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Biology of the Cell Apr 2024Polycystic ovary syndrome or PCOS is an endocrine disorder in women of reproductive age. It is a diversified multi factorial disorder and diagnosis is very complicated... (Review)
Review
Polycystic ovary syndrome or PCOS is an endocrine disorder in women of reproductive age. It is a diversified multi factorial disorder and diagnosis is very complicated because of its overlapping symptoms some of which are irregular menstrual cycle, acne in face, excess level of androgen (AE), insulin resistance, obesity, cardiovascular disease, mood disorder and type 2 diabetes (T2DM). PCOS may be caused by hormonal imbalance, genetic and epigenetic vulnerability, hypothalamic and ovarian troubles. PCOS is essentially hyperandrogenimia with oligo-anovulation. This review explains the abnormal regulation of autophagy related genes and proteins in different cells at various stages which leads to the genesis of PCOS. During nutrient starvation cells face stress condition, which it tries to overcome by activating its macroautophagy mechanism and by degrading the cytoplasmic material. This provides energy to the cell facilitating its survival. Downregulation of autophagy related genes in endometria has been observed in PCOS women. PCOS can be managed by maintaining proper lifestyle and medical treatment. Healthy meals and regular exercise can prevent the excessive weight and also reduce the PCOS complications. Medicines such as metformin, clomiphene, and the oral contraceptive pill can also balance the hormonal level. The imbalance in regulation of autophagy genes has been discussed with correlation to PCOS. The different management strategies for PCOS have also been summarized.
PubMed: 38679788
DOI: 10.1111/boc.202300069 -
Journal of Clinical Medicine Apr 2024Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder in women of reproductive age. Diagnosis is based on the evidence-based international...
Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder in women of reproductive age. Diagnosis is based on the evidence-based international guideline 2018 and the Rotterdam Consensus to classify PCOS phenotypes. This study aims to characterize the biodemographic, clinical, metabolic, and reproductive variables and their relationship with PCOS phenotypes in a population from the Ecuadorian Andes. A cross-sectional study was conducted with a non-random consecutive sample of 92 women who attended the outpatient gynecology and endocrinology clinic at the Hospital of the Technical University of Loja (UTPL)-Santa Inés, Loja, Ecuador, between January 2022 and July 2023. Descriptive statistics, mean calculations, standard deviation, parametric and nonparametric tests, odds ratios (OR), confidence intervals (CI), and -values were employed. The average age was 22 ± 3.4 years, with a predominantly mestizo, urban, single, highly educated, and medium-high socioeconomic level population. It was identified that phenotypes A + B are at a higher risk of developing oligomenorrhea and hypertriglyceridemia compared to phenotypes C + D, with statistically significant differences ( < 0.05). Furthermore, in terms of reproductive variables, phenotypes A + B exhibit a significantly higher frequency of elevated anti-Müllerian hormone (AMH) compared to phenotypes C + D, also with statistical significance ( < 0.05). The classical phenotypes A and B of PCOS are the most common in Ecuadorian Andean women and carry a higher risk of insulin resistance, anovulation, metabolic disorders, and elevated triglyceride levels compared to phenotypes C and D. Ethnic diversity and sociocultural habits influence the prevalence and clinical manifestations of these phenotypes.
PubMed: 38673649
DOI: 10.3390/jcm13082376 -
Human Reproduction Update Jul 2024The increasing prevalence of obesity worldwide poses a significant threat to reproductive function owing, in part, to hormonal disturbances caused by negative feedback... (Meta-Analysis)
Meta-Analysis
Comparative efficacy of exercise, diet and/or pharmacological interventions on BMI, ovulation, and hormonal profile in reproductive-aged women with overweight or obesity: a systematic review and network meta-analysis.
