Micronized Progesterone — Endometrial Protection and Symptom Support

Oral capsule: Administer orally in the evening or at bedtime, with food (peanut oil–based commercial capsules require fat for absorption; compounded formulations in various bases may differ — confirm with the dispensing pharmacy). Evening administration leverages the mild sedative effect and reduces awareness of any drowsiness. Vaginal use: If prescribed vaginally, insert the capsule high into the vagina using the applicator or gloved finger at bedtime. Vaginal administration achieves high uterine concentrations (first uterine pass effect) with lower systemic levels. Oral administration is required for confirmed endometrial protection based on established clinical trial data; the evidence base for transdermal progesterone providing adequate endometrial protection is insufficient per current clinical guidance.

Dosing is individualized and prescriber-determined based on the estrogen dose and regimen, cycle schedule, and clinical indication.

• Endometrial protection (cyclical): 200 mg orally once daily in the evening for 12–14 days per 28-day cycle — established in clinical trials as adequate protection with standard estrogen doses.
• Endometrial protection (continuous combined): 100–200 mg orally once daily — dose aligned with estrogen dose; higher estrogen doses may require 200–300 mg.
• Secondary amenorrhea: 400 mg orally once daily for 10 days per prescriber direction.
• Vaginal formulations: Dosing is prescriber-determined; evidence supports 45–200 mg/day for endometrial effects via vaginal route, though oral remains the best-evidenced route.

• Micronized Progesterone: Binds progesterone receptors (PR-A and PR-B) in the endometrium, myometrium, and breast tissue, opposing the proliferative effects of estrogen. In the endometrium, it induces secretory transformation, inhibits mitosis, and reduces estrogen receptor expression, thereby preventing hyperplasia and cancer. The oral micronized formulation is absorbed in the GI tract with first-pass hepatic metabolism yielding active metabolites including allopregnanolone and pregnanolone, which are positive allosteric modulators of GABA-A receptors — producing anxiolytic and sedative-like effects that may benefit sleep and mood. Micronized progesterone has a neutral-to-favorable cardiovascular profile compared to synthetic progestins, without the androgenic or glucocorticoid receptor activity associated with medroxyprogesterone acetate.

Primary indications in menopause hormone therapy (MHT): Prevention of endometrial hyperplasia and cancer in non-hysterectomized postmenopausal women receiving systemic estrogen. Secondary applications include management of secondary amenorrhea and adjunctive support for sleep disturbance and mood symptoms during perimenopause or menopause.

Prescriber monitoring:

• Annual pelvic examination and symptom review; endometrial biopsy if abnormal uterine bleeding occurs
• Mammography per routine screening guidelines — observational data suggests micronized progesterone carries lower breast cancer risk than synthetic progestins, though absolute risk increases with prolonged MHT duration
• Serum progesterone levels are not routinely monitored during oral therapy due to variable absorption and metabolite confounders; clinical and endometrial response guides adequacy
• Monitor for drowsiness, particularly with evening oral dosing in combination with other CNS depressants

Contraindications:

• Undiagnosed abnormal vaginal bleeding
• Known or suspected breast or estrogen-dependent malignancy
• Active or history of thromboembolic disorder (arterial or venous)
• Liver disease or dysfunction
• Hypersensitivity to progesterone or any component (commercial Prometrium contains peanut oil — confirm formulation basis for allergy risk)

Warnings & Precautions:

• Depression and mood changes — monitor patients with a history of depression
• Sedation/drowsiness — caution with concurrent CNS depressants; evening dosing is preferred
• Progesterone is not recommended as sole contraceptive method in perimenopausal women with ovarian activity
• Compounded progesterone: insufficient evidence supports equivalence to FDA-approved Prometrium for endometrial protection per some clinical guidelines — prescribers should document clinical rationale and monitor accordingly

Drug Interactions:

• CYP3A4 inducers (rifampin, carbamazepine, phenobarbital): accelerate progesterone metabolism, potentially reducing efficacy
• CYP3A4 inhibitors (ketoconazole, clarithromycin): may increase progesterone plasma levels
• CNS depressants, alcohol: additive sedation

Common Side Effects: Drowsiness, dizziness, headache, breast tenderness, bloating, mood changes, irregular vaginal bleeding or spotting (particularly initial cycles), abdominal cramping.

Store at controlled room temperature (20–25°C), away from moisture, heat, and light. Keep the container tightly closed. Vaginal dosage forms should also be stored away from heat. Observe the beyond-use date assigned by Genesis Compounding. Do not refrigerate unless specifically directed on the label.

Why do I need progesterone if I am taking estrogen?

Unopposed estrogen stimulates endometrial cell proliferation, significantly increasing the risk of endometrial hyperplasia and cancer in women with an intact uterus. Progesterone opposes this effect, converting the endometrium from a proliferative to a secretory state and dramatically reducing cancer risk.

Is micronized progesterone safer than synthetic progestins?

Observational data and biological mechanisms suggest that bioidentical micronized progesterone carries a more favorable cardiovascular, thromboembolic, and breast cancer risk profile compared to synthetic progestins such as medroxyprogesterone acetate. However, randomized trial confirmation of superiority over all progestins is limited.

Why should I take this at bedtime?

Oral micronized progesterone metabolites stimulate GABA-A receptors, producing mild sedation. Taking the dose at bedtime reduces the impact of drowsiness and may improve sleep quality in perimenopausal patients.

Can I use a progesterone cream instead of this capsule?

Transdermal progesterone cream does not reliably provide adequate endometrial protection at standard doses — evidence supports only oral (and to a lesser extent vaginal) micronized progesterone for this indication. Your prescriber has determined the appropriate route for your situation.

Is this FDA-approved?

Commercial micronized progesterone (Prometrium) is FDA-approved. This preparation is a prescriber-directed, patient-specific 503A compounded formulation and has not been independently evaluated by the FDA as a compounded product.