Progesterone
Progesterone
Generic Name
Progesterone
Mechanism
- Receptor Binding: Binds to cytoplasmic progesterone receptors (PR-A and PR-B), translocates to the nucleus, and regulates gene transcription.
- Genomic Effects: Induces genes that:
- Promote endometrial secretory transformation (“decidualization”).
- Suppress luteinizing hormone (LH) surge → inhibits ovulation.
- Non‑genomic Effects: Activates membrane progesterone receptors (mPRα/β) to modulate intracellular calcium, chloride channels, and signal transduction pathways.
- Immunomodulation: Enhances regulatory T‑cell activity, crucial for maternal tolerance of the fetus.
Pharmacokinetics
| Parameter | Typical Values (oral) | Notes |
| Absorption | 30–90 % oral bioavailability (low due to first‑pass metabolism) | Transdermal and intramuscular routes bypass hepatic metabolism |
| Distribution | Highly lipophilic; ~2000 L Vd (fat‑tissue depot) | Protein binding ~90 % (e.g., albumin, alpha‑1 acid glycoprotein) |
| Metabolism | Hepatic 17α‑hydroxylase, reductases; conjugation (glucuronidation) | Rapid metabolism → short half‑life in plasma |
| Elimination | Renal (excretion of metabolites) | Half‑life 4–6 h (oral); 7–15 h (transdermal), >10 h (IM) |
| Dose‑Response | Linear over therapeutic range | Peak plasma levels 1–4 h post‑dose (oral) |
Indications
- Menstrual disorders: Treats dysmenorrhea, heavy bleeding, and endometrial hyperplasia.
- Ovulation induction: Used in assisted reproductive technology (ART) protocols.
- Pregnancy support: Augmentation for luteal phase deficiency in IVF; prevention of miscarriage in high‑risk patients.
- Hormone replacement therapy (HRT): Combined with estrogen to mitigate endometrial hyperplasia risk.
- Contraception (topical): Delays ovulation and prevents implantation in combined oral contraceptives.
- Gynecologic surgeries: Short‑term postsurgery progesterone supplementation to restore endometrium.
Contraindications
- Absolute Contraindications
- Known hypersensitivity to progesterone or excipients.
- Pregnant women (except for therapeutic use in pregnancy).
- Relative Contraindications
- Uncontrolled hypertension or thromboembolic disorders.
- Untreated breast or endometrial cancer.
- Severe liver disease (due to impaired metabolism).
- Warnings
- Thromboembolism: ↑ risk when combined with estrogen; monitor for symptoms.
- Endometrial hyperplasia: Long‑term estrogen‑only therapy -> add progesterone.
- Cardiovascular: Possible arrhythmias in susceptible patients.
Dosing
| Indication | Dosage Form | Typical Dose & Schedule | Notes |
| Menstrual cycle bleeding | Oral micronized progesterone | 200 mg daily (days 15–25) | Adjust based on bleeding pattern |
| Ovulation induction (ART) | Intramuscular (IM) | 600–1000 mg weekly up to 5 weeks | Monitor serum progesterone ≥ 20 ng/mL |
| Luteal phase support | Subdermal implant (Implanon®) | 78 mg/implant (12‑month release) | Single‑dose option for IVF patients |
| Hormone replacement | Transdermal gel | 0.2 mg/day | Preferred in patients with GI intolerance |
| Pregnancy support (≤ 24 weeks) | Oral | 200–400 mg/day | Daily dosing starting 6 weeks gestation |
• Administration Tips
• For oral: take with a fatty meal to enhance absorption.
• Transdermal: apply to clean, dry skin; alternate sites to prevent irritation.
• IM: rotate injection sites (gluteal muscle).
Adverse Effects
Common (≤ 10 %):
• Nausea, vomiting
• Headache, dizziness
• Breast tenderness/blosom
• Weight gain (fat storage)
• Minor mood changes
Serious (≤ 1 %):
• Thromboembolic events (deep vein thrombosis, pulmonary embolism)
• Endometrial cancer (long‑term unopposed estrogen use)
• Severe hepatic dysfunction (rare, with cholestasis)
• Severe hypersensitivity reactions (anaphylaxis)
Monitoring
- Serum progesterone levels (especially in IVF/luteal support) – target ≥ 20 ng/mL for implantation.
- Liver function tests (ALT, AST, bilirubin) – baseline and periodic.
- Endometrial thickness (via transvaginal ultrasound) in long‑term HRT.
- Coagulation profile (if patient has thromboembolic risk).
- Blood pressure & weight – routine monitoring in hormone‑replacement regimens.
Clinical Pearls
- Micronization ↑ bioavailability: The micronized form increases surface area, making 200 mg oral dose roughly equivalent to 100 mg non‑micronized.
- Timing matters: For luteal support, start progesterone 6 weeks of gestation, i.e., during 2nd trimester, to reduce miscarriage risk.
- Depot advantage: The subdermal implant provides steady serum levels and eliminates daily compliance issues—ideal for patients with adherence challenges.
- Non‑reproductive uses: Progesterone‑rich extracts have been explored for neuroprotection in perinatal hypoxic injury.
- Drug interactions: Concomitant rifampicin or carbamazepine decreases progesterone levels via CYP3A4 induction—consider higher dosing.
> *Remember*: Progesterone’s diverse actions—from stromal differentiation to immune modulation—underscore its central role in female reproductive health and the importance of tailored therapy for individual patients.