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Central and Local Modulators of Reproduction and Fertility: An Update...
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Central and Local Modulators of Reproduction and Fertility: An Update (4th Edition)

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: 20 June 2025 | Viewed by 5682

Special Issue Editor

Prof. Dr. Rosaria Meccariello

E-Mail Website
Guest Editor
Department of Medical, Human Movement and Well-being Sciences, University of Naples “Parthenope”, 80133 Naples, Italy
Interests: endocannabinoid system; endocannabinoids–GnRH–steroids crosstalk; kisspeptins; reproduction; HPG axis; spermatogenesis; spermatozoa; endocrine disruptors; epigenetics
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Special Issue Information

Dear Colleagues,

Reproduction and fertility depend on the hypothalamus–pituitary–gonad (HPG) axis. The key actor in HPG axis activity is the hypothalamic gonadotropin-releasing hormone (GnRH), which is a decapeptide able to induce the discharge of pituitary gonadotropins (follicle-stimulating hormone (FSH) and luteinizing hormone (LH)), which in turn sustain the production of sex steroids by the gonads, with successful gametogenesis as a result. In addition to intricate endocrine communication routes, paracrine and autocrine communications along the HPG axis also ensure successful gametogenesis. In this respect, the list of centrally and peripherally produced modulators of reproduction is growing and deserves attention in order to preserve both reproduction and fertility through the formation of high-quality gametes. In fact, reproduction is highly sensitive to environmental factors such as diet, stress, or endocrine disruptors, among others, and the possibility of the epigenetic modulation of reproduction with transgenerational outcomes has recently been raised. To date, several modulators exert their activity within the hypothalamus, modulating the activity of GnRH-secreting neurons in response to exogenous and endogenous environmental “cues”; similarly, peripherally produced modulators directly affect gametogenesis with effects on reproduction and fertility. Despite the experimental evidence, molecular and epigenetic regulatory mechanisms of HPG activity remain to be fully elucidated, hence the need to fill this gap in order to devise clinically effective treatment strategies.

This Special Issue aims at expanding the current knowledge on central and local modulators of reproduction and fertility in both physiological and pathological conditions, as well as on their possible therapeutic exploitation. Experimental studies in vitro and in vivo models, review articles, and clinical studies are all welcome for consideration.

Prof. Dr. Rosaria Meccariello
Guest Editor

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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

  • reproduction
  • fertility
  • HPG axis
  • testis
  • ovary
  • spermatogenesis
  • ovogenesis
  • gametes
  • GnRH
  • gonadotropins
  • sex steroids
  • kisspeptins
  • GnIH
  • metabolic sensors
  • leptin
  • endocannabinoids
  • autocrine/paracrine regulators
  • protein/peptide hormones
  • lipid mediators
  • epigenetics

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Related Special Issues

Published Papers (4 papers)

