page_title: Pharmacokinetics of progesterone
section_title: First-pass effect and neurosteroids
hierarchical_section_title: Pharmacokinetics of progesterone / Routes of administration / Oral administration / First-pass effect and neurosteroids
caption_attribution_description: English: Levels of progesterone, allopregnanolone, and pregnanolone in nine premenopausal women following a single dose of 200 mg oral micronized progesterone or 400 mg vaginal (suppository) progesterone. Source of the values: &#32;(April 1995).&#32;"Influence of route of administration on progesterone metabolism". Maturitas&#32;21&#32;(3): 251–7. DOI:10.1016/0378-5122(94)00882-8. PMID 7616875.
context_page_description: The pharmacokinetics of progesterone, concerns the pharmacodynamics, pharmacokinetics, and various routes of administration of progesterone.
  Progesterone is a naturally occurring and bioidentical progestogen, or an agonist of the progesterone receptor, the biological target of progestogens like endogenous progesterone. Progesterone also has antimineralocorticoid and inhibitory neurosteroid activity, whereas it appears to have little or no glucocorticoid or antiandrogenic activity and has no androgenic activity. Because of its progestogenic activity, progesterone has functional antiestrogenic effects in certain tissues such as the uterus, cervix, and vagina. In addition, progesterone has antigonadotropic effects due to its progestogenic activity and can inhibit fertility and suppress sex hormone production. Progesterone differs from progestins like medroxyprogesterone acetate and norethisterone, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety.
  Progesterone can be taken by mouth, in through the vagina, and by injection into muscle or fat, among other routes.
context_section_description: Progesterone is metabolized into allopregnanolone and pregnanolone, which are neurosteroids and potent potentiators of the GABAA receptor. The conversion of progesterone into these metabolites is catalyzed by the enzymes 5α- and 5β-reductase and 3α-hydroxysteroid dehydrogenase, and occurs primarily in the liver, but also occurs in reproductive endocrine tissues, the skin, the brain, and other tissues. Due to extensive first-pass metabolism with oral progesterone, about 80 to 90% or more of progesterone is rapidly transformed into these metabolites, and massive quantities of these neurosteroids are consequently formed and circulate throughout the body and brain. It is for this reason that commonly reported side effects of oral progesterone include dizziness, drowsiness, sedation, somnolence, and fatigue. Both oral and sufficiently high doses of intramuscular progesterone can produce these sedative effects. However, compared to oral progesterone, the levels of these neurosteroids have been found to be very low with parenteral routes like vaginal and intramuscular progesterone. As with the bioavailability of oral progesterone, there is high interindividual variability in the formation and levels of allopregnanolone and pregnanolone with oral progesterone. As a result, some individuals may experience considerable central depressant effects with oral progesterone, whereas others may experience minimal such effects.
  With oral administration of progesterone, allopregnanolone and pregnanolone circulate at higher concentrations than does progesterone. These neurosteroid metabolites of progesterone have relatively short biological half-lives in the circulation. Because of this, there are dramatic and highly supraphysiological spikes in allopregnanolone and pregnanolone concentrations followed by steep declines with each oral intake of progesterone. As such, neurosteroid levels fluctuate substantially (e.g., 15-fold in the case of allopregnanolone) and in an unphysiological manner with oral progesterone therapy. In addition, consumption of food with oral progesterone increases its absorption by 2-fold, and this may also further amplify fluctuations in neurosteroid levels, particularly if food intake with progesterone is not consistent from dose to dose.
  In contrast to oral administration, parenteral progesterone, such as with vaginal administration, avoids the first-pass effect, and is not associated with supraphysiological levels of neurosteroid metabolites, nor with spikes or marked fluctuations in neurosteroid levels. Parenteral routes can be used instead of oral administration to avoid adverse effects related to neurosteroid fluctuations if they prove to be problematic. Lower doses of oral progesterone (e.g., 100 mg/day) are also associated with relatively reduced formation of neurosteroid metabolites, and may similarly help to alleviate such side effects. In addition, the 5α-reductase inhibitor dutasteride, which blocks the production of allopregnanolone (though not of pregnanolone) from progesterone, has been found to diminish symptoms of premenstrual syndrome.
  Pregnenolone, an over-the-counter supplement and close analogue of progesterone, is extensively converted into neurosteroids such as allopregnanolone and pregnanolone with oral administration similarly to progesterone. Conversely, this was not seen with transdermal administration of pregnenolone.
caption: Levels of progesterone, allopregnanolone, and pregnanolone in premenopausal women following a single dose of 200 mg oral progesterone or 400 mg vaginal progesterone (as a suppository).[53] Allopregnanolone and pregnanolone levels were determined by GC-MS, while progesterone levels were determined by IA with chromatographic separation via LC–MS.[53]
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