Hypothalamus and Pituitary

1. Hypothalamus and Pituitary

2. Hypothalamus and Pituitary • The hypothalamus-pituitary unit is the most dominant portion of the entire endocrine system. • The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and reproductive glands and also controls somatic growth, lactation, milk secretion and water metabolism.

3. Hypothalamus and Pituitary • Pituitary function depends on the hypothalamus and the anatomical organization of the hypothalamus-pituitary unit reflects this relationship. • The pituitary gland lies in a pocket of bone at the base of the brain, just below the hypothalamus to which it is connected by a stalk containing nerve fibers and blood vessels. The pituitary is composed to two lobes-- anterior and posterior

4. Posterior Pituitary: neurohypophysis • Posterior pituitary: an outgrowth of the hypothalamus composed of neural tissue. • Hypothalamic neurons pass through the neural stalk and end in the posterior pituitary. • The upper portion of the neural stalk extends into the hypothalamus and is called the median eminence.

5. Anterior pituitary: adenohypophysis • Anterior pituitary: connected to the hypothalamus by the superior hypophyseal artery. • The antererior pituitary is an amalgam of hormone producing glandular cells. • The anterior pituitary produces six peptide hormones: prolactin, growth hormone (GH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).

6. Hypothalamus and pituitary gland

7. Hypothalamus and pituitary gland

8. Regulation of Hypothalamus

9. Anatomical and functional organization

10. Hypothalamic releasing factors for anterior pituitary hormones • Travel to adenohypophysis via hypophyseal-portal circulation • Travel to specific cells in anterior pituitary to stimulate synthesis and secretion of trophic hormones

11. Hypothalamic releasing hormone Effect on pituitary Corticotropin releasing hormone (CRH) Stimulates ACTH secretion Thyrotropin releasing hormone (TRH) Stimulates TSH and Prolactin secretion Growth hormone releasing hormone (GHRH) Stimulates GH secretion Somatostatin Inhibits GH (and other hormone) secretion Gonadotropin releasing hormone (GnRH) Stimulates LH and FSH secretion Prolactin releasing hormone (PRH) Stimulates PRL secretion Prolactin inhibiting hormone (dopamine) Inhibits PRL secretion Hypothalamic releasing hormones

12. Characteristics of hypothalamic releasing hormones • Secretion in pulses • Act on specific membrane receptors • Transduce signals via second messengers • Stimulate release of stored pituitary hormones • Stimulate synthesis of pituitary hormones • Stimulates hyperplasia and hypertophy of target cells • Regulates its own receptor

13. Anterior pituitary • Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels. • The anterior pituitary produces six peptide hormones: • prolactin, growth hormone (GH), • thyroid stimulating hormone (TSH), • adrenocorticotropic hormone (ACTH), • follicle-stimulating hormone (FSH), • luteinizing hormone (LH).

14. Anterior pituitary cells and hormones

15. Hypothalamus and anterior pituitary

16. Anterior pituitary hormones

17. Feedback regulation of hypothalmus/pituitary • A prominent feature of each of the hormonal sequences initiated by the hypothalamic releasing hormones is negative feedback exerted upon the hypothalamic-pituitary system by the hormones whose production are stimulated in the sequence.

18. Hypothalamus-pituitary axis

19. Feedback control

20. Feedback control of thyroid function

21. Feedback and restoration of homeostasis

22. Feedback control of growth hormone

23. Growth hormone vs. metabolic state • When protein and energy intake are adequate, it is appropriate to convert amino acids to protein and stimulate growth. hence GH and insulin promote anabolic reactions during protein intake • During carbohydrate intake, GH antagonizes insulin effects-- blocks glucose uptake to prevent hypoglycemia. (if there is too much insulin, all the glucose would be taken up). • When there is adequate glucose as during absorptive phase, and glucose uptake is required, then GH secretion is inhibited so it won't counter act insulin action.

24. Growth hormone vs. metabolic state • During fasting, GH antagonizes insulin action and helps mediate glucose sparing, ie stimulates gluconeogenesis • In general, duing anabolic or absorptive phase, GH facilitates insulin action, to promote growth. • during fasting or post-absorptive phase, GH opposes insulin action, to promote catabolism or glucose sparing

25. Growth hormone and metabolic state

26. ACTH: adrenocorticotropic hormone: synthesis and regulation of secrtion • Produced in corticotrophs • ACTH is produced in the anterior pituitary by proteolytic processing of Prepro-opiomelanocortin (POMC). • Other neuropeptide products include b and g lipotropin, b-endorphin, and a-melanocyte-stimulating hormone (a-MSH). • ACTH is a key regulator of the stress response

27. ACTH synthesis

28. ACTH • ACTH is made up of 39 amino acids • Regulates adrenal cortex and synthesis of adrenocorticosteroids • a-MSH resides in first 13 AA of ACTH • a-MSH stimulates melanocytes and can darken skin • Overproduction of ACTH may accompany increased pigmentation due to a-MSH.

