Jane Tran MBBS, FRACP (Aust), Alvin Ng MMED, MRCP(UK)
Department of Endocrinology, SGH

Abstract

Hirsutism is the presence of excess coarse terminal hairs at androgen-dependent skin sites in females. For many women, hirsutism is a cause of emotional distress and subsequent negative impact on their self-esteem and psychosocial development. It is important to recognise that hirsutism is one of the signs of hyperandrogenism and underlying disorders such as polycystic ovarian syndrome, androgen-secreting tumours and late onset congenital adrenal hyperplasia are excluded. Treatment of hirsutism involves a combination of cosmetic and pharmacological measures. Its success varies from patient to patient and usually involves prolonged courses of treatment to achieve an aesthetically pleasing result.

Keywords: hirsutism, hyperandrogenism, polycystic ovarian syndrome, testosterone

Introduction

Hirsutism affects 2 to 10% of women between the ages 18 to 45.¹ It results from an increased production of androgens and/or an increased skin sensitivity to androgen activity due to an exaggerated peripheral 5a-reductase activity. This enzyme catalyses the conversion of testosterone (T) to more potent dihydrotestosterone (DHT) in the skin.

Hirsutism must be distinguished from hypertrichosis, which is excess growth of thin non-pigmented vellus hair at any body site. Hypertrichosis is usually familial or associated with hypothyroidism, anorexia nervosa or drugs such as phenytoin, minoxidil, penicillamine and cyclosporine. Hirsutism however, is characterised by a substantial increase in male-pattern hair growth affecting sites such as upper lip, chin, chest, lower abdomen, back, and upper thighs. Hirsutism is often associated with other signs of androgen excess — acne, androgenetic alopecia, chronic anovulation and virilisation.

Aetiology of Hirsutism

Hirsutism can be caused by a variety of conditions (Table 1). The majority of cases are due to increased androgen effects — either due to excess androgen secretion by ovaries or adrenal glands, increased skin sensitivity, or exogenous pharmacological sources of androgens. The most common cause of hirsutism is polycystic ovarian syndrome (PCOS).² PCOS is characterised by oligo/anovulation, clinical or biochemical signs of hyperandrogenism and polycystic ovaries on ultrasound.³ It affects 5 to 10% of women of reproductive age.⁴ Onset of symptoms occurs in adolescence and early adulthood, and patients may complain of menstrual irregularities, hirsutism, weight gain and infertility. Among PCOS patients, 70% have signs of androgen excess, while 50% demonstrate insulin resistance and secondary hyperinsulinaemia, with subsequent increased risk for diabetes mellitus and cardiovascular disease.^4-6

Table 1. Differential diagnosis of hirsutism. Adapted from Azziz.2

Congenital adrenal hyperplasia (CAH) is a group of inherited disorders of adrenal steroidogenesis resulting from various enzyme deficiencies (for example, 21-hydroxylase, 11-beta hydroxylase). As a consequence, there is decreased cortisol production and excessive accumulation of precursors to this enzyme (17-hydroxyprogesterone, dihydroepiandrosterone, androstenedione, testosterone). Patients present with excess hair growth, acne, menstrual irregularities and infertility.

It is vital to differentiate hirsute patients without signs of virilisation from those with signs of virilisation (acne, deepening of voice, clitoromegaly, increased libido, and increased muscle mass). An androgen-secreting tumour (ovary or adrenal adenoma/carcinoma) usually causes the latter. These tumours are heralded by sudden onset and rapid progression of hirsutism, virilisation features and pelvic or abdominal mass. They are associated with elevated total testosterone and dihydroepiandrosterone sulphate (DHEAS) levels.

