Evaluation of premenopausal women with hirsutism

INTRODUCTION — Hirsutism is defined as excessive male-pattern hair growth in women of reproductive age. It may be the initial, and possibly only, sign of an underlying androgen disorder, the cutaneous manifestations of which may also include acne and female-pattern hair loss (androgenetic alopecia). The most common cause of hirsutism is polycystic ovary syndrome (PCOS). In some cases, hirsutism is mild and requires only reassurance and local (nonsystemic) therapy, while in others, it causes significant psychological distress and requires more extensive therapy.

The evaluation and laboratory testing of hirsutism will be discussed here, while its pathophysiology, causes, and treatment are discussed elsewhere (table 1). (See "Pathophysiology and causes of hirsutism" and "Management of hirsutism in premenopausal women".)

DEFINITIONS AND EPIDEMIOLOGY

●Hirsutism – Hirsutism is a clinical diagnosis defined by the presence of excess terminal hair growth (dark, coarse hairs) in androgen-dependent areas (eg, upper lip, chin, midsternum, upper and lower abdomen, upper arms, upper and lower back, and inner thigh/buttocks) in which women typically have little or no hair [1,2].

●Hyperandrogemia/hyperandrogenism – Elevated serum concentrations of androgens in women are referred to as hyperandrogenemia, which can manifest as hyperandrogenism: hirsutism, acne, androgenetic alopecia, and virilization. Hirsutism, defined as excessive growth of terminal hair in women in a male-like pattern, is the most commonly used clinical diagnostic criterion of hyperandrogenism [1,2]. Virilization, which is rare, occurs only with severe hyperandrogenemia and typically includes deepening of the voice and clitoromegaly.

●Other types of excess hair – There are several conditions characterized by generalized or "excess" hair growth that do not represent hirsutism and do not require biochemical evaluation with serum androgens:

•Vellus (lanugo) hair – The soft, androgen-independent unpigmented hair that covers the entire body of a fetus or newborn. It may also be seen in women with disorders that include anorexia nervosa.

•Hypertrichosis – The excessive growth of androgen-independent hair that is vellus, prominent in nonsexual areas, and most commonly familial or caused by systemic disorders (hypothyroidism, anorexia nervosa, malnutrition, porphyria, and dermatomyositis) or oral medications (phenytoin, penicillamine, diazoxide, minoxidil, or cyclosporine). Hypertrichosis is typically managed with hair removal techniques. (See "Removal of unwanted hair".)

•"Unwanted hair" – This term refers to any hair growth (usually facial) that the patient finds bothersome. However, the hairs are typically not dark terminal hairs but rather light, unpigmented hairs. This type of hair is not a sign of androgen excess. (See "Removal of unwanted hair".)

APPROACH TO THE PATIENT — Although women with hirsutism typically present because of concerns regarding their excessive hair growth, most also have an underlying endocrine disorder that should be identified (table 1). Important clues to the severity of androgen excess and the presence of an underlying disorder can be obtained by the history, physical examination, and appropriate laboratory testing (algorithm 1) [3,4].

Goals — The most important goals of the evaluation include (algorithm 1):

●Distinguish true hirsutism from other causes of bothersome hair growth.

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

●Identify the most serious causes of hirsutism, including androgen-secreting tumors (ovarian or adrenal) and ovarian hyperthecosis. The latter is characterized by severe hyperandrogenemia and insulin resistance, seen primarily in postmenopausal women but occasionally in premenopausal women. (See 'Additional evaluation for severe hyperandrogenemia' below and "Ovarian hyperthecosis".)

Androgen-secreting tumors are rare, particularly in premenopausal women (0.2 percent of women with hirsutism) [5], but 50 percent are malignant at the time of diagnosis.

●Identify polycystic ovary syndrome (PCOS), the underlying disorder in approximately 75 to 80 percent of women who present with hirsutism (table 2).

The diagnosis of PCOS is important because, in addition to oligomenorrhea and hyperandrogenism, PCOS is associated with other important medical conditions including obesity, insulin resistance, and an increased risk for type 2 diabetes, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), hypertension, and obstructive sleep apnea. The clinical features and evaluation of patients with suspected PCOS are reviewed in detail separately. (See "Clinical manifestations of polycystic ovary syndrome in adults" and "Diagnosis of polycystic ovary syndrome in adults".)

