Progesterone

In the Women's Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in women ≥65 years with daily conjugated estrogens combined with medroxyprogesterone. This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson 2012). An increase in abnormal mammogram findings has also been reported with estrogen in combination with progestin therapy. Use is contraindicated in patients with known or suspected breast cancer.

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

Progestin plus estrogens should not be used for the prevention of dementia. In the Women's Health Initiative Memory Study (WHIMS), an increased risk of developing probable dementia was observed in women ≥65 years with daily conjugated estrogens combined with medroxyprogesterone.

Progesterone is used to reduce the risk of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogens. The use of unopposed estrogen in women with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal persistent or recurring vaginal bleeding. Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.

May cause fluid retention; use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, cardiac impairment, epilepsy, migraine, and diabetes.

Progesterone plus estrogen therapy may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS 2012).

Discontinue pending examination in cases of sudden partial or complete vision loss, sudden onset of proptosis, diplopia, or migraine; discontinue permanently if papilledema or retinal vascular lesions are observed on examination. Disease-related concerns:

Progestin plus estrogen should not be used for the prevention of cardiovascular disease. In the WHI studies, an increased risk of DVT, PE, stroke, and myocardial infarction was observed in women ≥65 years with daily conjugated estrogens combined with medroxyprogesterone. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Risk factors should be managed appropriately; discontinue use if adverse cardiovascular events occur or are suspected.

Use with caution in patients with a history of depression.

Use with caution in patients with diabetes; decreased glucose tolerance may occur.

Use is contraindicated in hepatic impairment or disease.

Use with caution in patients with renal impairment; progestins may cause fluid retention. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Not for use prior to menarche.

Whenever possible, progestins in combination with estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization. Dosage form specific issues:

Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity ("gasping syndrome") in neonates; the "gasping syndrome" consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.

Some products may contain palm oil.

Some products may contain peanut oil.

Some products may contain sesame oil. Other warnings/precautions:

Oral: [US Boxed Warning]: Progestin with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral conjugated estrogens with medroxyprogesterone relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using conjugated estrogens with medroxyprogesterone should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.