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Effects of primary hypothyroidism (HYPO) on the male gonadal axis are controversial, with only scanty data on the gonadotroph cell response and no information on GnRH tuberoinfundibular neurons, even in animal models. HYPO has been reported to variably induce hypogonadotropic hypogonadism, a hypergonadotropic state, or to have no effects on basal levels of pituitary gonadotropins, both in adult male rats and humans. Similarly, the exogenous administration of GnRH to HYPO rats and humans may increase or decrease gonadotropin secretion. Since inhibitory effects of HYPO on the GnRH-gonadotropin axis are reversed by replacement with L-T4, it has been suggested that thyroid hormone (TH) may regulate tuberoinfundibular GnRH and pituitary gonadotropin biosynthesis and/or secretion. To shed light on this hypothesis, we conducted immunocytochemical studies on the distribution and immunostaining characteristics of hypophysiotropic GnRH neurons, LH, PRL and vasoactive intestinal polypeptide (VIP) immunoreactive (IR) cells in the pituitary of adult, male rats. We show that HYPO reduces IR-GnRH in a restricted population of tuberoinfundibular perikarya and their proximal axons compared to euthyroid controls, but increases IR-VIP both in pituitary cells in direct association with LH-gonadotrophs and within IR-LH cells, itself. We propose that VIP may serve as a juxtacrine/paracrine/autocrine regulator of LH secretion and that, when GnRH biosynthesis is reduced by HYPO, gonadotropin secretion may be rescued by local activating effects of VIP. Polychlorinated biphenyls (PCB), industry toxicants found in food and water, also have inhibitory effects on the gonadal axis, decreasing fertility and suppressing basal and GnRHinduced LH release in male rats. Since PCB may also exert endocrine disruptor-dependent (EDD) effects on the thyroid axis producing a non-thyroidal illness syndrome (NTIS) (coined EDD-NTIS), we developed a rat model of EDD-NTIS to determine whether central hypothyroidism may contribute to the pathophysiology of PCB-induced hypogonadism. On the basis of preliminary animal data, we speculate that one of the mechanisms for Partial Androgen Deficiency of the Aging Male may involve central hypothyroidism and EDD-NTIS, resulting in inhibition of the GnRH-gonadotroph axis.

The neuroendocrine system (NES) of Vertebrates can be defined as a set of cells organized in single organs and diffuse elements, sharing co-production of amine hormone/transmitters, peptide hormone/transmitters and specific markers of neural determination. In this perspective, the hypothalamic-pituitary-target organ axis (H-P axis), the autonomic nervous system (ANS) and the diffuse neuroendocrine or APUD system contribute to the NES. However, in Mammals and man virtually any compartment of the body harbors elements, often with different embryologic origin, having at least some of the NES features. Thus, all anatomical structures may be part of a wide functional circuitry, based on "internal secretions", that supersedes the current view of the NES. Historically, metaphysical antecedents of this concept can be found in the biomedical tradition dealing with the idea of the so called "vital energy". Currently, the "internal secretions" circuitry can be envisaged as an informational supersystem encompassing the H-P axis, ANS, APUD, immune and any other body system performing autocrine, paracrine and/or endocrine regulations, that superintends the homeostatic balance. Evolutionary evidence shows that diffuse autocrine/paracrine/endocrine, peptidergic secretions would be the oldest and hierachically simplest signals, with respect to the later and hierarchically more complex ANS and H-P axis outputs, to regulate body homeostasis. Therefore, the new acronym "Triune Information Network" (TIN) is proposed for the informational supersystem of internal secretions acting in Mammals and man via progressively higher levels of control (diffuse autocrine/paracrine/endocrine secretions, ANS and H-P axis) on a common energetic substrate: the internal body milieu.

Neuroendocrine, endocrine and autocrine/paracrine signals contribute to the regulation of basal thyrotroph growth. Thyrotropin-releasing hormone (TRH), somatostatin, thyroid hormone (TH), estrogens (Es) and epidermal growth factor, all may play a role both in normal and tumoral thyrotroph proliferation, acting via either plasma membrane receptors and non-genomic steps or nuclear receptors and gene transcription. Signaling features common to all these ligands are involvement of G protein-coupled receptors, mitogen-activated protein kinase cascade and nuclear polyphosphoinositide cycle. In addition, each growth information, independently from the eliciting factor, may be routed intracellularly following a branched pathway, that often links different transduction systems at common check-points, as the Shc-Grb2-SOS complex. Finally, some ligands (e.g. TRH, TH, Es) may display opposite effects on thyrotroph growth, depending on environmental conditions and state of cell differentiation. These ambiguities of response can be interpreted using a "fuzzy" logic-based model of intracellular signaling. Accordingly, check-points common to different transduction cascades may be envisaged as targets for antitumoral therapy selective to the neoplastic thyrotroph cell.

Historical investigation suggests that the role of the hypothalamus as a site of integration for endocrine with autonomic and behavioral responses in man rises from ideas and observations first appearing between the 14th and 18th centuries. Research on human, post-mortem brains and by in vivo magnetic resonance techniques reveal that the functional morphology of the hypothalamus in man is very similar to that in Rodents and Primates. As such, the adult human hypothalamus can be subdivided in three longitudinal zones, representing the source and target of neural informations traveling back and forth the brain stem, thalamus, limbic system, basal ganglia and neocortex. In addition, the human hypothalamus can be further partitioned in three anterior-posterior regions, of which the rostral one exerts a prominent regulation in predictive homeostasis, as opposed to the two caudal ones, primarily involved in reactive homeostasis. Finally, nuclear distribution in the human hypothalamus largely coincides with that in higher Mammals. Nevertheless, it is still unclear how the hypothalamus may give rise to specific homeostatic behaviors like hunger, thirst, reproductive and parental attitude, thermoregulation, aggressive-defensive performance, affective-motivational tone, circadian rhythmicity, sleep-wake cycle and immune regulation. The recent advent of new theories for nervous communication, like volume transmission and neural Darwinism, is progressively enlightening our understanding of the role played by the hypothalamic architecture in homeostatic responses, both in Mammals and man.