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BACKGROUNDKisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders.METHODSWe conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP1) and Ca2+ signaling in cell lines and on action potential firing of GnRH neurons in brain slices.RESULTSIn healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP1 accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012).CONCLUSIONTaken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders.TRIAL REGISTRATIONInternational Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316.FUNDINGNational Institute for Health Research and NIH.

Objective The aim of this study was to determine the effect of vitamin D and probiotic co-administration on mental health, hormonal, inflammatory and oxidative stress parameters in women with polycystic ovary syndrome (PCOS). Methods This randomized, double-blinded, placebo-controlled clinical trial was carried out on 60 subjects, aged 18–40 years old. Subjects were randomly allocated to take either 50,000 IU vitamin D every 2 weeks plus 8 × 10 9  CFU/day probiotic ( n  = 30) or placebo (n = 30) for 12 weeks. Results Vitamin D and probiotic co-supplementation, compared with the placebo, significantly improved beck depression inventory [β (difference in the mean of outcomes measures between treatment groups) − 0.58; 95% CI, − 1.15, − 0.02; P  = 0.04], general health questionnaire scores (β − 0.93; 95% CI, − 1.78, − 0.08; P  = 0.03) and depression, anxiety and stress scale scores (β − 0.90; 95% CI, − 1.67, − 0.13; P  = 0.02). Vitamin D and probiotic co-supplementation was associated with a significant reduction in total testosterone (β − 0.19 ng/mL; 95% CI, − 0.28, − 0.10; P  < 0.001), hirsutism (β − 0.95; 95% CI, − 1.39, − 0.51; P < 0.001), high-sensitivity C-reactive protein (hs-CRP) (β − 0.67 mg/L; 95% CI, − 0.97, − 0.38; P  < 0.001) and malondialdehyde (MDA) levels (β − 0.25 μmol/L; 95% CI, − 0.40, − 0.10; P  = 0.001), and a significant increase in total antioxidant capacity (TAC) (β 82.81 mmol/L; 95% CI, 42.86, 122.75; P < 0.001) and total glutathione (GSH) levels (β 40.42 μmol/L; 95% CI, 4.69, 76.19; P  = 0.02), compared with the placebo. Conclusions Overall, the co-administration of vitamin D and probiotic for 12 weeks to women with PCOS had beneficial effects on mental health parameters, serum total testosterone, hirsutism, hs-CRP, plasma TAC, GSH and MDA levels. Trial Registration This study was retrospectively registered in the Iranian website ( www.irct.ir ) for registration of clinical trials ( IRCT20170513033941N37 ).

IntroductionPolycystic ovary syndrome (PCOS) is one of the most common abnormalities in women of reproductive age that can lead to a variety of metabolic and reproductive disorders. Studies reveal that a healthy diet is the most effective way for treating the risk factors associated with metabolic disorders and place greater emphasis on the consumption of prebiotic foods. The present study aims to determine the effect of resistant Dextrin on metabolic parameters, including lipid profile, fasting blood glucose (FBS) and high sensitivity C-reactive protein (hsCRP), and androgen levels, including serum levels of dehydroepiandrosterone sulfate (DHEA-S) and free testosterone, as the primary outcomes, and manifestations of PCOS including menstrual cycle irregularity and hirsutism, as the secondary outcomes.MethodsThis randomized, controlled, triple-blind, clinical trial was conducted on 62 women aged 18–45 in Tabriz, Iran, in 2016–2017. The participants were divided into a prebiotic group and a placebo group using block randomization. The prebiotic group consumed 20 g of resistant dextrin dissolved in a glass of water and the placebo group 20 g of maltodextrin also dissolved in a glass of water on a daily basis for 3 months. To measure the serum lipid profile, FBS, hsCRP, DHEA-S and free testosterone before and 3 months after the intervention, 5-ml blood samples were collected from the participants and analyzed using the ELISA method. The Ferriman–Gallwey scale for assessing hirsutism and a checklist for assessing menstrual cycle characteristics were completed before and 3 months after the intervention. A general linear model was used to analyze the data.ResultsNo statistically significant differences were observed between the two groups in terms of sociodemographic characteristics and baseline values. 3 months after the intervention, based on the ANCOVA and after adjusting for the baseline values, the mean serum levels of LDL-C (adjusted mean difference = − 29.79; 95% CI = − 43.37 to − 16.21; P < 0.001), triglyceride (AMD = − 38.50; 95% CI = − 59.73 to − 17.28; P = 0.001), total cholesterol (AMD = − 29.98; 95% CI = − 40.14 to − 19.82; P < 0.001), FBS (AMD = − 11.24; 95% CI = − 15.43 to − 7.06; P < 0.001), hsCRP (AMD = − 1.75; 95% CI = − 2.92 to − 0.57; P = 0.004), DHEA-S (AMD = − 0.7; 95% CI = − 1.34 to − 0.13; P = 0.017) and free testosterone (AMD = − 0.32; 95% CI = − 0.56 to − 0.08; P = 0.010) revealed a statistically significant decrease in the intervention group compared to the placebo group, while the mean serum HDL-C showed a statistically significant increase in this group compared to the placebo group (AMD = 5.82; 95% CI = 2.27–9.37; P = 0.002). 3 months after the intervention, there was a significant difference between the two groups in terms of menstrual cycle intervals and hirsutism (P < 0.001).ConclusionResistant dextrin consumption can regulate metabolic parameters and androgen levels and manifestations including hirsutism and menstrual cycle irregularity in women with PCOS.

