PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: A prospective, randomized, placebo- and drug-controlled study

Abstract

Objective-To determine the effects of a thiazolidinedione (TZD) agonist of peroxisome proliferator-activated receptor (PPAR)-γ, rosiglitazone, in a baboon model of established endometriosis.Design-Prospective, randomized, placebo-controlled study.Setting-Experimental surgery laboratory at the Institute of Primate Research in Nairobi, Kenya.Animal(s)-Endometriosis was induced using intrapelvic injection of eutopic menstrual endometrium in 12 female baboons with a normal pelvis that had undergone at least one menstrual cycle since the time of captivity.Intervention(s)-Induction of endometriosis by laparoscopy was performed in 12 baboons with a normal pelvis. Endometrial tissue was extracted from each baboon by curettage and a standard amount of endometrium was then seeded onto several peritoneal sites as previously described. About 34-68 days after the induction of laparoscopy, a pre-treatment laparoscopy (baseline disease assessment) was performed in the baboons to record the extent of endometriotic lesions. The 12 baboons were randomized into 3 groups and treated from the day after the staging laparoscopy for a total duration of 30 days. They received either PBS tablets (n=4, placebo control; placebo tablets once a day by mouth for 30 days), GnRH-antagonists (n=4, active control; Ganirelix acetate 125 μg/day for 30 days) or rosiglitazone (n=4, test drug, 2 mg by mouth each day for 30 days). A 3 rd and final laparoscopy on day 30 after the start of treatment was performed to record the extent of endometriosis. The type of lesion (typical, red, white and suspicious) was recorded. Biopsies were obtained to confirm the histological presence of endometriosis.Main Outcome Measure(s)-A videolaparoscopy was performed 30 days after treatment to document the number and surface area of endometriotic lesions as well as to calculate the revised American Society for Reproductive Medicine score (rAFS) and stage.Corresponding author Dan I. Lebovic, M.D., M.A., Department of Obstetrics and Gynecology, University of Michigan, Tel: 734-615-8257, Fax: 734-647-1006, E-mail: lebovic@umich.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access

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“…It still remains unclear whether immunological abnormalities in the pelvis of patients with endometriosis are the cause of disease or a consequence of disease. Several anti-inflammatory modulators such as cyclooxygenase 2 inhibitors (Matsuzaki et al, 2004), peroxisome proliferator-activated receptor-␥ agonist (Lebovic et al, 2007), and TNF␣ inhibitors (Barrier et al, 2004;D'Antonio et al, 2000) were effective in animal models of endometriosis. Overall, data emerging from these anti-inflammatory treatments are extremely promising and suggest potential for targeting the immune system to treat patients with endometriosis.…”

Unsuccessful Induction of Endometriosis in Female Rhesus Macaques <i>(Macaca mulatta)</i>

“…It could therefore take many years of exposure to endometrial stroma, even in experimental conditions, before significant endometriotic lesions are seen in rhesus monkeys. In baboons, induced lesions were first observed after 3 months [48] , 2 months [49] and 1 month [50][51][52] after retroperitoneal injection in mature animals. Induction of endometriosis in cynomolgus monkeys ( M. fascicularis ) occurred in the weeks following subperitoneal injection of endometrial stroma [53][54][55] .…”

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