Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson, Leslie

doi:10.1016/j.neuropharm.2007.01.022

Cited by 63 publications

(54 citation statements)

References 151 publications

(190 reference statements)

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“…Perhaps because of its close structural resemblance to progesterone, it has similar actions in some systems (van Heuverswyn et al 1939) and gives, for example, decidual responses in ovariectomised guinea pig uteri (Blaha & Leavitt 1978). It also induces relaxation of the symphysis pubis in these animals, apparently because, like progesterone, it induces release of relaxin (Hall 1960).…”

Section: Other Actions and Doc In Other Speciesmentioning

confidence: 99%

“…THDOC and allopregnanolone also have actions on the hypothalamus pituitary-adrenal axis and thereby on the effects of stress (Girdler & Klatzkin 2007). Such positive GABA A potentiation may also indirectly affect reproduction via the pituitary (Henderson 2007). Negative GABA A regulators include the sulphated derivatives of pregnenolone and DHEA as well as the 3a,5a-and 3a,5b-reduced metabolites of cortisol (Morrow 2007).…”

Section: Other Actions and Doc In Other Speciesmentioning

confidence: 99%

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The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

Vinson¹

2011

Journal of Endocrinology

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Over the 70 or so years since their discovery, there has been continuous interest and activity in the field of corticosteroid functions. However, despite major advances in the characterisation of receptors and coregulators, in some ways we still lack clear insight into the mechanism of receptor activation, and, in particular, the relationship between steroid hormone structure and function remains obscure. Thus, why should deoxycorticosterone (DOC) reportedly be a weak mineralocorticoid, while the addition of an 11b-hydroxyl group produces glucocorticoid activity, yet further hydroxylation at C18 leads to the most potent mineralocorticoid, aldosterone? This review aims to show that the field has been confused by the misreading of the earlier literature and that DOC, far from being relatively inactive, in fact has a wide range of activities not shared by the other corticoids. In contrast to the accepted view, the presence of an 11b-hydroxyl group yields, in corticosterone or cortisol, hormones with more limited functions, and also more readily regulated, by 11b-hydroxysteroid dehydrogenase. This interpretation leads to a more systematic understanding of structure-function relationships in the corticosteroids and may assist more rational drug design.

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Section: Other Actions and Doc In Other Speciesmentioning

confidence: 99%

Section: Other Actions and Doc In Other Speciesmentioning

confidence: 99%

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

Vinson¹

2011

Journal of Endocrinology

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“…Recent mammalian studies provide evidence for a stimulatory effect of S-fluoxetine on allopregnalone at doses 10 -50 times lower than the doses needed to inhibit serotonin reuptake (43). This neurosteroid in turn allosterically modulates the ␥-aminobutyric acid A (GABA A ) receptor, with potential effects on reproductive function (26). GABA A receptor subunit mRNA and proteins are known to be expressed on oxytocin neurons (18).…”

Section: Fluoxetine In Female Goldfishmentioning

confidence: 99%

Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus)

