0021-972X/90/7101-0001$02.

00/0 Journal of Clinical Endocrinology and Metabolism Copyright 1990 by The Endocrine Society

Vol. 71, No. 1 Printed in U.S.A.

CLINICAL REVIEW 10 An Endocrinologic Approach to the Patient with Hirsutism*

DAVID A. EHRMANN AND ROBERT L. ROSENFIELD
Departments of Medicine and Pediatrics, University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637

IRSUTISM is a common clinical condition in women characterized by the excessive growth of terminal hair in a male pattern. Like acne or anovulation, it is a variably expressed manifestation of androgen excess and thus may be a cutaneous sign of an androgenic disorder. This review will focus on current concepts of the role of androgens in the pathogenesis of hirsutism, the etiology of androgen excess, the use of GnRH agonists as both diagnostic and therapeutic tools, and finally the place of antiandrogens in the treatment of hirsutism.

Biosynthesis, Transport, and Action of Androgens

Androgens are secreted by both the ovaries and adrenal glands in response to the respective tropic hormones LH and ACTH (Fig. 2) (2, 3). Unlike estradiol and cortisol, their secretion is not tightly regulated. Biosynthesis begins with the rate-limiting conversion of cholesterol to pregnenolone by the side chain cleavage enzyme. Thereafter, pregnenolone undergoes a two-step conversion to the 17-ketosteroid (17-KS) dehydroepiandrosterone (DHA) along the A5-steroid pathway. This conversion is accomplished via cytochrome P450cl7a, an enzyme with Pathophysiology of Hirsutism both 17a-hydroxylase and C-17,20-lyase activities. Progesterone undergoes a parallel transformation to androRole of Androgens in Pilosebaceous Unit Development. stenedione (AD) in the A4-steroid path. The metabolism Androgens are a prerequisite for sexual hair and sebaof A5- to A4-intermediates is accomplished via A5-isoceous gland development (1). In conjunction with other merase-3jS-hydroxysteroid dehydrogenase. regulatory factors, including induction factor(s) from the Ovarian theca-interstitial-stromal (thecal) cells sedermal papilla and insulin-like growth factor(s), androcrete AD in response to LH. This secretion is augmented gens cause the prepubertal pilosebaceous unit (PSU) in by both insulin and insulin-like growth factor. Subseandrogen-dependent areas to differentiate into either a quently, AD is aromatized within the granulosa cell, terminal hair follicle (in which the vellus hair transforms under the influence of FSH, to form estrogens. Using the into a terminal hair) or into a sebaceous follicle (in which 'potent GnRH agonist nafarelin as a test of ovarian the sebaceous component proliferates and the hair refunction, we recently discovered that most women with mains fine) (Fig. 1) (2). Antiandrogens reverse this procpolycystic ovary syndrome (PCOS) have exaggerated ess, causing PSUs to revert toward the vellus state. Maleresponses of all steroids on the pathway from 17-hydroxpattern sexual hair development {e.g. moustache and yprogesterone to estrone without evidence of an enzybeard) occurs in sites where relatively high levels of matic block (4). Abnormal coordination of ovarian anandrogen are necessary for PSU differentiation. The drogen and estrogen synthesis, probably due to abnormal greater density of terminal hairs in the androgen-sensiregulation of P450cl7a, seems to underlie this abnortive areas of men than women is accounted for by a mality (3). greater proportion of PSUs with terminal rather than Adrenal 17-KS secretion begins peripubertally (adrenvellus hairs. Androgenetic alopecia is largely the result arche) with an adrenal secretory response to ACTH that of conversion of terminal hair to sebaceous follicles. is characterized by the preferential secretion of A5-steroids, including DHA sulfate (DHAS). This results, in Received February 16, 1990. part, from a differential increase in the lyase activity of Address requests for reprints to: David A. Ehrmann, M.D., the P450cl7a; the nature of the factor(s) modulating this University of Chicago, Pritzker School of Medicine, Department of Medicine, 5841 South Maryland Avenue, Box 138, Chicago, Illinois change in adrenal function is unclear, but it is independ60637. ent of known tropic hormone control. An exaggeration "This work was supported in part by USPHS Grants RR-0055, HDof adrenarche seems to underlie most adrenal 17-KS 06308, and a grant from Syntex Research.

