Author : Richard J. Santen Endocrinologist University of Virginia, Charlottesville, VA
2008-10-22
2008-10-22
Libido Problems in Women : Use of Male Hormones
* Underlined words are defined in the glossary
Introduction
Many women are distressed when they experience a decrease in interest in sexual activity (libido)*
and often bring this up with their health care providers (1;2).
Previous estimates suggest that 8 to 50% of women report a decrease in
libido (3). The prevalence increases with age and after surgical removal
of the ovaries. Women frequently ask if any specific, effective, and
safe treatments to improve libido are available. Until recently,
information regarding this issue was not readily accessible to women or
to their health care providers. However, physicians specially trained in
the management of menopause have recently begun to study this
problem, evaluate it critically, summarize all available information,
and offer potential solutions. One of the solutions suggested is the
administration of male hormones. A key to critically examining this issue involves careful clinical studies
in women. In order to do this, a generally agreed upon understanding of
the word libido is needed and precise definitions of what are normal or
abnormal levels of libido. For practical use, the term, “Hypoactive sexual desire disorder’
(defined below) (4) has been coined and used to define who is eligible
to enter into clinical trials of male hormone therapy in women.
Recently, several new methods have been developed to administer male
hormones and particularly the natural male hormone called testosterone. However, as yet, only a limited number of these medications have been approved for use in women. These
methods include patches and gels to deliver a small amount of
testosterone to the skin for absorption into the bloodstream. Very large
studies using these methods have added substantially to our
understanding of the effects of male hormone in women.
The
recent interest in the problem of diminished libido in women has led to
much discussion by experts in the field and controversy about the use
of male hormones in women. This treatise will discuss the pros and cons
of male hormone therapy for women. Two guideline statements published by
prestigious scientific societies serve as the basis for the information
provided in this Knol (5;6). Since these two guideline statements differ in some key respects, the opinion of an expert who melded the information from
both guidelines to propose a compromise and a reasoned practical approach will be discussed (7).
Where do male hormones come from in women?
Women normally make both female and male hormones but their levels of
male hormone are about one–tenth those in men. Circulating male hormones
(androgens) are normally produced by the ovaries and the adrenal glands
in women, but they are also made in other tissues of the body. Certain
inactive hormones made by the ovaries and adrenals can be changed into
(converted to) male hormones in fat, liver, and muscle. For example, compounds such as androstenedione, DHEA, and DHEA- S can be changed into testosterone in these tissues and then go back into the blood for delivery to all parts of the body. About
one-third of the male hormone circulating in the blood of women comes
directly from the ovaries and two-thirds comes from the conversion of
precursors made by the ovary and adrenal gland which are converted into
(changed into) testosterone in other tissues (8).
Because
the ovaries account either directly or indirectly for approximately 50%
of the testosterone in blood, removal of the ovaries surgically in
pre-menopausal women significantly lowers levels of male hormones (9).
For this reason, experts recommending use of male hormones in women
suggest that young women whose ovaries have been removed surgically are
the best candidates for male hormone therapy.
Spontaneous
menopause in and of itself is not associated with a significant change
in the levels of male hormone in the blood. While postmenopausal women
have lower levels of male hormones than pre-menopausal, the decrease is
very gradual and likely results from declining ovarian and adrenal
function with aging. Not everyone is in agreement about this, but it
would appear that the postmenopausal ovary appears to produce male
hormone to some extent throughout the woman's life.
What circulates in blood with respect to male hormone?
The major male hormone circulating in the blood
is testosterone. However, much of this hormone is tightly bound to
proteins in the blood such as sex hormone binding globulin
(SHBG)(10;11). Only the unbound amount of testosterone is free to enter
tissues. Many things can alter the levels of SHBG, including oral
estrogen therapy, obesity, and underactive thyroid function. While this
results in low total male hormone levels, the amount of “free hormone”
available to go into tissues may be normal. For this reason, many
experts recommend that the “free amount” of testosterone be measured in
the blood if one wants to measure male hormone. There is no general
agreement regarding the best way to measure “free hormone” and several
methods exist. However, experts agree that measurement in
the saliva, as has been suggested by some, is not accurate because these
assays have not been well standardized.
What does the term “hypoactive sexual desire” actually mean?
The technical name for decreased libido used in most clinical trial studies is “Hypoactive sexual desire disorder.” The American Psychiatric Association (12) has defined this in its diagnostic and statistical manual (“bible” of diagnoses) as follows: “persistently recurrent, deficient or absent sexual fantasies and desire for sexual activity.” The manual qualifies this by saying that “the judgment of deficiency or absence is made by the health care provider, taking into account factors that affect sexual function, such as age, and context of the person’s life. The disturbance causes marked distress or difficulty with interpersonal relationships.” The “bible” notes “lack of desire and sexual thoughts at the onset of sexual engagement are common for women who are otherwise sexually content.” Furthermore, it comments that “the frequency of sexual fantasies has little correlation with sexual satisfaction.”What causes “hypoactive sexual desire” in women?
