[kat note: this article is long, but very good]
HIRSUTISM AND OTHER SIGNS OF ANDROGEN EXCESS
Hirsutism is defined as the presence of terminal hairs in skin areas in which hair growth is considered masculine (Fig. 3). Excessive growth of coarse hairs on the lower forearms and lower legs alone does not constitute hirsutism. However, a woman with hirsutism (i.e., terminal hair growth in areas in which hair growth is exclusively masculine) also may note an increase in the pigmentation and growth rate of hairs on the lower forearm and leg. Although hirsutism usually is obvious, it may be important to standardize the examination for future reference with the use of a scoring system (see Fig. 3). Not all hyperandrogenic women have hirsutism (e.g., Asian women rarely do),15 although some patients with obvious hirsutism have normal circulating androgen levels.
In addition to hirsutism, excess androgen levels in women may lead to a number of other problems, including acne, oligomenorrhea or amenorrhea, weight gain and, if the condition is severe, virilization or masculinization.
In addition to the hair follicle, the pilosebaceous unit contains a sebaceous gland that produces an oily protective secretion known as sebum. The excessive production of sebum in response to androgen action leads to oily skin, clogged hair follicles, folliculitis, and acne. Elevations in serum androgen levels have been found in patients with acne,16,17,18,19,20 particularly those with concurrent hirsutism, although not all investigators agree.21,22,23,24 All androgens may lead to acne, but the presence of acne without hirsutism often is associated with excessive levels of the adrenal androgens, DHA and DHEAS.25,26,27,28 These steroids are relatively weak in their stimulation of terminal hair growth, but they are effective in increasing sebum production. Nevertheless, there are conflicting reports of the incidence of adrenocortical abnormalities in women with acne.29,30
Some investigators have reported that although serum androgen levels may be relatively normal, the metabolism of such androgens to DHT by means of 5a-reductase is increased in the affected skin.31,32,33 However, acne frequently improves after treatment with oral contraceptives, glucocorticoid suppression, spironolactone, or cyproterone acetate.34,35,36,37,38,39,40 Although many teenagers have acne, skin problems that persist into the 20s should raise the suspicion of androgen excess. Empiric treatment with spironolactone, low-dose glucocorticoid, or oral contraceptives may be justified in patients who have no other evidence of overt androgen excess.
Oligo-Ovulation or Anovulation
Androgens can be converted to estrogens in peripheral and hepatic tissue, and excessive levels of both androgens and estrogens may alter the hypothalamic-pituitary production of gonadotropins. Further, excessive androgen levels directly inhibit follicular development,41,42 which may result in the accumulation of multiple small cysts within the ovarian cortex (polycystic ovary).
Virilization or Masculinization
If androgen levels are elevated for a substantial period, the patient’s body habitus may become masculinized, with amenorrhea, an absence of breast development, an increase in muscle mass, upper body obesity, and features of virilization. Virilization includes temporal and frontal balding, clitoromegaly, reduction in breast size, and severe hirsutism. In general, virilization or masculinization should raise the suspicion of an androgen-producing tumor or congenital (not late-onset) adrenal hyperplasia. Occasionally, girls who have severe hyperthecosis or hyperandrogenic insulin-resistant acanthosis nigricans (HAIRAN) syndrome exhibit a moderate degree of virilization.
Androgenic Causes of Hirsutism
The diagnosis of an androgenic cause of hirsutism is based on the finding of elevated androgen production or elevated circulating levels.
ANDROGENIC DRUGS. In rare cases, the accidental or deliberate ingestion of drugs such as danazol, methyltestosterone, and stanozol, leads to the development of acne and hirsutism, particularly in young women who are engaged in body building.
MALE PSEUDOHERMAPHRODITISM. The peripubertal onset of hirsutism, breast development, and clitoromegaly accompanied by primary amenorrhea suggests the presence of incomplete testicular feminization or a Y-bearing dysgenetic gonad.45,46 If undiagnosed, progressive masculinization may result. These patients have a blind vaginal pouch and varying degrees of clitoromegaly and labial fusion. They also may have bilateral or unilateral vulvar swelling secondary to the descent of one or both gonads. In some patients with XY gonadal dysgenesis, a uterine remnant may be present, invariably accompanied by some degree of genital asymmetry.
LATE-ONSET ADRENAL HYPERPLASIA. Adrenal enzyme deficiencies that lead to the appearance of hyperandrogenic symptoms at some time after birth have been called nonclassic, postpubertal, attenuated, mild, acquired, or late-onset adrenal hyperplasia (LOAH). By definition, LOAH is an autosomal-recessive disorder that causes symptomatic hyperandrogenemia (e.g., hirsutism, acne, oligomenorrhea) peripubertally or postpubertally, in the presence of normal female external genitalia. If a girl has evidence of an adrenal enzyme deficiency and demonstrates virilization of the genitalia, however minor, the disorder should be classified as congenital or classic adrenal hyperplasia (CAH). This designation is used because the adrenal hyperandrogenemia was present in utero during genital development.
Adrenal enzyme deficiencies leading to androgen excess involve either 3b-hydroxysteroid dehydrogenase (3b-HSD), 21-hydroxylase (21-OH), or 11-hydroxylase (11-OH) (Fig. 4). These patients have a genetic defect of one of these enzymes that decreases their catalyzing efficiency. In contrast to patients with CAH, those with LOAH do not show a decrease in cortisol production or an elevation in circulating adrenocorticotropic hormone (ACTH) levels.47 More precisely, in LOAH, the production of appropriate amounts of enzymatic products requires greater concentrations of precursor because the enzyme activity constant has been altered.
