Abstract
Hirsutism is thought to affect 1 in 10 premenopausal women. The most common cause remains polycystic ovarian syndrome, however, other rare but serious diagnoses must be excluded. Regardless of the cause, hirsutism can have a significant effect on self-esteem and quality of life for those affected and GPs need to know how this condition can be managed.
The GP curriculum and hirsutism
Manage appropriately primary contact with patients who have a metabolic problem Know indications for referral to an endocrinologist, metabolic medicine or nephrologist for investigation of suspected endocrine disease Recognise that patients with metabolic problems frequently have non-specific symptoms and that diagnosis is often made by recognising symptom complexes and arranging appropriate investigations Demonstrate a logical, incremental approach to investigation and diagnosis of metabolic problems
Recognise how disfigurement and cosmetic skin changes fundamentally affect patients' confidence, mood and interpersonal relationships Appreciate the importance of the social and psychological impact of skin problems on the patients' quality of life
The human body has two main types of hair: terminal and vellus. Terminal hair is typically dark, coarse and thick. It is naturally found in the scalp, eyebrows, eyelashes and, after puberty, in the pubic and axillary areas. Vellus (soft, fine) hair covers the rest of the body surface, with the exception of the lips, palms of the hands and soles of the feet.
Hirsutism is the presence of excessive terminal hair growth in a female; it follows an androgen- dependent (male pattern) distribution. Areas commonly affected are the face, upper lip and chin, chest (including areola), linea alba and lower abdomen, as well as the anterior thighs and buttocks. It is less typical to see the upper back and upper abdomen affected (Fig. 1). The amount of body hair can vary between individuals, families and ethnic groups. Terminal body hair is rare in Sub-Saharan African and East Asian populations and more common in South Asian and Mediterranean groups. Dark coloured hair on light coloured skin can also be more noticeable.
Thick, dark coloured terminal hair growth on the chin and face of a woman.
Hair growth and regulation
The number of individual hair follicles rarely increases after birth and begins to decrease after the age of 40. The initial number is dependent on both ethnic and genetic influences. Each individual hair follicle cycles through three phases of growth: anagen, catagen and telogen. Anagen signifies the growth phase, catagen is the arrest of growth and telogen is the resting phase. The hair follicle is then shed and the cycle repeats. Hair follicles are at differing stages of this cycle, which gives the impression of stable coverage in a particular area. The overall duration of each hair cycle is variable, depending on body area, and can last from several months to several years.
Hair growth itself is dependent on multiple factors. Androgen hormones are an important regulator of the growth, type and distribution of hair. The main circulating androgen, testosterone, is converted to the more potent dihydrotestosterone (DHT) in the hair follicle by the enzyme 5α-reductase. DHT stimulates hair growth within hair follicles; however, its sensitivity varies across the body. Eyebrows, eyelashes and some areas of the scalp are not dependent on androgenic influences at all, whereas the pubic and axilla regions are sensitive to low circulating levels. Areas of the body associated with male pattern hair growth respond only to higher circulating androgen levels. Exposure of hair follicles to constantly raised androgen levels not only promotes faster hair growth but also the transformation of vellus to terminal hair over several hair cycles.
Causes of hirsutism
In hirsutism an over-production of androgens, or an increased sensitivity to normal circulating levels, causes male pattern hair growth. It is important to exclude hypertrichosis when considering complaints of excess hair growth in female patients. Hypertrichosis is a general excess of hair in a non-androgen distribution and has an entirely different aetiology.
Causes of hirsutism.
Idiopathic hirsutism
In idiopathic hirsutism (IH), regular menstrual cycles are maintained and there are no other clinical features of androgen excess or virilisation. IH is thought to be a consequence of increased sensitivity to androgens, due to an increased function of the 5α-reductase enzyme or alteration to androgen receptors. This type of hirsutism has been reported within families and is more common in South Asian and Mediterranean ethnicities.
Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) is a common endocrine disorder, affecting 5–10% of premenopausal females. It is the most common cause of hirsutism, accounting for approximately 70% of cases (Carmina Rosato, Janni, Rizzo, & Longo, 2006).
Using the Rotterdam criteria (The Rotterdam ESHERE/ASRM-Sponsored PCOS Consensus Workshop Group, 2004), PCOS can be diagnosed when any two of the following three are present:
Oligomenorrhoea (cycle length of 35 days or more) and/or presence of anovulation (for 6 months or more) Clinical and/or biochemical signs of hyperandrogenism (see Box 2) Evidence of polycystic ovaries on ultrasound examination Points to cover in the history.
