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Cited by 298Hypothalamic control of reproductive hormonesStress Responses and CortisolReproductive Biology and Fertility

Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling

Open access
Acevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., Laconi, M.·2018·Journal of neuroendocrinology
DOI 10.1111/jne.12590PMC PMC6129417
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Abstract

Reproduction and fertility are regulated via hormones of the hypothalamic-pituitary-gonadal (HPG) axis. Control of this reproductive axis occurs at all levels, including the brain and pituitary, and allows for the promotion or inhibition of gonadal sex steroid secretion and function. In addition to guiding proper gonadal development and function, gonadal sex steroids also act in negative- and positive-feedback loops to regulate reproductive circuitry in the brain, including kisspeptin neurones, thereby modulating overall HPG axis status. Additional regulation is also provided by sex steroids made within the brain, including neuroprogestins. Furthermore, because reproduction and survival need to be coordinated and balanced, the HPG axis is able to modulate (and be modulated by) stress hormone signalling, including cortiscosterone, from the hypothalamic-pituitary-adrenal (HPA) axis. This review covers recent data related to the neural, hormonal and stress regulation of the HPG axis and emerging interactions between the HPG and HPA axes, focusing on actions at the level of the brain and pituitary.

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Crossref · 10.1111/jne.12590

Cites

112 of 112 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

126 of 224 cited sources checked · 52 supported · 3 flagged · accuracy not yet measured

  • Premisecitation

    A pathway of allopregnanolone action through membrane progesterone receptors mPR alpha and beta was discovered, allowing rapid responses.

    “Additionally in the last decade, a new pathway of ALLO action through membrane P4 receptors (mPR α and β) was discovered allowing for rapid responses65.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [65] source

      In “Is the LH Surge Stimulated by Progesterone or a Metabolite?” (page not specified), the paper says progesterone acted through mPRα and mPRβ, while allopregnanolone did not affect GnRH release in that study. It describes allopregnanolone as acting primarily at GABAA receptors, not as having a discovered pathway through those membrane progesterone receptors. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Kisspeptin made in the hypothalamus acts directly on GnRH cells via Kiss1R to drive the reproductive axis.

    “Subsequent studies from numerous species have now provided a wealth of information supporting the model that hypothalamic-derived kisspeptin directly activates GnRH neurons via kisspeptin receptor (Kiss1R) to stimulate the reproductive axis (reviewed in 1,2).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [1] source
    • cites [2] source
  • Premisecitation

    RFRP-3 neurons are located only in the rodent DMN.

    “RFRP-3 neurons are found exclusively in the dorsal-medial nucleus of the hypothalamus (DMN) of rodents7,8”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [7] source
    • cites [8] source

      The Introduction says that, in rodents, RFRP-3-producing neurons are localized exclusively within and immediately adjacent to the hypothalamic DMN. The claim omits the neurons immediately adjacent to the DMN, so its 'exclusively in' wording is too narrow. (LLM, conf=0.88)

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  • Premisecitation

    RFRP-3 strongly inhibits LH release in many mammals.

    “In contrast to kisspeptin, another neuropeptide, RFamide-related peptide-3 (RFRP-3), has potent inhibitory actions on LH secretion in many mammalian species6–8.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [6] source
    • cites [7] source
    • cites [8] source
  • Premisecitation

    The proximal 140 bp of the LHβ promoter contains tandem Egr-1 and SF-1 binding motifs.

    “The proximal 140bp consist of tandem copies of DNA binding motifs for the early growth response protein 1 (Egr-1) and steroidogenic factor 1 (SF-1) transcription factors22,23.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [22] source

      The Results (page unavailable) describe a proximal 142-bp LHβ promoter fragment with an SF-1 element at −120 and an Egr-1 motif at −45, supporting the approximate length and presence of both motifs. The paper does not describe these motifs as tandem copies; it also identifies a Ptx1 site in the fragment. (LLM, conf=0.86)

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    • cites [23] source

      The section “A Consensus SF-1 Binding Site Resides within the 5′ Flanking Regions” reports an SF-1 binding sequence in LHβ promoters, and its EMSA results establish SF-1 binding in the bovine promoter (page not provided). Our copy does not report Egr-1 motifs, tandem copies, or a proximal 140-bp region, so those parts of the attributed claim are unsupported. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • May combine two claims. 60
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Premisecitation

    NPY excites and inhibits GnRH neurons through Y1 and Y4 receptors, and AgRP via MC4 can also excite and inhibit GnRH neurons.

    “Furthermore, NPY can excite and inhibit GnRH neurons through the Y1 and Y4 receptors, respectively, and AgRP, an endogenous agonist to MC4 receptors, can also excite and inhibit GnRH neurons33,60.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [33] source
    • cites [60] source

      The Results and Discussion (page unavailable) report that NPY inhibits GnRH-1 neuronal activity through Y1 receptors—the opposite of the claim that Y1 mediates excitation. The paper discusses context-dependent stimulation of GnRH-1 secretion, but the passages do not link it to Y1; they also do not substantiate the Y4 or AgRP/MC4 assertions. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

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    Premisecitation

    Reduction of seminiferous tubule diameter and reduced T production were also observed after betamethasone exposure.

