PolyCystic Ovary Syndrome

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The Human Ovary and Future of Fertility Assessment in the Post-Genome Era.

Int J Mol Sci. 2019 Aug 28;20(17):

Authors: Ouni E, Vertommen D, Amorim CA

Proteomics has opened up new avenues in the field of gynecology in the post-genome era, making it possible to meet patient needs more effectively and improve their care. This mini-review aims to reveal the scope of proteomic applications through an overview of the technique and its applications in assisted procreation. Some of the latest technologies in this field are described in order to better understand the perspectives of its clinical applications. Proteomics seems destined for a promising future in gynecology, more particularly in relation to the ovary. Nevertheless, we know that reproductive biology proteomics is still in its infancy and major technical and ethical challenges must first be overcome.

PMID: 31466236 [PubMed - indexed for MEDLINE]

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Aberrant endometrial steroid receptor expression in in-vitro maturation cycles despite hormonal luteal support: A pilot study.

Reprod Biol. 2019 Jun;19(2):210-217

Authors: Ortega-Hrepich C, Drakopoulos P, Bourgain C, Van Vaerenbergh I, Guzman L, Tournaye H, Smitz J, De Vos M

Clinical outcomes of fresh embryo transfer in non-hCG triggered in vitro maturation (IVM) cycles are inferior compared to vitrified-warmed embryo transfer. This is a prospective observational pilot study in a consecutive cohort of 31 polycystic ovary syndrome (PCOS) patients and 37 normo-ovulatory egg donors who underwent IVM without fresh embryo transfer between July 2009 and June 2014. All subjects received 150 IU of highly purified menotropin (HP-hMG) daily for three days. On cycle day 6, all patients started transdermal oestradiol (E2) at a daily dose of 9 mg. There was no human chorionic gonadotropin (hCG) trigger before oocyte retrieval (OR). Vaginal micronized progesterone was commenced on the evening after OR, at a daily dose of 600 mg. Additional luteal phase support (LPS) was administered as follows: Group A: no additional LPS; Group B: 1500 IU of hCG administered 4 h after OR and Group C: 5000 IU of hCG administered 4 h after OR + an additional injection of 5000 IU of hCG 1 day before endometrial biopsy. Endometrial biopsy for histology and immunohistochemistry (IHC) was performed on day 5 or 6 after OR. Instead of being downregulated, both PR-B and ERα in endometrial glands and stroma were moderately to strongly expressed in all three protocols, suggesting that the mid-luteal histological signature of endometrial receptivity is deficient in a non-hCG-triggered IVM cycle. Poor clinical outcomes after fresh embryo transfer following IVM are probably related to inappropriate endometrial development which may be linked to the short follicular phase of IVM cycles.

PMID: 31262644 [PubMed - indexed for MEDLINE]

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Early onset of cabergoline therapy for prophylaxis from ovarian hyperstimulation syndrome (OHSS): A potentially safer and more effective protocol.

Reprod Biol. 2019 Jun;19(2):145-148

Authors: Gaafar S, El-Gezary D, El Maghraby HA

Vascular endothelial growth factor (VEGF) is the most important angiogenic mediator in ovarian hyperstimulation syndrome OHSS. Studies proved that cabergoline administration blocks the increase in vascular permeability via dephosphorylation of VEGF receptors and hence can be used as prophylactic agent against OHSS. This study aimed at evaluating the effectiveness of early administration of cabergoline in the prevention of OHSS in high risk cases prepared for ICSI. This case series study was conducted on 126 high risk patients prepared for ICSI using the fixed antagonist protocol. High risk patients were defined as having more than 20 follicles >12 mm in diameter, and/or E2 more than 3000 pg/ml when the size of the leading follicle is more than 15 mm. When the size of the leading follicle reached 15 mm, cabergoline was administered (0.5 mg/day) for 8 days. Patients were followed up clinically, ultrasonographically and hematologically. The final E2 was 6099.5 ± 2730 and the mean number of retrieved oocytes was 19.7 ± 7.8. The clinical pregnancy rate was 62/126 (49.2%). There were no significant changes (p > 0.05) comparing hematological parameters, renal function tests and liver function tests between the day of HCG and the day of blastocyst transfer. The incidence of severe OHSS in this group was 1/126 (0.9%), while moderate OHSS was 12 (9.5%) and there were no cases of critical OHSS. We concluded that early administration of cabergoline is a safe and potentially more effective approach for prophylaxis against OHSS in high risk cases.

