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Growth hormone ameliorates the age-associated depletion of ovarian reserve and decline of oocyte quality via inhibiting the activation of Fos and Jun signaling.

ABSTRACT: Oocyte quality typically begins to decline with aging, which contributes to subfertility and infertility. However, there is still no effective treatment to restore the ovarian reserve and improve aged-oocyte quality. According to the present study, growth hormone (GH) secretion changes with maternal age in female mice. After intraperitoneal injection with GH (1 mg/kg body weight) every two days for two months, the 10-month-old mice showed a better ovarian reserve and oocyte quality than control mice. GH treatment decreased the occurrence rate of aneuploidy caused by spindle/chromosome defects. Additionally, the single oocyte transcriptome analysis indicated that GH decreased the expression of apoptosis-related genes in oocytes. It was also observed that GH treatment reduced the expression of γH2AX and apoptosis of aged oocytes via decreasing the activation of Fos and Jun. Collectively, our results indicate that GH treatment is an effective way to reverse the age-associated depletion of ovarian reserve and the decline of oocyte quality by decreasing apoptosis.

SUBMITTER: Liu C

PROVIDER: S-EPMC7993724 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Growth hormone ameliorates the age-associated depletion of ovarian reserve and decline of oocyte quality via inhibiting the activation of Fos and Jun signaling.

Liu Chuanming C Li Shiyuan S Li Yifan Y Tian Jiao J Sun Xiaoling X Song Tianran T Yan Guijun G Ding Lijun L Sun Haixiang H

Aging 20210217 5

Oocyte quality typically begins to decline with aging, which contributes to subfertility and infertility. However, there is still no effective treatment to restore the ovarian reserve and improve aged-oocyte quality. According to the present study, growth hormone (GH) secretion changes with maternal age in female mice. After intraperitoneal injection with GH (1 mg/kg body weight) every two days for two months, the 10-month-old mice showed a better ovarian reserve and oocyte quality than control ...[more]

PMID: 33621201

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Project description:BackgroundAn estimated 1 in 350 women carry germline BRCA1/2 mutations, which confer an increased risk of developing breast and ovarian cancer, and may also contribute to subfertility. All mature, sex steroid-producing ovarian follicles are drawn from the pool of non-renewable primordial follicles, termed the 'ovarian reserve'. The clinical implications of early ovarian reserve exhaustion extend beyond infertility, to include the long-term adverse health consequences of loss of endocrine function and premature menopause. We aimed to determine whether conditional loss of Brca1 in oocytes impacts ovarian follicle numbers, oocyte quality and fertility in mice with advancing maternal age. We also aimed to determine the utility of AMH as a marker of ovarian function, by assessing circulating AMH levels in mice and women with BRCA1/2 mutations, and correlating this with ovarian follicle counts.MethodsIn this study, we addressed a longstanding question in the field regarding the functional consequences of BRCA1 inactivation in oocytes. To recapitulate loss of BRCA1 protein function in oocytes, we generated mice with conditional gene deletion of Brca1 in oocytes using Gdf9-Cre recombinase (WT: Brca1fl/flGdf9+/+; cKO: Brca1fl/flGdf9cre/+).FindingsWhile the length of the fertile lifespan was not altered between groups after a comprehensive breeding trial, conditional loss of Brca1 in oocytes led to reduced litter size in female mice. Brca1 cKO animals had a reduced ovarian reserve and oocyte maturation was impaired with advanced maternal age at postnatal day (PN)300, compared to WT animals. Serum anti-Müllerian hormone (AMH) concentrations (the gold-standard indirect marker of the ovarian reserve used in clinical practice) were not predictive of reduced primordial follicle number in Brca1 cKO mice versus WT. Furthermore, we found no correlation between follicle number or density and serum AMH concentrations in matched samples from a small cohort of premenopausal women with BRCA1/2 mutations.InterpretationTogether, our data demonstrate that BRCA1 is a key regulator of oocyte number and quality in females and suggest that caution should be used in relying on AMH as a reliable marker of the ovarian reserve in this context.FundingThis work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the Australian Research Council (ALW - DE21010037 and KJH - FT190100265), as well as the National Breast Cancer Foundation (IIRS-22-092) awarded to ALW and KJH. LRA, YML, LT, EOKS and MG were supported by Australian Government Research Training Program Scholarships. LRA, YML and LT were also supported by a Monash Graduate Excellence Scholarship. YC, SG and XC were supported by Monash Biomedicine Discovery Institute PhD Scholarships. LRA was also supported by a Monash University ECPF24-6809920940 Fellowship. JMS was supported by NHMRC funding (2011299). MH was supported by an NHMRC Investigator Grant (1193838).

Dataset Information

Growth hormone ameliorates the age-associated depletion of ovarian reserve and decline of oocyte quality via inhibiting the activation of Fos and Jun signaling.

Publications

Growth hormone ameliorates the age-associated depletion of ovarian reserve and decline of oocyte quality via inhibiting the activation of Fos and Jun signaling.

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