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

In the paper

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

What the sources say

• Disputed

  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.

  cites Lund, Hinds, & Handa, 2006 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Disputed

  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.

  cites Weiser, Foradori, & Handa, 2010 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The paper’s discussion of stress responses (labeled Abstract in our copy) says female rodents use more passive strategies than males and that passive coping responses are more common in women. The Conclusions also state that males and females respond differently to stress. (LLM, conf=0.92)

  cites Bale & Epperson, 2015 source

In the paper

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

What the sources say

• Partly 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)

  cites Dabrowska et al., 2011 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• ?Not matched

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

  cites Lalmansingh & Uht, 2008
• Supported

  The Discussion reports that ERβ isoforms substantially regulate the CRH promoter. It also reports E2-stimulated CRH transcription, while the ERβ isoform results describe the CRH gene’s response to E2. The effects depend on receptor isoform and experimental context. (LLM, conf=0.89)

  cites Miller, Suzuki, Miller, Handa, & Uht, 2004 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Akana, Cascio, Du, Levin, & Dallman, 1986 source
• ?Not checked — no full text of the sourcecites Dallman et al., 1987 source
• Supported

  In “The ‘falling’ phase: transsynaptic inhibition of the HPA axis,” the paper describes hippocampal projections through GABAergic neurons to inhibit PVN activation and notes that the hippocampus expresses both MR and GR. “Brain glucocorticoid feedback processes” explicitly identifies trans-synaptic modulation through the hippocampus as a route of GR-mediated inhibition. (LLM, conf=0.93)

  cites Herman et al., 2016 source

In the paper

“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)”

What the sources say

• ?Not checked — no full text of the sourcecites De Kloet, Veldhuis, Wagenaars, & Bergink, 1984 source
• Supported

  The section “Corticosteroid receptor diversity in brain and pituitary” states that MRs bind corticosterone with 10-fold higher affinity than GRs and gives an MR dissociation constant of approximately 0.5 nM, measured at 4°C. That ratio implies the cited GR value of approximately 5.0 nM. (LLM, conf=0.93)

  cites De Kloet, Vreugdenhil, Oitzl, & Joels, 1998 source

In the paper

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

What the sources say

• Supported

  The Results section reports that basal pituitary CRH-BP mRNA was more than 200-fold higher in female mice than in males. Restraint stress increased expression 11.8-fold in females and 3.2-fold in males, so female levels remained higher after stress. (LLM, conf=0.92)

  cites Stinnett, Westphal, & Seasholtz, 2015 source

In the paper

“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”

What the sources say

• Supported

  The Discussion describes BNST input to the PVN and suggests reciprocal input from the PVN to the BNST via CRFR2/OT-positive fibers. The Results report tracing evidence for OT- and CRFR2-positive fibers from the PVN in the BNST. The claim’s “presumably” appropriately reflects the proposed mechanism; page numbers are not provided in our copy. (LLM, conf=0.92)

  cites Dabrowska et al., 2011 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Jeanneteau et al., 2012 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Discussion states that ERβ isoforms, rather than ERα, substantially regulate the CRH promoter. The cell-transfection results report promoter activation by ERβ1 and only a small effect of ERα. Thus, 'but not α' is supported as a contrast in strength, not as a claim that ERα has no effect. (LLM, conf=0.93)

  cites Miller, Suzuki, Miller, Handa, & Uht, 2004 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Pak, Chung, Hinds, & Handa, 2009 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Pak, Chung, Hinds, & Handa, 2007 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Shapiro, Xu, & Dorsa, 2000 source

In the paper

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

What the sources say

• Supported

  The section titled “ERα exerts modest effects on CRH promoter transcription” reports only a small effect of ERα on the CRH promoter. The Discussion (J. Neurosci. 24:10628–10635) likewise describes ERα as an inherently weak transcriptional activator at that promoter. (LLM, conf=0.95)

  cites Miller, Suzuki, Miller, Handa, & Uht, 2004 source

In the paper

“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).”

What the sources say

• Supported

  The Results (Basal and Stress ACTH and B Levels in Cycling Rats; page unavailable) report significantly higher ACTH and corticosterone responses during restraint stress in proestrous rats than in estrous rats. The paper specifies that basal levels did not differ across cycle phases. (LLM, conf=0.93)

  cites Viau & Meaney, 1991 source

In the paper

“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).”

