8.1.10 Hirsutism

Hirsutism is defined as excess growth of body or facial terminal (coarse) hair in females, in a male-like pattern. The condition has a significant negative impact on a woman’s self-esteem and on her quality of life. Hirsutism affects 5–15% of the women, and is the most commonly used clinical diagnostic criterion of androgen excess or hyperandrogenism (1). Depending on age and race/ethnicity, 80–90% of women with hirsutism will have an androgen excess disorder, most often polycystic ovary syndrome (PCOS), and including idiopathic hirsutism, and non-classic congenital adrenal hyperplasia (NCAH), among the others.

This chapter outlines androgen metabolism in women, physiology and pathophysiology of hair growth, epidemiology of and differential diagnosis of hirsutism, other signs of androgen excess including acne, androgenetic alopecia, and virilization, and the clinical investigation, and treatment of the hirsute patient.

Androgens are 19 carbon (C19) steroids, synthesized from a steroid substrate pregnenolone, which is derived from cholesterol. Androgens are produced by both the ovary and the adrenal gland. They may also be derived from the conversion of other androgens or precursor steroids by the liver and some peripheral tissues including skin and adipose tissue. The main circulating androgens and androgen metabolites in women include testosterone, and its 5α-reduced metabolite dihydrotestosterone (DHT), androstenedione (A4), dehydroepiandrosterone (DHEA) and its metabolite dehydroepiandrosterone sulfate (DHEAS).

The regulation of androgen secretion involves stimulation of adrenal gland and the ovary by adrenocorticotropic hormone (ACTH) and luteinizing hormone, respectively, together with intraglandular paracrine and autocrine mechanisms. The zona reticularis of the adrenal gland preferentially secretes weak androgens DHEA and DHEAS in large amounts which may be converted to A4 and then to testosterone (2). The adrenal gland contributes 100% of DHEAS, 90% of DHEA, 50% of A4, and 25% of testosterone in the reproductive-aged women. The ovary secretes about 50% of circulating A4, 25% of testosterone, and 10% of DHEA. The remaining 50% of circulating testosterone is produced from the peripheral conversion of the weaker androgens A4 and DHEAS. Much of the extraglandular conversion of testosterone takes place in the liver and the skin. Testosterone and A4 are also metabolized to DHT, a potent androgen, via the action of 5α-reductase in the periphery. DHT is responsible for most of testosterone’s activity at the tissue level (Fig. 8.1.10.1).

DHEA and A4 are weaker androgens compared to testosterone and DHT. Similarly, DHEAS has almost no androgenic activity despite the fact that it is the most abundant androgen in the circulation. DHEA, DHEAS, and A4 exhibit a circadian rhythm similar to that of cortisol, with peak serum concentrations in early morning and the nadir in late evening. These androgens do not show a significant variability during the menstrual cycle, whereas testosterone levels exhibit a moderate change reaching highest levels during the mid-cycle.

DHEA and DHEAS circulate mostly unbound and A4 is only loosely bound to albumin, whereas testosterone and DHT circulate tightly bound to hepatic sex hormone-binding globulin (SHBG) and, to a lesser extent, to albumin. Approximately 75% of total testosterone is bound to SHBG and about 23% is weakly bound to albumin. Free testosterone constitutes less than 2% of the circulating testosterone. Free and weakly bound testosterone is called bioavailable testosterone.

Only free androgens are able to be active at androgen receptors on target tissues. Thus, biological action of testosterone and DHT is significantly influenced by the circulating SHBG level. Even without a change in total hormone concentrations, a decrease in SHBG will result in an increase in free fractions of testosterone and DHT that, in turn, increases androgenic action. Conversely, higher SHBG levels will result in a decrease in free fractions of testosterone and DHT, and a decrease in androgenic action. The SHBG levels also influence the clearance of testosterone and DHT from the circulation, because only free androgen can be metabolized by liver and peripheral tissues. SHBG levels are inversely correlated with androgen and insulin levels, whereas oestrogens increase circulating SHBG concentrations.

Androgen production and clearance are influenced by various physiological states. In obesity, androgen production and clearance are accelerated. Obesity, particularly the abdominal type, could increase formation of testosterone from A4, and decrease SHBG levels resulting in increased circulating free androgens in obese women. Additionally, because androgens are fat soluble, excess adipose tissue serves as an extravascular pool for androgens. The amount of androgens metabolized to oestrogens by the adipose tissue aromatase is also increased in obesity.

Normative ranges for androgens may differ depending on age and body mass index (BMI). Circulating levels of DHEA, DHEAS, and total and fT decline with age. There is a paucity of normative androgen data for adolescents and elderly women. However, it is well known that normal menopausal androgen levels are lower than those produced in the reproductive years.

