Probiotic Intervention in PCOS

Study Overview
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Brief Summary
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The investigators are conducting a double-blinded randomized controlled trial to determine whether a probiotic mixture is effective in reducing PCOS-related symptoms. For this purpose, 180 participants will be recruited in three intervention arms (Probiotic, Placebo and Metformin), with 60 participants per arm. The intervention period will last 6 months, with extensive medical history, blood work, urine and stool analysis at the beginning and the conclusion of the trial.

Official Title
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Probiotic Dietary Intervention in Polycystic Ovary Syndrome (PCOS) - A Randomized Controlled Trial

Conditions
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Polycystic Ovary Syndrome

Intervention / Treatment
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* Dietary Supplement: Probiotic
* Drug: Metformin Hydrochloride
* Dietary Supplement: Probiotic Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Polycystic Ovary Syndrome diagnosed based on at least two out of three rotterdam criteria: hyperandrogenism, polycystic ovarian morphology, oligo-/anovulation signed informed consent Exclusion Criteria: Missing or withdrawn consent Hyperandrogenism of a cause other than PCOS (Cushing´s syndrome, hyperprolactinemia, adrenal tumours, congenital adrenal hyperplasia, rare genetic disorders) Pregnancy or nursing period (first 6 months after giving birth) Soy or other allergies with respect to study procedures Diabetes mellitus type 1 Chronic inflammatory bowel disease, history of cancer in the gastrointestinal tract or acute gastrointestinal infection Any malignancies that required treatment within the last 3 years prior to study procedures Any other chronic disease requiring medical check-ups or hospital treatments at least once every three months (exception: diabetes mellitus type 2) Major surgery in the gastrointestinal tract (e.g. colectomy, gut segment excision with stoma surgery, Whipple´s surgery.) Surgical removal of the appendix and/or the gall bladder is NOT considered major surgery. Therapy with antidiabetic drugs (metformin, sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, Glucagon-like peptide 1 (GLP-1) analogs, sodium-glucose-cotransporter 2 (SGLT-2) inhibitors, insulin variants) within the last six months prior to study procedures Therapy with proton pump inhibitors within the last six months prior to study procedures Therapy with hormonal contraceptives or systemic (oral) intake of steroids within the last six months prior to study procedures Oral or intravenous therapy with antibiotics less than three months before the onset of study procedures Alcohol and/or drug abuse

