Abstract
Hirsutism in women is defined as an excess of body hair in the androgen-sensitive skin regions. The different genetic backgrounds of various populations may affect the causes of hirsutism. In fact, the most important reason for investigation is to identify those women with androgen-secreting tumors, since they require different therapy. Hirsutism may have various causes, such as polycystic ovary syndrome, enzyme defects in adrenal steroid biosynthesis, Cushing's syndrome, acromegaly, ovarian or adrenal tumors, or it may be idiopathic. In most patients, hirsutism is associated with hyperandrogenemia and the most common cause of androgen excess is polycystic ovary syndrome. Androgen-secreting tumors should be suspected when the onset and progression of hirsutism is rapid and/or when it is associated with virilization. Patients should be informed about the type and duration of therapy. The selection of drug/drugs depends on the severity of the hirsutism, associated conditions such as menstrual irregularities, systemic disorders such as diabetes mellitus, hypertension and any contraindication to possible therapeutic agents. Diane® 35 is the most common drug used for the suppression of ovarian androgen production. Peripheral blockade of androgen actions, by using spironolactone, finasteride or flutamide on the skin, is also effective in the treatment of hirsutism.
Hirsutism is defined as an excess of body hair in the androgen-sensitive skin regions of women. It is a common clinical problem in women and the treatment depends on the cause. Hirsutism affects 5–8% of the total female population of fertile age and may be associated with underlying endocrine and metabolic disturbances or may be the initial manifestation of an androgen-secreting tumor [1]. Hirsutism results from an increase in circulating androgen concentration, an increase in the sensitivity of the pilosebaceous unit (PSU) to normal androgen concentrations or a combination of these factors [2]. The management of hirsutism involves a range of diagnostic and therapeutic issues and it is particularly essential to identify the underlying cause of the disorder.
Diagnostic approach to the hirsute patient
Differences in the genetic background of various populations may affect the causes of hirsutism [3,4]. In fact, the most important purpose of investigation is to identify those women with androgen-secreting tumors, as they require different therapy. Hirsutism should be distinguished from hypertrichosis, which is an excess of vellus hair. Vellus hairs are short, soft, fine and usually nonpigmented. Terminal hairs are long, coarse, medullated and pigmented [5]. Hypertrichosis may be associated with anorexia nervosa, hypothyroidism and with some drugs such as cyclosporin, phenitoin and diazoxide [6,7].
The modified Ferriman–Gallwey scoring system [8] is commonly used for evaluation and also for monitoring the treatment of hirsutism. In this scoring system, hair growth at different body sites (e.g., upper lip, chin/face, chest, upper and lower back, upper and lower abdomen, arm and thigh) is evaluated. In each area, absence of terminal hairs (score 0) to extensive terminal hair growth (score 4) scores are assigned. Scoring hirsutism requires experience, and a score of 8 or more is accepted as hirsutism. Hirsutism may result from various causes (Table 1). Polycystic ovary syndrome (PCOS), enzyme defects in adrenal steroid biosynthesis, Cushing's syndrome, acromegaly, some drugs, ovarian tumors and adrenal tumors may be the underlying causes, or it may be idiopathic [1,9]. A detailed history, including medications, menstrual and reproductive history, the onset and the progression of hirsutism, acne and hair loss should be obtained. In addition to regular physical examination, the amount and distribution of excessive hair should be recorded. The presence/absence of some associated abnormalities such as galactorrhea, virilization (which is characterized by cliteromegaly, deepening of the voice and male-type musculature), body fat content and distribution or Cushingoid features should be noted. The hormonal status of the patient should be established during the follicular phase of the menstrual cycle (Table 2).
Cardinal features of the most common diseases associated with hirsutism.
17-OHP: 17-hydroxyprogesterone; DHEAS: Dehydroepiandrosterone sulfate; NCAH: Nonclassic adrenal hyperplasia
PCOS: Polycystic ovary syndrome.
Suggested laboratory investigations in women with hirsutism.
17-OHP: 17-hydroxyprogesterone; ACTH: Adrenocorticotrophic hormone
DHEAS: Dehydroepiandrosterone; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone
NACH: Nonclassic adrenal hyperplasia.
