رفتار جنسی در موش شیرده: نقش گیرنده پروژسترون ناشی از استروژن

Lactation is associated with suppression of reproductive function, the duration of which depends on the number of young suckled and food availability. Although previous studies have documented increasing responsivity to the positive feedback effects of estrogen on luteinizing hormone (LH) secretion with time postpartum, changes in the ability of estrogen to stimulate sexual behavior across these time points and the influence of food restriction on response to estrogen have not been investigated. Thus, we compared the ability of exogenous estrogen administration to stimulate proceptive and receptive behavior in ad libitum fed and food restricted rats on Days 15 and 20 postpartum. Because the ability of estrogen to induce sexual behavior depends on activation of both estrogen receptors and estrogen-induced progesterone receptors, a second study compared estrogen and progesterone-ir within the VMH and MPOA in similar groups. Finally, we investigated the role of the high levels of progesterone typical of lactation in the suppression of estrogen-induced sexual behavior by transient blockade of the progesterone receptor using RU486. As expected there was an increase across time in the ability of estrogen to stimulate sexual behavior that correlated with an increased ability of estrogen to induce progesterone receptors in the MPOA that was most evident in ad libitum fed rats. RU486 administration concomitant with estrogen administration increased solicitation behavior and was most effective in ad libitum fed rats suggesting an inhibitory role of progesterone on estrogen-induced sexual proceptivity in lactating rats.

In a variety of mammals lactation is accompanied by suppression of reproductive function (Lamming, 1978). Typically the length of this period of anovulation is a function of the number of young nursed and/or the availability of food (McGuire et al., 1992, Woodside, 1991 and Woodside and Popeski, 1999). For example, in ad libitum fed rats nursing litters of eight pups the period of lactational diestrus lasts for 20–21 days (Hansen et al., 1983) but is prolonged by almost a week if the rats are food restricted for the first 2 weeks postpartum (Woodside and Jans, 1995). Lactational infertility in rats is accompanied by low levels of circulating estrogen (Smith and Neill, 1977), and a reduction in sensitivity to exogenously administered estrogen (Abizaid et al., 2003, Abizaid et al., 2004, Coppings and McCann, 1979 and Smith, 1978). Maintenance of the corpora lutea formed following postpartum ovulation results in high plasma progesterone levels that peak around Day 10 postpartum (Gonzalez-Fernandez et al., 2008, Grota and Eik-Nes, 1967, Takiguchi et al., 2004 and Tomogane et al., 1969). Physiologically, high levels of progesterone decrease the ability of estrogen to induce a preovulatory luteinizing surge in lactating rats. (Abizaid et al., 2003 and Woodside, 1991). Progesterone concentrations are also negatively associated with the ability of estrogen to induce progesterone receptors in the anteroventral periventricular area (AVPV) of ad libitum fed and food restricted rats, an effect that is blocked by ovariectomy or RU486 (Abizaid et al., 2003). Returning to full reproductive capacity entails appropriate behavior as well as ovulation, yet comparatively few studies have examined the effect of lactation on the mechanisms underlying sexual behavior. Those that have done so have focused on the induction of sexual behavior in early lactation (Clarke and Roy, 1984 and Sodersten et al., 1983). Sodersten et al. (1983) reported that a single dose of estradiol benzoate with or without progesterone administration failed to stimulate sexual behavior in rats on Day 6 postpartum. Responsivity was restored if pups were removed, prolactin release was suppressed with bromocryptine, or if rats were ovariectomized. Progesterone replacement to ovariectomized postpartum rats resulted in a suppression of responsivity, but only if females continued to receive suckling stimulation or prolactin levels were maintained by domperidone treatment. Clarke and Roy (1984) found that repeated estrogen administration (10 μg/day for 3 days) induced a high level of receptivity in lactating rats on Days 5–9 postpartum that was not increased by supplementing estrogen administration with progesterone. Together, these studies suggest that during the first half of lactation female rats show estrogen-stimulated lordosis behavior following repeated estrogen administration or when the influences of progesterone and/or prolactin were eliminated. In neither of these studies was proceptive behavior measured and whether there are changes in the ability of estrogen to stimulate sexual behavior that correlate with the return of ovulation was not addressed. We have demonstrated previously that food restricting rats for the first 2 weeks postpartum extends the length of lactational infertility (Woodside, 1991). This state is accompanied by a longer period of elevated circulating progesterone levels (Woodside, 1991) as well as a prolongation of both suppression of pulsatile luteinizing hormone release (Walker et al., 1995) and hyporesponsivity to estrogen positive feedback (Abizaid et al., 2003). How combining restriction of food availability with lactation might affect the ability of estrogen to stimulate sexual behavior, however, has not yet been investigated. In the current studies we used the dose of estrogen described by Clarke and Roy (1984) to compare the ability of exogenous estrogen administration to stimulate both sexual receptivity and proceptivity between food restricted and ad libitum fed rats on Days 15 and 20 postpartum. If the pattern of estrogen responsivity in the neural circuits underlying sexual behavior are similar to those involved in initiating the LH surge then one would expect that ad libitum fed rats would show a greater response to exogenous estrogen on Day 20 than on Day 15 postpartum and that food restricted rats would show lower levels of sexual behavior, than ad libitum fed rats on Day 20 postpartum. Given that food deprivation has been shown to suppress choice of a male partner over food in female hamsters (Schneider et al., 2007), we hypothesized that solicitation behaviors as well as rejection of the male would be most affected by food restriction. The performance of both lordosis and solicitation behavior depends on the activation of steroid receptors in specific brain areas. The lordosis response depends primarily on the activation of ERα in the ventromedial hypothalamus (VMH) (Meisel et al., 1987 and Rubin and Barfield, 1980) and is potentiated by activation of progesterone receptors in the same area (Rubin and Barfield, 1983). On the other hand, the display of proceptive behavior is reduced by lesions of the medial preoptic area (MPOA) (Hoshina et al., 1994) and is dependent for its full expression on progesterone receptor activation (Erskine, 1989). In the second experiment, therefore, we compared levels of estrogen receptor alpha immunoreactivity in the VMH and MPOA between food restricted and ad libitum fed rats on Days 15 and 20 postpartum. Further, as the ability of estrogen to induce progesterone receptors within the AVPV was suppressed in food restricted lactating rats PR levels in both the VMH and MPOA of estrogen treated rats were also assessed. Our hypothesis was that the time course of restoration of solicitation behavior would be associated with increases in ERα and PR levels within these areas. The possibility that the blockade of progesterone receptors during estrogen priming might facilitate the ability of estrogen to stimulate sexual behavior, in the same way that this manipulation increases the ability of estrogen to stimulate a surge in LH (Abizaid et al., 2003), was examined in the third experiment. In this study, the effects of administering the progesterone receptor blocker RU 486 concurrent with estrogen treatment on sexual proceptivity and receptivity, in both ad lib fed and food restricted lactating rats on Day 15 postpartum were investigated.