Effects of recombinant human FSH (rhFSH), urinary purified FSH (uFSH), and hMG on small preantral follicles and tertiary follicles from normal adult and androgen-sterilized female mice

Liu, Xiaowei; Andoh, Kazumichi; Mizunuma, Hideki; Kamijo, Takanori; Kikuchi, Nobumasa; Yamada, Kiyohiko; Ibuki, Yoshito

doi:10.1016/s0015-0282(99)00494-x

Cited by 15 publications

(4 citation statements)

References 27 publications

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“…Currently, PCOS animal models are mainly divided into three types: genetic related (Houten & Visser, 2014), androgenic (Houten et al, 2012; Liu et al, 2000; Roland et al, 2010; Solano et al, 2011), and pharmacological‐induced models (Chaudhari et al, 2018; Coutinho & Kauffman, 2019; Kauffman et al, 2015). We are the first to develop a rat model of autoimmune PCOS using GnRHR ECL2 peptide immunization.…”

Section: Discussionmentioning

confidence: 99%

Autoimmune activation of the GnRH receptor induces insulin resistance independent of obesity in a female rat model

Zhang

Guo

et al. 2020

Physiol Rep

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Polycystic ovary syndrome (PCOS), a metabolic and reproductive disease, is frequently associated with type 2 diabetes. We have demonstrated activating autoantibodies (AAb) directed toward the second extracellular loop (ECL2) of the gonadotropin‐releasing hormone receptor (GnRHR) are present in a significant subgroup of PCOS patients. It is unclear whether GnRHR‐AAb can induce peripheral tissue insulin resistance (IR) in animal models. Sixteen rats were divided equally into a GnRHR ECL2 peptide‐immunized group (IMM group) and a control group (CON group). Sera GnRHR‐AAb titer, luteinizing hormone (LH), and testosterone (T) were higher in IMM rats compared with CON rats. No significant difference in fasting blood glucose was observed between the two groups. However, the plasma glucose level at other time points of the IMM group was higher than that of the CON group during an intraperitoneal glucose tolerance test (IPGTT) and an insulin tolerance test (ITT) ( p < 0.01). These data support the likelihood of the GnRHR‐AAb induction of glucose intolerance and IR. Compared with the CON group, the IMM group showed a significant increase in insulin‐stimulated phosphorylation of IRS‐1 (p‐IRS‐1 S636/639) and a decrease in insulin‐stimulated phosphorylation of Akt (p‐AKT S473). Expression of the glucose transport genes including GLUT‐2 in liver and GLUT‐4 in white adipose tissue and skeletal muscle was significantly decreased in IMM rats compared with the CON rats. Serum levels of proinflammatory cytokines (TNF‐α, IL‐1α, and IL‐18) were increased, while anti‐inflammatory cytokines (IL‐4 and IL‐10) were decreased in the IMM group. Taken together, elevated GnRHR‐AAb enhanced LH, hyperandrogenism, and inflammation. These changes are likely related to the observed peripheral tissue IR through the downregulation of the insulin‐stimulated IRS/PI3K/Akt/Glut signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Autoimmune activation of the GnRH receptor induces insulin resistance independent of obesity in a female rat model

Zhang

Guo

et al. 2020

Physiol Rep

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“…Urine-derived gonadotrophin preparations, which had been used widely for ovarian stimulation before the development of recombinant FSH, induced LH activity inevitably. Controversies have arisen with the discovery of the negative effect of this induced LH activity on the quality of oocytes in animal models (Liu et al, 2000). Concerns have arisen, however, that the widespread use of the protocol using recombinant FSH alone under the GnRH analogs in ovarian stimulation may excessively suppress the endogenous LH level in some patients, possibly affecting clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Clinical utility of newly developed highly purified human menopausal gonadotrophins: a randomized controlled trial

Koo

Kwon

Choi

et al. 2017

Reproductive BioMedicine Online

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She received her medical degree from Konyang University in Korea in 2007. Her main research interest is assisted reproduction technique outcomes. KEY MESSAGEThe newly developed HP-HMG, IVF-M HP, was not inferior to Menopur in number of retrieved oocytes when used for ovarian stimulation after GnRH antagonist protocol in women undergoing IVF. Additionally, IVF-M HP had a comparable clinical efficacy and safety profile to those of Menopur, without significant safety concerns.

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“…Many studies have shown that hyperandrogenaemia, IR, hyperinsulinaemia and inflammation are associated with the development of PCOS (Anagnostis et al., 2018; Rojas et al., 2014). Different animal models, including genetic (van Houten & Visser, 2014), androgenic (Liu et al., 2000; Roland et al., 2010; Solano et al., 2011; van Houten et al., 2012) and pharmacologically induced models (Chaudhari et al., 2018; Coutinho & Kauffman, 2019; Kauffman et al., 2015), have been used to investigate the underlying mechanisms of PCOS. In a recently developed autoimmune rat model, we demonstrated that induction of GnRHR‐AAb in the rat resulted in elevation of LH, testosterone (T) and circulating inflammatory cytokines, and peripheral IR through downregulation of the gene and protein levels of the IRS/PI3K/Akt/Glut insulin signalling pathway (Li et al., 2020).…”

Section: Introductionmentioning

confidence: 99%

Gonadotrophin‐releasing hormone receptor autoantibodies induce polycystic ovary syndrome‐like features in a rat model

Guo

Zhang

et al. 2021

Experimental Physiology

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Gonadotrophin-releasing hormone receptor-activating autoantibodies (GnRHR-AAb) are associated with polycystic ovary syndrome (PCOS). In the present study, we examined the impact of GnRHR-AAb on reproductive function in GnRHR-immunized female rats. All immunized rats produced high titres of GnRHR-AAb targeting a dominant epitope located in the central region of the second extracellular loop of the GnRHR. Increased pulsatile luteinizing hormone secretion and testosterone concentrations were found in immunized rats. These rats exhibited disrupted oestrous cycles, increased ovarian follicular atresia, and activation of insulin signalling in the pituitary and ovary, as indicated by increased mRNA expressions of insulin receptor substrate, phosphatidylinositol 3-kinase and glucose transporter 1. No significant changes in inflammatory cytokines were detected in the ovarian tissue. These features mimic those observed in humans with PCOS. Our findings support the concept that chronic stimulation of the GnRHR by GnRHR-AAb, with an associated increase in pituitary luteinizing hormone secretion and ovarian androgen overproduction, might represent a new aetiological mechanism for PCOS.

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Effects of recombinant human FSH (rhFSH), urinary purified FSH (uFSH), and hMG on small preantral follicles and tertiary follicles from normal adult and androgen-sterilized female mice

Cited by 15 publications

References 27 publications

Autoimmune activation of the GnRH receptor induces insulin resistance independent of obesity in a female rat model

Autoimmune activation of the GnRH receptor induces insulin resistance independent of obesity in a female rat model

Clinical utility of newly developed highly purified human menopausal gonadotrophins: a randomized controlled trial

Gonadotrophin‐releasing hormone receptor autoantibodies induce polycystic ovary syndrome‐like features in a rat model

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