BACKGROUND
The increasing prevalence of obesity worldwide poses a significant threat to reproductive function owing, in part, to hormonal disturbances caused by negative feedback between excess adiposity and the hypothalamic-pituitary-ovarian axis. Consequently, finding the most appropriate strategies to lose weight and improve ovulation in women with overweight or obesity is a clinically relevant matter that needs to be investigated. A comprehensive comparison of the independent and combined efficacy of lifestyle and/or pharmacological interventions on BMI, ovulation, and hormonal profile in women with overweight or obesity at risk of anovulatory infertility would facilitate improving fertility strategies in this population.
OBJECTIVE AND RATIONALE
This study aimed to evaluate the comparative efficacy of exercise, diet, and pharmacological interventions on BMI, ovulation, and hormonal profile in reproductive-aged women with overweight or obesity.
SEARCH METHODS
A systematic review was performed by searching PubMed, Scopus, Web of Science, PsycINFO, and Cochrane Library up to 14 December 2023, for randomized controlled trials assessing the effects of exercise, diet and/or pharmacological interventions (i.e. weight-lowering drugs or ovulation inducers) on BMI, ovulation, and/or hormonal profile in reproductive-aged women with overweight or obesity. We performed frequentist random-effect network meta-analyses and rated the certainty of the evidence. The primary outcomes were BMI and ovulation rate, and the secondary outcomes were serum reproductive hormone levels (gonadotrophins, androgens, or oestrogens). We performed sensitivity analyses, including the studies that only involved women with PCOS.
OUTCOMES
Among 1190 records screened, 148 full texts were assessed for eligibility resulting in 95 trials (9910 women), of which 53% presented a high or unclear risk of bias. The network meta-analyses revealed that, compared to control: diet combined with weight-lowering drugs (mean difference (MD) -2.61 kg/m2; 95% CI -3.04 to -2.19; τ2 = 0.22) and adding exercise (MD -2.35 kg/m2; 95% CI -2.81 to -1.89; τ2 = 0.22) led to the greatest decrease in BMI; exercise combined with diet and ovulation inducers (risk ratio (RR) 7.15; 95% CI 1.94-26.40; τ2 = 0.07) and exercise combined with diet and weight-lowering drugs (RR 4.80; 95% CI 1.67-13.84; τ2 = 0.07) produced the highest increase in ovulation rate; and exercise combined with diet and weight-lowering drugs was the most effective strategy in reducing testosterone levels (standardized mean difference (SMD) -2.91; 95% CI -4.07 to -1.74; τ2 = 2.25), the third most effective strategy in increasing sex hormone-binding globulin levels (SMD 2.37; 95% CI 0.99-3.76; τ2 = 2.48), and it was coupled with being ranked first in terms of free androgen index reduction (SMD -1.59; 95% CI -3.18 to 0.01; τ2 = 1.91). The surface under the cumulative ranking curve scores suggested that: diet combined with weight-lowering drugs is the strategy most likely (94%) to produce the highest BMI reduction; and exercise combined with diet and ovulation inducers is the strategy most likely (89%) to produce the highest ovulation rate improvement. The sensitivity analyses, which exclusively included studies involving women diagnosed with PCOS, were consistent with the results presented above.
WIDER IMPLICATIONS
Overall, the findings of this network meta-analysis indicate that the combination of exercise, diet, and pharmacological interventions is effective for weight loss, improving ovulation, and normalizing the androgen levels of women with overweight or obesity. Although higher quality studies are needed, these results support that the optimal treatment strategy for women with overweight or obesity wishing to conceive must consider exercise, diet, and pharmacological interventions during the shared decision-making process.
Topics: Humans; Female; Body Mass Index; Ovulation; Obesity; Overweight; Exercise; Network Meta-Analysis; Adult; Diet
PubMed: 38627233
DOI: 10.1093/humupd/dmae008 -
Human Reproduction Open 2024Does ovarian ferroptosis play an active role in the development of polycystic ovary syndrome (PCOS)?
