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Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies

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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: closed (31 May 2024) | Viewed by 34141

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Dr. Ebrahim Asadi

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Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada
Interests: reproduction; female fertility preservation; male fertility preservation; female infertility; male infertility; oocyte; sperm; embryo; ovarian tissue; spermatogonial stem cell; testicular tissue; reproductive cells and tissues culture; reproductive cells and tissues cryopreservation; apoptosis; oxidative stress; antioxidant therapy
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Dear Colleagues,

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine and metabolic disorders of women of reproductive age, which negatively affects the reproductive and mental health of women. Hyperandrogenism, ovulatory dysfunction, and polycystic ovary morphology are diagnostic criteria of PCOS. While obesity, increased cardiovascular risk factors, insulin resistance, hyperinsulinism, and type 2 diabetes mellitus are common symptoms among women with PCOS, they are not required criteria for diagnosis. Since PCOS leads to infertility, an early diagnosis, and treatments are critical, particularly at the extreme ends of the reproductive lifespan. Therefore, in recent years, understanding the underlying mechanisms, diagnosis, and clinical management of PCOS have become progressively significant. Lifestyle therapy, in vitro fertilization, surgical therapy, and pharmacotherapy are used to manage the infertility of women with PCOS. In fact, with the latest advances, potential therapeutic options have increased, giving patients and clinicians more choices.

This Special Issue of “Advances in Polycystic Ovary Syndrome Research” will include original research articles and review articles, addressing recent advances in our knowledge about etiology, pathophysiology and diagnosis of PCOS as well as advances in therapeutic options for managing PCOS. Oxidative stress roles and the outcome of antioxidant therapy in PCOS will be of great interest, too.

Dr. Ebrahim Asadi
Guest Editor

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Keywords

female infertility
endocrine disorder
metabolic disorder
polycystic ovary syndrome
polycystic ovarian morphology
hyperandrogenism
menstrual irregularity
therapeutics
oxidative stress
antioxidant

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Research

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15 pages, 837 KiB

Open AccessArticle

CYP21A2 Intron 2 Genetic Variants Might Be Associated with the Clinical Characteristics of Women with PCOS

by Ralitsa Robeva, Silvia Andonova, Tihomir Todorov, Aylin Feyzullova, Atanaska Elenkova, Georgi Kirilov, Alexey Savov, Sabina Zacharieva and Albena Todorova

Biomedicines 2024, 12(7), 1528; https://doi.org/10.3390/biomedicines12071528 - 9 Jul 2024

Viewed by 1007

Abstract

Aims: Pathogenic variants in the CYP21A2 gene are related to the classic and non-classic forms of congenital adrenal hyperplasia (CAH). However, the role of CAH carrier status in the clinical presentation of polycystic ovarian syndrome (PCOS) is still unclear. Moreover, the possible associations of different CYP21A2 gene polymorphisms with metabolic and reproductive abnormalities in PCOS have not been investigated. Therefore, the present study aims to examine the prevalence of the most common CYP21A2 pathogenic variant IVS2-13A/C>G (c.293-13A/C>G) in Eastern European women with PCOS and to evaluate the associations between common intron 2 genetic polymorphisms and the clinical symptoms of the patients. Methods: Sixty consecutively recruited women with PCOS were genotyped for the CYP21A2 intron 2 IVS2-13A/C>G genetic variant. Additionally, CYP21A2 intron 2 polymorphic variants rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) were tested and described. The clinical and hormonal characteristics were compared in women with PCOS and with polymorphic and wild-type genotypes. Results: The heterozygous CYP21A2 pathogenic variant IVS2-13A/C>G was found in one of the investigated PCOS patients (1.67%) with a non-hyperandrogenic type of PCOS. The presence of the rs6453 (c.293-44G>T) T-allele was associated with increased levels of DHEAS (15.18 vs. 9.14 µmol/L, p = 0.003) compared to the wild-type genotype in the investigated group. The rs6451 (c.293-67C>A/G) minor alleles were associated with an earlier age of menarche in the patients (12.0 vs. 13.0 years, p = 0.007). The polymorphic rs369651496 minor 6G allele was related to a better lipid profile in the women with PCOS, while the rs6474 variant modulated the blood pressure of the patients. Conclusions: The presence of CYP21A2 genetic minor alleles of rs6467 (IVS2-13A/C, c.293-13A/C), rs6453 (c.293-44G>T), rs6451 (c.293-67C>A/G), rs369651496 (c.293-104del), and rs6474 (c.308G>A/p.R103L) might modulate the adrenal androgens, age of menarche, and metabolic features in women with PCOS. Further studies on 21-hydroxylase genetic variants (pathogenic and polymorphisms) in different ethnic groups might help reveal the influence of adrenal steroidogenesis on PCOS development, clinical manifestations, and lifelong cardiovascular risks. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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16 pages, 1708 KiB