There
are multiple factors which can influence sexual desire (libido) in
women. Physical, psychological, emotional, and relationship factors
(i.e. regarding your relationship with your partner) all have a major
impact on sexual function. A group in Melbourne, Australia, conducted a
comprehensive evaluation of a large number of women in order to
determine the key factors determining sexual desire (The Melbourne
Women's Midlife Health Project) (13). They found that the
most important factors affecting a middle-aged woman's sexual interest,
arousal, and enjoyment were her prior level of sexual function, the
quality of her ongoing relationship and feelings toward her partner, and
the level of her female hormone (i.e., estrogen) levels. Declining
estradiol levels at menopause result in vaginal dryness and thinning of
the vagina, pain on intercourse, and frequent vaginal infections as a
result of intercourse. These hormonally related problems diminish
interest in having sexual relations. However, the Melbourne study found
that the impact of these hormonal factors was not as great as the
psychological and relationship factors reviewed above. The authors of
this study comment on how complex are the various combined factors that
go into influencing a woman’s overall level of sexual desire.
The
Guideline of the Endocrine Society notes that “sexual dysfunction can
result from the interplay of many personal, interpersonal, contextual,
and medical factors (14). In any one woman, changes in male hormone
levels may or may not be relevant. Apparent dysfunction frequently
results from adaptation to a non-conducive psychosocial milieu, often
with no defect in a woman’s physical sexual response system. Four
factors have been found to correlate robustly with a woman’s sexual
function/satisfaction: the woman’s mental and emotional health including
her sexual self image, her feelings for her partner both at the time of
sexual interaction and in general; her expectations regarding the
future of the relationship, and her past sexual experiences. Other
factors showing a strong correlation include the woman’s perception of
her general health; her perceived level of stress; her partner’s sexual
function and the duration of the relationship(15).”
What role does a reduced level of testosterone have in causing hypoactive sexual desire?
The
North American Menopause Society and the Endocrine Society both
convened expert panels to review the evidence that levels of male
hormones, measured in the blood, correlate with the level
of interest in sexual relations (libido). After reviewing numerous
studies, both groups could find no evidence of a relationship between
male hormone levels and libido in women who had no underlying disorders
that could cause low levels of testosterone(16;17). The first way they
evaluated this was to correlate the level of male hormone in the blood
of women with various aspects of sexual function such as frequency of
sexual episodes and degree of satisfaction. After a critical examination
of data, they commented that poorly run studies in the past had found
varying results and that this caused confusion among experts. They noted
several problems with earlier studies: (a) inclusion of only a small number of women of a limited age range (b)
lack of careful examination of the effect of specific reproductive
conditions such as having had children or whether or not the women had
gone through menopause (c) lack of precision of the methods to measure male hormones in the blood, and (d) the time in the monthly (menstrual) cycle that the male hormones were measured was not taken into account.
Most
of these problems were corrected in the two most recent and largest
studies which did not find a link between levels of male hormone in the
blood and sexual function in women (18;19). From all of this
information, both expert panels concluded that the relationship between
male hormone levels and sexual function in women is not very clear. As a
practical result, they concluded that it is not possible to tell women
that their decrease in sexual desire is because their male hormone
levels are too low. They cautioned health care providers against
measuring male hormone levels to make a diagnosis of male hormone
deficiency in women.
Do male hormone levels go down with aging?
Very
large studies are needed to know what actually happens to male hormone
levels as women get older. One such study, conducted in Melbourne,
Australia looking at women aged 45 to 55 years, showed that male hormone levels did not change
in the years before and after menopause (20). However, another study
examining women from ages 18 to 75 found that the active levels of male
hormone did decline with age and that this started in the early
reproductive years at about age 12 (21). Generally speaking, it is
thought that male hormone levels gradually decline with aging but that
this is not linked to menopause.
What conditions are known to reduce male hormone levels in women?
A number of factors can be associated with a substantial drop in female hormone levels in women, as shown in Table I taken from North American Menopause Society’s guidelines (22). The
most common involves surgical removal of both ovaries prior to the age
of menopause. Abnormalities of the pituitary or the adrenal glands can
also cause lower male hormone levels. Women taking cortisone or oral
estrogens as menopausal hormone therapy can also have a decreased level
of testosterone. Most commonly, chronic illnesses such as anorexia
nervosa, depression, advanced cancer, and severe burns can be
responsible.
Table I. Conditions that decrease testosterone levels in women
_______________________________________________________________________
· Bilateral oophorectomy. Surgical removal of both ovaries decreases testosterone levels by as much as 50%.
· Age.
Advancing age is associated with reduced levels of testosterone and its
precursors DHEA and androstenedione. This likely is caused by natural
aging of the ovaries and adrenal glands.
· Hypothalamic/pituitary/adrenal insufficiency.
Low testosterone levels are associated with hypopituitarism of any
cause, including Sheehan’s syndrome, and with adrenal disease, including
Addison’s disease.
· Systemic glucocorticoid or oral estrogen therapy.
Decreased testosterone levels are associated with the suppression of
adrenocorticotropic hormone levels with glucocorticoid use and
luteinizing hormone levels with oral estrogen therapy. Oral estrogen
users have significantly lower levels of free testosterone, due to
increased levels of SHBG.
· Hyperthyroidism. Both hyperthyroidism and excessive thyroid medication increase SHBG levels, leading to lower levels of free testosterone.
· Chronic illness.