Abstract Context The impact of vitamin D deficiency on the success of ovarian stimulation according to underlying infertility diagnosis has not been investigated. Objective To evaluate the relationship between vitamin D deficiency and reproductive outcomes after ovarian stimulation in women with either polycystic ovary syndrome (PCOS) or unexplained infertility. Design Retrospective cohort study. Setting Analysis of randomized controlled trial (RCT) data. Participants Participants from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) RCT (n = 607); participants from the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) RCT of unexplained infertility (n = 647). Interventions Serum 25(OH)D levels measured in banked sera. Main Outcome Measures Primary: live birth; secondary: ovulation (PPCOS II), pregnancy, and early pregnancy loss. Results In PPCOS II, subjects with vitamin D deficiency [25(OH)D < 20 ng/mL or 50 nmol/L] were less likely to ovulate (adjusted OR, 0.82; 95% CI, 0.68 to 0.99; P = 0.04) and experienced a 40% lower chance of live birth (adjusted OR, 0.63; 95% CI, 0.41 to 0.98; P = 0.04) than those not deficient. In AMIGOS, no significant association between vitamin D deficiency and live birth was noted. In pregnant subjects from both studies, vitamin D deficiency was associated with elevated risk of early pregnancy loss (OR, 1.6; 95% CI, 1.0 to 2.6; P = 0.05). Conclusions In this investigation of women pursuing ovarian stimulation, the association between vitamin D deficiency and diminished live birth relied on carrying the diagnosis of PCOS and was not observed in unexplained infertility. Given the generally modest success of ovarian stimulation, addressing vitamin D deficiency may prove an important treatment adjunct for many infertile women. In women with infertility undergoing ovarian stimulation, pretreatment vitamin D deficiency is associated with diminished live birth rates in those with PCOS but not those with unexplained infertility.

Background/Objectives: Vitamin D deficiency is common in women with polycystic ovary syndrome (PCOS) and may be associated with metabolic and endocrine disorders as well as ovulatory dysfunction. Vitamin D supplementation may improve ovarian dysfunction and follicular development by effecting gene expression. The aim of the present study was to investigate the effects of vitamin D supplementation in women with PCOS through a prospective, randomized, two-phase, parallel design, placebo-controlled trial. Methods: We assessed the impact on ovarian morphology, cycle length, and ovulatory dysfunction. Transvaginal ultrasonography (TVUS) examinations and clinical laboratory assessments were conducted at the baseline, and again after 12 and 24 weeks. The participants received vitamin D (30,000 IU/week) or a placebo (without concurrent metformin use) for 12 weeks, supplemented with calcium, followed by an additional 12 weeks of vitamin D treatment. Results: The treatment resulted in improvements in ovarian morphology and regularity of menstrual cycles in more than half of the patients. Additionally, vitamin D3 was associated with a significant increase in the ovulation rate. A statistically significant reduction in mean testosterone levels was observed in the subgroup of patients with an LH/FSH ratio greater than 2. Conclusions: Our results suggest that vitamin D3 treatment could function as either a standalone or an adjunctive therapy in the management of PCOS.

