Progesterone Receptors as Neuroendocrine Integrators

Levine, Jon E.; Chappell, Patrick E.; Schneider, Johanna S.; Sleiter, Nicole C.; Szabó, Márta

doi:10.1006/frne.2001.0210

Cited by 91 publications

(58 citation statements)

References 169 publications

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“…Thus, it is widely accepted that PR activation is an obligatory step for E 2 -increased pituitary response to LHRH (Chappell et al 1999) and LHRH self-priming (Turgeon & Waring 1994). These and other (Turgeon & Waring 1990, 1991 observations explicitly demonstrate that the presence of the neuroendocrine integrator PR (Levine et al 2001) is an absolute requirement for the transmission of E 2 -induced signals leading to LH surge. Accumulated evidence indicates that gonadotroph PR can be activated by the cognate ligand (Rao & Mahesh 1986) and, in a ligand-independent manner (Blaustein 2004), by LHRH intracellular signalling pathways (Turgeon & Waring 1994, Fink 1995.…”

Section: Introductionmentioning

confidence: 65%

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression

Gordon

Garrido‐Gracia

Aguilar

et al. 2007

Journal of Endocrinology

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Hyperstimulation of ovarian function with human FSH (hFSH) attenuates the preovulatory surge of LH. These experiments aimed at investigating the mechanism of ovarian-mediated FSH suppression of the progesterone (P 4 ) receptor (PR)-dependent LH surge in the rat. Four-day cycling rats were injected with hFSH, oestradiol benzoate (EB) or vehicle during the dioestrous phase. On pro-oestrus, their pituitaries were studied for PR mRNA and protein expression. Additionally, pro-oestrous pituitaries were incubated in the presence of oestradiol-17b (E 2 ), and primed with P 4 and LH-releasing hormone (LHRH), with or without the antiprogestin RU486. After 1 h of incubation, pituitaries were either challenged or not challenged with LHRH. Measured basal and LHRH-stimulated LH secretions and LHRH self-priming were compared with those exhibited by incubated pituitaries on day 4 from ovariectomized (OVX) rats in metoestrus (day 2) injected with hFSH and/or EB on days 2 and 3. The results showed that: i) hFSH lowered the spontaneous LH surge without affecting basal LH and E 2 levels, gonadotroph PR-A/PR-B mRNA ratio or immunohistochemical protein expression; ii) incubated pro-oestrous pituitaries from hFSH-treated rats did not respond to P 4 or LHRH, and lacked E 2 -augmenting and LHRH self-priming effects and iii) OVX reversed the inhibitory effects of hFSH on LH secretion. It is concluded that under the influence of hFSH, the ovaries produce a non-steroidal factor which suppresses all PR-dependent events of the LH surge elicited by E 2 . The action of such a factor seemed to be due to a blockade of gonadotroph PR action rather than to an inhibition of PR expression.

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Section: Introductionmentioning

confidence: 65%

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression

Gordon

Garrido‐Gracia

Aguilar

et al. 2007

Journal of Endocrinology

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“…Such observations are provocative. They contrast with the reported phenotype of Pgr mutant mice (19,20,29,30), insights gained from hormone replacement experiments (13,32), and the reported neuroendocrine actions of progesterone receptor antagonists (25)(26)(27)(28) and demand a rethinking of the hormonal control of reproductive cyclicity.…”

