Spontaneous Reproductive Outcomes After Oral Inositol Supplementation in Infertile Polycystic Ovarian Syndrome Women.

Study Overview
=================
Brief Summary
-----------------
Polycystic ovarian syndrome (PCOS) is a heterogeneous, multifaceted and complex disorder characterized by insulin resistance (IR), hyperinsulinemia, and hyperandrogenism leading ovarian disfunction and infertility. Given the central pathogenic role of IR in the endocrine, reproductive, and metabolic disturbances of PCOS, several pharmacological and non-pharmacological approaches have been proposed to counteract the hyper insulinemic IR typical of the syndrome. Two Inositol stereoisomers, Myo-Inositol (MI) and D-chiro-inositol (DCI), captured the attention of researchers for their insulin-sensitizing actions, which configure them as proper candidates for the treatment of PCOS. Very few studies reported on spontaneous clinical pregnancy rates, none were powered for this outcome, and none reported on the clinically relevant outcome of live birth. Therefore, data about clinical pregnancy rate, live birth rate, and miscarriage rate comparing inositols with placebo are limited. Conversely, about infertility and assisted reproduction techniques (ART), improvements have been reported in PCOS women who underwent fertility treatment using inositol in different forms, combinations or doses. This data, considering the different tissue-specific ratios (i.e., 100:1 in the ovary) and the different physiological roles of inositol stereoisomers, suggest that DCI supplementation alone might not be the optimal or appropriate approach for improving IVF outcomes in PCOS patients, and drawn attention to the importance of MI and DCI supplementation in a physiological ratio in order to restore normal ovary functionality. Indeed, the combination of MI and DCI, at a more physiological ratio of 40:1, was able to more quickly restore to normal the hormonal and metabolic parameters in PCOS women than MI treatment alone or DCI treatment alone, improving the endocrine profile and IR of women with PCOS. Nevertheless, regarding infertility the primary outcomes that should be considered are clinical pregnancy rate, miscarriage rate and live birth rate. Although many studies showed improved hormonal and metabolic profile and improved ovulation rate and higher quality and number of oocyte retrieved in ART in PCOS women after inositols administration, data about clinical pregnancy rate, live birth rate, and miscarriage rate are limited with several concerns regarding interpretation of the studies.

Official Title
-----------------
Effects of Oral Inositol Supplementation on Spontaneous Reproductive Outcomes in Infertile Polycystic Ovarian Syndrome Women.

Conditions
-----------------
Polycystic Ovarian Syndrome, Infertility, Female

Intervention / Treatment
-----------------
* Dietary Supplement: Inositol + Folic acid
* Dietary Supplement: Folic acid
* Behavioral: Regular intercourses


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women with PCOS diagnosed by Rotterdam criteria in couple that desire to conceive. Exclusion Criteria: Male infertility factor that require in vitro fertilization technique. Women with infertility factors that require in vitro fertilization technique. Couple with infertility factors that require in vitro fertilization technique. Diabetes mellitus that require insulin or oral drugs treatment. Any other pre-pregnancy or pregnancy-induced/related disease. Any other pharmacological, non-pharmacological or nutraceutical treatment (beside oral folic acid supplementation) more than 3 months before the enrollment (wash-out period) or during the trial.

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

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized multi centre double-blind controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inositol + Folic acid<br>Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Inositol (Myo-inositol and D-chiro-inositol at 40:1 ratio) plus Folic acid for 6 months. Couples are required to have regular intercourse with the aim to achieve a spontaneous conception. | Dietary Supplement: Inositol + Folic acid<br>* Daily oral supplementation of for 6 months or until pregnancy conception: Myo-Inositol: 1100 mg D-chiro-inositol: 27.6 mg Folic acid: 400 mcg<br>Behavioral: Regular intercourses<br>* Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.<br>|
| Placebo Comparator: Folic acid<br>Couples with PCOS infertile women, diagnosed according to the Rotterdam criteria, who access infertility center with conception desire. These women will receive oral supplementation with Folic acid for 6 months. Couples are required to have regular intercourse with the aim to achieve a spontaneous conception. | Dietary Supplement: Folic acid<br>* Daily oral supplementation of for 6 months: Folic acid: 400 mcg<br>Behavioral: Regular intercourses<br>* Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate | Number of spontaneous pregnancies conceived per women diagnosed by transvaginal ultrasound. Diagnosis is based on the identification of intrauterine gestational sac with embryo and/or yolk sac. | Within 6 months from the enrollment | 
| Miscarriage rate | Number of spontaneous abortion per women diagnosed by positive pregnancy test with subsequent spontaneous interruption of the pregnancy. | Within 6 months from the enrollment | 
| Live birth rate | Number of spontaneous pregnancies per women resulted in a delivered viable fetus. | Within 18 months from the enrollment | 
| Spontaneous ovulation rate | Spontaneous ovulation activity evaluated by menstrual cycle regularization. Menstrual cycles evaluated by intervals between menstruations (days), day of menstrual blood flow. Rate evaluate considering the number of women with restored regular menstrual cycles per women with irregular menstrual cycles. | Change in spontaneous ovulation rate, through study completion (an average of 18 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMI | Body mass index | Change in BMI, through study completion (an average of 18 months) | 
| Lipid metabolism | Lipid profile assessed by evaluation the high density lipoprotein level and triglycerides level. | Change in Lipid metabolism, through study completion (an average of 18 months) | 
| Blood pressure | systolic and diastolic blood pressure | Change in Blood pressure, through study completion (an average of 18 months) | 
| Androgens profile | Serum free testosterone, dehydroepiandrosterone sulfate, and serum SHBG serum concentrations. | Change in Androgens profile, through study completion (an average of 18 months) | 
| Glucose metabolism | OGTT: values of oral glucose tolerance test. Impaired glucose metabolism is diagnosed if fasting glucose values were abnormal (100-125 mg/dl) or glucose tolerance is impaired (2 h plasma glucose within OGTT range of 140-199 mg/dl), and when glucose values exceed threshold values for gestational diabetes (fasting glu- cose value ≥92mg/dl, 1-hour glucose value ≥180mg/dl or 2- hour glucose value ≥153mg/dl) | Change in glucose metabolism, through study completion (an average of 18 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Polycystic ovarian syndrome, Fertility, Clinical pregnancy rate, Inositol, Miscarriage rate, Live birth rate