What are the progesterone (progestin) options for a postmenopausal woman with a uterus?

Progestogen Options for Postmenopausal Women with a Uterus

Postmenopausal women with an intact uterus who are taking estrogen therapy must use a progestogen to prevent endometrial hyperplasia and cancer. 1 This is a critical safety requirement, as unopposed estrogen significantly increases endometrial cancer risk.

First-Line Progestogen Options

Oral Micronized Progesterone

• Recommended dosing: 200 mg daily at bedtime for 12-14 days per 28-day cycle (sequential regimen) 2, 1
• Alternative regimen: 100 mg daily for 25 days per month (continuous regimen) 3
• Benefits:
  • Natural progesterone identical to corpus luteum production 4
  • Less negative impact on lipid metabolism 5
  • May have less impact on breast cancer risk compared to synthetic progestins 6
  • Well-tolerated with minimal side effects 4
• Considerations:
  • Should be taken at bedtime due to potential drowsiness 2
  • Contains peanut oil (contraindicated in peanut allergies) 2

Medroxyprogesterone Acetate (MPA)

• Recommended dosing: 2.5-10 mg daily (continuous regimen) or 5-10 mg for 12-14 days per month (sequential regimen) 1, 5
• Considerations:
  • Widely used and well-established option
  • May have more negative effects on lipid metabolism than micronized progesterone 5
  • Associated with potential increased breast cancer risk 6

Dydrogesterone

• Recommended dosing: 5-10 mg daily for 12-14 days per month 5
• Benefits: Less negative effect on lipid metabolism 5

Alternative Progestogen Options

Norethisterone/Norethindrone

• Used in some combined hormone therapy formulations
• May have more androgenic effects than micronized progesterone 4

Levonorgestrel

• Available in some transdermal patch formulations 5
• Used in continuous combined patches (releasing 7 μg daily) 5

Administration Routes

Oral Administration

• Most common and well-studied route
• Provides reliable endometrial protection when dosed appropriately 7

Vaginal Administration

• Micronized progesterone 45 mg/day (4% gel) or 100 mg every other day for at least 10 days/month may provide endometrial protection 7
• Less systemic absorption and potentially fewer side effects

Transdermal Administration

• Combined estrogen-progestogen patches available
• Note: Transdermal micronized progesterone alone does not provide adequate endometrial protection 7

Regimen Options

Sequential Regimen

• Estrogen daily with progestogen added 12-14 days per month
• Results in regular withdrawal bleeding
• Example: 0.625 mg conjugated estrogen daily with 200 mg micronized progesterone for 12-14 days per month 2

Continuous Combined Regimen

• Both estrogen and progestogen taken daily without interruption
• Aims to prevent withdrawal bleeding
• Example: 0.625 mg conjugated estrogen with 2.5 mg MPA daily 1
• Alternative: 0.625 mg conjugated estrogen with 100 mg micronized progesterone daily 3

Important Considerations

Safety Monitoring

• Regular follow-up every 3-6 months initially to assess symptom control and side effects 1
• Annual gynecological assessment recommended 1
• Monitor for abnormal bleeding, which requires evaluation

Contraindications

• History of breast cancer
• Active or recent venous thromboembolism
• Active liver disease
• Uncontrolled hypertension
• Current smoking, especially if >35 years
• History of stroke or cardiovascular disease 1, 2

Side Effects to Monitor

• Increased risk of venous thromboembolism (RR 2.14) 1
• Increased risk of gallbladder disease (RR 1.8) 1
• Potential increased risk of breast cancer with combined therapy 1
• Common side effects: headaches, breast pain, irregular bleeding, abdominal cramps, nausea 2

Clinical Decision-Making

1. For women prioritizing minimal side effects and natural options: Micronized progesterone 200 mg daily for 12-14 days per month
2. For women wanting to avoid withdrawal bleeding: Continuous combined regimen with daily micronized progesterone 100 mg
3. For women with contraindications to micronized progesterone (e.g., peanut allergy): MPA or dydrogesterone

Remember that the primary purpose of progestogen therapy in postmenopausal women with a uterus is endometrial protection, and the regimen should be maintained as long as estrogen therapy continues.