Idiopathic hirsutism is usually a diagnosis of exclusion once specific aetiologies are excluded. There is excess hair growth but in the presence of normal androgen levels and often normal ovulatory cycles. Its pathogenesis is thought to be secondary to exaggerated end-organ 5a -reductase activity.⁷

Clinical Evaluation

The amount, distribution and progression of human body hair have racial, familial, genetic and hormonal influences. Mediterranean people tend to be more hairy compared to Nordic, Anglo-Saxon Europeans and Asians. A woman’s tolerance of the extent of her facial or body hair varies depending on her personal, social and cultural background. Therefore, only a proportion of hirsute women will present for medical advice. It is important to identify those hirsute patients, whose excessive hair growth may be secondary to a potentially reversible pathological cause. A thorough history and physical examination is critical in assessing a hirsute patient to provide initial diagnostic information. Laboratory investigations serve to confirm the presence of hyperandrogenism and to exclude serious underlying disorders. History should include the time of onset of hirsutism and its relation to puberty as well as its progression. Extent of weight gain should also be determined. Detailed history regarding menstrual cycles and reproductive history should be elicited. Other symptoms of hyperandrogenism as well as family history of hirsutism, infertility, diabetes mellitus and cardiovascular disease should be addressed.

Examination includes not only routine vital signs, but also the measurement of height, weight, waist circumference and determination of body mass index (BMI), as 50 to 80% of women with PCOS may be obese.⁸ The degree of hirsutism can be made by using a scoring system devised by Ferriman et al.⁹ It involves grading 9 regions of the body on a scale of 0 to 4, depending on the extent of cover by terminal hair. The areas assessed include upper lip, chin, chest, upper lower back, upper-lower abdomen, upper arm and thighs. Maximum score is 36. Mild hirsutism is defined as a score 8 to 12, moderate 13 to 18, and severe >19. The scoring system is helpful in evaluating response to therapy.

Inspection for other signs of hyperandrogenism is essential — acne, seborrhoea, and temporal balding. Acanthosis nigricans, characterised by brown, verrucous hyperpigmentation on the sides and back of the neck, axillae, and submammary region, usually indicates insulin resistance. Central obesity, thin skin, bruising, violaceous striae are warning signs of Cushing’s syndrome. Features of virilisation suggest the possibility of adrenal secreting tumours. Gynaecological examination may be necessary to rule out clitoromegaly and ovarian masses. Pelvic or transvaginal ultrasound can help to demonstrate the presence of polycystic ovaries.

The extent of laboratory studies will vary depending on the individual’s presenting complaint, severity of hirsutism and examination findings. Initial assessment should include determinations of total and free testosterone, follicle stimulating hormone (FSH), luteinising hormone (LH), estradiol (E2), thyroid function tests and prolactin levels. These latter two parameters are important to exclude thyroid dysfunction and hyperprolactinaemia as causes of menstrual irregularities. Usefulness of a high LH level or an elevated LH/FSH ratio (>2.5) in diagnosing PCOS is limited as it may not be observed in one-third of patients.¹⁰ Testosterone circulates in plasma predominantly bound to sex hormone binding globulin (SHBG; 66%) and albumin (32%). The remaining 1 to 2% of total testosterone is unbound and represents biologically active fraction. Variation in levels of SHBG can therefore influence free testosterone levels. For example, hyperinsulinaemia, obesity, excess growth hormone and glucocorticoid intake tend to result in decreased SHBG levels, thereby increasing free testosterone concentration. SHBG assays, however, are not readily available in Singapore. Total testosterone levels >7mmol/L (>200mg/dl) or DHEAS>19umol/L (700ug/dl) strongly indicate the presence of virilising tumours.¹¹ Early morning 17-hydroxy progesterone level >6mmol/L is suggestive of late onset congenital adrenal hyperplasia (21-hydroxylase deficiency), and ACTH-stimulation test should therefore be carried out to confirm the diagnosis. Plasma cortisol and 17-hydroxyprogesterone levels are measured at baseline and 60 minutes after 250mcg of ACTH is administered intravenously. Imaging with pelvic ultrasound, abdominal/pelvic CT/MRI scans may be required to localise such tumours. In patients with PCOS, evaluation of associated co-morbidities may be warranted, such as ovulation testing, fasting glucose or oral glucose tolerance test for diabetes mellitus, and lipid profile.