Open AccessArticle

The Comparative Effects of Myo-Inositol and Metformin Therapy on the Clinical and Biochemical Parameters of Women of Normal Weight Suffering from Polycystic Ovary Syndrome

by Aleksandra Gudović, Zoran Bukumirić, Milos Milincic, Miljan Pupovac, Mladen Andjić, Katarina Ivanovic and Svetlana Spremović-Rađenović

Biomedicines 2024, 12(2), 349; https://doi.org/10.3390/biomedicines12020349 - 2 Feb 2024

Cited by 2 | Viewed by 7023

Abstract

Background: Polycystic ovary syndrome (PCOS) is a multisystem reproductive–metabolic disorder and the most common endocrine cause of infertility. The objective of our study was to determine the influence of myo-inositol (MI) on insulin resistance (IR), menstrual cycle regularity, and hyperandrogenism in women suffering from PCOS with normal BMI and diagnosed IR. Methods: We performed a prospective randomized controlled trial (RCT) that included 60 participants with PCOS who had IR and a normal BMI. Two groups were formed. A group of thirty patients received MI, and thirty patients in the control group received metformin (MET). Results: A statistically significant reduction in the area under the curve (AUC) of insulin values during the oral glucose tolerance test (OGTT) was recorded in both examined groups after the applied therapy with MI and MET. The regularity of the menstrual cycle in both groups was improved in >90% of patients. A statistically significant decrease in androgenic hormones (testosterone, SHBG, free androgen index—FAI, androstenedione) was recorded in both groups and did not differ between the groups. Conclusions: Both MI and MET can be considered very effective in the regulation of IR, menstrual cycle irregularities, and hyperandrogenism in women with PCOS. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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12 pages, 1593 KiB

Open AccessArticle

Genetic and Epigenetic Profiles of Polycystic Ovarian Syndrome and In Vitro Bisphenol Exposure in a Human Granulosa Cell Model

by Reem Sabry, Jenna F. Gallo, Charlie Rooney, Olivia L. M. Scandlan, Ola S. Davis, Shilpa Amin, Mehrnoosh Faghih, Megan Karnis, Michael S. Neal and Laura A. Favetta

Biomedicines 2024, 12(1), 237; https://doi.org/10.3390/biomedicines12010237 - 21 Jan 2024

Cited by 2 | Viewed by 2071

Abstract

Higher levels of bisphenols are found in granulosa cells of women with polycystic ovary syndrome (PCOS), posing the question: Is bisphenol exposure linked to PCOS pathophysiology? Human granulosa cells were obtained from women with and without PCOS, and genes and microRNAs associated with PCOS were investigated. The first phase compared healthy women and those with PCOS, revealing distinct patterns: PCOS subjects had lower 11β-HSD1 (p = 0.0217) and CYP11A1 (p = 0.0114) levels and elevated miR-21 expression (p = 0.02535), elucidating the molecular landscape of PCOS, and emphasizing key players in its pathogenesis. The second phase focused on healthy women, examining the impact of bisphenols (BPA, BPS, BPF) on the same genes. Results revealed alterations in gene expression profiles, with BPS exposure increasing 11β-HSD1 (p = 0.02821) and miR-21 (p = 0.01515) expression, with the latest mirroring patterns in women with PCOS. BPA exposure led to elevated androgen receptor (AR) expression (p = 0.0298), while BPF exposure was associated with higher levels of miR-155. Of particular interest was the parallel epigenetic expression profile between BPS and PCOS, suggesting a potential link. These results contribute valuable insights into the nuanced impact of bisphenol exposure on granulosa cell genes, allowing the study to speculate potential shared mechanisms with the pathophysiology of PCOS. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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11 pages, 1230 KiB

Open AccessArticle

Meteorin-like Protein and Zonulin in Polycystic Ovary Syndrome: Exploring Associations with Obesity, Metabolic Parameters, and Inflammation

by Plamena Kabakchieva, Antoaneta Gateva, Tsvetelina Velikova, Tsvetoslav Georgiev, Kyosuke Yamanishi, Haruki Okamura and Zdravko Kamenov

Biomedicines 2024, 12(1), 222; https://doi.org/10.3390/biomedicines12010222 - 19 Jan 2024

