Independent and Additive Effects Of Micronutrients With Metformin In Patients With PCOS

Study Overview
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Brief Summary
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The investigators aim to conduct a double blind randomized clinical trial to study the independent and additive effects of micronutrients (Resveratrol, Acetyl-L Carnitine, L Arginine and COQ10 ) with Metformin in patients with PCOS .Women diagnosed with PCOS according to National Institute of Health( NIH) 2012 extension of European Society of Human Reproduction and Embryology /American Society of Reproductive Medicine ESHRE /ASRM 2003 criteria will be included according to a specific phenotype including Hyperandrogenism, Ovulatory dysfunction and Polycystic Ovarian Morphology. The investigators propose that by using combination therapy with micro supplements like Resveratrol, Acetyl-L Carnitine, L Arginine and COQ10 will produce greater improvement better than or at least comparable to Metformin in metabolic and endocrine profile of patients with PCOS.

Detailed Description
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Polycystic ovary syndrome is a condition which is manifested by certain polycystic ovarian morphologic features, hyperandrogenism and ovulatory dysfunction. As per the revised diagnostic criteria by National Institute of Health 2012, about 6 to 10% women of the reproductive age are affected by the classic polycystic ovarian syndrome, the prevalence of which is twice as more according to the broader Rotterdam standards . One important cause of distress in patients with this syndrome is the excessive expression of androgens (e.g., hirsutism) which leads to infertility. A number of reports based on PCOS suggest that genetic anomalies of follicular maturation and ovarian steroidogenesis also have a crucial role in the development and occurrence of PCOS. This disorder is polygenic in nature and contributes towards metabolic diseases like obesity . About 50 to 80% women having PCOS are obese . Not only has this but PCOS also had a connection with an elevated risk of cardiovascular disease . Type-2 diabetes amongst women with this syndrome is reported to be 8 to 10%, and the compromised glucose tolerance cases are reported as high as 30 to 35% of US. Moreover, the chances of occurrence of this disease is highly associated with changes in age, history of diabetes in family and obesity . PCOS is a multifaceted health issue having several short and long term effects on woman's health. These include cardiovascular diseases, metabolic and sexual dysfunction, depression and anxiety that effects the overall quality of life. The present study documents the impact of PCOS and its complications on overall quality of life and how new treatment options can help minimize the signs and symptoms associated with the disease condition. Some of the recent focused therapeutic compounds reported in this context are Resveratrol, L-Carnitine, Co-Q10, L-Arginine and Decanoic acid as naturally occurring nutraceuticals and metformin as standard therapeutic drug against PCOS. Resveratrol (3,5,4-trihydroxystilbene)-A naturally occurring polyphenol, found in grapes, peanuts, red wine and many medicinal plants . According to studies, this compound may have many antidiabetic, anti-inflammatory and antioxidant actions . Kong et al. highlighted that resveratrol decreases the atretic follicles which significantly increase the number of oocytes . This leads to an inhibition of both, apoptosis and primordial to the developing follicle in rats of different age groups . Resveratrol has been reported to interact with multiple cell targets, but its major effects are brought about by the activation of SIRT1 (silent information regulator 1) . SIRT1, which is a key player in energy metabolism and homeostasis, is a mammalian homologue of Sir2 (yeast) which deacetylates many mammalian cell targets. The SIRT1 is basically 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 . Resveratrol has a tendency to suppress inflammation by activating SIRT1 and as a result the symptoms of inflammation are reduced in many autoimmune disease models like rheumatoid arthritis, colitis, encephalomyelitis and type I diabetes L-Carnitine is involved in fatty acid oxidation by long chain fatty acids transport inside the mitochondria for oxidation to produce metabolic energy and have effects on glucose metabolism in tissues. L-Carnitine is known to regulate energy production . Studies have shown that patients treated with L-Carnitine have improved ovulation and pregnancy rates and is very well tolerated by the patients . Coenzyme Q10 (CoQ10) a lipid soluble coenzyme which is an important component of the inner membrane of mitochondria. It is a key regulator of oxidative phosphorylation in the electron transport chain for ATP synthesis. A number of studies have reported a protective role of CoQ10 in ovaries by restoring aging of ovaries and improving mitochondrial function . According to a recent finding, administration of 20 mg/kg of CoQ10 in a rat model led to increased insulin sensitivity, suggesting its antidiabetic potential . Decanoic acid- is naturally occurring fatty acid present in palm and coconut oils . Lee et al suggested that decanoic acid along with metformin altered cAMP signaling and normalized the androgen synthesis. Moreover, in a diabetic mouse model, treatment with decanoic acid led to improved glucose sensitivity. In another study, letrozole-induced rat PCOS model, the administration of decanoic acid reduced the levels of androgen and 3-HSD which led to restoration of the estrous cycle . These studies suggest a positive role of decanoic acid in management and treatment of insulin resistance and hyperandrogenism in PCOS patients. L-Arginine is an amino acid that plays a role in a number of metabolic pathways and serves as a substrate for NOS (Nitric Oxide synthase) enzyme which is essentially involved in normal insulin signaling and endothelial function . In other findings, it is proposed that L-Arginine also enhances metabolic profile, β-cell function and has anti-oxidant potential . The ovarian health was also improved along with follicular growth, luteal function and oocyte development by the administration of L-Arginine. According to a previous study, PCOS patients had lowered levels of NO (nitric oxide) due to reduced expression of NOS which consequently led to a decline in arginine bioavailability. Therefore, L-arginine supplementation can have a therapeutic potential . Metformin a biguanide which is used in type 2 diabetes and is mostly used as a gold standard drug for PCOS therapy . The mechanism of action is such that it helps in inhibition of hepatic gluconeogenesis and intestinal glucose absorption which ultimately improves insulin signaling . Metformin has a direct and important role in human ovarian steroidogenesis. It inhibits insulin stimulated progesterone and gonadotrophin dose dependently in granulosa cells . According to a recent research report, it was reported that metformin treatment in infertile, anovulatory PCOS women, resulted in pregnancy, higher ovulation and live birth rates as compared to placebo . PCOS is a systemic condition, an endocrinopathy whose etiology is still not understood, correct treatment regimens of PCOS will not only improve menstrual cycle irregularities 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 the investigators goal will be to come up with a better treatment option to treat the disease effectively.

