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Home , Androgen prohormone, Androsterone, Dihydrotestosterone

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 , 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 and DHEA: The role of in women

ABSTRACT strogens are the principal sex E responsible for female reproductive matu- In women, the androgens testosterone and dehydroepi- ration and sexual characteristics. However, (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 synthesis, but these indications and best-practice recommendations for the hormones also have independent effects on use of 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, 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 sulfate (DHEA-S), ing. Decisions to continue treatment are based on clinical dehydroepiandrosterone (DHEA), androstene- response; levels do not correlate with symptom dione, testosterone, and . 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, , 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 .

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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 -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- 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- 1 Exogenous estrogen therapy sure of adrenal androgen production. cirrhosis Hyperthyroidism ■ ANDROGEN EFFECTS IN WOMEN Cardiometabolic The effects of sex 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 production a marked decrease in circulating testosterone and infl uences both potassium and on the levels, though serum concentrations of DHEA 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 -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 .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

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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 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 profi le.12 Testos- oxidative stress and accumulation of amyloid terone therapy (oral or transdermal) does not beta within the 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. 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- , 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 . 13,17,18 Women with female tend or mood in postmenopausal women. 19 to have higher androgen-to-estrogen ratios. Davis et al found that postmenopausal Activation of androgen receptors at hair fol- women taking transdermal testosterone licles on the chin, cheeks, and upper lips leads 300 μg/day for 26 weeks and not taking other 16 hormonal therapies showed signifi cant im- to coarse hair growth or . In women There is no with polycystic ovary syndrome, hirsutism may provement in verbal learning and memory but 18 be related to excess ovarian testosterone pro- not well-being. Huang et al, in a randomized absolute duction, whereas most women with idiopathic controlled trial in hysterectomized women testosterone hirsutism have normal serum androgen levels, (with or without oophorectomy) found that suggesting exaggerated 5-alpha-reductase ac- intramuscular testosterone therapy at physi- level that tivity.16 A meta-analysis found the risk of hir- ologic and supraphysiologic doses with con- defi nes current transdermal estradiol did not affect sutism to be 10.7% in women on testosterone ‘androgen therapy compared with 6.6% with placebo (P cognitive function. 14 defi ciency’ = .011). Musculoskeletal Androgens stimulate the growth and secre- Androgen receptors are present on osteoblasts. tory function of sebaceous glands, leading to Low endogenous androgen levels in men- increased sebum production, in turn provid- struating and postmenopausal women have ing a growth medium for Cutibacterium acnes.15 been associated with low bone mass and in- Although most women with have nor- creased risk of vertebral and hip fractures.20,21 mal serum androgen levels, a meta-analysis Conversely, higher free testosterone levels in reported the risk of acne to be 7.0% in women postmenopausal women have been associated on testosterone therapy vs 4.7% with placebo with lower hip fracture risk.22 However, lack- (P < .001).14 ing randomized controlled trials to assess the Cognition and mood effect of testosterone therapy on fracture risk, The brain, like many organs, is affected by the use of androgens for bone health and frac- ovarian hormone withdrawal. Studies have ture prevention cannot be recommended. shown that both estrogen and testosterone The Testosterone Dose Response in Sur- have anti-infl ammatory and neuroprotec- gically Menopausal Women trial was a multi- tive effects on the brain.17 There are andro- center, double-blind, placebo-controlled trial

