Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity

Estradiol-dependent regulation of CRH neurons in the PVN is thought to be mediated by estrogen receptor β.

“The estradiol-dependent regulation of CRH neurons in the PVN is thought to be regulated by the estrogen receptor β”

• cites Lund, Hinds, & Handa, 2006 sourceDisputed

  The Discussion says that estradiol (E2) enhances the stress response through an ERα-dependent mechanism, not ERβ. It also says that only a small population of neuroendocrine CRH neurons in the PVN appear to contain ERβ; the proposed ERβ pathways concern inhibition by other compounds. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Peripheral administration of ERβ agonist R-DPN prevents increased HPA axis reactivity and increased anxiety-like behaviors in female rats in response to GR agonist implant adjacent to the central nucleus of the amygdala.

“Peripheral administration of the estrogen receptor β agonist, R-DPN, prevented the increased HPA axis reactivity and increased anxiety-like behaviors in female rats in response to the implantation of a wax pellet containing a GR agonist, adjacent to the central nucleus of the amygdala (Weiser, Foradori, & Handa, 2010).”

• cites Weiser, Foradori, & Handa, 2010 sourceDisputed

  The Results (§2) report that peripheral S-DPN blocked the anxiety-like behaviors and increased stress-induced corticosterone associated with RU28362 implants. But the claim names R-DPN. Drug treatments (§4; page not provided) explicitly states that only the S-enantiomer was tested. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Coping mechanisms for stressors differ between males and females.

“the mechanisms to cope with stressors differ between males and females”

• cites Bale & Epperson, 2015 sourceSupported

OT and CRHR2 fibers in the BnST originate in the PVN.

“OT and CRHR2 fibers present in the BnST originated in the PVN.”

• cites Dabrowska et al., 2011 sourcePartly supported

  The Results report PVN-labeled fibers in the BNST that co-localized with both OT and CRFR2. The Discussion specifies that OT fibers in the BNST originate from PVN neurons “at least partially,” so the paper does not establish a PVN origin for all such fibers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

CORT can act indirectly in extra-PVN regions expressing MR and GR, such as the hippocampus, to inhibit CORT secretion through a trans-synaptic mechanism.

“CORT can also act indirectly in extra-PVN regions expressing MR and GR, such as the hippocampus, to inhibit the secretion of CORT (Akana, Cascio, Du, Levin, & Dallman, 1986; Dallman et al., 1987; Kovacs, Foldes, & Sawchenko, 2000; Sawchenko, 1987) through a trans-synaptic mechanism (Herman et al., 2016).”

• cites Akana, Cascio, Du, Levin, & Dallman, 1986 sourceNot checked — no full text of the source
• cites Dallman et al., 1987 sourceNot checked — no full text of the source
• cites Herman et al., 2016 sourceSupported

MRs have a much higher affinity for CORT (Kd = 0.5 nM) than GRs (Kd = 5.0 nM).

“Mineralocorticoid receptors have a much higher affinity (Kd = 0.5 nM) for CORT than do GRs (Kd =5.0 nM) (De Kloet, Veldhuis, Wagenaars, & Bergink, 1984; De Kloet, Vreugdenhil, Oitzl, & Joels, 1998)”

• cites De Kloet, Veldhuis, Wagenaars, & Bergink, 1984 sourceNot checked — no full text of the source
• cites De Kloet, Vreugdenhil, Oitzl, & Joels, 1998 sourceSupported

Female mice have higher pituitary Crh-BP mRNA transcripts than male mice, even after restraint stress.

“Stinnett et al. (2015), indicated higher Crh-BP mRNA transcripts in pituitary from female mice versus male mice, even after restraint stress”

• cites Stinnett, Westphal, & Seasholtz, 2015 sourceSupported

The BnST and PVN interact reciprocally, presumably through OT and CRHR2 mechanisms.

“Dabrowska et al. (2011) have shown that not only does the BnST interact with the PVN, but also vice versa, presumably through an OT and CRHR2 mechanism”

• cites Dabrowska et al., 2011 sourceSupported

Targeted deletion of GR in the PVN increases CRH expression and CORT and ACTH levels in male mice.

“Additional evidence for CORT acting directly on PVN neurons comes from studies where targeted deletion of GR in the PVN increased CRH expression and CORT and ACTH levels in male mice (Jeanneteau et al., 2012).”

• cites Jeanneteau et al., 2012 sourcePartly supported

  In “Reduced Expression of the GR in the PVN Disinhibits the HPA Axis,” the paper reports increased PVN CRH and elevated plasma ACTH and corticosterone in GR flox/+;Sim1Cre mice. The Methods specify adult males. The deletion was of one floxed GR allele, producing reduced GR expression rather than complete deletion; Sim1-Cre expression was also not confined to the PVN. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In pre- and post-pubertal gonadectomized female rats, the DHT metabolite 3β-diol increases the number of Avp mRNA-expressing cells in the BST, though less than estradiol.

“In vivo studies using pre- and post-pubertal gonadectomized female rats showed that the DHT metabolite, 5α androstane 3β-17β-diol (3β-diol), increased the number of Avp mRNA-expressing cells in the BST, although this increment was not as marked as in animals treated with estradiol (Pak, Chung, Hinds, & Handa, 2009).”

• cites Pak, Chung, Hinds, & Handa, 2009 sourcePartly supported

  The Results report that 3β-diol treatment restored AVP expression in the juvenile BST less than estradiol did. But the Animals section identifies the rats as male, not female, and the Results say treated adults had virtually no BST AVP expression (2.4% restored). (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The Avp promoter can be differentially regulated by ERα and ERβ in vitro through an upstream ERE.

“For instance, it was shown that the Avp promoter could be differentially regulated by ERα and ERβ in vitro through an upstream ERE.”

• cites Pak, Chung, Hinds, & Handa, 2007 sourcePartly supported

  The Discussion (page not available) describes different AVP promoter responses to ERα and ERβ. The section on ERE deletion reports that distal EREs contribute to some ERα-mediated regulation, but the Discussion says deleting the tested proximal ERE did not abolish ERβ-mediated activity. Thus the paper does not support the claim that regulation by both receptors occurs through an upstream ERE. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Shapiro, Xu, & Dorsa, 2000 sourceNot checked — no full text of the source

In female rats, stress hormone levels are higher on proestrus than on estrus.

