PROGESTERONE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Progesterone binds to progesterone receptors (PR-A and PR-B) in target tissues, modulating gene expression to induce secretory changes in the endometrium, support pregnancy, and regulate gonadotropin secretion via negative feedback on the hypothalamic-pituitary axis.
| Metabolism | Primarily hepatic via CYP3A4 and CYP2C19 to metabolites such as 5α-dihydroprogesterone, allopregnanolone, and 20α-hydroxypregn-4-en-3-one, which are further conjugated and excreted renally. |
| Excretion | Renal (50-60% as metabolites) and fecal (10-20%). Biliary excretion of metabolites occurs; enterohepatic recirculation may contribute to prolonged presence. Unchanged drug negligible in urine. |
| Half-life | Elimination half-life: approximately 5-15 minutes for intravenous progesterone; terminal half-life of metabolites (pregnanediol) is about 2-8 hours, but clinical effects (e.g., endometrial transformation) persist for days due to receptor-mediated activity. |
| Protein binding | 96-99% bound: primarily to albumin (50-54%), corticosteroid-binding globulin (CBG, 43-48%), and sex hormone-binding globulin (SHBG, <1%). |
| Volume of Distribution | Approximately 0.8-1.0 L/kg. Higher Vd in women (due to adipose tissue distribution). Clinical meaning: extensive tissue distribution, including breast, adipose, and reproductive organs. |
| Bioavailability | Oral: <10% (extensive first-pass metabolism). Intramuscular: close to 100% (but slow absorption via depot effect). Vaginal: about 20-40% (bypasses first-pass partially). Subcutaneous: 100% (when formulated for injection). Topical: variable (5-20% depending on formulation). |
| Onset of Action | Oral: within 2-6 hours (first pass effect delays peak). Intramuscular: within 30 minutes. Vaginal: within 2-4 hours (rapid absorption). Topical: within 1-2 hours. |
| Duration of Action | Oral: 12-24 hours (single dose). Intramuscular: 24-48 hours (depot effect). Vaginal: 24 hours (continuous absorption). Topical: 12-24 hours. Clinical effects (e.g., secretory endometrium) persist for duration of therapy. |
Oral: 200-400 mg daily in 1-2 divided doses; Intramuscular: 50-100 mg daily; Vaginal: 200-400 mg daily in 1-2 divided doses.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for GFR >15 mL/min; insufficient data for GFR <15 mL/min. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | Not FDA-approved for pediatrics; limited data: 10-20 mg/kg/day IM for luteal support in adolescents. |
| Geriatric use | No specific dose adjustment; start at lower end of dosing range due to potential hepatic impairment and increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP3A4 inducers can decrease efficacy Can cause thromboembolic disorders.
| Breastfeeding | Progesterone is excreted into breast milk in small amounts; the milk-to-plasma ratio (M/P) is approximately 0.43 to 0.55. Levels are unlikely to affect the nursing infant, but caution is advised. American Academy of Pediatrics considers progesterone compatible with breastfeeding. |
| Teratogenic Risk | Progesterone is not associated with a significant increase in major birth defects when used in the first trimester for luteal phase support. Second and third trimester exposure from endogenous production or exogenous administration does not demonstrate teratogenicity; however, high doses may cause fetal genital ambiguity in animal models, but human data are reassuring. Overall, risk is low. |
■ FDA Black Box Warning
Cardiovascular and thromboembolic risks: Progestins with estrogen increase the risk of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women, particularly in those with underlying risk factors. Progesterone alone may also increase thromboembolic risk.
| Common Effects | abnormal uterine bleeding |
| Serious Effects |
["Known or suspected pregnancy (for non-pregnancy indications)","Undiagnosed vaginal bleeding","Active thromboembolic disorder (e.g., deep vein thrombosis, pulmonary embolism)","History of thromboembolic disorders or thrombophlebitis","Known or suspected breast cancer","Severe hepatic impairment or liver disease","Hypersensitivity to progesterone or any formulation components"]
| Precautions | ["Thromboembolic disorders: Use with caution in patients with a history of thrombosis or thrombophlebitis.","Cardiovascular disease: May increase risk of myocardial infarction or stroke, especially in older women or those with hypertension.","Breast cancer: Prolonged use with estrogen may increase risk of breast cancer; evaluate risk-benefit.","Hepatic impairment: Use cautiously in patients with liver disease; monitor liver function.","Depression: May exacerbate mood disorders; discontinue if severe depression recurs.","Visual disturbances: Discontinue if sudden partial or complete vision loss occurs.","Gallbladder disease: Associated with increased risk of cholelithiasis.","Fluid retention: May worsen conditions such as asthma, migraine, epilepsy, or renal impairment."] |
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| Fetal Monitoring | Monitor for signs of thromboembolic events, blood pressure, glucose levels, and fetal growth via ultrasound. In women using progesterone for preterm birth prevention, monitor cervical length and uterine activity. Also assess liver function and lipid profile periodically. |
| Fertility Effects | Progesterone is essential for maintaining pregnancy and is used in assisted reproductive technology to support implantation and early pregnancy. It does not impair fertility; rather, it is used to enhance fertility. Exogenous progesterone may delay ovulation if administered prior to ovulation, but when used appropriately, it supports the luteal phase. |