Human Endocrine Human Endocrine PhysiologyPhysiology

March 13, 2014

Binding ProteinsBinding Proteins

Hormone Binding ProteinsHormone 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

GnRHGnRH

10 amino acid peptide hormone

Male Reproductive Male Reproductive Endocrinology OverviewEndocrinology Overview

Testes PhysiologyTestes Physiology

GnRH

Pituitary

Testes

LH

FSH

InhibinSperm

Testosterone

-

-

PubertyPuberty

Adrenal activationHypothalamic-pituitary-

gonadal activation

Adrenal Steroid PathwaysAdrenal Steroid Pathways

Progesterone

Pregnenolone

Cholesterol

Cortisol

17OH-Prog

17OH-Preg DHEA

Testosterone

Androstenedione

Aldosterone

ACTH

Glycoprotein family of hormones

Testes Steroid PathwaysTestes Steroid Pathways

Progesterone

Pregnenolone

Cholesterol

17OH-Prog

17OH-Preg

Testosterone

Androstenedione

LH

Stages of pubertyStages of puberty

• Thelarche (breast development)• Adrenarche or pubarche

(appearance of pubic/axillary hair)• Menarche

Adrenal Steroid PathwaysAdrenal Steroid Pathways

Progesterone

Pregnenolone

Cholesterol

Cortisol

17OH-Prog

17OH-Preg DHEA

Testosterone

Androstenedione

Aldosterone

ACTH

Adrenal Pathways:Adrenal Pathways:Pre-AdrenarchePre-Adrenarche

Progesterone

Pregnenolone

Cholesterol

Cortisol

17OH-Prog

17OH-Preg DHEA

Testosterone

Androstenedione

Aldosterone

ACTH

Adrenal Pathways:Adrenal Pathways:Post-AdrenarchePost-Adrenarche

Progesterone

Pregnenolone

Cholesterol

Cortisol

17OH-Prog

17OH-Preg DHEA

Testosterone

Androstenedione

Aldosterone

ACTH

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

LeptinLeptin

• 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)

KisspeptinKisspeptin

• 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 Mechanisms of Activation of GnRH Secretion in PubertyGnRH 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)

Granulosa Theca cells

(animals)

Granulosa Theca cells

Increased kisspeptin stimulation of GnRH secretion

(animals)

Granulosa Theca cells

Decreased sensitivity to negative feedback from sex steroids.

(animals)

Granulosa Theca cells

Decreased sensitivity to negative feedback from sex steroids.

Tanner Staging of Puberty

Abnormal PubertyAbnormal Puberty

• Onset of secondary sexual characteristics• <8yo in girls• <9yo in boys

• Delayed• Precocious

Precocious PubertyPrecocious Puberty

• Gain of function mutation in the LH receptors

• Defects in Kiss1 receptor

GrowthGrowth

Growth HormoneGrowth Hormone

Actions of GHActions 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 StimulatingFactors StimulatingGH SecretionGH Secretion

• Fasting or low glucose• Exercise• Sleep• Protein intake

The Insulin-likeThe Insulin-likeGrowth FactorsGrowth 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 rats2) Treat with an oxytocin antagonist

How IGF-1 Exerts How IGF-1 Exerts Insulin-like EffectsInsulin-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 ProteinsIGF 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 How Insulin Affects IGF-1 ActionIGF-1 Action

• Complementary actions• Can bind weakly to IGF-1 receptor• Suppresses IGFBP3 production by

the liver

Growth Hormone

IGF-1

+

-

GH Releasing Hormone (GHRH)

+

(liver)

Somatostatin-

Roles of GH and IGF-1Roles of GH and IGF-1in Growth of Bonesin Growth of Bones

+

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Growth Hormone

IGF-1

+

-

GH Releasing Hormone (GHRH)

+

(liver)

Somatostatin-

Growth Hormone

IGF-1

+

-

GH Releasing Hormone (GHRH)

+

(liver)

Somatostatin-

GrowthHormone

IGF-1+

-

GH Releasing Hormone (GHRH)

+

(somatic effects)

Somatostatin-

*Insulin-like growth factor 1

Pubertal GrowthPubertal Growth

Pubertal Growth: Effect of Pubertal Growth: Effect of Sex Steroids on GrowthSex 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.