Blockade of the neonatal increase in testosterone by a GnRH antagonist: the free androgen index, reproductive capacity and postmortem findings in the male marmoset monkey

Abstract

Male marmoset monkeys which had received gonadotrophin-releasing hormone (GnRH) antagonist treatment as neonates to block the postnatal increase in testosterone were studied, with the object of determining potential long-term effects of treatment on the reproductive system, including tests of fertilising capacity. To obtain information on the nature of the circulating testosterone during this neonatal period, sequential blood samples were collected from a further control group of ten neonates, aged between birth and 3 months, and from 11 adult, normally fertile males, to examine the relative proportions of free, sex-hormone-binding globulin (SHBG)-bound, and non-SHBG-bound testosterone. In control neonates, 11% of the circulating testosterone was free, and a further 19% non-SHBG-bound, and therefore presumed to be biologically available. The remaining 70% was SHBG-bound and considered to be biologically inert. This indicates that the neonatal increase in marmoset testosterone has a biological function. After pairing with females, time to first positive vaginal lavage and first delivery was similar for females, whether they were with control or treated male partners. Pregnancy outcome, in terms of number of young delivered and sex ratio, did not differ. This indicates that there appear to be no long-term sequelae in terms of procreative ability in male marmosets treated neonatally with a GnRH antagonist. Autopsy revealed no gross changes, except in the thymus, which was significantly heavier in the treated group. These results indicate that, although the circulating testosterone is in a biologically active form during the neonatal period, inhibition of testicular function in the neonate is without major effect on the adult male reproductive system. Treatment with a GnRH antagonist may have long-term effects on the immune system.

Changes in endocrine profile and reproductive organs during puberty in the male marmoset monkey (Callithrix jacchus)

“…The quiescent period was reported to continue until the age of 35 wk with non-detectable testosterone concentrations (Lunn et al 1997, Kelnar et al 2002. According to these observations, our first age group of 21 wk represented the age at which the activation of hypothalamus-pituitarygonadal axis was not expected.…”

“…Marmosets have been shown to have sex hormone binding globulin. Although Hodges et al (1983) reported low free testosterone levels (approximately 1.7-4.5%) in marmoset serum, Lunn et al (1997) more recently demonstrated higher levels of biologically active testosterone. Pugeat et al (1984) reported that plasma testosterone-estradiol binding protein in New World monkeys (including marmosets) has a low affinity despite high binding capacity for testosterone, resulting in high levels of unbound plasma testosterone in New World monkeys (20-40 ng/dl), as compared to those in Old World monkeys (3-9 ng/dl) or humans (10 ng/dl).…”

“…As in human, male marmosets reproductive development leading to puberty also has three phases of endocrine events (1) neonatal activation of the pituitary-gonadal axis up to 16 weeks (wk) of age, (2) a quiescent phase up to 35 wk of age (Lunn et al 1994(Lunn et al , 1997, and (3) reactivation of the pituitary-gonadal axis leading to onset of puberty, which was found to occur in our colony of marmosets between 40 and 52 wk (Wistuba et al 2006). The onset of puberty was ascertained in intact controls by an increase in serum testosterone levels from values below 10 nmol/l to values above 80 nmol/l (Wistuba et al 2006).…”

Effect of Neonatal Gonadotropin-Releasing Hormone Antagonist Administration on Sertoli Cell Number and Testicular Development in the Marmoset: Comparison with the Rat1

“…Marmosets treated neonatally with a GnRH antagonist exhibited grossly normal spermatogenesis in adulthood and are normally fertile [20]. However, comparison of individual control and treated co-twins revealed a tendency toward a decrease in germ cell volume per Sertoli cell in those GnRHa-treated co-twins in which Sertoli cell number ex-FIG.…”

“…This design enabled pair-wise comparison of data for each control and treated co-twin, thus minimizing the number of animals required for study. The primary use of the animals from which testes were obtained for the present studies (9 sets of control/GnRHa-treated co-twins; 7 other vehicle-treated controls) was for other studies [20,21] unconnected with those presented here. Starting on the day of birth, co-twins received s.c. injections of either 10 mg/kg GnRHa (Antide: Contraceptive development branch, Center for Population Research, National Institute of Child Health and Human Development [NICHD], Bethesda, MD) in propylene glycol:water (1:1, v:v) or with the vehicle alone (control).…”