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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [33] source
• Disputed

  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.

  cites [60] sourceExperimental — accuracy not yet measured

In the paper

“Reduction of the seminiferous tubules diameter as well as reduced T production were also observed by Borges et al107,108.”

What the sources say

• Disputed

  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.

  cites [107] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [108] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [3] sourceExperimental — accuracy not yet measured

In the paper

“Lim et al. showed that the gene encoding LHβ, Lhb, is occupied by histone deacetylases (HDACs) in αT3-1 cells resulting in transcriptional silencing27.”

What the sources say

• Supported

  The Results report that ChIP detected multiple HDACs at the LHβ gene promoter in αT3-1 cells. They also report that untreated cells did not express LHβ, whereas HDAC inhibition or knockdown allowed its expression, supporting HDAC-mediated transcriptional repression. (LLM, conf=0.94)

  cites [27] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [3] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [5] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [9] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [10] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [11] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [12] source
• ?Not checked — no full text of the sourcecites [13] source

In the paper

“Kisspeptin neurons in the ARC are likely involved in promoting pulsatile GnRH and LH secretion and responding to sex steroid hormone negative feedback1,2.”

What the sources say

• ?Not checked — no full text of the sourcecites [1] source
• Partly supported

  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)

  cites [2] sourceExperimental — accuracy not yet measured

In the paper

“Both 5α-reductase and 3α-HSD are expressed in the cortex, hippocampus, and amygdala62, supporting ALLO’s potential ability to modulate behavior.”

What the sources say

• Supported

  The Introduction (page not specified) states that 5α-reductase and 3α-HSD are co-localized in the cortex, hippocampus, and basolateral amygdala. It also describes Allo’s action at GABA_A receptors and its potential role in regulating emotional behaviour. (LLM, conf=0.94)

  cites [62] source

In the paper

“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.”

What the sources say

• Supported

  The Abstract reports rapid membrane-initiated estradiol signaling through Gq-mER and ERα in NPY/AgRP neurons, and the Discussion identifies these neurons as part of the arcuate nucleus (ARC). The suggestion that the same mechanism may regulate RFRP-3 neurons is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.93)

  cites [54] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [53] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [39] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [33] source
• Partly supported

  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)

  cites [59] sourceExperimental — accuracy not yet measured

In the paper

“In females, ARC kisspeptin expression is suppressed through ERα-mediated, ERE-independent mechanisms or de-repressed through a hormone response element44,46.”

What the sources say

• Partly supported

  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)

  cites [44] sourceExperimental — accuracy not yet measured
• ?Not matched

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

  cites [46]

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [32] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [52] sourceExperimental — accuracy not yet measured

In the paper

“Both populations of kisspeptin neurons express ERα (with low ERβ expression) but respond differentially to E2 through ERE-dependent and ERE-independent mechanisms44,45.”

What the sources say

• Partly supported

  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)

  cites [44] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [45] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [42] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [43] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [40] sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, both neurons express the Gq-mER, which disinhibits GABA and μ-opioid tone in POMC neurons and augments GABAergic tone in NPY neurons54.”

What the sources say

• Supported

  The Abstract describes Gq-mER signaling in POMC neurons as attenuating GABAB and μ-opioid receptor coupling to GIRK channels, thereby reducing their inhibitory effects. The Discussion reports that the Gq-mER-selective ligand STX enhances GABAB signaling in NPY/AgRP neurons and describes the receptor’s reciprocal effects in the two cell types. The paper calls Gq-mER in NPY/AgRP neurons putative, so the claim is best read as describing functional signaling rather than direct identification of the receptor. (LLM, conf=0.88)

  cites [54] source

In the paper

“After ligand-dependent receptor activation, ER disassociates from molecular chaperones, dimerizes, and binds to coactivators or corepressors to initiate or suppress transcription34.”

What the sources say

• Partly supported

  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)

  cites [34] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [34] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results report that Cort reduced the percentage of AVPV/PeN Kiss1 neurons coexpressing cfos from 65% in vehicle controls to 14%. The same section reports fewer detectable Kiss1 cells in Cort-treated females than in controls. (LLM, conf=0.95)

  cites [84] source

In the paper

“All cholesterol-treated females showed a clear LH surge, whereas LH levels were undetectable in CORT-treated females84.”