Abstract Context Large, longitudinal studies on androgen levels in pregnant women with polycystic ovary syndrome (PCOS) are lacking. While metformin has a mild androgen-lowering effect in non-pregnant women with PCOS, its effects on maternal androgen levels in pregnancy are less well understood. Objective To describe androgen patterns in pregnant women with PCOS and in healthy control women, and to explore the potential effects of metformin on maternal androgen levels in PCOS. Design and Setting A post hoc analysis from a randomized, placebo-controlled, multicenter study carried out at 11 secondary care centers and a longitudinal single-center study on healthy pregnant women in Norway. Participants A total of 262 women with PCOS and 119 controls. Intervention The participants with PCOS were randomly assigned to metformin (2 g daily) or placebo, from first trimester to delivery. Main Outcome Measures Androstenedione (A4), testosterone (T), sex-hormone binding globulin (SHBG), and free testosterone index (FTI) at 4 time points in pregnancy. Results Women with PCOS versus healthy controls had higher A4, T, and FTI, and lower SHBG at all measured time points in pregnancy. In the overall cohort of women with PCOS, metformin had no effect on A4, T, SHBG, and FTI. In subgroup analyses, metformin reduced A4 (P = 0.019) in nonobese women. Metformin also reduced A4 (P = 0.036), T (P = 0.023), and SHBG (P = 0.010) levels through pregnancy in mothers with a male fetus. Conclusion Metformin had no effect on maternal androgens in PCOS pregnancies. In subgroup analyses, a modest androgen-lowering effect was observed in nonobese women with PCOS. In PCOS women carrying a male fetus, metformin exhibited an androgen-lowering effect.

Background Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied with an increased risk of developing type 2 diabetes mellitus and cardiovascular disease; despite being a common condition, the pathogenesis of PCOS remains unclear. Our aim was to investigate the potential metabolic profiles for different phenotypes of PCOS, as well as for the early prognosis of complications. Methods A total of 217 women with PCOS and 48 healthy women as normal controls were studied. Plasma samples of subjects were tested using two different analytical platforms of metabolomics: 1 H nuclear magnetic resonance (NMR) and gas chromatography/time-of-flight mass spectrometry (GC/TOF-MS). Results Our results showed that carbohydrate, lipid and amino acid metabolisms were influenced in PCOS. The levels of lactate, long-chain fatty acids, triglyceride and very low-density lipoprotein were elevated, while glucose, phosphatidylcholine and high-density lipoprotein (HDL) concentrations were reduced in PCOS patients as compared with controls. Additionally, the levels of alanine, valine, serine, threonine, ornithine, phenylalanine, tyrosine and tryptophan were generally increased, whereas the levels of glycine and proline were significantly reduced in PCOS samples compared to controls. Furthermore, the ratio of branched-chain amino acid to aromatic amino acid concentrations (BCAA/AAA) in PCOS plasma was significantly reduced in PCOS patients and was insusceptible to obesity and insulin sensitivity. Conclusions Our results suggested that the enhanced glycolysis and inhibited tricarboxylic acid cycle (TAC) in women with PCOS. Decrease of BCAA/AAA ratio was directly correlated with the development of PCOS. Ovulatory dysfunction of PCOS patients was associated with raised production of serine, threonine, phenylalanine, tyrosine and ornithine. Elevated levels of valine and leucine, and decreased concentrations of glycine in PCOS plasma could contribute to insulin sensitivity and could be considered as the potential biomarkers for long-term risk assessment of diabetes mellitus.

Purpose To determine whether long-term administration of synbiotics affects clinical, endocrine and metabolic aspects of polycystic ovary syndrome (PCOS) in overweight and obese subjects undergoing intensive lifestyle modifications. Methods During six-month trial, all subjects underwent intensive lifestyle modifications (diet and exercise). The subjects were randomized (1:1) to receive synbiotic supplementation (Synbiotic Group) or placebo (Placebo Group). Results Subjects in the Placebo Group and the Synbiotic Group experienced significant reduction of BMI (− 8% and − 11%, respectively; both at P  < 0.0001) and body fat percentage (− 11% and − 14%, respectively; both at P  < 0.0001). These effects were statistically comparable for both groups. Total testosterone was not significantly changed in the Placebo Group (− 5%, P  = 0.41) while it greatly declined in the Synbiotic Group (− 40%; P  < 0.0001); the difference between these groups was significant ( P  = 0.0002). Synbiotic supplementation was superior to placebo in reducing LH (− 21%; P  = 0.047), total cholesterol (− 6%; P  = 0.002), low-density lipoprotein cholesterol (− 6%; P  = 0.044), triglycerides (− 29%; P  = 0.049), LPS (− 23%; P  = 0.001) and LPS-binding protein (− 21%; P  = 0.001). Conclusions Synbiotic supplementation led to a marked improvement of several key clinical and laboratory aspects of PCOS including an improvement of hyperandrogenism, lipid profile, and markers of endotoxemia. Trial registration Clinical Trial Registration Number: NCT03325023 (URL, clinicaltrials.gov; date of registration 10/26/2017).