Low testosterone concentrations are found in women with anorexia
nervosa, clinical depression, advanced cancer, and burn trauma, although
the precipitating mechanism is not known.
______________________________________________________________________
How is it known if male hormones increase libido in women?
Carefully
conducted clinical studies are really the only way to know. For these
studies, women are selected if they meet the criteria of “Hypoactive
sexual desire disorder” and given either a placebo or a form of androgen
(male hormone). Before the treatment period and during the time of
hormone administration, the women are given a detailed and previously
validated questionnaire to fill out as to various aspects of their
sexual feelings and number and quality of sexual encounters. A large enough group of women must be included in order to know that the results are meaningful. All of these studies involve post-menopausal women since hormonal fluctuations are too great in pre-menopausal
women to know if the added male hormone is effective in them. Another
factor is that the post-menopausal women were given estrogen first and
then a male hormone was added to the androgens. Accordingly, we only
have information about the combination of estrogen and male hormone
(testosterone) and not about testosterone alone.
Two
general types of study are conducted in clinical trials. One type is
called observational because women taking the therapy are observed but a
group randomized to a placebo is not part of the study. The second type
is called a randomized, clinical trial (RCT). Here subjects are
randomized to taking either a placebo or a type of male hormone and
neither the healthcare provider nor the patient knows which therapy is
being given. This type of randomized, placebo controlled, blinded trial
is the most accurate way to know if the male hormones work better than
placebo. In this type of study, placebos actually work pretty well since
women receiving a placebo might feel more confident about having a
satisfying sexual event. In fact, placebos result in about a 45%
improvement in libido in the studies examining its effect (23). For this
reason, only placebo controlled trials really allow an understanding of
the effect of male hormones on libido.
What have studies told us about the effectiveness of male hormones to improve libido in post-menopausal women?
Nearly
all studies show that administration of male hormones to women with
reduced libido improves their sexual desire. If you are interested in
all of the evidence available, you can go to Table 3 in the guidelines
published by the North American Menopause Society(24). We can sum
up the available information briefly by commenting on earlier studies
and then on later and more carefully controlled trials. Some studies
used injections of male and female hormones into the muscle (I.M. or
intramuscular injection) in women who had previously had their ovaries
removed surgically(25). During the treatment phases, adding testosterone
significantly increased the intensity of sexual desire, sexual arousal,
and frequency of sexual fantasies compared with estrogen alone or
placebo. The testosterone levels in the blood after these injections were often well above the normal range for women of this age.
Other studies used implants put under the skin to deliver male and
female hormones to women with menopause induced by surgical removal of
the ovaries or natural spontaneous menopause (26). After
six weeks, significant improvements in libido and sexual enjoyment were
noted in the testosterone treated patients and these improvements
persisted throughout a 24-week trial (27). In a two-year trial, the
women given testosterone had significantly greater improvements in
sexual activity, satisfaction, libido and frequency of orgasm, compared
with women receiving placebo (28). Male hormones by pill (methyl-testosterone)
combined with an estrogen were also shown to work (29;30). At eight
weeks, methyl-testosterone recipients had significantly improved sexual
desire and satisfaction. This effect was due to the male hormone since
no improvement in sexual desire occurred if just the female hormone was
taken.
All of these studies showed that giving male hormones worked to increase libido. However,
there was a great deal of concern from experts since the levels of male
hormone in the blood during these studies were higher than the levels
found in normal women. It was suggested that one might need male hormone
levels to be higher than normal to get a good effect on libido. Some
experts suggested that this could be like men taking high doses of male
hormone to increase their athletic prowess and to run faster, hit more
home runs, or lift more weight.
Because
of the concern about very high levels, the next phase of studies was to
develop ways to deliver male hormones in women that would only slightly
increase levels, but still keep them within the range found in normal
women. For this reason, skin patches were developed to
precisely deliver male hormones through the skin into the blood. In this
way, the effects of an increase in male hormone which did not go beyond
normal levels could be studied. Over the past five years,
three very large randomized, placebo controlled, blinded trials have
evaluated the effect of testosterone skin patches in women (31-33).
These studies chose women experiencing impaired sexual function after
surgically induced menopause. This was done because it was known that
male hormone levels drop substantially after surgical removal of the
ovaries.
All
three studies showed an increase in sexual desire, frequency of
satisfying sexual activity, and a decrease in personal distress. The
experts concluded from these later studies that giving small amounts of
male hormone did improve sexual functioning However, the improvement, on
average, was relatively small, with only one additional satisfying
sexual event per month on average. These later studies led
experts to conclude that ”replacement of male hormone” in women whose
ovaries had been removed surgically could help to increase libido but
the effect was relatively small. As discussed below, the ovaries are a
source of male hormones, even after menopause, and their removal lowers
male hormone levels circulating in the blood.
What other beneficial effects could male hormone therapy have in women?
Several
small randomized studies have suggested that adding testosterone to
estrogen has a favorable effect on bone, either by improving the amount
of bone (bone mineral density) or by reducing markers of bone
turnover (34;35). The key issue, however, is whether or not this effect
would decrease bone fractures (i.e., broken bones) and this has not yet
been shown.
What are the potential adverse effects of male hormones?
