Androgen excess is the most common endocrine disorder in women of reproductive age. Androgens are produced primarily from the adrenal glands and the ovaries. However, peripheral tissues such as fat and skin also play roles in converting weak androgens to more potent ones. Androgen excess can affect different tissues and organs, causing variable clinical features such as acne, hirsutism, virilization, and reproductive dysfunction.[1]
The endocrine glands secrete 5 androgens through a similar pathway: testosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, and androstenediol, the latter of which has both androgenic and estrogenic activity. Testosterone and its biologically active metabolite dihydrotestosterone (DHT) are the only androgens with direct androgenic activity. DHEAS, DHEA, and androstenedione are all precursors of testosterone.
View Image | Androgen secretion pathway in adrenal glands and ovaries. |
The ovaries produce 25% of circulating testosterone, which is dependent on luteinizing hormone (LH) secreted by the anterior pituitary. The ovaries also secrete 50% of the androstenedione and 20% of DHEA. Testosterone is used as a marker of ovarian androgen secretion. However, the adrenals also contribute to circulating testosterone via peripheral conversion of androstenedione to testosterone.
The adrenal glands produce all of the DHEAS and 80% of the DHEA. The adrenals also secrete 50% of androstenedione and 25% of circulating testosterone. DHEAS and 11-androstenedione are not secreted by the ovaries and, therefore, are used as markers of adrenal androgen secretion. Adrenal androgen secretion is dependent on adrenocorticotropic hormone (ACTH) secreted by the anterior pituitary. Both prolactin and estrogen can affect adrenal androgen production.
Skin, fat, liver, and urogenital systems are important peripheral sites of androgen production. Androstenedione, and to some degree DHEA, are converted to testosterone in the skin.
Of the circulating androgens, only testosterone and DHT are able to activate androgen receptors. In reproductive-aged women, 25% of the circulating testosterone comes from the adrenals; the ovaries contribute another 25%. The rest of the testosterone is produced by the peripheral conversion of androstenedione in adipose tissue.[2] In healthy women, 80% of testosterone is bound to sex hormone binding globulin (SHBG), 19% is bound to albumin, and 1% circulates freely in the blood stream. The androgenicity depends mainly on the unbound fraction due to the high affinity of SHBG to the bound androgens. The levels of SHBG increase and decrease based on conditions and medications.
The remaining androgens, DHEAS, DHEA, and androstenedione are almost entirely bound to albumin. Unlike SHBG; albumin has a low affinity for sex hormones, so the albumin-bound androgens are readily available to tissues.
Adrenal androgens increase in response to ACTH stimulation, while androgens do not influence the ACTH secretion. Also, LH stimulates theca cells of the ovaries to secrete androgens; however, there is no feedback regulatory loop that controls androgen secretion in women.
Most of the circulating testosterone is metabolized in the liver into androsterone and etiocholanolone, which are conjugated with glucuronic acid or sulfuric acid and execrated in the urine as 17-ketosteroids. Only 20-30% of urinary 17-ketosteroids are derived from testosterone metabolism; the rest originates from the metabolism of adrenal steroids.[3]
Androgens induce virilization and are responsible for forming the male external genitalia in the fetus. Their absence or the absence of androgen receptors results in a female phenotype, despite the presence of a 46 XY karyotype (eg, androgen insensitivity syndrome). Androgens are also responsible for the development of the secondary sexual organs and ducts, the seminal vesicles, and the prostate.
Postnatal females are not as sensitive as the fetus to androgens, which induce the growth of sexual hair, temporal balding, acne, clitoral growth, sebum production, and a deepening of the voice.
Oral androgens decrease high-density lipoprotein (HDL) cholesterol and increase low-density lipoprotein (LDL) cholesterol. With androgen excess, the extent of these changes is dependent on the level of androgens in the blood.
