Arafat, E. S., Hargrove, J. T., Maxson, W. S., Desiderio, D. M., Wentz, A. C., & Andersen, R. N. (1988). Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. American Journal of Obstetrics and Gynecology, 159(5), 1203-1209. https://doi.org/10.1016/0002-9378(88)90448-6
Arafat ES, Hargrove JT, Maxson WS, Desiderio DM, Wentz AC, Andersen RN. Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites. Am J Obstet Gynecol. 1988;159(5):1203-1209. doi:10.1016/0002-9378(88)90448-6
Arafat, ElSayed S., et al. "Sedative and hypnotic effects of oral administration of micronized progesterone may be mediated through its metabolites." American Journal of Obstetrics and Gynecology, vol. 159, no. 5, 1988, pp. 1203-1209.
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Oral progesterone sedation may stem from its metabolites
Oral micronized progesterone was followed by metabolites with reported anesthetic qualities in eight postmenopausal women. One woman fell into a hypnotic state for about 2 hours. The authors suggest the metabolites may explain the sedation.
Key Findings
After the women took micronized progesterone by mouth, blood levels of progesterone and its metabolites climbed significantly and peaked 2 to 6 hours later.
Five compounds with reported anesthetic properties appeared in significant amounts: progesterone and four of its metabolites.
Metabolites first showed up 1 to 2 hours after dosing, and the woman who became hypnotic formed the most of any participant, 10 in all.
At a lower oral dose she had only transient sleepiness, and after a vaginal suppository of the same size as the hypnotic oral dose she had no symptoms.
All but one of the eight women formed 5 alpha-pregnan-3 alpha-ol-20-one and 5 beta-pregnan-3 alpha-ol-20-one, which the authors suggest were most active in the hypnotic case, judging by timing.
Interpretation
The study followed eight healthy postmenopausal women and gave a detailed account of the one who became hypnotic. Blood was sampled for up to 24 hours. Metabolite levels were measured semiquantitatively. The proposed link between metabolites and sedation rests on timing and on animal findings. At the lower oral dose given to the group, only one other woman reported drowsiness. The authors suggest that strong responders may be sensitive to a metabolite or may process progesterone differently. Women before menopause were not studied.
RRM Context
In restorative reproductive medicine, progesterone is the hormone that rises after ovulation. The study used micronized progesterone, a bioidentical form of that hormone. Synthetic progestins were not the compounds under study. The authors cite rat work showing that one of these metabolites binds the brain's GABA receptor. They suggest the reported benefit of oral progesterone in premenstrual syndrome may arise in part through this mechanism.
Our editorial summary of this paper, not the article's abstract.
Abstract
Progesterone and its metabolites were measured in serum extracts by radioimmunoassay and gas chromatography-mass spectrometry, respectively, after ingestion of micronized progesterone by eight postmenopausal women. One subject received 400 mg of micronized progesterone orally that induced a hypnotic state that lasted for approximately 2 hours. Blood samples were drawn periodically from all subjects for measurement of progesterone and its metabolites in serum. Levels of serum progesterone and its metabolites increased significantly from baseline values and reached a peak between 2 and 6 hours after oral progesterone administration. Significant quantities of five compounds (progesterone, 5 alpha-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha-ol-20-one, 5 beta-pregnan-3 alpha,20 beta-diol, and 5 beta-pregnan-3 alpha-ol-11,20-dione) that have been reported to possess anesthetic qualities were identified. The sedative and hypnotic effects of oral administration of progesterone may be mediated through those compounds.
