Reference
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.
Design
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).
Participants
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.
Intervention
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.
Key Findings
Two participants failed to complete the trial, with 1 withdrawing at 2 weeks and the other prior to follow-up. The reasons were unspecified.
Anthropometric status
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.
Cardiometabolic status
Measures of insulin resistance (insulin, glucose, and HOMA-IR) and lipid status (TGs, total cholesterol, LDL, and HDL) all significantly improved.
Hormonal status
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.
Practice Implications
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?
