-101.
15. Paul RG, Bailey AJ. Int J Biochem Cell Biol. 1996;28:1297-1310.
16. Rantala MJ, et al. Biol Lett. 2013;9:20130255.
17. Gubanova EI, et al. J Drugs Dermatol. 2015;14:288-98.
18. Lee do H, et al. J Cosmet Laser Ther. 2015;17:20-3.
19. Simpson RM, et al. Am J Pathol. 2009;175:1915-28.
20. Schlesinger T, Powell CR. J Clin Aesthet Dermatol. 2014;7:15-8.
21. Schlesinger TE, Powell CR. J Drugs Dermatol. 2013;12:664-7.
22. Sharp L, Little J. Am J Epidemiol. 2004;159:423-43.
23. de Arruda IT, et al. Genet Mol Biol. 2013;36:490-3.
24. Han J, et al. Carcinogenesis. 2007;28:390-7.
25. Lesiak A, et al. Exp Dermatol. 2011;20:800-4.
26. Hasoun LZ, et al. Am J Clin Nutr. 2013;98:42-8.
27. van Ede AE, et al. Arthritis Rheum. 2001;44:2525-30.
28. Ulrich CM, et al. Blood. 2001;98:231-4.
29. Wilmanns C, et al. EBioMedicine. 2015;2:158-64.
30. Lai YC, Yew YW. J Cutan Med Surg. 2015 Aug 27. [Epub ahead of print.]
31. Gottlieb AB, Dann F. Am J Med. 2009;122:1150.e1-9.
32. Barrea L, et al. J Transl Med. 2015;13:303.
33. Pérez-Rubio KG, et al. Metab Syndr Relat Disord. 2013;11:366-9.
34. Weryńska-Kalemba M, et al. Postepy Dermatol Alergol. 2016;33:18-22.
35. Orgaz-Molina J, et al. J Am Acad Dermatol. 2012;67:931-8.
36. Gisondi P, et al. Br J Dermatol. 2012;166:505-10.
37. Maldonado F, et al. Chest. 2008;134:375-81.
38. Taki H, Tobe K. BMJ Case Rep. 2012 Mar 20;2012.
39. D’Alessandro A, et al. Eur Respir J. 2001;17:149-52.
40. Fawcett RS, et al. Am Fam Physician. 2004;69:1417-24.
41. Saccente M, Cobbs CG. Cardiol Clin. 1996;14:351-62.
42. Robertson JC, Braune ML. Br Med J. 1974;4:279-81.
43. Terry R. Lancet. 1954;266:757-9.
44. Holzberg M, Walker HK. Lancet. 1984;1:896-9.
Natural Support for One of Men’s Most Distressing
Problems
By David Wolfson, ND
Almost 20 years into the age of Viagra®, most men still feel reticent
discussing the topic of erectile dysfunction (ED). Erectile problems
can be a source of embarrassment, anxiety, shame or, worse, feelings
of depression and despair. It is nonetheless important for men to
consult with a healthcare professional if they are experiencing
erectile difficulties, as ED can adversely impact quality of life and
may be an indicator of serious underlying health issues.
Symptoms of ED are much more common in older men than in
younger men, the prevalence rising from 6.5% in men 20 to 39
years of age to 77.5% in men 75 and older.2 ED affects tens of
millions of men in the US and over 150 million men worldwide.3
Yet despite two decades of aggressive advertising on the part of ED
drug manufacturers, the stigma of ED persists and most cases of
ED remain undiagnosed and untreated.4-6
ED (formerly called “impotence”) is defined as a consistent or
recurrent inability to achieve an erection satisfactory for sexual
intercourse.1 The diagnosis is typically made on the basis of
self-reported symptoms for a minimum duration of three months,
except in cases where ED is caused by trauma or surgery.
WHAT CAUSES ED?
The origin of ED can be complex, often involving both physical and
psychological factors. A normal erection occurs as a result of sexual
stimuli triggering vascular smooth muscle relaxation in the corpora
cavernosa of the penis causing an influx of arterial blood. The
resulting increase of pressure within erectile tissue blocks the return
of venous blood,
Continued on page 6
5
Continued from page 5
leading to a sustained erection. A number of factors can interfere
with these processes, especially in older men.
