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https://obgyn.onlinelibrary.wiley.com/doi/abs/10.1002/ijgo.12902

https://www.ncbi.nlm.nih.gov/pubmed/31273783?dopt=Abstract

Related Articles

Randomized controlled trial of N-acetylcysteine versus l-carnitine among women with clomiphene-citrate-resistant polycystic ovary syndrome.

Int J Gynaecol Obstet. 2019 Jul 04;:

Authors: El Sharkwy IA, Abd El Aziz WM

Abstract

OBJECTIVE: To compare clinical and metabolic profiles between N-acetylcysteine and l-carnitine in among women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS).

METHODS: A randomized trial at Zagazig University between January 2017 and March 2018. Women with CC-resistant PCOS were allocated randomly to receive CC plus N-acetylcysteine or CC plus l-carnitine. The primary outcome was clinical pregnancy rate; secondary outcomes were ovulation rate and metabolic changes.

RESULTS: Overall, 162 women completed the study (N-acetylcysteine group, n=82; l-carnitine group, n=80). After 3 months, there was no difference in pregnancy (P=0.15), ovulation (P=0.21), or spontaneous abortion (P=0.11) rates between the two groups. There was no significant decrease in BMI in either group (both P>0.05). There were improvements in menstrual pattern, follicle-stimulating hormone, luteinizing hormone, free testosterone, and insulin resistance markers in both groups (all P<0.05). An improvement in lipid profile was observed only in the l-carnitine group (P<0.001). N-Acetylcysteine treatment led to significantly greater improvement in free testosterone and insulin resistance parameters as compared with l-carnitine (all P<0.05). CONCLUSIONS: Both N-acetylcysteine and l-carnitine were equally effective in improving pregnancy and ovulation rates among women with CC-resistant PCOS. However, N-acetylcysteine was superior in ameliorating insulin resistance and only l-carnitine improved lipid profile. This article is protected by copyright. All rights reserved. PMID: 31273783 [PubMed - as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/31270279?dopt=Abstract

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Inulin and metformin ameliorate polycystic ovary syndrome via anti-inflammation and modulating gut microbiota in mice.

Endocr J. 2019 Jul 03;:

Authors: Xue J, Li X, Liu P, Li K, Sha L, Yang X, Zhu L, Wang Z, Dong Y, Zhang L, Lei H, Zhang X, Dong X, Wang H

Abstract

Polycystic ovary syndrome (PCOS) represents an endocrine disorder, which is closely related with gut microbiota. Inulin, a kind of probiotics, has been proven to alleviate gut microbiota dysbiosis. Metformin, a biguanide agent, shows beneficial effects on chronic metabolic diseases. Our objective was to assess the effects and associated mechanisms of inulin and metforin on attenuation of PCOS in mice. Mice were divided into 4 groups: control group (CON), model group (MOD), inulin group (INU), metformin group (MET). The last three groups were fed 6 mg of dehydroepiandrosterone (DHEA) per 100 g body weight and 60% high-fat diet to generate mice model. After 21 days of intervention, mice were euthanized and associated indications were investigated. Body weight (BW) and testosterone (T) levels were significantly decreased, but estradiol (E2) levels were increased in INU or MET group, respectively. Ovary HE staining demonstrated that inulin or metformin ameliorated PCOS morphology. Inflammatory indicators from plasma and ovary including TNF-α, IL-6, and IL-17A were decreased in INU or MET group. Moreover, IL-10 in ovary of INU or MET group was increased. Sequencing and analysis of gut microbiota showed that compared to MOD group, Bifidobacterium was increased, but Proteobacteria, Helicobacter and Parasutterella were decreased in INU group. Helicobacter was decreased in MET group. Correlation analysis showed that gut microbiota was correlated with inflammatory factors. Our results revealed that inulin and metformin alleviated PCOS via anti-inflammation and modulating gut microbiota, which may contribute to potential clinical therapy for the disease.

PMID: 31270279 [PubMed – as supplied by publisher]

https://www.spandidos-publications.com/10.3892/mmr.2019.10446

https://www.ncbi.nlm.nih.gov/pubmed/31322191?dopt=Abstract

miR‑28‑5p suppresses cell proliferation and weakens the progression of polycystic ovary syndrome by targeting prokineticin‑1.

Mol Med Rep. 2019 Jul 01;:

Authors: Meng L, Yang H, Jin C, Quan S

Abstract

Prokineticin‑1 (PROK1) serves important roles in the pathogenesis of polycystic ovary syndrome (PCOS); however, the association between microRNA (miR)‑28‑5p and PROK1 remains unclear. In the present study, the roles of miR‑28‑5p and PROK1, and their interaction in PCOS were investigated. Rat ovary granule cells were transfected with miR‑28‑5p mimics, and PROK1 expression levels were measured by reverse transcription‑quantitative PCR and western blotting. A dual‑luciferase reporter assay was performed to determine the association between miR‑28‑5p and PROK1. Additionally, pcDNA‑PROK1 was co‑transfected into rat ovary granule cells with miR‑28‑5p mimics. Cell proliferation, apoptosis, cell cycle and the expression of signaling proteins were investigated using Cell Counting Kit‑8 assays, 5‑ethynyl‑2’‑deoxyuridine staining, flow cytometry and western blotting, respectively. PROK1 expression was suppressed in rat ovary granule cells by miR‑28‑5p mimics, but upregulated following transfection with miR‑28‑5p inhibitors. The dual‑luciferase reporter assay revealed that miR‑28‑5p binds to the 3’‑untranslated region of PROK1. Proliferation activity was increased in PROK1‑overexpressing cells; this effect was eliminated by co‑transfection with miR‑28‑5p mimics. PROK1‑overexpressing rat ovary granule cells exhibited significantly suppressed cell apoptosis and a decreased number of cells in G1; miR‑28‑5p mimics reversed these effects. Western blotting revealed that the PI3K/AKT/mTOR signaling pathway was activated by PROK1. The present results suggested that miR‑28‑5p attenuated the progression of PCOS by targeting PROK1, which may promote the pathogenesis of PCOS via the PI3K/AKT/mTOR pathway, indicating that the miR‑28‑5p/PROK1 axis may be a potential therapeutic target for patients with PCOS.

PMID: 31322191 [PubMed – as supplied by publisher]

https://onlinelibrary.wiley.com/doi/abs/10.1002/mrd.23222

https://www.ncbi.nlm.nih.gov/pubmed/31209968?dopt=Abstract

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Thymoquinone reduces intracytoplasmic oxidative stress and improves epigenetic modification in polycystic ovary syndrome mice oocytes, during in-vitro maturation.

Mol Reprod Dev. 2019 Jun 17;:

Authors: Eini F, Bidadkosh A, Nazarian H, Piryaei A, Ghaffari Novin M, Joharchi K

Abstract

Although in-vitro maturation (IVM) of oocytes has been presented as an alternative treatment to traditional stimulated in-vitro fertilization, the culture condition can be improved by natural antioxidants. Thus, we investigated the protective effect of Thymoquinone (TQ) during IVM in the polycystic ovary syndrome (PCOS) mice model. The induction of PCOS was made by dehydroepiandrosterone via subcutaneous injection, in prepubertal female B6D2F1-mice. After 21 days later, germinal vesicle (GV)-stage-oocytes were extracted and incubated in IVM media containing 0, 1.0, 10.0, and 100.0 μM of TQ. To assess fertilization and blastulation rates, after 22-24 hr, the treated oocytes were fertilized in-vitro with epididymal spermatozoa. Some other oocytes were evaluated for maturation, epigenetic, and oxidative stress markers. Similarly, the mRNA expression of epigenetic enzymes genes (Dnmt1 and Hdac1), three maternally derived genes (Mapk, CyclinB, and Cdk1) and apoptosis-related genes (Bax and Bcl2) were assessed. Our results showed that the maturation, fertilization, and blastulation rates were significantly higher in the 10.0 μM TQ-treated group compared with the untreated group and likewise with in-vivo matured oocytes. The Bax expression was reduced in 10.0 μM TQ matured oocytes, but Bcl2, Dnmt1, Hdac1, Cdk1, and Mapk were upregulated in this group compared to other groups. Furthermore, dimethylation of histone-3 at lysine-9 (H3K9m2) and DNA methylation were significantly increased whereas H4K12 acetylation (H4K12ac) was decreased in the 10.0 μM TQ-treated group in comparison with control and in-vivo matured oocytes. Therefore, our results are suggesting that 10.0 μM TQ may enhance the developmental competence of PCOS oocytes via the modulation of oxidative stress and epigenetic alterations.

