Hypothalamus dr.

Dini Sri Damayanti,MKes

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.

Hypothalamus and pituitary

gland

Hypothalamic Nuclei
preoptic nuclei temperature, heart rate, blood pressure, bladder control

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Hypothalamic Nuclei
supraoptic nucleus antidiuretic hormone (vasopressin) paraventricular nucleus - antidiuretic hormone, oxytocin, water conservation ventromedial nucleus - satiety
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Hypothalamic Nuclei
lateral hypothalamic nucleus /area hunger, thirst, blood pressure, heart rate suprachiasmatic nucleus - circadian rhythms

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CNS Control of Autonomic Functions

ANS regulation by hypothalamus: the hypothalamus makes up 1% of brain volume but controls temperature regulation, heart rate, blood pressure, blood osmolarity, food and water intake, emotion and sex drives.

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Cardiovascular Regulation
Lateral hypothalamic nucleus excitatory cardiovascular center Posterior hypothalamic nucleus and preoptic nucleus inhibitory cardiovascular center
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Cardiovascular Control
Lateral hypothalamus increases arterial pressure, heart rate Preoptic area decreases arterial pressure, heart rate Both effects mediated through cardiovascular control centers in reticular regions of medulla and pons

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Respiratory Regulation, Urination and Defecation

Respiration Medullary centers (CO2, O2, H+ receptors in hypothalamus) Urination and defecation spinal reflexes modulated through higher centers, especially the cortex
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Appetite
Hunger
Ventromedial hypothalamic nucleus satiety center Lateral hypothalamic area hunger center Glukose reseptor

Thirst
Stimuli: cell dehydration, body fluid volume changes
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Hypothalamic Control of Food Intake

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Hypothalamic Control of Food Intake

Lesions in ventromedial hypothalamic nuclei produce voracious appetite (and rage) and obesity. the ventromedial nucleus is believed to be the satiety center.

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Hypothalamic Control of Food Intake

Lesions to the lateral hypothalamic area abolishes the urge to eat (loss of appetite) resulting in anorexia. This area is thought to be the hunger center. Therefore, stimulation of the ventromedial hypothalamic nucleus produces satiety and stimulation of the lateral hypothalamic area produces hunger.
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Appetite
Thirst Receptors: osmoreceptors, stretch receptors Roles of ADH, renin/angiotensin

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Hypotalamic Posterior Hormone

antidiuretic hormone (ADH), oxytocin
neurohormones synthesized by neurons in the supraoptic and paraventricular nuclei

ADH
Antidiuretic action: increases permeability of the collecting ducts to water V2 receptor Vasopressor action: - constricts vascular smooth muscle cells - V1 receptors

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Thirst

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Water Balance and Drinking

Water deprivation
Cell dehydration (intracellular volume decrease, e.g., fluid deprivation or by hypertonic saline solutions) Increase in hypothalamic cell dehydration receptor activity (osmoreceptors) Increase in supraoptic nucleus activity Increase in ADH release from posterior pituitary Water reabsorption by kidney
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Water Balance and Drinking

Or increase in thirst center activity Increase in water intake

Body fluids (extracellular volume) decrease, e.g., decrease in volume

Cardiopulmonary stretch receptor activity (low pressure side, e.g., atria, great veins, pulmonary vessels)

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Water Balance and Drinking

Increase in sympathetic activity (vasoconstriction) Increase in renin release by kidney Increased production of angiotensin II Vasoconstriction and decreased excretion of salt and water by kidney Angiotensin II also acts on supraoptic nucleus of hypothalamus (ADH) and thirst center Result increased arterial pressure and fluid volume
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Water Balance and Drinking

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Temperature
Anterior hypothalamus prevents temperature rise (panting, sweating, vasodilation) site of vascular temperature receptors Posterior hypothalamus prevents temperature loss glucose oxidation, vasoconstriction, piloerection, shivering Hypothalamic thermostat affected by aspirin, alcohol, interleukins

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Temperature Regulation

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Temperature Regulation

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Summary of Temperature Regulation

Skin temperature skin thermoreceptors (cold and warm receptors) Blood temperature preoptic hypothalamic thermoreceptors Voluntary responses (cortex) Unconscious responses (anterior hypothalamic temperature regulating center)

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Temperature Regulation cont.

