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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 (20 January 2024) | Viewed by 22662

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Special Issue Editors

Prof. Dr. Gábor L. Kovács

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Guest Editor

Szentagothai Research Centre, University of Pecs, 7624 Pecs, Hungary
Interests: in vitro fertilization; biomarkers; molecular mechanisms; lab-on-a-chip
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Dénes Molnár

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Guest Editor

1. Department of Pediatrics, Medical School, University of Pécs, 7623 Pécs, Hungary
2. National Laboratory on Human Reproduction, University of Pécs, 7623 Pécs, Hungary
Interests: childhood obesity; intrauterine and infant nutrition; obesity-related diseases; metabolic syndrome; epigenetics
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Emese Mezõsi

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Guest Editor

First Department of Medicine, Medical School, University of Pecs, 7624 Pecs, Hungary
Interests: thyroid cancer; radioiodine treatment; neuroendocrine neoplasm; multiple endocrine neoplasia syndromes; targeted therapies; paraneoplastic syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Reproductive endocrinology describes the hormones and the control mechanisms that regulate reproduction. Disorders of reproductive endocrinology can occur due to abnormal changes anywhere in the hypothalamus–pituitary–gonadal axis, and can include a wide range of symptoms, including infertility, hirsutism, virilization, oligomenorrhea and amenorrhea in women, and infertility and altered sexual function in men. This Special Issue describes the approach to the diagnosis and evaluation of disorders of the reproductive endocrinology system, with a special emphasis on the roles of obesity, hypothyroidism and PCO in infertility. The importance of epigenetic factors and evidence-based treatments can also be addressed as well. Of interest are stimulation protocols during IVF, with a special reference to the benefits and pitfalls of these protocols. The hormonal profile of the cord blood—in IVF babies compared to regular babies—is a project to be included. Please note that papers published in the International Journal of Molecular Sciences are encouraged to include results at the molecular level. Both original research articles and reviews on these topics are welcome.

Prof. Dr. Gábor L. Kovács
Prof. Dr. Dénes Molnár
Prof. Dr. Emese Mezõsi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

reproductive endocrinology
molecular research
IVF
epigenetic factors
obesity

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Published Papers (10 papers)

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Research

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17 pages, 4004 KiB

Open AccessArticle

Single-Cell Transcriptional Profile Construction of Rat Pituitary Glands before and after Sexual Maturation and Identification of Novel Marker Spp1 in Gonadotropes

by Qing-Hua Huang, Guo-Kun Zhao, Hao-Qi Wang, Fan-Hao Wei, Jin-Yu Zhang, Jia-Bao Zhang, Fei Gao and Bao Yuan

Int. J. Mol. Sci. 2024, 25(9), 4694; https://doi.org/10.3390/ijms25094694 - 25 Apr 2024

Viewed by 1237

Abstract

The mammalian pituitary gland drives highly conserved physiological processes such as somatic cell growth, pubertal transformation, fertility, and metabolism by secreting a variety of hormones. Recently, single-cell transcriptomics techniques have been used in pituitary gland research. However, more studies have focused on adult pituitary gland tissues from different species or different sexes, and no research has yet resolved cellular differences in pituitary gland tissue before and after sexual maturation. Here, we identified a total of 15 cell clusters and constructed single-cell transcriptional profiles of rats before and after sexual maturation. Furthermore, focusing on the gonadotrope cluster, 106 genes were found to be differentially expressed before and after sexual maturation. It was verified that Spp1, which is specifically expressed in gonadotrope cells, could serve as a novel marker for this cell cluster and has a promotional effect on the synthesis and secretion of follicle-stimulating hormone. The results provide a new resource for further resolving the regulatory mechanism of pituitary gland development and pituitary hormone synthesis and secretion. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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16 pages, 2181 KiB

Open AccessArticle

Dysregulation of Glucocorticoid Receptor Homeostasis and Glucocorticoid-Associated Genes in Umbilical Cord Endothelial Cells of Diet-Induced Obese Pregnant Sheep

by Eugenia Mata-Greenwood, Wendy L. Chow, Nana A. O. Anti, LeeAnna D. Sands, Olayemi Adeoye, Stephen P. Ford and Peter W. Nathanielsz

Int. J. Mol. Sci. 2024, 25(4), 2311; https://doi.org/10.3390/ijms25042311 - 15 Feb 2024

