THE METABOLIC DISPOSITION OF PLASMA 5-ALPHA-DIHYDROPROGESTERONE (5-ALPHA-PREGNANE-3,20-DIONE) IN WOMEN AND MEN

This study was conducted 1) to ascertain whether the high levels of plasma 5alpha-dihydroprogesterone (5alphaDHP) 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 5alphaDHP, i.e. hepatic compared with extrahepatic clearance of plasma 5alphaDHP. The concentration of 5alphaDHP in plasma of women during the luteal phase of the ovarian cycle and pregnancy is very high, viz. 12-40% that of progesterone. Thus, a potentially large source of steroid precursor is available for the formation of bioactive 5alpha-pregnanolone metabolites. We found that the MCR of 5alphaDHP in women and men is 4187 +/- 312 L plasma/24 h (range, 3181-5506; n = 6). The MCR of 5alphaDHP as a function of body surface area was 2406 +/- 240 L/24 h . m2. The MCR of 5alphaDHP, 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 (75-85%) of lipophilic steroids that are not specifically bound in plasma with high affinity to binding proteins as determined by other investigators (e.g. 5alphaDHP), we estimate that approximately 1200 L plasma/24 h are cleared of 5alphaDHP by liver and approximately 2800 L plasma/24 h are cleared of 5alphaDHP (70%) by metabolism in extrahepatic tissues. Thus, 5alphaDHP can serve as a precursor for bioactive 5alpha-pregnanolone(s).