Obesity associated with PCOS increases insulin resistance and leads to hyperinsulinaemia. Increasing insulin levels encourage ovarian theca cells to overproduce androgens. Higher insulin levels also decrease the production of sex-hormone-binding globulin (SHBG) by the liver. Testosterone is bound to SHBG, therefore if SHBG is reduced, the level of free, active serum testosterone rises. The total testosterone level may also be raised but often is within the normal range.
Congenital adrenal hyperplasia
CAH is an autosomal recessive disorder in which cortisol production is impaired. CAH is usually picked up in childhood, classically presenting with ambiguous genitalia in girls or as precocious puberty. Adult-onset (non-classic) CAH tends to be a milder phenotype and symptoms associated with glucocorticoid deficiency are rare. However, it can be a cause of hirsutism and may mimic PCOS.
Adult-onset CAH is an autosomal recessive condition due to a genetic defect on the CYP21A2 gene. There is a partial defect of the 21-hydroxylase enzyme, which increases levels of androgenic 17α-hydroxyprogesterone. Prevalence among Caucasians is 0.1–0.2%, but it is 10 times more common among Ashkenazi Jews, Southern Mediterraneans and Eastern Europeans (Speiser et al., 1985).
Identifying CAH may be of benefit for women trying to conceive, as glucocorticoid therapy may reduce the incidence of miscarriage (Bidet et al., 2010). Furthermore, pre-pregnancy genetic testing and counselling may be appropriate.
Androgen-secreting tumours
Androgen-secreting tumours (of the ovary and adrenal gland) are rare, accounting for only 0.2% of androgen disorders in women (Carmina et al., 2006). However, since half of these tumours are malignant, it is important to rule out this diagnosis. A rapid onset of hirsutism or virilisation, particularly after puberty, should increase suspicion. Lutenising hormone (LH) and follicle-stimulating hormone (FSH) levels are suppressed and testosterone levels are 1.5–2.0 times greater than the normal range in those presenting with androgenic tumours.
Other causes
Uncontrolled hypothyroidism can cause dry, brittle hair and influences the anogen-to-telogen ratio of the hair cycle (Swigler, Awala, & Gordon, 2009). It also decreases production of SHBG and therefore the level of circulating free testosterone rises, leading to hirsutism. Other endocrine conditions, such as hyperprolactinaemia and Cushing's disease, similarly lead to androgen excess. Usually with these diagnoses, other typical symptoms are present in addition to hirsutism.
Hyperandrogenic insulin resistant acanthosis nigricans (HAIR-AN) syndrome is an inherited condition that may present with features of PCOS. Severe insulin resistance causes high circulating levels of insulin and marked acanthosis nigricans is found on examination. Virilisation may also be a feature. Both insulin resistance and hirsutism in this cohort are particularly difficult to manage.
Pregnancy can be a rare trigger of hirsutism; this may be due to transient luteomas or thecomas that increase circulating levels of androgens by increasing ovarian production. In older women the menopause can be a potential trigger, as oestrogen levels fall faster than androgen levels during this time. Also, the rise in LH during the menopause separately leads to an increase in testosterone levels.
Medications such as steroids (anabolic and corticosteroids), sodium valporate, phenytoin, minoxidil, danazol and progestogens (systemic and intrauterine devices) can promote hirsutism. It is not known why non-androgen-based drugs have this effect. If medication is identified as a potential cause it is important to weigh-up the risks and benefits of stopping on an individual patient basis.
Assessing hirsutism
Start with a focused medical history including menstrual, drug and family history (Box 2). In addition, it is important to explore the psychological impact of the symptom. Hirsutism can cause low self-confidence, negative body image and perceived feelings of decreased femininity. Anxiety, social withdrawal and depressive symptoms can ensue.
Examine the woman to establish the extent of the problem, looking for terminal hairs and noting the pattern of distribution. This can be quite a subjective process. One way to categorise hirsutism severity is by using the modified Ferriman–Gallwey scale (FGS) (Fig. 2). A cumulative score above eight signifies hirsutism, with scores of 8–15 indicating mild and greater than 15 moderate to severe hirsutism.
Modified FGS. American Journal of Obstetrics and Gynecology, 1981, 140(7): 815–830, Hatch, R., Rosenfield, R. L., Kim, M. H., & Tredway, D. Hirsutism implications etiology and management, with permission from Elsevier.