Cold?
heat production: shivering and exercise (muscle work), epinephrine (adrenal medulla), thyroid hormone heat conservation: cutaneous vasoconstriction, behavior changes (curl up, seek heat, piloerection)

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Temperature Regulation cont.

Hot?
heat loss: body surface radiation, conduction and evaporation cutaneous vasodilation, sweating behavior seek shade, reduce muscle activity

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Sleep, Waking, Circadian Rhythm

The suprachiasmatic nucleus is thought to be the primary biological clock in mammals. It works in conjunction with the reticular activating system, and other brain stem nuclei

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Emotional Behavior
Lesions in the ventromedial hypothalamic nuclei produce savage and vicious behavior, indicative of extreme rage. Stimulation of the dorsomedial nuclei also produces this reaction
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Sexual Stages
Excitement (CNS, PSNS) Plateau Orgasm (SNS) Resolution

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Nervous-Immune System Interactions

Nervous system can influence immune responses Immune system can alter nerve cell activity, acting as a sensory system Nervous system originally thought to have privileged immune status now known that glial and other cells can perform immune functions

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Nervous System Effects on Immune Function

Immune system suppression by stress Via hypothalamo-pituitary-adrenal axis CRF release Rats can be conditioned to suppress immune responses ANS/SNS innervates immune tissues: spleen, lymph nodes, intestinal Peyers patches, bone marrow Immune cells have receptors for neurotransmitters Different CNS lesions can decrease or increase immune functions
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 Immunotransmitters (cytokines etc.) produce changes in neuron firing Interleukin 1 acts on the hypothalamus to reset body thermostat and produce fever during infection Activated lymphocytes can produce various classical neurotransmitters

Immune System Effects on Neural Function

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Autoimmune Neural Diseases

Myasthenia gravis antibodies against skeletal muscle nicotinic ACh receptors Multiple sclerosis antibodies against myelin Asthma chronic inflammatory disease Arthritis inflammatory joint disease

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OXITOCIN
Function : contracts the myoepithelial cells of the alveoli in late pregnancy, uterine smooth muscle - (myometrium) becomes sensitive to oxytocin

Growth Hormone
Dr. Dini Sri Damayanti,MKes

 Figure 18.1 The Endocrine System

Endocrine regulation in growth

What is Growth?

Growth is an increase in size of a tissue/organism due to - increase in cell size (hypertrophy) - increase in number of cells (hyperplasia) - increase in extracellular matrix around cells
hypertrophy

hyperplasia

Hormones and Growth

A number of hormones influence growth of specific target tissues: - FSH; ovary - ACTH; adrenal - estrogen; breast, uterus - TSH; thyroid - testosterone; prostate gland.

Growth Hormone (GH; Somatotropin)

The major hormone regulating growth in the body is growth hormone (GH; somatotropin). Actions of Growth Hormone: - increases skeletal growth - increases muscular growth - increases amino acid uptake and protein synthesis - increased use of lipids for energy - decreased storage of carbohydrates

Structure and Source of Growth Hormone GH is a large peptide hormone, with 191 amino acids GH is produced by somatotroph cells of the anterior pituitary

Regulation of GH Levels
GH is released from the pituitary in a pulsatile manner:
hormone level

time

GH levels are low during the day, but increase during sleep. There is an overall increase in GH levels during puberty.

Control of GH Release (cont)

GH release is stimulated by deep (nonREM) sleep, but is inhibited during REM sleep. GH release is also stimulated by stress and exercise. GH release is inhibited by elevated glucose, and stimulated by high levels of certain amino acids (arginine).

