By Nelson Vergel
There is so much confusion
about the use of hormones in pre and post menopausal women, especially after
the largest study ever undertaken using two female hormones was halted due to
increased incidence of breast cancer in women.
I will try to attempt to distill issues related not only to female based
hormone therapy (estrogen and progestin) but also to the use of testosterone
replacement therapy in women.
WHAT IS TESTOSTERONE? ISN'T IT A MALE HORMONE?
Testosterone is the hormone
responsible for normal growth and development and maintenance of male sex
characteristics. It also affects lean
body mass, mood and sexual function in both males and females, so it is not only a "male" hormone. It is the
primary androgenic (responsible for masculine characteristics) and anabolic
(muscle building) hormone.
Testosterone is produced by the
testicles in males and by the ovaries in females, with small amounts also
produced by the adrenal glands in both genders. Men produce about 7-8 times more testosterone than women.
Testosterone is also the precursor of estradiol (a "female" hormone) in men and women.
SEXUAL DYSFUNCTION IN WOMEN
As we all know if we watch TV
for more than an hour, we are bombarded daily by ads selling erectile
dysfunction drugs for men. But we hardly
hear anything about sexual dysfunction in women, and there are many reasons why
women’s sexual desire and other hormone related quality of life issues are so
misunderstood, under-diagnosed and under treated.
There is no FDA approved
product for the treatment of sexual dysfunction in women. There is also no FDA approved testosterone replacement product for women in 2012, although some physicians are prescribing it to women in an "off-label" manner (legal but not for the FDA approved "intended use") using low doses of commercial products approved for men (Androgel, Testim, Fortesta, Testopel, Depo Testosterone and Axiron) or via compounded pharmacy gel/cream formulations.
Sexual dysfunction in pre and post-menopausal women has been a very controversial topic that has been poorly researched even though a February, 1999 study
published in the Journal of the American Medical Association, titled, “Sexual
Dysfunction in the United States: Prevalence and Predictors,” found that
approximately 43% of postmenopausal women suffer from some form of female
sexual dysfunction.
It wasn’t until June 2011 that
an FDA advisory committee to the division of Reproductive and Urologic Drug
Products stated that HSDD (Hypoactive Sexual Desire Syndrome) is a significant
medical condition for women. This may open the door for companies to apply for
new drug applications for that indication.
It is important to note that unlike erectile dysfunction drugs approved for men like Viagra that increase blood flow to the genitals as long as a man is aroused, testosterone therapy is systemic and needs to be applied over a period of weeks to have a noticeable effect on sex drive in men and women.
Some companies have tried to
enter the female sexual dysfunction market in the past. In December 2004 the
United States theFDA rejected Procter and Gamble's fast-track request for Intrinsa (a
testosterone patch for women) for HSDD
citing concerns about potential off-label use of the product was to be approved.
In Canada, post-menopausal women have been able to obtain government-approved
testosterone treatment since 2002. In
2007, Intrinsa was granted a license from the European Medicines Agency in
July, and is available on Britain's National Health Service.
According to a P&G's survey on female
health, 30 million women in the U.S. are naturally menopausal, 3 million are
distressed by their lack of sexual desire, and 20% of 25 million women who are
surgically menopausal are distressed.
Other companies that attempted
to get their drugs approved for this indication (Boehringer Ingelheim and
Warner Chilcott) have each pulled the plug on their competing HSDD treatments
for menopausal and pre-menopausal women.
BioSante Pharmaceuticals is
the only company left in the race for a treatment for HSDD. This company is in late stage clinical
studies using LibiGel (testosterone gel) treatment of HSDD but has had issues in the approval of this product by the FDA. More on this product at the end of this
article.
HORMONE THERAPY IN POST MENOUPAUSAL WOMEN
Menopause can cause symptoms
such as hot flashes might result from the changing hormone levels during the
menopause transition. After a woman's last menstrual period, when her ovaries
make much less estrogen and progesterone, some symptoms of menopause might
disappear, but others may continue.
To help relieve these
symptoms, some women use hormones. This is called hormone therapy (HT) which
includes estrogen alone or in combination with progestin. HT is available orally or in gel formulations
made by specialized compounding pharmacies.