Remember that women may have tried some method of hair removal before presentation to their GP and this will alter what is seen on assessment and the FGS. Therefore, it is essential to ask about hair removal during the consultation.
Examination should also include assessment for signs suggestive of PCOS or other conditions that may cause hirsutism. Such signs include: acanthosis nigricans, acne, frontal balding, or signs of hypothyroidism, Cushing's disease or acromegaly. An abdominal and/or pelvic examination may be appropriate if symptoms have had a rapid onset (less than 6 months), to identify palpable pelvic tumours. Examination of external genitalia is not advised unless other virilising features are seen, or the patient describes cliteromegaly.
Investigating hirsutism
Although the level of hirsutism does not directly correlate with androgen levels, women with a score of above 15 on the FGS are more likely to have an androgenic cause and should undergo investigation. This is also the case for women with rapid onset of symptoms, menstrual irregularity, infertility, acanthosis nigricans or signs of virilisation regardless of the degree of hirsutism.
In women with mild hirsutism with no other symptoms and regular menstruation IH is the most likely diagnosis and further investigation is not routinely recommended. The only exception to this is women from an African or East Asian background, where body hair is uncommon; in this circumstance mild hirsutism requires further investigation (Supplementary figure 1).
A raised free-testosterone level is the most sensitive marker for hyperandrogenism. Testosterone naturally varies with the menstrual cycle; lower levels are found premenstrually and higher levels mid-cycle. When testing for testosterone, an early morning sample taken between days 4 and 10 of the menstrual cycle is recommended. Current guidance suggests that a total testosterone level is a sufficient first-line investigation to distinguish a hyperandrogenic cause (The Endocrine Society, 2008), but if the total testosterone is normal the test should be repeated, checking free-testosterone levels and SHBG. Take care when interpreting testosterone results of patients using combined hormonal contraception, as this reduces free testosterone by increasing the level of SHBG.
If other symptoms, in addition to hirsutism, are present it is appropriate to assess hormonal status more thoroughly to identify common causes. This includes checking prolactin, LH, FSH levels and thyroid function tests. Although the LH and FSH ratio is no longer part of the diagnostic criteria for PCOS, it can be useful as the result helps eliminate premature ovarian failure as a potential cause of menstrual disturbance. A pelvic ultrasound may be arranged if PCOS is still suspected.
If there is a clinical suspicion of CAH, acromegaly or Cushing's syndrome, the patient should be further investigated. In adult-onset CAH an early morning follicular phase (days 1 to 14) serum 17 α-hydroxyprogesterone is substantially elevated in addition to a raised testosterone level. If either metabolic syndrome or HAIR-AN syndrome is suspected initial investigation with blood tests for fasting glucose and lipids is appropriate.
When to refer patients with hirsutism to a specialist.
Managing hirsutism
There is no complete cure for hirsutism. However, once treatable causes are excluded, there are three main management strategies available: lifestyle modifications, mechanical treatments and pharmacological therapies (Supplementary figure 2). Often a combination of approaches is adopted. Due to the duration of the hair cycle it may take 6–9 months to see any benefits. The NHS rarely funds hair removal therapies.
Lifestyle measures
Weight loss should be encouraged in patients who are overweight or obese, and advice given about a low fat, low calorie diet and increased exercise. One study showed that within 6 months of achieving a 5–10% weight loss the level of hirsutism had improved by up to 50% (Pasquali et al., 1989). Support patients through the involvement of dieticians and local weight reduction programmes, if appropriate.
Spearmint tea is also a potential treatment option for hirsutism. In a non-blinded randomised controlled trial of twice daily spearmint tea for 30 days in women with PCOS-associated hirsuitism, there was a statistically significant decline in both free and total testosterone levels compared with the placebo group. Patients drinking spearmint tea felt their hirsutism had improved, although objectively no difference was seen using the FGS (Grant, 2010). Another small study lasting 5 days demonstrated lower free- testosterone levels in those who drank spearmint tea. (Akdoğan et al., 2007). Although evidence is limited, this straightforward, side-effect-free approach may appeal to some women.
Recently, a small study found that daily Omega-3 fish oil supplements taken by women with PCOS-associated hirsutism for 6 months improved FGS scores, and increased SHBG and decreased androgen levels (Oner & Muderris, 2013). This option could be tried in certain, suitable patients.
