Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E-2)-treated, progesterone receptor knockout (PRKO) mice

Northwestern University, Evanston, Illinois, United States
Endocrinology (Impact Factor: 4.5). 09/1999; 140(8):3653-8. DOI: 10.1210/en.140.8.3653
Source: PubMed


It is well known that estrogen (E2) stimulates expression of progesterone receptors (PRs), thereby inducing responsiveness of several tissues to the actions of progesterone (P). Recent studies have also suggested, however, that biological actions previously ascribed to E2 alone may also be mediated by activation of E2-induced PRs, even independently of signal changes in P concentrations. In the present experiments, the progesterone receptor knockout (PRKO) mice were used to assess the role of PR activation in the positive feedback actions of E2 on gonadotropin release. Ovariectomized (OVX) PRKO mice were tested for their capacity to mount primary gonadotropin surges in response to exogenous E2, and to exhibit a GnRH self-priming effect in response to sequential injections of the decapeptide. Wild-type (WT) and PRKO mice were OVX, treated with both 17beta-estradiol and estradiol benzoate (EB), and then killed at 1900 h on day 7 postOVX. Plasma LH RIA revealed that WT mice exhibited surges in response to the E2 treatment; the PRKO mice, however, showed no elevation in plasma LH above untreated controls. Instead, plasma LH levels in E2-treated, OVX PRKO mice decreased significantly in comparison to untreated OVX PRKO mice, suggesting that E2 can exert a negative feedback influence on LH release in PRKO mice, despite the absence of positive feedback effects. A slight but significant rise in plasma FSH was observed in E2-treated OVX WT mice in comparison to untreated controls: an effect not seen in E2-treated OVX PRKO mice, reinforcing the observation that estrogen's positive feedback effects are compromised in PRKO mice. In a second experiment, E2-treated OVX WT and PRKO mice were given either one or two pulses of GnRH 60 min apart, and killed 10 min later. The WT mice were found to exhibit a robust GnRH self-priming effect, as WT mice receiving two GnRH pulses displayed LH responses approximately 2-fold greater than those receiving only one pulse. By contrast, PRKO mice receiving two GnRH pulses exhibited no additional increase in plasma LH levels. We conclude that PR activation is obligatory for expression of the GnRH self-priming effect as well as for generation of E2-induced LH and FSH surges. The extent to which failure of LH surge secretion in PRKO mice is due to the absence of GnRH self-priming, lack of hypothalamic GnRH surges, and/or defects in other processes remains to be determined. These observations clearly demonstrate, however, that the presence of PR is an absolute requirement for the transmission of E2-induced signals leading to gonadotropin surges.

