Androgens in Women

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Mary Lake Polan, MD, PhD, MPH Katharine Dexter McCormick and Stanley Androgens in women: McCormick Memorial Professor and Chair Emeritus, Department of Obstetrics and Gynecology, Stanford University To replace or not? School of Medicine, Stanford, Calif Dr. Polan is a consultant to Procter & Androgen therapy can improve sexual desire Gamble, serving as Chair of the Feminine Protection Scientifi c Advisory Board. She is also a Director for Wyeth. and response—here’s how

lthough women produce only ly divided between the adrenal gland one tenth the amount of andro- and the ovaries. Androstenedione from A gen that men do, testosterone both is converted to testosterone and and related androgen metabolites are as then irreversibly to dihydrotestosterone important to women® throughoutDowden the life-Health(DHT). Media Androstenedione, testosterone, span as is estrogen. Androgens modulate and even DHEA are secreted in equal a feeling of well-being, increase energy, quantities by the adrenals and ovaries. supportCopyright bone Formetabolism, personal and improve use Theonly only androgen that is predominant- sexual function in women.1–3 But too ly adrenal is DHEAS, which is sulfated much androgen production, with elevat- in the adrenal gland. ed levels of testosterone and dehydroepi- In premenopausal women, andro- IN THIS ARTICLE androsterone (DHEA), can result in hir- stenedione is the precursor to testoster- ❙ How menopause sutism, acne, and infertility in the setting one, which is then metabolized to DHT, of polycystic ovary syndrome (PCOS), the androgen most active in hair fol- affects plasma all of which present clinical problems. licles and implicated in hirsutism. It has hormone levels An equally complicated topic is an- been clear for many years that DHEA, Page 75 drogen insuffi ciency in women. Not only although a weak androgen, is present in ❙ How to measure is it diffi cult to diagnose, it is a major the greatest quantity in the circulation clinical issue to decide whether, when, and and is secreted during adrenarche, prior testosterone how to replace androgens in women. In to menarche, beginning at ages 8 to 10. Page 76 this article, I look at androgen production DHEAS peaks in young adulthood and ❙ Androgens and throughout the female lifespan, particular- begins to decline after age 40.4 The same ly the relationship between estrogen and is true for both total testosterone and women’s health: androgen. I also describe the evaluation of free testosterone levels, which also de- 11 important facts androgen insuffi ciency, which requires un- cline in women after about age 25. Thus, Page 80 derstanding of androgen physiology and peri- and postmenopausal women have ovarian function before and after meno- approximately half the level of circulat- pause. These issues form the basis of the ing androgens of women in their 20s decision to replace androgen in women. (FIGURE 1, TABLE 1, page 75).5

It matters how menopause happens Androgen over the lifespan Circulating androgen levels are greatly In the premenopausal woman, andro- infl uenced by menopause—how much gen production is approximately equal- depends on whether it occurs naturally CONTINUED

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with the ovaries intact, or by surgical re- FIGURE 1 moval of the ovaries. Not only does es- Testosterone levels in women decline with aging tradiol diminish signifi cantly in naturally menopausal women, but all androgens 25 do as well. In young oophorectomized 20

women, estrogen levels are similar to lev- levels els in naturally menopausal women, but 15 androgen levels—including testosterone,

DHT, and androstenedione—are signifi - (pmol/L) 10

cantly lower than in naturally menopaus- testosterone al women, demonstrating that the circu- 5 Free lating levels of androgen after natural 0 menopause are still signifi cantly greater 18-25 25-35 35-45 45-55 55-65 65-75 than those in oophorectomized women.6 Years

Thus, the postmenopausal ovary contrib- N=595 utes signifi cantly to circulating levels of SOURCE: Davison S, et al5 androgen.

