# Comparative Analysis of Letrozole and Estradiol Valerate PCOS Models: Reproductive and Metabolic Outcomes with and Without High-Fat Diet

## TL;DR

This study compares two animal models of PCOS and finds that letrozole with a high-fat diet best replicates both reproductive and metabolic issues seen in humans.

## Contribution

The study identifies letrozole plus high-fat diet as the most effective PCOS model for studying both hormonal and metabolic features.

## Key findings

- Letrozole with high-fat diet caused weight gain, hormone imbalances, and ovarian changes similar to human PCOS.
- Estradiol valerate had fewer metabolic and hormonal effects compared to letrozole.
- Letrozole combined with high-fat diet impaired glucose tolerance, indicating metabolic dysfunction.

## Abstract

Polycystic ovary syndrome (PCOS) is a common condition in women that affects hormones and periods, and can make it harder to get pregnant. It is also linked to problems like weight gain and difficulty processing sugar. Scientists use animal models to study PCOS, but not all models show both the hormone and metabolism problems seen in people with PCOS. In this study, two common ways to create PCOS in animals using hormone treatments—letrozole and estradiol valerate (EV)—with or without a high-fat diet were tested. It was found that letrozole, especially when combined with a high-fat diet, caused weight gain, hormone imbalances, and changes in the ovaries similar to PCOS in humans. On the other hand, EV had fewer of these effects. This suggests that the letrozole plus high-fat diet model is the most useful for studying both the hormone and metabolism issues of PCOS.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in reproductive-aged women, characterized by hyperandrogenism, oligoanovulation, and polycystic ovarian morphology. Despite its classification as a reproductive disorder, PCOS is closely associated with metabolic dysregulation, including insulin resistance and obesity. An ideal animal model for PCOS should replicate both reproductive and metabolic features of the condition. In this study, we compared two widely used postnatal PCOS models (letrozole and estradiol valerate [EV]) administered alone or in combination with a high-fat diet (HFD), assessing their ability to induce both the reproductive and metabolic features. Letrozole treatment led to significant weight gain and increased visceral adiposity, effects that were amplified by HFD. Conversely, EV treatment showed a tendency toward reduced body mass. While neither model significantly altered fasting glucose levels, letrozole combined with HFD impaired glucose tolerance, supporting its role in metabolic dysfunction. Hyperandrogenism was more consistently induced by letrozole compared to EV, aligning with clinical PCOS phenotypes. Both treatments disrupted estrous cyclicity and induced polycystic ovarian morphology, though metabolic disturbances were more pronounced in the letrozole model. These findings suggest that letrozole, particularly in combination with HFD, provides a more consistent model for studying both the reproductive and metabolic facets of PCOS.