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TABLE 2 A recent systematic review and meta-anal- ysis found no change in breast density after tes- Conditions that cause a low tosterone therapy.12 In addition, short-term tes- androgen state in women tosterone therapy was not associated with any of the following adverse effects: breast pain, ten- Decreased ovarian androgen production derness, engorgement, masses, or breast cancer.13 Chemotherapy Radiation In an open-label study of transdermal testos- Ovarian failure or insuffi ciency terone 300 μg daily, 900 surgically menopausal Oophorectomy women, ages 20 through 70, were followed for up to 4 years.26 Three cases of invasive breast Decreased adrenal androgen production cancer were reported in that time, consistent Adrenal insuffi ciency with population background rates of breast Hypothalamic-pituitary axis cancer. Malnutrition Androgen therapy poses a theoretical risk Anorexia of endometrial hyperplasia; however the risk Hypopituitarism is likely very low at physiologic levels because levels of endometrial expression are low. Early studies have shown no evidence of Hormonal contraceptives endometrial stimulation with androgen thera- Antiandrogenic agents py in postmenopausal women.1 Oral estrogen therapy Opioids ■ SHOULD WOMEN BE SCREENED FOR LOW ANDROGEN LEVELS? of testosterone in hysterectomized women with Symptoms of “female androgen insuffi ciency” or without oophorectomy, after a 12-week run- have been popularly described as including sexu- in period of transdermal estradiol administra- al dysfunction, chronic fatigue, dysphoric mood, tion. Testosterone recipients demonstrated im- The Endocrine and diminished sense of well-being. However, proved lean body mass and muscle performance low serum androgen levels do not reliably cor- Society in a dose-dependent fashion, with women on relate with a clinically defi ned syndrome. Even supraphysiologic doses having the most im- recommends 23 among oophorectomized women, a decline in provement compared with placebo. serum testosterone level does not consistently against In contrast, other studies have found neu- correlate with clinical symptoms.27 Lack of con- diagnosing tral effects on lean body mass, total body fat, gruency among current laboratory assays also or muscle strength when testosterone is given limits the development of biochemical criteria ‘female 7 at physiologic doses. It is diffi cult to draw to diagnose androgen insuffi ciency in women. androgen defi nitive conclusions, given that the studies For these and other reasons, the Endocrine defi ciency’ were typically small and were conducted in Society recommends against diagnosing “fe- women on concomitant estrogen therapy. male androgen defi ciency” or using testoster- Breast and endometrium one to treat low androgen states in women.28 Breast tissue has abundant levels of aroma- There is no evidence to support testosterone tase; thus, in theory, testosterone may have therapy for female well-being, mood, vasomo- indirect proliferative effects on the breast by tor symptoms, bone health, cardiovascular 8,27,29 being converted to estrogen. However, in vi- health, or metabolic dysfunction. tro breast cultures and in vivo primate stud- It is important to remember that numerous ies demonstrate that testosterone’s effects on medical conditions and medications can result breast tissue is antiproliferative and proapop- in low androgen levels in women (Table 2). totic, with inhibition of ■ alpha as well as breast cancer cell growth.24 ROLE OF ANDROGEN THERAPY These effects largely depend on the type and IN FEMALE SEXUAL HEALTH dose of androgen therapy as well as the breast The only evidence-based indication for testos- cancer cell line.25 terone therapy in women is to treat hypoactive