Treatment

Initial management is to identify and treat any underlying cause of hirsutism. For the majority of women, the primary aim of treatment is to achieve a body image that they find aesthetically acceptable. This will inevitably involve the combination of pharmacological agents and mechanical/cosmetic measures to ameliorate and destroy unwanted hairs.

Cosmetic Measures

Common cosmetic approaches are shaving, bleaching or chemical depilation. These methods are effective for mild forms of hirsutism but their effects are only temporary. Problems with such treatments include skin irritation from the bleaching and depilatory creams, and development of sharp hair ends that feel like stubble after shaving. Plucking and waxing are usually discouraged as it can induce folliculitis and trauma to the hair shaft with subsequent development of ingrown hairs and further skin damage.² Plucking can also rapidly induce the anagen (active/growth) stage and hair follicle growth.¹²

Electrolysis and laser photothermolysis are techniques that can potentially destroy hair follicles permanently. With repeated treatments over several months’ efficacy of electrolysis ranges from 15 to 50% permanent hair loss.⁷ However, it can be expensive, painful and can lead to scarring in inexperienced hands.

Advances in laser therapy make this a promising means of permanent hair removal. It causes thermal damage to hair follicles without destroying adjacent tissues. It is most successful in patients with lighter skin colour who have dark coloured hairs. Similar to electrolysis, multiple treatments are required and can be expensive. Problems include transient erythema, oedema, blistering or crusting (10 to 15%), and hyper/hypopigmentation (10 to 25%).²

Weight Loss

Obesity has been shown to be associated with decreased SHBG levels with subsequent increased free testosterone levels. Moderate weight loss can increase SHBG, thereby improving hyperandrogenaemia and in turn improve hirsutism.¹³ Weight loss seems to be beneficial in all obese hyperandrogenic women regardless of the presence of polycystic ovaries.¹⁴ Therefore, all obese hirsute patients should be advised to lose weight as part of their management regimen.

Pharmacological Agents

Drugs to treat hirsutism slow growth of new hair but do not lead to loss of established hair. Therefore, they are most effective when used in conjunction with cosmetic measures. Current available therapies fall into 4 main groups (Table 2). Drug effect may take up to 6 to 12 months and are only effective when taken and benefits fade when drugs are discontinued.

Table 2. Pharmacological agents.

Oral Contraceptive Pill

The oral contraceptive pill (OCP) suppresses FSH and LH production, resulting in reduced ovarian and adrenal androgen secretion. The estradiol component of the pill increases SHBG, thereby lowering free testosterone levels. The OCP is ideal for women requiring cycle control and/or contraception. Formulations containing less androgenic progestogens (for example, desogestrol, norgestrel, norethindrone, gestodene) or low dose cyproterone acetate (CPA) (for example, Diane-35: 2mg CPA and 35ug ethinyl estradiol) can result in significant improvement in hirsutism.^15-17 Combination of OCP’s with other anti-androgenic agents, such as GnRH agonists, finasteride or spironolactone, has also been shown to be effective.^15,18,19 An additional benefit of the use of OCP in PCOS patients with chronic anovulation is a reduction of risk of endometrial and ovarian cancer.

Gonadotrophin Releasing Hormone Analogues

Gonadotrophin releasing hormone (GnRH) analogues work by suppressing LH and FSH secretion via continuous saturation of pituitary receptors. As a result, ovarian estradiol and testosterone production is markedly reduced. Administration of these agents is by parenteral route (subcutaneous, intramuscular, intranasal spray or subcutaneous depot injections). Nafarelin (1000ug/d) given to hirsute women for 6 months resulted in slower hair growth, and decreased coarseness of new hair.²⁰ Similarly, Bertoli et al showed that 6 months of treatment with buserelin nasal spray significantly decreased both total testosterone levels and hirsutism scores.²¹

