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Prescribing Testosterone and DHEA: the Role of Androgens in Women

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Prescribing Testosterone and DHEA: the Role of Androgens in Women CURRENT DRUG THERAPY CME MOC Taryn Smith, MD, NCMP Pelin Batur, MD, FACP, NCMP Section of Women’s Health, Division of Department of Subspecialty Women’s Health, Ob/Gyn & General Internal Medicine, Mayo Clinic, Women’s Health Institute, Cleveland Clinic; Associate Jacksonville, FL Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH; Deputy Editor, Cleveland Clinic Journal of Medicine Prescribing testosterone and DHEA: The role of androgens in women ABSTRACT strogens are the principal sex hormones E responsible for female reproductive matu- In women, the androgens testosterone and dehydroepi- ration and sexual characteristics. However, androsterone (DHEA) play important physiologic roles in androgens are also important for female sexual reproductive tissues, mood, cognition, the breast, bone, health and well-being.1 The physiologic ef- muscle, vasculature, and other systems. This article re- fects of androgens are in part due to their role views the effects of androgens in women, as well as the as precursors for estrogen synthesis, but these indications and best-practice recommendations for the hormones also have independent effects on use of androgen therapy. female reproductive tissues, mood, cognition, breasts, bones, muscles, vasculature, and other systems.1 ■ KEY POINTS Currently, the only evidenced-based indication for testos- See related editorial, page 44 terone therapy in women is for treating hypoactive sexual Here we will discuss the physiologic roles desire disorder in postmenopausal women. Several ran- of androgens as well as the indications and domized controlled trials have established the short-term best-practice recommendations for androgen safety and effi cacy of prescribed testosterone in women therapy in women. when doses approximate physiologic levels. ■ ANDROGEN SYNTHESIS, PRODUCTION, When treatment is offered, transdermal preparations AND MEASUREMENT IN WOMEN are preferred, and testosterone levels should be checked The biologically active androgens in women before and during treatment to ensure physiologic dos- are dehydroepiandrosterone sulfate (DHEA-S), ing. Decisions to continue treatment are based on clinical dehydroepiandrosterone (DHEA), androstene- response; hormone levels do not correlate with symptom dione, testosterone, and dihydrotestosterone. burden, and testing is intended only to ensure safe deliv- In women, roughly 25% of androgen pro- ery of treatment. duction occurs in the adrenal glands, 25% occurs in the ovaries, and the rest occurs pe- ripherally.2 DHEA-S, DHEA, and androstene- Clinicians should avoid diagnosing female androgen defi - dione are the main prohormones that are pe- ciency on the basis of hormonal testing, as the syndrome ripherally converted to the active androgens is not well defi ned, and interpreting androgen levels and testosterone and dihydrotestosterone. DHEA- their physiologic effects is complex. S is almost exclusively produced in the adre- nal glands, whereas DHEA, androstenedione, and testosterone are produced in the adrenal glands and ovaries and by peripheral conver- sion. In target tissues, circulating testosterone is converted to dihydrotestosterone by 5-al- doi:10.3949/ccjm.88a.20030 pha-reductase and aromatized to estradiol . CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 88 • NUMBER 1 JANUARY 2021 35 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. ANDROGENS IN WOMEN TABLE 1 sensitivity. Therefore, androgen effects on body tissues are complex, and there is no abso- Conditions that affect circulating lute testosterone level that defi nes “androgen levels of sex hormone-binding defi ciency.” Low serum testosterone levels in globulin (SHBG) women should be interpreted with caution. Liquid or gas chromatography and tandem Decrease SHBG mass spectrometry assays are reliable and ac- (increase free [active] testosterone) curate laboratory methods for measuring total Obesity Exogenous androgen therapy testosterone and give reproducible results. In Insulin contrast, direct radioimmunoassays for mea- Glucocorticoids suring testosterone are considerably less accu- rate.7 Salivary assays are neither sensitive nor Increase SHBG specifi c and are not recommended for clinical (decrease free [active] testosterone) use.2 Serum DHEA-S is the most reliable mea- Pregnancy 1 Exogenous estrogen therapy sure of adrenal androgen production. Liver cirrhosis Hyperthyroidism ■ ANDROGEN EFFECTS IN WOMEN Cardiometabolic The effects of sex steroids on the cardiovas- cular system are not fully understood. Similar Androgen levels decline with age through- to the vascular benefi ts of estrogen