PMID: 31133458 [PubMed - indexed for MEDLINE]

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

Gynecol Endocrinol. 2019 Aug;35(8):669-672

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

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 - indexed for MEDLINE]

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Associations of preconception Body Mass Index in women with PCOS and BMI and blood pressure of their offspring.

Gynecol Endocrinol. 2019 Aug;35(8):673-678

Authors: Gunning MN, van Rijn BB, Bekker MN, de Wilde MA, Eijkemans MJC, Fauser BCJM

Women with polycystic ovary syndrome (PCOS) have unfavorable metabolic profiles. Their offspring may be affected by such risks. The objective of the current study was to disclose associations between preconception health of these women and health of their offspring. 74 women diagnosed with PCOS according to the Rotterdam criteria were screened systematically before conception. Cardiovascular health of their offspring was assessed at 2.5-4 (n = 42) or at 6-8 years of age (n = 32). Multivariate linear regression analysis was performed with adjustments for potential confounders. In the primary analyses the association between preconception Body Mass index (BMI) and offspring BMI was evaluated. Secondly associations between preconception blood pressure, androgens, insulin-resistance (HOMA-IR), and LDL-cholesterol in women with PCOS and BMI and blood pressure of offspring were assessed. Results show that preconception BMI of women with PCOS was positively associated with sex- and age-adjusted BMI of their offspring at 6-8 years of age (β = 0.55 (95% CI: 0.12 to 0.97), p = .012). No other significant associations were found. In conclusion, our data suggest that preconception BMI in PCOS is significantly associated with offspring BMI at 6-8 year of age. If this suggestion could be confirmed this may provide an opportunity for improving the future health of these children.

PMID: 31030581 [PubMed - indexed for MEDLINE]

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High prevalence of benign mammary tumors in a rat model of polycystic ovary syndrome during postmenopausal period.

Gynecol Endocrinol. 2019 Aug;35(8):679-684

Authors: Noroozzadeh M, Behboudi-Gandevani S, Mosaffa N, Tohidi M, Ramezani Tehrani F

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-age women. Significant associations between PCOS and benign breast diseases (BBD) and a possibly potential association between PCOS and breast cancer have been reported. The etiology of these events of mammary glands in PCOS remains unclear. Animal models that show BBD and breast cancer may contribute to further understanding about these diseases. We aimed to examine the spontaneous occurrence of mammary tumors, their prevalence, and type in our rat model of PCOS. Prenatal androgen-induced PCOS rats and controls were examined in later life. Benign mammary tumors were observed in 75% and 33.33% of PCOS rats and controls during the postmenopausal period, respectively (p = .0158). Mammary tumors were non-invasive, margins of excision were normal and tumors were freely movable, in both groups. After microscopic evaluations of tumors, proliferative breast lesions and adenomas with a tubular growth pattern were observed in both groups. However, in PCOS rats, of benign tumors two had a mixed pattern of fibroadenoma/fibroma and cysts. High prevalence of benign mammary tumors was observed in our rat model of PCOS during the postmenopausal period, possibly due to hormonal imbalances during their reproductive lifespan; this model may contribute to current data available regarding the events of mammary glands in PCOS.

PMID: 30990105 [PubMed - indexed for MEDLINE]

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Long non-coding RNA H19 is associated with polycystic ovary syndrome in Chinese women: a preliminary study.