PMID: 31209968 [PubMed – as supplied by publisher]

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217495

https://www.ncbi.nlm.nih.gov/pubmed/31170164?dopt=Abstract

Related Articles

ETA-mediated anti-TNF-α therapy ameliorates the phenotype of PCOS model induced by letrozole.

PLoS One. 2019;14(6):e0217495

Authors: Lang Q, Yidong X, Xueguang Z, Sixian W, Wenming X, Tao Z

Abstract

Chronic inflammation is a typical characteristic of polycystic ovary syndrome (PCOS), in which, tumor necrosis factor (TNF)-α plays an important role. We investigated whether anti-TNF-α therapy can alleviate the core phenotypes of PCOS. In pubertal female Wistar rats, release pellets of letrozole (LET) were administered continuously for 90 days to induce PCOS-like phenotypes, followed by treatment with etanercept (ETA), a TNF-α inhibitor. ETA significantly inhibited increases in body weight and androgen, TNF-α, and MCP-1 levels, excessive recruitment of lipid droplets, altered levels of pre-adipose differentiation markers, and abnormal development of follicles. In addition, TNF-α and testosterone (T) levels in the rat sera were significantly positively correlated. Further experiments were performed to investigate the relationship between TNF-α and androgen. Persistent exposure of the RAW 264.7 cell line to low doses of testosterone significantly enhanced TNF-α expression and activated the NF-κB signaling pathway, which were blocked by ETA. Furthermore, treatment with TNF-α promoted the production of testosterone in KGN granulosa cells by reducing CYP19A1 expression, whereas ETA treatment blocked this process. In conclusion, anti-TNF-α therapy with ETA may be an efficient method to alleviate PCOS, whose underlying mechanism may be associated with its ability to reduce excessive androgen levels.

PMID: 31170164 [PubMed – in process]

https://www.ebiomedicine.com/article/S2352-3964(19)30373-1/fulltext

https://www.ncbi.nlm.nih.gov/pubmed/31178425?dopt=Abstract

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Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome.

EBioMedicine. 2019 Jun 06;:

Authors: Silva MSB, Desroziers E, Hessler S, Prescott M, Coyle C, Herbison AE, Campbell RE

Abstract

BACKGROUND: Enhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined.

METHODS: We employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features.

FINDINGS: Acute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABAA-dependent changes in GnRH neuron firing were observed in brain slices. Chronic activation of ARN GABA neurons in healthy females impaired estrous cyclicity, decreased corpora lutea number and increased circulating testosterone levels.

INTERPRETATION: ARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.

PMID: 31178425 [PubMed – as supplied by publisher]

https://www.sciencedirect.com/science/article/pii/S0303720719301807?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31173821?dopt=Abstract

Altered miR-186 and miR-135a contribute to granulosa cell dysfunction by targeting ESR2: A possible role in polycystic ovary syndrome.

Mol Cell Endocrinol. 2019 Jun 04;:110478

Authors: Song Y, Yu G, Xiang Y, Li Y, Wan L, Tan L

Abstract

MicroRNAs (miRNAs) are a group of negative regulators of gene expression that function at the posttranscriptional level. Dysregulation of miRNAs is involved in many pathophysiological processes, including polycystic ovary syndrome (PCOS). In this study, we first detected the expression levels of 6 candidate miRNA in granulosa cells (GCs) from 63 women with PCOS and 20 healthy controls. We found that miR-186 and miR-135a were overexpressed in GCs from PCOS patients. Subsequently, the direct targets of miR-186 and miR-135a were predicted using bioinformatics analysis and verified by luciferase assays and immunoblotting. The present study determined that miR-186 and miR-135a repressed ESR2 expression in GCs, which further inhibited CDKN1A expression, promoted GC proliferation and repressed GC apoptosis. Meanwhile, the levels of miR-186 and miR-135a in GCs were found to positively correlate with serum estradiol levels in patients with PCOS. Furthermore, estradiol treatment directly increased miR-186 and miR-135a levels in KGN and primary GCs, which provides new insight into understanding the pathophysiology of PCOS.

PMID: 31173821 [PubMed – as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/31091067?dopt=Abstract

The Effect of Vitamin D Supplementation on Insulin Resistance among Women with Polycystic Ovary Syndrome.

JBRA Assist Reprod. 2019 May 15;:

Authors: Salehpour S, Hosseini S, Nazari L, Hosseini M, Saharkhiz N

Abstract

OBJECTIVE: To explore the effect of vitamin D supplementation on insulin resistance in a group of Iranian patients with polycystic ovary syndrome and vitamin D deficiency.

METHODS: This was a clinical trial conducted in a tertiary medical center in Tehran, the capital city of Iran, from May 2015 to September 2015. The participants included 41 women between 20 and 40 years of age with polycystic ovary syndrome based on the Rotterdam criteria and vitamin D deficiency. The fasting blood glucose and insulin levels, as well as serum 25-hydroxyvitamin D and homeostasis model assessment of insulin resistance (HOMA-IR) levels were measured at baseline and two months post treatment with a single dose of 300,000IU intramuscular vitamin D3. The main outcome measures were plasma levels of vitamin D, fasting blood sugar and insulin levels, as well as insulin resistance.

RESULTS: The mean age of participants was 26.6±4.1. The serum level of 25-hydroxyvitamin D increased (5.7±1.77 to 16.34±8.99 ng/mL, p<0.001). The mean fasting blood glucose reading significantly decreased from 109.56±14.59mg/dL in pre-treatment to 103.71±13.72mg/dL post treatment (p=0.003). There was a significant decrease in the mean fasting serum insulin level from 8.52±5.48 mcU/mL before treatment with vitamin D to 7.07±5.03 (p=0.019) µU/mL after the treatment. The mean HOMA-IR, as a sign of insulin resistance, significantly decreased from 2.37±1.76 to 1.87±1.49, indicating less insulin resistance. CONCLUSIONS: A single injection of vitamin D significantly decreased serum insulin levels and insulin resistance among patients with polycystic ovary syndrome. PMID: 31091067 [PubMed - as supplied by publisher]

https://www.frontiersin.org/articles/10.3389/fendo.2019.00273/full

https://www.ncbi.nlm.nih.gov/pubmed/31139144?dopt=Abstract

Related Articles

Effects of Melatonin Supplementation on Hormonal, Inflammatory, Genetic, and Oxidative Stress Parameters in Women With Polycystic Ovary Syndrome.

Front Endocrinol (Lausanne). 2019;10:273

Authors: Jamilian M, Foroozanfard F, Mirhosseini N, Kavossian E, Aghadavod E, Bahmani F, Ostadmohammadi V, Kia M, Eftekhar T, Ayati E, Mahdavinia M, Asemi Z

Abstract

Purpose: The aim of the current study was to evaluate the effect of melatonin administration on clinical, hormonal, inflammatory, and genetic parameters in women with polycystic ovarian syndrome (PCOS). Methods: The present randomized, double-blinded, placebo-controlled clinical trial was conducted among 56 patients with PCOS, aged 18-40 years old. Subjects were randomly allocated to take either 5 mg melatonin supplements (n = 28) or placebo (n = 28) twice a day for 12 weeks. Results: Melatonin administration significantly reduced hirsutism (β -0.47; 95% CI, -0.86, -0.09; P = 0.01), serum total testosterone (β -0.11 ng/mL; 95% CI, -0.21, -0.02; P = 0.01), high-sensitivity C-reactive protein (hs-CRP) (β -0.61 mg/L; 95% CI, -0.95, -0.26; P = 0.001), and plasma malondialdehyde (MDA) levels (β -0.25 μmol/L; 95% CI, -0.38, -0.11; P < 0.001), and significantly increased plasma total antioxidant capacity (TAC) levels (β 106.07 mmol/L; 95% CI, 62.87, 149.28; P < 0.001) and total glutathione (GSH) (β 81.05 μmol/L; 95% CI, 36.08, 126.03; P = 0.001) compared with the placebo. Moreover, melatonin supplementation downregulated gene expression of interleukin-1 (IL-1) (P = 0.03) and tumor necrosis factor alpha (TNF-α) (P = 0.01) compared with the placebo. Conclusions: Overall, melatonin administration for 12 weeks to women with PCOS significantly reduced hirsutism, total testosterone, hs-CRP, and MDA, while increasing TAC and GSH levels. In addition, melatonin administration reduced gene expression of IL-1 and TNF-α. Clinical Trial Registration: www.irct.ir, identifier IRCT2017082733941N9, Available online at: https://www.irct.ir/trial/26051. PMID: 31139144 [PubMed]

https://www.sciencedirect.com/science/article/pii/S0306987719300386?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31203910?dopt=Abstract

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Fluorine may intensify the mechanisms of polycystic ovary syndrome (PCOS) development via increased insulin resistance and disturbed thyroid-stimulating hormone (TSH) synthesis even at reference levels.