    “Reduction of the seminiferous tubules diameter as well as reduced T production were also observed by Borges et al107,108.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [107] source

      In §3.1 (page unavailable), the paper reports no difference in testicular morphometric measures between control and betamethasone-treated rats, contrary to the claimed reduction in seminiferous tubule diameter. In §4 (page unavailable), it says testosterone levels were unaltered, although Leydig-cell volume and a measure of Leydig-cell function decreased; it does not report reduced testosterone production as an observed result. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

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    • cites [108] source

      The Results report reduced seminiferous tubule diameter at both ages and lower serum testosterone at PND45 after prenatal betamethasone exposure. They report no testosterone difference at PND110. The paper measured circulating testosterone, not testosterone production directly, so the claim omits an important age qualifier and overstates what was measured. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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    Premisecitation

    GnRH cells lack ERα and AR, so other steroid-sensitive circuits upstream relay feedback to them.

    “Importantly, GnRH neurons do not express estrogen receptor α (ERα) or the androgen receptor (AR), the receptors that mediate sex steroid feedback, indicating that other sex steroid-sensitive circuits “upstream” of GnRH neurons receive and relay sex steroid feedback signals to GnRH cells3.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] source

      The ‘Mechanism of estrogen positive feedback to GnRH neurons’ section states that GnRH neurons lack ERα and that ERα-expressing neurons mediate indirect estrogen feedback. It does not address whether GnRH neurons lack androgen receptors or whether upstream circuits relay androgen feedback. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In αT3-1 cells, HDACs occupy Lhb and silence transcription.

    “Lim et al. showed that the gene encoding LHβ, Lhb, is occupied by histone deacetylases (HDACs) in αT3-1 cells resulting in transcriptional silencing27.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Evidence supports the AVPV/PeN kisspeptin role in the LH surge: Kiss1 expression is higher in females, these neurons have ERα and activate during the surge, and Kiss1 or Kiss1R knockout mice lack the surge even with E2.

    “Supporting this hypothesis, AVPV/PeN Kiss1 gene expression is greater in females than males (males do not show an LH surge), Kiss1 neurons in the AVPV/PeN express ERα and show increased neuronal activation exclusively during the LH surge, and Kiss1 knockout (KO) mice and Kiss1R KO mice do not exhibit an LH surge even with exogenous E2 treatment3,5.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [3] source

      The “Neurochemical phenotypes of RP3V neurons” section describes a female-dominant distribution of AVPV/PVpo kisspeptin neurons, ERα expression, and c-Fos activation at the time of estrogen positive feedback. It also reports evidence that kisspeptin is required for the GnRH surge, but does not report that Kiss1 or Kiss1R knockout mice lack an LH surge despite exogenous E2 treatment. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [5] source

      In “The kisspeptin system: function and neuroanatomy” (page unavailable), the paper reports higher AVPV/PeN Kiss1 expression in females, ERα expression and surge-time activation in these neurons, and absent LH surges in Kiss1- and Kiss1R-null mice after E2 treatment. But it also reports a conflicting study in which E2-treated Kiss1R-null mice displayed small LH surges, so the categorical knockout claim omits an important qualification. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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    Premisecitation

    RFRP-3 neurons may affect puberty onset, seasonal cyclicity, and suppression of GnRH-induced gonadotropin release.

    “may be involved in influencing the onset of puberty, the onset of cyclicity in seasonally reproductive mammals, and the suppression of GnRH-induced release of gonadotropins9,10.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] source

      The Discussion (pp. 8–9) proposes that RFRP helps control seasonal breeding in ewes, and p. 2 reports that RFRP-3 inhibits gonadotropin secretion. The passages do not address puberty onset or establish suppression specifically of GnRH-induced gonadotropin release; searches for those terms found no such result. (LLM, conf=0.87)

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    • cites [10] source

  • May combine two claims.

    Premisecitation

    RFRP-3 inhibits firing of some GnRH and ARC kisspeptin neurons, suggesting it may inhibit reproduction partly by signaling to these populations.

    “RFRP-3 has been functionally shown to inhibit the electrical firing of some GnRH and ARC kisspeptin neurons11–13 suggesting that RFRP-3 may inhibit the reproductive axis, in part, by signaling to kisspeptin and/or GnRH populations.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [11] source

      The Introduction reports that GnIH hyperpolarizes GnRH neurons, and the Results identify RFRP-3 as its mammalian analog. The Results show RFRP-3 reducing firing in arcuate POMC neurons, not ARC kisspeptin neurons; the paper does not report RFRP-3 inhibiting kisspeptin-neuron firing or signaling to that population. Page numbers were not available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [12] source
    • cites [13] source

  • May combine two claims.

    Premisecitation

    ARC kisspeptin neurons likely promote pulsatile GnRH and LH release and respond to negative steroid feedback.