TABLE 1 Androgen physiology How menopause affects plasma hormone levels Both androgens and estrogens circulate in the bloodstream tightly bound to the HORMONE MEAN PLASMA LEVEL protein sex hormone-binding globulin REPRODUCTIVE NATURALLY AGE* MENOPAUSAL OOPHORECTOMIZED (SHBG), and more loosely bound to al- (N = 15) (N = 18) (N = 8) bumin. The SHBG-bound fraction is un- available for biologic activity. Therefore, Estrone (pg/mL) 58 49 48 the amount of SHBG a woman produces Estradiol (pg/mL) 40 20† 18 is a key determinant of her level of an- Testosterone 44 30† 12‡ drogen bioactivity. For this reason, it is (ng/dL) crucial to measure circulating SHBG. DHT (ng/dL) 30 10† <5‡ In a feedback mechanism, SHBG Androstenedione 166 99† 64‡ production is regulated by androgen and (ng/dL) estrogen levels, with estrogen stimulating SHBG production and testosterone de- DHEA (ng/dL) 542 197† 126§ creasing it.7 In the normal woman, about DHT = dihydrotestosterone, DHEA = dehydroepiandrosterone 65% of testosterone is bound to SHBG * Mean value during early follicular phase † P<.01 for comparison with reproductive age and 30% is bound to albumin, leaving ‡ P<.01 for comparison with naturally menopausal women only 0.5% to 2% free and bioactively § P<.05 for comparison with naturally menopausal women 18 available.8 In postmenopausal women SOURCE: Vermeulen taking hormone replacement therapy, SHBG increases, but the addition of me- sure to steroids. Therefore, oral forms of thyltestosterone lowers the overall levels estrogen replacement, which stimulate of SHBG, even in the presence of estro- the liver because of the “fi rst pass” effect, gen, increasing the amount of bioavail- result in a greater increase in SHBG than able testosterone simply by lowering do transdermal estrogen preparations. SHBG levels. Postmenopausal replacement with estrogen alone decreases the Elevated androgen levels amount of bioavailable testosterone be- have both ill and good effects cause of higher SHBG levels. As I stated earlier, an appropriate level of SHBG is synthesized in the liver, androgen is optimal for women as well as whose metabolism is increased by expo- men. Elevated androgen levels are prob-

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FIGURE 2 decreased bioavailable testosterone and 11 How estrogen plus androgen normal estrogen.” affects sexual function

EE Assessing androgen levels 3.5 *

EE+MT Clinical signs and symptoms of andro- 3 gen insuffi ciency are important in es-

from 2.5 therapy * 2 tablishing the diagnosis. They include † a diminished sense of well-being, un- score 1.5

in 1 explained fatigue, decreased sexual hormone 0.5 desire, and thinning and loss of pubic 11

Change 0 hair. Although it is possible to assess

previous -0.5 testosterone production and availability Sensation Sensation Desire Frequency Vaginal and desire changes in women by measuring serum testos- *P<.01; †P≤.05 terone levels, a lack of consensus about EE=esterifi ed estrogens; MT=methyltestosterone the best measurement technique and in- SOURCE: Sarrel PM, et al19 terpretation of results makes it diffi cult to base the diagnosis of androgen insuf- lematic, in that they are the hallmark of fi ciency solely on serum levels.12 There- PCOS, usually resulting from increased fore, the diagnosis of androgen insuffi - ovarian production of androgen. This el- ciency is primarily a clinical diagnosis evation can cause anovulation, infertility, of symptoms.11 hirsutism, and other androgen-mediated physiologic effects. Androgen is also as- How to measure testosterone sociated with elevated low-density lipo- Obtain serum samples between 8 and 10 protein and decreased high-density lipo- AM after day 8 and before day 20 of the protein cholesterol, implying a possible normal menstrual cycle because testoster- relationship with cardiovascular disease. one is subject to diurnal variation, peak- FAST TRACK At the same time, however, elevated tes- ing in the early morning, as well as cyclic Signs and symptoms tosterone has been correlated with in- variation, peaking around midcycle. creased bone density in both the hip and Because free testosterone is the only of androgen the femoral neck.9 bioavailable steroid, total testosterone insufﬁ ciency include It is clear that appropriate androgen and either free testosterone or SHBG a diminished sense secretion, which does not elicit the side must be measured to assess how much of well-being, effects described above, is best for both androgen is actually available. From to- unexplained fatigue, the health and well-being of the woman. tal testosterone and SHBG, one can assess the free testosterone index as a measure of decreased sexual How androgen affects bioavailable androgen (the free testoster- desire, and thinning female sexual function one index is a ratio of the amount of total of pubic hair We have known for years that andro- testosterone divided by the SHBG level).11 gen—not estrogen—is associated with In fact, using the free testosterone index is satisfactory sexual function. Although es- preferable to the actual measurement of trogen replacement increases vaginal lu- free testosterone because commercial as- brication, it is androgen, most commonly says lack the sensitivity and reliability to in the form of oral methyltestosterone accurately measure the low levels of an- or injectable testosterone, that increases drogen found in women. frequency of intercourse, desire, and Several different testosterone assays sexual sensation (FIGURE 2).10 The defi ni- exist, and the immunoassay for total tes- tion of androgen insuffi ciency has been tosterone is reasonably accurate. Howev- hotly debated, and is currently “a pattern er, measurements of free testosterone are of clinical symptoms in the presence of relatively inaccurate and poorly repro- CONTINUED

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FIGURE 3

Assessing testosterone status in women

Does the patient have signs and symptoms of testosterone insufﬁ ciency?

