Progesterone-Progestin Receptors

Jp, Raynaud; Philibert, D.; Azadian-Boulanger, G.

doi:10.1007/978-1-4684-2889-6_10

Cited by 9 publications

(8 citation statements)

References 23 publications

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“…Although we cannot rule out the possibility that the dose of indomethacin was too low, we attribute the absence of an effect of indomethacin as suggestive evidence that allopregnanolone, rather than dihydroprogesterone binding to the PR, was responsible for protection against the effects of restraint. Allopregnanolone does not interact with the intracellular PR (Raynaud et al, 1974; Smith et al, 1974) so these findings are consistent with the possibility that progesterone metabolites can protect against the effects of mild stress. Such metabolites do not, however, appear to be essential for progesterone’s protection because finasteride did not attenuate the effects of progesterone.…”

Section: Discussionmentioning

confidence: 56%

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint II. Role of progesterone metabolites

Miryala¹,

Hassell²,

Adams³

et al. 2011

Hormones and Behavior

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When ovariectomized Fischer female rats are hormonally primed with 10 μg estradiol benzoate, a 5 min restraint experience rapidly inhibits lordosis behavior. Addition of progesterone to the hormonal priming prevents this restraint-induced inhibition. In prior work, we reported evidence that progesterone receptors (PR) may contribute to this protective effect of progesterone. In the current manuscript, we provide evidence that progesterone metabolites may also contribute to progesterone’s ability to reduce the effects of restraint. Ovariectomized female rats were hormonally primed with 10 μg estradiol benzoate followed 2 days later with 4.0 mg/kg of the progesterone metabolite, allopregnanolone. Allopregnanolone, administered either 4 hr or 2 hr before the restraint experience, was as effective as progesterone in reducing the lordosis-inhibitory effects of restraint. In the second experiment, progesterone metabolism was blocked with 50 mg/kg of the 5α-reductase inhibitor, finasteride. Surprisingly, finasteride did not prevent progesterone from reducing the effects of restraint. In a third experiment, we tested the possibility that allopregnanolone acted through metabolism to dihydroprogesterone. Rats were treated with allopregnanolone or with allopregnanolone plus the 3α-hydroxysteroid dehydrogenase inhibitor, indomethacin. Indomethacin did not prevent allopregnanolone from reducing the effects of restraint. Mechanisms are discussed whereby cross-talk between PR-mediated and metabolite-mediated events may converge in producing progesterone’s attenuation of the effect of restraint.

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Section: Discussionmentioning

confidence: 56%

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint II. Role of progesterone metabolites

Miryala¹,

Hassell²,

Adams³

et al. 2011

Hormones and Behavior

View full text Add to dashboard Cite

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“…Allopregnanolone does not bind to this intracellular receptor (Raynaud et al, 1974; Smith et al, 1974). However, the intracellular progesterone receptor can be activated by both ligand-dependent and ligand-independent mechanisms (Dressing et al, 2011; Mani, 2006; Mani et al, 1997; Pluchino et al, 2009).…”

Section: 0 Discussionmentioning

confidence: 99%

“…. Since allopregnanolone does not interact with the classical intracellular progesterone receptor (Raynaud et al, 1974), the effect of RU486 allows the suggestion that allopregnanolone may indirectly lead to activation of the intracellular progesterone receptor. However, since RU486 also antagonizes glucocorticoid receptors (Lee et al, 2009), it is possible that RU486 attenuated the effects of allopregnanolone through interaction with the glucocorticoid receptor.…”

Section: 0 Introductionmentioning

confidence: 99%

Allopregnanolone's attenuation of the lordosis-inhibiting effects of restraint is blocked by the antiprogestin, CDB-4124

Uphouse

Hiegel

2014

Pharmacology Biochemistry and Behavior

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A brief restraint experience reduces lordosis behavior in ovariectomized females that have been hormonally primed with estradiol benzoate. The addition of progesterone to the priming prevents the lordosis inhibition. Based on prior studies with an inhibitor of progesterone metabolism, we have implicated the intracellular progesterone receptor, rather than progesterone metabolites, as responsible for this protection. However, the progesterone metabolite, allopregnanolone (3α-hydroxy-5α-pregnan-20-one), also prevents lordosis inhibition after restraint. In a prior study, we reported that the progestin receptor antagonist, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), attenuated the effect of allopregnanolone. Because RU486 can also block the glucocorticoid receptor, in the current studies, we evaluated the effect of the progestin receptor antagonist, CDB-4124 (17 α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione), which is relatively devoid of antiglucocorticoid activity. Ovariectomized, Fischer rats were injected with 10 μg estradiol benzoate. Two days later, rats received either 60 mg/kg CDB-4124 or the 20% DMSO/propylene glycol vehicle 1 hr before injection with 4 mg/kg allopregnanolone. After a pretest to confirm sexual receptivity, rats were restrained for 5 min and immediately tested for sexual behavior. Lordosis behavior was reduced by the restraint and attenuated by allopregnanolone. Pretreatment with CDB-4124 reduced allopregnanolone’s effect. These findings support prior suggestions that allopreganolone reduces the response to restraint by mechanisms that require activation of the intracellular progesterone receptor.