VASCULAR FACTORS
Vascular pathology is the principal cause of ED. As men age,
changes in penile blood vessels begin to compromise the flow of
blood to the penis.7 Just as atherosclerosis affects the blood vessels
of the heart, it can cause plaque formation in the vascular bed of
the penis that impedes blood flow to erectile tissues.6
Aging can also disrupt the activity and expression of an enzyme
called endothelial nitric oxide synthase. This enzyme facilitates
production of nitric oxide, a molecule needed for proper dilation
of penile blood vessels.8 Common disorders of aging such as
diabetes and elevated levels of cholesterol and triglycerides further
compromise blood vessel function and increase the risk for ED.9,10
In addition to reduced arterial inflow of blood, excess venous
outflow may also contribute to ED. Penile tissues in aging men are
subject to alterations. In particular, smooth muscle content of the
corpora cavernosa tends to diminish while deposition of collagen
fibers in corporal tissues increases.8 These changes result in a loss
of elasticity and compliance that can reduce pressure on small veins
in the penis and compromise the mechanism required to maintain
an erection.11
In some cases, vascular damage from trauma to the perineal area
between the anus and the scrotum can cause ED in younger men.
One study found that intensive bicycle riding (three or more hours/
week) increased the risk of developing ED by 72%.12 Seat design
plays a major role in this phenomenon as bicycle seats with
protruding noses have been shown to dramatically reduce blood
flow within cavernosal arteries compared to noseless seats.13
NEUROLOGICAL FACTORS
Penile erection is a neurovascular phenomenon in which erectile
impulses are transmitted from the brain and spinal cord to blood
vessels in the penis.14 Dopamine appears to be the primary
neurotransmitter (signaling chemical in the brain) responsible for
mediating both sexual arousal and proerectile impulses.15
Because of the central role the nervous system plays in regulating
sexual function, neurological abnormalities can adversely impact
erectile function. Men with Parkinson’s disease, for example, have
an increased risk of developing ED, likely due to the degradation of
dopamine-related neural pathways characteristic of this disease.16
Epilepsy, multiple sclerosis, stroke, spinal cord injury, and perineal
nerve damage due to trauma or surgery are other neurological
conditions that can give rise to ED.6,17
HORMONAL FACTORS
Hormonal imbalances are not a common cause of ED. Despite the
importance of testosterone in overall male sexual function, its role
in facilitating and maintaining an erection appears to be limited in
most men.18 Studies show that administering a standard replacement
dose of testosterone to men who have underfunctioning testes
with low to low-normal testosterone levels significantly improves
multiple aspects of sexual function, including erectile capacity.
However, administering the same testosterone dose to men who
have normal testicular function and testosterone levels typically has
no effect on erectile function.19
Evidence suggests testosterone administration may generally
enhance sexual activity by increasing sexual thoughts and/or the
intensity of sexual feelings, even in the absence of a direct erectile
effect.19 -21 Studies also indicate testosterone supplementation
may be beneficial in particular subsets of men who have normal
testicular function along with ED – for example, those with chronic
obstructive pulmonary disease (COPD).22 Doctors should obtain
a thorough medical history and evaluate androgen levels in men
presenting with ED to determine if testosterone supplementation
may be appropriate.
MEDICATIONS
Many medications can cause or worsen ED, the most common
being thiazide diuretics, beta-blockers, and antidepressants.23
Other drug classes that could potentially contribute to ED include
antiepileptics, antihistamines (including histamine blockers used
for stomach acid reduction), centrally acting antihypertensives,
nonsteroidal anti-inflammatories, anti-Parkinson’s medications,
antipsychotics, benzodiazepines, and certain chemotherapeutic
agents.16,17 If you have ED and are taking medications, ask your
doctor if adjusting the dose or switching to a different medication
would be appropriate. Also note that recreational drugs such as
alcohol, amphetamines, barbiturates, marijuana, nicotine, and
opioids have also been linked to ED.16,24
PSYCHOLOGICAL FACTORS
Although the majority of ED cases are thought to be physical in
origin,25 psychological disorders can still play a significant
contributory role. Depression, anxiety, stress, relationship
dissatisfaction, and dementia have all been linked with ED.6,25 In
addition, cognitive-emotional models have been developed that
predict an increased occurrence of ED in men who harbor a
negative emotional outlook.26
Some studies also show emotional trauma can markedly predispose
to sexual dysfunction. For example, researchers found that male
victims of adult-child sexual contact are three times as likely to
experience ED later in life.27 The potentially complex nature of ED
associated with psychological factors may require counseling by a
licensed mental health professional.