Endocr J. 2019 Jul 28;66(7):587-595

Authors: Qin L, Huang CC, Yan XM, Wang Y, Li ZY, Wei XC

Polycystic ovary syndrome (PCOS) represents a serious reproductive and endocrine condition and is associated with high incidence rates. H19 is a compelling long noncoding RNA (lncRNA) which carries out a range of biological functions. However, prior to this study, little was known as to whether there was an association between lncRNA H19 and PCOS. In the current study, we used quantitative real-time polymerase chain reaction (qRT-PCR) to determine lncRNA H19 expression levels in peripheral blood leukocytes from patients with PCOS and compared this data with that derived from normal controls. We also screened data for potential relationships between lncRNA H19 and a range of endocrine variables in PCOS. The expression of lncRNA H19 was significantly higher in cases of PCOS than in controls. Individuals exhibiting higher expression levels of lncRNA H19 were associated with a significantly higher risk of PCOS than those with lower expression levels. Moreover, lncRNA H19 expression was positively correlated with fasting plasma glucose levels; this was the case with both raw data, and after adjustment for age and BMI in the PCOS group. However, lncRNA H19 expression showed no significant correlation with total testosterone or insulin resistance in either PCOS cases or the controls. In conclusion, we demonstrate the first evidence to indicate that lncRNA H19 is associated with PCOS, suggesting that elevated lncRNA H19 levels are a risk factor for PCOS. For susceptible individuals, lncRNA H19 may represent a useful biomarker of the early stages of endocrine and metabolic disorders in PCOS.

PMID: 30982795 [PubMed - indexed for MEDLINE]

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Serum and follicular fluid irisin levels in women with polycystic ovaries undergoing ovarian stimulation: correlation with insulin resistance and lipoprotein lipid profiles.

Gynecol Endocrinol. 2019 Sep;35(9):803-806

Authors: Bousmpoula A, Benidis E, Demeridou S, Kapeta-Kourkouli R, Chasiakou A, Chasiakou S, Kouskouni E, Baka S

Irisin, a novel exercise-induced myokine, has been implicated in different aspects of human metabolism and could be connected to polycystic ovary syndrome (PCOS). This study aimed to investigate serum and follicular fluid (FF) irisin levels in PCOS and normal women undergoing controlled ovarian stimulation and correlate them to the lipid and lipoprotein levels as well as with other metabolic parameters. Serum and FF irisin, together with serum lipid and lipoprotein levels were assessed in 70 women with diagnosed PCOS and 70 non-PCOS controls, under in vitro fertilization (IVF) treatment. Regardless of BMI, PCOS women had a significantly increased number of oocytes retrieved, fertilized oocytes and transferred embryos, although the number of women achieving pregnancies did not differ between groups. No correlation between FF irisin levels and pregnancy could be established. Serum and FF irisin levels were significantly higher in PCOS and overweight women and were positively associated with BMI and dyslipidemia. FF irisin levels correlated positively to and were lower than serum irisin levels. Further research would be helpful to analyze irisin's role in female reproduction, if any, as well as in human metabolism and the pathophysiology of PCOS.

PMID: 30982370 [PubMed - indexed for MEDLINE]

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DNA methylome profiling of granulosa cells reveals altered methylation in genes regulating vital ovarian functions in polycystic ovary syndrome.