29. Addison’s Disease • Disease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH production • Result: overproduction of ACTH • Skin color will darken • JFK had Addison’s disease and was treated with cortisol injections

30. b-endorphin • Produced as a result of ACTH synthesis • Binds to opiate receptors • Results in “runner’s high” • Role in anterior pituitary not completely understood • One of many endogenous opiods such as enkephalins

31. Regulation of ACTH secretion

32. Regulation of ACTH • Stimulation of release • CRH and ADH • Stress • Hypoglycemia • CRH and ADH both synthesized in hypothalamus • ADH is released by posertior pituitary and reaches anterior pituitary via inferior hypophyseal artery.

33. ACTH • Circadian pattern of release • Highest levels of cortisol are in early AM following ACTH release • Depends on sleep-wake cycle, jet-lag can result in alteration of pattern • Opposes the circadian pattern of growth hormone secretion

34. Regulation of ACTH

35. ACTH • Acts on adrenal cortex • stimulates growth of cortex (trophic action) • Stimulates steroid hormone synthesis • Lack of negative feedback from cortisol results in aberrantly high ACTH, elevated levels of other adrenal corticosteroids– adrenal androgens • Adrenogenital syndrome: masculization of female fetus

36. Glycoprotein hormones • LH, FSH, TSH and hCG • a and b subunits • Each subunit encoded by different gene • a subunit is identical for all hormones • b subunit are unique and provide biological specificity

37. Glycoprotein hormones Glycoprotein hormones contain two subunits, a common a subunit and a distinct b subunit: TSH, LH, FSH and hCG.

38. Gonadotrophs • Cells in anterior pituitary that produce LH and FSH • Synthesis and secretion stimulated by GnRH– major effect on LH • FSH secretion controlled by inhibin • Pulsitile secretion of GnRH and inhibin cause distinct patterns of LH and FSH secretion

39. LH/FSH • Pulsatile pattern of secretion • LH pulses are biphasic (every 1 minute, then large pulse at 1 hour) • FSH pulses are uniphasic • Diurnal– LH/FSH more pronounced during puberty • Cyclic in females– ovarian cycle with LH surge at time of ovulation • Males are not cyclic, but constant pulses of LH cause pulses of testosterone to be produced

40. Pulsitile secretion of GnRH and LH

41. Regulation of LH/FSH • Negative feed-back • Inhibin produced by testes and ovaries Decreases FSH b-subunit expression • Testosterone from Leydig cells– synthesis stimulated by LH, feedsback to inhibit GnRH production from hypothalamus and down-regulates GnRH receptors • Progesterone– suppresses ovulation, basis for oral contraceptives. Works at both the level of pituitary and hypothalamus.

42. Regulation of LH/FSH • Dopamine, endorphin, and prolactin inhibit GnRH release. • Prolactin inhibition affords post-partum contraceptive effect • Overproduction of prolactin via pituitary tumor can cause amenorrhea– shuts off GnRH • Treated with bromocryptine (dopamine agonist) • Surgical removal of pituitary tumor

43. Regulation of LH/FSH • Positive feedback • Estradiol at high plasma concentrations in late follicular phase of ovarian cycle stimulates GnRH and LH surge– triggers ovulation

44. Regulation of gonadotropin secretion

45. Thyrotrophs • Site of TSH synthesis • Pattern of secretion is relatively steady • TSH secretion stimulated by TRH • Feedback control by T3 (thyroid hormone)

46. Feedback control of thyroid function

47. Lacotrophs • Site of production of prolactin • Lactogenesis (milk synthesis) requires prolactin • Tonically inhibited • Of the anterior pituitary hormones, the only one • Multifactoral control, balance favors inhibition • Dopamine inhibits prolactin • Prolactin releasing hormone is TRH • Ocytocin also stimulates prolactin release • Estradiol enhances prolactin synthesis

48. Prolactin • Stimulates breast development and lactogenesis • May be involved in development of Leydig cells in pre-pubertal males • Immunomodulatory effects– stimulates T cell functions • Prolactin receptors in thymus

49. Posterior pituitary hormones: ADH (AVP) and Oxytocin (really hypothalamic hormones) • Both are synthesized in the cell bodies of hypothalamic neurons • ADH: supraoptic nucleus • Oxytocin: paraventricular nucleus • Both are synthesized as preprohormones and processed into nonapeptides (nine amino acids). • They are released from the termini in response to an action potential which travels from the axon body in the hypothalamus

50. Hypothalamus and posterior pituitary