Anti-androgen therapy

Introduction Uses How it works Anti-androgenic drugs Clinical effects Oral contraceptives Spironolactone Cyproterone acetate

What is anti-androgen therapy?

Anti-androgen therapymale sex hormones

What are anti-androgens used for?

Anti-androgen medicationshyperandrogenism

• Acne
• Seborrhoea
• Hirsutism
• Female pattern hair loss
• Hidradenitis suppurativa

How does anti-androgen therapy work?

Anti-androgen therapy

1. Block androgen receptor
2. Reduce adrenal androgen production
3. Reduce ovarian androgen production
4. Reduce pituitary production of prolactin
5. Inhibit 5-alpha reductase (this enzyme acts in the skin to increase dihyroxytestosterone)
6. Reduce insulin resistance

Which drugs have anti-androgenic action?

Androgen receptor blockers act on the sebaceous gland and base of the hair follicle. They include:

• Oral contraceptive (birth control pill) containing ethinylestrodiol (oestrogen) and an antiandrogenic progesterone. These include cyproterone acetate (co-cyprindiol or Diane™-35, Estelle™ 35 and Ginet-84™), drospirenone (Yasmin™, Yaz™) or dienogest (Valette™).
• Other low-dose combined oral contraceptives with minimal androgen effect. These contain ethinylestrodiol and desorgestrel, gestodene or norgestimate.
• Spironolactone 25-200 mg daily (Aldactone™, Spirotone™, Spiractin™), which is most useful in women over the age of 30 years.
• Cyproterone acetate 50 to 200 mg (Androcur™, Procur™, Siterone™ – available in New Zealand only on a specialist's prescription). This powerful anti-androgen is usually taken on days 1 to 10 of the menstrual cycle (conventionally, day 1 is the first day of menstruation).
• Flutamide 250-500 mg daily. This is normally used as a hormonal antineoplastic agent in males with prostate cancer. It can cause hepatitis and should not be used for skin disorders.
• Topical clascoterone cream 1% (Winlevi®) applied twice daily for the treatment of acne vulgaris in patients aged 12 years and older.

Spironolactone and cyproterone may be effectively combined with cyproterone acetate/ethinyloestradiol or other oral contraceptive agent, partly because they cause menstrual irregularities and partly to prevent pregnancy. The combined treatment is not necessary in post-menopausal women.

Low-dose oral corticosteroid (eg prednisone 2.5 mg in the morning, 5 mg at night) acts to reduce adrenal androgen production. In congenital adrenal hyperplasia, DHEAS levels should reduce to normal.

Limecycline, roxithromycin and ketoconazole (no longer available in New Zealand) are antimicrobial drugs that have also been noted to reduce androgen synthesis.

Drugs acting on ovarian androgen production include:

• Gonadotrophin receptor hormone (GnRH) agonist (buserelin, leuprolide), which stop ovulation and suppress androgen production. Because they also stop oestrogen production, they may lead to menopausal symptoms, headache and osteoporosis.
• Combined oral contraceptives
• Progestins

Excessive prolactin is reduced by bromocriptine, cabergoline and quinagolide.

5-alpha reductase inhibitors include zinc, finasteride, azelaic acid, saw palmetto and other plant extracts. Spironolactone inhibits 5-alpha reductase weakly. Unfortunately, finasteride does not reduce sebum production and is not effective in the treatment of acne. However, we now know that isotretinoin reduces sebum partly by reducing dihyrotestosterone production in the sebaceous gland.

Insulin resistance can be reduced using metformin, mainly prescribed for type 2 diabetes mellitus and obesity / metabolic syndrome. It may also reduce signs of hyperandrogenism. Metformin 250 mg to 2 g daily is safe but can cause diarrhoea and should be taken after food in gradually increasing doses. Rosiglitazone and pioglitazone can cause heart and liver toxicity.

What are the clinical effects of anti-androgen therapy?

In acne, the effects of anti-androgens include:

• Reduced sebum production
• Reduced comedone formation

They can be combined with other topical and oral treatments for acne.

In hirsutism, the results are:

• Slower growth of hair
• Lighter coloured hair
• Finer textured hair

Physical methods of hair removal such as waxing, shaving, electrolysis or laser epilation, can be used at the same time as anti-androgens are taken. They often work better than prior to the medication.

