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Special Issue "Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0"

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Endocrinology and Metabolism Research".

Deadline for manuscript submissions: 31 March 2024 | Viewed by 12892

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Prof. Dr. Paolo Giovanni Artini

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Division of Gynecology and Obstetrics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
Interests: embryogenesis; in vitro fertilization; oxidative stress; inflammation; endometriosis; polycystic ovarian syndrome
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Dear Colleagues,

Polycystic ovarian syndrome (PCOS) is one of the most prevalent endocrine disorders affecting women of reproductive age, which negatively affects the quality of life and psychological wellbeing. Hyperandrogenism, chronic anovulation, and polycystic ovaries have been associated with an increased risk of infertility, but also with metabolic alterations, including insulin resistance and hyperinsulinism, type 2 diabetes mellitus, dyslipidemia, cardiovascular disease, and endometrial carcinoma.

PCOS is a polygenic and multifactorial syndromic disorder. Despite progress in its diagnosis and management, little is known about the molecular mechanisms and signaling pathways underlying the pathogenic mechanisms. In this sense, recent research has suggested that the influence of multiple factors, including age, environment, lifestyle, and disease state environment, can change the clinical presentation of PCOS via epigenetic modifications.

This Special Issue will emphasize the molecular mechanisms and signaling pathways related to the development and progression of PCOS. Research mechanisms by which variants in the genes confer risk to PCOS and the interaction between the genetic and environmental elements will be of great interest, too. Finally, this issue will also discuss clinical studies and novel therapeutic approaches in PCOS treatment. We welcome original manuscripts and review articles addressing this topic.

Prof. Dr. Paolo Giovanni Artini
Guest Editor

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Keywords

polycystic ovary syndrome
ovarian steroidogenesis
insulin resistance
chronic inflammation
infertility
genetic predisposition
epigenetic mechanisms

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Molecular Research on Polycystic Ovary Syndrome (PCOS) in Biomedicines (18 articles)

Published Papers (9 papers)

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13 pages, 293 KiB

Open AccessArticle

Inflammatory and Anti-Inflammatory Parameters in PCOS Patients Depending on Body Mass Index: A Case-Control Study

and

Biomedicines 2023, 11(10), 2791; https://doi.org/10.3390/biomedicines11102791 - 14 Oct 2023

Viewed by 845

Abstract

Background: it has been suggested that chronic low-grade inflammation plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). According to previous studies, it remains unclear which cytokines influence the development of this syndrome and whether their increase is associated with the presence of excess weight/obesity or is an independent factor. The aim of our research was to determine the parameters of chronic inflammation in women with PCOS in comparison with healthy women in the normal weight and the overweight subgroups. Methods: This case-control study included 44 patients with PCOS (19 women with a body mass index (BMI) < 25 kg/m² and 25 women with a BMI ≥ 25 kg/m²) and 45 women without symptoms of PCOS (22 women with a BMI < 25 kg/m² and 23 women with a BMI ≥ 25 kg/m²). Thirty-two cytokines were analyzed in the plasma of the participants using Immunology multiplex assay HCYTA-60K-PX48 (Merck Life Science, LLC, Germany). Results: Cytokines: interleukin-1 receptor antagonist (IL-1 RA), IL-2, IL-6, IL-17 E, IL-17 A, IL-18, and macrophage inflammatory protein-1 alpha (MIP-1 α) were increased in women with PCOS compared to controls, both in lean and overweight/obese subgroups (p < 0.05). Moreover, only lean women with PCOS had higher levels of IL-1 alpha, IL-4, IL-9, IL-12, IL-13, IL-15, tumor necrosis factor (TNF- α) alpha and beta, soluble CD40 and its ligand (SCD40L), fractalkine (FKN), monocyte-chemotactic protein 3 (MCP-3), and MIP-1 β compared to the control group (p < 0.05). IL-22 was increased in the combined group of women with PCOS (lean and overweight/obese) compared to the control group (p = 0.012). Conclusion: Chronic low-grade inflammation is an independent factor affecting the occurrence of PCOS and does not depend on the presence of excess weight/obesity. For the first time, we obtained data on the increase in such inflammatory parameters as IL-9, MCP-3, and MIP-1α in women with PCOS. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

18 pages, 3553 KiB

Open AccessArticle

Acyl-Carnitines Exert Positive Effects on Mitochondrial Activity under Oxidative Stress in Mouse Oocytes: A Potential Mechanism Underlying Carnitine Efficacy on PCOS

Paolo Giovanni Artini

Ashraf Virmani

Samuele Zanatta

Anna Maria D’Alessandro

Carla Tatone

and

Giovanna Di Emidio

Biomedicines 2023, 11(9), 2474; https://doi.org/10.3390/biomedicines11092474 - 06 Sep 2023