Estrogen is a hormone used to
relieve the symptoms of menopause. Estrogen alone (E) may be used by a woman
whose uterus has been removed. But a
woman who still has a uterus must add progesterone or a progestin (synthetic
progesterone) along with the estrogen (E+P). This combination lowers the chance
of an unwanted thickening of the lining of the uterus and reduces the risk of
cancer of the uterus, an uncommon, but possible result of using estrogen alone.
But the use of hormone therapy in women
has been subject of a lot on controversy in recent past.
Researchers from the Harvard School of Public Health analyzed
data from the landmark Women's Health Initiative (WHI) clinical trial of the
effects of combination hormone therapy (estrogen+ progestin) in 16,608 postmenopausal
women with an intact uterus, ages 50 to 79 years (average age of 63) at enrollment.
This study did not include the use of testosterone. In this study, 8,506 participants were randomly assigned to
receive a combination of estrogen (0.625 milligrams of conjugated equine
estrogens per day) plus progestin (2.5 mg of medroxyprogesterone acetate), and
8,102 women were given placebo.
The study was stopped in 2002 after an average
of 5.6 years of treatment due to an increase in breast cancer in the women on
hormone therapy. Compared to women on placebo, women on combination hormone
therapy were also at increased risk of stroke, dangerous blood clots, and heart
disease, while their risk of colorectal cancer and hip fractures was lower.
It is important
to note that these hormones were provided orally and that some clinicians claim
that transdermal (on the skin) application of estrogen alone or in combination with testosterone would show a
different and more favorable side effect profile.
The
halting of the WHI study raised concerns about safety of all hormone therapy in women (oral or transdermal), even if no androgens will included in
this study and only oral delivery forms were used. Many physicians stopped
prescribing hormone therapy (HT) even for women who had dramatic improvements in their quality of
life while using it. Experts today don't
recommend hormone therapy unless a woman suffers difficult menopause symptoms.
Emerging data on the use of androgens (testosterone and DHEA) alone or in combination with HT are showing that there may be potential
benefits of these hormones in women with androgen deficiency and sexual
dysfunction.
Androgens are also precursors
of all estrogens (estrone (E1), estradiol (E2), and estriol (E3)) in women's
bodies. The primary and most well-known androgen is testosterone (which
aromatizes into estradiol), other less important androgens are
dihydrotestosterone (DHEA) and androstenedione. Androgens are directly secreted
by the ovaries and adrenals in women.
Presently, there is no
agreement about whether androgen deficiency is a clinical problem in aging
women and if the addition of androgens to HT can ameliorate the cardiovascular
risks seen in the WHI study.
Causes of androgen
insufficiency in women can have ovarian, adrenal, hypothalamic-pituitary,
drug-related, and unknown origins. Symptoms of androgen insufficiency in women
may include a diminished sense of well-being, low mood, fatigue, and hypoactive
sexual desire disorder (HSDD) with
decreased libido, or decreased sexual receptivity and pleasure that causes a
great deal of personal distress.
There is increasing evidence
to suggest that many postmenopausal women experience symptoms alleviated by androgen
therapy and that such symptoms may be caused by androgen deficiency. Affected
women complain of fatigue, low libido, and diminished well-being, which are
symptoms easily and frequently attributed to psychosocial and environmental
factors.
The question of whether adding
testosterone therapy to conventional postmenopausal HT is
effective or safe is unresolved. Therefore, a Cochrane review was performed to
determine the efficacy and safety of testosterone therapy for postmenopausal women
using HT. Thirty-five trials with a total of 4768 participants were included in
the review. The median study duration was six months (range 1.5 to 24 months).
Most of the trials were of adequate quality with regard to randomization. The
pooled estimate suggested that the addition of testosterone to HT regimens
improved sexual function scores and number of satisfying sexual episodes for
postmenopausal women. Some of the few adverse effects were decreased
high-density lipoprotein (HDL) cholesterol levels and an increased incidence of
hair growth and acne. The discontinuation rate was not significantly greater
with the addition of testosterone therapy.
OTHER USES IN WOMEN
Emerging and controversial
potential indications for androgen therapy in women have been or are being
evaluated. These include use in women with premature ovarian failure,
premenopausal androgen deficiency symptoms, postmenopausal and
glucocorticosteroid-related bone loss, treatment of HIV related wasting, and
management of premenstrual syndrome. Whether or not any of these indications
will actually have approved products in the future is unknown.