The main side effect with these agents is hypoestrogenism, resulting in hot flushes, menstrual irregularities, emotional lability and decreased bone density. Such side effects can be ameliorated with the addition of an OCP. Often, the addition of OCP results in more rapid and significant improvement in hirsutism compared to when GnRH analogue is used alone.^18,22

Peripheral Blockade of Androgens

This group of drugs includes androgen receptor blockers, which act by inhibiting binding of testosterone and DHT to the androgen receptor in the skin; and 5a -reductase inhibitors, which act by decreasing conversion of testosterone to the more potent DHT. Generally, it is not advisable to give such drugs to women planning to conceive. Women of reproductive age must therefore use effective contraception when taking antiandrogens, as there is transplacental passage of the drug, which may adversely lead to feminisation of genital development in male foetuses. All of these drugs show similar efficacy in the treatment of hirsutism. Therefore, drug selection will depend largely on availability, side effects and cost of the drug.

Spironolactone

Spironolactone is an aldosterone antagonist, a weak progestogen and a competitive inhibitor of androgen receptor. It is usually the first line treatment for excess hair growth. It can be used as a single agent. Spritzer demonstrated that 12 months of therapy of spironolactone 200mg/day significantly reduced Ferriman-Gallwey hirsutism scores and hair diameters in patients with idiopathic hirsutism or PCOS.²³ Six months of therapy with spironolactone is as equally effective as CPA, flutamide or finasteride.^24,25

Alternatively, spironolactone can be used in combination with other agents such as finasteride. Such combinations (spironolactone 100mg/day and finasteride 5mg/day) can reduce hirsutism scores by 51% compared to spironolactone alone.²⁶ It can also be used effectively with the addition of OCP.¹⁵

Doses range from 50 to 300mg/day and side effects tend to be dose-related. These include menstrual irregularities, breast tenderness, fatigue and hyperkalaemia.

Cyproterone Acetate

Cyproterone acetate is a potent progestin, an androgen receptor blocker and has anti-gonadotrophic effect. Small doses used in combination with oestrogen (Diane-35) as OCP may be adequate treatment for mild hirsutes.¹⁵ However, higher doses (100mg/d) are required in more severe cases.²⁴ In premenopausal women, CPA is administered in a reverse sequential manner with low dose OCP. That is, CPA 50 to 100mg/d on Day 5 to 15 of each cycle. Co-administration of OCP is essential to avoid menstrual irregularities. Common side effects include weight gain, breast tenderness, decreased libido, nausea, headache and lethargy.

Flutamide

This is a pure non-steroidal androgen receptor blocker. It is licensed as treatment of prostate cancer. Several studies have shown its efficacy in hirsutism with significant reductions in Ferriman-Gallwey scores after 6 to 12 months of treatment.^27,28 One randomised controlled trial reported flutamide to be superior to spironolactone.²⁹ Flutamide caused a maximal reduction in the hirsutism score to a value within almost normal range; during the same period, spironolactone caused only a 30% reduction of the hirsutism score. Furthermore, flutamide resulted in better improvements in seborrhoea and acne compared to spironolactone.²⁹

Flutamide dosage varies from 250mg/d or bd. However, lower doses of 62.5mg/d have been shown to result in 70% reduction of hirsutism scores at 12 months.³⁰ One potential serious complication of flutamide is hepatotoxicity and fulminant liver failure.³¹ Thus, it is not considered as first line treatment for hirsutism.