Commonly
reported adverse effects are acne and excess facial hair. High
testosterone doses causing testosterone levels in the male range could
result in lowering of the voice (which could be permanent), clitoral
enlargement, excess body hair, edema, and liver dysfunction. While increased facial and body
hair could occur with male hormone administration, this has not been
shown in most of the clinical trials, particularly in a 24-month study
of methyl-testosterone (36). There is also an increase in the number of
red blood cells, which rise to levels approaching those found in men.
Psychological changes such as increased anger and aggression also are
potential risks. Adverse changes in blood fat levels such
as good and bad cholesterol, have been observed with testosterone but
primarily with oral formulations. Studies have found that the risk of masculinizing side effects is generally low and dose dependent. With
topical testosterone, hair growth may occur at the skin application
site. In general, adverse effects can be minimized if testosterone
levels are maintained within normal ranges for women.
Some of the other potential risks associated with testosterone therapy in postmenopausal women are not well defined (37;38). Small studies on cardiovascular disease,
cognition, body weight and body composition have shown no harmful
effects (39;40). However, the duration of therapy is not thought to be
sufficient to know much about these factors, and particularly heart
disease. There is no evidence that testosterone increases the risk of breast cancer. There should be caution about this, however, since other studies have correlated a high testosterone level with the later risk of developing breast cancer (41).
When
examining the evidence regarding possible harmful effects of low doses
of male hormone, an expert committee of the Food and Drug Administration
(FDA) in the United States recently concluded that more safety data are
needed before the low dose testosterone patch can be approved for
general use by women.
http://uspolitics.about.com/od/healthcare/a/Intrinsa_d03.htm
What are the contraindications to use of male hormones?
Contraindications
are focused primarily on those associated with postmenopausal estrogen
therapy because most data were collected in women receiving concomitant
estrogen therapy. Nevertheless, testosterone is generally not
recommended for use in women with breast or uterine cancer or with
cardiovascular or liver disease. Adverse effects of testosterone therapy
in postmenopausal women not receiving concomitant estrogen therapy have
not been determined.
What types of medications are available to replace male hormone in women?
No
male hormone product is FDA approved in the United States for treating
symptoms of sexual dysfunction in women. The range of available
preparations and the amount of male hormone delivered are covered in
Table II. Injectable male hormone can be given in the preparation called
testosterone enanthate but this produces male hormone levels much
higher than normal in women. Custom compounded formulations containing
testosterone are also available but as noted below, these have
relatively poor quality control. When taken orally, micronized
testosterone is generally not well absorbed and does not result in
measurable blood levels. In Europe and Canada, a preparation called
testosterone undecanoate is available and can be absorbed in pill form. A
commonly used dosage for women is 40 mg per day but the
optimal dose is not known (42). Chemical changes in testosterone have
been made to allow better oral adsorption. One of these preparations,
called fluoxymesterone, is available only in a tablet that is about four
times larger (i.e., 10 mg) than the dose needed (i.e., 2.5 mg).
Table II. Androgen Preparations Available for Women
Agent
|
Mode of Delivery
|
Dose
|
Government Approval
|
Comments
|
Estrotest
|
Oral
|
Conjugated estrogen 1.25 mg
Methyl-testosterone 2.5 mg daily
|
Approved for menopausal symptoms; not for libido
|
Practical means to administer estrogen/androgen combination
|
Estrotest half-strength
|
Oral
|
Conjugated estrogen 0.625 mg
Methyl-testosterone 1.25 mg daily
|
Approved for menopausal symptoms; not for libido
|
Practical means to administer estrogen/androgen combination
|
Fluoxymestrone
|
Oral
|
2.5 mg daily
|
Approved for breast cancer treatment in women
|
Requires breaking 10 mg tablet into fourths; non-aromatizable; no data on dose response effects for libido
|
Androgen gels
|
Put on skin
|
300 mcg daily
|
Approved for men
|
Impractical; requires administration of ¼ of the gel delivered by androgel pump; must discard ¾ of each dose
|
Androgen patch
|
Put on skin
|
150 mcg daily
|
Not approved
|
Not yet available; clinical trial data extensive
|
Testosterone enanthate
|
I.M.
|
Dose estimated to be 20 mg I.M. every 2 weeks
|
Approved for men
|
Impractical to use such a small dose; formulation developed for men
|
Testosterone undecanoate
|
Oral
|
40 mg daily
|
Approved for men in Canada
|
Optimal dose unknown;40 mg daily commonly used in Canada
|
The
only testosterone containing product with US Food and Drug
Administration approval to treat menopause-related symptoms is an oral
tablet which contains esterified estrogens and methyl testosterone. This
is called Estratest and comes in preparations with 1.25 mg of
esterified estrogens plus 2.5 mg of methyl testosterone and another
which contains 0.625 mg esterified estrogens plus 1.25 mg methyl
testosterone. This product is FDA-approved for the treatment of moderate
to severe vasomotor symptoms unresponsive to estrogen. However, it is
often used off label to treat symptoms of sexual desire disorders in
postmenopausal women.
Testosterone is well-absorbed through the skin and testosterone transdermal patches
and gels have been FDA approved for men in the United States. However,
the amount administered is high by a factor of approximately 4 for
treatment of postmenopausal women and therefore these preparations are
not practical. Despite the lack of clinical trials and quality control
standards, custom-compounded testosterone gels and creams and ointments
are being used for improving women's sexual desire.