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“…However, RU486’s ability to block allopregnanolone’s reduction of the effects of restraint implicates the progesterone receptor. Even though allopregnanolone does not bind to the progesterone receptor (Raynaud et al, 1974; Smith et al, 1974), it is possible that allopregnanolone was metabolized via 3α-hydroxysteroid dehydrogenase into dihydroprogesterone, which can bind to the progesterone receptor (Rupprecht, 2003; Rupprecht et al, 1993). This is an unlikely explanation for the current findings since, in a prior study, indomethacin (which blocks 3α-HSD) did not alter the effect of allopregnanolone on the response to restraint (Miryala et al, 2011).…”

Section: 0 Discussionmentioning

confidence: 99%

“…Allopregnanolone does not bind directly to intracellular progesterone receptors (Raynaud et al, 1974; Smith et al, 1974) but may indirectly activate progesterone receptors through a variety of intracellular signaling pathways (Etgen et al, 2006; Frye and Walf, 2008; Gonzalez-Flores et al, 2010; Mani et al, 2000). PKC, MAPK, and Src kinase-dependent signaling are modulated by allopregnanolone (Etgen and Acosta-Martinez, 2003; Frye and Walf, 2008; Gonzalez-Flores et al, 2006; Mani et al, 2000) and each of these mechanisms can contribute to ligand-independent activation of progesterone receptors (Boonyaratanakornkit et al, 2007; Gonzalez-Flores et al, 2006; Li and Shang, 2007; Mani and Portillo, 2010; Tetel, 2009).…”

Section: 0 Introductionmentioning

confidence: 99%

RU486 blocks effects of allopregnanolone on the response to restraint stress

Uphouse

Adams

Miryala

et al. 2013

Pharmacology Biochemistry and Behavior

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These experiments were designed to provide information about the potential involvement of progesterone receptors in the ability of allopregnanolone (3α-hydroxy-5α-pregnan-20-one) to reduce the lordosis-inhibiting effects of restraint stress. Ovariectomized Fischer rats were hormonally primed with 10 μg estradiol benzoate and 4 mg/kg allopregnanolone or vehicle. One hr before allopregnanolone, rats were injected with the progesterone receptor antagonist, RU486 (11β-(4-dimethylamino)phenyl-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one), or vehicle. Four hr after allopregnanolone or vehicle, sexual behavior was examined before and after a 5-min restraint stress. Lordosis behavior of rats primed only with estradiol benzoate declined after the 5 min of restraint while allopregnanolone prevented this decline. RU486 attenuated the ability of allopregnanolone to prevent the restraint-induced decline in lordosis behavior. These findings are consistent with earlier suggestions that progesterone receptors are involved in allopregnanolone's ability to reduce the effects of restraint stress.Keywords lordosis behavior; proceptivity; progesterone metabolites; progesterone receptors; female rats IntroductionFemale rat sexual behavior is temporally coordinated with ovulation to maximize reproductive fitness (Blaustein, 2008;Sodersten, 1981). Both estrogens and progestins influence this reproductive synchrony (Auger, 2004;Mani et al., 1997;Pfaff, 1970) so that reproductive behavior abruptly ceases following ovariectomy. However, sexual behavior can be restored in ovariectomized rats by exogenous treatment with gonadal hormones (Auger, 2004;Pfaff, 2005). The full repertoire of female sexual behavior includes appetitive, precopulatory and copulatory activities and gonadal hormones appear to differentially influence these various events (Blaustein, 2008;Erskine, 1989;Frye, 2007). The lordosis reflex (required for copulation) is thought to depend exclusively on estradiol (Auger, 2004;Blaustein, 2008). Progesterone is not required, but the probability and frequency of lordosis © 2012 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. behavior can be increased by progesterone; and progesterone may be required for the occurrence of precopulatory activity such as hopping and darting behavior (Erskine, 1989;Frye and Vongher, 1999;Sodersten, 1981). Progesterone also reduces measures of anxiety (Auger and Forbes-Lorman, 2008;Gomez et al., 2002) and we have previously suggested that progesterone's anxiolytic action contributes to its facilitation of female rat...

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Progesterone-Progestin Receptors

Cited by 9 publications

References 23 publications

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint II. Role of progesterone metabolites

Mechanisms responsible for progesterone's protection against lordosis-inhibiting effects of restraint II. Role of progesterone metabolites

Allopregnanolone's attenuation of the lordosis-inhibiting effects of restraint is blocked by the antiprogestin, CDB-4124

RU486 blocks effects of allopregnanolone on the response to restraint stress

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