Suppressive effects of linzagolix, a novel non‐peptide antagonist of gonadotropin‐releasing hormone receptors, in experimental endometriosis model rats

Tezuka, Motohiro; Tsuchioka, Kumi; Kobayashi, Kaoru; Kuramochi, Yu; Kiguchi, Sumiyoshi

doi:10.1111/1440-1681.13778

Cited by 1 publication

(4 citation statements)

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“…Pharmacokinetic analysis in dogs showed that a dose of 5 mg/kg linzagolix effectively suppressed testosterone levels, with a trough serum linzagolix concentration of ~8 μg/mL, a free form concentration ~8 times higher than its IC 50 value for the dog GnRH receptor. This relationship between linzagolix concentration and IC 50 value was similar to that reported in our previous in vitro study 5 . In normal dogs, the current study found that circulating testosterone concentrations exhibited a circadian rhythm like that reported in humans 14,15 .…”

Section: Discussionsupporting

confidence: 91%

“…This relationship between linzagolix concentration and IC 50 value was similar to that reported in our previous in vitro study. 5 In normal dogs, the current study found that circulating testosterone concentrations exhibited a circadian rhythm like that reported in humans. 14,15 Therefore, the dog provided a suitable model animal to examine the clinically relevant effects of linzagolix on testosterone levels.…”

Section: Discussionsupporting

confidence: 76%

“…Furthermore, linzagolix dose‐dependently controlled the menstrual cycle in sexually mature female monkeys 4 . In addition, linzagolix suppressed oestradiol levels in rats and reduced ectopic endometrial lesions in an endometriosis rat model 5 . Based on the results of these non‐clinical studies, linzagolix (also known as Yselty) is in clinical development for the treatment of uterine fibroids and endometriosis 6,7 …”

Section: Introductionmentioning

confidence: 99%

“…4 In addition, linzagolix suppressed oestradiol levels in rats and reduced ectopic endometrial lesions in an endometriosis rat model. 5 Based on the results of these non-clinical studies, linzagolix (also known as Yselty) is in clinical development for the treatment of uterine fibroids and endometriosis. 6,7 Suppression of the HPG axis by GnRH analogues is also expected to be effective for the treatment of benign prostatic hyperplasia (BPH) and polycystic ovary syndrome (PCOS) because of the pathophysiological characteristics of these conditions as described follows.…”

mentioning

confidence: 99%

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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

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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.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 76%