Hair covers the vast majority of the body, sparing only the lips, palms of the hands, and the soles of the feet. There are about 5 million hair follicles on a human, of which 1 million are on the head. Almost all hair follicles are present at birth and no additional follicles arise thereafter, although the size of the follicles may change over time. A hair follicle is present in conjunction with a sebaceous gland, and arrector pili muscle forming the pilosebaceous unit (PSU) (Fig. 8.1.10.2).

Structurally, there are three types of hair. Lanugo is soft hair covering the surface of the fetus, which is shed sometime in late gestation or the early postpartum. Vellus hair is soft, fine, nonpigmented or containing little pigment, generally measuring less than 2 mm in length, and covering apparently hairless areas of the body. It does not contain a core of compacted keratinocytes (i.e. medulla). Terminal hair is long, coarse, thick, pigmented, and contains a central core of compacted keratinocytes (i.e. medullated). Terminal hairs are found primarily in the midline, back, chest, abdomen, axillary, and pubic area. These type of hairs show significant regional morphological differences (i.e. longer in some sites, more pigmented in others, etc.) due to genetically determined differences in the follicles. Nonsexual terminal hair presents in the scalp, eyebrows, and eyelashes (3).

Race and ethnicity influence the body hair type and distribution. The number of hair follicles per unit skin area and the rate of hair growth vary among ethnic groups. For example, Asians have less dense hair than Blacks, who in turn have less dense hair than Whites. However, men and women within the same race or ethnic group have similar follicle numbers and the visible differences between them are related to the type of hair arising from these follicles (i.e. terminal versus vellus hairs).

Hair follicles undergo cyclic changes and there are three phases of the hair follicle growth cycle (Fig. 8.1.10.3). Anagen is the active growing phase of hair. During this phase, keratinocytes are dividing extensively with downwards progression of the dermal papilla. Anagen is followed by the transitional catagen phase in which the hair stops growing and the hair bud shrinks forming a club end, and finally by a resting, or telogen phase, after which the hair sheds (3). Although in many animals the growth cycles of all hair follicles are in synchrony, in humans, the growth phases of different hair follicles are not synchronous and, for that reason, hairs appear to be continuously growing. The length of hair cycle phases varies significantly in different parts of the human body. Scalp follicles have the longest anagen phase, which may last 2–6 years. They have a catagen phase of 1–3 weeks and a telogen phase of up to 3 months. Normally, 80–85% of scalp hairs are in anagen. The anagen phase of body hairs may only last 3–6 months (terminal hairs on forearms or legs), or may be as long as 2–3 years (e.g. on scalp).

Development and growth of hair follicles are regulated by hormonal factors. Growth and thyroid hormones stimulate a generalized increase in hair growth. Both hypo- and hyperthyroidism are associated with hair loss. Pregnancy temporarily increases the number of hair follicles in anagen, of which many enter catagen or telogen postpartum resulting in diffuse hair loss. Oestrogens oppose the effects of androgens, by increasing SHBG levels and reducing free androgens rather than showing a direct effect on hair follicles (3).

Androgens are the principal hormonal regulator in determining the type and distribution of hairs over the body, and are necessary to produce development of terminal hair. In the hair follicle, circulating testosterone is metabolized by 5α-reductase to the more potent DHT, and both hormones (and to a limited extent, A4, and DHEA) bind to the same androgen receptor. In turn, the hormone-receptor complex binds to DNA, altering expression of specific androgen-dependent genes, and modulating protein synthesis. These androgen actions lead to (1) increased sebum production; (2) the differentiation of the hair follicle from vellus to terminal hairs; and (3) the prolongation of the anagen phase resulting in longer thicker hairs (Fig. 8.1.10.4).

Androgens, particularly in excess, may transform vellus hairs into terminal hairs in androgen-sensitive areas of the skin in an irreversible manner (i.e. terminalization). Paradoxically, terminal hairs may transform into vellus hairs under the influence of androgens (i.e. miniaturization), as is observed in male-pattern balding. Androgens prolong the anagen phase of body hairs, while shortening the anagen phase of scalp hairs. The process of transformation (i.e. terminalization or miniaturization), occurs progressively over many hair growth cycles, requiring months to years of androgen exposure. Interruption of the process sufficiently early (e.g. through use of antiandrogens in case of vellus hair terminalization) can reverse the effects observed.

