What is the mechanism of action of Provera (medroxyprogesterone acetate)?

Mechanism of Action of Provera (Medroxyprogesterone Acetate)

Provera (medroxyprogesterone acetate) works primarily by binding to progesterone receptors in target tissues, producing both progestational effects and additional actions through cross-reactivity with androgen and glucocorticoid receptors. 1

Primary Mechanism: Progesterone Receptor Binding

• Medroxyprogesterone acetate binds to cytosolic progesterone receptors with potency equal to natural progesterone, preventing endogenous progesterone from exerting its effects 2
• The drug-receptor complex acts as a transcription factor that alters gene expression in target tissues, producing characteristic progestational effects 3
• MPA demonstrates full effectiveness in inducing secretory transformation of the endometrium when combined with estrogen, making it the gold standard progestin for endometrial protection 3

Contraceptive Effects (Depot Formulation)

When administered as depot medroxyprogesterone acetate (DMPA) at 150 mg intramuscularly every 3 months, the mechanism includes: 1, 4

• Inhibition of gonadotropin secretion (LH and FSH), which prevents follicular maturation and ovulation 1, 5
• Endometrial thinning and atrophy, creating an unfavorable environment for implantation 1, 4
• Thickening of cervical mucus, which impairs sperm penetration 4
• Serum progesterone levels remain suppressed (<0.4 ng/mL) for several months, confirming anovulation 4

Multi-Receptor Activity

MPA exhibits clinically significant cross-reactivity beyond progesterone receptors, which distinguishes it from natural progesterone: 2

• Androgen receptor binding at 20-fold lower potency than testosterone 2
• Glucocorticoid receptor binding at 10-fold lower potency than dexamethasone 2
• This multi-receptor activity explains both therapeutic effects and adverse metabolic consequences (lipid profile changes, insulin resistance) 3

Tissue-Specific Effects

Endometrium

• Induces secretory changes, pseudodecidualization, and eventual atrophy depending on dose and duration 5, 6
• Suppresses epithelial DNA synthesis in a dose-dependent manner 6
• Reduces estradiol receptor expression, though not as effectively as some other progestins 6

Hypothalamic-Pituitary Axis

• Suppresses LH surge, preventing ovulation 4, 5
• Maintains FSH and LH in luteal-phase ranges rather than complete suppression 4
• Estradiol levels decrease to early-to-mid follicular phase (approximately 40-50 pg/mL) with chronic use 4

Ovarian Tissue

• Direct antiproliferative effects on ovarian cells through progesterone receptor-mediated pathways 2
• At high concentrations (>10⁻⁶ M), inhibits progesterone and estrogen production 2

Clinical Caveats

Important metabolic and cardiovascular considerations stem from MPA's glucocorticoid and androgenic activity: 3

• Adverse effects on lipid profiles (attenuates HDL increases from estrogen, may worsen LDL) 3
• Negative impact on vasomotion and carbohydrate metabolism compared to natural progesterone 3
• Increased cardiovascular risk markers including C-reactive protein, factor VII, and decreased antithrombin III 3
• Despite these concerns, MPA remains first-line for endometrial protection due to proven efficacy in preventing hyperplasia 3

One critical warning: MPA may act as a radiosensitizing agent and should be used cautiously in patients receiving pelvic radiation, as it can enhance ovarian injury rather than provide protection 7

Pharmacokinetics

• Following 150 mg IM injection, MPA reaches peak concentrations (1-7 ng/mL) at approximately 3 weeks 1
• Plasma levels plateau at ~1.0 ng/mL for 3 months, then decline exponentially 1, 4
• Apparent half-life is approximately 50 days after IM administration 1
• MPA can be detected for up to 9 months after a single injection in some women, explaining delayed return to fertility 4