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Abstract

Objective: Polycystic ovary syndrome (PCOS) is a prevalent hormonal and metabolic disorder, wherein the adipose tissue and gut microbiome have been demonstrated to contribute to its pathogenesis. This study aims to assess the concentrations of the adipokine, meteorin-like protein (Metrnl) and the protein, zonulin, related to intestine permeability, in individuals with PCOS with a particular emphasis on their relationship with obesity, clinical manifestations, hormonal profiles, and metabolic parameters. Methods: A cohort comprising 58 women with PCOS, classified according to the Rotterdam criteria, was enrolled. The study also considered age, body mass index (BMI), and ethnicity-matched controls (n = 30). Comprehensive anthropometric and clinical evaluations, hormonal assays, and biochemical analyses were conducted during the follicular phase. Subsequent subgroup analyses were executed within the PCOS cohort based on waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum concentrations of Metrnl and zonulin were quantified via the enzyme-linked immunosorbent assay (ELISA) technique. Results: The Metrnl and zonulin levels exhibited no significant disparity between PCOS patients and controls. Nevertheless, within the entire participant cohort and the PCOS group exclusively, overweight/obese participants demonstrated higher Metrnl concentrations relative to their normal-weight counterparts (p < 0.001, p = 0.001, respectively). Furthermore, higher Metrnl concentrations were identified in subgroups characterized by high WHtR and IR in comparison to those with low WHtR (p = 0.001) and without IR (p = 0.001), respectively. A correlation emerged between Metrnl levels and various anthropometric and metabolic parameters, as well as sex-hormone-binding globulin (SHBG) and interleukin-18 (IL-18) within the PCOS group. Multiple linear regression analysis identified HOMA-IR as the sole independent predictor of Metrnl levels. Conclusion: While Metrnl and zonulin levels do not serve as diagnostic indicators of PCOS, elevated Metrnl concentrations exhibited robust associations with proinflammatory and metabolic irregularities within the PCOS population. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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12 pages, 601 KiB

Open AccessArticle

Elevated Anti-Müllerian Hormone as a Prognostic Factor for Poor Outcomes of In Vitro Fertilization in Women with Polycystic Ovary Syndrome

by Emídio Vale-Fernandes, Márcia Barreiro, Carla Leal, Rosa Zulmira Macedo, António Tomé and Mariana P. Monteiro

Biomedicines 2023, 11(12), 3150; https://doi.org/10.3390/biomedicines11123150 - 27 Nov 2023

Cited by 5 | Viewed by 2482

Abstract

Women with polycystic ovary syndrome (PCOS) tend to have elevated anti-Müllerian hormone (AMH) levels, which appear to correlate with disease severity and pregnancy outcomes. This was a retrospective observational study designed to assess the relationship between circulating AMH levels and in vitro fertilization (IVF) outcomes. The study involved 150 women with PCOS who underwent IVF treatments. The women’s IVF cycles were allocated into three subgroups according to AMH levels: ‘low’ (AMH < 3.7 ng/mL; n = 49), ‘middle’ (AMH 3.7–7.4 ng/mL; n = 94), and ‘high’ (AMH > 7.4 ng/mL; n = 56). All pregnancy-related outcomes (positive beta human chorionic gonadotropin (βHCG), clinical pregnancy rate, live birth rate, and cumulative live birth rate) were greater in women’s IVF cycles with ‘low’ AMH when compared to those with ‘middle’ or ‘high’ AMH (p < 0.05). AMH levels below 3.7 ng/mL were found to be associated with lower oocyte immaturity rate and better pregnancy outcomes, although baseline AMH was not shown to have any significant predictive power for live birth and cumulative live birth in the multivariable logistic regression analysis after adjusting for possible confounders nor in the ROC analyses. In summary, the current study lays the groundwork to validate high AMH levels as a poor prognostic factor for pregnancy outcomes after IVF in women with PCOS. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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12 pages, 544 KiB

Open AccessArticle

Overnight Melatonin Concentration and Sleep Quality Are Associated with the Clinical Features of Polycystic Ovary Syndrome

by Adam T. Evans, Heidi Vanden Brink, Jessica S. Lim, Brittany Y. Jarrett, Annie W. Lin, Marla E. Lujan and Kathleen Hoeger

Biomedicines 2023, 11(10), 2763; https://doi.org/10.3390/biomedicines11102763 - 12 Oct 2023

