Dysregulation of granulosal bone morphogenetic protein receptor 1B density is associated with reduced ovarian reserve and the age-related decline in human fertility

Regan, Sheena L.P.; Knight, P. G.; Yovich, John L.; Stanger, James; Leung, Yee; Arfuso, Frank; Dharmarajan, Arun; Almahbobi, Ghanim

doi:10.1016/j.mce.2016.01.016

Cited by 26 publications

(28 citation statements)

References 55 publications

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“…LHR expression is suppressed by the LH surge. The LH surge downregulates GC LH receptor expression in preovulatory follicles in women [28,29]. The mid-cycle LH surge activates mural GC LH receptors which activates adenylate cyclase [30] and increases follicle cAMP levels (Fig.…”

Section: Lh Receptormentioning

confidence: 99%

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Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Arroyo

Kim²,

Yeh

2020

Reprod. Sci.

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The ovarian follicle luteinizing hormone (LH) signaling molecules that regulate oocyte meiotic maturation have recently been identified. The LH signal reduces preovulatory follicle cyclic nucleotide levels which releases oocytes from the first meiotic arrest. In the ovarian follicle, the LH signal reduces cyclic nucleotide levels via the CNP/NPR2 system, the EGF/EGF receptor network, and follicle/oocyte gap junctions. In the oocyte, reduced cyclic nucleotide levels activate the maturation promoting factor (MPF). The activated MPF induces chromosome segregation and completion of the first and second meiotic divisions. The purpose of this paper is to present an overview of the current understanding of human LH signaling regulation of oocyte meiotic maturation by identifying and integrating the human studies on this topic. We found 89 human studies in the literature that identified 24 LH follicle/oocyte signaling proteins. These studies show that human oocyte meiotic maturation is regulated by the same proteins that regulate animal oocyte meiotic maturation. We also found that these LH signaling pathway molecules regulate human oocyte quality and subsequent embryo quality. Remarkably, in vitro maturation (IVM) prematuration culture (PMC) protocols that manipulate the LH signaling pathway improve human oocyte quality of cultured human oocytes. This knowledge has improved clinical human IVM efficiency which may become a routine alternative ART for some infertile patients.

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Section: Lh Receptormentioning

confidence: 99%

“…Higher oocyte quality was found in oocytes from follicles with high cumulus cell BMP2 expression levels [278]. Dysregulation of activin receptor-like kinase 6 (ALK6) in human GCs is correlated with decreased ovarian reserve [28]. A BMP15 single nucleotide polymorphism is associated with ovarian hyperstimulation [279].…”

Section: Bmp15mentioning

confidence: 99%

Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Arroyo

Kim²,

Yeh

2020

Reprod. Sci.

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“…In comparison with the type I receptors ALK1, ALK2 and ALK7, four type I receptors ALK3, ALK4, ALK5 and ALK6 are expressed at modest levels in the human pre-antral follicles (Kristensen et al ., 2014). A recent study showed that the dysregulation of ALK6 in human GCs is associated with reduced ovarian reserve and the age-related decline in fertility (Regan et al ., 2016). …”