Yes

Optimize estrogen Is the patient No therapy optimally estrogenized?

Yes

Does the patient have other Treat Yes cause(s) of symptoms? cause(s)

Laboratory testing? Trial of testosterone No consensus* replacement

Adapted from Braunstein GD20 *Bachmann G, et al11 ducible. Equilibrium dialysis is thought vaginal cytology, or both, and by deter- to be the gold standard for measuring mining whether symptoms of estrogen free testosterone, but it is a diffi cult and insuffi ciency are present, such as hot time-consuming assay.12 fl ashes, night sweats, and vaginal dry- ness. If the patient is estrogen-insuf- Causes of low testosterone fi cient, the fi rst step in resolving her FAST TRACK In women, low testosterone secretion symptoms is estrogen replacement. If Estrogen plus is usually the result of normal aging. estrogen levels are adequate and there is Other conditions that alter testoster- no other reason for the patient’s symp- methyltestosterone one production include oophorectomy, toms of fatigue, lack of sexual desire, improves sexual ovarian failure, adrenal insuffi ciency, or low energy, a trial of testosterone is desire in women hypopituitarism, and other forms of reasonable. after 12 to 16 weeks chronic illness. Treatment with corticosteroids and estrogen therapy lowers active androgen Treating androgen levels in women. insufﬁ ciency Current therapies include oral methyl- What levels are cause for concern? testosterone combined with estrogen, If androgen levels are at or below the and intramuscular testosterone pro- 25th percentile of the normal range for pionate, testosterone cypionate, and reproductive-aged women, consider the testosterone enanthate. Subcutaneous possibility of androgen insuffi ciency and implants of testosterone propionate are determine whether androgen replace- also available, as are transdermal prepa- ment is in order.11 rations (TABLE 2, page 82). However, the When the signs and symptoms of transdermal formulations are designed testosterone insuffi ciency are present, for androgen insuffi ciency in men, one must fi rst assess estrogen levels by and therefore deliver approximately measuring serum estradiol, obtaining 10 times as much androgen as women

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Androgens and women’s health: 11 important facts

The role of testosterone therapy in postmenopausal women: to albumin (~30%). Because oral estrogen therapy position statement of The North American Menopause Society. increases SHBG levels, it lowers unbound testoster- Menopause. 2005;12:497–511. one. Conversely, obesity and hypothyroidism depress n 2005, the North American Menopause Society is- SHBG levels and increase free testosterone. sued a comprehensive position statement on the role The simplest method to determine the amount of Iof testosterone therapy in postmenopausal women. bioavailable testosterone is to measure total testos- Its purpose was to offer recommendations based on terone and SHBG, dividing total testosterone (ng/dL) reliable evidence, and it refl ects a thorough analysis by SHBG (nmol/L). Multiply this fi gure by 3.47 to of the data to date. Note that its fi ndings, highlighted obtain the free testosterone index. If the total testos- below, pertain to postmenopausal women only. terone value is reported in nmol/L, the multiplication factor is 100. 1. Endogenous testosterone levels have During the menopausal transition, free testoster- no clear link to sexual function one concentrations appear to remain fairly constant No defi nitive studies have established a relationship or increase slightly, probably because SHBG declines between endogenous testosterone levels and sexual as ovarian estrogen production diminishes. One function, and observational data have been mixed. small study found little difference in total testoster- Because of this lack of clarity, we do not have specifi c one between younger premenopausal women (age total or free testosterone values that indicate clinical 19–37 years) and older women (age 43–47), although testosterone defi ciency. the older age group lacked the midcycle rise in free Exogenous testosterone is a different story. Ran- testosterone and androstenedione.16 domized controlled trials have demonstrated greater sexual desire and sexual responsiveness and more 3. Causes of androgen insufﬁ ciency: Chronic frequent sexual activity when exogenous testoster- illness, age, and oophorectomy, to name a few one is given. Almost all trials involved testosterone Bilateral oophorectomy can lower testosterone levels combined with estrogen or estrogen–progestogen by as much as 50%. Other contributors include therapy. The only trial that included a testosterone- increasing age, hypothalamic–pituitary–adrenal alone arm found that testosterone added to estro- insuffi ciency, systemic glucocorticoids, hyperthyroid- gen therapy or given alone increased sexual desire, ism and excessive thyroid medication, and chronic arousal, and frequency of sexual fantasies, compared illness such as depression and advanced cancer. with placebo or estrogen alone.14 Both endogenous and exogenous estrogens lower testosterone levels by raising SHBG. 2. Use the free testosterone index to determine testosterone bioavailability 4. Sexual dysfunction is the only indication Only 1% to 2% of circulating testosterone is free or Thus far, we lack suffi cient data to justify use of bioavailable. The remainder binds tightly to sex hor- testosterone for any other indication, including mone-binding globulin (SHBG, about 65%) or loosely preserving bone mineral density, reducing hot

