Prevention of Endometrial Changes Associated with Estrogens
Medroxyprogesterone acetate is used orally to reduce the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy. When estrogens are used in combination with progestins, such therapy usually is referred to as hormone replacement therapy (HRT) or postmenopausal replacement therapy. Evidence from the Women's Health Initiative (WHI) study indicates that combined estrogen (conjugated estrogens 0.625 mg daily) and medroxyprogesterone acetate (2.5 mg daily) therapy in postmenopausal women is associated with increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep-vein thrombosis. The risks identified in this study should be assumed to be similar with other hormonal regimens, including different dosages of these drugs as well as other estrogen/progestin combinations not studied in WHI, in the absence of comparable data to the contrary. If HRT is used, it should be prescribed in the lowest effective dosage and for the shortest duration consistent with treatment goals and risks for the individual women.
While there appears to be no increased risk of endometrial carcinoma in postmenopausal women receiving estrogen therapy for less than 1 year, prolonged estrogen therapy may be associated with an increased risk of such carcinoma. The risk of endometrial cancer reportedly is increased 2- to 12-fold in postmenopausal women receiving unopposed estrogen therapy compared with those not receiving estrogens; such increased risk may depend on dosage and duration of estrogen therapy and may be increased 15- to 24-fold in women receiving long-term (5 years or more) estrogen therapy. Limited data indicate that a substantial increased risk of endometrial carcinoma may persist for up to 15 years following discontinuance of estrogen therapy. Results of several studies indicate that addition of a progestin (e.g., medroxyprogesterone acetate) to estrogen replacement therapy reduces the incidence of endometrial hyperplasia and risk of endometrial carcinoma in women with an intact uterus. In a randomized, double-blind, controlled, multicenter study in postmenopausal women, endometrial hyperplasia occurred in 20 or 1% or less of women receiving conjugated estrogens alone or in conjunction with medroxyprogesterone acetate, respectively. Although estrogen-associated risk of endometrial carcinoma is substantially reduced when estrogens are administered concomitantly with progestins, a risk still exists. Therefore, clinical evaluation of all menopausal women receiving estrogen therapy in conjunction with a progestin is essential. Existing data do not support addition of a progestin in women who have undergone hysterectomy and are receiving estrogen replacement therapy.
Clinical studies indicate that use of a progestin in conjunction with estrogen replacement therapy does not interfere with the efficacy of the estrogen in the management of vasomotor symptoms associated with menopause, treatment of vulvar and vaginal atrophy, or prevention of osteoporosis. However, addition of a progestin to estrogen therapy may adversely affect some metabolic effects associated with long-term estrogen therapy and potential risks of concomitant therapy may include adverse effects on lipid metabolism and glucose tolerance. Results of several clinical studies in postmenopausal women indicate that replacement therapy with unopposed conjugated estrogens may reduce LDL-cholesterol and increase HDL-cholesterol by about 8-15%; concomitant progestin therapy may blunt some of the favorable effects of estrogens on the lipid profile of menopausal women. Data from several studies suggest that administration of a progestin concomitantly with estrogen therapy is associated with an increased risk of breast cancer beyond that associated with estrogen alone.
Contraception in Females
Medroxyprogesterone acetate (alone or in fixed combination with estradiol cypionate) is used parenterally as a long-acting contraceptive in women.
Medroxyprogesterone acetate (e.g., Depo-Provera Contraceptive, depo-subQ provera 104) is used parenterally for the prevention of conception. However, long-term use of parenteral medroxyprogesterone is associated with loss in bone mineral density (BMD). The loss of BMD in women of all ages and the possible impact on peak bone mass in adolescents should be considered when assessing the risks versus benefits of this contraceptive method. Parenteral medroxyprogesterone should be used as a long-term contraceptive method (e.g., longer than 2 years) only if other contraceptive methods are inadequate and the benefits are expected to outweigh the risks. (See Cautions: Precautions and Contraindications). Contraceptive measures other than parenteral medroxyprogesterone should be considered in women at risk for osteoporosis. When used according to the prescribed regimen (once every 3 months), parenteral medroxyprogesterone used alone provides almost completely effective contraception. The pregnancy rate in women using the drug alone generally is reported as less than 1 pregnancy per 100 women-years of use (as calculated via the Pearl index method) or as ranging from 0-0.7% during the first year of use (as calculated via life-table analysis). Compared with common contraceptive methods (e.g., estrogen-progestin combinations, condoms) other than intrauterine devices, implants, and sterilization, for which efficacy depends in large part on the reliability of appropriate use (patient compliance), contraceptive efficacy of parenteral medroxyprogesterone monotherapy depends on substantially less frequent patient-initiated actions (i.e., compliance with receipt of the injection only once every 3 months).
