Progestin therapy for obese women with complex atypical hyperplasia

Obese women who used the levonorgestrel intrauterine system (LNG-IUS) were nearly three times as likely to achieve a complete response to progestin treatment, along with a 70% reduction in risk of progression to cancer, compared to those who received systemic progestin therapy, according to a retrospective study. Published in the American Journal of Obstetrics and Gynecology, it also concluded that superiority of the LNG-IUS in treatment response rose incrementally with increasing body mass index (BMI), while morbidly obese women derived the highest relative benefit. 

“Endometrial hyperplasia is a diagnosis we unfortunately encounter rather frequently in our population with high obesity rates,” said senior author Rachel Mandelbaum, MD, a resident physician in ob/gyn at the University of Southern California in Los Angeles. “However, there are no clear treatment guidelines for the medical management of these patients when hysterectomy is not performed. Knowledge gaps exist with regards to route of progestin therapy, how long to treat, and when and how to resample in follow-up. There is a great need to study these important clinical questions to ensure high quality and effective care for these patients.” 

Methods
Led by Matsuo Koji, Associate Professor of Obstetrics & Gynecology, the study comprised 245 obese women with a mean age of 36.9 years and a mean BMI of 40.0 kg/m², all of whom had complex atypical hyperplasia. Participants received either the LNG-IUS (n = 69) or systemic progestin therapy (n = 176) at the Los Angeles County Medical Center between 2003 and 2018. 

Findings
Women in the LNG-IUS group had higher rates of complete response: 78.7% vs. 46.7%, respectively; adjusted hazard ratio (aHR) = 3.32; 95% confidence interval (CI): 2.39 to 4.62. The LNG-IUS group also had a lower likelihood of progression to cancer: 4.5% vs. 15.7%; aHR = 0.28; 95% CI: 0.11 to 0.73.

In particular, women with class III obesity derived a higher relative benefit from the LNG-IUS in achieving complete response compared to systemic therapy: aHR = 4.72; 95% CI: 2.83 to 7.89.

“The margin of difference between the LNG-IUS and systemic therapy is striking in our study,” Dr. Mandelbaum told Contemporary OB/GYN. “As clinicians, we are aware of many of the benefits of the LNG-IUS compared to systemic progestins; daily patient compliance is not necessary, there are usually fewer side effects and bleeding profile often improves. But, to add this evidence for superior treatment efficacy is a great tool to advocate for LNG-IUS use in appropriate candidates.” 

Conclusions
The difference in efficacy between the LNG-IUS and systemic therapy is likely multifactorial, according to Dr. Mandelbaum. “First, local therapy may lead to higher levels of progestin at the level of the endometrium compared to systemic therapy,” she said. “Second, the LNG-IUS does not require daily patient compliance, which if poor, may drastically decrease the efficacy of oral therapies.”

The LNG-IUS is also reported to have an improved side effect profile compared to systemic formulations. “Weight gain, specifically, is a concern with systemic progestin formulations, as obesity is a major risk factor for hyperplasia and endometrial cancer,” Dr. Mandelbaum said. 

Dr. Mandelbaum noted that inserting the LNG-IUS in endometrial hyperplasia patients is simple and easy. “Placement can be performed in the office and confirmed at subsequent visits on ultrasound or by verifying the presence of IUS strings,” she said. In addition, endometrial resampling can be scheduled at regular intervals around the IUS, leaving it in-situ. 

“Moreover, once clearance of hyperplasia has been demonstrated, the device can be removed with nearly immediate return of fertility in patients who desire this option,” Dr. Mandelbaum said. 

Adjunctive therapies with the LNG-IUS are of particular interest for future study, including antiestrogenic agents such as leuprolide or aromatase inhibitors, combination progestin therapy, and metformin, “which may have an antiproliferative effect on the endometrium,” she said.