Editorial: The Role of Androgens in Women

Peter J. Snyder

Division of Endocrinology, Diabetes and Metabolism University of Pennsylvania Philadelphia, Pennsylvania 19104-6149

Address correspondence and requests for reprints to: Dr. Peter J. Snyder, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6149.


    Introduction
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 Introduction
 Sources of androgens in...
 Conditions in which androgens...
 Possible roles for androgens...
 References
 
Interest has been building in recent years about possible roles of androgens in women. Several roles have been postulated, including increasing libido, energy, bone mineral density, and muscle mass and strength. Although these roles have theoretical underpinnings and some experimental support, the experimental support at this time is not fully convincing, for two general reasons. The first is that, until now, the best experimental circumstances in which to study the potential roles of androgens in women have not been well defined. The study by Miller et al. (1), in February issue of the journal, makes an important contribution in remedying this situation by demonstrating a severe deficiency of estrogen in women who have panhypopituitarism. The second reason is that, until recently, pharmacological preparations that will replace androgens physiologically in women have not been available. The development of transdermal testosterone preparations for men raises the possibility that these delivery systems could be adapted for use in women.


    Sources of androgens in women
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 Introduction
 Sources of androgens in...
 Conditions in which androgens...
 Possible roles for androgens...
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Androgens are secreted by both the ovaries and adrenal glands, as shown by studies before and after ovariectomy and before and after suppression of adrenal function by dexamethasone administration and suppression of ovarian function by estrogen administration. In premenopausal women, ovariectomy results in a fall in the serum testosterone and androstenedione concentrations by approximately 50% each (2), suggesting that these two androgens come equally from the ovaries and adrenal glands in premenopausal women. In postmenopausal women, the serum testosterone concentration is only slightly lower than that in premenopausal women and falls by 50% following ovariectomy (2). In contrast, the androstenedione concentration in postmenopausal women is approximately 50% of that in premenopausal women and does not fall appreciably following ovariectomy. These results suggest that the secretion of testosterone, but not androstenedione, by the ovaries is maintained in the menopause.

Dehydroepiandrosterone and dehydroepiandrosterone sulfate seem to be secreted almost exclusively by the adrenal glands in both premenopausal and postmenopausal women, as demonstrated by hormonal suppression studies. Administration of dexamethasone causes an 80–90% reduction in the serum concentrations of these steroids in pre- and postmenopausal women (3), but estrogen administration does not.


    Conditions in which androgens might be subnormal in women
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 Introduction
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Because androgens are secreted by both the ovaries and the adrenal glands, one would expect that diseases that affect the secretion of one or both would result in decreased androgen secretion. That has been found in some circumstances, but not all. As for diseases of the ovary, oophorectomy causes 50% decreases in the serum concentrations of androstenedione and testosterone (2). In menopause, however, androstenedione is about 50% of that before menopause, but testosterone is minimally lower (2).

As for pituitary disease, one would predict that panhypopituitarism, by causing decreased secretion of both ovarian and adrenal androgens, would result in severe androgen deficiency. The study by Miller et al. (1) confirms this prediction. They measured the serum concentrations of testosterone, free testosterone, androstenedione, and dehydroepiandrosterone sulfate in 55 women who had pituitary disease and in 92 control women. Whether the women who had pituitary disease were of premenopausal or postmenopausal age, or if they were taking exogenous estrogen or not, they had serum concentrations of all of these androgens that were far below those of comparable women who did not have pituitary disease. If any women have deleterious consequences of androgen deficiency, therefore, women with hypopituitarism are the most likely. The question, then, is what deleterious effects might result from androgen deficiency?


    Possible roles for androgens in women
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 Introduction
 Sources of androgens in...
 Conditions in which androgens...
 Possible roles for androgens...
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Androgens have been postulated to have several effects in women, based on studies in women who are deficient in androgens before and after androgen treatment.

