Non polycystic ovary syndrome–related endocrine disorders associated with hirsutism

Authors


Prof Dr Fahrettin Kelestimur, Department of Endocrinology, Erciyes University Medical School, 38039, Kayseri, Turkey. Tel.: + 90 352 437 49 37; fax: + 90 352 437 49 31; e-mail: fktimur@erciyes.edu.tr

Abstract

Eur J Clin Invest 2012; 42 (1): 86–94

Abstract

Background  Hyperandrogenism refers to classical androgen-dependent signs such as hirsutism, acne and androgenetic alopecia. Hirsutism is the main hyperandrogenic symptom, defined as an excess of body hair in the androgen-sensitive skin regions of the women. In this review, we attempt to focus on the pathogenesis of hirsutism related to disorders other than polycystic ovary syndrome (PCOS). Also, we will discuss their clinical and biochemical features as well as therapeutic options.

Design  Several original articles, meta-analysis and reviews have been screened in the field of hirsutism and hyperandrogenic disorders.

Results  Current English literature including our studies suggests that PCOS is the most common cause of hirsutism. The most important purpose for investigation is to identify those women with androgen-secreting tumours because of their life-threatening potential. In approximately 1–8% of the women with hirsutism, the underlying cause is nonclassical adrenal hyperplasia because of 21-hydroxylase deficiency. Depending on ethnicity and the geographic area, idiopathic hirsutism constitutes 5–17% of the patients with hirsutism. Approximately 3% of hyperandrogenic women were observed to suffer from hyperandrogenic-insulin-resistant acanthosis nigricans syndrome. More rare causes are glucocorticoid resistance syndrome, hyperprolactinemia, acromegaly, Cushing’s syndrome and some drugs. Specific causes of hirsutism such as Cushing’s syndrome and adrenal/ovarian tumours should be treated specifically. In other patients, pharmacological approach is the mainstay of therapy.

Conclusions  A number of patients presenting with hirsutism and exhibiting similar features to PCOS may have other underlying diagnoses. Unlike PCOS, some of these disorders can occasionally be life threatening and require prompt diagnosis and treatment.

Introduction

Hyperandrogenism/hyperandrogenemia is the most common endocrinopathy among women of the reproductive age, and it comprises a heterogeneous group of disorders [1]. Hyperandrogenism refers to classical androgen-dependent signs such as hirsutism, acne, androgenetic alopecia (AGA) and seborrhoea [2]. Hirsutism is the main hyperandrogenic symptom defined as an excess of body hair in androgen-sensitive skin regions of women [3]. Hirsutism results from an increase in circulating androgen concentrations, an increase in the sensitivity of the pilosebaceous unit [PSU] to normal androgen concentrations or a combination of these factors [4]. A modified Ferriman-Gallwey scoring system [5] is commonly used for the evaluation and treatment of hirsutism. In this scoring system, hair growth at different body sites (upper lip, chin/face, chest, upper and lower back, upper and lower abdomen, arm, thigh) is evaluated. In each area, absence of terminal hairs (score 0) to extensive terminal hair growth (score 4) is assigned. Scoring hirsutism requires considerable experience and a score of 8 or more is accepted as indicative of hirsutism. Acne and AGA may also be considered as a sign of androgen excess, particularly in the presence of other androgen-dependent signs and irregular menses. The great majority of women presenting with hirsutism and other symptoms/signs of hyperandrogenism suffer from polycystic ovary syndrome (PCOS) [1,6]. However, it is important to have an index of clinical suspicion to identify the minority of patients that may harbour another pathology that can occasionally be life threatening.

Depending on the severity of androgenization, signs of virilization, an uncommon clinical finding of androgen excess, may also be seen. This condition is usually associated with remarkably elevated serum androgen levels and is characterized by AGA, clitoromegaly, deepening of the voice, increased muscle mass and decreased/atrophic breast size.