●Identify nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency (<5 percent of women with hirsutism, depending upon population). Although this diagnosis will not alter the approach to managing hirsutism in most cases, it is important for future genetic counseling when pursuing fertility. If her partner has NCCAH (which is asymptomatic in adult males) or is a heterozygote carrier, there is a risk that their offspring could have classic 21-hydroxylase deficiency (the severe form of the disease). (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●Identify other uncommon causes of hirsutism that would require different management than PCOS, NCCAH, or idiopathic hirsutism, such as Cushing syndrome or acromegaly (table 1). (See 'Other' below.)

●Determine the degree of emotional distress caused by the excess hair as this has important implications for treatment. (See "Management of hirsutism in premenopausal women", section on 'Initial visit'.)

Overview of our approach

●The history should focus initially on the time course of symptoms, whether the patient has become virilized, and the degree of emotional distress caused by the excess hair. (See 'History' below.)

●The physical examination should focus on determining if the patient has evidence of virilization, an indicator of severe hyperandrogenism, in addition to determining whether the patient has true hirsutism (and its severity if present) (figure 1). (See 'Physical examination' below.)

●We agree with the 2018 Endocrine Society Clinical Guidelines and suggest measuring a serum total testosterone in all women with an abnormal hirsutism score (algorithm 1). We do not measure testosterone in women with normal menstrual cycles and "unwanted local hair growth." Some women who present with hirsutism are already on combination oral contraceptives (COCs). Their management is described below. (See 'Women already taking pharmacologic therapy' below.)

The choice of additional tests is based upon the patient's presentation (time of onset, pace of progression, presence or absence of virilization, and menstrual cycle status). As noted, 75 to 80 percent of women who present with hirsutism have PCOS, but it is essential to identify those who have a more serious cause (androgen-secreting tumors and ovarian hyperthecosis). (See 'Biochemical testing' below.)

●Further evaluation is indicated in all women when an ovarian androgen-secreting tumor is suspected (serum total testosterone >150 ng/dL [5.2 nmol/L]) (algorithm 1). We suggest pelvic ultrasound as the next diagnostic step. If the ultrasound is negative and/or serum dehydroepiandrosterone sulfate (DHEAS) is greater than 700 mcg/dL (18.9 micromol/L), we suggest adrenal computed tomography (CT) to look for an androgen-secreting adrenal tumor. (See 'Additional evaluation for severe hyperandrogenemia' below.)

History — The history should focus initially on the time course of symptoms, whether the patient has become virilized, and the degree of emotional distress caused by the excess hair.

Age of onset — Women with PCOS, the most common cause of hirsutism, typically have a peripubertal onset of hirsutism. This is not always the case, however, as adolescent girls with PCOS often take COCs for irregular periods and/or for acne, which may mask or delay the recognition of hirsutism. Women with NCCAH due to 21-hydroxylase deficiency and idiopathic hirsutism have a similar age of symptom onset. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Hyperandrogenism'.)

In contrast, women with androgen-secreting tumors or ovarian hyperthecosis develop hirsutism in the third decade of life or later. Both diagnoses are most common after menopause but sometimes occur before. (See "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults" and "Ovarian hyperthecosis".)

Stable versus progressive hair growth — Once women with PCOS develop hirsutism, the pattern of hair growth may be variable. Hirsutism is stable in some women and may worsen in others, but changes occur over years, not weeks or months. Women with NCCAH due to 21-hydroxylase deficiency and idiopathic hirsutism have a similar presentation.

In contrast, women with androgen-secreting tumors present with recent-onset, short-duration (typically less than one year), or rapidly progressive hirsutism (algorithm 1).

Virilization — Signs of virilization, including frontal balding, clitoromegaly, increased muscle mass, or deepening of the voice, are seen when the serum testosterone concentration is more severely elevated (eg, over 150 ng/dL), which occurs in ovarian hyperthecosis and androgen-secreting ovarian or adrenal tumors. Although serum testosterone levels may be somewhat elevated in women with PCOS, they are not in a range that can cause virilization. Some disorders cause virilization during pregnancy. (See "Ovarian hyperthecosis" and "Gestational hyperandrogenism" and "Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults".)

