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Central and Local Modulators of Reproduction and Fertility: An Update 3.0

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 (30 April 2024) | Viewed by 10347

Special Issue Editor


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Guest Editor
Department of Movement and Wellness Sciences, Parthenope University of Naples, Via Medina 40, I-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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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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Published Papers (9 papers)

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Research

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26 pages, 3035 KiB  
Article
Comparison of Steroidogenic and Ovulation-Inducing Effects of Orthosteric and Allosteric Agonists of Luteinizing Hormone/Chorionic Gonadotropin Receptor in Immature Female Rats
by Kira V. Derkach, Ivan A. Lebedev, Irina Yu. Morina, Andrey A. Bakhtyukov, Alena S. Pechalnova, Viktor N. Sorokoumov, Veronica S. Kuznetsova, Irina V. Romanova and Alexander O. Shpakov
Int. J. Mol. Sci. 2023, 24(23), 16618; https://doi.org/10.3390/ijms242316618 - 22 Nov 2023
Viewed by 912
Abstract
Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active [...] Read more.
Gonadotropins, including human chorionic gonadotropin (hCG), are used to induce ovulation, but they have a number of side effects, including ovarian hyperstimulation syndrome (OHSS). A possible alternative is allosteric luteinizing hormone (LH)/hCG receptor agonists, including the compound TP4/2 we developed, which remains active when administered orally. The aim was to study the effectiveness of TP4/2 (orally, 40 mg/kg) as an ovulation inducer in FSH-stimulated immature female rats, compared with hCG (s.c., 15 IU/rat). TP4/2 stimulated progesterone production and corpus luteum formation; time-dependently increased the ovarian expression of steroidogenic genes (Star, Cyp11a1, Cyp17a1) and genes involved in ovulation regulation (Adamts-1, Cox-2, Egr-1, Mt-1); and increased the content of metalloproteinase ADAMTS-1 in the ovaries. These effects were similar to those of hCG, although in some cases they were less pronounced. TP4/2, in contrast to hCG, maintained normal LH levels and increased the ovarian expression of the LH/hCG receptor gene, indicating preservation of ovarian sensitivity to LH, and did not cause a sustained increase in expression of vascular endothelial growth factor-A involved in OHSS. Thus, TP4/2 is an effective ovulation inducer that, unlike hCG, has a lower risk of OHSS and ovarian LH resistance due to its moderate stimulating effect on steroidogenesis. Full article
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17 pages, 4488 KiB  
Article
Insulin-like Androgenic Gland Hormone Induced Sex Reversal and Molecular Pathways in Macrobrachium nipponense: Insights into Reproduction, Growth, and Sex Differentiation
by Pengfei Cai, Wenyi Zhang, Sufei Jiang, Yiwei Xiong, Huwei Yuan, Zijian Gao, Xuanbing Gao, Cheng Ma, Yongkang Zhou, Yongsheng Gong, Hui Qiao, Shubo Jin and Hongtuo Fu
Int. J. Mol. Sci. 2023, 24(18), 14306; https://doi.org/10.3390/ijms241814306 - 19 Sep 2023
Cited by 1 | Viewed by 1235
Abstract
This study investigated the potential to use double-stranded RNA insulin-like androgenic gland hormone (dsIAG) to induce sex reversal in Macrobrachium nipponense and identified the molecular mechanisms underlying crustacean reproduction and sex differentiation. The study aimed to determine whether dsIAG could induce [...] Read more.
