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Alsaab HO, Almutairy B, Almobarki AO, Mughaedh MAA, Alzahrani MS. Exosome's role in ovarian disease pathogenesis and therapy; Focus on ovarian cancer and failure. J Reprod Immunol 2025; 167:104403. [PMID: 39662240 DOI: 10.1016/j.jri.2024.104403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 11/16/2024] [Accepted: 11/28/2024] [Indexed: 12/13/2024]
Abstract
In the eukaryotic system, exosomes are categorized as unique extracellular vesicles with dimensions ranging from 30 to 150 nm. These vesicles contain a variety of endogenous molecules, such as proteins, DNA, mRNA, microRNA, and circular RNA. They are essential for a wide range of metabolic events and have the potential to be used as therapeutic or diagnostic targets for a number of diseases, including ovarian diseases. By inducing changes in the surrounding environment, the donor exosomes transfer their contents to the receiving cells, so demonstrating the biological implications of major interactions between cells. Mesenchymal stem cells (MSCs) have produced exosomes have shown promise as a treatment for premature organ failure (POF or POI). Furthermore, exosomal transport has many complexities, and contributes to the pathophysiology of ovarian cancer by affecting cell growth, migration, metastastsis and etc. Owing to these facts, in this paper, we present the progress developed in the understanding of exosomes as a viable therapeutic avenue and indisputable prognostic targets in ovarian disorders.
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Affiliation(s)
- Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 21944, Saudi Arabia.
| | - Bandar Almutairy
- Department of Pharmacology, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia.
| | | | | | - Mohammad S Alzahrani
- Department of Clinical Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif , Saudi Arabia
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2
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Knight A, Sugin S, Jurisicova A. Searching for the 'X' factor: investigating the genetics of primary ovarian insufficiency. J Ovarian Res 2024; 17:238. [PMID: 39609914 PMCID: PMC11603650 DOI: 10.1186/s13048-024-01555-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 11/10/2024] [Indexed: 11/30/2024] Open
Abstract
Primary ovarian insufficiency (POI) is the cessation of ovarian function before the age of 40. The causes of POI are heterogeneous, but substantial evidence exists to support a genetic basis of POI, particularly in the critical involvement of genes on the X chromosome. Recent studies have revealed novel candidate genes through the identification of copy number variations associated with POI. This review summarizes the genes located on the X chromosome with variants shown to be associated with POI in humans and/or in mice. Additionally, we present evidence to support the potential involvement of these candidate genes in the etiology of POI. We conducted a literature search in PubMed to identify case studies and screenings for the genetic causes of POI. We then performed systematic searches for the proposed candidate genes to investigate their potential reproductive roles. Of the X-linked candidate genes investigated, 10 were found to have variants associated with cases of POI in humans. An additional 10 genes were found to play a supportive role in POI. Other genes were not implicated in any cases of POI but were associated with various roles in reproduction. In the majority of cases where variants were identified through whole-exome sequencing, rather than targeted screening of candidate genes, more than one genetic variant was identified. Overall, this review supports past findings that the X chromosome plays a critical role in ovarian function, as demonstrated by a link between POI and various disruptions to genes on the X chromosome. Current genetic screening for POI, which includes only FMR1, is inadequate to capture the majority of cases with a genetic origin. An expanded genetic testing may improve health outcomes for individuals with POI as it could lead to better early interventions and education about these health risks.
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Affiliation(s)
- Anya Knight
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Sara Sugin
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 25 Orde Street, Room 6-1016-1, Toronto, ON, M5T 3H7, Canada
| | - Andrea Jurisicova
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.
- Department of Obstetrics and Gynecology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 25 Orde Street, Room 6-1016-1, Toronto, ON, M5T 3H7, Canada.
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Federici S, Rossetti R, Moleri S, Munari EV, Frixou M, Bonomi M, Persani L. Primary ovarian insufficiency: update on clinical and genetic findings. Front Endocrinol (Lausanne) 2024; 15:1464803. [PMID: 39391877 PMCID: PMC11466302 DOI: 10.3389/fendo.2024.1464803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 09/02/2024] [Indexed: 10/12/2024] Open
Abstract
Primary ovarian insufficiency (POI) is a disorder of insufficient ovarian follicle function before the age of 40 years with an estimated prevalence of 3.7% worldwide. Its relevance is emerging due to the increasing number of women desiring conception late or beyond the third decade of their lives. POI clinical presentation is extremely heterogeneous with a possible exordium as primary amenorrhea due to ovarian dysgenesis or with a secondary amenorrhea due to different congenital or acquired abnormalities. POI significantly impacts non only on the fertility prospect of the affected women but also on their general, psychological, sexual quality of life, and, furthermore, on their long-term bone, cardiovascular, and cognitive health. In several cases the underlying cause of POI remains unknown and, thus, these forms are still classified as idiopathic. However, we now know the age of menopause is an inheritable trait and POI has a strong genetic background. This is confirmed by the existence of several candidate genes, experimental and natural models. The most common genetic contributors to POI are the X chromosome-linked defects. Moreover, the variable expressivity of POI defect suggests it can be considered as a multifactorial or oligogenic defect. Here, we present an updated review on clinical findings and on the principal X-linked and autosomal genes involved in syndromic and non-syndromic forms of POI. We also provide current information on the management of the premature hypoestrogenic state as well as on fertility preservation in subjects at risk of POI.
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Affiliation(s)
- Silvia Federici
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Raffaella Rossetti
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Silvia Moleri
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Elisabetta V. Munari
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Maria Frixou
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Marco Bonomi
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - Luca Persani
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
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Barata IS, Rueff J, Kranendonk M, Esteves F. Pleiotropy of Progesterone Receptor Membrane Component 1 in Modulation of Cytochrome P450 Activity. J Xenobiot 2024; 14:575-603. [PMID: 38804287 PMCID: PMC11130977 DOI: 10.3390/jox14020034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is one of few proteins that have been recently described as direct modulators of the activity of human cytochrome P450 enzymes (CYP)s. These enzymes form a superfamily of membrane-bound hemoproteins that metabolize a wide variety of physiological, dietary, environmental, and pharmacological compounds. Modulation of CYP activity impacts the detoxification of xenobiotics as well as endogenous pathways such as steroid and fatty acid metabolism, thus playing a central role in homeostasis. This review is focused on nine main topics that include the most relevant aspects of past and current PGRMC1 research, focusing on its role in CYP-mediated drug metabolism. Firstly, a general overview of the main aspects of xenobiotic metabolism is presented (I), followed by an overview of the role of the CYP enzymatic complex (IIa), a section on human disorders associated with defects in CYP enzyme complex activity (IIb), and a brief account of cytochrome b5 (cyt b5)'s effect on CYP activity (IIc). Subsequently, we present a background overview of the history of the molecular characterization of PGRMC1 (III), regarding its structure, expression, and intracellular location (IIIa), and its heme-binding capability and dimerization (IIIb). The next section reflects the different effects PGRMC1 may have on CYP activity (IV), presenting a description of studies on the direct effects on CYP activity (IVa), and a summary of pathways in which PGRMC1's involvement may indirectly affect CYP activity (IVb). The last section of the review is focused on the current challenges of research on the effect of PGRMC1 on CYP activity (V), presenting some future perspectives of research in the field (VI).
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Affiliation(s)
- Isabel S. Barata
- Department of Pediatrics, Division of Endocrinology, Diabetology and Metabolism, University Children’s Hospital, University of Bern, 3010 Bern, Switzerland;
- Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland
| | - José Rueff
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal;
| | - Michel Kranendonk
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal;
| | - Francisco Esteves
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa, Campo Mártires da Pátria 130, 1169-056 Lisboa, Portugal;
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Lodde V, Luciano AM, Garcia Barros R, Giovanardi G, Sivelli G, Franciosi F. Review: The putative role of Progesterone Receptor membrane Component 1 in bovine oocyte development and competence. Animal 2023; 17 Suppl 1:100783. [PMID: 37567656 DOI: 10.1016/j.animal.2023.100783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 03/14/2023] [Accepted: 03/17/2023] [Indexed: 08/13/2023] Open
Abstract
Acquisition of developmental competence is a complex process in which many cell types cooperate to support oocyte maturation, fertilisation, and preimplantation embryonic development. In recent years, compelling evidence has shown that Progesterone Receptor Membra Component 1 (PGRMC1) is expressed in many cell types of the mammalian reproductive system where it exerts diverse functions. In the ovary, PGRMC1 affects follicular growth by controlling cell viability and proliferation of granulosa cells. PGRMC1 has also a direct role in promoting a proper completion of bovine oocyte maturation, as altering its function leads to defective chromosome segregation and polar body extrusion. Strikingly, the mechanism by which PGRMC1 controls mitotic and meiotic cell division seems to be conserved, involving an association with the spindle apparatus and the chromosomal passenger complex through Aurora kinase B. Conclusive data on a possible role of PGRMC1 in the preimplantation embryo are lacking and further research is needed to test whether the mechanisms that are set in place in mitotic cells also govern blastomere cleavage and subsequent differentiation. Finally, PGRMC1 is also expressed in oviductal cells and, as such, it might also impact fertilisation and early embryonic development, although this issue is completely unexplored. However, the study of PGRMC1 function in the mammalian reproductive system remains a complex matter, due to its pleiotropic function.
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Affiliation(s)
- V Lodde
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, via dell'Università 6, 26900 Lodi, Italy.
| | - A M Luciano
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, via dell'Università 6, 26900 Lodi, Italy
| | - R Garcia Barros
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, via dell'Università 6, 26900 Lodi, Italy
| | - G Giovanardi
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, via dell'Università 6, 26900 Lodi, Italy
| | - G Sivelli
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, via dell'Università 6, 26900 Lodi, Italy
| | - F Franciosi
- Reproductive and Developmental Biology Laboratory, Department of Veterinary Medicine and Animal Sciences, Università degli Studi di Milano, via dell'Università 6, 26900 Lodi, Italy
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Besson MDR, Taiarol MDS, Fernandes EB, Ghiorzi IB, Nunes MR, Zen PRG, Rosa RFM. Chromosomal abnormalities detected by karyotyping among patients with secondary amenorrhea: a retrospective study. SAO PAULO MED J 2023; 141:e2022426. [PMID: 37042862 PMCID: PMC10085534 DOI: 10.1590/1516-3180.2022.0426.r1.14012023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 01/14/2023] [Indexed: 04/13/2023] Open
Abstract
BACKGROUND Chromosomal abnormalities (CAs) have been described in patients with secondary amenorrhea (SA). However, studies on this association are scarce. OBJECTIVES To evaluate the frequency and types of CAs detected by karyotyping in patients with SA. DESIGN AND SETTING This retrospective study was performed in a reference clinical genetic service in South Brazil. METHODS Data were obtained from the medical records of patients with SA who were evaluated between 1975 and 2022. Fisher's bicaudate exact test and Student's t-test were used, and P < 0.05 was considered significant. RESULTS Among 43 patients with SA, 14 (32.6%) had CAs, namely del (Xq) (n = 3), 45,X (n = 2), 46,X,r(X)/45,X (n = 2), 46,XX/45,X (n = 1), 46,X,i(q10)/45,X (n = 1), 47,XXX (n = 1), 46,XX/47,XXX (n = 1), 46,XX/47,XX,+mar (n = 1), 45,XX,trob(13;14)(q10;q10)/46,XXX,trob(13;14)(q10;q10) (n = 1), and 46,XX,t(2;21)(q23;q11.2) (n = 1). Additional findings were observed mostly among patients with CA compared with those without CA (P = 0.0021). No difference in the mean age was observed between the patients with SA with or without CAs (P = 0.268025). CONCLUSIONS CAs are common among patients with SA, especially those with short stature and additional findings. They are predominantly structural, involve the X chromosome in a mosaic, and are compatible with the Turner syndrome. Patients with SA, even if isolated, may have CAs, particularly del (Xq) and triple X.
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Affiliation(s)
- Marina da Rocha Besson
- BSc. Master´s Student, Postgraduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
| | - Mateus Dos Santos Taiarol
- Undergraduate Student, Department of Clinical Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
| | - Eliaquim Beck Fernandes
- Undergraduate Student, Department of Clinical Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
| | - Isadora Bueloni Ghiorzi
- Undergraduate Student, Department of Clinical Medicine, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
| | - Maurício Rouvel Nunes
- BSc. Doctoral Student, Postgraduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
| | - Paulo Ricardo Gazzola Zen
- PhD. Professor, Departments of Clinical Medicine and Clinical Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
| | - Rafael Fabiano Machado Rosa
- PhD. Professor, Departments of Clinical Medicine and Clinical Genetics, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre (RS), Brazil
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7
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Fukami M. Ovarian dysfunction in women with Turner syndrome. Front Endocrinol (Lausanne) 2023; 14:1160258. [PMID: 37033245 PMCID: PMC10076527 DOI: 10.3389/fendo.2023.1160258] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/09/2023] [Indexed: 04/11/2023] Open
Abstract
Ovarian dysfunction is one of the most common features of women with Turner syndrome. In these women, oocyte apoptosis is markedly accelerated from the early stage of fetal life. Reduction in the number of germ cells disturbs primordial follicle development and thereby leads to the formation of streak gonads. There are three possible causes of accelerated germ cell loss in 45,X ovaries. First, chromosomal pairing failure due to X chromosomal aneuploidy is believed to induce meiotic arrest. Indeed, it has been suggested that the dosage of the X chromosome is more critical for the survival of the oocytes than for other cells in the ovary. Second, impaired coupling between oocytes and granulosa cells may also contribute to germ cell apoptosis. Previous studies have shown that 45,X ovaries may tend to lose tight junctions which are essential for intercellular interactions. Lastly, ovarian dysfunction in women with Turner syndrome is partly attributable to the reduced dosage of several genes on the X chromosome. Specifically, BMP15, PGRMC1, and some other genes on the X chromosome have been implicated in ovarian function. Further studies on the mechanisms of ovarian dysfunction are necessary to improve the reproductive outcomes of women with Turner syndrome.
