SummaryThe integrated signaling of insulin and gonadotropin-releasing hormone in the pituitary gonadotropes may have a profound bearing on reproductive function, although the cross-receptor signaling mechanisms are unclear. We demonstrate that the insulin receptor is constitutively localized to noncaveolar lipid raft microdomains in the pituitary gonadotrope cell line LβT2. The localization to rafts is consistent with similar localization of the GnRH receptor. Insulin receptor phosphorylation occurs in raft domains and activates the downstream signaling targets Insulin Receptor Substrate1 and Akt/ Protein Kinase B. Although insulin alone does not strongly activate the extracellular signal-regulated kinase second messenger cascade, co-stimulation potentiates the phosphorylation of the extracellular signal-regulated kinase by gonadotropin-releasing hormone. The co-stimulatory effect of insulin and gonadotropin-releasing hormone is also evident in increased activation of cap-dependent translation. In contrast, co-stimulation attenuates Akt/Protein Kinase B activation. Our results show that both gonadotropin-releasing hormone and insulin are capable of mutually altering their respective regulatory signaling cascades. We suggest that this provides a mechanism to integrate neuropeptide and energy homeostatic signals to modulate reproductive function.

Context We hypothesize, based on the degree of residual hypothalamic-pituitary function, that some, but not all, children with growth hormone deficiency (GHD) may have beneficial growth responses to the orally administered GH secretagogue LUM-201. Objective To determine if pretreatment testing can identify predictive enrichment markers (PEM) for subjects with adequate residual function that are responsive to LUM-201. Methods Analysis of a completed, randomized, placebo-controlled trial of LUM-201 a recombinant human growth hormone (rhGH) in which all randomized subjects had pretreatment testing Setting International multicenter study conducted in pediatric endocrinology clinics. Participants 68 naïve-to-treatment, prepubertal children with established diagnoses of GHD. Outcome Measures Sensitivity, specificity and predictive accuracy of potential markers to predict 6-month growth responses to oral LUM-201 and daily rhGH. Results Two PEM were identified: baseline insulin like growth factor- -I (IGF-I) concentration > 30 ng/mL and peak GH to single dose LUM-201 2: 5 ng/mL are defined as PEM-positive.PEM -positive status enriches a population for better growth responses to LUM-201.PEM -negative status enriches a population for better growth responses to rhGH. Conclusion The combination of peak GH to single-dose LUM-201 and baseline IGF-I concentration are effective PEMs for 6-month growth responses to LUM-201 and rhGH in prepubertal children with GHD.

Creatine Transporter Deficiency (CTD) is an inborn error of metabolism presenting with intellectual disability, behavioral disturbances and epilepsy. There is currently no cure for this disorder. Here, we employed novel biomarkers for monitoring brain function, together with well-established behavioral readouts for CTD mice, to longitudinally study the therapeutic efficacy of cyclocreatine (cCr) at the preclinical level. Our results show that cCr treatment is able to partially correct hemodynamic responses and EEG abnormalities, improve cognitive deficits, revert autistic-like behaviors and protect against seizures. This study provides encouraging data to support the potential therapeutic benefit of cyclocreatine or other chemically modified lipophilic analogs of Cr.

The study of gene expression in gonadotropes has largely focused on the variety of mechanisms regulating transcription of the gonadotropin genes and ancillary factors that contribute to the overall phenotype and function of these cells in reproduction. However, there are aspects of the response to GNRH signaling that are not readily explained by changes at the level of transcription. As our understanding of regulation at the level of mRNA translation has increased, it has become evident that GNRH receptor signaling engages multiple aspects of translational regulation. This includes activation of cap-dependent translation initiation, translational pausing caused by the unfolded protein response and RNA binding protein interaction. Gonadotropin mRNAs and the mRNAs of other factors that control the transcriptional and signaling responses to GNRH have been identified as targets of regulation at the level of translation. In this review we examine the impact of translational control of the expression of gonadotropin genes and other genes relevant to GNRH-mediated control of gonadotrope function.