Esmaeilinezhad Z, Babajafari S, Sohrabi Z, Eskandari M, Amooee S, Barati-Boldaji R. Effect of synbiotic pomegranate juice on glycemic, sex hormone profile and anthropometric indices in PCOS: a randomized, triple-blind, controlled trial. Nutr Metab Cardiovasc Dis. 2018;29(2):201-208.
To determine if a synbiotic pomegranate beverage improves insulin resistance in women with polycystic ovary syndrome (PCOS); a secondary objective was to assess changes in serum sex hormone levels and anthropometric measures.
Randomized, triple-blind, placebo-controlled, parallel study
Participants were recruited out of the Motahari Clinic in Shiraz, Iran between January 2017 and July 2017; 92 women aged 15-48 met the diagnostic criteria for PCOS and 86 completed the trial. The Rotterdam criteria for PCOS are met when 2 or more of the following features are present and other potential causes have been ruled out: 1) oligo- or anovulation; 2) clinical or laboratory findings of hyperandrogenism; 3) multiple ovarian cysts observed on ultrasound.
Women were excluded from the study if they were smokers, lactating, had a major disease (including autoimmunity and significant organ dysfunction), or were taking certain interventions (including chemotherapy, corticosteroids, antibiotics, hormones, and supplemental vitamins, minerals, or antioxidants). The researchers also excluded individuals with “special diet and physical activity” but did not elaborate this statement further.
Participants were randomized into 4 study groups delineated by intervention received: synbiotic pomegranate juice (SPJ); synbiotic beverage (SB); pomegranate juice (PJ); and placebo (control).
The synbiotic pomegranate beverage was composed of pomegranate juice, inulin (20 g/L), and equal parts of 3 species of bacteria: Lactobacillus rhamnosus GG, Bacillus coagulans, and Bacillus indicus (108 colony-forming units [CFU]/g/L). The synbiotic beverage had the same concentration of inulin and lactobacillus, but with a water base plus pomegranate flavoring. Beverages were prepared fresh weekly throughout the trial. The placebo beverage was water plus pomegranate flavoring, and the pomegranate beverage was pure juice. Participants consumed 2 liters of their beverage per week for 8 weeks.
Study Parameters Assessed
Researchers measured fasting blood levels of insulin, glucose, total testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) at baseline and 8 weeks. Using fasting glucose and insulin, they calculated homeostatic model assessment for insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI). They also took 3-day diet recalls and measured BMI, waist circumference, and hip circumference at baseline and 8 weeks.
Primary Outcome Measures
The primary outcome measure of the study is insulin resistance, as measured by HOMA-IR. Secondary outcome measures were blood glucose, insulin, total testosterone, LH, and FSH.
Statistical analysis was done using intergroup parameters with the control group serving as comparator. Statistically significant reduction in insulin resistance (HOMA-IR) was observed in the SPJ and SB groups from baseline to 8 weeks (P<0.05).
Similarly, insulin sensitivity (as assessed by QUICKI score) increased significantly in these 2 groups vs the control group (P<0.05). This reflected reductions in fasting insulin and glucose in these groups, but the reduction in fasting insulin was only statistically significant in the SB group.
Researchers hypothesized that these differing mechanisms would produce synergistic effects when combined; however, there was no greater improvement observed in the synbiotic + pomegranate juice group over the SB group, except for waist-to-hip circumference.
In terms of anthropometric changes, BMI, weight, and waist circumference significantly decreased in the SPJ and SB groups (P<0.05). There was no significant change in hip circumference, but waist-to-hip ratio decreased in the SPJ group. Total testosterone dropped in the SPJ and SB groups (P<0.05), but there was no significant change in FSH or LH.
Synbiotics are believed to be beneficial for PCOS because of their impact on carbohydrate metabolism, insulin sensitivity, and inflammation. These effects are achieved via increased production of glucagon-like peptide-1 (GLP-1), short-chain fatty acids (SCFAs), and natural killer cells.1,2 Pomegranate juice (particularly its punicic and catalpic acid constituents) is also believed to improve insulin sensitivity and reduce inflammation but via different mechanisms, including upregulation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and reduction in tumor necrosis factor alpha (TNF-α).3
Researchers hypothesized that these differing mechanisms would produce synergistic effects when combined; however, there was no greater improvement observed in the synbiotic + pomegranate juice group over the SB group, except for waist-to-hip circumference. The authors attribute the lack of improvement to the short duration of the trial and suspect a longer trial would reveal differences between these interventions. However, the pomegranate juice (PJ) group saw no improvements in any of the outcome measures assessed, and it does not seem prudent to put an individual with insulin resistance on a regimen that—according to the United States Department of Agriculture (USDA)—adds an estimated 279 g carbohydrates (269 g sugar) to their weekly macronutrient intake without clear data demonstrating independent benefits.