Phases of Sleep: REM versus NonREM

Characteristics Eye movements Brain activity Muscle activity Vital signs REM Sleep State NREM Sleep State REM, closed lids Lacks REM Active (dreaming) Resting phase Bursts of twitching Diminished Active, irregular Decreased

Control of GH Release (cont)

Perhaps the major regulation is achieved by negative feedback by GH and somatomedins (IGFs) at the pituitary and hypothalamic levels. Increased GH or IGF levels result in inhibition of GHRH and stimulation of somatostatin release. Net result: inhibition of GH levels.

Growth Hormone Receptor

Growth hormone binds to a receptor that is closely associated with an intracellular tyrosine kinase (JAK-2).

JAK-2

Growth Hormone Receptor

Binding of GH to the receptor results in phosphorylation of various substrates within the cell, resulting in a biological response. This triggers a number of pathways: - Insulin responsive substrates, MAP kinase - phospholipase C/IP3/PKC

Transport of GH in the Blood

About 50% of GH is found in the blood bound to a Growth Hormone-Binding Protein (GHBP). GHBP increases the half-life of GH, but decreases biological activity (bound GH is not biologically available). The GHBP is identical to the ligand binding domain of the GH receptor, and may be derived from alternative splicing of the GH receptor RNA.

Relationship between GH Receptor and GH Binding Protein

extracellular ligand-binding region

associated tyrosine kinase

growth hormone binding protein

growth hormone receptor

Metabolic effect of GH
Increased rate of protein synthesis in all body cells Increased mobilization and use of fatty acids from adipose tissue for energy Decreased rate of glucose utilization throughout the body (i.e. enhances body protein, uses up fat stores and conserves CHO)

Direct Actions of GH
GH appears to act directly on cells to cause Lipolysis (breakdown of stored fat into free fatty acids) Glycogenolysis (breakdown of glycogen to form glucose)

Therefore, it makes sense that increased glucose levels will inhibit GH release.

Role of Somatomedins in GH Actions

The effects of GH on skeletal and muscular growth appear to be due to the activity of somatomedins, or insulin-like growth factors (IGF-1 and IGF-2). GH acts on the liver, and some other tissues, to increase the production of IGFs. IGFs then enter the circulation and act on target tissues to enhance growth.

IGF Receptors
IGFs bind to specific receptors (type-I IGF receptor and the insulin receptor) to stimulate growth. The type-I IGF receptor is similar to the insulin receptor, with intrinsic tyrosine kinase activity. Binding of IGFs to their receptors results in phosphorylation of insulin-responsive substrates (IRSs), which stimulate tissue growth and differentiation.
extracellular domains (ligand binding) plasma membrane tyrosine kinase domains growth & differentiation

phosphorylation of IRSs

Some Observations in Knockout Mice: IGF-II

Gene knockout experiments can create mice which lack expression of certain genes. Knockout of IGF-II gene results in slower fetal development, with low birth weights. However, after birth these mice grow at normal rates. This finding suggests that IGF-II is an important fetal growth factor, with unclear role in growth after birth.

Some Observations in Knockout Mice: IGF-I

Knockout of the IGF-I gene also results in slow fetal development and low birth weights. However, these mice also display marked lack of growth after birth as well. Thus, IGF-I is important for growth at all stages of development (before and after birth).

Some Observations in Knockout Mice: GH

Knockout of the GH gene results in normal fetal growth, and normal birthweight. However, after birth, growth is impaired. Together these results indicate that IGF-I and IGF-II are NOT regulated by GH during fetal development.