Although hyperandrogenism is a common finding among women of the reproductive age [7], there is wide heterogeneity in its expression in such women. In addition, the degree and distribution of androgen-dependent signs do not indicate any specific cause of hyperandrogenism. Furthermore, clinical manifestations of hyperandrogenism may be observed in the presence of normal serum androgen levels. In this review, we attempt to focus on the pathogenesis of hirsutism/hyperandrogenism that is related to disorders other than PCOS and discuss their clinical, biochemical features and therapeutic options of hirsutism. As there are currently several review papers [8,9] highlighting the pathogenesis, diagnosis and treatment of PCOS, we will not cover this issue.

Mechanisms of hair growth

There are three phases of hair growth. An active growing phase (anagen); followed by an involutional stage (catagen), in which the hair stops growing and the hair bud shrinks; and finally, the telogen phase in which the hair is resting and then sheds, as new hair displaces it [10]. Sex steroids and a number of local and systemic factors can act directly and indirectly on dermal papilla to regulate hair growth. Various growth factors and cytokines have been observed to affect hair growth, and it has been suggested that these factors operate by increasing the synthesis of stromolysin, a matrix metalloproteinase that acts on the dermal papilla to accelerate growth [11–14]. Hormones such as thyroid and growth hormone (GH) can also alter hair growth [15–17]. Among the sex steroids, androgens are the most important determining the type and distribution of hairs over the human body. Under the influence of androgens, hair follicles that are producing vellus-type hairs can be transformed to terminal hairs. Additionally, androgens prolong the anagen phase of body hairs, while shortening the anagen phase of scalp hairs which eventually leads to hirsutism and alopecia [18]. It should be noted that sex steroids may act on the hair follicle independently of their circulating levels.

The effect of androgens on the development of terminal hairs is mediated through 5-alpha reductase (5α-R) activity which is the product of the function of two distinct isoenzymes, type 1 and type 2 5α-R, distributed widely throughout the body [19]. Both types of 5α-R can be localized to the outer root sheath of the hair follicle. The activity of local 5α-R activity determines the production of dihydrotestosterone (DHT) and consequently the effect of androgens on hair follicles. In body hair, DHT stimulates increased sebum production, the differentiation of the hair follicle from vellus to terminal hairs and the prolongation of the anagen phase resulting in longer thicker hairs.

Causes of hyperandrogenism

The management of hyperandrogenism involves a range of diagnostic and therapeutic issues and it is therefore essential to identify the underlying cause of hyperandrogenism. Hirsutism affects 5–8% of the whole female population of the reproductive age, and it may be associated with underlying endocrine and metabolic disturbances or may be the initial manifestation of potentially life-threatening disease such as androgen-secreting tumours [1,3,20]. Although PCOS is responsible for the most of the cases of hyperandrogenism, a number of other pathologic entities can be present with hirsutism either alone or associated with other symptoms/signs of hyperandrogenism and/or other symptoms/signs suggestive of a specific disease (Table 1).

Table 1.   Causes of hyperandrogenism
Frequent causes
 Polycystic ovary syndrome
 Idiopathic hirsutism
 Non-classical adrenal hyperplasia
 Idiopathic hyperandrogenemia
Rare causes
 Adrenal/ovarian tumours
 Cushing’s syndrome
 Acromegaly
 Hyperprolactinemia
 Hyperandrogenic-insulin-resistant acanthosis nigricans syndrome
 Hyperthecosis
 Glucocorticoid resistance syndrome
 Drugs

Clinical evaluation

A detailed history and physical examination is essential for the evaluation of hyperandrogenism taking into consideration specific variations mainly because of differences in the genetic background of the various populations affected by hirsutism [1,3,6,21]. The most important purpose for investigation is to identify those women with pathologies that can be potentially life threatening owing to either their systemic effects or malignant potential. Apart from adrenal/ovarian tumours, there are numerous disorders of androgen excess in women including PCOS, non-classical congenital adrenal hyperplasia (NCAH), idiopathic hyperandrogenemia (IHA), Cushing’s syndrome, acromegaly, some drugs or it may be idiopathic [3,21]. A practical diagnostic approach has been given in Fig. 1.

Figure 1.

 Diagnostic approach to hyperandrogenism.

A detailed history including medication, 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 the distribution of the excessive hair should be recorded. The presence/absence of some associated abnormalities such as galactorrhoea, virilization, body fat content and distribution, and presence of Cushingoid features should be noted.