Temporary hair removal
Waxing, shaving, plucking and depilatory creams are all methods of temporary removal of unwanted hair. There is no significant evidence to indicate that one method is superior to another. The choice of method is dependent on what is acceptable to the patient, as each has associated problems. Shaving can cause stubble, which many women find uncomfortable and unsightly. Plucking, waxing and epilation may lead to ingrown hairs, folliculitis and scarring of the skin. Depilatory and bleaching creams risk causing skin irritation, particularly on more sensitive areas of the body such as the face.
Permanent hair removal or reduction
Electrolysis and laser therapy is the only permanent method of hair removal and laser therapy can permanently reduce excess hair. Both can be used alone or in conjunction with other methods of treatment. If hirsutism is associated with hyperandrogenism, this should be tackled first, otherwise further terminal hairs will continue to appear following treatment due to androgen excess. With both electrolysis and laser therapies it is advisable to avoid waxing or plucking between treatments and to only shave or cut hairs in the area, in the hope that the hair can be treated while in the growing (anagen) phase of the hair cycle.
During electrolysis, a fine, sterile needle is inserted into each individual hair follicle. Once the needle has been correctly placed, a small electric current is applied, causing destruction of the hair follicle. This can cause some discomfort, with a sensation similar to hair plucking being described. All hairs apart from those within the nose or ear canal can be treated by electrolysis. Inflammation of the treated area often develops immediately after electrolysis. This redness and swelling usually subsides within a few hours. In the next day or so small pinpoint scabs over each treated follicle may develop. These drop off naturally after a week; if picked off before this time scarring can occur. As each hair follicle is treated individually, the process can take some time and is expensive. For permanent results, multiple treatments of a particular area are required. Laser therapy, also called photoepilation, causes destruction of the hair follicle itself, without damage to surrounding skin. Often 6–10 treatment sessions are required per area to see maximal results. The process is not painless, but is often well tolerated. Side effects are rare, but potentially include depigmentation of skin, burns and scarring; they are more common in patients with darker skin colour.
The NHS rarely funds electrolysis or laser therapy for hirsutism; where available, it is limited to patients with hormone imbalance causing hirsutism and can only be accessed via secondary care specialists. Private treatment can be expensive, but advise patients to always use a fully trained professional registered with a recognised regulatory body and holding professional indemnity insurance.
Topical medication
Eflornithine hydrochloride (Vaniqa®) is licensed solely for topical use in facial hirsutism. Eflornithine irreversibly inhibits an enzyme (ornithine decarboxylase) that is involved in hair growth. This treatment therefore slows down or stops hair growth completely. The effect occurs only while treatment is undertaken and it can be combined with laser hair removal for facial hirsutism. Eflornithine needs to be thinly applied to the affected area twice a day, and it should be rubbed in thoroughly. Other cosmetic products can be used, but it is advised to wait at least 5 minutes after application. The treated area, however, should not be washed within 4 hours. Side effects include rashes, tingling and in some cases acne. It takes 8 weeks for any benefits to be noted. If no improvement is seen after 4 months of correct use, treatment should be stopped.
Eflornithine is available through the NHS and, depending on local policies, can be initiated in general practice. However, it is expensive, and local prescribing guidelines may restrict its availability.
Systemic medication
Oral medication can be used to reduce the effect of hirsutism, with the aim of limiting the amount of androgen produced or reducing androgenic effects on hair follicles. The combined oral contraceptive pill (COCP) is recommended as first-line drug therapy for premenopausal women with problematic hair growth (Barbieri, 2013; The Endocrine Society, 2008). Other systemic medications to control moderate or severe hirsutism are prescribed off-licence and usually initiated by secondary care specialists. Unfortunately, oral medications are never a permanent solution; they help while taken but hirsutism reappears when they are ceased.
The COCP works by several mechanisms to reduce circulating testosterone. LH secretion is suppressed, reducing ovarian testosterone production and increasing the production of SHBG in the liver, which encourages more testosterone binding and a fall in free-testosterone levels. A slight decrease in adrenal production of testosterone and a mild effect on testosterone receptor binding also occurs. The COCP does not treat hirsutism but can make the symptoms more manageable and stop progression of the condition. Lower testosterone levels encourage terminal hairs to revert back to vellus type. It can take at least 6–12 months of treatment before the potential benefits are seen. The COCP is less effective when used in obese women with PCOS-associated hirsutism compared with those with a normal body mass index) (Cibula, Hill, Fanta, Sindelka, & Zivny, 2001). Obese women should be encouraged to lose weight.