21-Hydroxylase–Deficient LOAH. A deficiency in 21-OH activity is the most common cause of LOAH. This type of LOAH appears to affect between 1% and 2% of hyperandrogenic women,48,49,50,51 although studies of more select populations (e.g., those from tertiary medical centers that treat high-risk populations) report a higher frequency (6% to 20%).52,53 Prevalence of the disorder appears to be particularly high among Ashkenazi Jews (3.7%), Hispanics (1.9%), Yugoslavs (1.6%), and Italians (0.3%), compared with other white subjects (0.1% or 1:1000).54
In contrast to CAH, patients with LOAH do not have virilization of the external genitalia. Hyperandrogenic symptoms most commonly appear peripubertally or postpubertally, although some children have premature adrenarche. In women with LOAH, symptoms of hyperandrogenism generally are mild, if they are present at all.55 Biochemically, it is difficult to distinguish women with LOAH from other hyperandrogenic patients.48,51,55,56 Circulating T and DHEAS levels are not different from those observed in patients with polycystic ovarian syndrome (PCOS). In fact, the level of DHEAS, an exclusive adrenal androgen, often is normal (Fig. 5).
The measurement of a morning 17-hydroxyprogesterone (17-HP) level in the follicular phase of the menstrual cycle can be used to screen for 21-OH-deficient LOAH.48 Most untreated women with LOAH have basal 17-HP levels of more than 200 ng/dl. In a large hyperandrogenic population, a basal follicular phase 17-HP level of less than 200 ng/ml almost completely excluded 21-OH-deficient LOAH.48 Thus, hyperandrogenic women who have a basal follicular phase 17-HP level of greater than 200 ng/dl should undergo an ACTH stimulation test to exclude LOAH. If the 17-HP level 30 or 60 minutes after the intravenous administration of cosyntropin (Cortrosyn, Organon, West Orange, NJ) is greater than 1000 ng/dl, the diagnosis is established (Fig. 6).51,55,57,58 Dewailly and colleagues suggested that if the basal 17-HP level is greater than 500 ng/dl, the diagnosis of LOAH is confirmed, and further adrenal testing is not needed.55 The basal 17-HP level should be obtained in the follicular phase of the menstrual cycle because the level of 17-HP increases in the luteal phase. Further, dexamethasone should not be administered before sampling because it may decrease the circulating 17-HP level.
The genetics of 21-OH-deficient LOAH have been characterized extensively. The 21-OH gene is located on the short arm of chromosome 6, in the human leukocyte antigen (HLA) region. The HLA complex encodes for a large number of leukocyte surface antigens, which are important in human organ transplantation. Because of the extreme heterogeneity of the HLA antigens, it is unlikely that two randomly selected persons will have the same HLA haplotype. Because of the close linkage between the 21-OH genes and specific HLA alleles, HLA typing has been used in family studies to determine the inheritance pattern of the 21-OH deficiencies. In this regard, CAH appears to be closely linked to the HLA-B47 allele, whereas patients with LOAH have a greater frequency of HLA-B14,DR1.54
Specifically, molecular genetic studies have established the majority of the mutations that result in 21-OH-deficient LOAH.59 In close proximity to the active 21-OH gene (CYP21B) lies a pseudogene (CYP21A) that is not active, but is similar in DNA sequence. The proximity of the active genes and the pseudogenes probably accounts for the high frequency of inherited abnormalities of the 21-OH gene because of gene conversion or deletion. Patients with phenotypic LOAH may carry a mutation in each homologous 21-OH gene that encodes for LOAH and that usually is different. Alternatively, a patient with LOAH may be a compound heterozygote, carrying a mutation for LOAH on one allele and a mutation for CAH on the other homologous 21-OH gene.60
11-Hydroxylase-Deficient LOAH. Patients with 11-OH-deficient LOAH, as with the 21-OH variant, are clinically indistinguishable from other hyperandrogenic women.61 The blood pressure in 11-OH-deficient patients with LOAH ranges from normal to moderately elevated. Their basal hormonal profile also is not distinctive. The prevalence of 11-OH-deficient LOAH and its diagnostic criteria are less clear. In the absence of a reliable genetic marker, the diagnosis of 11-OH-deficient LOAH can be presumed when the 11-deoxycortisol level after ACTH stimulation exceeds a preestablished arbitrary value. Based on my experience with 21-OH-deficient LOAH, whose genetics have been characterized more thoroughly, I have selected an 11-deoxycortisol response to stimulation greater than threefold the upper 95th percentile of normal as consistent with 11-OH-deficient LOAH. In my laboratory, this value is a poststimulation 11-deoxycortisol serum level of greater than 25 ng/ml. Based on this definition, the prevalence of presumed 11-OH-deficient LOAH among hirsute patients appears to be 1% or less.61,62
3b-Hydroxysteroid Dehydrogenase-Deficient LOAH. The diagnosis of 3b-HSD deficiency is based on an abnormally elevated 17-hydroxypregnenolone (17-HPREG) or DHA response to ACTH stimulation. Various reports have documented the existence of a 3b-HSD-deficient form of LOAH. However, the diagnostic criteria for this disorder are not clear. Some authors have presumed 3b-HSD-deficient LOAH when the stimulated 17-HPREG level was greater than the normal limit (either mean plus two standard deviations or the upper 95th percentile).63,64 However, if the experience with 21-OH deficiency is used as a model, 3b-HSD-deficient patients should have a 17-HPREG-stimulated value of at least threefold the upper normal limit. In my laboratory, the upper 95th percentile value for the 17-HPREG level 60 minutes after ACTH administration is 5 ng/ml. Thus, the diagnosis of 3b-HSD-deficient LOAH is presumed if the stimulated 17-HPREG level is greater than 15 ng/ml. With this definition, no patients with 3b-HSD-deficient LOAH were found among 78 consecutively studied hyperandrogenic women (Fig. 7).65 Thus, it appears that 3b-HSD deficiency is the least common LOAH.
