Evaluation and management of postmenopausal hyperandrogenism

INTRODUCTION — The presentation of new-onset hyperandrogenism is extremely rare in postmenopausal women. In premenopausal women, the most common cause of androgen excess is polycystic ovary syndrome (PCOS). In contrast, when hyperandrogenism develops de novo or progresses in postmenopausal women, it is usually associated with other causes, such as ovarian hyperthecosis or an androgen-secreting tumor.

The etiology, clinical presentation, diagnosis, and management of postmenopausal hyperandrogenism are reviewed here. Detailed information on the severe causes of postmenopausal hyperandrogenism and the evaluation of hyperandrogenism in premenopausal women are reviewed separately. (See "Ovarian hyperthecosis" and "Clinical presentation and evaluation of adrenocortical tumors" and "Evaluation of premenopausal women with hirsutism" and "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

OVERVIEW — Endogenous androgens are produced by the adrenal glands and the ovaries in both pre- and postmenopausal women [1]. With aging, there is a dramatic decrease in adrenal androgens, principally dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), from their peak in early adulthood [2-4]. Changes in ovarian androgen secretion as a function of age and menopause are far less dramatic, with longitudinal studies centered on the final menstrual period showing that total testosterone levels decrease only slightly, with a somewhat greater decrease in sex hormone-binding globulin (SHBG) [2,5]. (See "Overview of androgen deficiency and therapy in females", section on 'Androgen production'.)

Normal androgen levels in postmenopausal women vary depending on the type of assay done and the laboratory in which they are done, but they are generally within or near the following ranges [6-9]:

●Total testosterone – 20 to 70 ng/dL (0.5 to 2.8 nmol/L)

●Androstenedione – 0.5 to 2.8 ng/mL (1.5 to 12.0 nmol/L)

●DHEAS – 18 to 185 mcg/dL (0.5 to 5 micromol/L)

Levels higher than these are usually considered pathological, particularly if accompanied by signs or symptoms of hyperandrogenism. Depending on the disease process, certain androgens may elevate more than others.

Signs of androgen excess — Signs of androgen excess in women may include the following:

●Hirsutism

●Acne

●Alopecia (male-pattern baldness)

●Anabolic appearance

●Lowering of the voice

●Clitoromegaly

Hirsutism and alopecia are the most common symptoms of hyperandrogenism in postmenopausal women, while clitoromegaly, lowering of the voice, and increased muscle strength and an anabolic appearance are associated with higher androgen levels [10-12].

Some postmenopausal women with hyperandrogenism caused by a tumor also experience uterine bleeding due to peripheral aromatization of androgens to estrogens [12]. In addition, some may develop endometrial hyperplasia or endometrial carcinoma.

APPROACH TO THE PATIENT

Initial evaluation — There are a number of potential causes of hyperandrogenism in postmenopausal women. Some of the processes responsible for hirsutism or virilization may have been present from a younger age, while others more often develop de novo in postmenopausal women. The differential diagnosis of clinical hyperandrogenism for women presenting at any age is shown in the table [13]. (table 1)

Goals — The goals of the evaluation include:

●Identify the most serious causes of hirsutism, including androgen-secreting tumors (ovarian or adrenal) and ovarian hyperthecosis. Androgen-secreting tumors are rare, but they may be malignant at the time of diagnosis. (See 'Ovarian and adrenal neoplasms' below.)

Ovarian hyperthecosis, a disorder characterized by severe hyperandrogenism and insulin resistance, is seen primarily in postmenopausal women but occasionally in premenopausal women [14]. (See "Ovarian hyperthecosis".)

●Determine if the patient is taking any drugs that could cause excessive hair growth (minoxidil, androgenic steroids). (See 'Medications' below and "Use of androgens and other hormones by athletes".)

●Distinguish true hirsutism from other causes of bothersome hair growth. (See "Evaluation of premenopausal women with hirsutism".)

History and physical examination — In the postmenopausal woman with hyperandrogenic symptoms, the history and physical examination should focus on the time course of symptoms and on whether the patient has become virilized.