Finasteride

Finasteride is a 5a -reductase inhibitor and is used as treatment for benign prostatic hypertrophy. It has also been shown to be efficacious in treating excess hair growth. Seventeen women treated with finasteride (5mg/d) had their mean hirsutism scores reduced by 47% after 6 months of therapy.³² Another study of 25 hirsutes, secondary to idiopathic hirsutism or PCOS, revealed a 60 to 63.8% reduction in hirsutism scores after 6 months of treatment with finasteride.³³ It has similar efficacy to spironolactone and flutamide and is generally well tolerated.²⁵

Insulin Sensitisers

It is well recognised that insulin resistance and hyperinsulinemia contribute to pathophysiology of PCOS. Thus, in the past decade there has been increasing interest in the use of insulin sensitising agents to improve endocrine and reproductive abnormalities of PCOS. Weight loss alone or used in conjunction with insulin sensitisers (metformin, pioglitazone, troglitazone) improve not only insulin resistance, but also hyperandrogenism and ovulatory function in PCOS patients.^13,14,34

Metformin (850mg bd), added to low calorie diet, resulted in decreased androgen levels and improved hirsutism in PCOS and non-PCOS patients.³⁵ A prospective study of 39 PCOS patients given metformin (500mg tds) for 12 weeks showed a significant decrease in fasting insulin and total T and an increase in SHBG, leading to a decrease in the free T index. In addition, there was a significant decline in mean BMI, waist-hip ratio, hirsutism, and acne, as well as an improvement in the menstrual cycle.³⁶ A recent randomised study investigated the effects of metformin versus low dose CPA specifically on hirsutism.³⁷ Fifty-two patients were randomised to either metformin (500mg tds) or ethinyl estradiol (35ug) combined with CPA 2mg (Dianette OCP) for 12 months. There was similar hair diameter reduction in both treatment groups. But in some respects (Ferriman-Gallwey score and patient self-assessment), metformin seemed more efficacious than low dose CPA.

Troglitazone belongs to the thiazolidinedione (TZD) family and is a potent insulin sensitiser. It was first introduced as an effective agent in treatment of diabetes.³⁸ It has been shown to improve ovulatory function, insulin resistance, hyperandrogenemia and hirsutism scores in PCOS women.³⁹ However, it is no longer available on the market because of its associated fatal hepatotoxicity.⁴⁰

Pioglitazone is also a TZD. It has been commonly used as treatment for diabetes mellitus overseas, but is currently not available in Singapore.⁴¹ An open-labelled study of pioglitazone (45mg/d) in PCOS patients showed a decrease in hirsutism scores from 16.3±6.63 to 7.9±5.48 after 6 months.⁴² Acne improved, and menstrual cyclicity was restored in 83% of patients. Brettenthaler et al reported decreases in insulin resistance and free androgen index and increase in ovulation rates in 40 PCOS patients given pioglitazone (30mg/d). However, hirsutism scores did not change throughout the study.⁴³

Certainly there is now good evidence to suggest that insulin sensitisers have a role in PCOS patients by reducing hyperinsulinemia, regulating menstrual cycles, reducing hyperandrogenism and reducing cardiovascular risk factors.⁵ However, their role in the treatment of specifically hirsutism in PCOS and non-PCOS patients still requires further evaluation.

Others

Eflornithine hydrochloride 13.9% cream (Vaniqua), although not available in Singapore, has been approved overseas for topical treatment of unwanted facial hair growth. It acts as an irreversible inhibitor on an enzyme controlling hair growth. It slows and miniaturises the hairs so they are much less visible and coarse. It is effective in 32 to 58% of patients within 8 weeks, but its use must be continued to maintain its effect.2 Side effects can include skin tingling and rash in <10% patients.

Follow-Up

Patients should be advised that long-term therapy may be required with any of the above drugs and that drug-effect may not be evident until 6 to 12 months after starting treatment. Clinical response is the primary marker followed, rather than hormonal levels. A good measure of treatment efficacy is the reduction in frequency and duration of mechanical hair removal. Effects of these drugs last only as long as treatment is continued and can abate a few months after therapy ceases.

Conclusion

Treatment of hirsutism remains challenging. Management of a hirsute patient is individualised. It requires detailed medical evaluation to exclude potentially reversible causes, and therapy will ultimately involve both mechanical/cosmetic measures as well as medications. As most drug therapies display similar efficacy, the choice of treatment will predominantly depend on its availability, side effect profile and its cost.

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