In a perimenopausal woman who still menstruates and is using a 50 µg transdermal estradiol patch, what continuous combined estrogen‑progestogen regimen should be used to achieve amenorrhea?

Continuous Combined Hormone Therapy for Perimenopausal Amenorrhea

For a perimenopausal woman using a 50 µg transdermal estradiol patch who desires amenorrhea, switch to a continuous combined regimen with 5 mg oral dydrogesterone daily or 2.5 mg medroxyprogesterone acetate daily, both given without interruption alongside the existing estradiol patch. 1

Recommended Continuous Combined Regimens

First-Line Option: Dydrogesterone

• Add 5 mg oral dydrogesterone daily continuously (without interruption) to the existing 50 µg transdermal estradiol patch 1
• This continuous regimen avoids withdrawal bleeding and induces amenorrhea, which is the patient's stated goal 1
• Dydrogesterone is endorsed by the European Society of Human Reproduction and Embryology as an effective progestogen for endometrial protection in continuous regimens 1

Second-Line Option: Medroxyprogesterone Acetate

• Add 2.5 mg oral medroxyprogesterone acetate (MPA) daily continuously to the 50 µg transdermal estradiol patch 1
• MPA has the most extensive safety data among synthetic progestins and provides proven endometrial protection in continuous regimens 1
• However, MPA has a less favorable cardiovascular and metabolic profile compared to dydrogesterone or micronized progesterone 1

Third-Line Option: Norethisterone

• Add 1 mg oral norethisterone daily continuously to the existing estradiol patch 1
• This is the minimum effective dose for continuous combined regimens 1

Why Continuous Rather Than Sequential

• Sequential regimens (12–14 days of progestogen per month) induce predictable withdrawal bleeding, which contradicts the patient's goal of amenorrhea 1, 2
• Continuous combined therapy (daily progestogen without interruption) is specifically designed to achieve amenorrhea by preventing endometrial proliferation 1, 3
• Amenorrhea rates with continuous combined regimens reach 53% by 3 months, 67% by 6 months, and 93% by 12 months 4

Critical Timing and Breakthrough Bleeding

• Expect irregular spotting or breakthrough bleeding during the first 3–6 months as the endometrium adjusts to continuous progestogen exposure 4, 3
• Approximately 12–30% of women experience isolated spotting episodes during the first year, but this typically resolves 4, 3
• Any breakthrough bleeding occurring after achieving prolonged amenorrhea (>6 months) requires endometrial biopsy to exclude hyperplasia or malignancy 5

Endometrial Safety Monitoring

• Continuous combined regimens induce endometrial atrophy within 6–12 months, providing adequate protection against endometrial hyperplasia and cancer 4, 3
• Perform endometrial biopsy if breakthrough bleeding persists beyond 6 months or recurs after achieving amenorrhea 5, 4
• Annual clinical review focusing on bleeding patterns, symptom control, and compliance is recommended 1
• No routine laboratory monitoring is required unless specific symptoms arise 1

Why Not Micronized Progesterone for Continuous Regimens

• While micronized progesterone 200 mg daily for 12–14 days per month is the preferred first-line option for sequential regimens due to superior cardiovascular safety, there is no established guideline-endorsed continuous daily dose of micronized progesterone for achieving amenorrhea 1
• The guideline-recommended continuous combined regimens specifically cite dydrogesterone 5 mg daily, MPA 2.5 mg daily, or norethisterone 1 mg daily as the minimum effective doses 1

Common Pitfalls to Avoid

• Do not use sequential progestogen regimens (12–14 days per month) if the patient desires amenorrhea, as these induce withdrawal bleeding by design 1, 2
• Do not discontinue therapy prematurely due to early breakthrough bleeding—this is expected during the first 3–6 months and typically resolves 4, 3
• Never use unopposed estrogen in a woman with an intact uterus, as this dramatically increases endometrial cancer risk 1, 2