Myo-inositol for the Management of Poor Ovarian Responders: A Prospective Randomized Controlled Trial

Study Overview
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Brief Summary
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The management of poor ovarian responders (POR) remains the most challenging in In-Vitro Fertilization (IVF). The incidence of POR ranges between 9 and 24% (Caprio F, et al, 2015). POR refers to a reduction in the quantity of primordial follicle pool in reproductive age group (Jirge, P. R., 2016, Sunkara, S. K., et al, 2014), in addition to a higher risk of implantation failure (Kailasam C, et al, 2004). To overcome this condition, fertility treatments using controlled ovarian stimulation along with IVF is needed to achieve pregnancy. Despite the use of various treatments including high dose gonadotropins, patients with POR have lower rates of pregnancy compared to patients with normal ovarian response (Oudendijk, J. F., et al, 2011). Studies now suggest a variety of regimens like the use of growth hormones, DHEA or androgens to improve the outcomes (Kyrou D, et al, 2009). The main interest of this study is the use of myo-inositol prior to IVF cycles for improvement of reproductive outcomes in poor ovarian responders.

Detailed Description
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The management of poor ovarian responders (POR) remains the most challenging in In-Vitro Fertilization (IVF). The incidence of POR ranges between 9 and 24% (Caprio F, et al, 2015). POR refers to a reduction in the quantity of primordial follicle pool in reproductive age group (Jirge, P. R., 2016, Sunkara, S. K., et al, 2014), in addition to a higher risk of implantation failure (Kailasam C, et al, 2004). To overcome this condition, adjuvant fertility treatments using controlled ovarian stimulation along with IVF is needed to achieve pregnancy. Despite the use of various treatments including high dose gonadotropins, patients with POR have lower rates of pregnancy compared to patients with normal ovarian response (Oudendijk, J. F., et al, 2011). Studies now suggest a variety of regimens like the use of growth hormones, DHEA or androgens to improve the outcomes (Kyrou D, et al, 2009). Inositol belongs to the vitamin B group, precursor for the synthesis of phosphatidylinositol polyphosphates (PIPs). PIPs belong to the signal transduction system involved in the regulation of different cellular functions such as signal transduction, cell morphogenesis and cytogenesis (Kutateladze TG, 2010). It is involved in cell membrane formation, lipid synthesis and cell growth (Unfer V, et al, 2012). It has been extensively studied in patients with insulin resistance, as inositol has an insulin sensitizing action (Croze ML & Soulage CO, 2013). In addition, researchers have hypothesized different mechanisms of action on different cell types especially at the level of the ovaries. An international consensus has confirmed that myo-inositol pre-treatment is able to improve the oocyte and the embryo quality via enhancing the intracellular Ca2+ oscillation with meiotic progression of germinal vesicle oocytes. Therefore, it acts on improving the oocyte maturation and embryo development (Nestler JE, et al, 1999, Papaleo E, et al, 2009). Previous studies showed that higher concentrations of myo-inositol in follicular fluid are correlated with a better oocyte quality (Chiu TT, et al, 2002). A study by Jiang demonstrated that inositol supplementation reduces oxidative stress by different agents such as increasing superoxide dismutase and catalase levels (Jiang WD, et al, 2011). In view of its effects on oocyte maturation and quality, the use of myo-inositol in women with POR is promising. However, data is still sparse whether supplementation with myo-inostiol prior to IVF cycles does improve the pregnancy outcomes. The main interest of this study is the use of myo-inositol prior to IVF cycles for improvement of reproductive outcomes in poor ovarian responders.

Official Title
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Myo-inositol for the Management of Poor Ovarian Responders: A Prospective Randomized Controlled Trial

Conditions
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Poor Ovarian Response

Intervention / Treatment
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* Drug: Myo-inositol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18-44 years at the time of interview POR patients defined as: AMH<1.5 ng/nl, AFC of 7 or less, 5 oocytes or less retrieved in a previous cycle Patients undergoing controlled ovarian stimulation for any indication: Male factor Female factor Exclusion Criteria: Patients with diabetes, thyroid dysfunction Patients with abnormal uterine cavity

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 44 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
Interventional Model Description: Upon consent, recruited women will be randomly allocated into either one of the study groups using a simple randomization method by computer-generated random numbers
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Myo-inositol arm<br>Patients will be supplemented with 2 grams of Myo-inositol + at least 400 μg of folic acid (received from routinely prescribed multivitamins) every day for 3 months before the IVF cycle. | Drug: Myo-inositol<br>* patients who will be supplemented with 2 grams of Myo-inositol daily for 3 months prior to their in-vitro fertilization cycle<br>* Other names: Celine;|
| No Intervention: Control arm<br>Patients will receive at least 400 μg of folic acid from routinely prescribed multivitamins every day for 3 months before the IVF cycle. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Retrieved oocytes | Number of oocytes retrieved (MII), including total number, number of mature MII, and proportion of dysmorphic oocytes | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cycle cancellation rate | number of cycles cancelled before reaching embryo transfer | 4 months | 
| Fertilization rate | number of zygotes per number of oocytes inseminated | 4 months | 
| Implantation rate | number of intrauterine gestational sacs observed on transvaginal ultrasound divided by the number of transferred embryos | 5 months | 
| Clinical pregnancy rate per started treatment cycle (CPR) | the presence of a fetal heart beat on transvaginal ultrasound after 6-7 weeks of gestation | 6 months | 
| Ongoing pregnancy per embryo transferred | number of viable fetuses beyond 20 weeks' gestation per number of embryos transferred | 7 months | 
| Miscarriage rates | pregnancy loss prior to 12 weeks' gestation | 7 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myo-inositol, In-vitro fertilization, Poor Ovarian Responders, Infertility