When should perimenopausal women with an intact uterus taking estrogen (hormone) replacement therapy take progesterone (progestin) for 12 to 14 days a month instead of daily?

Progesterone Administration in Perimenopausal Women on Estrogen Therapy

Perimenopausal women with an intact uterus taking estrogen replacement therapy should use a sequential regimen with progesterone for 12-14 days per month if they can tolerate or prefer withdrawal bleeding, while continuous daily progesterone should be reserved for those who prefer to avoid bleeding. 1, 2

Sequential vs. Continuous Regimens

Sequential Regimen (12-14 days/month)

• Recommended for perimenopausal women who accept or prefer withdrawal bleeding 1
• Involves administration of progesterone for 12-14 days every 28-day cycle while estrogen is given continuously 3, 1
• Standard adult doses include:
  • 200 mg of oral or vaginal micronized progesterone for 12-14 days every 28 days 3, 2
  • 10 mg of medroxyprogesterone acetate for 12-14 days per month 3, 1
  • 10 mg of dydrogesterone for 12-14 days per month 3, 1
• Provides effective endometrial protection as demonstrated in clinical trials 2, 4

Continuous Regimen (Daily)

• Recommended for women who prefer to avoid withdrawal bleeding 1
• Involves daily administration of both estrogen and progesterone without interruption 1
• Standard adult doses include:
  • 1 mg of oral norethisterone daily 3
  • 2.5 mg of oral medroxyprogesterone acetate daily 3, 1
  • 5 mg of oral dydrogesterone daily 3, 1

Clinical Decision Algorithm

Choose Sequential Regimen (12-14 days/month) When:

• Patient accepts or prefers withdrawal bleeding 1
• Patient is early in perimenopause and still experiencing some natural cycles 1
• Patient has concerns about continuous progesterone exposure 1
• Patient experiences side effects with continuous progesterone administration 1

Choose Continuous Regimen (Daily) When:

• Patient prefers to avoid withdrawal bleeding 1
• Patient experiences problematic breakthrough bleeding with sequential regimen 1
• Patient has difficulty adhering to a cyclical regimen 1

Progesterone Type Selection

• Micronized progesterone is the first choice among progestins due to:
  • Lower risk of cardiovascular disease and venous thromboembolism when taken cyclically 3, 1
  • Better safety profile regarding metabolic effects 1
  • Lower breast cancer risk compared to synthetic progestins 1, 5
• FDA-approved dosing for endometrial protection: 200 mg orally for 12 days sequentially per 28-day cycle 2

Important Clinical Considerations

• Endometrial hyperplasia risk increases significantly with unopposed estrogen therapy (64% vs. 6% with combined therapy) 2
• Sequential progesterone administration for 12-14 days per month provides adequate endometrial protection for up to 5 years 5
• Attempts to limit progesterone to every third month have been studied but may not provide optimal endometrial protection 6
• The minimum effective dose of progesterone should be used to minimize side effects while maintaining endometrial protection 7
• Patient preference regarding bleeding patterns is a key factor in regimen selection 1, 2

Monitoring Recommendations

• Annual clinical review with attention to compliance 3
• Evaluate for breakthrough bleeding, which may indicate inadequate endometrial protection 3, 1
• No routine monitoring tests are required but may be prompted by specific symptoms or concerns 3