What are the recommended progesterone dosing regimens for luteal‑phase support in assisted reproductive technology, hormone replacement therapy, treatment of abnormal uterine bleeding, and progestin‑only contraception, and what safety considerations apply?

Progesterone Dosing Across Clinical Indications

Luteal-Phase Support in Assisted Reproductive Technology

For luteal-phase support in IVF/ART, vaginal micronized progesterone 200 mg twice daily (400 mg total) is the evidence-based regimen, providing superior uterine tissue concentrations through the "uterine first-pass effect" while avoiding systemic side effects. 1

• Vaginal administration achieves a mean peak concentration (Cmax) of 31.53 nmol/L at approximately 7 hours, with a terminal half-life of 16.4 hours 2
• The vaginal route bypasses hepatic first-pass metabolism and delivers higher progesterone concentrations directly to the uterus compared to oral administration 2
• Vaginal tablets demonstrate significantly higher Cmax (31.95 nmol/L) compared to vaginal gelatin capsules (23.85 nmol/L, P < 0.05) 2
• Continuous vaginal progesterone use does not adversely affect hormonal, hepatic, or lipid profiles and causes no endometrial hyperplasia 2

Hormone Replacement Therapy (Sequential Regimens)

For postmenopausal women with an intact uterus requiring sequential HRT, oral micronized progesterone 200 mg at bedtime for 12–14 days per 28-day cycle is the first-line progestogen due to superior cardiovascular and breast safety compared to synthetic progestins. 1

Primary Sequential Options:

• Micronized progesterone: 200 mg orally at bedtime for 12–14 days per month (preferred) 1
• Medroxyprogesterone acetate: 10 mg daily for 12–14 days per month (alternative) 1
• Dydrogesterone: 10 mg daily for 12–14 days per month (alternative) 1
• Norethisterone: 5 mg daily for 12–14 days per month (alternative) 1

Critical Duration Requirement:

• Never prescribe progesterone for fewer than 12 days per cycle—durations under 10 days increase endometrial cancer risk 1.8-fold 1
• The 12–14 day duration replicates the natural luteal phase and ensures complete secretory transformation of the endometrium 1

Vaginal Alternative:

• Vaginal micronized progesterone 200 mg nightly for 12–14 days per month provides equivalent endometrial protection with potentially fewer systemic side effects 1

Hormone Replacement Therapy (Continuous Regimens)

For women preferring amenorrhea, continuous daily micronized progesterone 100 mg at bedtime provides complete endometrial protection with lower daily dosing than sequential regimens. 1

Continuous Dosing Options:

• Micronized progesterone: 100 mg orally daily (preferred) 1
• Medroxyprogesterone acetate: 2.5 mg orally daily (alternative) 1
• Dydrogesterone: 5 mg orally daily (alternative) 1
• Norethisterone: 1 mg orally daily (alternative) 1

Key Advantage:

• Continuous regimens eliminate withdrawal bleeding while maintaining 90% reduction in endometrial cancer risk compared to unopposed estrogen 1

Treatment of Abnormal Uterine Bleeding

Acute Abnormal Uterine Bleeding:

For outpatient management of acute AUB, administer depot medroxyprogesterone acetate 150 mg intramuscularly plus oral medroxyprogesterone acetate 20 mg every 8 hours for 3 days (9 doses total). 3

• This regimen stops bleeding in 100% of women within 5 days, with mean cessation time of 2.6 days 3
• Side effects are infrequent and patient satisfaction is high 3
• Four women experienced only spotting by day 5 in the pilot study 3

Chronic Dysfunctional Uterine Bleeding (Premenopausal):

For premenopausal women aged 40–49 with dysfunctional uterine bleeding, vaginal micronized progesterone 300 mg twice daily (3 tablets × 100 mg, twice per day) starting on day 14 of the menstrual cycle for 12 days, continued for 6 months. 4

• This regimen significantly reduces bleeding intensity (p = 0.0068) and duration (p < 0.001) 4
• Endometrial thickness decreases significantly (p < 0.001) 4
• No significant effect on hemoglobin levels (p = 0.47) or vegetative symptoms (p = 0.96) 4
• Provides effective prevention of recurrent bleeding episodes 4

Progestin-Only Contraception

The evidence provided does not include specific dosing for progestin-only contraceptive pills, but depot medroxyprogesterone acetate 150 mg intramuscularly every 12 weeks is the standard contraceptive regimen. 3

• This dose provides reliable contraception through ovulation suppression 3
• The same 150 mg dose used for acute AUB management demonstrates the therapeutic range 3

Safety Considerations Across All Indications

Formulation Safety Hierarchy:

Micronized natural progesterone has the most favorable safety profile, followed by natural progesterone, with synthetic progestins carrying the highest risk of adverse effects. 5

• Synthetic progestins (Provera, PremPro, Cycrin) cause fatigue, fluid retention, lipid alterations, dysphoria, hypercoagulant states, and increased androgenicity 5
• Micronized natural progesterone has better bioavailability, fewer side effects, and is convenient for oral administration 5
• Natural progesterone has milder adverse effects than synthetic forms, with severity depending on route of administration 5

Cardiovascular and Metabolic Safety:

• Oral micronized progesterone shows neutral or beneficial effects on blood pressure 1
• Micronized progesterone exhibits the lowest thrombotic risk among all progestogen options 1
• Medroxyprogesterone acetate has less favorable cardiovascular and metabolic profiles compared to micronized progesterone 1

Route-Specific Considerations:

• Vaginal administration avoids hepatic first-pass metabolism, reduces systemic side effects, and achieves higher uterine concentrations 2
• Oral administration is convenient but may cause drowsiness (take at bedtime to minimize this effect) 1
• Intramuscular depot formulations provide sustained release but cannot be reversed once administered 3

Absolute Contraindications:

• Active liver disease 1
• Current or history of breast cancer 1
• Active or history of venous thromboembolism 1
• Active or history of stroke 1
• Antiphospholipid syndrome or positive antiphospholipid antibodies 1

Monitoring Requirements:

• Annual clinical review focusing on compliance, bleeding patterns, and symptom control 1
• No routine laboratory monitoring required unless specific symptoms arise 1
• Adjust dose according to tolerance and sense of wellbeing 1

Special Populations

Adolescents with Premature Ovarian Insufficiency:

• Begin cyclic progestogens after at least 2 years of estrogen-only therapy or when breakthrough bleeding occurs 1
• Oral micronized progesterone: 100–200 mg/day for 12–14 days per month 1
• Dydrogesterone: 5–10 mg/day for 12–14 days per month 1

Women with Premature Ovarian Insufficiency:

• Continue treatment until the average age of natural menopause (45–55 years) 1
• Use the same dosing regimens as standard HRT 1

Perimenopausal Women:

• Oral micronized progesterone 200 mg daily for 12–14 days per 28-day cycle combined with transdermal 17β-estradiol 50–100 μg daily 1
• Never prescribe progestin alone without estrogen in perimenopausal women requiring hormone therapy—this may increase endometrial cancer risk 1

Common Pitfalls to Avoid

• Never use progesterone for fewer than 12 days per cycle in sequential regimens—this provides inadequate endometrial protection 1
• Never prescribe estrogen without progesterone in women with an intact uterus—unopposed estrogen increases endometrial cancer risk 10- to 30-fold after 5 years 1
• Do not assume all progestogens have equivalent safety—micronized progesterone has superior cardiovascular and breast safety compared to synthetic progestins 1, 5
• Avoid synthetic progestins when micronized progesterone is available—synthetic forms cause significantly more side effects 5