Medroxyprogesterone Acetate 71-58-9

History

Medroxyprogesterone 17-acetate was independently discovered in 1956 by Syntex and the Upjohn Company.

Preclinical pharmacology

While both the parent medroxyprogesterone (MP) and its acylated derivative medroxyprogesterone acetate (MPA) bind to the progesterone receptor (PR) and both act as agonists, MPA has approximately 100 fold higher binding affinity and transactivation potency compared to MP:

Indications

In females, the most common use of MPA is as an oral or depot-injected contraceptive and also as the progestin component of menopausal hormone replacement therapy to prevent endometrial hyperplasia and cancer. MPA is also used as a treatment for endometriosis, dysmenorrhea, and amenorrhea. MPA, along with other progestins were developed to allow the hormones to be taken orally, as progesterone (the hormone made by the human body) could not be taken orally before the process of micronization was developed. In males, MPA has been used to control inappropriate sexual behavior to chemically castrate convicted sex offenders. MPA is an extremely effective contraceptive when used with relatively high doses to prevent ovulation. It has also been used to treat benign prostatic hyperplasia, as a palliative appetite stimulant for cancer patients, and at high doses (800 mg per day) to treat hormone-dependent cancers of primarily the breast, but also other types.

Adverse effects

In females, the most common adverse effects are acne, changes in menstrual flow, drowsiness, and can cause birth defects if taken by pregnant women. Other common side effects include breast tenderness, increased facial hair, decreased scalp hair, difficulty falling or remaining asleep, stomach pain, and weight loss or gain. At high doses for the treatment of breast cancer, MPA can cause weight gain, worsen diabetes mellitus and edema (particularly of the face). Adverse effects peak at five weeks, and are reduced with lower doses. Less frequent effects may include thrombosis (though it is not clear if this is truly a risk, it can not be ruled out), painful urination, anxiety, headache, nausea and vomiting. When used to treat benign prostatic hyperplasia, more frequent complaints include reduced libido, impotence, reduced ejaculate volume, and within three days, chemical castration. MPA may cause reduced bone density though this appears to be reversible to a normal level even after years of use. At extremely high doses (used to treat cancer, not for contraception) MPA may cause adrenal suppression and interfere with carbohydrate metabolism but does not cause diabetes. Fetuses exposed to progesterones have demonstrated higher rates of genital abnormalities, low birth weight, and increased ectopic pregnancy particularly when MPA is used as an injected form of long-term birth control. When used as a form of injected birth control, MPA can reduce fertility for as long as 10 months, taking longer for overweight or obese women. When combined with conjugated equine estrogens (Premarin), MPA has been associated with an increased risk of breast cancer, dementia and thrombus in the eye. In combination with estrogens in general, MPA may increase the risk of cardiovascular disease, with a stronger association when used by post-menopausal women also taking CEE. MPA is not recommended for use prior to menarche or before or during recovery from surgery. producing a dramatic decrease in both new and renewal prescriptions for hormone therapy.

Physical and chemical properties

MPA is stable at room temperature.

Pharmacodynamics

In females, MPA inhibits gonadotropin secretion from the pituitary which in turn prevents ovarian follicle maturation and ovulation, as well as thining the endometrium. The evidence for this view has been questioned; medroxyprogesterone is better absorbed when taken orally, with a much longer half life leading to more stable blood levels though it may lead to greater breast tenderness and more sporadic vaginal bleeding. The two compounds have not been adequately compared in direct tests to clear conclusions about safety and superiority.

Synthesis

Medroxyprogesterone 17-acetate can be prepared by the following sequence:500px