Androgens have direct effects on different body systems and also act as precursor hormones for ovarian and extragonadal estrogen synthesis. Androgen receptors are present in a variety of tissues like skeletal muscles, skin, gastrointestinal tract, genitourinary tract, bone, brain, cardiovascular system, placenta, and adipose tissues. Androgen actions are not completely understood in all of these tissues.[4, 5]
Androgen receptors are distributed throughout the brain in close proximity to estrogen receptors. The highest concentrations are present in the preoptic area of the hypothalamus. Some areas contain 5α-reductase and aromatase and are able to convert testosterone to DHT or estradiol.[6] Androgen can have activational behavior on women and may have some negative effects on the cognitive functions of older women.[7]
Growing evidence supports the role of androgens in physiologic levels and sexual desire. Decreased sexual function has been reported in hyperandrogenic women receiving antiandrogens; on the other hand, administration of testosterone in women with hypoactive sexual desire disorder results in improvements in libido and sexual function.[8, 9]
Androgens have important roles in bone mineralization either directly or through aromatization to estrogen. Lower androgen concentrations have been associated with bone loss in various age groups.[10]
Androgen receptors are present in mammary epithelial cells in addition to estrogen and progesterone receptors. The proposed mechanisms include either direct stimulation of the androgen receptors or conversion to estradiol by the aromatase enzyme present in breast tissue. Androgens, particularly DHEA and testosterone, have been reported to protect against mammary epithelial proliferation in female monkeys. The reverse effect was reported when the antiandrogen flutamide was given to those animals.[11]
Few data are available regarding the effects of androgens on human breasts. Hyperandrogenemia in women with polycystic ovary syndrome (PCOS) doesn’t appear to have significant risk of breast cancer.[12] In a prospective randomized controlled study in postmenopausal women evaluating breast cell proliferation and testosterone, the authors found no significant difference when testosterone was added to estrogen and progesterone, while they found a 5-fold increase in breast cell proliferation in women taking the placebo.[13]
Unopposed estrogen stimulation of the endometrium increases the risk of endometrial hyperplasia and eventually cancer. The proposed mechanism of androgen aromatization to estradiol may not be applicable because the aromatase expression has not been detected in normal endometrium and stromal cells.[14] In vitro studies have shown that androgens have an inhibitory effect on endometrial proliferation.[15]
There is a great concern about the relation between sex hormones and cardiovascular events. Women with PCOS have hyperandrogenemia and are at higher risk of cardiovascular events.[16, 17, 18, 19] However, the insulin resistance associated with PCOS is likely more relevant to the pathogenesis of cardiovascular disease. Moreover, the exogenous administration of testosterone for female to male transsexual has not been associated with the increased risk of cardiovascular disease.[20]
In the target tissues, androgens enter the cell cytoplasm by simple diffusion across the cell membrane. Once inside the cell, the androgens bind and activate the androgen receptors. The androgen-receptor complex attaches to a specific DNA site and stimulates the production of messenger RNA, which, in turn, stimulates the production of the enzymes and proteins necessary to affect androgen action.
Androgen excess affects mainly the pilosebaceous unit (PSU) and the reproductive system. The PSU secretes sebum and is the unit from which hair grows. Three types of hair, lanugo, vellus, and terminal hairs, exist. The fine hairs of the fetus are lanugo and the peach fuzz hair of adults is vellus hair. These hairs are fine, short, and nonpigmented. Thick and pigmented hair is referred to as terminal hair. Those hairs of the pubic, axillary, sternal, and facial areas are responsive to androgens and those in scalp, eyelashes, and eyebrows are androgen-independent. Their prevalence depends largely on genetics. As androgen levels rise, more vellus hairs in the androgen-sensitive areas are converted into terminal hairs, resulting in hirsutism.
Androgens prolong the growth phase of hair and promote their conversion from vellus to terminal type. Hirsutism affects 70-80% of women with androgen excess. Sebum production from the PSU is also increased by androgens.[21]
Acne vulgaris can be aggravated or initiated by increased androgen levels as the excess sebum production and the shedding of hyperkeratinized epithelium may occlude the hair follicle. Propionibacterium acnes proliferates and triglycerides of sebum are then hydrolyzed by the bacterial lipases to form glycerol and free fatty acids, which, together with other bacterial metabolites, cause inflammation. It is also commonly proposed that hypersensitivity of PSU to androgens is the cause of acne.[22] Sebum production increases markedly during the prepubertal period, a time when serum levels of DHEAS, a precursor to testosterone, are also elevated. Individuals who are insensitive to androgen have less active sebaceous glands and do not develop acne.
Although there has been some controversy over whether acne is common enough in androgen excess to be considered a sign of hyperandrogenemia, a study by Uysal et al indicated that it is indeed evidence of the condition. The study found that of 207 women aged 18-45 years suffering primarily from acne, 72% demonstrated clinical and/or biochemical hyperandrogenemia.[23]
Androgen excess is a common feature of PCOS, which is also the most common cause of anovulatory infertility. The ovarian theca cells increase their ovarian androgen production under the stimulatory activity of the raised LH levels, and in many cases, raised insulin levels.
Hyperinsulinemia due to peripheral insulin resistance is often present in women with PCOS and it promotes hyperandrogenemia through the binding of insulin to the insulin-like growth factor–1 (IGF-1) receptor. Insulin mimics the action of insulin growth factor 1 (IGF-1), which augments androgen production by the theca cell in response to LH. Since insulin decreases levels of SHBG, the circulating levels of free testosterone are also increased.
A retrospective study by Elhassan et al indicated that in women with androgen excess, the pattern of excess varies according to the etiology. The investigators found, for example, increased androstenedione levels in all cases of adrenocortical carcinoma, while all ovarian hyperthecosis cases showed increased testosterone. Androstenedione and/or testosterone increases allowed identification of all but one instance of congenital adrenal hyperplasia. In postmenopausal women, adrenocortical carcinoma was responsible for all occurrences of severe DHEAS and androstenedione excess, while adrenocortical carcinoma and ovarian hyperthecosis were equally responsible for severe testosterone excess. In premenopausal women, polycystic ovary syndrome was the primary cause of severe DHEAS excess.[24]
United States
The prevalence of androgen excess is 8%.