STUDY QUESTION
Does ovarian ferroptosis play an active role in the development of polycystic ovary syndrome (PCOS)?
SUMMARY ANSWER
Increased ovarian ferroptosis was present in PCOS ovaries and the inhibition of ferroptosis with ferrostatin-1 (Fer-1) ameliorated polycystic ovary morphology and anovulation.
WHAT IS KNOWN ALREADY
Programmed cell death plays a fundamental role in ovarian follicle development. However, the types and mechanisms of cell death involved in the ovary are yet to be elucidated. Ferroptosis is a recently discovered iron-dependent programmed cell death. Impaired iron metabolism and cell death have been observed in women with PCOS, the main cause of anovulatory infertility. Additionally, previous studies reported that an abnormal expression of noncoding RNA may promote ferroptosis in immortalized ovarian granulosa cell lines. However, little is known about whether ovarian ferroptosis is increased in PCOS, and there is insufficient direct evidence for a role of ferroptosis in PCOS, and the underlying mechanism. Moreover, the effect of the inhibition of ferroptosis with Fer-1 in PCOS remains unclear.
STUDY DESIGN SIZE DURATION
Ferroptosis was evaluated in human granulosa cells (hGCs) from non-PCOS (n = 6-16) and PCOS (n = 7-18) patients. The experimental study was completed using primary hGCs from women undergoing IVF. Improvements in PCOS indicators following ferroptosis inhibition with Fer-1 were investigated in a dehydroepiandrosterone (DHEA)-induced PCOS rat model (n = 8 per group).
PARTICIPANTS/MATERIALS SETTING METHODS
Ovarian ferroptosis was evaluated in the following ways: by detecting iron concentrations via ELISA and fluorescent probes; measuring malondialdehyde (MDA) concentrations via ELISA; assessing ferroptosis-related protein abundance with western blotting; observing mitochondrial morphology with transmission electron microscopy; and determining cell viability. Primary hGCs were collected from women undergoing IVF. They were treated with dihydrotestosterone (DHT) for 24 h. The effect of DHT on ferroptosis was examined in the presence or absence of small interfering RNA-mediated knockdown of the putative receptor coregulator for signaling molecules. The role of ovarian ferroptosis in PCOS progression was explored in rats. The DHEA-induced PCOS rat model was treated with the ferroptosis inhibitor, Fer-1, and the oocytes and metaphase II oocytes were counted after ovarian stimulation. Additionally, rats were treated with the ferroptosis inducer, RSL3, to further explore the effect of ferroptosis. The concentrations of testosterone, FSH, and LH were assessed.
MAIN RESULTS AND THE ROLE OF CHANCE
Increased ferroptosis was detected in the ovaries of patients with PCOS and in rats with DHEA-induced PCOS. Increased concentrations of Fe (<0.05) and MDA (<0.05), and upregulated nuclear receptor coactivator 4 protein levels, and downregulated ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) proteins were observed in the hGCs in patients with PCOS and ovaries of PCOS rats (<0.05 versus control). DHT was shown to induce ferroptosis via activation of NOCA4-dependent ferritinophagy. The inhibition of ferroptosis with Fer-1 in rats ameliorated a cluster of PCOS traits including impaired glucose tolerance, irregular estrous cycles, reproductive hormone dysfunction, hyperandrogenism, polycystic ovaries, anovulation, and oocyte quality (<0.05). Treating rats with RSL3 resulted in polycystic ovaries and hyperandrogenism (<0.05).
LARGE-SCALE DATA
N/A.
LIMITATIONS REASONS FOR CAUTION
Although ovarian-targeted ferroptosis inhibition may be a more targeted treatment for PCOS, the underlying mechanisms in the cycle between ferroptosis and hyperandrogenism require further exploration. Additionally, since PCOS shows high heterogeneity, it is important to investigate whether ferroptosis increases are present in all patients with PCOS.
