Paoli A, Mancin L, Giacona MC, Bianco A, Caprio M. Effects of a ketogenic diet in overweight women with polycystic ovary syndrome. J Transl Med. 2020;18(1):104.
Researchers conducted a 12-week single-arm study to determine the impact of a ketogenic diet on anthropometric, cardiometabolic, and hormonal parameters in overweight women with polycystic ovary syndrome (PCOS).
A total of 16 women with PCOS diagnosed by the Rotterdam Criteria, aged 18 to 45 years, with a body mass index (BMI) ≥ 25 kg/m2 were enrolled in the study. All participants were desiring weight loss and agreed to abstain from contraceptive use during the trial. Though unspecified by the authors, the prohibited contraception is assumed to have included hormonal methods only.
Those pregnant or lactating, with hepatic, renal, or heart disease, or with symptoms explained by another condition (such as congenital adrenal hyperplasia, androgen secreting tumors, Cushing syndrome, or hypothyroidism) were excluded. Additional exclusion criteria included use of hormonal therapy or insulin sensitizers within 2 months and local hirsutism treatment.
All participants followed a modified ketogenic protocol for 12 weeks. The KEMEPHY (ketogenic Mediterranean with phytoextracts) diet of approximately 1,600 to 1,700 kcal/day was limited to meat (120 g), fish (20 g), eggs (2), and vegetables including green leafy, cruciferous, zucchini, cucumbers, and eggplant (no limit). Also incorporated were daily high-protein, low-carbohydrate food supplements with dried phytoextracts and liquid herbal extracts.
Study Parameters Assessed
Researchers obtained the following at weeks 0 and 12 to assess anthropometric, cardiometabolic, and hormonal status: body weight, BMI, fat body mass (FBM), lean body mass (LBM), percentages of FBM and LBM, visceral adipose tissue (VAT), insulin, glucose, homeostasis model assessment–insulin resistance (HOMA-IR), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TGs), total and free testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, dehydroepiandrosterone sulfate (DHEA-S), estradiol, progesterone, sex hormone–binding globulin (SHBG), and Ferriman-Gallwey score.
To ensure that participants attained ketosis, the researchers measured serum 3-hydroxybutyrate (BHB) levels every other day for the first 6 days, and every 6 days for the remainder of the trial.
Primary Outcome Measures
Researchers compared findings at 12 weeks to those at baseline.
Two participants failed to complete the trial, with 1 withdrawing at 2 weeks and the other prior to follow-up. The reasons were unspecified.
Participants achieved an average weight loss of 9.43 kg and decrease in BMI by 3.35. Researchers noted statistically significant improvements in body composition, with decreased fat body mass and increased percent lean body mass, as well as decreased visceral adipose tissue and waist circumference.
Measures of insulin resistance (insulin, glucose, and HOMA-IR) and lipid status (TGs, total cholesterol, LDL, and HDL) all significantly improved.
LH, total testosterone, free testosterone, percentage of free testosterone, and DHEA-S levels decreased while estradiol, progesterone, and SHBG levels increased. FSH also modestly increased, improving LH/FSH ratio. Ferriman-Gallwey score slightly, though nonsignificantly, decreased.
PCOS is an increasingly prevalent endocrine disorder, affecting up to 18% of reproductive-aged women.1 It is regarded as a heterogenous condition, given variations in clinical presentation and pathophysiologic mechanism. PCOS subtypes have been identified, based on aspects of Rotterdam Criteria present.2 Categorization according to BMI (lean: BMI < 25 vs overweight/obese: BMI ≥ 25) has also proven useful, given biochemical, hormonal, and metabolic dissimilarities between types.3
Obese PCOS is associated with a higher prevalence of insulin resistance and greater risk for long-term complications.3 Weight loss is considered a first-line intervention to improve insulin sensitivity and subsequently reduce symptomology and disease risk.4 Improvements in androgen levels, menstrual regularity, cardiovascular risk, pregnancy rates, and birth outcomes have all been documented.5,6 The literature suggests that only modest weight reduction is necessary, with positive effects noted with as little as 3.5% loss of body weight.7
Lifestyle intervention, particularly dietary modification, is a fundamental component of treatment targeting weight loss. A 2019 meta-analysis on dietary intervention and PCOS revealed that long-term low-carbohydrate diets (less than 45% of total daily caloric intake for more than 4 weeks) and low-fat/low-carbohydrate diets (less than 35% of fat and less than 45% of carbohydrates) are particularly effective.8 This finding is unsurprising given that carbohydrate excess is associated with inflammation, hyperinsulinemia, and hyperandrogenism.9
The present study under review here aimed to determine the impact of a ketogenic diet on PCOS. Prior research reveals benefits in insulin resistance, diabetes, cardiovascular disease, and weight loss, though literature on PCOS is lacking.10 A small pilot study conducted in 2005 is the only other documented study. The earlier findings were consistent with those found by Paoli et al, demonstrating positive effects of ketosis on anthropometric, hormonal, and metabolic parameters in PCOS. Additionally, 2 of the 5 participants achieved pregnancy, despite previous fertility issues.11
The literature suggests that only modest weight reduction is necessary, with positive effects noted with as little as 3.5% loss of body weight.
Paoli et al elected to have participants follow a modified ketogenic diet, referred to as KEMEPHY (ketogenic Mediterranean with phytonutrients). The authors poorly reported the methodologic approach, with no clear explanation of the diet or supplement protocol. KEMEPHY is a term mostly limited to Paoli et al, as referenced in past studies conducted by the team, so no objective background information is available. While the exact approach is not reproducible, the findings still appear useful.
