Effects of Fasting Mimicking Diet (FMD) in Women With Polycystic Ovary Syndrome (PCOS)

Study Overview
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Brief Summary
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Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-aged women, affecting 6-21% (depending on the applied diagnostic criteria) of this population worldwide. PCOS is characterized by hyperandrogenism and/or chronic anovulation which can manifest with a range of symptoms (e.g., hirsutism, acne, oligomenorrhea, and infertility) and is associated with increased risk of cardiometabolic diseases, including hypertension, dyslipidemia, insulin resistance (IR), and type 2 diabetes mellitus (T2DM). Moreover, PCOS is linked to increased psychological morbidity (e.g., increased risk of stress, depression, low self-esteem, and poor body image). The exact PCOS etiology is unknown, but increased adiposity is considered pivotal. Indeed, almost 90% of women with PCOS are overweight or obese, and even moderate weight loss may result in clinically meaningful improvements in hyperandrogenism and menstrual regularity. Also, women with PCOS often have more severe IR than weight-matched women without PCOS, whilst their increased susceptibility to obesity may further exacerbate IR and the accompanying metabolic and reproductive dysfunctions. As such, women with PCOS exhibit an increased risk of impaired glucose tolerance and T2DM regardless of weight and age. Management of overweight/obese women with PCOS focuses on weight loss through regular exercise and diet, aiming to alleviate its clinical manifestations and lower the related risk of T2DM and cardiovascular disease. Fasting-induced negative energy also potently affects the hormones such as estradiol, testosterone, and leptin, and complex interactions exist between metabolic signals and ovarian steroids. However, fasting is difficult to implement. It is of great interest to develop feasible and efficacious fasting-mimicking diets (FMD) to alleviate the burden of fasting while preserving the beneficial effects of fasting. In a case study, the investigators observed that a 23-year-old female diagnosed with PCOS had her persistent cystic acne resolved after just 3 cycles of self-administered fasting-mimicking dieting. In addition, FDM induces a reduction in insulin levels, fasting glucose, BMI, decreased adiposity, and inflammation rates. The investigators hypothesize that a specially designed FMD will induce physiological changes similar to prolonged fasting and will decrease risk factors associated with metabolic syndrome and alleviate symptoms of PCOS.

Detailed Description
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Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive-aged women, affecting 6-21% (depending on the applied diagnostic criteria) of this population worldwide. PCOS is characterized by hyperandrogenism and/or chronic anovulation which can manifest with a range of symptoms (e.g., hirsutism, acne, oligomenorrhea, and infertility) and is associated with increased risk of cardiometabolic diseases, including hypertension, dyslipidemia, insulin resistance (IR), and type 2 diabetes mellitus (T2DM). Moreover, PCOS is linked to increased psychological morbidity (e.g., increased risk of stress, depression, low self-esteem, poor body image, and reduced health-related quality of life). The exact PCOS etiology is unknown, but increased adiposity is considered pivotal. Indeed, almost 90% of women with PCOS are overweight or obese, and even moderate weight loss (e.g., 5%) may result in clinically meaningful improvements in hyperandrogenism and menstrual regularity. Also, women with PCOS often have more severe IR than weight-matched women without PCOS, whilst their increased susceptibility to obesity may further exacerbate IR and the accompanying metabolic and reproductive dysfunctions. As such, women with PCOS exhibit an increased risk of impaired glucose tolerance and T2DM regardless of weight and age. Management of overweight/obese women with PCOS focuses on weight loss through regular exercise and diet, aiming to alleviate its clinical manifestations and lower the related risk of T2DM and cardiovascular disease. Fasting-induced negative energy also potently affects the hormones such as estradiol, testosterone, and leptin; and complex interactions exist between metabolic signals and ovarian steroids. However, fasting is difficult to implement. It is of great interest to develop feasible and efficacious fasting-mimicking diets (FMD) to alleviate the burden of fasting while preserving the beneficial effects of fasting. In a case study, a 23-year-old female diagnosed with PCOS had her persistent cystic acne resolved after just 3 cycles of self-administered fasting-mimicking dieting. In addition, FDM induces a reduction in insulin levels, fasting glucose, BMI, decreased adiposity, and inflammation rates. The investigators hypothesize that a specially designed FMD will induce physiological changes similar to prolonged fasting and will decrease risk factors associated with metabolic syndrome and alleviate symptoms of PCOS. The purpose of the study is to evaluate the effect of FMD in women with PCOS. Regarding the study model, a crossover will be applied. Our crossover design is the simplest model known as 2 x 2 where two treatments are compared in two-period, two-sequence model. Each washout, between consecutive periods, is done so that the previous treatment does not affect the response to the next treatment. The main advantage of a crossover design over the parallel group is the opportunity it offers to compare the effects of treatments within-subjects, which is not possible with a conventional parallel-group design. Additionally, a crossover design usually requires a smaller sample size to reliably estimate the magnitude of the treatment effect. That is, any component of an individual's response that is consistent over time is removed from the treatment comparison. Study participants will be randomized and assigned to arm 1 (n° = 50, control patients) or arm 2 (n° = 50, patients undergoing FMD). Patients in the FMD group will be asked to consume FMD, which will be provided with a box, for 5 continuous days, and to return to their normal diet after completion until the next cycle which will start 25 days later, for a total of three months. The two groups will then be exchanged in the third month so that the control group will also be subjected to FMD in the following three months. The main parameters that will be texted, are all major symptoms associated with PCOS, including menstrual cycle regularity, ovarian morphology (by ultrasound); hirsutism (by the Ferriman-Gallwey (FG) scoring method), and acne score. Moreover, improvement in metabolic, inflammatory, and psychological markers will be also evaluated. Both control and FMD patients will complete anthropometric measurements every month (at the end of each FMD cycle). After three months, patients will be crossed for another 3 months: patients with arm 1 control will be instructed to follow FMD, while patients with arm 2 undergoing FMD will be asked to continue their normal diet. Follow-up exams will be conducted for both groups at the end of the 6th month. Thereafter, all patients will be asked to continue their normal diet for another three months and will undergo further follow-up at the end of the ninth month. Blood chemistry analyzes will be performed at time zero, at 3 and 6 months, while gynecological and nutritional checks will be performed at time zero at 3 to 6 months and at the end of the study (t = 9 months). The total duration of the study is 9 months. The evaluation of the menstrual history and the anthropometric parameters will be measured during the gynecological and nutritional checks. The psychological/psychiatric evaluation will be carried out at T0, at 3 to 6 months, and at 9 months. Blood samples will also be used for IGF-1 analyzes (IFOM, Milan). Both control and FMD patients will fill out a food diary. Patients undergoing FMD will be contacted by phone for nutritional assistance once a day during the 5 days of FMD. Additionally, to assess adherence to the 5-day nutritional plan for FMD, patients will independently assess their ketonuria with appropriate sticks. Every month, all enrolled patients will note the possible date of menstruation and the duration of the cycle.

