Prenatal Exposure to Androgen Excess Increases LH Pulse Amplitude During Postnatal Life in Male Sheep

Abstract

Prenatal exposure to excess testosterone has a profound impact on reproductive and metabolic functions in young and adult female sheep. Nevertheless, few studies have addressed the impact of prenatal exposure to an excess of androgens on reproductive and metabolic functions in males. The aim of the present study was to assess the impact of prenatal exposure to an excess of testosterone or dihydrotestosterone on the luteinizing hormone (LH) pulse characteristics during sexual development in male sheep. Control male sheep (C-males) and males born to mothers exposed to twice weekly injections of 30 mg testosterone or dihydrotestosterone from day 30-90 and 40 mg from day 90-120 of gestation (T-males, DHT-males) were studied at 5, 10, and 20 weeks of age, ages that represent infancy, early prepubertal, and late prepubertal stages of sexual development in this species, respectively. Patterns of LH pulsatility showed that T- and DHT-males exhibited a higher secretion of LH during the 6-h study and a higher amplitude of the LH pulses compared with C-males. Moreover, nadir of the pulses was higher in T- and DHT-males compared with C-males. Frequency of LH pulses, however, was not different within ages or between groups. These results show that males can be responsive to prenatal androgenization and suggest that treatment transiently alters the amplitude of LH pulses probably as the result of defects in the pituitary responsiveness pattern or in the gonadotropin-releasing hormone (GnRH) release pattern.

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

“…Findings of increased LH release following GNRH analog administration in this study indicate that pituitary responsiveness to GNRH is also increased in the males (this study) as was the case with the females (Manikkam et al 2008). Together, these findings support a role for increased pituitary responsiveness to GNRH as a contributing factor in the observed increase in the LH pulse amplitude of endogenous LH pulses of the testosterone-males (Recabarren et al 2012). Whether the mechanism mediating this increase relates to an increase in LH synthesis or an increased GNRH receptor expression remains to be investigated.…”

“…Recently, we have found that the LH pulse amplitude of prenatal testosterone-and dihydrotestosterone (DHT)-treated males is increased (Recabarren et al 2012). In these Asterisks indicate significant differences between control males and testosterone-exposed males.…”

“…More acidic forms are predominant in eugonadal men (Bergendah & Veldhuis 2001). 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).…”

Developmental and Functional Effects of Steroid Hormones on the Neuroendocrine Axis and Spinal Cord

“…This is apparent in the characteristics of the LH pulsatility, as well as the response of the pituitary gland and testis to a GnRH stimulus. Features of LH pulsatility such as LH pulse amplitude and LH pulse nadir were higher in T‐males than in C‐males, suggesting a reprogramming of GnRH secretion or a higher pituitary responsiveness to GnRH because the LH pulse frequency was not modified . The latter explanation was supported by another study reporting that pituitary gland responsiveness to a GnRH challenge was higher in T‐males of 30 weeks of age than in T‐males of 20 weeks of age.…”

Hormonal Programming Across the Lifespan

“…LH levels and pulse amplitudes in T- exposed males were halfway between DHT- and control males. The frequency of LH pulses was not different between groups suggesting that pituitary gland sensitivity to endogenous GnRH pulses was higher in DHT- and T- exposed males than in control males [140]. This suggestion was evaluated using a GnRH analogue test which showed that LH secretion was higher in T- exposed males of 20 weeks of age compared to T- exposed males of 30 weeks of age.…”