This study investigated the potential to use double-stranded RNA insulin-like androgenic gland hormone (dsIAG) to induce sex reversal in Macrobrachium nipponense and identified the molecular mechanisms underlying crustacean reproduction and sex differentiation. The study aimed to determine whether dsIAG could induce sex reversal in PL30-male M. nipponense during a critical period. The sex-related genes were selected by performing the gonadal transcriptome analysis of normal male (dsM), normal female (dsFM), neo-female sex-reversed individuals (dsRM), and unreversed males (dsNRM). After six injections, the experiment finally resulted in a 20% production of dsRM. Histologically, dsRM ovaries developed slower than dsFM, but dsNRM spermathecae developed normally. A total of 1718, 1069, and 255 differentially expressed genes were identified through transcriptome sequencing of the gonads in three comparison groups, revealing crucial genes related to reproduction and sex differentiation, such as GnRHR, VGR, SG, and LWS. Principal Component Analysis (PCA) also distinguished dsM and dsRM very well. In addition, this study predicted that the eyestalks and the “phototransduction-fly” photoperiodic pathways of M. nipponense could play an important role in sex reversal. The enrichment of related pathways and growth traits in dsNRM were combined to establish that IAG played a significant role in reproduction, growth regulation, and metabolism. Finally, complete sex reversal may depend on specific stimuli at critical periods. Overall, this study provides valuable findings for the IAG regulation of sex differentiation, reproduction, and growth of M. nipponense in establishing a monoculture. Full article
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13 pages, 1399 KiB  
Article
Identification of Male Sex-Related Genes Regulated by SDHB in Macrobrachium nipponense Based on Transcriptome Analysis after an RNAi Knockdown
by Zijian Gao, Wenyi Zhang, Sufei Jiang, Huwei Yuan, Pengfei Cai, Shubo Jin and Hongtuo Fu
Int. J. Mol. Sci. 2023, 24(17), 13176; https://doi.org/10.3390/ijms241713176 - 24 Aug 2023
Viewed by 1007
Abstract
The oriental river prawn (Macrobrachium nipponense) is a commercially important species in Asia. A previous study showed that the succinate dehydrogenase complex iron sulfur subunit B (SDHB) gene participates in testes development in this species through its effect on [...] Read more.
The oriental river prawn (Macrobrachium nipponense) is a commercially important species in Asia. A previous study showed that the succinate dehydrogenase complex iron sulfur subunit B (SDHB) gene participates in testes development in this species through its effect on the expression of the insulin-like androgenic gland hormone gene. This study knocked-down the Mn-SDHB genes in M. nipponense using RNAi. A transcriptome analysis of the androgenic gland and testes was then performed to discover the male sex-related genes regulated by SDHB and investigate the mechanism of male sexual development in this species. More than 16,623 unigenes were discovered in each sample generated. In the androgenic gland, most of the differentially expressed genes were enriched in the hypertrophic cardiomyopathy pathway, while in the testes, they were enriched in the citrate cycle pathway. In addition, after Mn-SDHB knockdown, five genes were found to be downregulated in the androgenic gland in a series of biological processes associated with phosphorylated carbohydrate synthesis and transformations in the glycolysis/gluconeogenesis pathway. Moreover, a total of nine male sex-related genes were identified including Pro-resilin, insulin-like androgenic gland hormone, Protein mono-ADP-ribosyltransferase PAPR11, DNAJC2, C-type Lectin-1, Tyrosine-protein kinase Yes, Vigilin, and Sperm motility kinase Y-like, demonstrating the regulatory effects of Mn-SDHB, and providing a reference for the further study of the mechanisms of male development in M. nipponense. Full article
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22 pages, 5498 KiB  
Article
The Trophoblast Compartment Helps Maintain Embryonic Pluripotency and Delays Differentiation towards Cardiomyocytes
by Xiang Zhao, Bethany N. Radford, Mark Ungrin, Wendy Dean and Myriam Hemberger
Int. J. Mol. Sci. 2023, 24(15), 12423; https://doi.org/10.3390/ijms241512423 - 4 Aug 2023
Cited by 1 | Viewed by 1214
Abstract
Normal developmental progression relies on close interactions between the embryonic and extraembryonic lineages in the pre- and peri-gastrulation stage conceptus. For example, mouse epiblast-derived FGF and NODAL signals are required to maintain a stem-like state in trophoblast cells of the extraembryonic ectoderm, while [...] Read more.