The growth and differentiation of hair follicles vary greatly in their sensitivity to androgens by body area and presumably the local content of the AR, 5α-reductase, l-ornithine decarboxylase (ODC), 17β-hydroxysteroid dehydrogenase and others (Table 8.1.10.1). Some skin areas (e.g. that of the eyelashes, eyebrows, and lateral and occipital aspects of the scalp) are relatively independent of the effect of androgens, and are defined as nonsexual skin areas. Alternatively, other skin areas (e.g. lower pubic triangle and the axilla) are quite sensitive to androgens, and hair follicles are terminalized even in the presence of relatively low levels of circulating androgens. These areas begin to develop terminal hair even in early puberty, when only minimal increases in adrenal androgens are observed, and are defined as ambosexual skin areas. Finally, other areas of skin respond to androgens, but only to significantly higher levels, including the chest, upper and lower abdomen (i.e. the upper pelvic triangle or male escutcheon), upper and lower back, thighs, upper arms, and the chin, cheeks and sideburn areas. These areas are defined as sexual skin areas (4). In women, the presence of terminal hairs in sexual skin areas is considered pathological and, defined as hirsutism.

The prevalence of hirsutism, in part, will depend on the method used to determine its presence, and the population under investigation. Although objective methods are available for the assessment of hair growth including photographic evaluations and microscopic measurements, they are not suitable for clinical use due to a significant degree of complexity and high cost. Alternatively, various methods, based on visual assessment of hair type and growth, have been proposed to evaluate patients suspected of hirsutism (5).

The most common method of scoring body and facial terminal hair growth used today for defining the presence of hirsutism is based on a modification of the method originally described by Ferriman and Gallwey in 1961 (6, 7). Ferriman and Gallwey described this subjective assessment which scores the presence of hair growth between 0 (absence of terminal hairs) and 4 (extensive terminal hair growth) at 11 different body sites (upper lip, chin, chest, upper and lower back, upper and lower abdomen, arm, forearm, thigh, and lower leg) (6). Other methods scoring only five body sites (upper lip, chin, chest, abdomen, and thighs) or including in the assessment the sideburn area, lower jaw, upper neck, and perineal region were proposed (8).

Hatch et al (7) suggested a method scoring 9 of the 11 body areas originally assessed by Ferriman and Gallwey, excluding the less androgen-sensitive areas of lower legs and lower arms (Fig. 8.1.10.5). Accordingly, excessive growth of terminal hairs only on the lower forearms and lower legs does not constitute hirsutism, although a woman suffering from hirsutism may also note worsening of hair growth in these areas. The modified scoring system suggested by Hatch et al. (7) is the preferred method today for the assessment of hirsutism. However, this system is semiquantitative at best, and subject to inherent problems including the inter-observer variability in results and the lack of consensus on what score (usually a modified Ferriman-Gallwey score ≥6) defines hirsutism (5).

Using their data from the 161 women whose age was between 18 and 38 years, Ferriman and Gallwey observed that 9.9% had scores ≥6, 4.3% had scores above ≥8, and only 1.2% of women had combined scores ≥10, for the nine body areas they termed ‘hormonal’, excluding forearm and lower leg (6). Hatch and colleagues, in a review of hirsutism, proposed that a combined score of 8 or greater using the mFG score defined the population of women with hirsutism (7), as this degree of hair growth was observed in only 4.3% (i.e. <5%) of the reproductive-age population of women studied by Ferriman and Gallwey (6).

To determine the prevalence of hirsutism in general population, we studied 633 unselected (278 White with a mean age of 37.4 years and 349 Black with a mean age of 23.8 years) women presenting for a pre-employment physical exam (9). The degree of facial and body terminal hair growth was similar in Black and White women, and the 95th percentile mFG value of the combined population was 7.7 (Fig. 8.1.10.6). Overall, 7.5% of the overall population could be defined as being hirsute by an mFG scores ≥8.

The degree of body hair growth, and consequently the cut-off value for diagnosing hirsutism, may be affected by ethnicity and race. Although the prevalence rates of hirsutism are similar between the Black and White women, it is unlikely that Asian women would have similar degrees of hair to that of White or Black women. For example, in a study of 531 Thai women seen for an uncomplicated annual gynaecological exam, 97.8% of all subjects had an mFG score of 2 or less, and none of the subjects had a score above 5 (10).

Acne is a common disorder of the PSU. It occurs in adolescence, and may persist into adulthood. Acne presents most commonly on the face, neck, chest, shoulders, and back. A combination of increased sebum production together with infection and inflammation due to Propionibacterium acnes within the sebaceous glands result in acne lesions on a background of seborrhoea. It appears that androgens have major autocrine and paracrine effects in the development of acne, although the cellular and molecular mechanisms by which these hormones exert their influence on the sebaceous glands yet to be fully elucidated. Androgens stimulate sebocyte proliferation, cause the sebaceous glands to enlarge and produce more sebum. Acne observed during puberty is associated with increased adrenal androgen production, and acne formation is often associated with increased serum androgen levels. Moreover, sebum production and acne are not observed in androgen-insensitive individuals who lack functional androgen receptors. Nevertheless, acne as an isolated symptom might not be considered a sign of hyperandrogenism. In women whose acne is severe, or associated with hirsutism or irregular menstrual periods, hyperandrogenism should be considered (11).