●Women with androgen-secreting tumors present with recent-onset (typically less than one year) or rapidly progressive hirsutism. In contrast, women with polycystic ovary syndrome (PCOS) develop hirsutism in their premenopausal years, and the pattern of hair growth tends to be stable in many women. If it worsens, changes occur over years, not weeks or months (see "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Hyperandrogenism'). Hirsutism remains stable or improves after menopause.

A detailed history is essential for determining the presence of a more chronic condition such as PCOS or nonclassic congenital adrenal hyperplasia (NCCAH). A drug history should exclude anabolic steroid use or exposure to exogenous androgens (eg, transfer from a partner's testosterone gel) [15].

●Hirsutism and alopecia are the most common symptoms of hyperandrogenism in postmenopausal women. Signs of virilization include deepening of the voice, increased muscle mass, and clitoromegaly. Clitoral enlargement is typically determined on the basis of clitoral length or the clitoral index (length x width): length >10 mm or an index >35 mm² is considered abnormal [16].

Virilization is only seen with more severe hyperandrogenemia (serum testosterone concentration >150 ng/dL [5.2 nmol/L]). Although serum testosterone levels may be elevated in postmenopausal women with a history of PCOS, they are not in a range that can cause virilization. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Hyperandrogenism'.)

Hyperandrogenism in certain ethnic groups may have more subtle clinical manifestations. The evaluation of body hair must consider the individual's ethnic background. Most Asian and Native American women have little body hair, while Mediterranean women, on average, have substantially greater quantities of body hair, even though serum androgen concentrations are similar in the three groups.

Some postmenopausal women with hyperandrogenism caused by a tumor also experience uterine bleeding due to peripheral aromatization of androgens to estrogens [12].

Biochemical testing — The best test to evaluate postmenopausal women with hyperandrogenism, particular those with severe hyperandrogenism, is a total testosterone concentration. This is best assessed by liquid chromatography-tandem mass spectroscopy (LC-MS/MS), an accurate and specific method. The immunoassays that are available in most hospital laboratories are not suitable to accurately measure testosterone in women [17,18]. Free testosterone measured by equilibrium dialysis is more sensitive but must be performed in a specialty laboratory. Free testosterone by analog method ("direct") is not accurate and should not be ordered. (See "Evaluation of premenopausal women with hirsutism", section on 'Biochemical testing'.)

We also suggest measuring serum dehydroepiandrosterone sulfate (DHEAS), an adrenal androgen, to try to identify an adrenal source of excess androgens (most importantly, adrenal androgen-secreting neoplasms). However, mildly elevated levels of DHEAS are unlikely to affect management, and elevated DHEAS concentrations do not discriminate as well as serum testosterone between malignant and benign causes of adrenal hyperandrogenism. In addition, it is unclear whether DHEAS is the best marker for androgen-secreting carcinomas. However, we do measure it in women who present with signs and symptoms suggestive of an androgen-secreting tumor. Serum DHEAS values above 700 mcg/dL (18.9 micromol/L) require further evaluation. In patients with hyperandrogenism in whom testosterone and DHEAS levels are not elevated, measurement of ketosteroids (KS) in a 24-hour urine collection may provide evidence of an adrenal tumor that does not make DHEAS or testosterone, although this is rare. If an androgen-secreting tumor is not suspected, measurement of DHEAS or 17-KS is not necessary.

Other routine testing for women presenting with hyperandrogenism includes serum prolactin (hyperprolactinemia is thought to be an extremely rare cause of hirsutism or alopecia) and 17-hydroxyprogesterone to evaluate for NCCAH due to 21-hydroxylase deficiency (although this almost always presents in the reproductive years). (See "Evaluation of premenopausal women with hirsutism".)

Other laboratory testing depends upon the presence of signs or symptoms of other endocrinopathies (eg, biochemical testing for Cushing's syndrome or acromegaly should be done if other features of these conditions are present). (See "Establishing the diagnosis of Cushing syndrome", section on 'Available tests' and "Diagnosis of acromegaly", section on 'Serum IGF-1 concentration'.)