during the out a woman’s life, starting in her mid-30s.3 premenopausal years (promoting vasodilation, Menopause is not associated with a rapid de- limiting atherosclerotic plaque progression, cline in androgen production; the postmeno- reducing infl ammation),8,9 testosterone acts pausal ovary is hormonally active and accounts directly on the vasculature in a concentration- for 40% to 50% of postmenopausal testoster- 4, 5 dependent fashion, and indirectly after being The effects one production. Consequently, women who converted to estradiol. At physiologic levels, have undergone bilateral oophorectomy have of sex steroids testosterone enhances nitric oxide production a marked decrease in circulating testosterone and infl uences both potassium and calcium on the levels, though serum concentrations of DHEA ion channels, leading to vasorelaxation.8 Low and androstenedione remain stable due to ad- testosterone levels have been associated with cardiovascular 4 renal compensation. Ten years after the onset unfavorable cardiovascular outcomes.8 How- system of menopause, circulating testosterone and ever, testosterone promotes vasoconstriction are not fully androstenedione levels are half of perimeno- at supraphysiologic levels.8 pausal levels.6 understood A prospective study of over 2,800 post- In circulation, active testosterone is free or menopausal women showed that a higher bound to albumin. Testing of total testoster- testosterone-to-estrogen ratio correlated with one levels also measures inactive testosterone, a higher risk of heart failure and coronary which is bound to sex hormone-binding glob- heart disease, whereas higher levels of estro- ulin (SHBG), a liver-synthesized protein with gen seemed to have a protective effect.10 a high affi nity for sex steroids. Conditions that The effects of exogenous testosterone on increase or decrease SHBG inversely affect the cardiovascular system have been investi- circulating levels of free (active) testosterone gated in prospective, randomized controlled (Table 1). trials, though these trials have typically been Peripheral conversion of precursor hor- of limited duration (less than 2 years). Most mones to active testosterone is tissue-specifi c of them showed no increase in adverse car- and depends on membrane and cellular recep- diovascular events with testosterone therapy tor expression as well as activity of converting as long as testosterone levels remained within enzymes.1 Measured serum testosterone con- normal physiologic ranges,8,9,11 but most of centrations do not correlate with peripheral them excluded women at high risk of cardio- tissue androgen production or tissue receptor vascular disease.7 36 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 88 • NUMBER 1 JANUARY 2021 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. SMITH AND BATUR Meta-analyses have shown that, compared gen receptors throughout the central nervous with placebo, oral testosterone is associated system, with actions that affect sexual desire, with an increase in low-density lipoprotein thermoregulation, cognition, sleep, visual cholesterol and decreases in high-density li- spatial skills, and language.16 A review of the poprotein cholesterol and triglycerides,12–14 protective effects of sex steroids on Alzheim- though transdermal testosterone therapy has er disease suggests that testosterone reduces neutral effects on the lipid profi le.12 Testos- oxidative stress and accumulation of amyloid terone therapy (oral or transdermal) does not beta within the brain and accelerates nerve signifi cantly affect glycemic markers, blood regneration.17 pressure, body mass index, or hematocrit Though most women going through meno- when serum testosterone levels remain within pause do not have major cognitive changes, normal physiologic ranges.7,12 some have changes that signifi cantly affect A nonsignifi cant increase in risk of venous their quality of life; this may be especially thromboembolism has been reported; howev- concerning to young women undergoing oo- er, concurrent estrogen use may be a factor.7 phorectomy. Skin and hair Only a few randomized controlled tri- Dihydrotestosterone, converted from testos- als have evaluated the effects of testosterone terone by 5-alpha-reductase, is the most po- treatment on cognition, and they are limited tent androgen acting on hair follicles.15 In the by small sample size and, in some trials, by con- scalp, dihydrotestosterone promotes miniatur- current estradiol therapy. That said, the avail- ization of hair follicles and shortens the anti- able data do not suggest any negative effects of 15 testosterone therapy on cognition, well-being, gen phase of hair growth, leading to hair loss. 13,17,18 Women with female pattern hair loss tend or mood in postmenopausal women.
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