Med Hypotheses. 2019 Jul;128:58-63

Authors: Szczuko M, Splinter J, Zapałowska-Chwyć M, Ziętek M, Maciejewska D

Abstract

We were interested whether fluorine, at the concentrations regarded as normal, can play a role in PCOS pathogenesis. The effect was not described in PCOS. Women with PCOS were diagnosed according to Rotterdam’s criteria. The average age of 40 examined women with PCOS was 26.3 ± 5.5 years, BMI-29.16 ± 0.8, WHR-0.91 ± 0.08. Main Outcome Measures: ECLIA was used to analyse testosterone, FSH, LH, oestradiol, TSH, prolactin, insulin and SHBG. Fluorine content was analysed by potentiometry using ion selective electrode. Fluorine content in serum of women with PCOS did not statistically significantly differ from that of the control group and amounted to 0.224 ± 0.043 and 0.228 ± 0.023 ppm, respectively. There were significant differences in the levels of TSH and HOMA-IR between the groups. Based on the correlation matrix, a negative correlation with the level of SHBG protein and the level of glucose on fasting was showed for the group with a lower of fluorine, and a positive correlation with HDL level was observed in the group with higher concentration of fluorine. In the phenotype with a higher level of androgens, there was a negative correlation with triglycerides level and a positive correlation with HDL. Fluorine, even in concentrations regarded as proper, takes part in PCOS pathogenesis. It increases the synthesis of TSH and increases insulin resistance. Higher insulin resistance leads to the reduced synthesis of SHBG transport protein. Therefore, the key factor in PCOS pathogenesis is testosterone, but fluorine facilitates disruptions in carbohydrates and lipids metabolism leading to increased levels of androgens in blood.

PMID: 31203910 [PubMed – in process]

https://www.tandfonline.com/doi/abs/10.1080/09513590.2018.1540567?journalCode=igye20

https://www.ncbi.nlm.nih.gov/pubmed/31056990?dopt=Abstract

The role of androgen in autophagy of granulosa cells from PCOS.

Gynecol Endocrinol. 2019 May 06;:1-4

Authors: Li X, Qi J, Zhu Q, He Y, Wang Y, Lu Y, Wu H, Sun Y

Abstract

Hyperandrogenism is one of the most common causes for anovulation in women and increases the risk for metabolic disorder in PCOS patients. Autophagy plays an important role in dysfunction of endocrine and anovulation. However, the relationship between hyperandrogenism and autophagy in human granulosa cells of PCOS patients remains unclear. By collecting granulosa cells from PCOS patients and non-PCOS patients, we found that the abundance of autophagy-related genes ATG5, ATG7, BECN1 mRNA and the ratio of autophagy marker protein light chain 3B II/I (LC3 II/I) were significantly increased whereas the abundance of the autophagy substrate SQSTM1/p62 was decreased in ovarian granulosa cells from PCOS patients. Furthermore, we demonstrated that BECN1 mRNA abundance in human granulosa cells positively correlated with the basal level of serum total testosterone and androgen up-regulated the abundance of BECN1 mRNA and the ratio of LC3II/LC3I in a dose-dependent manner in cultured granulosa cells. These observations indicated that androgen-induced activation of autophagy may play an important role in the development of PCOS and to explore the autophagy mechanisms involved in PCOS yield new insight into the pathophysiology and therapy of the disorder.

PMID: 31056990 [PubMed – as supplied by publisher]

https://www.sciencedirect.com/science/article/pii/S0378427419301390?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31071422?dopt=Abstract

Mercury Leads to Features of Polycystic Ovary Syndrome in Rats.

Toxicol Lett. 2019 May 06;:

Authors: Merlo E, Schereider IRG, Simões MR, Vassallo DV, Graceli JB

Abstract

Mercury (Hg) is a heavy metal and Hg exposure is associated with various neural, immune, and cardiovascular abnormalities. However, few studies have evaluated Hg’s toxicologic effect on reproductive and metabolic functions. In this study, we assessed whether Hg exposure results in reproductive and metabolic abnormalities. Hg was administered to adult female Wistar rats, mimicking the Hg levels found in exposed human blood, and their reproductive and metabolic function was assessed. Rats exposed to Hg displayed abnormal estrous cyclicity and ovarian follicular development, with a reduction in ovarian antral follicles and an increase in atretic and cystic ovarian follicles. Uterine atrophy with the presence of inflammatory cells was observed in Hg-exposed rats. The presence of abnormal ovarian fat accumulation, as well as increased ovarian lipid drops accumulation, was observed in Hg-exposed rats. Ovarian oxidative stress was also present in the Hg-exposed rats. High fasting glucose levels, glucose, and insulin intolerance were observed in Hg-exposed rats. Thus, these data suggest that Hg exposure led to abnormal reproductive and metabolic features similar to those found in the polycystic ovary syndrome (PCOS) rat models.

PMID: 31071422 [PubMed – as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/31038695?dopt=Abstract

Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in polycystic ovary syndrome.

J Clin Endocrinol Metab. 2019 Apr 30;:

Authors: Dapas M, Sisk R, Legro RS, Urbanek M, Dunaif A, Hayes MG

Abstract

CONTEXT: Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.

OBJECTIVE: The objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and Methods: We performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.

RESULTS: We found rare variants in DENND1A (P=5.31×10-5, Padj=0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.

CONCLUSIONS: Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.

PMID: 31038695 [PubMed – as supplied by publisher]

https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3313-8

https://www.ncbi.nlm.nih.gov/pubmed/30992038?dopt=Abstract

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The effectiveness of high intensity intermittent training on metabolic, reproductive and mental health in women with polycystic ovary syndrome: study protocol for the iHIT- randomised controlled trial.

Trials. 2019 Apr 16;20(1):221

Authors: Hiam D, Patten R, Gibson-Helm M, Moreno-Asso A, McIlvenna L, Levinger I, Harrison C, Moran LJ, Joham A, Parker A, Shorakae S, Simar D, Stepto N

Abstract

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive-metabolic condition. Insulin resistance is a hallmark of PCOS and is related to increased hyperandrogenism that drives inherent metabolic, reproductive and psychological features of the syndrome. Insulin resistance in women with PCOS is managed by weight loss, lifestyle interventions (i.e. exercise, diet) and insulin-sensitising medications. This manuscript describes the protocol of our study evaluating the effectiveness of high intensity intermittent training (HIIT) or moderate intensity exercise on cardiometabolic, reproductive and mental health in overweight women with PCOS.

METHODS/DESIGN: We will employ a three arm, parallel-group, randomised controlled trial recruiting 60 women diagnosed with PCOS, aged between 18 and 45 years and with a body mass index (BMI) greater than 25 kg/m2. Following screening and baseline testing, women will be randomised by simple randomisation procedure using computer generated sequence allocation to undergo one of two 12-week supervised interventions: either HIIT or moderate intensity exercise (standard supervised exercise), or to standard care [Con] (unsupervised lifestyle advice) at a 1:1:1 allocation ratio. The primary outcome for this trial is to measure the improvements in metabolic health; specifically changes in insulin sensitivity in response to different exercise intensities. Baseline and post-intervention testing include anthropometric measurements, cardiorespiratory fitness testing, reproductive hormone profiles (anti-müllerian hormone and steroid profiles), metabolic health, health-related quality of life and mental health questionnaires and objective and subjective lifestyle monitoring. Reporting of the study will follow the CONSORT statement.