Women without virilization or severe hyperandrogenemia

Additional evaluation — Additional evaluation depends on the clinical scenario. Women without virilization or severe hyperandrogenemia (eg, serum total testosterone <150 ng/dL [5.2 nmol/L]) most likely have benign causes of hyperandrogenism such as PCOS, NCCAH due to 21-hydroxylase deficiency, hyperandrogenism due to medications, or other uncommon endocrine disorders such as Cushing's syndrome or acromegaly. PCOS and NCCAH almost always present initially in adolescence or early adulthood rather than menopause, but women may experience persistent signs and symptoms of hyperandrogenism after menopause. (See 'Polycystic ovary syndrome' below and 'Nonclassic congenital adrenal hyperplasia' below.)

In general, additional evaluation is not needed for a patient with known PCOS, with the possible exception of a metabolic evaluation (see 'Polycystic ovary syndrome' below and "Diagnosis of polycystic ovary syndrome in adults", section on 'Further evaluation after diagnosis'). As noted, almost all women with NCCAH will have been diagnosed earlier in life with an elevated 17-hydroxyprogesterone concentration. (See 'Nonclassic congenital adrenal hyperplasia' below.)

Patients with possible Cushing's syndrome or acromegaly on initial biochemical testing should undergo the standard additional evaluation for these disorders. (See 'Other' below and "Establishing the diagnosis of Cushing syndrome" and "Diagnosis of acromegaly".)

Polycystic ovary syndrome — A history of irregular menstrual cycles with clinical hyperandrogenism prior to menopause may suggest a premenopausal diagnosis of PCOS [19]. Androgen levels normally fall in both PCOS and healthy women after menopause; however, postmenopausal women with a history of PCOS continue to have higher androgen levels than healthy postmenopausal women [20].

One study found that postmenopausal women diagnosed with PCOS had average testosterone, androstenedione, and DHEAS levels of 47 ng/dL (1.63 nmol/L), 205 ng/dL (7.2 nmol/L), and 143 mcg/dL (3.88 micromol/L), respectively, while postmenopausal women who were healthy before menopause had average testosterone, androstenedione, and DHEAS levels of 37 ng/dL (1.28 nmol/L), 107 ng/dL (3.74 nmol/L), and 60.2 mcg/dL (1.63 micromol/L) [20].

The decrease in androgen levels in PCOS women after menopause has not been associated with decreased clinical signs [21]. Therefore, worsening hirsutism or new signs of hyperandrogenism should prompt evaluation for other causes in women with PCOS, as they do in women without this history. The natural history of the metabolic abnormalities of PCOS after menopause remain unclear [20]. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Reproductive aging/menopause'.)

Nonclassic congenital adrenal hyperplasia — Before menopause, the prevalence of hirsutism increases over time among women with NCAAH [22]. While occasional cases of NCAAH are diagnosed in the perimenopausal years [22], there is only one case report of a 67-year-old woman who presented with uterine bleeding due to endometrial hyperplasia, mild hyperandrogenemia, and genetic confirmation of NCCAH [23].

There are no reports of adrenal rest tumors as a cause of hyperandrogenism in postmenopausal women, although these have been reported in premenopausal women with elevated 17-hydroxyprogesterone [24-26]. As almost all cases of NCCAH are diagnosed in the premenopausal years, we do not recommend routine measurement of 17-hydroxyprogesterone in postmenopausal women with hyperandrogenism. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

Medications — Exposure to particular exogenous substance should always be excluded as a cause for postmenopausal hyperandrogenism prior to further investigation. Exposure to a partner's topical androgenic gel may cause increased androgen levels and hyperandrogenic signs [27,28], as can the use of oral DHEA. Hyperandrogenism resulting from exposure to a topical androgen gel is easily reversed by minimizing exposure to the gel [28]. Anabolic steroid use can cause a range of hyperandrogenic effects, including virilization. (See "Use of androgens and other hormones by athletes", section on 'When to suspect exogenous androgen use'.)

Valproate, used in the management of seizures or bipolar disorder, has been associated with a PCOS-like syndrome in premenopausal women [29] and increases androgen production by theca cells in vitro [30]. Hyperandrogenic effects of this medication have not been reported in postmenopausal women. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults".)

Historically, danazol, which was used for treatment of endometriosis, was reported to cause hirsutism, but it is no longer used. Certain medications such as minoxidil, phenytoin, and cyclosporine can cause hypertrichosis, which may be confused with hirsutism but differs in that hair growth is characterized by increased length and density without an increase in coarseness and may be found in non-androgen-dependent as well as androgen-dependent areas. These drugs do not act through androgenic pathways.

