Maternal aromatase inhibition via letrozole altered RFamide-related peptide-3 and gonadotropin-releasing hormone expression in pubertal female rats

Despite prevalence of polycystic ovary syndrome (PCOS) among childbearing women and development of many animal models for this syndrome, information on its etiology is still scarce. The intrauterine hyperandrogenic environment may underlie changes at the level of hypothalamus, pituitary, ovary organization in female offspring, and PCOS later in life. Letrozole has been shown to mimic reproductive and metabolic characteristics of PCOS in adult rodent models. Therefore, this research aimed to assess the condition in a prenatal letrozole-treated rat model. 

Twenty-eight female rats dams receiving letrozole at certain doses during late pregnancy were used in the trial.  Pregnant Sprague-Dawley rats (n=21) received letrozole treatment on gestation days 16–18 at doses of 1.25, 1.0, 0.75, 0.5, and 0.25 mg/kg body weight (BW).    

Prenatal letrozole treatment delayed parturition time and reduced the litter size in pregnant dams (P<0.0001). Late puberty onset, irregular ovarian cyclicity, increased anogenital distance (AGD), body weight gain, serum testosterone concentration, and reduced estradiol levels (P<0.0001) were observed in the female offspring of dams receiving 1.25 and 1 mg/kg BW letrozole. Furthermore, letrozole at 1.25 and 1 mg/kg BW showed increased RFRP and decreased GnRH mRNA expression (P<0.0001). Letrozole treatment at doses of 1 mg/kg BW and lower was not fetotoxic. 

It was concluded that 1 mg/kg BW letrozole may be suggested for prenatal PCOS induction.