Section: Discussionmentioning

confidence: 88%

Rethinking progesterone regulation of female reproductive cyclicity

Kubota

Cui

Dhakal

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The progesterone receptor (PGR) is a ligand-activated transcription factor with key roles in the regulation of female fertility. Much has been learned of the actions of PGR signaling through the use of pharmacologic inhibitors and genetic manipulation, using mouse mutagenesis. Characterization of rats with a null mutation at the Pgr locus has forced a reexamination of the role of progesterone in the regulation of the female reproductive cycle. We generated two Pgr mutant rat models, using genome editing. In both cases, deletions yielded a null mutation resulting from a nonsense frame-shift and the emergence of a stop codon. Similar to Pgr null mice, Pgr null rats were infertile because of deficits in sexual behavior, ovulation, and uterine endometrial differentiation. However, in contrast to the reported phenotype of female mice with disruptions in Pgr signaling, Pgr null female rats exhibit robust estrous cycles. Cyclic changes in vaginal cytology, uterine histology, serum hormone levels, and wheel running activity were evident in Pgr null female rats, similar to wild-type controls. Furthermore, exogenous progesterone treatment inhibited estrous cycles in wild-type female rats but not in Pgr-null female rats. As previously reported, pharmacologic antagonism supports a role for PGR signaling in the regulation of the ovulatory gonadotropin surge, a result at variance with experimentation using genetic ablation of PGR signaling. To conclude, our findings in the Pgr null rat challenge current assumptions and prompt a reevaluation of the hormonal control of reproductive cyclicity.progesterone | rat | reproductive cycles | PGR T he fundamental elements regulating the female reproductive cycle have been universally accepted for decades and include a hierarchy of control involving the hypothalamic/anterior pituitary/ ovarian axis (1,2). The hypothalamus, through its secretion of gonadotropin-releasing hormone, drives anterior pituitary production of gonadotropins [luteinizing hormone (LH) and folliclestimulating hormone (FSH)], which act on the ovaries to promote follicle development, ovulation, formation of the corpus luteum, and secretion of sex steroid hormones estrogen and progesterone. These two sex steroid hormones possess well-established actions on the female reproductive tract. At the core of the female reproductive cycle is a balance of sex steroid hormone negative and positive feedback regulation of gonadotropin secretion. Both estrogen and progesterone signaling pathways have been implicated in feedback control of gonadotropins and regulation of the female reproductive cycle (3-5). These concepts have been reinforced through phenotypic examination of mice possessing null mutations at either Esr1 or Pgr loci (6-8), and through the use of pharmacologic inhibitors of estrogen and progesterone signaling. Esr1 and Pgr encode the estrogen receptor 1 (also referred to as ER alpha) and progesterone receptor, respectively. These two nuclear receptors mediate many of the actions of estrogen and progesterone on the fe...

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“…One possibility is that estrogen alters neurochemical secretion by the SCN or the signaling efficacy of these chemicals via second messenger systems and kinases Levine, 1997). An alternative hypothesis is that estrogen stimulates ligand-independent progesterone receptor production, and the timed neuronal signal acts on progesterone receptors Levine, 1997;Levine et al, 2001). This scheme suggests that the effects of estrogen are integrated with the SCN signal at the level of progesterone receptors to ensure that the GnRH system is sensitive to the daily signal only during the preovulatory estrogen surge.…”

Section: Neural Scn Output and Estrus Regulationmentioning

confidence: 99%

The regulation of neuroendocrine function: Timing is everything

Kriegsfeld

Silver

2006

Hormones and Behavior

131

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Hormone secretion is highly organized temporally, achieving optimal biological functioning and health. The master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus coordinates the timing of circadian rhythms, including daily control of hormone secretion. In the brain, the SCN drives hormone secretion. In some instances, SCN neurons make direct synaptic connections with neurosecretory neurons. In other instances, SCN signals set the phase of "clock genes" that regulate circadian function at the cellular level within neurosecretory cells. The protein products of these clock genes can also exert direct transcriptional control over neuroendocrine releasing factors. Clock genes and proteins are also expressed in peripheral endocrine organs providing additional modes of temporal control. Finally, the SCN signals endocrine glands via the autonomic nervous system, allowing for rapid regulation via multisynaptic pathways. Thus, the circadian system achieves temporal regulation of endocrine function by a combination of genetic, cellular, and neural regulatory mechanisms to ensure that each response occurs in its correct temporal niche. The availability of tools to assess the phase of molecular/cellular clocks and of powerful tract tracing methods to assess connections between "clock cells" and their targets provides an opportunity to examine circadian-controlled aspects of neurosecretion, in the search for general principles by which the endocrine system is organized. KeywordsCircadian; Diurnal; Endocrinel; Neurosecretion; Clock genes; Suprachiasmatic Circadian aspects of reproductionThe importance of circadian (about a day) timing in hormone production/secretion has been known since the 1950s when Everett and Sawyer determined that a stimulatory signal occurring during a narrow temporal window on the afternoon of proestrus is necessary for induction of ovulation later that night (Everett and Sawyer, 1950). Such close temporal organization is important for successful reproduction, as numerous hormone-dependent behavioral and physiological processes must be coordinated. If optimal temporal relationships are disrupted, pronounced deficits in fertility can result. For example, ovulation, behavioral estrus, fertilization, and pregnancy maintenance require a specific

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Progesterone Receptors as Neuroendocrine Integrators

Cited by 91 publications

References 169 publications

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression

Rethinking progesterone regulation of female reproductive cyclicity

The regulation of neuroendocrine function: Timing is everything

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