International
The international incidence rate is dependent on the particular culture, but, essentially, it is similar to that of the United States.
Androgen excess per se does not cause mortality or morbidity, but it is associated with insulin resistance, dyslipidemia, hypertension, and vascular diseases;[5] therefore, it is a forerunner of cardiovascular disease.
Androgen excess occurs equally in all races. Congenital adrenal hyperplasia prevalence due to 21-hydroxylase deficiency is greater among those of Ashkenazi Jewish descent.
Congenital adrenal hyperplasia occurs equally in both sexes; however, this article focuses on females.
The most common causes of hyperandrogenism begin in early adolescence or in childbearing age. Androgen-producing tumors may rarely affect postmenopausal women.
Detailed history taking from the patient is the cornerstone in patients with hirsutism. Most of the patients with hirsutism will develop excess hair around puberty or a few years thereafter. Onset of mild hirsutism with a slowly progressive course is usually associated with a functional disturbance. On the other hand, rapid progression of hair growth suggests an androgen secreting tumor.[26]
Patients with hirsutism are often most concerned with unwanted hair in their face. However, areas covered by clothes may be less of a concern. Hence, it is important to ask about increased hair growth in other areas, including the upper chest, abdomen, inner aspects of the thighs, and the upper and lower back. The frequency and the method used to remove unwanted hair should be elicited because this often gives some idea of the extent of hair growth.
Rapid virilization associated with hirsutism is suggestive of androgen secreting neoplasm or exogenous androgenic drug use. History should include acne, alopecia, clitoromegaly, deepening of voice, masculinization, breast atrophy, and amenorrhea.
Hirsutism is almost always a manifestation of other disease (more than 90% of the time). Because PCOS represents 80% of the etiology, it is important to ask about symptoms of this disorder. Oligomenorrhea or amenorrhea with hirsutism is sufficient to diagnose PCOS according to the revised Rotterdam criteria[27] after exclusion of other causes.
Regular menses, however, do not predict normal androgen status in hirsute women. Although 40% of women with hirsute have regular menses, half of them will be found to have elevated levels of one or more androgens.[28] Other cutaneous manifestations of PCOS like acne, oily skin, androgenic alopecia, seborrhea, and obesity may be present with hirsutism.
An increased prevalence of hirsutism, acne, and male pattern baldness have been found to run in some families.[29] PCOS often presents with familial clustering. However, it is unclear if this is due to genetic pattern alone or due to environmental factors such as diet.[30] Congenital adrenal hyperplasia also presents with familial clustering. The ethnic differences in hair quantity and distribution should be kept in mind.
Focused physical examination is essential for the evaluation of women with hirsutism. The clinician should determine whether hirsutism is truly present, as many women who complain of excess hair growth might not actually have hirsutism, especially those with ethnic and genetic predisposition (South European, and Middle East). Excess hair should be established as villus or terminal. Also, hirsutism should be distinguished from hypertrichosis, where hair growth is not mediated by androgens and hairs are not distributed in an androgen sensitive (male) pattern.[31]
Height, weight, body mass index (BMI), and waist-to-hip ratio (WHR) should be determined. Increased BMI and WHR are associated with PCOS, insulin resistance, and increased risk of coronary artery disease.[32]
Ferriman and Gallwey[33] published a hirsutism rating scale that is illustrated in the table below. This scale allows the physician to measure a response to therapy objectively. This system is the most widely used and evaluates body areas for absent-to-severe hirsutism with scores of 0-4, respectively. Scores of 8 and higher are consistent with a diagnosis of hirsutism. This scale does not measure the thickness of the hair, which is another way of objectively assessing excess hair.
Scoring systems are a useful aid in quantifying hirsutism and in evaluating treatment response. However, they are somewhat subjective, so the absolute score is not used to define hirsutism. Even with scores >8, the patient determines if she is hirsute. When evaluating treatment response, the patient can determine if he or she notices a difference. Photographs are helpful for documentation and for following the progress of therapy.
Table. Ferriman-Gallwey Scoring System
View Table | See Table |
Acne and oily skin are both associated with hirsutism. Androgen acts on the PSU to increase sebum production and has an important role in acne development. However, many cases of acne are not associated with hyperandrogenism.
Androgenic alopecia is another distressing condition associated with androgen excess. It is characterized by hair loss from the crown of the scalp sparing the frontal and occipital hairline (male pattern baldness).[34]
Acanthosis nigricans is a mucocutaneous condition where velvety hyperpigmentation patches appear mainly in the skin of the base of the neck, axilla, antecubital fossae, and groin. Acanthosis nigricans is a marker of insulin resistance.[35] In contrast, acanthosis nigricans is rarely seen with androgen secreting tumors.[36]
Virilization suggests an androgen secreting tumors. Features of virilization include temporal male pattern balding, laryngeal hypertrophy, loss of feminine body contour and clitoral hypertrophy.[37] Clitoromegaly is diagnosed when the clitoral length times diameter is >35 mm2.