The term ‘alopecia’ refers to loss of scalp hair. Androgenic alopecia (sometimes referred to as ‘androgenetic’ alopecia on the presumption of an underlying, yet to be determined genetic factor) is the most common form of alopecia in women (12). In the presence of androgens, anagen phase is shortened, and hair follicles shrink or become miniaturized. With successive anagen cycles, the follicles become smaller and short, nonpigmented vellus hairs replace thick, pigmented terminal hairs. The thinning may be diffuse involving most of the scalp, but more marked in the frontal and parietal regions. In general, the frontal hairline is maintained with temporal recession in some women. Rarely, advanced thinning with the recession of frontal hairline occurs in virilization associated with markedly elevated circulating androgen levels.

Women with androgenic alopecia do not appear to have increased levels of circulating androgens. However, they have been found to have higher levels of 5α-reductase (which converts testosterone to dihydrotestosterone), more androgen receptors, and lower levels of cytochrome P450 (which converts testosterone to oestrogen). While most of the women with androgenic alopecia have normal endocrine function, and regular ovulatory cycles, it is not uncommon that androgenic alopecia is accompanied by other androgenic skin manifestations, such as hirsutism and acne in the same patient. If history and physical examination in a woman with androgenic alopecia reveal irregular menses, or other clinical signs and symptoms of androgen excess including hirsutism, acne or virilization, hormonal and biochemical evaluation would be appropriate.

Virilization is a relatively uncommon clinical finding of androgen excess, and its presence is usually associated with markedly elevated levels of circulating androgens. Hirsutism and acne are invariably present, and signs of virilization usually occur over a relatively short time. Virilization is characterized by androgenic alopecia, clitoromegaly, deepening of the voice, increased muscle mass, and decreased breast size. Women with virilization are nearly always amenorrhoeic (13).

In virilization, alopecia usually presents a male-pattern form of balding with bitemporal recession. Clitoromegaly is defined as a clitoral index, which is the product of the sagittal and transverse diameters of the glans of the clitoris, greater than 35 mm². The presence of an androgen-secreting neoplasm should always be suspected in any woman who develops signs of virilization, particularly if the onset is sudden with a rapid progression. However, virilization does not necessarily indicate severe hyperandrogenism, since any pattern or degree of androgen excess features might also be observed in women with hyperandrogenism due to nonneoplastic causes such as PCOS and idiopathic hirsutism.

The causes of hirsutism are summarized in Box 8.1.10.1. Over 80% of hirsute patients will have PCOS while about 10–15% having idiopathic hirsutism, and less than 10% having other rare disorders including non-classic congenital adrenal hyperplasia (NCAH), hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN), and androgen-secreting neoplasms (14). Although Cushing’s syndrome, acromegaly, thyroid dysfunction and hyperprolactinaemia might be associated with hirsutism, patients usually present with other common clinical features of these disorders.

Polycystic ovary syndrome is a common and complex disorder characterized by androgen excess, ovulatory dysfunction and polycystic ovaries (15). PCOS affects 5–10% of the women of reproductive age, and over 80% of hirsute women. There are at least three currently available criteria for diagnosing PCOS. The most widely used 1990 National Institute of Child Health and Human Development (NICHD) conference diagnostic criteria includes: (1) clinical and/or biochemical signs of hyperandrogenism, (2) oligo-ovulation and (3) exclusion of other known disorders, such as Cushing’s syndrome, hyperprolactinaemia and non-classic adrenal hyperplasia (16). An expert meeting held in 2003, and sponsored by European Society of Human Reproduction and Embryology (ESHRE)/American Society for Reproductive Medicine (ASRM) suggested that the definition of PCOS should include two of the following three criteria: (1) oligo- and/or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, (3) polycystic ovaries on ultrasonography, and exclusion of related disorders (17, 18). Finally, in an attempt to provide an evidence-based definition, Androgen Excess and PCOS Society indicated that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders (19).

The aetiology(s) and genetic basis of the syndrome remain largely unknown. Patients with PCOS have several interrelated characteristics including dysregulated ovarian and adrenal steroidogenesis, altered gonadotropin dynamics, chronic anovulation, polycystic ovaries, and insulin resistance (15). It is noteworthy that insulin resistance and hyperinsulinaemia are dominant features of PCOS both in obese and lean patients, and up to 60% of patients with PCOS demonstrate varying degrees of insulin resistance (20).

The resistance to the action of insulin leads to a compensatory hyperinsulinaemia, which in turn, directly enhance luteinizing hormone-stimulated androgen secretion from the ovarian theca cells. Increased insulin levels also serve to decrease the synthesis of SHBG by the liver and reduce the circulating SHBG levels, thus resulting in higher concentrations of free androgens.