Would insulin resistance improve further with longer-term use? It is a question worth asking in future research.
If pomegranate juice is removed from the equation, the question then becomes: Is there an advantage to delivering synbiotics via beverage instead of capsule? The latter offers ease and consistency of dosage and perhaps better delivery of organisms to the large intestine, if enteric-coated. However, getting adequate amounts of inulin would likely require the addition of a powdered supplement. A recent meta-analysis and systematic review of probiotics and synbiotics in PCOS found only negligible benefits of these supplements on metabolic metrics,4 while another systematic review noted significant improvement in metabolic metrics and testosterone but not anthropometric measures.5 The confusion could be attributable to variability in composition and potency of the studied probiotics/synbiotics. One study that demonstrated benefits for HOMA-IR and other metabolic parameters used a synbiotic with Lactobacillus acidophilus, L casei, Bifidobacterium bifidum, and inulin at a concentration of 2 billion CFU and 800 mg, respectively.6 Another study that found benefits for apelin-36 (a peptide with effects on metabolic and cardiovascular health) but not HOMA-IR or inflammatory markers used a blend of L acidophilus, L casei, L bulgaricus, L rhamnosus, B longum, B breve, and Streptococcus thermophilus with inulin.7
Reduction in serum testosterone in the SPJ and SB groups is an intriguing secondary finding of this study. More research is warranted to determine if this reduction leads to improvement in symptoms of hyperandrogenism, including acne, hirsutism, and oligo/anovulation. A study of a synbiotic containing L acidophilus, L casei, B bifidum (2 billion CFU), and inulin (800 mg) showed reductions in modified Ferriman-Gallwey score for hirsutism in addition to sex hormone and inflammatory markers.8
Given the expanding body of research showing benefits of probiotics and synbiotics in a variety of conditions and minimal risk of side effects, it is worth a 12-week trial of synbiotics with inulin and a blend of Lactobacillus and Bifidobacterium species in cases of PCOS. Potential benefits include improvement in insulin resistance, BMI, waist circumference, and symptoms of hyperandrogenism. From the present research, there is not a compelling reason to combine synbiotics with pomegranate juice in the treatment of PCOS.
- Tremaroli V, Bäckhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489(7415):242-249.
- Ma X, Hua J, Li Z. Probiotics improve high fat diet-induced hepatic steatosis and insulin resistance by increasing hepatic NKT cells. J Hepatol. 2008;49(5):821-830.
- Viladomiu M, Hontecillas R, Lu P, Bassaganya-Riera J. Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. J Evid Based Complementary Altern Med. 2013;2013:1-18.
- Heshmati J, Farsi F, Yosaee S, et al. The effects of probiotics or synbiotics supplementation in women with polycystic ovarian syndrome: a systematic review and meta-analysis of randomized clinical trials [published online ahead of print December 13, 2019]. Probiotics Antimicrob Proteins.
- Hadi A, Moradi S, Ghavami A, Khalesi S, Kafeshani M. Effect of probiotics and synbiotics on selected anthropometric and biochemical measures in women with polycystic ovary syndrome: a systematic review and meta-analysis [published online ahead of print May 3, 2019]. Eur J Clin Nutr.
- Samimi M, Dadkhah A, Haddad Kashani H, Tajabadi-Ebrahimi M, Seyed Hosseini E, Asemi Z. The effects of synbiotic supplementation on metabolic status in women with polycystic ovary syndrome: a randomized double-blind clinical trial [published online ahead of print March 12, 2018]. Probiotics Antimicrob Proteins.
- Karimi E, Moini A, Yaseri M, et al. Effects of synbiotic supplementation on metabolic parameters and apelin in women with polycystic ovary syndrome: a randomised double-blind placebo-controlled trial. Br J Nutr. 2018;119(4):398-406.
- Nasri K, Jamilian M, Rahmani E, Bahmani F, Tajabadi-Ebrahimi M, Asemi Z. The effects of synbiotic supplementation on hormonal status, biomarkers of inflammation and oxidative stress in subjects with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial. BMC Endocr Disord. 2018;18(1):21.