The progesterones found in certain types of COCP can demonstrate androgenic features and be a cause of hirsutism. Levonorgestrel and norethisterone (second-generation progesterones) are highly androgenic, whereas norgestimate, desogestrel and gestodene (third generation) are less so (Koulouri & Conway, 2009). If considering contraception for a patient with mild hirsutism, this should be taken into account. For patients with moderate to severe hirsutism COCPs containing progestogens with anti-androgenic properties, such as cyproterone acetate (e.g. Dianette®) and drospirenone (e.g. Yasmin®), are recommended (National Institute for Health and Clinical Excellence (NICE), 2010).
Co-cyprindiol contains 35 µg ethinylestradiol and 2 mg cyproterone acetate. It is licensed in the UK for use in moderately severe hirsutism and severe acne not responding to antibiotics. Common side effects include weight gain, depression, fatigue and headache. Very rarely it can cause liver dysfunction. Co-cyprindiol should be stopped 3–4 months after complete resolution of symptoms and can be restarted if symptoms recur. If no benefit is seen after 6 months, a COCP-containing drospirenone can be trialled. Co-cyprindiol should not be used solely as a contraceptive and is contraindicated in women with a previous history of thromboembolism.
Systemic medication – secondary care
If oral therapy initiated in primary care has had limited success a referral to secondary care should be considered. Secondary care physicians are able to initiate alternative systemic medications.
Spironolactone and flutamide are anti-androgen drugs used to manage hirsutism, although they are unlicensed for this indication. The diuretic effects of spironolactone are not seen clinically in women being treated for hirsuitism; a typical dose of 100 mg daily is surprisingly well tolerated. Spironolactone has been shown to improve the FGS by 15–40% after 6 months of use, which is similar to the effect of co-cyprindiol (Rosenfeld, 2005). Flutamide, a drug used to treat prostate cancer, also works as well as spironolactone for hirsutism management (The Endocrine Society, 2008) but is not widely used due to its potential to cause liver failure.
Finasteride is a 5-α-reductase inhibitor used for male pattern balding that may also be utilised for hirsutism management. A 5 mg/day regime is prescribed. There are no major side effects and it works as well as anti-androgens, although study quality in this area is weak. Feminisation of the male fetus can occur on this medication. Therefore, adequate contraceptive cover is imperative.
Metformin, an oral biguanide, reduces the insulin sensitivity of the liver. This lowers circulating insulin levels, and subsequently also free testosterone levels. It has been suggested that using metformin in PCOS can offer long-term benefits, for example, preventing Type 2 diabetes and cardiovascular disease, however, there is currently insufficient evidence. A meta-analysis concluded that insulin-sensitising medication has no significant benefit compared with the COCP or anti-androgens for treatment of hirsutism (Cosma et al., 2008; NICE, 2013).
Gonadotrophin agonists are only used in women with severe symptoms of hyperandrogenism, typically associated with ovarian tumours. Sub-optimal response to both the COCP and anti-androgens have to be reported first, as gonadotrophin agonists have limited therapeutic advantages over these medications and can additionally cause side effects of bone demineralisation and other related menopausal-type symptoms.
In patients with adult-onset CAH, steroid therapy is an option. However, there is little evidence this is more helpful than oral contraceptives or anti-androgens for managing hirsutism, and steroids may even increase the symptoms of hirsuitism. These women are generally treated like those with PCOS-associated hirsutism with steroid therapy only initiated if required for other symptoms associated with CAH.
Psychological aspects of hirsutism
Women with hirsutism often experience deep-rooted emotional distress. This is particularly true for those with facial symptoms. By the time of presentation to the GP, many have tried several methods of hair removal. They may have been subjected to discrimination or ridicule as a result of the condition. Preoccupation with body hair – their own and that of others – can dominate sufferers’ lives, leading to low self-esteem and depression. Establishing close personal and sexual relationships may be problematic. Patients may benefit from referral to psychological therapy and consideration for antidepressant medication, although there has been little research conducted in this area.
Key points
Hirsutism can affect 1 in 10 women, with PCOS being the most common cause Hirsutism is often a marker of disease, it should not be considered as simply a cosmetic problem The psychological impact of hirsutism should be considered, explored and acknowledged If serum testosterone is approaching or above twice the upper limit of the reference range, refer to secondary care to rule out ovarian/adrenal tumours First-line medical therapy is a COCP – ensure the patient is aware it may take up to 12 months for improvements to be seen and that symptoms will recur when medication is stopped All other oral medication used off-licence in the management of hirsutism should be initiated in secondary care
References
Supplementary Material
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