Effect of Transient Hypothyroidism During Infancy on the Postnatal Ontogeny of Luteinising Hormone Release in the Agonadal Male Rhesus Monkey (Macaca mulatta) : Implications for the Timing of Puberty in Higher Primates

Postnatal development of the hypothalamic–pituitary–gonadal axis in higher primates may be divided into three distinct phases: infantile, juvenile and pubertal, although, in man, the infancy and the juvenile phases of development are separated by childhood (1). Infancy in the male primate is characterised by an active period of gonadotrophin and testosterone secretion but, during the transition from infancy to childhood in boys, and directly to the juvenile phase of development in monkeys, gonadotrophin and testosterone secretion decline to low levels characteristic of subsequent prepubertal development (2, 3). This quiescent period in the activity of the pituitary–gonadal axis continues until there is a resurgence of gonadotrophin secretion that leads to the initiation of puberty at the end of juvenile development (2, 3). This postnatal pattern of activity in the pituitary–gonadal axis is considered to be dictated by parallel changes in pulsatile release of gonadotrophin-releasing hormone (GnRH) by the hypothalamus (2, 3). Although our current understanding of the neurobiological control systems that regulate the postnatal ontogeny of pulsatile GnRH release in humans and other higher primates remains rudimentary, it is generally recognised that both structural and molecular remodeling within the developing hypothalamus are involved particularly during the infant–juvenile (on–off phase) and the juvenile–pubertal (off–on phase) transitions (3, 4). In regard to neuronal plasticity, thyroid hormone plays an important role in normal brain development and differentiation, particularly late brain development, which extends from the third trimester of gestation through the first 3 months of postnatal life in humans (5). Late brain development is characterised by neuronal cell migration, synaptogenesis, myelination, and proliferation of specific types of cells (e.g. glial); processes that are regulated by thyroid hormone either directly or indirectly (6). That structural remodeling within the hypothalamus may contribute to the on–off–on pattern of pulsatile GnRH release during postnatal development in primates is supported by findings in the male monkey, that embryonic neuronal cell adhesion molecule, a marker of neuronal plasticity (7), is expressed in the medial basal hypothalamus of prepubertal animals (8), and, synaptic input to GnRH perikarya declines in association with the pubertal resurgence of pulsatile GnRH release (9). A GnRH dictated reversible hypogonadotrophic state reminiscent of the juvenile hiatus in GnRH release in primates is also observed during the nonbreeding season in animals such as the sheep (10, 11). Interestingly, the seasonal changes in pulsatile GnRH release in sheep are associated with plasticity in neuronal inputs to the GnRH neuronal network that is dependent on thyroid hormone (12, 13). The foregoing considerations have led us to systematically examine the influence of thyroid hormone deficiency on the post-natal ontogeny of pulsatile GnRH release in the male monkey. The impact of a methimazole-induced thyroid hormone deficiency during juvenile development (post infantile) on the pubertal resurgence of gonadotrophin secretion was recently reported (14). The present study aimed to test the hypothesis that a transient thyroid hormone deficiency restricted to infancy would compromise the arrest of pulsatile GnRH release during the transition from infancy to the juvenile phase of development, and/or alter the characteristics of the pubertal resurgence in the release of this neuropeptide. Transient hypothyrodism during infancy was achieved by thyroidectomising the animals at 2 days of age and delaying thyroid hormone replacement until 4–5 months of age during juvenile development. The agonadal model was again employed for several reasons. First, the hiatus in pulsatile GnRH release during juvenile development in primates occurs independently of the testis, and castration greatly amplifies the initiation and termination of this hiatus in neuroendocrine activity (15) enhancing the reliability of using circulating luteinising hormone (LH) to indirectly monitor developmental changers in pulsatile GnRH release (16). Second, gonadectomy eliminates any direct action of thyroid hormone on testicular steroid secretion and therefore the potential confounding action of testicular feedback on the developmental pattern of pulsatile GnRH release.