    “Kisspeptin neurons in the ARC are likely involved in promoting pulsatile GnRH and LH secretion and responding to sex steroid hormone negative feedback1,2.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [1] source
    • cites [2] source

      Section 2.3 says ARC Kiss1 neurons likely mediate sex-steroid negative feedback and links their activity to GnRH and LH secretion. But Section 4.3 says that although kisspeptin pulses coincide with GnRH pulses, their anatomical source was not determined; the paper does not establish that ARC neurons promote pulsatile GnRH and LH release. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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    Premisecitation

    5α-reductase and 3α-HSD are expressed in cortex, hippocampus, and amygdala, supporting ALLO's potential to modulate behavior.

    “Both 5α-reductase and 3α-HSD are expressed in the cortex, hippocampus, and amygdala62, supporting ALLO’s potential ability to modulate behavior.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationreasoning

    Low ERα/ERβ in RFRP-3 neurons suggests membrane-initiated estrogen signaling may regulate them, as shown in ARC NPY neurons.

    “The low expression of ERα and ERβ in RFRP-3 neurons suggests that membrane-initiated estrogen signaling may be key to the regulation of these neurons, as has recently been characterized in ARC NPY neurons54.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    E2 lowers RFRP-3 expression in mouse DMN, though only about 20% of RFRP-3 neurons have detectable ERα and none have ERβ.

    “E2 reduces RFRP-3 expression in the DMN of mice, although only ~20% of RFRP-3 neurons express detectable levels of ERα protein and no detectable ERβ53.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] source

      Figure 1 (p. 4) shows that E2 reduced prepro-RFRP mRNA in the mouse dorsomedial nucleus. The receptor results (pp. 4–5) found detectable ERα in 18.7 ± 3.8% of RFRP neurons and no detectable ERβ. The paper measured precursor mRNA and identified neurons using RFRP-1 immunoreactivity; it did not specifically measure RFRP-3 expression or establish those receptor percentages for RFRP-3-identified neurons. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    E2 modulates GABAergic tone in POA; deleting ERα in hypothalamic GABA neurons makes female mice infertile due to failure of the LH surge and ovulation.

    “E2 also modulates GABAergic tone of GABA neurons in the POA, and specific deletion of ERα in hypothalamic GABA neurons produces infertile female mice due to a failure to generate an LH surge and ovulation39.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [39] source

      The Abstract and the results on Esr1 deletion report infertility and an absent estrogen-induced LH surge in female mice lacking ESR1 in GABAergic neurons. The Introduction links the preovulatory surge to ovulation, and the GABAergic-function discussion describes estradiol-modulated GABA transmission near GnRH neurons. However, the deletion targeted GABAergic neurons broadly, not specifically hypothalamic GABA neurons, and ovulation failure was not directly measured. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    α-MSH via MC4 increases GnRH firing, while β-endorphin via μ-opioid receptors inhibits GnRH excitability.

    “α-MSH activation of the melanocortin 4 (MC4) receptor increases GnRH action potential firing while β-endorphin signaling through μ-opioid receptors inhibit GnRH excitability33,59.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [33] source
    • cites [59] source

      In “Activation of melanocortin receptors increases GnRH neuron activity” (page not specified), the paper reports increased GnRH firing after treatment with MTII, an MC3/4 receptor agonist; it also reports MC4R expression in GnRH neurons. It does not establish that α-MSH acting specifically through MC4R caused the firing increase, and the passages found do not address β-endorphin inhibition through μ-opioid receptors (searched: endorphin, opioid). (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In females, ARC kisspeptin expression is suppressed by ERα-mediated ERE-independent mechanisms or de-repressed via a hormone response element.

    “In females, ARC kisspeptin expression is suppressed through ERα-mediated, ERE-independent mechanisms or de-repressed through a hormone response element44,46.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [44] source

      The Results and Discussion (page not provided) show that estradiol suppresses ARC Kiss1 expression in female mice through an ERα-mediated, ERE-independent mechanism. The Discussion notes that the mouse model may permit signaling through other hormone response elements, but it does not show that ARC kisspeptin expression is de-repressed through one. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [46]

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

  • May combine two claims.

    Premisecitation

    Rising E2 before the GnRH/LH surge activates SCN neurons to speed downstream kisspeptin release and reduce RFRP-3 inhibition of GnRH.

    “Elevated E2 levels preceding the surge of GnRH and LH activate SCN neurons to accelerate the downstream release of kisspeptin and simultaneously decrease the inhibition of GnRH secretion provided by RFRP-332,52.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [32] source

      The Discussion (page not supplied) proposes that the SCN stimulates the kisspeptin system while suppressing RFRP-3-mediated negative feedback at the LH surge. It does not say that rising estradiol activates SCN neurons or that kisspeptin release accelerates; it describes estrogen-responsive cells as integrating estrogenic and SCN-derived cues. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [52] source

      The Discussion (page unavailable) proposes that E2 permits SCN signals to activate Kiss1 neurons, which may then signal to GnRH neurons. It does not establish that rising E2 activates SCN neurons or accelerates kisspeptin release, and the passages do not address reduced RFRP-3 inhibition. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Both kisspeptin populations have ERα and low ERβ but respond differently to E2 via ERE-dependent and ERE-independent mechanisms.

