Introduction: The optimal dietary strategy to improve the metabolic and reproductive endocrine profile in adolescents with obesity and polycystic ovary syndrome (PCOS) is undefined. This study was conducted to evaluate the efficacy of the MEtabolic Syndrome REduction in NAvarra (RESMENA) diet versus a control diet based on American Heart Association (AHA) recommendations for the treatment of PCOS in adolescents with PCOS. Methods: A total of 40 adolescents diagnosed with PCOS between the ages of 13–18 years were randomized to either a RESMENA or control diet for 6 months. Dietary status, anthropometry, body composition, biochemical parameters, and reproductive endocrine hormones were compared between the 2 groups before and after the intervention. Results: Both diet groups showed significant decreases in anthropometric parameters, whereas the RESMENA diet provided a greater decrease in all these parameters except neck circumference and fat percentage (p <0.05). At the end of the study, fasting insulin, ALT, and total cholesterol levels decreased in both control and RESMENA groups; HbA1c, HOMA-IR, and hs-CRP levels decreased; and QUICKI score increased in the RESMENA group (p <0.05). There was no statistical difference in the androgen levels of the control group compared to the baseline. In the RESMENA group, there were a significant decrease in total testosterone, free testosterone, 17-OH progesterone, androstenedione, LH levels and LH/FSH ratio, and free androgen index and a significant increase in SHBG levels (p <0.05). Conclusions: Both dietary patterns resulted in significant improvement in anthropometric measurements and body composition, but the RESMENA diet showed beneficial effects on insulin resistance parameters and androgen levels.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine metabolic disorders affecting 8–13% of women and 3.4–19.6% of adolescent girls depending on the diagnostic criteria used and the population studied [1, 2]. PCOS is a multifactorial disorder and is characterized by a combination of clinical (anovulation and hyperandrogenism), biochemical (excessive androgen and luteinizing hormone [LH] concentrations), and ovarian morphological (polycystic ovaries) features [3].

While PCOS causes reproductive endocrine disorders in the short term, it may lead to metabolic abnormalities including fatty liver disease, excessive weight or obesity, type 2 diabetes, cardiovascular risk, and increased risk of endometrial cancer in the long term [1, 4]. Adolescents with PCOS usually have hyperinsulinemia and insulin resistance (IR). IR is an important mechanism leading to abnormal glycolipid metabolism and reproductive dysfunction [5]. Approximately 30% of adolescents with PCOS are reported to be overweight. Obesity increases IR and compensatory hyperinsulinemia, which in turn increases adipogenesis and decreases lipolysis, promotes ovarian androgen production, and exacerbates ovarian androgen hypersecretion disorder, resulting in reproductive endocrine disorders, increased cardiometabolic risk, and decreased quality of life in patients with PCOS [6, 7]. In addition, obesity-related inflammation may have potential effects on ovarian physiology due to dysregulated adipokine secretion affecting insulin sensitivity [6]. Therefore, body weight management is very important in adolescents with PCOS. It has been reported that 5–10% weight loss for 6 months in overweight individuals with PCOS improves metabolic disorders [1].

The aim of PCOS treatment is not only to improve menstrual cycles and hirsutism but also to reduce metabolic syndrome and risk factors for cardiovascular events such as IR, dyslipidemia, and obesity [5]. The first-line treatment for individuals with PCOS is lifestyle modifications including nutritional therapy, physical activity, and behavioral therapy. Dietary modifications play an important role in treatment [1]. It has been reported that high-fat and high-carbohydrate diets aggravate the development of obesity and clinical features of PCOS [8]. It has been suggested that alternative dietary approaches such as low calorie, sugar and refined carbohydrate intake restricted, low glycemic index, low glycemic load, high protein, low carbohydrate or modified fatty acid (FA) diets, or/and the Mediterranean diet have more favorable hormonal or metabolic effects and are more effective in achieving and maintaining long-term weight loss in PCOS [9‒12]. There are also studies showing that achieving weight loss by providing an energy deficit improves androgen levels, regardless of diet composition [9, 11].

However, the composition and macronutrient balance of the optimal diet to be applied for individuals with PCOS are undefined, and data on the effects of diets in which the amount or type of protein, fat, or carbohydrate is changed independently of weight loss on the metabolic, reproductive, and psychological characteristics of PCOS, especially in adolescents, are limited [7, 13]. In most of the studies on nutritional strategies in this field, the effects of some selected dietary components have been examined separately [14‒16]. The therapeutic effect of a complete dietary pattern rather than a single dietary factor on PCOS remains unclear. In this study, we hypothesized that a combination of all components (carbohydrate, protein, n-3 FAs, total antioxidant capacity, glycemic index, glycemic load, meal frequency) may be effective on PCOS when included in an integrated adequate dietary pattern. The MEtabolic Syndrome REduction in NAvarra (RESMENA) diet is characterized by increased meal frequency (7 meals/day), low glycemic load, high antioxidant capacity, high n-3 FAs, high protein, and healthy FA content. The RESMENA diet has been shown to improve body composition, biochemical markers, lipid profile, and oxidative stress markers in patients with metabolic syndrome, especially in patients with central obesity [17], but no study has been conducted to examine the therapeutic effect of this diet pattern in individuals with PCOS. The aim of this study was to investigate the effect of the RESMENA diet, a new dietary strategy, on body weight, body composition, and metabolic and reproductive endocrine profile in adolescents with obesity and PCOS.

Study Design

The study was designed as a single-blind, randomized, two-arm, parallel 6-month dietary intervention. Adolescents who met the study criteria and volunteered to participate were randomly assigned to two different diet groups, control or experimental diet (the control and the RESMENA groups, respectively), by the research assistant with an allocation ratio of 1:1, during the study period. A statistician performed the random allocation process. All cases were assigned codes. The codes were sealed in opaque envelopes and kept in statistician office until the last patient completed the study. Study personnel involved in the analysis of the results (endocrinologist, radiologist, nurse, and laboratory technicians) were blinded to group assignments.

All adolescents were invited to a face-to-face interview at the start of study and every 2 weeks for 6 months. Anthropometric measurements, body composition analysis, and a physical activity questionnaire were performed, and 3-day food consumption records and blood samples for the measurement of biochemical parameters were taken. Physical activity and food consumption records of the adolescents were repeated, and anthropometric measurements and body composition were analyzed every 2 weeks until the study end. Blood samples were collected at baseline and at the end of the study.

The primary outcomes were changes in androgen profile and IR. Secondary outcomes included changes in anthropometric measurements, body composition, lipid profile, and inflammatory profile.

Participants

Adolescents with PCOS aged 13–18 years were recruited from Gazi University Hospital Paediatric Endocrinology Outpatient Clinic between January and December 2021, with all data collection completed in June 2022. The inclusion criteria were as follows: (a) diagnosis of PCOS in adolescent girls according to the Rotterdam criteria [18], (b) age 13–18 years, and (c) body mass index (BMI) ≥95th percentile. Exclusion criteria were other endocrine etiological disorders (Cushing’s syndrome, congenital adrenal hyperplasia, McCune-Albright syndrome, mutations in the glucocorticoid receptor gene, ovarian and adrenal androgen-secreting tumors, hyperprolactinemia, diabetes mellitus, thyroid dysfunction, and other endocrine disorders), cardiovascular and cerebrovascular diseases, hematologic disorders, liver and kidney failure and other serious diseases, mental disorders, eating disorders, contraceptive use in the last 3 months, use of insulin-sensitizing agents, use of drugs affecting lipid metabolism (such as fish oil), and smoking. Adolescents who refused to participate and did not meet inclusion criteria were excluded (Fig. 1).