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Research

25 pages, 2236 KiB  
Article
Secretory Profile Analysis of Human Granulosa Cell Line Following Gonadotropin Stimulation
by Francesca Mancini, Emanuela Teveroni, Michela Cicchinelli, Federica Iavarone, Anna Laura Astorri, Giuseppe Maulucci, Cassandra Serantoni, Duaa Hatem, Daniela Gallo, Carla Di Nardo, Andrea Urbani, Alfredo Pontecorvi, Domenico Milardi and Fiorella Di Nicuolo
Int. J. Mol. Sci. 2025, 26(9), 4108; https://doi.org/10.3390/ijms26094108 - 25 Apr 2025
Viewed by 281
Abstract
Granulosa cell (GC) differentiation, stimulated by FSH and LH, drives oocyte maturation and follicle development. FSH promotes GC proliferation, and LH triggers ovulation. In clinical practice, hCG is used to mimic LH. Despite various controlled ovarian stimulation (COS) protocols employing exogenous gonadotropins and [...] Read more.
Granulosa cell (GC) differentiation, stimulated by FSH and LH, drives oocyte maturation and follicle development. FSH promotes GC proliferation, and LH triggers ovulation. In clinical practice, hCG is used to mimic LH. Despite various controlled ovarian stimulation (COS) protocols employing exogenous gonadotropins and GnRH analogs to prevent premature ovulation, their effectiveness and safety remain debated. To identify markers predicting a positive treatment response, the secretome of gonadotropin-stimulated GC using the human granulosa-like tumor cell line (KGN) via proteomics was analyzed. Additionally, a novel 2D-FFT quantitative method was employed to assess cytoskeleton fiber aggregation and polymerization, which are critical processes for GC differentiation. Furthermore, the activation of key kinases, focal adhesion kinase (FAK), and Rho-associated coiled-coil-containing protein kinase 1 (ROCK-1), which are implicated in cytoskeleton dynamics and hormone signaling, was evaluated. The proteomic analysis revealed significant modulation of proteins involved in extracellular matrix organization, steroidogenesis, and cytoskeleton remodeling. Notably, the combined FSH/hCG treatment led to a dynamic upregulation of the semaphorin pathway, specifically semaphorin 7A. Finally, a significant reorganization of the cytoskeleton network and signaling was detected. These findings enhance our understanding of folliculogenesis and suggest potential novel molecular markers for predicting patient responses to gonadotropin stimulation. Full article
(This article belongs to the Special Issue Central and Local Modulators of Reproduction and Fertility: An Update (4th Edition))
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14 pages, 6271 KiB  
Article
Preliminary Study on the Positive Expression Regulation of Alpha2-Macroglobulin in the Testicular Tissue of Male Mice by Environmental Estrogens
by Hong-Mei Li, Yan-Rong Gao, Chang Liu, Yu-Xin Sheng, Ya-Jia Pu, Jia-He Sun, Ya-Nan Tian, Li Yang, Hui-Ming Ma and Hai-Ming Xu
Int. J. Mol. Sci. 2024, 25(24), 13434; https://doi.org/10.3390/ijms252413434 - 15 Dec 2024
Viewed by 855
Abstract
The male reproductive impairment caused by environmental estrogens (EEs) stands as a pivotal research area in environmental toxicology. Alpha2-macroglobulin (A2M) emerges as a promising molecule capable of counteracting oxidative stress induced by EEs. This study conducted exposure experiments spanning PND1 to PND56 employing [...] Read more.
The male reproductive impairment caused by environmental estrogens (EEs) stands as a pivotal research area in environmental toxicology. Alpha2-macroglobulin (A2M) emerges as a promising molecule capable of counteracting oxidative stress induced by EEs. This study conducted exposure experiments spanning PND1 to PND56 employing ICR mice, aiming to delve into the expression patterns of A2M and its modulated IL-6 in the testicular tissue of mice subsequent to diethylstilbestrol (DES) and benzophenone (BP) exposure, while elucidating the pivotal role of ERs in this intricate process. Our findings revealed that upon DES exposure (10 and 100 nM), there was a pronounced upregulation of A2M (mRNA and in situ protein levels) in mouse testicular tissue. Similarly, exposure to BPs (BP-1, BP-2, and BP-3, each at 10 and 1000 nM) exhibited comparable effects and increasing A2M levels in serum. Notably, BP exposure also caused an elevation in IL-6 levels (which could be directly regulated by A2M) within testicular tissue (mRNA and in situ protein). Remarkably, the specific estrogen receptor antagonist ICI 182780 (0.5 mg/kg/day) was effective in reversing the upregulation of both A2M and IL-6 induced by BP exposure. Significantly, the results of theoretical prediction of the potential ERE site in the A2m gene promoter region and ChIP-qPCR experiment provide essential and strong evidence for the key conclusion that A2m is the target gene of ER. Taken together, our study highlights EEs’ ability to regulate A2M expression in the male reproductive system via the ER signaling pathway. This vital insight deepens our understanding of molecular mechanisms protecting against oxidative stress caused by EEs. Full article