WIDER IMPLICATIONS OF THE FINDINGS
Androgen-induced ovarian ferroptosis appears to play a role in the pathogenesis of PCOS, which potentially makes it a promising treatment target in PCOS.
STUDY FUNDING/COMPETING INTERESTS
This study was supported by the National Key R&D Program of China (2023YFC2705500, 2023YFC2705505, 2019YFA0802604), National Natural Science Foundation of China (No. 82130046, 82320108009, 82101708, 82101747, and 82001517), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (No. SHSMU-ZLCX20210201, No. SSMU-ZLCX20180401), Shanghai Jiaotong University School of Medicine, Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003) and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (No. 20161413), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), and Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36). The authors report no competing interests.
PubMed: 38550897
DOI: 10.1093/hropen/hoae013 -
BMC Endocrine Disorders Mar 2024Polycystic ovary syndrome (PCOS) is a serious health condition affecting women of reproductive age. High prevalence of PCOS and associated metabolic complications needs...
BACKGROUND
Polycystic ovary syndrome (PCOS) is a serious health condition affecting women of reproductive age. High prevalence of PCOS and associated metabolic complications needs effective treatment and management. This study evaluated the efficacy of optimal nutraceutical combinations in improving PCOS characteristics using system biology-based mathematical modelling and simulation.
METHODS
A shortlisting of eight potent nutraceuticals was carried out with literature search. Menstrual cycle model was used to perform simulations on an in-silico population of 2000 individuals to test individual and combined effects of shortlisted nutraceuticals on five PCOS characteristics [oligomenorrhea, anovulation, hirsutism, infertility, and polycystic ovarian morphology (PCOM)] for a duration of 6 months. Efficacy was tested across lean and obese phenotypes and age groups.
RESULTS
Individual assessment of nutraceuticals revealed seven most potent compounds. Myo-inositol among them was observed to be the most effective in alleviating the PCOS characteristics. The in-silico population analysis showed that the combination of melatonin and ALA along with myo-inositol was efficacious in restoring the hormonal balance across age-groups and Body Mass Index (BMI) categories.
CONCLUSION
Supplementation with the combination of myo-inositol, melatonin, and ALA demonstrated potential in managing PCOS symptoms in our in-silico analysis of a heterogeneous population, including lean and obese phenotypes across various severities and age groups, over a 6-month period. Future clinical studies are recommended to validate these findings.
Topics: Female; Humans; Polycystic Ovary Syndrome; Melatonin; Dietary Supplements; Inositol; Obesity
PubMed: 38549084
DOI: 10.1186/s12902-024-01571-y -
Reproduction (Cambridge, England) Jun 2024Brown adipose tissue impaired in polycystic ovary syndrome (PCOS) plays a crucial role in the treatment of PCOS. This study shows that myricetin potently improves PCOS...
IN BRIEF
Brown adipose tissue impaired in polycystic ovary syndrome (PCOS) plays a crucial role in the treatment of PCOS. This study shows that myricetin potently improves PCOS by activating brown adipose tissue (BAT).
ABSTRACT
PCOS is a complex endocrine disease characterized by hyperandrogenism, anovulation and polycystic ovary, and is often accompanied by metabolic disorder such as insulin resistance. BAT has been considered as a promising target for the treatment of obesity and other metabolic disease. In this study, we showed that 3 weeks of myricetin (a compound from natural product) treatment improved metabolic capacity and insulin sensitivity by activating BAT in dehydroepiandrosterone (DHEA)-induced PCOS mice. Furthermore, increased number of corpus luteum and decreased cystic formation were observed in PCOS mice. With the hormone levels such as luteinizing hormone (LH) were reversed, estrous cycle was also normalized after myricetin treatment. Eventually, myricetin markedly improved reproductive defects in PCOS mice. In short, our results suggest that myricetin treatment dramatically ameliorates ovarian dysfunction and metabolic disturbances in PCOS and provides a novel perspective for the treatment of PCOS.