Normal developmental progression relies on close interactions between the embryonic and extraembryonic lineages in the pre- and peri-gastrulation stage conceptus. For example, mouse epiblast-derived FGF and NODAL signals are required to maintain a stem-like state in trophoblast cells of the extraembryonic ectoderm, while visceral endoderm signals are pivotal to pattern the anterior region of the epiblast. These developmental stages also coincide with the specification of the first heart precursors. Here, we established a robust differentiation protocol of mouse embryonic stem cells (ESCs) into cardiomyocyte-containing embryoid bodies that we used to test the impact of trophoblast on this key developmental process. Using trophoblast stem cells (TSCs) to produce trophoblast-conditioned medium (TCM), we show that TCM profoundly slows down the cardiomyocyte differentiation dynamics and specifically delays the emergence of cardiac mesoderm progenitors. TCM also strongly promotes the retention of pluripotency transcription factors, thereby sustaining the stem cell state of ESCs. By applying TCM from various mutant TSCs, we further show that those mutations that cause a trophoblast-mediated effect on early heart development in vivo alter the normal cardiomyocyte differentiation trajectory. Our approaches provide a meaningful deconstruction of the intricate crosstalk between the embryonic and the extraembryonic compartments. They demonstrate that trophoblast helps prolong a pluripotent state in embryonic cells and delays early differentiative processes, likely through production of leukemia inhibitory factor (LIF). These data expand our knowledge of the multifaceted signaling interactions among distinct compartments of the early conceptus that ensure normal embryogenesis, insights that will be of significance for the field of synthetic embryo research. Full article
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20 pages, 6054 KiB  
Article
The Photoperiod-Driven Cyclical Secretion of Pineal Melatonin Regulates Seasonal Reproduction in Geese (Anser cygnoides)
by Qiang Bao, Wang Gu, Lina Song, Kaiqi Weng, Zhengfeng Cao, Yu Zhang, Yang Zhang, Ting Ji, Qi Xu and Guohong Chen
Int. J. Mol. Sci. 2023, 24(15), 11998; https://doi.org/10.3390/ijms241511998 - 26 Jul 2023
Cited by 1 | Viewed by 1184
Abstract
The photoperiod is the predominant environmental factor that governs seasonal reproduction in animals; however, the underlying molecular regulatory mechanism has yet to be fully elucidated. Herein, Yangzhou geese (Anser cygnoides) were selected at the spring equinox (SE), summer solstice (SS), autumn [...] Read more.
The photoperiod is the predominant environmental factor that governs seasonal reproduction in animals; however, the underlying molecular regulatory mechanism has yet to be fully elucidated. Herein, Yangzhou geese (Anser cygnoides) were selected at the spring equinox (SE), summer solstice (SS), autumn equinox (AE), and winter solstice (WS), and the regulation of seasonal reproduction via the light-driven cyclical secretion of pineal melatonin was investigated. We show that there were seasonal variations in the laying rate and GSI, while the ovarian area decreased 1.5-fold from the SS to the AE. Moreover, not only did the weight and volume of the pineal gland increase with a shortened photoperiod, but the secretory activity was also enhanced. Notably, tissue distribution further revealed seasonal oscillations in melatonin receptors (Mtnrs) in the pineal gland and the hypothalamus–pituitary–gonadal (HPG) axis. The immunohistochemical staining indicated higher Mtnr levels due to the shortened photoperiod. Furthermore, the upregulation of aralkylamine N-acetyltransferase (Aanat) was observed from the SS to the AE, concurrently resulting in a downregulation of the gonadotrophin-releasing hormone (GnRH) and gonadotropins (GtHs). This trend was also evident in the secretion of hormones. These data indicate that melatonin secretion during specific seasons is indicative of alterations in the photoperiod, thereby allowing for insight into the neuroendocrine regulation of reproduction via an intrinsic molecular depiction of external photoperiodic variations. Full article
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17 pages, 1027 KiB  
Article
Comparison of Estetrol Exposure between Women and Mice to Model Preclinical Experiments and Anticipate Human Treatment
by Anne Gallez, Gwenaël Nys, Vincent Wuidar, Isabelle Dias Da Silva, Mélanie Taziaux, Virginie Kinet, Ekaterine Tskitishvili, Agnès Noel, Jean-Michel Foidart, Géraldine Piel, Marianne Fillet and Christel Péqueux
Int. J. Mol. Sci. 2023, 24(11), 9718; https://doi.org/10.3390/ijms24119718 - 3 Jun 2023
Cited by 2 | Viewed by 1443
Abstract
Estetrol (E4) is a natural estrogen with promising therapeutic applications in humans. The European Medicines Agency and the Food and Drug Administration have approved the use of 15 mg E4/3 mg drospirenone for contraceptive indication. Phase III clinical trials with 15–20 mg E4 [...] Read more.