To evaluate the effects of a low-carbohydrate diet associated with strength training on the clinical signs of polycystic ovary syndrome (PCOS). A randomized clinical trial was carried out including 29 women over 18 years old diagnosed with PCOS, randomized into two groups, with follow-up for 12 weeks: the low-carbohydrate diet group associated with strength exercise (LCDE); and the standard diet group associated with strength exercise (SDE). We evaluated manifestations of acne, hirsutism by the Ferriman–Gallwey scale and alopecia by the Ludwig–Savin scale, and assessed laboratory tests for total and free testosterone, dehydroepiandrosterone, follicle-stimulating hormone, and luteinizing hormone. The collected data were analyzed using IBM-SPSS software version 21. The study showed statistically significant differences in the hormonal levels of dehydroepiandrosterone (P = 0.045), luteinizing hormone (P = 0.017) and follicle-stimulating hormone (P = 0.014) when comparing the LCDE and SDE groups. the intervention used can promote an improvement in the clinical presentation of PCOS, especially in hormonal parameters. The clinical trial was registered on the REBEC platform (Brazilian Registry of Clinical Trials) under number RBR4wjqxcv (Carbohydrate Reduction and Exercise in Women with PCOS) and is available on the website: https://ensaiosclinicos.gov.br/rg/RBR-4wjqxcv. •Low-carbohydrate diet associated with exercise improves DHEA, LH, and FSH in PCOS.•The hormonal improvement corroborates to a better clinical picture of PCOS.•Dietary management and exercise can be adjuvants in the treatment of PCOS.

Polycystic ovarian syndrome (PCOS) is related to pro‐apoptotic and pro‐inflammatory conditions generated by Endoplasmic reticulum (ER) stress. This study aimed to determine the effect of Astaxanthin (ASX), as carotenoid with potent antioxidant and anti‐inflammatory properties, on serum inflammatory markers, apoptotic factors and ER stress‐apoptotic genes in peripheral blood mononuclear cells (PBMCs) of women with PCOS. This randomized, double‐blind clinical trial included 56 PCOS patients aged 18–40. For 8 weeks, subjects were randomly assigned to one of two groups: either 12 mg ASX (n = 28) or placebo (n = 28). Real‐time PCR was used to quantify gene expression associated with ER stress‐apoptosis in PCOS women's PBMCs. The levels of TNF‐α, IL18, IL6 and CRP were determined by obtaining blood samples from all patients before and after the intervention using Enzyme‐linked immunosorbent assay (ELISA). Also, the levels of active caspase‐3 and caspase‐8 were detected in the PBMC by ELISA kit. Furthermore, we evaluated the efficacy of ASX on disease symptoms. Following the 8‐week intervention, ASX supplementation was able to reduce the expression of GRP78 (p = 0.051), CHOP (p = 0.008), XBP1 (p = 0.002), ATF4 (0.038), ATF6 (0.157) and DR5 (0.016) when compared to the placebo. However, this decrease was not statistically significant for ATF6 (p = 0.067) and marginally significant for GRP78 (p = 0.051). The levels of TNF‐α (p = 0.009), IL‐18 (p = 0.003), IL‐6 (p = 0.013) and active caspase‐3 (p = 0.012) were also statistically significant lower in the therapy group. However, there was no significant difference in CRP (p = 0.177) and caspase‐8 (p = 0.491) levels between the treatment and control groups. In our study, ASX had no significant positive effect on BMI, hirsutism, hair loss and regularity of the menstrual cycle. It appears that ASX may benefit PCOS by changing the ER stress‐apoptotic pathway and reducing serum inflammatory markers; however, additional research is required to determine this compound's potential relevance.