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    • "Based on the high levels of expression in the AVPV, it is possible that PGRMC1 may mediate one or both of these rapid effects of P4. Unfortunately, this idea is difficult to test because the LH surge does not occur in the absence of PR (Chappell et al., 1997, 1999). "
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    ABSTRACT: Progesterone (P4) regulates a wide range of neural functions and likely acts through multiple receptors. Over the past 30 years, most studies investigating neural effects of P4 focused on genomic and non-genomic actions of the classical progestin receptor (PGR). More recently the focus has widened to include two groups of non-classical P4 signaling molecules. Members of the Class II progestin and adipoQ receptor (PAQR) family are called membrane progestin receptors (mPRs) and include: mPRα (PAQR7), mPRβ (PAQR8), mPRγ (PAQR5), mPRδ (PAQR6), and mPRε (PAQR9). Members of the b5-like heme/steroid-binding protein family include progesterone receptor membrane component 1 (PGRMC1), PGRMC2, neudesin, and neuferricin. Results of our recent mapping studies show that members of the PGRMC1/S2R family, but not mPRs, are quite abundant in forebrain structures important for neuroendocrine regulation and other non-genomic effects of P4. Herein we describe the structures, neuroanatomical localization, and signaling mechanisms of these molecules. We also discuss possible roles for Pgrmc1/S2R in gonadotropin release, feminine sexual behaviors, fluid balance and neuroprotection, as well as catamenial epilepsy.
    Frontiers in Neuroscience 09/2013; 7(7):164. DOI:10.3389/fnins.2013.00164 · 3.66 Impact Factor
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    • "Estrogen induces the expression of both isoforms of PR, PRB, and the N-terminally truncated PRA, in the AVPV, as well as other hypothalamic and preoptic nuclei. We have determined that induction of PRs is obligatory for the successful release of GnRH surges; thus, GnRH and LH surges are absent in ovarian intact and estrogen-treated PR gene knock-out (PRKO) mice (Chappell et al., 1997, 1999), and in rats treated with a progesterone receptor antagonist or intra-cerebroventricular PR antisense oligonucleotides (Chappell and Levine, 2000). We have proposed a model for the release of GnRH surges that includes (1) the induction of PRs by estrogen in AVPV neurons, (2) delivery of the daily neural signal from the SCN to AVPV neurons by neurotransmitter circuitries, and (3) the neurotransmitter-mediated activation of intracellular second messenger production that in turn transactivates the PRs in a ligand-independent manner; thereafter, (4) induces signals to kiss1 neurons that evoke the neurosecretion for the GnRH surge, which is (5) further amplified by ovarian progesterone release in response to the LH surge. "
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    ABSTRACT: Reproductive function is regulated by the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary and the steroid hormones from the gonads. The dynamic changes in the levels of the reproductive hormones regulate secondary sex characteristics, gametogenesis, cellular function and behavior. Hypothalamic GnRH neurons, with cell bodies located in the basal hypothalamus, represent the final common pathway for neuronally derived signals to the pituitary. As such, they serve as integrators of a dizzying array of signals including sensory inputs mediating information about circadian, seasonal, behavioral, pheromonal and emotional cues. Additionally, information about peripheral physiological function may also be included in the integrative signal to the GnRH neuron. These signals may communicate information about metabolic status, disease or infection. Gonadal steroid hormones arguably exert the most important effects on GnRH neuronal function. In both males and females, the gonadal steroid hormones exert negative feedback regulation on axis activity at both the level of the pituitary and the hypothalamus. These negative feedback loops regulate homeostasis of steroid hormone levels. In females, a cyclic reversal of estrogen feedback produces a positive feedback loop at both the hypothalamic and pituitary levels. Central positive feedback results in a dramatic increase in GnRH secretion (Sisk and others 2001; Clarke 1993; Moenter, Brand and Karsch 1992; Xia and others 1992). This is coupled with an increase in pituitary sensitivity to GnRH (Turzillo, DiGregorio and Nett 1995; Savoy-Moore and others 1980), which produces the massive surge in secretion of LH that triggers ovulation.
    Frontiers in Endocrinology 04/2012; 3:52. DOI:10.3389/fendo.2012.00052
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    • "For example there is not a conditional or selective nPR knock out mouse, so we could not control for the effects of deficient nPR signaling in other tissues. Other investigators have previously reported on the reproductive and neurobiological aspects of the PRKO mice [28], [29], [30], [31], [32], [44], [89], [90]. We chose to use RU486 since it was the only pharmacological compound that was commercially available to block nPR. "
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    ABSTRACT: Augmentation of the peak bone mass (PBM) may be one of the most effective interventions to reduce the risk of developing osteoporosis later in life; however treatments to augment PBM are currently limited. Our study evaluated whether a greater PBM could be achieved either in the progesterone nuclear receptor knockout mice (PRKO) or by using a nuclear progesterone receptor (nPR) antagonist, RU486 in mice. Compared to their wild type (WT) littermates the female PRKO mice developed significantly higher cancellous and cortical mass in the distal femurs, and this was associated with increased bone formation. The high bone mass phenotype was partially reproduced by administering RU486 in female WT mice from 1-3 months of age. Our results suggest that the inhibition of the nPR during the rapid bone growth period (1-3 months) increases osteogenesis, which results in acquisition of higher bone mass. Our findings suggest a crucial role for progesterone signaling in bone acquisition and inhibition of the nPR as a novel approach to augment bone mass, which may have the potential to reduce the burden of osteoporosis.
    PLoS ONE 07/2010; 5(7):e11410. DOI:10.1371/journal.pone.0011410 · 3.23 Impact Factor
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