EHRMANN AND ROSENFIELD

JCE & M 1990 Vol 71 No 1

vellus follicle

\ androgen-\\ ization \ * 'sebaceous gland'

sexual hair*

terminal hair follicle

balding

sebaceous follicle

FIG. 1. Role of androgen in the development of the pilosebaceous unit. Solid lines indicate effects of androgens, dotted lines those of antiandrogens. Hairs are depicted only in the anagen phase of the growth cycle. Reproduced from Rosenfield, with permission (2).

CHOLESTEROL
\P4S0
tee

* V PREGNENOLONE - PROGESTERONE
P4S0 e17a

\P4S0 e17a 30
\

P4SO + e21 e11,1B PSSO >

ALDOSTERONE CORTISOL

17-HYDROXYPREGNENOLONE
\P450 I c17a

17-HYDROXYPROGESTERONE
\P450 I e17a
T

c2f

ell,16

DEHYOROEPIANOROSTERONE

- ANDROSTENEOIONE
170-R

P4S0 trom ESTRONE

17fi- R

TESTOSTERONE

DIHYDROTESTOSTERONE

ESTRADIOL

FIG. 2. Outline of the major steroid biosynthetic pathways. The enclosed area contains the core steroidogenic pathway used by the gonads and adrenal glands. The steroidogenic enzymes are italicized. P450, Cytochrome P450; sec, side chain cleavage; cYla, c21, ell,18, arom designate the site of action of specific P450 enzymes. Non-P450 enzymes are A5-isomerase-3/3-hydroxysteroid dehydrogenase (3/3), 17/3reductase (17/3-R) and 5a-reductase (5a-R). Modified from Rosenfield et al. (3).

hyperresponsiveness to ACTH; this often coexists with PCOS and may be explicable by similar dysregulation of adrenocortical P450cl7a. Despite their great abundance, the 17-KS are proandrogens: conversion to the 17j8-hydroxysteroids, testosterone (T) and dihydrotestosterone (DHT), is required for biological activity. T is the most important circulating androgen and approximately half is derived from the peripheral conversion of secreted AD, while half is derived from direct glandular secretion. The ovaries and adrenal glands contribute about equally to T production in women. Over 96% of 17/3-hydroxysteroids circulate bound to the carrier proteins albumin and sex hormone binding globulin (SHBG). Due to its high binding affinity, SHBG concentration is the major determinant of the distribution of 17/?-hydroxysteroids to the plasma albumin and free fractions. A number of physiological and pathological states impact on the SHBG concentration: it is increased by estrogens and thyroid hormone excess; it is decreased by androgen, glucocorticoid, and GH excess and is generally low in obesity. Because SHBG levels are often decreased in hyperandrogenic states, serum free T levels may be elevated in women whose total T levels are normal. Although there has been interest in the possibility that albumin-bound T is bioactive, most evidence suggests that it is the free steroid intermediate that is bioavailable (5, 6). The biological activity of T is effected in large part by its conversion to DHT by 5-reductase. DHT is more potent than T primarily because of its higher affinity for and slower dissociation from the androgen receptor. High androgen levels are neither necessary nor sufficient for hirsutism or acne; the apparent sensitivity of the PSU to androgens seems to be as great a factor as the plasma androgen level. That subset of women with hirsutism and normal androgen levels is properly designated idiopathic hirsutism. The etiology of hirsutism in these women has been ascribed to enhanced conversion of T to DHT by 5a-reductase (7). Some researchers contend that the plasma level of 3-androstanediol glucuronide (3a-AG), a metabolite of DHT, is an index of this. However, it has been difficult to conclusively demonstrate 3a-AG formation in skin by classical radiochemical means. Furthermore, the 5a-reductase activity of skin resides primarily in sebaceous and sweat glands, both of which are targets of androgens, rather than in hair. Thus, the etiologic role of increased skin 5a-reductase activity in idiopathic hirsutism is inconclusive.