Clin Epigenetics. 2019 04 11;11(1):61

Authors: Sagvekar P, Kumar P, Mangoli V, Desai S, Mukherjee S

BACKGROUND: Women with polycystic ovary syndrome (PCOS) manifest a host of ovarian defects like impaired folliculogenesis, anovulation, and poor oocyte quality, which grossly affect their reproductive health. Addressing the putative epigenetic anomalies that tightly regulate these events is of foremost importance in this disorder. We therefore aimed to carry out DNA methylome profiling of cumulus granulosa cells and assess the methylation and transcript expression profiles of a few differentially methylated genes contributing to ovarian defects in PCOS. A total of 20 controls and 20 women with PCOS were selected from a larger cohort of women undergoing IVF, after carefully screening their sera and follicular fluids for hormonal and biochemical parameters. DNA extracted from cumulus granulosa cells of three women each, from control and PCOS groups was subjected to high-throughput, next generation bisulfite sequencing, using the Illumina HiSeq 2500® platform. Remaining samples were used for the validation of methylation status of some identified genes by pyrosequencing, and the transcript expression profiles of these genes were assessed by quantitative real-time PCR.
RESULTS: In all, 6486 CpG sites representing 3840 genes associated with Wnt signaling, G protein receptor, endothelin/integrin signaling, angiogenesis, chemokine/cytokine-mediated inflammation, etc., showed differential methylation in PCOS. Hypomethylation was noted in 2977 CpGs representing 2063 genes while 2509 CpGs within 1777 genes showed hypermethylation. Methylation differences were also noted in noncoding RNAs regulating several ovarian functions that are dysregulated in PCOS. Few differentially methylated genes such as aldo-keto reductase family 1 member C3, calcium-sensing receptor, resistin, mastermind-like domain 1, growth hormone-releasing hormone receptor and tumor necrosis factor, which predominantly contribute to hyperandrogenism, premature luteolysis, and oocyte development defects, were explored as novel epigenetic candidates in mediating ovarian dysfunction. Methylation profiles of these genes matched with our NGS findings, and their transcript expression patterns correlated with the gene hypo- or hypermethylation status.
CONCLUSION: Our findings suggest that the epigenetic dysregulation of genes involved in important processes associated with follicular development may contribute to ovarian defects observed in women with PCOS.

PMID: 30975191 [PubMed - indexed for MEDLINE]

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Effects of kisspeptin on pathogenesis and energy metabolism in polycystic ovarian syndrome (PCOS).

Gynecol Endocrinol. 2019 Sep;35(9):807-810

Authors: Wang T, Han S, Tian W, Zhao M, Zhang H

Kisspeptin has been shown to participate in the regulation of pituitary hormone secretion and energy metabolism. In PCOS patients, there are disorders in pituitary hormone secretion and energy metabolism. The aim of this study was to investigate the serum kisspeptin and its relationship with abnormal metabolism in PCOS. This restrospective case-control study included 73 cases with PCOS and 63 control cases. All subjects were divided into obese and nonobese groups based on BMI. The serum kisspeptin levels, Cor, DHEA-S, plasma concentrations of glucose were tested. We found that the level of kisspeptin in PCOS group was higher than it in control group. The kisspeptin levels in nonobese PCOS group increased most obviously over than the other groups. The kisspeptin levels of all the subjects were positively correlated with LH levels, negatively correlated with the glucose-AUC, the insulin-AUC, and triglyceride levels. The findings of this study suggest that kisspeptin may play an important role in ovulation disorders in PCOS patients through regulating the level of LH and it could regulate the body's energy metabolism by regulating glucose and lipid metabolism.

PMID: 30957568 [PubMed - indexed for MEDLINE]

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Quantitative mass spectrometric analysis to unravel glycoproteomic signature of follicular fluid in women with polycystic ovary syndrome.

PLoS One. 2019;14(4):e0214742

Authors: Patil K, Yelamanchi S, Kumar M, Hinduja I, Prasad TSK, Gowda H, Mukherjee S