The exact mechanism by which ketosis achieves therapeutic benefit remains unclear, though several physiologic processes have been identified. In regard to PCOS, the research highlights activation of 5’ adenosine monophosphate–activated protein kinase (AMPK), a regulator of cellular metabolism and energy balance. PCOS-specific benefits of increased enzymatic activity include decreased inflammation, improved insulin sensitivity, and weight loss.12 Caloric restriction,13 exercise,14 berberine,15 cinnamon,16 resveratrol,17 quercetin,18 inositol,19 and metformin20 have also been reported to upregulate AMPK activity.
It is common for patients to become symptomatic during the early stages of the diet, as the body transitions from utilizing glucose to utilizing fat for energy production. Though transient, this may hinder compliance. To mitigate side effects, Paoli et al had participants ingest 4 herbal liquid extracts daily. Given that many of the herbs included have been studied for PCOS and PCOS-related pathology (Matricaria chamomilla, Glycyrrhiza glabra, Foeniculum vulgare, and Cynara scolymus), it is reasonable to think that these formulas provided added benefit.21,22
The ketogenic diet appears to be worth considering for overweight PCOS patients, as does a low-carbohydrate diet. Given the challenges associated with attaining and maintaining ketosis, it may be prudent to reserve the recommendation for those who are otherwise treatment-resistant or presenting with significant disease severity. Regardless of the dietary approach selected, the addition of interventions known to upregulate AMPK activity may offer further benefit. After all, a multimodal treatment approach has proven beneficial for this population.23
Given the limited evidence on the topic, there are numerous avenues for future research. Several questions that come to mind: Do benefits persist following cessation of the ketogenic diet? If so, could the diet be used short-term to reset metabolism? How do improvements in biomarkers translate to clinical outcomes? How would lean PCOS patients with insulin resistance benefit from the diet?
- Moran LJ, Norman RJ, Teede HJ. Metabolic risk in PCOS: phenotype and adiposity impact. Trends Endocrinol Metab. 2015;26(3):136-143.
- Lizneva D, Suturina L, Walker W, et al. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6-15.
- Goyal M, Dawood A. Debates regarding lean patients with polycystic ovary syndrome: a narrative review. J Hum Reprod Sci. 2017;10(3):154-161.
- Ibáñez L, Oberfield SE, Witchel SF, et al. An International Consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr. 2017;6:307-331.
- Marzouk T, Sayed Ahmed W. Effect of dietary weight loss on menstrual regularity in obese young adult women with polycystic ovary syndrome. J Pediatr Adolesc Gynecol. 2015:28(6):457-461.
- Legro RS, Dodson WC, Kunselman AR, et al. Benefit of delayed fertility therapy with preconception weight loss over immediate therapy in obese women with PCOS. J Clin Endocrinol Metab. 2016;101(7):2658-2666.
- Soares NP, Santos AC, Costa EC, et al. Diet-induced weight loss reduces DNA damage and cardiometabolic risk factors in overweight/obese women with polycystic ovary syndrome. Ann Nutr Metab. 2016;68(3):220-227.
- Zhang X, Zheng Y, Guo Y, Lai Z. The effect of low carbohydrate diet on polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2019;2019:4386401.
- Barrea L, Marzullo P, Muscogiuri G, et al. Source and amount of carbohydrate in the diet and inflammation in women with polycystic ovary syndrome. Nutr Res Rev. 2018;31(2):291-301.
- Paoli A, Rubini A, Volek JS, Grimaldi KA. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr. 2013;67(8):789-796.
- Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond). 2005;2:35.
- Lyons CL, Roche HM. Nutritional modulation of AMPK-impact upon metabolic-inflammation. Int J Mol Sci. 2018;19(10):3092.
- Speakman JR, Mitchell SE. Caloric restriction. Mol Aspects Med. 2011;32(3):159-221.
- Janzen NR, Whitfield J, Hoffman NJ. Interactive roles for AMPK and glycogen from cellular energy sensing to exercise metabolism. Int J Mol Sci. 2018;19(11). pii:E3344.
- Wang H, Zhu C, Ying Y, Luo L, Huang D, Luo Z. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases. Oncotarget. 2018;9(11):10135-10146.
- Shen Y, Honma N, Kobayashi K, et al. Cinnamon extract enhances glucose uptake in 3T3-L1 adipocytes and C2C12 myocytes by inducing LKB1-AMP-activated protein kinase signaling. PLoS One. 2014;9(2):e87894.
- Lan F, Weikel KA, Cacicedo JM, Ido Y. Resveratrol-induced AMP-activated protein kinase activation is cell-type dependent: lessons from basic research for clinical application. Nutrients. 2017;9(7). pii:E751.
- Shen Y, Croft KD, Hodgson JM, et al. Quercetin and its metabolites improve vessel function by inducing eNOS activity via phosphorylation of AMPK. Biochem Pharmacol. 2012;84(8):1036-1044.,
- Cabrera-Cruz H, Oróstica L, Plaza-Parrochia F, et al. The insulin-sensitizing mechanism of myo-inositol is associated with AMPK activation and GLUT-4 expression in human endometrial cells exposed to a PCOS environment. Am J Physiol Endocrinol Metab. 2020;318(2):E237-E248.
- Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253-270..
- Ashkar F, Rezaei S, Salahshoornezhad S, et al. The role of medicinal herbs in treatment of insulin resistance in patients with polycystic ovary syndrome: a literature review. Biomol Concepts. 2020;11(1):57-75.
- Mahboubi M. Cynara scolymus (artichoke) and its efficacy in management of obesity. Bull Fac Pharm Cairo Univ. 2018;56(2);115-120.
- Arentz S, Smith C, Abbott J, et al. Combined lifestyle and herbal medicine in overweight women with polycystic ovary syndrome (PCOS): a randomized controlled trial. Phytother Res. 2017;31:1330-1340.