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Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone.

ABSTRACT: Sex hormones appear to play a role in the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. The objective was to isolate the effects of estradiol (E2) on central activation of the HPA axis. We hypothesized that the HPA axis response to corticotropin-releasing hormone (CRH) under dexamethasone (Dex) suppression would be exaggerated in response to chronic ovarian hormone suppression and that physiologic E2 add-back would mitigate this response. Thirty premenopausal women underwent 20 wk of gonadotropin-releasing hormone agonist therapy (GnRHAG) and transdermal E2 (0.075 mg per day, GnRHAG?+ E2, n?= 15) or placebo (PL) patch (GnRHAG?+ PL, n?= 15). Women in the GnRHAG?+ PL and GnRHAG?+ E2 groups were of similar age (38?(SD 5) yr vs. 36?(SD 7) yr) and body mass index (27?(SD 6) kg/m2 vs. 27?(SD 6) kg/m2). Serum E2 changed differently between the groups ( P?= 0.01); it decreased in response to GnRHAG?+ PL (77.9?±?17.4 to 23.2?±?2.6 pg/ml; P?= 0.008) and did not change in response to GnRHAG?+ E2 (70.6?±?12.4 to 105?±?30.4 pg/ml; P?= 0.36). The incremental area under the curve (AUCINC) responses to CRH were different between the groups for total cortisol ( P?= 0.03) and cortisone ( P?= 0.04) but not serum adrenocorticotropic hormone (ACTH) ( P?= 0.28). When examining within-group changes, GnRHAG?+ PL did not alter the HPA axis response to Dex/CRH, but GnRHAG?+ E2 decreased the AUCINC for ACTH (AUCINC, 1,623?± 257 to 1,211?± 236 pg/ml·min, P?= 0.004), cortisone (1,795?±?367 to 1,090?±?281 ng/ml·min, P?= 0.009), and total cortisol (7,008?±?1,387 to 3,893?±?1,090 ng/ml·min, P?= 0.02). Suppression of ovarian hormones by GnRHAG therapy for 20 wk did not exaggerate the HPA axis response to CRH, but physiologic E2 add-back reduced HPA axis activity compared with preintervention levels.

SUBMITTER: Gavin KM

PROVIDER: S-EPMC6139491 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone.

Gavin Kathleen M KM Shea Karen L KL Gibbons Ellie E Wolfe Pamela P Schwartz Robert S RS Wierman Margaret E ME Kohrt Wendy M WM

American journal of physiology. Endocrinology and metabolism 20180406 2

Sex hormones appear to play a role in the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. The objective was to isolate the effects of estradiol (E<sub>2</sub>) on central activation of the HPA axis. We hypothesized that the HPA axis response to corticotropin-releasing hormone (CRH) under dexamethasone (Dex) suppression would be exaggerated in response to chronic ovarian hormone suppression and that physiologic E<sub>2</sub> add-back would mitigate this response. Thirty premenop ...[more]

PMID: 29631362

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Project description:CONTEXT:Both highly stress-reactive and novelty-seeking individuals are susceptible to alcohol use disorders. Variation in stress reactivity, exploration, and response to novelty have been attributed to differences in corticotropin-releasing hormone (CRH) system function. As such, CRH gene variation may influence risk for alcohol use and dependence. OBJECTIVE:To determine whether CRH variation influences relevant intermediate phenotypes, behavior, and alcohol consumption in rhesus macaques. DESIGN:We sequenced the rhesus macaque CRH locus (rhCRH) and performed cladistic clustering of haplotypes. In silico analysis, gel shift, and in vitro reporter assays were performed to identify functional variants. Cerebrospinal fluid (CSF) and blood samples were obtained, and levels of CRH and corticotropin (ACTH) were measured by radioimmunoassay. Behavioral data were collected from macaques during infancy. Among adolescent/adult animals, we recorded responses to an unfamiliar conspecific and measured levels of ethanol consumption. SETTING:National Institutes of Health Animal Center. PARTICIPANTS:Rhesus macaques. MAIN OUTCOME MEASURES:Animals were genotyped for a single-nucleotide polymorphism disrupting a glucocorticoid response element, rhCRH -2232 C>G, and the effects of this allele on CSF levels of CRH, plasma levels of ACTH, behavior, and ethanol consumption were assessed by analysis of variance. RESULTS:We show that -2232C>G alters DNA x protein interactions and confers decreased sensitivity of the CRH promoter to glucocorticoids in vitro. Consistent with the known effects of glucocorticoids on CRH expression in the brain, carriers of the G allele had lower CSF levels of CRH but higher levels of ACTH. Infants carrying the G allele were more exploratory and bold, and among adolescent and adult male macaques, the G allele was associated with exploratory/bold responding to an unfamiliar male. Adults with the C/G genotype also exhibited increased alcohol consumption in the social group, a model for high-risk alcohol-seeking behavior. CONCLUSION:Haplotypes that differ in terms of corticosteroid sensitivity have been identified in humans. Our data may suggest that functionally similar CRH variants could influence risk for externalizing disorders in human subjects.

Project description:BackgroundThe main objective of the present work was to compare the effects of the gonadotropin-releasing hormone agonist (GnRH-a) and GnRH antagonist (GnRH-ant) on the gene expression profiles of oocytes obtained from Iranian infertile couples undergoing in vitro fertilization (IVF).MethodsFifty infertile couples who underwent IVF between June 2012 and November 2013 at the Infertility Center of Tehran Women General Hospital, Tehran University of Medical Sciences, were included in this study. We included women that had undergone IVF treatment because of male factor, tubal factor, or unexplained infertility. The women randomly underwent controlled ovarian stimulation (COS) with either the GnRH-a (n = 26) or the GnRH-ant (n = 24). We obtained 50 germinal vesicle (GV) oocytes donated by women in each group. After the sampling, pool of 50 GV oocytes for each group was separately analyzed by quantitative polymerase chain reaction (qPCR).ResultThe expression levels of Adenosine triphosphatase 6 (ATPase 6), Bone morphogenetic protein 15 (BMP15), and Neuronal apoptosis inhibitory protein (NAIP) genes were significantly upregulated in the GnRH-ant group compared to the GnRH-a group, with the fold change of 3.990 (SD ± 1.325), 6.274 (SD ± 1.542), and 2.156 (SD ± 1.443), respectively, (P < 0.001). Growth differentiation factor 9 (GDF9) mRNA did not have any expression in the GnRH-a group; however, GDF9 mRNA was expressed in the GnRH-ant group. Finally, it was found that the genes involved in the DNA repairing and cell cycle checkpoint did not have any expression in either group.ConclusionThe present study showed, for the first time, the expression levels of genes involved in the cytoplasmic maturity (BMP15, GDF9), adenosine triphosphate production (ATPase 6), and antiapoptotic process (NAIP), in human GV oocytes were significantly higher in the GnRH-anta group than in the GnRH-a group in COS. Higher expression level of these genes when GnRH-ant protocol is applied, this protocol seems to be a more appropriate choice for women with poly cystic ovarian syndrome, because it can probably improve the expression of the aforementioned genes.Trial registrationCurrent Controlled Trials: IRCT 2014031112307 N3.

Dataset Information

Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone.

Publications

Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone.

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