Viewed by 1444

Abstract

Maternal obesity (MO) is associated with offspring cardiometabolic diseases that are hypothesized to be partly mediated by glucocorticoids. Therefore, we aimed to study fetal endothelial glucocorticoid sensitivity in an ovine model of MO. Rambouillet/Columbia ewes were fed either 100% (control) or 150% (MO) National Research Council recommendations from 60 d before mating until near-term (135 days gestation). Sheep umbilical vein and artery endothelial cells (ShUVECs and ShUAECs) were used to study glucocorticoid receptor (GR) expression and function in vitro. Dexamethasone dose–response studies of gene expression, activation of a glucocorticoid response element (GRE)-dependent luciferase reporter vector, and cytosolic/nuclear GR translocation were used to assess GR homeostasis. MO significantly increased basal GR protein levels in both ShUVECs and ShUAECs. Increased GR protein levels did not result in increased dexamethasone sensitivity in the regulation of key endothelial gene expression such as endothelial nitric oxide synthase, plasminogen activator inhibitor 1, vascular endothelial growth factor, or intercellular adhesion molecule 1. In ShUVECs, MO increased GRE-dependent transactivation and FKBP prolyl isomerase 5 (FKBP5) expression. ShUAECs showed generalized glucocorticoid resistance in both dietary groups. Finally, we found that ShUVECs were less sensitive to dexamethasone-induced activation of GR than human umbilical vein endothelial cells (HUVECs). These findings suggest that MO-mediated effects in the offspring endothelium could be further mediated by dysregulation of GR homeostasis in humans as compared with sheep. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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18 pages, 1026 KiB

Open AccessArticle

Reduced SIRT1 and SIRT3 and Lower Antioxidant Capacity of Seminal Plasma Is Associated with Shorter Sperm Telomere Length in Oligospermic Men

by Varinderpal S. Dhillon, Mohammad Shahid, Permal Deo and Michael Fenech

Int. J. Mol. Sci. 2024, 25(2), 718; https://doi.org/10.3390/ijms25020718 - 5 Jan 2024

Cited by 7 | Viewed by 1559

Abstract

Infertility affects millions of couples worldwide and has a profound impact not only on their families, but also on communities. Telomere attrition has been associated with infertility, DNA damage and fragmentation. Oxidative stress has been shown to affect sperm DNA integrity and telomere length. Sirtuins such as SIRT1 and SIRT3 are involved in aging and oxidative stress response. The aim of the present study is to determine the role of SIRT1 and SIRT3 in regulating oxidative stress, telomere shortening, and their association with oligospermia. Therefore, we assessed the protein levels of SIRT1 and SIRT3, total antioxidant capacity (TAC), superoxide dismutase (SOD), malondialdehyde (MDA) and catalase activity (CAT) in the seminal plasma of 272 patients with oligospermia and 251 fertile men. We also measured sperm telomere length (STL) and leukocyte telomere length (LTL) using a standard real-time quantitative PCR assay. Sperm chromatin and protamine deficiency were also measured as per standard methods. Our results for oligospermic patients demonstrate significant reductions in semen parameters, shorter STL and LTL, lower levels of SOD, TAC, CAT, SIRT1 and SIRT3 levels, and also significant protamine deficiency and higher levels of MDA and DNA fragmentation. We conclude that a shorter TL in sperms and leukocytes is associated with increased oxidative stress that also accounts for high levels of DNA fragmentation in sperms. Our results support the hypothesis that various sperm parameters in the state of oligospermia are associated with or caused by reduced levels of SIRT1 and SIRT3 proteins. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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15 pages, 1851 KiB

Open AccessArticle

Amino Acid Profiling of Follicular Fluid in Assisted Reproduction Reveals Important Roles of Several Amino Acids in Patients with Insulin Resistance

by Csilla Kurdi, Vanessza Lelovics, Dávid Hesszenberger, Anikó Lajtai, Ágnes Lakatos, Róbert Herczeg, Krisztina Gödöny, Péter Mauchart, Ákos Várnagy, Gábor L. Kovács and Tamás Kőszegi

Int. J. Mol. Sci. 2023, 24(15), 12458; https://doi.org/10.3390/ijms241512458 - 5 Aug 2023

Viewed by 1432

Abstract

The global prevalence of insulin resistance (IR) is increasing continuously, influencing metabolic parameters and fertility. The metabolic changes due to IR can alter the molecular composition of plasma and other body fluids. Follicular fluid (FF) is derived mainly from plasma, and it is a critical microenvironment for the developing oocytes. It contains various metabolites and amino acids, and the quality of the oocytes is linked at least partially to amino acid metabolism. Our goal was to quantitatively determine the amino acid (AA) profile of FF in IVF patients and to compare IR and non-insulin resistance (NIR) groups to investigate the AA changes in their FF. Using UHPLC-based methods, we quantified the main 20 amino acids from human FF samples in the IR and NIR groups. Several amino acids (aspartate, glycine, glutamate, and cysteine) differed significantly (p < 0.05 or less) between the two groups. The most significant alterations between the IR and NIR groups were related to the glutathione metabolic pathway involving glycine, serine, and threonine. Since insulin resistance alters the amino acid composition of the FF, the oocytes may undergo metabolism-induced changes resulting in poor oocyte quality and less fertility in the insulin resistance groups. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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10 pages, 1441 KiB