Official Title
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Pilot Study on the Effects of Fasting Mimicking Diet (FMD) in Women With Polycystic

Conditions
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Polycystic Ovarian Syndrome

Intervention / Treatment
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* Dietary Supplement: Fasting mimicking diet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female 18-40 years BMI 20-40 Reproductive age women with PCOS diagnosis Irregular menstrual cycles Chronic oligo/anovulation defined as an intermenstrual interval of >45 days < 8 menstrual cycles/year evidence of either hyperandrogenemia (elevation of total or free testosterone above the normal range for women) clinical hyerandrogenism (hirsutism and or acne) 3 years from menarche Agree to avoidance of pregnancy and to use barrier contraception for duration of study Exclusion Criteria: • Clinically ascertained presence of type I and type II Diabetes Pregnancy and/or nursing Medication exclusion Use of medications and/or supplements that influence either ovarian function or insulin sensitivity, within 2 months: including oral contraceptive pills, hormonal implants, anti-androgens, antipsychotics or antihypertensives metformin, glucocorticoids, and/or health food remedies other than multi-vitamins and calcium; Subjects who are on oral contraception, metformin, or nutritional supplements must agree to discontinue these drugs and undergo an 8 week washout period before the tests are performed Other drugs that cannot be suspended during the FMD phase Alcohol usage more than 7 drinks/week

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: patients not treated with the mimic fasting diet<br>Group treated with the mimic fasting diet | |
| Experimental: patients treated with the mimic fasting diet<br>Group treated with the mimic fasting diet | Dietary Supplement: Fasting mimicking diet<br>* Women will be given three administrations of fasting mimicking diet once a month<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Restoration of menstrual regularity | The main parameter that will be taken into consideration as an improvement of the syndrome is the restoration of the menstrual cycle, which is not regular in the woman with polycystic ovary syndrome | End of the treatment (three months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of blood glucose values (mg / dl) | All improvements in glycemia values that are generally increased in polycystic ovary syndrome are considered | End of the treatment (three months) | 
| Improvement of blood insulinemic values (µU/mL) | Improvements in the parameter that is generally increased in polycystic ovary | End of the treatment (three months) | 
| Improvement of blood glycated hemoglobin (%) | Improvements in the parameter that is generally increased in polycystic ovary | End of the treatment (three months) | 
| Improvement of blood LDL, HDL, total cholesterol and triglycerides (mg/dl) | All improvements in plasma lipid parameters that are generally modified in polycystic ovary | End of the treatment (three months) | 
| Improvement in plasma sexual hormones | Improvements in plasma values of FSH, LH, E2, SHBG, Total Testosterone, DHEA-S, Δ4androstenedione, TSH, generally altered in polycystic ovary | End of the treatment (three months) | 
| Improvemet in the PCR value | Improvements in inflammatory parameters that are modified in polycystic ovary syndrome are considered | End of the treatment (three months) | 
| Improvement in depression syntoms evaluated bu Basic Self- Esteem Scale and improvement in quality of life, assessed by WHOQOL-BREF test | Improvements of the parameters related to the psychiatric sphere that are modified in the polycystic ovary syndrome are considered | End of the treatment (three months) |