What the sources say

• Supported

  The Materials and Methods (LH surge induction) describe ovariectomized mice given an estradiol implant and either a corticosterone or cholesterol pellet. The Results report robust evening LH surges in all vehicle controls, but no surge and undetectable evening LH values in the corticosterone-treated females. (LLM, conf=0.95)

  cites [84] source

In the paper

“Anxiety and mood disorders are associated with HPA axis dysregulation and show large gender disparities, with women being more likely to experience these disorders86.”

What the sources say

• Partly supported

  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)

  cites [86] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  Section 5.4 reports that testosterone implanted in the medial preoptic area or bed nucleus of the stria terminalis reduces the corticosterone (CORT) response to acute stress; it identifies these regions as providing input to the PVN or peri-PVN. The same section reports that DHT applied just above the PVN inhibits HPA-axis function. The supplied passages do not give page numbers. (LLM, conf=0.88)

  cites [86] source
• Supported

  The citation to this paper is attached to the DHT portion of the sentence. In the Results section, the paper reports that DHT pellets implanted directly above the PVN significantly reduced plasma corticosterone after restraint stress compared with vehicle controls. (LLM, conf=0.93)

  cites [88] source

In the paper

“Oxytocin has been shown to reduce HPA axis reactivity, and E2, via ERβ signaling, increases oxytocin mRNA levels (for review see 93).”

What the sources say

• Supported

  The “Oxytocin Regulation of Hypothalamic–Pituitary–Adrenal Axis” section (page unavailable) reports that central oxytocin administration inhibits stress-related HPA axis reactivity in rodents. The “Estrogen Receptor β and Oxytocin Interactions” section (page unavailable) reports that estradiol increases oxytocin mRNA in wild-type mice but not ERβ-knockout mice, supporting the ERβ-mediated part of the claim. (LLM, conf=0.93)

  cites [93] source

In the paper

“Signaling through these 2 receptors yield opposing effects on HPA axis reactivity, with ERα increasing and ERβ inhibiting HPA axis reactivity (vide infra).”

What the sources say

• Supported

  Section 5.3 reports that ERα agonist treatment increases the ACTH and corticosterone responses to stress, whereas ERβ agonist treatment decreases them. The review concludes that ERβ activation reduces the gain of the HPA-axis response to an acute stressor. (LLM, conf=0.93)

  cites [86] source

In the paper

“While E2 increases HPA axis reactivity, T has been found to reduce HPA axis reactivity86.”

What the sources say

• Supported

  Section 5.4 reports that testosterone replacement reverses heightened stress-induced HPA responses after gonadectomy in male rats and describes an inhibitory effect of androgen treatment on HPA reactivity. Section 5.2 also links higher estradiol levels with stronger stress responses in female rats. These passages support the contrast in the citing sentence, particularly the testosterone claim to which the citation is attached. (LLM, conf=0.93)

  cites [86] sourceExperimental — accuracy not yet measured

In the paper

“Stress increases brain and plasma P4 and ALLO concentrations”

What the sources say

• Partly supported

  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)

  cites [63] sourceExperimental — accuracy not yet measured

In the paper

“T binds to AR, which is expressed in hypothalamic reproductive areas, such as the ARC, VMN and POA nuclei86.”

What the sources say

• Supported

  Section 4.2, “Androgen receptor distribution in brain” (page not supplied), describes binding sites identified using radiolabeled testosterone and states that AR expression is highest in reproductive hypothalamic areas, including the arcuate nucleus, ventromedial nucleus and medial preoptic area. (LLM, conf=0.93)

  cites [86] source

In the paper

“Progesterone and ALLO have also been implicated in HPA axis modulation and in human psychopathology (for review see 63).”