Mennigen

Martyniuk

Crump

et al. 2008

Physiological Genomics

125

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. Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus). Physiol Genomics 35: 273-282, 2008. First published September 2, 2008; doi:10.1152/physiolgenomics.90263.2008.-We investigated the effects of fluoxetine, a selective serotonin reuptake inhibitor, on neuroendocrine function and the reproductive axis in female goldfish. Fish were given intraperitoneal injections of fluoxetine twice a week for 14 days, resulting in five injections of 5 g fluoxetine/g body wt. We measured the monoamine neurotransmitters serotonin, dopamine, and norepinephrine in addition to their metabolites with HPLC. Homovanillic acid, a metabolite in the dopaminergic pathway, increased significantly in the hypothalamus. Plasma estradiol levels were measured by radioimmunoassay and were significantly reduced approximately threefold after fluoxetine treatment. We found that fluoxetine also significantly reduced the expression of estrogen receptor (ER)␤1 mRNA by 4-fold in both the hypothalamus and the telencephalon and ER␣ mRNA by 1.7-fold in the telencephalon. Fluoxetine had no effect on the expression of ER␤2 mRNA in the hypothalamus or telencephalon. Microarray analysis identified isotocin, a neuropeptide that stimulates reproductive behavior in fish, as a candidate gene affected by fluoxetine treatment. Real-time RT-PCR verified that isotocin mRNA was downregulated approximately sixfold in the hypothalamus and fivefold in the telencephalon. Intraperitoneal injection of isotocin (1 g/g) increased plasma estradiol, providing a potential link between changes in isotocin gene expression and decreased circulating estrogen in fluoxetine-injected fish. Our results reveal targets of serotonergic modulation in the neuroendocrine brain and indicate that fluoxetine has the potential to affect sex hormones and modulate genes involved in reproductive function and behavior in the brain of female goldfish. We discuss these findings in the context of endocrine disruption because fluoxetine has been detected in the environment. brain; estrogen receptors; isotocin; microarray; Prozac FLUOXETINE (PROZAC), a selective serotonin reuptake inhibitor (SSRI) (46), has been used in several studies in fish to investigate the serotonergic modulation of the endocrine system (55). A racemic mixture of two lipophilic enantiomers, fluoxetine is metabolized by cytochrome P-450 isoenzymes to the active metabolite norfluoxetine (46). In humans, fluoxetine is primarily excreted in urine as ϳ20%-30% unchanged parent compound, while metabolites are largely excreted as pharmacologically active norfluoxetine and inactive fluoxetine glucuronide (62).Fluoxetine also has effects on reproduction in several vertebrates. For example, in the goldfish (Carassius auratus), combined intraperitoneal administration of 10 g/g fluoxetine and 10 g/g serotonin (5-HT) elevated luteinizing hormone (LH) levels relative to 5-HT administration alone 2 h after treatment (55). Japanese medaka (Oryzias latipes) exposed to waterborne 0.1 and 0.5 g/l fluoxetine for 4 wk sh...

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“…In addition, DHP itself is a substrate for further metabolism by 3α-reduction in the synthesis of allopregnanolone, a potent neurosteroid that can both allosterically regulate and directly activate γ-aminobutyric acid (GABA) receptors. Activation of GABA receptors may be of importance in both male and female reproduction centrally (Henderson 2007, Brunton et al 2014 and perhaps also peripherally. For example, sperm membranes express GABA receptors that are involved in initiating the acrosome reaction (Meizel 1997, Vigil et al 2011.…”

Section: Introductionmentioning

confidence: 99%

Equine 5α-reductase activity and expression in epididymis

Corbin

Legacki

Ball

et al. 2016

Journal of Endocrinology

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The 5α-reductase enzymes play an important role during male sexual differentiation, and in pregnant females, especially equine species where maintenance relies on 5α-reduced progesterone, 5α-dihydroprogesterone (DHP). Epididymis expresses 5α-reductases but was not studied elaborately in horses. Epididymis from younger and older postpubertal stallions was divided into caput, corpus and cauda and examined for 5α-reductase activity and expression of type 1 and 2 isoforms by quantitative realtime polymerase chain reaction (qPCR). Metabolism of progesterone and testosterone to DHP and dihydrotestosterone (DHT), respectively, by epididymal microsomal protein was examined by thin-layer chromatography and verified by liquid chromatography tandem mass spectrometry (LC-MS/MS). Relative inhibitory potencies of finasteride and dutasteride toward equine 5α-reductase activity were investigated. Pregnenolone was investigated as an additional potential substrate for 5α-reductase, suggested previously from in vivo studies in mares but never directly examined. No regional gradient of 5α-reductase expression was observed by either enzyme activity or transcript analysis. Results of PCR experiments suggested that type 1 isoform predominates in equine epididymis. Primers for the type 2 isoform were unable to amplify product from any samples examined. Progesterone and testosterone were readily reduced to DHP and DHT, and activity was effectively inhibited by both inhibitors. Using epididymis as an enzyme source, no experimental evidence was obtained supporting the notion that pregnenolone could be directly metabolized by equine 5α-reductases as has been suggested by previous investigators speculating on alternative metabolic pathways leading to DHP synthesis in placenta during equine pregnancies.

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Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Cited by 63 publications

References 151 publications

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

Effects of fluoxetine on the reproductive axis of female goldfish (Carassius auratus)

Equine 5α-reductase activity and expression in epididymis

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