Weight Cycling on Hyperandrogenemia and Insulin Resistance in Polycystic Ovary Syndrome

Official title

The Effect and Mechanism Of Weight Cycling on Hyperandrogenemia And Insulin Resistance in Polycystic Ovary Syndrome

Overview

This study prospectively includes PCOS patients with normal weight and overweight/obesity, closely follows up and intensively manages them, and observes the level and distribution of weight reduction achieved by patients after lifestyle intervention (high-protein diet for weight loss). Additionally, it aims to provide reference for setting weight loss targets for future PCOS patients by comparing the differences in clinical improvement among patients achieving different degrees of weight reduction (\<2% \[equivalent to no weight loss\], 2-5%, 5-10%, ≥10%) at different time points (3 months, 6 months) following dietary intervention. Furthermore, this study will compare the differences in reproductive and metabolic marker improvements between baseline PCOS patients experiencing weight rebound, those who successfully lost weight, and those who experienced weight rebound. This will help explore the impact of weight cycling on PCOS-related manifestations. Finally, at a genetic level, the study will analyze potential mechanisms underlying different outcome indicators by comparing differences in metagenomics, transcriptomics, and metabolomics among patient groups. Ancillary/Nested Sub-study (12-week Precision Nutrition Trial): Within the WHIP cohort, we will conduct a nested, prospective interventional sub-study to evaluate the efficacy of an insulin-resistance-phenotype-guided precision dietary prescription versus a standard guideline-based energy-restricted diet. Eligible participants are women with PCOS and insulin resistance enrolled in the cohort. The sub-study lasts 12 weeks with assessments at baseline and week 12. Primary endpoints include change in HOMA-IR and change in the core11 metabolic risk composite. Secondary endpoints include changes in gonadotropins (FSH, LH), sex steroid hormones (e.g., estradiol, progesterone), and patient-reported symptom scores.

Detailed description

This study is a single-center, prospective cohort study that enrolled PCOS patients after screening. The patients were categorized into two groups based on their BMI: a normal weight group (18.5 kg/m2 ≤ BMI \< 24 kg/m2) with a sample size of 45 and an overweight/obese group (BMI ≥ 24 kg/m2) with a sample size of 380, totaling 425 cases.

For the normal weight PCOS patients, interventions included control of total energy intake, adjustment of dietary structure, exercise, and behavioral intervention to prevent weight gain over a follow-up period of three months. If weight gain occurred during the follow-up period, these patients were transferred to the overweight/obese group for intensified intervention.

The overweight/obese PCOS patients received intensive intervention in accordance with high-protein diet adaptation criteria. This involved high-protein diets combined with exercise and behavioral intervention for weight reduction. After three months of follow-up, if they achieved their weight-loss goal, they transitioned to a low-energy diet and exercise intervention program to maintain their weight. If the goal was not met after three months, they continued with the high-protein weight-loss program.

The study compared differences in improvement in indicators such as insulin resistance (IR), blood androgen levels, inflammatory factors among different degrees of weight loss (\<2%, 2% ≤weight loss \<5%, 5%≤weight loss\<10%, ≥10%), analyzing potential mechanisms.

For individuals experiencing weight cycling, differences in IR levels before and after rebounding from body mass were compared alongside changes in androgen levels and other metabolic indicators. This aimed to explore the impact of body mass cycling on clinical indicators while analyzing potential causes.

Ancillary/Nested Sub-study (12-week Precision Nutrition Trial):

A subset of cohort participants meeting criteria for PCOS with insulin resistance will enter a 12-week dietary intervention sub-study. Participants will be allocated in a 1:1 ratio to: (1) a phenotype-guided precision dietary prescription tailored to the individual's insulin-resistance metabolic subtype; or (2) a standard low-energy diet based on current Chinese clinical guidelines for overweight/obesity medical nutrition therapy. Both groups receive standardized lifestyle counseling and follow-up. Study visits occur at baseline and week 12. This nested sub-study is designed to test whether subtype-matched dietary prescriptions yield greater improvements in insulin resistance and metabolic risk than a uniform guideline diet, while remaining integrated within the parent WHIP cohort.

Interventions

• Other Adjusting dietary structure + exercise + behavioral intervention
  Adjusting to a healthy diet involves consuming low GI and low-fat foods, avoiding sugary drinks, increasing dietary fiber intake, reducing saturated fat while increasing omega-3 unsaturated fat intake, and limiting trans fat consumption. A weight loss program includes a high-protein diet, exercise, and behavioral intervention with daily total energy needs calculated based on ideal body weight (kg) x 15-20 kcal/kg/d; developing a daily meal plan with regular protein supplementation; limiting salt
• Behavioral Precision dietary prescription
  A 12-week precision diet program individualized to baseline insulin-resistance metabolic subphenotype, including personalized macronutrient targets, food-based meal plans, and dietitian-led counseling with regular follow-ups.
• Behavioral Standard guideline-based low-energy diet
  A 12-week standardized low-energy diet based on national guideline recommendations for overweight/obesity, with the same counseling frequency as the precision-diet arm but without metabolic tailoring.

