Overview of androgen deficiency and therapy in females

Author:: Laurence C Udoff, MD
Section Editors:: Robert L Barbieri, MD; William F Crowley, Jr, MD
Deputy Editor:: Kathryn A Martin, MD

Literature review current through: May 2024.

This topic last updated: Nov 30, 2023.

INTRODUCTION — All females produce androgens, which may contribute to maintaining normal ovarian function, bone metabolism, cognition, and sexual function. This topic will review androgen production and the physiologic role of androgens in pre- and postmenopausal females and the possible consequences of androgen deficiency. A more detailed discussion of the diagnosis and management of female sexual dysfunction, including the role of androgen therapy is found separately. (See "Overview of sexual dysfunction in females: Management".)

ANDROGEN PRODUCTION

Premenopausal females — The major androgens in the serum of normal cycling females are dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT), in descending order of serum concentrations [1]. Though abundant in the circulation, DHEAS, DHEA, and androstenedione may be considered prohormones, requiring conversion to testosterone or DHT to express their androgenic effects. DHT is the main intracellular androgen.

Androgens are produced in the adrenal gland, the ovary, and from the peripheral conversion of prohormones.

●DHEAS, although a weak androgen, is the most abundant androgen. It is produced solely by the adrenal gland at a rate of 3.5 to 20 mg per day [2]. Circulating levels are in the range of 75 to 375 mcg/dL (2 to 10 micromol/L).

●DHEA is also produced in the adrenal gland (50 percent), the ovary (20 percent), and from peripheral conversion of DHEAS (30 percent), with total production rates of 6 to 8 mg per day [3]. Serum DHEA concentrations range from 0.2 to 0.9 mcg/dL (7 to 31 nmol/L). DHEA is converted to DHEAS in the adrenal, liver, and intestines (which contain a sulfotransferase).

●In the adrenal glands and peripheral tissues such as adipose tissue, small amounts of DHEA and DHEAS are converted to more active androgens, such as androstenedione, androstenediol, testosterone, and DHT, and estrogens such as estradiol and estrone. These hormones then exert their usual androgenic and estrogenic effects via the androgen and estrogen receptors, respectively.

●Androstenedione production is split equally between the adrenal gland and the ovary. Daily rates of production are 1.4 to 6.2 mg/day, and circulating levels are in the range of 160 to 200 ng/dL (5.6 to 7 nmol/L) [4,5].

●Testosterone is synthesized in the adrenal gland (25 percent), the ovary (25 percent), and from the peripheral conversion of androstenedione (50 percent). Daily production rates in females are in the range of 0.1 to 0.4 mg/day, compared with 5 to 7 mg a day in men, and circulating levels are between 20 and 60 ng/dL (0.7 to 2.08 nmol/L) with the lowest concentrations found during the early follicular phase followed by a 20 percent increase at midcycle [3].

Nearly all (99 percent) of circulating testosterone is protein bound (mainly to sex hormone-binding globulin [SHBG]) [6]. Therefore, any impact on SHBG concentration (eg, oral estrogen-mediated increase in SHBG) affects the concentration of free/active testosterone. SHBG normally decreases after menopause, at least partially due to the decline in serum estradiol.

●DHT is largely an intracellular androgen. DHT is produced within target cells by the 5-alpha reduction of testosterone. DHT acts within the cell, and little DHT re-enters the circulation; hence, the serum concentration is relatively low [7].

Effect of age and menopause — Cross-sectional and longitudinal studies show that serum androgen concentrations (total and free testosterone, androstenedione) gradually decline in females of reproductive age, with no further decrease after clinical menopause [8-11].

The secretion and serum concentrations of both DHEA and DHEAS decrease markedly with age from the third decade onward, so that in 70 to 80 year olds, serum concentrations of both are approximately 20 percent of those in persons 20 to 30 years old (figure 1) [8,12]. In females, this decline is accompanied by a substantial fall in urinary 17-ketosteroid (17-KS) excretion (figure 1).

The vast majority of evidence, with the exception of one study [13], suggests that the postmenopausal ovary continues to be an important source of androgen production [14-25] but not estrogen production. Ovarian testosterone production remains relatively constant after natural menopause, thereby increasing the relative ovarian contribution to overall testosterone production [14]. These observations are substantiated by the larger ovarian-to-peripheral serum gradient of testosterone in postmenopausal than in premenopausal females [26] and by the 40 to 50 percent decrease in serum testosterone concentration seen after oophorectomy in postmenopausal females [15,16].