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Mauvais-Jarvis F, Lange CA, Levin ER. Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease. Endocr Rev 2022; 43:720-742. [PMID: 34791092 PMCID: PMC9277649 DOI: 10.1210/endrev/bnab041] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Indexed: 12/15/2022]
Abstract
Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized steroid receptor (SR) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.
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Affiliation(s)
- Franck Mauvais-Jarvis
- Department of Medicine, Section of Endocrinology and Metabolism, Tulane University School of Medicine, New Orleans, LA, 70112, USA.,Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, 70112, USA.,Southeast Louisiana Veterans Affairs Medical Center, New Orleans, LA, 70119, USA
| | - Carol A Lange
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.,Department of Medicine (Division of Hematology, Oncology, and Transplantation), University of Minnesota, Minneapolis, MN 55455, USA.,Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA
| | - Ellis R Levin
- Division of Endocrinology, Department of Medicine, University of California, Irvine, Irvine, CA, 92697, USA.,Department of Veterans Affairs Medical Center, Long Beach, Long Beach, CA, 90822, USA
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9
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Abstract
Progesterone receptor membrane component (PGRMC) proteins play important roles in tumor growth, progression, and chemoresistance, of which PGRMC1 is the best characterized. The ancestral member predates the evolution of metazoans, so it is perhaps not surprising that many of the purported actions of PGRMC proteins are rooted in fundamental metabolic processes such as proliferation, apoptosis, and DNA damage responses. Despite mediating some of the actions of progesterone (P4) and being fundamentally required for female fertility, PGRMC1 and PGRMC2 are broadly expressed in most tissues. As such, these proteins likely have both progesterone-dependent and progesterone-independent functions. It has been proposed that PGRMC1 acquired the ability to mediate P4 actions over evolutionary time through acquisition of its cytochrome b5-like heme/sterol-binding domain. Diverse reproductive and nonreproductive diseases associate with altered PGRMC1 expression, epigenetic regulation, or gene silencing mechanisms, some of which include polycystic ovarian disease, premature ovarian insufficiency, endometriosis, Alzheimer disease, and cancer. Although many studies have been completed using transformed cell lines in culture or in xenograft tumor approaches, recently developed transgenic model organisms are offering new insights in the physiological actions of PGRMC proteins, as well as pathophysiological and oncogenic consequences when PGRMC expression is altered. The purpose of this mini-review is to provide an overview of PGRMC proteins in cancer and to offer discussion of where this field must go to solidify PGRMC proteins as central contributors to the oncogenic process.
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Affiliation(s)
- James K Pru
- Correspondence: James K. Pru, PhD, Program in Reproductive Biology, Department of Animal Science, University of Wyoming, Laramie, WY, USA.
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Peluso JJ. Progesterone Signaling and Mammalian Ovarian Follicle Growth Mediated by Progesterone Receptor Membrane Component Family Members. Cells 2022; 11:1632. [PMID: 35626669 PMCID: PMC9139379 DOI: 10.3390/cells11101632] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/02/2022] [Accepted: 05/09/2022] [Indexed: 02/01/2023] Open
Abstract
How progesterone influences ovarian follicle growth is a difficult question to answer because ovarian cells synthesize progesterone and express not only the classic nuclear progesterone receptor but also members of the progestin and adipoQ receptor family and the progesterone receptor membrane component (PGRMC) family. Which type of progestin receptor is expressed depends on the ovarian cell type as well as the stage of the estrous/menstrual cycle. Given the complex nature of the mammalian ovary, this review will focus on progesterone signaling that is transduced by PGRMC1 and PGRMC2 specifically as it relates to ovarian follicle growth. PGRMC1 was identified as a progesterone binding protein cloned from porcine liver in 1996 and detected in the mammalian ovary in 2005. Subsequent studies focused on PGRMC family members as regulators of granulosa cell proliferation and survival, two physiological processes required for follicle development. This review will present evidence that demonstrates a causal relationship between PGRMC family members and the promotion of ovarian follicle growth. The mechanisms through which PGRMC-dependent signaling regulates granulosa cell proliferation and viability will also be discussed in order to provide a more complete understanding of our current concept of how progesterone regulates ovarian follicle growth.
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Affiliation(s)
- John J. Peluso
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA;
- Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, CT 06030, USA
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11
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Zhang X, Lu Y, Wu S, Zhao X, Li S, Zhang S, Tan J. Estimates of global research productivity in primary ovarian insufficiency from 2000 to 2021: Bibliometric analysis. Front Endocrinol (Lausanne) 2022; 13:959905. [PMID: 36387882 PMCID: PMC9645456 DOI: 10.3389/fendo.2022.959905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/11/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Primary ovarian insufficiency (POI) is a heterogeneous disease with diverse clinical phenotypes and etiologies, which is defined as ovarian dysfunction under the age of 40 years. The global prevalence of POI is approximately about 1.1%, and it severely affects female fertility. Nevertheless, bibliometric analysis in this field is extremely limited. We aimed to visualize the research hotspots and trends of POI using bibliometric analysis and tried to predict the future development of this field. METHODS The original articles regarding POI were culled from the Web of Science Core Collection. Countries, institutions, journals, authors, and keywords in this field were visually analyzed by employing CiteSpace software and Microsoft Excel 2021 software. RESULTS A total of 2,999 publications were included for further bibliometric analysis after screening the titles and abstracts stringently. The number of literature regarding POI significantly increased yearly. These publications come from 78 countries. The USA was dominant in the field of POI in terms of the number of publications (865), average citations per item (57.36), and h-index (112). The Institut National De La Sante Et De La Recherche Medicale Inserm is the most high-yield institution in this field with 351 publications. Fertility and Sterility ranked first with the highest number of publications (152), followed by Human Reproduction (138). According to the keyword cluster analysis from 2000 to 2021, the eight keyword clusters encountered frequently were apoptosis, osteoporosis, fertility preservation, mutation, fragile x syndrome, adrenal insufficiency, DNA repair, ovarian reserve. Keyword citation burst analysis revealed that whole-exome sequencing, ovarian tissue cryopreservation, and DNA repair had a citation burst until 2021. CONCLUSIONS Great progress has been made in POI research over the past 20 years, which is widely researched but unevenly developed in the world. In terms of influence, the United States may be in the lead. The research hotspots in POI are mainly pathogenesis and treatment, including genetic mutation, hormone therapy, fertility preservation, and stem cell transplantation.
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Affiliation(s)
- Xudong Zhang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Yimeng Lu
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Shanshan Wu
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Xinyang Zhao
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Shuyu Li
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Siwen Zhang
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
| | - Jichun Tan
- Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
- Key Laboratory of Reproductive Dysfunction Disease and Fertility Remodeling of Liaoning Province, Shenyang, China
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Abstract
Primary ovarian insufficiency (POI) is determined by exhaustion of follicles in the ovaries, which leads to infertility before the age of 40 years. It is characterized by a strong familial and heterogeneous genetic background. Therefore, we will mainly discuss the genetic basis of POI in this review. We identified 107 genes related to POI etiology in mammals described by several independent groups. Thirty-four of these genes (AARS2, AIRE, ANTXR1, ATM, BMPR1B, CLPP, CYP17A1, CYP19A1, DCAF17, EIF2B, ERAL1, FANCA, FANCC, FMR1, FOXL2, GALT, GNAS, HARS2, HSD17B4, LARS2, LMNA, MGME1, NBN, PMM2, POLG, PREPL, RCBTB1, RECQL2/3/4, STAR, TWNK, and XRCC4/9) have been linked to syndromic POI and are mainly implicated in metabolism function and meiosis/DNA repair. In addition, the majority of genes associated with nonsyndromic POI, widely expanded by high-throughput techniques over the last decade, have been implicated in ovarian development and meiosis/DNA repair pathways (ATG7, ATG9, ANKRD31, BMP8B, BMP15, BMPR1A, BMPR1B, BMPR2, BNC1, BRCA2, CPEB1, C14ORF39, DAZL, DIAPH2, DMC1, ERCC6, FANCL, FANCM, FIGLA, FSHR, GATA4, GDF9, GJA4, HELQ, HSF2BP, HFM1, INSL3, LHCGR, LHX8, MCM8, MCM9, MEIOB, MSH4, MSH5, NANOS3, NOBOX, NOTCH2, NR5A1, NUP107, PGRMC1, POLR3H, PRDM1, PRDM9, PSMC3IP, SOHLH1, SOHLH2, SPIDR, STAG3, SYCE1, TP63, UBR2, WDR62, and XRCC2), whereas a few are related to metabolic functions (EIF4ENIF1, KHDRBS1, MRPS22, POLR2C). Some genes, such as STRA8, FOXO3A, KIT, KITL, WNT4, and FANCE, have been shown to cause ovarian insufficiency in rodents, but mutations in these genes have yet to be elucidated in women affected by POI. Lastly, some genes have been rarely implicated in its etiology (AMH, AMHR2, ERRC2, ESR1, INHA, LMN4, POF1B, POU5F1, REC8, SMC1B). Considering the heterogeneous genetic and familial background of this disorder, we hope that an overview of literature data would reinforce that genetic screening of those patients is worthwhile and helpful for better genetic counseling and patient management.
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Affiliation(s)
- Monica Malheiros França
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Section of Endocrinology Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL, USA.
| | - Berenice Bilharinho Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
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13
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Medina-Laver Y, Rodríguez-Varela C, Salsano S, Labarta E, Domínguez F. What Do We Know about Classical and Non-Classical Progesterone Receptors in the Human Female Reproductive Tract? A Review. Int J Mol Sci 2021; 22:11278. [PMID: 34681937 PMCID: PMC8538361 DOI: 10.3390/ijms222011278] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/14/2021] [Accepted: 10/15/2021] [Indexed: 01/22/2023] Open
Abstract
The progesterone hormone regulates the human menstrual cycle, pregnancy, and parturition by its action via the different progesterone receptors and signaling pathways in the female reproductive tract. Progesterone actions can be exerted through classical and non-classical receptors, or even a combination of both. The former are nuclear receptors whose activation leads to transcriptional activity regulation and thus in turn leads to slower but long-lasting responses. The latter are composed of progesterone receptors membrane components (PGRMC) and membrane progestin receptors (mPRs). These receptors rapidly activate the appropriate intracellular signal transduction pathways, and they can subsequently initiate specific cell responses or even modulate genomic cell responses. This review covers our current knowledge on the mechanisms of action and the relevance of classical and non-classical progesterone receptors in female reproductive tissues ranging from the ovary and uterus to the cervix, and it exposes their crucial role in female infertility.
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Affiliation(s)
- Yassmin Medina-Laver
- IVI Foundation—IIS La Fe, 46026 Valencia, Spain; (Y.M.-L.); (C.R.-V.); (S.S.); (E.L.)
| | | | - Stefania Salsano
- IVI Foundation—IIS La Fe, 46026 Valencia, Spain; (Y.M.-L.); (C.R.-V.); (S.S.); (E.L.)
| | - Elena Labarta
- IVI Foundation—IIS La Fe, 46026 Valencia, Spain; (Y.M.-L.); (C.R.-V.); (S.S.); (E.L.)
- IVI RMA Valencia, 46015 Valencia, Spain
| | - Francisco Domínguez
- IVI Foundation—IIS La Fe, 46026 Valencia, Spain; (Y.M.-L.); (C.R.-V.); (S.S.); (E.L.)
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14
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Kim S, Lee S, Park HT, Song JY, Kim T. Genomic Consideration in Chemotherapy-Induced Ovarian Damage and Fertility Preservation. Genes (Basel) 2021; 12:1525. [PMID: 34680919 PMCID: PMC8535252 DOI: 10.3390/genes12101525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/25/2021] [Accepted: 09/25/2021] [Indexed: 11/25/2022] Open
Abstract
Chemotherapy-induced ovarian damage and fertility preservation in young patients with cancer are emerging disciplines. The mechanism of treatment-related gonadal damage provides important information for targeting prevention methods. The genomic aspects of ovarian damage after chemotherapy are not fully understood. Several studies have demonstrated that gene alterations related to follicular apoptosis or accelerated follicle activation are related to ovarian insufficiency and susceptibility to ovarian damage following chemotherapy. This may accelerate follicular apoptosis and follicle reservoir utilization and damage the ovarian stroma via multiple molecular reactions after chemotherapy. This review highlights the importance of genomic considerations in chemotherapy-induced ovarian damage and multidisciplinary oncofertility strategies for providing high-quality care to young female cancer patients.