Emotional distress/depression — Hirsutism is associated with significant emotional distress and depression [6-8]. Those with PCOS are more likely to have mood disorders and are at risk for eating disorders, eg, binge eating [9,10]. Therefore, women should be asked about mood symptoms, and a dietary history should be obtained. The degree of emotional distress caused by the hirsutism can affect treatment decisions. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Psychosocial issues' and "Management of hirsutism in premenopausal women", section on 'Initial visit'.)

Other — Other components of the history that help determine the underlying etiology include the following:

●Menstrual history – Does the patient have oligomenorrhea or amenorrhea? The presence of menstrual dysfunction suggests PCOS, but most disorders that cause hirsutism can be associated with irregular menstrual cycles, with the exception of idiopathic hirsutism, whose diagnosis requires the presence of regular menstrual cycles (algorithm 1).

●Family history – A family history of hirsutism, acne, menstrual irregularity, infertility, early cardiovascular disease, and obesity suggests the possibility of PCOS in the patient. (See "Epidemiology, phenotype, and genetics of the polycystic ovary syndrome in adults", section on 'Epidemiology'.)

●Weight history – Obese women have increased androgen production and clearance rates [11] and decreased sex hormone-binding globulin (SHBG), each of which aggravates hirsutism and increases the likelihood of menstrual irregularity, especially in those with PCOS. (See "Clinical manifestations of polycystic ovary syndrome in adults", section on 'Obesity and insulin resistance'.)

●Ethnicity – The evaluation of body hair must consider the individual's ethnic background. (See 'Physical examination' below.)

●Medication history – Drugs that cause hirsutism or have other androgenic effects include testosterone and dehydroepiandrosterone (DHEA) (sometimes used for the management of sexual dysfunction) or "androgenic steroids," used by athletes to improve their performance. Valproate has been associated with the development of PCOS (table 1). (See "Overview of sexual dysfunction in females: Management", section on 'Androgens' and "Use of androgens and other hormones by athletes".)

●Other endocrine disorders associated with hirsutism – These usually present with the typical manifestations of the specific endocrinopathy, such as weight gain and hypertension (Cushing syndrome) (table 1). (See "Pathophysiology and causes of hirsutism", section on 'Causes'.)

●Women with NCCAH due to 21-hydroxylase deficiency have a clinical presentation that is indistinguishable from PCOS. One clue, however, is ethnicity. NCCAH is most common in Mediterranean, Hispanic, and Ashkenazi Jewish women.

A family history of irregular menses and hirsutism may be present in women with NCCAH [12]. (See "Genetics and clinical presentation of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency" and "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●Some women present with hirsutism and normal ovulatory cycles. While some will meet PCOS criteria after further evaluation (if there is evidence of biochemical hyperandrogenism or polycystic ovaries on ultrasound), others will have normal androgens and a normal ultrasound. These women are considered to have "idiopathic hirsutism." (See "Pathophysiology and causes of hirsutism", section on 'Idiopathic hirsutism'.)

Physical examination

●Ferriman-Gallwey score – We suggest using a simple and commonly used method to grade hair growth that makes use of the modified scale of Ferriman and Gallwey, derived from a population study of White women in England [1]. It is the most widely used method to quantify hair growth, particularly in trials of pharmacologic therapy for hirsutism. Using this method, nine androgen-sensitive sites are graded from 0 to 4 (figure 1) [1,13]. The criteria for identifying hirsutism using the Ferriman-Gallwey score are variable because the expression of hair growth varies among racial/ethnic groups, as follows:

•Interpretation of scores – A Ferriman-Gallwey score >8 is considered abnormal for Black or White women, a reasonable cutoff based upon data from two population studies in which only 5 percent of women had scores higher than 7 or 8 [1,14]. In one study, however, many women with scores between 1 and 5 reported excess hair growth [15]. Scores between 8 and 15 are usually considered to be mild hirsutism, 16 to 25 moderate, and scores >25 severe hirsutism.

