The Effect of Fasting on ICSI Outcomes in Patients With Polycystic Ovary Syndrome

Study Overview
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Brief Summary
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Design and protocol of PCO fasting research: This study is a pilot prospective, single-blinded (to the health assessor), randomized controlled trial conducted at the In Vitro Fertilization ( IVF) center of the Department of Obstetrics & Gynecology, Kasr El-Ainy Hospital, Cairo University, Egypt, from October 2018 to September 2019, to determine the clinical effect of fasting on ICSI outcomes in PCOS patients. Ethical committee approval was obtained. The study will include 100 infertile patients with PCOS diagnosed according to Rotterdam criteria of PCOS and who are candidates for ICSI cycle. Women with diabetes, thyroid disorder or other endocrine dysfunctions, uterine abnormalities were excluded. All patients are informed about the study and consent is given by those who accept to participate. Careful history taking include infertility type, duration , cause, obstetric history, medical and surgical history and demographic distribution is taken. Full physical examination and 2 dimensional (2D) transvaginal sonography (TVS) are done on day 2 to 5 of menses to assess antral follicle count, uterus and adnexa . Body mass index (BMI) and waist/hip ratio (WHR) are calculated, Blood samples are taken for Fasting insulin , fasting plasma glucose, Homeostatic model assessment (HOMA index), lipid profile and hormonal profile are done. All 100 participants will be randomized withdrawing closed envelopes for each patient into group A and group B . Group (A): patients will have periodic fasting for 4 weeks prior to the treatment cycle. The fasting method involves daily fasts of 14-16hours and restrict eating to an 8-10 hour eating window as 2-3 or more meals of balanced diet. Group (B): no fasting, patients will have usual balanced diet as 3 meals and 2 snacks all over the day. Both groups should take adequate water and non calorie beverages intake daily (2-3 liters) Subjects are instructed to wait for spontaneous menses, or to be prescribed progestins orally (as Norethisterone 5mg) twice daily for 21 days starting from the fifth day of menses. Patients should continue taking oral metformin 500-1000 mg daily, until confirmation of pregnancy. The next visit is scheduled on day 2 of next cycle when transvaginal ultrasound is done to confirm that endometrial thickness <5mm, no ovarian cyst by ultrasound. Body mass index (BMI) and waist/hip ratio (WHR) are calculated. Blood samples are taken for Fasting insulin , fasting plasma glucose, Homeostatic model assessment (HOMA) index, lipid profile ( Triglycerides (TGs), total cholesterol, High density Lipoprotein (HDL), Low density Lipoprotein (LDL), free and total testosterone , Sex Hormone Binding Globulin (SHBG), Free Androgen index (FAI), AntiMullerian Hormone (AMH), Basal Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2),and then antagonist protocol is followed. Gonadotropins as Intramuscular (I.M.) injections of 150-300 (International units) I.U. of highly purified Human Menopausal Gonadotropins daily (Merional, 75 I.U. /vial, IBSA). and Urofollitropin or highly purified human follicle stimulating hormone(Fostimon®, 75 I.U. /vial, IBSA) are give in a ratio of 1:1.The dose is adjusted according to the age, BMI, Antral follicle count (AFC), serum levels of AMH, FSH and ovarian response. Fixed antagonist protocol is given and follow up until embryo transfer(ET). Quantitative ß- HCG in serum after is done after 14 days of embryo transfer.TVS is performed to detect clinical pregnancy at 6-7 weeks of gestation. Primary outcome is clinical pregnancy rate per cycle. Secondary outcomes include Body mass index (BMI) and waist/hip ratio (WHR), fasting insulin , fasting plasma glucose, Homeostatic model assessment (HOMA) index, lipid profile and other ICSI outcomes.

