What is the recommended dosing schedule, route options, contraindications, and monitoring for a total daily dose of 300 mg progesterone in an adult woman?

Progesterone 300 mg Dosing Recommendations

Primary Recommendation

For a 300 mg daily dose of progesterone, the evidence supports oral micronized progesterone 300 mg taken at bedtime as a single dose for 10 days per month in sequential regimens, or divided as 100 mg three times daily for continuous tocolysis applications. 1

Route of Administration

Oral Route (Preferred for 300 mg dose)

• Oral micronized progesterone 300 mg taken at bedtime as a single dose is the established regimen for postmenopausal women requiring sequential hormone replacement therapy 2
• The bedtime dosing minimizes the mild transient drowsiness that occurs as the only specific side effect of this formulation 2
• Oral administration at 300 mg/day produces luteal phase serum concentrations ranging from 15.72-625.98 ng/ml, though considerable intersubject variability exists 3

Vaginal Route (Alternative)

• Vaginal progesterone 300 mg daily (divided as 100 mg three times daily or 300 mg once daily) has been studied but shows lower serum progesterone levels and higher IGFBP-1 levels compared to oral administration, which may reduce efficacy 4
• Vaginal administration may be considered when oral side effects are intolerable, though endometrial protection data at this dose are limited 5

Intramuscular Route

• Not applicable for 300 mg daily dosing—17-hydroxyprogesterone caproate (17P) uses 250-500 mg IM weekly, not daily 1

Dosing Schedules by Clinical Indication

Sequential Hormone Replacement Therapy

• 300 mg oral micronized progesterone daily at bedtime for 10 days per month when combined with estradiol 3 mg/day for 25 days induces withdrawal bleeding 6
• This regimen provides complete endometrial protection with no hyperplasia observed in clinical trials 6
• Alternative: 100 mg daily for 25 days per month induces amenorrhea in 91.6% of women at 6 months while maintaining endometrial protection 6

Adjunctive Tocolysis

• 400 mg orally every 6 hours for 24 hours, then 400 mg every 8 hours for 24 hours, then 300 mg every 8 hours ongoing when used with ritodrine for threatened preterm labor 1
• This stepped-down regimen reduced total ritodrine dose and shortened maternal hospital stay compared to placebo 1

Contraindications

Absolute Contraindications

• Active liver disease 5
• Current or history of breast cancer or other hormone-sensitive malignancies 5
• Active venous thromboembolism or arterial thromboembolic disease 5
• Undiagnosed abnormal uterine bleeding 5

Relative Contraindications

• History of venous thromboembolism (consider alternative progestogens or routes) 5
• Cardiovascular disease (micronized progesterone preferred over synthetic progestins) 5, 7

Monitoring Requirements

Clinical Monitoring

• Annual clinical review focusing on compliance, bleeding patterns, and symptom control is recommended 5
• No routine laboratory monitoring required unless specific symptoms arise 5
• Adjust dose according to tolerance and feeling of wellbeing 5

Endometrial Monitoring

• Baseline endometrial ultrasound to document endometrial thickness when initiating therapy 8
• Consider annual endometrial thickness monitoring if using off-label regimens 8
• Endometrial biopsy at 6-month minimum showed 61% quiescent endometrium, 23% mildly active, 8% partial secretory, with no hyperplasia at 300 mg dose 6

Critical Clinical Considerations

Bioavailability and Timing

• Oral micronized progesterone has similar bioavailability to other natural steroids with clear dose-ranging effects 2
• Taking 300 mg at bedtime minimizes drowsiness while maintaining therapeutic efficacy 2
• Extent of absorption increases with increasing age, requiring attention in elderly patients 3

Safety Profile Advantages

• Micronized natural progesterone has milder adverse effects than synthetic progestins (medroxyprogesterone acetate, norethisterone) 7
• Does not suppress the vasodilating effect of estrogens, unlike synthetic progestins 2
• No detrimental effect on lipoprotein profile 3
• Lower risk of cardiovascular disease and venous thromboembolism compared to synthetic progestins 5

Common Pitfalls to Avoid

• Never use progesterone for fewer than 10-12 days per cycle in sequential regimens—this provides inadequate endometrial protection 1, 5
• Avoid vaginal administration when oral route is tolerated, as vaginal progesterone at 300 mg may have lower pregnancy rates due to increased IGFBP-1 production 4
• Do not prescribe progesterone alone without estrogen in perimenopausal women requiring hormone therapy 5

Special Populations

Postmenopausal Women

• 300 mg daily for 10 days per month combined with estradiol 3 mg/day for 25 days is an established regimen 6
• Alternative lower-dose regimens (100-200 mg) may be preferred as first-line due to similar efficacy with better tolerability 5, 2

Preterm Birth Prevention

• Insufficient evidence to recommend 300 mg progesterone for primary, adjunctive, or maintenance tocolysis 1
• The 300 mg every 8 hours regimen showed similar PTB rates but reduced ritodrine requirements 1

Women with Premature Ovarian Insufficiency

• Begin cyclic progesterone after at least 2 years of estrogen therapy or when breakthrough bleeding occurs 5
• Continue treatment until average age of natural menopause (45-55 years) 5