Prenatal Testosterone Excess Reduces Sperm Count and Motility

Abstract

The reproductive system is extremely susceptible to insults from exposure to exogenous steroids during development. Excess prenatal testosterone exposure programs neuroendocrine, ovarian, and metabolic deficits in the female, features seen in women with polycystic ovary disease. The objective of this study was to determine whether prenatal testosterone excess also disrupts the male reproductive system, using sheep as a model system. The extent of reproductive disruption was tested by assessing sperm quantity and quality as well as Leydig cell responsiveness to human chorionic gonadotropin. Males born to mothers treated with 30 mg testosterone propionate twice weekly from d 30 to 90 and with 40 mg testosterone propionate from d 90 to 120 of pregnancy (T-males) showed a significant reduction (P < 0.05) in body weight, scrotal circumference, and sperm count compared with control males. Mean straight line velocity of sperms was also lower in T-males (P < 0.05). Circulating testosterone levels in response to the human chorionic gonadotropin did not differ between groups. These findings demonstrate that exposure to excess testosterone during fetal development has a negative impact on reproductive health of the male offspring, raising concerns relative to unintended human exposure to steroidal mimics in the environment.

Pituitary and testis responsiveness of young male sheep exposed to testosterone excess during fetal development

“…The altered pattern of endogenous GNRH release (assessed from LH pulsatility) during post-development trajectory Fetal programming of gonadal axis responsiveness in the testosterone-exposed males (Recabarren et al 2012) may have contributed to the production of less acidic fast-clearing LH that does not provide sustained support in the testosterone-exposed males as in the control males. This premise is consistent with our earlier finding that hCG stimulation of the control males and testosterone-exposed males elicits similar testosterone responses at 40 weeks of age (Recabarren et al 2008a). Reduced expression of LHR mRNA of the testosterone-exposed males compared with the expression in the control males may be responsible for the reduced testicular response.…”

“…These findings provide evidence that exposure to excess testosterone during fetal development not only disrupts testicular differentiation, leading to a reduced number of sperm cells and compromised Sertoli cell function (Recabarren et al 2008a, 2008b, Rojas-García et al 2010, but also disrupts the interface of the pituitary-gonadal axis. How these findings are enchained remains to be investigated.…”

“…Adult Suffolk Down females were mated as described previously (Recabarren et al 2008a). After synchronization of estrous and controlled mating, pregnant sheep were allocated randomly to one of two treatments.…”

“…Another group served as a control and received an oil vehicle twice weekly from days 30 to 120 of gestation. This regimen of testosterone administration was chosen to reflect the higher levels of testosterone observed in women with PCOS during their pregnancies and has been used in previous studies (Sir-Petermann et al 2002, Recabarren et al 2008a.…”

“…Male offspring of PCOS mothers manifest metabolic disarrangements beginning at birth and culminating in altered lipid profile, insulin resistance and excess weight gain in adulthood (Recabarren et al 2008b). Adult male sheep exposed to excess testosterone manifest a significant reduction in the sperm count, scrotal circumference and sperm motility (Recabarren et al 2008a), an increased number of Sertoli cells and an altered expression of FSH receptors and TGFB1 and TGFB3 (Rojas-García et al 2010). To expand our understanding of the developmental consequences of testosterone excess in male sheep, we examined the response of the pituitarygonadal axis following the administration of a GNRH analog, the expression patterns of LH receptor (LHR) and key steroidogenic enzymes P450c17,20 lyase, 17b-hydroxysteroid dehydrogenase (17b-HSD type 3 (17BHSD type 3)), P450 aromatase, P450scc, and 3b-HSD (3BHSD) in whole testicular tissue and the expression of P450c17, P450scc, 17BHSD type 3, and 3BHSD in Leydig cells cultured before and after an human chorionic gonadotrophin (hCG) challenge.…”