•Impact of ethnicity – The expression of hair growth varies among racial groups. Most East Asian women have little body hair, White and Black women have an intermediate amount, and most Mediterranean, South Asian, and Middle Eastern women have substantially greater quantities of body hair, even though serum androgen concentrations are similar in all groups [16-18]. A much lower Ferriman-Gallwey score (≥2) is considered to be abnormal in Asian women than other groups as they are less likely to manifest hirsutism resulting from androgen excess [5,19]. For Mediterranean, Hispanic, and Middle Eastern women, a Ferriman-Gallwey score ≥9 to 10 is considered abnormal and for East Asian and Asian American women, a score ≥2 is abnormal. (See "Pathophysiology and causes of hirsutism", section on 'Ethnicity'.)

•Limitations – Although we use the Ferriman-Gallwey score to assess the severity of hirsutism at baseline and at follow-up visits to monitor response to pharmacologic and direct hair removal therapies [20,21], it has a number of limitations in clinical practice including [21]:

-Many clinicians are unfamiliar with the Ferriman-Gallwey score and are therefore unlikely to use it.

-Most women have been using cosmetic (mechanical) measures (shaving, plucking), especially on the face, by the time they see a clinician, so their Ferriman-Gallwey score at baseline may not be an accurate reflection of the severity and distribution of their hair growth. However, details about the distribution and severity of facial hair (before cosmetic [mechanical] measures were used) can be obtained from the patient. In addition, nonfacial skin is less often shaved or plucked and therefore may reflect the actual hirsutism status better.

-There is only a modest correlation between the quantity of hair growth and serum androgen levels [15,22]. This is thought to result from the fact that stimulation of hair growth from the follicle does not depend solely on circulating androgen concentrations but also upon local factors and variability in end-organ sensitivity to circulating androgens [23]. (See "Pathophysiology and causes of hirsutism", section on 'Androgens and androgen action'.)

-Intraobserver agreement appears to be relatively good when using the modified Ferriman-Gallwey score [24], but interobserver agreement appears to be poor [25].

-Women's self-ratings of hirsutism using the Ferriman-Gallwey score tend to be higher than clinician ratings [26]. Therefore, treatment decisions are often based upon the degree to which the hirsutism affects the patient's well-being and not just on the severity score. (See "Management of hirsutism in premenopausal women", section on 'Initial visit'.)

●Evidence of virilization – In addition to determining whether the patient has true hirsutism (picture 1) and assessing its severity (figure 1), the most important goal of the physical examination is to determine if the patient has evidence of virilization, an indicator of severe hyperandrogenism. Findings include deepening of the voice, temporal and/or crown balding, increased muscle mass, and clitoromegaly. There is significant variability in clitoral size in normal women [27,28]. Clitoral enlargement is typically determined on the basis of clitoral length (of the glans) or the clitoral index (length times width): length >10 mm or an index >35 mm² is considered above normal [29].

Women with virilization are likely to have a serious cause for their hirsutism, either an androgen-secreting tumor (ovarian or adrenal) or ovarian hyperthecosis. (See 'Additional evaluation for severe hyperandrogenemia' below and "Pathophysiology and causes of hirsutism", section on 'Causes'.)

●Other important findings – Other aspects of the physical examination that are important in the evaluation of hirsutism include:

•Other skin findings – Acne, keratosis pilaris, or seborrhea (which are additional signs of androgen excess), acanthosis nigricans, striae, thin skin, or bruising should be looked for on exam. The last three findings suggest the possible presence of Cushing syndrome, whereas acanthosis nigricans suggests insulin resistance.

•Body mass index (BMI) – Height, weight, and a calculation of BMI should be obtained. Many women with PCOS are obese (BMI ≥30 kg/m²). In addition, the pattern of body fat distribution (truncal obesity, cervicodorsal fat deposition, and supraclavicular fat) may suggest the presence of Cushing syndrome. (See "Epidemiology and clinical manifestations of Cushing syndrome".)