The relatively high rate of androgen production in the postmenopausal ovary is due to the increase in gonadotropin secretion, which stimulates steroidogenesis in ovarian hilar cells or luteinized stromal cells [19]. Ovarian stromal tissue has receptors for both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [17,20], and human chorionic gonadotropin (hCG) stimulates androstenedione, estradiol, and progesterone secretion by isolated ovarian cortical stromal and hilar cells [21,22]. In addition, postmenopausal females given hCG have a small increase in serum testosterone [23], but not estradiol, concentrations [25].

PHYSIOLOGIC ROLE OF ANDROGENS

Follicular development — Androgens play a critical role in male reproductive development and function, but their role in female reproduction is less clear. In addition to providing the substrate for estrogen synthesis during follicular development, studies have shown the importance of appropriate androgen balance, as both androgen excess and androgen deficiency are associated with abnormalities in follicular development [27,28]. In addition, some data suggest a role for androgens in prevention of follicular atresia and promotion of follicle growth [29].

Sexual function — It has also been proposed that androgens play a role in female sexual function, but the magnitude of the role is uncertain [30]. The assertion that low androgen levels play a role in female sexual function is based upon the known role of androgens in male sexuality as well as clinical trials of exogenous testosterone in postmenopausal females in which small benefits on some aspects of female sexuality were observed. In females with hypopituitarism, testosterone therapy may have benefits in sexual function in females with both corticotropin (ACTH) and gonadotropin deficiency, but only when serum testosterone concentration is increased to the upper limit of normal for females [31]. (See "Treatment of hypopituitarism", section on 'Androgen replacement'.)

However, in studies that measure serum hormone levels and sexual function in females, the correlation between androgen concentrations and sexual function is weak. In addition, females with hyperandrogenism (eg, polycystic ovary syndrome [PCOS]) do not exhibit beneficial sexual effects (although females with severe hyperandrogenism from ovarian or adrenal androgen-secreting tumors sometimes experience intrusive sexual thoughts). (See "Overview of sexual dysfunction in females: Epidemiology, risk factors, and evaluation", section on 'Role of androgens'.)

Nonreproductive functions — Androgen receptors are found in many other tissues in females including the vasculature [32,33], brain [34], breast, skin, muscle, adipose, and bone [35-37], suggesting that androgens have nonreproductive functions, as well (see 'Risks and side effects of androgen therapy' below). These possible effects include:

●Adverse cardiovascular effects – In females, androgens have been thought to be atherogenic, largely based upon on the higher rates of cardiovascular disease in men compared with females and the possible higher risk in females with androgen excess (eg, PCOS) compared with normal females [38,39]. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Coronary heart disease'.)

One proposed mechanism by which androgens may adversely affect the risk of cardiovascular disease is through a decrease in serum high-density lipoprotein (HDL) cholesterol concentrations. Females with PCOS are more likely to have lower HDL, higher triglycerides, higher low-density lipoprotein (LDL), and an increase in small dense LDL particles when compared with females of similar body mass index (BMI) and insulin resistance without PCOS [40-44]. (See 'Risks and side effects of androgen therapy' below.)

●Beneficial effects on bone health – In men, both androgens and estrogens regulate skeletal homeostasis, but the relative magnitude of each hormonal effect is unknown. In females, estrogen is the primary sex steroid regulator of bone (see "Pathogenesis of osteoporosis", section on 'Estrogen'). Low serum androgen concentrations have been associated with lower bone mineral density (BMD) and an increase in fracture risk in some studies [45-48], but an effect of exogenous testosterone on BMD or fracture risk has not been demonstrated.

●Effects on mood and cognitive function – The role of endogenous androgens on mood and cognition in females is not known. Short-term administration of supraphysiologic doses of testosterone does not appear to have a major effect on either parameter. (See "Management of primary ovarian insufficiency (premature ovarian failure)", section on 'Role of androgen replacement'.)

ANDROGEN DEFICIENCY

Is there an androgen deficiency syndrome in females? — We agree with the Endocrine Society Clinical Practice Guideline, which suggests against making a diagnosis of androgen deficiency because of the lack of both a well-defined clinical syndrome and age-based normative data for serum testosterone and free testosterone concentrations [49].