In most patients, hirsutism is associated with hyperandrogenemia and the most common cause of androgen excess is PCOS. PCOS remains a diagnosis of exclusion of specific disorders of the ovaries, adrenal glands and pituitary gland (Box 1) [10]. In women with PCOS, provacative testing using a gonadotrophin-releasing hormone (GnRH) analog has shown an ovarian source of hyperandrogenemia characterized by an elevated 17-α-hydroxyprogesterone (17-OHP) response. GnRH analogs, including buserelin, are potent and specific stimulators of the pituitary–gonadal axis. It has been suggested that ovarian 17-hydroxylase activity is increased in most cases of PCOS as evidenced by an exaggerated 17-OHP secretion after acute GnRH stimulation. The 17-hydroxylase enzyme has two activities: hydroxylase and lyase. Due to a relatively increased hydroxylase activity when compared with lyase activity, 17-OHP level is increased after buserelin test. Buserelin test gives information about ovarian steroidogenesis [11]. The presence of hirsutism from peripubertal ages with low progression is generally consistent with PCOS. The pathogenesis of PCOS is heterogeneous, but insulin resistance may have a central role in most patients [12,13]. In the ovary, the cardinal feature is functional hyperandrogenism, which leads to anovulation, hirsutism and infertility. In accordance with insulin resistance, women with PCOS have metabolic disturbances such as impaired glucose tolerance, dyslipidemia and cardiovascular disease.
In 1–8% of women with hirsutism, the underlying cause of the disease is nonclassic adrenal hyperplasia (NCAH). It results from a defect in the enzymes necessary for the biosynthesis of cortisol and/or aldosterone [14]. The clinical picture is very similar to the clinical presentation of PCOS in terms of the onset and progression of symptoms. It has been suggested that the most common form of NCAH is 2-hydroxylase (21-OH) deficiency [15]; however, it has previously been reported that NCAH due to 11-β hydroxylase (11-β OH) deficiency may be more common in some populations [16]. 21-OH deficiency may be diagnosed by the measurement of a basal 17-OHP level. If the 17-OHP level is over 2 ng/ml, the patient should undergo an adrenocorticotropic hormone (ACTH) stimulation test [17]. An ACTH stimulated 17-OHP concentration of more than 30 nmol/l was considered as the criteria for NCAH due to 21-OH deficiency [18], although it would be better if the gene mutations were confirmed by molecular biology studies. The diagnosis of 11-β OH deficiency was made if the adrenal 11 deoxycortisol (11-S) response to ACTH stimulation exceeded threefold the 95th percentile of controls [15]. Patients with late-onset NCAH can be indistinguishable from those with PCOS.
Some hirsute patients do not show evidence of detectable androgen excess or endocrine imbalance, as in women with idiopathic hirsutism (IH). IH can be diagnosed in hirsute patients who have normal serum androgen levels and regular menstrual cycles. Until now, the pathogenesis of IH could not be clearly established. Currently, the pathophysiology of IH is presumed to be a primary increase in skin 5α-reductase activity and, possibly, an alteration in androgen receptor function [19]. On the other hand, the authors have shown that, although the serum androgen levels were considered normal, patients with IH had significantly higher free testosterone levels and lower estradiol levels than healthy women. In other words, the ratio of estradiol to testosterone, which is the product of aromatase activity, is lower in patients with hirsutism. It is possible that an inbalance between these hormones may have a pathogenic role in IH and these patients were considered to be hyperandrogenic at tissue level [20].
A number of patients have hyperandrogenemia with normal ovaries and regular cycles. These patients present with different features, and other disorders, such as NCAH, androgen-secreting tumors and Cushing's syndrome, can be easily excluded. These patients also exhibit similar basal follicle-stimulating hormone (FSH), luteinizing hormone (LH), free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS) levels compared with PCOS subjects. The authors have defined these patients as having idiopathic hyperandrogenemia (IHA) [3]. This group of patients may have functional ovarian and/or adrenal hyperandrogenism [3,21].
Androgen-secreting tumors are relatively rare. These tumors usually arise from the ovaries or adrenal glands. It has been suggested that ovarian androgen-secreting tumors are associated with serum testosterone concentrations of greater than 200 ng/dl [22]. However, there is no clear-cut level of androgen concentration for the differential diagnosis of benign versus malign etiologies, and androgen-secreting tumors should be suspected when the onset and progression of hirsutism is rapid and/or when it is associated with virilization. Some ovarian tumors may be too small to be shown easily by imaging techniques. Further investigations such as venous sampling may be necessary when a high clinical suspicion exists.
