The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95 percent CI, 0.77–3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.
In the WHIMS estrogen plus progestin ancillary study, of WHI, a population of 4,532 postmenopausal women aged 65 to 79 years was randomized to daily CE (0.625 mg) plus MPA (2.5 mg) or placebo.
After an average follow-up of 4 years, 40 women in the CE plus MPA group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21–3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL STUDIES and PRECAUTIONS, Geriatric Use.)
Discontinue estrogen plus progestin therapy pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia or migraine. If examination reveals papilledema or retinal vascular lesions, estrogen plus progestin therapy should be permanently discontinued.
Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer.
There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.
In cases of unexpected abnormal vaginal bleeding, adequate diagnostic measures are indicated.
Blood pressure should be monitored at regular intervals with estrogen plus progestin therapy.
In women with pre-existing hypertriglyceridemia, estrogen plus progestin therapy may be associated with elevations of plasma triglycerides leading to pancreatitis Consider discontinuation of treatment if pancreatitis occurs.
Estrogens plus progestins may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued.
Progestins may cause some degree of fluid retention. Women who have conditions which might be influenced by this factor, such as cardiac or renal impairment, warrant careful observation when estrogen plus progestin are prescribed.
Estrogen plus progestin therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
Estrogen plus progestin therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
Physicians are advised to discuss the Patient Information leaflet with women for whom they prescribe MPA tablets.
There may be an increased risk of minor birth defects in children whose mothers are exposed to progestins during the first trimester of pregnancy. The possible risk to the male baby is hypospadias, a condition in which the opening of the penis is on the underside rather than the tip of the penis. This condition occurs naturally in approximately 5 to 8 per 1,000 male births. The risk may be increased with exposure to MPA tablets. Enlargement of the clitoris and fusion of the labia may occur in female babies. However, a clear association between hypospadias, clitoral enlargement and labial fusion with use of MPA tablets has not been established.
Inform the patient of the importance of reporting exposure to MPA tablets in early pregnancy.
The following laboratory results may be altered by the use of estrogen plus progestin therapy:
- Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX , X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
- Increased thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay, T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free hormone concentrations,such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels.
- Impaired glucose tolerance.
Long-term intramuscular administration of MPA has been shown to produce mammary tumors in beagle dogs. There was no evidence of a carcinogenic effect associated with the oral administration of MPA to rats and mice.
Medroxyprogesterone acetate was not mutagenic in a battery of in vitro or in vivo genetic toxicity assays.
Medroxyprogesterone acetate at high doses is an antifertility drug and high doses would be expected to impair fertility until the cessation of treatment.
Pregnancy Category X
MPA tablets should not be used during pregnancy. (See CONTRAINDICATIONS.)
There may be increased risks for hypospadias, clitoral enlargement and labial fusion in children whose mothers are exposed to MPA tablets during the first trimester of pregnancy. However, a clear association between these conditions with use of MPA tablets has not been established.
MPA tablets should not be used during lactation. Detectable amounts of progestin have been identified in the breast milk of nursing mothers receiving progestins.
MPA tablets are not indicated in children. Clinical studies have not been conducted in the pediatric population.
There have not been sufficient numbers of geriatric women involved in clinical studies utilizing MPA alone to determine whether those over 65 years of age differ from younger subjects in their response to MPA alone.
In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age. (See CLINICAL STUDIES.)
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