A specific underlying cause can be identified in most patients with androgen excess.[38]
Approximately 80-90% of women with excess androgens have PCOS.[39, 38] PCOS is the most common endocrinological disorder affecting women in their reproductive years.[40] The prevalence in the United States has been estimated at 5-7%[41] and appears to be rising. Approximately 70% of women with PCOS are found to have mildly elevated free testosterone, and 20-30% have mildly elevated dehydroepiandrosterone sulphate (DHEAS).[42, 43]
Evidence suggests that hyperandrogenemia may be associated with chronic inflammation in PCOS by affecting adipocyte attributes and morphology.[44]
A literature review by Escobar-Morreale and Roldán-Martín suggested that in women with type 1 diabetes mellitus, the prevalences of PCOS and associated traits, including hyperandrogenemia, are greater than in the general population without diabetes. The investigators found that out of 475 adolescent or adult women with type 1 diabetes, the prevalences of PCOS and hyperandrogenemia were 24% and 25%, respectively, while those for hirsutism, menstrual dysfunction, and polycystic ovarian morphology were 25%, 24%, and 33%, respectively.[45]
HAIR-AN syndrome is a subset of women with PCOS who present with hyperandrogenism, insulin resistance, acanthosis nigricans, and obesity in the absence of insulin receptor defect.[46] This syndrome is found in 1-3% of hyperandrogenic women.[47] HAIR-AN syndrome is characterized by high levels of post-glucose challenge insulin levels that may reach 300-500 µU/mL.[48]
Ovarian hyperthecosis is another condition related to PCOS that most often presents in the perimenopausal period. This condition accounts for less than 1% of women with elevated androgens in their reproductive years, but most of the cases of hyperandrogenemia in postmenopausal women.[49]
Ovarian hyperthecosis is described when luteinized theca cell nests are present in the ovarian stroma. Although there is a considerable overlap between hyperthecosis and PCOS, hyperthecosis is associated with a more severe form of hyperandrogenism and virilization. Testosterone levels are much higher than PCOS and may reach levels greater than 200 ng/dL.[50]
Approximately 2% of women with androgen excess are found to have late-onset, nonclassical, congenital adrenal hyperplasia.[39] Congenital adrenal hyperplasia is a group of autosomal recessive disorders resulting from mutations in the genes coding for steroidogenic enzymes. In these disorders, a block in cortisol biosynthesis leads to loss of negative feedback inhibition, increased ACTH secretion, and subsequent excessive adrenal androgen production.[51]
The most common cause of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which accounts for 90-95% of patients with this condition.[51] The remaining patients with congenital adrenal hyperplasia have either 11 β-hydroxylase deficiency or 3 β-hydroxysteroid deficiency.[52, 53]
Cushing syndrome is a rare but important cause of androgen excess, and hirsutism is present in approximately 81% of these patients.[54] Cushing syndrome (also called hypercorticism) is primarily the result of increasing levels of circulating cortisol or exogenous glucocorticoids. This syndrome can present insidiously with a spectrum of classic symptoms including rapid central weight gain (central obesity and “moon face”), abdominal striae, and signs of hyperandrogenemia including hirsutism, acne, and baldness.
Glucocorticoid therapy is currently the most common cause of Cushing syndrome but is unlikely to be associated with signs of increased androgens. In contrast, endogenous Cushing syndrome is often associated with hirsutism. Cushing syndrome can be secondary to an ACTH secreting pituitary tumor, which is called Cushing disease. Other cases of Cushing syndrome are related to autonomous cortisol secretion by the adrenal glands.[55] Adrenal tumors are associated with rapid onset of Cushing syndrome symptoms, often with hirsutism.[56] Rarely, Cushing syndrome is caused by ACTH secretion by other types of tumors such as small cell lung cancer.
Androgen secreting tumors of the ovaries or adrenal glands are rare causes of hyperandrogenism that often mimic PCOS. Women with these tumors tend to have sudden onset of symptoms, rapid progression of hyperandrogenism and early development of frank virilization.
The most common virilizing ovarian tumors are Sertoli Leydig cell tumors and account for 0.5% of all ovarian neoplasms.[50] However, any type of ovarian tumor can present with signs of hyperandrogenism.
Androgen-secreting adrenal neoplasms are less common than ovarian neoplasms.[57] Patients with these tumors usually present with mixed picture of Cushing syndrome and virilization.[58]
Elevated prolactin levels are found in as many as 6% of women with hirsutism.[59] The exact relationship between elevated prolactin levels and androgen excess is still unclear. Elevated prolactin levels might directly stimulate the adrenal cortex.[60]
Testosterone rises throughout the normal pregnancy, reaching values around 600-800 ng/dL by term. The increase in SHBG and the placental aromatization of androgens to estrogens protect the mother and her fetus. Placental aromatase enzyme deficiency can cause hyperandrogenemia in both mother and fetus and result in virilization.[61]
Ingestion of androgens or agents with androgenlike activity can result in hirsutism, acne, and virilization. Various anabolic steroids are used by professional athletes, both men and women, to attain a competitive edge or to assist in recovery from injury. These drugs are also used by a large number of noncompetitive body builders for cosmetic purposes and by women to increase libido.
