Anti-Müllerian Hormone, Growth Hormone, and Insulin-Like Growth Factor 1 Modulate the Migratory and Secretory Patterns of GnRH Neurons

Abstract

Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5–150 ng/mL), GH (3–1000 ng/mL), or IGF1 (1.5–150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty.

Role of the GH-IGF1 axis on the hypothalamus–pituitary–testicular axis function: lessons from Laron syndrome

“…In another study, Laron reported that the testes of these patients remained small even in the two patients who reached full sexual maturity with a volume of about 8 mL, as we have estimated from the graph reported in his article ( 14 ). GH and IGF1 may be able to stimulate the GnRH neuron migration and function, as in vitro data have recently shown ( 6 ). Therefore, their deficiency may adversely affect the function of the GnRH neurons, thus explaining the lower testicular volume of patients with Laron syndrome.…”

“…The presence of micropenis in patients with Laron syndrome might be firstly ascribable to the effects of the GH-IGF1 axis on the HPT one. In fact, low IGF1 levels might affect the GnRH neuron secretion and function, inducing hypogonadism ( 6 ). However, the direct effects of IGF1 on the penis may also be involved in pathogenesis.…”

“…These findings may explain the reduced testicular volume found in patients with Laron syndrome. In addition to its direct effects at the testicular level, IGF1 may also have an indirect impact on testicular function by interfering with the migration and function of GnRH neurons ( 6 ).…”

“…Gn11 and GT1-7 cells represent in vitro models of immature and mature (GnRH secreting) neurons, respectively. Therefore, these findings suggest that GH and IGF1 may stimulate the GnRH neuron migration and secretion and that their deficiency may adversely affect the function of the GnRH neurons ( 6 ). Interestingly, in mouse models with a constitutive knockout for the IGF1R, IGF1 appears to be involved in testicular development and sex determination.…”

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

“…It has been shown that AMHR2 is expressed by GnRH neurons during both the fetal and postnatal periods [219], and AMH has been detected during GnRH migration, both in mice and human fetuses [220]. Specifically, AMH appears to promote both GnRH neuron migration [220,221] and GnRH secretion [219]. In addition, the disruption of AMHR2 signaling in vivo causes a defective GnRH migration consequent to VN/ TN misrouted projections, resulting in a reduced number of GnRH neurons in the adult brain and an altered fertility [220].…”