Should progesterone be given with estrogen and what is the recommended dosage?

Should Progesterone Be Given with Estrogen and Dosing Recommendations

Yes, progesterone must be added to estrogen therapy in all postmenopausal women with an intact uterus to prevent endometrial hyperplasia and cancer. 1, 2, 3

Absolute Requirement for Combined Therapy

• Women with an intact uterus require progestogen with estrogen because unopposed estrogen increases endometrial hyperplasia risk dramatically—from 2% with placebo to 62% at 36 months of moderate-dose estrogen therapy. 4
• Unopposed estrogen at all doses and durations (6-36 months) significantly increases endometrial hyperplasia risk (odds ratios ranging from 5.4 to 15.0). 5, 4
• Women who have undergone hysterectomy should receive estrogen-only therapy—there is no therapeutic advantage to adding progestogen in this population. 1

Recommended Progesterone Dosing Regimens

First-Line: Micronized Progesterone (Preferred)

Micronized progesterone is the preferred progestogen due to superior cardiovascular and breast cancer safety profiles compared to synthetic progestins. 2, 6, 7, 8

Sequential Regimen (Induces Monthly Withdrawal Bleeding):

• 200 mg oral micronized progesterone daily for 12-14 days per 28-day cycle 2, 9, 3
• Alternative: 200 mg vaginal micronized progesterone daily for 12-14 days per month 2
• Critical: Never use progesterone for fewer than 12 days per cycle—this provides inadequate endometrial protection 2, 9

Continuous Combined Regimen (Avoids Withdrawal Bleeding):

• 100 mg oral micronized progesterone daily without interruption 2, 9

Alternative Progestogen Options (Second-Line)

If micronized progesterone is unavailable or not tolerated:

Sequential Regimens:

• Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month 2
• Dydrogesterone 10 mg daily for 12-14 days per month 2
• Norethisterone 5 mg daily for 12-14 days per month 2

Continuous Combined Regimens:

• Medroxyprogesterone acetate 2.5 mg daily 2
• Dydrogesterone 5 mg daily 2
• Norethisterone 1 mg daily 2

Estrogen Component Pairing

Transdermal 17β-estradiol 50-100 μg daily is the preferred estrogen formulation due to lower cardiovascular and thrombotic risk compared to oral preparations. 1, 2, 6

• Transdermal delivery avoids hepatic first-pass metabolism, minimizing impact on clotting factors and providing better lipid, inflammatory marker, and blood pressure profiles. 1
• Alternative: Oral 17β-estradiol 1-2 mg daily 1, 6
• Alternative: Conjugated equine estrogens 0.625-1.25 mg daily 1

Evidence Supporting Regimen Selection

Continuous vs. Sequential Therapy:

• Continuous combined therapy provides superior endometrial protection compared to sequential therapy at longer treatment durations. 5, 4
• Sequential therapy causes more irregular bleeding during the second year of treatment, while continuous therapy causes more bleeding during the first year. 4
• Long-cycle sequential therapy (progestogen every 3 months) has higher hyperplasia rates than monthly sequential therapy and should be avoided. 4

Micronized Progesterone vs. Synthetic Progestins:

• Micronized progesterone does not increase breast cell proliferation, unlike medroxyprogesterone acetate (MPA). 7
• Large observational studies suggest natural progesterone and dydrogesterone are associated with lower breast cancer risk compared to other synthetic progestins. 8
• However, one systematic review found micronized progesterone increased endometrial cancer risk notably, even when administered continuously—this highlights the importance of adequate dosing (200 mg for sequential, 100 mg for continuous). 10

Special Population: Premature Ovarian Insufficiency

For adolescents and young women with premature ovarian insufficiency:

• Begin with estrogen-only therapy for at least 2 years to allow breast development, then add cyclic progesterone when breakthrough bleeding occurs. 2, 6
• Recommended progesterone: 100-200 mg daily for 12-14 days per month 2
• Alternative: Dydrogesterone 5-10 mg daily for 12-14 days per month 2
• Continue treatment until the average age of natural menopause (45-55 years). 2, 6

Monitoring and Duration

• Annual clinical review focusing on compliance, bleeding patterns, symptom control, and risk-benefit reassessment 2, 6
• No routine laboratory monitoring required unless specific symptoms arise 2, 6
• Use the lowest effective dose for the shortest duration consistent with treatment goals 2
• Adjust dose according to the woman's tolerance and feeling of wellbeing 2

Critical Pitfalls to Avoid

• Never prescribe unopposed estrogen to women with an intact uterus—this dramatically increases endometrial hyperplasia and cancer risk. 1, 3, 5, 4
• Never use sequential progesterone for fewer than 12 days per cycle—inadequate duration fails to protect the endometrium. 2, 9
• Avoid long-cycle sequential regimens (progestogen every 3 months) due to higher hyperplasia rates. 4
• Do not prescribe progesterone to women who are allergic to peanuts (micronized progesterone capsules contain peanut oil). 3
• Recognize that risks (venous thromboembolism, coronary events, stroke) occur within the first 1-2 years of therapy, while breast cancer risk increases with longer-term use. 2

Contraindications to Combined Therapy

• Current or history of breast cancer or hormone-sensitive malignancies 2, 6
• Active liver disease 2
• Current or history of blood clots, stroke, or heart attack 3
• Unexplained vaginal bleeding 3
• Pregnancy 3