HYPOGONADISM IN MEN, BUT WHAT TO CALL IT
IN WOMEN?
The term hypogonadism is used as a diagnosis term for testosterone
deficiency in men. Besides HSDD as one
of the potential symptoms, there is no agreement on what to call androgen
deficiency in women. In clinical guidelines published in 2002
called the Princeton consensus statement (Fertil Steril. 2002
Apr;77(4):660-5) used the term
"female androgen insufficiency"
as defined as by
a pattern of clinical symptoms in the presence of decreased bioavailable
testosterone and normal estrogen status .
The panel warned that currently
available testosterone assays were found to be lacking in sensitivity and
reliability at the lower testosterone blood level ranges present in women, and
the need for an equilibrium dialysis measure was strongly emphasized as the
most adequate method to test women’s testosterone blood levels.
TESTOSTERONE REPLACEMENT IN WOMEN-
POTENTIAL BENEFITS
Circulating testosterone in
women declines during the late reproductive years such that otherwise healthy
women in their 40s have approximately half the testosterone level as women in
their 20s. The levels remain stable across the menopausal transition and then
either remain stable or continue to decline with diminishing adrenal androgen
production with increasing age. In the
decade preceding menopause, there is loss of the mid-cycle surge of free
testosterone. Despite this, research
showing the benefits of androgen replacement has been limited to the
postmenopausal years.
Some small studies have been
done in premenopausal women, however. One evaluated the efficacy of transdermal
testosterone therapy on mood, well-being, and sexual function in eugonadal
(normal testosterone blood levels), premenopausal women presenting with low
libido. Testosterone therapy improved well-being, mood, and sexual function in
these women. Since a substantial number of women experience diminished sexual
interest and well-being during their late reproductive years, further research
is warranted to evaluate the benefits and safety of longer-term intervention.
Potential side effects that are dose dependent may be unwanted hair growth,
masculinization, and lowering of high density lipoprotein (HDL).
TESTOSTERONE IN HIV+ WOMEN:
Dr Bhasin and his team (JCEM
83 (4): 1312) has found that the higher the HIV viral load, the lower the blood levels of testosterone in HIV+
women. In general, HIV+ women had lower testosterone than HIV- women. Low
testosterone was not correlated to unintentional weight loss in Bhasin's data.
In healthy women, the ovaries
and the adrenal glands contribute equally to the maintenance of circulating
testosterone levels. Bhasin presumes that there may be some HIV effect on the
ovaries that may be one of the root causes of testosterone deficiency in women
with HIV.
In HIV+ women with
unintentional weight loss, a placebo controlled study using testosterone a
testosterone patch did not improve lean mass and strength, although Bhasin
mentions that the study was not powered to determine if women with low serum
free testosterone at baseline had different gains that those who had normal
testosterone (the study allowed any baseline testosterone blood level as long
as there had been a weight loss of 5% or more at baseline).
A study done by Dr Grinspoon’s team (Arch Intern Med.
2004 Apr 26;164(8):897-904.) showed that low dose testosterone supplementation
in HIV+ women with unintentional weight loss increased lean body mass and
strength. The study did not specify how many of these women had low
testosterone at baseline, however.
Presented in CROI-2009 (Abstract 976), a 18 month
randomized placebo-controlled study performed by Dr. Labby and colleagues from
Harvard Medical School investigated the effects of transdermal (patch) testosterone
replacement (300 mcg twice weekly vs. placebo) on body composition, bone
density, metabolic parameters, quality of life, and safety among relatively
androgen deficient women with HIV.
Significantly benefits were seen with the
use of testosterone replacement in body
composition, quality of life and bone density in HIV positive women who had
baseline free testosterone levels below 3 picograms per milliliter (pg/mL) (the
normal range is between 1.1 and 6.3 pg/m). Testosterone use was well tolerated
without virilizing effects and did not affect lipids, liver function, or HIV
viral load.
Most HIV+ women that I talk to have never had their
testosterone blood levels checked. Unfortunately, most HIV clinical practices in the United States
have not recognized androgen deficiency diagnosis and treatment even in well
insured women with symptoms of low sex drive, fatigue, loss of lean body mass,
and menstrual irregularities.