COEXISTING DISEASES
ED has been linked with a number of coexisting diseases including
cardiovascular disease (CVD), diabetes, obesity, and lower urinary
tract symptoms (usually associated with an enlarged prostate). ED
is a fairly strong predictor of cardiovascular events28,29 and shares
a number of underlying features with CVD such as endothelial
dysfunction (abnormalities of the blood vessel lining) and atherosclerotic processes.30 In one study, ED was present in almost half of
300 men presenting with chest pain and coronary artery disease.31
The shared features of ED and CVD have led some researchers to
postulate the two disorders may be different manifestations of the
same underlying disease process.32
ED has also been strongly linked with diabetes. While prevalence
statistics vary, men with type 1 or 2 diabetes reportedly have up to
three times the risk of developing ED than do nondiabetic men.33-35
Conversely, ED may present as an early symptom of diabetes. One
study found that in a sample of 499 men with new or recently
diagnosed type 2 diabetes, 66.8% reported some degree of ED.36
A connection between ED and obesity has also been established.37,38
Excessive fat, especially around the abdominal organs, is associated
with both impaired endothelial function and reduced testosterone
levels, providing two possible mechanisms by which obesity might
contribute to ED.39
Finally, robust epidemiological evidence indicates a positive
correlation between ED and lower urinary tract symptoms.
Continued on page 7
6
Continued from page 6
Population-based studies across Europe, Asia, and the US all
indicate ED is more common in men with lower urinary tract
symptoms.40-42 Moreover, the Multinational Survey of the Aging
Male found the frequency of ED increases in direct, linear relation
to the severity of lower urinary tract symptoms across all age
categories and regardless of other coexisting diseases.42
CONVENTIONAL ED TREATMENT
With the advent of Viagra® in the late 1990s, phosphodiesterase-5
inhibitors (PDE-5i) became the mainstay of treatment for ED.
Inhibition of the enzyme PDE-5 enhances blood vessel dilation,
increases blood flow, and ultimately augments erectile capacity.1
Viagra® and other PDE-5i drugs have advanced ED treatment by
making it more effective, accessible, and relatively safe.
However, not all men respond to PDE-5i therapy. In diabetics, for
example, impaired production of nitric oxide, upstream from PDE-5
activity, may be the primary cause of ED, thus rendering PDE-5i
medications less effective.43 PDE-5i may also be of limited benefit
to men with ED of neurological or hormonal origin.44 Moreover,
PDE-5i drugs are contraindicated in persons taking nitrates for
angina as the combination may produce a dangerous lowering
of blood pressure. If PDE-5i therapy fails, doctors may try more
invasive interventions including injection of blood vessel dilating
agents and implantation of penile prostheses.17
NATURAL APPROACHES TO ED
Despite the popularity of PDE-5i medications, 30% to 40% of men
either do not respond to therapy or are dissatisfied with the results
of treatment.45 Side effects including headache, flushing, visual
disturbances, and myalgia (muscle pain) can also occur with PDE-5i
use.44 For these reasons, healthcare practitioners may wish to
consider nonpharmaceutical approaches to ED before resorting to
PDE-5i treatment.
In cases of ED with a suspected psychological origin, referral to a
licensed therapist for counseling may be an appropriate treatment
option.46,47 In individuals with known coexisting diseases for ED,
lifestyle modifications can benefit sexual function. Improving
glycemic control in men with diabetes, for example, significantly
reduces the risk of developing ED.48,49 A study in male smokers
found smoking cessation significantly ameliorates ED symptoms.50
And weight loss in obese individuals has been shown to markedly
improve scores on the International Index of Erectile Function.51
A variety of scientifically researched nutraceuticals are also
available for men with ED. Practitioners may choose one or more
depending on the suspected origin of the ED.