Section: Intra-ovarian Bmps and Oocyte–somatic Cell Interactionsmentioning

confidence: 99%

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

Chang

Qiao

Leung

2016

Hum. Reprod. Update

226

207

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BACKGROUNDInitially identified for their capability to induce heterotopic bone formation, bone morphogenetic proteins (BMPs) are multifunctional growth factors that belong to the transforming growth factor β superfamily. Using cellular and molecular genetic approaches, recent studies have implicated intra-ovarian BMPs as potent regulators of ovarian follicular function. The bi-directional communication of oocytes and the surrounding somatic cells is mandatory for normal follicle development and oocyte maturation. This review summarizes the current knowledge on the physiological role and molecular determinants of these ovarian regulatory factors within the human germline-somatic regulatory loop.OBJECTIVE AND RATIONALEThe regulation of ovarian function remains poorly characterized in humans because, while the fundamental process of follicular development and oocyte maturation is highly similar across species, most information on the regulation of ovarian function is obtained from studies using rodent models. Thus, this review focuses on the studies that used human biological materials to gain knowledge about human ovarian biology and disorders and to develop strategies for preventing, diagnosing and treating these abnormalities.SEARCH METHODSRelevant English-language publications describing the roles of BMPs or growth differentiation factors (GDFs) in human ovarian biology and phenotypes were comprehensively searched using PubMed and the Google Scholar database. The publications included those published since the initial identification of BMPs in the mammalian ovary in 1999 through July 2016.OUTCOMESStudies using human biological materials have revealed the expression of BMPs, GDFs and their putative receptors as well as their molecular signaling in the fundamental cells (oocyte, cumulus/granulosa cells (GCs) and theca/stroma cells) of the ovarian follicles throughout follicle development. With the availability of recombinant human BMPs/GDFs and the development of immortalized human cell lines, functional studies have demonstrated the physiological role of intra-ovarian BMPs/GDFs in all aspects of ovarian functions, from follicle development to steroidogenesis, cell–cell communication, oocyte maturation, ovulation and luteal function. Furthermore, there is crosstalk between these potent ovarian regulators and the endocrine signaling system. Dysregulation or naturally occurring mutations within the BMP system may lead to several female reproductive diseases. The latest development of recombinant BMPs, synthetic BMP inhibitors, gene therapy and tools for BMP-ligand sequestration has made the BMP pathway a potential therapeutic target in certain human fertility disorders; however, further clinical trials are needed. Recent studies have indicated that GDF8 is an intra-ovarian factor that may play a novel role in regulating ovarian functions in the human ovary.WIDER IMPLICATIONSIntra-ovarian BMPs/GDFs are critical regulators of folliculogenesis and human ovarian functions. Any dysregulation or variations in these ligand...

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“…A total of 198 follicles were collected from 31 patients undergoing standard in vitro fertilisation treatment (Table 1). Patients were aged between 23 and 45 years, with a range of infertility factors, but limited to exclude unusual medical conditions, endocrine dysfunction, polycystic ovarian syndrome and endometriosis, and were comprised of male factor, low ovarian reserve, donor sperm or unexplained Ovulation was triggered with 10 000 IU HCG, and oocyte retrieval was 36 hours later by transvaginal oocyte aspiration (Regan et al, 2016). Body mass index (BMI) differences were not significant in this study.…”

Section: Methodsmentioning

confidence: 95%

The effect of ovarian reserve and receptor signalling on granulosa cell apoptosis during human follicle development

Regan

Knight

Yovich

et al. 2018

Molecular and Cellular Endocrinology

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The poor oocyte quality in older women has previously been linked to the depletion of the ovarian reserve of primordial follicles and an increase in granulosal apoptosis. Granulosa cells were collected from 198 follicles and individually analysed by flow cytometry. In the young IVF patients, the level of apoptosis was inversely proportional to the expression of bone morphogenetic protein (BMPR1B) and follicle stimulating hormone (FSH) receptors. Conversely, in the older patients this relationship became dysregulated. In the older patients, at the time of preovulatory maturation, the reduced apoptosis reflects the poor mitogenic growth turnover rate of healthy follicles rather than the death rate in an atretic follicle. Restoring an optimum receptor density and down-regulation of receptors may improve oocyte quality and the pregnancy rate in older women.

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Dysregulation of granulosal bone morphogenetic protein receptor 1B density is associated with reduced ovarian reserve and the age-related decline in human fertility

Cited by 26 publications

References 55 publications

Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Luteinizing Hormone Action in Human Oocyte Maturation and Quality: Signaling Pathways, Regulation, and Clinical Impact

Oocyte–somatic cell interactions in the human ovary—novel role of bone morphogenetic proteins and growth differentiation factors

The effect of ovarian reserve and receptor signalling on granulosa cell apoptosis during human follicle development

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