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sexual desire disorder after menopause.7,28,29 in natural and surgically menopausal women Currently, no testosterone formulation for with compared transder- women has been approved by the US Food and mal testosterone patches (300 μg/day) and Drug Administration (FDA), though vaginal placebo.33–36 The patch signifi cantly increased DHEA () has been approved for sexual desire and sexually satisfying events treatment of moderate to severe dyspareunia. while decreasing sexual-related distress (in 3 of 4 studies) compared with placebo. In one Female sexual dysfunction study,36 sexually satisfying events increased by Female sexual dysfunction is multifactorial, 2.1 episodes per month with the transdermal often infl uenced by biologic, emotional, cul- patch compared with 0.98 with placebo (P < tural, and interpersonal factors. It can mani- .001). fest as decreased sexual desire, painful inter- The safety and effi cacy of the patch in course, and diminished arousal or orgasmic postmenopausal women was also evaluated in response, or both. the 52-week APHRODITE study (A Phase III The American Psychiatric Association’s Research Study of Female Sexual Dysfunction Diagnostic and Statistical Manual of Mental Dis- in Women on Testosterone Patch Without 30 orders, Fifth Edition (DSM-5) merged the pre- Estrogen).37 Two doses, 150 μg/day and 300 vious diagnoses of female hypoactive sexual μg/day, were compared with placebo. Signifi - desire disorder (HSDD) and female arousal cant improvements were noted in sexual de- disorder (FAD) into a single diagnosis of female sire and sex-related distress in both treatment sexual interest/arousal disorder (FSIAD). While groups (300 μg/day, P < .001, and 150 μg/day, HSDD and FAD have overlapping features, P = .04). Adverse events were minimal, the the Fourth International Consultation on most common being application-site reaction, Sexual Medicine and the International Society acne, breast pain, headache, and hirsutism. of the Study of Women’s Sexual Health (ISS- All metabolic markers remained stable, in- WSH) recommend against combining these cluding liver enzymes, serum , complete diagnoses for clinical purposes.31,32 According blood cell counts, and metabolic panels. to the ISSWSH, HSDD can be defi ned by 6 or Many randomized controlled trials have Female sexual 32 more months of any of the following : shown insignifi cant changes in levels of total dysfunction is 1. Lack of motivation for sexual activity, in- or free testosterone after treatment with the cluding 300 μg/day transdermal testosterone patch.27 multifactorial • Absent or decreased spontaneous sexual A transdermal testosterone spray was stud- thoughts or fantasies ied in a randomized controlled trial in women • Absent or decreased responsive desire to with FSIAD and low serum free testosterone. erotic cues and stimulation or inability to The self-reported frequency of satisfactory maintain desire or interest through sexual sexual events was greater with active treat- activity. ment than with placebo.38 2. Loss of desire to initiate or participate in A 12-week, double-blind randomized con- sexual activity, including behavioral respons- trolled trial found improved well-being (P = es such as avoidance of situations that could .003), mood (P < .06), and sexual function lead to sexual activity, that is not secondary (P < .001) in women receiving testosterone to sexual pain disorders and is combined with cream 10 mg/day compared with placebo.39 clinically signifi cant personal distress that in- During the study period, serum testoster- cludes frustration, grief, incompetence, loss, one levels stayed in the high-normal range sadness, sorrow, or worry. for postmenopausal women, and no adverse Randomized controlled trials in postmeno- events were noted. pausal women who reported decreased sexual In contrast, 2 large phase 3 randomized desire have demonstrated that testosterone controlled trials investigating transdermal tes- therapy positively infl uences sexual function, tosterone gel 0.22 g/day in women with sexual though none have defi ned target serum andro- dysfunction showed no statistically signifi cant gen levels that correlate with sexual function.8,27 differences in sexually satisfying events or Four 24-week randomized controlled trials sexual desire between treatment and placebo

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groups.28 Inconsistencies between studies could androgens regulate vaginal mucin production be due to dosing and route of administration. in epithelial cells, improve blood fl ow by in- Comments. There is suffi cient high-quali- creasing nitric oxide, and infl uence neurotrans- ty evidence to support letting postmenopausal mitter content and nerve density.41 There is a women with HSDD try testosterone, for a positive correlation between testosterone lev- short time, after other reasons for their sexual els and volume of urethrovaginal tissue.39 concerns have been excluded. Evidence is DHEA therapy for GSM lacking to support the use of testosterone for The only FDA-approved vaginal andro- sexual dysfunction in premenopausal women. gen for GSM is intravaginal DHEA 6.5 mg Before starting testosterone therapy for (prasterone), which improves cell matura- HSDD, all women should undergo a thorough tion, pH, and dyspareunia compared with pla- medical and psychosocial assessment and cebo,42 leads to improvements in all domains physical examination. Other contributors to of sexual function,43 and has neutral effects on symptoms should be identifi ed and addressed the endometrium after 12 months of therapy.44 before starting testosterone therapy, including Most studies suggest no signifi cant increase in side effects, mood disorders, rela- serum levels of sex steroids with the use of tionship concerns, or the genitourinary syn- vaginal DHEA.45 Women who have no his- drome of menopause. tory of estrogen-dependent cancers should Though there is evidence of benefi t, cur- be routinely offered treatment for GSM with rently there are no approved testosterone for- vaginal estrogen or DHEA. mulations for women in the United States. In a 12-week 3-armed randomized con- Regulated, safe delivery methods are needed. trolled trial,46 postmenopausal women with Systemic DHEA therapy has not been a history of breast or gynecologic cancer, re- shown to improve symptoms of sexual dys- ceived compounded vaginal DHEA 3.25 mg/ function in women who have normal adrenal day, DHEA 6.5 mg/day, or a nonhormonal function.7 moisturizer. Dyspareunia and dryness im- Before starting proved in all groups, with no signifi cant differ- ■ GENITOURINARY SYNDROME ences between either dose of vaginal DHEA testosterone, OF MENOPAUSE and plain moisturizer (P < .005). However, women Genitourinary syndrome of menopause women in the DHEA 6.5-mg/day group re- ported a signifi cant improvement in sexual should undergo (GSM), formerly known as vulvovaginal at- rophy, is an umbrella term describing urinary, health compared with the other groups (P < a thorough genital, and sexual dysfunction as a result of .0001). (DHEA is currently not approved to medical and a decline in sex hormone levels. It affects up treat sexual dysfunction.) In a secondary analysis in breast cancer to 70% of postmenopausal women, and with- 45 psychosocial out treatment, symptoms tend to progress over survivors, serum DHEA-S and testosterone assessment time.40 Common symptoms of GSM include concentrations were signifi cantly higher in dyspareunia, vaginal dryness and irritation, both DHEA groups than in women using plain dysuria, urinary frequency, urinary urgency, moisturizer, though levels remained within recurrent urinary tract infection, and alkaline normal postmenopausal ranges. Serum estra- shift in vaginal pH.39 diol levels were increased in the DHEA 6.5- mg/day group but not the DHEA 3.25-mg/day Nonhormonal therapies, such as vaginal group. The subgroup of women concurrently moisturizers and lubricants, do not restore the taking aromatase inhibitors had no difference integrity of genitourinary tissues. Hormonal in serum hormone levels with vaginal DHEA therapies, including vaginal estrogen and compared with a plain moisturizer. DHEA, are safe and the most effective treat- ments for GSM.38,39 Testosterone therapy for GSM Androgen and estrogen receptors are pres- Data on the safety and effi cacy of testoster- ent in the vaginal mucosa, submucosa, stroma, one therapy for treating symptoms of GSM smooth muscle (vaginal, urethral, and blad- are scant and results are inconsistent. Several der), and vascular endothelium. In the , studies suggest that vaginal testosterone im-

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proves symptoms.28 However, these studies are (EEMT) has been on the limited by small sample sizes, supraphysiologic market since the 1960s. It was approved by serum levels, inconclusive effi cacy and safety, the FDA on the basis of its safety before the and lack of power. More research demonstrat- current safety and effi cacy requirements were ing safety and effi cacy is needed before clinical enacted. The manufacturers have not sought use is considered. reapproval. Oral EEMT is indicated for use in postmenopausal women with moderate to ■ PRESCRIBING TESTOSTERONE THERAPY severe vasomotor symptoms not improved on Despite studies showing potential benefi ts in estrogen alone. Two doses are available (estro- sexual health, no testosterone formulations gen 1.25 mg plus methyltestosterone 2.5 mg, for women have been approved for use in the and estrogen 0.625 mg plus methyltestosterone United States for this indication. Short-term 1.25 mg), and short-term use is recommended. low-dose transdermal formulations are the A 2003 postmarketing safety surveillance study revealed very