Women with PCOS typically present with clinical evidence of hyperandrogenism (e.g. hirsutism), menstrual irregularity, and infertility. In a series of pathologically diagnosed PCOS, 60–90% of the patients were hirsute, 50–90% had oligomenorrhoea, and 55–75% complained of infertility (21). Additionally, PCOS is associated with increased risk of type 2 diabetes, dyslipidaemia, cardiovascular disease (CVD), and endometrial carcinoma. Current treatment regimens are directed at reduction of hirsutism, menstrual cycle regulation, and achieving pregnancy. In addition, improvement of insulin sensitivity, weight control and prevention of long-term health consequences that attracted the most attention in the last two decades are now included in the therapeutic goals.

Hirsute patients with normal ovarian function (i.e. regular ovulation, and no polycystic ovaries on ultrasound) are diagnosed as having idiopathic hirsutism, in the absence of features that suggest other specific identifiable causes of hirsutism. Approximately 10–15% of hirsute women will have the diagnosis of idiopathic hirsutism. Although most of these patients will have normal circulating androgen levels, some will present with biochemical hyperandrogenaemia. It is important to note that routine androgen assays may not be suitable to detect mild to moderate hyperandrogenaemia. In the face of normal circulating total testosterone, a decrease in SHBG can lead to hyperandrogenism via increases in free testosterone. In many patients with idiopathic hirsutism, the activity of 5α-reductase in the hair follicle, which converts testosterone to the more potent androgen DHT, appears to be increased. Finally, available evidence suggest that up to 40% of hirsute women who claim to have regular menses actually demonstrate oligo-ovulation, and are diagnosed as having PCOS (22).

Between 1 and 5% of patients with hirsutism will have the diagnosis of NCAH. The most common form is adrenocortical 21-hydroxylase (21-OH) deficiency, resulting from the activity of the enzyme P450c21. In this autosomal recessive disorder, the precursors to 21-OH, particularly 17α-hydroxyprogesterone (17-HP) and A4, accumulate in excess. Hyperandrogenic symptoms most commonly appear in the peri- or postpubertal period. In addition to hirsutism, acne, oligo-ovulation, and polycystic ovaries may be the features. Some children might present with premature pubarche. Clinically, it is difficult to distinguish these patients from other patients with androgen excess. Biochemically, the levels of the exclusive adrenal androgen metabolite DHEAS are not any higher than those of other hyperandrogenic women. The measurement of a baseline early morning 17-HP obtained in the morning is used to screen for this disorder. The other rare forms of NCAH include deficiencies of 11β-hydroxylase (11-OH), and 3β-hydroxysteroid dehydrogenase (3β-HSD) (23).

These patients will present with marked acanthosis and extreme degrees of hyperandrogenism (24). Normal or low luteinizing hormone levels accompany increased androgen levels. Clinical distinction between HAIRAN and PCOS is not very clear, and some authors believe that HAIRAN is an extreme variant of PCOS. Nevertheless, HAIRAN is defined, in a patient with hyperandrogenism and acanthosis, by the presence of severe insulin resistance determined arbitrarily as circulating insulin levels higher than 80 μU/ml in the fasting state, and/or 500 μU/ml per ml following an oral glucose challenge. The insulin resistance is generally caused by a genetic defect in post-receptor insulin action. Many of these individuals demonstrate ovarian hyperthecosis. The ovaries are enlarged with proliferating islands of luteinized theca cells in the ovarian stroma. These ovaries tend to be less cystic in distinction to the typical polycystic ovary.

Androgen-secreting tumours, either ovarian or adrenal, are relatively rare. The onset of these tumours is usually sudden and they may rapidly lead to virilization and masculinization. Other systemic symptoms, such as weight loss and anorexia might also be observed. Functional ovarian neoplasms are usually not malignant, and include Sertoli–Leydig cell tumours and lipoid cell tumours. They are usually palpable on pelvic exam and/or associated with unilateral ovarian enlargement on imaging. Most of the androgen-secreting tumours of the adrenal gland are carcinomas, and are associated with Cushingoid features.

Biochemical suppression or stimulation tests are not recommended for the diagnosis as these tests could be misleading. Clinical presentation is the most sensitive indicator of an androgen-producing tumour. In cases of high clinical and biochemical suspicion of an adrenal or ovarian androgen-producing tumour, imaging studies and venous sampling could be of value in identifying the tumour (13).

Excessive adrenocortical function, either ACTH-dependent (Cushing’s disease, ectopic ACTH producing tumour) or ACTH-independent (adrenal adenoma) might result in hirsutism, usually associated with menstrual abnormalities. Adrenal and ovarian androgen secretion accounts for the hyperandrogenism of these patients. Direct effect of long-term cortisol excess on hair growth can not be ruled out.