“These hormonal changes correlate with higher stress hormone levels in female rats noted on proestrus when compared to rats that are in estrus, a time when estradiol and progesterone levels are reduced (Viau & Meaney, 1991).”

• cites Viau & Meaney, 1991 sourceSupported

GR is implicated in maintenance of baseline HPA axis control.

“thus implicating GR in the maintenance of baseline levels of HPA axis control as well.”

• cites Solomon et al., 2015 sourceSupported

In transgenic female mice with reduced PVN GR, responses to acute and chronic stress-induced ACTH are suppressed.

“Further, there were suppressed responses to acute and chronic stress-induced ACTH in the transgenic female mice (Solomon et al., 2015)”

• cites Solomon et al., 2015 sourcePartly supported

  The Results report significantly less ACTH in female PVN GR knockdown mice after acute restraint stress. They do not report suppressed ACTH responses after chronic stress; the chronic-stress Results instead report no genotype-specific difference in corticosterone responses. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Forebrain GR plays a smaller role in regulating the HPA axis in female mice than in males.

“Previous studies by this group showed that forebrain GR does not play as large a role in regulating the HPA of female mice compared to males”

• cites Solomon et al., 2012 sourceSupported

Estradiol inhibits HPA axis reactivity through ERβ.

“Together, such data suggest a possible mechanism for estradiol actions in inhibiting HPA axis reactivity through estrogen receptor β.”

• cites Weiser, Foradori, & Handa, 2010 sourceSupported

Estradiol treatment inhibits the negative feedback effects of dexamethasone, likely through effects on or near the PVN.

“Weiser and Handa (2009) showed that treatment with estradiol could inhibit the negative feedback effects of the synthetic glucocorticoid, dexamethasone, likely through effects on or near the PVN (Weiser & Handa, 2009).”

• cites Weiser & Handa, 2009 sourceSupported

In female rats, anxiety-like behavioral responses to stressors are increased during proestrus compared to estrus.

“These internal changes are further reflected behaviorally by increased anxiety-like behavioral responses to stressors during proestrus, as compared to estrus (Lovick, 2012).”

• cites Lovick, 2012 sourcePartly supported

  The section ‘Responsiveness to stress varies during the estrous cycle in rodents’ reports cycle-linked changes in anxiety and stress responsiveness. It identifies diestrus—not proestrus—as the phase with higher responsiveness compared with the receptive phases of proestrus and estrus; it does not establish the claimed proestrus-versus-estrus difference. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

When delivered to the PVN, OT decreases HPA axis gain, as shown by decreased CORT and ACTH levels.

“Although OT can act at the pituitary to enhance CRH action, when delivered to the PVN, OT decreased HPA axis gain, as shown by decreased CORT and ACTH levels (Neumann, Krömer, Toschi, & Ebner, 2000; Windle et al., 2004; Windle, Shanks, Lightman, & Ingram, 1997).”

• cites Neumann, Krömer, Toschi, & Ebner, 2000 sourceNot checked — no full text of the source
• cites Windle et al., 2004 sourcePartly supported

  The Results section reports that oxytocin reduced restraint-induced ACTH and corticosterone levels. However, the Methods section specifies delivery into the lateral ventricle, not directly into the PVN; the Discussion describes a PVN site of action as a possibility, not a demonstrated delivery site. Page numbers were not provided in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Windle, Shanks, Lightman, & Ingram, 1997 sourceNot checked — no full text of the source

Direct implant of E2 or ERα agonist PPT proximal to the PVN increases stress-induced and diurnal peak CORT.

“In this work, direct implant of wax pellets containing E2 or the ERα agonist (PPT) proximal to the PVN increased stress-induced and diurnal peak CORT.”

• cites Weiser & Handa, 2009 sourceSupported

PVN GR directly mediates negative feedback.

“thus supporting the hypothesis that PVN GR directly mediates negative feedback.”

• cites Solomon et al., 2015 sourcePartly supported

  The Abstract reports that reducing PVN GR impairs feedback regulation of acute stress responses in male mice, supporting the hypothesis in that setting. It also reports different effects in females and PVN-independent regulation after chronic stress, so the unqualified claim is broader than the findings. The Discussion describes GR knockdown rather than a complete, exclusively PVN-specific deletion. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

The Crh promoter contains several ERE half sites.

“Examination of the regulation of CRH by estradiol was first described by Vamvakopoulos & Chrousos (1993), who demonstrated that the Crh promoter contains several ERE half sites, suggesting the involvement of ERE-mediated effects of estrogen receptor.”

• cites Vamvakopoulos & Chrousos, 1993 sourceSupported

Estradiol treatment increases human Crh promoter activity by almost twofold in vitro in cells co-transfected with ERα and a Crh promoter-reporter gene construct.

“In support of this, they showed that estradiol treatment increased human Crh promoter activity by almost twofold in vitro in cells co-transfected with the ER α and a Crh promoter–reporter gene construct.”

• cites Vamvakopoulos & Chrousos, 1993 sourceSupported

GR negative feedback occurs predominantly at the hypothalamus.

“indicating that GR negative feedback occurred predominantly at the hypothalamus.”

• cites Solomon et al., 2015 sourcePartly supported

  The Abstract (page unavailable) reports that hypothalamic PVN glucocorticoid receptors help limit acute stress responses in male mice. It does not establish that GR negative feedback occurs predominantly at the hypothalamus across conditions: the Abstract also reports sex differences and a PVN-independent mechanism after chronic stress. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Reduction of GR in the PVN increases the diurnal CORT nadir.

“The same reduction in GR in the PVN increased the levels of the diurnal CORT nadir”

• cites Solomon et al., 2015 sourcePartly supported

  The Results report that PVN GR knockdown significantly increased circadian corticosterone nadir concentrations in female mice. The same section reports no nadir difference in male mice, so the claim omits an important sex-specific qualifier. Page numbers are not provided in our copy's passages. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In transgenic mice with reduced GR targeted to the PVN, ACTH and CORT levels increase after acute but not chronic stress.

