How should cyclic estrogen and progesterone be administered to a postmenopausal woman with an intact uterus?

How to Give Cyclic Estrogen and Progesterone

For postmenopausal women with an intact uterus, administer transdermal 17β-estradiol 50-100 μg daily continuously (changed twice weekly) combined with oral micronized progesterone 200 mg daily for 12-14 consecutive days per 28-day cycle, taken at bedtime. 1, 2, 3

Estrogen Component Selection and Dosing

• Transdermal 17β-estradiol is the preferred formulation over oral estrogens, ethinylestradiol, or conjugated equine estrogens due to significantly lower cardiovascular and thrombotic risk 1, 4
• Apply 50-100 μg patches twice weekly to clean, dry skin on the trunk (abdomen or buttocks), avoiding breasts and waistline 5
• Administer estrogen continuously without interruption—do not cycle the estrogen component 4, 5
• Oral 17β-estradiol 1-2 mg daily is an acceptable second-line alternative if transdermal delivery is not tolerated 4

Progesterone Component Selection and Dosing

• Oral micronized progesterone 200 mg daily is the first-line progestogen due to superior cardiovascular safety profile and lowest thrombotic risk compared to synthetic progestins 1, 4, 3
• Administer for exactly 12-14 consecutive days per 28-day cycle—never use fewer than 12 days as this provides inadequate endometrial protection 1, 4, 3
• Take as a single dose at bedtime with a glass of water while standing to facilitate swallowing 2
• The 12-14 day duration is critical for proven endometrial protection; shorter durations increase hyperplasia risk 1, 3

Alternative Progestogen Options (If Micronized Progesterone Unavailable)

• Second-line: Dydrogesterone 10 mg daily for 12-14 days per month 1, 4
• Third-line: Medroxyprogesterone acetate 10 mg daily for 12-14 days per month (has less favorable metabolic effects on lipid profiles) 6, 4
• Fourth-line: Norethindrone acetate 1 mg daily for 12-14 days per month (better cardiovascular profile than MPA but still inferior to micronized progesterone) 6, 4

Expected Bleeding Pattern

• This sequential regimen induces predictable withdrawal bleeding 2-3 days after completing each 12-14 day progesterone course 7, 8
• Withdrawal bleeding confirms endometrial shedding but does not guarantee endometrial safety—regular bleeding can occur with both normal and hyperplastic endometrium 7
• If breakthrough bleeding occurs during the estrogen-only phase, this may indicate insufficient progestogen exposure requiring dose adjustment 9, 7

Monitoring Requirements

• Conduct annual clinical review focusing on compliance, bleeding patterns, and symptom control 1, 4
• No routine laboratory monitoring or endometrial surveillance is required unless specific symptoms arise (persistent irregular bleeding, bleeding after amenorrhea) 1, 4
• Any breakthrough bleeding occurring after achieving amenorrhea or outside the expected withdrawal period mandates endometrial biopsy 10

Critical Pitfalls to Avoid

• Never administer progesterone for fewer than 12 days per cycle—this is the most common error and provides inadequate endometrial protection against hyperplasia and cancer 1, 4, 3
• Do not use transdermal progesterone for endometrial protection—it does not provide adequate protection 3
• Avoid starting with high estrogen doses; use the lowest effective dose for the shortest duration consistent with treatment goals 4
• Do not prescribe estrogen without progestogen in women with an intact uterus (except during the first 2 years in adolescents with premature ovarian insufficiency) 1

Special Population: Premature Ovarian Insufficiency

• In adolescents or young women with POI, begin with estrogen alone for at least 2 years to allow breast development 1
• Add cyclic progesterone only after 2 years of estrogen therapy or when breakthrough bleeding occurs 1
• Continue treatment until the average age of natural menopause (45-55 years) 4

Alternative Regimen: Continuous Combined Therapy

• If the patient wishes to avoid withdrawal bleeding, switch to continuous combined therapy: transdermal 17β-estradiol 50-100 μg daily plus micronized progesterone 100 mg daily without interruption 4, 9
• Expect irregular breakthrough bleeding for the first 3 months, which typically resolves as the endometrium becomes atrophic 9, 7
• This regimen eliminates scheduled bleeding but requires 3-6 months for bleeding to cease completely 9, 10