Gonadotropin-Suppressing Activity of Human Recombinant Inhibin in the Male Rat is Age Dependent1

Abstract

We have examined the age-dependent effects of human recombinant inhibin A (hrI) on gonadotropin levels in intact male rats. A single s.c. injection of hrI in the dose range 6.25-100 ng/g BW resulted in a significant and consistent decrease (20-40%) in serum FSH measured 6 h later, at the higher (50 and 100 ng/g) doses, in animals 25-91 days of age. Administration of the same doses in animals < or = 20 days old had no significant effect on serum FSH levels. Similarly, no effect of hrI (100 ng/g) on serum FSH levels was observed in 15-day-old rats when FSH levels were monitored from 1 to 8 h. No effect of hrI was observed on serum LH levels except in 40-day-old rats, which exhibited a consistent and significant reduction at the higher (25-100 ng/g) doses of inhibin. Serum inhibin levels 6 h after the injection were not significantly altered at any dose in young animals (< or = 30 days); however, in older animals (40, 50, and 91 days) there was a significant elevation in circulating inhibin levels at the higher doses, strongly suggesting an age-related change in clearance. Testicular inhibin levels were not affected by administration of the exogenous material except at the highest dose (100 ng/g) in the oldest animals (91 days), when an approximately 30% reduction in both the concentration and the total content of inhibin was observed. The data clearly demonstrate that the effect of hrI on serum gonadotropins is age dependent and that changes in clearance may contribute to the period during which circulating inhibin levels are elevated postinjection.

Activin C Antagonizes Activin A in Vitro and Overexpression Leads to Pathologies in Vivo

“…1989) as tracer and a rat ovarian extract as a standard. 22 No significant cross-reactivity is detected with activin A, however, the assay cross-reacts with pro-␣c. Consequently, inhibin levels are reported as immunoreactive total inhibin.…”

Inhibins in Normal Male Physiology

“…17 Inhibin, in turn, provides the negative feedback signal that regulates FSH secretion. Administration of human recombinant (hr) inhibin A to rats, 58 castrate rams, 59 and monkeys 60 led to the specific suppression of FSH with no effect on testosterone or LH. However, inhibin synergizes with testosterone in the regulation of FSH, supporting the extensive data showing that testosterone can also suppress FSH.…”

“…Further, hr inhibin A was shown to exert a greater effect on FSH suppression in immature male rats than adults. 58 The second phase of Sertoli cell activity, again FSH stimulated, occurs with the first appearance of spermatids and increased FSH levels, and although circulating concentrations of inhibin B decline at this time, the total testicular content rises progressively from day 25 post partum. 28 Does Inhibin B Correlate with the State of Spermatogenesis?…”

Changes in the suppressive effects of recombinant inhibin A on FSH secretion in ram lambs during sexual maturation: evidence for alterations in the clearance rate of inhibin

“…The testes of prepubertal males synthesize and secrete significant amounts of inhibin and the pattern of secretion of inhibin changes during sexual development although there appears to be substantial differences between species. For example, circulating concentrations of inhibin during sexual maturation have been found to increase in male monkeys (Keeping et al 1990, Marson et al 1993) and in boys (Burger et al 1988, Crofton et al 1997 but to decrease in male rats (Wreford et al 1994), bulls (Miyamoto et al 1989, MacDonald et al 1991 and rams (Schanbacher 1988, Isaacs et al 1995. Several studies indicate that a functional negative feedback system between inhibin and FSH exists before puberty as shown by the decrease in plasma concentrations of inhibin and an increase in FSH in 1-week-old ram lambs (Schanbacher 1988), and the demonstration that active immunization against inhibin in prepubertal ram lambs (Al-Obaidi et al 1987) and bull calves (Martin et al 1991, Schanbacher 1991 caused an increase in plasma concentrations of FSH.…”

“…There are only limited data in which the ability of inhibin to suppress FSH has been assessed over an age range encompassing sexual maturation. In a study designed to address these issues, intact male rats were given a single injection of human recombinant inhibin A (hr-inhibin A) which caused a significant decrease in serum concentrations of FSH measured 6 h later in animals aged 25-91 days of age but had no effect on FSH in younger animals (Wreford et al 1994). Nevertheless, this study was limited by an insufficient sampling regimen that did not allow assessment of the time course of response of FSH to treatment with hr-inhibin A or of the clearance rate of inhibin from the blood.…”