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Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 75611

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Special Issue Editors

Prof. Dr. Micheline Misrahi

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Guest Editor

Unité de Génétique Moléculaire des Maladies Métaboliques et de la Reproduction, APHP Hôpitaux Universitaires Paris-Saclay, Hôpital Bicêtre, Faculté de Médecine Paris Saclay, 94275 Le Kremlin-Bicêtre, France
Interests: molecular and cellular mechanisms in reproductive endocrinology; nuclear receptors; membrane receptors; gonadotropins and their receptors; thyrotropin receptor; reproductive genetics; genetics of male and female infertility; primary ovarian insufficiency; disorders of puberty; genetic diseases of GPCR
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ilpo Huhtaniemi

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Guest Editor

Institute of Reproductive and Developmental Biology, Department of Surgery & Cancer, Imperial College London, Hammersmith Campus, Du Canoe Roan London W12 0NN, UK
Interests: Gonadotrophin action; G-Protein coupled receptor signalling in reproduction and cancer; Physiology and pathophysiology of the hypothalamic-pituitary-gonadal axis; Male contraception; Endocrinology of ageing

Special Issue Information

Dear Colleagues,

Despite the major developments that have taken place in the field in the last few decades, infertility still poses a major diagnostic and therapeutic challenge, and overall, less than 50% of couples attending infertility treatments can be helped. About 1 out of 7 couples have difficulties to conceive, and the figure is bound to increase due to the demographic change with regard to the increase in maternal age when acquiring children. Very roughly, in about 1/3 of couples, the cause of infertility can be traced back to the female side, 1/3 to the male side, and in 1/3 of cases, the cause can be found in both. Primary ovarian insufficiency (POI) affects ~1% of women before they reach 40 years of age. The most frustrating cases are idiopathic (15–30% of couples), where no cause and no rational treatment can be offered. For these reasons, new information about the pathogenesis, diagnosis, and treatment of male and female infertility is urgently needed. This Special Issue aims to review recent research on male and female infertility. The recent leap in genetic knowledge obtained through next-generation sequencing (NGS) together with animal models has further elucidated their molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes or more than 100 genes in isolated female and male infertility, respectively, emphasize the high genetic heterogeneity. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling. Defects in meiosis or DNA repair genes may predispose to tumors. Specific gene mutations may predict the risk of a rapid loss of a persistent ovarian reserve in women, an important determinant in fertility preservation. Novel physiology and newly identified regulators of ovarian folliculogenesis and ovulation will be developed. Novel mechanisms that regulate the activation of primordial follicles have been unraveled, and they lead to innovative treatments. Indeed, a recent treatment of POI by in vitro activation of dormant follicles (IVA) proved successful. Other innovative treatments are in development (e.g., stem cells). On the male side, the latest data on hormonal regulation of spermatogenesis, genetic and epigenetic approaches to addressing idiopathic failure of spermatogenesis, attempts to achieve in vitro spermatogenesis, the effect of general health on male fertility, and new treatment modalities and their outcome will be reviewed.

Prof. Dr. Micheline Misrahi
Prof. Dr. Ilpo Huhtaniemi
Guest Editors

Manuscript Submission Information

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Keywords

Spermatogenesis
Infertility
Hypothalamic–pituitary–gonadal axis
In vitro fertilization (IVF)
Intracytoplasmic sperm injection (ICVSI)
Hypogonadism
Primary ovarian insufficiency
Next generation sequencing
Meiosis
DNA repair
In vitro activation of dormant follicles (IVA)
Stem cells

Published Papers (10 papers)

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Research

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13 pages, 4372 KiB

Open AccessArticle

Cbx2, a PcG Family Gene, Plays a Regulatory Role in Medaka Gonadal Development

by Qinghe Chao, Fengfeng Shen, Yidong Xue, Jikui Wu and Junling Zhang

Int. J. Mol. Sci. 2020, 21(4), 1288; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041288 - 14 Feb 2020

Cited by 8 | Viewed by 2555

Abstract

Chromobox homolog 2 (CBX2), a key member of the polycomb group (PcG) family, is essential for gonadal development in mammals. A functional deficiency or genetic mutation in cbx2 can lead to sex reversal in mice and humans. However, little is known about the function of cbx2 in gonadal development in fish. In this study, the cbx2 gene was identified in medaka, which is a model species for the study of gonadal development in fish. Transcription of cbx2 was abundant in the gonads, with testicular levels relatively higher than ovarian levels. In situ hybridization (ISH) revealed that cbx2 mRNA was predominately localized in spermatogonia and spermatocytes, and was also observed in oocytes at stages I, II, and III. Furthermore, cbx2 and vasa (a marker gene) were co-localized in germ cells by fluorescent in situ hybridization (FISH). After cbx2 knockdown in the gonads by RNA interference (RNAi), the sex-related genes, including sox9 and foxl2, were influenced. These results suggest that cbx2 not only plays a positive role in spermatogenesis and oogenesis but is also involved in gonadal differentiation through regulating the expression levels of sex-related genes in fish. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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Review

