Sex, Hormones, and Hysterectomies

In this issue of the Journal, Shifren and coworkers (1) postulate that the reduction in androgens resulting from
bilateral oophorectomy is associated with sexual dysfunction in some women and that testosterone replacement
can reverse this decline in sexual function and also improve psychological well-being. The potential importance of
these postulates is substantial.

Recent survey data suggest that the prevalence of sexual dysfunction among women in the United States is
approximately 40 percent. (2) Many of these women have had hysterectomies, about 600,000 of which are
performed here annually. (3) Bilateral oophorectomy is performed in conjunction with hysterectomy in about half
of women 40 to 44 years of age who undergo the procedure and in almost 80 percent of women 45 to 54 years
old. (3) Many of these women ask their doctors about androgen-replacement therapy.

Although the production of estrogens and oocytes is its chief function, the ovary is also an important source of
androgens. In contrast to the dramatic reduction in estradiol production that occurs after menopause, the decline
in testosterone production is smaller, from 250 to 180 �g per day. (4) Clearly, ovarian testosterone production
continues in postmenopausal women. Testosterone concentrations in ovarian venous serum are almost 15 times as
high as in peripheral serum, (5) and serum testosterone concentrations decline by 50 percent after oophorectomy
in postmenopausal women. Thus, natural menopause does not result in nearly the reduction in androgen
production that occurs after oophorectomy. Surgically induced menopause can therefore serve as a useful model
for studying the effects of androgen deficiency and androgen replacement, but the results may not apply to natural
menopause.

The theory of a relation among menopause, serum androgen concentrations, mood, and sexual function is
controversial. Using age-matched, premenopausal women as controls for women undergoing menopause,
Matthews and coworkers (6) did not find a significant effect of menopause on mood. In an observational study of
210 women who had undergone natural menopause but who were not receiving estrogen-replacement therapy,
serum testosterone concentrations did not correlate with libido or any other aspect of sexual function. (7)
Moreover, despite a steady decline in serum testosterone concentrations with age, such that women in their 40s
have about half the serum testosterone concentration of women in their 20s, survey data indicate a greater
prevalence of sexual dysfunction among younger women. (2) In a randomized, placebo-controlled trial of high
doses of intramuscular testosterone enanthate in women in whom menopause had been surgically induced, the
women given testosterone reported higher libido on a questionnaire than the women in the placebo group. (8)
However, in a study comparing estrogen and methyltestosterone with estrogen alone in postmenopausal women,
neither treatment altered sexual behavior, as compared with placebo. (9)

In the present study by Shifren et al., (1) transdermal testosterone was used for androgen-replacement therapy in
women concurrently treated with estrogen. The use of transdermal testosterone had the advantage of producing
steady-state serum testosterone concentrations that did not raise serum lipid concentrations -- a recognized
problem with orally administered testosterone. Another important feature of the study was its placebo-controlled
design. Had a placebo effect not been demonstrated, the change in perceived sexual function with the lower-dose
testosterone patch (150 �g per day) would have seemed quite dramatic. When compared with the equally
impressive change in the placebo group, however, the apparent effect of the 150-�g patch on sexual functioning
disappeared. Taking placebo effects into account, the only significant effects on sexual functioning occurred with
the 300-�g patch in older women.

From the perspective of clinical utility, several issues can be raised about the use of the testosterone patch in
women with impaired sexual function. First, the 300-�g testosterone patch resulted in a mean serum total
testosterone concentration of 102 ng per deciliter (3.5 nmol per liter), a value that is well above the upper limit of
normal for menstruating women, and serum free and bioavailable testosterone concentrations were in the
high-normal range. Thus, long-term daily use of the 300-�g patch is likely to be associated with clinically important
androgenic effects. Second, the higher dose of testosterone was effective only in women at least 48 years old who
had undergone hysterectomy plus bilateral oophorectomy and reported significantly impaired sexual function at
base line. Third, in clinical practice many women who report sexual dysfunction have one or more potentially
confounding variables, such as use of antidepressant-drug therapy or dyspareunia, that would have excluded them
from the study by Shifren and colleagues. This fact further restricts the generalizability of the results.

Additional questions remain about the role of androgens in postmenopausal women. Menopause is associated
with an increase in bone loss, which is diminished by estrogen therapy. In a two-year study of women with
surgically induced menopause who did not have established osteoporosis, those receiving an estrogen-androgen
combination had significantly higher vertebral bone density than those receiving estrogen alone. (10) A possible
role for androgen therapy in women with osteoporosis remains to be clearly defined.

The possibility of a relation between sexual function and the decline in androgen production that occurs after
menopause (especially after menopause induced by prophylactic oophorectomy) is a potentially important issue
worthy of further study. If such a relation is consistently demonstrated, and if a testosterone dose is found that can
reverse sexual impairment and improve psychological well-being without exerting unwanted androgenic effects on
a long-term basis, transdermal testosterone may prove to be a useful treatment.

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LAte

Since it was a long article to wade through, here is the short version of interest.

"......serum testosterone concentrations did not correlate with libido or any other aspect of sexual function. (7)
Moreover, despite a steady decline in serum testosterone concentrations with age, such that women in their 40s
have about half the serum testosterone concentration of women in their 20s, survey data indicate a greater
prevalence of sexual dysfunction among younger women. (2) In a randomized, placebo-controlled trial of high
doses of intramuscular testosterone enanthate in women in whom menopause had been surgically induced, the
women given testosterone reported higher libido on a questionnaire than the women in the placebo group. (8)
However, in a study comparing estrogen and methyltestosterone with estrogen alone in postmenopausal women,
neither treatment altered sexual behavior, as compared with placebo."

"Another important feature of the study was its placebo-controlled
design. Had a placebo effect not been demonstrated, the change in perceived sexual function with the lower-dose
testosterone patch (150 �g per day) would have seemed quite dramatic. When compared with the equally
impressive change in the placebo group, however, the apparent effect of the 150-�g patch on sexual functioning
disappeared. Taking placebo effects into account, the only significant effects on sexual functioning occurred with
the 300-�g patch in older women. "

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LAte

It seems (from my wife and she telling me about her friends) that women in their 30's have no sex drive at all. It is a hugh problem and yet no one in the field of human sexuallity is studying it.