Hirsutism must be differentiated from hypertrichosis which refers to vellus-type hair growth all over the body which does not reflect hyperandrogenism. Vellus hairs are short, soft, fine and usually non-pigmented. Terminal hairs are long, coarse, medullated and pigmented [5,22]. Hypertrichosis is characterized by increased hair growth located in nonandrogen-dependent area and may be encountered in anorexia nervosa, hypothyroidism, administration of drugs such as cyclosporin, phenytoin and diazoxide or it may be a paraneoplastic manifestation, a condition called hypertrichosis lanuginosa [23]. However, some patients exhibit both hirsutism and hypertrichosis; in these cases, clinical expression of hirsutism is more severe than its actual hirsutism score.

Differential diagnosis and laboratory evaluation in nonpolycystic ovary syndrome–related hirsutism

After obtaining a detailed medical history and performing physical examination, basal hormonal and ultrasonographic examination of the ovaries and the adrenal glands is a useful screening procedure. If the symptoms suggest the presence of a neoplasm with negative ultrasonographic imaging, computerized tomography of the adrenal glands or the ovaries should be obtained. A correct aetiological diagnosis is essential in order to exclude life-threatening conditions such as androgen-secreting tumours or the lifelong consequences of some disorders associated with hirsutism such as PCOS and NCAH. Thus, certain tests must be conducted to ascertain properly the aetiology of hirsutism. Approach to a patient with hirsutism has been shown in Fig. 2. However, there is no universal consensus regarding the least required tests for the differential diagnosis of hirsutism. Hormonal status of the patient should be established during the follicular phase of menstrual cycle. The initial laboratory investigations include free androgen index, thyroid function tests, prolactin and 17-hydroxyprogesterone (17-OHP) levels. Cushing’s syndrome should be excluded in patients with possible diagnosis of PCOS in the presence of clinical suspicion and appropriate tests should be employed.

Figure 2.

 Evaluation of patients with hirsutism.

In approximately 1–8% of the women with hirsutism, the underlying cause of the disease is NCAH based on ethnicity and the geographic area of the study [24,25]. The clinical presentation of NCAH and PCOS shares many features including oligo-amenorrhoea, hirsutism, hyperandrogenemia, acne and infertility. Although 21-hydroxylase (21-OH) deficiency represents the most common form of NCAH [25–27], it has been previously reported that NCAH because of 11-beta hydroxylase (11-β OH) deficiency may be more common in some populations [28]. 21-Hydroxylase deficiency may be diagnosed by the measurement of a basal 17-OHP level. If the 17-OHP level is more than 2 ng mL−1, the patient should undergo an adrenocorticotropic hormone (ACTH) stimulation test [29]. Basal 17-OHP levels are not strong enough criteria to diagnose all patients with 21-OH deficiency, and to enhance screening efficiency, ACTH stimulation test has been advocated [26]. An ACTH stimulated 17-OHP concentration greater than 10 ng mL−1 was considered as the criteria for NCAH because of 21-OH deficiency [26,30,31], although it has recently been advocated that gene mutations should be confirmed by molecular biology studies. It has been shown that nearly 100% had peak 17-OHP levels above 10 ng mL−1 regardless of the type of mutation.

Being heterozygotic carrier is an another important aspect of the disease, and the specificity of ACTH test is slightly reduced by a few healthy patients carrying usually severe heterozygous mutations that have peak 17-OHP levels above the cut-off value [26,32]. It should be noted that being heterozygotic carrier may not be clinically silent because it has been shown that there is an increased risk for androgen excess in carriers of CYP 21 mutations [32]. Witchel et al. [33] performed a study among the relatives of patients with congenital adrenal hyperplasia to determine the sensitivity of ACTH stimulation test to detect heterozygotes and to correlate stimulated 17-OHP responses with molecular genetic analysis of the CYP21 gene. Of 51, molecular genetic analysis classified 28 individuals as heterozygotic carriers and 23 individuals as normal for all mutations tested. As a group, the heterozygotes had significantly greater stimulated 17-OHP responses to ACTH test; however, on an individual basis, 14/28 (50%) genotyped heterozygotic carriers had stimulated 17-OHP responses were indistinguishable from the genotyped normal individuals. From clinical point of view, this means that if normal 17-OHP responses to ACTH test were interpreted to indicate noncarrier status, inaccurate genetic counselling would have ensues. Overall, there is currently no consensus regarding systematic screening of the population of women with signs of hyperandrogenism for NCAH, given the lack of clear-cut evidence for the medical benefit and cost-effectiveness of such policy.

