The potential role of GLP-1 receptor agonist targeting in fertility-sparing treatment in obese patients with endometrial malignant pathology: a call for research

ABSTRACT

Introduction

Most patients diagnosed with endometrial hyperplasia or cancer are obese. Obesity, along with polycystic ovarian syndrome (PCOS) and type-2 diabetes mellitus (T2DM), may act synergistically to increase risk of malignant endometrial pathology. Incidence of malignant endometrial pathology is increasing, particularly in reproductive aged women. In patients who desire future fertility, the levonorgestrel intrauterine device (LNG-IUD) is often utilized. If the first-line progestin therapy fails, there is not an effective second-line adjunct option. Moreover, pregnancy rates following fertility-sparing treatment are lower-than-expected in these patients.

Areas covered

This clinical opinion provides a summary of recent studies exploring risk factors for the development of malignant endometrial pathology including obesity, PCOS, and T2DM. Studies assessing efficacy of fertility-sparing treatment of malignant endometrial pathology are reviewed, and a potential new adjunct treatment approach to LNG-IUD is explored.

Expert opinion

There is an unmet-need for a personalized treatment approach in cases of first-line progestin treatment failure. Glucagon-like peptide 1 receptor agonists are a class of anti-diabetic agents, but may have a role in fertility-sparing treatment of obese patients with malignant endometrial pathology by reducing weight, decreasing inflammation, and decreasing insulin resistance; these changes may also improve chances of subsequent pregnancy. This hypothesis warrants further exploration.

KEYWORDS:

• Endometrial cancer
• endometrial intraepithelial neoplasm
• obesity
• insulin resistance
• glucagon-like peptide 1 receptor agonist
• GLP-1RA
• fertility sparing
• progestin therapy
• polycystic ovary syndrome
• type-2 diabetes

Article highlights

• Approximately 70% of patients with endometrial hyperplasia or cancer have a BMI ≥30 kg/m² and are often impacted by other metabolic conditions, such as PCOS and T2DM that also increase the risk of malignant endometrial pathology.

• While progestin therapy is effective in fertility-sparing management of endometrial malignant pathology, in cases of first-line failure, a personalized and evidenced-based approach to treatment with a second-line adjunct agent is needed.

• GLP-1 receptor agonists have been shown to reduce weight, decrease inflammatory markers, decrease insulin resistance, and inhibit tumorigenesis.

• Further studies on the effect of GLP-1 receptor agonists in patients with endometrial hyperplasia or cancer are suggested.

Declaration of interest

RJ Paulson has served as a consultant for Ferring. JD Wright has received research grants from Merck, royalties from UpToDate consultant and CooperSurgical. M Klar has received royalties from KLS Martin and has served as a consultant for Quantgene (L.D.R.). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper has received an Ensign Endowment for Gynecologic Cancer Research.