Ovary-Driven Hyperandrogenemia Does Not Induce Metabolic Disorder.

Abstract

Obesity, metabolic disorder, and infertility have an intertwined relationship as shown in patients with polycystic ovarian syndrome; however, the causal relationships among them are yet to be determined. Our previous studies showed that a high-fat diet (34% fat)-induced metabolic disorder caused defects in folliculogenesis, ovulation, and corpus luteum formation, eventually resulting in the loss of fertility. In this study, we aimed to determine whether ovarian dysfunction leads to metabolic disorder. A strain of mice that exhibits constant hyperandrogenemia (HA) was subjected to metabolic examination. We generated this HA mouse line by inducing a null mutation in estrogen receptor alpha (ERa or Esr1) gene selectively in the ovarian theca cells (theca specific Esr1 knockout; thEsr1KO). The thEsr1KO (HA) and wild type littermates (control) were housed together at the age of 1.5 months and fed with regular diet, and their weight growth patterns were measured for next 3 months. Until then, no differences in weight growth (22.6±0.6g HA vs. 22.7±0.8g control) and metabolic indices (body fat ratio, glucose tolerance, insulin resistance, food consumption and energy expenditure) were seen between the HA and control mice. The mice were then fed with either regular or high fat diet for next 3 months, followed by measurement of weight growth patterns and metabolic indices. There was no difference in weight between HA (28.9±1.7g) and control mice (31.0±2.1g), but was between the mice fed with high fat diet (32.6±1.6g) and regular diet (25.9±0.5g). Furthermore, no significant differences in metabolic indices were noted between HA and control mice: for example, body fat ratio (37.2±4.1% HA vs. 40.5±2.0% control), food consumption (11.1±0.9g HA vs. 10.8±1.7g control), and energy expenditure (13.8±0.8Kcal HA vs. 13.6±0.7Kcal). In all of the metabolic indices measured, significant differences were seen between high-fat diet group and regular diet groups of mice. Taken together, while metabolic disorder does cause ovarian dysfunction, this study demonstrates that ovary-driven hyperandrogenemia does not induce metabolic disorder.