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Affiliation(s)
- Seongmin Kim
- Gynecologic Cancer Center, CHA Ilsan Medical Center, CHA University College of Medicine, 1205 Jungang-ro, Ilsandong-gu, Goyang-si 10414, Korea;
| | - Sanghoon Lee
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Hyun-Tae Park
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Jae-Yun Song
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
| | - Tak Kim
- Department of Obstetrics and Gynecology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea; (H.-T.P.); (J.-Y.S.); (T.K.)
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15
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Abstract
Premature ovarian insufficiency (POI) is a life-long disorder of heterogeneous etiology, presenting as adolescent primary amenorrhea in its most severe form, with an overall incidence of 1%. Idiopathic POI accounts for up to 70% of women with POI; and genomic, genetic, epidemiological, familial and cohort studies demonstrate a genetic component to this condition. Currently, the only genetic tests routinely performed in non-syndromic POI are FMR1 premutation and cytogenetics, the latter specifically for X-chromosome abnormalities. However, a myriad of genetic aberrations has been identified and implicated, some of which act in a monogenic Mendelian fashion. The presence of multiple genetic aberrations and the complexity of POI genomics are hardly surprising since the embryological formation of the primordial oocyte pool, postnatal oogenesis and folliculogenesis are all highly complex pathways. With this review, the aim is to discuss the current genetic etiologies in the emerging field of POI genomics. Promising candidate genes include STAG3, SYCE1, FIGLA, NOBOX, FSHR, BMP15 and INHA. This area has the potential to progress rapidly in light of advances in genomic technologies. The development of a POI genomic map not only will assist in understanding the underlying molecular mechanisms affecting ovarian function but will also be essential in designing predictive and diagnostic gene panels as well as future novel therapeutic strategies.
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Affiliation(s)
- B Cloke
- Menopause Research Unit, McNair Gynaecology Centre, Guy's Hospital, Guy's and St Thomas' Hospitals NHS Trust, London, UK
| | - J Rymer
- Menopause Research Unit, McNair Gynaecology Centre, Guy's Hospital, Guy's and St Thomas' Hospitals NHS Trust, London, UK.,School of Medical Education, Faculty of Life Sciences and Medicine, King's College London, London, UK
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16
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Yang Q, Mumusoglu S, Qin Y, Sun Y, Hsueh AJ. A kaleidoscopic view of ovarian genes associated with premature ovarian insufficiency and senescence. FASEB J 2021; 35:e21753. [PMID: 34233068 DOI: 10.1096/fj.202100756r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 06/04/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022]
Abstract
Ovarian infertility and subfertility presenting with premature ovarian insufficiency (POI) and diminished ovarian reserve are major issues facing the developed world due to the trend of delaying childbirth. Ovarian senescence and POI represent a continuum of physiological/pathophysiological changes in ovarian follicle functions. Based on advances in whole exome sequencing, evaluation of gene copy variants, together with family-based and genome-wide association studies, we discussed genes responsible for POI and ovarian senescence. We used a gene-centric approach to sort out literature deposited in the Ovarian Kaleidoscope database (http://okdb.appliedbioinfo.net) by sub-categorizing candidate genes as ligand-receptor signaling, meiosis and DNA repair, transcriptional factors, RNA metabolism, enzymes, and others. We discussed individual gene mutations found in POI patients and verification of gene functions in gene-deleted model organisms. Decreased expression of some of the POI genes could be responsible for ovarian senescence, especially those essential for DNA repair, meiosis and mitochondrial functions. We propose to set up a candidate gene panel for targeted sequencing in POI patients together with studies on mitochondria-associated genes in middle-aged subfertile patients.
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Affiliation(s)
- Qingling Yang
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
| | - Sezcan Mumusoglu
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.,Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey
| | - Yingying Qin
- Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yingpu Sun
- Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Aaron J Hsueh
- Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA
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17
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Salsano S, González-Martín R, Quiñonero A, Pérez-Debén S, Domínguez F. Deciphering the Role of PGRMC1 During Human Decidualization Using an In Vitro Approach. J Clin Endocrinol Metab 2021; 106:2313-2327. [PMID: 33955452 DOI: 10.1210/clinem/dgab303] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Indexed: 02/07/2023]
Abstract
CONTEXT Non-classical membrane progesterone receptor (mPRs) and progesterone receptor membrane component 1 (PGRMC1) expression have been detected in endometrium, but their role in decidualization had not yet been investigated. We previously demonstrated PGRMC1 downregulation in receptive endometrium and that its overexpression inhibits decidualization. Furthermore, during decidualization, PGRMC1 mainly interacts with proteins involved in biosynthesis, intracellular transport, and mitochondrial activity. OBJECTIVE To determine PGRMC1 and mPRs signaling role during decidualization. METHODS Isolated primary endometrial stromal cells (EnSC) were decidualized in vitro in the presence of classic stimuli (E2 + P4), PGRMC1 inhibitor (AG205), or membrane-impermeable P4 (P4-BSA). Endometrial biopsies were obtained from 19 fertile oocyte donors attending the IVI-Valencia in vitro fertilization (IVF) clinic. EnSC decidualization was evaluated by prolactin ELISA and F-actin immunostaining. Progesterone receptor localization was evaluated by immunofluorescence. EnSC transcriptomic profiles were analyzed by microarray technology. RESULTS PGRMC1 inhibition during EnSC decidualization (AG205dEnSC) does not interfere with EnSC cytoskeletal rearrangements and prolactin secretion. However, global transcriptional profiling revealed more differentially expressed genes in AG205dEnSC than in dEnSC, compared with nondecidualized EnSC (ndEnSC). In silico analysis showed that PGRMC1 inhibition upregulated more genes related to metabolism, molecular transport, and hormonal biosynthesis compared with control dEnSC. EnSC decidualized in the presence of P4-BSA showed a similar behavior as ndEnSC in terms of morphological features, absence of prolactin secretion, and transcriptomic pattern. CONCLUSION Our findings associate PGRMC1 to hormonal biosynthesis, metabolism, and vesicular transport-important cellular functions for dEnSC supporting pregnancy. Activation of membrane P4 receptor signaling alone was unable to induce downstream effects needed for proper decidualization.
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Affiliation(s)
| | | | | | | | - Francisco Domínguez
- IVI Foundation-RMA Global, 46026, Valencia, Spain
- IIS La Fe, 46026, Valencia, Spain
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18
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Sun B, Yeh J. Onco-fertility and personalized testing for potential for loss of ovarian reserve in patients undergoing chemotherapy: proposed next steps for development of genetic testing to predict changes in ovarian reserve. FERTILITY RESEARCH AND PRACTICE 2021; 7:13. [PMID: 34193292 PMCID: PMC8244159 DOI: 10.1186/s40738-021-00105-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/19/2021] [Indexed: 12/29/2022]
Abstract
Women of reproductive age undergoing chemotherapy face the risk of irreversible ovarian insufficiency. Current methods of ovarian reserve testing do not accurately predict future reproductive potential for patients undergoing chemotherapy. Genetic markers that more accurately predict the reproductive potential of each patient undergoing chemotherapy would be critical tools that would be useful for evidence-based fertility preservation counselling. To assess the possible approaches to take to develop personalized genetic testing for these patients, we review current literature regarding mechanisms of ovarian damage due to chemotherapy and genetic variants associated with both the damage mechanisms and primary ovarian insufficiency. The medical literature point to a number of genetic variants associated with mechanisms of ovarian damage and primary ovarian insufficiency. Those variants that appear at a higher frequency, with known pathways, may be considered as potential genetic markers for predictive ovarian reserve testing. We propose developing personalized testing of the potential for loss of ovarian function for patients with cancer, prior to chemotherapy treatment. There are advantages of using genetic markers complementary to the current ovarian reserve markers of AMH, antral follicle count and day 3 FSH as predictors of preservation of fertility after chemotherapy. Genetic markers will help identify upstream pathways leading to high risk of ovarian failure not detected by present clinical markers. Their predictive value is mechanism-based and will encourage research towards understanding the multiple pathways contributing to ovarian failure after chemotherapy.
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Affiliation(s)
- Bei Sun
- Sackler School of Medicine, New York State/American Program of Tel Aviv University, Tel Aviv University, Ramat Aviv 69978, Tel Aviv, Israel
| | - John Yeh
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics & Gynecology, University of Massachusetts Medical School, UMass Memorial Medical Center, 119 Belmont Street, Worcester, MA, 01605, USA.
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19
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Eskenazi S, Bachelot A, Hugon-Rodin J, Plu-Bureau G, Gompel A, Catteau-Jonard S, Molina-Gomes D, Dewailly D, Dodé C, Christin-Maitre S, Touraine P. Next Generation Sequencing Should Be Proposed to Every Woman With "Idiopathic" Primary Ovarian Insufficiency. J Endocr Soc 2021; 5:bvab032. [PMID: 34095689 PMCID: PMC8169040 DOI: 10.1210/jendso/bvab032] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Indexed: 12/14/2022] Open
Abstract
Context Primary ovarian insufficiency (POI) affects 1% of women under 40 years of age. POI is idiopathic in more than 70% of cases. Though many candidate genes have been identified in recent years, the prevalence and pathogenicity of abnormalities are still difficult to establish. Objective Our primary objective was to evaluate the prevalence of gene variations in a large prospective multicentric POI cohort. Our secondary objective was to evaluate the correlation between phenotype and genotype. Methods Two hundred and sixty-nine well-phenotyped POI patients were screened for variants of 18 known POI genes (BMP15, DMC1, EIF2S2, FIGLA, FOXL2, FSHR, GDF9, GPR3, HFM1, LHX8, MSH5, NOBOX, NR5A1, PGRMC1, STAG3, XPNPEP2, BHLB, and FSHB) by next generation sequencing (NGS). Abnormalities were classified as "variant" or "variant of unknown signification" (VUS) according to available functional tests or algorithms (SIFT, Polyphen-2, MutationTaster). Results One hundred and two patients (38%) were identified as having at least 1 genetic abnormality. Sixty-seven patients (25%) presented at least 1 variant. Forty-eight patients presented at least 1 VUS (18%). Thirteen patients (5%) had combined abnormalities. NOBOX variants were the most common gene variants involved in POI (9%). Interestingly, we saw no significant differences in the previous family history of POI, ethnic origin, age at onset of POI, primary amenorrhea, or secondary menstrual disturbances between the different genotypes. Conclusion In our study, a high percentage of patients presented gene variants detected by NGS analysis (38%). Every POI patient should undergo NGS analysis to improve medical cares of the patients.
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Affiliation(s)
- Sarah Eskenazi
- Department of Reproductive Endocrinology, Saint-Antoine Hospital, AP-HP, Paris, France; Center for Rare Growth Disorders and Center for Developmental Disorders: CMERC.,Sorbonne University Medicine, Paris, France
| | - Anne Bachelot
- Sorbonne University Medicine, Paris, France.,Department of Endocrinology and Reproductive Medicine, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Center for Rare Endocrine Disorders and Center for Rare Gynecological Disorders: CMERC
| | - Justine Hugon-Rodin
- Department of Gynecology and Endocrinology, Cochin/Port-Royal Hospital, AP-HP, Paris, France.,Paris Descartes University, Paris, France.,INSERM UMR 1153, EPOPE group, Paris, France
| | - Genevieve Plu-Bureau
- Department of Gynecology and Endocrinology, Cochin/Port-Royal Hospital, AP-HP, Paris, France.,Paris Descartes University, Paris, France.,INSERM UMR 1153, EPOPE group, Paris, France
| | - Anne Gompel
- Department of Gynecology and Endocrinology, Cochin/Port-Royal Hospital, AP-HP, Paris, France.,Paris Descartes University, Paris, France
| | - Sophie Catteau-Jonard
- Department of Medical Gynaecology, CHU Lille, University of Lillle, F-59000 Lille, France
| | - Denise Molina-Gomes
- Department of Assisted Reproductive Technics, Poissy Saint-Germain-en-Laye Hospital, Poissy, France
| | - Didier Dewailly
- Department of Medical Gynaecology, CHU Lille, University of Lillle, F-59000 Lille, France
| | - Catherine Dodé
- Department of Genetics and Molecular Biology, Cochin/Port-Royal Hospital, AP-HP, Paris, France
| | - Sophie Christin-Maitre
- Department of Reproductive Endocrinology, Saint-Antoine Hospital, AP-HP, Paris, France; Center for Rare Growth Disorders and Center for Developmental Disorders: CMERC.,Sorbonne University Medicine, Paris, France.,INSERM UMR-S933, 75012 Paris, France
| | - Philippe Touraine
- Sorbonne University Medicine, Paris, France.,Department of Endocrinology and Reproductive Medicine, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Center for Rare Endocrine Disorders and Center for Rare Gynecological Disorders: CMERC
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20
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Hosseinirad H, Novin MG, Hosseini S, Nazarian H, Safaei Z, Hashemi T, Paktinat S, Mofarahe ZS. Evaluation of Expression and Phosphorylation of Progesterone Receptor in Endometrial Stromal Cells of Patients with Recurrent Implantation Failure Compared to Healthy Fertile Women. Reprod Sci 2021; 28:1457-1465. [PMID: 33449351 DOI: 10.1007/s43032-020-00428-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Accepted: 12/10/2020] [Indexed: 11/30/2022]
Abstract
Recurrent implantation failure (RIF) is the repeated failure of good-quality embryos in implantation process following several assisted reproduction cycles. Disruption of the endometrial receptivity is one of the main causes of RIF. Progesterone plays a pivotal role in the endometrial receptivity through the regulation of gene expression pattern by binding to its receptors in the endometrial cells. The aim of this study was to evaluate the expression level of progesterone receptor (PR) and its phosphorylated form in the endometrial stromal cells (eSC) of RIF patients and compare it to the eSC of healthy fertile women as control group. After isolation of the eSC from biopsy samples of RIF patients and healthy fertile women and their characterization, expression levels of PR mRNA, PR protein, and phospho-Ser294 PR protein were evaluated by quantitative real-time PCR and immunofluorescence staining, respectively. The results demonstrated a significant reduction in PR mRNA expression (P < 0.01.) and phospho-Ser294 PR protein (P < 0.05) level in RIF patients compared to the control group. These data for the first time suggest that the expression of PR and its phosphorylated form are impaired in RIF patients. Therefore, designing therapeutic methods for improving PR expression status and its regulation in the endometrium of RIF patients may help in improving the final reproductive outcomes of these cases.