normally produce. Testosterone gel testosterone patch under development preparations are available that can be delivers 300 μg per day. When used with applied in lower levels to achieve nor- conjugated equine estrogens, this patch mal female androgen levels. has been shown to increase bioavailable testosterone in women without ovaries How long until relief? who have very low androgen levels.3 It is clear from a number of studies13,14 In a 2005 study,15 more than 500 that estrogen plus methyltestosterone women with hypoactive sexual desire oral replacement improves sexual de- who had undergone a total abdominal sire in women after 12 to 16 weeks, and hysterectomy–bilateral salpingo-oopho- that this improvement is based on an rectomy were randomized to placebo increase in bioavailable testosterone. A or a testosterone patch that delivered

80 OBG MANAGEMENT • May 2007 fl ashes, and improving the patient’s overall sense of no randomized trial has reported its effects on fracture well-being. risk in postmenopausal women.

5. A comprehensive clinical exam is mandatory 8. No testosterone product is FDA-approved This includes a psychosexual and psychosocial his- for sexual dysfunction in women tory; a thorough medical history, including use of pre- However, a few testosterone-containing prescription scription and other drugs (such as selective serotonin products are approved for use by women and men; reuptake inhibitors, which can reduce sexual desire); some of these are used “off-label” to treat diminished and a physical exam. It may also be appropriate to sexual desire in women. measure thyroid-stimulating hormone and prolactin Be wary of custom-compounded prescription and get a complete blood cell count. Consider the formulations because they do not undergo the same effects of other physical, psychological, and emotional rigorous quality control as FDA-approved products. complaints on sexual function, and ask about the A number of testosterone products are under relationship itself. development specifi cally for female sexual desire A study from Australia17 concluded that a post- disorders, including an oral product, a cream, gels, a menopausal woman’s previous level of sexual func- patch, a spray, and a vaginal ring. tion, her feelings toward her partner, any change in partner status, and estradiol levels have the greatest 9. Avoid testosterone in cancer infl uence on her sexual interest, arousal, and enjoy- and in heart and liver disease ment. Declining levels of estradiol at menopause Testosterone therapy is contraindicated in patients have a smaller impact than these psychological who have cancer of the breast or uterus, or cardiovas- factors. cular or liver disease.

6. Non-oral forms of testosterone are preferred 10. As with estrogen, use the lowest dosage To avoid the fi rst-pass hepatic effects of oral admin- for the shortest time possible istration, prescribe transdermal patches and topical Once therapy meets treatment goals, it should be gels and creams whenever possible, rather than oral curtailed, if possible. And the dose should be kept as testosterone. low as possible. Oral testosterone in combination with oral estrogen Most trials of testosterone therapy lasted 6 reduces high-density lipoprotein cholesterol and triglyc- months or less, so we lack long-term data on safety erides in postmenopausal women, but non-oral testos- and effi cacy. terone has no signifi cant effect on these parameters. Extended use of high doses of oral testosterone 11. Supraphysiologic levels can cause adverse can cause liver dysfunction in women. effects, some of them permanent Risks include lowering of the voice (which may be per- 7. Impact on fracture risk is unclear manent), enlargement of the clitoris, excess body hair, Adding testosterone to estrogen therapy increases erythrocytosis, edema, and liver dysfunction. Psycho- bone mineral density or reduces bone turnover, but logical effects are also possible.

300 μg per day for 24 weeks. Not only Watch for side effects, did serum testosterone levels increase, and follow closely but satisfying sexual activity and the Testosterone therapy is most appropriate numbers of sexual interactions and or- for women who have undergone surgi- gasms increased (FIGURE 3, page 79). Side cal menopause and for postmenopausal effects of therapy included increased fa- women who are dissatisfi ed with estro- cial hair and acne, but there was no in- gen therapy because of symptoms such crease in serious adverse effects, and no as decreased libido and a diminished increase in withdrawal from the study sense of well-being, including headaches because of side effects. Unfortunately, and fatigue. Side effects of testosterone this patch is in development and unavail- therapy include hirsutism, acne, alopecia, able commercially in the United States. worsening lipoproteins, and, in the case