At
the present time than, the only practical way of giving testosterone to
women is to use the estrogen /methyl testosterone preparation called
Estratest. Some physicians advise dividing the fluoxymestrone pill into
four quarters with a knife and recommend use of one quarter tablet per
day. This dosage provides a small amount of male hormone but this method
has not been well studied. Another way is to put the androgen gel onto
wax paper and split this into four parts for administration of one
fourth. This provides about the amount of testosterone (300 micrograms
daily) that was studied using the patch (43). Testosterone
undecanoate at 40mg also provides male hormone levels too high for
women (44). It is not practical to administer appropriate doses of
testosterone by injection because this preparation is designed for use
in men. In summary, none of these methods is ideal to produce normal
levels of male hormone in women. For that reason, there are a number of
male hormone products being developed specifically for women including
patches, gels, nasal sprays and vaginal ring. It will take several years
before these become approved in commonly used.
What can be said about compounding pharmacies?
Compounding pharmacies weigh
out male hormone in a powder form and put it into creams for use.
Health care providers can write prescriptions for these products. The
expert guidelines point out many problems with this approach. The North
America Menopause Society’s guideline states, “custom–compounded
formulations containing testosterone are also available through
prescription, but these formulations are not subject to the stringent
quality control standards of government approved products. As a result,
they may have inconsistent quality and dosing. Also, clinical trials
have not evaluated either their safety or efficacy for any indication,
including improvement of sexual function in women”(45). The FDA has also
recently published a document warning against use of compounding
pharmacies to obtain hormones for use in women. http://www.fda.gov/cder/pharmcomp/default.htm. “The FDA
is concerned that the claims for safety, effectiveness, and superiority
that these pharmacy operations are making may mislead patients, as well
as doctors and other health care professionals. Compounded drugs are
not reviewed by the FDA for safety and effectiveness, and FDA encourages
patients to use FDA-approved drugs whenever possible. The FDA sent
warning letters to seven compounding pharmacies stating that the
pharmacy operations violate federal law by making false and misleading
claims about their hormone therapy drugs.” Dr. Janet Woodcock, FDA's
chief medical officer and acting director of the agency's Center for
Drug Evaluation and Research, was quoted in this document as saying “We
want to assure that Americans receive accurate information about the
risks and benefits of drug therapies."
What do the experts agree about?
Both expert guidelines agree that the
level of circulating male hormone levels have not been clearly linked
to disorders of sexual desire in postmenopausal women(46;47). Although
data are limited, consistent evidence suggests that adding testosterone
to estrogen therapy in postmenopausal women with sexual concerns results
in a positive effect on sexual function and sexual desire. They also
agree that insufficient information is available to know about effects
on bone, menopausal symptoms (other than decreased libido), well-being,
body composition, or cognition. There is agreement that hair growth and
acne may occur with testosterone therapy, but the actual risks have not
been well-estimated. The frequency of these symptoms appears to be low
when testosterone levels are maintained within the normal range for
women. Oral testosterone formulations are associated with a reduction in
good cholesterol that is not observed when male hormone is given by
skin patch, implant, or injection. Whether male hormone therapy
increases the risk for breast cancer, cardiovascular disease, or blood
clots in the legs or lungs is not known.
Where do experts not agree?
The North American menopause Society recommends
that “postmenopausal women may be candidates for testosterone therapy
if they present with symptoms of decreased sexual desire associated with
personal distress and have no other identifiable cause for their sexual
concerns.(48)” In contrast, the Endocrine Society recommends
“against the generalized use of testosterone by women because the
indications are inadequate and evidence of safety in the long-term
studies are lacking (49).”
What other recommendations do the expert groups make?
The North American Menopause Society (NAMS) recommends
that male hormone therapy should always be used with concomitant
estrogen therapy (50). Before starting male hormone treatment, a series
of blood tests should be obtained which include measurements of good and
bad cholesterol and liver function. Retesting should be done at three
months, and yearly thereafter. Testosterone therapy should be
administered at the lowest dose for the shortest time that meets
treatment goals.” The NAMS guideline indicates that there are not good
data for conclusions to be drawn regarding the efficacy and safety of
testosterone therapy for a period longer than six months. Monitoring of
therapy should include subjective assessments of sexual response,
desire, and satisfaction, as well as evaluation for potential adverse
effects. If adverse effects are observed, dose reductions are advised.
If the adverse effects do not diminish with lowering the doses, therapy
should be discontinued. Contraindications are focused primarily on those
associated with estrogen therapy. However, testosterone therapy
should not be initiated in postmenopausal women with breast or uterine
cancer or with cardiovascular or liver disease. Counseling regarding
the potential risks and benefits of male hormone use and the
limitations of formulations not government approved should be provided
before initiating therapy.
The Endocrine Society recommends
against making a diagnosis of androgen deficiency in women at
present(51). They base this on the lack of a well-defined clinical
condition clearly related to male hormone deficiency. Further, they
state that “normative data on male hormone levels across a spectrum of
women that can be used to define the disorder” do not exist. This
guideline agrees that there is evidence for short-term efficacy of
testosterone in selected populations such as surgically menopausal
women. The Endocrine Society believes that additional studies and
additional data will be necessary before making a general recommendation
about using male hormones in women.