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Affiliation(s)
- Hossein Hosseinirad
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marefat Ghaffari Novin
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sedighe Hosseini
- Preventative Gynecology Research Center (PGRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Nazarian
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Safaei
- Department of Anatomical Sciences, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Teibeh Hashemi
- Preventative Gynecology Research Center (PGRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahrokh Paktinat
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Shams Mofarahe
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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21
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Yang X, Zhang F, Shi Q, Wu Y. "Response to the letter to the editor "Concerns regarding the potentially causal role of FANCA heterozygous variants in human primary ovarian insufficiency"". Hum Genet 2020; 140:695-697. [PMID: 33175223 DOI: 10.1007/s00439-020-02233-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 10/20/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Xi Yang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China
| | - Feng Zhang
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China.,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China
| | - Qinghua Shi
- The First Affiliated Hospital of USTC, The CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Life Sciences, CAS Center for Excellence in Molecular Cell Science, University of Science and Technology of China, Hefei, 230027, China.
| | - Yanhua Wu
- Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, Shanghai, 200011, China. .,Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, China. .,National Demonstration Center for Experimental Biology Education, School of Life Sciences, Fudan University, Shanghai, 200433, China.
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22
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Progesterone receptor membrane component 1 regulates lipid homeostasis and drives oncogenic signaling resulting in breast cancer progression. Breast Cancer Res 2020; 22:75. [PMID: 32660617 PMCID: PMC7359014 DOI: 10.1186/s13058-020-01312-8] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 06/30/2020] [Indexed: 01/05/2023] Open
Abstract
Background PGRMC1 (progesterone receptor membrane component 1) is a highly conserved heme binding protein, which is overexpressed especially in hormone receptor-positive breast cancer and plays an important role in breast carcinogenesis. Nevertheless, little is known about the mechanisms by which PGRMC1 drives tumor progression. The aim of our study was to investigate the involvement of PGRMC1 in cholesterol metabolism to detect new mechanisms by which PGRMC1 can increase lipid metabolism and alter cancer-related signaling pathways leading to breast cancer progression. Methods The effect of PGRMC1 overexpression and silencing on cellular proliferation was examined in vitro and in a xenograft mouse model. Next, we investigated the interaction of PGRMC1 with enzymes involved in the cholesterol synthesis pathway such as CYP51, FDFT1, and SCD1. Further, the impact of PGRMC1 expression on lipid levels and expression of enzymes involved in lipid homeostasis was examined. Additionally, we assessed the role of PGRMC1 in key cancer-related signaling pathways including EGFR/HER2 and ERα signaling. Results Overexpression of PGRMC1 resulted in significantly enhanced proliferation. PGRMC1 interacted with key enzymes of the cholesterol synthesis pathway, alters the expression of proteins, and results in increased lipid levels. PGRMC1 also influenced lipid raft formation leading to altered expression of growth receptors in membranes of breast cancer cells. Analysis of activation of proteins revealed facilitated ERα and EGFR activation and downstream signaling dependent on PGRMC1 overexpression in hormone receptor-positive breast cancer cells. Depletion of cholesterol and fatty acids induced by statins reversed this growth benefit. Conclusion PGRMC1 may mediate proliferation and progression of breast cancer cells potentially by altering lipid metabolism and by activating key oncogenic signaling pathways, such as ERα expression and activation, as well as EGFR signaling. Our present study underlines the potential of PGRMC1 as a target for anti-cancer therapy.
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23
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Sinchak K, Mohr MA, Micevych PE. Hypothalamic Astrocyte Development and Physiology for Neuroprogesterone Induction of the Luteinizing Hormone Surge. Front Endocrinol (Lausanne) 2020; 11:420. [PMID: 32670203 PMCID: PMC7333179 DOI: 10.3389/fendo.2020.00420] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 05/26/2020] [Indexed: 12/26/2022] Open
Abstract
Neural circuits in female rats sequentially exposed to estradiol and progesterone underlie so-called estrogen positive feedback that induce the surge release of pituitary luteinizing hormone (LH) leading to ovulation and luteinization of the corpus hemorrhagicum. It is now well-established that gonadotropin releasing hormone (GnRH) neurons express neither the reproductively critical estrogen receptor-α (ERα) nor classical progesterone receptor (PGR). Estradiol from developing ovarian follicles acts on ERα-expressing kisspeptin neurons in the rostral periventricular region of the third ventricle (RP3V) to induce PGR expression, and kisspeptin release. Circulating estradiol levels that induce positive feedback also induce neuroprogesterone (neuroP) synthesis in hypothalamic astrocytes. This local neuroP acts on kisspeptin neurons that express PGR to augment kisspeptin expression and release needed to stimulate GnRH release, triggering the LH surge. In vitro and in vivo studies demonstrate that neuroP signaling in kisspeptin neurons occurs through membrane PGR activation of Src family kinase (Src). This signaling cascade has been also implicated in PGR signaling in the arcuate nucleus of the hypothalamus, suggesting that Src may be a common mode of membrane PGR signaling. Sexual maturation requires that signaling between neuroP synthesizing astrocytes, kisspeptin and GnRH neurons be established. Prior to puberty, estradiol does not facilitate the synthesis of neuroP in hypothalamic astrocytes. During pubertal development, levels of membrane ERα increase in astrocytes coincident with an increase of PKA phosphorylation needed for neuroP synthesis. Currently, it is not clear whether these developmental changes occur in existing astrocytes or are due to a new population of astrocytes born during puberty. However, strong evidence suggests that it is the former. Blocking new cell addition during puberty attenuates the LH surge. Together these results demonstrate the importance of pubertal maturation involving hypothalamic astrocytes, estradiol-induced neuroP synthesis and membrane-initiated progesterone signaling for the CNS control of ovulation and reproduction.
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Affiliation(s)
- Kevin Sinchak
- Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States
| | - Margaret A Mohr
- The Laboratory of Neuroendocrinology, Department of Neurobiology, David Geffen School of Medicine at UCLA, Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, United States
| | - Paul E Micevych
- The Laboratory of Neuroendocrinology, Department of Neurobiology, David Geffen School of Medicine at UCLA, Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, United States
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Vaitsopoulou CI, Kolibianakis EM, Bosdou JK, Neofytou E, Lymperi S, Makedos A, Savvaidou D, Chatzimeletiou K, Grimbizis GF, Lambropoulos A, Tarlatzis BC. Expression of genes that regulate follicle development and maturation during ovarian stimulation in poor responders. Reprod Biomed Online 2020; 42:248-259. [PMID: 33214084 DOI: 10.1016/j.rbmo.2020.05.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/12/2020] [Accepted: 05/18/2020] [Indexed: 12/17/2022]
Abstract
RESEARCH QUESTION Sex hormone-binding globulin (SHBG), androgen receptor (AR), LH beta polypeptide (LHB), progesterone receptor membrane component 1 (PGRMC1) and progesterone receptor membrane component 2 (PGRMC2) regulate follicle development and maturation. Their mRNA expression was assessed in peripheral blood mononuclear cells (PBMC) of normal and poor responders, during ovarian stimulation. DESIGN Fifty-two normal responders and 15 poor responders according to the Bologna criteria were enrolled for IVF and intracytoplasmic sperm injection and stimulated with 200 IU of follitrophin alpha and gonadotrophin-releasing hormone antagonist. HCG was administered for final oocyte maturation. On days 1, 6 and 10 of stimulation, blood samples were obtained, serum hormone levels were measured, RNA was extracted from PBMC and real-time polymerase chain reaction was carried out to identify the mRNA levels. Relative mRNA expression of each gene was calculated by the comparative 2-DDCt method. RESULTS Differences between mRNA levels of each gene on the same time point between the two groups were not significant. PGRMC1 and PGRMC2 mRNA levels were downregulated, adjusted for ovarian response and age. Positive correlations between PGRMC1 and AR (standardized beta = 0.890, P < 0.001) from day 1 to 6 and PGRMC1 and LHB (standardized beta = 0.806, P < 0.001) from day 1 to 10 were found in poor responders. PGRMC1 and PGRMC2 were positively correlated on days 6 and 10 in normal responders. CONCLUSIONS PGRMC1 and PGRMC2 mRNA are significantly decreased during ovarian stimulation, with some potential differences between normal and poor responders.
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Affiliation(s)
- Christine I Vaitsopoulou
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece.
| | - Efstratios M Kolibianakis
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Julia K Bosdou
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Eirini Neofytou
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Stefania Lymperi
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Anastasios Makedos
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Despina Savvaidou
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Katerina Chatzimeletiou
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Grigoris F Grimbizis
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Alexandros Lambropoulos
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
| | - Basil C Tarlatzis
- Unit for Human Reproduction, Laboratory of Genetics, 1st Department of Obstetrics and Gynaecology, School of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road, Nea Efkarpia Thessaloniki 56403, Greece
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Li J, Ge W. Zebrafish as a model for studying ovarian development: Recent advances from targeted gene knockout studies. Mol Cell Endocrinol 2020; 507:110778. [PMID: 32142861 DOI: 10.1016/j.mce.2020.110778] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 02/27/2020] [Accepted: 02/27/2020] [Indexed: 12/11/2022]
Abstract
Ovarian development is a complex process controlled by precise coordination of multiple factors. The targeted gene knockout technique is a powerful tool to study the functions of these factors. The successful application of this technique in mice in the past three decades has significantly enhanced our understanding on the molecular mechanism of ovarian development. Recently, with the advent of genome editing techniques, targeted gene knockout research can be carried out in many species. Zebrafish has emerged as an excellent model system to study the control of ovarian development. Dozens of genes related to ovarian development have been knocked out in zebrafish in recent years. Much new information and perspectives on the molecular mechanism of ovarian development have been obtained from these mutant zebrafish. Some findings have challenged conventional views. Several genes have been identified for the first time in vertebrates to control ovarian development. Focusing on ovarian development, the purpose of this review is to briefly summarize recent findings using these gene knockout zebrafish models, and compare these findings with mammalian models. These established mutants and rapid development of gene knockout techniques have prompted zebrafish as an ideal animal model for studying ovarian development.
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Affiliation(s)
- Jianzhen Li
- College of Life Sciences, Northwest Normal University, Lanzhou, Gansu, China, 730070.
| | - Wei Ge
- Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
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26
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Novel nonclassic progesterone receptor PGRMC1 pulldown-precipitated proteins reveal a key role during human decidualization. Fertil Steril 2020; 113:1050-1066.e7. [DOI: 10.1016/j.fertnstert.2020.01.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/12/2019] [Accepted: 01/02/2020] [Indexed: 12/20/2022]
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França MM, Mendonca BB. Genetics of Primary Ovarian Insufficiency in the Next-Generation Sequencing Era. J Endocr Soc 2020; 4:bvz037. [PMID: 32099950 PMCID: PMC7033037 DOI: 10.1210/jendso/bvz037] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Accepted: 12/17/2019] [Indexed: 01/12/2023] Open
Abstract
Primary ovarian insufficiency (POI) is characterized by amenorrhea, increased follicle-stimulating hormone (FSH) levels, and hypoestrogenism, leading to infertility before the age of 40 years. Elucidating the cause of POI is a key point for diagnosing and treating affected women. Here, we review the genetic etiology of POI, highlighting new genes identified in the last few years using next-generation sequencing (NGS) approaches. We searched the MEDLINE/PubMed, Cochrane, and Web of Science databases for articles published in or translated to English. Several genes were found to be associated with POI genetic etiology in humans and animal models (SPIDR, BMPR2, MSH4, MSH5, GJA4, FANCM, POLR2C, MRPS22, KHDRBS1, BNC1, WDR62, ATG7/ATG9, BRCA2, NOTCH2, POLR3H, and TP63). The heterogeneity of POI etiology has been revealed to be remarkable in the NGS era, and discoveries have indicated that meiosis and DNA repair play key roles in POI development.
