The evaluation and management of hirsutism

Abstract

Hirsutism is the presence of terminal (coarse) hairs in females in a male-like pattern, affecting between 5% and 15% of women, depending on definition. Hirsutism has a significant negative impact on psychosocial development and is usually a sign of an underlying endocrine abnormality—namely, androgen excess. The most common cause of androgen excess is the polycystic ovary syndrome (PCOS), with 21-hydroxylase–deficient nonclassic adrenal hyperplasia, the hyperandrogenic insulin-resistant acanthosis nigricans syndrome, androgen-secreting tumors, and androgenic drug intake occurring less frequently. However, although 70–80% of patients with androgen excess demonstrate hirsutism, this sign may be less prevalent among women of Asian extraction. Conversely, not all hirsute patients have evidence of detectable androgen excess, as 5–15% of these women have “idiopathic hirsutism,” with normal ovulatory function and androgen levels. There is a strong familial predilection for hirsutism, primarily because the underlying endocrine disorders (eg, PCOS) and the factors regulating the development of hair growth (eg, androgen receptor activity, 5α-reductase activity) have a strong genetic component. The diagnostic evaluation of the potentially hirsute patient first involves confirming the presence of hirsutism and then excluding associated or etiological abnormalities and disorders (eg, ovulatory dysfunction, adrenal hyperplasia, diabetes, thyroid hormone abnormalities). Treatment should be undertaken using combination therapy, to possibly include 1) hormonal suppression (oral contraceptives, long-acting gonadotropin-releasing hormone analogues, and insulin sensitizers), 2) peripheral androgen blockade (spironolactone, flutamide, cyproterone acetate, or finasteride), and 3) mechanical/cosmetic amelioration and destruction of the unwanted hairs (electrology and, potentially, laser hair removal). The application of eflornithine hydrochloride 13.9% topical cream may also be useful to ameliorate unwanted facial hair growth. Overall, although hirsutism is a frequent and distressing abnormality often signaling an underlying endocrine disorder, a systematic approach to evaluation will uncover the etiology, and combination therapy will provide satisfactory treatment for most patients.

Introduction

We have invited select authorities to present background information on challenging clinical problems and practical information on diagnosis and treatment for use by practitioners.

Hirsutism is the presence of terminal (coarse) hairs in females in a male-like pattern, and affects between 5% and 15% of women surveyed.1, 2, 3, 4 The presence of hirsutism is extremely distressing to patients, with a significant negative impact on their psychosocial development.5, 6 Furthermore, hirsutism is, with few exceptions, a sign of an underlying endocrine abnormality—namely, androgen excess or hyperandrogenism.4

The prevalence of hirsutism will depend, to a certain degree, on the method used to determine its presence and the population under study. Generally, the clinical evaluation of hirsutism relies on the observer’s assessment of whether a patient demonstrates male-like body hair growth or not. The most common method of scoring hirsutism follows that originally described by Ferriman and Gallwey in 1961.1 These investigators subjectively scored the presence of hair growth at 11 different body sites (upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, arm, forearm, thigh, and lower leg) in 430 consecutive women attending a general medical clinic in the United Kingdom, presumably predominantly of white race, ages 15 to 74 years. In each of these areas a score of 0 (absence of terminal hairs) to 4 (extensive terminal hair growth) was assigned. This study noted that the hair growth over the forearm and lower leg appeared to be less sensitive, or indifferent, to androgens. Considering only the remaining nine body areas, 4.3% of subjects studied had a score of greater than 7, leading these investigators to choose a score of 8 or more as defining hirsutism.

Other methods for visually (and subjectively) assessing body hair growth have been reported. Lorenzo7 studied 300 unselected women from a community health study in Michigan, scoring only five body areas (chin, upper lip, chest, abdomen, and thighs) also from 0 to 4. The racial or ethnic composition of these control women was not stated. Using this scoring method, this investigator did not observe a hirsutism score over 5 among any of these women. Obviously, the overall cutoff score will vary as the number of areas assessed changes. A number of other modifications of the original Ferriman-Gallwey scoring method have been published. For example, women with hirsutism may also have excessive hair growth preferentially in the sideburn area, lower jaw, and upper neck, or perineal region, and these areas have also been included in newer scoring systems.8 Hatch and colleagues9 reported a method that scored (from 0 to 4) only nine of the body areas originally assessed by Ferriman and Gallwey, excluding the lower legs and lower arms. This latter method is the one that we have preferred for our clinical or investigational assessment of hirsutism (Figure 1).