Estetrol (E4) is a natural estrogen with promising therapeutic applications in humans. The European Medicines Agency and the Food and Drug Administration have approved the use of 15 mg E4/3 mg drospirenone for contraceptive indication. Phase III clinical trials with 15–20 mg E4 for the relief of climacteric complaints are currently running. Relevant data from preclinical animal models are needed to characterize the molecular mechanisms and the pharmacological effects of E4 and possibly to reveal new therapeutic applications and to anticipate potential adverse effects. Therefore, it is important to design experimental procedures in rodents that closely mimic or anticipate human E4 exposure. In this study, we compared the effects of E4 exposure after acute or chronic administration in women and mice. Women who received chronic E4 treatment per os at a dose of 15 mg once daily reached a steady state within 6 to 8 days, with a mean plasma concentration of 3.20 ng/mL. Importantly, with subcutaneous, intraperitoneal or oral administration of E4 in mice, a stable concentration over time that would mimic human pharmacokinetics could not be achieved. The use of osmotic minipumps continuously releasing E4 for several weeks provided an exposure profile mimicking chronic oral administration in women. Measurements of the circulating concentration of E4 in mice revealed that the mouse equivalent dose necessary to mimic human treatment does not fit with the allometric prediction. In conclusion, this study highlights the importance of precise definition of the most appropriate dose and route of administration to utilize when developing predictive preclinical animal models to mimic or anticipate specific human treatment. Full article
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Review

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47 pages, 1192 KiB  
Review
The Role of One-Carbon Metabolism and Methyl Donors in Medically Assisted Reproduction: A Narrative Review of the Literature
by Konstantinos Sfakianoudis, Athanasios Zikopoulos, Sokratis Grigoriadis, Nikolaos Seretis, Evangelos Maziotis, George Anifandis, Paraskevi Xystra, Charilaos Kostoulas, Urania Giougli, Konstantinos Pantos, Mara Simopoulou and Ioannis Georgiou
Int. J. Mol. Sci. 2024, 25(9), 4977; https://doi.org/10.3390/ijms25094977 - 2 May 2024
Viewed by 599
Abstract
One-carbon (1-C) metabolic deficiency impairs homeostasis, driving disease development, including infertility. It is of importance to summarize the current evidence regarding the clinical utility of 1-C metabolism-related biomolecules and methyl donors, namely, folate, betaine, choline, vitamin B12, homocysteine (Hcy), and zinc, as potential [...] Read more.
One-carbon (1-C) metabolic deficiency impairs homeostasis, driving disease development, including infertility. It is of importance to summarize the current evidence regarding the clinical utility of 1-C metabolism-related biomolecules and methyl donors, namely, folate, betaine, choline, vitamin B12, homocysteine (Hcy), and zinc, as potential biomarkers, dietary supplements, and culture media supplements in the context of medically assisted reproduction (MAR). A narrative review of the literature was conducted in the PubMed/Medline database. Diet, ageing, and the endocrine milieu of individuals affect both 1-C metabolism and fertility status. In vitro fertilization (IVF) techniques, and culture conditions in particular, have a direct impact on 1-C metabolic activity in gametes and embryos. Critical analysis indicated that zinc supplementation in cryopreservation media may be a promising approach to reducing oxidative damage, while female serum homocysteine levels may be employed as a possible biomarker for predicting IVF outcomes. Nonetheless, the level of evidence is low, and future studies are needed to verify these data. One-carbon metabolism-related processes, including redox defense and epigenetic regulation, may be compromised in IVF-derived embryos. The study of 1-C metabolism may lead the way towards improving MAR efficiency and safety and ensuring the lifelong health of MAR infants. Full article
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12 pages, 2416 KiB  
Review
Thrombocytes and Platelet-Rich Plasma as Modulators of Reproduction and Fertility
by Bernadett Nagy, Kálmán Kovács, Endre Sulyok, Ákos Várnagy and József Bódis
Int. J. Mol. Sci. 2023, 24(24), 17336; https://doi.org/10.3390/ijms242417336 - 11 Dec 2023
Cited by 1 | Viewed by 1344
Abstract
Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The platelet-activating factor and the controlled activation of platelets have important roles in folliculogenesis, ovulation, placental development, implantation and embryo development. Activated [...] Read more.