Detailed Description
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Design and protocol of PCO fasting research: This study is a pilot prospective, single-blinded (to the health assessor), randomized controlled trial conducted at the In Vitro Fertilization ( IVF) center of the Department of Obstetrics & Gynecology, Kasr El-Ainy Hospital, Cairo University, Egypt, from October 2018 to September 2019, to determine the clinical effect of fasting on ICSI outcomes in PCOS patients. Ethical committee approval was obtained. The study will include 100 infertile patients with PCOS diagnosed according to Rotterdam criteria of PCOS and who are candidates for ICSI cycle. Women with diabetes, thyroid disorder or other endocrine dysfunctions, uterine abnormalities were excluded. All patients are informed about the study and consent is given by those who accept to participate. Careful history taking include infertility type, duration , cause, obstetric history, medical and surgical history and demographic distribution is taken. Full physical examination and 2 dimensional (2D) transvaginal sonography (TVS) are done on day 2 to 5 of menses to assess antral follicle count, uterus and adnexa . Body mass index (BMI) and waist/hip ratio (WHR) are calculated, Blood samples are taken for Fasting insulin , fasting plasma glucose, Homeostatic model assessment (HOMA index), lipid profile ( Triglycerides, total cholesterol, High density Lipoprotein (HDL), Low density Lipoprotein (LDL), free and total testosterone , Sex Hormone Binding Globulin (SHBG), Free Androgen index (FAI), AntiMullerian Hormone (AMH), Basal Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2) All 100 participants will be randomized withdrawing closed envelopes for each patient into group A and group B . Group (A): patients will have periodic fasting for 4 weeks prior to the treatment cycle. The fasting method involves daily fasts of 14-16hours and restrict eating to an 8-10 hour eating window as 2-3 or more meals of balanced diet. Group (B): no fasting, patients will have usual balanced diet as 3 meals and 2 snacks all over the day. Both groups should take adequate water and non calorie beverages intake daily (2-3 liters) Subjects are instructed to wait for spontaneous menses, or to be prescribed progestins orally (as Norethisterone 5mg) twice daily for 21 days starting from the fifth day of menses. Patients should continue taking oral metformin 500-1000 mg daily, until confirmation of pregnancy. The next visit is scheduled on day 2 of next cycle when transvaginal ultrasound is done to confirm that endometrial thickness <5mm, no ovarian cyst by ultrasound. Body mass index (BMI) and waist/hip ratio (WHR) are calculated. Blood samples are taken for Fasting insulin , fasting plasma glucose, Homeostatic model assessment (HOMA) index, lipid profile ( Triglycerides (TGs), total cholesterol, High density Lipoprotein (HDL), Low density Lipoprotein (LDL), free and total testosterone , Sex Hormone Binding Globulin (SHBG), Free Androgen index (FAI), AntiMullerian Hormone (AMH), Basal Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2),and then antagonist protocol is followed. Gonadotropins as Intramuscular (I.M.) injections of 150-300 (International units) I.U. of highly purified Human Menopausal Gonadotropins daily (Merional, 75 I.U. /vial, IBSA). and Urofollitropin or highly purified human follicle stimulating hormone(Fostimon®, 75 I.U. /vial, IBSA) are give in a ratio of 1:1.The dose is adjusted according to the age, BMI, Antral follicle count (AFC), serum levels of AMH, FSH and ovarian response. On the sixth day of stimulation , a visit is scheduled to assess the ovarian response ( folliculometry) by TVS. Gonadotrophin releasing hormone antagonist (GnRH antagonist) which is Cetrorelix 0.25mg ( Cetrotide®, 0.25 mg/ vial, Merck Serono, is filled and mixed with diluent from a prefilled syringe with a 20 gauge needle) is given subcutaneously (S.C.) by 27-gauge needle starting from the 6th day of stimulation (fixed antagonist protocol). Next visits are every other day for follow up using the TVS. The trigger by Human Chorionic Gonadotrophin (HCG)10000 I.U., I.M. ( Pregnyl, Organon) is given when at least 3 follicles reach 18mm in mean diameter or more and E2 level is less than 2500 pg/ml. Ovum retrieval is done 34 hours after HCG injection and embryo transfer using Wallace catheter on day 2 to 3. Luteal support includes natural Progesterone 400 mg 1x2 as rectal suppository, Folic acid 0.5 mg orally once daily, Amoxicillin-Clavulanic Acid 1gm 1x2x7 orally, Progesterone 100 I.M. injections daily for 10 days, Acetylsalicylic Acid (75 mg) orally once daily, metformin 500-1000 mg orally daily . Quantitative ß- HCG in serum after is done after 14 days of embryo transfer.TVS is performed to detect clinical pregnancy at 6-7 weeks of gestation. Primary outcome is clinical pregnancy rate per cycle. Secondary outcomes include Body mass index (BMI) and waist/hip ratio (WHR), fasting insulin , fasting plasma glucose, Homeostatic model assessment (HOMA) index, lipid profile ( Triglycerides (TGs), total cholesterol, High density Lipoprotein (HDL), Low density Lipoprotein (LDL), free and total testosterone , Sex Hormone Binding Globulin (SHBG)u, Free Androgen index (FAI), AntiMullerian Hormone (AMH), Basal Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol (E2, Days of stimulation , dose of gonadotrophins, number of M II oocytes retrieved, number of grade1and 2 embryos, number of frozen embryos, freeze all cycles, Ovarian Hyperstimulation syndrome (OHSS), Chemical pregnancy rate, clinical pregnancy, twins, abortion, ectopic pregnancy, preterm labour, live birth rate