Treatment and Outcome of LOAH. In spite of the attention received by patients with LOAH concerning pathophysiology and diagnosis, little information about treatment and outcome is available. In one 16-year-old patient with LOAH who had acne only, alternate-day low-dose dexamethasone improved the symptoms significantly. In another seven patients with LOAH who reported mild hirsutism and oligomenorrhea, low-dose glucocorticoid therapy improved hirsutism in two (28%) and oligomenorrhea in five (71%). Two patients with LOAH had oligomenorrhea that did not respond to low-dose glucocorticoid replacement. At 32 and 38 years of age, these patients were the oldest of the group at the time of diagnosis. Long-standing adrenal hyperandrogenism may alter the hypothalamic-pituitary-ovarian axis so that the suppression of adrenal androgens is not sufficient to induce normal ovulation.
Some investigators reported a significant improvement in hirsutism when patients with LOAH were treated with an anti-androgen in addition to glucocorticoid replacement.66 I recommend the use of spironolactone in the treatment of hirsutism of any origin. Overall, the prognosis for fertility in oligomenorrheic patients with LOAH is good, and should not be any different from that of other hyperandrogenic patients who seek ovulation induction.67
HYPERANDROGENIC INSULIN-RESISTANT ACANTHOSIS NIGRICANS SYNDROME. Between 1% and 5% of hyperandrogenic women have HAIRAN syndrome. These girls can be severely hyperandrogenic, and even can be virilized or masculinized. Patients with HAIRAN syndrome also have acanthosis nigricans, a velvety hyperpigmented change of the creases of the skin (Fig. 8). Many also have hypertension and lipid abnormalities. This disorder can be diagnosed by the high circulating levels of insulin, generally greater than 80 mU/ml in the fasting state and greater than 300 mU/ml after an oral glucose tolerance test.68,69,70 In general, their glucose levels are relatively normal.
The high levels of insulin may be caused by a genetic deficiency in the function of the insulin receptors or by a postreceptor defect.71,72,73,74,75 Some of these women have circulating anti-insulin–receptor antibodies.76,77 The elevated circulating insulin levels act synergistically with LH to augment ovarian androgen (but not adrenal) production. This syndrome should not be confused with the insulin resistance that is noted among many patients with PCOS, where the increase in insulin level generally is mild.
Most of these patients respond to standard therapy with antiandrogens and oral contraceptives, although some require more aggressive treatment.78 Ketoconazole79 and long-acting gonadotropin-releasing hormone analogs (GnRH-a)78,80 have been used in nonresponsive patients, with good results (see Fig. 8). Long-acting GnRH-a inhibits luteinizing hormone (LH)-dependent androgen production by reducing circulating gonadotropin levels to castrate levels. At least 3 to 6 months of gonadotropin suppression is required to achieve full androgen suppression in patients with HAIRAN syndrome. If all treatment fails, a bilateral ovarian wedge resection, or even oophorectomy, may be required.
CUSHING’S DISEASE. Hirsutism is present in 60% to 70% of women with Cushing’s syndrome. Generally, it is diffuse and mild, and is accompanied by varying degrees of hypertrichosis. Hirsutism, with or without menstrual irregularity, was among the presenting symptoms in 15 to 45 such women, and the only presenting symptom in 11.81 Overall menstrual irregularity is seen in 80% to 100% of women with Cushing’s syndrome, and acne is present in 40% to 50%.82,83,84
Excessive ACTH-dependent adrenocortical function caused by an ectopic ACTH-producing tumor or a pituitary tumor (Cushing’s disease) can lead to excessive adrenal androgen secretion and hyperandrogenemia. Ectopic ACTH- and CRH-producing tumors are not frequently associated with virilization because they are rare tumors in women. Imura and colleagues85 did not note virilization in women with ectopic ACTH-producing neoplasms. However, all of the patients were Asian, a population that is notably resistant to the development of hirsutism. In contrast, circulating T levels are elevated in women with pituitary Cushing’s syndrome.86 An adrenal origin was attributed to the increased androgen level because dexamethasone caused a parallel decrease in cortisol and T levels, ACTH stimulation induced an increase in T level that was more profound in women with Cushing’s disease compared with normal subjects, and bilateral adrenalectomy dramatically decreased the level of circulating T, correcting the oligomenorrhea and hirsutism. Nonetheless, an increase in the adrenal secretion of androgens may not be the only factor that accounts for the androgenic symptoms in patients with Cushing’s disease. Patients with adrenal adenomas generally have low levels of adrenal androgens, particularly DHEAS.87 Nevertheless, these women have a similar frequency of menstrual irregularity, hirsutism, and acne compared with patients with generalized adrenal hyperplasia. This similarity reflects the increased ACTH stimulation.83 An increase in ovarian androgen secretion may contribute to the hyperandrogenism. The role of the increased insulin resistance and gonadotropin abnormalities noted in Cushing’s syndrome in promoting ovarian hyperandrogenemia is unknown. Finally, a direct effect of long-term hypercortisolemia on hair growth, particularly that of vellus hairs, cannot be excluded.
