Hyperandrogenism, excessive production of androgens, may have a profound effect on the women it affects, and 70–80% of patients with androgen excess demonstrate hirsutism.117,118 The most common cause of androgen excess is PCOS; most frequent cutaneous symptoms in these patients are hirsutism, acne, androgenetic alopecia (AGA) seborrhoea, obesity and acanthosis nigricans; less frequently virilization or clitoromegaly can be observed. Oligo- or amenorrhoea, secondary infertility, diabetes mellitus or insulin resistance may be systemic consequences of PCOS. Hirsutism, acne, and AGA will be discussed in more detail below.
Hirsutism is defined as the growth of excess terminal (coarse) hairs in females in a pattern typically seen in adult males,117,119 sometimes (although rare) leading to virilization (deepening of the voice, clitoro-megaly, and loss of female body shape). The Ferriman–Gallwey score.
(F-G score) is a method of evaluating and quantifying hirsutism, and was first introduced in 1961. Hair growth is rated depending on density and intensity from 0 (no growth of terminal hair) to 4 (complete and heavy cover), in nine locations, giving a maximum score of 36. The nine locations measured are the upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, the upper arms and the thighs,120 A score of at least 6 is needed for a diagnosis of hirsutism,121 but care should be taken to consider the amount of hair growth that is normal for the individual's ethnic background, and the F-G score is not applicable in Asian patients and may be difficult to apply in routine clinical practise. Recent publications suggest high national variations in F-G scoring for hirsutism; from a score of 3 in an American population122 to 8 in a Finish population and above 6 in German populations, indicating that there are differences depending on ethnicity.
PCOS is the most common cause of hirsutism, which in turn is the main dermatological symptom of the condition.123,124 The clinician should always keep in mind that not every increase in hair growth is hirsutism. Attention must be paid to the differential diagnosis of hypertrichosis that is independent of androgen influence and characterized by the superfluous and uniform growth of non-terminal (vellus) hair over the body, particularly in non-sexual areas and without pattern.124 This has to be considered during diagnosis as hypertrichosis may occur congenitally (or as a result of a patient's ethnicity), but it is also frequently caused by systemic drug intake such as glucocorticosteroids, cyclosporin, latanoprost, bimatoprost, interferon a, or minoxidil.
Hirsutism is usually the result of an underlying adrenal, ovarian or central endocrine abnormality. Elevated secretion of androgens, increased bioavailability of testosterone and increased sensitivity of hair follicles to androgens all contribute to the condition. It is characterized by the transformation of vellus into terminal hairs in androgen-sensitive areas125 and can present clinically with excess hair growth on the face, chest, between the breasts, and on the abdomen.103 The main androgen involved in the development of hirsutism is dihydrotestosterone (DHT, which is produced in the skin from testosterone by the enzyme 5α-reductase). Androstenedione and DHEA are also overproduced by the ovary and adrenal glands. Women with hirsutism have increased activity of 5α-reductase in their hair follicles.126,127 Besides PCOS related hirsutism, idiopathic and neoplasia associated hirsutism, and drug induced hirsutism should be excluded during diagnosis. The main drug candidates to be investigated include anabolic agents, gestagens, a gonadotrophin inhibitor (danazol), testosterone, DHEA, tibolone, and valproic acid.
Current management of hirsutism. A careful diagnostic work-up of the patient is mandatory in this condition. A diagnostic evaluation should be made to eliminate PCOS, or any serious cause of excess hair growth, for example, androgen secreting neoplasia, and consideration should be given to possible referrals to – or from – other specialists (e.g. a dermatologist, endocrinologist, or gynaecologist).
Treatment of hirsutism aims to rectify any causal hormonal imbalance and improve the cosmetic appearance of the disorder. Treatment may be non-pharmacological intervention (weight reduction, physical or chemical procedures, laser epilation), or pharmacological intervention (central or peripheral androgen suppression, androgen blockers, insulin sensitizers, inhibitors of androgen production, or a topical enzyme inhibitor – eflornithine).
Non-pharmacological interventions. Weight reduction in obese women decreases hirsutism, the production of ovarian androgens, and the conversion of androstenedione to testosterone.128 Physical methods of hair removal are temporary solutions to the problem of facial or body hirsutism, and most women who present with facial hirsutism will have already tried several or all of the methods.
