What are the guidelines for initiating progesterone therapy?

Guidelines for Initiating Progesterone Therapy

Progesterone therapy should be initiated using micronized progesterone 200 mg daily for 12-14 days per 28-day cycle in women requiring endometrial protection with estrogen therapy, as this formulation provides superior cardiovascular and thrombotic safety compared to synthetic progestins. 1

Clinical Context Assessment

Before initiating progesterone, determine the specific indication:

• Postmenopausal hormone replacement therapy (HRT): Progesterone is required for endometrial protection in women with an intact uterus receiving estrogen therapy 2, 1
• Premature ovarian insufficiency (POI): Begin cyclic progestogens after at least 2 years of estrogen therapy or when breakthrough bleeding occurs 2, 1
• Secondary amenorrhea: Progesterone induces withdrawal bleeding and secretory transformation 3

Formulation Selection Priority

Micronized progesterone is the preferred first-line choice due to lower cardiovascular disease and venous thromboembolism risk compared to synthetic progestins 1. The American Heart Association and American College of Cardiology both recommend this formulation for its superior safety profile 1.

Alternative formulations (if micronized progesterone is contraindicated or not tolerated):

• Dydrogesterone: 10 mg daily for 12-14 days per month (sequential regimen) or 5 mg daily (continuous regimen) 1
• Medroxyprogesterone acetate (MPA): 10 mg daily for 12-14 days per month (sequential) or 2.5 mg daily (continuous) 1
• Norethisterone: 5 mg daily for 12-14 days per month (sequential) or 1 mg daily (continuous) 2, 1

Dosing Regimens by Clinical Scenario

For Postmenopausal Women with Intact Uterus on Estrogen:

Sequential regimen (preferred for women desiring regular bleeding):

• Micronized progesterone 200 mg orally daily for 12-14 days per 28-day cycle 1, 3
• Alternative route: 200 mg vaginal micronized progesterone daily for 12-14 days per month provides good endometrial protection 1

Continuous regimen (for women preferring amenorrhea):

• Micronized progesterone 100 mg daily for 25 days per month 4
• Adjust dose according to tolerance and wellbeing 1

For Adolescents and Young Women with POI:

Timing of initiation: Begin cyclic progestogens after at least 2 years of estrogen therapy or when breakthrough bleeding occurs 2, 1

Dosing:

• Oral micronized progesterone 100-200 mg/day for 12-14 days of the month 2, 1
• Alternative: Dydrogesterone 5-10 mg/day for 12-14 days of the month 2, 1
• Medroxyprogesterone acetate 5-10 mg daily for 12-14 days per month 2

Duration: Continue treatment until the average age of natural menopause (45-55 years) 1

For Secondary Amenorrhea:

• Progesterone 300-400 mg daily for 10 days induces withdrawal bleeding in 73.8-80% of women 3
• Lower doses (200 mg daily for 12-14 days) may be used for maintenance after initial response 1

Route of Administration Considerations

Oral route: Standard first-line approach with micronized progesterone 1

Vaginal route: 200 mg micronized progesterone provides adequate endometrial protection with potentially fewer systemic side effects 1, 5

Transdermal patches: Combined estrogen/progestogen patches available in some countries for sequential or continuous administration 2

Critical Contraindications

Absolute contraindications:

• Active breast cancer (HRT generally contraindicated in breast cancer survivors) 2
• Acute cardiovascular events: Hormone therapy should NOT be initiated de novo after unstable angina/non-ST-elevation myocardial infarction 2
• Women hospitalized on bedrest should discontinue hormone therapy 2

Relative considerations:

• Women with BRCA1/2 mutations without personal breast cancer history may use HRT after prophylactic oophorectomy 2
• Migraine is NOT a contraindication to HRT in women with POI 2

Monitoring and Follow-up

• Annual clinical review to assess compliance, tolerance, and side effects 2, 1
• No routine monitoring tests required unless prompted by specific symptoms 2
• Baseline ultrasonographic assessment may guide dosing in adolescents with POI, particularly if pubertal arrest occurred after initial development 2
• Endometrial thickness evaluation before adding progestin in adolescents to confirm adequate estrogenization 2

Common Pitfalls to Avoid

Do not use hormone therapy for cardiovascular disease prevention: The Women's Health Initiative demonstrated increased cardiovascular events (7 additional CHD events, 8 more strokes, 10 more pulmonary emboli per 10,000 women-years) with estrogen plus progestin therapy 2, 1, 3

Do not start with high doses: Use the lowest effective dose for the shortest duration consistent with treatment goals 1

Do not use synthetic progestins as first-line: Medroxyprogesterone acetate and norethisterone have been associated with metabolic and vascular side effects, including suppression of estrogen's vasodilating effects 4

Do not forget endometrial protection: Unopposed estrogen carries a 64% risk of endometrial hyperplasia versus 6% with combined estrogen-progesterone therapy over 36 months 3

Special Clinical Scenarios

Women with endometriosis requiring oophorectomy: Combined estrogen/progestogen therapy reduces risk of disease reactivation 2

Women requiring contraception: Consider 17β-estradiol-based combined oral contraceptives with nomegestrol acetate or dienogest as first choice 2, 1

Food interaction: Concomitant food ingestion increases bioavailability of oral progesterone capsules 3

Drug interactions: Ketoconazole and other cytochrome P450 3A4 inhibitors may increase progesterone bioavailability 3