Assessment of Cod Protein as an Insulin-sensitizing Agent in Women With Polycystic Ovary Syndrome.

Study Overview
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Brief Summary
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The objective of our study is to determine the effects of fish protein on insulin sensitivity in PCOS women with insulin resistance, and its mechanism of action on glucose and endocrine metabolism. Our working hypothesis is that dietary fish protein improves insulin sensitivity, glucose tolerance, and related plasma endocrine and lipid abnormalities in PCOS women by restoring secretory β-cell function and insulin signaling to the PI 3-kinase activity/Akt pathway. We further hypothesize that fish protein will improve cycle regularity and ovarian function.

Detailed Description
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Women with polycystic ovary syndrome are at high risk of developing diabetes. Apart from a primary ovarian defect, up to 10% and 40-50% of those women develop diabetes and insulin resistance (IR) respectively. IR and associated hyperinsulinemia are recognized as important pathogenic factors in determining diabetes in the majority of PCOS women, particularly when obesity is present. Treating IR might reduce the risk of diabetes and improve ovulation and fertility in PCOS women. We recently found that obese, IR men and women consuming a cod protein diet showed a 30% improvement in insulin sensitivity compared with other animal proteins, and also a 24% decrease in high-sensitive C-reactive protein plasma concentration. Therefore, dietary fish protein could represent a natural, safe and practical means to improve insulin sensitivity in PCOS women with IR, and a new non-pharmaceutical approach for the treatment of the multiple endocrine and metabolic abnormalities of PCOS women (see outcome measures for a more extensive description).

Official Title
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Assessment of Cod Protein as an Insulin-sensitizing Agent in Women With Polycystic Ovary Syndrome.

Conditions
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Insulin Sensitivity, Polycystic Ovarian Syndrome

Intervention / Treatment
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* Other: Semi-controlled nutritional intervention with fish protein diet
* Other: Semi-controlled intervention with other animal proteins


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: women 18 to 45 years old having polycystic ovarian syndrome overweight (BMI>27) insulin resistance based on fasting insulin levels in the upper 95th percentile (>90pmol/L) non-diabetic Exclusion Criteria: diabetes hysterectomy abnormal endometrial biopsy if abnormal bleeding in the last 6 months clinical evidence of Cushing's syndrome congenital adrenal hyperplasia (17-OH progesterone>10nmol/l) excessive androgens suspicious of a tumour prolactins levels >50μg/l previous breast, uterus, ovary or liver neoplasia use of medication known to affect glucose and lipid metabolisms (e.g. steroid hormones, oral contraceptives, ß-blockers, glitazones, statins, insulin) depo-medroxyprogesterone acetate injection in the last year important weight loss or weight gain within the last 6 months chronic, metabolic (except well controlled chronic hypothyroidism) or acute disease or major surgery within the last 3 months dietary incompatibility with calcium supplementation and/or fish consumption (allergy, intolerance, dislike)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Semi-controlled intervention with fish protein diet<br>Women with polycystic ovarian syndrome who are assigned to a 12 weeks experimental diet containing cod as the protein source. | Other: Semi-controlled nutritional intervention with fish protein diet<br>* After a controlled NCEP-based diet for 3 months, women are assigned to a cod fillet diet. At the end of this first 3 months experimental period, participants return to their NCEP-based diet for a wash-out period of 3 months. Then, each group receive the other diet for an additional 3 months period. The fish protein intake come from cod fillets and correspond to 50% of total protein, the remaining dietary proteins being from BPVEM (20%) and vegetable (30%). Lunches incorporating cod fillets are prepared by professional dietitians, provided two time per week, and are self-consumed. Participants make their breakfasts and dinners using foods from a pre-approved list. Alcohol is strictly prohibited during all periods.<br>|
| Active Comparator: Semi-controlled intervention with other animal proteins<br>Women with polycystic ovarian syndrome who are assigned to a 12 week experimental diet containing beef, pork, veal, eggs and milk products (BPVEM) as protein sources. | Other: Semi-controlled intervention with other animal proteins<br>* Prior to experimental period, participants follow a controlled NCEP-based diet for 3 months. Then women are assigned to a diet containing beef, pork, veal, eggs, milk and milk products. At the end of this first 3 months experimental period, participants return to their NCEP-based diet for a wash-out period of 3 months. The two diets are isoenergetic. The protein intake from BPVEM correspond to 70% of total protein, other dietary proteins are from vegetable (30%) origin. Lunches incorporating animal proteins are prepared by professional dietitians, provided two time per week, and are self-consumed. Participants make their breakfasts and dinners using foods from a pre-approved list. The content in n-3 fatty acids is adjusted to provide equivalent amounts of n-3 fatty acids then in the cod protein diet. Alcohol is strictly prohibited during all periods.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sex hormones, during intervention and from baseline to the end of each intervention period. | Detailed plasma androgen profile including active androgens (testosterone and dihydrotestosterone), adrenal androgens (androstenedione, dehydroepiandrosterone and its sulphate), major glucuronide-conjugated androgen metabolites, plasma levels of the sex hormone transport protein Sex Hormone-Binding Globulin (SHBG). | At baseline, after the wash-out period, at the end of each intervention period (12 weeks), and at weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11 during the intervention. | 
| Change in cycle regularity during intervention period. | menstrual diaries | At weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 during the intervention | 
| Change in ovarian function during intervention period. | progesterone measurements | At weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 during the intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in nutritional variables from baseline to the end of each intervention period. | Food frequency questionnaire | At baseline and at the end of the intervention period (12 weeks). | 
| Change in cardiometabolic statute from baseline to the end of each intervention period | Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, glucose and insulin concentrations during a 180-min euglycemic-hyperinsulinemic clamp, GDR, MI, β-cell function, systolic and diastolic blood pressure, glucose and insulin concentrations during a 120-min oral glucose tolerance test, plasma C-peptide concentration, apolipoprotein apoA-1, A-2 and B plasma concentrations, hsCRP, MCP-1, IL-1β, IL-6 and adiponectin concentrations. | At baseline (at the beginning of the intervention), after the 12 weeks wash-out period, and at the end of each intervention period (12 weeks each) | 
| Muscle insulin signaling | Muscle biopsies for expression and phosphorylation of IRS-1-associated PI3-K activity, as well as Akt and aPKC activation by insulin. | After each intervention period (12 weeks) | 
| Change in physical activity habits from baseline to the end of each intervention period. | Physical activity habits questionnaire | At baseline and at the end of the intervention period (12 weeks) | 
| Change in anthropometric measurements from baseline to the end of each intervention period. | anthropometric measurements (body mass index, waist and hip circumferences) | At baseline and at the end of the intervention period (12 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Polycystic ovarian syndrome, sex hormones, ovarian function, women, fish protein, insulin sensitivity, glucose tolerance, β-cell function, inflammation