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Affiliation(s)
- Monica Malheiros França
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
| | - Berenice Bilharinho Mendonca
- Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brazil
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Colleti C, Melo-Hanchuk TD, da Silva FRM, Saito Â, Kobarg J. Complex interactomes and post-translational modifications of the regulatory proteins HABP4 and SERBP1 suggest pleiotropic cellular functions. World J Biol Chem 2019; 10:44-64. [PMID: 31768228 PMCID: PMC6872977 DOI: 10.4331/wjbc.v10.i3.44] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 08/30/2019] [Accepted: 10/15/2019] [Indexed: 02/05/2023] Open
Abstract
The 57 kDa antigen recognized by the Ki-1 antibody, is also known as intracellular hyaluronic acid binding protein 4 and shares 40.7% identity and 67.4% similarity with serpin mRNA binding protein 1, which is also named CGI-55, or plasminogen activator inhibitor type-1-RNA binding protein-1, indicating that they might be paralog proteins, possibly with similar or redundant functions in human cells. Through the identification of their protein interactomes, both regulatory proteins have been functionally implicated in transcriptional regulation, mRNA metabolism, specifically RNA splicing, the regulation of mRNA stability, especially, in the context of the progesterone hormone response, and the DNA damage response. Both proteins also show a complex pattern of post-translational modifications, involving Ser/Thr phosphorylation, mainly through protein kinase C, arginine methylation and SUMOylation, suggesting that their functions and locations are highly regulated. Furthermore, they show a highly dynamic cellular localization pattern with localizations in both the cytoplasm and nucleus as well as punctuated localizations in both granular cytoplasmic protein bodies, upon stress, and nuclear splicing speckles. Several reports in the literature show altered expressions of both regulatory proteins in a series of cancers as well as mutations in their genes that may contribute to tumorigenesis. This review highlights important aspects of the structure, interactome, post-translational modifications, sub-cellular localization and function of both regulatory proteins and further discusses their possible functions and their potential as tumor markers in different cancer settings.
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Affiliation(s)
- Carolina Colleti
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083-871, Brazil
- Institute of Biology, Departament of Biochemistry and Tissue Biology, University of Campinas, Campinas 13083-862, Brazil
| | - Talita Diniz Melo-Hanchuk
- Institute of Biology, Departament of Biochemistry and Tissue Biology, University of Campinas, Campinas 13083-862, Brazil
| | - Flávia Regina Moraes da Silva
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083-871, Brazil
- Institute of Biology, Departament of Biochemistry and Tissue Biology, University of Campinas, Campinas 13083-862, Brazil
| | - Ângela Saito
- Laboratório Nacional de Biociências, CNPEM, Campinas 13083-970, Brazil
| | - Jörg Kobarg
- Faculty of Pharmaceutical Sciences, University of Campinas, Campinas 13083-871, Brazil
- Institute of Biology, Departament of Biochemistry and Tissue Biology, University of Campinas, Campinas 13083-862, Brazil
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Venturella R, De Vivo V, Carlea A, D'Alessandro P, Saccone G, Arduino B, Improda FP, Lico D, Rania E, De Marco C, Viglietto G, Zullo F. The Genetics of Non-Syndromic Primary Ovarian Insufficiency: A Systematic Review. INTERNATIONAL JOURNAL OF FERTILITY & STERILITY 2019; 13:161-168. [PMID: 31310068 PMCID: PMC6642427 DOI: 10.22074/ijfs.2019.5599] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 01/15/2019] [Indexed: 01/19/2023]
Abstract
Several causes for primary ovarian insufficiency (POI) have been described, including iatrogenic and environmental
factor, viral infections, chronic disease as well as genetic alterations. The aim of this review was to collect all the ge-
netic mutations associated with non-syndromic POI. All studies, including gene screening, genome-wide study and as-
sessing genetic mutations associated with POI, were included and analyzed in this systematic review. Syndromic POI
and chromosomal abnormalities were not evaluated. Single gene perturbations, including genes on the X chromosome
(such as BMP15, PGRMC1 and FMR1) and genes on autosomal chromosomes (such as GDF9, FIGLA, NOBOX,
ESR1, FSHR and NANOS3) have a positive correlation with non-syndromic POI. Future strategies include linkage
analysis of families with multiple affected members, array comparative genomic hybridization (CGH) for analysis of
copy number variations, next generation sequencing technology and genome-wide data analysis. This review showed
variability of the genetic factors associated with POI. These findings may help future genetic screening studies on
large cohort of women.
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Affiliation(s)
- Roberta Venturella
- Department of Obstetrics and Gynaecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Valentino De Vivo
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Annunziata Carlea
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Pietro D'Alessandro
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Gabriele Saccone
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy. Electronic Address:
| | - Bruno Arduino
- Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Francesco Paolo Improda
- Department of Obstetrics and Gynaecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Daniela Lico
- Department of Obstetrics and Gynaecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Erika Rania
- Department of Obstetrics and Gynaecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Carmela De Marco
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Giuseppe Viglietto
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Fulvio Zullo
- Department of Obstetrics and Gynaecology, Magna Graecia University of Catanzaro, Catanzaro, Italy
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Peluso JJ, Pru CA, Liu X, Kelp NC, Pru JK. Progesterone receptor membrane component 1 and 2 regulate granulosa cell mitosis and survival through a NFΚB-dependent mechanism†. Biol Reprod 2019; 100:1571-1580. [PMID: 30877763 PMCID: PMC6561858 DOI: 10.1093/biolre/ioz043] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 02/13/2019] [Accepted: 03/15/2019] [Indexed: 12/27/2022] Open
Abstract
Progesterone receptor membrane component 1 (PGRMC1) interacts with PGRMC2, and disrupting this interaction in spontaneously immortalized granulosa cells (SIGCS) leads to an inappropriate entry into the cell cycle, mitotic arrest, and ultimately cell death. The present study revealed that PGRMC1 and PGRMC2 localize to the cytoplasm of murine granulosa cells of nonatretric follicles with their staining intensity being somewhat diminished in granulosa cells of atretic follicles. Compared to controls (Pgrmc1fl/fl), the rate at which granulosa cells entered the cell cycle increased in nonatretic and atretic follicles of mice in which Pgrmc1 was conditionally deleted (Pgrmc1d/d) from granulosa cells. This increased rate of entry into the cell cycle was associated with a ≥ 2-fold increase in follicular atresia and the nuclear localization of nuclear factor-kappa-B transcription factor P65; (NFΚB/p65, or RELA). GTPase activating protein binding protein 2 (G3BP2) binds NFΚB/p65 through an interaction with NFΚB inhibitor alpha (IκBα), thereby maintaining NFΚB/p65's cytoplasmic localization and restricting its transcriptional activity. Since PGRMC1 and PGRMC2 bind G3BP2, studies were designed to assess the functional relationship between PGRMC1, PGRMC2, and NFΚB/p65 in SIGCs. In these studies, disrupting the interaction between PGRMC1 and PGRMC2 increased the nuclear localization of NFΚB/p65, and depleting PGRMC1, PGRMC2, or G3BP2 increased NFΚB transcriptional activity and the progression into the cell cycle. Taken together, these studies suggest that PGRMC1 and 2 regulate granulosa cell cycle entry in follicles by precisely controlling the localization and thereby the transcriptional activity of NFΚB/p65.
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Affiliation(s)
- John J Peluso
- Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA
- Department of and Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Cindy A Pru
- Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USA
| | - Xiufang Liu
- Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - Nicole C Kelp
- Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USA
| | - James K Pru
- Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, Washington, USA
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Xu X, Zhang Y, Zhao S, Bian Y, Ning Y, Qin Y. Mutational analysis of theFAM175A gene in patients with premature ovarian insufficiency. Reprod Biomed Online 2019; 38:943-950. [PMID: 31000350 DOI: 10.1016/j.rbmo.2019.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 12/30/2018] [Accepted: 02/01/2019] [Indexed: 01/15/2023]
Abstract
RESEARCH QUESTION The family with sequence similarity 175 member A gene (FAM175A; also known as ABRAXAS1, CCDC98 and ABRA1), a member of the DNA repair family, contributes to the BRCA1 (BRCA1 DNA repair associated)-dependent DNA damage response and is associated with age at natural menopause. However, it remains poorly understood whether sequence variants in FAM175A are causative for premature ovarian insufficiency (POI). The aim of this study was to investigate whether mutations in the gene FAM175A were present in patients with POI. DESIGN A total of 400 women with idiopathic POI and 498 control women with regular menstruation (306 age-matched women and 192 women over 40 years old) were recruited. After Sanger sequencing of FAM175A, functional experiments were carried out to explore the deleterious effects of the identified variation. DNA damage was subsequently induced by mitomycin C (MMC), and DNA repair capacity and G2-M checkpoint activation were evaluated by examining the phosphorylation level of H2AX (H2A histone family, member X) and the percentage of mitotic cells, respectively. RESULTS One rare single-nucleotide polymorphism, rs755187051 in gene FAM175A, c.C727G (p.L243V), was identified in two patients but absent in the 498 controls. The functional experiments demonstrated that overexpression of variant p.L243V in HeLa cells resulted in a similar sensitivity to MMC-induced damage compared with cells transfected with wild-type FAM175A. Moreover, after treatment with MMC, there were no differences in DNA repair capacity and G2-M checkpoint activation between the mutant and wild-type genes. CONCLUSION Our results suggest that the p.L243V variant of FAM175A may not be causative for POI. The contribution of FAM175A to POI needs further exploration.
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Affiliation(s)
- Xiaofei Xu
- Centre for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China; Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Yingxin Zhang
- Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong, China
| | - Shidou Zhao
- Centre for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
| | - Yuehong Bian
- Centre for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
| | - Yunna Ning
- Centre for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
| | - Yingying Qin
- Centre for Reproductive Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China.
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Jedidi I, Ouchari M, Yin Q. Sex chromosomes-linked single-gene disorders involved in human infertility. Eur J Med Genet 2018; 62:103560. [PMID: 31402110 DOI: 10.1016/j.ejmg.2018.10.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 10/01/2018] [Accepted: 10/24/2018] [Indexed: 10/28/2022]
Abstract
Human infertility is a healthcare problem that has a worldwide impact. Genetic causes of human infertility include chromosomal aneuploidies and rearrangements and single-gene defects. The sex chromosomes (X and Y) are critical players in human fertility since they contain several genes essential for sex determination and reproductive traits for both men and women. This paper provides a review of the most common sex chromosomes-linked single-gene disorders involved in human infertility and their corresponding phenotypes. In addition to the Y-linked SRY gene, which mutations may cause XY gonadal dysgenesis and sex reversal, the deletions of genes present in AZF regions of the Y chromosome (DAZ, RBMY, DBY and USP9Y genes) are implicated in varying degrees of spermatogenic dysfunction. Furthermore, a list of X-linked genes (KAL1, NR0B1, AR, TEX11, FMR1, PGRMC1, BMP15 and POF1 and 2 regions genes (XPNPEP2, POF1B, DACH2, CHM and DIAPH2)) were reported to have critical roles in pubertal and reproductive deficiencies in humans, affecting only men, only women or both sexes. Mutations in these genes may be transmitted to the offspring by a dominant or a recessive inheritance.
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Affiliation(s)
- Ines Jedidi
- Faculty of Medicine of Sousse, Sousse, Tunisia.
| | - Mouna Ouchari
- Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Qinan Yin
- Clinical Center, National Institutes of Health, Bethesda, MD, USA; Department of Obstetrics and Gynecology, China Meitan General Hospital, Beijing, China
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Zargar MH, Shafia S, Masoodi SR, Mahajan Q, Khan N, Ahmad R. Variations in the inhibin gene in Kashmiri women with primary ovarian insufficiency. HUM FERTIL 2018; 23:111-116. [PMID: 30340444 DOI: 10.1080/14647273.2018.1525502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Inhibin is a glycoprotein produced by granulosa cells and its main function is the negative feedback control of follicle stimulating hormone (FSH) which has an important role in folliculogenesis. Mutation in the INHα gene leading to decreased bioactive inhibin has been associated with primary ovarian insufficiency (POI). The aim of this study was to investigate the role of variations in the INHα gene in increasing the susceptibility to POI in Kashmiri women. INHα c.769G > A mutation was analysed in 100 POI cases and 100 controls using PCR-RFLP and agarose gel electrophoresis. The INHα c.769G > A mutation was found in 10% of POI cases with 8% having heterozygous mutation and 2% having a homozygous mutation. The frequency of mutation in healthy controls was zero. Statistically, a very significant association was found between INHα c.769G > A mutation and the occurrence of POI (p = 0.0015). Moreover, the mutation was also significantly associated with high levels of FSH in POI patients (p < 0.0001). Given the significant association of INHα c.769G > A mutation with the increased FSH levels and POI in Kashmiri population, we suggest this mutation can be used to identify POI variants for screening of women susceptible to POI before the disease onset and can further facilitate putative therapy for such patients.
