Induction of a Hypothyroid State During Juvenile Development Delays Pubertal Reactivation of the Neuroendocrine System Governing Luteinising Hormone Secretion in the Male Rhesus Monkey (Macaca mulatta)

Abstract

The present study aimed to determine the influence of thyroid status on the timing of the pubertal resurgence in gonadotrophin-releasing hormone pulse generator activity [tracked by circulating luteinising hormone (LH) levels] in male rhesus monkeys. Six juvenile monkeys were orchidectomised and then treated with the antithyroid drug, methimazole, from 15-19 months until 36 months of age, at which time thyroxine (T(4)) replacement was initiated. Four additional agonadal monkeys served as controls. Blood samples were drawn weekly for hormonal assessments. Body weight, crown-rump length and bone age were monitored at regular intervals. By 8 weeks of methimazole treatment, plasma T(4) had fallen sharply, and the decline was associated with a plasma thyroid-stimulating hormone increase. In controls, plasma LH levels remained undetectable until the pubertal rise occurred at 29.3 +/- 0.2 months of age. This developmental event occurred in only half of the methimazole-treated animals before 36 months of age when T(4) replacement was initiated. The hypothyroid state was associated with a profound arrest of growth and bone maturation, but increased body mass indices and plasma leptin levels. T(4) replacement in methimazole-treated monkeys was associated with the pubertal rise in LH in the remaining three animals and accelerated somatic development in all six animals. Although pubertal resurgence in LH secretion occurred at a later chronological age in methimazole-treated animals compared to controls, bone age, crown-rump length and body weight at that time did not differ between groups. There were no long-term differences in plasma prolactin between groups. We conclude that juvenile hypothyroidism in male primates causes a marked delay in the pubertal resurgence of LH secretion, probably occasioned at the hypothalamic level. Whether this effect is meditated by an action of thyroid hormone directly on the hypothalamus or indirectly as a result of the concomitant deficit in somatic development remains to be determined.

Bone growth in juvenile rhesus monkeys is influenced by 5HTTLPR polymorphisms and interactions between 5HTTLPR polymorphisms and fluoxetine

“…Puberty in male rhesus, as indexed by onset of pulsatile LH release from the pituitary, begins between two and three years of age (onset average 29.5 months stabilizing at 32 months of age [40] or 118±9 weeks [41]). Yearly growth was calculated as the difference between values at one and two years of age and the difference between values at two and three years of age.…”

The role and potential sites of action of thyroid hormone in timing the onset of puberty in male primates

“…Note the hypothyroid state was associated with a delay in the pubertal resurgence of pulsatile GnRH release as reflected by circulating LH concentrations. Reproduced by modifying Figures 1 and 2 from Mann et al (2006) (Copyright Blackwell Publishing Ltd).…”

“…A TH deficit in juvenile agonadal monkeys (15-19 mo of age) was created by oral treatment with the antithyroid drug, methimazole (MMI; 0.025 % in drinking water) described by Mann et al (2006). Within eight weeks of initiating treatment, plasma T 4 concentrations had fallen to near undetectable levels.…”

“…The TH deficiency in agonadal juvenile monkeys was associated with a severe retardation of somatic development including that of body weight gain, linear growth, and bone maturation (Mann et al, 2006). Although nutritional status is known to influence growth and the timing of puberty (Plant and Witchel, 2006), the retarded somatic development observed in the hypothyroid animals was unlikely to be the result of a chronic state of reduced energy intake because body mass indexes and circulating leptin levels (two indices of body fat and energy stores) indicated that the TH deficit did not result in a chronic energy deficiency.…”

“…To this end, three juvenile agonadal male monkeys (17 mo of age) were placed on oral MMI at a dose used in the earlier study to induce a profound hypothyroidism (Mann et al, 2006). Animals were immediately placed on T 3 replacement therapy (0.75 to 3 μg/kgBW/day) using sc implanted osmotic minipumps.…”