-
1.
Regulation of circulating CTRP-2/CTRP-9 and GDF-8/GDF-15 by intralipids and insulin in healthy control and polycystic ovary syndrome women following chronic exercise training.
Jerobin, J, Ramanjaneya, M, Bettahi, I, Parammal, R, Siveen, KS, Alkasem, M, Aye, M, Sathyapalan, T, Skarulis, M, Atkin, SL, et al
Lipids in health and disease. 2021;(1):34
Abstract
BACKGROUND Polycystic ovary syndrome (PCOS) is associated with obesity, diabetes, and insulin resistance. The circulating C1Q/TNF-related proteins (CTRP-2, CTRP-9) and growth differentiation factors (GDF-8, GDF-15) contribute to glucose and lipid homeostasis. The effects of intralipids and insulin infusion on CTRP-2, CTRP-9, GDF-8 and GDF-15 in PCOS and control subjects before and after chronic exercise training were examined. METHODS Ten PCOS and nine healthy subjects were studied at baseline status and after moderate-intensity chronic exercise training (1 h exercise, 3 times per week, 8 weeks). All participants were infused with 1.5 mL/min of saline or intralipids (20%) for 5 h, and during the last 2 h of saline or intralipids infusion hyperinsulinemic-euglycemic clamp (HIEC) was performed. CTRP-2, CTRP-9, GDF-8 and GDF-15 levels were measured at 0, 3 and 5 h. RESULTS Intralipids dramatically increased CTRP-2 levels in PCOS (P = 0.02) and control (P = 0.004) subjects, which was not affected by insulin infusion or by exercise. Intralipids alone had no effects on CTRP-9, GDF-8, or GDF-15. Insulin increased the levels of GDF-15 in control subjects (P = 0.05) during the saline study and in PCOS subjects (P = 0.04) during the intralipid infusion. Insulin suppressed CTRP9 levels during the intralipid study in both PCOS (P = 0.04) and control (P = 0.01) subjects. Exercise significantly reduced fasting GDF-8 levels in PCOS (P = 0.03) and control (P = 0.04) subjects; however, intralipids infusion after chronic exercise training increased GDF-8 levels in both PCOS (P = 0.003) and control (P = 0.05) subjects and insulin infusion during intralipid infusion reduced the rise of GDF-8 levels. CONCLUSION This study showed that exogenous lipids modulate CTRP-2, which might have a physiological role in lipid metabolism. Since chronic exercise training reduced fasting GDF-8 levels; GDF-8 might have a role in humoral adaptation to exercise. GDF-15 and CTRP-9 levels are responsive to insulin, and thus they may play a role in insulin responses.
-
2.
A multicenter clinical study with myo-inositol and alpha-lactalbumin in Mexican and Italian PCOS patients.
Hernandez Marin, I, Picconi, O, Laganà, AS, Costabile, L, Unfer, V
European review for medical and pharmacological sciences. 2021;(8):3316-3324
Abstract
OBJECTIVE This open-label non-randomized clinical study aimed at evaluating the effects of myo-inositol plus alpha-lactalbumin in two groups of PCOS women, treated in Mexico and Italy. Alpha-lactalbumin was used being effective in increasing myo-inositol intestinal absorption. This effect is very useful in greatly reducing the therapeutic failure of myo-inositol in some patients (inositol resistant subjects). PATIENTS AND METHODS The study involved 34 normal weight or overweight patients (14 in Mexico and 20 in Italy), aged 18 to 40 years, with anovulation and infertility > 1 year and insulin resistance diagnosed by HOMA-Index. Patients were administered orally with 2 g myo-inositol, 50 mg alpha-lactalbumin, and 200 µg of folic acid twice a day for 6 months. Controls were the same patients at t0 (baseline). The primary outcome was HOMA-index decrease after 3 and 6 months of treatment. Other parameters monitored were BMI, progesterone, LH, FSH, total testosterone, free testosterone, androstenedione, total cholesterol, HDL, LDL, triglycerides. RESULTS Recovery was general, and its relevance was higher when the starting point was further away from the normal range. The most important results were obtained with insulin, HOMA-index, LH, and androstenedione. No significant adverse effects were detected in both groups of patients. CONCLUSIONS This clinical trial demonstrated for the first time that myo-inositol and alpha-lactalbumin improve important parameters in PCOS patients characterized by different metabolic profiles.
-
3.
Effects of curcumin on body weight, glycemic control and serum lipids in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial.
