Progestins

Progestins are primarily used postmenopausally to reduce the risk of endometrial hyperplasia due to estrogen replacement therapy. They also help relieve hot flashes and prevent osteoporosis in patients in whom estrogen replacement therapy is contraindicated.

Pharmacology

Oral absorption of progesterone is highly variable, differing as much as threefold among patients. Thus, a dose that is adequate for one patient may be excessive for another. After absorption, oral progestins reach the liver in high concentration and may greatly affect the hepatic metabolism of serum lipoproteins. Progesterone and its derivatives are well absorbed when given vaginally, rectally, or intramuscularly.

Medroxyprogesterone acetate, the most commonly used progestin in the USA, is effective against endometrial hyperplasia and has only minor adverse effects on serum lipid levels. It may be given orally with estrogens; the minimal effective dose is 5 mg po when given as cyclic treatment (days 1 through 13 each month) and 2.5 mg po when given continuously. Alternatively, it may be given as an IM depot formulation, which is well absorbed but has a highly variable duration of action and often causes irregular vaginal bleeding. The usual dose is 50 to 150 mg IM every 1 to 3 months, with the amount and interval depending on bleeding patterns and the effect on symptoms; the 50-mg dose is usually adequate to relieve hot flashes, and the 150-mg dose reduces urinary calcium loss as effectively as conjugated estrogens 0.625 mg.

Micronized progesterone, 200 mg po daily for cyclic treatment and 100 mg po daily for continuous treatment, does not significantly alter serum lipid levels but does prevent endometrial hyperplasia. Megestrol acetate 40 to 80 mg/day po suppresses hot flashes. These high doses are necessary because megestrol acetate has one fourth to one eighth the potency of medroxyprogesterone acetate on a per-weight basis.

19-Nortestosterone derivatives are used in oral contraceptives; they have partial androgenic properties and an adverse effect on serum lipid levels. However, norethindrone (norethisterone) 1 mg/day treats endometrial hyperplasia with no adverse effect on lipid levels. d,l-Norgestrel is not commonly used because it has more potent androgenic properties than norethindrone.

Adverse Effects

Progestins may produce abdominal bleeding, mastalgia, headache, mood changes, and acne. All progestins, particularly the 19-nortestosterone derivatives, adversely affect serum lipid levels, decreasing HDL cholesterol and increasing LDL cholesterol in a dose-dependent manner. Thus, the risk of developing cardiovascular disease may outweigh the benefit of preventing endometrial cancer. Because the protective activity of progestins on the endometrium appears related more to the duration of use (ie, 13 out of 25 days) than to the dose, the lowest effective dose should be used. Because of cardiovascular risk and because progestins have not been proved to protect against breast cancer, these drugs are not recommended for women without an intact uterus receiving estrogen replacement therapy.