Fig. 1.

Study flow diagram.

Fig. 1.

Study flow diagram.

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This study was carried out in accordance with the guidelines laid down in the Declaration of Helsinki, and written informed consent was obtained from all participants and their parents. The protocol study was approved by the Ethics Committee of Clinical Research at Gazi University (No: 345, March 29, 2021)

Dietary Interventions

Both diets were designed without calorie restriction. The calories of the diets were calculated according to the 85th percentile energy requirement values of adolescents of the same age and gender with low physical activity levels (PALs) according to the Turkish Dietary Guidelines-2015, prescribed by a dietician [19]. The two interventions were as follows:

The RESMENA diet: It was characterized by a higher meal frequency, consisting of seven meals/d (including breakfast, lunch, dinner, and two snacks in the morning and two snacks in the afternoon), and by a different macronutrient distribution – 40% total energy value from carbohydrates, 30% from proteins, and 30% from lipids. This pattern tried to reinforce high n-3 polyunsaturated FA (n-3 PUFA) and high natural antioxidant food consumption and promoted low GL CHO intake. It also maintained a healthy FA profile and a cholesterol content of less than 300 mg/day [17]. Control diet: It was based on the American Heart Association (AHA) guidelines [20], including 3–5 meals per day, macronutrient distribution of 55% total energy value from carbohydrates, 15% proteins, and 30% lipids, a healthy FA profile, and a cholesterol consumption lower than 300 mg/day.

In order for both study groups to follow the recommended diets correctly and appropriately, the participants were contacted by the dietitian twice a week by phone, WhatsApp groups were formed, and continuous communication was provided via social media. Daily meal plans were prepared for each participant in both groups based on their energy requirement and eating habits and sent to the participants via social media at the beginning of each week. Participants were asked to keep 3-day dietary records to evaluate their compliance with the diet and were invited to the research center to be checked every 2 weeks. Participants were contacted via video chat at the end of each week to review whether the intervention created psychological pressure, evaluate participant adherence and satisfaction, provide counseling support to facilitate the effectiveness of the intervention. Dietary records were analyzed using the BeBiS program (Nutrition Information System, Version, Stuttgart, Germany). At each interview, participants were informed about mistakes and/or deficiencies in their diet (skipping main and snacks, inability to adjust portions). The sum of EPA and DHA (EPA+DHA) intake obtained using the BeBiS program was used to estimate n-3 PUFA consumption. The antioxidant capacity of the diet was calculated according to the raw and cooked forms of foods using the data of Carlsen et al. [21].

The Healthy Eating Index-2010 (HEI-2010) from food consumption records was used to assess diet quality. HEI-2010 is evaluated on a “100 points” scale. When the diet quality of individuals is categorized according to the total HEI-2010 score, “poor diet” is defined if the scores are below 51, “needing dietary improvement” if the scores are between 51 and 80, and “good diet” if the scores are above 80 [22]. GI and GL were obtained from Foster-Powell et al. [23].

Assessment of Physical Activity

Physical activity was assessed using a 24-h physical activity recording form. Using the physical activity record form, the time spent for daily sleeping, lying down, sitting activities, light activities, moderate activities, and heavy activities was recorded. The physical activity ratio values determined for the physical activity types were multiplied by the recorded activity durations of the individuals, and the total energy cost was calculated. PAL was found by dividing the total energy cost by 24 h [24]. Participants were advised to maintain their usual activity levels during the study.

Anthropometric Measurements and Body Composition Analysis

Anthropometric measurements and body composition analysis were performed by trained dietitians in the early morning with at least 8-h fasting. Body weight measurement and body composition analysis (fat mass, fat percentage, fat-free mass) were made by using the InBody 720 device (1–1,000 kHz; InBody Co., Ltd., Korea). Height was measured with a stadiometer. BMI was calculated using the following formula: “BMI = [body weight (kg)/(height [m])2].” WHO AnthroPlus program was used to calculate BMI z scores [25]. Neck circumference was measured in the midway of the neck, between the mid-cervical spine and mid-anterior neck of subjects standing upright. Waist circumference (cm) was measured from the midpoint between the lowest rib and the iliac crest. Hip circumference (cm) was measured horizontally at the largest circumference of the hip. The waist-to-hip ratio was calculated by dividing the waist circumference by the hip circumference.

Biochemical Analyses

Venous blood samples were collected at baseline and at the end of the study. Samples were centrifuged and stored at −80°C until further analysis. The fasting blood glucose, insulin, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol (LDL-C), HDL cholesterol, triglyceride, alanine aminotransferase (ALT), aspartate aminotransferase, HbA1c, LH, follicle-stimulating hormone (FSH), total and free testosterone, prolactin, dehydroepiandrosterone sulfate, androstenedione, 17-hydroxyprogesterone (17-OH progesterone), sex hormone-binding globulin (SHBG), high-sensitivity CRP (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels of the adolescents were assayed in the Research Centre Hospital according to conventional laboratory standard methods. Venous blood samples were measured from all of the patients from the antecubital region between 8:00 and 8:30 am after an 8–12-h overnight fast. Fasting glucose was measured with the enzymatic UV (hexokinase method) test method using the autoanalyzer AU5800 (Beckman Coulter Inc). HDL cholesterol, LDL-C, total cholesterol, and triglyceride levels were measured with the enzymatic colorimetric method using the autoanalyzer AU5800 (Beckman Coulter Inc). Insulin levels were measured with the one-step principle enzymatic immunoassay method using the autoanalyzer UniCel DxI 800 (Beckman Coulter Inc). Serum aspartate aminotransferase and ALT levels were measured by kinetic UV method using the autoanalyzer AU5800 (Beckman Coulter Inc). HbA1c levels were measured with the high-performance liquid chromatography method using the Tosoh G8 device. LH, FSH, and prolactin levels were measured with sandwich chemiluminescent immunoenzymatic assay (Beckman Coulter Inc). Total testosterone and dehydroepiandrosterone sulfate levels were measured with the competitive chemiluminescent immunoenzymatic assay method (Beckman Coulter Inc). Free testosterone, androstenedione, and 17-OH progesterone levels were measured with the radioimmunoassay method (DIA Source Inc). SHBG and IL-6 levels were measured with the Roche Cobas electrochemiluminescence immunoassay method. Hs-CRP levels were measured with a latex-enhanced turbidimetric immunoassay method (Beckman Coulter Inc). TNF-α levels were measured by ELISA method.

The HOMA-IR index value was calculated using the “fasting blood glucose (mmol/L) × fasting insulin (μU/mL)/22.5” formula [26]. The QUICKI index was calculated as 1/[log(fasting insulin in μU/ml)+log(fasting glucose in mg/dL)] [27].

Free androgen index (FAI) was calculated according to the following equation: FAI = [(Total testosterone/SHBG) × 100] [28]. Bioavailable testosterone was calculated using SHBG, serum albumin, and total testosterone level data using Vermeulen’s formula available online at the website “http://www.issam.ch/freetesto.htm” [29]. LH/FSH ratios of participants were calculated as one of the androgen markers. The Ferriman-Gallwey score was completed by a health professional and used to evaluate hirsutism. The density of terminal hairs at 11 different body sites (the lip, chin, chest, upper abdomen, lower abdomen, upper arm, forearm, thigh, lower leg, upper back, and lower back) was scored from 0 to 4, and the total score was calculated.