TESTOSTERONE IN HIV+ WOMEN WITH LIPODYSTROPHY
Dr Grispoon and his team have
surprisingly found that free serum testosterone was three times higher in women
with lipodystrophy compared to those without lipodystrophy and healthy controls
(J Clin Endocrinol Metab. 2000 Oct;85(10):3544-50). In the past 15 years
lecturing on metabolic disorders in HIV around the country, I have met dozens of
HIV+ women that have been on antiretrovirals for years who have some
signs of masculinization (facial hair growth and wider jaw line). Some had been diagnosed with Polycystic Ovary
Syndrome (PCOS) but others had never been examined for this diagnosis.
Women with Polycystic Ovary
Syndrome (PCOS) have higher levels of testosterone and insulin in general. The main symptoms of PCOS are menstrual
irregularities, hirsutism, acne, infertility metabolic syndrome, and
others. Metformin, an insulin
sensitizer, and finasteride, a dehydrotestosterone (DHT) inhibitor, have been
shown to normalize testosterone in women with PCOS.
Dr Grispoon and his team found
that HIV+ women with severe lipodystrophy had no higher incidence of PCOS, but
some other reports contradict this finding (JCEM 90 (10): 5596).
So, is higher testosterone in
HIV+ women with lipodystrophy caused by HIV, inflammatory factors, or
multifactorial? I do not think we will
ever find out, but I think it is prudent to measure total and free testosterone
in HIV+ women with lipodystrophy that may be experiencing menstrual problems
and/or excessive hair growth.
TESTOSTERONE REPLACEMENT AND CARDIOVASCULAR RISKS IN
WOMEN
A direct association between
testosterone and heart disease has never been established, but for many years,
doctors have suspected that a link exists. The reasoning goes like this: men
have much more testosterone than women, and they develop heart disease about 10
years before their female counterparts.
Women with systolic heart
failure who took low-dose testosterone for six months, on top of standard
medical therapy, showed significant gains in exercise and ventilatory capacity
and large-muscle strength along with heightened insulin sensitivity, in a small
placebo-controlled trial ( J Am Coll Cardiol 2010; 56:1310-1316).
Despite the entrenched belief
that higher blood levels of testosterone increase the risk of CVD in women,
data from recent observational studies mostly show an inverse relationship
between testosterone and CVD risk. A pilot study (JCEM 86 (1): 158) suggested favorable effects
of transdermal testosterone treatment of women with established congestive
cardiac failure which merits further evaluation. Preliminary data indicate
that injectable testosterone therapy improves both endothelial-dependent
(flow-mediated) and endothelium-independent (GTN-mediated) brachial artery
vasodilation in postmenopausal women using long-term estrogen therapy. The
mechanisms underlying these potentially beneficial cardiovascular effects
require further investigation.
TESTOSTERONE REPLACEMENT AND CANCER IN WOMEN
The relationship between
endogenous testosterone production and breast cancer risk remains contentious,
with recent studies indicating either no relationship, or a possible increase
in risk when estrone and estradiol are not taken into account. No randomized
controlled trial of testosterone therapy has been sufficiently large or of
sufficient duration to establish whether such treatment may influence breast
cancer occurrence. There does not appear to be an association between
testosterone and endometrial cancer, or other malignancies on review of
published studies.
There is now convincing
evidence that usual estrogen based hormone therapy for ovarian failure
increases the risk for breast cancer. However, some studies have previously
shown that ovarian androgens normally protect mammary epithelial cells from
excessive estrogenic stimulation, and therefore a study hypothesized that the
addition of testosterone to usual hormone therapy might protect women from
breast cancer (Menopause: Sept/Oct 2004 - Volume 11 - Issue 5 - pp 531-535).
This was a retrospective, observational study that followed 508 postmenopausal
women receiving testosterone in addition to usual hormone therapy in South
Australia. Breast cancer status was ascertained by mammography at the
initiation of testosterone treatment and biannually thereafter. The average age
at the start of follow-up was 56.4 years, and the mean duration 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 population rates.
There were seven cases of invasive
breast cancer in this population of testosterone users, for an incidence of 238
per 100,000 woman-years. The rate for estrogen/progestin and testosterone users
was 293 per 100,000 woman-years-substantially less than women receiving
estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000
woman-years) or in the Million Women Study (521 per 100,000 woman-years). The
breast cancer rate in testosterone users
in this study was closest to that reported for users who never used hormone therapy in the latter study (283 per 100,000
woman-years), and their age-standardized rate was the same as for the general
population in South Australia.