This cause of hirsutism is extremely rare, although 10–15% of acromegalic women have been reported to present with hirsutism. Clinical features include signs of acral overgrowth, such as an enlargement of the hands and feet, and a coarsening of the facial features. The diagnosis is based on a determination of excessive growth hormone secretion.

A number of nonandrogenic drugs, such as phenytoin, cyclosporine, and diazoxide might result in generalized growth of body and facial hair, leading to vellus hypertrichosis. Alternatively, the use or abuse of androgenic drugs, such as danazol, and methyltestosterone may produce hirsutism in addition to amenorrhoea and liver dysfunction.

Because teleologically, hair is designed to protect the skin, any chronic skin irritation or injury has the potential to stimulate hair growth. Excessive waxing or plucking, and abuse of depilating agents can convert vellus to terminal hairs and worsen hirsutism.

Clinical distinction between hirsutism and hypertrichosis is necessary for subsequent evaluation and appropriate management. Hypertrichosis is characterized by increased hair growth in a generalized Nonsexual distribution and is not caused by androgen excess. (25). Nevertheless, some of the patients with hyperandrogenism will have excess growth of both terminal and vellus type hair.

A thorough history and a focused physical examination are essential for evaluation of the patient with hirsutism. Determination of clinical manifestations not only serves to diagnose hyperandrogenism, but it is quite helpful for the differential diagnosis of androgen excess disorders even before hormonal and biochemical work-up.

In a patient with suspected hyperandrogenism, androgenic drug or skin irritant use should be excluded. Onset and progression of hirsutism and the other features of androgen excess including acne, oily skin, or signs of virilization should be determined. Peripubertal onset of hirsutism with slow progression over several years is more consistent with nonneoplastic disorders, such as PCOS. The amount and location of the central hair growth vary, but hair growth is usually gradual in these disorders. Alternatively, rapid progression of excessive terminal hair growth with signs of virilization in a previously asymptomatic woman often raises the suspicion of androgen excess due to neoplasia. Thus, it is important to determine the onset and rate of the new hair growth.

A detailed history of menstrual pattern should be obtained. Menstrual irregularities including oligo-amenorrhoea and dysfunctional uterine bleeding may accompany hirsutism, while hirsute women can also have normal ovulatory menstrual cycles. History of galactorrhoea or symptoms of thyroid dysfunction should also be investigated. Finally, a detailed family history of endocrine, metabolic and reproductive disorders should be obtained. Hirsutism or other features of androgen excess may have occurred in members of the patient’s family.

It should be noted whether the features of hyperandrogenism truly present. Hyperandrogenism in women may present as hirsutism, acne, androgenic alopecia, or virilization. The type, pattern, and extent of excessive hair growth should be established and preferably scored by using a standardized method. Comparison of current clinical condition with a past photograph can be useful adjunct in the evaluation. A few terminal hairs on the face, areola, lower back, and lower abdomen may be normal, whereas terminal hairs on the upper back, shoulders, and upper abdomen usually results from hyperandrogenism. In hirsutism, any pattern and degree of hair growth might be observed. However, it should be kept in mind that ethnic and genetic factors play an important role on the amount and distribution of body hair. Many women complaining of unwanted hair may actually do not have hirsutism, particularly those with ethnic/genetic predisposition for some facial hair growth (e.g. South European, Mediterranean, and Middle Eastern ancestry).

In addition to evidence of hyperandrogenism, the presence of acanthosis nigricans (a velvety thickening and hyperpigmentation of the skin found on intertrigenous areas suggestive of insulin resistance), obesity, Cushingoid features (e.g. purple striae, thin skin, truncal obesity with proximal muscle weakness, moon facies, buffalo hump), blunting of facial features suggestive of acromegaly, and signs of systemic illness should be investigated.

Initial laboratory work-up of a hirsute woman includes the measurement of 17-HP levels to exclude NCAH. Prolactin and thyroid stimulating hormone (TSH) levels should be checked if oligo-amenorrhea is present to exclude hyperprolactinaemia and thyroid dysfunction respectively. If baseline 17-HP obtained during the follicular phase of the menstrual cycle is above 2 ng/ml (200 ng/dl), ACTH stimulation test should be performed for the diagnosis of NCAH. For this test, 250 µg of 1–24 ACTH is injected intravenously, and 17-HP levels are measured at 60 min. The diagnosis of 21-OH-deficient NCAH is made biochemically if the stimulated levels are greater than 10 ng/ml (1000 ng/dl).

