Progesterone

Progesterone is an endogenous steroid hormone produced primarily by the corpus luteum of the ovary during the second half of the menstrual cycle (the luteal phase) and, during pregnancy, by the placenta. It acts through progesterone receptors distributed in the uterus, breast, brain, and other tissues. In the menstrual cycle, progesterone prepares the endometrium for embryo implantation and, in the absence of fertilization, its withdrawal triggers menstruation. Progesterone is one of two major classes of progestogens — the other being synthetic progestins such as medroxyprogesterone acetate and norethindrone — and the two classes differ in receptor selectivity, metabolic effects, and potential risks.¹

The pharmaceutical form used in the United States is micronized progesterone (Prometrium and generics), in which progesterone is ground into very fine particles to improve oral absorption. Because progesterone is extensively metabolized in the gut and liver, unmicronized oral progesterone is poorly absorbed; micronization substantially improves bioavailability. Prometrium contains peanut oil and is contraindicated in patients with peanut allergy.¹

Micronized progesterone capsules (Prometrium and generics) are FDA-approved for:¹

• Endometrial protection in postmenopausal women on estrogen therapy: Prevention of endometrial hyperplasia in non-hysterectomized postmenopausal women who are receiving conjugated estrogens (0.625 mg). This is the primary use — women with an intact uterus taking systemic estrogen require concurrent progesterone or progestin to prevent endometrial cancer.
• Secondary amenorrhea in premenopausal women.

Off-label uses: Progesterone is frequently prescribed off-label as part of gender-affirming hormone therapy, for luteal phase support in fertility treatment, for premenstrual syndrome or premenstrual dysphoric disorder, and for the management of perimenopause symptoms. Some menopausal hormone therapy protocols use micronized progesterone at doses and schedules not strictly covered by the labeled indication.

For endometrial protection in postmenopausal women on estrogen therapy:¹

• Cyclical dosing: 200 mg once daily for 12 consecutive days per 28-day cycle.
• Continuous combined dosing: Lower doses (often 100 mg daily) are used off-label for continuous administration alongside continuous estrogen; clinical evidence supports this but it falls outside the primary labeled schedule.

Progesterone capsules are generally taken at bedtime because sedation is a common side effect at the doses used for hormone therapy. They should be taken with a full glass of water while standing to reduce the risk of capsule lodging in the esophagus.

Oral (micronized capsules). Progesterone is also used vaginally in fertility medicine (off-label for some preparations; other progesterone vaginal products have specific FDA approvals for assisted reproduction).

Store at room temperature between 59°F and 86°F (15°C to 30°C). Keep away from moisture and excessive heat. Capsules contain peanut oil; keep out of reach of children.¹

Peanut allergy: Prometrium capsules contain peanut oil; use is contraindicated in patients with known peanut allergy. Patients with peanut allergy who require progestogen coverage for endometrial protection may need a synthetic progestin alternative.¹

Key considerations from the FDA label and clinical context:¹

• CNS effects: Micronized progesterone produces dose-dependent sedation, dizziness, and mood effects — a consequence of its conversion in the brain to allopregnanolone and other neurosteroids that act on GABA-A receptors. Evening dosing is recommended for this reason. The same neuroactive metabolite pathway is also associated with anxiolytic and sleep-promoting effects that are sometimes cited as advantages over synthetic progestins.
• Breast cancer risk: Combined estrogen-progestogen menopausal therapy, as studied in the Women's Health Initiative, was associated with a modest increase in breast cancer risk. Some observational evidence suggests micronized progesterone may carry lower breast cancer risk than synthetic progestins (notably medroxyprogesterone acetate), but randomized controlled trial data comparing these agents on this specific endpoint are limited.
• Cardiovascular effects: The cardiovascular risk profile of micronized progesterone is generally considered more favorable than some synthetic progestins based on observational data, but this distinction is not established by randomized trial evidence.
• Pregnancy: Progesterone is classified as not for use during pregnancy when used for the menopausal indications; separate products with specific FDA approvals are used for pregnancy support in assisted reproduction.
• Drug interactions: Progesterone can affect cytochrome P450 enzymes and may interact with other medications metabolized by these pathways.