Other — Other less common causes of hyperandrogenism include Cushing's syndrome (due to adrenal secretion of androgens) and acromegaly (a rare cause) (table 2). Up to 50 percent of patients with Cushing's syndrome and acromegaly may have hirsutism [20]. These patients usually present with the typical manifestations of the specific endocrinopathy, such as weight gain and hypertension (Cushing's syndrome). (See "Establishing the diagnosis of Cushing syndrome", section on 'Available tests' and "Diagnosis of acromegaly", section on 'Serum IGF-1 concentration'.)

Women with virilization or severe hyperandrogenemia — Virilization of recent onset and rapid progression, a serum total testosterone >150 ng/dL (5.2 nmol/L), or a serum DHEAS >700 to 800 mcg/dL (18.9 to 21.7 micromol/L) suggests a neoplastic source of hyperandrogenism. Although many women with ovarian hyperthecosis develop symptoms gradually, some with severe hyperthecosis may have a more rapid course and severe hyperandrogenemia that mimics androgen-secreting tumors [31,32].

Women with androgen-secreting adrenal tumors may present with symptoms of Cushing's syndrome in addition to virilization [33]. Unlike ovarian tumors, adrenal androgen-secreting tumors often, but not always [11,34,35], cause elevation in serum levels of the adrenal androgens DHEA and/or DHEAS [36]. Serum DHEAS levels higher than 700 mcg/dL strongly suggest an adrenal source of the androgen excess and warrant further investigation [36,37]. (See "Clinical presentation and evaluation of adrenocortical tumors".)

Any woman with extremely high serum androgen concentrations, as described above (even in the absence of virilization), needs further evaluation, as there is ethnic variability in expression of hair growth in response to androgen excess. The absence of virilization is not reassuring evidence that a severe cause of hyperandrogenism is not present. (See "Evaluation of premenopausal women with hirsutism".)

Caution must be exercised when using basal laboratory results to determine the cause of virilization, and repeat measurements are suggested if initial results are not clearly diagnostic. Approximately 20 percent of ovarian androgen-secreting neoplasms result in testosterone levels under 150 ng/dL (5.2 nmol/L), although androgen-secreting tumors often cause testosterone levels of well over 200 ng/dL, and small tumors can cause fluctuating androgen levels [33,38]. Furthermore, there are case reports of adrenal tumors that secrete testosterone directly and exclusively [34,35], and some adrenal tumors may cause only a mild elevation in DHEAS [38].

Pelvic ultrasonography — Pelvic ultrasonography is indicated in patients with an elevated serum testosterone concentration when an ovarian androgen-secreting tumor is suspected (total testosterone >150 ng/dL [5.2 nmol/L]) [10]. Failure to identify a tumor does not rule out its presence, as these tumors may be very small. Small hilus-cell tumors of the ovary that produce large amounts of testosterone may not be seen by ultrasonography or even at the time of surgery. In addition, other tumors, including androgen-secreting sex cord-stromal tumors, are often not visualized [39]. The ovaries may be described as "normal" size, or slight asymmetry may be detected. Pelvic magnetic resonance imaging (MRI) and fludeoxyglucose-positron emission tomography (FDG-PET) imaging have identified small tumors in case reports, but data are limited [40].

Ovarian tumors are best visualized via transvaginal ultrasonography (TVUS) with color Doppler [7,11,12,41] or with MRI [37].

One study that compared the sensitivity of ultrasonography and MRI in the detection of ovarian tumors found the latter to be more sensitive than the former [37]. Leydig and Sertoli-Leydig cell tumors are generally small. For example, Leydig cell tumors <3 cm diameter [8,10,42-44] are solid tumors without calcification or ascites and are often isoechoic to the ovary upon ultrasound, further complicating detection [10]. Detection of Leydig cell tumors, which usually have a high lipid content, may be aided by color Doppler TVUS [43]. In general, the signal intensity of Sertoli-Leydig cell and Leydig cell tumors on T2-weighted MRI reflects the contents of the stroma [43,44]. Chemical shift MRI has been reported to successfully reveal the intracytoplasmic lipid stores characteristic of steroid cell tumors [45]. Intracytoplasmic crystals of Reinke, found at histologic examination, are suggestive but not diagnostic of Leydig cell tumor [43]. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

