Abstract
Prenatal hyperandrogenism is able to induce polycystic ovary syndrome (PCOS) in rats. The aim of the present study was to establish if the levels of prenatal testosterone may determine the extent of metabolic and endocrine alterations during the adult life. Pregnant Sprague Dawley rats were prenatally injected with either 2 or 5 mg free testosterone (groups T2 and T5 respectively) from day 16 to day 19 day of gestation. Female offspring from T2 and T5 displayed different phenotype of PCOS during adult life. Offspring from T2 showed hyperandrogenism, ovarian cysts and ovulatory cycles whereas those from T5 displayed hyperandrogenism, ovarian cysts and anovulatory cycles. Both group showed increased circulating glucose levels after the intraperitoneal glucose tolerance test (IPGTT; an evaluation of insulin resistance). IPGTT was higher in T5 rats and directly correlated with body weight at prepubertal age. However, the decrease in the body weight at prepubertal age was compensated during adult life. Although both groups showed enhanced ovarian steroidogenesis, it appears that the molecular mechanisms involved were different. The higher dose of testosterone enhanced the expression of both the protein that regulates cholesterol availability (the steroidogenic acute regulatory protein (StAR)) and the protein expression of the transcriptional factor: peroxisome proliferator-activated receptor gamma (PPAR gamma). Prenatal hyperandrogenization induced an anti-oxidant response that prevented a possible pro-oxidant status. The higher dose of testosterone induced a pro-inflammatory state in ovarian tissue mediated by increased levels of prostaglandin E (PG) and the protein expression of cyclooxygenase 2 (COX2, the limiting enzyme of PGs synthesis). In summary, our data show that the levels of testosterone prenatally injected modulate the uterine environment and that this, in turn, would be responsible for the endocrine and metabolic abnormalities and the phenotype of PCOS during the adult life.
Highlights
Polycystic ovary syndrome (PCOS), one of the most common reproductive disorders, affects between 8 to 12% women in their reproductive ages [1]
As shown by the increased uro-genital distance (UGD), we found that both doses of free testosterone induced defeminization
These findings are in agreement with previous reports [13] and suggest that prenatal hyperandrogenism affects the neurosecretory system of gonadotropin-releasing hormone (GnRH)
Summary
Polycystic ovary syndrome (PCOS), one of the most common reproductive disorders, affects between 8 to 12% women in their reproductive ages [1]. PCOS is frequently associated with hyperinsulinaemia, insulin resistance syndrome, increased cardiovascular risk and type 2 diabetes mellitus [3,4,5]. Prenatal androgen exposure is able to induce PCOS and metabolic syndrome in adult female rats [6,7,8], monkeys [9] and sheep [10,11,12]. A prenatal excess of testosterone induces sex differences [9] and defeminization by increasing pulses of gonadotropin-releasing hormone (GnRH) [13]. A prenatal excess of testosterone increases body weight, induces insulin resistance [8] and deficiency of 21-hydroxylase [14] during the adult life. Data concerning the mechanisms involved in the prenatal excess of androgen and change in the secretion of hormones is still controversial [8,13,16]
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