Probiotic Intervention in PCOS (ProPCO-RCT)

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

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.

Study Overview

• Status: Completed
• Conditions: Polycystic Ovary Syndrome
• Intervention / Treatment: Dietary supplement: Probiotic; Dietary supplement: Probiotic Placebo; Drug: Metformin Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 4

Contacts and Locations

Study Locations

• Austria
  • Styria
    • Graz, Styria, Austria, 8036
      • Medical University of Graz, Division of Endocrinology and Diabetology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

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• Missing or withdrawn consent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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Probiotic; 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; See Arm description
Placebo Comparator: Placebo; 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; See Arm description
Active Comparator: Metformin; 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; See Arm description

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lipid metabolism	Low-density lipoproteins (LDL), high-density lipoproteins (HDL), lipoprotein a (LP(a)), triacylglycerols	6 months
Fluorescence-activated cell sorting (FACS) analysis	B cell subtypes measured via FACS from whole blood	6 months

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Collaborators: Winclove Probiotics B.V.; Institut AllergoSan
• Investigators: Principal Investigator: Barbara Obermayer-Pietsch, Prof. MD, Medical University of Graz, Division of Endocrinology and Diabetology

Publications and helpful links

General Publications

• Lindheim L, Bashir M, Munzker J, Trummer C, Zachhuber V, Leber B, Horvath A, Pieber TR, Gorkiewicz G, Stadlbauer V, Obermayer-Pietsch B. Alterations in Gut Microbiome Composition and Barrier Function Are Associated with Reproductive and Metabolic Defects in Women with Polycystic Ovary Syndrome (PCOS): A Pilot Study. PLoS One. 2017 Jan 3;12(1):e0168390. doi: 10.1371/journal.pone.0168390. eCollection 2017.
• Haudum C, Lindheim L, Ascani A, Trummer C, Horvath A, Munzker J, Obermayer-Pietsch B. Impact of Short-Term Isoflavone Intervention in Polycystic Ovary Syndrome (PCOS) Patients on Microbiota Composition and Metagenomics. Nutrients. 2020 Jun 1;12(6):1622. doi: 10.3390/nu12061622.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2020
• Primary Completion (Actual): October 16, 2023
• Study Completion (Actual): October 16, 2023

Study Registration Dates

• First Submitted: October 12, 2020
• First Submitted That Met QC Criteria: October 19, 2020
• First Posted (Actual): October 20, 2020

Study Record Updates

• Last Update Posted (Actual): March 22, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: PCOS; Metformin; RCT; Probiotic
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Polycystic Ovary Syndrome; Syndrome; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 160120200001; 2020-000228-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For research and cooperation purposes, pseudonymized individual participant data may be shared with other researchers, the decision to do so lies with the principal investigator. In case of publication of our results in a peer-reviewed journal, all relevant data will be made publicly accessible without any personal information
• IPD Sharing Time Frame: to be determined
• IPD Sharing Access Criteria: to be determined
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No