Human Endocrine Physiology March 13, 2014

Binding Proteins

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

GnRH 10 amino acid peptide hormone

Male Reproductive Endocrinology Overview

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

Puberty Adrenal activation Hypothalamic-pituitary-gonadal activation

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

Glycoprotein family of hormones

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

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

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

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

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

Mechanisms of Activation of GnRH Secretion in Puberty Mechanisms of Activation of GnRH Secretion in Puberty

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)

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.

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.

(animals) GranulosaTheca cells

(animals) GranulosaTheca cells Increased kisspeptin stimulation of GnRH secretion

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

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

Tanner Staging of Puberty

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

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

Growth

Growth Hormone

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

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

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)

IGF-1 Similar structures of insulin and IGF-1

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

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

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.

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

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

Roles of GH and IGF-1 in Growth of Bones

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

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

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

Pubertal Growth

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.