Why Progesterone is Prescribed at Night
Progesterone is prescribed at bedtime because it causes drowsiness, dizziness, and sometimes blurred vision or difficulty with coordination—side effects that are minimized when patients sleep through them. 1
Primary Rationale: Sedative Side Effects
The FDA label explicitly warns that progesterone capsules should be taken at bedtime because "some women become very drowsy and/or dizzy after taking progesterone capsules," with symptoms potentially including blurred vision, difficulty speaking, difficulty walking, and feeling abnormal. 1 The label specifically cautions about driving or operating machinery due to these effects. 1
Mechanism of Sedation
- Progesterone and its metabolites (particularly 5-alpha reduced metabolites) act as neurosteroids that produce sedative-like effects on the central nervous system. 2, 3
- When taken orally, progesterone undergoes extensive first-pass hepatic metabolism, creating unphysiologically high levels of these sedating metabolites. 2
- These metabolites can cause drowsiness severe enough to prevent safe operation of motor vehicles. 2
Additional Benefits of Nighttime Dosing
Sleep Quality Improvement
- Progesterone actively improves sleep architecture, particularly when sleep is disturbed. 4
- In postmenopausal women, progesterone 300 mg at bedtime increased slow-wave sleep duration by almost 50% and reduced wake time after sleep onset by 53% compared to placebo when sleep was disrupted. 4
- Progesterone acts as a "physiologic regulator" rather than a traditional hypnotic—it restores normal sleep when disturbed but doesn't suppress deep sleep like conventional sleep medications. 4
Safety Optimization
- Evening dosing minimizes the risk of falls, accidents, or impaired coordination during waking hours. 5
- Taking the medication with a glass of water while standing at bedtime reduces swallowing difficulties. 1
Standard Dosing Schedules by Indication
Hormone Replacement Therapy (Endometrial Protection)
- 200 mg at bedtime for 12 continuous days per 28-day cycle when combined with estrogen therapy in postmenopausal women with a uterus. 1, 5
- This timing provides endometrial protection while minimizing daytime sedation. 5
Secondary Amenorrhea
- 400 mg at bedtime for 10 days. 1
Preterm Birth Prevention
- For short cervical length: 100-200 mg vaginally at night from diagnosis (18-24 weeks) until 36 weeks gestation. 5, 6
- Vaginal administration avoids the sedative effects of oral dosing while maintaining efficacy. 6
Clinical Pitfalls to Avoid
- Never advise daytime dosing of oral progesterone 300-400 mg without warning about sedation and coordination impairment. 1, 3
- The drowsiness is not a sign of intolerance but an expected pharmacologic effect that can be well-tolerated with nocturnal administration. 3
- Patients should be counseled that these effects are most pronounced during initial therapy and to use caution if they must wake during the night. 1
Alternative Routes When Sedation is Problematic
- Vaginal progesterone avoids first-pass hepatic metabolism and the resulting high levels of sedating metabolites, making it suitable for patients who cannot tolerate oral sedation even at night. 2, 6
- Vaginal administration provides adequate endometrial protection with fewer systemic side effects. 7, 6