How should cyclic estrogen and progesterone be administered to treat abnormal uterine bleeding due to ovulatory dysfunction?

How to Give Cyclic Estrogen and Progesterone for AUB-O

For abnormal uterine bleeding due to ovulatory dysfunction (AUB-O), administer medroxyprogesterone acetate 10 mg orally daily for 12-14 days every 28 days as the primary evidence-based regimen, which transforms proliferative endometrium into secretory endometrium and prevents endometrial hyperplasia. 1

Primary Treatment Protocol

The standard cyclic progestin regimen consists of:

• Medroxyprogesterone acetate 10 mg orally daily for 12-14 days every 28 days 1
• The 12-14 day duration is critical to adequately protect against endometrial hyperplasia and cancer 1
• Expect withdrawal bleeding after each progestin cycle, which is a normal and expected outcome 1

Important timing consideration: A recent high-quality study demonstrated that administering MPA between days 16-25 (10-day protocol) more effectively regulated menstrual cycles and stopped AUB compared to days 11-25 (15-day protocol), with 3 cycles of treatment sufficient to achieve bleeding cessation 2. This suggests that timing the progestin to the predicted luteal phase (days 16-25) may optimize outcomes 2.

Preferred Alternative Progestin Options

If medroxyprogesterone acetate is not tolerated or contraindicated:

• Oral micronized progesterone 200 mg daily for 12-14 days every 28 days offers a more favorable cardiovascular and metabolic profile 1
• Norethindrone acetate 1 mg daily provides superior cardiovascular and metabolic outcomes compared to medroxyprogesterone acetate while maintaining excellent endometrial protection 1, 3

When to Add Estrogen (Cyclic Estrogen-Progesterone Regimen)

Cyclic estrogen-progesterone is specifically indicated for perimenopausal patients with AUB-O:

• Administer cyclic conjugated equine estrogens for 25 days with concomitant medroxyprogesterone acetate for days 18-25 4
• Alternatively, use transdermal 17β-estradiol patches releasing 50-100 μg daily with oral medroxyprogesterone acetate 10 mg daily for 12-14 days every 28 days 3

Critical caveat: Estrogen is NOT typically needed for reproductive-age women with simple anovulatory bleeding 1. Estrogen addition is reserved for perimenopausal patients or those with hypoestrogenic states 4.

Pre-Treatment Requirements

Before initiating cyclic progestin therapy:

• Perform baseline transvaginal ultrasound to confirm appropriate endometrial thickness and rule out structural pathology 1
• Rule out pregnancy in all reproductive-age women 5
• Consider endometrial sampling if persistent or recurrent abnormal bleeding is present to exclude malignancy 6

Special Population Considerations

For reproductive-age women requiring contraception:

• Combined oral contraceptives are an appropriate alternative for managing anovulatory bleeding while providing contraception 1, 4

For patients with cardiovascular disease:

• Avoid NSAIDs and tranexamic acid due to MI and thrombosis risk 5
• The levonorgestrel intrauterine system becomes the preferred option with minimal systemic absorption 5

When Medical Management Fails

If cyclic progestin therapy fails or is contraindicated:

• Consider the levonorgestrel intrauterine system, which delivers progestogen directly to the uterus with fewer systemic side effects and reduces menstrual blood loss by 71-95% 1, 5
• Surgical options including endometrial ablation or hysterectomy may be considered if the patient has concomitant significant intracavitary lesions or no longer desires fertility 1

Monitoring and Follow-Up

• The sequential dosing approach is most evidence-based if the patient tolerates withdrawal bleeding 1
• Reevaluate patients periodically at 3-6 month intervals to determine if treatment is still necessary 6
• If bleeding persists despite initial therapy, further investigation with imaging or hysteroscopy is indicated 5

Common Pitfalls to Avoid

Duration matters: The full 12-14 day duration of progestin is essential for complete endometrial protection 1. Shorter durations may provide insufficient protection against endometrial hyperplasia 3.

Don't use estrogen alone: When estrogen is prescribed for a woman with a uterus, a progestin must also be initiated to reduce the risk of endometrial cancer 6.

Timing optimization: Consider using the days 16-25 protocol rather than days 11-25 for better cycle regulation and bleeding cessation 2.