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33 pages, 1435 KiB

Open AccessReview

Genetics of Azoospermia

by Francesca Cioppi, Viktoria Rosta and Csilla Krausz

Int. J. Mol. Sci. 2021, 22(6), 3264; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063264 - 23 Mar 2021

Cited by 52 | Viewed by 10799

Abstract

Azoospermia affects 1% of men, and it can be due to: (i) hypothalamic-pituitary dysfunction, (ii) primary quantitative spermatogenic disturbances, (iii) urogenital duct obstruction. Known genetic factors contribute to all these categories, and genetic testing is part of the routine diagnostic workup of azoospermic men. The diagnostic yield of genetic tests in azoospermia is different in the different etiological categories, with the highest in Congenital Bilateral Absence of Vas Deferens (90%) and the lowest in Non-Obstructive Azoospermia (NOA) due to primary testicular failure (~30%). Whole-Exome Sequencing allowed the discovery of an increasing number of monogenic defects of NOA with a current list of 38 candidate genes. These genes are of potential clinical relevance for future gene panel-based screening. We classified these genes according to the associated-testicular histology underlying the NOA phenotype. The validation and the discovery of novel NOA genes will radically improve patient management. Interestingly, approximately 37% of candidate genes are shared in human male and female gonadal failure, implying that genetic counselling should be extended also to female family members of NOA patients. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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13 pages, 1452 KiB

Open AccessReview

Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility

by Isabelle M. McGrath, Sally Mortlock and Grant W. Montgomery

Int. J. Mol. Sci. 2021, 22(5), 2556; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052556 - 04 Mar 2021

Cited by 17 | Viewed by 3747

Abstract

There is substantial genetic variation for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Progress in high-throughput sequencing and genome-wide association studies (GWAS) have transformed our understanding of common genetic risk factors for complex traits and diseases influencing reproductive lifespan and fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. The observations also identify unique genetic risk factors specific to different reproductive diseases impacting on female fertility. Sequencing in patients with primary ovarian insufficiency (POI) have identified mutations in a large number of genes while GWAS have revealed shared genetic risk factors for POI and ovarian ageing. Studies on age at menopause implicate DNA damage/repair genes with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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26 pages, 1506 KiB

Open AccessReview

Metabolic Syndrome and Reproduction

by Francesco Lotti, Sara Marchiani, Giovanni Corona and Mario Maggi

Int. J. Mol. Sci. 2021, 22(4), 1988; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041988 - 17 Feb 2021

Cited by 22 | Viewed by 5273

Abstract

Metabolic syndrome (MetS) and infertility are two afflictions with a high prevalence in the general population. MetS is a global health problem increasing worldwide, while infertility affects up to 12% of men. Despite the high prevalence of these conditions, the possible impact of MetS on male fertility has been investigated by a few authors only in the last decade. In addition, underlying mechanism(s) connecting the two conditions have been investigated in few preclinical studies. The aim of this review is to summarize and critically discuss available clinical and preclinical studies on the role of MetS (and its treatment) in male fertility. An extensive Medline search was performed identifying studies in the English language. While several studies support an association between MetS and hypogonadism, contrasting results have been reported on the relationship between MetS and semen parameters/male infertility, and the available studies considered heterogeneous MetS definitions and populations. So far, only two meta-analyses in clinical and preclinical studies, respectively, evaluated this topic, reporting a negative association between MetS and sperm parameters, testosterone and FSH levels, advocating, however, larger prospective investigations. In conclusion, a possible negative impact of MetS on male reproductive potential was reported; however, larger studies are needed. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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21 pages, 1382 KiB

Open AccessReview

Metabolomic Insight into Polycystic Ovary Syndrome—An Overview

by Anna Rajska, Magdalena Buszewska-Forajta, Dominik Rachoń and Michał Jan Markuszewski

Int. J. Mol. Sci. 2020, 21(14), 4853; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144853 - 09 Jul 2020