•Abdominal and pelvic exam – Abdominal and pelvic examination should be performed to look for mass lesions that could indicate an androgen-secreting tumor.

Biochemical testing — Our approach is consistent with the 2018 Endocrine Society Clinical Guidelines on hirsutism. We suggest measuring a serum total testosterone in all women with clinical evidence of hirsutism (defined by the presence of excess terminal hair growth [dark, coarse hairs] in androgen-dependent areas [21]. The choice of additional tests is based upon the patient's presentation (time of onset, pace of progression, presence or absence of virilization, and menstrual cycle status). As noted, 75 to 80 percent of women who present with hirsutism have PCOS, but it is essential to identify those who have a more serious cause (androgen-secreting tumors and ovarian hyperthecosis).

"Unwanted hair" — Excess hair that is not true hirsutism, ie, is not dark, coarse, and in androgen-dependent areas, does not need biochemical evaluation and does not respond to the pharmacologic therapies for androgen-dependent hair.

Hirsutism and normal menstrual cycles — Women with hirsutism and normal menstrual cycles are most likely to fall into the category of PCOS or idiopathic hirsutism and are unlikely to have a more serious cause for their hirsutism. We suggest measuring only a serum total testosterone. This is consistent with guidelines from expert groups (algorithm 1) [21]. (See "Pathophysiology and causes of hirsutism", section on 'Causes'.)

Hirsutism with oligomenorrhea/amenorrhea — Women with hirsutism and irregular menstrual cycles have an underlying endocrine disorder. Many, if not most, women will be diagnosed with PCOS. We suggest measuring serum total testosterone as well as a routine evaluation for oligo/amenorrhea (human chorionic gonadotropin [hCG], prolactin, follicle-stimulating hormone [FSH], thyroid-stimulating hormone [TSH]) and an early morning 17-hydroxyprogesterone (around 8 AM). Although the menstrual dysfunction will almost always be due to PCOS or, in some cases, NCCAH due to 21-hydroxylase deficiency, the possibilities of pregnancy, hyperprolactinemia, primary ovarian insufficiency, and thyroid disease should not be overlooked (algorithm 1). (See "Evaluation and management of secondary amenorrhea", section on 'Laboratory testing'.)

Serum androgens — Suggestions for serum androgen testing include the following:

●Serum total testosterone – We measure serum total testosterone in women with any degree of hirsutism. It is best assessed by liquid chromatography-tandem mass spectroscopy (LC-MS/MS), an accurate and specific method. With LC-MS/MS, the upper limit of normal for serum testosterone in women is in the 45 to 60 ng/dL range (1.6 to 2.1 nmol/L). The immunoassays that are available in most hospital laboratories are not suitable to accurately measure testosterone in women [30,31].

Women with PCOS have serum testosterone concentrations that may be in the normal range (up to the upper limit of normal, which varies between 45 and 60 ng/dL depending upon the laboratory [0.69 to 2.1 nmol/L]), or elevated but below 150 ng/dL (5.2 nmol/L). Although the degree of hyperandrogenemia may not correlate well with the severity of hirsutism, it does appear to correlate with metabolic risks observed in women with PCOS [32].

●17-hydroxyprogesterone – We also suggest testing for NCCAH due to 21-serum hydroxylase deficiency in hyperandrogenemic women by measuring an 8 AM 17-hydroxyprogesterone level. In clinical practice, it is unusual to identify NCCAH in a woman having an endocrine work-up for hirsutism unless a circulating androgen is elevated.

This test is most important in high-risk women, including Mediterranean, Hispanic, and Ashkenazi Jewish women [12]. The most common form of CAH, 21-hydroxylase deficiency, affects approximately 1:10,000 to 1:15,000 people in the United States and Europe. Among the Inuit population, the occurrence of the classic salt-wasting form of this disorder may be as high as 1 in 282 individuals [33]. For women who have some spontaneous menstrual cycles, this should be done in the early follicular phase, while for those without cycles, it can be drawn on a random day. A morning value of 17-hydroxyprogesterone greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis, which may be confirmed by a high-dose (250 mcg) corticotropin (ACTH) 1-24 (cosyntropin) stimulation test. The response to cosyntropin is exaggerated, with most patients having values exceeding 1500 ng/dL (43 nmol/L) 60 minutes after administration of cosyntropin. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

●Free testosterone – We do not routinely measure free testosterone. Free testosterone measured by equilibrium dialysis is a sensitive test for detecting hyperandrogenic disorders, but it must be performed in a specialty laboratory. Free testosterone by analog method ("direct") is not accurate and should not be ordered.

