Various drugs have been used in the treatment of hirsutism and acne when these are due to mildly or moderately elevated androgen levels. Significantly elevated androgen levels must be appropriately investigated before starting medical treatment.
Androgen action may be reduced either by decreasing circulating androgen levels or by reducing androgen action at cellular level. Androgen production by the ovaries can be reduced by the administration of a suitable combined contraceptive pill. This will decrease LH output by the pituitary and thus diminish LH stimulation of androgen production by the ovaries. An oestrogenic combined oral contraceptive pill has the added advantage of increasing sex hormone binding globulin (SHBG) levels and thus reducing circulating free testosterone levels. Suitable pills include Ovysmen/Brevinor (35 µg ethinyloestradiol and 500 µg norethisterone) and Dianette (35 µg ethinyloestradiol and 2 mg cyproterone acetate). Adrenal androgen production can be reduced by the administration of a corticosteroid, and in women with idiopathic elevation of adrenal androgen levels, or mild adrenal hyperplasia, treatment with a corticosteroid is appropriate.
Androgen action at cellular level can be reduced by the administration of an antiandrogen. Cyproterone acetate is the antiandrogen that has been most widely used in gynaecological practice. The use of spironolactone is no longer recommended because of possible long-term toxicity. Cimetidine is rarely used as an antiandrogen and in one recent study it was found to be ineffective in the treatment of hirsutism, but it was only given for 3 months (). Antiandrogens must not be given to women who are pregnant or who may become pregnant during treatment as they can cause feminization of a male fetus.
Cyproterone acetate () has been in clinical use for about 20 years. It is both an antiandrogen and a progestogen. It acts by reducing androgen action at cellular level, by blocking androgen receptors and by decreasing 5a-reductase activity, and by reducing LH secretion. It was originally prescribed in a reversed sequential regimen devised to ensure adequate contraception and regular withdrawal bleeding; cyproterone acetate (100mg/day) was given from the 5th to the 15th day of the menstrual cycle with ethinyloestradiol 50 µg/day from the 5th to the 25th day of the cycle. The contraceptive pill Diane (cyproterone acetate 2mg and ethinyloestradiol 50 µg, from the 5th to 25th day of the cycle) was subsequently introduced and has now been replaced by Dianette (cyproterone acetate 2 mg and ethinyl oestradiol 35 µg). Cyproterone acetate and ethinyloestradiol both decrease LH output by the pituitary and therefore reduce androgen production by the ovary. Ethinyloestradiol also increases circulating levels of SHBG and thus reduces the free (biologically available) levels of testosterone. These effects combine to reduce androgen availability for action at cellular level.
It was found that 70% of women with hirsutism respond well to the high-dose (reversed sequential) regimen and about 50% to the low-dose (2mg) regimen (). The maximum response may take several months and unfortunately the relapse rate on stopping treatment is high ().
High doses of cyproterone acetate can cause suppression of adrenal function in animals and it was initially feared that this might occur with long-term therapy in humans, but this does not appear to be a problem in practice (). Other reported side-effects include breast tenderness, oedema, nausea, headache, fatigue and decreased libido ().
In a woman with severe hirsutism, a combination of cyproterone acetate 50 mg from the 5th to the 15th day of the cycle and ethinyloestradiol 30 µg from the 5th to the 25th day of the cycle will often be effective. It should be continued for at least a year to obtain the maximum effect and cyclical maintenance treatment with Dianette or an oestrogenic combined contraceptive pill can then be substituted. The initial dosages of cyproterone acetate and ethinyl oestradiol can be increased to 100mg/day and 50µg/day if necessary. In women with less severe hirsutism, treatment with Dianette can be given in the first instance.
Spironolactone binds not only to mineralocorticoid receptors but also to androgen receptors. In addition it decreases testosterone production and increases the peripheral conversion of androgens to oestrogens (). It has been used on its own in a dose of 50-200 mg/day, or in combination with an oral contraceptive, with some success in the treatment of hirsutism () but it is no longer advocated for this indication because of concern about long-term toxicity. Other side-effects include irregular vaginal bleeding (). It has recently been recommended by the Committee on Safety of Medicines that spironolactone should only be prescribed for life-threatening conditions such as the nephrotic syndrome.
Selections from the book: “Introduction to Clinical Reproductive Endocrinology”. Edited by Gillian C. L. Lachelin, 1991.