Granulosa cell tumors are generally larger and more cystic than Leydig or Sertoli-Leydig cell tumors, although, like the latter, they are typically isoechoic on ultrasound [10]. The imaging characteristics of thecomas depend on the particular composition (eg, the amount of fibrosis and lipid content) of the tumor [42,43]. Krukenberg tumors (ovarian metastases of primary gastrointestinal tumors) usually appear as solid masses on ultrasound, but they may be cystic. Also, consistent with their metastatic nature, they are usually found bilaterally [46,47].

Ultrasonography in women with ovarian hyperthecosis usually shows a bilateral increase in ovarian stroma. Unlike PCOS, where the ovaries characteristically have 12 or more antral follicles of 2 to 9 mm per ovary and/or ovarian volume >10 cm³, few cysts are seen in severe hyperthecosis, and the ovaries appear more solid. (See "Ovarian hyperthecosis", section on 'Imaging studies'.)

Adrenal imaging — Adrenal imaging is indicated to look for an adrenal mass if the woman has a markedly elevated serum testosterone (if pelvic ultrasound is negative) or a serum DHEAS concentration >700 mcg/dL (18.9 micromol/L). Adrenal imaging is otherwise not indicated and may be misleading, because nonfunctioning adrenal masses (adrenal incidentalomas) are common [10]. (See "Evaluation and management of the adrenal incidentaloma".)

Adrenal tumors are best visualized by computed tomography (CT) scan, which can detect nodules smaller than 5 mm, and/or MRI [48,49]. They most often appear as a small (eg, 2 to 2.5 cm), well-defined, homogenous mass with attenuation on CT depending on the lipid content of the particular tumor [50]; approximately 70 percent of adenomas contain intracellular lipid stores [51]. With MRI, they show vigorous enhancement with early washout of contrast material [51].

Adrenocortical carcinomas are typically larger (4 to 25 cm) than adenomas. These tumors are heterogeneous, often with necrosis or calcification, and they appear bright on MRI due to their high water content [50,51]. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Radiographic studies'.)

Ovarian and adrenal vein sampling — Combined ovarian and adrenal vein sampling (selective venous sampling) is performed on occasion for further evaluation in women with high serum testosterone concentrations (testosterone >150 ng/dL [5.2 nmol/L]) and normal pelvic ultrasonography and adrenal imaging [11,52]. In this setting, the ovary is likely to be the source of androgen hypersecretion because adrenal tumors are almost always visualized on adrenal CT [48,49], while ovarian tumors are often too small to be seen on imaging studies [39]. This scenario is far more common in postmenopausal women than premenopausal women.

The procedure includes selective catheterization of the ovarian and adrenal veins to demonstrate a left-to-right difference in androgen concentrations. However, this procedure is technically difficult and should only be performed by an interventional radiologist who is highly experienced in this procedure.

In premenopausal women, we typically suggest this procedure only in those interested in future fertility. In this instance, successful localization to one ovary would change management (eg, the patient could undergo a unilateral rather than a bilateral oophorectomy if a tumor source was located). (See "Evaluation of premenopausal women with hirsutism", section on 'Ovarian and adrenal vein sampling'.)

However, in postmenopausal women, we suggest bilateral oophorectomy rather than further diagnostic evaluation with ovarian vein sampling. In these women, the potential risks of the procedure are unlikely to outweigh the benefits of a definitive surgical procedure [11,53]. (See 'Surgery' below.)

An exception would be the postmenopausal woman presenting with gradual onset hirsutism and virilization (over years) with a small adrenal nodule (incidentaloma). The gradual onset in this scenario is more suggestive of a benign ovarian source of androgens than adrenal carcinoma. Therefore, a sampling procedure would be indicated before proceeding with adrenal exploration [54].