While females with low levels of circulating androgens are said to have androgen deficiency or androgen insufficiency syndrome, there are currently no biochemical criteria for this diagnosis. Symptoms of androgen deficiency are not well characterized, measurement of serum androgen concentrations using many available assays for total and free testosterone are problematic and age-based normative data are limited [50], and serum androgen concentrations do not appear to be an independent predictor of sexual function in females [49,51-54].

Conditions associated with low androgen levels — Although syndromes of androgen excess or hyperandrogenism, such as polycystic ovary syndrome (PCOS), are common and well defined (see "Clinical manifestations of polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults"), syndromes of androgen deficiency are not.

That said, there are a number of conditions that may represent androgen deficiency syndromes:

●Bilateral oophorectomy – While serum androgen concentrations are low in females after natural menopause, they are considerably lower in females after bilateral oophorectomy because the postmenopausal ovary continues to produce and secrete testosterone. (See 'Effect of age and menopause' above.)

●Primary adrenal insufficiency.

●Hypopituitarism, particularly females with both corticotropin (ACTH) and gonadotropin deficiencies [55].

Other possible conditions that may represent androgen deficiency or relative androgen deficiency include:

●Anorexia nervosa (low testosterone, free testosterone, but normal dehydroepiandrosterone sulfate [DHEAS] compared with normal-weight females with hypothalamic amenorrhea or healthy controls [56]).

●Medications, including oral contraceptives and glucocorticoids, may cause a relative androgen deficiency due to ovarian and adrenal androgen suppression, respectively. Oral estrogens, even at low doses (menopausal replacement), reduce serum free testosterone concentrations by increasing serum sex hormone-binding globulin (SHBG) levels.

●Human immunodeficiency virus (HIV) – Low serum androgen concentrations have been reported in HIV-positive females. Some trials of transdermal testosterone therapy for wasting have shown small improvements in weight and lean body mass, but data are inconclusive [49].

Risks and side effects of androgen therapy — The role of testosterone therapy for females with hypoactive sexual desire disorder is reviewed separately. Indications for its use are limited [57], and there are some potential adverse effects of testosterone therapy. (See "Overview of sexual dysfunction in females: Management", section on 'Androgens'.)

●Androgenic – Systemic testosterone therapy for postmenopausal females (targeting premenopausal testosterone concentrations) has been associated with increases in acne and hirsutism, but not clitoromegaly, deepening of the voice, or alopecia [58-60].

●Lipids – Oral, but not parenteral or transdermal, testosterone is associated with a decrease in serum high-density lipoprotein (HDL) concentrations, which could have a negative impact on cardiovascular risk. However, in one systematic review of available studies, no adverse effects on blood pressure, vascular reactivity, blood viscosity, hemoglobin concentration, coagulation factors, or insulin sensitivity were described [61].

●Cardiovascular – The impact of testosterone therapy on the risk of myocardial infarction remains unclear. Testosterone administration does not appear to have an adverse effect on brachial artery vasodilatation in postmenopausal females on menopausal hormone therapy (MHT) [62]. In 33 postmenopausal females on MHT compared with 15 controls, both endothelial-dependent and -independent brachial artery vasodilatation were improved by the addition of a testosterone implant (50 mg) for six weeks. Similar results were shown in a second report of 60 postmenopausal females [63].

●Breast effects – Although data are limited, testosterone therapy does not appear to have adverse effects on breast health in females. Mammographic density does not appear to be affected by the addition of testosterone to estrogen therapy [64]. In the Women's Health Initiative (WHI) observational study, combination conjugated estrogen-methyltestosterone therapy did not appear to be associated with an excess risk of breast cancer (hazard ratio [HR] 1.06, 95% CI 0.82-1.36) [65].

●Endometrial effects – Most androgens are aromatized to estrogens; thus, risks of estrogen therapy, including endometrial hyperplasia, are also possible with androgen treatment. Some females on testosterone develop abnormal uterine bleeding. Although there is no evidence of an increased risk of endometrial hyperplasia or cancer, data on long-term use and risk are limited [66].

DHEA — While there is a well-known decline in serum DHEA and DHEA sulfate (DHEAS) concentrations with age, the role of adrenal androgen replacement in peri- and postmenopausal females is unclear. Exogenous DHEA has been proposed to have a number of potential benefits (on sexual function, depression, cognition, and inflammation), but available clinical trial data do not support these claims [67-70]. It is widely available in some countries as a dietary supplement; however, quality control of these products has been shown to be quite poor [71,72].

