Spontaneous Reproductive Outcomes After Oral Inositol Supplementation in Infertile Polycystic Ovarian Syndrome Women. (IROP-1)

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Polycystic Ovarian Syndrome; Infertility, Female
• Intervention / Treatment: Dietary supplement: Inositol + Folic acid; Behavioral: Regular intercourses; Dietary supplement: Folic acid

• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Inositol + Folic acid; 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; 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; Behavioral: Regular intercourses; Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.
PLACEBO_COMPARATOR: Folic acid; 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.	Behavioral: Regular intercourses; Couples are required to have regular intercourses with the aim to achieve a spontaneous conception.; Dietary supplement: Folic acid; Daily oral supplementation of for 6 months: Folic acid: 400 mcg

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
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)
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)

Collaborators and Investigators

• Sponsor: Università degli Studi dell'Insubria
• Collaborators: Universita di Verona
• Investigators: Study Chair: Massimo Franchi, M.D., Universita di Verona

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 1, 2022
• Primary Completion (ANTICIPATED): June 30, 2023
• Study Completion (ANTICIPATED): December 31, 2024

Study Registration Dates

• First Submitted: June 29, 2018
• First Submitted That Met QC Criteria: July 15, 2018
• First Posted (ACTUAL): July 26, 2018

Study Record Updates

• Last Update Posted (ACTUAL): September 30, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Fertility; Polycystic ovarian syndrome; Clinical pregnancy rate; Live birth rate; Inositol; Miscarriage rate
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Endocrine System Diseases; Disease; Ovarian Cysts; Cysts; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Polycystic Ovary Syndrome; Syndrome; Infertility; Infertility, Female; Physiological Effects of Drugs; Micronutrients; Vitamins; Hematinics; Folic Acid; Vitamin B Complex; Inositol
• Other Study ID Numbers: IROP-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No