Treatment of hirsutism
Patients should be informed about the type and duration of therapy. Generally, more than 6 months of treatment are necessary in order to evaluate the success of medical therapy. The treatment of hirsutism involves the prevention of excessive androgen secretion and/or the blockade of androgens. In addition, mechanical amelioration of the unwanted hairs may be adjunctive. The selection of drug/drugs depends on the severity of the hirsutism score, associated conditions such as menstrual irregularities, systemic disorders such as diabetes mellitus and hypertension, and any contraindications to possible therapeutic agents. Patients should be aware that most of the drugs used in the management of hirsutism are contraindicated in women desiring pregnancy and simultaneous treatment of infertility and hirsutism is difficult.
Diagnostic criteria for polycystic ovary syndrome.
Chronic oligo-anovulation
Clinical and/or biochemical evidence of hyperandrogenism
Polycystic ovarian changes
Exclusion of other etiologies (e.g., Cushing's syndrome, congenital adrenal hyperplasia and androgen-secreting tumors).
Require two out of the first three.
Adapted from [10].
PCOS is the most common cause of hirsutism. Nearly 70% of women with PCOS are obese and should be encouraged to lose weight. Obesity has clear effects on the metabolic and gynecologic aspects of the disease and even modest (5%) weight loss has been shown to have a beneficial effect. Oral contraceptive pills (OCPs) are the most common drugs used for the suppression of ovarian androgen production [23]. Estrogen in OCPs increases sex hormone-binding globulin (SHBG) levels and thereby decreases free testosterone levels. Among OCPs, those containing a progestin with low androgenic activity may be preferable. Drospirenone, an analog of spironolactone with unique antimineralocorticoid and antiandrogen activities, is potentially ideal for the treatment of women with PCOS. However, controversy persists regarding the use of OCPs as first-line therapy in women with PCOS due to their potential adverse effects on insulin resistance and glucose tolerance. Diane® 35, which contains cyproterone acetate, has a specific antiandrogen activity. Diane 35 may be used alone or in combination with antiandrogens such as finasteride [24] or spironolactone [25]. Side effects of the OCPs include weight gain and breast tenderness, and they are contraindicated in women with a history of venous thrombosis. Addition of spironolactone or finasteride to Diane 35 has been shown to have a synergisitic effect on hirsutism without increased side effects. Women with PCOS who are also oligomenorrheic may benefit from OCPs alone or in combination with antiantiandrogens.
GnRH agonists, used in a continuous manner, decrease gonadotropin secretion and ovarian steroid secretion. However, its parenteral administration and high cost confines its widespread use in the treatment of hirsutism.
Peripheral blockade of androgen action at the skin is also effective in the treatment of hirsutism. 5-α reductase inhibitors reduce the conversion of testosterone to the more potent dihydrotestosterone. Finasteride has been used in the treatment of hirsutism at various doses [26,27]. It has teratogenic potential and should be used with effective contraception.
Spironolactone is an androgen receptor antagonist with some inhibitory effects on androgen production. It is generally effective at doses of 50–200 mg. The most common complaints are polymenorrhea, gastrointestinal disturbances and dizziness [28]. It has been shown that a combination of two antiandrogens with different mechanisms of action may be used in women with hirsutism [29].
Flutamide is a nonsteroidal antiandrogen. In comparison to spironolactone and finasteride it has a lower safety profile and serious liver toxicities have been reported, particularly at high doses. Low or ultra-low doses of flutamide (62.5–250 mg/day) have been shown to be effective in the treatment of hirsutism and, particularly when combined with metformin plus an OCP, were found to confer benefit on multiple PCOS markers such as interleukin-6, adiponectin and abdominal and total fat mass without any hepatotoxicity [30–32].
