Effects of Combined Resveratrol and Myo-inositol on Altered Metabolic, Endocrine Parameters and Perceived Stress in Patients With Polycystic Ovarian Syndrome

Study Overview
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Brief Summary
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The investigators aim is to conduct a double blind randomized clinical trial, to study the effects of combined Resveratrol and Myo-Inositol on altered metabolic, endocrine parameters and perceived stress response in patients with Polycystic Ovary Syndrome (PCOS). Women diagnosed with PCOS, using criteria proposed in November 2015, by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), and Androgen Excess and PCOS Society (AES) for PCOS should include two of the following three criteria: chronic an ovulation, hyperandrogenism (clinical/biologic), and polycystic ovaries. The investigators propose that PCOS women may have altered metabolic, endocrine levels and increased perceived stress response and combination therapy may have beneficial influences on these parameters in women diagnosed with PCOS.

Detailed Description
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Polycystic ovarian syndrome (PCOS) is extremely prevalent and considered to be the most common heterogeneous endocrine disorder in reproductive age women. This affects up to 10-15% of women in reproductive age. PCOS is a multifaceted health issue characterized by chronic anovulation with excess ovarian activity, hyperandrogenism and polycystic ovaries. The most disappointment for women with PCOS is pregnancy loss. This endocrine disorder has some long term effects including cardiovascular diseases, metabolic and sexual dysfunction, depression and anxiety that effects the overall quality of life. Women with PCOS have a greater risk of developing hyperinsulinemia and insulin resistance and this explains the substantially increased prevalence of glucose intolerance in PCOS. Recent long-term follow up studies of the syndrome have shown that dyslipidemia and hyperlipidemia is a very common metabolic abnormality in these women. The key pathophysiology of PCOS is Insulin resistance, thus dyslipidemia in women may be constant with those found in an insulin resistant state. Low adiponectin levels in PCOS have been largely associated with obesity which is common among these patients. Serum adiponectin levels are associated with PCOS independently and are only explained by IR partly. An independent biomarker, adiponectin can be used for diagnosing PCOS in young and lean women or women with a family history of PCOS. Resveratrol (3,5,4-trihydroxy-trans-stilbene) belongs to polyphenols stilbene group found in grapes, peanuts, red wine and many medicinal plants. Studies have shown that patients treated with resveratrol have shown improve glucose homeostasis and reverse insulin resistance. Treatment with resveratrol improved the elevated number of atretic and secondary follicles and the decreased number of Graafian follicles in the PCOS group, which indicates the effect of the treatments on the maintenance of folliculogenesis. It has been reported to interact with multiple cell targets, but its major effects are brought about by the activation of SIRT1 (silent information regulator1).The SIRT1 is expressed in oocytes and human granulosa nuclei cells at multiple developmental stages of the follicles. It is also responsible for suppressing inflammation. Moreover, SIRT1 is also involved in protecting the oocytes from age dependent insufficiencies through oxidative stress. Myo-Inositol is a carbocyclic sugar, belongs to Inositol group and is an important component of structural lipids. Inositol's or its phosphates and the associated lipids are found in different fruits specially cantaloupe and oranges. It is the precursor of inositol triphosphate, acting as an intracellular second messenger and regulating a number of hormones such as thyroid-stimulating hormone, follicle-stimulating hormone (FSH) and insulin. One of the insulin-sensitizing compounds, Myo-Inositol is capable of restoring spontaneous ovarian activity, and consequently fertility, in most patients with PCOS. Inositol's improve the metabolic and endocrine parameters in young, overweight PCOS patients and regulate the monthly cycles. Treatment with inositol's in obese PCOS patients is also effective in reducing BMI. The decrease in BMI is without any lifestyle modification. PCOS is a systemic condition, an endocrinopathy whose etiology is still not understood, correct treatment regimens of PCOS will not only improve menstrual cycles of the patients but will also improve the metabolic or endocrinological parameters. PCOS sufferers are also known to have increased levels of perceived stress which will be considered in the study. Very little evidence is available on combination therapy for treatment of PCOS patients. In this study our goal will be to come up with a better treatment option to treat the disease effectively. Study Objectives: To investigate the effects of combined Resveratrol and Myo-Inositol treatment after 3 months on metabolic, endocrine alterations and perceived stress response in patients with PCOS.

Official Title
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Effects of Combined Resveratrol and Myo-inositol on Altered Metabolic, Endocrine Parameters and Perceived Stress in Patients With Polycystic Ovarian Syndrome

Conditions
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PCOS

Intervention / Treatment
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* Drug: Resveratrol (1000mg twice a day), Myoinositol 1000mg (Twice a day)
* Drug: Metformin (500 mg Twice a day), Pioglitazone (15 mg Twice a day)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment naive PCOS women having age from 14-45 years with scanty or no menstruation, hirsutism and elevated serum androgen levels, will be diagnosed on the basis of AES (Androgen access society) guidelines 2006 according to which when two of the following criteria are present patient will be said to have the syndrome Hirsutism or hyperandrogenism Oligo or an-ovulation and or polycystic ovaries Exclusion Criteria: Women with previous history of Cushing syndrome Thyroid disorders Hyperprolactinemia Ovarian tumors Congenital adrenal hyperplasia androgen-producing tumors, History of seizures Patients on warfarin, Coumadin and Sintrom because of drug interaction with acetyl-L-Carnitine, Pregnancy or using contraceptive medications, Patients on hormonal therapy that alters the biochemical or hormonal profile

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 35 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination Therapy Group<br>ARM 1: Resveratrol (1000mg Twice a day) Myoinositol (1000mg Twice a day) | Drug: Resveratrol (1000mg twice a day), Myoinositol 1000mg (Twice a day)<br>* 51 Patients with PCOS receiving Resveratrol and Myoinositol 1000mg and 1000mg BD daily respectively<br>|
| Other: Standard Therapy Group<br>ARM 2:Metformin 500mg (Twice a day) Pioglitazone (15mg Twice a day) | Drug: Metformin (500 mg Twice a day), Pioglitazone (15 mg Twice a day)<br>* 51 Patients with PCOS receiving Metformin and Pioglitazone 500 mg and 15 mg BD daily respectively<br>* Other names: Zolid Plus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin Resistance | PCOS associated insulin resistance and hyperinsulinemia through HOMA-IR | 3 months | 
| Hypoadiponectinemia | PCOS associated Hypoadiponectinemia. Measurement of adiponectin levels through human adiponectin enzyme-linked immunosorbent assay (ELISA ) kit and the values of serum adiponectin reported in microgram/mL. | 3 months | 
| Ovary volume | Polycystic ovaries volume measurement by abdominopelvic ultrasound | 3 months | 
| Stress response | Perceived stress response and profile of mood stress by structured questionnaire | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Body fat analysis | Body fats measurement through measurement scale | 3 months | 
| Hirsutism | Hirsutism grading scale, Ferriman Gallwey Score is used to evaluate hirsutism. A score of 1 to 4 is given for nine areas of the bod including upper lip, chin, chest, upper abdomen, lower abdomen, arms, thighs, upper back and lower back. A total score less than 8 is considered normal, a score of 8 to 15 indicates mild hirsutism, and a score greater than 15 indicates moderate or severe hirsutism. A score of 0 indicates absence of terminal hair. | 3 months | 
| Abnormal menstruation patterns both oligomenorrhea or amenorrhea attributed to chronic anovulation | Oligomenorrhea evaluated by menstrual bleeding that has occurred at intervals of 35 days to 6 months, with < 9 menstrual periods per year and secondary amenorrhea assessed by absence of menstruation for 6 months. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCOS, Resveratrol and Myoinositol