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Probiotic vs placebo (double-blinded) vs metformin (open-label)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotic<br>Probiotic product consisting of these 7 bacterial strains: Lactobacillus salivarius W57 Lactobacillus casei W56 Lactobacillus rhamnosus W71 Lactococcus lactis W58 Enterococcus faecium W54 Lactobacillus plantarum W62 Lactobacillus acidophilus W22 Additional ingredients: Corn starch, maltodextrin, fructo-oligosaccharides, galacto-oligosaccharides, polydextrose, plant proteins, potassium chloride, magnesium sulfate, bacterial strains, manganese sulfate, lactose, 2000 IU vitamin D Participants ingest one sachet of powder (5 grams) in 200 ml of water per day for 6 months | Dietary Supplement: Probiotic<br>* See Arm description<br>|
| Placebo Comparator: Placebo<br>Similar to probiotic product in optics and smell, less ingredients and no bacterial strains or vitamin D Ingredients: Corn starch, maltodextrin, potassium chloride, magnesium sulphate, manganese sulphate | Dietary Supplement: Probiotic Placebo<br>* See Arm description<br>|
| Active Comparator: Metformin<br>Metformin is an established drug for treating PCOS-related symptoms. The investigators are comparing the probiotic not only to a placebo group, but also to the benchmark treatment. Participants in the metformin arm will start treatment with 500 mg daily for the first week, then increasing the dose to 2x500 mg daily for the duration of the intervention. | Drug: Metformin Hydrochloride<br>* See Arm description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free testosterone | Changes in free testosterone levels [pg/ml] in serum after intervention | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-Müllerian hormone (AMH) | Changes in AMH levels in serum after intervention [ng/ml] | 6 months | 
| Androstenedione | Changes in androstenedione levels in serum after intervention [ng/ml] | 6 months | 
| Dehydroepiandrosterone-sulphate (DHEA-S) | Changes in DHEA-S levels in serum after intervention [µg/ml] | 6 months | 
| 17-Hydroxyprogesterone (17-OH-progesterone) | Changes in 17-OH-progesterone levels in serum after intervention [ng/ml] | 6 months | 
| 17-OH-estradiol | Changes in 17-OH-estradiol levels in serum after intervention [ng/ml] | 6 months | 
| Total testosterone | Changes in total testosterone levels in serum after intervention [ng/ml] | 6 months | 
| 25-OH-cholecalciferol | Changes in 25-OH-cholecalciferol levels in serum after intervention [ng/ml] | 6 months | 
| Luteinizing hormone (LH), Follicle-stimulating hormone (FSH) | Changes in LH and FSH levels in serum after intervention [mU/ml] | 6 months | 
| LH to FSH ratio | Changes in LH to FSH ratio after intervention [1] | 6 months | 
| Insulin | Changes in insulin levels in serum as measured with a two-hour oral glucose tolerance test (75 mg glucose in 300 ml water, blood draws at 0 minutes, 30 min, 60 min and 120 min) [mU/l] | 6 months | 
| Glucose | Changes in glucose levels in sodium-fluoride plasma as measured with a two-hour oral glucose tolerance test (75 mg glucose in 300 ml water, blood draws at 0 minutes, 30 min, 60 min and 120 min) [mg/dl] | 6 months | 
| Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) index | Changes in HOMA-IR index (fasting insulin [mU/l] * fasting glucose [mg/dl]/405) after intervention | 6 months | 
| Glucose mean | Changes in mean glucose levels (measured with oral glucose tolerance test with the formula g=(glucose0 + 2*glucose30 + 3*glucose60 + 2*glucose120)/8 [mg/dl] | 6 months | 
| Insulin mean | Changes in mean insulin levels (measured with oral glucose tolerance test with the formula i=(insulin0 + 2*insulin30 + 3*insulin0 + 2*insulin120)/8 [mU/l] | 6 months | 
| Matsuda index | Changes in matsuda index after intervention measured with the formula M=10000/squareroot(glucose0 * insulin0 * glucose mean (see outcome 14) * insulin mean (see outcome 15)) | 6 months | 
| Hirsutism | measured by modified Ferriman-Gallwey-score (mFG-score), ranging from 0 to 36, with 0 being the best possible value and 36 the worst | 6 months | 
| Body-mass-index (BMI) | BMI measured with the formula BMI=weight [kg]/height² [m] | 6 months | 
| waist-to-hip ratio | Calculated with the formula: waist circumference/hip circumference [1] | 6 months | 
| Sucrose-lactulose-mannitol test | Functional gut permeability test consisting of ingesting 20 g sucrose, 5 g mannitol and 10 g lactulose in 100 ml water solution. Measurement of those three component concentrations in urine collected for 5 hours after solution ingestion by the participants. Lactulose to mannitol ratio may be calculated. | 6 months | 
| Diaminooxidase | Changes in serum diaminooxidase levels after intervention | 6 months | 
| Stool and serum zonulin | Changes in stool and serum zonulin levels after intervention [ng/ml] | 6 months | 
| Lipopolysaccharide | Changes in lipopolysaccharide levels after intervention | 6 months | 
| Soluble cluster of differentiation (sCD14) | Changes in sCD14 levels in serum after intervention | 6 months | 
| Calprotectin | Changes in stool calprotectin levels after intervention | 6 months | 
| Bacterial DNA | Changes in bacterial DNA amounts in serum after intervention | 6 months | 
| Gut lumen and mucosa microbiome composition and metagenomic profile | Measured from stool samples via 16S-RNA gene sequencing | 6 months | 
| Phytoestrogen production | Changes in daidzein and equol concentrations after intervention [ng/ml] measured in urine samples of participants after ingestion of soy milk | 6 months | 
| Equol producer status | Equol producer status as determined by the decadic logarithm of the equol/daidzein ratio [1]: A value above -0.5 is defined as an equol producer | 6 months | 
| Quality of life (QOL) | QOL assessed by General Depression Scale (German: Allgemeine Depressionsskala), German equivalent of the Depression Scale by the Center for Epidemiological Studies (CES-D). The scale ranges from 0 to 60, with 0 being the best possible score and 60 the worst. | 6 months | 
| QOL | QOL assessed by Beck´s Depression Inventory (BDI), a scale ranging from 0 to 63, with 0 being the best possible score and 63 the worst. | 6 months | 
| QOL | Quality of Life measured by a PCOS questionnaire ranging from 0 to 156, with 0 being the best possible score and 156 the worst | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCOS, Probiotic, Metformin, RCT