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A "growing" realization.

Activation of the somatotropic and gonadotropic axes are well-documented phenomena in the temporal sequence of human development. An increase in GHRH and a decrease in somatostatin from neurons in the hypothalamus have the net action of increasing GH secretion from the anterior pituitary. The increase in GnRH from the GnRH-containing neurons of the hypothalamus also acts at the anterior pituitary to stimulate release of the gonadotropins LH and FSH. The release of GH stimulates production of IGF-I from its target tissues such as bone, muscle, and liver. Likewise, gonadotropins act on the gonad and support steroidogenesis. Working in tandem, GH and the gonadotropins account for the somatic and physiological changes that we collectively recognize as puberty (see Ref. 1 for review). 
 
Numerous studies have focused on the causal link between somatic growth and puberty. The mechanisms that activate GnRH neurons and, thus, underlie the pubertal increase in GnRH secretion are unknown. However, the so-called somatometer hypothesis proposed that some aspect of growth served as a signal to the brain that activation of GnRH neurons was appropriate. This central growth-tracking device would be one that responded to growth-related cues from the periphery and by some undefined mechanism induce GnRH release. 
 
Notwithstanding the somatometer hypothesis, the link between growth and sexual maturation is perhaps best exemplified by the interaction between somatic growth and gonadal steroids. For instance, rising levels of gonadal steroids are implicated in the increase in GH release from the pituitary around the time of puberty. Likewise, androgens are reported to stimulate IGF-I production in bone and muscle and, thus, account at least in part for the changes in body composition and linear growth during adolescence. Accordingly, the dominant component of the link between somatic growth and sexual maturation has been outside the hypothalamus (Fig. 1). 
 
 
 
Fig. 1. 
 
Do somatostatin-containing neurons compose the pubertal somatostat? Somatostatin robustly inhibits activity of GnRH neurons at a dendritic site and inhibits GH secretion at the anterior pituitary. Thus, a decrease in activity of somatostatin neurons would ... 
 
 
 
The work of Koyama et al. (2) in this month's Endocrinology solidifies a common hypothalamic link for the control of growth and sexual maturation. Interestingly, this is a direct mechanism for the control of the output of GnRH neurons. Using a combination of anatomical and electrophysiological approaches, they show that GnRH neurons and somatostatin neurons are closely associated in the organum vasculosum of the lamina terminalis of the rat, a finding that is consistent with an earlier finding in mice (3). Moreover, both studies indicate that somatostatin, which is inhibitory to GH secretion from the anterior pituitary, is also strongly inhibitory in GnRH neurons in the hypothalamus (Fig. 1). Of particular interest was the observation derived from studying responses to somatostatin in both GnRH neurons in slices and isolated GnRH somata from the same rat model. Using this approach, the authors demonstrate that the hyperpolarizing influence of somatostatin was lost in isolated GnRH somata, indicating that the dendrites of GnRH neurons are the most likely site of action of somatostatin. 
 
Although the present study focused on GnRH neurons in adult animals, the direct inhibition of GnRH neuronal activity by somatostatin represents a potential shift of the current paradigm of growth and sexual maturation. Instead of somatic growth altering GnRH secretion, these present data suggest that factors controlling GH secretion might also directly regulate GnRH secretion. Specifically, it suggests whatever physiological cues unleash GH secretion by decreasing somatostatin release would also dramatically reduce inhibition of GnRH neurons. Based on the electrophysiological studies, the reversal potential of somatostatin was about −65 mV. This voltage is substantially below reported spike thresholds in GnRH neurons (see Table 1 in Ref. 4). Moreover, the change in conductance in response to somatostatin application was relatively large. Thus, somatostatin would strongly curtail depolarization of GnRH neurons, both through its direct actions and via the reduction in membrane resistance due to the opening of large conductances. 
 
In most species, the distribution of the somatostatin neurons is similar. Most somatostatin neurons in the periventricular area innervate the external layer of the median eminence and are therefore poised to regulate GH secretion. However, additional somatostatin fibers are found in the regions that contain GnRH neurons (5). Thus, the question remains as to the origin of the somatostatin fibers that interact with GnRH neurons. This consideration notwithstanding, given the striking potency of somatostatin in inhibition of GnRH neurons, it would not be surprising if somatostatin were a major contributor to the presumed quiescence of GnRH neurons in prepubertal animals.