Endocrine Defects in Mice Carrying a Null Mutation for the Progesterone Receptor Gene*

Mice carrying a null mutation of the progesterone receptor gene exhibit several reproductive abnormalities, including anovulation, attenuated lordotic behavior, uterine hyperplasia, and lack of mammary gland development. The hormonal correlates of these abnormalities are unknown, however, and were the focus of these studies. Serum samples from female wild-type (WT) and progesterone receptor knockout (PRKO) mice were obtained and analyzed by RIA for LH, FSH, PRL, estrogen (E2), and progesterone. Hypothalamic tissues were also processed for measurement of LHRH by RIA. Serum LH levels in PRKO mice were found to be elevated by approximately 2-fold over basal (metestrus) values in WT mice. By contrast, basal FSH levels were not different in PRKO and WT mice. Basal levels of E2 and progesterone in serum were likewise similar in the two groups, as were hypothalamic LHRH concentrations. Basal PRL levels were slightly higher in PRKO vs. WT mice. Ovariectomy of both groups of mice was accompanied by significant increases in both LH and FSH. At 5 days following ovariectomy, LH levels were elevated in both groups by 2-fold over PRKO basal and 4-fold over WT basal levels; however, by 10 days postovariectomy LH levels had continued to rise to a greater extent in PRKO mice than in WT animals. The FSH response to ovariectomy was greater for the PRKO mice at 5 days, but was no different from WT at 10 days. Of seven PRKO mice that were exposed to male odor, none exhibited preovulatory surges 3 days later, on the day of presumptive proestrus; this was in marked contrast with WT females, in which 100% exhibited robust LH surges. These results confirm the essential role of progesterone receptors in the regulation of hypothalamic and/or pituitary processes that govern gonadotropin secretion. The finding that basal LH levels are elevated in PRKO mice confirms that circulating progesterone normally conveys a significant portion of the total ovarian negative feedback control of the gonadotropin. That gonadotropin responses to ovariectomy are slightly enhanced in PRKO mice suggests that adrenal progesterone may contribute to the imposition of negative feedback control. The apparent inability of PRKO mice to respond to male odor suggests that anovulation in these mice may not be solely due to reproductive abnormalities within the ovary itself; rather, PRKO mice additionally harbor neuroendocrine defects that render them incapable of mounting normal preovulatory gonadotropin surges. It remains to be determined how the absence of PR in brain and pituitary of PRKO mice may produce this hormonal acyclicity and, conversely, how the presence of PR in brain and pituitary of WT mice may be obligatory in the generation of gonadotropin surges.