Measurement of androgens is not routinely performed in patients with isolated mild hirsutism because hirsute women are already deemed hyperandrogenic and the added diagnostic value of these tests is limited. Measurement of total and free testosterone, and DHEAS may be recommended in moderate to severe hirsutism or hirsutism with menstrual dysfunction in order to determine the severity of androgen excess and the need for further evaluation in patients with the risk of rare androgen-producing tumours (26). Nevertheless, the best predictor for such a tumour is the clinical presentation of the patient including sudden onset and rapid progression of hirsutism and the presence of virilization.

Measurement of early morning total testosterone during follicular phase with an accurate, high-quality immunoassay or by gas or liquid chromatography, and mass spectrometry in a specialty laboratory might be sufficient for evaluation of excessive androgen production in a patient with mild to moderate hirsutism. Alternatively, free testosterone correlates better with the clinical presentation of hirsute patients with mild androgen excess. Equilibrium dialysis, ammonium sulphate precipitation to measure bioavailable testosterone or calculation of free androgen index (FAI) after measurement of total testosterone and SHBG by accurate assays are recommended methods for determination of free testosterone. Currently, available direct assays for the measurement of free testosterone are not reliable to be used in hirsute women (27).

Many women with hirsutism present with oligo- or amenorrhoea. However, as noted earlier, regular menstrual cycles (albeit anovulatory in up to 40% of the patients) could accompany hirsutism. In hirsute women with apparently regular menses, normal ovulatory function should be confirmed by obtaining a luteal phase progesterone level on D20–22 (i.e. 20–22 days after the start of menstruation). Ovulatory dysfunction may be evidenced by a luteal phase progesterone level lower than 3–5 ng/ml in a eumenorrhoeic patient. Additionally, All hirsute patients should undergo pelvic ultrasonography to check whether they have polycystic ovaries according to 2003 Rotterdam or 2006 AE-PCOS Society criteria for the diagnosis of PCOS. In a hirsute PCOS patient, a standard 75-g 2-h oral glucose tolerance test should be performed and individual cardiometabolic risk factors should be screened at diagnosis.

Combination of pharmacological therapies and cosmetic amelioration is recommended in hirsutism. Weight loss is likely to improve hirsutism in obese patients. If the underlying cause is one of the very rare disorders, standard therapies for these disorders should be undertaken. Patients should be informed from the beginning that the effect of treatment will be observed after at least 6 months and the achievement of optimal results will require 12–24 months. The primary aim of the treatment of hirsutism is to stop the development of any new terminal hairs. Hormonal therapy may also decrease the growth rate, diameter, and pigmentation of terminal hairs that are already present. However, it does not generally reverse the transformation of vellus to terminal hairs. Any terminal hairs remaining after adequate medical therapy must be destroyed mechanically.

Hirsute women usually have high levels of emotional distress and some patients will have significant psychological morbidity including anxiety and depression. Thus, education and psychological support are key elements of the overall therapeutic approach. Diagnosis, treatment alternatives, and expectations should be discussed in detail. Patients need to participate in shared decision-making regarding treatment choice that would address their concerns. Observable decrease in unwanted hair with therapy might reduce the emotional burden. Nevertheless, professional psychological counselling might be needed in severe cases.

Current treatment of hirsutism includes; (1) suppression of androgen production, (2) blockade of peripheral androgen action, and (3) mechanical means of hair removal.

Ovarian androgen suppression can be accomplished with combination contraceptives, long-acting gonadotropin-releasing hormone (GnRH) analogues, and insulin-sensitizers.

Combination (oestrogen-progestin) oral contraceptivess have been a mainstay for the treatment of hirsutism (26). The oral contraceptive suppresses the secretion of luteinizing hormone, and lead to a decrease in ovarian androgen production. The oestrogenic fraction increases the levels of SHBG, which, in turn, results in a decrease in free testosterone levels. The progestin in the pill can compete for 5α-reductase and the androgen receptor. Combined oral contraceptives have also been shown to decrease adrenal androgen production by a mechanism yet unclear, possibly due to decrease in ACTH levels.

Most combined oral contraceptives contain ethinyl oestradiol as the oestrogenic fraction. Progestins in the oral contraceptives vary in their androgenic potential and may decrease SHBG levels. Norethindrone, norgestrel and levonorgestrel are known to have androgenic activity. Alternatively, third generation newer progestins norgestimate and desogestrel are nonandrogenic and have

the advantage of less metabolic side effects, including the minimal impact on glucose, insulin, and lipids.

There are a number of combined oral contraceptives containing anti-androgenic progestins. Of those, ethinyl oestradiol and cyproterone acetate combination has been widely used in hirsutism. Other anti-androgenic progestins that are used in combination with ethinyl oestradiol include drospirenone, dienogest, and chlormadinone acetate. We should note that most of the experience with combination contraceptive therapy in hirsutism is with oral contraceptives; it is possible, however, that similar results may be obtainable with vaginal, transdermal, or percutaneous forms of combination contraceptives, although these preparations appear to have a lesser impact on circulating SHBG levels.