Viewed by 532

Abstract

Carnitines play a key physiological role in oocyte metabolism and redox homeostasis. In clinical and animal studies, carnitine administration alleviated metabolic and reproductive dysfunction associated with polycystic ovarian syndrome (PCOS). Oxidative stress (OS) at systemic, intraovarian, and intrafollicular levels is one of the main factors involved in the pathogenesis of PCOS. We investigated the ability of different acyl-carnitines to act at the oocyte level by counteracting the effects of OS on carnitine shuttle system and mitochondrial activity in mouse oocytes. Germinal vesicle (GV) oocytes were exposed to hydrogen peroxide and propionyl-l-carnitine (PLC) alone or in association with l-carnitine (LC) and acetyl-l-carnitine (ALC) under different conditions. Expression of carnitine palmitoyltransferase-1 (Cpt1) was monitored by RT-PCR. In in vitro matured oocytes, metaphase II (MII) apparatus was assessed by immunofluorescence. Oocyte mitochondrial respiration was evaluated by Seahorse Cell Mito Stress Test. We found that Cpt1a and Cpt1c isoforms increased under prooxidant conditions. PLC alone significantly improved meiosis completion and oocyte quality with a synergistic effect when combined with LC + ALC. Acyl-carnitines prevented Cpt1c increased expression, modifications of oocyte respiration, and ATP production observed upon OS. Specific effects of PLC on spare respiratory capacity were observed. Therefore, carnitine supplementation modulated the intramitochondrial transfer of fatty acids with positive effects on mitochondrial activity under OS. This knowledge contributes to defining molecular mechanism underlying carnitine efficacy on PCOS. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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16 pages, 5220 KiB

Open AccessArticle

AMPK Activation as a Protective Mechanism to Restrain Oxidative Stress in the Insulin-Resistant State in Skeletal Muscle of Rat Model of PCOS Subjected to Postnatal Overfeeding

and

Danijela Vojnović Milutinović

Biomedicines 2023, 11(6), 1586; https://doi.org/10.3390/biomedicines11061586 - 30 May 2023

Viewed by 1054

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age, often associated with obesity and insulin resistance. Childhood obesity is an important predisposing factor for the development of PCOS later in life. Being particularly interested in the interplay between prepubertal obesity and hyperandrogenemia, we investigated the effects of early postnatal overfeeding, accomplished by reducing litter size during the period of suckling, on energy sensing and insulin signaling pathways in the gastrocnemius muscle of a rat model of PCOS-induced by 5α-dihydrotestosterone (DHT). The combination of overfeeding and DHT treatment caused hyperinsulinemia and decreased systemic insulin sensitivity. Early postnatal overfeeding induced defects at critical nodes of the insulin signaling pathway in skeletal muscle, which was associated with reduced glucose uptake in the presence of hyperandrogenemia. In this setting, under a combination of overfeeding and DHT treatment, skeletal muscle switched to mitochondrial β-oxidation of fatty acids, resulting in oxidative stress and inflammation that stimulated AMP-activated protein kinase (AMPK) activity and its downstream targets involved in mitochondrial biogenesis and antioxidant protection. Overall, a combination of overfeeding and hyperandrogenemia resulted in a prooxidative and insulin-resistant state in skeletal muscle. This was accompanied by the activation of AMPK, which could represent a potential therapeutic target in insulin-resistant PCOS patients. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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19 pages, 4564 KiB

Open AccessArticle

Chlorogenic Acid Restores Ovarian Functions in Mice with Letrozole-Induced Polycystic Ovarian Syndrome Via Modulation of Adiponectin Receptor

Mohd Zahoor ul Haq Shah

Vinoy Kumar Shrivastava

and

Biomedicines 2023, 11(3), 900; https://doi.org/10.3390/biomedicines11030900 - 14 Mar 2023