Laboratory evaluation should be part of the workup for every woman who seeks treatment for signs or symptoms of androgen excess, such as hirsutism. Although the most common cause of androgen excess in women is PCOS, some women with only mild hirsutism are found to have an androgen-secreting neoplasm, for which early diagnosis and treatment can be life saving. Furthermore, delay in diagnosis and appropriate treatment of non-life-threatening conditions can result in irreversible virilization. Fortunately, the basic laboratory evaluation for hirsutism is relatively inexpensive.
Some organizations recommend laboratory evaluation (and imaging studies) only for women with moderate or severe hirsutism (mFG >15).[62] Exceptions are made for Asian women, hirsutism of sudden onset, and the presence of other symptoms suggesting underlying pathology. However, for the reasons mentioned above, a basic laboratory evaluation can be justified in all women seeking treatment for hirsutism.[63, 64] A 2012 position statement from the Androgen Excess and Polycystic Ovary Syndrome Society recommends basic hormonal evaluations for every woman who presents with hirsutism.[65]
Laboratory tests can be divided into basic screening tests, and diagnostic tests indicated for signs and symptoms suggestive of specific pathology.[64] The following screening tests should be performed in all women presenting with signs of increased androgens.
Total testosterone levels are often mildly elevated in women with PCOS, so values between the upper limit of the normal range and 2 ng/dL (2 ng/mL, 8.92 nmol/L) can be consistent with PCOS. Total testosterone levels >2 ng/dL (2 ng/mL, 8.92 nmol/L) suggest a virilizing ovarian tumor[66] or hyperthecosis.
DHEAS is secreted exclusively by the adrenal glands and is therefore a good marker for adrenal androgen production. A mildly elevated DHEAS level is common in women with PCOS.[67] In contrast, DHEAS values above 700 ng/dL (7µg/ml, 18umol/L) are suggestive of adrenal neoplasm.[68]
Measuring serum levels of 17-hydroxyprogesterone is a screening test for nonclassic congenital adrenal hyperplasia.[69] Enzyme defects (most commonly 21-hydroxylase) result in increased levels of 17-hydroxyprogesterone. Women with levels > 200 ng/dL (6.05 nmol/L) should be further evaluated with a corticotrophin stimulation test.
Hypothyroidism and hyperthyroidism should be evaluated in women with androgen excess. Subclinical thyroid dysfunction may be the cause of anovulation and menstrual irregularities. Thyroid-stimulating hormone (TSH) is the screening test of choice, particularly in patients with irregular cycles.[68]
Hyperprolactinemia has been shown to be associated with androgen excess. Prolactin can be elevated in women with hypothyroidism. When prolactin levels are elevated in women with normal thyroid function, magnetic resonance imaging (MRI) of the pituitary may be warranted to exclude pituitary tumors.
Patients with signs or symptoms suggestive of specific diagnoses should undergo more extensive testing. These tests are listed below, under Other Tests.
Analogous to laboratory evaluation, some organizations recommend imaging studies only for women with moderate or severe hirsutism (mFG >15),[62] However, many clinicians recommend pelvic ultrasonography for all women seeking treatment for signs of increased androgens since this technology is noninvasive, relatively inexpensive, and very accurate for diagnosing both PCOS and ovarian neoplasms.[64]
The diagnosis of PCOS is made in women with hirsutism when at least 1 ovary is found to have 12 or more follicles < 10 mm in diameter, assuming other pathology is excluded.[27] The presence of a large, complex ovarian cyst can indicate the presence of an androgen-secreting ovarian tumor.[70]
Adrenal pathology is suggested by significantly elevated DHEAS levels or abnormal 24-hour urine free cortisol. Women suspected of having an adrenal neoplasm should be further evaluated with either computerized tomography (CT) or MRI. Both techniques can usually differentiate between benign adenomas and malignant nodules of the adrenal gland.[71] CT can diagnose an adrenal nodule of less than 5 mm, whereas MRI can determine if a tumor has invaded into the blood vessels.[58]
Tests in addition to routine screening tests should be obtained in patients with signs or symptoms suggestive of specific diagnoses.