Emphasis on research:
The Endocrine Society believes that much research is needed. They point
out that we need to know if not giving male hormone therapy to those
with symptoms will have adverse health consequences in women. They
believe that it is necessary to define the clinical and laboratory
factors that distinguish women benefiting from male hormones from those
that do not. They believe that it is critically necessary to determine
the long-term safety of androgen administration on outcomes that are
important to women diagnosed with these conditions. Finally, they
conclude that we need to know more about what male hormones do in women
in various tissues in the body and about the interplay between hormones
and psychological factors. Until these things are better understood,
they do not believe that male hormones for women should be generally
recommended.
How is a woman faced with declining sexual desire and distressed because of this to interpret these conflicting recommendations?
Glenn
D. Braunstein, MD, a noted expert in reproductive endocrinology,
recently tried to put together information from both guidelines in order
to provide a practical approach regarding male hormone therapy. As a
practicing clinician, he attempted to take a middle ground between the
two guidelines and suggested that male hormone therapy has a place in
some women(52). Dr. Braunstein wrote his recommendations in a
prestigious peer-reviewed scholarly journal called the Journal of Clinical Endocrinology and Metabolism.
He recommends that the health care providers carefully evaluate a woman
prior to shared decision making. He indicates to his physician
colleagues that “When faced with a woman who has developed a distressing
decrease in her libido and sexual activity after surgical or natural
menopause or the development of hypopituitarism or adrenal
insufficiency, he usually recommends treatment with testosterone.
However, he advises that it is necessary to exclude other causes of low
libido and sexual dysfunction such as depression, relationship
disorders, medications, and systemic illnesses. The woman
must be informed that testosterone is not approved by the Food and Drug
Administration for this indication and that the therapy should be
adjusted to maintain the serum free testosterone in the upper part of
the normal range but not beyond normal levels. In this way, a
reproductively aged woman can minimize androgenic side effects.” He
believes that the data from well-controlled clinical trials support this
approach as being efficacious and safe, particularly if used for
relatively short periods of time.
Practically speaking, what should a women distressed by symptoms of decreased sexual desire do?
The
first thing to do is to consult a knowledgeable health care provider,
preferably one specializing in the area of menopause. Many gynecologists
now specialize in menopause as do doctors trained in reproductive
endocrinology. The health care provider knows that clinical factors are
generally of much greater importance than measurement of male hormone
levels in blood. Together with your health care provider, you can go
over the issues and make a decision knowing that postmenopausal women
presenting with complaints of decreased sexual desire, arousal, or
response may be appropriate candidates to evaluate for male hormone
therapy. You need to be informed that experts disagree about using male
hormones in women. Prior to starting therapy, it is probably best that
you sign a consent form indicating that you understand that the FDA has
not approved male hormone therapy for decreased libido.
Should I ask my health care provider to measure my male hormone levels?
Experts
conclude that testosterone levels should not be used to diagnose
testosterone insufficiency or to monitor the efficacy of therapy in
postmenopausal women(53;54). Testosterone levels may be helpful as a
safety measure to ensure that the levels are not elevated before or
during male hormone therapy. Surprisingly, neither the normal
physiological range for male hormone levels in women, nor an absolute
threshold for testosterone deficiency in postmenopausal women has been
established. For this reason, measurement of male hormone levels is not
considered to be of much benefit.
How should your physician monitor therapy if you choose to take male hormones?
You
should be monitored for potential harmful effects acting in your system
as these may be signs of taking too much hormone. Determining baseline
levels of lipids such as good and bad cholesterol and liver function
tests may be prudent before starting testosterone therapy, particularly
with oral testosterone. The tests may be performed three months after
starting treatment and at infrequent intervals thereafter. Male
hormone treatment should be reduced or stopped if adverse events occur.
The level of “free” male hormone levels in blood may be used to
determine whether your testosterone levels exceed the appropriate normal
range to help reduce the risk of harmful effects.
What degree of counseling is necessary?
Any
recommendation for male hormone therapy should be accompanied by a full
explanation of the potential benefits and risks of treatment(55). Women
must be informed that none of the commonly used male hormone therapies
are government approved for the treatment of symptoms related to female
sexual function and therefore therapeutic use will be off label. In
addition, they should understand that potential risks are associated
with a therapy for which safety and efficacy data are limited, including
data on long-term administration or use without concomitant estrogen
therapy.
What is new or emerging regarding our understanding of libido in women?
The
definitions of libido and sexual function in women are continually
being changed. A recently revised definition of sexual desire/interest
disorder in women describes several characteristics(56). One is “absent
or diminished feelings of sexual interest and desire or absence of
sexual thoughts or fantasies, and a lack of responsive desire. Another
indicates that motivation (defined as reasons or incentives) for
attempting to become sexually aroused are scarce or absent. The lack of
interest is considered to be beyond the normative lessening with
lifecycle and relationship duration." The revised definition clarifies
that the lack of spontaneous or natural desire is not of itself
dysfunctional: rather it is the additional inability to become aroused,
to sense pleasure and trigger response and desire during the sexual
encounter that constitutes the disorder. Of note, the recent
testosterone patch trials reported an increase not only in desire but
also in arousal, pleasure, and orgasmic response. In the future, it
would therefore be important to study women recruited on the basis of
the new definitions of desire or interest disorder. In addition, the
focus will be on restoring subjective arousal such that desire is
triggered during the sexual experience and not during the spontaneous or
initial desire phase. The later is typically present at the beginning
of the relationship but it is known to have a broad range of frequency
across sexually satisfied women.
