Dihydrotestosterone differentially modulates the cortisol response of the hypothalamic–pituitary–adrenal axis in male and female rhesus macaques, and restores circadian secretion of cortisol in females

Toufexis, Donna; Wilson, Mark

doi:10.1016/j.brainres.2011.10.024

Cited by 17 publications

(16 citation statements)

References 74 publications

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“…Specifically, an intravenous CRF challenge increases cortisol levels more in female than male rhesus monkeys and common marmosets [61,62]. This sex difference is linked to dihydrotestosterone, which reduces CRF-stimulated cortisol release in male monkeys [63]. Although these findings suggest sex differences in CRF sensitivity, the CRF challenge in marmosets did not increase ACTH levels more in females than males, suggesting sex differences in the adrenal response to ACTH in this species [62].…”

Section: Sex Differences In Crf-mediated Responses To Stresscontrasting

confidence: 48%

Sex differences in stress responses: a critical role for corticotropin-releasing factor

2018

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Rates of post-traumatic stress disorder, panic disorder, and major depression are higher in women than in men. Another shared feature of these disorders is that dysregulation of the stress neuropeptide, corticotropin-releasing factor (CRF), is thought to contribute to their pathophysiology. Therefore, sex differences in responses to CRF could contribute to this sex bias in disease prevalence. Here, we review emerging data from non-human animal models that reveal extensive sex differences in CRF functions ranging from its presynaptic regulation to its postsynaptic efficacy. Specifically, detailed are sex differences in the regulation of CRF-containing neurons and the amount of CRF that they produce. We also describe sex differences in CRF receptor expression, distribution, trafficking, and signaling. Finally, we highlight sex differences in the processes that mitigate the effects of CRF. In most cases, the identified sex differences can lead to increased stress sensitivity in females. Thus, the relevance of these differences for the increased risk of depression and anxiety disorders in women compared to men is also discussed.

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Section: Sex Differences In Crf-mediated Responses To Stresscontrasting

confidence: 48%

Sex differences in stress responses: a critical role for corticotropin-releasing factor

2018

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“…This effect has been shown in multiple species including primates (Toufexis and Wilson, 2012). In order to demonstrate that the elevation in stress-reactive CORT secretion following orchidectomy occurs within a timeframe that was amenable to study by pharmacological blockade of 5αR, we first identified the time course for the gonadectomy effect.…”

Section: Discussionmentioning

confidence: 73%

“…Depending on dose, timing, or age of treatment, estradiol (E) treatment of gonadectomized animals can either enhance or inhibit (Serova et al, 2010, Evuarherhe et al, 2009, Weiser and Handa, 2009, Young et al, 2001) HPA activity, whereas androgen treatment has consistently been shown to inhibit HPA reactivity in rodents, monkeys and humans (Kalil et al, 2013, Williamson and Viau, 2008, Handa et al, 1994b, Toufexis and Wilson, 2012, Rubinow et al, 2005). To date, the mechanism(s) by which T and E act to influence HPA function have not been completely resolved.…”

Section: Introductionmentioning

confidence: 99%

Central 5-alpha reduction of testosterone is required for testosterone's inhibition of the hypothalamo-pituitary–adrenal axis response to restraint stress in adult male rats

et al. 2013

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In rodents, the hypothalamo-pituitary-adrenal (HPA) axis is controlled by a precise regulatory mechanism that is influenced by circulating gonadal and adrenal hormones. In males, gonadectomy increases the adrenocorticotropic hormone (ACTH) and corticosterone (CORT) response to stressors, and androgen replacement returns the response to that of the intact male. Testosterone (T) actions in regulating HPA activity may be through aromatization to estradiol, or by 5α-reduction to the more potent androgen, dihydrotestosterone (DHT). To determine if the latter pathway is involved, we assessed the function of the HPA axis response to restraint stress following hormone treatments, or after peripheral or central treatment with the 5α-reductase inhibitor, finasteride. Initially, we examined the timecourse whereby gonadectomy alters the CORT response to restraint stress. Enhanced CORT responses were evident within 48hrs following gonadectomy. Correspondingly, treatment of intact male rats with the 5α-reductase inhibitor, finasteride, for 48 hrs, enhanced the CORT and ACTH response to restraint stress. Peripheral injections of gonadectomized male rats with DHT or T for 48 hrs reduced the ACTH and CORT response to restraint stress. The effects of T, but not DHT, could be blocked by the third ventricle administration of finasteride prior to stress application. These data indicate that the actions of T in modulating HPA axis activity involve 5α-reductase within the central nervous system. These results further our understanding of how T acts to modulate the neuroendocrine stress responses and indicate that 5α reduction to DHT is a necessary step for T action.

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“…Indeed, there is abundant evidence supporting a role of estrogen both in increasing and decreasing HPA axis activity through alteration of GR signaling pathways (Burgess and Handa 1992, Weiser and Handa 2009, Weiser et al 2010). Moreover, androgens are also known to decrease HPA axis activity by reducing glucocorticoid secretion (Toufexis and Wilson 2012, Kalil et al 2013). Additionally, interactions between the estrogen/androgen receptors and GR exist (Miranda et al 2013, Lightman and George 2014) that may contribute to the observed sex differences.…”

Section: Discussionmentioning

confidence: 99%

Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice

Laryea

Arnett

Muglia

2015

Stress

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Glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) are important regulators of negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Previous evaluation of endogenous PVN GR function in adult mice demonstrated that mice with loss of GR exon 3 in the PVN (Sim1Cre-GRe3Δ) have a hyperactive HPA axis, growth impairment, and metabolic disruptions. Here, we hypothesized that lack of negative feedback inhibition of the HPA axis through PVN GR, as demonstrated through loss of PVN GR early in life, will have developmental-stage-specific consequences. Immunofluorescence revealed that Sim1Cre-GRe3Δ mice display PVN GR loss as early as postnatal day 2 compared to control mice. Sim1Cre-GRe3Δ mice compared to controls also displayed increased corticotropin-releasing hormone (CRH) mRNA in the PVN at postnatal day 10, as shown by in situ hybridization. Corticosterone radioimmunoassay revealed that the disruptions in PVN GR and CRH expression led to elevated basal corticosterone secretion in male Sim1Cre-GRe3Δ mice by early adolescence and increased stress-induced (restraint) corticosterone secretion in late adolescence into adulthood. In comparison, female Sim1Cre-GRe3Δ mice did not display corticosterone disruption until adulthood. Circadian rhythmicity of corticosterone secretion was normal for male and female mice at all age groups regardless of genotype with one exception. In late adolescence, female Sim1Cre-GRe3Δ mice had disrupted circadian corticosterone secretion due to significantly elevated circulating levels at nadir. We conclude that PVN GR function matures at an earlier developmental time point in male than in female mice and thus leads to later differential stress responsiveness between sexes.

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Dihydrotestosterone differentially modulates the cortisol response of the hypothalamic–pituitary–adrenal axis in male and female rhesus macaques, and restores circadian secretion of cortisol in females

Cited by 17 publications

References 74 publications

Sex differences in stress responses: a critical role for corticotropin-releasing factor

Sex differences in stress responses: a critical role for corticotropin-releasing factor

Central 5-alpha reduction of testosterone is required for testosterone's inhibition of the hypothalamo-pituitary–adrenal axis response to restraint stress in adult male rats

Ontogeny of hypothalamic glucocorticoid receptor-mediated inhibition of the hypothalamic-pituitary-adrenal axis in mice

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