Women diagnosed with PCOS should be periodically screened for glucose intolerance and diabetes mellitus.[27, 72, 73, 74] Traditionally, a 2-hour OGTT has been recommended for both initial and periodic screening. More recently, the American Diabetic Association has recommended measuring hemoglobin A1c for diagnosing type 2 diabetes mellitus in the general population.[75, 76, 77]
Women with clinical evidence of Cushing syndrome (moon face, buffalo hump, obesity, hypertension, and dyslipidemia) should be evaluated by measuring 24-hour urine free cortisol. This test has a sensitivity >95% and specificity of 98% for diagnosing Cushing syndrome and is more specific than the dexamethasone suppression test.[78, 55]
The corticotrophin stimulation test is a diagnostic test for nonclassic congenital adrenal hyperplasia when levels of 17-hydroxyprogesterone are < 200 ng/dL (6.05 nmol/L).[69] For this test, 17-hydroxyprogesterone is measured 1 hour after injection of synthetic corticotrophin. levels >10 ng/dL (30.02 nmol/L) are diagnostic for nonclassic adrenal hyperplasia.
This test can be used to determine the source of significantly elevated androgens. After drawing baseline DHEAS, testosterone, and cortisol, the patient is give 8 doses of 0.5 mg of dexamethasone over a period of 48 hours and these tests are redrawn. An adrenal source is suggested if testosterone is suppressed more than 40% and DHEAS is suppressed more than 60%. An ovarian source is suggested if testosterone is not suppressed while DHEAS and cortisol are both suppressed. A combined source is suggested if DHEAS and cortisol are suppressed and testosterone is suppressed less than 40%. If DHEAS is not suppressed, Cushing syndrome or adrenal cancer must be considered.
A GnRH agonist (eg, leuprolide acetate) can be given by injection to confirm the ovarian origin of significant hyperandrogenemia when no obvious ovarian neoplasm can be found by ultrasonography.[79] The goal is to downregulate the pituitary to eliminate ovarian stimulation by FSH and LH. A GnRH agonist must be given for >2 weeks to attain this effect. More recently, GnRH agonists have become available that suppress ovarian function within days. Dexamethasone can be given as described above to suppress any contribution of the adrenal glands.
Normally, FSH, LH, estradiol, and testosterone are extremely low after suppression with a GnRH analog and dexamethasone. Inability to suppress some or all of these suggests a hormone secreting tumor.
Ovarian and adrenal vein sampling is used when laboratory values indicate a tumor but no tumor can be identified by imaging studies. Sampling of blood from the ovarian and adrenal veins helps determine the source of elevated androgen levels and whether 1 or both glands are involved. Involvement of a single gland is highly suggestive of a tumor.[39]
Women with mild hirsutism can be treated safely and effectively by most primary care providers after serious etiologies have been excluded. Those with more significant symptoms or life-threatening disease should be referred to specialists. Women with emotional distress regardless of the degree of symptoms often benefit from referral for psychological support.
Women with significant acne or hirsutism that does not respond to standard therapy are often best treated in conjunction with a dermatologist and sometimes a medical or reproductive endocrinologist. Women with signs of virilization should be evaluated by a medical endocrinologist. Likewise, women with significant adrenal disease require the expertise of a medical endocrinologist and possibly a surgeon specializing in adrenal tumors.
Women with PCOS should be comanaged with an obstetrician-gynecologist or reproductive endocrinologist, particularly if infertility is a factor. Those with ovarian tumors should be evaluated and treated by an obstetrician-gynecologist or a gynecologic oncologist.
Many women are familiar with different hair removal methods like shaving, waxing, and using depilatory creams. They are all easy, safe, and inexpensive; however, mild skin irritation either due to local trauma or chemical reaction may occur.[80] Women using these methods can be reassured that these methods do not exacerbate hair growth, but they will not lower the androgen levels if they are elevated. Combining one of these local measures with systemic treatment might help achieve rapid response and better patient satisfaction.
Surgical removal is the standard therapy for ovarian and adrenal tumors that result in androgen excess. Surgery for PCOS is less commonly performed today, since adhesions routinely occur after both wedge resection and ovarian drilling. However, infertile women with PCOS who are resistant to clomiphene citrate are sometimes treated with laparoscopic ovarian drilling to avoid the risks and expenses associated with ovulation induction with gonadotropins or IVF.[81]
A retrospective study by Christ and Falcone found that in women with PCOS, bariatric surgery significantly reduced androgen levels, leading to a substantial drop in the percentage of women who met the criteria for hyperandrogenism.[82]
Women with mild hirsutism can be treated safely and effectively by most primary care providers after serious etiologies have been excluded. Those with more significant symptoms or life-threatening disease should be referred to specialists. Women with emotional distress regardless of the degree of symptoms often benefit from referral for psychological support.
Women with significant acne or hirsutism that does not respond to standard therapy are often best treated in conjunction with a dermatologist and sometimes a medical or reproductive endocrinologist. Women with signs of virilization should be evaluated by a medical endocrinologist. Likewise, women with significant adrenal disease require the expertise of a medical endocrinologist and possibly a surgeon specializing in adrenal tumors.
Women with PCOS are should be comanaged with an obstetrician-gynecologist or reproductive endocrinologist, particularly if infertility is a factor. Those with ovarian tumors should be evaluated and treated by an obstetrician-gynecologist or a gynecologic oncologist.
