Research

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]

https://www.tandfonline.com/doi/abs/10.1080/09513590.2019.1576616?journalCode=igye20

https://www.ncbi.nlm.nih.gov/pubmed/30806529?dopt=Abstract [Read more…] about Potential roles of carnitine in patients with polycystic ovary syndrome: a systematic review

https://link.springer.com/article/10.1007%2Fs11154-019-09482-3

https://www.ncbi.nlm.nih.gov/pubmed/30798426?dopt=Abstract

Differential activity of the corticosteroidogenic enzymes in normal cycling women and women with polycystic ovary syndrome.

Rev Endocr Metab Disord. 2019 Feb 23;:

Authors: Yamamoto MMW, de Medeiros SF

Abstract

The phenotypic complex of patients with definitive diagnosis of polycystic ovary syndrome may include patients with normal and high serum androgen levels. Patients with hyperandrogenemia seem to present higher risk of changes to the glucose and lipid metabolism and, eventually, of earlier development of cardiovascular diseases than normoandrogenemic patients or healthy women. From a laboratory and clinical point of view, it is important to check androgen levels in patients with polycystic ovary syndrome. The identification of partial insufficiency of a given corticosteroidogenic enzyme is also relevant to understand the physiopathology of androgen increase in polycystic ovary syndrome. Therefore, the present review analyzes the functions of the different enzymes involved in the ovary and adrenal steroidogenesis in normal cycling women and in patients with polycystic ovary syndrome. In addition, it emphasizes appropriate reason for investigating eventual enzyme deficiency to provide rationale for prescription and follow-up of women with polycystic ovary syndrome.

PMID: 30798426 [PubMed – as supplied by publisher]

AMH signaling cascade plays an important role in PCOS etiology.

https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/jc.2018-02178/5342940?redirectedFrom=fulltext

https://www.ncbi.nlm.nih.gov/pubmed/30786001?dopt=Abstract

Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women with Polycystic Ovary Syndrome.

J Clin Endocrinol Metab. 2019 Feb 20;:

Authors: Gorsic LK, Dapas M, Legro RS, Hayes MG, Urbanek M

Abstract

CONTEXT: PCOS is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH.

OBJECTIVE: To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS.

PARTICIPANTS/METHODS: Targeted re-sequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2 was performed on 608 PCOS-affected women and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function.

RESULTS: We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (p=2.3 x 10-5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (p<1×10-9).

CONCLUSIONS: AMH signaling cascade plays an important role in PCOS etiology.

PMID: 30786001 [PubMed – as supplied by publisher]

https://www.ncbi.nlm.nih.gov/pubmed/30672430?dopt=Abstract

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Patatin-like phospholipase domain containing 3-gene (adiponutrin), preptin, kisspeptin and amylin regulates oocyte developmental capacity in PCOS.

Cell Mol Biol (Noisy-le-grand). 2018 Dec 31;64(15):7-12

Authors: Celik N, Aydin S, Ugur K, Yardim M, Acet M, Yavuzkir S, Sahin İ, Celik O

Abstract

This study was planned to test whether follicular fluid (FF) levels of patatin-like phospholipase domain containing 3-gene (PNPLA3:adiponutrin), preptin, kisspeptin, and amylin change in polycystic ovarian syndrome (PCOS). A total of 40 infertile volunteers undergoing IVF/ICSI were included in the study. They were divided into two groups as PCOS (n=20) and control group without PCOS (n=20). The controls were recruited from subjects with a poor ovarian response. The PCOS and control participants were matched according to their body mass index (BMI). Each group of participants underwent ovarian stimulation with GnRH antagonist protocol. Blood and FF samples of one dominant follicle were obtained from each subject during the oocyte pick-up. FF and serum levels of PNPLA3, preptin, kisspeptin and amylin were measured through ELISA. Amylin and adiponutrin median values were not different according to study groups (p>0.05). FF-preptin median values in the control group were similar to the serum preptin values of control and PCOS groups (Z=0.970, p=1.000 and Z=2.631, p=0.051, respectively). Medians of the serum preptin in control and PCOS groups were the same (Z=1.649; p=0.595). FF-preptin median values of PCOS group were significantly lower than the preptin median values of the control group. Serum preptin levels were positively correlated with HOMA-IR, but not with pregnancy rates and the number of retrieved oocytes. Serum kisspeptin levels were negatively correlated with the number of retrieved oocytes and pregnancy rates. While amylin and adiponutrin have no role in the folliculogenesis, kisspeptin and preptin work together for regulating follicle developmental capacity in PCOS.