    “Both populations of kisspeptin neurons express ERα (with low ERβ expression) but respond differentially to E2 through ERE-dependent and ERE-independent mechanisms44,45.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [44] source

      The Discussion identifies kisspeptin populations in the AVPV and ARC, and reports E2 regulation of ARC Kiss1 through an ERE-independent mechanism. It also says ERα is more highly expressed than ERβ in the ARC. The paper does not establish ERα and low ERβ expression in both kisspeptin populations or compare their E2 responses through these mechanisms; its study focuses on the ARC. Page numbers are unavailable in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [45] source

      The Abstract and Discussion report that E2 induces Kiss1 in the AVPV through an ERE-dependent ERα pathway but inhibits Kiss1 in the arcuate nucleus through an ERE-independent pathway. The Introduction says regulation in both regions requires ERα. The passages do not establish the claim that both populations have low ERβ expression (page numbers are unavailable in our copy). (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    GPER activation by STX in mouse GnRH neurons controls cation channels for burst firing and hyperpolarization, showing E2 uses multiple pathways/receptors to control GnRH excitability, gene expression, and peptide release.

    “Furthermore, activation of GPER by its selective ligand STX in mouse GnRH neurons controlled the expression and activity of cation channels involved in burst firing and membrane hyperpolarization42,43, indicating the E2 has multiple pathways and receptors to control GnRH neuronal excitability, gene expression, and peptide release.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [42] source

      The Results section reports that STX increased Cav3.3 mRNA expression in mouse GnRH neurons, and the Discussion identifies STX as an agonist of a membrane estrogen receptor. The paper does not identify that receptor as GPER or show that STX changed channel activity or channels involved in membrane hyperpolarization. It links E2—not STX—to increased T-type current and excitability, and proposes a possible role in GnRH release. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [43] source

      The Abstract and ‘Estrogen upregulates K ATP channel function in GnRH neurons’ report that E2 enhances K ATP channel activity and hyperpolarization, affecting GnRH neuronal excitability and peptide release. But the paper does not establish activation by STX or GPER; it says the receptor mechanism is uncertain. It also reports that E2 did not increase Kir6.2 or SUR1 transcript expression. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Membrane ERβ signaling activates PLC and retrograde endocannabinoid signaling, reducing presynaptic GABA release and spontaneous postsynaptic currents.

    “Indeed, membrane-initiated signaling via ERβ activates a PLC-mediated signaling cascade leading to retrograde endocannabinoid signaling to reduce the frequency of presynaptic GABA release and spontaneous postsynaptic currents40.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] source

      The Results and Figure 9 caption report that estradiol acting through ERβ engages retrograde 2-AG signaling, suppressing presynaptic GABA release and reducing postsynaptic-current frequency in GnRH neurons of metestrous mice. The Discussion describes membrane-associated signaling as a suggestion, while Figure 9 labels part of its proposed pathway putative; the paper does not establish that ERβ activates PLC. No page numbers are available in our copy. (LLM, conf=0.86)

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  • May combine two claims.

    Premisecitation

    Both POMC and NPY neurons express Gq-mER, which disinhibits GABA and μ-opioid tone in POMC neurons and increases GABAergic tone in NPY neurons.

    “Furthermore, both neurons express the Gq-mER, which disinhibits GABA and μ-opioid tone in POMC neurons and augments GABAergic tone in NPY neurons54.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    After ligand activation, ER leaves chaperones, dimerizes, and binds coactivators or corepressors to start or stop transcription.

    “After ligand-dependent receptor activation, ER disassociates from molecular chaperones, dimerizes, and binds to coactivators or corepressors to initiate or suppress transcription34.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] source

      The Introduction says that estradiol-bound intracellular ERs dimerize and recruit transcriptional machinery and cofactors to regulate gene expression. It does not say that ERs dissociate from molecular chaperones or specifically bind coactivators or corepressors to initiate or suppress transcription. No page number is available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    These hypothalamic circuits express various ERs and use nuclear and membrane-initiated estrogen signaling.

    “These hypothalamic circuits collectively express the range of ER and employ both nuclear-initiated estrogen signaling (through estrogen response element (ERE)-dependent and ERE-independent pathways) and membrane-initiated estrogen signaling (through palmitoylated nuclear ER (α/β) and E2-responsive GPCR)34.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] source

      The Introduction describes ERE-dependent and ERE-independent nuclear signaling, while Extranuclear ERα and ERβ Expression and Physiology of Membrane ERs describe membrane signaling in hypothalamic-related circuits. The Summary supports palmitoylated ERα/ERβ at membranes, but Novel ERs treats the E2-responsive GPCR candidates as uncertain rather than establishing that these circuits employ them. Page numbers are unavailable in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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    Premisecitation

    CORT suppressed the percentage of AVPV/PeN Kiss1 cells co-expressing cfos and reduced the number of AVPV/PeN Kiss1-expressing cells compared with controls.

    “Brain analyses revealed that CORT robustly suppressed the percentage of AVPV/PeN Kiss1 cells co-expressing cfos, as well as reduced the number of AVPV/PeN Kiss1-expressing cells, compared to expression in control brains84.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    In OVX female mice with an LH surge-inducing E2 implant, all cholesterol-treated controls showed a clear LH surge, whereas LH levels were undetectable in CORT-treated females.