Some patients with hirsutism do not have evidence of detectable androgen excess or endocrine imbalance, as in women with ‘idiopathic hirsutism’. Idiopathic hirsutism (IH) can be diagnosed in patients with hirsutism who have normal serum androgen levels and regular menstrual cycles. Depending on ethnicity and the geographic area, IH constitutes 5–17% of the patients with hirsutism [34–36]. Until now, the pathogenesis of IH has not been elucidated. Currently, the pathophysiology of IH is presumed to be secondary to an increase in skin 5α-reductase activity and/or alteration in androgen receptor function [37]. Vottero et al. [38] showed that skewing of X-chromosome inactivation may lead to higher expression of more potent androgen receptor molecules, conferring hypersensitivity to the skin of hirsute women. Additionally, it has been shown that patients with IH had significantly higher free testosterone levels and lower estradiol levels than healthy women. It has been suggested that the ratio of estradiol to testosterone, which is the product of aromatase activity, is lower in patients with IH and that such an imbalance may have a pathogenic role in IH as these patients are considered as hyperandrogenic at the tissue level [39].

A number of patients have hyperandrogenemia with normal ovarian morphology and regular cycles. These patients also exhibit similar hormonal features to PCOS subjects and are named as IHA [21]. This group of patients may have functional ovarian and/or adrenal hyperandrogenism [3,40,41].

Insulin resistance is associated with some disorders, either inherited or acquired, which may result in acanthosis nigricans, ovarian hyperandrogenism and menstrual dysfunction. One of the important causes of insulin resistance is obesity. There is a vicious circle of abdominal obesity, insulin resistance and hyperandrogenemia. In many cases, whatever the origin of (severe) insulin resistance, in vivo hyperinsulinemia has been clearly shown to promote ovarian androgen synthesis independent of gonadotropins.

Apart from type A and type B insulin resistance syndromes, a number of patients suffering from hyperandrogenic-insulin resistant acanthosis nigricans (HAIR-AN) syndrome have been described [42,43]. The type A syndrome of severe insulin resistance is typically recognized in adolescent girls who are seen for the evaluation of hirsutism or menstrual irregularities. Classical type A syndrome is characterized by a defect in the function of the insulin receptor or rarely postreceptor defects that alter the signal transduction system for insulin action. These patients are frequently seen in endocrine clinics for the evaluation of infertility and hirsutism [44]. Type B syndrome of severe insulin resistance is an autoimmune syndrome caused by circulating antibodies directed at the insulin receptor. Because of insulin resistance and endogenous hyperinsulinemia, patients with type B syndrome have some clinical features seen in patients with type A syndrome including acanthosis nigricans, hirsutism, oligomenorrhea and hyperandrogenism [45]. Approximately 3% of hyperandrogenic woman suffer from HAIR-AN syndrome that is considered as a distinct subgroup of hyperandrogenic patients with severe metabolic abnormalities [43]. Another entity that is related to ovarian hyperandrogenism is hyperthecosis. It may account for the majority of cases of postmenopausal hyperandrogenemia, and virilization may be seen [46,47].