During the last two decades, it has been shown that women with PCOS have some degree of insulin resistance and associated hyperinsulinemia [33–35]. Hyperinsulinemia results in reduced SHBG levels and increased testosterone levels from theca cells, which act as a cogonadotropin. Treatment of insulin resistance, primarily by lifestyle modifications or insulin sensitizers (e.g., metformin, pioglitazone or rosiglitazone), has been demonstrated to improve hyperandrogenemia and ovulatory function in many women with PCOS. Due to the relatively fewer side effects and some safety issues during pregnancy, metformin should be the first choice among insulin sensitizers [35–37]. It has been suggested that treatment of insulin resistance reverses the underlying pathophysiology of the disease and may be the treatment of choice alone or in combination with antiandrogens [38–40]. However, its effectiveness in the treatment of PCOS-associated hirsutism is controversial [41,42].
Patients with NCAH have a similar clinical presentation to those with PCOS. Routine use of a short ACTH test in daily practice cannot be recommended, since treatment of hirsute women with NCAH is not influenced by the diagnosis. These patients do not need protection against stress-related glucocorticoid deficiency and antiandrogens work well in the treatment of hirsutism [43].
Cosmetic measures play an adjunctive role in the treatment of hirsutism. Bleaching, by using hydrogen peroxide in most cases, will soften and oxidise the unwanted hair [44]. Plucking may be used in areas where little hair is present, although it may result in pain and skin irritation. Electrolysis is a form of permanent hair removal. The hair follicle is destroyed using an electric current and then hair is removed [45]. Laser therapy has been used to induce a prolonged telogen phase and delay hair growth [46]. All these treatments might be more effective when used in conjunction with antiandrogen therapy. In very mild cases, they represent the mainstay of treatment.
Conclusion
Hirsutism has a strong negative impact on the psychosocial status of the patient and sometimes, as in androgen-secreting tumors, may be a sign of serious malign disease. However, in most patients, PCOS is the underlying cause. Drugs that aim to reduce serum androgen concentrations and/or block the effects of the androgens are most commonly used. Adult women with PCOS have increased prevalence of impaired glucose tolerance (IGT) or Type 2 diabetes mellitus, which are independent risk factors for cardiovascular disease. Accordingly, there has been increased interest in identifying individuals at risk for IGT. Women with PCOS should be periodically screened for the presence of IGT or diabetes due to increasing glucose intolerance over time.
Future perspective
Unfortunately, most of the treatment strategies in hirsutism are symptomatic. Ideally, treatment should be directed at the cause of the problem. With this in mind, clinical and experimental studies have been published for identifying the pathophysiologic mechanisms of hirsutism in women with PCOS and it has been shown that insulin resistance has a significant role. Women with idiopathic hirsutism represent another group of patients. The mechanisms of the disease are not clearly known, but the authors' studies and experience suggest that these patients are hyperandrogenic at the tissue level and it may be a very early stage or mild form of PCOS. These patients, particularly those who are obese, also show some degree of insulin resistance. By establishing the pathogenetic mechanisms underlying the causes of hirsutism, new therapeutic strategies may play an important role in offering more effective therapies.
Executive summary
Hirsutism is a common clinical problem with various underlying causes. It affects 5–8#x0025; of premenopausal women and polycystic ovary syndrome (PCOS), idiopathic hirsutism and nonclassic adrenal hyperplasia are the most common causes.
Apart from patients with ovarian or adrenal androgen-secreting tumors, the clinical picture is very similar among patients with varying causes. Androgen-secreting tumors should be suspected when the onset and progression of hirsutism is rapid and/or when it is associated with virilization. In patients with benign causes, the symptoms begin from peripubertal ages with low progression.
Medical history, including the onset and the progression of hirsutism, menstrual and reproductive history should be obtained.
Physical examination including the scoring of hirsutism, evaluation of acne, hair loss, galactorrhea, virilizing symptoms, obesity and Cushingoid features should be noted.
Hormonal status of the patient (unless clinical suspicion requires other hormones) including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, testosterone, dehydroepiandrosterone sulfate (DHEAS) and 17-a-hydroxyprogesterone (17-OHP) should be established during the follicular phase of the menstrual cycle.
Most of the treatment strategies in hirsutism are symptomatic.
Before starting any kind of medication, the physician should exclude androgen-secreting tumors.
For other causes, oral contraceptive pills and antiandrogen drugs, either alone or in combination, may be given.
Weight loss should be encouraged in obese women.
Women with PCOS who have features of the metabolic syndrome may experience beneficial effects from metformin.
Cosmetic measures only play an adjunctive role in most patients.