Jamilian, M, Foroozanfard, F, Kavossian, E, Aghadavod, E, Shafabakhsh, R, Hoseini, A, Asemi, Z
Clinical nutrition ESPEN. 2020;:128-133
Abstract
OBJECTIVE The aim of this study was to evaluate the effect of curcumin on body weight, glycemic control and serum lipids in women suffering from polycystic ovary syndrome (PCOS). METHODS The current randomized, double-blinded, placebo-controlled clinical trial was performed on 60 subjects with PCOS, aged 18-40 years old. Subjects were randomly allocated to take 500 mg/day curcumin (n = 30) or placebo (n = 30) for 12 weeks. Glycemic control and serum lipids were measured at baseline and after the 12-week intervention. Using RT-PCR method, gene expression related to insulin and lipid metabolism was evaluated. RESULTS Curcumin significantly decreased weight (-0.8 ± 0.9 vs. -0.2 ± 0.8 kg, P = 0.03) and BMI (-0.3 ± 0.4 vs. -0.1 ± 0.3 kg/m2, P = 0.03). Curcumin, compared with the placebo, significantly reduced fasting glucose (β -2.63 mg/dL; 95% CI, -4.21, -1.05; P = 0.002), serum insulin (β -1.16 μIU/mL; 95% CI, -2.12, -0.19; P = 0.02), insulin resistance (β -0.26; 95% CI, -0.48, -0.03; P = 0.02), and significantly increased insulin sensitivity (β 0.006; 95% CI, 0.001, 0.01; P = 0.02). In addition, taking curcumin was associated with a significant reduction in total cholesterol (β -15.86 mg/dL; 95% CI, -24.48, -7.24; P = 0.001), LDL-cholesterol (β -16.09 mg/dL; 95% CI, -25.11, -7.06; P = 0.001) and total-/HDL-cholesterol ratio (β -0.62; 95% CI, -0.93, -0.30; P < 0.001), and a significant increase in HDL-cholesterol levels (β 2.14 mg/dL; 95% CI, 0.36, 3.92; P = 0.01) compared with the placebo. Additionally, curcumin administration up-regulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.03) and low-density lipoprotein receptor (LDLR) (P < 0.001) compared with the placebo. CONCLUSIONS Overall, curcumin administration for 12 weeks to women with PCOS had beneficial effects on body weight, glycemic control, serum lipids except triglycerides and VLDL-cholesterol levels, and gene expression of PPAR-γ and LDLR. Registered under Clinical Trials.gov Identifier no. http://www.irct.ir: IRCT20170513033941N50.
-
4.
Status of Serum Copper, Magnesium, and Total Antioxidant Capacity in Patients with Polycystic Ovary Syndrome.
Kanafchian, M, Esmaeilzadeh, S, Mahjoub, S, Rahsepar, M, Ghasemi, M
Biological trace element research. 2020;(1):111-117
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.
-
5.
The effect of myoinositol on ovarian blood flows in women with polycystic ovary syndrome.
Özay, AC, Emekçi Özay, Ö, Okyay, RE, Gülekli, B
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019;(3):237-241
Abstract
To evaluate whether 4 gram myoinositol and 400 mcg folic acid(MYO) therapy has any effects on ovarian stromal blood flow by using pulsed and color Doppler at 3 months follow-up period in polycystic ovary syndrome (PCOS). One-hundred eighty patients were designed into six groups; Group 1: PCOS patients that received OCP containing 30 mcg ethinyl estradiol (EE) plus 3 mg drospirenone (DRP); Group 2: PCOS patients that received MYO; Group 3: PCOS patients that received no medication. Group 4: Healthy patients that received OCP; Group 5: Healthy patients that received MYO; Group 6: Healthy patients that received no medication. Resistance index (RI) and pulsatility index (PI) of both ovaries were assessed. There was a significant increase in RI and PI of both ovarian stromal blood flow women with PCOS who received OCP (Group 1, p < .001) and MYO (Group 2, p < .001). The rate of increment in both RI and PI values were similar for OCP users (Group 1) and MYO users(Group2) in PCOS patients. MYO therapy reduced ovarian vascularization in both PCOS and healthy users after 3 months and this decrease is especially noticeable in women with PCOS compared to healthy women. OCP therapy also reduced ovarian vascularization just like MYO therapy.
-
6.
Assessing ICSI outcome by combining non-invasive indicators: Early time-lapse morphokinetics and apoptosis in associated cumulus cells among women with the polycystic ovarian syndrome.