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Society Clinical Practice guideline. Journal of Clinical Endocrinology
& Metabolism 2006; 91(10):3697-3710.
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Society. [Review] [66 refs]. Menopause 649; 12(5):496-511.
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Society Clinical Practice guideline. Journal of Clinical Endocrinology
& Metabolism 2006; 91(10):3697-3710.
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postmenopausal women: position statement of The North American Menopause
Society. [Review] [66 refs]. Menopause 649; 12(5):496-511.
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ME, Basson R, Davis SR et al. Androgen therapy in women: an Endocrine
Society Clinical Practice guideline. Journal of Clinical Endocrinology
& Metabolism 2006; 91(10):3697-3710.
52. Braunstein
GD. The Endocrine Society Clinical Practice Guideline and The North
American Menopause Society position statement on androgen therapy in
women: another one of Yogi's forks. Journal of Clinical Endocrinology
& Metabolism 2007; 92(11):4091-4093.
53. North
American Menopause Society. The role of testosterone therapy in
postmenopausal women: position statement of The North American Menopause
Society. [Review] [66 refs]. Menopause 649; 12(5):496-511.
54. Wierman
ME, Basson R, Davis SR et al. Androgen therapy in women: an Endocrine
Society Clinical Practice guideline. Journal of Clinical Endocrinology
& Metabolism 2006; 91(10):3697-3710.
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American Menopause Society. The role of testosterone therapy in
postmenopausal women: position statement of The North American Menopause
Society. [Review] [66 refs]. Menopause 649; 12(5):496-511.
56. Wierman
ME, Basson R, Davis SR et al. Androgen therapy in women: an Endocrine
Society Clinical Practice guideline. Journal of Clinical Endocrinology
& Metabolism 2006; 91(10):3697-3710.
Glossary
American Psychiatric Association
This
is a professional society of psychiatrists who provide information on
the definitions of various mood and emotional disorders.
Androgen
This
is a general name for male hormones. There are several male hormones
which circulate in the blood. The most potent male hormone is called
testosterone
Androstenedione
A
compound made by the ovaries and the adrenals which can be changed into
testosterone in tissues of the body outside of the ovaries or adrenals
such as the liver, fat tissue, and muscle
Bad cholesterol (Low Density Lipoprotein LDL)
A type of cholesterol that increases the risk of heart disease. It is also called LDL cholesterol.
Blood clots
Blood
cells can form a thickened area, which is called a clot that moves
through the blood and can cause damage by blocking blood vessels.
Bone formation
A
process in which new bone is made to replace old bone, which is
removed. This occurs during the process of bone remodeling, just like
the remodeling of a house, where old things are removed and new things
are put in.
Bone mineral density
This
is a term used to describe the amount of calcium present in bone. When
the bone mineral density is low, there is a reduced amount of bone and
either osteopenia, which is a moderate loss of bone or osteoporosis,
which is severe loss of bone occurs. This is determined by an X-ray
technique called DEXA ( see below)
Bone resorption
A
process in which bone is removed to make way for new bone that forms.
This occurs during the process of bone remodeling, just like the
remodeling of a house, and old things are removed.
Clinical trial
When
physicians want to learn how a medication works, they design a clinical
trial in which patients are treated in a certain way. They closely
examine what happens in groups of patients studied and followed over
time. Usually one group is given one drug and a second group another
drug. Sometimes the one drug is compared with a placebo.
Cognitive function
Intellectual
capacity such as memory, ability to make decisions, to use numbers, to
exercise judgment, or to understand difficult concepts is defined as
cognitive function.
Compounding pharmacies
Pharmacies
or drug stores that prepare testosterone and estrogens for use in
patients by weighing out the hormone in a powder form and then putting
them into creams or other forms to administer to patients
Conjugated estrogen
A
form of estrogen that can be given by mouth. The word conjugated means
that the estrogen has been attached to another chemical substance. The
most common conjugated estrogen is Premarin, an estrogen used in
menopausal women.
Contraindication
Medical reasons not to take a medication.
Coronary
This
word refers to the main arteries supplying blood to the heart. When the
coronary arteries are clogged, heart problems can develop.
DHEA
A
compound made by the ovaries and the adrenals which can be changed into
testosterone in tissues of the body outside of the ovaries or adrenals
such as the liver, fat tissue, and muscle
DHEA-S
A
compound made exclusively by the adrenals which can be changed into
testosterone in tissues of the body outside of the ovaries or adrenals
such as the liver, fat tissue, and muscle
Edema
Increased water in the tissues, usually of the legs, which causes ankle and leg swelling.
Estradiol
This is the major female hormone which is made primarily in the ovaries.
Estrogen
This
is a general term for female hormone. There are three specific female
hormones which are called estradiol, estrone, and estriol. These female
hormones cause breast development of young girls and regulation of the
monthly menstrual cycle. In the absence of estrogens, several of the
symptoms of menopause occur.