Cited by 56 | Viewed by 14938

Abstract

Searching for the mechanisms of the polycystic ovary syndrome (PCOS) pathophysiology has become a crucial aspect of research performed in the last decades. However, the pathogenesis of this complex and heterogeneous endocrinopathy remains unknown. Thus, there is a need to investigate the metabolic pathways, which could be involved in the pathophysiology of PCOS and to find the metabolic markers of this disorder. The application of metabolomics gives a promising insight into the research on PCOS. It is a valuable and rapidly expanding tool, enabling the discovery of novel metabolites, which may be the potential biomarkers of several metabolic and endocrine disorders. The utilization of this approach could also improve the process of diagnosis and therefore, make treatment more effective. This review article aims to summarize actual and meaningful metabolomic studies in PCOS and point to the potential biomarkers detected in serum, urine, and follicular fluid of the affected women. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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18 pages, 315 KiB

Open AccessReview

Newly Identified Regulators of Ovarian Folliculogenesis and Ovulation

by Eran Gershon and Nava Dekel

Int. J. Mol. Sci. 2020, 21(12), 4565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124565 - 26 Jun 2020

Cited by 78 | Viewed by 6731

Abstract

Each follicle represents the basic functional unit of the ovary. From its very initial stage of development, the follicle consists of an oocyte surrounded by somatic cells. The oocyte grows and matures to become fertilizable and the somatic cells proliferate and differentiate into the major suppliers of steroid sex hormones as well as generators of other local regulators. The process by which a follicle forms, proceeds through several growing stages, develops to eventually release the mature oocyte, and turns into a corpus luteum (CL) is known as “folliculogenesis”. The task of this review is to define the different stages of folliculogenesis culminating at ovulation and CL formation, and to summarize the most recent information regarding the newly identified factors that regulate the specific stages of this highly intricated process. This information comprises of either novel regulators involved in ovarian biology, such as Ube2i, Phoenixin/GPR73, C1QTNF, and α-SNAP, or recently identified members of signaling pathways previously reported in this context, namely PKB/Akt, HIPPO, and Notch. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

14 pages, 1248 KiB

Open AccessReview

Kisspeptin and Testicular Function—Is It Necessary?

by Aditi Sharma, Thilipan Thaventhiran, Suks Minhas, Waljit S. Dhillo and Channa N. Jayasena

Int. J. Mol. Sci. 2020, 21(8), 2958; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082958 - 22 Apr 2020

Cited by 27 | Viewed by 5881

Abstract

The role of kisspeptin in stimulating hypothalamic GnRH is undisputed. However, the role of kisspeptin signaling in testicular function is less clear. The testes are essential for male reproduction through their functions of spermatogenesis and steroidogenesis. Our review focused on the current literature investigating the distribution, regulation and effects of kisspeptin and its receptor (KISS1/KISS1R) within the testes of species studied to date. There is substantial evidence of localised KISS1/KISS1R expression and peptide distribution in the testes. However, variability is observed in the testicular cell types expressing KISS1/KISS1R. Evidence is presented for modulation of steroidogenesis and sperm function by kisspeptin signaling. However, the physiological importance of such effects, and whether these are paracrine or endocrine manifestations, remain unclear. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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31 pages, 3119 KiB

Open AccessReview

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

by Nathalia Lisboa Gomes, Tarini Chetty, Anne Jorgensen and Rod T Mitchell

Int. J. Mol. Sci. 2020, 21(7), 2282; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072282 - 26 Mar 2020

Cited by 27 | Viewed by 7479

Abstract

Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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21 pages, 1092 KiB

Open AccessReview

FSH for the Treatment of Male Infertility

by Livio Casarini, Pascale Crépieux, Eric Reiter, Clara Lazzaretti, Elia Paradiso, Vincenzo Rochira, Giulia Brigante, Daniele Santi and Manuela Simoni

Int. J. Mol. Sci. 2020, 21(7), 2270; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072270 - 25 Mar 2020

Cited by 36 | Viewed by 10188

Abstract

Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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20 pages, 7644 KiB

Open AccessReview

Novel Physiology and Definition of Poor Ovarian Response; Clinical Recommendations

by Antoine Abu-Musa, Thor Haahr and Peter Humaidan

Int. J. Mol. Sci. 2020, 21(6), 2110; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062110 - 19 Mar 2020

Cited by 38 | Viewed by 7199

Abstract

Poor ovarian response (POR) to controlled ovarian stimulation (OS) presents a major challenge in assisted reproduction. The Bologna criteria represented the first serious attempt to set clear criteria for the definition of POR. However, the Bologna criteria were questioned because of the persistent heterogeneity among POR patients and the inability to provide management strategies. Based on these facts, a more recent classification, the POSEIDON (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) classification, was developed to provide a homogeneous and refined definition of POR that significantly reduces the heterogeneity of the Bologna criteria definition of POR and helps in the clinical handling and counseling of patients. In this review, we discuss the impact of the POSEIDON classification on the clinical management of patients with POR. Full article

(This article belongs to the Special Issue Novel Physiology and Molecular Pathology of Reproduction, Novel Treatments of Infertility)

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