Impeded Androgens / Antiandrogens

IMPEDED ANDROGENS / ANTIANDROGENS

Superactive GnRH agonists are the most potent inhibitors of gonadal function. Administered over a few days, they markedly inhibit LH and FSH release, resulting in loss of androgen secretion.

Ketoconazole at high doses inhibits steroidogenic CYP 450 enzymes: testosterone as well as adrenal steroid production is interfered. Plasma protein binding of testosterone is also reduced. However, toxicity of high doses precludes its use to suppress androgens.

Cimetidine and spironolactone have weak antiandrogenic action which manifests as side effects. Progesterone has weak androgen receptor blocking action.

Drugs that have been clinically used to modify androgen action are:

Danazol

It is an orally active ethisterone derivative having weak androgenic, anabolic and progestational activities. Though labelled as an impeded/attenuated androgen, because it binds to the androgen receptor and induces some androgenspecific mRNA production, the most prominent action is suppression of Gn secretion from pituitary in both men and women → inhibition of testicular/ovarian function. It suppresses gonadal function directly as well by inhibiting steroidogenic enzymes. Endometrial atrophy occurs over few a weeks and amenorrhoea may supervene. Danazol is metabolized with a t½ of 12–18 hours.

Dose: 200–600 mg/day; DANAZOL, LADOGAL, DANOGEN, GONABLOK 50, 100, 200 mg cap.

Uses are:

1. Endometriosis

Danazol causes marked improvement in ~75% cases. Relief of dysmenorrhoea is prompt. Pain, dyspareunia and excessive bleeding regress slowly. After a 3–6 month course, prolonged relief occurs in over half of the patients. Severe cases derive incomplete relief. Androgenic side effects are the limiting feature, because of which use has declined.

2. Menorrhagia

It reduces menstrual blood loss. Usually complete amenorrhoea does not occur with 200 mg/day. When withdrawn after 3 months therapy—blood loss continues to be smaller than previously in many cases.

3. Fibrocystic Breast Disease (Chronic Cystic Mastitis):

3–6 months treatment causes improvement with decrease in pain, nodularity and engorgement in 75% cases.

4.  Hereditary Angioneurotic Edema (See Above)

5. Infertility

Withdrawal of danazol after 3 month treatment results in resumption of ovulation and rebound fertility in some women; pregnancy rate is increased in the subsequent 6 months.

Side Effects are frequent and dose related. Complete amenorrhoea occurs with higher doses as long as drug is given. Occasional spotting may be seen in some.

Androgenic side effects are acne, hirsutism, decreased breast size, deepening of voice, edema and weight gain. Loss of libido in men, hot flashes in women and night sweats, muscle cramps, g.i. upset, elivation of hepatic enzymes are the other side effects.

Cyproterone Acetate

It is chemically related to progesterone—has progestational activity which inhibits LH release augmenting the direct antiandrogenic action. More importantly, it competes with dihydrotestosterone for the intracellular androgen receptor and inhibits its binding. Larger doses prevent pubertal changes while in the adult libido and androgenic anabolism are lost, gynaecomastia can occur.

Cyproterone has been clinically tested in precocious puberty in boys, inappropriate sexual behaviour in men, acne and virilization in women, but is not marketed.

Flutamide

A nonsteroidal drug having specific antiandrogenic, but no other hormonal activity. Its active metabolite 2hydroxyflutamide competitively blocks androgen action on accessory sex organs as well as on pituitary—increases LH secretion by blocking feedback inhibition. Plasma testosterone levels increase in males which partially overcome the direct antiandrogenic action. Palliative effect may occur in metastatic prostatic carcinoma, but it is better used in conjunction with a GnRH agonist (to suppress LH and testosterone secretion) or after castration to block residual action of adrenal androgens. Along with oral contraceptives it has been tried in female hirsutism. Though gynaecomastia and breast tenderness occur frequently, libido and potency are largely preserved. Reports of liver damage have restricted its use.

Dose: 250 mg TDS; PROSTAMID, FLUTIDE, CYTOMID 250 mg tab.

Bicalutamide

This more potent and longer acting congener of flutamide is suitable for once daily administration in metastatic carcinoma of prostate. When used along with a GnRH agonist or castration, 50 mg OD affords marked relief in bone pain and other symptoms due to the metastasis. Side effects are hot flashes, chills, edema and loose stools, but it is better tolerated and less hepatotoxic than flutamide. Elevation of hepatic transaminase above twice normal is a signal for stopping the drug.

BIPROSTA, CALUTIDE, TABI 50 mg tab.