ED OF VASCULAR ORIGIN
As vascular pathology is likely to be involved in most cases of ED,
dietary supplements that influence nitric oxide production, improve
endothelial function, and/or enhance blood vessel relaxation hold
particular promise for treating ED symptoms. The amino acid
L-arginine is the primary source of nitric oxide in the body. In the
blood vessel lining, endothelial nitric oxide synthase catalyzes the
conversion of L-arginine to nitric oxide and L-citrulline.52 Clinical
trials indicate L-arginine at high doses (5 g/day) can improve
subjective symptoms of ED, especially in persons with low baseline
levels of nitric oxide,53 but may not be effective at lower doses
(1.5 g/day).54
The efficacy of L-arginine appears to be augmented when
administered in conjunction with pine bark extract, a polyphenolrich compound that also stimulates nitric oxide production.55 Two
double-blind, placebo-controlled clinical trials have found the
combination of L-arginine aspartate (2.8 to 3 g/day) and pine bark
extract (80 mg/day) significantly improves sexual function in men
with mild to moderate ED.56,57
Clinical studies also show L-citrulline supplementation boosts blood
L-arginine levels, stimulates nitric oxide activity, and significantly
reduces ED symptoms.58,59 Administration of L-citrulline is thought
to be preferable to L-arginine as it escapes the extensive metabolism
L-arginine undergoes in the intestinal tract and liver. In a single-blind,
placebo-controlled trial, administration of 1.5 g/day of L-citrulline
for 30 days significantly improved erection hardness scores and
mean number of intercourses per month in a group of men with
mild ED.59
Dietary nitrates can also bolster nitric oxide production and are
notable for their capacity to reduce blood pressure, most likely
through a dilating effect on blood vessels.60,61 Nitrates consumed
in the diet are converted to biologically active nitric oxide.62 Many
green leafy vegetables contain nitrates, but beetroot is a particularly
rich source that has been shown to exert a blood vessel relaxing
effect.63,64
Saw palmetto (Serenoa repens) is an herb best known for its use
in treating prostate enlargement and its associated lower urinary
tract symptoms.65 But studies indicate saw palmetto may also have
a beneficial impact on ED. A preclinical trial found administration
of saw palmetto extract to rats increases the relaxation response in
erectile tissue to a degree comparable with Viagra®.66 This effect
is thought to be due to increased nitric oxide activity and/or PDE-5
inhibition.
Clinical trials evaluating the efficacy of saw palmetto in humans
have yielded mixed results. One multicenter study demonstrated
improvements in International Index of Erectile Function (IIEF)
scores over a six-month period,67 while another trial showed only
minimal improvements compared to placebo over a 12-week
period.68 Some evidence suggests saw palmetto may work best for
combating both lower urinary tract and ED symptoms when used in
combination with other botanicals and nutraceuticals like stinging
nettle (Urtica dioica) and the enzyme bromelain.69
Asian ginseng (Panax ginseng) has been shown in several studies to
have a beneficial impact on ED.70-72 Preclinical research indicates
ginsenosides, the active constituents of ginseng, increase nitric oxide
release from endothelial cells and neurons within erectile tissue.73
In two double-blind, placebo-controlled trials, 900 to 1,000 mg
of Asian ginseng three times per day was shown to significantly
improve scores on the IIEF, including evaluations of penetration,
maintenance, and rigidity.71,74
Finally, vitamin D supplementation should be considered in ED
caused by vascular problems. A recent study found serum vitamin
D levels to be significantly lower in men whose ED originates from
abnormalities in the arteries supplying blood to the penis compared
to those whose ED had other origins. In this study, vitamin D levels
also negatively correlated with the severity of ED.75
ED OF OTHER ORIGIN
In men that present with ED of mixed or unclear origin, trying other
natural substances may be warranted. Dehydroepiandrosterone
(DHEA) and dehydroepiandrosterone sulfate (DHEA-S) are the most
abundant circulating steroid hormones.76 Both decline markedly
with age.77 The 1994 Massachusetts Male Aging Study found that
of 17 hormones studied, including testosterone, only DHEA-S
Continued on page 8
7
Continued from page 7
showed a strong inverse correlation with ED (as DHEA-S levels
went down, the incidence of ED went up).78 In one double-blind,
placebo-controlled trial, men with clinically diagnosed ED receiving
50 mg/day of DHEA experienced steady improvements in all five
domains of the IIEF including erectile function, orgasmic function,
sexual desire, intercourse satisfaction, and overall satisfaction over
a 24-week period.79 In spite of this positive clinical data, however,
not all researchers agree DHEA has a beneficial impact on ED.80 A
mechanism of action by which DHEA improves erectile function
has also yet to be clearly elucidated.