.Good cholesterol (High Density Lipoprotein HDL)
A type of cholesterol that protects against heart disease. It is also called HDL cholesterol.
Hormone
A
substance formed in a type of organ in the body called a gland. The
hormone is then carried through the blood to another organ where it acts
on that tissue in a specific manner.
Hypoactive sexual desire disorder.
The American Psychiatric Association has defined this as: “ persistently recurrent, deficient or absent sexual fantasies and desire for sexual activity”.
Ischemic heart disease
Type
of heart disease that causes heart attacks. The word ischemic refers to
the lack of blood flow to the critical areas of the heart.
LDL cholesterol
A type of cholesterol that increases the risk of heart disease It is commonly called bad cholesterol
Libido
The interest in and the urge to have sex (intimacy/sexual intercourse).
Male hormones
Male
hormones circulate in the blood in both women and men. The major male
hormone is testosterone which is about ten-fold higher in men than in
women. However, both men and women make this hormone. Testosterone
increases facial hair and muscle mass in men and causes the voice to
deepen at puberty. In men, the major hormone that influences sex drive
or libido is testosterone. In women, testosterone is linked to sex drive
but does not appear to serve other major functions.
Masculinizing
This
term refers to the effects of male hormone to increase facial hair,
deepen the voice, cause balding of the scalp, and to increase muscle
mass.
Menopause
Time of life when the ovaries stop making estrogen and the monthly menstrual periods stop. Change of life is another way to describe the menopause.
Menstrual
Refers to the process of menstruation (see below)
Menstruation
When
female hormone levels fall during the monthly cycle, the lining of the
uterus is shed and bleeding occurs through the vagina. Some call this a
“monthly” or a monthly period.
Methyl-testosterone
A synthetic form of testosterone that an be given by mouth in a pill
North American Menopause Society
A
professional society of health care workers who provide information and
educational material for those interested in all aspects of the
menopause
Observational study
In this type of study, groups of patients who are already receiving certain therapies are carefully observed to see the safety and effectiveness of one therapy compared to another. Because there's no random selection procedure, bias may
influence the results and sometimes this type of study gives results
that are incorrect. Randomized trials are much more accurate means of
testing the safety and efficacy of drugs.
Oophorectomy
Removal of the ovaries by surgery.
Osteopenia
Represents
a condition where there is a moderate loss of bone. A woman with
osteopenia has a risk of broken bones that is higher than normal but not
as high as with the more severe condition called osteoporosis.
Osteopenia is detected by an X-Ray method called a DEXA scan (see
above).
Osteoporosis.
This
is a condition of very low amounts of bone. With this problem, there is
a high frequency of broken bones, especially in the spine and hip. As
osteoporosis progresses, a woman becomes shorter in overall height
because the vertebrae in the spine collapse. The spine also becomes
curved resulting in what is called a Widow’s Hump. Osteoporosis is
detected with a radiologic method called a DEXA scan.
Ovary
One
of a pair of female glands that produce eggs and the female hormones,
estrogen and progesterone. The ovary also produces male type hormones
called androgens.
Peri-menopausal Transition
Describes
the approximately 2-5 years of life just before menstrual periods stop
completely because of the menopause. During this time, symptoms of
menopause may occur but then later disappear, only to recur again.
Placebo
During
a clinical trial, one group of women is often given a “dummy pill”
which looks similar to the hormone pill used in the trial but has no
active ingredient. The common word for “placebo” which was used formerly
was “sugar pill.”
Post-menopausal
Describes the time after menopause when the monthly menstrual periods stop and the
ovaries no longer make estrogen. This condition usually continues for
the remainder of a woman’s life. In rare instances, a few menstrual
cycles return, even after they have stopped for more than one year. This
is the reason that some women are said to have “menopausal babies”.
Pre-menopausal
Describes a time of life when a woman gets monthly periods and her reproductive function is normal..
Randomized trial
A
type of clinical trial in which two or more types of treatment or one
treatment and a placebo are compared. The purpose of a randomized trial
is to eliminate bias and to learn how the treatments affect groups of
patients. A randomization process is used to tell patients which therapy
they will receive. That decision is not made by the researchers running
the study. Randomization is a method that determines the
therapy for a participant of the study by a coin toss or similar
computer technique. The advantage of a randomized trial is that the
groups being treated usually have similar ages, ethnic backgrounds, and
risk factors. The outcomes being studied ( for example the number of
heart attacks) are primarily determined by the treatments themselves and
not other factors. The randomized clinical trial is thought to be the
most accurate way of finding out information about hormone or other
therapy and is the least susceptible to potential bias.
Testosterone
The major male hormone circulating in the blood of men and women.
Vagina
The canal through which babies are born. It leads from the woman's outer sex organs into the uterus.
Vascular system.
The system of blood vessels including the arteries, veins and capillaries that are found throughout the body.
VTE
Veno-thrombotic
event. This refers to a problem in the veins whereby blood clots form
and cause two types of events; deep venous thrombosis (blood clots in
the veins of the leg which are deep down below the skin) or blood clots
that break off and travel to the lungs (pulmonary emboli).