Roles of IGF Binding Proteins

IGFs bind to several (at least ten) IGF binding proteins (IGFBPs). Several possible actions of IGFBPs have been proposed. Some IGFBPs are believed to inhibit the action of IGFs by binding them and making them less biologically available:

IGF IGFBP

Roles of IGF Binding Proteins

Some IGFBPs may also enhance IGF action (possibly by delivering IGFs to the cell, or increasing half-life), resulting in increased stimulation of the IGF receptor. Also, IGFBPs may act independently of IGFs. Specific IGFBP receptors have been observed on cell membranes. Thus, regulating the expression of IGFBPs influences IGF activity.

IGFBP Proteases
The activity of IGFBPs is also regulated by proteases which degrade IGFBPs. By regulating IGFBPs, these proteases may be important regulators of IGF bioactivity and bioavailability. Specific proteases have been identified for most IGFBPs.
IGFBP protease IGF

IGFBP

Example: Prostate-Specific Antigen

Prostate cancer: hyperplasia of prostate cells Normally, the action of IGF-I on prostate cells is inhibited by binding to IGFBP3. Patients with prostate cancer have elevated levels of prostate-specific antigen (PSA), which is a protease for IFGBP3. Increased protease levels may result in increased mitogenic effect of IGF on prostate cells.

PSA

IGF

IGFBP3

Other Factors Regulating Growth

Recall that estrogen and androgens stimulate skeletal and muscular growth. -estrogens (and androgens) act on and maintain bone, inhibit osteoclast activity -androgens act on muscle, increasing size -estrogens and androgens also stimulate GH release

Other Factors Regulating Growth

vitamin D and PTH were involved in regulation of bone growth. Also recall that thyroid hormone is required for GH synthesis and action: - TRE on GH gene (effects synthesis of GH) - T3 induces GH receptor expression

Genetic Factors: Inheritance of Height

The genetic factors responsible for the inheritance of height are largely unknown. Identical twins show a high correlation for height (0.9), but not for weight (0.2)

Effects of Nutrition
There is also an interaction between genetic factors and nutrition. Adequate intake of nutrients (ie, vitamins and minerals) and calories is required to reach full growth potential, especially during childhood. Recall that arginine (an amino acid) stimulates GH release.
food
vitamins, minerals, calories from lipids, carbohydrates, and proteins

growth

GH

Other Growth Factors: Fibroblast Growth Factor (FGF)

Several forms of FGFs exist FGFs act as local regulators of growth and differentiation (autocrine/paracrine function). A number of FGF receptors have been identified. FGFs stimulate the development of organs and of bone.

Epidermal Growth Factor (EGF)

EGF is named after its stimulatory effect on skin cell proliferation. EGF appears to play a role in development and growth. EGF acts through the intrinsic tyrosine kinase activity of its receptor. Interestingly, knockout of EGF has little effect on growth.

Nerve Growth Factor (NGF)

NGF appears to be important in survival of neurons, and in the innervation of target tissues. Acts through a tyrosine kinase activity. Also, NGF acts as a IGFBP-3 protease, increasing the influence of IGFs on nerve cells. May be important in recovery from damage to nervous tissue.

Inhibitory Growth Factors

Transforming growth factor alpha (TGFa): local factor which can act to both stimulate cell growth as well as inhibiting cell growth, depending upon the situation. Tumor Necrosis Factor (TNF): Inhibits growth of tumor and other cells by initiating programmed cell death.

Hormone - Stress
Stress = any condition that threatens homeostasis GAS (General Adaptation Syndrome) is our bodies response to stress-causing factors Three phases to GAS
Alarm phase (immediate, fight or flight, directed by the sympathetic nervous system) Resistance phase (dominated by glucocorticoids) Exhaustion phase (breakdown of homeostatic regulation and failure of one or more organ systems)

Growth hormone disorders

Excess GH
Pre-puberty: gigantism
bone growth, > 7 ft. tall

Post-puberty: acromegaly
Some tissues still grow: cartilage in nose, hands, feet, ridges of eyebrow, chin, tongue Metabolic effects: constant increase in blood sugar, increased insulin type 2 diabetes. Can also increase muscle narrowing of arteries, heart attack

Pituitary Dwarfism
Due to lack of GH release from the pituitary, or lack of GH receptor expression (or other deficits.) Results in delayed growth and short stature (below 5 ft) in adult. Body development is proportional.