In spite of the high frequency of hirsutism reported among women with Cushing’s syndrome, hirsute women rarely are diagnosed as cushingoid. Of approximately 400 hyperandrogenic women whom I have treated, only 1 was diagnosed as having Cushing’s disease. Screening for Cushing’s syndrome in patients with hyperandrogenism probably should be restricted to those with cushingoid features, particularly those with recent weight gain, easy bruising and generalized weakness, and centripetal obesity. In general, the diagnosis of excessive cortisol production (Cushing’s syndrome) can best be established by a 24-hour urine free cortisol test. A simpler screening method is the measurement of the morning fasting cortisol level after the administration of 1 mg dexamethasone the evening before. The false-positive rate for this test can be significant, however, particularly among patients who have endogenous depression, are obese, or are receiving diphenylhydantoin (Dilantin) therapy.88,89 A patient with an abnormal overnight dexamethasone suppression finding requires a 24-hour urine free cortisol measurement to confirm the hypercortisolemia. In patients with rapid or severe virilization, especially children, liberal use of adrenal computerized tomography (CT) scanning may be justified.
ANDROGENIC TUMORS. Androgen-producing tumors are rare. They should be suspected when the onset of androgenic symptoms is rapid and sudden, and when virilization and masculinization ensue. Steroid-secreting neoplasms also may be associated with other systemic symptoms, including weight loss, anorexia, abdominal bloating, and back pain. These tumors usually are of ovarian or adrenal origin. Suppression and stimulation tests, including corticosteroid, oral contraceptive, human chorionic gonadotropin, and ACTH administration, can be misleading, and are not encouraged for the screening or diagnosis of these neoplasms.90 Further, because CT scanning for the diagnosis of an adrenal neoplasm and transvaginal sonography for the diagnosis of an ovarian tumor are relatively noninvasive procedures, there is little need for adrenal or ovarian vein catheterization in the diagnosis of androgen-secreting neoplasms.
Androgen-producing tumors of the adrenal gland are rare, and include adenomas and carcinomas. Adrenal carcinomas usually are associated with cushingoid features, and generally are large (greater than 6 cm) and irregular on CT scanning. Unfortunately, their prognosis is poor. The frequency with which these symptoms of oligo-ovulation and hirsutism present depends on the histopathologic features of the tumor. More differentiated tumors tend to produce an increased level of androgens, whereas less differentiated tumors do not.91 Overall, adrenocortical neoplasms have less efficient steroidogenesis than normal adrenocortical tissue. However, because these tumors frequently are large, the overall steroid secretion by these neoplasms can be significant. Adrenal adenomas that secrete only androgens are rare. Thus, most patients with androgen-secreting adrenal neoplasms also have cushingoid features. Further, physicians should remember that signs and symptoms of virilization (e.g., clitoromegaly, deepening of the voice, breast atrophy) are encountered with equal frequency in patients with androgen-secreting adrenal adenomas and adrenal carcinomas.92 The diagnosis of adrenal neoplasm usually is established by CT scan of the adrenal gland, with images obtained at 0.5-cm intervals.
Ovarian tumors are more common than androgen-secreting adrenal neoplasms. They usually are palpable on pelvic examination or are associated with unilateral ovarian enlargement on ultrasound or CT scan. Functional ovarian neoplasms generally are not malignant, and include Sertoli-Leydig cell tumors and lipoid cell tumors. Ovarian tumors should be suspected when hirsutism or virilization is of sudden onset and is rapidly progressive. The diagnosis can be further suspected when transvaginal sonography shows asymmetric ovarian enlargement.
The serum T level often is elevated in patients with adrenal or ovarian androgen-secreting tumors, generally to more than 200 ng/dl.93,94 However, the use of this specific cutoff point depends on the particular T assay used by each laboratory, and does not permit differentiation between an ovarian and an adrenal neoplasm. However, 20% to 50% of androgen-producing ovarian tumors may have T levels below this value,95 and most women with T levels of greater than 200 ng/dl have either HAIRAN syndrome, hyperthecosis, or PCOS, and not a functional tumor.96
Urinary values of 17-ketosteroids usually are above normal in patients with adrenal androgen-secreting neoplasms.92,94 More recently, determinations of circulating DHEAS levels have replaced urinary 17-ketosteroid measurements.97 McKenna and colleagues98 noted that circulating DHEAS levels were mildly to moderately elevated in two androgenized women with adrenal carcinoma and normal in one man with a similar tumor. Based on a single case report, Ho Yuen and colleagues99 suggested that a DHEAS level of greater than 6600 ng/ml was consistent with the presence of an adrenal tumor. For these levels to be useful in the screening of virilizing adrenal adenomas, Ho Yuen and associates99 emphasized the need for serial measurements of serum T and DHEAS. Nevertheless, patients with T-secreting adenomas and normal DHEAS and urinary 17-ketosteroid levels have been reported.100,101 In a series of patients with virilizing tumors, Surrey and colleagues102 noted that the circulating DHEAS level was greater than 7000 ng/ml in one patient with an ovarian lipoid cell tumor and not in the only patient with an adrenal adenoma.102 Thus, DHEAS measurements may not be useful for the screening of androgen-secreting adrenal adenomas.
