Progestogens

Desogestrel

Desogestrel, one of the so-called third-generation progestogenic steroids intended for use in oral contraceptives, is metabolized to estrogen. It was developed and introduced because of its relatively favorable effect on blood lipids in experimental work; this led to the hope that it might, in the long run, have a relatively favorable effect on the risk of atherogenesis. However, it is not clear that this does in fact happen, and the third-generation progestogens have been associated with an increased risk of thromboembolism.

Gestodene

Gestodene is a third-generation progestogen that has been implicated in an increased risk of thromboembolism.

Gestonorone caproate

Gestonorone (17-hydroxy-19-norprogesterone) has been used in doses of 200 mg intramuscularly weekly for benign prostatic hyperplasia [ ]. Mild adverse effects included loss of appetite and mild fever, but more remarkable were significant reductions in erythrocyte count, hemoglobin, and hematocrit, which normalized after drug withdrawal [ ].

Hydroxyprogesterone caproate

High doses of hydroxyprogesterone and the related nor-derivative have been used to treat benign prostatic hyperplasia. Very striking is the high incidence of impotence recorded in these studies, which can affect two-thirds of patients and seems to persist in some patients after withdrawal [ ].

Levonorgestrel

Extensive clinical trials and premarketing studies were conducted before the Norplant (levonorgestrel) implant was registered and approved, in order to elucidate its mode of action, effectiveness, and adverse effects. However, none of these trials included either teenagers under 18 years of age or nulligravid women.

In an 18-month observational study of 136 adolescents (13–18 years) and 542 adults (19–46 years) who were given Norplant levonorgestrel contraceptive implants problems were reported by 110 patients, mostly irregular bleeding (53% of the adolescents and 38% of the adults) [ ]. Removal of the implant was requested by 11% of both adolescents and adults, most commonly for intolerable menstrual cycle changes, and in 6% of all the adults for irregular bleeding; the time from insertion to removal was 3–15 months for the adolescents and 1–17 months for the adults. Other problems that led to removal (in 5% of adolescents and 7.5% of adults), apart from a desire to become pregnant, included headache, weight gain, and acne.

Lynestrenol

Lynestrenol is one of the older progestogens used in oral contraceptives and has been very widely and successfully employed for nearly 40 years; as monotherapy it has been used to treat irregularity of the menstrual cycle.

In a Finnish study analysis of the association between the prolonged use of lynestrenol (to suppress menstruation in mentally retarded women) and arterial disease detected at autopsy, the conclusion was that such treatment, here given for a mean of more than 6 years, increases the risk of arterial disease and that such treatment must be very carefully considered [ ].

Medroxyprogesterone acetate

Medroxyprogesterone acetate is the subject of a separate monograph.

Megestrol

Megestrol acetate, like medroxyprogesterone acetate, is used for metastatic breast cancer in postmenopausal women. Its commonest adverse effects are typical of the progestogens as a group, but glucocorticoid-like effects are less prominent than with medroxyprogesterone acetate. Typical effects and incidence figures for effective doses in patients with cancers [ , ] have been cited as including weight gain in some 81–88% of cases, mild edema in up to 34%, and hypertension in up to 25%. There are lower but appreciable occurrences of constipation, dyspnea or chest tightness, heartburn, hyperglycemia, and increased urinary frequency; a few cases of phlebitis or thrombosis have been described. Vaginal bleeding, nervousness, sweating, vertigo, gastrointestinal symptoms, rashes pruritus, and thrombocytopenia have also been incidentally recorded.

Megestrol acetate has also proved of value in patients with metastatic prostatic cancer, epithelial ovarian cancer, or malignant melanoma and is therefore used in both sexes. The adverse effects are very similar in men to those seen with oncological doses in women; loss of libido and potency is likely to occur in male patients. In one clinical study of 43 men with recurrent and metastatic cancer of the prostate given megestrol acetate 160 mg/day orally, five developed a symptomatic rise in liver enzymes but it resolved during further treatment. In three patients, increasing bone pain occurred, no doubt relating to changes in bony metastases and requiring analgesia. Another patient developed hypercalcemia and one patient developed convulsive epilepsy [ ]. These latter problems are characteristic of the primary condition as it responds, and not typical for megestrol acetate. The glucocorticoid-induced gain in body weight when it occurs is often linked to improved appetite [ ], which can be a positive advantage in cachectic patients with advanced cancers.

When megestrol acetate was used alongside diethylstilbestrol or ethinylestradiol in men with previously untreated metastatic carcinoma of the prostate, there was a high incidence of feminizing adverse effects (70–74%), no doubt attributable to the estrogens; a higher than expected rate of cardiovascular complications (18%) and an unexplained need for cortisone replacement (13%) were also observed [ ].