The combined impact of testosterone and Western-style diet on endometriosis severity and progression in rhesus macaques

Abstract

Polycystic ovary syndrome (PCOS) is associated with irregular menstrual cycles, hyperandrogenemia and obesity. It is currently accepted that women with PCOS are also at risk for endometriosis, but the effect of androgen and obesity on endometriosis has been underexplored. The goal of this study was to determine how testosterone (T) and an obesogenic diet impact the progression of endometriosis in a nonhuman primate (NHP) model. Female rhesus macaques were treated with T (serum levels approximately 1.35 ng/mL), Western- style diet (WSD; 36% of calories from fat compared to 16% in standard monkey chow) or the combination (T + WSD) at the time of menarche as part of a longitudinal study for ~7 years. Severity of endometriosis was determined based on ASRM revised criteria, and staged 1–4. Stages 1 and 2 were associated with extent of abdominal adhesions, while Stages 3 and 4 were associated with presence of chocolate cysts. The combined treatment of T + WSD resulted in earlier onset of endometriosis and more severe types associated with large chocolate cysts compared to all other treatments. There was a strong correlation between glucose clearance, HOMA-IR and total percentage of body fat with presence of cysts, indicating possible indirect contribution of hyperandrogenemia via metabolic dysfunction. An RNA-seq analysis of omental adipose tissue revealed significant impacts on a number of inflammatory signaling pathways. The interactions between obesity, hyperandrogenemia and abdominal inflammation deserves additional investigation in nonhuman primate model species.

A protocol for creating endometriosis in rhesus macaques (Macaca mulatta)

“…The observation that nearly all of the animals in this study developed endometriosis supports the premise that multiple surgical seeding events exacerbates pelvic inflammation. The role of pelvic inflammation in the development of endometriotic disease is evidenced in our recent reports that factors associated with polycystic ovarian syndrome including an obesogenic western style diet and exogenous androgen can lead to increased incidence of endometriosis in macaques 53 . Recently, neuropeptide S receptor has been identified in women and macaques and may provide a novel target for treatment of endometriosis 54 .…”

“…The role of pelvic inflammation in the development of endometriotic disease is evidenced in our recent reports that factors associated with polycystic ovarian syndrome including an obesogenic western style diet and exogenous androgen can lead to increased incidence of endometriosis in macaques. 53 Recently, neuropeptide S receptor has been identified in women and macaques and may provide a novel target for treatment of endometriosis. 54 Our induced model in the macaque will provide a working system that can be explored for addressing factors that increase the likelihood of developing the disease.…”

High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia

“…In non-human primates, rhesus macaque females exposed to testosterone (T) and/or consumed Western-style diets (WSD) at the time of menarche for 7 years developed endometriosis, especially T+WSD resulted in earlier onset of disease with high stages and large chocolate cysts (56). In a mouse model of endometriosis, HFD-induced obese mice increased lesion number and weight, which depended on leptin or leptin receptor (57).…”

Uterine uptake of estrogen and progestogen-based radiotracers in rhesus macaques with endometriosis

“…Rhesus macaques are menstruating nonhuman primates with approximately 28-day menstrual cycles similar to those of humans [15][16]. Like humans, macaques develop spontaneous endometriosis [17][18][19]. Additionally, the strengths of the macaque model include:…”