“Solomon et al. (2015) reported that in a transgenic mouse model, where reductions in the levels of GR were targeted to the PVN, there were corresponding increases in ACTH and CORT levels after acute but not chronic stress”

• cites Solomon et al., 2015 sourcePartly supported

  The Abstract and Results report increased ACTH and corticosterone responses to acute stress in male PVN GR knockdown mice, but not increased corticosterone responses after chronic stress exposure. The claim omits the sex restriction: the Results report decreased acute-stress ACTH in females and no corresponding increase in corticosterone. The chronic-stress Results report corticosterone, not ACTH, for that comparison. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

Gonadal steroids can act in a synergistic manner to decrease HPA axis gain and anxiety-related behaviors.

“Gonadal steroids can act in a synergistic manner to decrease HPA axis gain and anxiety-related behaviors (Kudwa, McGivern, & Handa, 2014; McCarthy, McDonald, Brooks, & Goldman, 1996)”

• cites Kudwa, McGivern, & Handa, 2014 sourcePartly supported

  The Abstract (page unavailable) reports that activating estrogen receptor β reduced anxiety-like behavior and stress-induced HPA hormone responses in gonadectomized rats. The Introduction (page unavailable) describes an interaction with an oxytocin pathway, but oxytocin is not a gonadal steroid; the paper does not establish that gonadal steroids act synergistically to produce these effects. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites McCarthy, McDonald, Brooks, & Goldman, 1996 sourceNot checked — no full text of the source

The effects of ERβ agonists on Ot gene expression are tracked to an ERE half-site in the Ot proximal promoter.

“These effects of ERβ agonists were tracked to an ERE half-site in the Ot proximal promoter and thereby verify some molecular mechanisms for Ot gene expression regulation by ERβ.”

• cites Hiroi et al., 2013 sourcePartly supported

  In the section on OT promoter activation (page unavailable), mutating the proximal promoter’s cHRE eliminated reporter responses to E2, DPN and 3β-diol with ERβ. The paper identifies that element as a complex hormone response element, not specifically an ERE half-site, and does not establish that ERβ acts directly at such a half-site. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Some immunohistochemistry studies in rat brain have detected ERβ in GnRH neurons.

“Some studies using immunohistochemistry in rat brain have indeed shown the presence of ERβ in GnRH neuron (Butler, Sjoberg, & Coen, 1999; Hrabovszky et al., 2007; Hrabovszky et al., 2001; Kallo, Butler, Barkovics-Kallo, Goubillon, & Coen, 2001; Navarro et al., 2003; Roy, Angelini, & Belsham, 1999).”

• cites Butler, Sjoberg, & Coen, 1999 sourceNot checked — no full text of the source
• cites Hrabovszky et al., 2007 sourceSupported
• cites Hrabovszky et al., 2001 sourceNot checked — no full text of the source

In women with hypogonadotrophic hypogonadism, regular ovulatory cycles can be reinstated by timed pulsatile infusion of GnRH but not by similar levels of GnRH delivered constantly.

“In women with hypogonadotrophic hypogonadism, regular ovulatory cycles can be reinstated by the timed pulsatile infusion of GnRH but not by similar levels of GnRH delivered in a constant fashion (Tsutsumi & Webster, 2009).”

• cites Tsutsumi & Webster, 2009 sourcePartly supported

  The Introduction says disrupted GnRH pulsatility is associated with hypogonadotropic hypogonadism in women. It also reports that intermittent, but not constant, GnRH administration restored sustained gonadotropin secretion in rhesus monkeys. It does not report reinstated regular ovulatory cycles in women or compare similar GnRH doses delivered by the two methods. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

3β-diol treatment increases OT mRNA levels in a rat hypothalamic cell line that constitutively expresses OT.

“Supporting this possibility, studies using a rat hypothalamic cell line that constitutively expresses OT, reported that levels of OT mRNA were significantly increased following 3β-diol treatment (Sharma, Handa, & Uht, 2012)”

• cites Sharma, Handa, & Uht, 2012 sourcePartly supported

  The Results report a significant increase in Oxt mRNA after 3β-diol treatment at 30 and 60 minutes. However, the cell-characterization section identifies mHypoE-38 as derived from embryonic mouse hypothalami, not as a rat cell line. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

85% of OT neurons in the PVN express ERβ in the rat and in mice.

“However, 85% of OT neurons in the PVN also express ERβ in the rat (Hrabovszky et al., 2004; Suzuki & Handa, 2004) and in mice (Oyola, Thomson, Handa, & Handa, 2017).”

• cites Hrabovszky et al., 2004 sourceNot checked — no full text of the source
• cites Suzuki & Handa, 2004 sourceNot checked — no full text of the source
• cites Oyola, Thomson, Handa, & Handa, 2017 sourcePartly supported

  The citation to Oyola et al. supports the mouse portion of the sentence: Discussion §4.1 says that more than 80% of OT cells contained ERβ-EGFP in male and female mice. Results §3.2 gives regional averages of 76–81%, however, rather than the stated 85%. The rat portion is attached to other citations and is not assessed here. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Kisspeptin neurons are located in the arcuate nucleus and the anteroventral periventricular nucleus.

“Kisspeptin neurons have been found in two main brain areas: the arcuate nucleus and the anteroventral periventricular nucleus (Clarkson, d’Anglemont de Tassigny, Colledge, Caraty, & Herbison, 2009; Clarkson & Herbison, 2006).”

• cites Clarkson, d’Anglemont de Tassigny, Colledge, Caraty, & Herbison, 2009 sourceNot checked — no full text of the source
• cites Clarkson & Herbison, 2006 sourceSupported

3β-diol increases Ot mRNA in hypothalamic N38 cells.

“This study also reported an increase in Ot mRNA in hypothalamic N38 cells following 3β-diol treatment, indicating it effectiveness in regulating OT in vivo and in vitro.”

• cites Hiroi et al., 2013 sourceSupported

GnRH pulses are required for reproductive functions in both sexes.

“GnRH pulses are required for reproductive functions in both sexes, and the importance of these pulses in driving reproduction has been described in primates and humans (Tsutsumi & Webster, 2009).”