Power Calculation and Statistical Analysis

When the change between the baseline and sixth month insulin averages was 6.51 and the maximum standard deviation was 8.81, the minimum observation values required for 80%, 85%, 90%, and 95% statistical power were 17, 19, 22, and 26, respectively. The statistical power of this study with 20 individuals in each group is above 85%. The reason for including more than 20 participants (34 participants) in each group after the start of the study was the possibility that the number of participants who would not be able to adapt to the diet and come to regular controls may be high due to the emergence of the COVID-19 outbreak.

The data of the study were analyzed using the Statistical Package for the Social Sciences (SPSS) 22 program. In this study, the mean values of some variables measured at the baseline and end of the study in the two diet groups were statistically analyzed for differences in the decrease or increase between the groups and for differences in the decrease or increase between the groups at baseline and end of the study. The information obtained was interpreted at a 95% confidence level. Since all of the measured variables were continuous quantitative variables, normal distribution was examined with the Kolmogorov-Smirnov test. For variables with parametric structure, mean and standard deviation were given, while for other measurements, median (minimum-maximum) was reported. In parametric cases, baseline-end line comparisons were made by dependent t test, and comparisons of differences between groups were made by independent t test. In nonparametric cases, the Wilcoxon sign test was used for baseline-end line differences, and the Mann-Whitney U test was used for comparisons of differences between groups. Differences were considered significant when p <0.05.

A total of 84 adolescents were invited to the study, 16 of whom were excluded for various reasons. The remaining 68 adolescents were randomly divided into two groups. The study was completed with a total of 40 adolescents for 6-month intervention period. The study flow is presented in Figure 1. The RESMENA group consisted of 20 adolescent girls (age: 15.7 ± 1.66 years), and the control group consisted of 20 adolescent girls (age: 16.0 ± 1.49 years).

Dietary Intake

At baseline, there were no significant differences in the dietary characteristics of the two groups, except for HEI. Changes in diet composition after the dietary intervention differed between the groups as intended (Table 1). Both groups showed a statistically significant decrease in total daily energy intake compared to baseline [control: 2,144.48 kcal/day to 1,771.86 kcal/day; RESMENA: 2,085.89 kcal/day to 1,795.44 kcal/day] (p <0.001).

Table 1.

Dietary intake and physical activity profile at baseline and after the intervention

ParametersControl group (n = 20)p value1RESMENA group (n = 20)p value2p value*p value**
baseline, mean ± SDb6 monthsa, mean ± SDbbaseline, mean ± SDb6 monthsa, mean ± SDb
Energy, kcal/day 2,144.48 (1,867.17–2,411.24) 1,771.86 (1,594.17–2,017.53) <0.001 2,085.89 (1,913–2,289.4) 1,795.44 (1,486.51–1,929.54) <0.001 0.565 0.565 
Carbohydrate (%E) 47.6±3.66 52.17±3.08 <0.001 49.23±4.62 40.94±1.35 <0.001 <0.001 0.265 
Protein (E%) 14.87±1.61 15.93±1.39 0.274 15.87±2.38 25.58±1.1 0.010 <0.001 0.157 
Fat (E%) 37.48±3.72 31.9±3.46 <0.001 34.95±3.9 33.88±1.66 <0.001 0.001 0.052 
Saturated FA (% E) 14.31±1.59 9.8±1.22 <0.001 15.94±2.3 9.9±1 <0.001 0.040 0.120 
MUFA (%E) 12.41±2.14 15.26±1.89 <0.001 11.98±1.65 17.78±2.41 0.002 0.001 0.547 
PUFA (%E) 7.25±1.41 5.79±1.05 0.003 6.87±1.43 8.31±1.22 <0.001 <0.001 0.398 
Omega 3, g 1.16±0.28 1.18±0.34 0.429 1.4±0.41 3.01±0.55 <0.001 <0.001 0.068 
Cholesterol, mg/day 400.01±62.26 266.54±39.03 <0.001 414.95±75.99 210.15±42.09 <0.001 0.003 0.355 
Fiber, g 18.38±2.27 18.95±2.19 0.302 19.79±3.09 32.65±4.52 <0.001 <0.001 0.102 
Diet antioxidant capacity, mmoL 1.86±0.48 1.94±0.46 <0.001 2.42±0.97 5.54±1.24 <0.001 <0.001 0.142 
HEI score 60.54±5.78 72.21±6.12 0.530 54.55±3.88 75.77±5.21 <0.001 0.001 0.001 
Meal frequency 4 (2–6) 4 (3–5) 0.447 4 (3–5) 7 (6–7) <0.001 0.583 0.583 
Glycemic index 88.7±7.96 80.53±9.45 <0.001 83.15±8.35 50.69±4.67 <0.001 <0.001 0.369 
Glycemic load 121.75±31.19 103.87±18.8 <0.001 118.25±36.18 77.89±10.06 <0.001 0.046 0.069 
Physical activity level (PAL) 1.42±0.04 1.43±0.03 0.402 1.41±0.05 1.42±0.06 0.426 0.860 0.289 
ParametersControl group (n = 20)p value1RESMENA group (n = 20)p value2p value*p value**
baseline, mean ± SDb6 monthsa, mean ± SDbbaseline, mean ± SDb6 monthsa, mean ± SDb
Energy, kcal/day 2,144.48 (1,867.17–2,411.24) 1,771.86 (1,594.17–2,017.53) <0.001 2,085.89 (1,913–2,289.4) 1,795.44 (1,486.51–1,929.54) <0.001 0.565 0.565 
Carbohydrate (%E) 47.6±3.66 52.17±3.08 <0.001 49.23±4.62 40.94±1.35 <0.001 <0.001 0.265 
Protein (E%) 14.87±1.61 15.93±1.39 0.274 15.87±2.38 25.58±1.1 0.010 <0.001 0.157 
Fat (E%) 37.48±3.72 31.9±3.46 <0.001 34.95±3.9 33.88±1.66 <0.001 0.001 0.052 
Saturated FA (% E) 14.31±1.59 9.8±1.22 <0.001 15.94±2.3 9.9±1 <0.001 0.040 0.120 
MUFA (%E) 12.41±2.14 15.26±1.89 <0.001 11.98±1.65 17.78±2.41 0.002 0.001 0.547 
PUFA (%E) 7.25±1.41 5.79±1.05 0.003 6.87±1.43 8.31±1.22 <0.001 <0.001 0.398 
Omega 3, g 1.16±0.28 1.18±0.34 0.429 1.4±0.41 3.01±0.55 <0.001 <0.001 0.068 
Cholesterol, mg/day 400.01±62.26 266.54±39.03 <0.001 414.95±75.99 210.15±42.09 <0.001 0.003 0.355 
Fiber, g 18.38±2.27 18.95±2.19 0.302 19.79±3.09 32.65±4.52 <0.001 <0.001 0.102 
Diet antioxidant capacity, mmoL 1.86±0.48 1.94±0.46 <0.001 2.42±0.97 5.54±1.24 <0.001 <0.001 0.142 
HEI score 60.54±5.78 72.21±6.12 0.530 54.55±3.88 75.77±5.21 <0.001 0.001 0.001 
Meal frequency 4 (2–6) 4 (3–5) 0.447 4 (3–5) 7 (6–7) <0.001 0.583 0.583 
Glycemic index 88.7±7.96 80.53±9.45 <0.001 83.15±8.35 50.69±4.67 <0.001 <0.001 0.369 
Glycemic load 121.75±31.19 103.87±18.8 <0.001 118.25±36.18 77.89±10.06 <0.001 0.046 0.069 
Physical activity level (PAL) 1.42±0.04 1.43±0.03 0.402 1.41±0.05 1.42±0.06 0.426 0.860 0.289 

p1: value of the baseline 6-month difference in the control group.

p2: value of the baseline 6-month difference in the RESMENA group.

p*: value of the difference between groups.

p**: value of the baseline difference between the control group and the RESMENA group.

aThese are the averages of the values every 2 weeks over a 6-month period.

bMean ± SD was given when the distribution of the data was parametric, and median (Min-Max) was given when it was not parametric.

