PİTUİTARY and HYPOTHALAMİC HORMONES

1. PİTUİTARY and HYPOTHALAMİC HORMONES P PROF.DR.ARZU SEVEN

2. The hypotalamic hormones are released from the hypothalamic nerve fiber endings around the capillaries of the hypothalamic_hypophysial system in the pituitary stalk and reach the anterior lobe of the pituitary gland through the special portal system

4. The hypothalamic releasing hormones are released in a pulsatile manner  • The pituitary gland is a pea_sized oval organ encased in a bone cavity of the skull (sella turcica) below the brain  • The pituitary gland is divided into 2 lobes: the posterior pituitary (neurohypophysis) is embryo logically part of the brain and consists largely of neurones which have cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus

6. Hormones of the posterior pituitary are synthesızed and packed in supraoptic and paraventricular nuclei of the hypothalamus, transported along axons and stored in the posterior pituitary before release in the circulation • The anterior lobe (adenohypophysis) accounts approximately 80% of the gland, is embryologically derived from ectoderm, has no direct anatomic continuity with the brain

7. Both posterior and anterior pituitary hormones are controlled largely by the hpothalamus • The hypothalamus functions as an integrative center which orchestrates a large number of endocrine and neural processes, and entrains them to relevant external stimuli

8. The endocrine systems that involve the hypothalamus, pituitary and downstream organs are usually termed “AXES” and are most usefully viewed as functional units for the purposes of clinical diagnosis and managemant

12. AXES: • 1-hypothalamo_pituitary_thyroid axis • 2- hypothalamo_pituitary_adrenal axis • 3- hypothalamo_pituitary_gonadal axis • 4-the growth hormone axis • 5-the prolactin axis

13. Growthhormonereleasinghormone(GHRH) • 44_amino acidpeptidesynthesized as a part of a 108_amino acidprohormone in thearcuateandventromedialnuclei of hypothalamusandmedianeminence • GHRH + R --------adenylcyclase --------calcium-calmodulinsystem GH secretion

14. Negative feedback from GH and IGF-1 GHRH SOMATOSTATİN

15. Growthhormonereleasinginhibitinghormone: somatostatin(GHRIH) • 2 forms 14_amino acids 28_amino acids   • Produced from the same 116_amino acid gene product • Somatostatin and its receptors are found throughout the brain, and in other organs, notably gut

16. Binding of somatostatin to its receptor is coupled to adenyl cyclase by an inhibitory guanine nucleotide-binding protein- cAMP • Somatostatin inhibits: TSH INSULIN GLUCAGON GASTRIN

18. Growthhormone(GH), prolactinandchorionicsomatotropin(CS: plasentallactogen) constituteonehormonegroup • They range in size from 190_199 amino acids • Each has a single tryptophan residue • Each has 2 homologous disulfide bonds • Share common antigenic determinants • All have growth promoting and lactogenic activity

19. GH • Synthesized in somatotropes, a subclass of the pituitary acidophilic cells • Released in bursts with a periodicity of 3-4 hours and greatest secretory activity occurs during sleep  no meaningful referance interval • Provocative tests / multipl samples over the course of a day • GH is essential for postnatal growth and for normal carbohydrate, lipid and nitrogen metabolism:

20.  Transport of amino acids into muscle cells (during growth) Protein synthesis RNA synthesis like insulin DNA synthesis

21.  GH antogonizes the effects of insulin in carbohydrate metabolism: • Peripheral utilization of glucose + gluconeogenesis hyperglycemia • İnhibition of glycolysis in muscle • Prolonged GH administration may result in diabetes mellitus

22. GH promotes the release of free fatty acids and glycerol from adipose tissue,lipolysis (hormone sensitive lipase activity ) • Oxidation of free fatty acids in liver • Prolactin like effects such as stimulation of mammary glands lactogenesis • GH or more likely IGF-1 promotes (+) Ca,Mg and phosphate balance and causes the retention of Na, K, Cl (like IGF-1)

23. During hypoglycemia GH stimulates lipolysis and induces peripheral resistance to insulin • The indirect growth-releated actions of GH are mediated by IGF-1 : • Promoting the proliferation of chondrocytes and the synthesis of cartilage matrix in skeletal tissues: stimulating linear growth

24. IGF-1 (insulinlikegrowthfactor 1): •   70 amino-acid single chain basic peptide • Homology with proinsulin • Acts like a paracrin hormone • Liver is the major source of circulating IGF-1 whose function is primarly feedback inhibition of GH secretion

25. In plasma and other extracellular fluids, IGF-1 is complexed to IGF-1 bindings proteins (IGFBPs) • IGF-1 works through the type 1 IGF receptor (similar to insulin receptor) and linked to intracellular tyrosine kinase activity

26.  Plasma reference interval for IGF-1 in adults aged 20-60 years is fairly constant -a good marker of integrated GH activity • Lower in young children, rises dramatically during period of growth and progression through puberty , falls after 6th. decade of life