In female pattern hair loss, the results are:

• Reduced hair shedding
• Reduced hair thinning
• Sometimes, restoration of thicker hair

These effects are not always clinically significant.

Oral contraceptives

Progesterone-only oral contraceptivesandrogen-mediated skin conditions

Combined oral contraceptives contain two hormones, ethinyloestrodiol 20–35 mcg (an oestrogen) and a progesterone. They prevent pregnancy by suppressing ovulation and changing cervical mucus. There are various kinds of progesterone, which may be androgenic in nature and thus unsuitable for those androgen-mediated skin conditions (particularly levonorgesterol and norgestrel). Anti-androgenic or minimally androgenic progesterones (see above) are indicated in these women.

Their effect in hyperandrogenism is to reduce production of androgens by the ovaries, by the adrenals and at the receptor level in the skin. They also decrease circulating testosterone by increasing sex hormone binding globulin (SHBG).

Combined oral contraceptives are available as 21-day and 28-day packs; start on Day 1 (conventionally, day 1 is the first day of menstruation) and take one a day for 21 days. Then have a 7-day break (21-day pack) or take the placebo tablets for a week (28-day pack) before starting the cycle again. During this time, you can expect a withdrawal bleed (a period).

Combined oral contraceptives can increase the risk of thromboembolism (blood clots blocking blood vessels), especially in those with an inherited tendency ("thrombophilia"), or who smoke. Please refer to the New Zealand Ministry of Health (Medsafe) advice on the use of combined oral contraceptives.

The combined oral contraceptive may be unsuitable if the patient:

• Has had a previous blood clot (thrombosis, embolism or ‘DVT’)
• Has high blood pressure (hypertension) or heart disease
• Smokes
• Is significantly overweight (obese)
• Has recently undergone surgery or trauma or is immobile
• Is undertaking long distance air travel (4 hours or more)
• Has a family member aged less than 50 years who has had blood clots or high blood pressure

Many of these women can instead use progesterone-only contraceptive pills while they are being treated with spironolactone or cyproterone.

Oral contraceptives can sometimes aggravate migraine and are inadvisable in those with significant liver disease. They may occasionally increase the risk of certain uncommon forms of breast cancer. They must not be taken in pregnancy.

On the other hand, the combined oral contraceptive reduces the risk of ovarian and endometrial cancer, benign breast disease, ectopic pregnancy, painful periods, iron deficiency anaemia and pelvic inflammatory disease.

Cyproterone acetate/ethinyloestradiol (co-pyrindiol) should be discontinued in the following circumstances:

• Severe migraine (headache, visual disturbance, numb feelings)
• Any form of thrombosis (such as heart attack, stroke) or increased blood pressure
• In case of immobility (including due to surgery) or trauma (eg bad sprains)
• If an increase in number or severity of epileptic seizures occurs, or liver disease arises during treatment
• Pregnancy

As with other oral contraceptives, minor side effects may arise, especially in the first few weeks. These include:

• Breast tenderness (20%) and increase in bra size
• "Spotting" (irregular mild bleeding between periods) occurs in 10% of women in the first month, but only affects 3% by the sixth month. Rarely, periods may stop altogether (amenorrhoea). If you have spotting (bleeding in between periods), see your doctor. He or she may advise you to take the active medication continuously for 3 months or more. This is quite safe and often prevents unwanted bleeding.
• Nausea, loss of appetite and bloating
• Headaches
• Increased appetite and weight increase (uncommon)
• Mood changes including depression and reduced libido
• Melasma (facial pigmentation)
• Hair loss (it is more common for hair fall to occur when the medication has been discontinued however)
• Acne

Other medications can interfere with the contraceptive effectiveness.

• Barbiturates
• Phenytoin
• Rifampicin
• Some antibiotics

Combined oral contraceptives with anti-androgenic components have advantages:

• They regulate the menstrual cycle in the majority of women
• Lighter, less painful periods occur in the majority of women
• Iron deficiency anaemia is less common because of less bleeding
• Increased "good" HDL cholesterol may protect against atherosclerosis (hardened arteries predisposing to heart disease)
• A decrease in the number and size of ovarian cysts occurs in polycystic ovarian syndrome
• Sebum production is reduced by 30%, resulting in worthwhile improvement in 80% of those with seborrhoea
• Acne usually improves by 40-50% by the third cycle and by 80-90% by the ninth cycle.
• More than 40% of women with facial hair (hirsutism) find it improves within 9 months, and many get worthwhile reduction in hair growth elsewhere as well.