POLYCYSTIC OVARIAN SYNDROME. Although this disorder commonly is called the polycystic ovarian syndrome (PCOS), not all patients have polycystic-appearing ovaries.103,104 The appearance of polycystic ovaries, either on laparoscopy or, more commonly, sonography, is not diagnostic for PCOS.103,104,105,106 Excessive levels of circulating androgens from any source will cause the disruption of follicular development and the accumulation of many small, atretic follicles in the ovarian cortex, producing a polycystic picture.41,42 Thus, the diagnosis of PCOS should be made endocrinologically, and not by sonography or laparoscopy. Kim and colleagues107 observed ovarian hyperandrogenism in histologically normal and abnormal ovaries, although patients with polycystic ovaries appeared to have a greater degree of androgen excess.
Between 80% and 90% of all hyperandrogenic women seen are patients with PCOS.108 Overall, the diagnosis of PCOS in hyperandrogenic patients is established by exclusion, after elimination of the other causes of hyperandrogenemia, such as LOAH and HAIRAN syndrome. Patients with PCOS have elevated circulating levels of free T and a reduction in SHBG, accompanied by variable increases in total T.7,109,110 Approximately 50% have an abnormally high level of DHEAS, rarely greater than 6000 ng/ml.111 The prolactin level usually is normal, although 17% to 23% of such patients have mild elevations (generally less than 80 ng/ml, depending on the assay) without any other apparent cause.112 The LH: follicle-stimulating hormone (FSH) ratio usually is 3:1 or greater113,114,115; this ratio is observed in approximately 60% of these patients.113 Pathologically, the ovarian cortex contains multiple intermediate and atretic follicles that measure 2 to 5 mm in diameter. They give the ovary its polycystic appearance. Approximately 40% of these patients are obese. Patients with PCOS frequently are oligo-ovulatory116 and may have primary amenorrhea,117,118 which may be evident as early as age 12 years.119 Nevertheless, 15% of these patients have regular menses.116 Although most patients with PCOS have variable degrees of hirsutism, not all patients have this hyperandrogenic sign.15,116,120,121 These patients generally do not have virilization or masculinization. PCOS is discussed further in another chapter.
HYPERTHECOSIS. Patients with hyperthecosis usually are severely androgenized and have high levels of circulating T, often greater than 200 ng/dl.122,123,124,125 The diagnosis is established pathologically after removal or wedge resection of the ovary. Islands of hyperplastic luteinized theca cells are noted throughout the stroma, with relatively few small atretic follicles.126 Circulating LH and FSH levels may be normal to low (4 to 8 mIU/ml) due to the high circulating levels of T. These patients are difficult to treat and may not respond to conventional therapy.125 Ovarian wedge resection or oophorectomy may be necessary, although the use of long-acting GnRH-a appears promising.127
Etiologically, these patients have either HAIRAN syndrome or extreme forms of PCOS. In fact, hyperthecosis may be one end of the spectrum of ovarian hyperandrogenism. In patients with mild degrees of hyperandrogenemia, the ovarian pathologic features may be relatively normal.107 As the degree of hyperandrogenemia increases, so does the accumulation of atretic midsized follicles in the ovary, resulting in their polycystic appearance (Fig. 9). With worsening hyperandrogenemia, possibly due to the synergistic effect of hyperinsulinemia on thecal proliferation and androgen secretion, follicular development is arrested at an increasingly earlier stage, resulting in the absence of cortical cysts and the predominance of hyperthecosis.128
The diagnosis of idiopathic hirsutism (IH) is made only when circulating androgen levels appear to be consistently normal, even when the free androgen levels are assessed, and the patient obviously is hirsute. Further, these patients usually do not have oligo-ovulation. Approximately 5% to 25% of hirsute women have IH, depending on the extent of endocrine evaluation. Many of these patients simply have degrees of androgen excess that are not detectable by routine clinical androgen assays. The diagnosis of IH actually may reflect an insufficiently sensitive laboratory assay129 or an incomplete evaluation.
Some women with IH have excessive 5a-reductase activity of the hair follicles, which results in hirsutism in spite of normal circulating androgen levels.130 The measurement of serum 3a-androstanediol glucuronide (3a-adiol-G), a metabolite of DHT, may reflect peripheral 5a-reductase activity and help to confirm hyperfunction of this enzyme.130,131,132 Nevertheless, the diagnosis of IH usually is established by exclusion, when repeated measurements of free and total circulating androgen levels are normal in a patient with hirsutism and regular menses. Measurements of 3a-adiol-G may be more useful for monitoring the efficacy of antiandrogen therapy because it takes at least 6 months for an improvement in hirsutism to become clinically noticeable.132 Standard serum androgen assays cannot be used to determine the adequacy of treatment in IH because by definition, these levels were normal before therapy.
WORKUP OF HIRSUTISM
The pace of pubertal development and its relation to the onset of hirsutism, acne, or obesity should be established. Any history of drug or medication use and exposure to skin irritants should be elicited. Menstrual history, onset and progression of hirsutism or acne, increase in extremity or head size, change in facial contour, and balding and hair loss should be noted. A family history of similar signs and symptoms is a clue to the inherited basis of the disorder. The etiology of hirsutism often can be established from the history alone.
The type and pattern of excessive hair growth or acne should be noted and scored (see Fig. 3). The presence of galactorrhea, virilization, masculinization, clitoromegaly, pelvic and abdominal masses, obesity, cushingoid features, bluntness of facial features, thyroid enlargement, or signs of systemic illness should be sought. It is important to determine whether hirsutism is truly present and, if it is, whether it is related to other endocrinologic features. The excessive growth of vellus hairs, producing a fuzzy appearance, is called hypertrichosis. It should not be considered hirsutism. A number of medical problems or medications can cause hypertrichosis, but more commonly it is familial, particularly in persons of Scandinavian or Mediterranean descent. Further, excessive hair growth affecting only the lower legs or forearms does not constitute hirsutism because these areas normally are covered by a mixture of terminal and vellus hairs.