In parametric cases, comparisons between the dependent t test and the differences between groups were made with the independent t test. In nonparametric cases, the Wilcoxon sign test was used for the baseline 6-month differences and the Mann-Whitney U test was used for the comparisons of the differences between groups.

The carbohydrate intake (%E) increased in the control group and decreased in the RESMENA group, leading to a significant difference between the groups (p <0.001). Protein intake (%E) significantly increased in the RESMENA group (p <0.001). Total fat (%E), saturated FA, and cholesterol intakes decreased significantly in both groups compared to baseline (p <0.001). MUFA intake (%E) and total antioxidant capacity increased significantly in both groups, but the RESMENA group showed a greater increase than the control group (p <0.001). PUFA intake (%E) decreased significantly in the control group but increased significantly in the RESMENA group (p <0.001). Significant increases were observed in fiber and omega-3 intake, HEI scores, and meal frequency of the RESMENA group compared to baseline (p <0.001). Significant decreases were observed in cholesterol intake and GI and GL values of both groups (p <0.001), but the RESMENA group showed a greater decrease than the control group (p <0.05). PALs did not change either during the intervention.

Anthropometric and Body Composition Measurements

At baseline, there were no significant differences in the anthropometric characteristics of the two groups. At the end of the study, body weight, neck circumference, waist circumference, hip circumference, BMI z score, BMI, fat mass, fat percentage, and fat mass/lean body mass ratio measurements decreased in both the control and RESMENA groups, and when the differences of the decreases in the groups were examined, it was found that the changes in the RESMENA group were significantly higher than the changes in the control group in all parameters except neck circumference (p = 0.133) and fat percentage (p = 0.052) (p <0.05) (Table 2).

Table 2.

Anthropometric measurements and body composition at baseline and after the intervention

Control group (n = 20)p value1RESMENA group (n = 20)p2 valuep value*p value**
baseline, mean ± SDb6 monthsa, mean ± SDbbaseline, mean ± SDb6 monthsa, mean ± SDb
Years 16±1.49 16±1.49 1.000 15.7±1.66 15.7±1.66 1.000 1.000 0.583 
Body weight, kg 91.22±9.97 83.92±9.05 <0.001 90.76±14.69 79.36±12.73 <0.001 0.008 0.883 
Neck circumference, cm 37.7±2.22 33.98±1.79 <0.001 37.78±3.72 33.03±2.49 <0.001 0.133 0.758 
Hip circumference, cm 111.25±8.65 106.3±9.65 <0.001 106.9±12.2 96.3±9.54 <0.001 0.003 0.301 
Waist circumference, cm 121.02±6.18 112.98±6.28 <0.001 119.18±8.87 106.2±7.12 <0.001 0.001 0.820 
Waist to hip 0.91 (0.8–1.01) 0.9 (0.78–1.01) 0.304 0.91 (0.78–0.96) 0.87 (0.76–0.95) 0.176 0.314 0.314 
BMI z score 2.72±0.42 2.31±0.43 <0.001 2.8±0.67 2.04±0.65 <0.001 0.001 0.398 
BMI, kg/m2 33.63±3.47 30.94±3.09 <0.001 33.71±3.95 29.11±3.4 <0.001 0.001 0.883 
Fat mass, kg 35.64±5.75 31.75±5.58 <0.001 42.01±11.36 35.79±10.65 <0.001 0.027 0.063 
Body fat (%) 38.9 (33–45.88) 35.85 (27.6–38.79) <0.001 49.85 (27–60.8) 37.62 (25.1–54.5) <0.001 0.052 0.052 
Skeletal muscle mass, kg 53.41±6.63 53.58±6.09 0.683 48.42±8.84 48.66±7.36 0.791 0.939 0.060 
Fat-free mass, kg 48.8 (31.7–51.8) 50.5 (33.15–53.20) 0.365 44.33 (36.4–56.7) 45.45 (30.5–55.4) 0.232 0.640 0.640 
Lean body mass, kg 52.34 (42.8–58.8) 51.06 (44–59.3) 0.488 51.07 (40.4–64.10) 51.85 (39.9–67.2) 0.517 0.705 0.612 
Fat mass/lean body mass ratio 0.68±0.92 0.62±0.85 <0.001 0.78±0.17 0.71±0.18 <0.001 0.041 0.059 
Control group (n = 20)p value1RESMENA group (n = 20)p2 valuep value*p value**
baseline, mean ± SDb6 monthsa, mean ± SDbbaseline, mean ± SDb6 monthsa, mean ± SDb
Years 16±1.49 16±1.49 1.000 15.7±1.66 15.7±1.66 1.000 1.000 0.583 
Body weight, kg 91.22±9.97 83.92±9.05 <0.001 90.76±14.69 79.36±12.73 <0.001 0.008 0.883 
Neck circumference, cm 37.7±2.22 33.98±1.79 <0.001 37.78±3.72 33.03±2.49 <0.001 0.133 0.758 
Hip circumference, cm 111.25±8.65 106.3±9.65 <0.001 106.9±12.2 96.3±9.54 <0.001 0.003 0.301 
Waist circumference, cm 121.02±6.18 112.98±6.28 <0.001 119.18±8.87 106.2±7.12 <0.001 0.001 0.820 
Waist to hip 0.91 (0.8–1.01) 0.9 (0.78–1.01) 0.304 0.91 (0.78–0.96) 0.87 (0.76–0.95) 0.176 0.314 0.314 
BMI z score 2.72±0.42 2.31±0.43 <0.001 2.8±0.67 2.04±0.65 <0.001 0.001 0.398 
BMI, kg/m2 33.63±3.47 30.94±3.09 <0.001 33.71±3.95 29.11±3.4 <0.001 0.001 0.883 
Fat mass, kg 35.64±5.75 31.75±5.58 <0.001 42.01±11.36 35.79±10.65 <0.001 0.027 0.063 
Body fat (%) 38.9 (33–45.88) 35.85 (27.6–38.79) <0.001 49.85 (27–60.8) 37.62 (25.1–54.5) <0.001 0.052 0.052 
Skeletal muscle mass, kg 53.41±6.63 53.58±6.09 0.683 48.42±8.84 48.66±7.36 0.791 0.939 0.060 
Fat-free mass, kg 48.8 (31.7–51.8) 50.5 (33.15–53.20) 0.365 44.33 (36.4–56.7) 45.45 (30.5–55.4) 0.232 0.640 0.640 
Lean body mass, kg 52.34 (42.8–58.8) 51.06 (44–59.3) 0.488 51.07 (40.4–64.10) 51.85 (39.9–67.2) 0.517 0.705 0.612 
Fat mass/lean body mass ratio 0.68±0.92 0.62±0.85 <0.001 0.78±0.17 0.71±0.18 <0.001 0.041 0.059 

p1: value of the baseline 6-month difference in the control group.

p2: value of the baseline 6-month difference in the RESMENA group.

p*: value of the difference between groups.

p**: value of the baseline difference between the control group and the RESMENA group.

aThese are the averages of the values every 2 weeks over a 6-month period.

bMean ± SD was given when the distribution of the data was parametric, and median (Min-Max) was given when it was not parametric.

