How long should a patient be on progesterone (medroxyprogesterone acetate (MPA)) after 6 months of estrogen pellets without progesterone to induce a withdrawal bleed and shed the uterine wall?

Progesterone Duration for Endometrial Shedding After Unopposed Estrogen

After 6 months of unopposed estrogen pellet therapy, administer medroxyprogesterone acetate 10 mg daily for 12-14 days to induce withdrawal bleeding and shed the endometrial lining. 1, 2

Standard Progesterone Regimen

The established protocol for endometrial protection and withdrawal bleeding induction involves:

• Medroxyprogesterone acetate (MPA) 10 mg orally daily for 12-14 days 1, 2
• This duration is the standard recommendation from ACOG for sequential hormone therapy regimens 1
• Alternative: Micronized progesterone 200 mg orally or vaginally for 12-14 days 1

Expected Bleeding Response

Withdrawal bleeding typically occurs within 2-7 days after completing the progesterone course:

• 90% of women experience withdrawal bleeding with adequate progesterone dosing (300 mg micronized progesterone showed 90% response rate) 3
• Lower doses (200 mg micronized progesterone) induced bleeding in only 58% of women 3
• The 10 mg MPA dose for 12-14 days is the established standard that reliably induces endometrial shedding 2

Critical Considerations After Prolonged Unopposed Estrogen

Six months of unopposed estrogen significantly increases endometrial hyperplasia risk:

• At 6 months of unopposed moderate-dose estrogen, the odds ratio for hyperplasia is 5.4 (95% CI 1.4-20.9) compared to placebo 4
• By 24 months, this risk increases to OR 9.6 (95% CI 5.9-15.5) 4
• Endometrial biopsy should be strongly considered before initiating progesterone if the patient has had any irregular bleeding or risk factors for endometrial pathology 2

Ongoing Management After Initial Withdrawal Bleed

Do not stop after one cycle—establish regular progesterone cycling:

• Continue MPA 10 mg for 12-14 days every month for at least 6 months 2
• This sequential regimen provides adequate endometrial protection while allowing predictable withdrawal bleeding 1
• Alternatively, transition to continuous combined therapy (estrogen + progesterone daily) if the patient prefers to avoid monthly bleeding 1

Monitoring and Follow-up

Clinical review should occur at 3 months to assess:

• Bleeding pattern normalization (predictable withdrawal bleeding should occur with each cycle) 1
• Side effects such as mood changes, breast tenderness, or bloating (typically resolve within 3 months) 1
• If breakthrough bleeding persists beyond 3 months or is heavy/prolonged, endometrial evaluation is indicated 5

Common Pitfall to Avoid

The most critical error is administering only a single course of progesterone and then resuming unopposed estrogen. After inducing the initial withdrawal bleed, you must either:

• Continue monthly sequential progesterone (12-14 days per month) indefinitely 1, 2, OR
• Switch to continuous combined therapy (daily estrogen + progesterone) 1

Returning to unopposed estrogen will rapidly re-establish hyperplasia risk, with the endometrium showing mitotic activity and hyperplastic changes within months 4, 6.