Evaluation of Hirsutism
The initial step in the clinical evaluation of the patient with excessive hair growth is the distinction of hirsutism from hypertrichosis. Hypertrichosis is the term reserved

CLINICAL REVIEW to describe androgen-independent growth of hair which is vellus, prominent in nonsexual areas, and most commonly congenital or caused by metabolic disorders (e.g. hypothyroidism, anorexia nervosa, porphyria cutanea tarda), or medications (e.g. phenytoin, minoxidil, cyclosporine). The degree of hirsutism is clinically, though imperfectly, assessed by the method of Ferriman and Gallwey (Fig. 3) in which the body areas possessing androgensensitive PSUs are graded and summed. A total score of 8 or more is seen in only 5% of premenopausal Caucasian women; these women, by definition, are hirsute. We recommend screening hirsute women for hyperandrogenemia by measuring blood levels of free T, AD, and DHAS; LH, FSH, and PRL may also be obtained at the time of initial evaluation. Hyperandrogenemia is present in most severe cases of hirsutism or acne. Because of the episodic and cyclic secretion of androgens, however, a random value may be misleadingly normal. Clearly, it is both costly and impractical to measure many steroids on multiple occasions; a strategy must be used to derive maximal diagnostic information from limited sampling. If key historical and/or physical features do not point to a specific diagnosis (e.g. ovarian mass), we feel diagnostic screening usually is reasonably accomplished using dexamethasone (dex) suppression testing. Dex is given for 5 days (or longer in patients who are very obese or have relatively high DHAS levels) in a low dose of 1.5-2.0 mg daily by mouth in divided doses. The pattern of response of plasma free T, DHAS, and cortisol segregates patients diagnostically (Fig. 4). Normal suppression of androgen is most specifically indicated by a reduction of the plasma free T into the normal range for dex-suppressed nonhirsute women. In our laboratory dex suppressibility is considered normal in a postmenarchial female if the plasma free T is 8 pg/ml (27.5 pM) or less. Normal adrenal suppression is indicated by a reduction of both DHAS and cortisol to levels below the
CORTISOL FREE TESTOSTERONE DHAS

DEX I M G / M ' X 5 - 7 DAYS

PCOS

TUMOR

6H EXCESS PROL'OMA

IDIOPATHIC

FIG. 4. Algorithm for the differential diagnosis of hyperandrogenemia. The response of the plasma free T, DHAS, and cortisol to DEX for 5 days or more is evaluated. Subnormal suppression of androgens by DEX points toward PCOS (if both DHAS and cortisol suppress normally), tumor (if only cortisol suppresses normally), or Cushing's syndrome (if cortisol does not suppress normally). Normal suppression of hyperandrogenemia by DEX is indication for an ACTH test. PROL'OMA, Prolactinoma. Reproduced from Rosenfield, with permission (2).

normal adult control range. Subnormal suppressibility of free T with normal adrenal suppression rules out congenital adrenal hyperplasia. PCOS is present in the vast majority of patients in this category. Serum LH measurement is a useful corroborative test; however, elevation of serum LH is not specific for PCOS and perhaps 25% of PCOS have levels that are normal (type II PCOS) (3). A pelvic ultrasound examination may also be supportive of the diagnosis, but the sensitivity and specificity for PCOS are low. A serum
17-hydroxyprogesterone level over 224 ng/dl (6.4 nM) in

response to a 100 fig sc test dose of the GnRH agonist nafarelin appears promising as a diagnostic test (4). Further extensive diagnostic studies are not indicated unless there is reason to suspect a virilizing tumor. Tumor is suggested by a baseline plasma T level over 200 ng/dL (7 nM); a basal DHAS level over 800 fig/dL (18.5 ixM) suggests an adrenal tumor. Ultrasound, CT, or MRI scan will usually demonstrate the mass in such cases. Inadequate cortisol suppression suggests Cushing's syndrome or noncompliance. If androgens are suppressed to normal levels, ACTH testing is indicated. The responses usually are more compatible with exaggerated adrenarche than with nonclassical CAH. Hyperprolactinemia or acromegaly are other causes of adrenal androgenic hyperfunction. Abnormal peripheral androgen metabolism may account for some idiopathic hyperandrogenemia. Our experience with GnRH agonist testing suggests that much hyperandrogenemia that is now considered idiopathic may prove to be due to PCOS.

FIG. 3. Hirsutism scoring scale of Ferriman and Gallwey. The nine body areas possessing androgen-sensitive PSUs are graded from 0 (no terminal hair) to 4 (frankly virile). Reproduced from Rosenfield, with permission (1).