Androgen-secreting tumours are relatively rare, and they are one of the most important issues in the differential diagnosis of hirsutism. These tumours usually arise from the ovaries or the adrenal glands. It has been suggested that ovarian androgen-secreting tumours are associated with serum testosterone concentrations > 200 ng dL−1 [48]. However, there is no clear-cut level of androgen concentrations for the differential diagnosis of benign vs. malign aetiologies. Some tumours may run an indolent course with subtle symptoms resembling those of patients with nontumorous hyperandrogenism. Adrenal or ovarian tumours should be suspected when there is worsening of their clinical and hormonal features despite treatment, and in such cases, low-dose dexamethasone suppression test (LDDST) for 48 h may help for differential diagnosis. It has been suggested that women presenting with hyperandrogenism, lack of testosterone suppression (> 40% suppression or normalization of serum testosterone) during the LDDST is associated with 100% sensitivity and 88% specificity in distinguishing patients with ovarian and adrenal androgen-secreting tumours from patients with nontumorous hyperandrogenism [49]. A rapidly progressive onset of hyperandrogenism, particularly in postmenopausal women and/or development of frank virilization, suggests an androgen-secreting tumours arising either from the ovaries or from the adrenal glands. Functional ovarian tumours may include sertoli–leydig cell tumours and some granulosa cell tumours. Some ovarian tumours may be too small and cannot be shown by imaging techniques easily. Further investigations such as venous sampling may be necessary when a high clinical suspicion exists [50]. Androgen-secreting adrenal tumours, mostly carcinomas, are usually associated with the development of Cushingoid features and can be diagnosed as a typically large (> 6 cm) on ultrasound or adrenal computerized tomography. Increased production of adrenal androgens including DHEAS has been shown in patients with carcinoma than that in adenoma [51].

Glucocorticoid resistance syndrome (GRS; also known as Chrousos syndrome) is characterized by reduced cortisol effects because of glucocorticoid receptor defect, which is compensated by hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis [52]. As a consequence, patients present with signs of adrenal overproduction of mineralocorticoid, and in women, hyperandrogenic symptoms occur. The clinical spectrum of the GRS is broad, ranging from most severe to mild forms although a number of patients may be asymptomatic. Women may present with ambiguous genitalia, clitoromegaly, premature adrenarche, hirsutism, acne and menstrual dysfunction. Absence of clinical features of Cushing’s syndrome in the presence of increased serum cortisol and ACTH levels and resistance of the HPA axis to dexamethasone suppression are characteristics of the disease [52–54].

It has been suggested that hyperprolactinemia may be associated with hirsutism, and it is involved among the differential diagnosis of hirsutism. Hagag et al. [55] evaluated 80 hirsute hyperprolactinaemic women with neuroleptic treatment, prolactinoma and idiopathic hyperprolactinemia. During the 11 months of treatment with dopamine agonists, hirsutism scores, serum DHEAS and free testosterone levels decreased. The authors suggest that hyperprolactinemia can modulate adrenal androgen production, and its treatment results in improvement in acne and hirsutism. However, hirsutism because of prolactinoma is not a common condition. Thyroid dysfunction is considered in the differential diagnosis of hirsutism; however, hypothyroidism is more associated with coarsening of the hair rather than true hirsutism through androgen excess. Acromegaly is another rare cause of hirsutism. PCOS is relatively common in women with acromegaly, and it has been suggested that it may account for some of the symptoms related to gonadal dysfunction irrespective of the size of the pituitary tumour and it is likely that IGF-1 alone or in combination with GH and/or insulin resistance may be involved [56].

Some drugs may also cause hirsutism, e.g. danazol, valproic acid (VPA; which is an important anticonvulsant drug that raises serum testosterone levels), anabolic and androgenic steroids (which are mostly taken by athletes and patients with endometriosis). Isojarvi and colleagues [57] reported an increased prevalence of PCOS among women with epilepsy treated by VPA. They reported that 80% of women who were treated with VPA prior to the age of 20 years had polycystic ovaries or hyperandrogenism [57].

Metabolic abnormalities in women with hirsutism

Hyperandrogenism and lipid metabolism were shown to be related intimately. Despite the many correlations between hyperandrogenemia and metabolic abnormalities, the appropriate sequence in the pathogenesis of these conditions has not been fully defined. Women with hyperandrogenism are thought to be at greater risk for cardiovascular morbidity and mortality than their normoandrogenic counterparts [58]. These women often are obese and hypertensive and have glucose intolerance and/or insulin resistance. All these abnormalities are well-known independent risk factors for the development of lipid abnormalities and cardiovascular disease [59]. Among women with hirsutism, metabolic abnormalities have consistently been shown in women with PCOS. Compared with normal subjects, patients with classical congenital adrenal hyperplasia have an increased incidence of obesity and visceral adiposity, hyperinsulinism and insulin resistance, hyperleptinemia, hypertension and hyperandrogenism [60]. It is likely that intermittent treatment-related hypercortisolism may account for the above abnormalities and may predispose these subjects to the development of metabolic syndrome-related endothelial dysfunction and atherosclerotic cardiovascular disease in adulthood.