few serious adverse events in preferred method of testosterone delivery for 47 women, based on available safety data and women using EEMT between 1989 and 2002. side effect profi les. The twice-weekly 300-μg/ If oral therapy is chosen, cardiometabolic day patch was previously approved in Europe; risks should be assessed at follow-up visits. In however, it is no longer available due to low addition, liver function tests should be moni- sales.27 This product was never approved in tored periodically. the United States. Intramuscular and pellet therapies should be avoided. These options expose users to po- Testosterone formulations available in tential for prolonged exposure and supraphysi- the United States are indicated for use in ologic dosing.8 men only, and clinicians should use caution when prescribing them to women. To avoid Monitoring during treatment supraphysiologic dosing, women should be Once a decision to start systemic testosterone prescribed a tenth of the recommend male has been made, the Endocrine Society and the dose—or less. However, even when only 1 Global consensus position statement on the The only month’s worth of a male product is prescribed, use of testosterone therapy for women recom- FDA-approved a patient will have a year’s supply of medica- mend checking baseline testosterone levels be- tion, which increases the risk for supraphysi- fore initiating therapy.7,8,28 Levels should then vaginal ologic dosing if she applies the product more be followed 3 to 6 weeks after therapy is initi- androgen than recommended, and does not return to be ated and every 6 months thereafter to avoid assessed for safe blood levels. Compounded toxicity and supraphysiologic dosing.28 Serum for GSM formulations are frequently used for women; hormone levels do not correlate with clinical is intravaginal however, these products are not subject to po- response, and measuring them is intended to DHEA tency and purity regulations. ensure safe delivery of treatment. In contrast, Topical products should be applied to women using vaginal DHEA should not have the inner thigh, buttock, abdomen, or vulva blood hormone levels checked, as the serum to avoid transfer to contacts. The breast and concentration of sex steroids is minimally af- arms should be avoided. We recommend use fected by this route of administration. in an area that can be shaved, in case of in- The follow-up should focus on a clinical crease in hair growth. Adverse events are lim- assessment of perceived risks vs benefi ts. The ited when serum testosterone levels remain in goals are to improve sexual desire, arousal, physiologic ranges. orgasmic function, pleasure, or sexual respon- Oral testosterone undergoes fi rst-pass me- siveness, with a reduction in sexual concerns tabolism in the liver and tends to be associ- and distress. The treatment should be stopped ated with more side effects and adverse events in women who do not respond to therapy after than other formulations.13,14 For this reason, 6 months of consistent use. the most recent consensus statement discour- When hormone levels on treatment ap- ages the use of oral testosterone.8 proximate the normal physiologic levels of a Oral combination esterifi ed estrogen- premenopausal woman, there is no signifi cant

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increased risk of alopecia, clitoromegaly, or ■ TAKE-HOME POINTS 8,28 voice changes. However, these potential • Androgens play an important physiologic concerns should be reviewed with patients. role in women and can promote sexual Mild increases in acne or hirsutism may be health. seen. The risk of vaginal bleeding was in- • Clinicians should avoid making a diagno- creased in the users of the 300-μg/day patch, sis of androgen defi ciency in women, as the though no increased risk of endometrial hy- syndrome is not well defi ned. 28 pertrophy was observed over 12 months. Any • Well-designed, randomized, placebo-controlled woman with postmenopausal bleeding should trials are needed to establish long-term safety, undergo endometrial assessment, whether or effi cacy, and appropriate dosing of testosterone not she is using hormonal therapies. therapy in women. There is no indication to perform addi- • Evidence suggests that testosterone thera- tional breast imaging, cardiac testing, or other py in women is associated with few adverse laboratory tests. However, patients should be events when serum hormone levels remain seen at least annually in clinic to ensure they within physiologic ranges. are up-to-date with their preventive screen- • Currently, the only evidence-based indica- ings. When serum testosterone levels remain tion for testosterone therapy in women is in normal physiologic ranges, studies show that for the treatment of HSDD in postmeno- neither oral nor nonoral testosterone therapy pausal women, but only after a thorough signifi cantly affects the lipid profi le, glycemic evaluation and consideration of other markers, blood pressure, body mass index, or causes of the sexual concerns. 