What the sources say

• Partly supported

  The Results section (‘ERβ isoforms elicit different patterns of CRH promoter regulation’; page not provided) reports that ERβ1 activated a CRH promoter reporter, supporting transcriptional regulation. It does not establish that ERβ binds the promoter. The Transcription experiments section (page not provided) describes transfected HeLa cells, not transformed rat hypothalamic neurons. (LLM, conf=0.90)

  cites Miller, Suzuki, Miller, Handa, & Uht, 2004 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Results report that female mice with PVN GR depletion had higher circadian nadir and prestress corticosterone levels, implicating GR in baseline HPA-axis control. The effect was sex-dependent: the same section reports no difference in nadir or peak corticosterone in males. (LLM, conf=0.88)

  cites Solomon et al., 2015 source

In the paper

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

What the sources say

• Partly 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)

  cites Solomon et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Supported

  The Discussion reports a sex difference in forebrain GR regulation of HPA-axis activity: male knockout mice showed elevated corticosterone or enhanced stress responsiveness, while female knockout mice showed no differences in HPA function. It also reports similar GR knockdown in males and females, supporting the comparison. (LLM, conf=0.94)

  cites Solomon et al., 2012 source

In the paper

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

What the sources say

• Supported

  The Results (section 2; page unavailable) report that the ERβ agonist S-DPN lowered stress-induced corticosterone and blocked the increase caused by a GR agonist. The Discussion (section 3; page unavailable) describes ERβ signaling as having effects on HPA-axis activity opposite to those of ERα signaling. This supports the citing sentence’s tentative proposal of an ERβ-mediated mechanism, although the experiment used an ERβ agonist rather than estradiol itself. (LLM, conf=0.88)

  cites Weiser, Foradori, & Handa, 2010 source

In the paper

“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).”

What the sources say

• Supported

  The Discussion (page not provided) states that ERβ δ3 splice variants substantially changed the ligand responsiveness of ERβ1 and ERβ2 at the CRH promoter, with different effects for the two isoforms. This directly supports differential regulation by ERβ splice variants. (LLM, conf=0.94)

  cites Miller, Suzuki, Miller, Handa, & Uht, 2004 source
• ?Not checked — no full text of the sourcecites Price et al., 2001 source

In the paper

“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).”

What the sources say

• Supported

  The Results section on ERα near the PVN reports that estradiol treatment significantly impaired dexamethasone (DEX) suppression of CORT and ACTH. The Discussion concludes that estradiol impairs glucocorticoid-mediated negative feedback through effects in the region of the PVN. (LLM, conf=0.94)

  cites Weiser & Handa, 2009 source

In the paper

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

What the sources say

• Partly 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)

  cites Lovick, 2012 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Neumann, Krömer, Toschi, & Ebner, 2000 source
• Partly 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)

  cites Windle et al., 2004 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Windle, Shanks, Lightman, & Ingram, 1997 source

In the paper

“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.”

What the sources say

• Supported

  The Results sections on the diurnal rise and restraint-induced secretion report that wax pellets targeted just above the PVN delivered estradiol or PPT and significantly increased CORT relative to wax-only controls in both conditions. PPT is identified as an ERα agonist in the Discussion. (LLM, conf=0.94)

  cites Weiser & Handa, 2009 source

In the paper

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

What the sources say

• Partly 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)

  cites Solomon et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results state that the human CRH 5′ flanking sequence contains two perfect half-palindromic EREs in one construct and four in a longer construct. The Results and Discussion also report estrogen-receptor binding and estradiol-dependent transcriptional activity, supporting the suggested ERE-mediated effect. (LLM, conf=0.93)

  cites Vamvakopoulos & Chrousos, 1993 source

In the paper

“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.”

What the sources say

• Supported

  The Results describe CV-1 cells co-transfected with a human CRH reporter construct and an estrogen-receptor expression plasmid. Table I reports that estradiol increased CAT activity for construct 2 from 2.6 to 5.7, approximately a twofold increase; construct 1 showed a larger increase. Page numbers are not available in our copy. (LLM, conf=0.88)

  cites Vamvakopoulos & Chrousos, 1993 source

In the paper

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

What the sources say

• Partly 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)

  cites Solomon et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Partly 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)

  cites Solomon et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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”

What the sources say

• Partly 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)

  cites Solomon et al., 2015 sourceExperimental — accuracy not yet measured

In the paper

“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)”

What the sources say

• Partly 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)

  cites Kudwa, McGivern, & Handa, 2014 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites McCarthy, McDonald, Brooks, & Goldman, 1996 source

In the paper

“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.”