Cited by 2 | Viewed by 2178

Abstract

Circulating melatonin is elevated in women with polycystic ovary syndrome (PCOS); whether circadian disruptions coincide with sleep disturbances in women with PCOS or their symptom severity is unclear. The objective of this observational pilot study was to determine whether altered patterns of melatonin excretion are associated with reduced sleep quality in women with versus without PCOS. Participants underwent a clinical assessment, transvaginal ultrasound, and reproductive hormone testing. Morning and evening urine samples were assayed for urinary 6-sulfatoxymelatonin (MEL) as a proxy for melatonin production. The night (morning MEL)-to-day (evening MEL) ratio, or N:D ratio, was determined to approximate the rhythm of MEL production. Sleep quality and duration were assessed using the Pittsburgh Sleep Quality Index (PSQI) and wrist actigraphy. No differences were detected in overnight MEL, daytime MEL, or the N:D ratio in participants with PCOS versus controls. The PCOS group experienced reduced weekend sleep efficiency vs. controls (81% vs. 88% p < 0.05). The number of follicles per ovary (FNPO) was positively associated with overnight MEL (r = 0.359, p < 0.05). Weekend sleep time and overnight MEL concentrations were dependent on PCOS status. Therefore, diagnostic features of PCOS were associated with MEL production and sleep disturbances, suggesting that women with a more severe clinical presentation of PCOS may be more likely to experience altered MEL production or sleep disturbances. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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15 pages, 9205 KiB

Open AccessArticle

Abnormal Expression of Prolyl Oligopeptidase (POP) and Its Catalytic Products Ac-SDKP Contributes to the Ovarian Fibrosis Change in Polycystic Ovary Syndrome (PCOS) Mice

by Suo Han, Shimeng Wang, Xiang Fan, Mengchi Chen, Xiaojie Wang, Yingtong Huang, Hongdan Zhang, Yinyin Ma, Jing Wang and Chunping Zhang

Biomedicines 2023, 11(7), 1927; https://doi.org/10.3390/biomedicines11071927 - 7 Jul 2023

Viewed by 1710

Abstract

Polycystic ovary syndrome (PCOS) is an endocrine disorder and metabolic syndrome. Ovarian fibrosis pathological change in PCOS has gradually attracted people’s attention. In this study, we constructed a PCOS mouse model through the use of dehydroepiandrosterone. Sirius red staining showed that the ovarian tissues in PCOS mice had obvious fibrosis. Prolyl oligopeptidase (POP) is a serine protease and N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is its catalytic product. Studies show that abnormal expression and activity of POP and Ac-SDKP are closely related to tissue fibrosis. It was found that the expression of POP and Ac-SDKP was decreased in the ovaries of PCOS mice. Further studies showed that POP and Ac-SDKP promoted the expression of matrix metalloproteinases 2 (MMP-2) expression and decreased the expression of transforming growth factor beta 1 (TGF-β1) in granulosa cells. Hyperandrogenemia is a typical symptom of PCOS. We found that testosterone induced the low expression of POP and MMP2 and high expression of TGF-β1 in granulosa cells. POP overexpression and Ac-SDKP treatment inhibited the effect of testosterone on TGF-β1 and MMP2 in vitro and inhibited ovarian fibrosis in the PCOS mouse model. In conclusion, PCOS ovarian tissue showed obvious fibrosis. Low expression of POP and Ac-SDKP and changes in fibrotic factors contribute to the ovarian pathological fibrosis induced by androgen. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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11 pages, 567 KiB

Open AccessArticle

Treatment with Myo-Inositol Does Not Improve the Clinical Features in All PCOS Phenotypes

by Vittorio Unfer, Michele Russo, Cesare Aragona, Gabriele Bilotta, Mario Montanino Oliva and Mariano Bizzarri

Biomedicines 2023, 11(6), 1759; https://doi.org/10.3390/biomedicines11061759 - 19 Jun 2023

Cited by 6 | Viewed by 6794

Abstract

Background: The aim of the present study is to investigate the effects produced by a treatment with myo-Inositol (myo-Ins) in women presenting polycystic ovary syndrome (PCOS) of different phenotypes. Methods: We performed a retrospective study to evaluate whether patients presenting different PCOS phenotypes, treated for 6 months with myo-Ins, might exhibit a differential response to the treatment. On this premise, we clustered women with PCOS phenotypes A, B, and C in the first study group (hyperandrogenic PCOS or H-PCOS), and women presenting PCOS phenotype D in a separate study group (non-hyperandrogenic PCOS or NH-PCOS) to evaluate if the presence of hyperandrogenism, shared by H-PCOS, might imply a metabolic/endocrine condition rather than a gynecological issue. Results: The administration of myo-Ins induced a significant improvement in metabolic and endocrine parameters in H-PCOS, while the effects on NH-PCOS were negligible. Additionally, myo-Ins treatment improved the endometrial thickness of H-PCOS. Conclusions: Subjects selected for the study exhibited a differential response to myo-Ins therapy according to their PCOS phenotypes. The data suggest that the same treatment might not equally improve the parameters of the PCOS condition in each sub-group of patients. It is crucial to distinguish the various phenotypes to properly select the therapeutical approach. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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Review