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy affecting women of reproductive age, and whose etiology is not well understood yet. In these women, the follicular growth is arrested at preantral stage leading to cyst formation, consequently resulting in anovulatory infertility in these women. As the follicular fluid provides the conducive microenvironment for the growth of oocytes, molecular profiling of the fluid may provide unique information about pathophysiology associated with follicular development in PCOS. Post-translational addition of oligosaccharide residues is one of the many modifications of secreted proteins influencing their functions. These glycoproteins play a significant role in disease pathology. Despite glycoproteins having such essential functions, very limited information is available on their profiling in human reproductive system, and glycoproteomic profile of follicular fluid of women with PCOS is yet unexplored. In the present study, we performed a comparative glycoproteomic analysis of follicular fluid between women with PCOS and controls undergoing in vitro fertilization, by enrichment of glycoproteins using three different lectins viz. concanavalin A, wheat germ agglutinin and Jacalin. Peptides generated by trypsin digestion were labeled with isobaric tags for relative and absolute quantification reagents and analyzed by liquid chromatography tandem mass spectrometry. We identified 10 differentially expressed glycoproteins, in the follicular fluid of women with PCOS compared to controls. Two important differentially expressed proteins- SERPINA1 and ITIH4, were consistently upregulated and downregulated respectively, upon validation by immunoblotting in follicular fluid and real-time polymerase chain reaction in granulosa cells. These proteins play a role in angiogenesis and extracellular matrix stabilization, vital for follicle maturation. In conclusion, a comparative glycoproteomic profiling of follicular fluid from women with PCOS and controls revealed an altered expression of proteins which may contribute to the defects in follicle development in PCOS pathophysiology.

PMID: 30946770 [PubMed - indexed for MEDLINE]

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Association between the vascular endothelial growth factor gene polymorphisms and the risk of polycystic ovary syndrome in Northern Chinese women.

Gynecol Endocrinol. 2019 Aug;35(8):706-709

Authors: Huang X, Hao YL, Zhen XL, Zhou RM, Wang N, Cao SR, Li Y

The present study aimed to investigate whether the single nucleotide polymorphisms (SNPs) rs2010963 and rs833061 in vascular endothelial growth factor (VEGF) gene is correlated with the risk of polycystic ovary syndrome (PCOS) in Northern Chinese women, as a preliminary study. This case-control study comprised 118 women with PCOS and 130 healthy women as controls. Genotyping of the two polymorphisms within the VEGF gene 5'-untranslated region and promoter region were performed using polymerase chain reaction ligase detection reaction method. The data showed that there was a significant difference in the genotype and allele distribution of the rs2010963 polymorphism between the PCOS group and the control group (p = .020 and .033, respectively). The women carrying the C allele (G/C + C/C genotype) had a lower risk of PCOS compared with the women with G/G genotype [odds ratio (OR = 0.55; 95% confidence interval (CI) = 0.33-0.91]. Our study shows for the first time that the rs2010963 polymorphism may be associated with a risk of PCOS in Northern Chinese women.

PMID: 30935253 [PubMed - indexed for MEDLINE]

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Influence of metabolic syndrome on female fertility and in vitro fertilization outcomes in PCOS women.

Am J Obstet Gynecol. 2019 08;221(2):138.e1-138.e12

Authors: He Y, Lu Y, Zhu Q, Wang Y, Lindheim SR, Qi J, Li X, Ding Y, Shi Y, Wei D, Chen ZJ, Sun Y

OBJECTIVE: With a high incidence of insulin resistance, central obesity and dyslipidemia, women with polycystic ovary syndrome are susceptible to metabolic syndrome (MetS). Our objective was to explore whether metabolic syndrome had an effect on overall female fertility and in vitro fertilization outcomes in infertile women with polycystic ovary syndrome.
STUDY DESIGN: This was a secondary analysis of a multicenter randomized trial in 1508 women with polycystic ovary syndrome, which was originally designed to compare the live birth rate after fresh-embryo transfer vs frozen embryo transfer (Frefro-PCOS). At baseline, metabolic parameters, including body mass index, waist and hip circumference, blood pressure, lipid profile, fasting, and 2 hour glucose and insulin levels after a 75 g oral glucose tolerance test were measured. All subjects were divided into a metabolic syndrome group (metabolic syndrome) and absence of metabolic syndrome group (nonmetabolic syndrome) according to diagnostic criteria. Descriptive statistics and logistic regression models tested the association between metabolic syndrome and overall fertility and in vitro fertilization cycle stimulation characteristics and clinical outcomes.
RESULTS: Metabolic syndrome was identified in 410 of 1508 infertile women with polycystic ovary syndrome (27.2%). Patients with metabolic syndrome had longer infertility duration (4.0 ± 2.2 vs 3.7 ± 2.2, P = .004) compared with those without metabolic syndrome. During ovarian stimulation, those with metabolic syndrome required significantly higher and longer doses of gonadotropin and had lower peak estradiol level, fewer retrieved oocytes, available embryos, a lower oocyte utilization rate, and ovarian hyperstimulation syndrome than those with nonmetabolic syndrome. The cumulative live birth rate did not show a significant between-group difference (57.8% vs 62.2%, P = .119). Multivariate logistic regression analysis adjusted for age, duration of infertility, body mass index, thyroid-stimulating hormone, metabolic syndrome group, homeostatic model assessment of insulin resistance, metformin utilization, number of available embryos, and embryos transferred showed that the number of embryos transferred and the number of available embryos were positively but metabolic syndrome negatively associated with the cumulative live birth rate (odds ratio, 2.18, 1.10, and 0.70, respectively, P < .05).
CONCLUSION: Women with polycystic ovary syndrome with metabolic syndrome have a negative impact from female fecundity, and this suggests an adverse effect on in vitro fertilization cycle stimulation characteristics and clinical outcomes.