What the sources say

• Partly 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)

  cites Hiroi et al., 2013 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Butler, Sjoberg, & Coen, 1999 source
• Supported

  The introductory passage reports that two groups detected nuclear ERβ immunoreactivity in 63–73% of rat GnRH neurons. The Discussion also refers to a previous immunocytochemical study in rats. Although this paper's own experiments used human tissue, it supports the attributed statement about rat studies. (LLM, conf=0.93)

  cites Hrabovszky et al., 2007 source
• ?Not checked — no full text of the sourcecites Hrabovszky et al., 2001 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Tsutsumi & Webster, 2009 sourceExperimental — accuracy not yet measured

In the paper

“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)”

What the sources say

• Partly 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)

  cites Sharma, Handa, & Uht, 2012 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hrabovszky et al., 2004 source
• ?Not checked — no full text of the sourcecites Suzuki & Handa, 2004 source
• Partly 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)

  cites Oyola, Thomson, Handa, & Handa, 2017 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Clarkson, d’Anglemont de Tassigny, Colledge, Caraty, & Herbison, 2009 source
• Supported

  The Results (Distribution of kisspeptin-10 immunoreactivity in adult female mouse hypothalamus) identify kisspeptin cell bodies in both the anteroventral periventricular nucleus and the arcuate nucleus. The paper also identifies a smaller, scattered dorsomedial population; the claim says “two main” areas, not that these are the only locations. (LLM, conf=0.88)

  cites Clarkson & Herbison, 2006 source

In the paper

“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.”

What the sources say

• Supported

  Figure 2 identifies the treated cells as N38 cells and describes measurement of OT mRNA after 3β-diol treatment. The Discussion reports that after 24 hours, 3β-diol increased OT mRNA levels. The paper also reports an in vivo increase, limited to the midcaudal PVN of ovariectomized rats. (LLM, conf=0.92)

  cites Hiroi et al., 2013 source

In the paper

“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).”

What the sources say

• Supported

  The Introduction says GnRH is released in pulses and drives gonadotropins that regulate gonadal function, including spermatogenesis and ovulation. It also describes LH pulses observed in monkeys and humans and reports that intermittent, but not constant, GnRH restored sustained gonadotropin secretion in rhesus monkeys. (LLM, conf=0.90)

  cites Tsutsumi & Webster, 2009 source

In the paper

“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).”

What the sources say

• Supported

  The Results section reports that 3β-diol significantly increased OT mRNA in the midcaudal PVN of ovariectomized rats, while no significant difference was found in the rostral PVN. The Figure 1 caption specifies that rats received treatment daily for four days. (LLM, conf=0.94)

  cites Hiroi et al., 2013 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Amateau & McCarthy, 2004 source
• Supported

  The Abstract says that comparing males and females has revealed previously unknown mechanisms of neural development. The section “Parallel hormonal effects on diverse pathways and circuits” describes a possible shared neural network that is differently organized in the two sexes, supporting the claim’s broad reference to similarities and differences. (LLM, conf=0.88)

  cites McCarthy & Arnold, 2011 source
• ?Not checked — no full text of the sourcecites Schwarz, Liang, Thompson, & McCarthy, 2008 source

In the paper

“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).”

What the sources say

• Partly 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)

  cites Han et al., 2005 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Millar et al., 2010 source

In the paper

“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).”

What the sources say

• Supported

  The Results section reports over 10-fold more kisspeptin-immunoreactive cell bodies in the AVPV and preoptic periventricular nucleus of adult female mice than in males. The Discussion describes this as a marked sexual dimorphism in kisspeptin expression in that region. (LLM, conf=0.93)

  cites Clarkson & Herbison, 2006 source

In the paper

“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).”

What the sources say

• Supported

  The Discussion reports that central finasteride prevented testosterone treatment from inhibiting HPA-axis responses. The finding concerns the response to restraint stress in male rats, rather than HPA activity under all conditions. (LLM, conf=0.93)

  cites Handa, Kudwa, Donner, McGivern, & Brown, 2013 source

In the paper

“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.”