Topics: Polycystic Ovary Syndrome; Animals; Female; Flavonoids; Adipose Tissue, Brown; Mice; Insulin Resistance; Mice, Inbred C57BL
PubMed: 38520750
DOI: 10.1530/REP-24-0034 -
Cureus Feb 2024The 29-year-old participant in the case study has been grappling with infertility for the last six years. Following an assessment of her symptoms, hormone profile, and...
A Comprehensive Approach to Polycystic Ovarian Syndrome: A Case Report of Successful Intracytoplasmic Sperm Injection Treatment Utilizing the Short Antagonist Protocol and Hatching.
The 29-year-old participant in the case study has been grappling with infertility for the last six years. Following an assessment of her symptoms, hormone profile, and ultrasound results, she received a diagnosis of polycystic ovarian syndrome (PCOS). PCOS is a multifaceted endocrine and metabolic disorder characterized by symptoms such as obesity, insulin resistance, anovulation, and polycystic ovaries. Various factors, including heredity, intestinal dysbiosis, obesity, environmental pollutants, lifestyle choices, and neuroendocrine abnormalities, contribute to the susceptibility of women to PCOS. In planning polycystic ovarian stimulation, it is crucial to consider parameters such as antral follicle count (AFC), luteinizing hormone (LH), and anti-Müllerian hormone (AMH). Careful planning of the gonadotrophin dose is essential to achieve an optimal response during a gonadotropin-releasing hormone antagonist (GnRH-ant) cycle. In our case, the brief antagonist protocol was used, resulting in a favorable outcome with minimal risk of ovarian hyperstimulation syndrome (OHSS). Despite multiple unsuccessful attempts at natural conception, the patient successfully conceived with the help of intracytoplasmic sperm injection (ICSI), leading to a positive pregnancy outcome. In addition to incorporating mechanical hatching to promote implantation, we diligently selected the most beneficial medications for the patient.
PubMed: 38510892
DOI: 10.7759/cureus.54457 -
Human Reproduction (Oxford, England) May 2024Is resumption of ovulation after a 6-month lifestyle intervention in women with PCOS and obesity associated with differential changes in endocrine and metabolic... (Randomized Controlled Trial)
Randomized Controlled Trial
STUDY QUESTION
Is resumption of ovulation after a 6-month lifestyle intervention in women with PCOS and obesity associated with differential changes in endocrine and metabolic parameters (weight, insulin resistance, anti-Müllerian hormone (AMH), and androgens) compared to women with PCOS who remained anovulatory?
SUMMARY ANSWER
Resumption of ovulation after a 6-month lifestyle intervention in women with PCOS and obesity is associated with changes in serum 11β-hydroxyandrostenedione (11OHA4) concentrations.
WHAT IS KNOWN ALREADY
Lifestyle interventions have been shown to reduce clinical and biochemical hyperandrogenism in women with PCOS. Weight loss of 5-10% may reverse anovulatory status, thereby increasing natural conception rates. However, the mechanisms underlying why some women with PCOS remain anovulatory and others resume ovulation after weight loss are unclear. Reproductive characteristics at baseline and a greater degree of change in endocrine and metabolic features with lifestyle intervention may be crucial for ovulatory response.
STUDY DESIGN, SIZE, DURATION
We used data and samples originating from an earlier randomized controlled trial (RCT), which examined the efficacy of a 6-month lifestyle intervention prior to infertility treatment compared to prompt infertility treatment on live birth rate in women with obesity. A total of 577 women with obesity (BMI > 29 kg/m2) were randomized between 2009 and 2012. Anovulatory women with PCOS who were allocated to the intervention arm of the original RCT (n = 95) were included in the current analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We defined women as having resumed ovulation (RO+) based on the following criteria: spontaneous pregnancy; or assignment to expectant management; or IUI in natural cycles as the treatment strategy after lifestyle intervention. Steroid hormones were measured using liquid chromatography tandem mass spectrometry. Generalized estimating equations with adjustment for baseline measures and interaction between group and time was used to examine differences in changes of endocrine and metabolic parameters between RO+ (n = 34) and persistently anovulatory women (RO-, n = 61) at 3 and 6 months after intervention.