Cited by 3 | Viewed by 1333

Abstract

Around the world, polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic condition that typically affects 6–20% of females. Our study’s major goal was to examine how chlorogenic acid (CGA) affected mice with endocrine and metabolic problems brought on by letrozole-induced PCOS. Group I served as the control for 81 days; Group II was given Letrozole (LETZ) orally at a dose of 6 mg/kg bw for 21 days to induce PCOS; Group III was given LETZ (6 mg/kg) for 21 days, followed by treatment with CGA (50 mg/kg bw daily) for 60 days. The study indicated that LETZ-treated mice displayed symptoms of PCOS, such as dyslipidemia, hyperinsulinemia, elevated testosterone, increases in inflammatory markers and malonaldehyde, and a decline in antioxidants (Ar, lhr, fshr, and esr2) in the ovaries. These alterations were affected when the mice were given CGA and were associated with reduced levels of adiponectin. Adiponectin showed interactions with hub genes, namely MLX interacting protein like (MLXIPL), peroxisome proliferator-activated receptor gamma Coactivator 1- alpha (PPARGC1), peroxisome proliferator-activated receptor gamma (Pparg), and adiponectin receptor 1 (Adipor1). Lastly, the gene ontology of adiponectin revealed that adiponectin was highly involved in biological processes. The findings from our research suggest that adiponectin has direct impacts on metabolic and endocrine facets of PCOS. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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16 pages, 26991 KiB

Open AccessArticle

Weighted Gene Co-Expression Network Analysis (WGCNA) Discovered Novel Long Non-Coding RNAs for Polycystic Ovary Syndrome

Roozbeh Heidarzadehpilehrood

and

Biomedicines 2023, 11(2), 518; https://doi.org/10.3390/biomedicines11020518 - 10 Feb 2023

Cited by 1 | Viewed by 1753

Abstract

Polycystic ovary syndrome (PCOS) affects reproductive-age women. This condition causes infertility, insulin resistance, obesity, and heart difficulties. The molecular basis and mechanism of PCOS might potentially generate effective treatments. Long non-coding RNAs (lncRNAs) show control over multifactorial disorders’ growth and incidence. Numerous studies have emphasized its significance and alterations in PCOS. We used bioinformatic methods to find novel dysregulated lncRNAs in PCOS. To achieve this objective, the gene expression profile of GSE48301, comprising PCOS patients and normal control tissue samples, was evaluated using the R limma package with the following cut-off criterion: p-value < 0.05. Firstly, weighted gene co-expression network analysis (WGCNA) was used to determine the co-expression genes of lncRNAs; subsequently, hub gene identification and pathway enrichment analysis were used. With the defined criteria, nine novel dysregulated lncRNAs were identified. In WGCNA, different colors represent different modules. In the current study, WGCNA resulted in turquoise, gray, blue, and black co-expression modules with dysregulated lncRNAs. The pathway enrichment analysis of these co-expressed modules revealed enrichment in PCOS-associated pathways, including gene expression, signal transduction, metabolism, and apoptosis. In addition, CCT7, EFTUD2, ESR1, JUN, NDUFAB1, CTTNB1, GRB2, and CTNNB1 were identified as hub genes, and some of them have been investigated in PCOS. This study uncovered nine novel PCOS-related lncRNAs. To confirm how these lncRNAs control translational modification in PCOS, functional studies are required. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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10 pages, 290 KiB

Open AccessCommunication

Pharmacological Management of Obesity in Patients with Polycystic Ovary Syndrome

Christodoula Kourtidou

and

Konstantinos Tziomalos

Biomedicines 2023, 11(2), 496; https://doi.org/10.3390/biomedicines11020496 - 08 Feb 2023

Viewed by 1059

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. A substantial proportion of patients with PCOS are either overweight or obese, and excess body weight aggravates the hormonal, reproductive and metabolic manifestations of PCOS. In recent years, several studies evaluated the role of various pharmacological agents in the management of obesity in this population. Most reports assessed glucagon-like peptide-1 receptor agonists and showed a substantial reduction in body weight. More limited data suggest that sodium-glucose cotransporter-2 inhibitors and phosphodiesterase-4 inhibitors might also be effective in the management of obesity in these patients. In the present review, we discuss the current evidence on the safety and efficacy of these agents in overweight and obese patients with PCOS. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

19 pages, 8804 KiB

Open AccessArticle

Modulating Morphological and Redox/Glycative Alterations in the PCOS Uterus: Effects of Carnitines in PCOS Mice

Maria Grazia Palmerini

Guido Macchiarelli

Domenica Cocciolone

Ilaria Antenisca Mascitti

and

Biomedicines 2023, 11(2), 374; https://doi.org/10.3390/biomedicines11020374 - 27 Jan 2023