In women who are obese, a modification of life style and weight loss are pivotal. Suppression of hair growth is unlikely without weight loss.[26] A loss of 5-10% of body weight for obese women with PCOS in a 6-month period is enough to greatly improve hirsutism in most women.[83]
Regular exercise and behavioral modification programs are essential for acute and long-term weight management. Different exercise regimens have been advocated from 30 minutes 3 times a week, to 10 minutes multiple times a day, to 1 hour of exercise most days of the week. The best program is one that the patient will actually follow.[84]
Restricting calories should accompany increased energy expenditure. When applying calorie restriction and exercise to a group of women with PCOS, one study found an average weight loss of 15 lb, a 92% ovulation rate, and a 33-45% spontaneous pregnancy rate.[85]
Unfortunately, lifestyle modification and weight loss programs require prolonged patient motivation and are therefore difficult to achieve beyond the research setting. Advice alone is typically ineffective at promoting sustained weight loss.
Medical treatment of androgen excess is aimed at lowering ovarian or adrenal androgen production, reducing the free androgen level, and blocking the peripheral androgen action. However, patients with androgen excess typically seek medical attention for the treatment of primary symptoms, such as hirsutism, acne, and menstrual disorders.
Hirsutism is best treated by a combination of mechanical and chemical methods. The mechanical methods remove hair immediately, and the chemical methods prevent further differentiation of vellus to terminal hairs.
PCOS associated with insulin resistance can be treated with metformin and/or an OC with or without an added antiandrogen (spironolactone).[86] PCOS not associated with insulin resistance is best treated with an OC with or without added spironolactone.
Acne treatment is aimed at decreasing skin sloughing and proliferation of P acnes through the use of topical and systemic agents. Suppression of androgen production decreases production of sebum and reduces acne.
Clinical Context: Ethinyl estradiol reduces the secretion of LH and FSH from the pituitary by decreasing the amount of GnRH. Use ethinyl estradiol 30-35 mg combined with any form of progesterone. Improvements of hyperandrogenic effects are seen in 60-100% of women but usually require a least 6-12 months of use. Perform a pregnancy test before therapy. If the patient has had no menstrual period for 3 months, induce withdrawal bleeding with medroxyprogesterone acetate (Provera) 5-10 mg/day for 10 days, then begin therapy with oral contraceptives.
Clinical Context: Combination of estrogen and progestin treats hirsutism in adult women. Suppresses ovarian production of androgens.
Clinical Context: Combination of estrogen and progestin treats hirsutism in adult women. Suppresses ovarian production of androgens.
Clinical Context: Combination of estrogen and progestin treats hirsutism in adult women. Suppresses ovarian production of androgens.
Clinical Context: Combination of estrogen and progestin treats hirsutism in adult women. Suppresses ovarian production of androgens.
Oral contraceptives (OCs) decrease ovarian androgen production and increase SHBG, therefore reducing free testosterone by approximately 50%. OCs also decrease adrenal androgen production, particularly DHEAS. The reduction in ovarian androgens is in relation to the OCs capacity to inhibit ovulation. Low-strength preparations (20 µg ethinyl estradiol) are less efficient than standard or high-strength preparations in inhibiting ovulation. The presence of less androgenic progestin (desogestrel, norgestimate) in third-generation OCs is not associated with better outcome compared with older OCs. By promoting regular bleeding, OCs reduce the incidence of endometrial hyperplasia and cancer.
OCs alone or in combination with antiandrogens are the first choice for the treatment of hirsutism in women needing contraception. All strengths of OC pills have been shown to improve acne. The choice of an OC should be based solely on personal preference of the health care provider and patient. The new OC containing the antiandrogens drospirenone and ethinyl estradiol (Yasmin) has not shown advantages over other preparations.
Clinical Context: Used most effectively in combination with an OC. First choice because of few adverse effects, cost, and clinical experience.
Clinical Context: Nonsteroidal antiandrogen that inhibits androgen uptake or binding of androgen to target tissues.
Clinical Context: Powerful antiandrogen usually administered with estrogens to maintain regular menstruation and to prevent conception. Not available in United States.
Antiandrogens are another group of agents used as a first-line therapy for hirsutism. However, the teratogenic potential of these drugs means that they should be used in conjunction with adequate contraception in women of reproductive age. Spironolactone, an aldosterone antagonist, competes with testosterone and dihydrotestosterone at the androgen receptor. Although its primary indication is as a diuretic, a dose of 50-200 mg/d will reduce facial hair growth in most patients after 6 cycles of treatment.[87] Concurrent use of spironolactone with OC pills has been shown to significantly improve hirsutism and reduce serum androgen levels.[88] For patients with hirsutism that is refractory to OCs after 6 months, adding spironolactone may be effective.