What the sources say

• Supported

  The section “A Hypothesis for a Broad Role for Progesterone and Allopregnanolone in Stress Coping and Recovery” (page not provided) links P/ALLO stress responses to HPA-axis activity and depression. The “Stress-Responsive?” section also reports evidence suggesting ALLO down-regulates the HPA axis in humans. Together, these support the review-level claim that the hormones have been implicated in both areas. (LLM, conf=0.92)

  cites [63] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [92] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Results section on restraint-induced CORT and ACTH reports that EB reduced dexamethasone (DEX) suppression after stress. The peri-PVN Results section reports that local estradiol and the ERα agonist PPT impaired DEX suppression of CORT, whereas suppression remained significant with the ERβ agonist DPN. EB was administered systemically; the near-PVN treatment was estradiol or PPT. (LLM, conf=0.91)

  cites [90] source

In the paper

“suggesting that ERα may reduce inhibitory input into the PVN, thereby reducing negative feedback from the glucocorticoids90.”

What the sources say

• Supported

  The Discussion explicitly proposes that ERα might impair glucocorticoid negative feedback by reducing inhibitory GABAergic input into the PVN. The citing sentence preserves that proposed, rather than established, mechanism. (LLM, conf=0.95)

  cites [90] source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [106] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [107] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [108] sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [109] source

In the paper

“Piffer et al. observed changes in serum T concentrations, sperm production and sexual preference of adult males following intrauterine betamethasone exposure100.”

What the sources say

• Partly supported

  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)

  cites [100] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [106] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [107] sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [108] sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [98] source
• ?Not checked — no full text of the sourcecites [99] source
• Partly supported

  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)

  cites [100] sourceExperimental — accuracy not yet measured

In the paper

“Increased GnRH pulse frequency and amplitude favor LH secretion, while a slower frequency favors FSH secretion16,17.”

What the sources say

• ?Not checked — no full text of the sourcecites [16] source
• ?Not checked — no full text of the sourcecites [17] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [19] source
• ?Not checked — no full text of the sourcecites [20] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [28] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [29] source

In the paper

“Additionally, GnRH stimulation results in an increase in Egr-1 mRNA and protein, which is tightly linked to an increase in LHβ synthesis26.”

What the sources say

• ?Not checked — no full text of the sourcecites [26] source

In the paper

“The GnRHR is a member of the rhodopsin like family of seven transmembrane domain G protein coupled receptors (GPCR)18.”

What the sources say

• ?Not checked — no full text of the sourcecites [18] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [21] source

In the paper

“Interestingly, both RFRP-3 and kisspeptin neurons are influenced by stress hormone regulation, as will be discussed further below.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [38] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [55] source
• ?Not checked — no full text of the sourcecites [56] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [58] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [47] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [7] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [82] source
• ?Not checked — no full text of the sourcecites [83] source

In the paper

“Rfrp neuronal activation in female mice was significantly increased after 45 min of restraint stress but not following longer stress durations”

What the sources say

• ?Not checked — no full text of the sourcecites [85] source

In the paper

“perhaps as a compensatory response to replenish RFRP-3 stores that were reduced when these neurons were more active during initial stress exposure85.”

What the sources say

• ?Not checked — no full text of the sourcecites [85] source

In the paper

“One ICV administered dose of ALLO on the morning of proestrus has an inhibitory effect on both ovulation rate and sexual receptivity71,72.”

What the sources say

• ?Not checked — no full text of the sourcecites [71] source
• ?Not matched

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

  cites [72]

In the paper

“In females, stress can disrupt ovarian cyclicity as well as upstream gonadotropin synthesis and secretion75,76.”

What the sources say

• ?Not checked — no full text of the sourcecites [75] source
• ?Not checked — no full text of the sourcecites [76] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [85] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [73] source

In the paper

“Serotonin signalling disruption is associated with mood disorders thereby suggesting an association between ALLO and serotonergic signalling.”

In the paper

“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.”

In the paper

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

In the paper

“Pereira & Piffer observed an incomplete masculinization of the hypothalamus followed by damage of seminal vesicle contractility in adult rats exposed in utero to hydrocortisone99.”

What the sources say

• ?Not checked — no full text of the sourcecites [99] source

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [102] source
• ?Not checked — no full text of the sourcecites [103] source

In the paper

“Altogether, we can see that the HPG axis is an elegantly-regulated endocrine system that allows for successful reproduction and species propagation.”