PMID: 30910544 [PubMed - indexed for MEDLINE]

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

Gynecol Endocrinol. 2019 Aug;35(8):714-718

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

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 - indexed for MEDLINE]

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Comparison of the effect of two combinations of myo-inositol and D-chiro-inositol in women with polycystic ovary syndrome undergoing ICSI: a randomized controlled trial.

Gynecol Endocrinol. 2019 Aug;35(8):695-700

Authors: Mendoza N, Diaz-Ropero MP, Aragon M, Maldonado V, Llaneza P, Lorente J, Mendoza-Tesarik R, Maldonado-Lobon J, Olivares M, Fonolla J

The purpose of this study was to evaluate the effect of two doses of D-chiro-inositol (DCI) in combination with Myo-inositol (MYO) in women with PCOS undergoing ICSI. This was a multicenter controlled, randomized, double-blind parallel group study with two MYO-DCI formulations for 12 weeks. The study group (SG) was administered 550 mg of MYO + 150 mg of DCI twice daily; the control group (CG) was administered 550 mg of MYO + 13.8 mg of DCI twice daily. The participants comprised 60 women with PCOS undergoing ICSI. At baseline, no differences were found between the two groups regarding age, BMI, HOMA-IR or testosterone levels. The pregnancy and live birth rates were significantly higher in the SG than in the CG (65.5 vs. 25.9 and 55.2 vs. 14.8, respectively) [risk ratio (RR) = 0.4; 95%CI (0.2, 0.79); p = .003 and RR = 0.27; 95%CI (0.10, 0.70); p = .002 respectively]. The risk of ovarian hyperstimulation syndrome (OHSS) was lower in the SG (3.44 vs. 18.5%, p = .07). The combination of MYO-DCI at high doses of DCI improves the pregnancy rates and reduces the risk of OHSS in women with PCOS undergoing ICSI.

PMID: 30880505 [PubMed - indexed for MEDLINE]

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Plasmatic free light chains in polycystic ovary syndrome.

Gynecol Endocrinol. 2019 Aug;35(8):710-713

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

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 - indexed for MEDLINE]

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l-Carnitine plus metformin in clomiphene-resistant obese PCOS women, reproductive and metabolic effects: a randomized clinical trial.