Other tests — Some centers perform a two- to five-day suppression test, but we do not suggest its routine use, as the diagnosis can almost always be made with the biochemical and imaging tests described above (see 'Women with virilization or severe hyperandrogenemia' above). A low-dose dexamethasone suppression test (LDDST) is a noninvasive way to differentiate hyperandrogenism of neoplastic origin from hyperandrogenism of non-neoplastic origin; androgen levels in the latter almost always suppress dramatically, while those in the former cases do not [12,36]. Different research teams have had success using different administration procedures for the LDDST; some administer 0.5 mg dexamethasone every six hours for two to four days [12,20,55], while others administer 1 mg every eight hours for five days [36].

Differential diagnosis

Androgen use — Anabolic steroid use. (See "Use of androgens and other hormones by athletes".)

Ovarian hyperthecosis — Ovarian hyperthecosis, a non-neoplastic, functional disorder characterized by severe hyperandrogenism and insulin resistance, is seen primarily in postmenopausal women [56]. Women typically present with slowly progressive acne and hirsutism and usually with virilization. It is characterized by a luteinization of the ovarian stromal cells so that they appear as thecal cells (picture 1 and image 1) [32,56,57]. (See "Ovarian hyperthecosis".)

Ovarian volume, as measured by TVUS, is usually, but not always [57], increased, often exceeding 10 cm³ [56], in a woman with ovarian hyperthecosis compared with a normal postmenopausal ovarian volume of approximately 2 to 4 cm³ [58,59]. Of note, normal ovarian size declines as time since the final menstrual period increases [58]. Thus, when interpreting ultrasound evidence, menopausal status is important as ovaries that are normal in size for a premenopausal woman may be enlarged for a postmenopausal woman [57,58]. Furthermore, the ovaries may be round (ie, width-to-length ratio >0.80) in hyperthecosis, as opposed to their typical ovoid shape [57].

The ovarian stroma typically appears homogenous on TVUS (unlike in PCOS) [57]. However, a nodular pattern may be apparent on TVUS, which likely reflects the finding that hyperthecosis can manifest in a nodular form in which the luteinized cells aggregate into nodules of 1 cm or less [57].

Ultrasound with color Doppler is useful to rule out a neoplastic cause of hyperandrogenism as this technique can show the vascularization of the ovaries; a hypervascularized region suggests a tumor, whereas hyperthecosis does not cause hypervascularization [57].

MRI is an increasingly common diagnostic tool. With MRI, the ovaries of one patient with confirmed hyperthecosis demonstrated homogenous T2 hypointensity and mild enhancement without a discrete lesion [60].

Although imaging data can suggest a diagnosis of hyperthecosis, biochemical data may suggest this diagnosis in a less expensive way. Compared with the hormonal profile of women with PCOS, women presenting with ovarian hyperthecosis tend to have higher testosterone levels and lower androstenedione levels, with testosterone being the major or sole contributor to overall high androgen levels [57]. Furthermore, total testosterone levels are usually lower in women with hyperthecosis than in women with androgen-secreting neoplasms, although there is a fair amount of overlap [11,12,36].

Ovarian and adrenal neoplasms — Androgen excess that develops de novo in postmenopausal women and with rapid worsening of symptoms is likely the result of an androgen-secreting tumor of the ovaries or adrenal glands.

A variety of ovarian tumors, most of which are benign, have been reported as the source of hyperandrogenism (figure 1). The most common are sex cord-stromal tumors, including Sertoli-Leydig cell tumors (picture 2) [42], and steroid cell tumors, most commonly Leydig (or hilus) cell tumors [43].

Granulosa cell tumors and thecomas are more often hyperestrogenic, but androgenic cases have been reported [10,43,61]. Benign cystic teratomas are common in postmenopausal women. While these rarely produce excess androgen, there have been case reports of androgenic teratomas that are responsible for virilization [62].

Adrenal tumors (both adenomas and carcinomas [12,36]) can also cause androgen excess in postmenopausal women. Adenomas are the most common type of adrenal tumor, although most are nonfunctional and they are typically benign (image 2) [51]. Carcinomas are less common, but they are more likely to be androgenic (image 3) [50].

Other rare tumors have been reported to cause hyperandrogenism and virilization in women. These include ovarian metastases from primary tumors of the gastrointestinal tract [63] (eg, Krukenberg tumors [46,64]) and gonadotropin (eg, luteinizing hormone [LH] or human chorionic gonadotropin [hCG])-secreting tumors of the pancreas [6].

