A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice1

Abstract

Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition.

Letrozole vs estradiol valerate induced PCOS in rats: glycemic, oxidative and inflammatory status assessment

“…However, this was not observed in all the cases, suggesting that MCP1 expression is not exclusively dependent on NFKB pathway and that it is tissue specific. The increased expression of MCP1 in POAT after letrozole administration is consistent with the results obtained in the parametrial adipose tissue in another study (Kauffman et al 2015), but our findings in the POAT after EV administration raised some questions: Why MCP1 was significantly decreased, even though the expressions of NFKB and pNFKB were elevated? Was it possible that EV administration as part of the induction protocol to interfere with MCP1 release in POAT?…”

“…Indeed, in our study the level of TNFa was increased in the POAT after administration of both L and EV, but not sufficiently to be considered statistically significant. Another study confirms the increased mRNA expression of TNFa in the parametrial adipose tissue of a transgenic PCOS mouse model induced by letrozole (Kauffman et al 2015). TNFa stimulates the hyperplasia of androgen producing theca cells which promotes hyperandrogenism (Spaczynski et al 1999).…”

Adiponectin protects against development of metabolic disturbances in a PCOS mouse model

“…The ovaries were sectioned at 3-3.5 μm, 40 μm between every section was discarded, and six sections from each ovary were collected, mounted on a glass slide, stained with H&E, and photographed (×20) and analyzed by conventional light microscopy. Definition of corpus luteum, atretic/cystic follicles, and antral follicles was done according to the paper by Kauffman et al (53). Pancreas analysis.…”

Efeitos do exercício sobre os aspectos metabólicos e reprodutivos de modelos murinos de síndrome dos ovários policísticos

“…Por outro lado, os modelos murinos de SOP induzida por LET, na mesma dose utilizada nesse estudo, não apresentaram diminuição das concentrações séricos de estradiol comparados com camundongos controle (30), indicando que os distúrbios metabólicos encontrados nesse modelo animal não são atribuídos ao hipoestrogenismo.…”

“…Ao contrário de estudos anteriores (29,30), os camundongos expostos ao LET e à DHT não apresentaram intolerância à glicose em nosso estudo. Essa divergência pode ser atribuída a diferentes vias de administração da glicose.…”