DISORDERS OF GROWTH AND DEVELOPMENT

Skeletal Maturation and Somatic Growth: The growth plate is dependent on a variety of hormonal stimuli including GH, IGF-I, sex steroids, thyroid hormones, paracrine growth factors. The growth-promoting process also requires caloric energy, amino acids, vitamins and trace metals and consumers about 10% of normal energy production. Bone age: is delayed because of GH deficiency, hypogonadism, thyroid hormone deficiency and elevated pubertal sex steroid levels.

GH deficiency in children
GH deficiency isolated GH deficiency is characterized by
short stature, micropenis, increased fat, high-pitched voice.

GHRH receptor mutations recessive mutations of the

GHRH receptor gene in subjects with severe proportionate dwarfism are associated with low basal GH levels that cant be stimulated by exogenous GHRH, GHRP or insulin-induced hypoglycemia.

 Growth hormone insensitivity: This is caused by defects of GH receptor structure or

signaling. homozygous or heterozygous mutations of the GH receptor are associated with partial or complete GH insensitivity and growth failure (laron syndrome) this diagnosis is based on normal or high GH levels

Nutritional short stature: Caloric deprivation and malnutrition, uncontrolled

diabetes and chronic renal failure represent secondary causes of GH receptor function. Children with these conditions typically exhibit features of acquired short stature with elevated GH and low IGFI levels. Circulating GH receptor antibodies may rarely cause peripheral GH insensitivity.

 Psychosocial short stature: Emotional and social deprivation lead to

growth retardation accompanied by delayed speech, discordant hyperphagia and attenuated response to administered GH.

Presentation and diagnosis

Short stature should be comprehensively evaluated if a patients height is <3SD below the mean for age or if the growth rate has decelerated. Skeletal maturation is best evaluated by measuring a radiological bone age, which is based mainly on the degree of growth plate fusion.

Laboratory investigation
GH deficiency is best assessed by examining the response to provocative stimuli including exercise, insulin-induced hypoglycemia and other pharmacologic tests which normally increase GH to<7g/L in children.

Adult GH deficiency (AGHD)

This disorder is usually caused by hypothalamic or pituitary somatotrope damage. Acquired pituitary hormone deficiency follows a typical sequential pattern whereby loss of adequate GH reverse foreshadows subsequent hormone deficits. The sequential order of hormone loss is usually GH FSH/LH TSH ACTH

Presentation and Diagnosis

The clinical features of AGHD include changes in body composition, lipid metabolism and quality of life and cardiovascular dysfunction.
Impaired quality of life: decreased energy and drive, poor
concentration, low self-esteem, social isolation.

Body composition changes: increased body fat mass,

central fat deposition, increased waist-hip ratio, decreased lean body mass

 Reduced exercise capacity Cardiovascular risk factors: Impaired cardiac structure and function, abnormal lipid
profile, decreased fibrinolytic activity, atherosclerosis, omental abesity.

Laboratory investigation
Testing should be restricted to patients with the following predisposing factors: 1. Pituitary surgery 2. Pituitary or hypothalamic tumor or granulomas 3. Cranial irradiation 4. Radiological evidence of a pituitary lesion 5. Childhood requirement for GH replacement therapy

Treatment
In children: With growth hormone deficiency, the usual dose in the U.K is0.5to0.7 units\Kg body-weight, or 12to20 units\m2 bodysurface weekly. This weekly dose may be given by intramuscular injection in 3 divided doses or by subcutaneous injection, usually in6or7 divided doses. In adults: With growth hormone deficiency lower doses are recommended. A suggested initial dose is0.125 units\Kg weekly, divided into daily subcutaneous injection, and increased according to requirements up to a max. of 0.25 units\Kg per week.