Official Title
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Independent and Additive Effects Of Micronutrients With Metformin In Patients With PCOS:A Double Blind Randomized Placebo Controlled Trial

Conditions
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PCOS

Intervention / Treatment
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* Dietary Supplement: Resveratrol
* Drug: Metformin
* Combination Product: Acetyl-L-Carnitin, L Arginine, Co-Q10


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PCOS women aged 16 -45 years.Diagnosis of PCOS will be made according to NIH 2012 extension of ESHRE/ASRM 2003 criteria Identification of specific phenotype will be included HA+OD+PCOM (Hyperandrogenism, Ovulatory dysfunctions, Polycystic ovarian morphology) HA+OD HA+PCOM PCOM+OD Exclusion Criteria: Women with hyperprolactenemia Diabetes Mellitus Cushing syndrome Androgen secreting tumours Non classical congenital adrenal hyperplasia History of seizures Patients on anti coagulants, anti platelets ,isoproterenol ,antidepressants, potassium sparing diuretics Pregnancy or use of contraceptives Patients with thyroid disease Patients on hormonal therapy -

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment of PCOS with Metformin vs Combination therapy
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>Resveratrol (2 gm daily) 50 patients with PCOS will receive Resveratrol 1000mg BD daily | Dietary Supplement: Resveratrol<br>* Resveratrol<br>|
| Active Comparator: Arm 2<br>Metformin (1000mg daily),Resveratrol(2 gm daily) 50 patients with PCOS will receive Metformin 500mg,Resveratrol 1000 mg BD daily | Dietary Supplement: Resveratrol<br>* Resveratrol<br>Drug: Metformin<br>* Metformin<br>|
| Active Comparator: Arm 3<br>L-Arginine(3 gm daily), Acetyl L-Carnitine (3 gm daily),CoQ10(200 mg daily) 50 patients with PCOS will receive L Arginine 1500mg,Acetyl L Carnitine 1500mg ,COQ10 100mg BD daily respectively | Combination Product: Acetyl-L-Carnitin, L Arginine, Co-Q10<br>* Treatment of PCOS with combination of Acetyl-L-Carnitin, L Arginine, Co-Q10<br>|
| Active Comparator: Arm 4<br>L-Arginine(3 gm daily), Acetyl L-Carnitine (3 gm daily),CoQ10(200 mg daily),Metformin (1000mg daily) 50 patients with PCOS will receive L Arginine 1500mg,Acetyl L Carnitine 1500mg,COQ10 100mg BD daily respectively | Drug: Metformin<br>* Metformin<br>Combination Product: Acetyl-L-Carnitin, L Arginine, Co-Q10<br>* Treatment of PCOS with combination of Acetyl-L-Carnitin, L Arginine, Co-Q10<br>|

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 by HOMA-IR | 6 months | 
| Menstural Irregularities | Oligo/Anovulation, Questionnaire based history taking of each participant | 6 months | 
| Anti mullerian Hormone | Measurement of Anti mullerian hormone by ELISA | 6 months | 
| Dehydroepiandrosterone | Measurement of Dehydroepiandrosterone using ELISA | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antioxidant Assays | Measuring Total AntiOxidant Capacity by FRAP ASSAY | 6 months | 
| Anti oxidant Assays | Measuring MDA (Malondialdehyde) by TBARS | 6 months | 
| Mental health questionnaire | Will be assessed by using Polycystic Ovarian Syndrome Quality Of Life Tool | 6 months | 
| Molecular characterisation | SNP genotyping of THADA and DENNDIA | 6 months | 
| perceived stress response (PSS-14) questionnaire | Stress response | 6 months | 
| profile of mood stress (POMS) by structured questionnaire | Stress response | 6 months |