In parametric cases, comparisons between the dependent t test and the differences between groups were made with the independent t test.

In nonparametric cases, the Wilcoxon sign test was used for the baseline 6-month differences and the Mann-Whitney U test was used for the comparisons of the differences between groups.

Metabolic Profile

At baseline, there were no significant differences in the metabolic profile of the two groups. At the end of the sixth month, a decrease was observed in fasting insulin (p = 0.037), ALT (p = 0.026), and total cholesterol (p = 0.023) levels in the control group. In the RESMENA group, there was a decrease in fasting insulin (p <0.001), ALT (p = 0.026), total cholesterol (p = 0.027), HbA1c and HOMA-IR levels (p = 0.001), and an increase in the QUICKI score (p <0.001). It was determined that the decrease in fasting insulin levels (p = 0.049) and HbA1c levels (p = 0.014) and the increase in the QUICKI score (p = 0.042) were higher in the RESMENA group (Table 3).

Table 3.

Metabolic profile at baseline and after the intervention

Control group (n = 20)p value1RESMENA group (n = 20)p value2p value*p value**
baseline, mean ± SDa6 months, mean ± SDabaseline, mean ± SDa6 months, mean ± SDa
Glycemic control and lipid profile 
 Fasting glucose, mg/dL 87 (57–106) 89.5 (77–110) 0.513 91 (81–114) 88 (74–101) 0.492 0.558 0.758 
 Postprandial blood glucose, mg/dL 141.3±24.01 143.1±20.02 0.591 141.3±33.04 140.35±19.12 0.897 0.732 0.820 
 Fasting insulin, IU/mL 17.13±7.73 14.52±3.84 0.037 21.9±8.81 15.39±3.74 <0.001 0.049 0.052 
 Aspartate aminotransferase (AST), U/L 20 (12–22.6) 19 (11–20.1) 0.166 18 (8–62) 19 (11–34) 0.920 0.738 0.738 
 ALT, U/L 19.5 (15–22.7) 17.5 (13–18.9) 0.026 18.5 (12–44) 16.5 (11–31) 0.026 0.461 0.461 
 Total cholesterol, mg/dL 170.3±32.08 155.78±27.69 0.023 177.7±37.18 162.8±26.64 0.027 0.965 0.820 
 HDL cholesterol, mg/dL 44±6.53 45.05±4.96 0.330 45.06±8.58 45.75±5.59 0.577 0.823 0.779 
 LDL cholesterol, mg/dL 102±20.38 103.01±16.42 0.818 105.5±21.17 95.75±19.05 0.053 0.101 0.698 
 Triglycerides, mg/dL 103 (57–127.8) 100.47 (66–120.45) 0.156 115 (34–300) 105.5 (69–200) 0.184 0.698 0.602 
 HbA1c, % 5.32±0.3 5.22±0.24 0.192 5.52±0.37 5.35±0.33 0.001 0.014 0.091 
 QUICKI 0.32±0.02 0.32±0.01 0.135 0.31±0.02 0.32±0.01 <0.001 0.042 0.076 
 HOMA-IR 3.42 (1.34–4.78) 3.19 (1.69–3.49) 0.099 4.12 (2.23–11.08) 3.83 (1.77–4.55) 0.001 0.076 0.076 
Inflammatory markers 
 Hs-CRP, mg/L 2.89±1.08 2.86±1.02 0.460 3.31±0.92 3.02±1.05 0.001 0.001 0.140 
 IL-6, pg/mL 4.76 (2.65–8.11) 4.97 (2.65–7.70) 0.646 4.11 (1.15–11.82) 4.04 (1.93–5.88) 0.747 0.327 0.327 
 TNF-α, pg/mL 5.63±1.26 5.46±1.51 0.174 7.34±2.44 6.99±1.95 0.315 0.641 0.004 
Control group (n = 20)p value1RESMENA group (n = 20)p value2p value*p value**
baseline, mean ± SDa6 months, mean ± SDabaseline, mean ± SDa6 months, mean ± SDa
Glycemic control and lipid profile 
 Fasting glucose, mg/dL 87 (57–106) 89.5 (77–110) 0.513 91 (81–114) 88 (74–101) 0.492 0.558 0.758 
 Postprandial blood glucose, mg/dL 141.3±24.01 143.1±20.02 0.591 141.3±33.04 140.35±19.12 0.897 0.732 0.820 
 Fasting insulin, IU/mL 17.13±7.73 14.52±3.84 0.037 21.9±8.81 15.39±3.74 <0.001 0.049 0.052 
 Aspartate aminotransferase (AST), U/L 20 (12–22.6) 19 (11–20.1) 0.166 18 (8–62) 19 (11–34) 0.920 0.738 0.738 
 ALT, U/L 19.5 (15–22.7) 17.5 (13–18.9) 0.026 18.5 (12–44) 16.5 (11–31) 0.026 0.461 0.461 
 Total cholesterol, mg/dL 170.3±32.08 155.78±27.69 0.023 177.7±37.18 162.8±26.64 0.027 0.965 0.820 
 HDL cholesterol, mg/dL 44±6.53 45.05±4.96 0.330 45.06±8.58 45.75±5.59 0.577 0.823 0.779 
 LDL cholesterol, mg/dL 102±20.38 103.01±16.42 0.818 105.5±21.17 95.75±19.05 0.053 0.101 0.698 
 Triglycerides, mg/dL 103 (57–127.8) 100.47 (66–120.45) 0.156 115 (34–300) 105.5 (69–200) 0.184 0.698 0.602 
 HbA1c, % 5.32±0.3 5.22±0.24 0.192 5.52±0.37 5.35±0.33 0.001 0.014 0.091 
 QUICKI 0.32±0.02 0.32±0.01 0.135 0.31±0.02 0.32±0.01 <0.001 0.042 0.076 
 HOMA-IR 3.42 (1.34–4.78) 3.19 (1.69–3.49) 0.099 4.12 (2.23–11.08) 3.83 (1.77–4.55) 0.001 0.076 0.076 
Inflammatory markers 
 Hs-CRP, mg/L 2.89±1.08 2.86±1.02 0.460 3.31±0.92 3.02±1.05 0.001 0.001 0.140 
 IL-6, pg/mL 4.76 (2.65–8.11) 4.97 (2.65–7.70) 0.646 4.11 (1.15–11.82) 4.04 (1.93–5.88) 0.747 0.327 0.327 
 TNF-α, pg/mL 5.63±1.26 5.46±1.51 0.174 7.34±2.44 6.99±1.95 0.315 0.641 0.004 

p1: value of the baseline 6-month difference in the control group.

p2: value of the baseline 6-month difference in the RESMENA group.

p*: value of the difference between groups.

p**: value of the baseline difference between the control group and the RESMENA group.

aMean ± SD was given when the distribution of the data was parametric, and median (Min-Max) was given when it was not parametric. In parametric cases, comparisons between the dependent t test and the differences between groups were made with the independent t test. In nonparametric cases, the Wilcoxon sign test was used for the baseline 6-month differences and the Mann-Whitney U test was used for the comparisons of the differences between groups.