Studies have demonstrated that the skin condition continues to improve even after the medication has been taken for a year. Combined oral contraceptives can usually be taken safely for many years.

Unfortunately, the skin condition tends to deteriorate again within a few months after the medication has been stopped.

New forms of oral contraceptive are introduced from time to time, to increase efficacy and reduce side effects.

Please refer to the New Zealand Ministry of Health (Medsafe) advice on the use of combined oral contraceptives.

Spironolactone

Spironolactone is a potassium-sparing medication used as a diuretic medication for heart failure, liver disease and high blood pressure. However, it has also been found useful for hirsutism, acne and seborrhoea because it has anti-androgenic properties. Spironolactone mainly works by blocking androgen receptors.

The dose of spironolactone is usually slowly increased from 25 to 200 mg daily, taken at night. It is sometimes prescribed cyclically to reduce menstrual irregularities, eg, for 3 weeks out of every 4 weeks or days 5–21 of the menstrual cycle. It may take six or more months to see improvement in the skin condition.

Side effects of spironolactone include:

• Nausea, diarrhoea, gastrointestinal bleeding
• Drowsiness (possibly due to high blood potassium levels)
• Headache and dizziness
• Menstrual cycle irregularities including increased frequency of menstruation, bleeding in the middle of the month or stopping periods altogether (amenorrhoea)
• Breast pain.

Potassium, other electrolytes and creatinine levels in the blood are often monitored in older women, if high doses are prescribed, in patients taking other medicines (due to drug interactions) and in those with heart or kidney problems. Monitoring is not considered necessary in healthy women. Spironolactone should not be taken in pregnancy or during lactation (see Lactation and medications used in dermatology).

• Serum potassium should be ≤5.0mmol/L and renal function should be normal before starting spironolactone.
• Monitor potassium and creatinine after one week on spironolactone, monthly for the first 3 months and then 2 to 4 times each year

Spironolactone is prohibited in athletic competition (requires therapeutic use exemption).

Cyproterone acetate

Higher doses of cyproterone acetate are indicated for more severe cases of androgenetic skin conditions. It is effective for 70% of those with hirsutism.

Several different regimes are prescribed with doses ranging from 25 to 200 mg daily. Prior to the menopause, the medication is usually combined with cyproterone acetate/ethinyloestradiol or other oral contraceptive agent:

• To regulate menstrual cycle irregularities caused by the high dose cyproterone
• To prevent pregnancy; there are concerns that cyproterone could harm a male fetus by "feminising" it.

One system is to take the high dose cyproterone for the first ten days of the cycle.

Postmenopausal women and women who have had a hysterectomy can take cyproterone every day. It may be advisable to have a 7-day break every month. They may also take spironolactone.

Occasional significant side effects include:

• Liver disturbance
• Tiredness and depression
• Weight increase.

Approved datasheets are the official source of information for medicines, including approved uses, doses, and safety information. Check the individual datasheet in your country for information about medicines.

We suggest you refer to your national drug approval agency such as the Australian Therapeutic Goods Administration (TGA), US Food and Drug Administration (FDA), UK Medicines and Healthcare products regulatory agency (MHRA) / emc, and NZ Medsafe, or a national or state-approved formulary eg, the New Zealand Formulary (NZF) and New Zealand Formulary for Children (NZFC) and the British National Formulary (BNF) and British National Formulary for Children (BNFC).

References

• Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris J Clin Aesthet Dermatol. 2012 March; 5(3): 37–50.
• Lakshmi C. Hormone therapy in acne. Indian J Dermatol Venereol Leprol. 2013 May-Jun;79(3):322–37. doi: 10.4103/0378-6323.110765. Review. PubMed
• Spironolactone—potion or poison? DTB 2017;55:13

On DermNet

• Acne
• Acne vulgaris
• Hirsutism
• Polycystic ovarian syndrome
• Female pattern hair loss
• Enlarged pores

Other websites

• Consumer medicine information and data sheets — Medsafe
• Drugs, Herbs and Supplements — MedlinePlus

Books about skin diseases

• Books about the skin
• Dermatology Made Easy - second edition

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