Hair removal options include physical procedures such as shaving, tweezing, waxing/sugaring and chemical approaches such as bleaching with H2O2 or the use of depilatory creams with thioglycolates. All these options are ‘self-therapy’ performed by the women themselves. In contrast, professional therapy options are carried out by a professionally qualified or competent person and include photoepilation, electrolysis, and electro-epilation (the use of electrosurgical methods, such as electrocautery or diathermy, for destroying hair follicles).129
Photoepilation. The most frequently used and successful technique for permanent epilation is photoepilation. This uses light focused on hair pigment, with accumulation of light energy within the pigmented hair shaft causing destruction of the hair follicle. Patients with skin types I-II (type I often burns, rarely tans. Tends to have freckles, red or fair hair, blue or green eyes. Type II usually burns, sometimes tans. Tends to have light hair, blue or brown eyes), and with dark hair, are the optimum candidates for laser treatment, since its efficacy is dependent on the hair colour and size of the hair follicle enabling the accumulation of the highest energy in the dark and thick hair shaft. There are various methods available, with differing results (Table 1).130
Table 1. Photoepilation methods and typical results
|Intense pulsed light source (590–1200 nm)||80% after 1 year|
|Normal mode Alexandrite laser (754 nm)||40–80% after 6 months|
|Pulsed diode laser (800 nm)||65–75% after 8 months|
|Ruby laser (694 nm)||38–49% after 1 year|
|Long-pulsed Nd-YAG lasers (1064 nm)||20–60% after 3 months, 0% after 6 months|
In general, there is a 20–40% hair loss following a single treatment with photoepilation, and additional hair loss with each treatment of 20–40%. Under ideal conditions, two to seven treatments are needed for complete, permanent hair loss in patients with dark hair. However, the outcome depends on the individual hair and skin conditions, the laser device used and the experience of the therapist. There is also a synergistic effect of laser treatment with topical eflornithine, which slows hair re-growth.131
Electrolysis. Electroysis is commonly used in hirsute PCOS patients and easily available due to the number of qualified practitioners. However, despite how widely available it is there is no single randomized controlled trial to guide its success in this patient group.
Pharmacological interventions. Systemic and topical pharmacological intervention strategies for the management of excessive hair growth can be distinguished as follows:
Systemic interventions. The main aim of pharmacological treatment is to block or inhibit androgen production or action. Central or peripheral androgen suppression can be achieved using three groups of drugs:
- 1Peripheral androgen blockers (e.g. cyproterone acetate, flutamide, or spironolactone) or antiandrogens (e.g. finasteride)
- 2Insulin-sensitizing agents (e.g. rosiglitazone, metformin)
- 3Inhibitors of androgen production (e.g. oral contraceptives, GnRH analogues)
Three recent meta-analyses on hirsutism have suggested that each of the above (but not placebo) had a positive effect on hirsutism; however, combination randomized controlled trials are lacking in this area.132–135 It is difficult to determine which treatment is most effective as there have been no systematic comparative trials undertaken, but there does not seem to be one agent clearly superior to the others.
Topical pharmacological intervention. Topical eflornithine 11·5% cream (Vaniqa®) may be used to inhibit hair growth. Eflornithine inhibits ornithine decarboxylase (ODC), a key enzyme of polyamine synthesis (responsible for cell proliferation, migration and differentiation). Blockage of ODC leads to apoptotic cell death and decreased hair growth.
Two studies have evaluated the efficacy and safety of eflornithine HCl 13·9% cream on excessive facial hair growth,135 Eflornithine cream, applied twice daily for 24 weeks, significantly reduced the growth of unwanted facial hair (measured by a physician's assessment and hair length/mass). Efficacy was not dependent on the method of hair removal. The treatment was generally well tolerated with some patients experiencing mild, transient burning, stinging, or tingling. The time-response profile suggested that the effect had not yet reached a plateau at week 24 and that a more pronounced response may be achieved with longer treatment periods. Recent reports have indicated that the combination of laser and eflornithine is more effective than laser alone for removing unwanted facial hair.131 The possibility that eflornithine may inhibit all hair types, including the thin and non-pigmented hairs which are not well targeted by laser treatment, requires further study.