If the patient has hirsutism or any other sign or symptom of androgen excess, the circulating levels of total and free T (which usually includes measures of SHBG activity), DHEAS, and 17-HP should be obtained. Optimally, these measurements are obtained in the morning (for maximal adrenal output) and in the follicular phase of the menstrual cycle. Although A4 easily is measured, it is of limited value in most patients, but the level should be obtained when androgen levels are normal in the presence of obvious hirsutism. DHA and DHT measurements rarely are used clinically. Serum 3a-diol-G levels may predict the effectiveness of antiandrogen therapy in patients with IH, and should be obtained before treatment is initiated.
If the basal 17-HP level is greater than 10 ng/ml and the measurement is not luteal, the patient is diagnosed as having 21-OH-deficient adrenal hyperplasia. Whether it is of the classic congenital or late-onset variety will depend on her clinical characteristics, for example, if she does or does not have genital virilization, respectively. Alternatively, if the patient has no signs of virilization, and her basal follicular 17-HP level is greater than 2 ng/ml (200 ng/dl) but less than 10 ng/ml, she should undergo an acute adrenal stimulation test to exclude LOAH.48 A dose of 250 mg (1 vial) Cortrosyn (1–24 ACTH) is administered intravenously, and blood is sampled 30 or 60 minutes later. If the poststimulation 17-HP level is greater than 10 ng/ml (or 1000 ng/dl), the diagnosis of 21-OH-deficient LOAH is established (see Fig. 6).51,55,57,58 To exclude rarer deficiencies of the adrenal cortex, such as 3b-HSD- and 11-OH-deficient LOAH, the levels of 17-HPREG and DHA or 11-deoxycortisol, respectively, may be measured after adrenal stimulation. My practice is to presume 11-OH-deficient LOAH (because actual genetic confirmation is not yet available) when the 11-deoxycortisol level exceeds 25 ng/ml,61 and 3b-HSD-deficient LOAH is suspected if the 17-HPREG level is greater than 15 ng/ml.65
If a hirsute patient also is oligo-ovulatory, thyroid-stimulating hormone (TSH) and prolactin levels and a basal body temperature chart should be obtained. Further, if the patient has overt signs or symptoms of thyroid disorder (e.g., myxedema, tachycardia, hair loss of the lateral eyebrows, goiter, heat or cold intolerance) a thyroid panel, including TSH and free T4 measurement, should be obtained. If the patient has features suggestive of acromegaly, a fasting growth hormone level should be obtained. The patient should be under as little stress as possible. The level normally is less than 10 ng/ml. If the patient has signs suggestive of Cushing’s syndrome, a fasting morning cortisol level after the administration of 1 mg dexamethasone the evening before, or a 24-hour urine free cortisol evaluation, should be obtained to confirm the hypercortisolemia. The 24-hour free cortisol level should be less than 100 mg/24 hours, whereas the morning cortisol level after evening dexamethasone administration should be less than 5 mg/dl. Obese and depressed patients may have slightly elevated fasting cortisol levels that require further testing. In patients suspected of having male pseudohermaphroditism or XY gonadal dysgenesis because of the presence of a blind vaginal pouch or abnormality of the external genitalia, karyotype evaluation should be done. In selected women, evaluation of liver function may be necessary because chronic liver disease (e.g., chronic active hepatitis, congenital causes of biliary cirrhosis, hemochromocytosis) may result in decreased SHBG production with a consequent elevation in free T and DHT levels.
TREATMENT OF HIRSUTISM
The treatment of hirsutism should be undertaken as soon as the diagnosis is established. Although in young children or teenagers the degree of hair growth may not be alarming, these disorders usually are progressive, and the formation of terminal hairs is not reversible. Any terminal hairs that remain after 6 months of adequate suppression with medical therapy must be removed by electrolysis, which can be painful and costly, and is not applicable to large areas of the body. Further, hirsutism can be cosmetically disfiguring, and can have a significant negative effect on a young woman’s social and emotional development. Hyperandrogenemia has other medical implications, including an increased risk of cardiovascular disease,133 endometrial hyperplasia, and carcinoma.134,135,136
To encourage optimal patient compliance, it is important to present realistic therapeutic expectations. The primary goal of treatment in hirsutism is to stop the development of any new terminal hairs. Generally, hormonal therapy decreases the growth rate, diameter, and pigmentation of terminal hairs that already are present; however, it will not reverse the transformation of vellus to terminal hairs. Finally, a clinical response to therapy for hirsutism may take as long as 6 months. Therapy for hirsutism consists of mechanical, hormonal, and surgical interventions.
Mechanical Means of Hair Removal
Mechanical means, by themselves, do little to improve the long-term course of hirsutism, and actually may worsen the problem. However, while awaiting the full effect of hormonal therapy, it is best to encourage the patient to maintain optimal cosmesis by either shaving or bleaching the affected area. Although shaving can lead to a blunt hair end, which may feel like stubble, it does not cause worsening of the hirsutism,137 and it causes little trauma to the skin. It is surprising how well shaving and the use of cosmetics results in a satisfactory appearance. Recording the interval between shavings before each office visit provides a simple way to monitor the efficacy of treatment.