Men with a known or suspected androgen deficiency, and for
whom testosterone replacement therapy is undesirable or contraindicated, may benefit from use of the herb tongkat ali (Eurycoma
longifolia). Oral administration of tongkat ali in male rats has been
shown to raise serum testosterone levels and improve some aspects
of sexual dysfunction.81
In men, a blinded, controlled clinical trial found administration
of 300 mg/day of tongkat ali extract for 12 weeks significantly
improved IIEF scores from baseline.82 The clinical relevance of these
findings, however, has been called into question since baseline IIEF
scores were already high, indicating the men had little to no ED at
the beginning of the study.83 Tongkat ali also failed to raise serum
testosterone levels in this study.
ELIMINATING ED
ED is a very common problem that often goes undiagnosed and
untreated. While most cases of ED are caused by vascular problems,
neurological, endocrinological, and/or psychological factors can
also cause or contribute to ED. In some cases, ED may be a side
effect of medication use or a complication of trauma or surgery. The
development of PDE-5i medications like Viagra® ushered in a new
era of convenient and effective treatment for ED, but not all men
with ED respond to this type of therapy and, in some cases, PDE-5i
drugs may be contraindicated or produce side effects. For this reason,
you may wish to consider natural alternatives to drug therapy.
In addition to counseling and lifestyle modifications, a number of
dietary supplements have demonstrated efficacy for ED. The amino
acids L-arginine and L-citrulline, supplemental nitrates from beetroot
or other sources, and Panax ginseng extract are best indicated for
ED of vascular origin. Other natural agents that may be of benefit,
but require more research, include saw palmetto extract, vitamin D,
DHEA, and Eurycoma longifolia.
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8
DID YOU KNOW?
•
•
•
•
Researchers have detected higher concentrations of
the toxic chemical phthalate in the urine of people who
report higher consumption of fast foods.
Average scores for stress and anxiety are higher in
people with asthma compared to the general population,
according to a study of 14- to 17-year-old asthma patients.
Whey protein is a rich source of amino acids that are
able to trigger the production of insulin by beta cells
of the pancreas, leading to a reduction in postprandial
hyperglycemia. Whey protein also inhibits appetite
through influencing the gut-brain axis and the
hypothalamus.
The death of a partner increases the risk of developing
atrial fibrillation, especially 8 to 14 days after the loss. The
risk is greatest in people under 60 and in people whose
partner died unexpectedly.
•
Scutellaria baicalensis (Chinese skullcap) has
antibacterial and antifungal effects.
•
Chemicals found in sunscreen can interfere with sperm
cell function.
•
Receptors for neurotransmitters are found on hair
follicle cells.
•
Supplementation with 600 mg/day of γ-oryzanol for
nine weeks increases muscular strength in young,
healthy men undergoing resistance training.
•
Components of Angelica sinensis (dong quai) suppress
cartilage damage and promote cartilage repair in animal
models of osteoarthritis and in human chondrocytes.
•
In a randomized, double-blind, placebo-controlled
trial of fibromyalgia patients, creatine monohydrate
enhanced intramuscular phosphocreatine content and
lower- and upper-body muscle function.
©Copyright 2016 ProThera®, Inc. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form by any means, including electronic, mechanical, photocopying, or otherwise,
without prior written permission of the copyright owner.
The information in this newsletter is not intended to provide personal medical advice, which should be obtained from a medical professional, and has not been approved by the U.S. FDA.
PROTHERA®, INC.
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protherainc.com
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