Primary outcome measures

• Weight loss rate [Time frame: 6 month]
• Levels of insulin resistance [Time frame: 6 month]

Secondary outcome measures (10)

• Fasting insulin level（FINS） [Time frame: 6 month]
• Fasting blood sugar（FBG） [Time frame: 6 month]
• Blood levels of androgen hormones (total testosterone, free testosterone index) [Time frame: 6 month]
• Blood lipid levels (LDL-C, HDL-C, total cholesterol) [Time frame: 6 month]
• Levels of inflammatory factors (CRP, IL-6, TAC, GSH) [Time frame: 6 month]
• BMI [Time frame: 6 month]
• Waist [Time frame: 6 month]
• waist-to-hip ratio [Time frame: 6 month]
• Body fat percentage and distribution [Time frame: 6 month]
• Weight rebound rate [Time frame: 6 month]

Eligibility criteria

Inclusion criteria

• Women aged 18-45 years in the reproductive period;
• Women who have previously met the Rotterdam diagnostic criteria (at least 2 of the following 3 criteria have been confirmed, and have been diagnosed with PCOS): 1) Oligomenorrhea and/or anovulation; 2) clinical and/or biochemical evidence of hyperandrogenism; 3) ultrasound showing the presence of unilateral or bilateral polycystic ovaries;
• Inclusion of 50 women in the normal weight group: 18.5 kg/m² ≤ BMI < 24 kg/m²; Inclusion of 400 women in the overweight/obese group: BMI ≥ 24 kg/m²;
• Voluntarily participate in the intervention and sign an informed consent form.

Exclusion criteria

• Currently pregnant or lactating, or have had a recent (within 6 months) plan for pregnancy;
• Currently using known prescription weight loss medications (such as GLP-1RA, orlistat, topiramate, etc.);
• History of weight loss surgery;
• History of severe cardiovascular or cerebrovascular diseases; severe liver or kidney dysfunction (ALT > 3 times the upper limit of normal, or creatinine > 1.5 times the upper limit of normal); chronic or active gastrointestinal inflammatory diseases; severe systemic diseases; active malignant tumors;
• Secondary obesity: including hypothalamic or pituitary obesity, obesity secondary to glucocorticoid use, hypogonadism-induced obesity, etc.;
• Known history of serious endocrine system diseases;
• Poor compliance with planned dietary interventions (psychiatric disorders such as binge eating disorder, anorexia nervosa, severe anxiety/depression);
• Unable to follow up on time or deemed non-cooperative by the investigator.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Other

Study locations

China · 1 center

• Peking Union Medical College Hospital — Beijing

Publications

• Lizneva D, Suturina L, Walker W, Brakta S, Gavrilova-Jordan L, Azziz R. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016 Jul;106(1):6-15. doi: 10.1016/j.fertnstert.2016.05.003. Epub 2016 May 24. PMID 27233760
• Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004 Jan;19(1):41-7. doi: 10.1093/humrep/deh098. PMID 14688154
• Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010 Jul-Aug;16(4):347-63. doi: 10.1093/humupd/dmq001. Epub 2010 Feb 16. PMID 20159883
• Barry JA, Kuczmierczyk AR, Hardiman PJ. Anxiety and depression in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2011 Sep;26(9):2442-51. doi: 10.1093/humrep/der197. Epub 2011 Jul 1. PMID 21725075
• Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018 Sep 1;33(9):1602-1618. doi: 10.1093/humrep/dey256. PMID 30052961
• Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ, Yildiz BO. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016 Aug 11;2:16057. doi: 10.1038/nrdp.2016.57. PMID 27510637
• Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, Lehnert H. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev. 2012 Oct;33(5):812-41. doi: 10.1210/er.2012-1003. Epub 2012 Jul 24. PMID 22829562
• Cowan S, Lim S, Alycia C, Pirotta S, Thomson R, Gibson-Helm M, Blackmore R, Naderpoor N, Bennett C, Ee C, Rao V, Mousa A, Alesi S, Moran L. Lifestyle management in polycystic ovary syndrome - beyond diet and physical activity. BMC Endocr Disord. 2023 Jan 16;23(1):14. doi: 10.1186/s12902-022-01208-y. PMID 36647089

Identifiers

NCT: NCT06545721 · K5204

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