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Affiliation(s)
- Mahrukh Hameed Zargar
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Syed Shafia
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Shariq Rashid Masoodi
- Department of Endocrinology, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Qurteeba Mahajan
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Nabeela Khan
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
| | - Rehana Ahmad
- Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
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Peluso JJ, Liu X, Uliasz T, Pru CA, Kelp NC, Pru JK. PGRMC1/2 promotes luteal vascularization and maintains the primordial follicles of mice. Reproduction 2018; 156:365-373. [PMID: 30306772 PMCID: PMC6348134 DOI: 10.1530/rep-18-0155] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 07/20/2018] [Accepted: 07/27/2018] [Indexed: 01/05/2023]
Abstract
To determine whether conditional depletion of progesterone receptor membrane component (PGRMC) 1 and PGRMC2 affected ovarian follicle development, follicle distribution was assessed in ovaries of young (≈3-month-old) and middle-aged (≈6-month-old) control (Pgrmc1/2fl/fl) and double conditional PGRMC1/2-knockout (Pgrmc1/2d/d) mice. This study revealed that the distribution of primary, preantral and antral follicles was not altered in Pgrmc1/2d/d mice, regardless of the age. Although the number of primordial follicles was similar at ≈3 months of age, their numbers were reduced by ≈80% in 6-month-old Pgrmc1/2d/d mice compared to age-matched Pgrmc1/2fl/fl mice. The Pgrmc1/2d/d mice were generated using Pgr-cre mice, so ablation of Pgrmc1 and Pgrmc2 in the ovary was restricted to peri-ovulatory follicles and subsequent corpora lutea (CL). In addition, the vascularization of CL was attenuated in Pgrmc1/2d/d mice, although mRNA levels of vascular endothelial growth factor A (Vegfa) were elevated. Moreover, depletion of Pgrmc1 and Pgrmc2 altered the gene expression profile in the non-luteal component of the ovary such that Vegfa expression, a stimulator of primordial follicle growth, was elevated; Kit Ligand expression, another stimulator of primordial follicle growth, was suppressed and anti-Mullerian hormone, an inhibitor of primordial follicle growth, was enhanced compared to Pgrmc1/2fl/fl mice. These data reveal that luteal cell depletion of Pgrmc1 and 2 alters the expression of growth factors within the non-luteal component of the ovary, which could account for the premature demise of the adult population of primordial follicles. In summary, the survival of adult primordial follicles is dependent in part on progesterone receptor membrane component 1 and 2.
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Affiliation(s)
- John J. Peluso
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030
- Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, CT 06030
| | - Xiufang Liu
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030
| | - Tracy Uliasz
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030
| | - Cindy A. Pru
- Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA 99164
| | - Nicole C. Kelp
- Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA 99164
| | - James K. Pru
- Department of Animal Sciences, Center for Reproductive Biology, Washington State University, Pullman, WA 99164
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Will EA, Liu X, Peluso JJ. AG 205, a progesterone receptor membrane component 1 antagonist, ablates progesterone's ability to block oxidative stress-induced apoptosis of human granulosa/luteal cells†. Biol Reprod 2018; 96:843-854. [PMID: 28371915 DOI: 10.1093/biolre/iox013] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 03/21/2017] [Indexed: 12/21/2022] Open
Abstract
The present studies were designed to determine whether progesterone (P4)-progesterone receptor membrane component 1 (PGRMC1) signaling is able to attenuate the apoptotic effects of oxidative stress induced by hydrogen peroxide (H2O2). To achieve this goal, freshly isolated human granulosa/luteal cells were maintained in culture. After several passages, the cells were treated with H2O2, which induced apoptosis within 2.5 h, while simultaneous treatment with P4 attenuated the apoptotic action of H2O2. AG 205, a PGRMC1 antagonist, eliminated P4's ability to prevent H2O2-induced apoptosis. AG 205 neither affected PGRMC1's cytoplasmic localization nor its interaction with PGRMC2, but appeared to reduce its presence within the nucleus. AG 205 also (1) increased the monomeric and decreased the higher molecular weight forms of PGRMC1 (i.e., dimers/oligomers) and (2) altered the expression of several genes involved in apoptosis. The most dramatic change was an approximate 8-fold increase in Harakiri (Hrk) mRNA. However, AG 205 did not induce apoptosis in the absence of H2O2. Taken together, these observations suggest that the higher molecular weight forms of PGRMC1 likely account in part for PGRMC1's ability to suppress the expression of Hrk. Harakiri is a BH-3 only member of the B-cell lymphoma 2 (BCL2) family that promotes apoptosis by binding to and antagonizing the antiapoptotic action of BCL2- and BCL2-like proteins. It is likely then that PGRMC1's ability to suppress Hrk is part of the mechanism through which P4-PGRMC1 signaling preserves the viability of human granulosa/luteal cells.
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Affiliation(s)
- Erica Anspach Will
- Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut, USA.,The Center for Advanced Reproductive Services, Farmington Connecticut, USA
| | - Xiufang Liu
- Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA
| | - John J Peluso
- Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut, USA
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Primary ovarian insufficiency associated with autosomal abnormalities: from chromosome to genome-wide and beyond. Menopause 2018; 23:806-15. [PMID: 27045702 DOI: 10.1097/gme.0000000000000603] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
OBJECTIVE The pathophysiology of primary ovarian insufficiency (POI) is not well elucidated. Many candidate genetic aberrations are on the X-chromosome; on the contrary, many genetic perturbations are also on the autosomes. The aim of this review is to summarize the knowledge of genetic aberrations on autosomes from chromosomal rearrangement, gene abnormality, genome-wide association studies and epigenetics. METHODS Searches of electronic databases were performed. Articles and abstracts relevant to POI and genetic studies associated with autosomes were summarized in this interpretive literature review. RESULTS Various genetic aberrations located on the autosomes were found. These abnormalities are from chromosomal rearrangement, which might disrupt the critical region on chromosome loci or disturbance of the meiosis process. Specific gene aberrations are also identified. The genes that have functions in ovarian development, folliculogenesis, and steroidogenesis on autosomes are proposed to be involved from gene association studies. Gene-to-gene interaction or epistasis also might play a role in POI occurrence. Recently, genetic techniques to study the whole genome have emerged. Although no specific conclusion has been made, the studies using genome-wide association to find the specific aberration throughout the genome in POI have been published. Epigenetic mechanisms might also take part in the pathogenesis of POI. CONCLUSIONS The considerably complex process of POI is still not well understood. Further research is needed for gene functional validation studies to confirm the contribution of genes in POI, or additional genome-wide association studies using novel clustered regularly interspaced short palindromic repeat/Cas9 technique might make these mechanisms more comprehensible.
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Hyon C. [Usefulness of CGH-array and SNP-array for the etiological diagnosis of premature ovarian insufficiency]. Biol Aujourdhui 2018; 211:199-205. [PMID: 29412129 DOI: 10.1051/jbio/2017025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Indexed: 11/14/2022]
Abstract
Premature ovarian insufficiency (POI) defined by the cessation of ovarian function before the age of 40 years and the increase of gonadotropins (> 25 UI/l) occurs in approximately 1-5% of women. Different mechanisms are responsible for POI: chemotherapy, radiotherapy, environmental factors or genetic causes but most frequently no cause is identified. In order to determine the etiology of POI, cytogenetic analyses such as karyotype are performed. The karyotype allows to identify abnormalities of the number of chromosomes as well as abnormalities of the structure such as translocations, deletions or insertions of a size greater than 5-10 Mb… Turner syndrome is the most frequent genetic cause of POI and deletions of the long arm of the X chromosome are other causes of POI identified by the karyotype. However, the resolution of the karyotype is low and other cytogenetic techniques were developed such as all genome microarray analysis. This technique includes CGH-array and SNP-array and allows to identify gain or loss of chromosomal material as small as 10 kb but not the balanced structural rearrangements. Different studies using microarray analysis in cohorts of patients presenting with POI identify candidate genes responsible for POI. Furthermore, they allowed to identify a recurrent microdeletion, which includes the CPEB1 gene, located in 15q25.2 in about 1.5% of patients with POI.
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Affiliation(s)
- Capucine Hyon
- AP-HP, GHUEP, Hôpital Armand Trousseau, Département de Génétique Médicale, Paris, France - INSERM, UMRS 933, Hôpital Armand Trousseau, Paris, France - Sorbonne Universités, UPMC Univ Paris 06, Paris, France
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Wu XJ, Thomas P, Zhu Y. Pgrmc1 Knockout Impairs Oocyte Maturation in Zebrafish. Front Endocrinol (Lausanne) 2018; 9:560. [PMID: 30319543 PMCID: PMC6165893 DOI: 10.3389/fendo.2018.00560] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 09/03/2018] [Indexed: 12/30/2022] Open
Abstract
Recent investigations suggest progestin receptor membrane component 1 (PGRMC1) associates with and transports a wide range of molecules such as heme, cytochromes P450, steroids with 21 carbons, membrane progestin receptor alpha (mPRα/Paqr7), epidermal growth factor receptor (EGFR), and insulin receptor. It is difficult to discriminate the true functions of PGRMC1 from the functions of its associated molecules using biochemical and pharmacological approaches. To determine the physiological function(s) of PGRMC1, we generated global knockouts for pgrmc1 (pgrmc1 -/-) in zebrafish. We found a reduction in both spawning frequency and the number of embryos produced by female mutants. We also observed reduced sensitivity of fully-grown immature oocytes to a progestin hormone and a reduced number of oocytes undergone meiotic maturation both in vivo and in vitro in pgrmc1 -/-. This reduced sensitivity to progestin corresponds well with significant reduced expression of mPRα, the receptor mainly responsible for mediating oocyte maturation and meiosis resumption in fish. The results provide in vivo and in vitro evidence for the physiological functions of Pgrmc1 in oocyte maturation and fertility, as well as a plausible molecular mechanism via regulation of mPRα, which in turn directly regulates oocyte maturation and affects fertility in zebrafish.
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Affiliation(s)
- Xin-Jun Wu
- Department of Biology, East Carolina University, Greenville, NC, United States
| | - Peter Thomas
- Marine Science Institute, University of Texas at Austin, Port Aransas, TX, United States
| | - Yong Zhu
- Department of Biology, East Carolina University, Greenville, NC, United States
- *Correspondence: Yong Zhu
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Thakur M, Feldman G, Puscheck EE. Primary ovarian insufficiency in classic galactosemia: current understanding and future research opportunities. J Assist Reprod Genet 2017; 35:3-16. [PMID: 28932969 DOI: 10.1007/s10815-017-1039-7] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 09/03/2017] [Indexed: 02/06/2023] Open
Abstract
Classic galactosemia is an inborn error of the metabolism with devastating consequences. Newborn screening has been successful in markedly reducing the acute neonatal symptoms from this disorder. The dramatic response to dietary treatment is one of the major success stories of newborn screening. However, as children with galactosemia achieve adulthood, they face long-term complications. A majority of women with classic galactosemia develop primary ovarian insufficiency and resulting morbidity. The underlying pathophysiology of this complication is not clear. This review focuses on the reproductive issues seen in girls and women with classic galactosemia. Literature on the effects of classic galactosemia on the female reproductive system was reviewed by an extensive Pubmed search (publications from January 1975 to January 2017) using the keywords: galactosemia, ovarian function/dysfunction, primary ovarian insufficiency/failure, FSH, oxidative stress, fertility preservation. In addition, articles cited in the search articles and literature known to the authors was also included in the review. Our understanding of the role of galactose metabolism in the ovary is limited and the pathogenic mechanisms involved in causing primary ovarian insufficiency are unclear. The relative rarity of galactosemia makes it difficult to accumulate data to determine factors defining timing of ovarian dysfunction or treatment/fertility preservation options for this group of women. In this review, we present reproductive challenges faced by women with classic galactosemia, highlight the gaps in our understanding of mechanisms leading to primary ovarian insufficiency in this population, discuss new advances in fertility preservation options, and recommend collaboration between reproductive medicine and metabolic specialists to improve fertility in these women.
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Affiliation(s)
- Mili Thakur
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, 48201, USA. .,Division of Genetic, Genomic and Metabolic Disorders, Department of Pediatrics and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA. .,The Fertility Center, 3230 Eagle Park Dr. NE, Suite 100, Grand Rapids, MI, 49525, USA.
| | - Gerald Feldman
- Division of Genetic, Genomic and Metabolic Disorders, Department of Pediatrics and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, 48201, USA.,Department of Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA
| | - Elizabeth E Puscheck
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, 48201, USA
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40
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Salsano S, Quiñonero A, Pérez S, Garrido Gómez T, Simón C, Dominguez F. Dynamic expression of PGRMC1 and SERBP1 in human endometrium: an implication in the human decidualization process. Fertil Steril 2017; 108:832-842.e1. [PMID: 28911927 DOI: 10.1016/j.fertnstert.2017.07.1163] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/18/2017] [Accepted: 07/27/2017] [Indexed: 11/27/2022]
Abstract
OBJECTIVE To characterize PGRMC1 and SERBP1 in human endometrium and to investigate the putative role of PGRMC1 in endometrial decidualization. DESIGN The PGRMC1 and SERBP1 expression in human endometrium was determined throughout the menstrual cycle. We analyzed the colocalization of PGRMC1 and SERBP1. Then, endometrial stromal cells (ESCs) were isolated to investigate the functional effect of PGRMC1 overexpression on decidualization. SETTING IVI clinic. PATIENT(S) Endometrial biopsies were collected from fertile volunteers (n = 61) attending the clinic as ovum donors. INTERVENTION(S) Endometrial samples of 61 healthy fertile women. MAIN OUTCOME MEASURE(S) In vivo localization of PGRMC1 and SERBP1 was assessed by immunohistochemistry. The PGRMC1/SERBP1 colocalization was investigated in vitro and in vivo. Decidualization effect of PGRMC1 overexpression was evaluated in primary ESC cultures. RESULT(S) The PGRMC1 was detected in the endometrial stroma throughout the menstrual cycle, but decreased in the late secretory phase. The SERBP1 immunostaining was present in stroma and increased in the entire the menstrual cycle. The PGRMC1 and SERBP1 colocalized in the cytoplasmic fractions of nondecidualized and decidualized ESC. The PGRMC1 overexpression significantly inhibited in vitro decidualization. CONCLUSION(S) Our results suggest that classic P receptors (PRs) are not the only kind playing a role in the normal physiology of the endometrium. The human decidualization process could be altered by the overexpression or mislocalization of PGRMC1 in ESC.
