What is the role of oral progesterone in hormone therapy?

Role of Oral Progesterone in Hormone Therapy

Oral progesterone is primarily used in hormone therapy to protect the endometrium against estrogen-induced hyperplasia and cancer in women with an intact uterus, with micronized progesterone being the preferred form due to its lower cardiovascular and breast cancer risk compared to synthetic progestins. 1, 2

Endometrial Protection

• Unopposed estrogen therapy significantly increases the risk of endometrial hyperplasia and cancer in women with an intact uterus
• Oral progesterone provides essential endometrial protection when added to estrogen therapy:
  • Reduces the risk of endometrial hyperplasia from 64% with estrogen alone to 6% with combined therapy 2
  • Induces secretory changes in the endometrium in a dose-dependent manner 3
  • Can be administered in either sequential or continuous regimens 1

Dosing and Administration Options

Sequential Regimen

• Oral micronized progesterone 200 mg daily for 12-14 days per month 1
• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month
• Dydrogesterone 10 mg daily for 12-14 days per month
• Results in monthly withdrawal bleeding

Continuous Regimen

• Oral micronized progesterone 100 mg daily for 25 days per month 4
• Minimum doses for continuous regimens: 2.5 mg MPA, 5 mg dydrogesterone, or 1 mg norethisterone daily 1
• Avoids withdrawal bleeding after initial adjustment period

Advantages of Micronized Progesterone

Micronized progesterone has several advantages over synthetic progestins:

• Lower risk of cardiovascular disease and venous thromboembolism 1
• More favorable effects on blood pressure 1
• Neutral or beneficial effects on lipid profiles 1, 4
• Associated with lower breast cancer risk compared to synthetic progestins 5, 6
• Minimal metabolic side effects compared to synthetic progestins 4

Practical Considerations

• Oral micronized progesterone is best taken at bedtime to minimize the mild drowsiness it may cause 4
• Bioavailability is similar to other natural steroids, with clear dose-ranging effects 4
• For optimal endometrial protection with estrogen therapy, doses of 300 mg daily for 10 days monthly or 200 mg for 14 days monthly are recommended 3
• In women with premature ovarian insufficiency, progesterone should be added to estrogen therapy after at least 2 years of estrogen or when breakthrough bleeding occurs 1

Potential Side Effects

• Mild and transient drowsiness (minimized by bedtime administration) 4
• May cause some degree of fluid retention (caution in cardiac or renal dysfunction) 2
• Dizziness (caution when driving or operating machinery) 2

Common Pitfalls to Avoid

1. Inadequate dosing: Suboptimal doses may not provide sufficient endometrial protection. A dose of 300 mg daily achieves responses within the physiological range 3

2. Long-cycle sequential therapy: Administering progesterone every three months rather than monthly increases the risk of endometrial hyperplasia 7

3. Ignoring bleeding patterns: Irregular bleeding during the first year is more common with continuous combined therapy, while in the second year it's more common with sequential regimens 7

4. Overlooking compliance issues: Poor adherence to progesterone therapy may explain some cases of endometrial hyperplasia despite prescribed therapy 8

Oral micronized progesterone is recommended as the first choice for opposing estrogen therapy in non-hysterectomized postmenopausal women due to its favorable safety profile while still providing effective endometrial protection 4.