• cites Tsutsumi & Webster, 2009 sourceSupported

3β-diol increases Ot mRNA expression in the midcaudal, but not the rostral, portion of the rat PVN.

“Consistent with these findings, 3β-diol also increases Ot mRNA expression in the midcaudal, but not the rostral portion, of the rat PVN (Hiroi et al., 2013).”

• cites Hiroi et al., 2013 sourceSupported

The study of sex differences in the brain has revealed similarities and dissimilarities in neuronal development mechanisms between the sexes.

“The study of sex differences in the brain has unveiled similarities and dissimilarities in the mechanism of neuronal development between sexes (Amateau & McCarthy, 2004; McCarthy & Arnold, 2011; Schwarz, Liang, Thompson, & McCarthy, 2008).”

• cites Amateau & McCarthy, 2004 sourceNot checked — no full text of the source
• cites McCarthy & Arnold, 2011 sourceSupported
• cites Schwarz, Liang, Thompson, & McCarthy, 2008 sourceNot checked — no full text of the source

Activation of arcuate nucleus kisspeptin neurons directly influences pulsatile GnRH release.

“In contrast, activation of kisspeptin neurons in the arcuate nucleus has been shown to directly influence the regulation of pulsatile GnRH release (Han et al., 2005; Millar et al., 2010).”

• cites Han et al., 2005 sourcePartly supported

  The Introduction mentions kisspeptin neurons in the arcuate nucleus, and the section on adult GnRH neurons reports that applied kisspeptin directly depolarized GnRH neurons. But the experiments did not activate arcuate kisspeptin neurons or show an effect on pulsatile GnRH release; the discussion instead focuses on possible input from the AVPV. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Millar et al., 2010 sourceNot checked — no full text of the source

Clarkson and Herbison (2006) found a female bias in kisspeptin expression in the anteroventral and pre-optic periventricular nucleus of the mouse hypothalamus.

“Moreover, Clarkson and Herbison (2006) detected a female bias in the levels of kisspeptin expression in the anteroventral and pre-optic periventricular nucleus of the mouse hypothalamus (Clarkson & Herbison, 2006).”

• cites Clarkson & Herbison, 2006 sourceSupported

In rodents, absence of testosterone during a critical perinatal period leads to expression of the default female-like brain program.

“In the rodent, the absence of testosterone during a critical perinatal period results in the expression of the default program of the brain, which is female-like (McCarthy & Arnold, 2011), whereas perinatal treatment of females with testosterone will defeminize the brain and prevent the expression of female reproductive behaviors in adulthood.”

• cites McCarthy & Arnold, 2011 sourcePartly supported

  The 'Classic model: hormone-mediated organization/activation' section says embryonic testosterone masculinizes the brain, and the paper describes a perinatal period of hormonal sensitivity. But 'Parallel hormonal effects on diverse pathways and circuits' says estradiol is required for normal female brain development, so the source does not support describing female-like development as simply a default program expressed in testosterone's absence. No page numbers are available in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

3β-Diol acts by binding and activating ERβ rather than the androgen receptor.

“3β-diol acts by binding and activating estrogen receptor β, rather than an androgen receptor (Weihua et al., 2001).”

• cites Weihua et al., 2001 sourceSupported

Sex-dependent patterns are observed in the activation of PVN neurons that control HPA axis reactivity after stress.

“Furthermore, these sex-dependent patterns are also observed in the activation of PVN neurons controlling HPA axis reactivity following stress (Larkin, Binks, Li, & Selvage, 2010; Seale, Wood, Atkinson, Harbuz, & Lightman, 2004; Viau, Bingham, Davis, Lee, & Wong, 2005).”

• cites Larkin, Binks, Li, & Selvage, 2010Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Seale, Wood, Atkinson, Harbuz, & Lightman, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Viau, Bingham, Davis, Lee, & Wong, 2005 sourceSupported

X and Y gene dose discrepancies account for several sex-biased phenotypes in the brain and periphery.

“Questions regarding the effects of X and Y gene imbalance have been explored over the past decade, and the data suggests that X and Y gene dose discrepancies account for several sex-biased phenotypes in the brain and periphery (Arnold, 2004; Arnold et al., 2016; Burgoyne et al., 1995).”

• cites Arnold, 2004 sourceNot checked — no full text of the source
• cites Arnold et al., 2016 sourcePartly supported

  The Conclusion and prospectus reports that differences in X and Y chromosome effects cause sex differences in non-gonadal tissues, and section 4 gives an example involving body weight. But the Conclusion says the responsible X genes have not yet been identified and nongenic effects cannot be ruled out. The paper therefore supports sex-chromosome effects on phenotypes, not the stronger claim that X and Y gene-dose discrepancies have been established as their cause. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Burgoyne et al., 1995 sourceNot checked — no full text of the source

Gonadal steroids modulate HPA axis gain by affecting sensitivity to releasing factors, neurotransmitters, and hormones, thereby tuning circulating stress hormone levels.

“By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation.”

Gonadal steroids may exert epigenetic and organizational effects on the HPA axis before puberty.

“gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty.”

In rodents and humans, male and female PVN morphology is largely similar, with some exceptions.

“in rodents and humans, the morphology of the male and female PVN is quite similar, with some exceptions.”

Persistent activation of the HPA axis by chronic or traumatic stress can dysregulate the axis and cause pathology.

“constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology.”

Fluctuating gonadal steroid levels across the estrous cycle are a major contributor to sex differences in HPA activity in females versus males.

“Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males.”

HPG-HPA interactions may worsen peripheral pathologies.

“such interactions may exacerbate peripheral pathologies.”

Circulating estradiol in females elevates stress hormone levels during non-threatening situations and during and after stressors.

“as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors.”

Female mice and rats have a more robust HPA axis response than males.

“Compared to males, female mice and rats show a more robust HPA axis response”

Gonadal steroids can differentially affect the HPA axis from early life through adulthood, producing sex differences in HPA responsivity.

“From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis.”

Gonadal hormones are central to the establishment, activation, and regulation of the HPA axis.

“Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic–pituitary–adrenal (HPA) axis.”

CRH and AVP neurons of the PVN express GR.

“CRH and AVP neurons of the PVN express GR (Uht, McKelvy, Harrison, & Bohn, 1988)”

• cites Uht, McKelvy, Harrison, & Bohn, 1988Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

These findings indicate a robust sexual dimorphism at the PVN level in mounting the HPA response to environmental threats.

“indicating a robust sexual dimorphism in mounting the HPA response to environmental threats at the PVN level.”

Corticosterone can act directly on CRH and AVP neurons of the PVN and anterior pituitary corticotropes to regulate synthesis of these secretagogues.

“and as a result, corticosterone can act directly on CRH and AVP neurons of the PVN as well as in anterior pituitary corticotropes to regulate synthesis of these key secretagogues.”

Estrogens regulate Crh gene and promoter activity.

“The Crh gene and promoter activity have been shown to be regulated by estrogens”

• cites Lalmansingh & Uht, 2008Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Miller, Suzuki, Miller, Handa, & Uht, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Female rats release much more AVP after stress than males.

“female rats have a much stronger release of AVP following stress”

• cites Williams, Carter, & Lightman, 1985 sourceNot checked — no full text of the source

The lack of sex differences in PVN morphology suggests that chemical composition or wiring of the PVN makes HPA activation more robust in females than males.

“the lack of sex differences in the morphology of the PVN suggests that the chemical composition or wiring of the PVN is what makes the activation of the HPA axis more robust in females than in males.”

Estradiol-dependent effects on HPA regulation may be driven by direct action through estrogen receptor β in PVN CRH neurons.

“These studies suggest that estradiol-dependent effects in the regulation of the HPA axis may be driven by their direct action through the estrogen receptor β in CRH neurons of the PVN.”

CRH-BP binds CRH with similar or greater affinity than the CRH receptor.

“CRH-binding protein (CRH-BP) is a secreted protein that binds CRH with similar or greater affinity than the CRH receptor.”

• cites Cortright, Nicoletti, & Seasholtz, 1995 sourceNot checked — no full text of the source
• cites Seasholtz, Burrows, Karolyi, & Camper, 2001 sourceNot checked — no full text of the source

These data suggest a local inhibitory role for CRH-BP at the pituitary.

“These data suggest a local inhibitory role at the pituitary level.”

Stress-induced biologically active corticosterone may be elevated in male rats partly because stress negatively regulates CBG.

“the levels of stress-induced biologically active CORT may be elevated in male rats in part because the CBG is negatively regulated by stress”

• cites Tannenbaum et al., 1997 sourceNot checked — no full text of the source

Gonadal steroids differentially affect HPA axis reactivity.

“gonadal steroids impact HPA axis reactivity differentially.”

Estrogens and androgens may both regulate the HPA axis partly through modulation of CBG levels.

“indicating that estrogens and androgens may both play a role in the regulation of the HPA axis in part, through modulation of CBG levels.”

MRs are mostly occupied when CORT levels are low, such as during the morning trough in rodents.

“and consequently, the MRs are mostly occupied when CORT levels are low, such as during the morning trough of CORT in rodents (Bradbury et al., 1991).”

• cites Bradbury et al., 1991 sourceNot checked — no full text of the source

Women have larger PVN AVP neurons than men.

“women reportedly have larger PVN AVP neurons than men”

• cites Ishunina & Swaab, 1999 sourceNot checked — no full text of the source

After stress, CRH release from PVN neurons triggers a larger ACTH response in female than male rats.

“following exposure to a stressor, the release of CRH from PVN neurons triggers a larger ACTH response in female than in male rats”

• cites Le Mevel, Abitbol, Beraud, & Maniey, 1979 sourceNot checked — no full text of the source

CBG regulates corticosterone bioavailability during high secretion.

“This interaction regulates bioavailability during high CORT secretion”

• cites Meyer, Nenke, Rankin, Lewis, & Torpy, 2016 sourceNot checked — no full text of the source

CORT binds GRs and MRs to directly regulate gene transcription in glucocorticoid-sensitive brain regions.

“CORT can affect glucocorticoid-sensitive brain regions by binding GRs and MRs to directly regulate gene transcription (Reul & de Kloet, 1985).”

• cites Reul & de Kloet, 1985 sourceNot checked — no full text of the source

Adrenal corticosterone release differs between sexes, especially after stress.

“The adrenal release of CORT has been shown to differ between the sexes, particularly following stress.”

Plasma CBG is the main control of corticosterone bioavailability, binding corticosterone in blood and rendering it inactive.

“The main control of CORT bioavailability is the plasma corticosteroid binding globulin (CBG), which binds CORT in the blood to render it inactive”

• cites de Kloet, Joels, & Holsboer, 2005 sourceNot checked — no full text of the source

The actions of CRH-BP on CRH efficacy at the pituitary appear context-specific, such as during pregnancy when CRH exposure is chronic.

“the actions of CRH-BP on the efficacy of CRH at the level of the pituitary seems to be context specific, or during periods like pregnancy, when exposure to CRH is chronic.”

HPA axis negative feedback includes at least two time domains: a delayed feedback and a fast non-genomic feedback.

“There are at least two time-domains known to be involved in negative feedback: a time-delayed feedback and a fast acting, non-genomic feedback (Keller-Wood & Dallman, 1984).”

• cites Keller-Wood & Dallman, 1984 sourceNot checked — no full text of the source

Estradiol treatment increases Crh gene expression and basal ACTH levels in ovariectomized rats.

“Estradiol treatment increases Crh gene expression and basal levels of ACTH in ovariectomized rats”

• cites Ochedalski, Subburaju, Wynn, & Aguilera, 2007 sourceNot checked — no full text of the source

In vitro, estrogen receptor β but not α strongly stimulates the Crh promoter.

“In vitro studies have shown that the estrogen receptor β, but not α, has a strong stimulatory action on the Crh promoter”

• cites Miller, Suzuki, Miller, Handa, & Uht, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

These data suggest potential reciprocal modulation between BnST and PVN.

“These data suggest a potential reciprocal modulation between these two nuclei.”

