Evaluation of ovarian and metabolic effects of GnRH modulators in two rat models of polycystic ovary syndrome

Patel, Roshni; Shah, Gaurang

doi:10.1002/mrd.23059

Cited by 8 publications

(8 citation statements)

References 75 publications

(106 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The gonadotropin produces its effects through binding to LHR [45]. Our results were in contrast to those of Patel at el., who observed the increased levels of LH and LHR in POS rats [46]. In our study, cold exposure caused irregular estrus cycle and ovarian abnormalities.…”

Section: Discussionsupporting

confidence: 61%

Impact of Cold Exposure on the Reproductive Function in Female Rats

Li²,

Lin

et al. 2018

BioMed Research International

View full text Add to dashboard Cite

Female reproductive system diseases caused by exposure to a cold environment are widely considered as important human health challenges. Although the projection of female reproduction in cold temperature has been studied, a holistic view on the probable effects of cold exposure on the functions of the female reproductive system has not been achieved. Our aim was to evaluate the effects of cold exposure to the functions of the ovary and uterus in female rats. For this purpose, female rats were randomly grouped as follows: (1) the cold group was exposed to -10°C, 4 h per day for 2 weeks, and (2) the normal temperature (23 ± 1°C) group was used as control. Alterations were observed in different parameters, including body weight gain, organ coefficients, estrus cycle, and pathology of the cold-exposed female rats. Similarly, the serum reproductive hormones and mRNA expression were evaluated. Cold exposure induced estrus cycle irregularity and some alterations in the morphology of the ovary. Cold exposure impairs the function of the ovary probably by changing the level of serum LH and increasing LHR expression. Cold exposure induced a significant reduction of uterine epithelium height. Cold exposure causes alterations in the morphology of the uterus probably because of the effect of progesterone, the increase in the PR level, and the decrease in the ER level.

show abstract

Section: Discussionsupporting

confidence: 61%

Impact of Cold Exposure on the Reproductive Function in Female Rats

Li²,

Lin

et al. 2018

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…Moreover, although testosterone, DHT and letrozole are commonly employed to induce PCOS-like characteristics in pubertal or adult female rodents, it is not well understood whether androgen excess during these time periods results in organizational or activational effects. Indeed, several recent studies have assumed that letrozole treatment of pubertal female rodents causes organizational effects [47][48][49][50]. Given that our study demonstrated that letrozole treatment exerted mostly activational effects during puberty, this finding implies that letrozole treatment needs to be present for the entire duration of the study to effectively model PCOS.…”

Section: Discussionsupporting

confidence: 58%

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

Arroyo

et al. 2019

PLoS ONE

View full text Add to dashboard Cite

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women that is comprised of two out of the following three features: hyperandrogenism, oligo-or amenorrhea, or polycystic ovaries. In addition to infertility, many women with PCOS have metabolic dysregulation that increases the risk of developing type 2 diabetes, hypertension, and non-alcoholic fatty liver disease. Changes in the gut microbiome are associated with PCOS and gut microbes may be involved in the pathology of this disorder. Since PCOS often manifests in the early reproductive years, puberty is considered to be a critical time period for the development of PCOS. Exposure to sex steroid hormones during development results in permanent, organizational effects, while activational effects are transient and require the continued presence of the hormone. Androgens exert organizational effects during prenatal or early post-natal development, but it is unclear whether androgen excess results in organizational or activational effects during puberty. We recently developed a letrozole-induced PCOS mouse model that recapitulates both reproductive and metabolic phenotypes of PCOS. In this study, we investigated whether letrozole treatment of pubertal female mice exerts organizational or activational effects on host physiology and the gut microbiome. Two months after letrozole removal, we observed recovery of reproductive and metabolic parameters, as well as diversity and composition of the gut microbiome, indicating that letrozole treatment of female mice during puberty resulted in predominantly activational effects. These results suggest that if exposure to excess androgens during puberty leads to the development of PCOS, reduction of androgen levels during this time may improve reproductive and metabolic phenotypes in women with PCOS. These results also imply that continuous letrozole exposure is required to model PCOS in pubertal female mice since letrozole exerts activational rather than organizational effects during puberty.

