Esplugues De Llobregat (barcelona), Spain

Inositol Supplementation to Treat PCOS (INSUPP-PCOS)

This trial will test prospectively the effects of inositol supplementation in a dose ranging double blind randomized controlled trial, according to CONSORT guidelines. This will be a four armed study of three doses of inositol vs. placebo over a three month period with the reduction in hyperandrogenism (based on serum testosterone levels) as the primary outcome and key secondary outcomes of the change in sex hormone binding globulin(SHBG) and the related free androgen index, fasting insulin levels and area under the curve glucose levels from an oral glucose challenge test (OGTT). The hypothesis is that women with PCOS who receive inositol supplementation will have a dose related reduction in hyperandrogenism. Further, we propose that the primary mechanism of inositol will be a significant improvement in hyperandrogenism (both ovarian and adrenal) vs. placebo, as documented by a lower free androgen index [decreased total testosterone and increased sex hormone blinding globulin (SHBG)], lower sebum measures and lower antral follicle counts of the ovary and anti-Mullerian hormone, all of which will correlate with the decrease in hyperandrogenism.

PCOS Patients' Immune Alterations

PCOS patients and healthy women were recruited in outpatient clinics of three hospitals, and peripheral blood was retained for flow cytometry after completing relevant examinations. In this study, flow cytometry was used to detect the antigenic antibody reaction between the surface differentiation antigen of lymphocyte membrane and fluorescence-labeled antibody in human peripheral blood, and the unlabeled cells were dissolved. The number and percentage of cell groups expressing different markers were counted by the fluorescence detection system on flow cytometry.

The PCOS Challenge Study

REFUEL PCOS Study 1

Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder, affecting 10-13% of all women, and is associated with a major healthcare and economic burden, estimated at $8 billion annually the US in 2020 (1, 2). Traditionally considered a reproductive disorder only, it is now increasingly clear that PCOS is associated with severe metabolic health consequences across the entire life course of women (3, 4). There is a two-fold increased risk of type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease, as well as emerging evidence of increased incidence of cardiovascular disease (CVD) (5-7). There are no disease-specific therapies to mitigate or treat metabolic risk in women with PCOS. This is consistently highlighted as the priority concern amongst PCOS patient advocacy groups. Androgen excess is a cardinal feature of PCOS and circulating androgen burden is closely correlated with metabolic complications (5, 8-12). In women with PCOS, the risk of developing metabolic dysfunction is above that conferred by simple obesity, suggesting that androgen excess is a key player; however, a distinct mechanistic role for androgens in this process remains to be elucidated (13, 14). Androgen excess is associated with metabolically deleterious visceral fat accumulation and circulating testosterone levels correlate directly with the risk of T2DM and NAFLD. Muscle is a critical metabolic target tissue that plays a central role in energy metabolism through processes such as glucose uptake and oxidation, as well as oxidation of fatty acids to generate ATP in the mitochondria (15). Recent mechanistic data have shown that androgen excess is associated with changes in the transcriptional profile of skeletal muscle genes linked with metabolism and energy balance (15-17). Therefore, skeletal muscle is likely to represent an important site of crosstalk between androgen excess, disturbances in energy metabolism and risk of metabolic disease in PCOS. Defective skeletal muscle glucose uptake is a key early step in the pathogenesis of insulin resistance in PCOS, and an early predictor of progression to overt type 2 diabetes mellitus. Impaired mitochondrial oxidation of free fatty acids in skeletal muscle, as well as other disturbances in skeletal muscle mitochondrial function such as oxidative phosphorylation, are increasingly implicated in the pathogenesis of metabolic disease such as T2DM (18-20). Abnormalities in skeletal muscle mitochondrial function have also been identified in small scale studies in women with PCOS, and were associated with impaired fatty acid oxidation, weight gain and an increased risk of diabetes (21, 22). The investigators hypothesise that androgen-mediated disturbances in skeletal muscle energy balance play a major role in the pathogenesis of metabolic disease in women with PCOS. The investigators propose to test this using cross-sectional and interventional approaches utilising state-of-the-art metabolic phenotyping tools.

PCOS (Polycystic Ovarian Syndrome) Patients

Polycystic ovary syndrome (PCOS) affects 8-13% of women. It is a multifaceted condition characterized by chronic anovulation and excess ovarian activity. Since last decade, Clinical Reproductive Medicine Management System/Electronic Medical Record Cohort Database (CCRM/EMRCD) has been used in Reproductive Medical Center, First Affiliated Hospital of Zhengzhou University, and Henan Province Key Laboratory for Reproduction and Genetics. Information of patients (POI, PCOS, Endometriosis, azoospermia, ect) were recorded comprehensively. The current project plans to recruit PCOS participants in our center. Biological samples, questionnaires and short/long term health data will be collected. The study is aimed to provide evidence for PCOS prognosis.

Efficacy of Mazdutide for Treating PCOS

PCOS Immune Function Predicts Metformin Efficacy

In this study, peripheral blood samples of PCOS patients were collected before and after intervention. Flow cytometry was used to detect the antigenic antibody reaction between the surface differentiation antigen of lymphocyte membrane and fluorescently labeled antibodies in human peripheral blood, and the unlabeled cells were dissolved. The number and percentage of cell groups expressing different markers were counted by the fluorescence detection system on flow cytometry.

