Progesterone - Drug Monograph

Introduction

Progesterone is a naturally occurring steroid hormone that plays a crucial role in the female reproductive system. As a medication, it is used in various formulations to address hormonal imbalances and support reproductive health. Synthetic versions, known as progestins, have been developed, but bioidentical progesterone remains an important therapeutic option with distinct physiological effects.

Mechanism of Action

Progesterone exerts its effects primarily through binding to intracellular progesterone receptors, resulting in genomic activation and transcription of target genes. It transforms the estrogen-primed endometrium from proliferative to secretory phase, supports embryo implantation, and maintains pregnancy. Progesterone also decreases gonadotropin secretion through negative feedback on the hypothalamic-pituitary axis, inhibits uterine contractility, and promotes mammary gland development.

Indications

• FDA-approved indications:

- Prevention of endometrial hyperplasia in postmenopausal women with intact uteri receiving estrogen therapy - Secondary amenorrhea - Abnormal uterine bleeding due to hormonal imbalance - Assisted reproductive technology (ART) procedures to support embryo implantation - Prevention of preterm birth in women with singleton pregnancy and short cervical length

• Off-label uses:

- Luteal phase support - Premenstrual dysphoric disorder (PMDD) - Menopausal symptom management - Endometriosis-associated pain

Dosage and Administration

• Menopausal hormone therapy: 200 mg daily at bedtime for 12 sequential days
• Secondary amenorrhea: 400 mg daily at bedtime for 10 days

• ART support: 90 mg once or twice daily
• Preterm birth prevention: 90-200 mg daily

• 50-400 mg weekly or more frequently based on indication

• Renal impairment: No dosage adjustment required
• Hepatic impairment: Use with caution; contraindicated in severe impairment
• Geriatric patients: Consider lower starting doses
• Pediatric: Not typically used

Pharmacokinetics

• Absorption: Oral bioavailability is low due to extensive first-pass metabolism; micronization improves absorption. Vaginal administration provides direct uterine delivery with lower systemic levels.
• Distribution: Highly protein-bound (96-99%) primarily to albumin and corticosteroid-binding globulin
• Metabolism: Extensive hepatic metabolism via CYP450 enzymes (primarily CYP3A4) to pregnanediol and pregnanolone metabolites
• Elimination: Renal excretion of metabolites (50-60%) and fecal excretion (10%)
• Half-life: Approximately 5-20 minutes (parent compound); metabolites have longer half-lives

Contraindications

• Known hypersensitivity to progesterone or any formulation components
• Undiagnosed abnormal genital bleeding
• Known or suspected breast cancer
• Active arterial thromboembolism or history of thrombotic disorders
• Severe hepatic dysfunction or disease
• Missed abortion or ectopic pregnancy
• History of progesterone-dependent neoplasms

Warnings and Precautions

• Boxed Warning: Increased risk of endometrial cancer in postmenopausal women with intact uterus using unopposed estrogen therapy
• Thromboembolic disorders: Increased risk of stroke, DVT, pulmonary embolism, and retinal thrombosis
• Breast cancer risk: Controversial data regarding association with increased risk
• Mood disorders: May cause depression, mood swings, and sleep disturbances
• Visual changes: May cause retinal vascular lesions; discontinue if sudden vision changes occur
• Carbohydrate metabolism: May decrease glucose tolerance
• Hepatic effects: May exacerbate hepatic impairments

Drug Interactions

• CYP3A4 inducers (rifampin, carbamazepine, St. John's wort): May decrease progesterone levels
• CYP3A4 inhibitors (ketoconazole, clarithromycin, grapefruit juice): May increase progesterone levels
• Anticoagulants: May diminish anticoagulant effect
• Antihypertensives: May decrease effectiveness
• Other hormones: May alter effects of concomitant hormonal therapies

Adverse Effects

• Drowsiness, fatigue
• Headache
• Breast tenderness
• Abdominal bloating
• Mood changes
• Dizziness
• Nausea

• Thromboembolic events
• Anaphylactic reactions
• Severe depression
• Visual changes
• Jaundice
• Allergic reactions

Monitoring Parameters

• Baseline and periodic breast examinations
• Endometrial monitoring in women with intact uterus
• Liver function tests (baseline and periodically)
• Lipid profile monitoring
• Blood pressure monitoring
• Signs and symptoms of thromboembolism
• Mood and mental status assessment
• Visual changes
• Pregnancy testing when indicated

Patient Education

• Take oral medication at bedtime to minimize dizziness and drowsiness
• Vaginal formulations may cause local irritation and discharge
• Report immediately: chest pain, shortness of breath, severe headache, visual changes, or leg pain
• Use effective contraception if sexually active unless trying to conceive
• Avoid alcohol during therapy as it may increase drowsiness
• Do not drive or operate machinery until effects are known
• Regular follow-up appointments are essential
• Notify all healthcare providers about progesterone use

References

1. American College of Obstetricians and Gynecologists. (2020). Practice Bulletin No. 221: Hormone Therapy. Obstetrics & Gynecology, 135(6), e249-e267. 2. FDA Prescribing Information: Prometrium® (progesterone) capsules 3. Stanczyk, F. Z., et al. (2013). Progesterone: The forgotten hormone in men? Journal of Steroid Biochemistry and Molecular Biology, 140, 73-78. 4. Schindler, A. E. (2009). Progestogen deficiency and endometrial cancer risk. Maturitas, 62(4), 334-337. 5. Carp, H. J. (2015). Progesterone and pregnancy. Current Opinion in Obstetrics and Gynecology, 27(6), 418-424. 6. Langer, R. D., et al. (2017). The Women's Health Initiative: Lessons for and from obstetrician-gynecologists. Current Opinion in Obstetrics and Gynecology, 29(6), 435-441. 7. UpToDate: Progesterone drug information (2023) 8. Micromedex Solutions: Progesterone monograph (2023)