Combination of laser with eflornithine in a double blind placebo-controlled study showed for the vehicle-laser treatment area, complete or almost complete hair removal achieved in 67·9% of patients compared with 96·4% of patients treated with laser combined with eflornithine.134
Acne vulgaris is an androgen dependent, self-limiting inflammatory disorder of the pilosebaceous unit, which is seen in nearly 80% of all adolescents.136,137 Persistent, severe, or acne of late onset in women is suggestive of PCOS. Although the prevalence of acne in PCOS is unknown the literature reports up to 83% in PCOS vs. 19% in a control group, and most women with severe acne have PCOS.137
Acne is less prevalent in PCOS than hirsutism, and this may be explained by the difference in the expression levels and type of 5α-reductase in the sebaceous gland compared with the hair follicle. Hair follicles have higher DHT levels than the sebaceous glands and express 5a-reductase type I, whereas type II is present in the dermal papillae; DHT has been implicated in the pathogenesis of acne.127,138 However, the pathogenesis of acne is complex.
Treatment of acne. Oral hormonal therapy (in women whose peripheral hyperandrogenism is caused by hormonal imbalance) is an excellent choice for women who need oral contraception. It should be started early in women with medium to severe grade acne, or with sseborrhoea, acne, hirsutism and alopecia (SAHA) syndrome. It is an important factor in the therapeutic management of women with or without endocrine abnormalities, and especially for women with acne tarda.139 Anti-androgens are used to antagonize the binding of testosterone and other androgens to the AR. Insulin sensitizing agents inhibit hepatic gluconeogenesis (biguanides) or increase glucose uptake in the muscle and fat (thiazolidinediones); 5α-reductase inhibitors reduce the action of the 5α-reductase enzymes type 1 and 2, and GnRH agonists suppress LH and FSH production.
The pathogenesis of acne vulgaris is complex and includes focusing on hyperproliferation and differentiation of keratinocytes using topical retinoids. Combination therapy using retinoids plus benzoyl peroxide or acelaic acid can treat existing acne lesions faster than the individual agents alone and can also prevent the development of new lesions.140 According to the consensus on management of acne,141 the choice of treatment depends on the degree of acne. Systemic antibiotics and systemic retinoids are included in the management for either acne resistant to local therapy or when scarring occurs. The dermatologist should be integrated in the management as early as possible if the patient first presents to the endocrinologist or the gynaecologist.
During pregnancy and breast feeding, topical therapeutic agents can be used, including benzoyl peroxide (2·5–10%), erythromycin (Aknemycin®, Eryaknen®), clindamycin (Basocin Lsg, Gel®), and acelaic acid (Skinoren®).
Androgenetic alopecia (AGA)
AGA is a progressive, non-scarring loss of scalp terminal hair with miniaturization of terminal to vellus hair types in which both ovarian and adrenal androgens have been implicated.141 Normally patients with AGA have normal androgen blood levels, but may also have a genetic predisposition for the disorder, with increased enzyme activation and metabolism in the target end organ with elevated AR density in the target organ.
The current treatment for AGA is to treat the underlying hormone dysregulation (using an oral contraceptive pill with antiandrogenic activity), plus supportive topical therapy using 2% minoxidil (Regaine® or Rogaine®) for women. Anti-androgens competitively inhibit the binding of testosterone and DHT to the AR, and are the treatment of choice for androgen-dependent alopecia. A recent publication by Vexiau et al.142 has clearly indicated that systemic antiandrogens in management of AGA are only indicated if there are elevated androgen levels. In idiopathic hirsutism and AGA the first choice will be the use of 2% topical minoxidil solution.
Hirsutism, acne, and androgenetic alopecia are common symptoms of hyperandrogenism in women. Although these symptoms may also indicate other underlying diseases, the most common cause of hyperandrogenism in women of childbearing age is PCOS.
Women presenting with these symptoms should therefore be investigated for PCOS, and to exclude other potential causes of hyperandrogenism. The impact of the dermatological manifestations of this disorder should not be underestimated, and many women find these symptoms extremely debilitating, since they can affect many aspects of their lives. The treatment plan should address not only the underlying cause of the androgen excess, but also its dermatological manifestations. For patients suffering from PCOS, treatment options include reduction of androgen production and action, lifestyle modification, oral contraceptives, antiandrogens, and insulin-sensitizing agents as well as topical treatment of acne, seborrhoea and androgenetic alopecia. Local management of hirsutism should in addition include photoepilation combined with eflornithine cream.