●Serum DHEAS – We do not suggest measuring serum DHEAS, because mildly elevated levels of DHEAS are unlikely to affect management. In addition, elevated DHEAS concentrations do not discriminate as well as serum testosterone between malignant and benign causes of adrenal hyperandrogenism. (See 'Severe hyperandrogenism' below.)

●Serum androstenedione – The role of serum androstenedione in the evaluation of PCOS and/or hirsutism is unclear [34]. However, its measurement in some populations with PCOS, for example, Icelandic women, may be important for documenting hyperandrogenism [35]. Two studies have reported isolated elevations of serum androstenedione concentrations in women with PCOS, but the percent of women with this biochemical pattern is variable (20 of 86 [23 percent] [36] and 49 of 1128 [4.1 percent] [37]). In the smaller study, serum androstenedione was negatively associated with insulin sensitivity. (See "Clinical manifestations of polycystic ovary syndrome in adults".)

●SHBG – Some experts calculate a free testosterone concentration from the total testosterone, SHBG, and albumin concentrations. However, there are many different equations for this calculation that give different results, some of which reflect the results obtained by equilibrium dialysis better than others.

As noted, most women with hirsutism and irregular menses will be diagnosed with PCOS. Once the diagnosis of PCOS is made, we suggest additional evaluation including a cardiometabolic risk assessment, as well as screening for mood disorders and sleep apnea. (See "Diagnosis of polycystic ovary syndrome in adults", section on 'Further evaluation after diagnosis'.)

Women already taking pharmacologic therapy — Some women with hirsutism seek advice when they are already taking pharmacotherapy, usually COCs. Measuring serum androgens is generally not useful in this setting, because COCs suppress serum gonadotropins and ovarian androgens, most importantly testosterone. However, if an evaluation is done, it is best to discontinue the COC for at least 8 to 12 weeks as it takes at least this length of time for serum androgens and SHBG levels to return to basal values [38].

Biochemical evaluation is usually not necessary unless the patient is experiencing severe or rapid worsening of her hirsutism despite COC therapy. In this setting, marked elevation of testosterone in spite of COC use strongly suggests a testosterone-secreting ovarian or adrenal tumor (algorithm 1). More commonly, the patient has had an inadequate response to COCs alone so a second medication is added, usually spironolactone. (See "Management of hirsutism in premenopausal women", section on 'Suboptimal response: Add antiandrogen'.)

Women with features of other endocrine disorders — Rarely, hirsute women have symptoms and signs of cortisol excess (such as centripetal obesity, hypertension, purple striae) that suggest Cushing syndrome, or growth hormone excess that suggests acromegaly. In addition to measuring serum total testosterone, women with suspected Cushing syndrome should undergo testing for hypercortisolism. Options for first-line tests include a 24-hour urinary excretion of free cortisol, late-night salivary cortisol, and the low-dose dexamethasone suppression test. At least two of these first-line tests should be abnormal to establish the diagnosis of excess cortisol production. For women with possible growth hormone excess, a serum insulin-like growth factor-1 (IGF-1) should be measured first. (See "Establishing the diagnosis of Cushing syndrome", section on 'Available tests' and "Diagnosis of acromegaly", section on 'Serum IGF-1 concentration'.)

Severe hyperandrogenism — For women with features of severe hyperandrogenism (virilization and/or hirsutism of recent onset that is rapidly progressive), we suggest measuring serum total testosterone, ideally using LC-MS/MS as described above, and serum DHEAS. In addition, these patients should be referred to an endocrinologist or reproductive endocrinologist for further evaluation.

These women usually have an androgen-secreting tumor (ovarian or adrenal) or ovarian hyperthecosis (although both are more common in postmenopausal than premenopausal women) (algorithm 1). (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Women with virilization or severe hyperandrogenemia'.)