DHEA does not appear to be effective for perimenopausal symptoms [73], nor has it been shown to be effective as an "anti-aging" agent, as its effects in trials on cognitive function, body composition, insulin resistance, and well-being have been inconsistent [12,74-81].

Based upon available data, we suggest against the routine use of dehydroepiandrosterone (DHEA) for sexual function (or other indications) in postmenopausal females, because of its limited efficacy and lack of long-term safety data [49]. Clinical trial data on the efficacy of DHEA therapy in females with primary adrenal insufficiency are reviewed separately. (See "Treatment of adrenal insufficiency in adults", section on 'Androgen replacement therapy for selected females'.)

In a systematic review and meta-analysis of 23 trials in 1188 postmenopausal females, DHEA therapy was not associated with an improvement in libido or other sexual function outcomes when compared with placebo [68]. In addition, DHEA and placebo had similar effects on lipid and glucose outcomes, hip and spine BMD, body weight, and body mass index (BMI). Many trials did not provide data on adverse events. Of those that did, androgenic side effects (acne and hirsutism) appeared to be more common with DHEA than placebo. Similar results were reported in a second meta-analysis of 28 trials of DHEA therapy in symptomatic postmenopausal females [82]. DHEA did not improve quality of life, menopausal symptoms, or sexual function but did increase androgenic side effects (acne and hirsutism) when compared with placebo or no treatment.

A vaginal preparation of DHEA is available for the treatment of dyspareunia associated with genitourinary syndrome of menopause. Although it is effective, it is associated with a slight increase in circulating DHEA, testosterone, and estrone levels, and its efficacy has not been compared directly with vaginal estrogen. (See "Genitourinary syndrome of menopause (vulvovaginal atrophy): Treatment", section on 'Dehydroepiandrosterone (prasterone)'.)

Androstenedione — When administered acutely to females, androstenedione increases serum testosterone and estrone concentrations [83]. However, the impact of regular use on sexual function or its potential androgenic side effects in females are unknown. (See "Use of androgens and other hormones by athletes", section on 'Androgen precursors'.)

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SUMMARY AND RECOMMENDATIONS

●The major androgens in the serum of normal cycling females are dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, testosterone, and dihydrotestosterone (DHT), in descending order of serum concentrations. Cross-sectional and longitudinal studies suggest that serum androgen concentrations (total and free testosterone, androstenedione) gradually decline in females of reproductive age, with no further decrease after clinical menopause. The secretion and serum concentrations of both DHEA and DHEAS decrease markedly with age from the third decade onward, so that in 70 to 80 year olds, serum concentrations of both are approximately 20 percent of those in persons 20 to 30 years old. (See 'Androgen production' above.)

●We agree with the Endocrine Society Clinical Practice Guideline, which suggests against making a diagnosis of androgen deficiency because of the lack of both a well-defined clinical syndrome and age-based normative data for serum testosterone and free testosterone concentrations. That said, there are a number of conditions that may represent androgen deficiency syndromes, including bilateral oophorectomy, primary adrenal insufficiency, and hypopituitarism, particularly in females with both corticotropin (ACTH) and gonadotropin deficiency. (See 'Androgen deficiency' above.)

●Serum high-density lipoprotein (HDL) cholesterol concentrations decline slightly in postmenopausal females receiving oral testosterone therapy, but it is not known if the change substantially affects overall cardiovascular risk. (See 'Risks and side effects of androgen therapy' above.)

●Side effects of testosterone therapy include hirsutism and acne; they are dose- and duration-dependent and generally reversible. Virilizing changes are rare. Deepening of the voice is thought to be irreversible. (See 'Risks and side effects of androgen therapy' above.)

●We suggest against the routine use of systemic DHEA therapy for sexual function or other indications in postmenopausal females because of its limited efficacy and lack of long-term safety data (Grade 2B). Vaginal DHEA may be recommended for the treatment of symptoms related to vulvovaginal atrophy. (See 'DHEA' above.)

●Clinical trial data on the efficacy of DHEA therapy in females with primary adrenal insufficiency are mixed, but some experts suggest a trial in females with significantly impaired mood or sense of well-being despite optimal glucocorticoid and mineralocorticoid replacement. (See 'DHEA' above.)

●Additional androgen therapy recommendations for females with sexual dysfunction are found separately. (See "Overview of sexual dysfunction in females: Management", section on 'Androgens'.)

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Topic 7447 Version 21.0

خرید پکیج

Overview of androgen deficiency and therapy in females

References