MAIN RESULTS AND THE ROLE OF CHANCE
At baseline, the mean ± SD age was 27.5 ± 3.6 years in the RO+ group and 27.9 ± 4.1 years in the RO- group (P = 0.65), and the mean ± SD weights were 101.2 ± 9.5 kg and 105.0 ± 14.6 kg, respectively (P = 0.13). Baseline AMH concentrations showed significant differences between RO+ and RO- women (median and interquartile range [IQR] 4.7 [3.2; 8.3] versus 7.2 [5.3; 10.8] ng/ml, respectively). Baseline androgen concentrations did not differ between the two groups. During and after lifestyle intervention, both groups showed weight loss; changes in 11OHA4 were significantly different between the RO+ and RO groups (P-value for interaction = 0.03). There was a similar trend for SHBG (interaction P-value = 0.07), and DHEA-S (interaction P-value = 0.06), with the most pronounced differences observed in the first 3 months. Other parameters, such as AMH and FAI, decreased over time but with no difference between the groups.
LIMITATIONS, REASONS FOR CAUTION
No high-resolution transvaginal ultrasonography was used to confirm ovulatory status at the end of the lifestyle program. The small sample size may limit the robustness of the results.
WIDER IMPLICATIONS OF THE FINDINGS
Reduction of androgen concentrations during and after lifestyle intervention is associated with recovery of ovulatory cycles. If our results are confirmed in other studies, androgen concentrations could be monitored during lifestyle intervention to provide individualized recommendations on the timing of resumption of ovulation in anovulatory women with PCOS and obesity.
STUDY FUNDING/COMPETING INTEREST(S)
The study was supported by a grant from ZonMw, the Dutch Organization for Health Research and Development (50-50110-96-518). The Department of Obstetrics and Gynecology of the UMCG received an unrestricted educational grant from Ferring Pharmaceuticals BV, The Netherlands. A.H. reports consultancy for the development and implementation of a lifestyle App MyFertiCoach developed by Ferring Pharmaceutical Company. All other authors have no conflicts to declare.
TRIAL REGISTRATION NUMBER
The LIFEstyle RCT was registered at the Dutch trial registry (NTR 1530).
Topics: Humans; Female; Obesity; Ovulation; Adult; Polycystic Ovary Syndrome; Anovulation; Androstenedione; Insulin Resistance; Pregnancy; Anti-Mullerian Hormone; Weight Loss
PubMed: 38503490
DOI: 10.1093/humrep/deae058 -
Developmental Dynamics : An Official... Mar 2024Gap junctions are specialized intercellular conduits that provide a direct pathway between neighboring cells, which are involved in numerous physiological processes,... (Review)
Review
Gap junctions are specialized intercellular conduits that provide a direct pathway between neighboring cells, which are involved in numerous physiological processes, such as cellular differentiation, cell growth, and metabolic coordination. The effect of gap junctional hemichannels in folliculogenesis is particularly obvious, and the down-regulation of connexins is related to abnormal follicle growth. Polycystic ovary syndrome (PCOS) is a ubiquitous endocrine disorder of the reproductive system, affecting the fertility of adult women due to anovulation. Exciting evidence shows that gap junction is involved in the pathological process related to PCOS and affects the development of follicles in women with PCOS. In this review, we examine the expression of connexins in follicular cells of PCOS and figure out whether such communication could have consequences for PCOS women. While along with results from clinical and related animal studies, we summarize the mechanism of connexins involved in the pathogenesis of PCOS.
PubMed: 38501340
DOI: 10.1002/dvdy.706