Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors

Schumacher, Michaël; Mattern, Claudia; Ghoumari, A.; Oudinet, Jean–Paul; Lière, Philippe; Labombarda, Florencia; Sitruk-Ware, Régine; Nicola, Alejandro F. De; Guennoun, Rachida

doi:10.1016/j.pneurobio.2013.09.004

Cited by 309 publications

(237 citation statements)

References 585 publications

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“…In addition, little is known about endogenous progesterone concentrations in the rodent brain during early development. Progesterone can either be locally produced or come from the circulation as it is secreted by the adrenal glands in both sexes (reviewed in Schumacher et al, 2014), and the ovaries starting around day 7 after birth in females (Mannan and O'Shaugnessy, 1991). Studies in male PRKO mice have provided opposite results, i.e.…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

Desroziers

Brock

Bakker

2017

Hormones and Behavior

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We previously showed that estradiol can have both defeminizing and feminizing effects on the developing mouse brain. Pre-and early postnatal estradiol defeminized the ability to show lordosis in adulthood, whereas prepubertal estradiol feminized this ability. Furthermore, we found that estradiol upregulates progesterone receptors (PR) during development, inducing both a male-and female-typical pattern of PR expression in the mouse hypothalamus. In the present study, we took advantage of a newly developed PR antagonist (ZK 137316) to determine whether PR contributes to either male-or female-typical sexual differentiation. Thus groups of male and female C57Bl/6j mice were treated with ZK 137316 or oil as control: males were treated neonatally (P0-P10), during the critical period for male sexual differentiation, and females were treated prepubertally (P15-P25), during the critical period for female sexual differentiation. In adulthood, mice were tested for sexual behavior. In males, some minor effects of neonatal ZK treatment on sexual behavior were observed: latencies to the first mount, intromission and ejaculation were decreased in neonatally ZK treated males; however, this effect disappeared by the second mating test. By contrast, female mice treated with ZK during the prepubertal period showed significantly less lordosis than OIL-treated females. Mate preferences were not affected in either males or females treated with ZK during development. Taken together, these results suggest a role for PR and thus perhaps progesterone in the development of lordosis behavior in female mice. By contrast, no obvious role for PR can be discerned in the development of male sexual behavior.

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Section: Accepted M Manuscriptmentioning

confidence: 99%

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

Desroziers

Brock

Bakker

2017

Hormones and Behavior

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“…Some studies in the past have indicated that progesterone withdrawal may be associated with PPD (Harris et al, 1994). Recent work has focused on allopregnanolone, one of progesterone's 3α-reduced metabolites and a strong allosteric modulator of the GABA-A receptor (Bali and Jaggi, 2014;Bristot et al, 2014;Schumacher et al, 2014). It is therefore also possible that our biomarker model may be associated with changes in progesterone or allopregnanolone.…”

Section: Introductionmentioning

confidence: 99%

Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

Osborne

Clive

Kimmel

et al. 2015

Neuropsychopharmacol

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DNA methylation variation at HP1BP3 and TTC9B is modified by estrogen exposure in the rodent hippocampus and was previously shown to be prospectively predictive of postpartum depression (PPD) when modeled in antenatal blood. The objective of this study was to replicate the predictive efficacy of the previously established model in women with and without a previous psychiatric diagnosis and to understand the effects of changing hormone levels on PPD biomarker loci. Using a statistical model trained on DNA methylation data from N = 51 high-risk women, we prospectively predicted PPD status in an independent N = 51 women using first trimester antenatal gene expression levels of HP1BP3 and TTC9B, with an area under the receiver operator characteristic curve (AUC) of 0.81 (95% CI: 0.69-0.92, po5 × 10 − 4 ). Modeling DNA methylation of these genes in N = 240 women without a previous psychiatric diagnosis resulted in a cross-sectional prediction of PPD status with an AUC of 0.81 (95% CI: 0.68-0.93, p = 0.01). TTC9B and HP1BP3 DNA methylation at early antenatal time points showed moderate evidence for association to the change in estradiol and allopregnanolone over the course of pregnancy, suggesting that epigenetic variation at these loci may be important for mediating hormonal sensitivity. In addition both loci showed PPD-specific trajectories with age, possibly mediated by age-associated hormonal changes. The data add to the growing body of evidence suggesting that PPD is mediated by differential gene expression and epigenetic sensitivity to pregnancy hormones and that modeling proxies of this sensitivity enable accurate prediction of PPD.

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“…Allopregnanolone, an endogenous neuroactive steroid, is a principal metabolite of progesterone [Schumacher et al 2014]. It exhibits a robust positive allosteric modulation on both synaptic and extrasynaptic GABA A receptors, enhancing GABA-mediated currents [Lambert et al 2003].…”

Section: Allopregnanolone (Sage-547)mentioning

confidence: 99%

Emerging strategies in the management of essential tremor

Hedera

2016

Ther Adv Neurol Disord

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Currently available therapies for essential tremor (ET) provide sufficient control only for less than a half of patients and many unmet needs exist. This is in part due to the empiric nature of existing treatment options and persisting uncertainties about the pathogenesis of ET. The emerging concept of ET as a possible neurodegenerative disorder, better understanding of associated biochemical changes, including alterations in the γ-aminobutyric acid (GABA)-ergic system and gap junctions, and the identification of the role of the leucine-rich repeat and immunoglobulin-like domain-containing 1 (LINGO-1) gene in ET pathogenesis suggest new avenues for more targeted therapies. Here we review the most promising new approaches to treating ET, including allosteric modulation of GABA receptors and modifications of the LINGO-1 pathway. Medically refractory tremor can be successfully treated by high-frequency deep brain stimulation (DBS) of the ventral intermediate nucleus, but surgical therapies are also fraught with limitations due to adverse effects of stimulation and the loss of therapeutic response. The selection of additional thalamic and extrathalamic targets for electrode placements and the development of a closed-loop DBS system enabling automatic adjustment of stimulation parameters in response to changes in electrophysiologic brain activity are also reviewed. Tremor cancellation methods using exoskeleton and external hand-held devices are also briefly discussed.

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Revisiting the roles of progesterone and allopregnanolone in the nervous system: Resurgence of the progesterone receptors

Cited by 309 publications

References 585 publications

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

Emerging strategies in the management of essential tremor

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