Inflammatory Profile

At baseline, there were no significant differences in the inflammatory profile of the two groups except for TNF-α. There was a significant decrease in hs-CRP levels only in the RESMENA group at the end of 6 months compared to the baseline (p = 0.001). There was no significant difference in terms of IL-6 and TNF-α levels (p >0.05) (Table 3).

Reproductive Profile

At the end of the study, the number of who returned to normal menstruation in the two groups was counted. A total of 60.0% (12/20) of patients in the control group returned to normal menstrual cycles, whereas 90.0% (18/20) of patients in the RESMENA group returned to normal menstrual cycles, with significant difference between the two groups (p = 0.036) (data not shown).

At baseline, there were no significant differences in the reproductive profile of the two groups. There was no statistical difference in the androgen levels of the control group compared to the baseline (p >0.05). In the RESMENA group, there were a significant decrease in total testosterone (p = 0.003), free testosterone (p <0.001), 17-OH progesterone (p = 0.037), androstenedione (p <0.001), LH (p = 0.001) levels and LH/FSH ratio (p <0.001), and FAI (p = 0.008) and a significant increase in SHBG levels (p = 0.048). When the changes over time were compared between the two groups, it was observed that the decreases in free testosterone (p = 0.003), 17-OH progesterone (p = 0.043), androstenedione (p = 0.005), LH (p = 0.014), LHF/SH ratio (p = 0.002) levels and increases in SHBG levels (p = 0.024) were statistically greater in the RESMENA group (Table 4).

Table 4.

Reproductive hormones levels at baseline and after the intervention

Control group (n = 20)p value1RESMENA group (n = 20)p value2p value*p value**
baseline, mean ± SDa6 months, mean ± SDabaseline, mean ± SDa6 months, mean ± SDa
BT, ng/mL 0.42±0.2 0.4±0.15 0.441 0.47±0.22 0.4±0.19 0.197 0.339 0.478 
BT, % 44.61±9.09 43.33±7.54 0.189 51.65±12.49 47.11±9.92 0.081 0.223 0.056 
Total testosterone, ng/mL 0.96 (0.48–1.66) 0.86 (0.18–1.45) 0.478 0.88 (0.51–1.62) 0.72 (0.25–1.12) 0.003 0.640 0.640 
Free testosterone, ng/mL 1.51±0.42 1.5±0.51 0.895 2.02±0.76 1.41±0.65 <0.001 0.003 0.052 
SHBG, nmol/L 25.64 (13.56–40.52) 27.92 (13.56–36.52) 0.331 21.79 (6–65.2) 26.81 (13.7–53.45) 0.048 0.024 0.084 
DHAS, µg/dL 310.34±95.81 313.12±91.36 0.865 293.29±104.14 265.74±90.32 0.140 0.215 0.678 
17-OH progesterone, ng/mL 2.54 (1.16–5.14) 2.49 (1.06–5.14) 0.137 1.95 (0.63–3.96) 1.49 (0.89–3.22) 0.037 0.043 0.073 
Androstenedione, ng/mL 3.53±0.78 3.34±0.78 0.211 4.53±1.44 3.6±1.17 <0.001 0.005 0.038 
FSH, IU/L 6.61±1.41 6.29±2.01 0.245 6.57±1.4 6.41±1.4 0.507 0.715 0.968 
LH, IU/L 8.09 (3.81–15.72) 9.49 (4.26–13.94) 0.872 13.22 (4.57–19.12) 8.99 (2.58–13.94) 0.001 0.014 0.014 
LH/FSH 1.72±0.41 1.7±0.7 0.865 2.13±0.61 1.42±0.49 <0.001 0.002 0.053 
Prolactin, ng/mL 11.26±2.41 11.93±2.82 0.480 12.21±2.77 12±2.76 0.640 0.399 0.301 
Ferriman-Gallwey score (FGS) 11.9±3.37 11.5±3.53 0.226 14.45±6.66 13.5±5.16 0.173 0.464 0.289 
FAI 3.8 (1.87–12.24) 3.13 (0.72–8.11) 0.763 3.77 (1.4–14.33) 3.01 (0.6–5.75) 0.008 0.547 0.547 
Control group (n = 20)p value1RESMENA group (n = 20)p value2p value*p value**
baseline, mean ± SDa6 months, mean ± SDabaseline, mean ± SDa6 months, mean ± SDa
BT, ng/mL 0.42±0.2 0.4±0.15 0.441 0.47±0.22 0.4±0.19 0.197 0.339 0.478 
BT, % 44.61±9.09 43.33±7.54 0.189 51.65±12.49 47.11±9.92 0.081 0.223 0.056 
Total testosterone, ng/mL 0.96 (0.48–1.66) 0.86 (0.18–1.45) 0.478 0.88 (0.51–1.62) 0.72 (0.25–1.12) 0.003 0.640 0.640 
Free testosterone, ng/mL 1.51±0.42 1.5±0.51 0.895 2.02±0.76 1.41±0.65 <0.001 0.003 0.052 
SHBG, nmol/L 25.64 (13.56–40.52) 27.92 (13.56–36.52) 0.331 21.79 (6–65.2) 26.81 (13.7–53.45) 0.048 0.024 0.084 
DHAS, µg/dL 310.34±95.81 313.12±91.36 0.865 293.29±104.14 265.74±90.32 0.140 0.215 0.678 
17-OH progesterone, ng/mL 2.54 (1.16–5.14) 2.49 (1.06–5.14) 0.137 1.95 (0.63–3.96) 1.49 (0.89–3.22) 0.037 0.043 0.073 
Androstenedione, ng/mL 3.53±0.78 3.34±0.78 0.211 4.53±1.44 3.6±1.17 <0.001 0.005 0.038 
FSH, IU/L 6.61±1.41 6.29±2.01 0.245 6.57±1.4 6.41±1.4 0.507 0.715 0.968 
LH, IU/L 8.09 (3.81–15.72) 9.49 (4.26–13.94) 0.872 13.22 (4.57–19.12) 8.99 (2.58–13.94) 0.001 0.014 0.014 
LH/FSH 1.72±0.41 1.7±0.7 0.865 2.13±0.61 1.42±0.49 <0.001 0.002 0.053 
Prolactin, ng/mL 11.26±2.41 11.93±2.82 0.480 12.21±2.77 12±2.76 0.640 0.399 0.301 
Ferriman-Gallwey score (FGS) 11.9±3.37 11.5±3.53 0.226 14.45±6.66 13.5±5.16 0.173 0.464 0.289 
FAI 3.8 (1.87–12.24) 3.13 (0.72–8.11) 0.763 3.77 (1.4–14.33) 3.01 (0.6–5.75) 0.008 0.547 0.547 

p1: value of the baseline 6-month difference in the control group.

p2: value of the baseline 6-month difference in the RESMENA group.

p*: value of the difference between groups.

p**: value of the baseline difference between the control group and the RESMENA group.

aMean ± SD was given when the distribution of the data was parametric, and median (Min-Max) was given when it was not parametric.

