Polycystic Ovary Syndrome Phenotype in Hyperinsulinemic but Normoandrogenic Monosodium L‐Glutamate Obese Rats

Abstract

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women. It is characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology; albeit metabolic syndrome is found in most cases. Such broad heterogeneity has kept PCOS etiology under intense research, since there is a lack of experimental models that comprise the variety of human PCOS phenotypes. In the present study, we hypothesized that reproductive disorders observed in monosodium L‐glutamate (MSG)‐induced obesity are associated with early development of PCOS. Newborn female rats were subcutaneously injected with MSG (4g/kg/day; MSG) or equiosmolar saline (CTR) on alternate days, up to 10th postnatal day. On postnatal day 60, we started to evaluate estrous cycle by vaginal smears twice a day for 15 days, which showed MSG rats to be oligocyclic, with more irregular cycles (CTR 66.67 ± 10.91 vs MSG 95.24 ± 4.76 %; p<0.05). Thereafter, animals were euthanized on estrous phase for blood and tissue collection. MSG rats had increased body mass (CTR 310.60 ± 1.71 vs MSG 337.30 ± 2.99 (g1/3/cm)*1000; p<0.01), retroperitoneal (CTR 1.08 ± 0.17 vs MSG 2.84 ± 0.26 g/100g BW; p<0.01) and visceral (CTR 1.08 ± 0.18 vs MSG 3.67 ± 0.33 g/100g BW; p<0.01) fat pads accumulation. MSG animals had also visceral adipocyte hypertrophy as compared to CTR (CTR 1551 ± 223.70 vs MSG 3632 ± 32.73 μm2; p<0.001). Of interest, our MSG rats presented hypertriglyceridemia (CTR 75.53 ± 8.07 vs MSG 106.80 ± 8.17 mg/dL; p<0.05) and hyperinsulinemic (CTR 0.32 ± 0.07 vs MSG 0.89 ± 0.2 ng/mL; p<0.05). By contrast, MSG animals displayed mild hipoglycemia (CTR 111.00 ± 1.98 vs MSG 92.86 ± 3.59 mg/dL; p<0.01) with unchanged serum testosterone (CTR 15.82 ± 0.66 vs MSG 15.15 ± 1.30 ng/mL), estradiol (CTR 14.23 ± 1.36 vs MSG 15.63 ± 2.46 pg/mL) and luteinizing hormone (LH) (CTR14.23 ± 1.36 vs MSG 15.63 ± 2.46 mUI/mL) levels. We then analyzed ovarian morphology, which showed MSG rats to have a 2‐fold decrease on ex vivo oocyte count (CTR 11.57 ± 0.37 vs MSG 5.57 ± 0.20, p<0.001), but an astonishing 6‐fold increase on ovarian follicular cysts (CTR 0.16 ± 0.07 vs MSG 0.90 ± 0.11, p<0.01). Additionally, they exhibited higher number of total (CTR 11.24 ± 2.27 vs MSG 16.69 ± 0.99, p<0.05), primordial (CTR 7.17 ± 1.68 vs MSG 11.82 ± 0.73, p<0.05) and atretic (CTR 0.62 ± 0.13 vs MSG 1.81 ± 0.38, p<0.05) follicles per section. Finally, we performed ovarian immunohistochemistry for anti‐Müllerian hormone, which showed MSG rats increased staining on antral follicles (CTR 2.07 ± 0.59 vs MSG 9.43 ± 2.06, p<0.01). Taken together, our data characterize MSG obese female rats as a novel model to study how metabolic syndrome affects PCOS pathogenesis in the absence of overactivated hypothalamus‐pituitary‐gonads axis.Support or Funding InformationThis study was funded by Fundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão – FAPEMA (Grant # 00280/12 and scholarships to RSG, ROB and JLLF) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – CAPES (Scholarship to CCV).