To determine the prevalence of hirsutism in the general population we prospectively studied 369 consecutive women of reproductive age seeking a preemployment physical.4 Of these, 7.6%, 4.6%, and 1.9% demonstrated a Ferriman and Gallwey score of 6 or more, 8, and 10, respectively, and there was no significant racial difference. Based on these data we have chosen to define hirsutism, in either black or white women, as a modified Ferriman and Gallwey score of 6 or more. Our estimate that hirsutism affects about 8% of women surveyed is consistent with the results of other studies.1, 2, 3, 4 Considering that there are about 52 million women aged 15–44 years (US Census Bureau, July 2000 estimates), we can estimate that there are over 4.0 million hirsute women of reproductive age in the United States alone, with a majority of these also having androgen excess.

Hirsutism, with few exceptions, is a sign of an underlying hormonal disorder—namely, androgen excess or hyperandrogenism. However, not all hirsute patients have evidence of detectable androgen excess or endocrine imbalance, as in women with “idiopathic hirsutism.” The most common cause of androgen excess is the polycystic ovary syndrome (PCOS), with 21-hydroxylase (21-OH)–deficient nonclassic adrenal hyperplasia, the hyperandrogenic insulin-resistant acanthosis nigricans syndrome, androgen-secreting tumors, and androgenic drug intake being much less frequent. Nonetheless, it is important to conceptually distinguish androgen excess, the endocrine disorder, from hirsutism, the dermatological sign, notwithstanding the significant overlap. Overall, 70–80% of patients with androgen excess demonstrate hirsutism (Sanchez LA, Knochenhauer ES, Gatlin R, Moran C, Azziz R. Differential diagnosis of clinically evident hyperandrogenism: Experience with over 1000 consecutive patients [abstract]. Fertil Steril 2001;76:S111),10 although this sign may be less prevalent among women of Asian extraction10 (Figure 2).

The physiology of hair growth and development has been recently reviewed.11 In brief, hair is composed of compressed keratinized melanocytes that grow from the dermal papilla towards the skin surface within the outer hair sheath that forms part of the epidermis (Figure 3). There are about 50 million hair follicles, generally associated with a sebaceous gland (ie, forming the pilosebaceous unit), covering the body, of which 20% are in the scalp. The only areas free of hair follicles are the soles of the feet, the palms of the hands, and the lips. Few new hair follicles are formed after birth, and their numbers begin to decline after age 40 such that a generalized thinning of the hair is normal with aging. There are three general phases of hair growth: 1) Anagen is the active growing phase, 2) catagen is the involutional stage in which the hair stops growing and the hair bud shrinks, and 3) telogen is the phase in which the hair is shed, completing the growth cycle.12 The overall length of a hair is determined primarily by the duration of the anagen phase. Hair appears to grow continuously because the growth cycles of the different hair follicles are in dysynchrony with each other.

There are three general types of hair.12 Lanugo is a dense, soft unmedullated hair over the surface of the fetus that is shed sometime late in gestation or early postpartum. Vellus hairs are soft, short (generally less than 2 mm in length), fine, unmedullated, and usually nonpigmented, and cover the apparently hairless areas of the body. Terminal hairs are long, coarse, medullated (ie, having a denser core of compacted melanocytes), and pigmented. This hair makes up the eyebrows, the eyelashes, the scalp hair, the pubic and axillary hair, etc.