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16 pages, 1743 KiB

Open AccessReview

Type and Frequency in Use of Nutraceutical and Micronutrient Supplementation for the Management of Polycystic Ovary Syndrome: A Systematic Scoping Review

by Nicole Scannell, Evangeline Mantzioris, Vibhuti Rao, Chhiti Pandey, Carolyn Ee, Aya Mousa, Lisa Moran and Anthony Villani

Biomedicines 2023, 11(12), 3349; https://doi.org/10.3390/biomedicines11123349 - 18 Dec 2023

Cited by 1 | Viewed by 2783

Abstract

Lifestyle strategies are considered first-line treatment for the management of polycystic ovary syndrome (PCOS). However, complementary therapies, including nutrient supplementation, have been identified as a potential adjunct therapy. Therefore, we systematically mapped the available literature to identify the type and frequency of the use of nutraceutical and micronutrient supplementation for the management of PCOS features. A systematic search of the literature was conducted using CINAHL, Cochrane reviews, Medline, PsycINFO, Scopus and LILACS. All types of study designs were included if they reported on the use of nutraceuticals and/or micronutrient supplementation on features of PCOS in women aged ≥18 years. A total of 344 articles were included. Forty-one supplements were identified, with the most frequently investigated being inositols (n = 86), vitamin D (n = 53), N-acetylcysteine (n = 27) and omega-3 fatty acids (n = 25). Reproductive outcomes were the most commonly reported (n = 285; 83%), followed by metabolic (n = 229; 67%), anthropometric (n = 197; 57%) and psychological (n = 8; 2%). Our results identified that nutraceutical and micronutrient supplementation require further investigation of psychological outcomes in women with PCOS. Moreover, adequately powered primary studies are warranted to investigate therapeutic doses needed for clinical benefits. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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11 pages, 886 KiB

Open AccessReview

Ovarian Torsion in Polycystic Ovary Syndrome: A Potential Threat?

by Iason Psilopatis, Christos Damaskos, Nikolaos Garmpis, Kleio Vrettou, Anna Garmpi, Efstathios A. Antoniou, Athanasios Chionis, Konstantinos Nikolettos, Konstantinos Kontzoglou and Dimitrios Dimitroulis

Biomedicines 2023, 11(9), 2503; https://doi.org/10.3390/biomedicines11092503 - 10 Sep 2023

Cited by 1 | Viewed by 4272

Abstract

Polycystic ovary syndrome (PCOS) constitutes the most prevalent endocrine disorder in women of reproductive age worldwide. Given the increased risk of ovarian torsion in the presence of large ovarian cysts, polycystic ovarian syndrome could be regarded as one of the most significant risk factors for ovarian and/or adnexal torsion in cases of significantly enlarged ovaries. The aim of the present review is to investigate, for the first time, the association between polycystic ovarian syndrome and ovarian torsion. We performed a review of the literature using the MEDLINE and LIVIVO databases in order to find relevant studies. By using the search terms “polycystic ovarian syndrome” and “ovarian torsion”, we were able to identify 14 studies published between 1995 and 2019. The present work constitutes the most up-to-date, comprehensive literature review focusing on the risk of ovarian/adnexal torsion in patients with polycystic ovaries. Ovarian/adnexal torsion seems to be a feared complication in patients with polycystic ovary syndrome. Acute lower abdominal pain in patients with known polycystic ovaries represents the most common symptom, while diagnostic assessment almost always incorporates transvaginal ultrasound and computer tomography or magnetic resonance tomography scans. In case of suspected torsion, emergency laparoscopy with ovarian or adnexal detorsion seems to be the standard therapeutic approach with a view to restitute the interrupted blood supply. In cases of repeated ovarian/adnexal torsions, ovariopexy or ovariectomy/adnexectomy had to be discussed with the patient in the context of risk recurrence minimization. Full article

(This article belongs to the Special Issue Advances in Polycystic Ovary Syndrome Research: From Molecular Mechanisms to Therapeutic Strategies)

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