    “All cholesterol-treated females showed a clear LH surge, whereas LH levels were undetectable in CORT-treated females84.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Anxiety and mood disorders are associated with HPA axis dysregulation and show large gender disparities, with women more likely to experience them.

    “Anxiety and mood disorders are associated with HPA axis dysregulation and show large gender disparities, with women being more likely to experience these disorders86.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [86] source

      The Introduction reports that many neuropsychiatric disorders involve HPA-axis dysregulation and sex differences in risk. It specifically says major depressive disorder is at least twice as common in women and is associated with altered HPA activity. The cited passages do not establish that women are also more likely to experience anxiety disorders. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    T treatment reduced CORT release in response to stressors when administered into brain areas that synapse onto the PVN, and DHT administered just above the PVN also reduced CORT release.

    “T treatment reduced CORT release in response to stressors when administered into brain areas that synapse onto the PVN86 as well as when DHT was administered just above the PVN88.”
    Quote in the paperSubstantial claim2 of 2 sources checked

  • May combine two claims.

    Premisecitation

    Oxytocin reduces HPA axis reactivity, and E2 via ERbeta signaling increases oxytocin mRNA levels.

    “Oxytocin has been shown to reduce HPA axis reactivity, and E2, via ERβ signaling, increases oxytocin mRNA levels (for review see 93).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Signaling through ERalpha and ERbeta yields opposing effects on HPA axis reactivity, with ERalpha increasing and ERbeta inhibiting it.

    “Signaling through these 2 receptors yield opposing effects on HPA axis reactivity, with ERα increasing and ERβ inhibiting HPA axis reactivity (vide infra).”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    While E2 increases HPA axis reactivity, T reduces HPA axis reactivity.

    “While E2 increases HPA axis reactivity, T has been found to reduce HPA axis reactivity86.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [86] source
      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Stress increases brain and plasma P4 and allopregnanolone concentrations.

    “Stress increases brain and plasma P4 and ALLO concentrations”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [63] source

      The “Neuroactive Steroids and Stress: Background and Research in Laboratory Animals” section (page not provided) states that brain and plasma progesterone (P4) and allopregnanolone (ALLO) rise during stress in rodents. The claim omits that species qualification. In the human-stress section (page not provided), the review describes mixed responses and does not establish increases in both brain and plasma concentrations during stress in humans. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    T binds to AR, which is expressed in hypothalamic reproductive areas such as the ARC, VMN and POA nuclei.

    “T binds to AR, which is expressed in hypothalamic reproductive areas, such as the ARC, VMN and POA nuclei86.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Progesterone and allopregnanolone have been implicated in HPA axis modulation and in human psychopathology.

    “Progesterone and ALLO have also been implicated in HPA axis modulation and in human psychopathology (for review see 63).”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Within the PVN, ERbeta is expressed in a large population of oxytocin neurons, approximately half of CRH neurons, and a small population of AVP neurons.

    “Within the PVN, ERβ is expressed in a large population of oxytocin neurons, in approximately half of CRH neurons, and a small population of AVP neurons92.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [92] source

      Results §§3.2–3.3 report ERβ in a large proportion of oxytocin neurons and relatively sparse ERβ–AVP colocalization in the mouse PVN. Results §3.6 finds ERβ in approximately half of CRH neurons in the middle PVN, but substantially fewer in the caudal and rostral PVN; the claim presents that regional figure as applying to the PVN generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In rats treated with EB or an ERalpha agonist near the PVN, GR-mediated suppression of CORT release following acute restraint stress was inhibited, and this inhibition was not seen with an ERbeta agonist.

    “When rats were treated with EB or an ERα agonist near the PVN, glucocorticoid receptor (GR)-mediated suppression of CORT release following acute restraint stress was inhibited, and this inhibition was not seen when animals were treated with an ERβ agonist.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Interpretationcitation

    ERalpha may reduce inhibitory input into the PVN, thereby reducing negative feedback from glucocorticoids.

    “suggesting that ERα may reduce inhibitory input into the PVN, thereby reducing negative feedback from the glucocorticoids90.”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    In utero betamethasone exposure acts mainly on the HPG axis, as the same pattern of hormonal alteration was observed in male and female pups and in the following two generations.

    “Indeed, in utero betamethasone exposure confirmed its effects acting mainly on the HPG axis, since the same pattern of hormonal alteration was observed in both, male and female pups, as well as in the following two generations106–109.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [106] source

      The Results (p. 3) report increased LH and decreased FSH in male rats exposed prenatally to betamethasone. The paper does not establish that betamethasone acts mainly on the HPG axis, nor does it report the same hormonal pattern in female offspring or the following two generations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [107] source

      The Results (section 3.1; page unavailable) report lower FSH and higher LH in second-generation male rats. The Discussion (section 4; page unavailable) says this resembles the pattern previously observed in prenatally exposed males, but only suggests an effect on the hypophyseal-pituitary-testicular axis. This paper does not report the same hormonal pattern in female pups or establish that betamethasone acts mainly on the HPG axis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [108] source

      The Discussion (page unavailable) reports altered testosterone and LH levels in male offspring after in utero betamethasone exposure. It does not establish that the drug acts mainly on the HPG axis; it also discusses possible testicular alterations. The paper does not report the same hormonal pattern in female pups or across the following two generations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [109] source

  • May combine two claims.