PMID: 30672430 [PubMed – indexed for MEDLINE]

Abnormal expression of PPARγ mRNA in ovarian granulosa cells may be related to the mechanism of PCOS.

https://www.ncbi.nlm.nih.gov/pubmed/30783446?dopt=Abstract

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Effect of testosterone on the expression of PPARγ mRNA in PCOS patients.

Exp Ther Med. 2019 Mar;17(3):1761-1765

Authors: Cao J, Maowulieti G, Yu T

Abstract

Expression of peroxisome proliferator-activated receptor γ (PPARγ) mRNA in ovarian granulosa cells of patients with polycystic ovary syndrome (PCOS) were explored. Ovarian granulosa cells were extracted from 5 patients with PCOS and 30 normal controls. Expression of PPARγ mRNA in granulosa cells of the 5 PCOS patients (observation group) and 5 normal controls (control group) was detected by RT-qPCR. The remaining 25 cases of normal human ovarian granulosa cells were cultured in vitro for 48 h, followed by cell culture for another 24 h with different concentrations of testosterone, insulin (INS), and rosiglitazone (RGZ). After that, expression of PPARγ mRNA was detected by RT-qPCR. Relative expression level of PPARγ mRNA in the observation group was significantly lower than that in the control group. Compared with testosterone concentration at 10-2 mol/ml, testosterone concentration at 10-3 mol/ml significantly reduced the expression level of PPARγ mRNA. When the INS concentration was 10-5 mol/ml, relative expression level of PPARγ mRNA was significantly higher than that of the control group (P<0.01). Relative expression level of PPARγ mRNA was significantly higher than that of the control group when INS concentration was 10-4 mol/ml. When the concentration of RGZ was 10-4 mol/ml, the relative expression level of PPARγ mRNA was significantly higher than that of the control group (P<0.01). When concentration of RGZ was 10-3 mol/ml, expression level of PPARγ mRNA was significantly increased comparing to that under a RGZ concentration of 10-4 mol/ml or that of the control group (P<0.01). Appropriate concentrations of testosterone can inhibit the expression of PPARγ mRNA in ovarian granulosa cells, and certain concentrations of INS and RGZ can induce the expression of PPARγ mRNA in ovarian granulosa cells. Abnormal expression of PPARγ mRNA in ovarian granulosa cells may be related to the mechanism of PCOS.

PMID: 30783446 [PubMed]

https://www.sciencedirect.com/science/article/pii/S2225411018300154?via%3Dihub

https://www.ncbi.nlm.nih.gov/pubmed/31453130?dopt=Abstract

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Effect of Vitex negundo L. seeds in letrozole induced polycystic ovarian syndrome.

J Tradit Complement Med. 2019 Oct;9(4):336-345

Authors: Kakadia N, Patel P, Deshpande S, Shah G

Abstract

The clinical management of PCOS is multifaceted but often unsatisfactory. The aim of the current study is to evaluate the effect of Vitex negundo L. in the letrozole-induced polycystic ovarian syndrome. Female Sprague-Dawley rats were divided into six groups, each containing 6 animals. Group I (Control) daily received 1% carboxymethylcellulose (CMC) suspension as a vehicle control. Letrozole (1 mg/kg) was administered per orally (p.o) for a period of 21 days for the induction of PCOS in Group II to VI. PCOS induced animals were treated with aqueous (Group III – 200 mg/kg and IV- 400 mg/kg) and hydroalcoholic extract (Group V- 200 mg/kg and VI- 400 mg/kg) of Vitex negundo up to 66 days using 0.5% w/v CMC as the vehicle. Body weight and estrous cycle phase were measured every day. Blood samples were collected on 0, 21 and 66 days for the measurement of fasting blood glucose, lipid profile, LH, FSH and hormonal level. Oral glucose tolerance test was performed to study insulin resistance effect. Toxicity markers; SGOT, SGPT, and creatinine also measured at the end of the study. The administration of Letrozole led to an abnormality in serum sex steroid profile, lipid profile, glucose and estrous cycle. It was able to successfully exert its protective effect by restoring parameters to the normal level and disappearance of cysts in ovaries. This can be attributed to phyto-components present in the extract. The aqueous and hydro-alcoholic extracts of seeds of Vitex negundo showed significant amelioration of Letrozole induced PCOS.

PMID: 31453130 [PubMed]