Flutamide is an antiandrogen used for the treatment of prostate cancer. It is more effective in treating hirsutism than spironolactone.[89] However, a recent study concluded that although flutamide is very effective in treating hirsutism, it is associated with frequent side effects and low long-term compliance.[90] Hepatic cell damage, the major complication of flutamide, may be fatal.[91] Consequently, flutamide is not approved by the FDA for treatment of hirsutism.[92]
Cyproterone acetate is an antiandrogen as well as a progestin. In one systematic review, cyproterone acetate (2 mg) was more effective than placebo, but not better than any other antiandrogen in the treatment of hirsutism.[90] It is also available in an OC pill as cyproterone acetate (2 mg) with 35 u ethinyl estradiol, which has been shown to be well tolerated. This drug is not currently available in the United States.
Finasteride, another antiandrogen, inhibits only the type 2 isoenzyme of 5 α-reductase. It is anticipated that the effect of finasteride may be partial. Whether it is equally effective or less effective than spironolactone is controversial.[93, 94] The FDA has not approved finasteride for treatment of hirsutism.
Clinical Context: Aldosterone antagonist that competes with testosterone and dihydrotestosterone receptor sites. It also reduces free testosterone levels as more is bound by the increased quantity of SHBG. Used most effectively in combination with an OC.
Aldosterone antagonists may reduce free testosterone levels and compete with androgens binding at receptor sites.
Clinical Context: Predominantly a type 2, 5α-reductase inhibitor. Inhibits the production of DHT. Efficacy in hirsutism is similar to that of spironolactone.
Agents in this class can markedly suppress serum dihydrotestosterone (DHT) levels.
Clinical Context: Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
Clinical Context: Suppresses secretion of LH and FSH, which in turn reduces ovarian and testicular steroid production. Available as nasal solution (2 mg/mL).
Clinical Context: Suppresses ovarian and testicular steroidogenesis by decreasing LH and FSH levels.
These agents, which suppress pituitary LH and FSH secretion, suppress ovarian hormone secretion to a greater degree than COCs. Examples of GnRH agonists in the United States include Lupron, Synarel, and Zoladex. The endometriosis doses are the ones used for hirsutism. Significant osteoporosis may occur if treatment lasts longer than 6 months; in these cases, estrogen add back with HRT or COC pills should be given.
Clinical Context: May reduce steroid hormone production. Decreases immune reactions.
Clinical Context: May reduce steroid hormone production. Decreases immune reactions.
Adrenal hyperandrogenism responds well to low-dose glucocorticoid therapy with dexamethasone or prednisolone. These agents are used with variable success in women with adrenal hirsutism, CAH, and idiopathic adrenal hyperandrogenism. Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects. Changes suggesting Cushing disease may develop in patients receiving long-term therapy.
Clinical Context: Reduces hepatic glucose output, decreases intestinal absorption of glucose, and increases glucose uptake in the peripheral tissues (muscle and adipocytes). Major drug used in patients who are obese and have type 2 diabetes. Effective in inducing ovulation in PCOS anovulatory women.
Hyperinsulinemia has been shown to increase ovarian androgen production[95] and decrease SHBG production[96] . Consequently, reducing insulin levels with insulin-sensitizing agents such as metformin should lower total and free androgen levels. However, the effects on hirsutism are not clearly better than if OCs are used; some studies have shown insulin-sensitizing agents to improve hirsutism and others have not.[97, 98, 99, 100] One systematic review and one meta-analysis of 8 trials collectively found no significant difference in hirsutism scores between COCs and metformin.[101, 102] On the other hand, antiandrogen drugs (spironolactone, cyproterone acetate, and flutamide) have been found to significantly reduce hirsutism scores when compared to metformin in a recent meta-analysis.[102]
Clinical Context: Prescription topical cream that acts as a growth inhibitor of hair. Takes up to 2 mo to work in approximately 30% of patients. Apply to skin bid at least 8 h apart, and area of application should not be washed for at least 4 h
May be used to reduce hair growth on the face and adjacent areas under the chin.
Clinical Context: Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist; partial dopamine D1-receptor agonist. Inhibits prolactin secretion with no effect on other pituitary hormones. May be given with food to minimize possibility of GI irritation.
Clinical Context: Semisynthetic ergot alkaloid derivative; strong dopamine D2-receptor agonist with low affinity for D1 receptors.
Women with hyperandrogenism who also have hyperprolactinemia may benefit from therapy with a dopamine receptor agonist (bromocriptine, cabergoline). These agents improve menstrual cycle, ovulation, and hirsutism in women with PCOS and hyperprolactinemia.
When medical therapy is started, a follow-up visit should be scheduled after 1 month to evaluate the patient for side effects and reinforce the treatment plan. Follow-up thereafter can be every 3-6 months until the patient's condition is stable. Once treatment goals have been achieved, annual visits are appropriate.
Therapies for most causes of androgen excess are life long. Occasionally, a woman with PCOS-related androgen excess has complete resolution after significant weight reduction. Most women, however, need continued therapy throughout their lifetime to minimize signs and symptoms of androgen excess.
Body Area Evaluated Score
(Graded from 0-4*)Upper lip Chin Upper abdomen Lower abdomen Upper arm Thighs Upper back Lower back/buttocks *0 = No hirsutism, 4 = Severe hirsutism