    Premisecitation

    Adult males exposed in utero to betamethasone showed changes in serum T concentrations, sperm production, and sexual preference.

    “Piffer et al. observed changes in serum T concentrations, sperm production and sexual preference of adult males following intrauterine betamethasone exposure100.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [100] source

      The Abstract reports lower adult testosterone levels and reduced female-partner preference in male rats exposed prenatally to betamethasone; Section 3.3 confirms the testosterone reduction in plasma. The paper reports changes in ejaculation and other sexual behaviors, but does not report a measure of sperm production, so that part of the claim is unsupported. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Fetal programming by betamethasone exposure was seen at birth as low pup weight, at puberty as reduced serum T levels and delayed puberty onset, and at adulthood as effects on gonadal morphology and function, sperm quality, and fertility.

    “Borges et al. reinforced these findings and also demonstrated that the impact of fetal programming promoted by betamethasone exposure was seen at birth, as low pup weight, at puberty, as reduced serum T levels and delayed puberty onset, and at adulthood, as direct effects on gonadal morphology and function, sperm quality and fertility106–108.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [106] source

      The Results (p. 3) report lower offspring weight at postnatal day 1 and adult changes in reproductive-organ weights and fertility. The Introduction (p. 1) also summarizes adult sperm-quality impairment. The passages do not establish reduced serum testosterone or delayed puberty onset at puberty; the reported hormonal results concern adult animals. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [107] source

      The Results (§3.1; page not provided) report lower birth weight, delayed puberty, reduced Leydig-cell volume and function, poorer sperm measures, and reduced fertility in F2 male rats whose fathers were exposed prenatally to betamethasone. But the same section explicitly says serum testosterone levels were unaltered, contrary to the claimed reduction. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [108] source

      The Results report lower offspring weight at PND1, delayed preputial separation and lower testosterone at PND45, as well as adult testicular abnormalities and reduced fertility. The Discussion links these findings to altered sperm quality, but describes reduced sperm quality as a possible explanation for the fertility result and refers to a previous study; this paper did not directly demonstrate a change in sperm quality. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    During GD 12 to GD 19, important fetal developmental changes occur, including gonadogenesis, establishment of the HPG axis, and morphogenesis of reproductive ducts and glands.

    “During this period of intrauterine growth, important changes in fetal development are occurring, such as the gonadogenesis, the establishment of the HPG axis and the morphogenesis of reproductive ducts and glands (epididymis, vas deferens, seminal vesicle and prostate)98–100.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [98] source
    • cites [99] source
    • cites [100] source

      The Introduction (page not specified) identifies gestational days 18–19 as a fetal testosterone-surge period important to sexual differentiation, and Methods §2.2 says treatment on days 18–19 coincided with brain sexual differentiation. Our copy does not say that gonadogenesis, establishment of the HPG axis, or morphogenesis of the listed reproductive ducts and glands occurs during GD 12–19. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Faster or larger GnRH pulses favor LH release, while slower pulses favor FSH release.

    “Increased GnRH pulse frequency and amplitude favor LH secretion, while a slower frequency favors FSH secretion16,17.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] source
    • cites [17] source

  • May combine two claims.

    Premisecitation

    GnRH binding activates Gαq/11 and phospholipases, producing IP3 and DAG.

    “Hormone binding the GnRHR activates Gαq/11 which initiates multiple phospholipase activities leading to formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol19,20.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] source
    • cites [20] source

  • May combine two claims.

    Premisecitation

    In αT3-1 cells, GnRH exports class IIa HDACs and increases gonadotropin gene acetylation; in LβT2 cells, GnRH increases p300 association with Lhb.

    “In this cell line, GnRH stimulated the export of class IIa HDACs resulting in increased acetylation of gonadotropin genes, while in LβT2 cells, another gonadotrope derived cell line, GnRH treatment enhanced the association of the histone acetyltransferase p300 with the Lhb gene28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] source

  • May combine two claims.

    Premisecitation

    β-subunit promoters have low H3K4me3; GnRH raises this mark, causing chromatin decondensation by menin and MLL1/2.

    “Chromatin organizing the β-subunit gene promoters also contains low levels of trimethylated histone H3 lysine 4 (H3K4me3). GnRH stimulation increases this modification resulting in chromatin decondensation by menin and the menin-mixed-lineage leukemia (MLL) 1/2 methyl transferase complex29.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

  • May combine two claims.

    Premisecitation

    GnRH raises Egr-1 mRNA and protein, which is linked to increased LHβ synthesis.

    “Additionally, GnRH stimulation results in an increase in Egr-1 mRNA and protein, which is tightly linked to an increase in LHβ synthesis26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    GnRHR is a rhodopsin-like seven-transmembrane GPCR.

    “The GnRHR is a member of the rhodopsin like family of seven transmembrane domain G protein coupled receptors (GPCR)18.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] source

  • May combine two claims.