GnRH analogues (e.g. lupron) have been reported to be useful in treatment of hirsutism. Long-term administration of these drugs suppresses the hypothalamic-pituitary-ovarian axis and decrease ovarian androgen production. The results are not permanent and this therapy is usually combined with an androgen blocker or an oral contraceptive. Suppression of androgen production with GnRH analogues is most useful in women with very high levels of androgens due to concomitant hyperinsulinaemia, such as patients with the HAIRAN syndrome.

Insulin-sensitizers including metformin and thiazolidinediones improve hyperinsulinaemia and ovulatory function in some women with androgen excess. However, their effect on hair growth is less clear. A recent meta-analysis of available data concluded that these agents provide limited or no important benefit for hirsute patients (28).

Agents that suppress androgen production (see above) when used alone usually have modest effect on hair growth, and in most hirsute patients, peripheral androgen blockers need to be added for an adequate treatment response (29). These include androgen receptor blockers (spironolactone, cyproterone acetate, or flutamide) and a 5α -reductase inhibitor (finasteride). All these agents are similarly efficacious, and the main problem is possible side effects. All have teratogenic potential, inducing feminization of a male fetus, and therefore should be used with effective contraception. The addition of combination contraceptives to peripheral androgen blockers provides protection against the risk of unwanted pregnancy, reduces the risk of irregular menstrual bleeding, and suppresses androgen levels by a different mechanism.

Spironolactone is a potent antimineralocorticoid and a mild diuretic. It is an effective therapy for hirsutism competing with the androgens for the androgen receptor, 5α-reductase, and SHBG. It also inhibits the activity of ovarian and adrenal enzymes involved in androgen biosynthesis. Doses of 100–200 mg/day are generally used for the treatment of hirsutism. Side effects include menstrual irregularity, dyspepsia, nausea, nocturia, and headaches. If the dose is increased from 25 mg/day in a progressive fashion to 200 mg/day, patients will develop minimum side effects. Menstrual irregularity may be prevented when spironolactone is given in conjunction with a combination oral contraceptive.

Cyproterone acetate is an anti-androgenic progestin effective in treatment of hirsutism and acne. It acts mainly by competitively binding the androgen receptor. In mild to moderate cases, cyproterone acetate in a dose of 2 mg/day combined with ethinyl oestradiol generally improves the symptoms. In severe hirsutism, high doses of cyproterone acetate (up to 100 mg/day) are required for significant improvement. The side effects include mood changes, loss of libido, and weight gain.

Flutamide is an androgen receptor blocker used as an adjuvant treatment for prostate cancer. It is as effective as spironolactone in the treatment of hirsutism between doses of 125–500 mg/day, but with significantly less side effects. Careful monitoring of liver function tests is required due to the potential hepatotoxicity.

Finasteride is a competitive inhibitor of type 2 5α-reductase used for the treatment of benign prostatic hyperplasia. Although type 1 5α-reductase is prominent in the pilosebaceous unit, finasteride 5 mg daily is reported to be useful for the treatment of hirsutism.

Pharmacological agents need to be combined with appropriate mechanical/cosmetic treatments for optimal results in hirsute patients. Shaving, bleaching, or chemical depilation may be useful to temporarily ameliorate unwanted hair. Shaving does not affect the rate or duration of the anagen phase or diameter of the hair. Thus, patients can be reassured that shaving does not lead to a worsening of hirsutism. However, it can lead to a blunt hair end, which would give the false impression of a thicker hair.

Plucking or waxing are not recommended because they cause discomfort and may lead to folliculitis with the subsequent development of in-grown hair. Excessive or indiscriminate use of any depilating agent can result in chronic skin irritation.

Efluornithine is a topical irreversible inhibitor of ODC, an enzyme which catalyses follicular polyamine synthesis that is necessary for hair growth. Efluornithine hydrochloride, marketed in a 13.9% cream, has been found to reduce unwanted facial hair in women. Efluornithine does not remove the hair, but rather reduces the rate of hair growth making it much less visible and coarse. Adverse effects are usually mild and include dry skin and itching.

Electrolysis and laser epilation can be used to achieve a more permanent destruction of unwanted hairs, although long-term efficacy of these therapies is not well established. Repeated sessions of electrolysis might result in 20–50% permanent hair loss, which may take months to years (30). Laser epilation, a technique of selective phototermolysis, is also available for the treatment of hirsutism. A recent meta-analysis of the available 11 randomized controlled trials involving 444 subjects reported that laser epilation has a short-term effect of about 50% hair reduction up to 6 months after final treatment (31). Laser epilation appears to be more effective for hirsute women with dark hair and light skin. Side effects that include scarring and discoloration might be observed after electrolysis or laser epilation.