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Affiliation(s)
- Stefania Salsano
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Valencia, Spain
| | - Alicia Quiñonero
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Valencia, Spain
| | - Silvia Pérez
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Valencia, Spain
| | - Tamara Garrido Gómez
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Valencia, Spain; Igenomix Academy, Valencia, Spain; Department of Pediatrics, Obstetrics and Gynaecology, School of Medicine, Valencia University, Valencia, Spain
| | - Carlos Simón
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain; Igenomix Academy, Valencia, Spain; Department of Pediatrics, Obstetrics and Gynaecology, School of Medicine, Valencia University, Valencia, Spain; Department of Obstetrics and Gynaecology, Stanford University School of Medicine, Stanford, California
| | - Francisco Dominguez
- Fundación Instituto Valenciano de Infertilidad (FIVI), Instituto Universitario IVI (IUIVI), Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain.
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Komatsu K, Masubuchi S. The concentration-dependent effect of progesterone on follicle growth in the mouse ovary. J Reprod Dev 2017; 63:271-277. [PMID: 28321005 PMCID: PMC5481629 DOI: 10.1262/jrd.2016-154] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Follicle growth in the mammalian ovary is coordinately controlled by multiple factors to sustain periodic ovulation. In this study, we investigated the role of progesterone on follicle growth in the mouse ovary. As the concentration of progesterone changes during the estrus cycle, we cultured the sliced mouse ovary in a medium containing 10 ng/ml, 100 ng/ml, and 1 μg/ml progesterone. Progesterone promoted the growth of primordial to primary follicles at 100 ng/ml, while it suppressed the growth of secondary follicles at 1 μg/ml. Follicles at other developmental stages in the cultured ovary were unaffected with different concentrations of progesterone. The number of ovulated oocytes increased in the medium containing 100 ng/ml progesterone but decreased in the presence of 1 μg/ml progesterone. Follicles expressed two types of progesterone receptors, progesterone receptor (PGR) and PGR membrane component 1 (PGRMC1). While PGR shows transient expression on granulosa cells of Graafian follicles, PGRMC1 expresses in granulosa cells of developing follicles. These results suggest that progesterone controls the growth of developing follicles through PGRMC1. Our study shows that the effect of progesterone on ovulation and follicle growth in mouse ovary is dependent on the concentration of progesterone and the follicle stage.
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Affiliation(s)
- Kouji Komatsu
- Department of Physiology, Aichi Medical University, Aichi 480-1195, Japan
| | - Satoru Masubuchi
- Department of Physiology, Aichi Medical University, Aichi 480-1195, Japan
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Rossetti R, Ferrari I, Bonomi M, Persani L. Genetics of primary ovarian insufficiency. Clin Genet 2016; 91:183-198. [PMID: 27861765 DOI: 10.1111/cge.12921] [Citation(s) in RCA: 132] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 11/10/2016] [Accepted: 11/11/2016] [Indexed: 12/15/2022]
Abstract
Primary ovarian insufficiency (POI) is characterized by a loss of ovarian function before the age of 40 and account for one major cause of female infertility. POI relevance is continuously growing because of the increasing number of women desiring conception beyond 30 years of age, when POI prevalence is >1%. POI is highly heterogeneous and can present with ovarian dysgenesis and primary amenorrhea, or with secondary amenorrhea, and it can be associated with other congenital or acquired abnormalities. In most cases POI remains classified as idiopathic. However, the age of menopause is an inheritable trait and POI has a strong genetic component. This is confirmed by the existence of several candidate genes, experimental and natural models. The variable expressivity of POI defect may indicate that, this disease may frequently be considered as a multifactorial or oligogenic defect. The most common genetic contributors to POI are the X chromosome-linked defects. Here, we review the principal X-linked and autosomal genes involved in syndromic and non-syndromic forms of POI with the expectation that this list will soon be upgraded, thus allowing the possibility to predict the risk of an early age at menopause in families with POI.
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Affiliation(s)
- R Rossetti
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - I Ferrari
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy
| | - M Bonomi
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - L Persani
- Department of Endocrine and Metabolic Diseases, IRCCS Istituto Auxologico Italiano, Milan, Italy.,Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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43
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Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum. Endocr Rev 2016; 37:609-635. [PMID: 27690531 DOI: 10.1210/er.2016-1047] [Citation(s) in RCA: 153] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Premature ovarian insufficiency (POI) is one form of female infertility, defined by loss of ovarian activity before the age of 40 and characterized by amenorrhea (primary or secondary) with raised gonadotropins and low estradiol. POI affects up to one in 100 females, including one in 1000 before the age of 30. Substantial evidence suggests a genetic basis for POI; however, the majority of cases remain unexplained, indicating that genes likely to be associated with this condition are yet to be discovered. This review discusses the current knowledge of the genetic basis of POI. We highlight genes typically known to cause syndromic POI that can be responsible for isolated POI. The role of mouse models in understanding POI pathogenesis is discussed, and a thorough list of candidate POI genes is provided. Identifying a genetic basis for POI has multiple advantages, such as enabling the identification of presymptomatic family members who can be offered counseling and cryopreservation of eggs before depletion, enabling personalized treatment based on the cause of an individual's condition, and providing better understanding of disease mechanisms that ultimately aid the development of improved treatments.
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Affiliation(s)
- Elena J Tucker
- Murdoch Children's Research Institute (E.J.T., S.R.G., A.H.S.), Royal Children's Hospital, Melbourne, VIC 3052 Australia; Department of Paediatrics (E.J.T., S.R.G., A.H.S.), University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatric and Adolescent Gynaecology (S.R.G.), Royal Children's Hospital, Melbourne, VIC 3052, Australia; Assistance Publique Hôpitaux de Paris, (A.B., P.T.), IE3M, Université Pierre et Marie Curie, Paris 6 University, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et des Pathologies Gynécologiques Rares, Pitié-Salpêtrière Hospital, Université Pierre et Marie Curie, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale (A.B., P.T.), 75654 Paris, France
| | - Sonia R Grover
- Murdoch Children's Research Institute (E.J.T., S.R.G., A.H.S.), Royal Children's Hospital, Melbourne, VIC 3052 Australia; Department of Paediatrics (E.J.T., S.R.G., A.H.S.), University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatric and Adolescent Gynaecology (S.R.G.), Royal Children's Hospital, Melbourne, VIC 3052, Australia; Assistance Publique Hôpitaux de Paris, (A.B., P.T.), IE3M, Université Pierre et Marie Curie, Paris 6 University, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et des Pathologies Gynécologiques Rares, Pitié-Salpêtrière Hospital, Université Pierre et Marie Curie, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale (A.B., P.T.), 75654 Paris, France
| | - Anne Bachelot
- Murdoch Children's Research Institute (E.J.T., S.R.G., A.H.S.), Royal Children's Hospital, Melbourne, VIC 3052 Australia; Department of Paediatrics (E.J.T., S.R.G., A.H.S.), University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatric and Adolescent Gynaecology (S.R.G.), Royal Children's Hospital, Melbourne, VIC 3052, Australia; Assistance Publique Hôpitaux de Paris, (A.B., P.T.), IE3M, Université Pierre et Marie Curie, Paris 6 University, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et des Pathologies Gynécologiques Rares, Pitié-Salpêtrière Hospital, Université Pierre et Marie Curie, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale (A.B., P.T.), 75654 Paris, France
| | - Philippe Touraine
- Murdoch Children's Research Institute (E.J.T., S.R.G., A.H.S.), Royal Children's Hospital, Melbourne, VIC 3052 Australia; Department of Paediatrics (E.J.T., S.R.G., A.H.S.), University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatric and Adolescent Gynaecology (S.R.G.), Royal Children's Hospital, Melbourne, VIC 3052, Australia; Assistance Publique Hôpitaux de Paris, (A.B., P.T.), IE3M, Université Pierre et Marie Curie, Paris 6 University, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et des Pathologies Gynécologiques Rares, Pitié-Salpêtrière Hospital, Université Pierre et Marie Curie, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale (A.B., P.T.), 75654 Paris, France
| | - Andrew H Sinclair
- Murdoch Children's Research Institute (E.J.T., S.R.G., A.H.S.), Royal Children's Hospital, Melbourne, VIC 3052 Australia; Department of Paediatrics (E.J.T., S.R.G., A.H.S.), University of Melbourne, Melbourne, VIC 3010, Australia; Department of Paediatric and Adolescent Gynaecology (S.R.G.), Royal Children's Hospital, Melbourne, VIC 3052, Australia; Assistance Publique Hôpitaux de Paris, (A.B., P.T.), IE3M, Université Pierre et Marie Curie, Paris 6 University, Department of Endocrinology and Reproductive Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et des Pathologies Gynécologiques Rares, Pitié-Salpêtrière Hospital, Université Pierre et Marie Curie, 75013 Paris, France; Institut National de la Santé et de la Recherche Médicale (A.B., P.T.), 75654 Paris, France
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Guo M, Zhang C, Wang Y, Feng L, Wang Z, Niu W, Du X, Tang W, Li Y, Wang C, Chen Z. Progesterone Receptor Membrane Component 1 Mediates Progesterone-Induced Suppression of Oocyte Meiotic Prophase I and Primordial Folliculogenesis. Sci Rep 2016; 6:36869. [PMID: 27848973 PMCID: PMC5111101 DOI: 10.1038/srep36869] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Accepted: 10/21/2016] [Indexed: 12/18/2022] Open
Abstract
Well-timed progression of primordial folliculogenesis is essential for mammalian female fertility. Progesterone (P4) inhibits primordial follicle formation under physiological conditions; however, P4 receptor that mediates this effect and its underlying mechanisms are unclear. In this study, we used an in vitro organ culture system to show that progesterone receptor membrane component 1 (PGRMC1) mediated P4-induced inhibition of oocyte meiotic prophase I and primordial follicle formation. We found that membrane-impermeable BSA-conjugated P4 inhibited primordial follicle formation similar to that by P4. Interestingly, PGRMC1 and its partner serpine1 mRNA-binding protein 1 were highly expressed in oocytes in perinatal ovaries. Inhibition or RNA interference of PGRMC1 abolished the suppressive effect of P4 on follicle formation. Furthermore, P4-PGRMC1 interaction blocked oocyte meiotic progression and decreased intra-oocyte cyclic AMP (cAMP) levels in perinatal ovaries. cAMP analog dibutyryl cAMP reversed P4–PGRMC1 interaction-induced inhibition of meiotic progression and follicle formation. Thus, our results indicated that PGRMC1 mediated P4-induced suppression of oocyte meiotic progression and primordial folliculogenesis by decreasing intra-oocyte cAMP levels.
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Affiliation(s)
- Meng Guo
- Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, Peoples' Republic of China
| | - Cheng Zhang
- College of Life Science, Capital Normal University, Beijing 100048, People's Republic of China
| | - Yan Wang
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, Peoples' Republic of China
| | - Lizhao Feng
- State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing 100193, Peoples' Republic of China
| | - Zhengpin Wang
- Laboratory of Cellular and Development Biology, NIDDK, National Institutes of Health, Bethesda MD 20892, USA
| | - Wanbo Niu
- State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing 100193, Peoples' Republic of China
| | - Xiaoyan Du
- Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing 100069, Peoples' Republic of China
| | - Wang Tang
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, Peoples' Republic of China
| | - Yuna Li
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, Peoples' Republic of China
| | - Chao Wang
- State Key Laboratory for Agro-Biotechnology, College of Biological Science, China Agricultural University, Beijing 100193, Peoples' Republic of China
| | - Zhenwen Chen
- Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Capital Medical University, Beijing 100069, Peoples' Republic of China
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Terzaghi L, Tessaro I, Raucci F, Merico V, Mazzini G, Garagna S, Zuccotti M, Franciosi F, Lodde V. PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis. Cell Cycle 2016; 15:2019-32. [PMID: 27260975 DOI: 10.1080/15384101.2016.1192731] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in both oocyte and ovarian somatic cells, where it is found in multiple cellular sub-compartments including the mitotic spindle apparatus. PGRMC1 localization in the maturing bovine oocytes mirrors its localization in mitotic cells, suggesting a possible common action in mitosis and meiosis. To test the hypothesis that altering PGRMC1 activity leads to similar defects in mitosis and meiosis, PGRMC1 function was perturbed in cultured bovine granulosa cells (bGC) and maturing oocytes and the effect on mitotic and meiotic progression assessed. RNA interference-mediated PGRMC1 silencing in bGC significantly reduced cell proliferation, with a concomitant increase in the percentage of cells arrested at G2/M phase, which is consistent with an arrested or prolonged M-phase. This observation was confirmed by time-lapse imaging that revealed defects in late karyokinesis. In agreement with a role during late mitotic events, a direct interaction between PGRMC1 and Aurora Kinase B (AURKB) was observed in the central spindle at of dividing cells. Similarly, treatment with the PGRMC1 inhibitor AG205 or PGRMC1 silencing in the oocyte impaired completion of meiosis I. Specifically the ability of the oocyte to extrude the first polar body was significantly impaired while meiotic figures aberration and chromatin scattering within the ooplasm increased. Finally, analysis of PGRMC1 and AURKB localization in AG205-treated oocytes confirmed an altered localization of both proteins when meiotic errors occur. The present findings demonstrate that PGRMC1 participates in late events of both mammalian mitosis and oocyte meiosis, consistent with PGRMC1's localization at the mid-zone and mid-body of the mitotic and meiotic spindle.
