To date, most research on progesterone action has concentrated on elucidating the mechanism by which this hormone modulates various aspects of female reproduction. However, an increasing number of reports have suggested progesterone's involvement in many diverse physiological systems that are apparently unrelated to female reproduction. Because PR's role is uncertain for many of these systems, we believe that the PRKO mouse model will be a powerful investigative tool in reaching a more comprehensive understanding of the relevant role of progesterone and its receptor in these areas.
For example, neurobiologists have previously detected PR in the adult brain of the male rat at levels equating those in the female (180). A more detailed investigation has revealed that the most significant differences in PR levels between the male and female adult rodent brain are restricted to differences in estrogen-induced PR in the VMNH, a region of the female brain involved in the induction of lordosis. Moreover, the physiological significance of equivalent levels of this nuclear receptor in regions of the female and male brain, other than the VMNH, is one of the more challenging questions concerning the neurobiology of this steroid. Intriguingly, recent PR-immunohistochemistry has revealed a significantly higher level of PR in the medial pre-optic nucleus (MPN) in the male fetal and neonatal rat, as compared to the female. The MPN is considered one of the most sexually dimorphic structures in the rodent, and is involved in many sexually differentiated behaviors (181). Based on these observations, it has been proposed that during pregnancy, high levels of maternally derived progesterone may exert sexual differentiative effects on the developing fetal CNS, and that PRs in the fetal MPN would mediate these effects (181).
The existence of PRs in the CA1 hippocampal neurons (182) and the finding that progesterone in concert with estrogen may regulate synaptic plasticity in this region (183) are of particular interest. Because this brain region controls learning and other cognitive skills (184), functional roles for these gonadal hormones in behaviors other than lordosis (i.e., cognition, learning, and memory) cannot be discounted (185,186).
In addition to evaluating the role of ovarian-derived progesterone on neuronal development and function, recent biochemical and electrophysiological investigations have underscored the physiological importance of neuronal-derived progesterone in local neuronal effects (187). For example, Baulieu et al. have recently demonstrated that progesterone and its metabolic derivatives (classified as "neurosteroids") are synthesized within glial (188) and Schwann (189) cells of the central and peripheral nervous systems, respectively. Furthermore, through in vitro studies, these neurosteroids have been shown to exert changes on local neurotransmission (188) as well as nerve morphology (189) through either the classical PR-signaling pathway (189) or through less clearly understood rapid membrane effects (nongenomic) (190). Clearly, the PRKO mouse model would be extremely useful in substantiating these observations within an in vivo context. From a clinical perspective, further studies on progesterone's role in brain development and function will be essential, as progesterone has been proposed as an alternative method to limit the extent of neuronal damage induced by delayed injury processes following cortical injury (186,191-193). Progesterone's neuroprotective effects have been reported to include improved blood-brain barrier integrity, containment of free-radical-induced lipid peroxidation, and a significant reduction in cerebral edema (186,191-194). Progesterone holds particular promise as a valid treatment regimen for brain injury, as it is equally effective at reducing cerebral edema in both males and females (192) without attendant undesirable side effects observed thus far. Whether PR mediates some or all of these progesterone-initiated neuroprotective effects is unclear. However, the utilization of the PRKO mouse model in conjunction with an ablation model of cortical injury (195) will be essential in addressing this question.
In addition to its proposed role in the nervous system, progesterone has been implicated to have a physiological role in cardiovascular biology. Premenopausal women have a significantly lower risk (ratio 1:10) of cardiovascular disease than men of equivalent age. However, this protection diminishes in the postmenopausal woman. At age 75, the incidence is essentially the same in both sexes, with cardiovascular disease the leading cause of mortality/morbidity in women by age 60 (reviewed in 196). Because natural and surgical (bilateral oophorectomy) menopause accelerates the development of coronary heart disease, ovarian hormones have been implicated in protection against cardiovascular disease in premenopausal women (197). Previously, estrogen replacement therapy has been shown to reduce cardiovascular mortality in premenopausal women by an average of 50% (198-200). It is believed that approx 25-50% of the cardioprotection afforded by estrogen can be attributed to beneficial changes in serum lipoprotein levels, while the remainder of this protection is associated, in part, with direct effects of estrogen on the cardiovascular system (199-201).
Because estrogen monotherapy has been linked to increases in the risk of endometrial cancer (202), progestins have usually been included to reduce this risk (203). The role of progesterone in combination with estrogen in cardioprotection is currently controversial. A number of previous investigations have proposed that progestins counteract the beneficial antiatherogenic effects of estrogen by its negative influence on serum lipids, particularly HDL cholesterol (204). However, these findings have recently been challenged (205), and as mentioned previously, estrogen-induced beneficial effects on serum lipoproteins accounts for less than 50% of the total cardioprotective effects of this hormone. Recent studies have demonstrated that those postmenopausal women, using both estrogen and progesterone replacement, exhibited a significantly lower incidence of cardiovascular deaths than those using estrogen monotherapy (206). These observations support a beneficial role for progesterone in cardiovascular disease.
As further support for this proposal, PRs as well as ERs have been detected in the vasculature of humans and other mammals (207-209). Indeed, recent studies on the proliferation of arterial smooth-muscle cells (an important constituent of atherosclerotic plaques) suggest that progesterone exerts beneficial effects in this process (209). To unequivocally define progesterone's role in atherosclerotic cardiovascular disease, the PRKO mouse will provide a powerful new approach in determining PR's role in these processes that are distinct from ER-mediated effects. We believe that the introduction of the PRKO mutation into existing mouse models for atherosclerosis (210), as well as its use in combination with current carotid-artery injury paradigms (211), will provide further insight into the mechanisms by which progesterone exerts its implicated atherosclerotic-protective effects.
In the case of bone homeostasis, inappropriate bone loss that occurs as a result of the onset of menopause is known to be associated with contemporaneous decreases in serum estrogen levels, as evidenced by the beneficial effects of estrogen replacement therapies in reversing this effect (212). Interestingly, with the addition of progesterone to such hormonal replacement therapies, a number of biochemical and morphometric investigations have offered support for the proposal that progesterone may synergistically interact with estrogen in some aspect of bone remodeling (213). The recent detection of PRs in osteoblast cells (214) would seem to further support this notion. However, because of the ambiguities concerning the individual roles of PR and ER in this process, we expect that the PRKO mouse will provide a meaningful investigative approach to mechanistically dissect the respective roles of PR and ER in this process.
Finally, the PRKO mouse model has provided an experimental platform for investigating the physiological functions of progesterone, as well as representing an unparalleled opportunity to examine the selective effects of estrogen and progesterone in vivo. As mentioned previously, considerable in vitro evidence has suggested that the A and B forms of the PR have distinct regulatory functions. It is conceptually plausible that the differential effects of these receptor isoforms could reflect, at the molecular level, the in vivo pleiotropic effects of progesterone action, as recently revealed by the phenotypic analysis of the PRKO mouse. While the significance of these in vitro investigations is well recognized, the in vivo functional relevance for the existence of these receptor isoforms is only now being understood. As for the seemingly intractable problem of dissecting estrogen and progesterone actions in vivo, a new generation of knockout mouse models has likewise been generated to examine the selective in vivo importance of the PRA and PRB isoforms (26a).
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