In parametric cases, comparisons between the dependent t test and the differences between groups were made with the independent t test.

In nonparametric cases, the Wilcoxon sign test was used for the baseline 6-month differences and the Mann-Whitney U test was used for the comparisons of the differences between groups.

To the best of our knowledge, this is the first study to compare the effects of a high meal frequency, low carbohydrate, high protein, high n-3 PUFA, healthy FA and antioxidant content, low glycemic load RESMENA diet or a control diet based on AHA recommendations on anthropometric measurements, body composition, IR, lipid metabolism levels, inflammatory markers, and reproductive endocrine levels in adolescents with PCOS. The RESMENA diet was found to provide more beneficial effects on anthropometric, metabolic, and androgen profile compared to the control group.

Effect on the Anthropometric Profile

Development of obesity, especially central and visceral obesity, is common in individuals with PCOS, and PCOS exacerbates the metabolic and reproductive abnormalities [10]. Successful body weight loss in individuals with obesity and PCOS leads to an improvement in the menstrual cycle and a decrease in androgens and cardiovascular risk factors [5, 7]. In this study, RESMENA and control diets administered for 6 months provided significant improvements in anthropometric measurements and body composition in adolescents with obesity and PCOS, but the decrease in body weight, waist and hip circumference, BMI, and fat mass compared to baseline was greater in RESMENA diet. Data on the effects of diet therapy alone on clinical and biochemical parameters of PCOS in adolescents are limited [15, 30]. In this study, adolescents were given their daily energy needs. In both groups, daily energy intake decreased during the intervention compared to baseline and weight loss occurred. At the beginning and at end of the study, the daily energy intake of both groups was similar, but more body weight and fat mass loss were observed in the RESMENA group, indicating that the diet pattern was effective in changing anthropometric measurements. Similarly, Wong et al. [15] found that a low glycemic index and low-fat diet showed beneficial effects on weight control in adolescents with obesity and PCOS, but this effect was greater in the low glycemic index diet. In another study, a low-carbohydrate, high-protein Mediterranean diet was found to be more effective in improving anthropometric parameters than a low-fat diet in patients with overweight and PCOS [9]. Mehrebani et al., on the other hand, compared hypocaloric low-carbohydrate, high-protein diet and hypocaloric traditional diet in women with obesity and PCOS and reported that weight loss was similar in both groups, but the decrease in the waist and hip circumference was greater in the low-carbohydrate, high-protein diet group [11]. The low-carbohydrate and high-protein content of the RESMENA diet may reduce appetite and energy intake [13, 16]. In addition, high dietary protein compared to carbohydrate may provide greater weight loss by increasing protein-induced thermogenesis and satiety due to increased insulin sensitivity and increased cholecystokinin production, as well as preservation of lean body mass [7, 31]. The Mediterranean diet may protect against diseases associated with IR such as obesity [3]. The RESMENA diet shares some nutritional features of the Mediterranean diet, such as being high in antioxidants, fiber, essential FAs, and low in saturated fat and cholesterol. Its low glycemic load may reduce weight gain by causing a decrease in appetite and food consumption and an increase in fat oxidation, lipogenesis, fat accumulation, and insulin secretion [14], high fiber content increases the feeling of satiety, and foods with high fiber content increase the production of short-chain FAs that regulate metabolic homeostasis and have beneficial effects in abdominal obesity [6]. In addition, increasing unsaturated FA consumption instead of saturated FAs may promote energy expenditure, diet-induced thermogenesis, and fat oxidation, leading to loss of body weight and fat mass [32]. The RESMENA group consumed more frequent meals than the control group. This may have shown beneficial effects on body weight by spreading the nutrient load, producing lower oscillating plasma glucose levels and lower postprandial insulin concentrations, and decreased hunger [7].

Effect on the Metabolic Profile

In this study, a decrease was observed in fasting insulin, total cholesterol, and ALT levels in both groups, while improvement was also observed in HbA1c, HOMA-IR, and QUICKI levels in the RESMENA group. In individuals with PCOS, central obesity and increased body fat exacerbate IR and dyslipidemia [10]. It has been reported that an increase in insulin sensitivity and a decrease in surrogate markers of IR (fasting insulin, HOMA-IR, glucose/insulin ratio, etc.) and lipids (triglycerides, total cholesterol, LDL-C) may occur with body weight loss independent of diet composition [11, 30, 33]. Transaminases, especially ALT, are markers of hepatocyte damage and are associated with IR and diabetes development. Weight loss leads to the depletion of these liver enzymes [17]. In this study, it is thought that body weight loss had beneficial effects on the reductions in fasting insulin, total cholesterol, and ALT levels in both diet groups. Trunk fat, waist circumference, and BMI are the best predictors of IR in PCOS [7]. In this study, significant reductions in IR markers were also observed in the RESMENA group, as fat mass and percentage, waist, and BMI levels improved significantly more in the RESMENA group compared to the control group. Although body weight loss was observed in both groups in our study (mean 8 kg in the control group; mean 11 kg in the RESMENA group), the decrease in IR markers was highest in the RESMENA group, suggesting that changing diet composition may also affect insulin sensitivity and dyslipidemia. The RESMENA diet may reduce the secretion of proinflammatory adipocytokines by providing a further reduction in visceral adiposity and may modulate insulin action and metabolism in insulin-sensitive tissues thanks to its plant-based phenolic compounds and high omega-3 content [3]. In this study, since the carbohydrate intake of the control group increased at the end of the sixth month compared to the beginning, an increase in fasting glucose levels was observed. Carbohydrate intake of the RESMENA group decreased at the end of 6 months, and a decrease was observed in fasting glucose levels. This may be because carbohydrates have a greater effect on stimulating insulin secretion. Therefore, controlling the daily dietary carbohydrate intake level of individuals with PCOS plays an important role [7]. Similarly, in a systematic review, low-carb diets in individuals with PCOS were reported to be associated with a greater reduction in surrogate markers of IR (acute insulin response to glucose) compared to a diet rich in MUFA and to be associated with lower fasting insulin and total cholesterol levels compared to high carbohydrate, standard protein, and low-fat diet [34]. In another study, it was found that a low-glycemic index weight loss diet provided a greater reduction in IR and fibrinogen compared to a healthy weight loss diet [35]. A low glycemic index diet provides better glycemic control by slowing the absorption of carbohydrates and blood glucose fluctuations. In addition, complex carbohydrates and fiber are associated with higher insulin sensitivity and healthier lipid profiles [36]. In our study, the dietary glycemic index and glycemic load values of both groups decreased over a 6-month period, but this decrease was significantly higher in the RESMENA group, and since the fiber and omega-3 FA intakes increased significantly in the RESMENA group, the decrease in insulin concentrations was higher. Mei et al. [9] reported that both low-fat and low-carbohydrate Mediterranean diets provide a significant decrease in fasting insulin, HOMA-IR and QUICKI, total cholesterol, triglyceride, and LDL cholesterol levels in women with obesity and PCOS. As a result of a meta-analysis, long-term administration of low-carb diets and low-fat/low-carb diets in individuals with PCOS has been shown to improve metabolic syndrome components such as high blood sugar, IR, and abnormal lipid metabolism [12]. In our study, although the amount of daily carbohydrate intake increased in the control group, the decrease in fasting insulin levels, total cholesterol, and ALT levels suggests the decrease in daily total and saturated fat ratios and this decrease may provide some improvement in insulin sensitivity in this group. It has been reported that dietary proteins stimulate insulin secretion, lower blood glucose levels, and relieve hyperglycemia and IR by changing the intestinal flora [9, 31]. IR is recognized to play an important role in the pathogenesis of dyslipidemia [37]. In a study conducted on women with PCOS, it was found that a high-protein (∼40% protein) diet positively affected glucose metabolism regardless of weight loss compared to a standard protein (∼15% protein) diet [16]. In addition, in a study, it was reported that a high-protein diet (30% protein) decreased the total/HDL cholesterol ratio in individuals with PCOS, but no such effect was observed in the low-protein diet (15% protein) [33]. In this study, it is thought that increasing the daily protein intake of the RESMENA group to approximately 26% of energy contributed to the improvement of IR markers and this may cause a decrease in total cholesterol levels.

