Metabolites of progesterone are measured in urine, including 5b-pregnanediol and 5a-pregnanediol. 5b-pregnanediol is inactive in the body but is the major metabolite of progesterone. 5a-pregnanediol is often a metabolite of more interest, as it can cross the blood brain barrier and up-regulate GABA activity and is considered neuroprotective to the brain. Both taken together represent the major metabolic end points for progesterone and can be used to represent total progesterone production.
Progesterone is produced by the corpus luteum following ovulation and to a lesser extent by the adrenal glands in both sexes. While found in the urine in small amounts, progesterone can be seen as a clinical marker of luteul activity and theraputic oral progesterone administration. The most important progesterone metabolite, pregnanediol (PDL), can serve as a urinary marker for endogenous progesterone levels and as an indicator of ovulation. PDL exists as two isomers, 5a-pregnanediol and 5b-pregnanediol. 5b-pregnanediol represents the majority end point of endogenous progesterone metabolism and appears to have little activity within the body, while 5α-pregnanediol, the lesser metabolite of PDL, can cross the blood brain barrier and may partially agonize GABA-A receptors. This action is possibly due to its role as an immediate precursor to allopregnanolone. Allopregnanolone is a potent neuroactive steroid capable of binding the GABA-A receptor often leading to sedative and anxiolytic action. The calming action of allopregnanolone is often seen with orally supplemented progesterone, as the liver metabolizes a large portion of oral progesterone to the neuroactive steroid allopregnanolone.
Lower levels of pregnanediol may be due to decreased progesterone or 5-alpha reductase activity.
If just one of the metabolites is high, his total progesterone in serum may be normal, or the patient could have a metabolic preference pushing the bulk of his metabolites one direction.
5a-reductase makes the a-pregnanediol metabolite and can be higher with inflammation, insulin resistance or obesity. Not much is known about the 5b-reductase enzyme, which makes b-pregnanediol.
Progesterone in men is positively associated with inflammation and tends to rise in response to higher testosterone production, high stress, and high cortisol.
High progesterone in men is also seen with liver issues.
→ Working on the root cause is the best approach.
If oral progesterone OR pregnenolone supplementation are used, please be aware these will increase progesterone metabolites in the urine due to first pass metabolism, but serum progesterone may not be elevated to the same degree as the urine implies.
5A-PD is a minor urinary metabolite of progesterone. Increased levels may be due to high levels of progesterone or pregnenolone, progesterone supplementation, or adrenocorticohyperplasia. 5A-PD may agonize GABA-A receptors.
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