Medroxyprogesterone has been used extensively and effectively worldwide for many years as a contraceptive and has been recommended for this use by the World Health Organization (WHO) and the International Planned Parenthood Federation (IPPF); contraceptive use of medroxyprogesterone was added to the labeling approved by the US Food and Drug Administration (FDA) in the early 1990s. FDA's delay of approval of medroxyprogesterone for use as a contraceptive was based on questions of safety raised by studies in beagles in which the drug was associated with an increased incidence of mammary tumors; the availability of safer alternate methods for contraception and the lack of clear evidence that a substantial patient population in need of the drug exists in the US; the possibility that increased drug-induced bleeding disturbances may necessitate concomitant administration of an estrogen, imposing an additional risk and decreasing the benefits of progestin-only contraception; the possibility that exposure (possibly prolonged) of the fetus to the drug, if contraception fails, poses a risk of congenital malformation; and concerns that postmarketing surveillance for breast and cervical carcinoma might not provide meaningful data. Subsequently, the WHO Toxicology Review Panel, the IPPF, and several scientific advisory panels concluded that available evidence does not indicate a risk of adverse effects associated with parenteral medroxyprogesterone that would preclude its use as a contraceptive. These conclusions generally have been confirmed by various epidemiologic studies, including those conducted by WHO regarding the risk of various neoplasms and contraceptive steroid use.
(See Cautions: Mutagenicity and Carcinogenicityand also see Pregnancy, Fertility, and Lactation.)
Medroxyprogesterone in a fixed combination with estradiol is used parenterally for the prevention of conception. In clinical trials with the fixed combination containing medroxyprogesterone acetate and estradiol cypionate (Lunelle), the 12-month pregnancy rate reportedly was less than 0.2%. Because of limitations of the available data (e.g., loss to follow-up, lack of pregnancy testing, use of barrier contraceptives, concomitant drug therapy), it is not possible to estimate precisely the contraceptive failure rate, but the failure rate is likely to range from 0.1-1%. As with other estrogen-progestin contraceptives, the efficacy of medroxyprogesterone acetate in fixed combination with estradiol cypionate depends largely on adherence to the recommended dosage schedule. To ensure that the fixed combination of medroxyprogesterone acetate and estradiol cypionate is not inadvertently administered to a pregnant woman, the first injection should be given during the first 5 days of a normal menstrual period.
(See Pregnancy, Fertility, and Lactation: Pregnancy, in Cautions.)
Medroxyprogesterone acetate (depo-subQ provera 104) is used parenterally in the management of pain associated with endometriosis. In controlled clinical studies, medroxyprogesterone acetate (104 mg administered subcutaneously every 3 months for 6 months) was effective in relieving clinical symptoms (e.g., dysmenorrhea, dyspareunia, pelvic pain) and signs (e.g., pelvic tenderness, pelvic induration) of endometriosis. Long-term use of parenteral medroxyprogesterone is associated with loss in bone mineral density (BMD). The loss of BMD in women of all ages and the possible impact on peak bone mass in adolescents should be considered when assessing the risks versus benefits of therapy with medroxyprogesterone. (See Cautions: Precautions and Contraindications).
Amenorrhea and Uterine Bleeding
Medroxyprogesterone acetate is used orally for the treatment of secondary amenorrhea and for the treatment of abnormal uterine bleeding caused by hormonal imbalance in patients without underlying organic pathology such as fibroids or uterine cancer.
Endometrial or Renal Carcinoma
Medroxyprogesterone acetate is used parenterally as adjunctive and palliative therapy for the treatment of inoperable, recurrent, and metastatic endometrial carcinoma. The initial treatment of the early stages (I and II) of endometrial carcinoma is surgery, sometimes combined with radiation therapy. In advanced endometrial carcinoma that is no longer amenable to surgery or radiation, hormonal therapy with progestins or chemotherapy should be considered.
Although medroxyprogesterone has been used in the treatment of metastatic renal cell carcinoma, other agents are considered more effective for the systemic treatment of this cancer. and
Paraphilia in Males
Medroxyprogesterone acetate has been used parenterally (e.g., 100-500 mg IM weekly) for the management of paraphilia (e.g., homosexual, heterosexual, or bisexual pedophilia; heterosexual voyeurism, sexual sadism, or exhibitionism; transvestism) in males. The drug has been shown to decrease the frequency of erotic imagery and the intensity of erotic cravings in most of these males. Sexual deviance generally returns following discontinuance of the drug.
Medroxyprogesterone acetate has been used for the management of both GnRH-dependent (central) and -independent (peripheral) forms of precocious puberty and was the most widely used drug for the management of various forms of precocity. However, use of medroxyprogesterone in the management of central (true) precocious puberty generally has been supplanted by GnRH analogs (e.g., leuprolide) because of the improved pharmacologic specificity and adverse effect profile of these latter drugs; occasionally, medroxyprogesterone continues to be used for central precocity in patients who do not tolerate GnRH analog therapy. The optimum therapeutic regimen for the management of familial male precocious puberty (testotoxicosis) or for McCune-Albright syndrome, both GnRH-independent forms of precocity, remains to be established, and medroxyprogesterone is one of several therapeutic regimens (e.g., medroxyprogesterone, testolactone/spironolactone, testolactone/flutamide, or ketoconazole for familial male precocity; medroxyprogesterone or testolactone for McCune-Albright syndrome) currently being employed. While comparative safety and efficacy have not been established by controlled studies, medroxyprogesterone may be less likely than other regimens to favorably affect growth rate and skeletal maturation and more likely to adversely affect adrenocortical function.
Medroxyprogesterone acetate also has been used in the management of postmenopausal symptoms in females, obesity-hypoventilation syndrome (Pickwickian syndrome), obstructive sleep apnea syndrome and hypersomnolence in adults, hirsutism and homozygous sickle-cell disease.