Female rats have a more robust ACTH response to stress than males.

“In female rats, there is a more robust ACTH response to stress as compared to males”

• cites Handa et al., 1994Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Young, 1996Not checked — no full text of the source

Regulation of the Crh promoter by ERα is weak.

“Of importance, regulation by ERα was weak (Miller, Suzuki, Miller, Handa, & Uht, 2004).”

• cites Miller, Suzuki, Miller, Handa, & Uht, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Fluctuations in gonadal hormones modulate the way males and females react to stress.

“Fluctuations in gonadal hormones have been shown to modulate the way that males and females react to stress, although the exact mechanism for this has yet to be completely resolved.”

ERβ can bind the Crh promoter to regulate transcription.

“Later in vitro studies by Miller et al. (2004) used the Crh proximal promoter in transformed rat hypothalamic neurons to show that ERβ can bind the Crh promoter to regulate transcription (Miller, Suzuki, Miller, Handa, & Uht, 2004).”

• cites Miller, Suzuki, Miller, Handa, & Uht, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In adrenalectomized rats implanted with pellets delivering physiological CORT levels, Avp transcription and mRNA levels are significantly elevated.

“In a study using adrenalectomized rats implanted with pellets delivering physiological CORT levels, Avp transcription and mRNA levels were significantly elevated (Herman, 1995).”

• cites Herman, 1995 sourceNot checked — no full text of the source

OT may regulate HPA axis gain at the PVN level as well as the pituitary.

“suggesting that OT may regulate HPA axis gain at the PVN level as well as the pituitary.”

• cites Mantella, Vollmer, Rinaman, Li, & Amico, 2004 sourceNot checked — no full text of the source
• cites Nomura et al., 2003 sourceNot checked — no full text of the source

Estrogen receptors are expressed in different proportions in CRH, AVP, and OT neurons populating the PVN.

“PVN neuropeptide neurons are the drivers of the HPA axis, yet, estrogen receptors are expressed in different proportions in CRH, AVP, and OT neurons populating the PVN (Hrabovszky et al., 2004; Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998; Suzuki & Handa, 2004).”

• cites Hrabovszky et al., 2004 sourceNot checked — no full text of the source
• cites Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Suzuki & Handa, 2004 sourceNot checked — no full text of the source

Estrogen and androgen regulation of AVP expression could be mediated by direct actions of ERβ.

“Data from our laboratory and others indicate that the estrogen and androgen regulation of AVP expression could be mediated by direct actions of ERβ.”

The Crh promoter is differentially regulated by splice variants of ERβ.

“In addition, the Crh promoter was differentially regulated by splice variants of ERβ, consistent with the demonstration that a variant that lacks the full DNA binding domain (ERβ1 delta3) could signal through non-classical mechanisms by protein: protein interactions involving an SP1 element rather than an ERE (Price et al., 2001).”

• cites Miller, Suzuki, Miller, Handa, & Uht, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Price et al., 2001 sourceNot checked — no full text of the source

Estrogen receptors are involved in estrogen-mediated regulation of the HPA axis.

“Such results suggest their involvement in the estrogen-mediated regulation of the HPA axis.”

There is a strong modulation of GR on the HPA axis, marked by a striking sex difference in negative feedback regulation as a result of estradiol interactions with estrogen receptors.

“These results suggest a strong modulation of GR on the HPA axis, marked by a striking sex difference in the negative feedback regulation as a result of estradiol interactions with estrogen receptors.”

The ERβ agonist 3β-diol increases Crh promoter activity in CHO-K1 cell lines overexpressing ERβ.

“Moreover, the ERβ agonist, 3β-diol, an important metabolite of the non-aromatizable androgen, DHT, can also increase Crh promoter activity in CHO-K1 cell lines overexpressing ERβ (Huang, Zhu, Fischer, & Zhou, 2008).”

• cites Huang, Zhu, Fischer, & Zhou, 2008 sourceNot checked — no full text of the source

Global deletion of OT in female mice results in increased stress-induced CORT secretion and Crh mRNA expression in the PVN.

“Furthermore, global deletion of OT in female mice results in increased stress-induced CORT secretion and Crh mRNA expression in the PVN (Mantella, Vollmer, Rinaman, Li, & Amico, 2004; Nomura et al., 2003)”

• cites Mantella, Vollmer, Rinaman, Li, & Amico, 2004 sourceNot checked — no full text of the source
• cites Nomura et al., 2003 sourceNot checked — no full text of the source

AVP plays a prominent role mediating glucocorticoid negative feedback upon the HPA axis.

“In particular, AVP has been shown to play a prominent role mediating the glucocorticoid negative feedback upon the HPA axis (Kovacs & Makara, 1988).”

• cites Kovacs & Makara, 1988Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The rise in testosterone during the pubertal period is key for the proper HPA axis response during adulthood.

“Subsequently, Evuarherhe et al. (2009) tested this hypothesis, and concluded that the rise in testosterone during the pubertal period is indeed key for the proper HPA axis response during adulthood.”

• cites Evuarherhe et al., 2009 sourceNot checked — no full text of the source

Estrogens modulate Crh gene expression by acting through ERβ directly.

“Together, these studies suggest that estrogens are able to modulate Crh gene expression by acting through ERβ directly.”

ERβ is expressed at different levels in various subdivisions of PVN CRH neurons in the rat, ranging from 5% co-localization in the medial PVN to 60-80% co-localization in the caudolateral division.

“As a mediator of estradiol actions, ERβ is expressed at different levels in various subdivisions of PVN CRH neurons in the rat, ranging from 5% co-localization in the medial PVN to 60–80% co-localization in the caudolateral division (Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998).”

• cites Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Changes in the transition from puberty to adulthood have a marked effect on the male HPA axis response to stress.

“These results suggest that changes in the transition from puberty to adulthood have a marked effect on the male HPA axis response to stress.”

Estrogen or testosterone treatment of neonatal females defeminizes the brain so that they no longer produce an LH surge in response to estradiol in adulthood.

“Conversely, estrogen or testosterone treatment of neonatal females defeminizes the brain such that they can no longer respond to estradiol in adulthood with a surge of LH (Handa, Corbier, Shryne, Schoonmaker, & Gorski, 1985).”

