# Comparison of the therapeutic effects of sacubitril and valsartan combination versus metformin in experimentally induced polycystic ovary syndrome in rats

## TL;DR

This study compares how well sacubitril and valsartan work together to treat polycystic ovary syndrome in rats compared to metformin.

## Contribution

The study introduces a novel combination therapy using sacubitril and valsartan for treating PCOS and insulin resistance in a rat model.

## Key findings

- The sacubitril and valsartan combination significantly improved glucose tolerance and reduced insulin resistance in PCOS rats.
- The combination therapy led to notable improvements in hormone, lipid, and peptide levels associated with PCOS.
- Histological and biochemical evidence confirmed the effectiveness of the combination in reducing cystic follicles and insulin resistance.

## Abstract

Our study aimed to demonstrate the therapeutic effects of sacubitril (an inhibitor of neprilysin) and/or valsartan (an ARB) in an experimentally induced polycystic ovary syndrome (PCOS) model and in PCOS-induced insulin resistance.

After 21 days of letrozole 1 mg/kg administration, rats were confirmed to have PCOS by the vaginal smear method. Following PCOS induction, the experiment was terminated after 15 days of drug treatment. Metformin 300 mg/kg, sacubitril 30 mg/kg, and valsartan 31 mg/kg were administered orally every 15 days. Fasting insulin levels and oral glucose tolerance test (OGTT) were performed to measure insulin resistance and calculate homeostatic model assessment - insulin resistance (HOMA-IR). At the end of the experiment, biochemical analyses were performed on blood samples, and histological studies were conducted on tissue samples.

The sacubitril and valsartan combination significantly improved impaired glucose tolerance and HOMA-IR. Serum neprilysin (NEP) levels were found to be significantly higher in the PCOS group than in the healthy group, while atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels were found to be significantly lower. The sacubitril+valsartan combination provided the greatest improvement in PCOS-related changes in serum NEP, ANP, BNP, angiotensin II (ANGII), hormone, and lipid levels. The application of sacubitril+valsartan provided an important treatment for insulin resistance due to PCOS by increasing the expression of insulin resistance (IR), insulin receptor substrate 1 (IRS-1), and insulin receptor substrate 2 (IRS-2).

Sacubitril and valsartan combination has been shown to have significant therapeutic benefits for PCOS. It markedly reduces cystic follicles and PCOS-associated insulin resistance, improves serum lipid levels, and is supported by pathological findings.