    Premisecitation

    Receptor activation raises intracellular calcium via stores and L-type channels, activating PKC isoforms.

    “Receptor activation also increases intracellular calcium concentrations through release of intracellular stores and opening of voltage gated L-type calcium channels, which underlie activation of protein kinase C (PKC) isoforms21.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] source

  • May combine two claims.

    Interpretationnone given

    Both RFRP-3 and kisspeptin neurons are influenced by stress hormone regulation.

    “Interestingly, both RFRP-3 and kisspeptin neurons are influenced by stress hormone regulation, as will be discussed further below.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Kisspeptin and RFRP-3 have potent stimulatory or inhibitory actions on GnRH secretion in mammals, modulating reproductive status.

    “Within the past decade, the neuropeptides kisspeptin and RFRP-3 have been shown to have potent stimulatory or inhibitory actions on GnRH secretion in mammals, thereby modulating reproductive status.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ERα knockout mice are infertile and lack normal estrous cycles and the proestrus LH surge; ERβ knockout mice are subfertile with regular cycles.

    “ERα KO mice are infertile and do not have a normal estrous cycle or the proestrus surge of LH, while ERβ KO mice are subfertile with regular estrous cycles38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] source

  • May combine two claims.

    Premisecitation

    ICV CRH suppresses LH pulsatility and the LH surge, and E2 enhances this suppression, possibly via CRH innervation of the locus coeruleus.

    “CRH intracerebroventricular (ICV) administration suppresses both LH pulsatility and the LH surge, and this suppression is enhanced by E255, potentially through CRH innervation of the locus coeruleus56.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] source
    • cites [56] source

  • May combine two claims.

    Premisecitation

    CRH neurons are activated by membrane-initiated E2 signaling through Gq-mER, suppressing M-current and increasing excitatory postsynaptic current amplitude.

    “CRH neurons are also activated by membrane-initiated E2 signaling through the Gq-mER to suppress the M-current and augment excitatory postsynaptic current amplitude58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] source

  • May combine two claims.

    Premisecitation

    SCN neurons make AVP and project to AVPV/PeN kisspeptin and RFRP-3 neurons, or make VIP and project to GnRH and RFRP-3 neurons, controlling LH surge timing.

    “These SCN neurons synthesize either AVP and project to AVPV/PeN kisspeptin and RFRP-3 neurons or synthesize VIP and project to GnRH and RFRP-3 neurons, thereby controlling the timing of the LH surge47.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] source

  • May combine two claims.

    Premisecitation

    In hamsters, E2 reduces RFRP-3 neuronal activation, perhaps to promote the GnRH surge, and about 40% of female hamster RFRP-3 neurons express ERα.

    “In the hamster, E2 reduces RFRP-3 neuronal activation, perhaps to promote downstream GnRH surge secretion, with ~40% of RFRP-3 neurons in the female hamster expressing ERα7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] source

  • May combine two claims.

    Premisecitation

    Isolation-restraint stress can block the LH surge in rats, and in sheep and monkeys the LH surge can be delayed or blocked by stress.

    “Isolation-restraint stress can block the LH surge in rats, and in sheep and monkeys, the LH surge can be delayed or blocked by stress82,83.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [82] source
    • cites [83] source

  • May combine two claims.

    Premisecitation

    Rfrp neuronal activation in female mice significantly increased after 45 min restraint stress but not after longer stress durations.

    “Rfrp neuronal activation in female mice was significantly increased after 45 min of restraint stress but not following longer stress durations”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The elevation in Rfrp mRNA after 180 min restraint may be a compensatory response to replenish RFRP-3 stores reduced during initial stress exposure.

    “perhaps as a compensatory response to replenish RFRP-3 stores that were reduced when these neurons were more active during initial stress exposure85.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] source

  • May combine two claims.

    Premisecitation

    A single ICV dose of allopregnanolone on the morning of proestrus inhibits ovulation rate and sexual receptivity.

    “One ICV administered dose of ALLO on the morning of proestrus has an inhibitory effect on both ovulation rate and sexual receptivity71,72.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] source
    • cites [72]

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

  • May combine two claims.

    Premisecitation

    In females, stress can disrupt ovarian cyclicity and upstream gonadotropin synthesis and secretion.

    “In females, stress can disrupt ovarian cyclicity as well as upstream gonadotropin synthesis and secretion75,76.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [75] source
    • cites [76] source

  • May combine two claims.

    Premisecitation

    In OVX female mice, 90 min restraint stress significantly and rapidly decreased LH pulse frequency and interpulse intervals compared with controls, with no effect on LH pulse amplitude.

    “LH pulse frequency and interpulse intervals were significantly and rapidly decreased in stressed female mice compared to controls, with no effects on LH pulse amplitude85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] source

  • May combine two claims.

    Premisecitation

    Giuliani et al. observed increased GnRH release from hypothalamic slices after allopregnanolone treatment, which was absent when slices were also treated with an NMDA receptor antagonist.

    “Giuliani et al. observed increased GnRH release from hypothalamic slices following treatment with ALLO which was absent when slices were also treated with an NMDA receptor antagonist.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

  • May combine two claims.