• cites Handa, Corbier, Shryne, Schoonmaker, & Gorski, 1985Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

OT neurons in the PVN express androgen receptors.

“OT neurons in the PVN express androgen receptors (Zhou, Blaustein, & De Vries, 1994).”

• cites Zhou, Blaustein, & De Vries, 1994 sourceNot checked — no full text of the source

ERβ-driven reduction in stress-induced CORT and ACTH levels and PVN neuronal activation is very similar to that observed following OT treatment.

“Interestingly, the ERβ-driven reduction in stress-induced CORT and ACTH levels, and PVN neuronal activation is very similar to that observed following OT treatment (Ochedalski, Subburaju, Wynn, & Aguilera, 2007; Windle et al., 2006, 2004).”

• cites Ochedalski, Subburaju, Wynn, & Aguilera, 2007 sourceNot checked — no full text of the source
• cites Windle et al., 2006, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Follicle growth and rising estradiol late on proestrus morning trigger an afternoon LH surge that drives ovulation.

“As a result of follicle growth and the rising titers of estradiol that culminate late on proestrus morning, a surge of LH is initiated in the afternoon, which drives ovulation.”

The post-pubertal female brain's ability to produce an LH surge in response to estradiol is organized by the absence of estradiol derived from testosterone during neonatal life.

“Thus, sensitivity of the post-pubertal female brain to respond to elevations in estradiol with a surge of LH is organized by the absence of estradiol derived from testosterone in neonatal females.”

Under basal conditions, estradiol restricts GnRH secretion through a negative feedback loop.

“Under basal conditions, estradiol acts through a negative feedback loop to restrict the secretion of GnRH (Figure 2).”

Coordinated LH and FSH action on thecal and granulosa cells raises circulating estradiol and supports the two cell-two gonadotropin hypothesis.

“The net result of this coordinated action of LH and FSH on thecal and granulosa cells of the ovary gives rise to increases in circulating estradiol and supports the two cell – two gonadotropin hypothesis (Stocco, 2001).”

• cites Stocco, 2001 sourceNot checked — no full text of the source

This feedback system helps keep HPG drive and gonadal hormone secretion relatively constant.

“This system helps maintain relatively constant levels of HPG drive and gonadal hormone secretion.”

Estradiol does not appear to act directly on GnRH neurons to limit their activity.

“Although it would be easy to hypothesize that estradiol acts directly on GnRH neurons to limit their activity, this does not appear to be the case.”

Neonatal castration of male rats enables them to respond to estradiol in adulthood with an LH surge.

“Evidence that positive feedback is sexually differentiated by the neonatal actions of testosterone comes from studies showing that neonatal castration of male rats allows them to respond to estradiol in adulthood with an LH surge (Handa, Corbier, Shryne, Schoonmaker, & Gorski, 1985).”

• cites Handa, Corbier, Shryne, Schoonmaker, & Gorski, 1985Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The organization of GnRH pulses is critical for puberty and reproduction.

“The organization of these pulses is critical for puberty and reproduction (Herbison, 2016).”

• cites Herbison, 2016 sourceNot checked — no full text of the source

Ovarian granulosa cells cannot directly convert progesterone into androgenic estrogen precursors and must obtain estrogenic precursors from thecal cells.

“While estrogens are made by the conversion of androstenedione into estradiol in ovarian granulosa cells, these cells lack the enzymes required to directly metabolize progesterone into the androgenic precursors of estrogens (Doshi & Agarwal, 2013) and must depend on the-cal cells to provide estrogenic precursors.”

• cites Doshi & Agarwal, 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Studying direct sex chromosome effects in brain sexual differentiation is challenging because chromosomal manipulation could confound gonadal steroid levels.

“The study of direct sex chromosomes effects in brain sexual differentiation, however, is challenging, mainly because chromosomal manipulation could lead to confounding changes in gonadal steroid levels.”

Testosterone's effects on the brain are often controlled by intracellular conversion to estradiol by aromatase or to DHT by 5α-reductase.

“For example, the effects of testosterone on the brain are often controlled by the intra-cellular conversion of testosterone to estradiol by the aromatase enzyme or to DHT by the 5α-reductase enzyme (Arevalo, Azcoitia, & Garcia-Segura, 2015).”

• cites Arevalo, Azcoitia, & Garcia-Segura, 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Brain-metabolized estradiol strongly influences stress, reproduction, learning, memory, and sexual behaviors.

“Brain-metabolized estradiol also has a strong influence on stress, reproduction, learning, and memory, as well as sexual behaviors (Blomqvist, 2000; Fink, Sumner, McQueen, Wilson, & Rosie, 1998).”

• cites Blomqvist, 2000Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Fink, Sumner, McQueen, Wilson, & Rosie, 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Aromatase expression is much higher in the male stria terminalis, paraventricular pre-optic area, ventromedial nucleus, pre-optic nucleus, and anterior nucleus of the hypothalamus.

“One of the most widely studied of these is aromatase, whose expression levels are much higher in the male stria terminalis, paraventricular pre-optic area, ventromedial nucleus, pre-optic nucleus, and anterior nucleus of the hypothalamus (Roselli, 1991).”

• cites Roselli, 1991 sourceNot checked — no full text of the source

DHT can be further metabolized to 3β-diol via 3β-HSD and then by CYP7B1.

“The non-aromatizeable androgen, DHT, may also be further metabolized to the estrogen-like androgen, 3β-diol, via 3β-HSD and then metabolized by the cytochrome P450 enzyme CYP7B1 (Handa, Weiser, & Zuloaga, 2009a).”

• cites Handa, Weiser, & Zuloaga, 2009aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Inhibition of 5α-reductase with finasteride abolishes testosterone's inhibitory effects on the HPA axis in male rats.

“Inhibition of 5α-reductase using finasteride abolishes the inhibitory effects of testosterone on the HPA axis in male rats (Handa, Kudwa, Donner, McGivern, & Brown, 2013).”

• cites Handa, Kudwa, Donner, McGivern, & Brown, 2013Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Aromatization of testosterone to estrogen triggers neurite growth and neuronal plasticity in sexually dimorphic brain regions, including the sexually dimorphic nucleus of the rat pre-optic area.

