Neuroendocrine metabolism of progesterone and related progestins

In mammalian neuroendocrine structures the metabolic processing of progesterone and related natural progestins is primarily a reductive process involving the C-4,5 double bond and the C-3 and C-20 ketones. The principal products of the neuroendocrine metabolism of progesterone in female rats are the two 5 alpha- and 3 alpha-reduced metabolites, 5 alpha-dihydroprogesterone and 3 alpha,5 alpha-tetrahydroprogesterone, with lesser amounts of the corresponding 20 alpha-reduced products. Certain of these metabolites produce some, but not all, of progesterone's biological effects. 5 alpha-Dihydroprogesterone and 3 alpha,5 alpha-tetrahydroprogesterone, in particular, have potent progesterone-like effects on neuroendocrine functions, such as gonadotropin regulation. The two other principal ovarian progestins, 20 alpha-dihydroprogesterone and 17 alpha-hydroxyprogesterone, are metabolized in an analogous manner. The major neuroendocrine progestin conversions therefore appear to be 5 alpha-reduction and 3 alpha-hydroxysteroid oxidoreduction. In the hypothalamus and anterior pituitary, the enzymic activities that catalyse these conversions appear to be under ovarian control and appear to vary with changing reproductive states. These quantitative changes in processing, together with the potent progesterone-like effects of certain metabolites, suggest that these neuroendocrine conversions may provide an important mechanism for mediating some of the effects of progesterone. Alternatively, some metabolites, by duplicating selected effects of progesterone, may provide a means of prolonging certain of its effects while others are terminated.