A Role for Norepinephrine in the Control of Puberty in the Female Rhesus Monkey,Macaca Mulatto*

Abstract

The onset of puberty in female rhesus monkeys is characterized by increases in pulsatile LHRH release. In this study we have tested the hypothesis that changes in input to the LHRH neurosecretory system from noradrenergic neurons contribute to this pubertal increase in LHRH release. In the first experiment, the ability of the LHRH neurosecretory system of prepubertal (12-20 months of age, no signs of puberty evident), early pubertal (24-30 months, premenarchial), and midpubertal (30-45 months, postmenarchial but prior to first ovulation) monkeys to respond to alpha 1-adrenergic stimulation was tested. LHRH release in the stalk-median eminence of conscious monkeys was measured using an in vivo push-pull perfusion method. During push-pull perfusion, perfusates were collected continuously in 10-min fractions, and the alpha 1-adrenergic stimulant methoxamine (MTX, 10(-8), 10(-5) M) or vehicle was infused through the push cannula for 10 min at 90 min intervals. LHRH levels in perfusates were estimated by RIA. Monkeys in all three age groups responded to MTX with significant increases in LHRH release, with the response of the prepubertal group being significantly greater than that of the older age groups. The results indicate that alpha 1-adrenergic receptors are present and functional prior to puberty. In the second experiment, norepinephrine (NE) release in perfusates collected from monkeys in the three age groups was measured by HPLC with electrochemical detection. NE release increased significantly from the pre- and early pubertal to the midpubertal stage. The enhanced sensitivity of prepubertal monkeys to MTX may be due to the absence of high levels of endogenous NE, which results in a situation similar to denervation hypersensitivity. During the early pubertal stage, increases in input from noradrenergic neurons to the LHRH neurosecretory system may occur, thereby resulting in increases in LHRH release, since early pubertal monkeys are highly sensitive to alpha-adrenergic input. Therefore, we propose that the increase in NE release during puberty contributes to the developmental increase in LHRH release.

gamma-Aminobutyric acid is an inhibitory neurotransmitter restricting the release of luteinizing hormone-releasing hormone before the onset of puberty.

“…Since we have found that excitatory inputs from norepinephrine and neuropeptide Y neurons to LHRH neurons are contributing factors for the pubertal increase in LHRH release (26,34), and since others have shown that stimulation of N-methyl-D-aspartate receptors results in precocious puberty (35,36) detailed studies are required to clarify the regulation of LHRH release by other neurotransmitters during puberty.…”

Developmental Expression of the Genes Encoding Transforming Growth Factor Alpha and Its Receptor in the Hypothalamus of Female Rhesus Macaques

“…First, the immunoreactive and biologically active content of LHRH is similar in pre pubertal and adult rhesus monkeys [4]. Second, neither the abundance of LHRH mRNA per cell nor the number of LHRH mRNA-containing cells, measured by in situ hybridization, differ between prepubertal and adult ani mals [5], Lastly, administration of either a r adrcncrgic agonists [6], a GABA-A receptor antagonist [7] or Nmethyl-D-aspartic acic [8], an N-methyl-D-aspartic acid receptor agonist, elicits LHRH release in juvenile mon keys, indicating that prepubertal LHRH neurons are per fectly capable of responding to changes in neurotransmit ter inputs with LHRH release. Based on these findings it would appear reasonable to postulate that the initiation of primate puberty is determined by 'upstream' events which presumably occur in cellular subsets anatomically and/or functionally connected to the LHRH neuronal net work [9], While the molecular basis of these events has not been elucidated, an obvious consequence of their occur rence appears to be a change in neuronal activity that leads to alterations in the excitatory/inhibitory transsynaptic control of LHRH neurons.…”

“…Based on these findings it would appear reasonable to postulate that the initiation of primate puberty is determined by 'upstream' events which presumably occur in cellular subsets anatomically and/or functionally connected to the LHRH neuronal net work [9], While the molecular basis of these events has not been elucidated, an obvious consequence of their occur rence appears to be a change in neuronal activity that leads to alterations in the excitatory/inhibitory transsynaptic control of LHRH neurons. The concerted effect of these alterations may, in turn, result in activation of LHRH release [6,7,10], While the importance of this transsynaptic control of LHRH neuronal function appears clear, we have raised the possibility of a glial involvement in the neuroendocrine process controlling the activation of LHRH neurons at puberty [10,11], In contrast to the scant innervation received by LHRH neurons in the primate hypothalamus [ 12], glial ensheathment of both LHRH neuronal perikarya and LHRH nerve terminals is substantial [12], suggesting the existence of meaningful interactions between the two cell types. That glial cells may affect LHRH secretion via secretion of defined bioactive molecules has been suggest ed by a series of experiments in rodents implicating hypo thalamic transforming growth factor alpha (TGFa) [ 13] of glial origin [11] in the regulatory process by which the hypothalamus controls the advent of normal sexual matu ration [11,14] and by which hypothalamic lesions induce sexual precocity [15,16], Whether TGFa, and hence glial cells, also contributes to the inititation of primate puberty is not knwon.…”

Gonadotropin-Releasing Hormone and NMDA Receptor Gene Expression and Colocalization Change during Puberty in Female Rats

“…Because the GnRH neurosecretory system is already morphologically and functionally mature long before the onset of puberty Goldsmith and Song, 1987), it is probable that changes in inputs to the GnRH system are responsible for the increase in pulsatile GnRH release that ultimately results in the attainment of adult reproductive function. For example, increases in stimulatory inputs from noradrenergic (Advis et al, 1978;Raum et al, 1980;Gore and Terasawa, 1991), neuropeptide Y (Sutton et al, 1988;Minami et al, 1990;Gore et al, 1993;Gruaz et al, 1993), and glutamatergic (Gay and Plant, 1987;Urbanski and Ojeda, 1990) neurons precede the onset of puberty. Similarly, a decrease in inhibition from GABAergic neurons probably also contributes to the timing of puberty (Mitsushima et al, 1994).…”