Cited by 2 | Viewed by 1186

Abstract

(1) Background: Polycystic ovarian syndrome (PCOS) is a common and multifactorial disease affecting reproductive-age women. Although PCOS ovarian and metabolic features have received extensive research, uterine dysfunction has been poorly investigated. This research aims to investigate morphological and molecular alterations in the PCOS uterus and search for modulating effects of different carnitine formulations. (2) Methods: CD1 mice were administered or not with dehydroepiandrosterone (DHEA, 6 mg/100 g body weight) for 20 days, alone or with 0.40 mg L-carnitine (LC) and 0.20 mg acetyl-L-carnitine (ALC) in the presence or absence of 0.08 mg propionyl-L-carnitine (PLC). Uterine horns from the four groups were subjected to histology, immunohistochemistry and immunoblotting analyses to evaluate their morphology, collagen deposition, autophagy and steroidogenesis. Oxidative-/methylglyoxal (MG)-dependent damage was investigated along with the effects on the mitochondria, SIRT1, SOD2, RAGE and GLO1 proteins. (3) Results: The PCOS uterus suffers from tissue and oxidative alterations associated with MG-AGE accumulation. LC-ALC administration alleviated PCOS uterine tissue alterations and molecular damage. The presence of PLC prevented fibrosis and maintained mitochondria content. (4) Conclusions: The present results provide evidence for oxidative and glycative damage as the main factors contributing to PCOS uterine alterations and include the uterus in the spectrum of action of carnitines on the PCOS phenotype. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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11 pages, 275 KiB

Open AccessArticle

Hyperandrogenic Symptoms Are a Persistent Suffering in Midlife Women with PCOS; a Prospective Cohort Study in Sweden

Sofia Persson

Kumari A. Ubhayasekera

Jonas Bergquist

Sahruh Turkmen

Inger Sundström Poromaa

and

Evangelia Elenis

Biomedicines 2023, 11(1), 96; https://doi.org/10.3390/biomedicines11010096 - 30 Dec 2022

Cited by 1 | Viewed by 1519

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among women, and the majority suffers from hyperandrogenism. Hyperandrogenism causes psychological morbidity and impaired quality of life in women with PCOS during the reproductive years, but data on prevalence and impact during midlife are lacking. Thus, this study aimed to address whether hyperandrogenism persists into midlife and, if so, what impact it has on quality of life. In order to answer this question, we performed a multicenter prospective cohort study, where we included women already diagnosed with PCOS who had reached the age of 45 years or more and age-matched controls. All participants underwent a physical exam, structured medical interview, biochemical testing and filled out self-assessment questionnaires. More than 40% of the women with PCOS and 82% of those who presented with the hyperandrogenic phenotype at the diagnostic work-up still suffered from hirsutism. Circulating testosterone levels were similar between women with PCOS and controls while free androgen index was higher in women with PCOS, independent of weight. Women with hyperandrogenic PCOS expressed persisting concerns regarding hirsutism at the follow-up assessment. In conclusion, women with PCOS who present with hyperandrogenic symptoms at the time they are diagnosed with PCOS have a higher risk of persistent androgenic symptoms and impaired quality of life in midlife. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

Review

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16 pages, 312 KiB

Open AccessReview

The Potential of SGLT-2 Inhibitors in the Treatment of Polycystic Ovary Syndrome: The Current Status and Future Perspectives

Aleksandra Dimitrijevic

Vladimir Petrovich Fisenko

Stefani Bolevich

Gala Zarkovic

and

Jovana Joksimovic Jovic

Biomedicines 2023, 11(4), 998; https://doi.org/10.3390/biomedicines11040998 - 23 Mar 2023

Viewed by 2250

Abstract

Polycystic ovary syndrome (PCOS) is the most frequent endocrinopathy during women’s reproductive age. PCOS is a heterogeneous disorder featuring specific cardiometabolic properties. The association between the presence of metabolic disorders and PCOS supports the claim that the regulation of glycemic status is very important in these patients. There is a wide range of therapeutic options (including those treating diabetes mellitus type 2) with potential advantages available for the management of PCOS. Sodium–glucose cotransporter type 2 inhibitors (SGLT-2is) improve glucose metabolism, reduce fat tissue, lower blood pressure, reduce oxidative stress and inflammation, and protect the cardiovascular system. Currently, the use of SGLT-2is is not widespread in PCOS therapy, although these drugs represent a promising new therapeutic approach. Therefore, it is necessary to initiate further study in order to determine more effective therapies for PCOS and investigate the effect of SGLT-2is, both as a monotherapy and in combination with other drugs. It is necessary to understand the mechanisms underlying SGLT-2is in PCOS and their effects on long-term complications, especially since the gold standard treatment for PCOS, such as metformin and oral contraceptives, do not have long-term cardioprotective effects. The effects of SGLT-2is seem to involve cardiac protection, while diminishing endocrine and reproductive abnormalities in PCOS. In the current narrative review, we examine the most recent clinical evidence and discuss the potential applications of SGLT-2is for PCOS therapy. Full article

(This article belongs to the Special Issue Molecular Research on Polycystic Ovary Syndrome (PCOS) 2.0)

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