show abstract

“…We hypothesised that because letrozole caused an excessive testosterone-enhancing effect and severe endocrine dysfunction, the inhibition of GnRH signalling by linzagolix could not sufficiently suppress LH and testosterone levels, consistent with previous reports using this PCOS model. 19 In this study, treatment with linzagolix significantly decreased the number of ovarian cysts and increased the number of corpora lutea compared with control rats. An increased number of corpora lutea suggested the restoration of ovulation in the linzagolix-treated group.…”

Section: Discussionmentioning

confidence: 49%

“…17 The letrozole model shows a marked increase in hormone levels and is considered a difficult model to confirm the hormone suppressive effects of GnRH antagonists. 19 However, we previously demonstrated the sex hormone-suppressive effects of linzagolix in several different animal models, so our current study used a letrozole-induced PCOS model to focus on reproductive dysfunction, a major feature of PCOS, and evaluate the effects of linzagolix on ovarian function. Administration of linzagolix significantly decreased serum FSH levels and tended to lower LH levels (P = 0.11), but testosterone levels were not decreased.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, letrozole treatment results in a PCOS model with reproductive and metabolic features resembling the syndrome in humans 17 . The letrozole model shows a marked increase in hormone levels and is considered a difficult model to confirm the hormone suppressive effects of GnRH antagonists 19 . However, we previously demonstrated the sex hormone‐suppressive effects of linzagolix in several different animal models, so our current study used a letrozole‐induced PCOS model to focus on reproductive dysfunction, a major feature of PCOS, and evaluate the effects of linzagolix on ovarian function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Suppression of hypothalamic–pituitary–gonadal function by linzagolix in benign prostatic hyperplasia and polycystic ovary syndrome animal models

Tezuka,

Yonekubo‐Awaka,

Tamai

et al. 2023

Clin Exp Pharma Physio

View full text Add to dashboard Cite

The hypothalamic–pituitary–gonadal (HPG) axis is an important regulatory mechanism involved primarily in the development and regulation of the reproductive systems. The suppression of the HPG axis by gonadotropin‐releasing hormone (GnRH) analogues is expected to be effective for the treatment of sex hormone‐dependent diseases, such as endometriosis, uterine fibroid, prostate cancer, benign prostatic hyperplasia (BPH) and polycystic ovary syndrome (PCOS). Despite the established involvement of GnRH signalling in these disorders, the therapeutic efficacy of small molecular GnRH antagonists for BPH and PCOS has not been adequately evaluated in non‐clinical studies. Therefore, the purpose of the present study was to evaluate the potential of linzagolix, a small molecular GnRH antagonist, as a potential new treatment option for BPH and PCOS. Dogs and rats exhibiting normal prostates and dogs diagnosed with prostatic hyperplasia were used to evaluate the effects of linzagolix in BPH. The effects of linzagolix were also examined in a rat model of PCOS induced by repeated administration of letrozole, an aromatase inhibitor. Linzagolix reduced serum luteinizing hormone and testosterone levels in male rats and normal or BPH model dogs and suppressed prostate weight without testosterone depletion, suggesting the existence of an optimal therapeutic testosterone level for BPH treatment. In a PCOS rat model, linzagolix improved both insulin resistance and ovarian dysfunction. Treatment with linzagolix decreased follicle‐stimulating hormone levels, but did not alter serum luteinizing hormone and testosterone levels. These results indicate that linzagolix may provide a new treatment option for GnRH‐related disorders, such as BPH and PCOS.

show abstract

Evaluation of ovarian and metabolic effects of GnRH modulators in two rat models of polycystic ovary syndrome

Cited by 8 publications

References 75 publications

Impact of Cold Exposure on the Reproductive Function in Female Rats

Impact of Cold Exposure on the Reproductive Function in Female Rats

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

Suppression of hypothalamic–pituitary–gonadal function by linzagolix in benign prostatic hyperplasia and polycystic ovary syndrome animal models

Contact Info

Product

Resources

About