Treatment strategies for hyperandrogenic women should not only be directed towards alleviation of the cosmetic problem of hirsutism but also towards the prevention and treatment of potential cardiovascular morbidity using modalities aimed at eradicating hyperinsulinemia, hypertension and dyslipidemia. These modalities should include modifications in diet, exercise and weight in addition to pharmacologic and/or surgical manipulation. Weight reduction will reduce many cardiovascular risk factors as well as serum androgen levels.

Principles of treatment in women with hirsutism

Specific causes of hirsutism such as Cushing’s syndrome and adrenal/ovarian tumours should be treated by surgical excision of the tumour. In the other patients, pharmacological approach is the mainstay of the therapy. Pharmacological treatment of hirsutism is directed at slowing the growth of new hair and the options are antiandrogens such as finasteride, spironolactone or flutamide, combined oral contraceptive pill with or without antiandrogen agents, gonadotrophin-releasing hormone agonists and rarely insulin sensitizers. A general overview of drugs used in the treatment of hirsutism is given in Table 2.

Table 2.   Available therapies in hirsutism
DrugUsual doseSpecial indicationDisadvantage
Spironolactone100–200 mgAny form of hirsutismMenstrual irregularities
Postural hypotension
Dizziness
Requires effective contraception
Finasteride2·5–5 mgAny form of hirsutismNo major adverse event
Requires effective contraception
Flutamide62·5–250 mgAny form of hirsutismHepatotoxicity
Requires effective contraception
Oral contraceptive pillsDepends on drugPCOSDeep vein thrombosis risk
GnRH analogueDepends on drugSevere hyperandrogenism such as hyperthecosisExpensive
Requires injection
Menopausal symptoms
GlucocorticoidsDepends on drugCAHDifficult to adjust dose
Non-classical congenital adrenal hyperplasia unresponsive to antiandrogens 
To facilitate ovulationCushingoid symptoms

Patients should be informed about the type and the duration of the therapy. Generally, more than 6 months are necessary to evaluate the success of the medical therapy. The treatment of hirsutism involves the prevention of excessive androgen secretion and/or the blockade of androgens. The selection of the drug/drugs depends on the severity of the hirsutism score, associated conditions such as menstrual irregularities, systemic disorders such as diabetes mellitus, hypertension and any contraindication to possible therapeutic agent. 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. In addition, mechanical amelioration of the unwanted hairs may be adjunctive.

PCOS is the most common cause of hirsutism. Nearly 70% of the women with PCOS are obese, and they should be encouraged to loose weight. Oral contraceptive pills (OCP) are the most common drugs used for the suppression of ovarian androgen production [4,61]. Among OCPs, containing a progestin with low androgenic activity may be preferable. Several new progestins have been synthesized in the past decade, including, drospirenone, nestorone and trimegestone. Drospirenone differs from the classic progestins which has antimineralocorticoid activity. In addition, it has no androgenic effects, but it exhibits partial antiandrogenic activity. Its antiandrogenic potency is about 30% of that of cyproterone acetate, the progestin with the most potent antiandrogenic activity [62]. OCPs can be used either alone or in combination with antiandrogens such as finasteride (5 mg day−1) [63] or spironolactone (100 mg day−1) [64]. In both of these combinations, combination therapy has been shown to be significantly more effective on hirsutism score than treatment with OCPs alone considered to have specific antiandrogen effect owing to the utilization of cyproterone acetate as a progestin. Side effects of the OCP include weight gain, breast tenderness and contraindicated in women with a history of venous thrombosis.

Peripheral blockade of androgen actions at the skin is also effective in the treatment of hirsutism. 5-α reductase inhibitors reduce the conversion of testosterone to the more potent DHT. Finasteride has been used in the treatment of hirsutism with various doses [65,66]. In those studies, the authors report that low (2·5 mg day−1)-dose finasteride therapy is also effective as high (5 mg day−1)-dose therapy with similar side effect profile. Finasteride has teratogenic potential and should be used with effective contraception.

