When is the optimal time to take progesterone?

Optimal Timing for Progesterone Administration

For hormone replacement therapy, progesterone should be taken at bedtime (evening dosing) to minimize side effects, particularly drowsiness and dizziness caused by progesterone metabolites. 1, 2

Timing Based on Clinical Indication

Hormone Replacement Therapy (HRT) in Postmenopausal Women

Evening administration is strongly preferred:

• Oral micronized progesterone 200 mg should be taken at bedtime to minimize the sedative effects of 5-alpha-reduced metabolites that can cause drowsiness and impair motor vehicle operation 2
• The FDA-approved regimen for endometrial protection uses 200 mg daily for 12 days per 28-day cycle in combination with conjugated estrogens, with evening dosing recommended 3
• Peak plasma concentrations occur approximately 2 hours after ingestion, making bedtime dosing ideal for sleeping through peak metabolite effects 4

Sequential Regimens for Premature Ovarian Insufficiency

For cyclical administration:

• Oral micronized progesterone (MP) 200 mg daily should be administered for 12-14 days every 28 days when combined with continuous estrogen 1
• Vaginal progesterone 200 mg daily can be given for 12-14 days every 28 days as an alternative route 1
• MP is the first-choice progestin due to lower cardiovascular and thromboembolism risk compared to synthetic progestins 1

Continuous Combined Regimens

For women desiring amenorrhea:

• Oral progesterone 100 mg daily taken continuously (25 days per month) can maintain amenorrhea 2
• Continuous combined patches with 17β-estradiol and progestin can be administered without interruptions 1

Preterm Birth Prevention

Timing varies by indication:

• For women with prior spontaneous preterm birth: 17-alpha-hydroxyprogesterone caproate (17P) 250 mg IM weekly starting at 16-20 weeks until 36 weeks gestation 1, 5
• For women with short cervical length (≤20 mm): vaginal progesterone 90-mg gel or 200-mg suppository daily from diagnosis (18-24 weeks) until 36 weeks 1, 5
• Vaginal progesterone 100 mg nightly from 24-34 weeks has demonstrated efficacy in reducing preterm birth 1

Route-Specific Timing Considerations

Oral Administration

• Twice-daily dosing (100 mg morning, 200 mg evening) maintains more sustained progesterone and metabolite levels over 24 hours compared to once-daily dosing 4
• However, single evening dosing of 200-300 mg is preferred for compliance and side effect management 2
• The 300 mg dose taken at bedtime is commonly used in Europe for endometrial protection 2

Vaginal Administration

• Vaginal progesterone can be administered once daily at any time due to direct uterine uptake via first-uterine-pass effect, which produces adequate endometrial effects despite lower systemic levels 6
• The bioadhesive gel formulation provides controlled, sustained release regardless of timing 6

Intramuscular Administration

• 17P injections are given weekly on the same day each week, with timing during the day being less critical than consistency 1

Critical Pitfalls to Avoid

• Do not administer oral progesterone in the morning if sedation is a concern, as peak metabolite levels coincide with daytime activities and can impair function 2
• Do not use synthetic progestins (medroxyprogesterone acetate, norethindrone) when natural progesterone is available, as they cause more metabolic, vascular, and psychological side effects 6, 2
• Do not start progestin before adequate endometrial development in pubertal induction—wait 2-3 years after estrogen initiation or until breakthrough bleeding occurs 1
• Do not confuse timing recommendations for different indications: preterm birth prevention requires different schedules than HRT 1, 5

Duration Considerations

• For endometrial protection in HRT: minimum 10-14 days per month for sequential regimens to prevent hyperplasia 3, 2
• For secondary amenorrhea: 10 days of progesterone 300-400 mg daily induces withdrawal bleeding in 73-80% of women 3
• For preterm birth prevention: continue until 36 weeks gestation 1, 5