(This article belongs to the Special Issue Central and Local Modulators of Reproduction and Fertility: An Update (4th Edition))
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16 pages, 9827 KiB  
Article
The Transcriptome Characterization of the Hypothalamus and the Identification of Key Genes during Sexual Maturation in Goats
by Qing Li, Tianle Chao, Yanyan Wang, Rong Xuan, Yanfei Guo, Peipei He, Lu Zhang and Jianmin Wang
Int. J. Mol. Sci. 2024, 25(18), 10055; https://doi.org/10.3390/ijms251810055 - 19 Sep 2024
Cited by 1 | Viewed by 1289
Abstract
Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic–pituitary–gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the [...] Read more.
Sexual maturation in goats is a dynamic process regulated precisely by the hypothalamic–pituitary–gonadal axis and is essential for reproduction. The hypothalamus plays a crucial role in this process and is the control center of the reproductive activity. It is significant to study the molecular mechanisms in the hypothalamus regulating sexual maturation in goats. We analyzed the serum hormone profiles and hypothalamic mRNA expression profiles of female goats during sexual development (1 day old (neonatal, D1, n = 5), 2 months old (prepuberty, M2, n = 5), 4 months old (sexual maturity, M4, n = 5), and 6 months old (breeding period, M6, n = 5)). The results indicated that from D1 to M6, serum hormone levels, including FSH, LH, progesterone, estradiol, IGF1, and leptin, exhibited an initial increase followed by a decline, peaking at M4. Furthermore, we identified a total of 508 differentially expressed genes in the hypothalamus, with a total of four distinct expression patterns. Nuclear receptor subfamily 1, group D, member 1 (NR1D1), glucagon-like peptide 1 receptor (GLP1R), and gonadotropin-releasing hormone 1 (GnRH-1) may contribute to hormone secretion, energy metabolism, and signal transduction during goat sexual maturation via circadian rhythm regulation, ECM receptor interactions, neuroactive ligand–receptor interactions, and Wnt signaling pathways. This investigation offers novel insights into the molecular mechanisms governing the hypothalamic regulation of goat sexual maturation. Full article
(This article belongs to the Special Issue Central and Local Modulators of Reproduction and Fertility: An Update (4th Edition))
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11 pages, 6633 KiB  
Article
MALDI Imaging Mass Spectrometry Reveals Lipid Alterations in Physiological and Sertoli Cell-Only Syndrome Human Testicular Tissue Sections
by Alexandra Sulc, Péter Czétány, Gábor Máté, András Balló, Dávid Semjén, Árpád Szántó and László Márk
Int. J. Mol. Sci. 2024, 25(15), 8358; https://doi.org/10.3390/ijms25158358 - 31 Jul 2024
Viewed by 2792
Abstract
Azoospermia, the absence of sperm cells in semen, affects around 15% of infertile males. Sertoli cell-only syndrome (SCOS) is the most common pathological lesion in the background of non-obstructive azoospermia and is characterised by the complete absence of germinal epithelium, with Sertoli cells [...] Read more.
Azoospermia, the absence of sperm cells in semen, affects around 15% of infertile males. Sertoli cell-only syndrome (SCOS) is the most common pathological lesion in the background of non-obstructive azoospermia and is characterised by the complete absence of germinal epithelium, with Sertoli cells exclusively present in the seminiferous tubules. Studies have shown a correlation between successful spermatogenesis and male fertility with lipid composition of spermatozoa, semen, seminal plasma or testis. The aim of this research was to discover the correlation between the Johnsen scoring system and phospholipid expressions in testicular cryosections of SCOS patients. MALDI imaging mass spectrometry is used to determine spatial distributions of molecular species, such as phospholipids. Phosphatidylcholines (PCs), phosphatidylethanolamines (PEs) and sphingomyelins (SMs) are the most abundant phospholipids in mammalian cells and testis. SMs, the structural components of plasma membranes, are crucial for spermatogenesis and sperm function. Plasmalogens, are unique PCs in testis with strong antioxidative properties. This study, using imaging mass spectrometry, demonstrates the local distribution of phospholipids, particularly SMs, PCs, plasmalogens and PEs in human testicular samples with SCOS for the first time. This study found a strong relationship between the Johnsen scoring system and phospholipid expression levels in human testicular tissues. Future findings could enable routine diagnostic techniques during microTESE procedures for successful sperm extraction. Full article
(This article belongs to the Special Issue Central and Local Modulators of Reproduction and Fertility: An Update (4th Edition))
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