Gynecol Endocrinol. 2019 Aug;35(8):701-705

Authors: El Sharkwy I, Sharaf El-Din M

To evaluate the reproductive and metabolic effects of L-carnitine plus metformin in clomiphene citrate (CC) resistant obese polycystic ovary syndrome (PCOS) women. A double-blinded randomized controlled clinical trial, clomiphene-citrate resistant obese women were allocated randomly to receive CC plus metformin and L-carnitine (n = 138) or CC plus metformin and placebo (n = 136). The primary outcome was clinical pregnancy rate. The secondary outcomes were hormonal and metabolic profile changes in addition to ovulation and first trimester (13 weeks) miscarriage rates. Clomiphene-citrate, L-carnitine, and metformin group showed significant improvement in the menstrual regularity, ovulation rate, and pregnancy rate compared to CC plus metformin and placebo group (29% vs. 9%, 34.7% vs.11%, and 28.2% vs. 6.6%, respectively). No statistically significant difference in the miscarriage rate between the two groups (p = .08). After three months of treatment, the reduction in body mass index (BMI) was non-significant (p = .061) between both groups. The hormonal and metabolic parameters were more significantly improved in the L-carnitine group compared with the placebo group. l-Carnitine may act synergistically with metformin for improvement of reproductive performance, insulin resistance, and lipid profile in clomiphene-resistant obese PCOS women.

PMID: 30806102 [PubMed - indexed for MEDLINE]

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Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries.

Mol Cell Endocrinol. 2019 04 15;486:47-54

Authors: Lerner A, Owens LA, Coates M, Simpson C, Poole G, Velupillai J, Liyanage M, Christopoulos G, Lavery S, Hardy K, Franks S

INTRODUCTION: Aberrant function of granulosa cells has been implicated in the pathophysiology of PCOS.
MATERIALS & METHODS: Granulosa lutein (GL) cells were collected during oocyte retrieval for IVF/ICSI. RT-qPCR was used to compare gene expression between 12 control women, 12 with ovulatory PCO and 12 with anovulatory PCOS. To examine which genes are directly regulated by androgens, GL cells from an additional 12 control women were treated in-vitro with 10 nM dihydrotestosterone (DHT).
RESULTS: GL cells from women with PCOS showed reduced expression of CYP11A1 3-fold (p = 0.005), HSD17B1 1.8-fold (p = 0.02) and increased expression of SULT1E1 7-fold (p = 0.0003). Similar results were seen in ovulatory women with PCO. GL cells treated with 10 nM DHT showed a 4-fold (p = 0.03) increase in expression of SULT1E1 and a 5-fold reduction in SRD5A1 (p = 0.03).
CONCLUSIONS: These findings support the notion that aberrant regulation of steroid metabolism or action play a part in ovarian dysfunction in PCOS.

PMID: 30802529 [PubMed - indexed for MEDLINE]

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MicroRNA-9 affects isolated ovarian granulosa cells proliferation and apoptosis via targeting vitamin D receptor.

Mol Cell Endocrinol. 2019 04 15;486:18-24

Authors: Kong F, Du C, Wang Y

MicroRNAs (miRNAs or miRs)-9 expression was reported to be upregulated in the follicular fluid of patients with polycystic ovary syndrome (PCOS). However, whether miR-9 affects ovarian dysfunction of PCOS and the related mechanisms are still unclear. Here we detected miR-9 and vitamin D receptor (VDR) expression in women with PCOS and controls, and investigated whether miR-9 affects ovarian granulosa cells (GCs) proliferation and apoptosis by targeting VDR. We found increased miR-9 and decreased VDR in the blood and isolated ovarian GCs of women with PCOS compared with the controls. MiR-9 promoted GCs proliferation and inhibited GCs apoptosis in vitro, and these effects were attenuated by its target VDR. High concentrations of insulin upregulated miR-9 expression in GCs. In conclusion this study firstly proved miR-9 affects ovarian GCs proliferation and apoptosis through targeting VDR. MiR-9 might be a potential molecular target for improving the dysfunction of GCs in PCOS.

PMID: 30794820 [PubMed - indexed for MEDLINE]

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Melanocortin 3 receptor gene polymorphism is associated with polycystic ovary syndrome in Turkish population.