There are also rare reports of functional adrenal rest tumors, ie, neoplasms that arise from an adrenal rest along the path of adrenal embryonic migration (eg, in the kidney, ovary, uterus, broad ligament, retroperitoneum) that produce adrenocortical steroids, although none have yet been described in postmenopausal women. Such tumors have been reported to cause signs of Cushing's syndrome and hyperandrogenism [65]. Rare tumors such as these should also be considered in the evaluation of women with hyperandrogenemia who have high adrenal androgens and negative adrenal imaging.

Treatment

Goals — In addition to the cosmetic concerns associated with hyperandrogenism in women, hyperandrogenism can be associated with an increased risk of endometrial and breast cancer. This association may be a result of peripheral aromatization of excess androgens to estrogens [66-69], a process that becomes more efficient with advancing age [70]. A strong association between elevated androstenedione levels and risk for endometrial cancer that was independent of body mass index (BMI) and estrogen levels was demonstrated in two large studies [71,72].

Severe hyperandrogenism

Surgery — For ovarian neoplasms and hyperthecosis, a bilateral salpingo-oophorectomy (BSO) is the procedure of choice if the patient is a good surgical candidate [33,56,66,73]. Hyperandrogenism of ovarian origin may be associated with endometrial hyperplasia and/or carcinoma [33,66,67,71,72]. TVUS may help to determine whether an endometrial biopsy is indicated (cancer is very unlikely if the endometrial thickness is <4 mm). If an endometrial biopsy does not suggest hyperplasia or cancer, a hysterectomy may not be necessary, although experts may disagree.

Androgen-secreting adrenal tumors should be removed. Although there have been case reports of gonadotropin-responsive adrenal tumors [34,35], which therefore may respond to treatment with a gonadotropin-releasing hormone (GnRH) agonist, this is very rare. Furthermore, given the generally poor response of such tumors to dexamethasone suppression [12,36], they are not likely to respond to glucocorticoid therapy.

GnRH agonist therapy — If the patient is not a good surgical candidate or the patient does not want surgery, gonadotropin-releasing hormone (GnRH) agonists have been shown to be an effective alternative treatment for some cases of hyperandrogenism of ovarian origin [8,32,41,56,74,75]. Dosing of GnRH agonists depends on the agonist used. One group achieved long-term (ie, at least 3.5 years after the last dose of GnRH agonist) suppression of testosterone (elevated by a presumed testosterone-secreting ovarian tumor) using 7.5 mg of depot leuprolide once monthly for three months, a dose that they then decreased to 3.75 mg per month for another year [41]. Another group achieved long-term suppression of testosterone levels by administering this latter dose for five months and then administering two doses of 11.25 mg every three months, for a total of 11 months of treatment [7].

Since no histologic diagnosis is available as final confirmation in women treated with GnRH agonists rather than surgery, we suggest careful follow-up, including periodic testing of androgen levels and ovarian imaging. If serum testosterone concentrations do not decrease after several months of GnRH agonist therapy, we suggest reconsidering surgery for histologic diagnosis.

Women without severe hyperandrogenism

●PCOS – The management of postmenopausal women with hyperandrogenism that is not severe (ie, hirsutism, acne, or scalp hair loss, most often due to PCOS) is similar to that for premenopausal women. However, estrogen-progestin contraceptives, the first-choice therapy for premenopausal women, are not suggested for hormonal suppression in postmenopausal women. Instead, antiandrogens are first-line therapy. We typically use spironolactone. Although metformin has not been studied for hirsutism in this population, it is ineffective in premenopausal women, and we therefore do not suggest its use. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Cardiovascular effects'.)

The management of the metabolic concerns associated with PCOS are reviewed separately. (See "Treatment of polycystic ovary syndrome in adults", section on 'Metabolic abnormalities'.)

●NCCAH – The standard treatments for premenopausal women with NCCAH due to 21-hydroxylase deficiency include oral contraceptives for hyperandrogenic symptoms and glucocorticoids for ovulation induction [76]. However, oral contraceptives should not be used in postmenopausal women, because of higher age-based cardiovascular risks. Antiandrogens, such as spironolactone, are a good choice. We reserve glucocorticoids for women who do not respond to antiandrogens. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency", section on 'Women'.)

