PCOS Clinical Trial
Official title:
Effects of a Combined Treatment With Myo-inositol, D-chiro-inositol and Glucomannan in Women With PCOS
The aim of this study is to analyze the metabolic profiles in women with PCOS before and after 3 months of therapy with a combination of myo-inositol, D-chiro-inositol and glucomannan, and compare these data with a group of healthy control women.
1. RATIONALE & BACKGROUND INFORMATION Polycystic ovary syndrome (PCOS) is a heterogeneous
syndrome and one of the most common female endocrine disorders, affecting 5-20% of women
in reproductive age . Clinical expression is highly variable, but typically includes
oligo-ovulation or anovulation, hyperandrogenism and polycystic ovaries . PCOS is
associated with an increased risk of type 2 diabetes, cardiovascular events and
endometrial cancer. Insulin Resistance (IR) plays a central role in approximately 70-80%
of obese women and in 15-30% of lean women with PCOS, and represents the pathogenic link
between metabolic and reproductive disorders in PCOS. According to recent guidelines,
insulin-sensitizer drugs, like inositols, are the first-line therapy in women with
metabolic abnormalities and irregular menstrual cycle with the purpose to improve
fertility, whereas a lifestyle change with weight loss and physical activity is the
first step in overweight and obese PCOS patients . Moreover, the association
inositols-glucomannan may represent a good therapeutic strategy in the treatment of PCOS
women with insulin resistance. Metabolomic approach is used to better define the
pathophysiology of PCOS and to describe how different therapies can modify metabolic
profiles. Although the association inositols-glucomannan may represent a good
therapeutic strategy in the treatment of PCOS women with insulin resistance, the effect
of inositols on the metabolomic profile of these women has not been described yet.
2. STUDY GOALDS AND OBJECTIVES The aim of this study is to analyze the metabolic profiles
in women with PCOS before and after 3 months of therapy with a combination of
myo-inositol, D-chiro-inositol and glucomannan, and compare these data with a group of
healthy control women.
3. STUDY DESIGN The study is a prospective and observation. The inclusion criteria are: age
between 18 and 35 years, overweight/obesity (BMI > 25 kg/m2), absence of any other acute
intercurrent or chronic illness, a positive diagnosis of PCOS according to Rotterdam
criteria. Exclusion criterion is using hormonal medications or drugs that affect insulin
sensitivity (e.g., inositols or metformin) before enrollment.
The use of myo-inositol (1.75 g), D-chiro-inositol (0.25 g) and glucomannan (4.0 g)/die
must precede the recruitment of no more than 30 days. The decision to start treatment
must have already been made before and independently of the start of the study. The use
of inositol and glucomannan must take place according to the technical data sheet. In
particular, myo-inositol (1.75 g), D-chiro-inositol (0.25 g) and glucomannan (4.0 g) are
expected to be subdivided into two doses before main meals.
4. METHODOLOGY 4.1 Admission visit (V0) Once the eligibility criteria have been checked,
the investigator will inform the patient about the objectives of the study during the
initial visit (V0) and obtain written informed consent form.
The compilation of a clinical card includes general information, anamnesis, BMI, the
characteristics of the menstrual cycle, the amount of menstrual loss, the degree of
hirsutism according to the Ferriman-Gallwey index and the degree of acne in agreement to
the Global evaluation scale proposed in 2002 by FDA.
The investigator will collect from the clinical documentation available the baseline
glycaemia, insulin, triglycerides, cholesterol values before the start of the treatment.
Furthermore, information on the ultrasound picture will be collected in terms of ovary
volumes and antral follicles.
A sample of 2-3 ml of basal blood will be collected for metabolomic evaluations, using a
BD vacutainer (Becton Dickinson, Oxfordshire, UK) blood collection red tube (with no
additives). After centrifugation, the sample will immediately freeze to -80 °C until the
time of analysis.