Several studies have addressed the role of androgens in increasing libido using different conditions of androgen deficiency and different androgen preparations. In one study, 71 women who had surgical oophorectomy but presumably intact adrenal function, who were being treated with conjugated equine estrogens, and who had impaired sexual function, were treated for 12 weeks each with two doses of testosterone by a transdermal patch or with a placebo patch in a double-blind fashion (4). The higher dose of testosterone, which resulted in an increase in the serum free testosterone concentration from just below the lower limit of normal to just within the upper end of normal, resulted in an increase in sexual function greater than that of placebo treatment, but the lower dose of testosterone, which resulted in an increase in the serum testosterone to mid-normal, did not increase sexual function more than placebo. In another study, 34 postmenopausal women were randomized to receive implants of estradiol alone or estradiol plus testosterone for 2 yr (5). Treatment with testosterone as well as estradiol increased the serum testosterone concentration to high in the normal range and increased several parameters of sexual function more than placebo did. In a third study, 24 women who had primary or secondary adrenal insufficiency were treated with dehydroepiandrosterone and placebo in random order for 4 months each (6). Dehydroepiandrosterone treatment increased the serum testosterone concentration from subnormal to the lower part of the normal range and increased several parameters of sexual function compared with placebo.

Several studies have also addressed the role of androgens on bone. In one study, 28 postmenopausal women who had not taken estrogen for at least 6 months were randomized to receive either conjugated equine estrogens or esterified estrogens plus 2.5 mg methyltestosterone a day for 9 weeks (7). Both treatment groups experienced a decrease in markers of bone breakdown, but only the group treated with methyltestosterone plus estrogen experienced an increase in markers of bone formation. In another study, 65 women who had undergone oophorectomy were randomized in a double-blind fashion to receive esterified estrogens alone or esterified estrogens plus 2.5 mg methyltestosterone for 2 yr (8). Bone mineral density was evaluated in only 48 of the 65 women and was not significantly different between the two groups after 2 yr of treatment. In a third study, 34 postmenopausal women were randomized to receive implants of estradiol alone or estradiol plus testosterone for 2 yr (5). A greater increase in bone mineral density in both the spine and trochanter occurred in the group treated with estradiol plus testosterone than in the group treated with estrogen alone.

Studies, to date, in short, offer tantalizing evidence that androgens may play an important role in women, but they are not fully convincing because most have been performed in women who are only partially deficient in androgens, and most have been performed with doses of androgens that are probably at least somewhat excessive. The value of the study by Miller et al. (1) is that it demonstrates that panhypopituitarism is the best condition in which to test the possibility that physiologic amounts of androgens affect libido, energy, muscle mass and strength, and bone mineral density in women.

Received January 9, 2001.

Accepted January 9, 2001.


    References
 Top
 Introduction
 Sources of androgens in...
 Conditions in which androgens...
 Possible roles for androgens...
 References
 

  1. Miller KK, Sesmilo G, Schiller A, Schoenfeld D, Burton S, Klibanski A. 2001 Androgen deficiency in women with hypopituitarism. J Clin Endocrinol Metab. 86:561–567.[Abstract/Free Full Text]
  2. Judd HL, Lucas WE, Yen SSC. 1974 Effect of oophorectomy on circulating testosterone and androsterone levels in patients with endometrial cancer. Am J Obstet Gynecol. 118:793–798.[Medline]
  3. Margolis GB, Abraham GE. 1976 Ovarian and adrenal contributions to peripheral steroid levels in postmenopausal women. Obstet Gynecol. 48:150–154.[Abstract]
  4. Shifren JL, Braunstein GD, Simon JA. 2000 Transdermal testosterone treatment in women with impaired sexual function after oophorectomy. N Engl J Med. 343:682–688.[Abstract/Free Full Text]
  5. Davis SR, McCloud P, Strauss BJG, Burger H. 1995 Testosterone enhances estradiol’s effect on postmenopausal bone density and sexuality. Maturitas. 21:227–236.[CrossRef][Medline]
  6. Arlt W, Callies F, Christoph J, et al. 1999 Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med. 341:1013–1020.[Abstract/Free Full Text]
  7. Raisz LG, Witta B, Artis A, et al. 1996 Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab. 81:37–43.[Abstract]
  8. Watts JB, Notelovitz M, Timmons MC, et al. 1995 Comparison of oral estrogens and estrogens plus androgen on bone mineral density, menopausal symptoms, and lipid-lipoprotein profiles in surgical menopause. Obstet Gynecol. 85:529–537.[Abstract/Free Full Text]