Spironolactone is an androgen receptor antagonist with some inhibiting effects on androgen production. It is generally effective in doses between 50 and 200 mg. The most common complaints are polymenorrhea, gastrointestinal disturbances and dizziness [67]. Spironolactone used as a single agent is as effective as cyproterone acetate combined with estradiol for long-term treatment of patients with hirsutism [67]. It has been shown that combination of two antiandrogens (spironolactone–finasteride) with different mechanisms of action may be used in women with hirsutism [68]. Although spironolactone and finasteride are classified as antiandrogen drugs, there are important differences in their mechanisms of action. It has been shown that after 1 year of treatment, combination of these agents resulted in significant per cent change (51·3%) in hirsutism score from baseline in comparison with spironolactone alone (36·6%) without increased side effects.

Flutamide is a non-steroidal antiandrogen. In comparison with spironolactone and finasteride, it has a lower safety profile and serious liver toxicities have been reported, particularly at high doses. The low-dose flutamide, 250 mg day−1, has been shown as effective in the treatment of hirsutism [69]. However, it has been shown that even the lowest (62·5 mg day−1) dose of flutamide has an important decrease (70% of basal) in hirsutism score at 1 year of therapy [70]. Although in several studies the effects of finasteride and flutamide have been clearly shown, combination of finasteride (5 mg day−1) plus flutamide (125 mg day−1) was not more effective than flutamide alone [71]. This result was unexpected because such a combination therapy with different (or at least theoretically, complementary) mechanisms of action might result in better improvement than either drug used alone. Thus, it should be emphasized that not all combination therapies for hirsutism work well.

In patients with NCAH, treatment should not be initiated merely to decrease abnormally elevated hormone concentrations. The use of antiandrogens such as spironolactone, finasteride, cyproterone acetate or flutamide should be considered in women complaining of hirsutism with appropriate contraceptive methods. In patients desiring pregnancy, glucocorticoid treatment may be used in the absence of ovulation. Almost all patients with NCAH secrete an adequate amount of glucocorticoids, so, apart from ovulatory dysfunction, the benefits of treatment should be weighted against the potential risks of acute adrenal insufficiency secondary to iatrogenic adrenal suppression.

In patients with GRS, to suppress adrenal androgen production, higher doses of mineralocorticoid-sparing synthetic glucocorticoids (dexamethasone) should be used and titrated appropriately.

Cosmetic measures play an adjunctive role in the treatment of hirsutism. Bleaching, by using hydrogen peroxide in most cases, will soften and oxidize the unwanted hair [72]. Plucking may be used in areas where little hair is present. It may result in pain and skin irritation. Electrolysis is a form of permanent hair removal. The hair follicle is destroyed by using current and then removing the hair [73]. Laser therapy has been induced a prolonged telogen phase and delay hair growth [74]. Although not widely available, eflornithine cream may be used for the reduction in unwanted facial hair in women. Eflornithine is a specific, irreversible inhibitor of the enzyme ornithine decarboxylase which is thought to slow hair growth by inhibiting this enzyme in hair follicles [75]. All these treatments might be more effective when used in conjunction with antiandrogen therapy. In very milder cases, they represent the mainstay of the treatment.

Conclusion

Hirsutism has a negative impact on psychosocial status of the patient and sometimes as in androgen-secreting tumours may be a sign of serious malignant disease. Although PCOS is the underlying cause in most of the patients, a number of patients presenting with hirsutism and exhibiting similar features to PCOS may have other underlying diagnoses. Unlike PCOS, some of these disorders can occasionally be life threatening and require prompt diagnosis and treatment. After the exclusion of adrenal/ovarian tumours, drugs aiming to reduce serum androgen concentrations and/or blocking the effects of the androgens are the most commonly used.

Disclosure

The authors have no conflict of interest including financial interests.

Address

Department of Endocrinology Erciyes University Medical School, Kayseri, Turkey (K. Unluhizarci, F. Kelestimur); Endocrine Unit, Department of Pathophysiology, National University of Athens, Greece (G. Kaltsas).

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