Health&Care: Antihormones
Antihormones
Agonists of GnRH
Agonists of GnRH are a recently introduced novel class of compound with many applications in gynaecology and the treatment of hormonedependent tumours. They act by binding to pituitary receptors at the site where naturally occurring GnRH would normally attach. Initially they mimic the effect of GnRH and stimulate the production of FSH and LH by the pituitary. However, pituitary stores of FSH and LH become exhausted and are not replaced. Low pituitary FSH and LH levels result in lack of stimulation of the ovaries in women and the testicles in men, resulting in hypogonadism. 
This situation persists for as long as the agonist is administered. These drugs, therefore, induce a reversible medical castration. GnRH agonists can be administered in the form of a nasal spray, subcutaneous injections or monthly intramuscular depot preparations. All GnRH agonists have a similar side effect profile. Currently available preparations include buserelin, naferelin, goserelin and leuprolide. In women, GnRH agonists are frequently used for the treatment of endometriosis. In this condition, they are administered for a maximum of 6 months.
Women having surgery for fibroids sometimes receive 3 months preoperative treatment with a GnRH agonist to reduce the volume of the fibroid before surgery. The use of GnRH agonists has also been proposed in menorrhagia, premenstrual syndrome and adjuvant therapy in breast cancer. In men, they are usually prescribed for adjuvant treatment of prostatic carcinoma and have also been assessed in the treatment of hypersexuality disorders and for male contraception.
The side effect profile of GnRH agonists can easily be deduced from knowledge of their mechanism of action. Women are rendered effectively menopausal during treatment. They are infertile as ovulation is suppressed. Furthermore, low circulating oestrogen levels are associated with vaginal dryness (a frequent cause of pain during sexual intercourse) and lack of libido.
In the European study cited above in which women with endometriosis were treated with danazol or a GnRH agonist, 66% of the 204 patients randomised to GnRH agonist noted a reduction in libido. Fortunately these effects are rapidly reversible following cessation of treatment. These compounds should not be administered to women for longer than 6 months as the prolonged hypo-oestrogenic state leads to a measurable reduction in bone density that may be irreversible.
Men being treated with GnRH agonists for prostatic cancer also experience loss of libido. A recent study of leuprolide in the treatment of benign prostatic hyperplasia confirmed that erectile function and sexual activity was lost during therapy. This effect has been put to clinical use in the treatment of men with deviant sexual behaviour.
Cyproterone acetate and spironolactone
Cyproterone acetate (CPA) is an antiandrogen with strong progestogenic activity. It acts by reducing circulating testosterone concentrations but also inhibits the action of natural occurring testosterone and its metabolic products at the receptor site.
Spironolactone is an aldosterone antagonist that has been used to treat primary aldosteronism, hypertension and hypokalaemia. Its use in these conditions is limited by the adverse side effects, including decreased libido, impotence and gynaecomastia in men and menstrual disturbance in women. This side effect profile led to its therapeutic use to treat hirsutism. Spironolactone causes variable suppression of glandular testosterone secretion and also competes with androgens at the target cell level. 
Antiandrogens have several therapeutic uses in circumstances where the disorder is related to overproduction of androgens or raised androgen activity in the skin. The most common uses are for the treatment of hirsutism, seborrhoea and acne in women. They have also been employed in the treatment of androgenic alopecia and hypersexuality in women and precocious puberty in children. CPA has been prescribed for male sexual offenders. As androgens are implicated in human sexuality, certainly in males and probably in females, it might be expected that the use of antiandrogens would impact negatively on sexual function.
Various studies have described reduced libido in women during treatment with CPA. The incidence varies between 1 and 25% and seems to be associated with the duration of treatment. Loss of libido was reported by 11% of women after the first 3 months of treatment, increasing to 33% after 9 months. This is important because typically therapeutic benefit only starts to be seen with CPA treatment after 3 months. Appelt and Strauss (1984) obtained details of sexual function in hirsute women both before and during CPA therapy. Before treatment, 21% of women were classified by these researchers as having sexual dysfunction (including orgasmic dysfunction, lack of sexual enjoyment and dyspareunia). During treatment this increased to 44% and reached 61% in women in a stable relationship.
It should also be noted that untreated hirsutism per se is associated with a reduction in libido. Many hirsute women are also overweight and concerned about their body image compared with an idealised portrait of femininity as depicted in the media. CPA was assessed in a group of male paedophiles and was associated with reduced sexual thoughts, decrease in frequency and pleasure of masturbation and diminished sexual frustration. Serum testosterone levels were reduced during drug therapy.
Flutamide
Flutamide is a non-steroidal pure antiandrogen that has been used in the treatment of prostatic carcinoma. It acts by inhibiting androgen uptake or inhibiting the binding of androgen to its receptor. One study showed that flutamide did not reduce libido or sexual potency in a group of men with advanced prostatic carcinoma. 
Another group using flutamide for the same indication showed that it reduced libido in only 20% of the men treated. In contrast, a Canadian study in which complete androgen blockade was obtained by associating flutamide with a GnRH agonist showed that 70% of patients noticed a major reduction in their interest in sexual intercourse during treatment. Only 19% were able to maintain erection during intercourse compared with 56% before treatment.
The sexual dysfunction was so marked that the authors suggested that this combination would constitute a useful treatment for sexual offenders.
Finasteride
Finasteride is an inhibitor of 5a-reductase and so it inhibits the conversion of testosterone to ihydrotestosterone, the active form within tissues. It is used in the management of benign prostatic hypertrophy. As an androgen inhibitor it is associated with reduced libido, erectile dysfunction and also produces a reduction in the volume of the seminal ejaculate. 
The Committee on Safety of Medicines in the UK has reported 800 adverse drug reactions in 65 000 patients who have been prescribed finasteride. The most common adverse reactions were the sexual effects described above. Finasteride is excreted in semen and can potentially exert an antiandrogenic effect on the genitalia of male fetuses, so condoms should be used by men whose partners are pregnant or who could become pregnant.
