Why should progesterone be administered for only 12–14 days each month in a 55‑year‑old woman with an intact uterus receiving estrogen?

Why Progesterone for Only 12–14 Days a Month?

Progesterone must be administered for 12–14 days each month in women with an intact uterus receiving estrogen because this duration replicates the luteal phase of the menstrual cycle and provides adequate endometrial protection against hyperplasia and cancer, while shorter durations fail to prevent endometrial proliferation. 1, 2, 3

The Physiological Basis

• During a normal menstrual cycle, progesterone is secreted for approximately 12–14 days during the luteal phase to counteract estrogen's proliferative effects on the endometrium 4
• This natural pattern must be mimicked in hormone replacement therapy to prevent unopposed estrogen stimulation, which increases endometrial cancer risk 10- to 30-fold after 5 years of use 1, 5
• Sequential progestogen regimens protect the endometrium only if exposure lasts at least 12 days per month—shorter intervals are unsafe 3, 6

Evidence for the 12–14 Day Requirement

• The FDA explicitly mandates that progesterone capsules be given "200 mg orally for 12 days sequentially per 28-day cycle" for prevention of endometrial hyperplasia 2
• International expert panels confirm that oral micronized progesterone provides endometrial protection when applied sequentially for 12–14 days/month at 200 mg/day for up to 5 years 3
• Multiple guidelines from ESHRE and other societies specify that progestogen must be delivered for at least the same duration as the luteal phase (12–14 days monthly) in sequential regimens to protect against endometrial hyperplasia and cancer 1, 7

Why Not Shorter Durations?

• Progestogen exposure shorter than 12 days per month fails to adequately oppose estrogen's proliferative effects on the endometrium 3, 6
• Studies demonstrate that intervals longer than the recommended 12–14 days (i.e., giving progestogen less frequently) are not safe for endometrial protection 6
• The endometrium requires sufficient progestogen exposure to induce secretory transformation and prevent hyperplastic changes 4

Alternative: Continuous Combined Regimens

• Continuous use of progestogens (daily, without interruption) provides the most effective endometrial protection and eliminates withdrawal bleeding 1, 6
• Continuous regimens require lower daily progestogen doses (e.g., micronized progesterone 100 mg daily or medroxyprogesterone acetate 2.5 mg daily) compared to sequential regimens 1, 7
• The choice between sequential (12–14 days/month) and continuous (daily) regimens depends on patient preference regarding withdrawal bleeding and tolerability 1, 5

Practical Dosing Recommendations

• Sequential regimen: Micronized progesterone 200 mg orally at bedtime for 12–14 days every 28 days 1, 2, 3
• Alternative sequential: Medroxyprogesterone acetate 10 mg daily for 12–14 days per month 1, 7
• Continuous regimen: Micronized progesterone 100–200 mg daily without interruption 1, 7
• Continuous alternative: Medroxyprogesterone acetate 2.5–5 mg daily 7

Common Pitfall to Avoid

• Never prescribe progestogen for fewer than 12 days per month in sequential regimens—this provides inadequate endometrial protection and increases cancer risk 3, 6
• Do not assume that lower estrogen doses eliminate the need for adequate progestogen duration; even low-dose estrogen requires full 12–14 day progestogen opposition in women with an intact uterus 5, 8
• Recognize that transdermal micronized progesterone does not provide endometrial protection and should not be used for this purpose 3