●Serum total testosterone – Serum total testosterone is the best test for detecting androgen-secreting tumors, in particular ovarian neoplasms. Although serum free testosterone may be the more sensitive test for the presence of hyperandrogenic disorders [39], an elevated total testosterone level alone is usually sufficient to identify those women who need further evaluation for a possible androgen-secreting tumor [40]. In addition, free testosterone measured by an analog method, which is the assay most commonly offered by hospital and commercial laboratories, does not correlate at all with the results of equilibrium dialysis, the most accurate method for measuring free testosterone [40]. (See 'Serum androgens' above.)

Total testosterone values above 150 ng/dL (5.2 nmol/L) should prompt additional evaluation for a testosterone-secreting ovarian or adrenal tumor [41-44] as well as ovarian hyperthecosis, a disorder characterized by severe hyperandrogenism and insulin resistance. Both disorders are seen more commonly in postmenopausal women but occur occasionally in premenopausal women. (See 'Additional evaluation for severe hyperandrogenemia' below and "Evaluation and management of postmenopausal hyperandrogenism", section on 'Women with virilization or severe hyperandrogenemia' and "Ovarian hyperthecosis", section on 'Biochemical findings'.)

●Serum DHEAS – Serum DHEAS is an adrenal androgen and is often measured to try to identify an adrenal source of excess androgens, most importantly adrenal androgen-secreting neoplasms. Mildly elevated levels of DHEAS are unlikely to affect management. Elevated DHEAS concentrations do not discriminate as well as serum testosterone between malignant and benign causes of adrenal hyperandrogenism, and it is unclear whether DHEAS is the best marker for androgen-secreting carcinomas. However, we do suggest its measurement 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 [5,21,41,42,45-47]. (See 'Additional evaluation for severe hyperandrogenemia' below.)

Adults with hormone-secreting adrenocortical carcinomas usually present with Cushing syndrome alone (45 percent) or a mixed Cushing and virilization syndrome due to overproduction of both glucocorticoids and androgens (25 percent). Fewer than 10 percent present with virilization alone, but the presence of virilization in a patient with an adrenal neoplasm suggests an adrenal carcinoma rather than an adenoma. (See "Clinical presentation and evaluation of adrenocortical tumors", section on 'Clinical presentation'.)

Additional evaluation for severe hyperandrogenemia — Further evaluation is indicated in all women when an ovarian androgen-secreting tumor is suspected (serum total testosterone >150 ng/dL [5.2 nmol/L]). We suggest pelvic ultrasound as the next diagnostic step. If the ultrasound is negative and/or serum DHEAS is greater than 700 mcg/dL (18.9 micromol/L), we suggest adrenal CT to look for an adrenal androgen-secreting tumor.

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]). However, failure to identify a tumor does not rule out its presence, as these tumors may be very small.

High-resolution pelvic ultrasonography with a transvaginal probe can identify ovarian follicles and cysts as small as 3 to 5 mm in diameter. It is therefore a safe and effective way to look for polycystic ovary morphology and to screen for ovarian androgen-secreting tumors. Suspicious findings include large cysts, solid masses, and complex cysts that do not resolve spontaneously in two to four weeks [48].

Ultrasonography in women with ovarian hyperthecosis usually shows a bilateral increase in ovarian stroma. Unlike PCOS, where the ovaries characteristically have a multifollicular appearance with 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'.)

The role of pelvic ultrasound in the evaluation of severe hyperandrogenism is reviewed in more detail separately. (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Pelvic ultrasonography' and "Adnexal mass: Ultrasound categorization".)

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 for a serum DHEAS concentration >700 mcg/dL [18.9 micromol/L]). Adrenal CT is the imaging test of choice and should readily identify androgen-secreting adrenal lesions [47,49]. Radiologic testing is otherwise not indicated and may be misleading, because nonfunctioning adrenal masses (adrenal incidentalomas) are common. (See "Evaluation and management of the adrenal incidentaloma".)