27. IGF-2 • 67 amino acids • Has activity similar/ identical to multiplication stimulating activity(MSA) • Plasma levels are twice those of IGF-1

29. Clinicaldisorders of GH sectionpathophysiology • Basal IGF-1 or IGFBP-3 measurements may serve as a preliminary screening test • GH deficient dwarfs respond normally to endogenous GH (regular injection of recombinant human GH)

30. Twotypes of target organ resistancehavebeendescribed : • 1-Larontypedwarfs GH levels IGF-1levels Lack of functionalhepatic GH receptors • 2-Pygmies • GH level normal Post GH receptordefect IGF-1level

31. Increased GH secreton later in life, after fusion of bony epiphyses, causes ACROMEGALY • The most likely cause is a pituitary adenoma

32. Clinical features include: • Coarse facial features • Soft tissue thickening e.g. lips • Spade-like hands • Protruding jaw (prognathism) • Sweating • İmpared glucose tolarance or DM

34. Diagnosis: • An inadequate GH supression during standart 75 gr.oral glucose tolerance test and an elevated IGF-1 levels • MRI evıdence of pituitary tumor

35. Treatment: • Surgery • Long acting somatostatin analogues (octreotide ) • Pegvisomant (a GH antagonist) • Radiation

36. Prolactin axis • 23KD a protein • Homologous to GH • Secreted by lactotropes ,acidophilic cells in the anterior pituitary • The number of these cells and their size increase dramatically during pregnancy • İt is under predominantly inhibitory control from the hypothalamus

37. Dopamine is an inhibitor of prolactin secretion • TRH has prolactin-releasing properties • The primary role ın humans occurs during pregnancy when PRL binds to its receptor in mammary tissue and stimulates the synthesis of milk proteins, including lactalbumin

38. PRL blocks FSH action on follicular estrogen secretion and enhances progesterone levels by inhibiting steroid metabolizing enzymes • Hyperprolactinemia may result from: • Prolactinoma (prolactin secreting pituitary tm) • Deficient supply of dopamine from hypothalamus • Use of antidopaminergic drugs

39. Symptoms • Female: amenorrhea galactorrhea Male: impotance prostatic hyperplasia

40. Diagnosis: • Pituitary imaging • Dynamic test for prolactin secretion • Treatment: • Long-acting dopamine agonist drugs • surgery

41. Thehypothalamo-pituitarythyroidaxis • TRH_manufactured in the hypothalamus and transported to the anterior pituitary by the portal circulation • Modified tripeptide, synthesized in pulsatile fashion • TRH stimulates TSH synthesis and secretion by binding to G_protein coupled receptors on the pituitary thyroptroph cell membrane, that are linked to phospholipase C IP3 Ca release preformed TSH secretion

42. Chronic actions of TRH: stimulation of TSH subunit biyosynthesis and TSH glycosylation • The number of TRH receptors are down regulated bythyroid hormones and TRH

43. TSH(THYROTROPIN) • Small glycoprotein, synthesized by pituitary thyrotrophs • α chain is identical to other glycoprotein hormones (LH,FSH,β HCG) • Specificity is conferned by the β-chain • Pulsatil and circadian rhythm • TSH, like TRH, acts via a specific G_protein coupled receptoradenyl cyclasecAMP dependent protein kinase

44. TSH controls every aspect of thyroid hormone biosynthesis and secretion : • iodide transport • İodothyronine formation • Thyroglobulin proteolysis • Thyroxine de_iodination

45. TSH also stimulates growth of thyroid gland • Negative feedback by thyroid hormones occurs at both hypothalamic and pituitary levels • At the pituitary level, T4 and T3 inhibit TSH secretion (through regulation of gene transcription and TSH glycosylation) • T3 is a more potent feedback inhibitor than T4 • Much of feedback inhibition by T4 requires its conversion to T3 by de_iodinase type2

46. THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS • Corcototropin releasing factor(CRF) • 41 amino acid peptide secreted by PVN • Acts via G_protein coupled receptor • cAMP second messenger system ; to stimulate both synthesis and secretion of ACTH • Vasopressin(VP) potentiates the response of the pituitary to CRH • Negative feedback by cortisol inhibits both CRH and VP secretion

48. Adrenocorticotropichoromone(ACTH) • Synthesized as a 241_amino acid precursor molecule,pro_opiomelanocortin (POMC) • POMC is cleaved at multiple sites to release hormonally active peptides,endorphins and MSH • POMC may be produced in large quantities by certain malignancies , giving rise to ectopic ACTH syndrome

50. ACTH is composed of 39_amino acids with biologic activity in the N_terminal 24 residues • Secreted in stress-releated bursts, diurnal rhythm with a peak at 05.00 h. • Transported unbound in plasma, half life~ 10min. • ACTH stimulates the synthesis and release of glucocorticoid hormones by enhancing the conversion of cholestrol to pregnenolone