Open AccessCommunication

Different Impacts of Cryopreservation in Endothelial and Epithelial Ovarian Cells

by Julian Marschalek, Marlene Hager, Sophie Wanderer, Johannes Ott, Maria Frank, Christian Schneeberger and Detlef Pietrowski

Int. J. Mol. Sci. 2023, 24(15), 12225; https://doi.org/10.3390/ijms241512225 - 31 Jul 2023

Cited by 1 | Viewed by 1222

Abstract

The aim of our laboratory-based study was to investigate the extent of delayed-onset cell death after cryopreservation in endothelial and epithelial cell lines of ovarian origin. We found differences in percentages of vital cells directly after warming and after cultivation for 48 to 72 h. A granulosa cell line of endothelial origin (KGN) and an epithelial cell line (OvCar-3) were used. In both DMSO-containing and DMSO-free protocols, significant differences in vitality rates between the different cell lines when using open and closed vitrification could be shown (DMSO-containing: KGN open vs. OvCar open, p = 0.001; KGN closed vs. OvCar closed, p = 0.001; DMSO-free: KGN open vs. OvCar open, p = 0.001; KGN closed vs. OvCar closed, p = 0.031). Furthermore, there was a marked difference in the percentage of vital cells immediately after warming and after cultivation for 48 to 72 h; whereas the KGN cell line showed a loss of cell viability of 41% using a DMSO-containing protocol, the OvCar-3 cell loss was only 11% after cultivation. Using a DMSO-free protocol, the percentages of late-onset cell death were 77% and 48% for KGN and OvCar-3 cells, respectively. Our data support the hypothesis that cryopreservation-induced damage is cell type and cryoprotective agent dependent. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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18 pages, 3169 KiB

Open AccessArticle

Epigenetic Modulation of Inflammatory Pathways in Myometrial Stem Cells and Risk of Uterine Fibroids

by Qiwei Yang, Mohamed Ali, Lindsey S. Treviño, Aymara Mas, Nahed Ismail and Ayman Al-Hendy

Int. J. Mol. Sci. 2023, 24(14), 11641; https://doi.org/10.3390/ijms241411641 - 19 Jul 2023

Cited by 8 | Viewed by 1625

Abstract

The period during which tissue and organ development occurs is particularly vulnerable to the influence of environmental exposures. However, the specific mechanisms through which biological pathways are disrupted in response to developmental insults, consequently elevating the risk of hormone-dependent diseases, such as uterine fibroids (UFs), remain poorly understood. Here, we show that developmental exposure to the endocrine-disrupting chemical (EDC), diethylstilbestrol (DES), activates the inflammatory pathways in myometrial stem cells (MMSCs), which are the origin of UFs. Significantly, the secretome of reprogrammed MMSCs enhances the expression of critical inflammation-related genes in differentiated myometrial cells through the paracrine mechanism, which amplifies pro-inflammatory and immune suppression signaling in the myometrium. The expression of reprogrammed inflammatory responsive genes (IRGs) is driven by activated mixed-lineage leukemia protein-1 (MLL1) in MMSCs. The deactivation of MLL reverses the reprogramming of IRG expression. In addition, the inhibition of histone deacetylases (HDACs) also reversed the reprogrammed IRG expression induced by EDC exposure. This work identifies the epigenetic mechanisms of MLL1/HDAC-mediated MMSC reprogramming, and EDC exposure epigenetically targets MMSCs and imparts an IRG expression pattern, which may result in a “hyper-inflammatory phenotype” and an increased hormone-dependent risk of UFs later in life. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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Review

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22 pages, 1331 KiB

Open AccessReview

The Role of MicroRNA, Long Non-Coding RNA and Circular RNA in the Pathogenesis of Polycystic Ovary Syndrome: A Literature Review

by Jenan Sh. Nasser, Noor Altahoo, Sayed Almosawi, Abrar Alhermi and Alexandra E. Butler

Int. J. Mol. Sci. 2024, 25(2), 903; https://doi.org/10.3390/ijms25020903 - 11 Jan 2024

