Disruption in the expression and immunolocalisation of steroid receptors and steroidogenic enzymes in letrozole-induced polycystic ovaries in rat

Abstract

The objective of the present study was to characterise the expression and tissue distribution of steroid receptors (oestrogen receptor-alpha and -beta (ERalpha, ERbeta), androgen receptor (AR) and progesterone receptor (PR)) and steroidogenic enzymes (P450 aromatase (P450arom), 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and steroidogenic acute regulatory protein (StAR)) in letrozole-induced polycystic ovaries of rats. Changes in serum hormone levels, protein expression in whole ovaries by western blot analysis and protein localisation by immunohistochemistry were determined in female rats treated with the aromatase inhibitor letrozole and compared with controls in proestrous and diestrous rats. Increases in the serum LH, FSH and testosterone concentrations were observed in letrozole-treated rats whereas serum oestradiol and progesterone levels were reduced. Protein expression as analysed by western immunoblot was consistent with the immunohistochemical data. Letrozole treatment induced an increase in the expression of AR, StAR and 3beta-HSD and a decrease in ERbeta. ERalpha, PR and P450arom showed partial changes in relation to some cycle stages. These results indicate that cystogenesis in this experimental model is characterised by changes in steroid receptors and steroidogenic enzyme expression that may be essential to proper ovarian functioning and are in agreement with similar changes observed in women with PCOS.

Analysis of the vascular responses in a murine model of polycystic ovary syndrome

“…This is in accordance with earlier studies reporting increased AR expression in endometrium of PCOS patients (Apparao et al 2002, Villavicencio et al 2006, as well as in ovaries in a rat PCOS model (Zurvarra et al 2009). It is known that AR signaling can be both genomic and nongenomic and may, in turn, activate other signaling pathways (Bennett et al 2010).…”

Rodent Models for Human Polycystic Ovary Syndrome1

“…Endocrine disruptions included elevated levels of LH, FSH, and T, reflecting the accumulation of endogenous ovarian androgen secretion due to a block in aromatase activity. In contrast, the decreased P secretion observed is consistent with the observed anovulation [40,[63][64][65]. E2 levels were either decreased [64,65] or unchanged [40].…”

“…In contrast, the decreased P secretion observed is consistent with the observed anovulation [40,[63][64][65]. E2 levels were either decreased [64,65] or unchanged [40]. Additionally, treated rats exhibited some metabolic features of human PCOS with increased body weight [40,66] and body fat but no change in insulin sensitivity or lipid metabolism [40].…”

“…The latter includes the rat PCOS model induced by letrozole, a nonsteroidal aromatase inhibitor, which blocks the conversion of androgens to estrogen [63]. Letrozole treatment of adult rats for at least 21 consecutive days induced acyclicity [40] or irregular estrous cycles [63] and anovulation, with ovaries exhibiting many large follicular cysts and either reduced numbers or no corpora lutea [40,[63][64][65]. Ovaries exhibited increased follicle atresia and multiple cysts with thin granulosa cell layers and thickened theca cell layers [40].…”

“…4), although further work is required to confirm the metabolic disruptions present before this model can be confirmed as a valid and useful model for the metabolic features of PCOS. Furthermore, the reduction in E2 observed [63][64][65] may be a limitation of this strategy as the polycystic ovaries, anovulation, absence of corpus luteum, and elevation of serum LH and T levels, also present in ER-a (Esr1) knockout female mice [67][68][69][70] may be a consequence of disruption of E2 action rather than the reflex increase in serum T.…”