Therapy
The pharmacological therapy of hirsutism is aimed at interrupting one or more of the steps in the pathway

EHRMANN AND ROSENFIELD

JCE&M1990 Vol71 -No 1

leading to its expression: 1) inhibition of adrenal or ovarian androgen synthesis and secretion; 2) alteration of binding of androgens to SHBG; 3) impairment of the peripheral conversion of androgen precursors to active androgen; and 4) inhibition of androgen action at the target tissue level. The maximal effect of pharmacological agents takes 9-12 months. Cosmetic measures are often necessary concomitantly. Combination estrogen-progestin therapy lowers free T levels by reducing serum gonadotropin, increasing SHBG levels, and modestly suppressing DHAS levels. It is most effective in functional ovarian hyperandrogenism (i.e. PCOS). The choice of progestin is important, however; ethynodiol diacetate has the least, while norethindrone acetate and norgestrel possess the highest, androgenic potential. In clinical trials of estrogen-progestin therapy alone the extent of hair growth (based upon shaving frequency) is improved in only approximately half of women (8). GnRH agonists have also been successfully used to treat hirsutism in women with PCOS. In contrast to their short term stimulatory effect on gonadotropin secretion, chronic administration of these agents inhibits the secretion of gonadotropins and hence ovarian androgens. Potential sequelae include hypoestrogenism and its effects on bone mass. It is unclear whether GnRH agonists have any advantage over estrogen-progestin therapy since the optimal use of GnRH agonists in treating hirsutism may include the combined administration of estrogen. Glucocorticoids are probably most effective in patients with functional adrenal hyperandrogenemia (e.g. CAH). The sequelae of glucocorticoid therapy can be minimized by using a modest bedtime dose (about 5 mg prednisone or 0.25 mg dex) to selectively reduce adrenal androgen secretion (9). Antiandrogens are available which act primarily to inhibit binding of androgens to the androgen receptor. A contraceptive regimen must be administered simultaneously. Agents in this category include cyproterone acetate, spironolactone, and most recently, flutamide. Cyproterone acetate in a 50 mg dose is quite effective in a reverse-sequential regimen and has limited adverse effects. It is not, however, available for use in the United

States. Spironolactone is clinically antiandrogenic and progestational in doses of 50-100 mg twice daily. It is most effective when administered in conjunction with cyclic estrogen. Spironolactone side effects include hyperkalemia and hypotension which may limit the longterm use necessary to sustain improvement. Flutamide is a potent, nonsteroidal, selective antiandrogen without progestational, estrogenic, corticoid, or antigonadotrophic activity. Preliminary data indicate that it is efficacious in the therapy of hirsutism. Cusan, et al. (10) successfully treated hirsute women with flutamide (250 mg twice daily) in combination with an estrogen-progestin without complications. After 7 months, the mean Ferriman-Gallwey score decreased by 56%. A marked improvement in acne and seborrhea was also noted. This agent is currently under investigation. Acknowledgment
Jean Moore assisted with the typescript.

References
1. Rosenfield RL. Pilosebaceous physiology in relation to hirsutism and acne. Clin Endocrinol Metab. 1986;15:341-361. 2. Rosenfield RL. The ovary and female sexual maturation. In: ed. Kaplan SA, Clinical pediatric endocrinology, Philadelphia: WB Saunders, 1989, 2nd ed. Chap 8:259-323. 3. Rosenfield RL, Barnes RB, Cara JF, Lucky AW. Dysregulation of cytochrome P450cl7a as the cause of polycystic ovary syndrome. Fertil Steril. 1990;53:785-91. 4. Barnes RB, Rosenfield RL, Burstein S, and Ehrmann DA. Pituitary-ovarian responses to nafarelin in the polycystic ovary syndrome. N Engl J Med. 1989;320:559-565. 5. Moll Jr GW, Rosenfield R. Estradiol inhibition of pituitary luteinizing hormone release is antagonized by serum proteins. J Steroid Biochem. 1986;25:309-314. 6. Rosner W. The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances. Endocr Rev. 1990;11:80-91. 7. Lobo RA, Paul WL, Gentzschein E, Serafini PC, Catalino JA, Paulson RJ, Horton R. Production of 3a-androstanediol glucuronide in human genital skin. J Clin Endocrinol Metab. 1987;65:711714. 8. Hancock KW, Levell MJ. The use of oestrogen/progestogen preparations in the treatment of hirsutism in the female. J Obstet Gynaecol Br Commonwealth 1974;81:804-811. 9. Rittmaster RS, Givner ML. Effect of daily and alternate day low dose prednisone on serum cortisol and adrenal androgens in hirsute women. J Clin Endocrinol Metab. 1988;67:400-3. 10. Cusan L, Dupont A, Tremblay R, Labrie F. Treatment of hirsutism with the pure antiandrogen flutamide. Recent Res Gynecol Endocrinol. 1988;l:577-582.