How does Provera (medroxyprogesterone acetate) cause withdrawal bleeding?

How Provera (Medroxyprogesterone Acetate) Causes Withdrawal Bleeding

Provera (medroxyprogesterone acetate) causes withdrawal bleeding by transforming proliferative endometrium into secretory endometrium when administered to women with adequate endogenous estrogen, and then when discontinued, the sudden drop in progesterone levels triggers endometrial shedding. 1

Mechanism of Action

• Medroxyprogesterone acetate transforms proliferative endometrium (built up under estrogen influence) into secretory endometrium when administered to women with adequate endogenous estrogen levels 1
• When administered parenterally in recommended doses, it inhibits pituitary gonadotropin secretion, which prevents follicular maturation and ovulation 1
• The withdrawal of progesterone after a course of treatment leads to destabilization of the endometrial lining, causing it to shed (withdrawal bleeding) 2

Physiological Process

• For withdrawal bleeding to occur, the endometrium must first be primed with estrogen (endogenous or exogenous) to build up the endometrial lining 2, 3
• The administration of progesterone then stabilizes this estrogen-primed endometrium 4
• When progesterone is withdrawn, the sudden drop in hormone levels leads to endometrial shedding, similar to what occurs during a normal menstrual period 2
• The thickness of the endometrium significantly correlates with the likelihood of withdrawal bleeding - endometrium ≥6.0 mm predicts withdrawal bleeding with 95.5% accuracy 3

Clinical Applications

• Provera is commonly used as a diagnostic tool in the form of a progesterone challenge test to assess endogenous estrogen status in women with amenorrhea 4, 5
• A positive test (withdrawal bleeding) indicates:
  • Adequate endogenous estrogen production 4
  • Functional outflow tract 4
  • Responsive endometrium 3
• The absence of withdrawal bleeding suggests one of the following:
  • Insufficient endogenous estrogen (hypoestrogenic state) 4, 3
  • Outflow tract obstruction 5
  • Endometrial pathology 5

Factors Affecting Withdrawal Bleeding Response

• Endogenous estradiol levels - higher levels correlate with increased likelihood of withdrawal bleeding 2, 3
• Endometrial thickness - thicker endometrium (≥6.0 mm) is more likely to result in withdrawal bleeding 3
• Dosage of progesterone - higher doses (e.g., 300 mg micronized progesterone) induce withdrawal bleeding more reliably than lower doses (e.g., 200 mg) 2
• Duration of administration - typically a 10-day course is used for diagnostic purposes 2, 5

Common Pitfalls and Considerations

• Provera is not recommended for treatment of secondary amenorrhea or dysfunctional uterine bleeding due to its prolonged action and difficulty in predicting the time of withdrawal bleeding 1
• For these conditions, oral therapy is recommended instead of parenteral administration 1
• Withdrawal bleeding cannot be reliably predicted from estradiol and progesterone concentrations alone - endometrial thickness measurement by transvaginal ultrasound provides better predictive value 3
• The absence of withdrawal bleeding after progesterone challenge in amenorrheic patients often correlates with smaller ovaries, absence of follicles or presence of only early-stage follicles, and poor response to gonadotropins 4

Clinical Significance

• The progesterone challenge test helps differentiate between various causes of amenorrhea 6, 5
• It can help distinguish between polycystic ovarian syndrome and functional hypothalamic amenorrhea 6
• The test is useful for timing blood sampling for diagnostic purposes in the early follicular phase in women with irregular cycles 5
• In women with amenorrhea, the presence or absence of withdrawal bleeding correlates closely with ovarian volume, morphology, and steroidogenic function 4