DISCUSSION: This trial aims to demonstrate the comparative efficacy and maintenance of different exercise intensities to advance the understanding of PCOS management and provide insight into the optimal exercise intensity for improved cardiometabolic outcomes. Secondary outcomes will include the impact of different exercise protocols on reproductive hormone profiles, mental health and health-related quality of life.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000242527 . Registered on 17 March 2015.

PMID: 30992038 [PubMed – in process]

https://ovarianresearch.biomedcentral.com/articles/10.1186/s13048-019-0505-5

https://www.ncbi.nlm.nih.gov/pubmed/30947734?dopt=Abstract

Related Articles

Androgen potentiates the expression of FSH receptor and supports preantral follicle development in mice.

J Ovarian Res. 2019 Apr 04;12(1):31

Authors: Fujibe Y, Baba T, Nagao S, Adachi S, Ikeda K, Morishita M, Kuno Y, Suzuki M, Mizuuchi M, Honnma H, Endo T, Saito T

Abstract

Hyperandrogenism is one of the cardinal symptoms in polycystic ovary syndrome and plays a key role in the pathogenesis of polycystic ovary syndrome. However, the precise effects and mechanisms of excess androgen during follicular development are still unclear. Here we investigated the effects of androgen on mouse follicle development in vitro. Androgen did not affect the growth of follicles smaller than 160-180 μm in the presence of follicle-stimulating hormone (FSH). However, in the presence of low FSH, androgen supported the growth of follicles larger than 160-180 μm, a size at which growing follicles acquire FSH-dependency. Androgen did not change the mRNA expression of various growth-promoting factors but did increase mRNA expression of the FSH receptor. We suggest that androgen has a positive impact on follicle development by augmentation of the actions of FSH. Therefore, FSH-responsive but FSH-independent follicles grow in the presence of a certain level of FSH or androgen, and androgen compensates for FSH deficiency in FSH-dependent follicles.

PMID: 30947734 [PubMed – in process]

https://link.springer.com/article/10.1007%2Fs12011-019-01705-7

https://www.ncbi.nlm.nih.gov/pubmed/30941676?dopt=Abstract

Related Articles

Status of Serum Copper, Magnesium, and Total Antioxidant Capacity in Patients with Polycystic Ovary Syndrome.

Biol Trace Elem Res. 2019 Apr 02;:

Authors: Kanafchian M, Esmaeilzadeh S, Mahjoub S, Rahsepar M, Ghasemi M

Abstract

This study evaluates serum copper and magnesium and total antioxidant capacity levels in PCOS patients. In this regard, the probable association of copper and magnesium with total antioxidant capacity (TAC) was investigated. In total, 150 women (60 PCOS patients and 90 healthy subjects) participated in this case-control study. PCOS was diagnosed according to the Rotterdam criteria (2003). Serum Cu, Mg, Ca, TAC, insulin levels, and insulin resistance indices were determined. Insulin was measured using ELISA methods. Serum Cu and Mg levels were measured by an atomic absorption spectrophotometer and the Xylidyl Blue method respectively. The correlations between the parameters were analyzed using the Spearman correlation test. Serum Cu level was significantly higher while TAC was significantly lower in the PCOS patients than those in the controls (p = 0.019 and p = 0.002 respectively). No significant difference was detected between the two groups in terms of serum Mg and Ca levels and Ca/Mg ratio. In insulin-resistant PCOS subjects, there was a negative correlation between Mg levels and homeostatic model assessment for insulin resistance (r = - 0.449, p = 0.006) but a positive correlation between Mg levels and quantitative insulin sensitivity check index (r = 0.480, p = 0.003). A negative correlation also existed between Mg levels and TAC in non-insulin-resistant PCOS patients (r = - 0.407, p = 0.04). According to the results, copper and magnesium seem to contribute to oxidative stress and insulin resistance in PCOS patients. Therefore, to prevent long-term metabolic complications in PCOS women, it is recommended that these elements be routinely monitored. Also, significantly lower levels of serum TAC in PCOS patients than in normal women may suggest increased oxidative stress in such patients.

PMID: 30941676 [PubMed – as supplied by publisher]

https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ18-0153/_article

https://www.ncbi.nlm.nih.gov/pubmed/30918134?dopt=Abstract

Circulating zinc-α2-glycoprotein is reduced in women with polycystic ovary syndrome, but can be increased by exenatide or metformin treatment.

Endocr J. 2019 Mar 26;:

Authors: Zheng S, Liu E, Zhang Y, Long T, Liu X, Gong Y, Mai T, Shen H, Chen H, Lin R, Zheng Y, Xie Y, Wang F

Abstract

The study was to investigate circulating zinc-α2-glycoprotein (ZAG) concentrations in women with PCOS, and changes in ZAG levels after exenatide or metformin treatment. One hundred eighty-two women with polycystic ovary syndrome (PCOS) who met the 2003 Rotterdam diagnostic criteria and 150 controls without PCOS were recruited. We partitioned women with PCOS into groups according to body mass index or blood glucose concentrations, determined serum ZAG, anthropometric parameters, metabolic and endocrine indicators, and inflammatory markers, and statistically analyzed the results. Eighty-two overweight/obese subjects of the recruited women with PCOS were then randomly assigned to groups administered either 12 weeks of exenatide injection (10 μg b.i.d.) or oral metformin (1,000 mg b.i.d.). Circulating ZAG levels were determined after 12 weeks of treatment. The results showed that circulating ZAG was significantly lower in PCOS women than in healthy women (p < 0.01). Overweight/obese women and those with higher blood glucose levels had lower circulating ZAG. After 12 weeks of exenatide or metformin treatment, there were significant increases (p < 0.01) in circulating ZAG in both treatment groups (the exenatide baseline level was 46.54 ± 2.38 ng/mL vs. 56.41 ± 2.02 ng/mL after treatment, p < 0.01; metformin baseline was 47.81 ± 2.14 ng/mL vs. 55.67 ± 2.01 ng/mL after treatment, p < 0.01), however there was no statistical difference between the 2 treatments (p > 0.05). Circulating ZAG is closely related to PCOS and could be an important adipokine involved in the occurrence and development of PCOS. ZAG might possibly be applicable as a new observational indicator in the treatment of PCOS.

PMID: 30918134 [PubMed – as supplied by publisher]

https://www.fertstert.org/article/S0015-0282(19)30064-0/fulltext

Higher chromosomal aberration rate in miscarried conceptus from polycystic ovary syndrome women undergoing assisted reproductive treatment

https://www.ncbi.nlm.nih.gov/pubmed/30915729?dopt=Abstract

Related Articles

Effect of microRNA-409 on the pathogenesis of polycystic ovary syndrome.

Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):1874-1881

Authors: Teng YL, Lin SY, Yang HY, Meng LH, Yu R, Zeng LC

Abstract

OBJECTIVE: To explore the expression level of microRNA-409 in PCOS (polycystic ovary syndrome) rats, as well as its potential effects on fertility of PCOS rats and phenotypes of offspring rats.

MATERIALS AND METHODS: PCOS model in rats was established by Letasazole administration. Follicular development of rats was evaluated by the percentages of the cystic follicle (FC) and corpus luteum (CL) of all follicles. The enzyme-linked immunosorbent assay (ELISA) was conducted to detect serum levels of hormones in rats, including LH, LH/FSH, T, INS, FSH, and E2. Subsequently, PCOS rats received a subcapsular injection of microRNA-409 mimics. The expression level of microRNA-409 in ovary was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Serum levels of LH, LH/FSH, T, INS, FSH, and E2 in PCOS rats with microRNA-409 overexpression were accessed by enzyme-linked immunosorbent assay (ELISA) as well. PCOS rats were mated with male rats for recording pregnancy rate. At 6-week-old of offspring, they were sacrificed for detecting microRNA-409 level, percentages of FC and CL, as well as serum levels of hormones.

