The Metabolic Disposition of Plasma 5cu- Dihydroprogesterone

This study was conducted 1) to ascertain whether the high levels of plasma 5adihydroprogesterone (5aDHP) during the luteal phase of the human ovarian cycle and pregnancy are attributable to high rates of production or, alternatively, low rates of clearance, and 2) to estimate the relative distribution of the irreversible metabolism of 5aDHP, i.e. hepatic compared with extrahepatic clearance of plasma 5aDHP. The concentration of 5aDHP in plasma of women during the luteal phase of the ovarian cycle and pregnancy is very high, uiz. 12-40% that of progesterone. Thus, a potentially large source of steroid precursor is available for the formation of bioactive Ba-pregnanolone metabolites. We found that the MCR of 5aDHP in women and men is 4187 rt 312 L plasma/24 h (range, 3181-5506; n = 6). The MCR of 5orDHP as a function of body surface area was 2406 + 240 L/24 b. m*. The MCR of 5aDHP, therefore, is the greatest of any steroid reported, except for that of the catechol estrogens, which are metabolized intravascularly by erythrocyte catechol-O-methyltransferase. Based on estimated rates of liver plasma flow (1500 L/24 h) and hepatic extraction (7585%) of lipophilic steroids that are not specifically bound in plasma with high affinity to binding proteins as determined by other investigators (e.g. 5aDHP), we estimate that -1200 L plasma/24 h are cleared of 5aDHP by liver and -2800 L plasma/24 h are cleared of 5aDHP (70%) by metabolism in extrahepatic tissues. Thus, 5aDHP can serve as a precursor for bioactive 5a-preguanolone(s). (J Clin Endocrirwl Metub