PCOS Indirect and Intangible Economic Burden

Myo-Inositol for Infertility in PCOS

At the screening visit, blood pressure and heart rate will be measured, weight and height obtained and body mass index calculated (kg/m2). If not already completed at their new patient visit, transvaginal ultrasound will be performed to assess uterine anatomy and obtain antral follicle count, TSH, prolactin, and testosterone will be drawn, and serum samples will be obtained and analyzed for metabolic parameters (fasting lipids, insulin, and complete metabolic panel). One additional tube of blood will be drawn to store for potential future analysis. Once enrolled, randomization will occur and subjects will start either inositols or placebo. 84 women will be stratified by BMI and randomized 1:1 into two treatment arms, A) "Control Arm" = twice daily placebo powder and B) "Inositol Arm" = twice daily myo-inositol (2,000mg) plus d-chiro-inositol (50mg) supplement powder. Treatment with either placebo or inositol will begin upon randomization. Participants will complete a validated quality of life in PCOS questionnaire (PCOSQ) at this visit and again upon study completion (11). Treatment with letrozole will begin after the baseline visit, which will occur after spontaneous menses or withdrawal bleeding induced by progestin administration. Because of this timing, participants will undergo pretreatment with inositol or placebo for a variable amount of time up to 6 weeks, with an anticipated average of 2-3 weeks. Metabolic parameters will be repeated after approximately 6 (7-9) and approximately 12 (11-13) weeks of inositol or placebo, at whichever study visit is most proximal in time to this goal timeframe. Both groups will receive letrozole 5mg every day for 5 days on days 3-7 of their menstrual cycle and instructed on timing intercourse with anticipated ovulation dates. Blood will be drawn for a serum progesterone each cycle between cycle days 20-22 to confirm ovulation, and repeated 1 week later if the initial progesterone level is below the threshold to confirm ovulation. Once ovulation is confirmed, they patient will expect a period 7-10 days later. They will call with cycle day 1 of bleeding if it occurs to start their next cycle of treatment, up to 5 cycles. If no bleeding occurs within the expected timeframe, they will check a home pregnancy test and call with results. Patients will complete medication side effect questionnaires at the first blood draw for progesterone of each cycle. This will be reviewed same-day and in person with the research nurse coordinator. Each patient will complete up to 5 cycles. Dose of letrozole will be increased in subsequent cycles for non-response or late ovulatory response (ovulation later than the progesterone blood draw) up to 10mg of letrozole a day. For patients with a second progesterone level below the threshold to confirm ovulation (day 21 and day 28), the higher dose of letrozole will be initiated following the receipt of the second low progesterone result. For patients who do not ovulate on the maximum dose of letrozole, their study participation will be considered complete. Data to be collected will include: demographic information and medical history [age, race/ethnicity, body mass index (BMI), antral follicle count, length of infertility, prior infertility treatment (yes or no), obstetrical history, medical history, surgical history, current medication and allergy lists], partner information [age, race/ethnicity, BMI, general medical health assessment, prior paternity history], transvaginal ultrasound results, and serum studies [TSH, prolactin, progesterone, hCG levels, androgen levels (total and free testosterone, SHBG), and metabolic factors (fasting lipid panel, fasting glucose, fasting insulin, glucose:insulin ratio, HOMA-IR index)]. Questionnaires to be completed include: PCOSQ validated questionnaire for PCOS-related quality of life, and a side effect questionnaire about known side effects of letrozole and inositols. In addition to the baseline transvaginal ultrasound, additional ultrasounds may be performed as indicated clinically (including for establishing clinical pregnancy). Pertinent demographic and clinical information on patients who are participating in the study will be entered into a study database REDCap secure software. Using the reported clinical pregnancy rate for infertile PCOS patients treated with letrozole of 31.3% (12) as the control group proportion (0.31) with a goal of 10% effect size (and therefore treatment group proportion 0.41), an alpha of 0.05, and power of 0.8, our sample size is estimated (for a full clinical trial) at ~361 in each arm. In considering the previously observed drop-out rate of ~20% in a similar patient population (3), we estimate that for a full clinical trial, we would need 452 participants randomized in each arm. Based on previously published literature regarding estimation of pilot randomized trial sample sizes, we will target 9% of this sample size for our pilot study to suggest or identify a significant difference (13). In conclusion, our planned study size will be 42 participants in each study arm.

Polycystic Ovarian Syndrome (PCOS) Biomarker Evaluation Study

The purpose of the study is to validate potential biomarkers for the aid in the diagnosis of PCOS in adolescent and young adult women in the age range of 15-25 years. Female subjects included in this study will have one visit where clinical data for assessing PCOS will be collected and a blood draw will be performed to collect serum for measurement of parameters relevant to PCOS will be performed. Study subjects that receive a PCOS diagnosis will have two follow up visits for follow up on treatment where additional serum and clinical data will be collected. The first visit will be 3 months after receiving the diagnosis and the second visit 6-12 months after the initial visit.