1. Hypothalamus and its hormones, hormones of the pituitary gland Romana Šlamberová, M.D. Ph.D. Department of Normal, Pathological and Clinical Physiology

2. The hypothalamus Hormonal (anterior portion) or nervous (posterior portion) control of the pituitary gland  Hormones – control secretion of hormones in the anterior pituitary Releasing hormones (factors) Inhibitory hormones (factors) Hormones secreted and transported to anterior pituitary through hypothalamic-hypophysial vessels to pituitary sinuses  Nerves – Magnocellular neurons in the supraoptic and paraventricular nuclei of the hypothalamus – axoplasm transport of hormones from the hypothalamus to the posterior pituitary

3.  Special neurons in the hypothalamus synthesize and secrete the hypothalamic releasing and inhibitory hormones that control secretion of anterior pituitary  These neurons originate in various parts of the hypothalamus and send their nerve fibers to the median eminence and tuber cinerreum (extension of hypothalamic tissue into the pituitary stalk)  Hormones are secreted to the tissue fluids, absorbed into the hypothalamic-hypophysial portal system and transported to the sinuses of the anterior pituitary Hypothalamic-hypophysial portal system (1)

4. Hypothalamic hormones controlling anterior pituitary gland (1) Major hypothalamic releasing hormones:  Thyreotropin-releasing hormone (TRH) – causes release of thyroid stimulating hormone (TSH)  Corticotropin-releasing hormone (CRH) – causes release of adrenocorticotropin hormone (ACTH)  Growth hormone releasing hormone (GHRH) – causes release of growth hormone  Gonadotropin releasing hormone (GnRH) – causes release of the 2 gonadotropic hormones (luteinizing and follicle-stimulating hormone)

5. Major hypothalamic inhibitory hormones:  Growth hormone inhibitory hormone (GHIH) = SOMATOSTATIN – inhibits release of growth hormone  Prolactin inhibitory hormone (PIH) – inhibits prolactin secretion Hypothalamic hormones controlling anterior pituitary gland (2)

6. The pituitary gland  1 cm in diameter  0.5 – 1 g in weight  In sella turcica (bony cavity at the base of the brain  Connected to the hypothalamus via pituitary stalk  Parts: Adenohypophysis – anterior Neurohypophysis - posterior Pars intermedia (almost absent in humans)

7. Hormones of the adenohypophysis (1)  Human growth hormone (hGH) – affects protein formation, cell multiplication, cell differentiation  Adrenocorticotropin (ACTH) – controls secretion of some of the adrenocortical hormones (affects metabolism of glucose, proteins and fats)  Thyroid-stimulating hormone (STH) – controls secretion of thyroxine and triodothyronine by the thyroid gland (controls rates of most intercellular chemical reactions of the entire body)  Prolactin – promotes mammary gland development and milk production  Follicle-stimulating hormone (FSH) and Luteinizing hormone – control growth of the ovaries and testes and their hormonal and reproductive functions

8. Hormones of the adenohypophysis (2) Other hormones of adenohypohysis  β-Lipotropin (β-LPH) – function unknown  γ-Melanocyte- stimulating hormone (γ-MSH) – stimulates melanin synthesis in melanocytes

9. Cell types in the anterior pituitary  Chromophobes – mostly inactive cells with only few secretory granules  Chromophils – active secretory cells Acidophils (stained with acidic dyes) Basophils (stained with basic dyes) Cell typeHormones secreted % of total secretory cells Stain affinityDiameter of secretory granules (nm) SomatotropehGH50Acidophilic300-400 LactotropeProlactin10-30Acidophilic200 CorticotropeACTH10Basophilic400-550 ThyrotropeTSH5Basophilic120-200 GonadotropeFSH, LH20Basophilic250-400

10. Hormones of Intermediate lobe  Melanocytes stimulating hormones (MSH) – types α, β, γ. In humans – stimulate melanin synthesis in melanocytes In fish, amphibians and reptiles – expand melanophores  γ- Lipotropin (γLPH) and Corticotropin-like intermetiate lobe peptide (CLIP) From prehormone POMC (pro-opiomelanocortin) Function unknown

11. Hormones of the neurohypophysis  Magnocellular neurons (long neurons) located in the supraoptic and paraventricular nuclei of the hypothalamus – axoplasm transport of hormones from the hypothalamus to the posterior pituitary  Hormones: Polypeptides with 9 amino acids ADH (vasopressin): Cys-Tyr-Phe-Gln-Asn-Cys- Pro-Arg-GlyNH 2 Oxytocin: Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu- GlyNH 2 Similar structure, similar action

12. Cell types in the posterior pituitary  Pituicytes = glial-like cells no hormone secretion supporting structure for terminal nerve fibers and endings  Axons of secretory neurons located in the supraoptic and paraventricular nuclei of the hypothalamus