7,13 hematocrit. No current evidence links phys- • Transdermal therapy is the preferred meth- iologic-dose testosterone therapy with adverse od of delivery. cardiovascular events, though most studies • Serum testosterone levels should be moni- followed patients for less than 5 years and ex- tored at regular intervals to avoid supra- cluded those considered at high risk for cardio- physiologic dosing ■ vascular disease and breast cancer.8,9,11 A recent meta-analysis showed that testosterone therapy ■ DISCLOSURES was not associated with more serious adverse The authors report no relevant fi nancial relationships which, in the context events than placebo or a comparator.12 of their contributions, could be perceived as a potential confl ict of interest. ■ REFERENCES 8. Dos Santos RL, Da Silva FB, Ribeiro RF, Stefanon I. Sex hormones in the cardiovascular system. Horm Mol Biol Clin Invest 2014; 1. Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transforma- 18(2):89–103. doi:10.1515/hmbci-2013-0048 tion into androgens and in peripheral target tissues: 9. Ouyang P, Michos ED, Karas RH. Hormone replacement therapy intracrinology. Front Neuroendocrinol 2001; 22(3):185–212. and the cardiovascular system. Lessons learned and unanswered doi:10.1006/frne.2001.0216 questions. J Am Coll Cardiol 2006; 47(9):1741–1753. 2. Bachmann G, Bancroft J, Braunstein G, et al. Female androgen doi:10.1016/j.jacc.2005.10.076 insuffi ciency: the Princeton consensus statement on defi nition, 10. Zhao D, Guallar E, Ouyang P, et al. Endogenous sex hormones and classifi cation, and assessment. Fertil Steril 2002; 77(4):660–665. incident cardiovascular disease in post-menopausal women. J Am doi:10.1016/S0015-0282(02)02969-2 Coll Cardiol 2018; 71(22):2555–2566. doi:10.1016/j.jacc.2018.01.083 3. Zumoff B, Strain GW, Miller LK, Rosner W. Twenty-four-hour mean 11. Reis SLB, Abdo CHN. Benefi ts and risks of testosterone treatment plasma testosterone concentration declines with age in normal for hypoactive sexual desire disorder in women: a critical review premenopausal women. J Clin Endocrinol Metab 1995; 80(4):1429– of studies published in the decades preceding and succeeding the 1430. doi:10.1210/jcem.80.4.7714119 advent of phosphodiesterase type 5 inhibitors. Clinics (Sao Paulo) 4. Fogle RH, Stanczyk FZ, Zhang X, Paulson RJ. Ovarian androgen 2014; 69(4):294–303. doi:10.6061/clinics/2014(04)11 production in postmenopausal women. J Clin Endocrinol Metab 12. Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and effi cacy 2007; 92(8):3040–3043. doi:10.1210/jc.2007-0581 of testosterone for women: a systematic review and meta-analysis 5. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, Von Mühlen D. of randomised controlled trial data. Lancet Diabetes Endocrinol Hysterectomy, oophorectomy, and endogenous sex hormone levels 2019; 7(10):754–766. doi:10.1016/S2213-8587(19)30189-5 in older women: the Rancho Bernardo study. J Clin Endocrinol 13. Somboonporn W, Bell RJ, Davis SR. Testosterone for peri- and Metab 2000; 85(2):645–651. doi:10.1210/jc.85.2.645 postmenopausal women. Cochrane Database Syst Rev 2005 Oct 6. Sarrel PM. Androgen defi ciency: menopause and estrogen-related 19;(4):CD004509. doi:10.1002/14651858.cd004509.pub2 factors. Fertil Steril 2002; 77(suppl 4):63–67. 14. Elraiyah T, Sonbol MB, Wang Z, et al. Clinical review: the benefi ts doi:10.1016/s0015-0282(02)02967-9 and harms of systemic testosterone therapy in postmenopausal 7. Davis SR, Baber R, Panay N, et al. Global consensus position state- women with normal adrenal function: a systematic review and ment on the use of testosterone therapy for women. Climacteric meta-analysis. 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Hypoactive sexual desire disorder: International Society for the Study of Women’s Sexual Address: Pelin Batur, MD, Subspecialty Care for Women’s health, A81, Health (ISSWSH) expert consensus panel review. Mayo Clin Proc Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; 2017; 92(1):114–128. doi:10.1016/j.mayocp.2016.09.018 [email protected]

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