Official Title
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The Effect of Fasting on ICSI Outcomes in Patients With Polycystic Ovary Syndrome

Conditions
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Infertility, Polycystic Ovary Syndrome

Intervention / Treatment
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* Behavioral: Fasting


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: infertile patients with polycystic ovary syndrome diagnosed according to the Rotterdam criteria scheduled for ICSI Exclusion Criteria: women with diabetes, thyroid disorders and other endocrinologic disorders women with uterine abnormalities

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fasting<br>Patients will have periodic fasting for 4 weeks prior to the treatment cycle. The fasting method involves daily fasts of 14-16hours and restrict eating to an 8-10 hour eating window as 2-3 or more meals of balanced diet with 2-3 litres of water and non calorie fluids allover the day. | Behavioral: Fasting<br>* No food for 14 -16 hours with water intake and non caloric beverages then eating balanced meals over 8 to 10 hours<br>* Other names: Periodic fasting;|
| No Intervention: Nonfasting<br>Patients will have usual balanced diet as 3 meals and 2 snacks all over the day. Both groups should take adequate water and non calorie beverages intake daily ( 2-3 liters daily) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of clinical pregnancy | detection of gestationalsac, embryonal pole and fetal pulsations by ultrasonography | 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body mass index | The weight in kilograms divided by the squared height in meters | 4 weeks of fasting | 
| Waist/ hip ratio | The ratio of waist circumference in centimeters to the hip circumference in centimeters | 4 weeks of fasting | 
| Concentration of fasting insulin | Insulin level in serum after fasting for 8 hours measured as mIU/ml | 4 weeks of fasting | 
| Concentration of free testosterone | Free testosterone level in serum measured as ng/dL | 4 weeks of fasting | 
| Number of days of stimulation with gonadotrophins | Days of stimulation with gonadotrophins | 6 weeks | 
| Number of ampoules of gonadotrophins | total number of ampoules of gonadotrophins | 6 weeks | 
| Number of M II oocytes retrieved | Number of M II oocytes retrieved | Average 6 weeks | 
| Number of grade1 and 2 embryos | Number of grade1 and 2 embryos | 6-7 weeks | 
| Number of frozen embryos | Number of frozen embryos | 6 to 7 weeks | 
| Number of freeze all cycles | total number of freeze all cycles | 6 to 7 weeks | 
| Number of cases with Ovarian Hyperstimulation Syndrome | number of cases diagnosed with Ovarian Hyperstimulation Syndrome | 6 to 8 weeks | 
| Rate of chemical pregnancy | number of cases with positive pregnancy test with no clinical pregnancy | 10weeks | 
| Rate of twin pregnancy | presence of two gestational sacs detected by ultrasonography | 10 weeks | 
| Rate of ectopic pregnancy | the presence of gestational sac outside the uterine cavity detected by ultrasound | 10 weeks | 
| Rate of Abortion | the number of abortions clinically diagnosed per cycle | 10-24 weeks | 
| Rate of preterm labour | labour after 20 weeks of gestation and before completed 37 weeks of gestation | After 24 weeks of start of study | 
| Rate of live birth | Live birth rate | After40 weeks of start of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICSI, Polycystic ovary syndrome, Infertility, Fasting