Tabibnejad, N, Aflatoonian, A, Motamedzadeh, L, Soleimani, M, Sadeghian-Nodoushan, F, Talebi, AR
Molecular reproduction and development. 2018;(11):865-874
Abstract
Cumulus cells features and embryo developmental events can be considered as noninvasive indicators for embryo selection and clinical outcomes. A combination of time-lapse morphokinetic parameters and cumulus cell apoptosis in women with polycystic ovarian syndrome (PCOS) was evaluated for predicting pregnancy outcome. We assessed a total of 547 embryos from 100 intracytoplasmic sperm injection (ICSI) cycles. Time-lapse records were interpreted in time to pronuclear fading (tPNf), time to 2 to 8 cells (t2-t8), direct cleavage, reverse cleavage, and also for the presence of multinucleation. Percentages of apoptosis were identified in 100 associated cumulus cell samples using the TDT-mediated dUTP-biotin nick end-labeling assay. The significant decrease of apoptotic cumulus cells was detected in patients with chemical and clinical pregnancies as well as live birth among patients PCOS and in the tubal infertility group (p > 0.05). Furthermore, significantly higher implantation rate and also significantly lower cases of early pregnancy loss were observed in the group of oocytes with less apoptotic cumulus cells. Multivariate logistic regression analysis showed that tPNf together with cumulus cell apoptosis were independent prognostic factors of chemical pregnancy, clinical pregnancy rate, and live birth. Time-lapse embryo parameters may not reflect the cumulus cell apoptosis rate. However, the rate of apoptotic cumulus cells is significantly associated with ICSI outcome using Day 3 embryo transfer.
-
7.
Could myo-inositol soft gel capsules outperform clomiphene in inducing ovulation? Results of a pilot study.
Rolland, AL, Peigné, M, Plouvier, P, Dumont, A, Catteau-Jonard, S, Dewailly, D
European review for medical and pharmacological sciences. 2017;(2 Suppl):10-14
Abstract
OBJECTIVE Insulin resistance is known to worsen polycystic ovarian syndrome (PCOS). The management of insulin resistance is crucial in the treatment of PCOS and insulin-sensitizing molecule as myo-inositol (MYO) seems to have promising effects. The aim of our pilot study was to study whether supplementation with MYO can improve patients' sensitivity to clomiphene citrate (CC) in terms of ovulation and pregnancy rates. PATIENTS AND METHODS This study included 26 patients with PCOS, eligible to ovulation induction with CC. All of them received MYO in combination with CC and folic acid, following the usual protocol. Results concerning ovulation and pregnancy rates were compared to those from our historical cohort of PCOS patients treated with CC alone. RESULTS Ovulation rate was significantly higher with MYO+CC than with CC alone (65.5% vs. 42%, p=0.0001). The number of patients sensitive to 50 mg/d was 54% with MYO vs. 40% in our reference cohort (NS). The total resistance rate was 19% vs. 27% in the reference cohort (NS). Cumulative pregnancy rate with MYO+CC was 53.8% vs. 42.2% with CC alone (NS). Pregnancy rates per initiated cycle were 16.1% with MYO vs. 12.6% in the historical cohort (NS). DISCUSSION Although the differences were not significant for most outcomes, probably due to the small number of patients, our pilot study seemed to show a benefit of supplementation with MYO during ovulation induction with CC in PCOS patients. CONCLUSIONS This study proves the great interest of a RCT and re-opens the possibilities of insulin-sensitizing agents in the treatment of anovulatory patients with PCOS, such as natural products like MYO.
-
8.
Basic and Meal Stimulated Plasma GIP Levels are Higher in Lean PCOS Women with FAI over 5.
Milewicz, T, Migacz, K, Kiałka, M, Rogatko, I, Kowalczuk, A, Spalkowska, M, Mrozińska, S, Czajkowska, Z, Sztefko, K
Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2016;(2):77-81
Abstract
OBJECTIVE Glucose dependent insulinotropic peptide (GIP) belongs to the incretins which are responsible for 70% of the insulin release after oral glucose intake. Its impaired secretion was noted in several conditions involving insulin resistance, including polycystic ovary syndrome (PCOS), known as the state with increased testosterone level. This paper considers a possible relationship between the free androgen index (FAI) and basal as well as meal stimulated level of GIP in lean women affected by PCOS. To our knowledge, no previous study has evaluated the matter so far. DESIGN cross-sectional study METHODS 50 age-matched lean women (BMI=20.76±1.83) were enrolled to the study and divided into 2 groups. Patients with phenotype with FAI<5 were classified as group 1, PCOS patients with FAI>5 formed group 2. All subjects underwent standard meal test. Serum GIP concentration was determined both at fasting and at 60 min of the test. Calculations were carried out using Statistica 10. RESULTS Mann-Whitney test indicated a statistically significant difference in medians values of GIP plasma levels between groups on fasting (36.4 pg/ml vs. 59.6 pg/ml; p=0.0007) and at 60 min after meal test (50.1 pg/ml vs. 72.5 pg/ml; p=0.006). Spearman test indicated significant positive correlation between FAI and GIP levels at 0' and 60' in total study population (0':R=0.37;p=0.008; 60':R=0.28; p=0.049). CONCLUSION Excess androgen activity might be a factor contributing to alter secretion of incretins in lean PCOS women. However it could not be ruled out that it is also possible that increased GIP levels might induce hyperandrogenemia in PCOS. An increased GIP levels may induce hyperinsulinemia and play an additive to insulin resistance role in progression to diabetes mellitus type 2 (DMT2).