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Affiliation(s)
- L Terzaghi
- a Reproductive and Developmental Biology Laboratory, Department of Health , Animal Science and Food Safety, University of Milan , Milan , Italy
| | - I Tessaro
- a Reproductive and Developmental Biology Laboratory, Department of Health , Animal Science and Food Safety, University of Milan , Milan , Italy
| | - F Raucci
- a Reproductive and Developmental Biology Laboratory, Department of Health , Animal Science and Food Safety, University of Milan , Milan , Italy
| | - V Merico
- b Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani," University of Pavia , Pavia , Italy
| | - G Mazzini
- c Istituto di Genetica Molecolare - Consiglio Nazionale delle Ricerche , Pavia , Italy
| | - S Garagna
- b Dipartimento di Biologia e Biotecnologie "Lazzaro Spallanzani," University of Pavia , Pavia , Italy
| | - M Zuccotti
- d Sezione di Anatomia, Istologia ed Embriologia, Dipartimento di Scienze Biomediche , Biotecnologiche e Traslazionali (S.Bi.Bi.T.), University of Parma , Italy
| | - F Franciosi
- a Reproductive and Developmental Biology Laboratory, Department of Health , Animal Science and Food Safety, University of Milan , Milan , Italy
| | - V Lodde
- a Reproductive and Developmental Biology Laboratory, Department of Health , Animal Science and Food Safety, University of Milan , Milan , Italy
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Vásquez-Velásquez AI, Rivera H, Castro AG, Jaloma-Cruz AR, Juárez CI, Lara-Navarro IJ, Córdova-Fletes C, Mendoza-Pérez P, García-Ortiz JE. Two girls with a de novo Xq rearrangement of paternal origin: t(X;9)(q24;q12) or rea(X)dup q. Taiwan J Obstet Gynecol 2016; 55:275-80. [PMID: 27125414 DOI: 10.1016/j.tjog.2015.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2015] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE We report on two rare Xq rearrangements, namely a t(X;9)(q24;q12) found in a mildly-affected girl (Patient 1) and a rea(X)dup q concomitant with a rob(14;21)mat in a Down syndrome girl (Patient 2). CASE REPORT Both rearrangements were characterized by banding techniques [Giemsa (G), constitutive heterochromatin (C), and bromodeoxyuridine (BrdU) pulse], fluorescence in situ hybridization (FISH) assays, human androgen receptor (HUMAR) assays, and microarray analyses. Patient 1 had a t(X;9)(q24;q12)dn. Patient 2 had a de novo rea(X)(qter→q23 or q24::p11.2→qter) concomitant with an unbalanced rob(14;21)mat. X-Inactivation studies in metaphases and DNA revealed a fully skewed inactivation: the normal homolog was silenced in Patient 1 and the rea(X) in Patient 2. Both rearranged X chromosomes were of paternal descent. Microarray analyses revealed no imbalances in Patient 1 whereas loss of Xp (∼52 Mb) and duplication of Xq (∼44 Mb) and 21q were confirmed in Patient 2. CONCLUSION Our observations further document the cytogenetic heterogeneity and predominant paternal origin of certain de novo X-chromosome rearrangements.
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Affiliation(s)
- Ana I Vásquez-Velásquez
- División de Genética, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
| | - Horacio Rivera
- División de Genética, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico; Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Ana G Castro
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico; Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Ana R Jaloma-Cruz
- División de Genética, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
| | - Clara I Juárez
- División de Medicina Molecular, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico; Doctorado en Genética Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Irving J Lara-Navarro
- Facultad de Biología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Guadalajara, Mexico
| | - Carlos Córdova-Fletes
- Laboratorio de Citogenómica y Microarreglos, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - Paul Mendoza-Pérez
- Laboratorio de Citogenómica y Microarreglos, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Monterrey, Mexico
| | - José E García-Ortiz
- División de Genética, Centro de Investigación Biomédica de Occidente, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico.
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Cavallini A, Lippolis C, Vacca M, Nardelli C, Castegna A, Arnesano F, Carella N, Depalo R. The Effects of Chronic Lifelong Activation of the AHR Pathway by Industrial Chemical Pollutants on Female Human Reproduction. PLoS One 2016; 11:e0152181. [PMID: 27008165 PMCID: PMC4805276 DOI: 10.1371/journal.pone.0152181] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 03/09/2016] [Indexed: 12/12/2022] Open
Abstract
Environmental chemicals, such as heavy metals, affect female reproductive function. A biological sensor of the signals of many toxic chemical compounds seems to be the aryl hydrocarbon receptor (AHR). Previous studies demonstrated the environmental of heavy metals in Taranto city (Italy), an area that has been influenced by anthropogenic factors such as industrial activities and waste treatments since 1986. However, the impact of these elements on female fertility in this geographic area has never been analyzed. Thus, in the present study, we evaluated the AHR pathway, sex steroid receptor pattern and apoptotic process in granulosa cells (GCs) retrieved from 30 women, born and living in Taranto, and 30 women who are living in non-contaminated areas (control group), who were undergoing in vitro fertilization (IVF) protocol. In follicular fluids (FFs) of both groups the toxic and essential heavy metals, such as chromiun (Cr), Manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd) and lead (Pb), were also analyzed. Higher levels of Cr, Fe, Zn and Pb were found in the FFs of the women from Taranto as compared to the control group, as were the levels of AHR and AHR-dependent cytochrome P450 1A1 and 1B1; while CYP19A1 expression was decreased. The anti-apoptotic process found in the GCs of women fromTaranto was associated with the highest levels of progesterone receptor membrane component 1 (PGRMC1), a novel progesterone receptor, the expression of which is subjected to AHR activated by its highest affinity ligands (e.g., dioxins) or indirectly by other environmental pollutants, such as heavy metals. In conclusion, decreased production of estradiol and decreased number of retrieved mature oocytes found in women from Taranto could be due to chronic exposure to heavy metals, in particular to Cr and Pb.
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Affiliation(s)
- Aldo Cavallini
- Laboratory of Cellular and Molecular Biology, Dept. Clinical Pathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, via Turi 27, 70013, Castellana Grotte (BA), Italy
- * E-mail:
| | - Catia Lippolis
- Laboratory of Cellular and Molecular Biology, Dept. Clinical Pathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, via Turi 27, 70013, Castellana Grotte (BA), Italy
| | - Margherita Vacca
- Unit of Pathophysiology of Human Reproduction and Gametes Cryopreservation, Dept. of General Surgery, Gynecology, Obstetrics and Anesthesiology, University Hospital of Bari, Consorziale, Policlinico. piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Claudia Nardelli
- Unit of Pathophysiology of Human Reproduction and Gametes Cryopreservation, Dept. of General Surgery, Gynecology, Obstetrics and Anesthesiology, University Hospital of Bari, Consorziale, Policlinico. piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Alessandra Castegna
- Dept. of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari “A. Moro”, via E. Orabona 4, 70125, Bari, Italy
| | - Fabio Arnesano
- Dept. of Chemistry, University of Bari “A. Moro”, via E. Orabona 4, 70125, Bari, Italy
| | - Nicola Carella
- Laboratory of Cellular and Molecular Biology, Dept. Clinical Pathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, via Turi 27, 70013, Castellana Grotte (BA), Italy
| | - Raffaella Depalo
- Unit of Pathophysiology of Human Reproduction and Gametes Cryopreservation, Dept. of General Surgery, Gynecology, Obstetrics and Anesthesiology, University Hospital of Bari, Consorziale, Policlinico. piazza Giulio Cesare 11, 70124, Bari, Italy
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48
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Meng Y, Murtha AP, Feng L. Progesterone, Inflammatory Cytokine (TNF-α), and Oxidative Stress (H2O2) Regulate Progesterone Receptor Membrane Component 1 Expression in Fetal Membrane Cells. Reprod Sci 2016; 23:1168-78. [PMID: 26919974 DOI: 10.1177/1933719116630412] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Progesterone receptor membrane component 1 (PGRMC1) is an important novel mediator of progesterone (P4) function in fetal membrane cells. We demonstrated previously that PGRMC1 is differentially expressed in fetal membranes among pregnancy subjects and diminished in preterm premature rupture of membrane subjects. In the current study, we aim to elucidate whether PGRMC1 expression is regulated by P4, tumor necrosis factor α (TNF-α), and H2O2 in fetal membrane cells. Primary cultured membrane cells were serum starved for 24 hours followed by treatments of P4, 17 hydroxyprogesterone caproate, and medroxyprogesterone 17 acetate (MPA) at 10(-7) mol/L with ethanol as vehicle control; TNF-α at 10, 20, and 50 ng/mL with phosphate-buffered saline (PBS) as control; and H2O2 at 10 and 100 μmol/L with culture media as control for 24, 48, and 72 hours. The messenger RNA (mRNA) and protein expression of PGRMC1 was quantified using polymerase chain reaction and Western blotting, respectively. We found that PGRMC1 protein expression was regulated by MPA, TNF-α, and H2O2 in a dose-dependent manner. This regulation is also specific to the type of cell (amnion, chorion, or decidua). The upregulation of PGRMC1 by MPA might be mediated through glucocorticoid receptor (GR) demonstrated using amnion and chorion cells model with GR knockdown by specific small interfering RNA transfection. The mRNA expression of PGRMC1 was decreased by H2O2 (100 μmol/L) treatment in amnion cells, which might ultimately result in downregulation of PGRMC1 protein as our data demonstrated. None of other treatments changed PGRMC1 mRNA level in these cells. We conclude that these stimuli act as regulatory factors of PGRMC1 in a cell-specific manner.
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Affiliation(s)
- Yan Meng
- Department of Obstetrics and Gynecology, Jishuitan Hospital, Beijing, China
| | - Amy P Murtha
- Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA
| | - Liping Feng
- Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA
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49
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Hampton KK, Stewart R, Napier D, Claudio PP, Craven RJ. PGRMC1 Elevation in Multiple Cancers and Essential Role in Stem Cell Survival. ACTA ACUST UNITED AC 2016; 4:37-51. [PMID: 27867772 PMCID: PMC5113835 DOI: 10.4236/alc.2015.43006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cancer is one of the leading causes of death in America, and there is an urgent need for new therapeutic approaches. The progesterone receptor membrane component 1 (PGRMC1) is a cytoch-rome b5 related protein that binds heme and is associated with signaling, apoptotic suppression and autophagy. PGRMC1 is essential for tumor formation, invasion and metastasis, and is upregulated in breast, colon, lung and thyroid tumors. In the present study, we have analyzed PGRMC1 levels in over 600 tumor sections, including a larger cohort of lung tumors than in previous studies, and report the first clinical analysis of PGRMC1 levels in human oral cavity and ovarian tumors compared to corresponding nonmalignant tissues. PGRMC1 was highly expressed in lung and ovarian cancers and correlated with patient survival. PGRMC1 has been previously associated with drug resistance, a characteristic of cancer stem cells. The stem cell theory proposes that a subset of cancerous stem cells contribute to drug resistance and tumor maintenance, and PGRMC1 was detected in lung-tumor derived stem cells. Drug treatment with a PGRMC1 inhibitor, AG-205, triggered stem cell death whereas treatment with erlotinib and the ERK inhibitor, PD98059, did not, suggesting a specific role for PGRMC1 in cancer stem cell viability. Together, our data demonstrate PGRMC1 as a potential tumor biomarker across a variety of tumors, as well as a therapeutic target for cancer stem cells.
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Affiliation(s)
- Kaia K Hampton
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Rachel Stewart
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Dana Napier
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Pier Paolo Claudio
- Department of Biomolecular Sciences and National Center for Natural Products Research, School of Pharmacy, University of Mississippi, Oxford, MS, USA; Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Rolf J Craven
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Markey Cancer Center, University of Kentucky, Lexington, KY, USA
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50
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Abstract
As age at pubertal onset declines and age at first pregnancy increases, the mechanisms that regulate female reproductive lifespan become increasingly relevant to population health. The timing of menarche and menopause can have profound effects not only on fertility but also on the risk of diseases such as type 2 diabetes mellitus, cardiovascular disease and breast cancer. Genetic studies have identified dozens of highly penetrant rare mutations associated with reproductive disorders, and also ∼175 common genetic variants associated with the timing of puberty or menopause. These findings, alongside other functional studies, have highlighted a diverse range of mechanisms involved in reproductive ageing, implicating core biological processes such as cell cycle regulation and energy homeostasis. The aim of this article is to review the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing, as well as the biological basis of the epidemiological links between reproductive ageing and disease risk.
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Affiliation(s)
- John R.B. Perry
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ
| | - Anna Murray
- Genetics of Complex Traits, University of Exeter Medical School, RILD Level 3, Royal Devon & Exeter Hospital, Barrack Road, Exeter, EX2 5DW
| | - Felix R Day
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ
| | - Ken K Ong
- MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0QQ
- Department of Paediatrics, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ
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