Progesterone IR/SR 50mg, 100mg, 150mg, 200mg, 300mg (Typical SIG 50-300mg PO QHS)

Route: Oral capsule, taken by mouth.

• Administer at bedtime (QHS) as prescribed. Progesterone has mild sedative properties mediated by its conversion to neuroactive steroids (allopregnanolone) that potentiate GABA-A receptors—QHS dosing exploits this for improved sleep while minimizing daytime drowsiness.
• Take with a small amount of food or a glass of milk to enhance bioavailability; food increases absorption by approximately 50% in comparison to fasting state.
• Swallow the capsule whole. Do not crush or chew.
• SR formulation is designed for once-daily dosing throughout the day or as directed by the prescriber.

All dosing is prescriber-directed and patient-specific. Reference ranges from established evidence:

• Endometrial protection (HRT): 200 mg/day continuously, or 200 mg/day sequentially for 12–14 consecutive days per 28-day cycle, in women on estrogen therapy with an intact uterus.
• Low-dose continuous (with ultra-low or low transdermal estrogen): 100 mg/day continuous.
• VMS and sleep improvement: 300 mg/day (sole progesterone therapy without estrogen) has demonstrated efficacy for vasomotor symptoms and sleep in some studies.
• Luteal phase support / secondary amenorrhea: 400 mg/day for 10 days (standard dosing per FDA labeling for Prometrium).
• The SR formulation may be preferred for once-daily dosing convenience and more stable diurnal plasma levels; dose equivalence to IR must be confirmed with the prescribing clinician.
• Serum or immunoassay progesterone monitoring is not reliable for oral micronized progesterone due to metabolite cross-reactivity; monitor clinically (endometrial thickness, bleeding patterns) rather than by serum levels.

• Micronized Progesterone: Diffuses into target cells (endometrium, breast, CNS, cardiovascular smooth muscle) and binds nuclear progesterone receptors (PR-A and PR-B), altering gene transcription. In the endometrium, PR activation opposes estrogen-stimulated proliferation, inducing secretory transformation and maintaining a stable endometrial lining. In the CNS, progesterone is metabolized to allopregnanolone (3α-5α-tetrahydroprogesterone), a potent positive allosteric modulator of GABA-A receptors, producing anxiolytic, sedative, and anti-convulsant effects. Bioidentical progesterone does not exhibit the mineralocorticoid, glucocorticoid, or androgenic activity associated with synthetic progestins, and has not been shown to increase breast cancer risk or thromboembolic risk at approved doses.

Indication context: Oral micronized progesterone is the standard-of-care progestogen for endometrial protection in women receiving systemic estrogen therapy (menopausal hormone therapy) who have an intact uterus. It is also used for secondary amenorrhea, luteal phase support in reproductive medicine, sleep disturbance, and vasomotor symptom management. Unlike synthetic progestins, oral micronized progesterone has a more favorable cardiovascular, metabolic, and breast safety profile based on available evidence.

Monitoring considerations:

• Endometrial assessment: annual clinical evaluation; transvaginal ultrasound (TVUS) for endometrial thickness if breakthrough bleeding, spotting, or irregular bleeding occurs. Thickness ≤5 mm generally indicates adequate progesterone protection.
• Breast: annual clinical breast exam and mammography per age-appropriate guidelines.
• Pap smear per standard gynecologic screening schedule.
• Monitor for excessive somnolence or dizziness, particularly with IR formulations—consider SR or dose reduction.
• Liver function: use with caution in hepatic impairment; progesterone is extensively hepatically metabolized.

Contraindications:

• Undiagnosed abnormal genital bleeding.
• Known, suspected, or history of breast cancer (unless directed by oncologist in specific circumstances).
• Known or suspected progesterone-dependent neoplasia.
• Active arterial thromboembolic disease (stroke, MI)—note oral micronized progesterone has not demonstrated increased VTE risk unlike many synthetic progestins.
• Hepatic impairment or disease.
• Peanut allergy (commercial Prometrium contains peanut oil; compounded formulations may use alternative excipients—confirm with Genesis Compounding).

Warnings & Precautions:

• Somnolence and dizziness: most common adverse effects, particularly with IR at bedtime dosing; caution regarding driving or operating machinery on the same evening.
• Breakthrough bleeding and spotting: more common with continuous low-dose or IR formulations; evaluate endometrial thickness if persistent.
• Fluid retention: may worsen conditions such as epilepsy, migraine, asthma, or cardiac/renal dysfunction.
• Depression: monitor for mood changes; progesterone's neuroactive metabolites can rarely exacerbate depression in susceptible individuals.

Drug Interactions:

• CYP3A4 inhibitors (ketoconazole, grapefruit juice): may increase progesterone plasma levels; monitor for excessive sedation.
• CYP3A4 inducers (rifampin, carbamazepine, St. John's Wort): may decrease progesterone efficacy.
• Anticoagulants: progesterone may affect clotting factors; monitor INR if applicable.

Common Side Effects: Dizziness (16%), breast pain (11%), headache (10%), abdominal pain (10%), fatigue (9%), mood lability, drowsiness (particularly with IR).

Store at room temperature (15–25°C). Protect from moisture, heat, and light. Keep tightly capped in the original dispensing container. SR capsules should not be punctured or opened. Use within the beyond-use date assigned by Genesis Compounding. Keep out of reach of children.

What is the difference between the IR and SR formulations?

The immediate-release (IR) capsule dissolves quickly, with plasma progesterone peaking within 1–3 hours and returning to baseline within 8 hours. It is well-suited to bedtime dosing, leveraging the sedative properties of its neuroactive metabolites. The sustained-release (SR) formulation releases progesterone over 24 hours, providing more stable plasma levels and once-daily dosing convenience with potentially fewer CNS sedative effects.

Why is progesterone taken at bedtime?

Oral progesterone is metabolized to allopregnanolone, which enhances GABA-A receptor activity and produces mild sedation. Taking it at bedtime exploits this property to support sleep quality while minimizing daytime drowsiness or dizziness.

How is endometrial protection monitored?

Clinical assessment of bleeding patterns (any unscheduled bleeding should be reported promptly) and transvaginal ultrasound to measure endometrial thickness are the primary monitoring tools. An endometrial thickness ≤5 mm typically indicates adequate protection. Serum progesterone immunoassays are not reliable monitoring tools when taking oral micronized progesterone due to metabolite cross-reactivity.

Is bioidentical progesterone safer than synthetic progestins?

Available evidence suggests oral micronized progesterone has a more favorable breast safety profile and does not increase thromboembolic risk, unlike some synthetic progestins. However, all HRT decisions involve individualized risk-benefit analysis; discuss your specific situation with your prescriber.

Is this medication FDA-approved?

Oral micronized progesterone (Prometrium) is FDA-approved in 100 mg and 200 mg strengths. This compounded preparation by Genesis Compounding offers the full dose range (50–300 mg) in both IR and SR formulations as patient-specific 503A preparations, which are not individually FDA-approved compounded products.