These observations suggest
that the addition of testosterone to conventional 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 population. But more studies are needed.
CURRENT USE IN THE UNITED STATES
As previously mentioned, there is not a FDA
approved testosterone product for women. The few physicians that are prescribing it
are doing so by having their female patients use low doses of products approved
for male hypogonadism (Androgel ,Testim,
Axiron, Testopel and Fortesta) in an off label manner, or prescribing gels with
small testosterone concentrations via compounding pharmacies.
LIBIGEL, THE FIRST GEL THAT COULD HAVE
BEEN APPROVED IN THE UNITED STATES FOR WOMEN
On January 24, 2008, the US
FDA notified BioSante that it had completed and reached agreement with BioSante
on a Special Protocol Assessment (SPA) for BioSante's Phase III safety and
efficacy clinical trials of LibiGel in the treatment of hypoactive sexual desire syndrome (HSDD).
Both Phase III safety and
efficacy trials were finished and were double-blind, placebo-controlled trials
that have enrolled approximately 500 surgically menopausal women each for
six-months of treatment.
Unfortunately, BioSante Pharmaceuticals reported
in December of 2011 that LibiGel did not meet the co-primary or secondary
endpoints in two pivotal Phase III efficacy trials in the treatment of
hypoactive sexual desire disorder in postmenopausal women, so the FDA did not approve it.
The co-primary endpoints of
both LibiGel efficacy trials were the change in the total number of days with a
satisfying sexual event from baseline, and the change in mean sexual desire
from baseline. The secondary endpoint for both trials was the change in sexual
distress from baseline.
Women in the first trial,
called BLOOM-1, who were treated with LibiGel showed an increase of 1.47 days
with a satisfying sexual event compared to baseline, while those receiving
placebo gel showed an increase of 1.26 days with a satisfying sexual event
compared to baseline.
Women in BLOOM-2 who were
treated with LibiGel showed an increase of 1.0 day with a satisfying sexual
event compared to baseline, while those receiving placebo gel showed an
increase of 1.28 days with a satisfying sexual event compared to baseline.
Although there were no
statistical differences in the endpoints, BioSante said all results were in the
appropriate directions. The LibiGel groups in both trials showed an increase in
free testosterone levels compared to baseline and placebo.
BioSante continues to conduct the
Phase III LibiGel safety study, a cardiovascular events and breast cancer study
that has completed enrollment of 3,656 women and has accrued over 5,100 women-years
of exposure, to date. The study is designed for a total of five years; however,
BioSante could use the safety study data as part of a New Drug Application (NDA) submission after the last subject enrolled has
completed 12 months of exposure to LibiGel or placebo.
CONCLUSION
In conclusion, testosterone
replacement in androgen deficient women with or without HIV may have a good
risk-to-benefit ratio for some patients, but conflicting data, lack of long
term studies and lack of a FDA approved product for that indication may be
barriers to making it part of standard of care of aging women. The approval of a testosterone product
specifically for women in the future may change that.
More studies need to be
performed with validated and meaningful endpoints. In the meanwhile, many women
are not waiting for long term studies and instead are getting off-label
prescriptions of compounded testosterone from physicians who specialize in
female hormone balance.
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Nelson Vergel is the author of "Testosterone: A Man's Guide" and co-author of the book "Built to Survive", the founder of the Body Positive Wellness Clinic in Houston, and an expert speaker on exercise, nutrition, testosterone replacement, metabolism , sexual function, body changes, lean body mass gain and fat loss. Aided by his chemical engineering degree and obsession for scientific data, he adds his own personal experience as he demystifies all testosterone and health myths. He has been involved in several clinical studies of supplements, hormones and exercise through his association with the National Institute of Health and private investigators. Via over 500 lectures, he has provided patient-friendly information accessible to all, independently of their knowledge base.For the last 20 years, his trial-and-error experience to improve his quality of life has paved the way for others to learn from his knowledge.
Book Web site: TestosteroneWisdom.com and Blog: testosteronewisdom.blogspot.com
Facebook page: Testosterone Replacement Discussion
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