RESULTS: PCOS rats showed irregular estrous cycle and they were mainly in the anestrum. Rats in the control group were in a regular estrous cycle. A higher percentage of FC and a lower percentage of CL were seen in PCOS rats compared with those of controls. ELISA data revealed higher serum levels of LH, LH/FSH, and T in PCOS rats compared with those of controls. However, levels of FSH and E2 were lower in PCOS rats. Although INS level increased in PCOS rats, we did not observe a significant difference in INS level between PCOS rats and control rats. MicroRNA-409 was lowly expressed in ovaries of PCOS rats than those of controls. After injection of microRNA-409 mimics into rat ovary, microRNA-409 expression remarkably upregulated than those PCOS rats without injection. Rats in PCOS+microRNA-409 mimics group showed the largest body weight compared with those in the PCOS group and control group. PCOS rats showed a lower pregnancy rate than those of controls, which was markedly increased after administration of microRNA-409 mimics. Rats in PCOS+microRNA-409 mimics group presented lower levels of LH, LH/FSH, T, and INS, but higher levels of FSH and E2 than those in PCOS group.

CONCLUSIONS: MicroRNA-409 is lowly expressed in the ovary of PCOS rats. Overexpression of microRNA-409 could improve hormone levels and pregnancy rate in PCOS rats, as well as affect clinical phenotypes of their offspring.

PMID: 30915729 [PubMed – in process]

https://www.europeanreview.org/article/17278

https://www.ncbi.nlm.nih.gov/pubmed/30915778?dopt=Abstract

Related Articles

Effects of three treatment modalities (diet, myoinositol or myoinositol associated with D-chiro-inositol) on clinical and body composition outcomes in women with polycystic ovary syndrome.

Eur Rev Med Pharmacol Sci. 2019 Mar;23(5):2293-2301

Authors: Le Donne M, Metro D, Alibrandi A, Papa M, Benvenga S

Abstract

OBJECTIVE: To evaluate, in overweight/obese PCOS women, which of three distinct treatment modalities achieved the greatest clinical benefits in terms of clinical and body composition outcomes.

PATIENTS AND METHODS: Forty-three polycystic ovary syndrome (PCOS) overweight/obese patients were randomly treated for 6 months with: only diet (Group 1, n = 21); diet and myo-inositol (MI) 4 g + folic acid 400 µg daily (group 2, n = 10); diet in association with MI 1.1 g + D-chiroinositol (DCI) 27.6 mg + folic acid 400 µg daily (group 3, n = 13). Menstrual cycle, Ferriman-Gallwey score, body mass index (BMI), waist circumference, hip circumference, waist-hip ratio (WHR), and body composition by bioimpedentiometry were measured at baseline, 3 and 6 months.

RESULTS: Body weight, BMI, waist and hip circumferences decreased significantly in all groups. There was a significant difference between the 3 groups regarding the restoration of menstrual regularity (p = 0.02) that was obtained in all patients only in-group 3.

CONCLUSIONS: MI+DCI in association with diet seems to accelerate the weight loss and the fat mass reduction with a slight increase of percent lean mass, and this treatment contributes significantly in restoring the regularity of the menstrual cycle.

PMID: 30915778 [PubMed – in process]

https://link.springer.com/article/10.1007%2Fs12020-019-01899-9

https://www.ncbi.nlm.nih.gov/pubmed/30900204?dopt=Abstract

Related Articles

Relationship among obesity, insulin resistance, and hyperinsulinemia in the polycystic ovary syndrome.

Endocrine. 2019 Mar 21;:

Authors: Dahan MH, Reaven G

Abstract

PURPOSE: To evaluate the relationship between obesity and insulin resistance among women with polycystic ovary syndrome (PCOS) using a gold standard test.

METHODS: A retrospective database analysis of 75 women with PCOS and 118 normal controls who underwent a modification of the insulin suppression test. The relationships between body mass index (BMI) and steady-state plasma glucose (SSPG) levels were investigated.

RESULTS: Mean SSPG score for PCOS subjects was statistically similar than that of the controls at all BMI groupings. Only when PCOS subjects reached a BMI of ≥30 kg/m2 that the PCOS subjects had higher mean SSPG score than the control subjects, although not significantly so (p = 0.07). The distribution of PCOS and control subjects in each SSPG quartile grouping was investigated. When comparing all PCOS and control subjects, PCOS subjects were more likely to be in the higher quartiles of SSPG score (p = 0.0001). However, when comparing the PCOS and control subjects, at each BMI grouping (<25, 25-29.9, and ≥30 kg/m2), there was no difference in the likelihood that a larger percent of subjects fell into a different quartile (p = 0.12, 0.69, 0.32, respectively). CONCLUSIONS: PCOS subjects have increased magnitudes of insulin resistance when compared to ovulatory controls, when controlling for age, BMI, fasting glucose, and insulin levels. However, the magnitude of this insulin resistance in lean subjects is mild. Quantity of excess body fat, particularly subjects with a BMI of at least 30 kg/m2 is the primary predictor of insulin resistance of sufficient magnitude to put PCOS subjects at increased risk for metabolic abnormalities. PMID: 30900204 [PubMed - as supplied by publisher]

https://www.tandfonline.com/doi/abs/10.1080/09513590.2019.1581165?journalCode=igye20

https://www.ncbi.nlm.nih.gov/pubmed/30896318?dopt=Abstract

Serum activities of dipeptidyl peptidase-4 and adenosine deaminase in polycystic ovary syndrome: association with obesity.

Gynecol Endocrinol. 2019 Mar 21;:1-5

Authors: Kahraman S, Eroglu Altinova A, Elgun S, Yalcin MM, Aktas Yilmaz B, Ozkan C, Akturk M, Balos Toruner F

Abstract

Dipeptidyl peptidase-4 (DPP-4) plays a role in metabolic and inflammatory diseases. Increased adenosine deaminase (ADA) has been suggested to induce insulin resistance and inflammation. We measured serum DPP-4 and ADA activities. Serum ADA activity was significantly higher in PCOS group (p = .006), whereas there was no difference in serum DPP-4 activity between the groups (p > .05). When the study subjects were divided into four groups in terms of obesity; an increasing trend in serum ADA activity between the groups was observed and ADA activity was significantly higher in overweight and obese patients with PCOS than nonobese controls (p = .016), there were no significant differences between the other groups (p > .05). A positive correlation was found between ADA and BMI in the whole group (p = .022). Multivariate regression analyses revealed that significant determinants were diastolic blood pressure, ADA, and the presence of PCOS for DPP-4 (R2 = 0.344, F = 9.079, p < .001); the presence of PCOS and DPP-4 for ADA (R2 = 0.123, F = 6.302, p = .003). We demonstrated increased serum ADA activity as well as its association with obesity in PCOS, while there was no change in serum DPP-4 activity in women with PCOS. PMID: 30896318 [PubMed - as supplied by publisher]

https://onlinelibrary.wiley.com/doi/abs/10.1002/dvdy.28

https://www.ncbi.nlm.nih.gov/pubmed/30884041?dopt=Abstract

Dennd1a, a susceptibility gene for polycystic ovary syndrome, is essential for mouse embryogenesis.

Dev Dyn. 2019 Mar 18;:

Authors: Shi J, Gao Q, Cao Y, Fu J

Abstract

BACKGROUND: The DENND1A has been identified as a guanine nucleotide exchange factor (GEF) for small GTPase Rab35, which functions in endocytic trafficking to mediate the recycling of selective cargos. Genetic alterations within the DENND1A gene have been implicated in human disease such as polycystic ovary syndrome (PCOS). However, the role of DENND1A in developmental and reproductive processes is largely unknown.

RESULTS: Using Dennd1a gene knockout mice, we uncovered that homogeneous Dennd1a-/- mutants died around embryonic day (E) 14.5. The brain of Dennd1a-/- embryos exhibited defects, partially attributed to the dysregulation of cell division and survival in the telencephalon. The transcription of Fgf8 mRNA was ectopically elevated in the dorsal midline of telencephalon, concomitant with a decrease of active β-catenin and Axin2 in the brain of Dennd1a-/- embryos. During liver morphogenesis, the ablation of Dennd1a impaired hepatic cell proliferation, the differentiation of hepatocyte, and hepatic hematopoiesis. In addition, loss of Dennd1a also affected the development of primordial germ cells (PGCs).