A number of hormones affect hair growth.13 Growth hormone produces a generalized growth in hair. Alternatively, thyroid dysfunction generally results in hair loss.14, 15, 16 For example, hyperthyroidism produces a fine, viable hair, which is easily lost, whereas hypothyroidism produces a coarse, brittle hair that is also easily lost and often associated with hair loss from the lateral eyebrows. Progesterone and estrogens have only minimal effects on hair growth.17, 18 Androgens are the most important determinant of the type of hairs distributed throughout the body. Androgens result in an increase in the growth rate and, most importantly, the transformation of vellus to terminal hairs in those areas that are androgen sensitive.13 Although the process of terminalization may take a number of growth cycles to complete, during which time the transformation may actually be reversed, it is not reversible thereafter. It is this latter effect of androgens on the hair follicle, produced in excess either centrally (eg, PCOS) or locally (eg, idiopathic hirsutism), that results in one of the most common signs of hyperandrogenism—namely, hirsutism.

The principle circulating androgen, testosterone, is converted in the hair follicle by 5α-reductase to dihydrotestosterone.19 Testosterone and the more potent dihydrotestosterone stimulate the dermal papilla to produce a terminal medullated hair where a vellus hair once grew. Other weaker androgens, such as androstenedione and dehydroepiandrosterone (DHEA), can also be metabolized in the skin to testosterone and dihydrotestosterone to produce excessive hair growth. The effect of androgens on hair growth is skin area specific,19 probably due to variations in androgen receptor and 5α-reductase content. Some skin areas (eg, those of the eyelashes, eyebrows, and lateral and occipital aspects of the scalp) are relatively independent of the effect of androgens (ie, nonsexual skin). Alternatively, other areas (ie, ambosexual skin) are quite sensitive to androgens, and hair follicles are terminalized even in the presence of relatively low levels of androgens; these areas include the lower pubic triangle and the axillary region. These areas begin to develop terminal hair even in early puberty, when only minimal increases in adrenal androgens are observed. Finally, other areas of skin respond only to high levels of androgens (ie, sexual skin) and include the chest, lower abdomen, the lower back, the upper thighs, the upper arms, the chin, the face, and the upper pelvic triangle (male escutcheon). The presence of terminal hairs in these areas is characteristically masculine and, if in women, considered pathologic (ie, hirsutism).

There is a strong familial component to hirsutism. For example, Lorenzo7 reported on 90 hirsute probands and their families. Family history was obtained from all probands, and a limited physical examination was conducted on willing mothers and sisters, restricted to evaluation of the face only. Three hundred control untreated women were picked at random from a community health study population and underwent a full assessment of hirsutism and other androgenic equivalents. This study found an increased prevalence of hirsutism among the female relatives and acne and/or frontal balding among the male relatives of the probands relative to controls. The high degree of heritability of hirsutism is not surprising. First, many of the endocrine disorders resulting in hirsutism have a strong genetic component, particularly PCOS.20, 21 Second, the factors regulating the development of hirsutism (eg, androgen receptor activity, 5α-reductase activity) may also be altered by heritability.

Extreme examples of the role that heritability plays in determining the development of hirsutism are the sparse terminal body hair of patients with androgen receptor insensitivity and 5α-reductase deficiency, and the much lower degree of hirsutism evident in Asian patients with PCOS notwithstanding similar circulating androgen levels. A common genetic variation possibly affecting the function of the androgen receptor is the number of trinucleotide CAG repeats in exon 1 of the androgen receptor gene. These trinucleotide repeats have been found to vary widely (ie, be polymorphic) among humans. The CAG codons encode for a long stretch of glutamines within the amino terminal of the transactivation domain of the androgen receptor. Shorter CAG repeat lengths in the N-terminal domain of the androgen have been implicated in the development of hirsutism,22 although other investigators disagree.23, 24 Nonetheless, although Vottero and colleagues23 did not find a difference in the number of CAG repeats between hirsute patients and controls and found no correlation between number of repeats and the Ferriman and Gallwey score, these investigators noted that in the peripheral blood lymphocytes of 16 patients with idiopathic hirsutism the longer of the two androgen receptor alleles (ie, possibly the less active receptor) was preferentially methylated (and hence inactivated). Hence, it is possible that genetic alterations of the androgen receptor function and, presumably, 5α-reductase function may modify the expression of hirsutism.