Plucking and waxing should be discouraged because these practices stimulate the growth of surrounding follicles,44 and may lead to folliculitis, with the subsequent development of ingrown hairs. Excessive use of depilating agents, particularly on the face, can result in chronic irritation and worsening of the condition of the skin. Electrolysis is the only method available for the irreversible destruction of hair follicles. Unfortunately, it cannot be used on large areas of the body or on sensitive areas, such as the periareolar region. Electrolysis must be combined with hormonal therapy and, for maximum cosmetic benefit, initiated after a clinical response has been observed.
Hormonal Treatment of Hirsutism
ORAL CONTRACEPTIVES. The mainstay of androgen excess treatment is the use of oral contraceptives. By suppressing the secretion of gonadotropins (LH and FSH), oral contraceptives cause a decrease in ovarian androgen production.138 Full suppression usually is seen within 1 month. Oral contraceptives also decrease adrenal androgen production by a mechanism that is not clear, but which may be related to a decrease in circulating ACTH level. The progestin in oral contraceptives also can compete for 5a-reductase and the androgen receptor.138 The estrogen fraction in oral contraceptives increases levels of circulating SHBG, with a subsequent decrease in free T levels. The progestin in the oral contraceptives may in turn decrease SHBG, so it is important to select the pill with the least androgenic form of progestin (e.g., norethindrone acetate, ethynodiol diacetate). Oral contraceptives should be administered in the usual cyclic fashion, and the circulating androgen levels should be checked periodically to assess the adequacy of hormonal suppression and stimulation of SHBG levels.
ESTROGENS AND PROGESTINS. The use of oral estrogen (with progestin administered in a cyclic fashion when the uterus is present) has been advocated for older women or those who do not tolerate oral contraceptives. The dose of estrogen needed is higher than that required for regular postmenopausal hormonal therapy. Oral, but not transdermal, estrogen therapy increases the level of circulating SHBG, decreasing the levels of free T and DHT. Estrogens also decrease the levels of circulating LH and FSH, reduce gonadal androgen secretion, and potentially antagonize the effect of androgens at the hair follicle.
High doses of progestins (e.g., 20 to 30 mg/day medroxyprogesterone acetate) have been used to treat hirsutism.139 Progestins increase the clearance of T by the liver and may lead to a decrease in circulating LH. However, this therapy also leads to a decrease in the circulating SHBG concentration, which may reduce its anti-androgenic effectiveness. Further, side effects may become unacceptable, and include break-through bleeding, liver dysfunction, vascular changes, weight gain, depression, and hot flashes.
ANTIANDROGENS. Spironolactone is an aldosterone antagonist and a mild diuretic. It also is an effective therapy for hirsutism,140,141,142,143,144,145,146 competing for the androgen receptor 5a-reductase and the binding of T to SHBG.147 Further, spironolactone blocks the action of various enzymes that are involved in androgen biosynthesis.147,148,149 Initially, a dose as high as 200 mg/day may be used. If the dose is increased slowly from 25 to 200 mg/day, by 25-mg increments every 3 days, the patient will have a minimum of adverse effects. The side effects most commonly associated with the use of spironolactone include polyuria, fatigue, headache, and irregular menses. The incidence of metrorrhagia may be decreased by administering spironolactone on days 4 through 21 of the menstrual cycle.150 The use of potassium-saving diuretics in hypertensive patients should be discontinued before spironolactone administration because of the risk of hyperkalemia.
Spironolactone is effective for treating hirsutism, particularly IH. Treatment should be continued for at least 1 year, with subsequent progressive reductions in dose. Because spironolactone acts through different mechanisms than oral contraceptives, the overall therapeutic effectiveness can be improved by combining these medications.151,152 Further, the use of oral contraceptives or estrogen and progestin therapy in combination with spironolactone minimizes the problems with dysfunctional uterine bleeding or worsening oligomenorrhea that often are observed in women who take spironolactone alone, while providing adequate contraception.151,152,153
Cyproterone acetate is a strong progestin and antiandrogen, and an effective treatment for hirsutism.154 It produces a decrease in circulating T and A4 levels through a reduction in LH. Further, cyproterone acetate antagonizes the effect of androgens at the receptor level. Side effects may include adrenal insufficiency and loss of libido. This drug currently is not available in the United States, and it is unlikely that it will be approved by the Food and Drug Administration because spironolactone appears to be equally effective. Cimetidine also competes for binding to the androgen receptor, although it does not change circulating levels of T, DHT, or adrenal androgens. Because it is a relatively weak androgen receptor antagonist, it offers no advantage over spironolactone and causes more severe side effects.155
GLUCOCORTICOID SUPPRESSION. Dexamethasone (0.25 to 0.5 mg every to every other evening) or prednisone (5 to 10 mg/day) can be used as an adjuvant for the treatment of hirsutism, particularly in patients with significant adrenal hyperandrogenemia or LOAH. Jones and colleagues156 first reported the use of corticosteroid suppression in the treatment of ovulatory dysfunction. Several investigators have reported the improvement of menstrual irregularity in 30% to 60% of patients.40,157,158 Corticosteroid administration reduces ACTH stimulation to the adrenal cortex, which leads to a decrease in the morning cortisol level and the levels of various androgens in hyperandrogenic women.159,160,161 However, the sole use of glucocorticoid suppression significantly improves ovulation and acne in many patients, but has little effect on hirsutism,162 even in patients with LOAH.66
HORMONAL THERAPY FOR NONRESPONSIVE PATIENTS: LONG-ACTING GnRH AGONISTS AND KETOCONAZOLE. The use of a long-acting GnRH-a may be the only method of treatment available for patients with severe ovarian androgen excess that is resistant to conventional therapy78,80,127 (see Fig. 8). Chang and associates163 studied the effects of a D-TRP6-PRO9-NET GnRH-a administered for 28 days to five patients with PCOS. Total T levels decreased from an average of 500 pg/ml to castrate levels, as did serum levels of A4. Other investigators observed a normalization of circulating T and A4 levels after GnRH-a treatment in patients with hyperandrogenism, with little effect on DHEAS values.163,164,165,166,167,168,169,170 In these reports, the decrease in T levels was coincidental with the drop in circulating LH. Complete androgen suppression usually was achieved 2 to 5 weeks after the initiation of treatment.
