How does medroxyprogesterone (MPA) help induce a menstrual period in individuals with amenorrhea?

How Medroxyprogesterone Induces Menstrual Bleeding in Amenorrhea

Medroxyprogesterone acetate (MPA) induces menstrual bleeding through progestin withdrawal: after priming an estrogen-exposed endometrium to a secretory state, discontinuation of MPA triggers organized endometrial shedding that mimics a natural menstrual period, with bleeding typically occurring 3-7 days after stopping the medication. 1

Mechanism of Action

Endometrial Transformation

• MPA converts an estrogen-primed proliferative endometrium into a secretory endometrium by inducing glandular secretory changes and decidualization of the stromal cells 2
• The standard dose of 10 mg daily for 10 days produces optimal secretory transformation when adequate endogenous or exogenous estrogen is present 1
• MPA is the only progestin with robust evidence demonstrating full effectiveness in inducing secretory endometrium when combined with replacement-dose estrogen 2

Withdrawal Bleeding Process

• Upon discontinuation of MPA, the sudden drop in progestin levels destabilizes the secretory endometrium, causing organized tissue breakdown and shedding 1
• Progestin withdrawal bleeding typically occurs within 3-7 days after completing the MPA course 1
• This mimics the natural luteal-follicular transition when progesterone levels fall in a normal menstrual cycle

Clinical Dosing for Amenorrhea

Secondary Amenorrhea

• Recommended dose: 5-10 mg daily for 5-10 days 1
• The optimal regimen is 10 mg daily for 10 days to ensure adequate secretory transformation 1
• Therapy may be started at any time in secondary amenorrhea since there is no predictable cycle 1

Predictive Factors for Success

• Endometrial thickness measured by transvaginal ultrasound significantly correlates with bleeding response, with thicker endometrium predicting successful withdrawal bleeding 3
• Endogenous estradiol and progesterone levels have limited predictive value for whether withdrawal bleeding will occur 3
• The presence of adequate estrogen priming (either endogenous or exogenous) is essential—MPA cannot induce bleeding from an atrophic, estrogen-deficient endometrium 1

Important Clinical Considerations

When MPA Will Not Work

• MPA will fail to induce bleeding if the endometrium has not been adequately primed with estrogen 1
• In cases of hypothalamic amenorrhea or premature ovarian insufficiency with very low estrogen levels, estrogen supplementation must precede or accompany progestin therapy 2
• Absence of withdrawal bleeding after MPA challenge suggests either inadequate estrogen priming or outflow tract obstruction requiring further evaluation

Cyclic Regimens for Ongoing Management

• For women with recurrent amenorrhea, planned menstrual cycling with MPA can be implemented using 5-10 mg daily for 5-10 days each month 1
• When used with continuous estrogen therapy (such as 0.625 mg conjugated estrogens), MPA 5-10 mg daily for 12-14 consecutive days per month provides endometrial protection and regular withdrawal bleeding 1
• Sequential regimens (MPA on days 16-26 of a 28-day cycle) produce regular withdrawal bleeding in approximately 77-81% of cycles 4

Comparison to Other Progestins

• While other progestins like norethisterone acetate and dydrogesterone can induce withdrawal bleeding, MPA has the most extensive evidence base for effectiveness in inducing secretory endometrium 2
• A study comparing MPA 5 mg twice daily versus dydrogesterone 10 mg twice daily for 5 days found 93% of women experienced withdrawal bleeding with either agent, with similar side effect profiles 3
• Natural micronized progesterone has a superior cardiovascular and thrombotic safety profile compared to MPA, though evidence for its effectiveness in inducing secretory changes in amenorrheic women is less robust 2

Common Pitfalls

• Starting MPA without confirming adequate estrogen status or endometrial thickness may result in treatment failure
• Using insufficient doses (less than 5 mg daily) or too short a duration (less than 5 days) may not achieve adequate secretory transformation 1
• Failing to counsel patients that absence of withdrawal bleeding requires further evaluation for estrogen deficiency or anatomic abnormalities

Safety Considerations

• MPA should not be used in pregnancy—rule out pregnancy before initiating therapy 1
• Cardiovascular risks with MPA include adverse effects on lipid profiles and vasomotion, though these are primarily concerns with long-term continuous use rather than short withdrawal bleeding protocols 2
• For women requiring long-term progestin therapy, consider that progestins should not be used continuously for more than 6 months due to potential meningioma risk 5