Cited by 5 | Viewed by 3249

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disease in females of reproductive age, affecting 4–20% of pre-menopausal women worldwide. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding, regulatory ribonucleic acid molecules found in eukaryotic cells. Abnormal miRNA expression has been associated with several diseases and could possibly explain their underlying pathophysiology. MiRNAs have been extensively studied for their potential diagnostic, prognostic, and therapeutic uses in many diseases, such as type 2 diabetes, obesity, cardiovascular disease, PCOS, and endometriosis. In women with PCOS, miRNAs were found to be abnormally expressed in theca cells, follicular fluid, granulosa cells, peripheral blood leukocytes, serum, and adipose tissue when compared to those without PCOS, making miRNAs a useful potential biomarker for the disease. Key pathways involved in PCOS, such as folliculogenesis, steroidogenesis, and cellular adhesion, are regulated by miRNA. This also highlights their importance as potential prognostic markers. In addition, recent evidence suggests a role for miRNAs in regulating the circadian rhythm (CR). CR is crucial for regulating reproduction through the various functions of the hypothalamic-pituitary-gonadal (HPG) axis and the ovaries. A disordered CR affects reproductive outcomes by inducing insulin resistance, oxidative stress, and systemic inflammation. Moreover, miRNAs were demonstrated to interact with lncRNA and circRNAs, which are thought to play a role in the pathogenesis of PCOS. This review discusses what is currently understood about miRNAs in PCOS, the cellular pathways involved, and their potential role as biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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16 pages, 1333 KiB

Open AccessReview

The Molecular Basis of Male Infertility in Obesity: A Literature Review

by Biji Thomas George, Malay Jhancy, Rajani Dube, Subhranshu Sekhar Kar and Lovely Muthiah Annamma

Int. J. Mol. Sci. 2024, 25(1), 179; https://doi.org/10.3390/ijms25010179 - 22 Dec 2023

Cited by 8 | Viewed by 2498

Abstract

The rising incidence of obesity has coincided with rising levels of poor reproductive outcomes. The molecular basis for the association of infertility in obese males is now being explained through various mechanisms. Insulin resistance, hyperglycemia, and changes in serum and gonadal concentrations of adipokines, like leptin, adiponectin, resistin, and ghrelin have been implicated as causes of male infertility in obese males. The effects of obesity and hypogonadism form a vicious cycle whereby dysregulation of the hypothalamic–pituitary–testicular axis—due to the effect of the release of multiple mediators, thus decreasing GnRH release from the hypothalamus—causes decreases in LH and FSH levels. This leads to lower levels of testosterone, which further increases adiposity because of increased lipogenesis. Cytokines such as TNF-α and interleukins, sirtuins, and other inflammatory mediators like reactive oxygen species are known to affect fertility in obese male adults. There is evidence that parental obesity can be transferred through subsequent generations to offspring through epigenetic marks. Thus, negative expressions like obesity and infertility have been linked to epigenetic marks being altered in previous generations. The interesting aspect is that these epigenetic expressions can be reverted by removing the triggering factors. These positive modifications are also transmitted to subsequent generations. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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21 pages, 832 KiB

Open AccessReview

Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility—A Systematic Review

by Rajani Dube, Subhranshu Sekhar Kar, Malay Jhancy and Biji Thomas George

Int. J. Mol. Sci. 2024, 25(1), 120; https://doi.org/10.3390/ijms25010120 - 21 Dec 2023

Cited by 2 | Viewed by 1475

Abstract

Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible. The exact etiology of MA is unknown, although several genes and mechanisms affect the development of Müllerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations, although the commonest involved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of various candidate genes in the studies. The etiology of MA seems to be multifactorial and complex, involving multiple genes and mechanisms including various mutations and mosaicism. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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27 pages, 2933 KiB

Open AccessReview

In Vitro Embryogenesis and Gastrulation Using Stem Cells in Mice and Humans

by Seung Yeon Oh, Seung Bin Na, Yoo Kyung Kang and Jeong Tae Do

Int. J. Mol. Sci. 2023, 24(17), 13655; https://doi.org/10.3390/ijms241713655 - 4 Sep 2023

Cited by 3 | Viewed by 5323

Abstract

During early mammalian embryonic development, fertilized one-cell embryos develop into pre-implantation blastocysts and subsequently establish three germ layers through gastrulation during post-implantation development. In recent years, stem cells have emerged as a powerful tool to study embryogenesis and gastrulation without the need for eggs, allowing for the generation of embryo-like structures known as synthetic embryos or embryoids. These in vitro models closely resemble early embryos in terms of morphology and gene expression and provide a faithful recapitulation of early pre- and post-implantation embryonic development. Synthetic embryos can be generated through a combinatorial culture of three blastocyst-derived stem cell types, such as embryonic stem cells, trophoblast stem cells, and extraembryonic endoderm cells, or totipotent-like stem cells alone. This review provides an overview of the progress and various approaches in studying in vitro embryogenesis and gastrulation in mice and humans using stem cells. Furthermore, recent findings and breakthroughs in synthetic embryos and gastruloids are outlined. Despite ethical considerations, synthetic embryo models hold promise for understanding mammalian (including humans) embryonic development and have potential implications for regenerative medicine and developmental research. Full article

(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology)

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