CONCLUSIONS: We demonstrate that Dennd1a, a susceptibility gene for PCOS, is essential for embryogenesis, probably through the mediation of endocytic recycling of selective cargos that are involved in cell signaling crucial for the development of multiple embryonic organ systems. This article is protected by copyright. All rights reserved.

PMID: 30884041 [PubMed – as supplied by publisher]

https://rbej.biomedcentral.com/articles/10.1186/s12958-019-0472-0

https://www.ncbi.nlm.nih.gov/pubmed/30878040?dopt=Abstract

Expression of the plasminogen system in the physiological mouse ovary and in the pathological polycystic ovary syndrome (PCOS) state.

Reprod Biol Endocrinol. 2019 Mar 16;17(1):33

Authors: Burchall GF, Pouniotis DS, Teede HJ, Ranasinha S, Walters KA, Piva TJ

Abstract

BACKGROUND: The fibrinolytic system and its inhibitors play a number of roles, apart from their function in blood haemostasis and thrombosis, namely in ovarian folliculogenesis and in ovulation. Plasminogen is converted to active plasmin at the time of follicular rupture through a decrease in plasminogen activator inhibitor-1 (PAI-1) and an increase in plasminogen activators. Oligo-/anovulation and follicle arrest are key characteristics of PCOS, but studies evaluating fibrinolytic/proteolytic markers within human or animal PCOS ovaries are lacking. We aimed to investigate and compare the expression and distribution of the plasminogen system markers in PCOS and control ovaries.

METHODS: A hyperandrogenised PCOS mouse model was used that mimics the ovarian, endocrine and metabolic features of the human condition. Immunohistochemistry and digital image analysis were used to investigate and compare fibrinolytic/proteolytic markers plasminogen, plasminogen/plasmin, tissue plasminogen activator, urokinase plasminogen activator and inhibitor PAI-1 in PCOS and control ovaries. Student’s t-test was used to compare data sets for normally distributed data and Wilcoxon-Mann Whitney test for non-normally distributed data.

RESULTS: We noted differences in the ovarian distribution of PAI-1 that was expressed throughout the PCOS ovary, unlike the peripheral distribution observed in control ovaries. Plasminogen was present in small follicles only in PCOS ovaries but not in small follicles of control ovaries. When we assessed and compared PAI-1 expression within follicles of different developmental stages we also noted significant differences for both the PCOS and control ovaries. While we noted differences in distribution and expression within specific ovarian structures, no differences were noted in the overall ovarian expression of markers assessed between acyclical PCOS mice and control mice at the diestrus stage of the estrous cycle.

CONCLUSIONS: Our novel study, that comprehensively assessed the fibrinolytic/proteolytic system in the mouse ovary, showed the expression, differential localisation and a potential role for the plasminogen system in the physiological mouse ovary and in PCOS. Androgens may be involved in regulating expression of the ovarian plasminogen system. Further studies evaluating these markers at different time-points of ovulation may help to further clarify both physiological and potential pathological actions these markers play in ovulatory processes distorted in PCOS.

PMID: 30878040 [PubMed – in process]

https://www.ncbi.nlm.nih.gov/pubmed/30875185?dopt=Abstract

Environmental toxins and the impact of other endocrine disrupting chemicals in women’s reproductive health.

JBRA Assist Reprod. 2019 Mar 15;:

Authors: Piazza MJ, Urbanetz AA

Abstract

This review aimed to look into agents and mechanisms characterized as endocrine disrupting chemicals (EDCs). These agents are known to cause several harmful effects to the reproductive system of women and wildlife. There is a wide range of chemicals, developed for commercial use mainly in agriculture, which may cause endocrine disruption. Numerous studies show evidence of environmental contamination. However, no one is being held liable for the damages. The most important potentially harmful agents are identified and described, along with the different effects they have on the female genital area. Brazil is a large consumer of pesticides and others chemicals that may interfere with a normal women’s life. We analyzed and described the mode of action and the impacts of different EDCs (bisphenols, phthalates, atrazine, polychlorinated and polybrominated biphenyls, DDT-dichlorodiphenyltrichloroethane; DDE-dichlorodiphenyldichloroethylene; DDD-dichlorodiphenyldichloroethane; and DES-diethylstilbestrol) on the genital area, ovarian steroidogenesis, polycystic ovary syndrome, endometriosis, the structure of the uterus and the vagina, and on the formation of leiomyomas.

PMID: 30875185 [PubMed – as supplied by publisher]

https://academic.oup.com/molehr/advance-article-abstract/doi/10.1093/molehr/gaz014/5379204?redirectedFrom=fulltext

https://www.ncbi.nlm.nih.gov/pubmed/30865275?dopt=Abstract

Dysregulated miR-142, -33b, and -423 in granulosa cells target TGFBR1 and SMAD7: a possible role in polycystic ovary syndrome.

Mol Hum Reprod. 2019 Mar 13;:

Authors: Li Y, Xiang Y, Song Y, Wan L, Yu G, Tan L

Abstract

It is well established that microRNA (miRNA) expression profiles are altered in patients with polycystic ovary syndrome (PCOS). In addition, abnormal transforming growth factor beta (TGFB) signaling in granulosa cells is related to the pathological conditions of PCOS. However, the function of dysregulated miRNAs in PCOS is still unclear. In this study, we aimed to elucidate the roles of specific miRNAs in PCOS. We collected follicular fluid from 46 patients with PCOS and 32 healthy controls. Granulosa cells (GCs) were separated and the levels of six candidate miRNAs were determined by quantitative RT-PCR. The direct targets of three dysregulated miRNAs were predicted using bioinformatic tools and confirmed using a dual luciferase assay and immunoblotting. The biological function of three dysregulated miRNAs in primary GCs was determined using a cell proliferation assay and flow cytometry. We found that miR-423 expression was downregulated (p = 0.038), and the levels of miR-33b (p = 0.032) and miR-142 (p = 0.021) were upregulated in GCs from patients with PCOS, compared to controls. miR-423 directly repressed SMAD family member 7 (SMAD7) expression, while transforming growth factor beta receptor 1 (TGFBR1) was a direct target of both miR-33b and miR-142. An RNA oligonucleotide mixture containing miR-423 inhibitor, miR-33b mimic, and miR-142 mimic repressed TGFB signaling, promoted cell proliferation (p = 0.0098), repressed apoptosis (p = 0.027), and increased S phase cell numbers (p = 0.0036) in primary cultures of GCs, compared to the cells treated with a sequence scrambled control RNA oligonucleotide. This study unveiled the possible roles of three miRNAs in PCOS and might provide candidate biomarkers for PCOS diagnosis while in vivo functional studies, using transgenic or knockout mouse models, are expected to confirm the roles of dysregulated miRNAs in the pathogenesis of PCOS.

PMID: 30865275 [PubMed – as supplied by publisher]

https://www.fasebj.org/doi/10.1096/fj.201802653RR

https://www.ncbi.nlm.nih.gov/pubmed/30866655?dopt=Abstract

Related Articles

Dysregulation of hypothalamic-pituitary estrogen receptor α-mediated signaling causes episodic LH secretion and cystic ovary.

