Summary

The current review article, published in the recent issue of the Indian Dermatology Online Journal, highlights the dermatological implications of PCOS, and appropriate therapeutic approaches needed to manage the morbidity of this syndrome as most patients require long-term treatment and follow-up.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder leading to reproductive as well as metabolic dysfunction in women. PCOS jeopardizes feminine identity of a woman due to alteration in her aesthetic standards in the form of hirsutism, acne, alopecia, obesity, menstrual irregularities, and infertility.

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Cutaneous manifestations of PCOS

Hirsutism

1. It is the most distressing and dermatology consultation seeking implication of PCOS. It is defined as the excessive growth of terminal hairs at androgen-dependent areas in females similar to male distribution. It is the most commonly used clinical criteria of androgen excess and seen in 50-80% of all women with hyperandrogenemia (HA).
2. The modified Ferriman Gallwey (FG) score is commonly used to evaluate and quantify hair growth in nine androgen-dependent areas of the body (upper lip, chin, chest, upper back, lower back, upper abdomen, lower abdomen, arm, and thigh).

• The score ranges from zero (no terminal hair growth visible) to four (extensive hair growth)
• A score of ≥8 indicates hirsutism. It is examiner dependent and has no correlation between circulating androgen levels and FG score

3. There is a difference in hair growth of all individuals due to the difference in 5-alpha reductase enzyme activity which converts testosterone to dihydrotestosterone (DHT).
4. In PCOS, there is increasing activity of 5-alpha-reductase in hair follicles which is also stimulated by hyperandrogenism, insulin-like growth factors, and insulin.
5. Testosterone and DHT also alter the hair cycle resulting in the transformation of vellus hair into terminal hairs which are thicker and darker, especially in face, neck, chest, and pubic region which are androgen-sensitive sites.

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Acne

1. Acne is one of the cutaneous manifestations of PCOS, but it is important to differentiate it from acne vulgaris which affects almost 80% of adolescents and majority of them remit before third decade of life.
2. Most women with PCOS exhibit facial acne lesions and up to 50% women have involvement of the neck, chest, and upper back as well. As compared to hirsutism, the prevalence of acne alone (excluding hirsutism) is very less.
3. The role of androgens in pathogenesis of acne is questionable because the androgen levels are found to be normal in acne vulgaris. However, it has been seen that there is increased receptor sensitivity to circulating androgen in women with acne as compared to normal counterparts.

• Androgens increases the sebum production, causing abnormal desquamation of follicular epithelial cells resulting in comedones formation
• Further colonization of the follicles by Propionibacterium acnes results in inflammation and further formation of papules, pustules, nodules, cysts, and scarring

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Acanthosis nigricans

The condition is characterised by brown velvety moist, verrucous hyperpigmentation of the skin, usually seen on the back of the neck and intertriginous areas like armpits and groins, underneath the breast, inside thighs. In PCOS, it has been reported in only 5% of women. It is due to excessive binding of serum insulin to IGF-1 receptors which results in the proliferation of keratinocytes and fibroblasts.

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Alopecia

It is characterized by progressive hair loss or thinning. In PCOS, usually there is thinning at the vertex with the maintenance of frontal hairline, but in a few, it is similar to androgenic alopecia in which there is loss of hairs in the central region of scalp.

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Seborrhoea

The presence of oily and shiny skin in the nasolabial folds, forehead, or behind the ear is defined as seborrhoea. It is seen in women with hyperandrogenemia and hyperinsulinaemia.

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Evaluation of Cutaneous Manifestations

• Obtain detailed clinical history owing to the wide variation in clinical presentation. History should include the duration of cutaneous manifestation, menstrual history, history of infertility, diet history, and family history
• Clinical examination should include grading of hirsutism with FG scale, site of acne and type of lesions, seborrhoea, and presence of alopecia
• Genital examination should be done keeping in mind the signs of virilization such as clitoromegaly.
• BMI, waist circumference, and blood pressure should also be measured

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Pharmacotherapy in PCOS

The therapeutic goal is to achieve inhibition of ovarian androgen production and decrease their bioavailability by increasing SHBG (Sex hormone binding globulin) levels.

Oral contraceptive (OC) pills

1. As per latest international evidence-based guideline for the assessment and management of polycystic ovary syndrome (2018), COCPs alone are recommended in adult women and adolescents with PCOS for management of hyperandrogenism and/or irregular menstrual cycles and can be considered in adolescents who are at risk but not yet diagnosed with PCOS.
2. Combined oral contraceptive pills (COCPs) are commonly prescribed, different combinations of COCPs are available with heterogeneous estrogen and progestin preparations with varying pharmacological and clinical properties. Thus, the efficacy and consequences of COCPs in PCOS may vary.
3. Oral contraceptive pills (OCPs) contain estrogen which suppresses the LH, increases SHBG, and decreases ovarian androgen production. These actions reduce the free testosterone which limits the cutaneous manifestations (acne and hirsutism) of PCOS. The progestins used in OCP are considered as per degree of androgenic properties as they are testosterone derivatives
4. Newer progestins like norethindrone, desogestrel, and norgestimate have some androgenic action whereas CPA (cyproterone acetate) and drosperinone are androgenic receptor antagonist

• CPA is more potent as it also inhibits 5-alpha reductase
• Drosperinone is an aldosterone antagonist with antimineralocorticoid action and some antiandrogenic property which counteract the action of estrogen on rennin-angiotensin-aldosterone system

5. COCPs should be prescribed by balancing efficacy, metabolic risk profile, side effects, cost, and availability as various preparations available with lowest effective estrogen doses (20–30 micrograms of ethinyloestradiol or equivalent) and have similar efficacy in treating hirsutism
6. OCPs should be continued for atleast 6-9 months before any improvement in hirsutism is noted.
7. OCPs significantly improve the cutaneous manifestations and protect the endometrium from unopposed estrogen action; however, worsening of insulin resistance and dyslipidemia have also been reported. Other concerns include hypercoagulability and vascular reactivity in women with a history of vascular diseases like migraine
8. Due to risk of adverse effects like venous thromboembolism, the 35-μm ethinyloestradiol plus CPA preparations (EE+CPA) should not be considered first line in PCOS.