The patient will then be invited to continue treatment with myo-inositol (1.75 g),
D-chiro-inositol (0.25 g) and glucomannan (4 g) die and to show up for control after 90
days (V1).
4.2 Follow-up visit 90th day (±15) after enrollment (V1) During the V1 the patient will
be interviewed on the regular therapy and clinical symptoms, any adverse events and the
course of the menstrual cycle.
Furthermore, all patients will be re-evaluated regarding the anthropometric, biochemical
and ultrasound parameters.
At V1 a second blood sample of 2-3 ml will be collected with the same methods describe
above.
4.3 Biochemical and metabolomics samples analysis Blood concentration of glucose,
insulin, triglycerides and cholesterol is evaluated for control subjects and for cases
at baseline and after 3 months of treatment. HOMA-IR si also calculated. Ovary volumes
and the antral follicles count were evaluated by a vaginal ultrasound performed by a
trained gynecologist.
Metabolome extraction, purification and derivatization is carried out with the
MetaboPrep GC kit (Theoreo srl, Montecorvino Pugliano [SA], Italy) according to the
manufacturer's instructions. Details regarding metabolite extraction and the overall
analytical scheme, including QA/QC sample analyses, were reported in Troisi et al.
(2017, 2018)
5. Follow-Up Three months.
6. Data Management and Statistical Analysis At the end of the treatments the data
collection of all patients is scheduled and the introduction of the same, in coded or
clear form, in a database (Excel for windows) appropriately structured to contain all
the expected items. In order to comply with the privacy law, the sensitive nominal data
will be appropriately replaced by the numerical codes assigned to each patient, so that
from the simple consultation of the data it will not be possible to deduce any
individual direct reference. Moreover, the only data that can be extracted from the
database are related to aggregated sets to be published for scientific purposes.
Data is reported as mean±standard deviation for continuous variables and number
(percentage) for categorical variables.
Statistical analysis are performed using Statistica software (StatSoft, Oklahoma, USA)
and Minitab (Minitab Inc, Pennsylvania, USA). Normal distribution of data is verified
using the Shapiro-Wilks test. Since the data are normally distributed, the investigators
use one-way ANOVA with the Tukey post hoc test for inter-group comparisons. The alpha
(ɑ) value is set to 0.05. Pearson's chi-squared test is used to determine differences
among groups for the categorical variables.
For multivariate data analysis, the chromatographic data are tabulated with one sample
per row and one variable (metabolite) per column. Data pre-treatment consists of
normalizing each metabolite peak area to that of the internal standard followed by
generalized log transformation and data scaling by autoscaling (mean-centered and divide
it by standard deviation of each variable). PLS-DA is performed using the statistical
software package R (Foundation for Statistical Computing, Vienna, Austria). Class
separation is achieved by PLS-DA, which is a supervised method that uses multivariate
regression techniques to extract, via linear combinations of original variables (X), the
information that can predict class membership (Y). PLS regression is performed using the
plsr function included in the R pls package. Classification and cross-validation is
performed using the corresponding wrapper function included in the caret package. A
permutation test is performed to assess the significance of class discrimination. In
each permutation, a PLS-DA model is built between the data (X) and the permuted class
labels (Y) using the optimal number of components determined by cross validation for the
model based on the original class assignment. Variable Importance in Projection (VIP)
scores are calculated for each metabolite. The VIP score is a weighted sum of squares of
the PLS loadings, taking into account the amount of explained Y-variation in each
dimension. The highest scoring VIP metabolites are compared in terms of fold changes
(FC). FC is the ratio of the mean abundances between any two classes and is a measure
describing how much a quantity changes going from an initial to a final value.
The metabolic pathways are constructed using MetScape application of the software
Cytoscape.
7. Expected Outcomes of the Study The goal of this pilot study is to identify a complex
network of serum molecules that appear to be correlated with PCOS, and with a combined
treatment with inositols and glucomannan.
8. Duration of the Project 24 months
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