Adrenal disorders that may be diagnosed during the evaluation for hirsutism and require surgery include adrenal adenomas and adrenal carcinoma (uncommon in premenopausal women). (See "Clinical presentation and evaluation of adrenocortical tumors".)

Ovarian and adrenal vein sampling — Combined ovarian and adrenal vein sampling (selective venous sampling) is sometimes (but not routinely) performed for further evaluation in women with high serum testosterone concentrations (testosterone >150 ng/dL [5.2 nmol/L]), as well as normal pelvic ultrasonography and adrenal imaging [50]. In this setting, the ovary is likely to be the source of androgen hypersecretion because adrenal tumors are almost always visualized on adrenal CT [47,49], while ovarian tumors are often too small to be seen on imaging studies [48]. (See 'Adrenal imaging' above and 'Pelvic ultrasonography' above.)

In premenopausal women, we typically suggest this procedure to help successfully localize the ovarian tumor so that the patient can have a unilateral oophorectomy. The role of ovarian and adrenal vein sampling in the evaluation of women with severe hyperandrogenemia is reviewed in detail separately. (See "Evaluation and management of postmenopausal hyperandrogenism", section on 'Ovarian and adrenal vein sampling'.)

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: Polycystic ovary syndrome" and "Society guideline links: Hirsutism" and "Society guideline links: Classic and nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

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●Basics topics (see "Patient education: Hirsutism (excess hair growth in women) (The Basics)")

●Beyond the Basics topics (see "Patient education: Hirsutism (excess hair growth in females) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Hirsutism is a clinical diagnosis defined by the presence of excess terminal hair growth (dark, coarse hairs) in androgen-sensitive areas (eg, upper lip, chin, midsternum, upper abdomen, back, and buttocks). (See 'Definitions and Epidemiology' above.)

●Prevalence and significance – Hirsutism affects approximately 5 to 10 percent of premenopausal women and is usually an indication of an underlying endocrine disorder (most commonly polycystic ovary syndrome [PCOS]) (table 1). Hirsutism is associated with significant emotional distress and depression. (See 'Definitions and Epidemiology' above and 'Emotional distress/depression' above.)

●Evaluation

•Goals – The most important goals of the evaluation are to identify polycystic ovary syndrome (present in 70 to 80 percent of patients with hirsutism), and to identify the most serious causes of hirsutism, including androgen-secreting ovarian and adrenal tumors. (See 'Goals' above and 'Severe hyperandrogenism' above.)

•Use of the Ferriman-Gallwey score – A simple and commonly used method to grade hair growth makes use of the modified scale of Ferriman and Gallwey, which grades nine androgen-sensitive sites on a scale from 0 to 4. Although commonly used, this score has a number of limitations (figure 1). (See 'Physical examination' above.)

•Biochemical testing – We suggest measuring a serum total testosterone in all women with hirsutism. (See 'Biochemical testing' above.)

Additional testing is based upon the patient's presentation (time of onset, pace of progression, presence or absence of virilization, and menstrual cycle status) (algorithm 1). As noted, 75 to 80 percent of women who present with hirsutism have PCOS, but it is essential to identify those who have a more serious cause (androgen-secreting tumors and ovarian hyperthecosis). (See 'Biochemical testing' above.)

Some women with hirsutism seek advice when they are already receiving pharmacotherapy, usually combination oral contraceptives (COCs). Measuring serum androgens is not useful in this setting, because COCs suppress serum gonadotropins and ovarian androgen, most importantly, testosterone. Biochemical evaluation is usually not necessary unless the patient is experiencing severe or rapid worsening of her hirsutism in spite of COCs (algorithm 1). More commonly, the patient has had an inadequate response to COCs alone so a second medication is added, usually spironolactone. (See 'Women already taking pharmacologic therapy' above.)

•Patients with severe hyperandrogenemia – A more extensive evaluation, including imaging studies, is needed for women with severe hyperandrogenemia (serum total testosterone concentration is ≥150 ng/dL (5.2 nmol/L). Details of this evaluation are reviewed in detail separately. (See "Evaluation and management of postmenopausal hyperandrogenism" and "Ovarian hyperthecosis" and 'Severe hyperandrogenism' above.)