What the sources say

• Partly 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)

  cites McCarthy & Arnold, 2011 sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Abstract states that 3βAdiol binds ERβ but not the androgen receptor. The Results report ERβ activation by prostate extracts whose major estrogenic component coeluted with 3βAdiol; the Abstract also reports an estrogenic response to the compound. The cited passages do not provide page numbers. (LLM, conf=0.93)

  cites Weihua et al., 2001 source

In the paper

“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).”

What the sources say

• ?Not matched

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

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

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

  cites Seale, Wood, Atkinson, Harbuz, & Lightman, 2004
• Supported

  The Abstract reports sex-dependent patterns in stress-induced activation of the ACTH-regulating medial parvocellular PVN neurons in rats. Restraint-induced activation markers declined with age in males but not females; the Discussion likewise describes this puberty-related shift as unique to males. (LLM, conf=0.94)

  cites Viau, Bingham, Davis, Lee, & Wong, 2005 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Arnold, 2004 source
• Partly 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)

  cites Arnold et al., 2016 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Burgoyne et al., 1995 source

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“such interactions may exacerbate peripheral pathologies.”

In the paper

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

In the paper

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

In the paper

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

In the paper

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

In the paper

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

What the sources say

• ?Not matched

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

  cites Uht, McKelvy, Harrison, & Bohn, 1988

In the paper

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

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Williams, Carter, & Lightman, 1985 source

In the paper

“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.”

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Cortright, Nicoletti, & Seasholtz, 1995 source
• ?Not checked — no full text of the sourcecites Seasholtz, Burrows, Karolyi, & Camper, 2001 source

In the paper

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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Tannenbaum et al., 1997 source

In the paper

“gonadal steroids impact HPA axis reactivity differentially.”

In the paper

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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Bradbury et al., 1991 source

In the paper

“women reportedly have larger PVN AVP neurons than men”

What the sources say

• ?Not checked — no full text of the sourcecites Ishunina & Swaab, 1999 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Le Mevel, Abitbol, Beraud, & Maniey, 1979 source

In the paper

“This interaction regulates bioavailability during high CORT secretion”

What the sources say

• ?Not checked — no full text of the sourcecites Meyer, Nenke, Rankin, Lewis, & Torpy, 2016 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Reul & de Kloet, 1985 source

In the paper

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

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites de Kloet, Joels, & Holsboer, 2005 source

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Keller-Wood & Dallman, 1984 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Ochedalski, Subburaju, Wynn, & Aguilera, 2007 source

In the paper

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

In the paper

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

What the sources say

• ?Not matched

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

  cites Handa et al., 1994
• ?Not checked — no full text of the sourcecites Young, 1996

In the paper

“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.”

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Herman, 1995 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Mantella, Vollmer, Rinaman, Li, & Amico, 2004 source
• ?Not checked — no full text of the sourcecites Nomura et al., 2003 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hrabovszky et al., 2004 source
• ?Not matched

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

  cites Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998
• ?Not checked — no full text of the sourcecites Suzuki & Handa, 2004 source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Huang, Zhu, Fischer, & Zhou, 2008 source

In the paper

“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)”

What the sources say

• ?Not checked — no full text of the sourcecites Mantella, Vollmer, Rinaman, Li, & Amico, 2004 source
• ?Not checked — no full text of the sourcecites Nomura et al., 2003 source

In the paper

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

What the sources say

• ?Not matched

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

  cites Kovacs & Makara, 1988

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites Evuarherhe et al., 2009 source

In the paper

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

In the paper

“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).”

What the sources say

• ?Not matched

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

  cites Laflamme, Nappi, Drolet, Labrie, & Rivest, 1998

In the paper

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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Handa, Corbier, Shryne, Schoonmaker, & Gorski, 1985 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Zhou, Blaustein, & De Vries, 1994 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Ochedalski, Subburaju, Wynn, & Aguilera, 2007 source
• ?Not matched

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

  cites Windle et al., 2006, 2004

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Stocco, 2001 source

In the paper

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

In the paper

“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.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Handa, Corbier, Shryne, Schoonmaker, & Gorski, 1985 source

In the paper

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

What the sources say

• ?Not checked — no full text of the sourcecites Herbison, 2016 source

In the paper

“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.”

What the sources say

• ?Not matched

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

  cites Doshi & Agarwal, 2013

In the paper

“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.”