“Also, aromatization of testosterone into estrogen is known to trigger neurite growth and neuronal plasticity in sexually dimorphic brain regions, including the sexually dimorphic nucleus of the rat pre-optic area (Davis, Popper, & Gorski, 1996; Davis, Shryne, & Gorski, 1996).”

• cites Davis, Popper, & Gorski, 1996 sourceNot checked — no full text of the source
• cites Davis, Shryne, & Gorski, 1996Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Neurokinin B mRNA levels are upregulated by gonadectomy.

“In addition to kisspeptin, mRNA levels of neurokinin B are also upregulated by gonadectomy (Sandoval-Guzman, Stalcup, Krajewski, Voytko, & Rance, 2004).”

• cites Sandoval-Guzman, Stalcup, Krajewski, Voytko, & Rance, 2004Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

A mutual relationship exists between the HPA and HPG axes for allostatic regulation and species survival.

“Thus, whether through peripheral hormones acting centrally, or metabolism to other steroids through the major metabolic pathways, a mutual relationship exists between the HPA and HPG axes for allo-static regulation and species survival.”

These stress responses are thought to be delineated in part by gonadal steroids acting during pre- and perinatal stages and at puberty.

“These responses are thought to be delineated in part by gonadal steroids acting during pre-and perinatal stages as well as at puberty (McCormick & Mathews, 2007).”

• cites McCormick & Mathews, 2007Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Castration of male rats during the peri-natal stage causes a female pattern of ACTH and CORT response to stress in adulthood.

“For example, removal of endogenous gonadal hormones by castration of male rats during the peri-natal stage causes a female pattern of ACTH and CORT response to stress during adulthood (McCormick, Furey, Child, Sawyer, & Donohue, 1998).”

• cites McCormick, Furey, Child, Sawyer, & Donohue, 1998Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Testosterone in males may act through estrogen receptors rather than androgen receptors after aromatization to estradiol.

“For example, testosterone in males may work through estrogen receptors, rather than androgen receptors, by its aromatization to estradiol.”

Aromatization blockade in males immediately after birth results in an augmented CORT and ACTH stress response in adulthood, similar to females.

“On the other hand, aromatization blockade in males immediately after birth results in an augmented CORT and ACTH response to stress in adulthood, similar to that of females (Bingham, Wang, Innala, & Viau, 2012), and akin to that observed following perinatal castration.”

• cites Bingham, Wang, Innala, & Viau, 2012 sourceNot checked — no full text of the source

Sexually dimorphic behavioral and physiological stress responses are evident from pre-pubertal stages through adulthood.

“The sexually dimorphic behavioral and physiological responses to stress are evident from pre-pubertal stages through adulthood.”

The CORT pulsatile pattern of adult female rats can be masculinized by testosterone treatment 24 h after birth, producing adult patterns similar to males.

“Interestingly, the CORT pulsatile pattern of adult female rats can be masculinized by treatment with testosterone 24 h after birth, resulting in CORT pulse patterns in adulthood that are similar to those observed in males (Seale, Wood, Atkinson, Harbuz, & Lightman, 2005).”

• cites Seale, Wood, Atkinson, Harbuz, & Lightman, 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

These studies demonstrate the importance of testosterone and its metabolites in the sexual differentiation of the HPA axis.

“Thus, these studies further demonstrate the importance of testosterone and its metabolites in the sexual differentiation of the HPA axis.”

Some enzymes involved in local estrogen and androgen metabolism in the brain are sexually dimorphic.

“Some of the enzymes involved in the local metabolism of estrogens and androgens in the brain are sexually dimorphic.”

These changes are thought to begin when sex chromosome genes determine internal and external morphology and thus fetal hormone levels.

“These changes are thought to begin when genes on the sex chromosomes (X and Y) determine the type of internal and external morphology to be developed, and hence the level of hormones to be present in the fetus.”

The effects of neonatal gonadectomy on male HPA axis function can be reversed by testosterone treatment during the perinatal period.

“In line with classical mechanisms for sexual differentiation of the rodent brain, the effects of neonatal gonadectomy on male HPA axis function can be reversed by testosterone treatment during the perinatal period (Bingham & Viau, 2008).”

• cites Bingham & Viau, 2008 sourceNot checked — no full text of the source

5α-Reductase converts progesterone and glucocorticoids into their metabolites in the brain.

“5α-Reductase also converts progesterone and glucocorticoids into their respective metabolites in the brain (Celotti, Negri-Cesi, & Poletti, 1997; Lephart, 1996; Lephart, Lund, & Horvath, 2001).”

• cites Celotti, Negri-Cesi, & Poletti, 1997 sourceNot checked — no full text of the source
• cites Lephart, 1996 sourceNot checked — no full text of the source
• cites Lephart, Lund, & Horvath, 2001 sourceNot checked — no full text of the source

The two kisspeptin neuron populations produce markedly different responses in GnRH neurons.

“These two populations of kisspeptin neurons are responsible for vastly different responses in GnRH neurons.”

The origin of sexual differences in the brain begins before gonadal hormones are detected in plasma.

“The origin of sexual differences in the brain starts even before gonadal hormones are detected in the plasma (Arnold, 1996; Wade & Arnold, 1996).”

• cites Arnold, 1996 sourceNot checked — no full text of the source
• cites Wade & Arnold, 1996 sourceNot checked — no full text of the source

The HPA and HPG axes work together to fine-tune each other, integrating environmental, psychological, reproductive, and genetic factors.

“To increase survival and reproductive success, the HPA and the HPG axes work together to fine-tune each other thereby integrating environmental, psychological, reproductive, and genetic factors.”

Hypothalamic neurons expressing gonadal steroid receptors are important for proper regulation of the HPA and HPG axes.

“Hypothalamic neurons expressing gonadal steroid receptors are of great importance for the proper regulation of the HPA and HPG axes, and thus, the composition of these cells requires further investigation.”

Dysregulation of either or both the HPA and HPG axes can compromise responses to stressful life events.

“Dysregulation of either or both of these axes can result in compromised responses to stressful life events.”