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The present study examined whether a transient thyroid hormone (T(4)) deficit during infancy in male monkeys would compromise the arrest of luteinising hormone (LH) secretion during the infant-juvenile transition, and/or interfere with the pubertal resurgence of LH. Animals were orchidectomized and thyroidectomized (n = 3; Tx) or sham Tx (n = 3) within 5 days of birth. T(4) replacement was initiated in two Tx monkeys at age 19 weeks to reestablish a euthyroid condition. Blood samples were drawn weekly for hormone assay. Body weight, crown-rump length, and bone age were assessed throughout the study. Within a week of Tx, plasma T(4) declined to undetectable levels and, by 6-8 weeks of age, signs of hypothyroidism were evident. Transient hypothyroidism during infancy failed to prevent either arrest of LH secretion during the infant-juvenile transition or the pubertal resurgence of LH secretion, both of which occurred at similar ages to sham Tx animals. Although body weight exhibited complete catch-up with T(4) replacement, crown-rump length and bone age did not. Thus, bone age at the time of the pubertal LH resurgence in Tx animals was less advanced than that in shams. Although Tx did not influence qualitatively the pattern of gonadotrophin secretion, LH levels during infancy and after pubertal LH resurgence were elevated in Tx monkeys. This was not associated with changes in LH pulse frequency and amplitude, but half-life (53 versus 65 min) of the slow second phase of LH clearance was greater in Tx animals. These results indicate that hypothalamic mechanisms dictating the pattern of gonadotrophin-releasing hormone release from birth to puberty are not dependent on T(4) action during infancy, and fail to support the notion that onset of puberty is causally coupled to skeletal maturation. They also indicate that LH renal clearance mechanisms may be programmed in a T(4) dependent manner during infancy.

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.

Opioid neurons are recognized to be an important component of the inhibitory "brake" in the CNS that restrains LHRH secretion. Opioid inhibition could be exerted directly on LHRH neurons, or it could be achieved via indirect mechanisms involving restrainment of excitatory "accelerator" neurons that facilitate LHRH release. The purpose of the present study was to explore the second hypothesis by investigating whether removal of opioid inhibition by administering the opioid antagonist, naloxone leads to enhanced activation of glutamate and nitric oxide (NO) neurons, which are known to be important excitatory "accelerator" components for the control of LHRH secretion. Naloxone administration (2.5 mg/kg) to adult male rats induced a significant elevation of serum LH levels at 20 min post injection. NOS activity in preoptic area (POA) and medial basal hypothalamic (MBH) fragments was demonstrated to be significantly elevated 20 min post naloxone injection. Administration of a glutamate (NMDA) receptor antagonist (MK-801, 0.2 mg/kg) abolished the naloxone-induced increase in NOS activity in the POA and MBH, with a corresponding block of the naloxone-induced LH release. Glutamate appears to only be involved in LH surge generation and not to regulate basal LH levels, as MK-801 had no effect on basal LH release. Because previous work by our laboratory and others have provided evidence that NO is a mediator of glutamate effects in the hypothalamus, these findings are interpreted to mean that opioid inhibition is mediated on glutamate neurons that are upstream of NO neurons. In support of this contention, we found that NMDA treatment enhanced NOS activity in the male rat POA and MBH fragments in vitro, an effect that was specific as it was completely blocked by the NMDA receptor antagonist, MK-801. Additionally, in vivo microdialysis studies revealed that naloxone treatment significantly enhances glutamate release in the preoptic area (POA) at 15 min post injection in conscious, unanesthetized, freely moving male rats. Release rates of the control amino acid, serine did not change significantly following naloxone injection. Taken as a whole, these findings provide evidence for an opioid-glutamate-NO pathway in the control of LHRH secretion, and they demonstrate the importance of "brake-accelerator" interactions in the control of LHRH and LH secretion.

Recent work has demonstrated that glutamate functions as a major transmitter involved in the regulation of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in female animals, although the specific receptors and mechanisms mediating its effects have not been completely worked out. The purpose of the present study, therefore, was to examine the role of the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid)-type glutamate receptor in the control of GnRH and LH secretion in female animals. Toward this end, the dose- and steroid-dependent effects of AMPA on GnRH and LH secretion in female rats were investigated using both in vitro and in vivo approaches, and the role of AMPA receptors in the production of the steroid-induced LH surge was also assessed. The results of the study revealed that central administration of AMPA resulted in a stimulation of LH release in the estrogen-primed ovariectomized adult rat. AMPA was also found to potently stimulate GnRH release in vitro from mediobasal hypothalamic (MBH) fragments obtained from estrogen-primed ovariectomized adult rats, and this effect was blocked by the selective AMPA receptor antagonist, NBQX. The mechanism of action of AMPA appeared to differ from that of N-methyl-D-aspartate (NMDA) as AMPA, in contrast to NMDA, failed to elevate nitric oxide synthase activity in the hypothalamus. The effect of AMPA on LH secretion was demonstrated to be steroid dependent, as central administration of AMPA stimulated LH release in estrogen-primed ovariectomized rats, but was inhibitory to LH release in non-estrogen-primed ovariectomized rats. In contrast, AMPA stimulated GnRH release equally well from MBH fragments obtained from estrogen-primed or non-estrogen-primed ovariectomized rats. The different effects of AMPA on LH release may be due to different pituitary sensitivities between the two models, or alternatively, AMPA may stimulate the release of LH inhibitory factors in the ovariectomized rat in the absence of estrogen. Finally, a physiological role for AMPA receptors in the production of the steroid-induced LH surge was suggested, based on the finding that central administration of the selective AMPA receptor antagonist, NBQX, into the third cerebroventricle significantly attenuated the steroid-induced LH surge in the ovariectomized adult female rat.