Gynecol Endocrinol. 2019 Aug;35(8):685-690

Authors: Hepsen S, Cakal E, Karakose M, Eyerci N, Saat H, Beysel S, Oztekin S, Pinarli F, Parlak M

Polycystic ovary syndrome (PCOS) is a frequent complex disorder with an ill-defined etiology. Genetic factors seem rather effective at the occurrence of the disease, however, the evidence of established various studies results are unsatisfied. We aimed to make a contribution to the genetic baseline of the disease by investigating melanocortin 3 receptor gene polymorphism in affected patients. 101 PCOS patients and 162 age-matched healthy volunteered control subjects recruited to the study. PCOS patients classified according to their BMI class and insulin resistance situation. Anthropometric measurements, physical examination results, laboratory findings, and hormone levels were recorded for each participant and analysis of two SNPs on the MC3R gene; rs3746619 and rs3827103 were performed. Although no significant difference was observed in rs3827103 polymorphism between PCOS patients and controls; rs3746619 polymorphism was determined associated with PCOS in the heritage of dominant (AA + AC) and co-dominant (AA) genotypes. Two polymorphisms did not found related to obesity and insulin resistance in PCOS subgroups analysis. MC3R gene rs 3746619 polymorphism was found associated with PCOS in the Turkish population and may make a contribution to the genetic baseline of the disease.

PMID: 30784330 [PubMed - indexed for MEDLINE]

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Epigenetic association analysis of clinical sub-phenotypes in patients with polycystic ovary syndrome (PCOS).

Gynecol Endocrinol. 2019 Aug;35(8):691-694

Authors: Jacobsen VM, Li S, Wang A, Zhu D, Liu M, Thomassen M, Kruse T, Tan Q

Polycystic ovarian syndrome (PCOS) is a complex disorder affecting up to 15-20% of reproductive women. PCOS has recently been investigated using genome-wide association studies revealing important mutations and DNA methylation sites associated with the syndrome. As a clinically highly heterogenous condition, studying the molecular basis of the differential manifestation of PCOS is both meaningful concerning individualized management and important for understanding the biology of PCOS. Using genome-wide DNA methylation data collected from PCOS patients, we performed a powerful region-based analysis to detect differentially methylated regions (DMR) by correlating DNA methylation pattern in a genomic region with the level of each PCOS clinical sub-phenotype. We identified seven significant DMRs on chromosome 19 (12877188-12876846 bp) and chromosome 6 (MHC region) associated with prolactin level, as well as chromosomes 11 and 2 associated with metabolic attributes. Functional annotation linked significant DNA methylation patterns to functional genes (HOOK2, BDNFl, HLA-G, HLA-H, HLA-J, RNF39, etc) of metabolic disorders and immunity or novel associations to serve as targets for validation and replication.

PMID: 30782033 [PubMed - indexed for MEDLINE]

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Association study between variants in LHCGR DENND1A and THADA with preeclampsia risk in Han Chinese populations.

J Matern Fetal Neonatal Med. 2019 Nov;32(22):3801-3805

Authors: Zhang YJ, Li L, Wang ZJ, Zhang XJ, Zhao H, Zhao Y, Wang XT, Li CZ, Wan JP

Objective: To evaluate the association between preeclampsia and three single nucleotide polymorphisms (rs13405728 in LHCGR gene; rs13429458 in THADA gene, and rs2479106 in DENND1A gene) which were identified to be genetic variants of polycystic ovary syndrome (PCOS) by genome-wide association study in Han Chinese populations. Methods: A total of 784 northern Han Chinese women (378 controls and 406 cases) were genotyped for the three genetic variants by polymerase chain reaction and direct sequencing. Unconditional logistic regression analysis was used to adjust the impact of prepregnancy body mass index, primiparas, and maternal age. Results: No significant difference was found in the allele frequencies of the three genetic variants between cases and controls (p > .05), but genotype frequency of the SNP rs2479106 was significantly differ between cases and controls when analyzed under recessive models (p = .02). There was also a substantial difference in the genotype frequencies of the SNP rs13429458 between cases and controls under additive models (p = .01). Conclusions: Genetic variants of PCOS (rs13405728 in LHCGR gene; rs13429458 in THADA gene and rs2479106 in DENND1A gene) may not be involved in the development of preeclampsia in Han Chinese women.

PMID: 29727258 [PubMed - indexed for MEDLINE]

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