The adrenal X-zone is involved in progesterone inactivation

20alpha-hydroxysteroid dehydrogenase (20aHSD) has been characterized as a progesterone metabolizing enzyme of the ovary mandatory for the final reduction of progesterone blood levels before parturition. As the exact zonal distribution and regulation of adrenal 20aHSD has not been defined, we determined adrenal 20aHSD expression and activity by western blotting, immunohistochemistry and enzymatic assays in wild type mice of both genders at different time points and following various hormonal treatments. In addition, to explore possible direct effects of 20aHSD expression on adrenal function, mice with targeted deletion of 20aHSD were studied for effects on adrenal morphology. Age related enzymatic activity and protein expression showed a gender difference with peak activity in males at 3 weeks and loss of activity thereafter but retained activity in virgin female mice. Interestingly, this time course of adrenal 20aHSD enzymatic activity is reminiscent of the growth kinetics of the adrenal X-zone. In fact, immunohistochemical staining confirmed X-zone restricted expression of 20aHSD. Accordingly, induction of X-zone regression in female mice by first pregnancy or testosterone treatment was accompanied by a rapid drop of adrenal 20aHSD expression. In contrast, induction of pseudo-pregnancy did not affect adrenal 20aHSD activity. Moreover, gonadectomy in post-pubertal male mice which is known to induce growth of a secondary X-zone results in the restoration of adrenal 20aHSD expression. Adrenal glands from 20aHSD knock out animals at various time points displayed normal timing of X-zone growth and regression. Taking together, these findings indicate that regulation of 20aHSD activity differs between the ovary and the adrenal. Moreover, although adrenal 20aHSD expression is restricted to the X-zone, adrenal 20aHSD expression is not required for X-zone proliferation and regression. Ongoing in vitro experiments aim at the further elucidation of factors involved in 20aHSD regulation through promoter activation vs. regulation through growth and apoptosis of the X-zone.