Women using antiandrogens for PCOS or NCCAH can also add local hair removal measures.

●Medications – Hyperandrogenic symptoms due to medications should be reversible by discontinuing the offending drug.

●Other – The management of hyperandrogenism due to other endocrine disorders (Cushing's syndrome or acromegaly) is treatment of the underlying disease. (See "Overview of the treatment of Cushing syndrome" and "Treatment of acromegaly".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hirsutism".)

SUMMARY

●The presentation of new-onset hyperandrogenism is extremely rare in postmenopausal women. Hirsutism and alopecia are the most common symptoms of hyperandrogenism in postmenopausal women, while signs of virilization (clitoromegaly, lowering of the voice, and increased muscle mass) are only seen with higher androgen levels (eg, serum testosterone concentration >150 ng/dL [5.2 nmol/L]). (See 'Signs of androgen excess' above.)

●While in younger women, hyperandrogenism is most often the result of polycystic ovary syndrome (PCOS), when hyperandrogenism develops de novo in postmenopausal women, it is likely the result of either an androgen-secreting tumor or ovarian hyperthecosis. (See 'History and physical examination' above.)

●A detailed history can help to exclude PCOS or late-onset congenital adrenal hyperplasia as causes of hyperandrogenism. Exogenous exposure to androgens or medications that may cause hirsutism should be ruled out. (See 'History and physical examination' above.)

●The most important initial test in the evaluation of postmenopausal hyperandrogenism is a serum total testosterone concentration. Although somewhat less useful, we also suggest measuring serum dehydroepiandrosterone sulfate (DHEAS), an adrenal androgen, to try to identify an adrenal source of excess androgens (most importantly, adrenal androgen-secreting neoplasms). Urinary 17-ketosteroids (17-KS) may occasionally be helpful if testosterone and DHEAS are not elevated; elevation would suggest adrenal carcinoma. (See 'Biochemical testing' above.)

Other laboratory tests include serum prolactin, 17-hydroxyprogesterone, and biochemical testing for Cushing's syndrome or acromegaly if features of these conditions are present. (See 'Biochemical testing' above.)

●Additional evaluation for women with virilization or severe hyperandrogenemia (total testosterone >150 ng/dL [5.2 nmol/L] or DHEAS >700 to 800 mcg/dL [18.9 to 21.7 micromol/L]) includes (see 'Women with virilization or severe hyperandrogenemia' above):

•Transvaginal ultrasound (TVUS) (for high testosterone) to look for ovarian hyperthecosis or androgen-secreting ovarian tumor (see 'Pelvic ultrasonography' above)

•Adrenal computed tomography (CT) or magnetic resonance imaging (MRI) for DHEAS >700 to 800 mcg/dL (18.9 to 21.7 micromol/L) or high testosterone and negative TVUS to look for androgen-secreting adrenal tumor (adenoma or carcinoma) (see 'Adrenal imaging' above)

•Ovarian and adrenal vein sampling is rarely indicated in postmenopausal women (see 'Ovarian and adrenal vein sampling' above)

●The most common ovarian virilizing tumors are Sertoli-Leydig cell tumors and Leydig cell tumors. Some adrenal tumors are androgenic, often elevating levels of DHEAS in addition to testosterone.

●Ovarian hyperthecosis, a non-neoplastic, functional disorder characterized by severe hyperandrogenism and insulin resistance, is seen primarily in postmenopausal women. Women typically present with slowly progressive acne and hirsutism, and they are likely to be virilized.

●For androgen-secreting ovarian tumors, bilateral salpingo-oophorectomy (BSO) is the treatment of choice (Grade 1B), with or without hysterectomy as indicated. (See 'Surgery' above.)

We suggest surgical resection of androgen-secreting adrenal tumors (Grade 1A). (See 'Surgery' above.)

●Oophorectomy (with or without hysterectomy, as indicated) is also the treatment of choice for ovarian hyperthecosis (Grade 1B), although gonadotropin-releasing hormone (GnRH) agonist therapy may suppress androgen levels in patients who are not good surgical candidates. (See 'GnRH agonist therapy' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Kathryn Williams and Anupam Gupta, MD, who contributed to an earlier version of this topic review.