Progesterone (IR/SR)

Progesterone is the endogenous C21 steroid hormone secreted mainly by the corpus luteum and, in pregnancy, the placenta. Pharmaceutical progesterone is chemically identical to the native hormone and is distinct from synthetic progestins such as medroxyprogesterone acetate or norethindrone. FDA-approved forms include oral micronized capsules (Prometrium), vaginal gel (Crinone), vaginal inserts (Endometrin) and intramuscular injection in oil.

• Prometrium (oral): prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women receiving conjugated estrogens, and treatment of secondary amenorrhea.
• Progesterone injection (intramuscular): amenorrhea and abnormal uterine bleeding due to hormonal imbalance without organic pathology.
• Crinone (vaginal): supplementation or replacement as part of assisted reproductive technology, and secondary amenorrhea. Endometrin (vaginal): support of embryo implantation and early pregnancy in assisted reproduction.
• Prescribers also use compounded progesterone preparations, including topical creams, troches and capsules, for individualized menopausal hormone therapy. Endometrial protection against estrogen is established only for labeled regimens such as oral Prometrium.

Progesterone binds intracellular progesterone receptors PR-A and PR-B; PR-B carries an additional 164 amino acids at the N-terminus. The ligand-bound receptor binds progesterone response elements on DNA and regulates transcription of target genes. In estrogen-primed endometrium it converts proliferative to secretory tissue and opposes estrogen-driven proliferation. It also slows hypothalamic GnRH pulse frequency, raises basal body temperature and relaxes uterine smooth muscle.

Membrane progesterone receptors mediate some rapid effects. The metabolite allopregnanolone is a positive allosteric modulator of GABA-A receptors, which accounts for the sedation and dizziness seen with oral and transmucosal dosing.

Oral micronized progesterone is well absorbed but undergoes extensive first-pass metabolism, so bioavailability is low; food increases absorption, and peak concentrations occur in about 1.5 to 3 hours. It is 96 to 99 percent protein bound, mainly to albumin and corticosteroid-binding globulin.

Metabolism is hepatic, chiefly by CYP3A4 (with CYP2C19 contributing), to pregnanediols and pregnanolones, including allopregnanolone; glucuronide and sulfate conjugates are excreted in urine and bile. Vaginal and intramuscular routes avoid first-pass metabolism. Sublingual and buccal absorption is variable. Topical absorption through skin is variable and produces low, inconsistent serum concentrations that may not reflect tissue exposure.

• Undiagnosed abnormal genital bleeding.
• Known, suspected or past breast cancer.
• Active or past deep vein thrombosis or pulmonary embolism, or active or past arterial thromboembolic disease such as stroke or myocardial infarction.
• Known liver dysfunction or disease.
• Hypersensitivity to progesterone or any excipient. Prometrium capsules contain peanut oil and are contraindicated with peanut allergy.

• Cardiovascular and thromboembolic events: stop immediately if stroke, myocardial infarction, deep vein thrombosis or pulmonary embolism occurs or is suspected; where feasible, stop 4 to 6 weeks before surgery associated with increased thrombosis risk or prolonged immobilization.
• Breast cancer: estrogen plus progestin therapy increased invasive breast cancer in WHI, and the increase appeared after about 3 years of use; ensure breast examination and mammography.
• Visual abnormalities: discontinue pending evaluation for sudden partial or complete vision loss, proptosis, diplopia or migraine, which may signal retinal vascular thrombosis.
• Other: fluid retention (caution in cardiac or renal dysfunction), worsening depression, decreased glucose tolerance, and drowsiness or dizziness with oral and transmucosal dosing.

• Strong CYP3A4 inducers such as rifampin, carbamazepine, phenytoin, phenobarbital and St John's wort may reduce progesterone exposure.
• CYP3A4 inhibitors such as ketoconazole, itraconazole, clarithromycin, ritonavir and grapefruit juice may increase exposure and sedation.
• Alcohol, benzodiazepines, opioids and other CNS depressants may add to sedation from oral or transmucosal progesterone.

In the PEPI trial of Prometrium with conjugated estrogens, frequent adverse effects included headache, breast tenderness, joint pain, depression, dizziness, abdominal bloating, hot flashes, urinary problems, abdominal pain, vaginal discharge, nausea and mood changes. Drowsiness is common with oral and sublingual dosing. Topical products can cause local skin irritation. Breakthrough bleeding or spotting can occur and needs evaluation when unexpected.

Menopausal progesterone therapy is not intended for use in pregnancy. Vaginal progesterone products (Crinone 8%, Endometrin) are FDA-labeled for luteal-phase support in assisted reproduction; intramuscular progesterone is used there off-label. Progesterone is used in pregnancy only under specialist direction. Detectable amounts of progestins appear in breast milk; the effect on the nursing infant is not established.

Reassess the need for hormone therapy periodically. Evaluate persistent or recurrent abnormal vaginal bleeding, including endometrial sampling where indicated. Maintain breast examination and mammography, blood pressure checks, attention to signs of thrombosis and visual changes, mood assessment, and glucose monitoring in patients with diabetes. Serum progesterone levels after topical use may not reflect tissue exposure.

• Prometrium (progesterone) capsules Prescribing Information.
• Crinone (progesterone gel) Prescribing Information.
• Endometrin (progesterone) vaginal insert Prescribing Information.
• Progesterone Injection USP (in sesame oil) Prescribing Information.
• The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Menopause. 2022.