Why Progesterone Causes Drowsiness
Oral micronized progesterone at 300 mg nightly causes somnolence through its conversion to neuroactive metabolites, particularly allopregnanolone, which act as positive modulators of GABA-A receptors in the central nervous system, producing sedative and anxiolytic effects similar to benzodiazepines. 1, 2
Mechanism of Action
Neurosteroid Conversion and GABA-A Modulation:
Progesterone is metabolized to allopregnanolone and pregnanolone, both of which are potent positive modulators of the GABA-A receptor system, the major inhibitory neurotransmitter system in the mammalian central nervous system 3
These metabolites produce effects similar to other GABA-A modulators including benzodiazepines, barbiturates, and alcohol, resulting in sedation, anxiolysis, and anticonvulsant properties 3
When administered orally, progesterone undergoes extensive first-pass hepatic metabolism (>90%), producing unphysiologically high levels of these 5-alpha reduced metabolites, which directly cause dizziness and drowsiness 4
Clinical Implications and Dosing Strategy
Timing of Administration:
The sedative effect is specifically leveraged in clinical practice by administering oral micronized progesterone at bedtime, which minimizes daytime impairment while providing therapeutic benefit 2
The 300 mg dose mentioned in your question is within the standard range (200-400 mg daily) used in hormone replacement therapy, typically given as a single nighttime dose to exploit the sedative properties 1, 2
Route-Dependent Effects:
The drowsiness is significantly more pronounced with oral administration compared to vaginal routes, because vaginal progesterone bypasses first-pass hepatic metabolism and produces lower systemic levels of sedating metabolites 5, 4
Vaginal administration achieves therapeutic endometrial effects through direct uterine uptake while maintaining subphysiologic plasma progesterone levels, resulting in fewer central nervous system side effects 4
Biphasic Dose-Response Relationship
Important Caveat - The Inverted U-Shaped Curve:
Allopregnanolone exhibits a paradoxical biphasic effect: low to moderate concentrations (similar to physiological luteal phase levels) can produce anxiety and negative mood in susceptible women, while higher concentrations produce the expected sedative and anxiolytic effects 3
The 300 mg nightly dose typically produces concentrations in the higher range that favor sedation rather than the paradoxical anxiogenic effects seen at lower doses 3
Individual sensitivity varies considerably, with some women experiencing adverse mood effects while others tolerate progesterone well, likely related to differences in GABA-A receptor sensitivity 3
Comparison to Synthetic Progestins
Metabolic Differences:
Synthetic progestins (medroxyprogesterone acetate, norethindrone) are specifically designed to resist enzymatic degradation and produce different metabolites that do not have the same neurosteroid effects as natural progesterone 2, 6
While synthetic progestins may cause fatigue, dysphoria, and other side effects through different mechanisms, they do not produce the same GABA-A mediated sedation as micronized progesterone 6
Micronized natural progesterone is preferred specifically because its sedative effect is predictable, dose-dependent, and can be managed with nighttime dosing, whereas synthetic progestins produce more variable psychological side effects 1, 2