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

Polycystic Ovarian Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05196568
• Other study ID #: VERBALE N° 56
• Status: Active, not recruiting
• Phase: N/A
• Start date: July 1, 2021
• Est. completion date: January 1, 2025

Study information

• Verified date: January 2023
• Source: University of Salento
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: January 1, 2025
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Polycystic Ovarian Syndrome
• Polycystic Ovary Syndrome
• Syndrome

Intervention

Dietary Supplement:
• Fasting mimicking diet
Women will be given three administrations of fasting mimicking diet once a month

Locations

Country	Name	City	State
Italy	Anna Maria Giudetti	Lecce

Sponsors (1)

Lead Sponsor	Collaborator
University of Salento

Country where clinical trial is conducted

Italy, 

References & Publications (21)

Azziz R, Carmina E, Chen Z, Dunaif A, Laven JS, Legro RS, Lizneva D, Natterson-Horowtiz B, Teede HJ, Yildiz BO. Polycystic ovary syndrome. Nat Rev Dis Primers. 2016 Aug 11;2:16057. doi: 10.1038/nrdp.2016.57. — View Citation

Balen AH, Conway GS, Kaltsas G, Techatrasak K, Manning PJ, West C, Jacobs HS. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod. 1995 Aug;10(8):2107-11. doi: 10.1093/oxfordjournals.humrep.a136243. — View Citation

Boyle JA, Cunningham J, O'Dea K, Dunbar T, Norman RJ. Prevalence of polycystic ovary syndrome in a sample of Indigenous women in Darwin, Australia. Med J Aust. 2012 Jan 16;196(1):62-6. doi: 10.5694/mja11.10553. — View Citation

Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, Dubeau L, Yap LP, Park R, Vinciguerra M, Di Biase S, Mirzaei H, Mirisola MG, Childress P, Ji L, Groshen S, Penna F, Odetti P, Perin L, Conti PS, Ikeno Y, Kennedy BK, Cohen P, Morgan TE, Dorff TB, Longo VD. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015 Jul 7;22(1):86-99. doi: 10.1016/j.cmet.2015.05.012. Epub 2015 Jun 18. — View Citation

Costello M, Shrestha B, Eden J, Sjoblom P, Johnson N. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005552. doi: 10.1002/14651858.CD005552.pub2. — View Citation

Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989 Sep;38(9):1165-74. doi: 10.2337/diab.38.9.1165. — View Citation

Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN; PCOS/Troglitazone Study Group. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006 Jan;91(1):48-53. doi: 10.1210/jc.2005-1329. Epub 2005 Oct 25. — View Citation

Glueck CJ, Dharashivkar S, Wang P, Zhu B, Gartside PS, Tracy T, Sieve L. Obesity and extreme obesity, manifest by ages 20-24 years, continuing through 32-41 years in women, should alert physicians to the diagnostic likelihood of polycystic ovary syndrome as a reversible underlying endocrinopathy. Eur J Obstet Gynecol Reprod Biol. 2005 Oct 1;122(2):206-12. doi: 10.1016/j.ejogrb.2005.03.010. — View Citation

Himelein MJ, Thatcher SS. Depression and body image among women with polycystic ovary syndrome. J Health Psychol. 2006 Jul;11(4):613-25. doi: 10.1177/1359105306065021. — View Citation

Holte J, Bergh T, Berne C, Wide L, Lithell H. Restored insulin sensitivity but persistently increased early insulin secretion after weight loss in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 1995 Sep;80(9):2586-93. doi: 10.1210/jcem.80.9.7673399. — View Citation

Kiddy DS, Sharp PS, White DM, Scanlon MF, Mason HD, Bray CS, Polson DW, Reed MJ, Franks S. Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin Endocrinol (Oxf). 1990 Feb;32(2):213-20. doi: 10.1111/j.1365-2265.1990.tb00857.x. — View Citation

Kumar S, Kaur G. Intermittent fasting dietary restriction regimen negatively influences reproduction in young rats: a study of hypothalamo-hypophysial-gonadal axis. PLoS One. 2013;8(1):e52416. doi: 10.1371/journal.pone.0052416. Epub 2013 Jan 29. — View Citation

Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999 Jan;84(1):165-9. doi: 10.1210/jcem.84.1.5393. — View Citation

Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am J Med. 2001 Dec 1;111(8):607-13. doi: 10.1016/s0002-9343(01)00948-2. — View Citation

Ma YM, Li R, Qiao J, Zhang XW, Wang SY, Zhang QF, Li L, Tu BB, Zhang X. Characteristics of abnormal menstrual cycle and polycystic ovary syndrome in community and hospital populations. Chin Med J (Engl). 2010 Aug;123(16):2185-9. — View Citation

Norman RJ, Masters L, Milner CR, Wang JX, Davies MJ. Relative risk of conversion from normoglycaemia to impaired glucose tolerance or non-insulin dependent diabetes mellitus in polycystic ovarian syndrome. Hum Reprod. 2001 Sep;16(9):1995-8. doi: 10.1093/humrep/16.9.1995. — View Citation

Parillo F, Zerani M, Maranesi M, Dall'Aglio C, Galeati G, Brecchia G, Boiti C, Gonzalez-Mariscal G. Ovarian hormones and fasting differentially regulate pituitary receptors for estrogen and gonadotropin-releasing hormone in rabbit female. Microsc Res Tech. 2014 Mar;77(3):201-10. doi: 10.1002/jemt.22328. Epub 2013 Dec 26. — View Citation

Sam S. Obesity and Polycystic Ovary Syndrome. Obes Manag. 2007 Apr;3(2):69-73. doi: 10.1089/obe.2007.0019. No abstract available. — View Citation

Sir-Petermann T, Codner E, Perez V, Echiburu B, Maliqueo M, Ladron de Guevara A, Preisler J, Crisosto N, Sanchez F, Cassorla F, Bhasin S. Metabolic and reproductive features before and during puberty in daughters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2009 Jun;94(6):1923-30. doi: 10.1210/jc.2008-2836. Epub 2009 Feb 17. — View Citation

Wei M, Brandhorst S, Shelehchi M, Mirzaei H, Cheng CW, Budniak J, Groshen S, Mack WJ, Guen E, Di Biase S, Cohen P, Morgan TE, Dorff T, Hong K, Michalsen A, Laviano A, Longo VD. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017 Feb 15;9(377):eaai8700. doi: 10.1126/scitranslmed.aai8700. — View Citation

Weiner CL, Primeau M, Ehrmann DA. Androgens and mood dysfunction in women: comparison of women with polycystic ovarian syndrome to healthy controls. Psychosom Med. 2004 May-Jun;66(3):356-62. doi: 10.1097/01.psy.0000127871.46309.fe. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	Improvement of blood insulinemic values (µU/mL)	Improvements in the parameter that is generally increased in polycystic ovary	End of the treatment (three months)
Secondary	Improvement of blood glycated hemoglobin (%)	Improvements in the parameter that is generally increased in polycystic ovary	End of the treatment (three months)
Secondary	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)
Secondary	Improvement in plasma sexual hormones	Improvements in plasma values of FSH, LH, E2, SHBG, Total Testosterone, DHEA-S, ?4androstenedione, TSH, generally altered in polycystic ovary	End of the treatment (three months)
Secondary	Improvemet in the PCR value	Improvements in inflammatory parameters that are modified in polycystic ovary syndrome are considered	End of the treatment (three months)
Secondary	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)