1. Human Endocrine Physiology March 13, 2014

2. Binding Proteins

3. Hormone Binding Proteins Usually produced by the liver Reversibly bind hormones Provide a pool of hormone in the circulation protected from metabolism Buffer changes in circulating free hormone levels: T4 + TBG ↔ T4TBG

5. GnRH 10 amino acid peptide hormone

13. Male Reproductive Endocrinology Overview

14. Testes Physiology GnRH Pituitary Testes LH FSH Inhibin Sperm Testosterone - -

18. Puberty Adrenal activation Hypothalamic-pituitary-gonadal activation

19. Adrenal Steroid Pathways Progesterone Pregnenolone Cholesterol Cortisol 17OH-Prog 17OH-PregDHEA Testosterone Androstenedione Aldosterone ACTH

21. Glycoprotein family of hormones

22. Testes Steroid Pathways Progesterone Pregnenolone Cholesterol 17OH-Prog 17OH-Preg Testosterone Androstenedione LH

25. Stages of puberty Stages of puberty Thelarche (breast development) Adrenarche or pubarche (appearance of pubic/axillary hair) Menarche

26. Adrenal Steroid Pathways Progesterone Pregnenolone Cholesterol Cortisol 17OH-Prog 17OH-PregDHEA Testosterone Androstenedione Aldosterone ACTH

27. Adrenal Pathways: Pre-Adrenarche Progesterone Pregnenolone Cholesterol Cortisol 17OH-Prog 17OH-Preg DHEA Testosterone Androstenedione Aldosterone ACTH

28. Adrenal Pathways: Post-Adrenarche Progesterone Pregnenolone Cholesterol Cortisol 17OH-Prog 17OH-PregDHEA Testosterone Androstenedione Aldosterone ACTH

30. Mechanisms of Activation of GnRH Secretion in Puberty Mechanisms of Activation of GnRH Secretion in Puberty

31. Leptin Leptin Peptide hormone produced by adipocytes Multiple sites of action. Reproductive axis. More fat mass; more leptin More leptin; more GnRH secretion (within normal limits of weight)

33. Kisspeptin Kisspeptin Peptide hormone produced at various sites within the hypothalamus Discovered in 1996 by cancer researchers at Penn State Hershey and named “metastin”. In 2003, found to have a major role in controlling GnRH secretion; renamed “kisspeptin”. Has receptors on GnRH neurons. Stimulates GnRH secretion.

34. Mechanisms of Activation of GnRH Secretion in Puberty Mechanisms of Activation of GnRH Secretion in Puberty Increased GnRH secretion. Via kisspeptin Probable + effect of leptin on kisspeptin Decreased sensitivity of the hypothalamus and pituitary to neg feedback from sex steroids.

35. (animals) GranulosaTheca cells

36. (animals) GranulosaTheca cells Increased kisspeptin stimulation of GnRH secretion

37. (animals) GranulosaTheca cells Decreased sensitivity to negative feedback from sex steroids.

40. (animals) GranulosaTheca cells Decreased sensitivity to negative feedback from sex steroids.

41. Tanner Staging of Puberty

43. Abnormal Puberty Onset of secondary sexual characteristics <8yo in girls <9yo in boys Delayed Precocious

44. Precocious Puberty Gain of function mutation in the LH receptors Defects in Kiss1 receptor

45. Growth

46. Growth Hormone

47. Actions of GH Protects against protein during calorie deprivation Block proteolysis Promotes use of fat as a source of energy to spare amino acids for protein synthesis Promotes glucose genesis Stimulates the liver to produce IGF-1 Growth actions are generally mediated through IGF-1

48. Factors Stimulating GH Secretion Fasting or low glucose Exercise Sleep Protein intake

49. The Insulin-like Growth Factors IFG-1: Responsible for anabolic actions of GH. ↑ DNA, RNA and protein synthesis ↑ Bone growth IGF-2: Role is during fetal growth (later section)

50. IGF-1 Similar structures of insulin and IGF-1

51. Experiments: 1)Inject oxytocin into ventricles of nonpregnant rats 2)Treat with an oxytocin antagonist

52. How IGF-1 Exerts Insulin-like Effects Actions through its own receptor Binds weakly to the insulin receptors When bound to IGF-1, the IGF-1 receptor can activate the insulin receptor

53. IGF Binding Proteins Six IGFBPs IGFBP-3 is the most important systemically Generally oppose IGF action Bind IGF Bind IGFBP-3 receptors that mediate actions in opposition to IGF-1 actions.

54. How Insulin Affects IGF-1 Action Complementary actions Can bind weakly to IGF-1 receptor Suppresses IGFBP3 production by the liver

55. Growth Hormone IGF-1 + - GH Releasing Hormone (GHRH) + (liver) Somatostatin -

59. Roles of GH and IGF-1 in Growth of Bones

61. +

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63. Growth Hormone IGF-1 + - GH Releasing Hormone (GHRH) + (liver) Somatostatin -

65. Growth Hormone IGF-1 + - GH Releasing Hormone (GHRH) + (liver) Somatostatin -

67. Growth Hormone IGF-1 + - GH Releasing Hormone (GHRH) + (somatic effects) Somatostatin - *Insulin-like growth factor 1

68. Pubertal Growth

70. Pubertal Growth: Effect of Sex Steroids on Growth Estrogen ↑ ’s GH secretion Intensifies growth at the bone’s epiphyses resulting in: rapid lengthening of the long bones closure of the epiphyses and cessation of growth. Testosterone acts indirectly by being converted to estrogen in the bone and pituitary.