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Antiandrogens

• Antiandrogens mainly act either by competitive inhibition of androgen-binding receptors or inhibit 5-alpha-reductase enzyme which decreases androgen production
• OCPs should be added with all antiandrogens in sexually active women as there is risk of feminization of male fetus if pregnancy occurs

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Spironolactone

• Spironolactone is an aldosterone antagonist having action on androgen receptor and 5-alpha-reductase inhibitor activity
• It is the most effective antiandrogen which has shown a considerable effect on hirsutism even over and above OCPs, it has been found to be effective for acne and alopecia
• The dose is 25-100 mg/day, which is generally well tolerated, but symptoms of fatigue, postural hypotension, and dizziness may be experienced by some women. So, start with a low dose (25 mg) and progressively increase over a week
• There is a dose-related menstrual irregularity; therefore, it is given in combination with OCP

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Cyproterone acetate

• It is a progestational antiandrogen which inhibits binding of testosterone and 5-alpha DHT to the androgen receptor. Although it is usually recommended for hirsutism only, it also found to be effective for alopecia as well
• It can be used alone in dose of 50-100 mg daily or with combination with ethinyloestradiol in reverse sequential regimen, it has found to be more effective than finasteride
• It is well tolerated; however, patients may complain of headache, weight gain, breast tenderness, and depression. Hepatotoxicity is a rare side effect

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Flutamide

• Finasteride is a potent competitive inhibitor of the type 2 isoenzyme of 5-alpha-reductase and blocks the conversion of testosterone to the more active metabolite DHT. It has no effect on DHT receptors or any known effect on steroid biosynthesis
• It is used in combination with OCPS and has found to have better results in patients who take OCPs alone. It is found to be equally effective when directly compared to OCP containing CPA
• These anti-androgens are the drug of choice for hirsutism in cases where estrogens are contraindicated. In such cases, a combination of finasteride+spironolactone has also been found effective

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Insulin sensitisers

• Weight reduction drugs may be helpful in reducing hyperandrogenaemia, but there is no direct evidence of the benefit of met for min on hirsutism or acne
• Metformin beneficial in women having insulin resistance or deranged blood glucose levels

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Cosmetic/local therapy

Options available are medical therapy or physical method of removing hairs by threading, waxing, plucking, bleaching, or shaving. The permanent hair-reduction techniques, such as electrolysis and photoepilation, also exist in which destruction of hair follicle is done with energy source.

Medical therapy

Eflornithine hydrochloride (13.9%)

• Eflornithine also known as difluoromethylornithine is an FDA approved drug for the treatment of unwanted facial hair growth. It is an irreversible inhibitor of l-ornithine decarboxylase, an enzyme that controls hair growth and proliferation. It helps in slowing and miniaturising the hair follicle rendering them less coarse
• Continuous use can cause reversible reduction in upto 70% of hair growth. The drug takes 8 weeks to show clinical improvement; however, the benefit reverses after withdrawal in 8 weeks' time
• Monotherapy is not considered to be effective and it can be used along with medical treatment in mild cases. Scottish Medicines Consortium guidelines 2007 recommended its use only after trying all available options, but in 2016, they stopped supporting it for routine use as well.

Fluridil

A new topical gel fluridil 2% has been developed for hyperandrogenic skin syndrome. It has shown to have a good safety profile, but larger clinical trials are not available to support its use.

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Permanent method of hair removal

1. The permanent techniques for destruction of hair follicles are electroepilation and laser photothermolysis.
2. In electrolysis, there is risk of post-inflammatory pigmentation and scarring, whereas laser is expensive but less painful and faster, the laser hair removal is more effective for women of fair skin with dark hairs.
3. Laser therapy selectively damages the hair follicle without destroying adjacent tissues by its photothermal and photochemical effect. Along with destruction of hair follicle, it also induces the miniaturization of terminal course hairs into vellus hairs. According to light source, laser may be grouped into three categories:

• Red light systems (694nm ruby)
• Infrared light systems (1064nm neodymium: yttrium-aluminum-garnet)
• Intense pulsed light sources (590–1200 nm)

4. Laser therapy requires multiple sittings at regular intervals and it has been observed that 65-75% hair reduction is possible at 3 months after one to two sittings whereas >75% hair reduction in 91% of cases at 8 months after four sittings with diode laser in women with hirsutism.

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Lifestyle modification and psychological support

1. Lifestyle modification is the first step of management which includes dietary restriction, exercise, and weight loss.

• It has been seen that just 5% loss of total body weight reduces the insulin resistance and testosterone levels with marked improvement in body composition and CV risk markers

2. Psychological support in PCOS women is of increased importance owing to the chronic nature of the disorder. Appropriate counselling along with adequate intervention should be offered to every PCOS patient.

• Most women are depressed due to the affliction of androgenic effects which threatens their feminine identity, obesity, and associated poor reproductive performance. They are more prone to substance abuse and smoking

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There is no effective treatment of PCOS and it is directed only to treat the symptoms of the individual patient. There is a genuine need to understand and diagnose this syndrome early so that holistic treatment of this syndrome can be initiated at the earliest, thereby preventing the long-term morbidity. Addressing the endocrine and metabolic deviations, inculcating life-style modifications and involving the use of lasers for hirsutism, forms the mainstay of the management.