-
9.
Roles of circulating WNT-signaling proteins and WNT-inhibitors in human adiposity, insulin resistance, insulin secretion, and inflammation.
Almario, RU, Karakas, SE
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2015;(2):152-7
Abstract
Wingless-type MMTV integration site family member (WNT) signaling and WNT-inhibitors have been implicated in regulation of adipogenesis, insulin resistance, pancreatic function, and inflammation. Our goal was to determine serum proteins involved in WNT signaling (WNT5 and WISP2) and WNT inhibition (SFRP4 and SFRP5) as they relate to obesity, serum adipokines, insulin resistance, insulin secretion, and inflammation in humans. Study population comprised 57 insulin resistant women with polycystic ovary syndrome (PCOS) and 27 reference women. In a cross-sectional study, blood samples were obtained at fasting, during oral, and frequently sampled intravenous glucose tolerance tests. Serum WNT5, WISP2, and SFRP4 concentrations did not differ between PCOS vs. reference women. Serum WNT5 correlated inversely with weight both in PCOS and reference women, and correlated directly with insulin response during oral glucose tolerance test in PCOS women. Serum WISP2 correlated directly with fatty acid binding protein 4. Serum SFRP5 did not differ between obese (n=32) vs. nonobese (n=25) PCOS women, but reference women had lower SFRP5 (p<5×10(-6) as compared to both PCOS groups). Serum SFRP5 correlated inversely with IL-1β, TNF-α, cholesterol, and apoprotein B. These findings demonstrated that WNT5 correlated inversely with adiposity and directly with insulin response, and the WNT-inhibitor SFRP5 may be anti-inflammatory. Better understanding of the role of WNT signaling in obesity, insulin resistance, insulin secretion, lipoprotein metabolism, and inflammation is important for prevention and treatment of metabolic syndrome, diabetes and cardiovascular disease.
-
10.
Quantitative methylation level of the EPHX1 promoter in peripheral blood DNA is associated with polycystic ovary syndrome.
Sang, Q, Li, X, Wang, H, Wang, H, Zhang, S, Feng, R, Xu, Y, Li, Q, Zhao, X, Xing, Q, et al
PloS one. 2014;(2):e88013
Abstract
Steroid synthesis and metabolic pathways play important roles in the pathophysiology of PCOS, but until now there have been no studies on the methylation profiles of specific genes in steroid synthesis pathways that are known to be associated with PCOS. Here we used MassARRAY quantitative methylation analysis to determine the methylation levels of each CpG site or cluster in the promoters of EPHX1, SRD5A1, and CYP11A1 in 64 peripheral blood samples. We further examined the methylation level of EPHX1 in an independent cohort consisting of 116 people. Finally, we investigated the role of EPHX1 in steroidogenesis in the KGN cell line. For SRD5A1 and CYP11A1, there was no significant difference in methylation level between patients and controls. For EPHX1, however, the methylation levels of a few consecutive CpG sites and clusters were found to be significantly associated with PCOS. The methylation levels of a number of CpG clusters or sites were significantly lower in patients than in controls in the first cohort consisting of 64 people, such as clusters 13-14 (P<0.05), 15-16 (P<0.001), and 19-24 (P<0.001) and sites CpG_53 (P<0.01) and CpG_54 (P<0.05). Among differentiated methylation sites and clusters, the methylation levels of the CpG cluster 13-14 and CpG cluster 19-24 in PCOS patients were significantly lower than in controls in the second cohort of 116 people (P<0.05 for both). In addition, knockdown and overexpression experiments in KGN cells showed that EPHX1 can regulate estradiol concentrations, and this indicates a role for EPHX1 in steroidogenesis. Our study has demonstrated that methylation of the EPHX1 promoter might be associated with PCOS. This study provides direct evidence that methylation plays an important role in PCOS and demonstrates a novel role for EPHX1 in female reproduction.