Only one of these studies was a randomized comparison with a previously accepted form of hyperandrogenic treatment. Couzinet and associates165 compared 3 months of treatment with D-TRP6 GnRH with the use of 50 mg/day antiandrogen cyproterone acetate in a randomized crossover study. They observed that GnRH-a treatment induced a more complete gonadotropin inhibition than did cyproterone acetate. In this study, the relative effect on hair growth could not be assessed because of the short duration of the treatment period. Andreyko and colleagues164 reported that 1000 mg/day nafarelin, administered as a nasal spray twice daily for 6 months, was associated with a significant decrease in hair growth rate and hirsutism score in six patients. Rittmaster170 treated 10 hirsute women with gradually increasing doses of leuprolide, starting with 5 or 10 mg/kg/day. He observed that the lower doses of leuprolide were sufficient to maximally suppress serum estradiol and the LH response to exogenous GnRH. However, the higher leuprolide doses were needed to maximally suppress the total T and basal LH levels. The administration of 20 mg/kg/day subcutaneous leuprolide effectively reduced hair growth in most of these patients. Patients were treated for 6 months. The mean hirsutism score fell significantly in five women, and hair growth rate decreased in six. Consistent with the selective inhibitory effect of long-acting GnRH-a on ovarian androgen secretion, an improvement in hair growth rate was more common among patients with PCOS than among those with IH. A good clinical response (see Fig. 8) to long-acting GnRH suppression was observed in hirsute women who were refractory to treatment with oral contraceptives and spironolactone.78 Rittmaster170 noted that a dose of 1.5 mg/day subcutaneous leuprolide generally was required, we have observed complete normalization of androgen levels following the administration of 3.75 mg of the depot form of leuprolide once monthly. In severely androgenized patients, up to 3 months of treatment with long-acting GnRH-a suppression may be needed to normalize androgen levels.
The most common side effects of GnRH-a suppression are associated with the resultant hypoestrogenemia. These include hot flashes, vaginal dryness, headache, and irritability. Small degrees of bone loss also may be noted. Because the efficacy of androgen excess treatment with GnRH-a suppression does not depend on hypoestrogenemia, it is appropriate to give these patients cyclic estrogen and progestin. The estrogen will prevent any hypoestrogenic side effects and will increase the circulating SHBG level, further decreasing the level of free T. The addition of spironolactone to the administration of long-acting GnRH-a and estrogen replacement is reasonable because hirsutism usually is severe in these patients.
Ketoconazole, an imidazole derivative, blocks adrenal and gonadal steroidogenesis by inhibiting cytochrome P450-dependent enzyme pathways. Therapy with 800 to 1200 mg/day ketoconazole decreases hirsutism171,172; treatment with lower doses (400 mg/day) is less effective.173 Unfortunately, side effects are common, and include headache, nausea, scalp hair loss, and liver function abnormalities. Treatment with ketoconazole may be considered in patients who do not respond to conventional therapy.79
Surgical Treatment of Androgen Excess
In the past, ovarian wedge resection provided satisfactory improvement in menstrual cycles,174,175 although it had little effect on hirsutism. However, patients rarely require a bilateral ovarian wedge resection, with the exception of those who are suspected of having an ovarian tumor, and some hyperthecotic patients or patients with HAIRAN syndrome. Rarely are patients so affected that bilateral oophorectomy is considered, although this approach may be applicable in some severely affected patients who have little hope of improvement otherwise. However, these patients are the exception, particularly with the advent of long-acting GnRH-a. More recently, laparoscopic wedge resection176 or fulguration of multiple areas of the ovarian cortex177,178,179 has been proposed, although long-term follow-up information is lacking. In general, these destructive procedures should be used as the last line of therapy, since they almost invariably lead to ovarian adhesions.
Women with hirsutism require long-term follow-up, counseling, and emotional support because these disorders usually are lifelong and progressive unless they are treated adequately. Most patients have PCOS or hyperthecosis, IH, LOAH, HAIRAN syndrome or, rarely, endocrine-active ovarian tumors (Table 1). The goal of hormonal therapy is to stop the progression of hirsutism. Hormonal therapy also may decrease the growth rate, diameter, and pigmentation of terminal hairs that already are present. A clinical response may not be evident until therapy has been administered for 6 months. However, because hormonal treatment does not reverse the transformation of vellus to terminal hairs, electrolysis is a useful adjuvant. Encouraging the patient to shave or bleach, rather than pluck or wax, also is helpful in controlling the condition.
TABLE 1. Distribution of the Various Etiologies of Hirsutism
Polycystic ovarian syndrome (including) ±80
Idiopathic hirsutism ±15
HAIRAN syndrome* 2-4
Late-onset adrenal hyperplasia 1-2
Ovarian tumors Rare
Others Very rare
* HAIRAN, hyperandrogenic insulin-resistant acanthosis nigricans