FASEB J. 2019 Mar 13;:fj201802653RR

Authors: Arao Y, Hamilton KJ, Wu SP, Tsai MJ, DeMayo FJ, Korach KS

Abstract

Polycystic ovary syndrome (PCOS) is a hypothalamic-pituitary-gonadal (HPG) axis disorder. PCOS symptoms most likely result from a disturbance in the complex feedback regulation system of the HPG axis, which involves gonadotrophic hormones and ovarian steroid hormones. However, the nature of this complex and interconnecting feedback regulation makes it difficult to dissect the molecular mechanisms responsible for PCOS phenotypes. Global estrogen receptor α (ERα) knockout (KO) mice exhibit a disruption of the HPG axis, resulting in hormonal dysregulation in which female ERα KO mice have elevated levels of serum estradiol (E2), testosterone, and LH. The ERα KO females are anovulatory and develop cystic hemorrhagic ovaries that are thought to be due to persistently high circulating levels of LH from the pituitary. However, the role of ERα in the pituitary is still controversial because of the varied phenotypes reported in pituitary-specific ERα KO mouse models. Therefore, we developed a mouse model where ERα is reintroduced to be exclusively expressed in the pituitary on the background of a global ERα-null (PitERtgKO) mouse. Serum E2 and LH levels were normalized in PitERtgKO females and were comparable to wild-type serum levels. However, the ovaries of PitERtgKO adult mice displayed a more overt cystic and hemorrhagic phenotype when compared with ERα KO littermates. We determined that anomalous sporadic LH secretion caused the severe ovarian phenotype of PitERtgKO females. Our observations suggest that pituitary ERα is involved in the estrogen negative feedback regulation, whereas hypothalamic ERα is necessary for the precise control of LH secretion. Uncontrolled, irregular LH secretion may be the root cause of the cystic ovarian phenotype with similarities to PCOS.-Arao, Y., Hamilton, K. J., Wu, S.-P., Tsai, M.-J., DeMayo, F. J., Korach, K. S. Dysregulation of hypothalamic-pituitary estrogen receptor α-mediated signaling causes episodic LH secretion and cystic ovary.

PMID: 30866655 [PubMed – as supplied by publisher]

https://www.physiology.org/doi/abs/10.1152/ajpendo.00359.2018

https://www.ncbi.nlm.nih.gov/pubmed/30860876?dopt=Abstract

Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant ROS production.

Am J Physiol Endocrinol Metab. 2019 Mar 12;:

Authors: Hu M, Zhang Y, Guo X, Jia W, Liu G, Zhang J, Li J, Cui P, Sferruzzi-Perri AN, Han Y, Wu X, Ma H, Brännström M, Shao LR, Billig H

Abstract

Women with polycystic ovary syndrome (PCOS) are at increased risk of miscarriage, which often accompanies the hyperandrogenism and insulin resistance seen in these patients. However, neither the combinatorial interaction between these two PCOS-related etiological factors nor the mechanisms of their actions in the uterus during pregnancy are well understood. We hypothesised that hyperandrogensim and insulin resistance exert a causative role in miscarriage by inducing defects in uterine function that are accompanied by mitochondrial-mediated oxidative stress, inflammation and perturbed gene expression. Here we tested this hypothesis by studying the metabolic, endocrine and uterine abnormalities in pregnant rats after exposure to daily injection of 5α-dihydrotestosterone (DHT, 1.66 mg/kg body weight/day) and/or insulin (6.0 IU/day) from gestational day 7.5 to 13.5. We showed that while DHT-exposed and insulin-exposed pregnant rats presented impaired insulin sensitivity, DHT+insulin-exposed pregnant rats exhibited hyperandrogenism and peripheral insulin resistance, which mirrors pregnant PCOS patients. Compared to controls, hyperandrogenism and insulin resistance in the dam was associated with alterations in uterine morphology and aberrant expression of genes responsible for decidualization, placentation, angiogenesis and insulin signaling. Moreover, we observed changes in uterine mitochondrial function and homeostasis and suppression of both oxidative and antioxidative defenses in response to the hyperandrogenism and insulin resistance. These findings demonstrate that hyperandrogenism and insulin resistance induce mitochondria-mediated damage and a resulting imbalance between oxidative and antioxidative stress responses in the gravid uterus.

PMID: 30860876 [PubMed – as supplied by publisher]

https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/JP277756

https://www.ncbi.nlm.nih.gov/pubmed/30847930?dopt=Abstract

Related Articles

Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: Role of the endothelin B receptor.

J Physiol. 2019 Mar 07;:

Authors: Usselman CW, Yarovinsky T, Steele FE, Leone CA, Taylor HS, Bender JR, Stachenfeld NS

Abstract

Endothelin-1 (ET-1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE-PCOS). The endothelin B receptor (ETB R) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE-PCOS women and estradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with AE-PCOS (7 lean and 7 obese) and without AE-PCOS (Controls, 6 lean, 7 obese). Only obese AE-PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVCmax) with laser Doppler flowmetry during low dose intradermal microdialysis ET-1perfusions (1, 3, 4, 5, and 7 pmol) with either lactated Ringer’s solution alone, or with ETB R (BQ-788), or nitric oxide (NO) inhibition (L-NAME). Log[ET-1] %CVCmax dose-response curves demonstrated reduced vasodilatory responses to ET-1 in lean AE-PCOS (logED50 , 0.59 ± 0.08) versus lean Controls (logED50 , 0.49 ± 0.09, P < 0.05), but not compared to obese AE-PCOS (logED50 , 0.65 ± 0.09). ETB R inhibition decreased ET-1-induced vasodilation in AE-PCOS women (logED50 , 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET-1-induced, DAF-FM-measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor-dependent manner. EE augmented the cutaneous vasodilating response to ET-1(logED50 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE-PCOS. We propose that the attenuated ET-1-induced vasodilation in AE-PCOS is a consequence of androgen receptor-mediated, suppressed ETB R-stimulated NO production, and is reversed with EE. This article is protected by copyright. All rights reserved. PMID: 30847930 [PubMed - as supplied by publisher]

https://www.sciencedirect.com/science/article/pii/S0753332218383045?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30851546?dopt=Abstract

Efficacy of electroacupuncture in regulating the imbalance of AMH and FSH to improve follicle development and hyperandrogenism in PCOS rats.

Biomed Pharmacother. 2019 Mar 06;113:108687

Authors: Shi Y, Li L, Zhou J, Sun J, Chen L, Zhao J, Wu L, Cui Y, Wu L, Wu H

Abstract

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and follicular arrest. These two characteristics may result from an imbalance between anti-Müllerian hormone and follicle stimulating hormone. Electroacupuncture is effective in improving hyperandrogenism and follicular arrest in PCOS; however, the mechanism is not sufficiently clear. This study aimed to elucidate whether electroacupuncture in PCOS is exerted by regulating an imbalance of anti-Müllerian hormone and follicle stimulating hormone. In this study, a rat model of polycystic ovary syndrome was treated with low-frequency electroacupuncture at acupoints (CV-3 and CV-4). To observe the mechanism of electroacupuncture in PCOS, we first observed the estrous cycle. We then observed ovarian morphology by hematoxylin-eosin staining and evaluated levels of testosterone, estradiol, P450arom, follicle stimulating hormone and its receptor, and anti-Müllerian hormone and its receptor by enzyme-linked immunosorbent assay, western blotting, double immunofluorescence assay and real-time PCR. Our results showed that in 80% of rats in the electroacupuncture acupoints group, their estrous cycle recovered, ovarian morphology significantly improved, testosterone level significantly decreased, and levels of estradiol and P450arom significantly increased in peripheral serum after 14 consecutive days of treatment (P < 0.01). The expression of anti-Müllerian hormone and anti-Müllerian hormone type II receptor decreased (P < 0.05), whereas the expression of follicle stimulating hormone receptor increased (P < 0.05). These results indicated that electroacupuncture improved hyperandrogenism and follicular arrest by decreasing the excessive expression of AMH to regulate FSH and AMH imbalance in granulosa cells in PCOS. PMID: 30851546 [PubMed - as supplied by publisher]

https://www.tandfonline.com/doi/abs/10.1080/09513590.2019.1581759?journalCode=igye20

https://www.ncbi.nlm.nih.gov/pubmed/30835572?dopt=Abstract

Plasmatic free light chains in polycystic ovary syndrome.

Gynecol Endocrinol. 2019 Mar 05;:1-4

Authors: Mancini A, Brunetti A, Bruno C, Vergani E, Pocino K, Napodano C, Gulli F, Santini SA, Basile U

Abstract

Polycystic ovary syndrome (PCOS), as systemic disease, is accompanied by different indexes of inflammation. Free light chains of immunoglobulins (FLCs), produced by plasmacells, are released in slight excess for the immune requests, with still poorly defined physiological role but surely they represent a marker of inflammation. In order to evaluate their levels and correlate them with hyperandrogenism, we have studied a group of PCOS patients, age range 18-37 yrs, mean ± SEM body mass index (BMI) 24.1 ± 0.9 kg/m2), compared with age- and BMI-matched controls, with assay of k and λ FLCs, by turbidimetric method, and their ratio in blood plasma. PCOs exhibited higher levels vs. controls: (mean ± SEM λ: 10.0 ± 0.85 mg/L vs. 8.41 ± 0.45 mg/L; k: 12.45 ± 0.72 mg/L vs. 6.41 ± 0.34 mg/L; k/λ: 1.31 ± 0.07 vs. 0.78 ± 0.04). A significant direct correlation was observed between λ-FLCs and testosterone levels, no correlation was indeed found with HOMA-IR index. These data confirm high levels of FLCs in PCOS, suggesting systemic inflammatory state and a possible role in the pathophysiology of such complex syndrome.

