The Neuroendocrinology of the Somatotropic and Thyroid Axes

1. The Neuroendocrinology of the Somatotropic and Thyroid Axes

3. Remarkable Characteristics of the Somatotropic Axis • The players in the axis • Regularity of the secretion • The complexity of the regulation of the axis • Importance to overall metabolism of the organism

4. Remarkable Characteristics of the Somatotropic Axis • The players in the axis • Regularity of the secretion • The complexity of the regulation of the axis • Importance to overall metabolism of the organism

5. 1. Growth Hormone Single aa chain. Produced by the pituitary somatotropes. Gene expression is regulated by POU transcription factor Pit-1. Gene located on Chromosome 17. Signals through transmembrane receptor of 620 aa. Receptor is a member of the cytokine family of receptors, extracellular domain is BP.

6. Growth Hormone Actions • Stimulation of IGF production by liver • Stimulation of skeletal and muscle growth • Increased bone density, reversal of osteoporosis. • Regulation of lipolysis - decrease in body fat • Promotes cellular uptake of amino acids • Anabolic effects • Diabetogenic - raises blood glucose levels • Improve immune function

7. 2. Insulin-like Growth Factor I and II • Single chain peptides of approximately 70 aa related structurally to insulin. • Produced by virtually every tissue in the body but the primary site related to the GH axis is in the liver. • IGFs circulate bound to specific proteins with IGFBP-3 being the predominate partner. There are 6 total. • Function of IGFs is to increase linear growth of the organism.

8. 3. Somatostatin Discovered by Krulich et al using bioassay system. SS is a14 aa peptide that also comes in an elongated form of 28 aa.

9. SS is produced in the periventricular region of the hypothalamus adjacent to the PVN. Transported to the external layer of the ME for release into the portal blood. SS is distributed throughout the brain and made in many different cell types which are most likely inhibitory neurons.

10. SS binds to 5 different receptors which are found in different areas of the brain.

14. 3. Growth Hormone- Releasing Hormone [GHRH] Isolated and characterized in 1980’s From human Pancreatic tumor. Structure determined by Vale et al. GHRH is a 44 aa peptide amidated like TRH and GnRH.

15. GHRH producing cells are present in the ARC nucleus of the hypothalamus. GHRH receptor has been cloned by Mayo et al. It is a typical GPCR with 7 TM domains and It is highly expressed in anterior pituitary somatotropes.

16. Expression of the GHRH Receptor is under Complex regulation by Pit-1 (yellow), GR (green), ER (red), cAMP (blue).

17. Demonstration of the Importance of Pit-1 For GHRH-R Expression. A patient with severe growth retardation was identified. Patient had a mutation in GHRH-R promoter that altered Pit-1 binding.

18. While one of the primary functions of GHRH is to stimulate GH release it also regulates GH cell growth and when over expressed GH cells become hyper- plastic. GHRH acts on pit cells and increase cAMP and Ca++ entry.

19. 5.Ghrelin - The newest member of this family. In the 1990’s synthetic compounds were developed to stimulate GH release. These compounds were found to activate a novel receptor in the pituitary, which was subsequently cloned. Then the ligand was identified from stomach extracts in 1999 and found to be Ghrelin. Ghrelin is the only peptide (28 aa) with a octanoyl group attached. This peptide binds to a GPCR in the pituitary.

21. Ghrelin strongly potentiates GHRH-induced production of cAMP. But the most dominant effect of Ghrelin and GHS is to depolarize cells via PLC and enhanced Ca++ entry.

22. Ghrelin acts to stimulate NPY containing neurons and inhibit POMC neurons in the arcuate. Ghrelin also works via GHRH to release GH. NPY POMC

23. Factors affecting Ghrelin secretion • Increasing Ghrelin • Fasting, low BMI • Leptin • GHRH • Thyroid hormones • Testosterone • Parasympathetics • Decreasing Ghrelin • Food Intake, high BMI • Glucose • Insulin • SS • GHS, ghrelin • PYY3-36

25. Remarkable Characteristics of the Somatotropic Axis • The players in the axis • Regularity of the secretion • The complexity of the regulation of the axis • Importance to overall metabolism of the organism

26. Male Female • GH is characterized by its • pulsatility. • Males • High amplitude • Low inter-peak levels • Roughly 3 hour period • Females • Low amplitude • Higher inter-peak levels • Irregular period

27. Male Female While the pattern of GH secretion may differ, the amount of GH secreted during a 24-hour period is approximately the same in male and females. Patterns are similar in humans.

28. Human GH secretion is similar to the rat in some respects except human females secrete more GH than males. • In rat GHRH is under androgen control, in human estrogen is the controlling hormone.

29. GH pattern of secretion is dynamic interplay of GHRH and SS. • Antiserum studies have helped identify role for GHRH and SS in this patter

30. The other critical factor in GH pattern is the gonadal steroid environment.

31. GH secretory pattern is generated by effects of gonadal steroids on brain neurons. GHRH neurons produce more GHRH in a androgenic environment and less under influence of estrogen. Similarly, SS is alsoincreased in males vs females.

32. Male • GH receptor signals through the STAT5 protein kinase system. • The pattern of GH dictates STAT5 signaling in the liver. Male pattern at top and female pattern at bottom. Female

33. Remarkable Characteristics of the Somatotropic Axis • The players in the axis • Regularity of the secretion • The complexity of the regulation of the axis • Importance to overall metabolism of the organism

34. Feedback in the Somatotropic Axis • Ultrashort Loop • Short Loop or autoregulation • Long Loop

35. Ultrashort loop feedback means the ability of SS and GHRH to reciprocally regulate each other via direct synaptic contacts.

36. Autoregulation of GH release by GH Neurons producing SS and GHRH have express GH-R mRNA. GH has been shown to get into the brain via the arcuate nucleus.

40. Implantation of GH producing tumor causes significant decrease in hypothalamic GHRH production and secretion.

41. In the spontaneous dwarf rat (SDR) that lacks GH, there are marked changes in both GHRH and SS that can be reversed by exogenous GH.

42. Long loop feedback of IGF-1 and 2 requires both peptides to be effective. • IGF-1 alone has no effect on GH release when given icv.

45. Remarkable Characteristics of the Somatotropic Axis • The players in the axis • Regularity of the secretion • The complexity of the regulation of the axis • Importance to overall metabolism of the organism

46. Factors that influence plasma GH levels • Sleep - Massive release during initial phases of sleep especially slow-wave sleep. • Stress - Activation in humans and inhibition in animals, e.g. hypoglycemia. GC, however, increase GH physiologically but not pathologically and reduce GHRH. • Exercise - Increases GH secretion • Puberty/Aging - GH secretion increases during puberty and facilitates the completion of puberty. As aging progresses, GH release decreases due to decreased GHRH and augmented SS tone. • Disease states - Acromegaly- GH hypersecretion due to pituitary tumor markedly affects bony structures where epiphyseal plates have closed.

48. Nutritional status has dramatic effects on circulating GH levels. Obesity, for example causes a significant inhibition in GH. Human Rat Leptin inhibits NPYwhich suppresses GH