    Interpretationreasoning

    Disruption of serotonin signalling is associated with mood disorders, suggesting an association between allopregnanolone and serotonergic signalling.

    “Serotonin signalling disruption is associated with mood disorders thereby suggesting an association between ALLO and serotonergic signalling.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because reproduction and survival are necessary for life, the HPG and HPA axes are interlinked.

    “As reproduction and survival are necessary for life, it follows that the two systems promoting these aspects, the HPG and HPA axes respectively, would be interlinked.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Many neural and hormonal components contribute to proper regulation of the HPG axis.

    “Many components, including neural and hormonal factors, contribute to the proper regulation of the HPG axis and provide many interesting avenues for future research.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adult rats exposed in utero to hydrocortisone showed incomplete hypothalamic masculinization followed by damage to seminal vesicle contractility.

    “Pereira & Piffer observed an incomplete masculinization of the hypothalamus followed by damage of seminal vesicle contractility in adult rats exposed in utero to hydrocortisone99.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

  • May combine two claims.

    Premisecitation

    Increased glucocorticoid concentration from antenatal therapy directly interferes with HPG axis control, leading to decreased GnRH release and consequently decreased FSH and LH.

    “The increase in glucocorticoid concentration with antenatal therapy directly interferes in the control of the HPG axis, leading to a decrease in GnRH release and, consequently, a decrease in FSH and LH102,103.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [102] source
    • cites [103] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The HPG axis is an elegantly regulated endocrine system that allows successful reproduction and species propagation.

    “Altogether, we can see that the HPG axis is an elegantly-regulated endocrine system that allows for successful reproduction and species propagation.”
    Quote in the paperNot a substantial claim
65 of 65

  • The paper relies on this without support.

    Many key mechanisms and factors controlling GnRH release, including its pulsatile and surge modes, remain poorly defined.

    “however, many of the key mechanisms and factors involved in the regulation of GnRH release, including modulation of GnRH pulsatile and surge modes of secretion, remain poorly-defined.”

  • The authors state this as an assumption.

    Inhibition of pulsatile LH release by psychosocial stress or exogenous CORT reflects inhibition of upstream GnRH pulsatile secretion.

    “which is assumed to reflect inhibition of upstream GnRH pulsatile secretion.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Most of the evidence on the dynamic interactions between the HPA and HPG axes comes from animal studies.

    “Most of the evidence on the dynamic interactions between the HPA and HPG axes comes from animal studies (Acevedo-Rodriguez et al., 2018; McCosh et al., 2019).”

    From Dynamic Hormone Control of Stress and Fertility (2020) · cites this paper as Acevedo-Rodriguez et al., 2018

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Pulse frequency and interpulse interval both reported to decrease

    Minor

    Over the same sampling period, fewer LH pulses would mean longer intervals between pulses, not shorter ones. The reported decreases in both measures conflict.

1 of 1

Cites

Flagged first, then by citations

1 of the 113 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Pelegrina LT, 2015, Pharmacological effect of one icv dose of allogregnanolone in the female rat: behavioral profile, Braz J Biol Sci, 2, 39

Cited by

Sorted by citations

Related

Authors
Acevedo‐Rodriguez, A., Kauffman, A. S., Cherrington, B. D., Borges, C. S., Roepke, T. A., & Laconi, M.
Affiliations
  • Department of Neuroscience Baylor College of Medicine Houston TX USA
  • University of California San Diego (US)
  • University of Wyoming (US)
  • Department of Morphology Institute of Biosciences São Paulo State University (Unesp) Botucatu Brazil
  • Rutgers, The State University of New Jersey (US)
  • University of Mendoza (AR)
ORCID
Venue
Journal of neuroendocrinology
Publisher
Wiley
Published
2018-08-07
Volume
30
Issue
10
Pages
e12590-e12590
ISSN
  • 0953-8194 (ISSN-L)
  • 1365-2826
DOI
10.1111/jne.12590
PMC
PMC6129417
OpenAlex
W2792526589
Semantic Scholar
ddaae3f6099839f5eb7b172e24dc865e4fd445d3
Cited by
298
References
113
Citations by year
2026: 63 · 2025: 60 · 2024: 48 · 2023: 32 · 2022: 28 · 2021: 29 · 2020: 25 · 2019: 8 · 2018: 5
FWCI
2.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • UNESP Institutional Repository (São Paulo State University) (submittedVersion)
Funders
  • National Institutes of Health (R21 ES027119, R01 HD090161, P50 HD012303)
  • National Science Foundation (IOS‐1457226)
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (2012/25350‐1, 2014/13660‐1)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (308842/2013‐8)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
hypothalamic-pituitary-gonadal axis, stress signaling, hypothalamic-pituitary-adrenal axis, kisspeptin neurons, sex steroid feedback, corticosterone, reproduction, fertility control, pituitary gland
MeSH terms
Animals, Estrogens, Female, Humans, Hypothalamic Hormones, Hypothalamo-Hypophyseal System, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Neuropeptides, Pituitary-Adrenal System, Reproduction, Stress, Psychological, Kisspeptins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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