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TABLE 2 2. Raisz LG, Wiita B, Artis A, et al. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption Testosterone therapies in postmenopausal women. J Clin Endocrinol Metab. available now—or in the pipeline 1996;81:37–43. 3. Shifren JL, Braunstein GD, Simon JA, et al. Transder- Oral mal testosterone treatment in women with impaired • Methyltestosterone sexual function after oophorectomy. N Engl J Med. • Undecanoate 2000;343:682–688. 4. Buster JE, et al. In: Lobo RA, ed. Treatment of the Intramuscular Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. Philadelphia: Lippincott, Williams & Wilkins; • Propionate 1999:142. • Cypionate 5. Davison S, et al. Testosterone levels in women de- • Enanthate cline with aging. Abstract presented at the Endocrine Society Annual Meeting, held June 16–19, 2004, New Subcutaneous (implant) Orleans. • Propionate pellets 6. Hughes CL Jr, Wall LL, Creasman WT. Reproductive hormone levels in gynecologic oncology patients un- • Crystalline pellets dergoing surgical castration after spontaneous meno- Transdermal pause. Gynecol Oncol. 1991;40:42–45. 7. Selby C. Sex hormone-binding globulin. Ann Clin Bio- • Patch chem. 1990;27:532–541. • Gel 8. Simon JA. Estrogen replacement therapy: effects on • Emulsion the endogenous androgen milieu. Fertil Steril. 2002;77: S77–S82. • Spray 9. Miller KK, Biller BM, Hier J, Arena E, Klibanski A. An- Other drogens and bone density in women with hypopituitarism. J Clin Endocrinol Metab. 2002;87:2770–2776. • Vaginal ring 10. Sarrel PM. Broadened spectrum of menopausal symp- • Sublingual (in propylene glycol) tom relief. J Reprod Med. 1998;43:734–740. 11. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen insuffi ciency: the Princeton consensus of methyltestosterone, the possibility of statement on defi nition, classifi cation, and assess- ment. Fertil Steril. 2002;77:660–665. liver toxicity, so women receiving testos- 12. Guay AT. Screening for androgen defi ciency in women: terone should be followed frequently and methodological and interpretive issues. Fertil Steril. carefully to detect any of these effects. 2002;77:S83–S88. 13. Lobo RA, Rosen RC, Yang HM, Block B, Van Der FAST TRACK Hoop RG. Comparative effects of oral and esterifi ed Methyltestosterone Androgen insufﬁ ciency in a nutshell estrogens with or without methyltestosterone on en- Androgens in women engender a general docrine profi les on dimensions of sexual function in can cause liver postmenopausal women with hypoactive sexual de- sense of well-being, which includes elevat- sire. Fertil Steril. 2003;79:1341–1352. toxicity, so close ed energy and mood and increased libido. 14. Sherwin BB, Gelfand MM, Brender W. Androgen en- hances sexual motivation in females: a prospective, follow-up is It is appropriate to consider androgen crossover study of sex steroid administration in the sur- warranted replacement using oral methyltestoster- gical menopause. Psychosom Med. 1985;47:339–351. one, androgen implants, or transdermal 15. Buster JE, Kingsberg SA, Aguirre O, et al. Testoster- one patch for low sexual desire in surgically meno- androgen gels in women with a clinical pausal women: a randomized trial. Obstet Gynecol. diagnosis of androgen insuffi ciency. 2005;105:938–940. 16. Mushayandebvu T, Castracane VD, Gimpel T, Adel T, Before initiating androgen therapy, Santoro N. Evidence for diminished midcycle ovar- however, it is important to measure total ian androgen production in older reproductive aged androgen level and assess clinical symp- women. Fertil Steril. 1996;65:721–723. 17. Dennerstein L, Lehert P, Burger H. The relative effects toms. Also, monitor the incidence of side of hormones and relationship factors on sexual func- effects to ensure that the patient does not tion of women through the natural menopausal transi- exceed normal female androgen levels. It tion. Fertil Steril. 2005;84:174–180. 18. Vermeulen A. The hormonal activity of the postmeno- is hoped that additional forms of andro- pausal ovary. J Clin Endocrinol Metab. 1976;42:247–253. gen replacement for women will become 19. Sarrel P, Dobay B, Wiita B. Estrogen and estrogen–an- available in the near future. ■ drogen replacement in postmenopausal women dissatisfi ed with estrogen-only therapy. Sexual behav- ior and neuroendocrine responses. J Reprod Med. References 1998;43:847–856. 1. Sherwin BB. Hormones, mood, and cognitive func- 20. Braunstein GD. Androgen insuffi ciency in women: tioning in postmenopausal women. Obstet Gynecol. summary of critical issues. Fertil Steril. 2002;77(suppl 1996;87:20S–26S. 4):S94–S99.

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