There are no studies examining the effect of diet patterns or body weight loss on inflammatory markers in adolescents with PCOS. In our study, a significant decrease was observed only in hs-CRP levels in the RESMENA group. Mehrabani et al. [11] found that both the modified (high protein, low glycemic load) hypocaloric diet and the traditional hypocaloric diet decreased TNF-α levels, but only the modified diet provided a decrease in hs-CRP levels. Decreases in hs-CRP levels are reported to be associated with weight loss [38]. In our study, the decrease in body weight and waist circumference in the RESMENA group may be associated with the decrease in this parameter compared to the control group. In addition, it is thought that the fact that the RESMENA diet is rich in high antioxidant content, omega-3 FAs, and phenolic compounds contributes to the decrease in hs-CRP levels.

Effect on the Reproductive Profile

In this study, it was observed that a significant improvement was achieved in abnormal reproductive hormones in the RESMENA group. Improvement in androgen levels is important for the improvement of follicular development and ovulation cycles in patients with PCOS [6]. In many studies, it has been reported that energy restriction and diets that provide body weight loss regardless of dietary composition modulate reproductive endocrine hormones in individuals with PCOS [9, 30, 35]. However, in this study, it was observed that RESMENA diet composition was effective on reproductive endocrine hormones, because body weight loss was observed in both groups. Studies examining the effects of dietary interventions on androgens in adolescents with PCOS are limited. Wong et al. [15] found that a low glycemic index and low-fat diet had no effect on biochemical hyperandrogenism in adolescents with obesity and PCOS. Mei et al. [9] found that both the low-carb diet and the low-fat diet were beneficial for reproductive endocrine disorders in women with PCOS, but the decrease in total testosterone, LH, LH/FSH, and prolactin levels was mostly achieved by the low-carb diet. A meta-analysis reported that the low-fat/low-carb diet (less than 35% of fat and less than 45% CHO) and low-carb diets applied for more than 4 weeks increased the SHBG and FSH levels in patients with PCOS and decreased the total testosterone levels [12]. In this study, although the total fat intake of both groups was less than 35%, only the RESMENA diet was beneficial on androgens, indicating that the amount and type of dietary carbohydrate, protein and fiber, antioxidant content, and meal frequency are effective on hyperandrogenism. The RESMENA diet significantly decreased IR and abdominal adiposity and decreased androgen concentrations compared to the control group. Excessive insulin concentrations cause hyperandrogenism by increasing the androgen secretion of the ovaries and adrenal glands and inhibiting the synthesis of SHBG in the liver [9, 12]. Low-carbohydrate and low glycemic index diets that reduce IGF-1, IGFBP1, glucose, and insulin levels may have beneficial effects on ovarian function [11, 12]. In addition, irregularity in inositol metabolism may lead to a decrease in insulin sensitivity, hyperinsulinemia, inhibition of maturation of follicles, and PCOS development. It has been reported that low-carb diets can increase insulin sensitivity, decrease androgen levels, and increase oocyte quality by regulating inositol balance [12]. In the RESMENA diet, the protein/carbohydrate ratio is higher than in the control group. In a similarly conducted study, it was found that a diet with an increased protein/carbohydrate ratio compared to a standard diet resulted in a greater decrease in testosterone levels [16]. In our study, the fact that a low carbohydrate, low glycemic load, high protein-containing RESMENA diet provided significant improvement in IR markers such as fasting insulin, HOMA-IR, and QUICKI with similar mechanisms may have resulted in a decrease in total and free testosterone, androstenedione, LH levels, LH/FSH ratio, and FAI levels and an increase in SHBG levels. Although a significant decrease in fasting insulin levels was observed in the control diet group, androgen levels did not change, suggesting that changes in fasting insulin concentration were not sufficient to ensure the reduction of androgens. In this study, unlike the control diet, the high dietary antioxidant capacity and the high omega-3 FA ratio of the RESMENA diet may also be responsible for its beneficial effects on reproductive endocrine hormones. Antioxidants have been reported to reduce oxidative stress, IR, and androgen levels and support follicular maturation in individuals with PCOS [39]. In a study, it was found that treating women with PCOS with omega-3 FA for 6 months reduced hirsutism, LH, and testosterone levels and increased SHBG levels [40].

Strengths and Limitations

The present study has a few limitations. First, sample size was small. Second, it was a single-center study. Third, the number of participants withdrawn from the study due to the COVID-19 pandemic was high. Fourth is reliance on participants’ self-reports to assess their prescribed diet. Strengths of this study include a single-blind randomized control design; a holistic evaluation of the effects of diets on IR, oxidative stress, and androgens using a range of complementary parameters; strict follow-up by a dietitian; the first study in which the RESMENA diet was applied to adolescents.

In conclusion, this study shows that in adolescents with obesity and PCOS, both the RESMENA diet and the control diet provide a decrease in body weight, BMI, body fat, waist, neck and hip circumference, cholesterol, and fasting insulin levels at the end of 6 months without energy restriction and that the RESMENA diet improves IR markers and reproductive endocrine hormones. These dietary approaches need to be tested for longer periods of time in larger cohorts to determine long-term health benefits.

The authors are grateful to the individuals who participated in the survey and to anonymous reviewers for their comments.

This study was carried out in accordance with the guidelines laid down in the Declaration of Helsinki, and written informed consent was obtained from all participants and their parents. The protocol study was approved by the Ethics Committee of Clinical Research at Gazi University (No: 345, March 29, 2021).

The authors declare no competing conflicts of interest to disclose.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conception, design, resources, and formal analysis: Rukiye Bozbulut, Esra Döğer, and Aysun Bideci; data collection: Rukiye Bozbulut and Esra Döğer; supervision and critical revision of the manuscript: Aysun Bideci and Mahmut Orhun Çamurdan; analysis, interpretation, and drafting the manuscript: Rukiye Bozbulut. All authors read and approved the final version of the manuscript.

Additional Information

Registered under ClinicalTrials.gov. The trial registration number (TRN): NCT05768724. Date of registration: March 14, 2023.Among the authors, Dr. Esra Döğer and Dr. Aysun Bideci are members of ESPE.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author (Rukiye Bozbulut).

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