PMID: 30835572 [PubMed – as supplied by publisher]

https://www.tandfonline.com/doi/abs/10.1080/0167482X.2018.1557144?journalCode=ipob20

https://www.ncbi.nlm.nih.gov/pubmed/30835597?dopt=Abstract

Carnitine and chromium co-supplementation affects mental health, hormonal, inflammatory, genetic, and oxidative stress parameters in women with polycystic ovary syndrome.

J Psychosom Obstet Gynaecol. 2019 Mar 05;:1-9

Authors: Jamilian M, Foroozanfard F, Kavossian E, Aghadavod E, Amirani E, Mahdavinia M, Mafi A, Asemi Z

Abstract

OBJECTIVE: The aim of this study was to evaluate the effect of the co-administration of carnitine and chromium on mental health, hormonal, inflammatory and genetic parameters in women with PCOS.

METHODS: This randomized, double-blinded, placebo-controlled clinical trial was conducted on 54 subjects, aged 18-40 years old. Subjects were randomly allocated to take either 1000 mg/d carnitine plus 200 µg/d chromium as chromium picolinate (n = 26) or placebo (n = 27) for 12 weeks.

RESULTS: Carnitine and chromium co-supplementation, compared with the placebo, significantly improved beck depression inventory (β - 0.84; 95% CI, -1.51, -0.17; p = 0.01), general health questionnaire scores (β - 1.13; 95% CI, -2.13, -0.14; p = 0.02) and depression anxiety and stress scale scores (β - 0.96; 95% CI, -0.78, -0.14; p = 0.02). Participants who received carnitine plus chromium supplements had significantly lower total testosterone (β - 0.15 ng/mL; 95% CI, -0.24, -0.06; p = 0.002), hirsutism (β - 0.48; 95% CI, -0.91, -0.06; p = 0.02), high-sensitivity C-reactive protein (hs-CRP) (β - 1.02 mg/L; 95% CI, -1.79, -0.25; p = 0.01), and malondialdehyde (MDA) levels (β - 0.38 µmol/L; 95% CI, -0.56, -0.20; p < 0.001), and higher total antioxidant capacity (TAC) levels (β 107.18 mmol/L; 95% CI, 44.24, 170.12; p = 0.001) compared with the placebo. Moreover, carnitine and chromium co-supplementation upregulated gene expression of interleukin-6 (IL-6) (p = 0.02) and tumor necrosis factor alpha (TNF-α) (p = 0.02) compared with the placebo. CONCLUSION: Overall, the co-administration of carnitine and chromium for 12 weeks to women with PCOS had beneficial effects on mental health parameters, serum total testosterone, mF-G scores, hs-CRP, TAC and MDA levels, and gene expression of IL-6 and TNF-α. PMID: 30835597 [PubMed - as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/30873121?dopt=Abstract

Related Articles

Metabolomics of Dynamic Changes in Insulin Resistance Before and After Exercise in PCOS.

Front Endocrinol (Lausanne). 2019;10:116

Authors: Halama A, Aye MM, Dargham SR, Kulinski M, Suhre K, Atkin SL

Abstract

Background: Plasma elevated levels of branched chain amino acids (BCAA) and aromatic amino acids (AAA) have been associated with obesity and insulin resistance, but their relationship to stimulated insulin resistance (IR) in PCOS and in response to exercise is unknown. Indeed, it is unknown whether the mechanism of IR in PCOS is mediated through changes in the metabolome. Methods: Twelve women with polycystic ovary syndrome (PCOS) and ten age and body mass index matched controls completed an 8 week supervised exercise program at 60% maximal oxygen consumption. Before and after the exercise program, all participants underwent maximal IR stimulation with intralipid infusions followed by insulin sensitivity (IS) measurement by hyperinsulinaemic euglycaemic clamps. Amino acid profiles and metabolites were taken at baseline and at maximal insulin resistance stimulation before and after the exercise program. Results: At baseline, PCOS subjects showed increased leucine/isoleucine, glutamate, methionine, ornithine, phenylalanine, tyrosine and proline (p < 0.05) that, following exercise, did not differ from controls. While compering within the groups, no significant changes in the amino acid levels before and after exercise were observed. Exercise improved VO2 max (p < 0.01) but did not alter weight. Amino acid profiles were unaffected by an acute increase in IR induced by the lipid infusion. IS was lower in PCOS (p < 0.001) and was further decreased by the lipid infusion in both PCOS and controls. Although, exercise improved IS in both PCOS and in controls, the IS remained compromised in PCOS. Conclusion: The baseline amino acid profile in PCOS reflected that seen in obese subjects and differed to controls. After exercise, and despite no change in weight in either group, there were no differences in the amino acid profile between PCOS and controls. This shows that exercise may normalize the amino acid metabolome, irrespective of weight. ISRCTN number: ISRCTN42448814.

PMID: 30873121 [PubMed]

https://www.sciencedirect.com/science/article/pii/S0165032718328210?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/30831541?dopt=Abstract

Effects of melatonin administration on mental health parameters, metabolic and genetic profiles in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial.

J Affect Disord. 2019 Feb 26;250:51-56

Authors: Shabani A, Foroozanfard F, Kavossian E, Aghadavod E, Ostadmohammadi V, Reiter RJ, Eftekhar T, Asemi Z

Abstract

OBJECTIVE: The aim of this study was to evaluate the effect of melatonin supplementation on mental health parameters, metabolic and genetic parameters in women suffering from polycystic ovary syndrome (PCOS).

METHODS: This randomized, double-blinded, placebo-controlled clinical trial was performed on 58 subjects, aged 18-40 years old. Subjects were randomly allocated to take either 10 mg melatonin (2 melatonin capsules, 5 mg each) (n = 29) or placebo (n = 29) once a day 1 h before bedtime for 12 weeks. Glycemic control and lipid profiles were measured at baseline and after the 12-week intervention. Using RT-PCR method, gene expression related to insulin and lipid metabolism was conducted on peripheral blood mononuclear cells (PBMCs) of PCOS women.

RESULTS: Melatonin supplementation significantly decreased Pittsburgh Sleep Quality Index (β -2.15; 95% CI, -3.62, -0.68; P = 0.005), Beck Depression Inventory index (β -3.62; 95% CI, -5.53, -1.78; P<0.001) and Beck Anxiety Inventory index (β -1.95; 95% CI, -3.41, -0.48; P = 0.01) compared with the placebo. In addition, melatonin administration, compared with the placebo, significantly reduced serum insulin (β -1.20 µIU/mL; 95% CI, -2.14, -0.26; P = 0.01), homeostasis model of assessment-insulin resistance (HOMA-IR) (β -0.28; 95% CI, -0.50, -0.05; P = 0.01), serum total- (β -7.96 mg/dL; 95% CI, -13.75, -2.17; P = 0.008) and LDL-cholesterol levels (β -5.88 mg/dL; 95% CI, -11.42, -0.33; P = 0.03), and significantly increased the quantitative insulin sensitivity check index (QUICKI) (β 0.008; 95% CI, 0.002, 0.014; P = 0.007). Moreover, melatonin supplementation upregulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.004) and low-density lipoprotein receptor (LDLR) (P = 0.01) compared with the placebo. CONCLUSIONS: Overall, melatonin administration for 12 weeks had beneficial effects on mental health parameters, insulin levels, HOMA-IR, QUICKI, total- and LDL-cholesterol levels, and gene expression of PPAR-γ and LDLR among women with PCOS. PMID: 30831541 [PubMed - as supplied by publisher]