Does the menopause society recommend cyclic progesterone (Progesterone) for women with an intact uterus?

Cyclic Progesterone for Women with an Intact Uterus

Yes, the North American Menopause Society explicitly recommends that progestogen must be added to estrogen therapy in all postmenopausal women with an intact uterus to prevent endometrial hyperplasia and cancer, and cyclic regimens are a standard, evidence-based approach for endometrial protection. 1, 2

Primary Indication: Endometrial Protection

• Women with an intact uterus taking estrogen therapy require progestogen to reduce the risk of endometrial hyperplasia by approximately 90%, preventing progression to endometrial cancer 3
• The North American Menopause Society states that unopposed estrogen therapy significantly increases the risk of endometrial hyperplasia and adenocarcinoma, and adding appropriate dose and duration of progestogen lowers this risk to the level found in never-users of estrogen 2
• Without progestogen, 64% of women on estrogen-alone develop endometrial hyperplasia within 3 years, compared to only 6% when cyclic progesterone is added 4

Recommended Cyclic Regimens

Standard Cyclic Dosing

• Micronized progesterone 200 mg orally at bedtime for 12-14 consecutive days per 28-day cycle is the first-line cyclic regimen when combined with continuous estrogen 3, 5, 6, 4
• The FDA-approved regimen is 200 mg progesterone capsules at bedtime for 12 continuous days per 28-day cycle in postmenopausal women taking estrogens 4
• Alternative cyclic options include medroxyprogesterone acetate 10 mg daily for 12-14 days per month or dydrogesterone 10 mg daily for 12-14 days per month 6

Critical Duration Requirement

• The 12-14 day duration is essential—shorter durations provide inadequate endometrial protection 6
• Cyclic regimens induce predictable withdrawal bleeding in approximately 80-92% of women, which occurs after progestogen is stopped each cycle 7, 8

Cyclic vs. Continuous Combined Regimens

• Cyclic progesterone results in predictable monthly withdrawal bleeding, while continuous combined regimens (progesterone daily) aim for amenorrhea 3, 7
• Women preferring to avoid monthly bleeding may opt for continuous combined therapy (micronized progesterone 100 mg daily continuously), though this is not a cyclic regimen 6
• The clinical goal is to provide endometrial protection while maintaining estrogen benefits and minimizing progestogen-induced side effects, particularly uterine bleeding 2

Preferred Progestogen: Micronized Progesterone

• Micronized progesterone is preferred over synthetic progestins (like medroxyprogesterone acetate) due to lower cardiovascular and thrombotic risks 3, 6
• Micronized progesterone has lower rates of venous thromboembolism and breast cancer risk compared to medroxyprogesterone acetate 3
• However, recent data suggest micronized progesterone may be slightly less efficient than synthetic progestins for endometrial protection, though it remains adequately protective at appropriate doses 9

Estrogen Component Pairing

• Cyclic progesterone should be paired with transdermal 17β-estradiol 50-100 μg daily as first-line therapy, as transdermal delivery has lower cardiovascular and thrombotic risk than oral formulations 3, 6
• Oral 17β-estradiol 1-2 mg daily is an acceptable alternative to transdermal delivery 6

Alternative Cyclic Schedules

• Quarterly cyclic progesterone (medroxyprogesterone 10 mg daily for 14 days every 3 months) has been studied and appears safe, though it results in longer, heavier menses and more unscheduled bleeding compared to monthly cycles 8
• Despite increased bleeding, women preferred quarterly regimens by nearly 4:1 in one study, with endometrial hyperplasia rates similar to monthly regimens (1.5% vs 0.9%) 8
• Vaginal progesterone gel (Crinone 4%, 45 mg daily for days 1-10 of each month) is another cyclic option with 91.9% of women experiencing predictable withdrawal bleeding 7

Monitoring and Duration

• Annual clinical review focusing on compliance, bleeding patterns, and symptom control is recommended, with no routine laboratory monitoring required unless specific symptoms arise 6
• Use the lowest effective dose for the shortest duration consistent with treatment goals, as risks including stroke, venous thromboembolism, and breast cancer increase with dose and duration 3
• For every 10,000 women taking combined estrogen-progestin for 1 year, expect 8 additional invasive breast cancers, 8 more strokes, and 8 more pulmonary emboli, balanced against 6 fewer colorectal cancers and 5 fewer hip fractures 3

Common Pitfalls to Avoid

• Never use progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection 6
• Do not assume all progestogens carry equal risks—micronized progesterone has a superior cardiovascular and breast safety profile compared to synthetic progestins 3, 6
• Avoid initiating hormone therapy solely for chronic disease prevention in asymptomatic women—this is explicitly contraindicated and increases morbidity and mortality 1, 3

Special Populations

Perimenopause

• For perimenopausal women with vasomotor symptoms, cyclic oral micronized progesterone 300 mg at bedtime on cycle days 14-27 addresses the underlying pathophysiology of progesterone deficiency with estrogen excess 5

Premature Ovarian Insufficiency

• In women with premature ovarian insufficiency, begin cyclic progestogens after at least 2 years of estrogen therapy alone or when breakthrough bleeding occurs 1, 6
• Continue treatment until the average age of natural menopause (45-55 years), then reassess 6