Thrombocytes play an essential role in hemostasis and thrombosis. Moreover, the controlled activation of thrombocytes is required in reproduction and fertility. The platelet-activating factor and the controlled activation of platelets have important roles in folliculogenesis, ovulation, placental development, implantation and embryo development. Activated platelets accumulate in the follicular vessels surrounding the follicle and, due to its released soluble molecules (factors, mediators, chemokines, cytokines, neurotransmitters), locally increase oocyte maturation and hormone secretion. Furthermore, activated platelets are involved in the pathogenesis of ovarian hyperstimulation syndrome (OHSS) and preeclampsia. Low-dose aspirin can prevent OHSS during ovulation induction, while intrauterine or intraovarian administration of platelet-rich plasma (PRP) increases the endometrium thickness and receptivity as well as oocyte maturation. Activated thrombocytes rapidly release the contents of intracellular granules and have multiple adhesion molecules and receptors on their surface. Considering the numerous homeostatic endocrine functions of thrombocytes, it is reasonable to suppose a platelet-associated regulatory system (PARS) in reproduction. Although we are far from a complete understanding of the regulatory processes, the results of PARS research and the therapeutic application of aspirin and PRP during in vitro fertilization are promising. Full article
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Other

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13 pages, 3925 KiB  
Brief Report
Kisspeptin-10 Improves Testicular Redox Status but Does Not Alter the Unfolded Protein Response (UPR) That Is Downregulated by Hypothyroidism in a Rat Model
by Luciano Cardoso Santos, Jeane Martinha dos Anjos Cordeiro, Maria Clara da Silva Galrão Cunha, Bianca Reis Santos, Luciana Santos de Oliveira, Adriana Lopes da Silva, Erikles Macêdo Barbosa, Raquel Vieira Niella, Gustavo José Cota de Freitas, Daniel de Assis Santos, Rogéria Serakides, Natália de Melo Ocarino, Stephanie Carvalho Borges, Mário Sérgio Lima de Lavor and Juneo Freitas Silva
Int. J. Mol. Sci. 2024, 25(3), 1514; https://doi.org/10.3390/ijms25031514 - 26 Jan 2024
Viewed by 910
Abstract
Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) [...] Read more.
Hypothyroidism compromises the testicular redox status and is associated with reduced sperm quality and infertility in men. In this regard, studies have demonstrated the antioxidant potential of kisspeptin in reproductive and metabolic diseases. In this study, we evaluate the effects of kisspeptin-10 (Kp10) on the testicular redox, as well as mediators of the unfolded protein response (UPR) in adult rats with hypothyroidism. Adult male Wistar rats were randomly separated into the Control (n = 15), Hypo (n = 13) and Hypo + Kp10 (n = 14) groups, and hypothyroidism was induced with 6-propyl-2-thiouracil (PTU) for three months. In the last month, half of the hypothyroid animals received Kp10. Testis samples were collected for enzymatic, immunohistochemical and/or gene evaluation of mediators of oxidative stress (TBARs, lipid hydroperoxides (LOOH), ROS, peroxynitrite, SOD, CAT and GPX), endoplasmic reticulum stress (GRP78, ATF6, PERK, CHOP, HO-1 and sXBP1) and antiapoptocytes (BCL-2). Hypothyroidism increased apoptosis index, TBARS and LOOH concentrations, and reduced testicular gene expression of Sod1, Sod2 and Gpx1, as well as the expression of Grp78, Atf6, Ho1 and Chop. Treatment with Kp10, in turn, reduced testicular apoptosis and the production of peroxynitrite, while increased SOD1 and GPX ½ expression, and enzymatic activity of CAT, but did not affect the lower expression of UPR mediators caused by hypothyroidism. This study demonstrated that hypothyroidism causes oxidative stress and dysregulated the UPR pathway in rat testes and that, although Kp10 does not influence the low expression of UPR mediators, it improves the testicular redox status, configuring it as an important antioxidant factor in situations of thyroid dysfunction. Full article
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