13.  Formed primarily in the supraoptic nuclei  Regulates water excretion by the kidneys Increases the permeability of collecting tubules and ducts to water - water reabsorption – concentrated urine Osmotic regulation – osmoreceptors in the hypothalamus or somewhere near  Causes vasoconstriction Constrict arterioles throughout the entire body Blood volume (activated when decreased blood volume) – stretch (volumoreceptors) in right atrium of the heart - baroreceptors in carotid, aortic and pulmonary regions ADH (vasopressin)

14. Oxytocin  Formed primarily in the paraventricular nuclei  Causes contraction of the pregnant uterus Oxytocin plasma levels increase in the last stage of labor Cervix stimulation during labor elicit nervous signals to hypothalamus and the secretion of oxytocin increases  Aids the milk ejection by the breasts The suckling stimuli cause signals to be transmitted through sensory nerves to the oxytocin neurons in the PV and SO nuclei of the hypothalamus. Oxytocin causes contraction of myoepithelial cells around the alveoli. In less than a minute after suckling started the milk begins to flow.

15. Growth hormone (somatotropic hormone, somatotropin)  Chemical structure: small protein (191 amino acids)  Function: hGH enhances body protein, uses up the fat stores and conserves carbohydrates Increases rate of protein synthesis in most cells of the body Increases mobilization of fatty acids in the blood and increases use of the fatty acids for energy Decreases rate of glucose utilization throughout the body

16. hGH - Function (1) Increase in protein deposition  Enhancement of amino acid transport through the cell membrane to the interior of the cells (more AAs available for protein synthesis)  Enhancement of RNA translation to cause protein synthesis by the ribosomes (even when the AAs concentration are not increased)  Increase in nuclear translation of DNA to form RNA  Decrease in catabolism of protein and amino acids

17. hGH - Function (2) Increase in fat utilization for energy  Causing release of fatty acids from adipose tissue (increase in fatty acid concentration in the body fluid)  Enhancement of conversion of fatty acids to acetyl coenzyme A (subsequent utilization of it for energy)  Ketogenic effect of hGH – ketosis may occur when the amount of hGH is too high and causes great mobilization of fatty acids from adipose tissue that requires large amount of acetoacetic acid formed by the liver (may cause fatty liver)

18. hGH - Function (3) Decrease in carbohydrate utilization  Decrease in glucose uptake in tissues (skeletal muscle and fat)  Increase in glucose production by the liver  Increase in insulin secretion hGH has DIABETOGENIC EFFECT = growth hormone-induced “insulin resistance” attenuates insulin’s actions, such as: To stimulate uptake and utilization of glucose in skeletal muscle and fat To inhibit glucose output by the liver This leads to increase of glucose concentration in the blood and compensatory increase of insulin. Excess in hGH may cause metabolic disturbance similar to those found in patients with DM II.

19. hGH stimulates cartilage and bone growth Cartilages and bones are the main tissues of hGH action  Increased deposition of protein by the chondrocytic and osteogenic cells that cause bone growth  Increased rate if reproduction of these cells  Specific effect of converting chondrocytes into osteogenic cells (causing specific deposition of new bone)  2 principle mechanisms of bone growth: Growth in length (during development before closing the epiphysal slit) Growth in width (also after adolescence) – hGH stimulates osteoblasts

20. Somatomedins  Secreted by the liver and other tissue based of the hGH stimulation  Similar effect as insulin = IGF (insulin-like growth factors)  Function: support the action of hGH (unclear is if the hGH may act without somatomedines or not)  Types: Somatomedin C = IGF I IGF II

21. Regulation of hGH secretion (1) - stimulation hGH is secreted in pulsation – increasing and decreasing  Factors stimulating secretion: Starvation (especially with protein deficiency) Hypoglycemia low fatty acids in the blood Exercise Excitement Trauma  The first 2 hrs of deep sleep (non-REM)  Hormones: GHRF = Growth hormone releasing factor Estrogens and androgens

22.  Factors inhibiting secretion: Hyperglycemia High fatty acids in the blood Aging Obesity  REM sleep  Hormones: GHIH = Growth hormone inhibitory hormone (Somatostatin) Exogenous growth hormones Somatomedins (IGF) Regulation of hGH secretion (2) - inhibition

23. Abnormalities of hGH secretion (1) - hypofunction  Panhypopituitarism = decrease of secretion of all anterior pituitary hormones Congenital Induced by tumor that destroys the gland  Dwarfism Decrease of all or more than 1 hormone of anterior pituitary (the person does not reach sexual maturation = missing gonadal hormones) Decrease just in hGH – only smaller person, but can maturate Missing somatomedins  Panhypopituitarism in the adulthood Due to: tumor or trombosis of the pituitary blood vessels Results in: hypothyroidism, decrease in glucocorticoids, suppression of gonadotropic hormones

24. Abnormalities of hGH secretion (2) - hyperfunction  Gigantism – increased growing (randomly) = giants Due to: increased activity of somatotropes or tumor during development Giants have hyperglycemia (DM)  Acromegaly – increased growing of acral parts of the body Due to: increased activity of somatotropes or tumor after puberty (after closure the epiphysal slits) Bones grow only to thickness ( enlargement of hands and feet, membranous bones such as cranium, nose, supraorbital ridges, chin etc.