Carnegie 3

Anabolic hormone major targets

Bones and skeletal muscle

Increased protein synthesis in bone and muscle to allow for what?

increased length of long bones and increased muscle tissue mass

Hyperplasia

increased cell number

Hypertrophy

increased cell size

Increased use of fats for fuel, thereby conserving glucose; hence, anabolic, but some effects are ______

anti-insulin

Conserving glucose essential for what?

CNS

Anti-insulin

Take glucose and store glycogen (keep glucose in circulatory system)

Somatomedins

Mediates growth-promoting effects of GH

IGF-1

key somatomedin whose production by the liver is stimulated by GH

Control of GH (and IGF-1) secretion

Stimulus (Exercise, stress, fasting, low plasma glucose, sleep) → Hypothalamus (increased GHRH and/or decreased SS secretion) → increased Plasma GHRH and/or decreased Plasma SS (in hypothalamo-pituitary portal vessels) → Anterior pituitary (increased GH secretion) → increased Plasma GH → Liver and other cells (increased IGF-1 secretion) → increased plasma IGF-1

GNRH (+) and SST (-) → GH (+)→ IGF-1 → (+)SST and (-) GHRH

GH important during childhood & adolescence for normal growth, but also important in adult life for __________; shown by rare instances in which there is hyposecretion of GH → signs of _______

maintenance, premature aging

Other factors that can influence growth include

• Genetics (parents height)

• Adequate diet (protein is especially important)

• Freedom from chronic disease and ongoing stress (these would promote increased cortisol release and cortisol promotes protein catabolism, inhibits GH secretion, reduces growth of long bones)

• Normal levels of other hormones that can influence growth (thyroid hormone, insulin, estrogen & testosterone [during puberty])

Cortisol inhibits what?

GH

Other hormones important for postnatal growth

• insulin and thyroid hormone: especially important during prenatal development (insulin receptor not that different from receptor for IGF-1)

• testosterone & estradiol: puberty- associated growth spurts

• cortisol is inhibitory

Pituitary dwarfism

Hyposecretion of GH (childhood)

Laron dwarfism

Abnormal GH receptors (GH levels will actually be high, but no IGF-1)

Gigantism

Hypersecretion of GH (childhood)

Acromegaly

Hypersecretion of GH (adults)

2 products of thyroid gland

thyroxine (T4) & triiodothyronine (T3)

Thyroglobulin

tyrosine-rich protein precursor protein to T4 and T3

Thyroglobulin stored where

in thyroid follicles surrounded by follicular cells

Colloid

gel-like emulsion

C-cells produce one

Calcitonin

Calcitonin

peptide hormone involved in regulation of blood calcium

T4

• primary hormone secreted from thyroid

• less active

• 2 DIT

T3

• most active thyroid hormone

• binds at higher affinity to receptor due to lack of one iodine

• MIT and DIT

Target cells of thyroid hormones contain what? what does it do?

• Deiodinases

  • removes iodine (T4 → T3 before entering nucleus

Synthesis of Thyroid Hormone

1. 6 interrelated processes in response to secretion of TSH by ant. pituitary

2. Formation & storage of thyroglobulin (follicle lumens)

3. Iodide trapping in follicular cells: against > 30-fold concentration gradient – secondary active transport of iodide (I-) into cells where it is oxidized to form iodine (I0; highly reactive) by thyroperoxidase (TPO)

4. Iodination of tyrosines in thyroglobulin: occurs at apical follicle cell- colloid junction (TPO is membrane-bound) → monoiodotyrosine (MIT) & diiodotyrosine (DIT)

5. Coupling of MIT & DIT: T4 = 2 DITs; T3 = 1 MIT + 1 DIT; this occurs while MIT & DIT are still part of the thyroglobulin molecule

6. Colloid endocytosis: iodinated thyroglobulin molecules taken back into follicular cells by endocytosis; vesicles linked with lysosomes

7. Cleavage of thyroglobulin to yield hormones for release: lipid- soluble so easily diffuse out of follicle cells into bloodstream; primarily T4 (where do we get T3?)

Regulation of thyroid hormone secretion

• typical 3-tiered system of regulation by the hypothalamic-pituitary axis

• negative feedback maintains setpoint

stress (-) or cold in infants (+) → hypothalamus → thyrotropin-releasing hormone (+) → anterior pituatary → Thyroid-stimulating hormone (+) → thyroid gland → thyroid hormone → increased metabolic rate and heat production; enhancement of growth and CNS development; enhancement of sympathetic activity

TSH

a glycoprotein – one alpha + one beta subunit

TSH stimulates

• secretion of T4 & T3

• follicular cell protein synthesis

• hypertrophy of follicular cells

• goiter

Goiter

enlargement of thyroid (makes more colloid)

How is TH transported?

• less than 1% is in free form – 99% is bound

• interaction with TBG prevents loss of TH via kidney

• T4 binds more tightly than T3

• T3 is more readily broken down

Half-lives of thyroid-related hormones (TSH and T4 and T3)

TSH: ~60 min

T4: 4-7 days

T3: 1.5 days

Binding protein transport

TBG- 2/3

TBPA- 1/3

Albumin- Whats left

TH activates what?

Transcription of a variety of genes associated with growth, development, and the use of food nutrients for ATP production

TH receptors are ________ in the body

widespread

TH effects kick in _________, but are _________

slowly (several hours to days)

long-lasting

METABOLIC RATE, INTERMEDIARY METABOLISM & HEAT PRODUCTION

• Increases oxygen consumption and energy expenditure under resting conditions (BMR); stimulates mobilization of fats to support that increase

• Increased metabolic activity means increased heat production – known as the calorigenic effect of TH

• Influences rates of synthesis and degradation of carbs and proteins; direction of effect depends on TH levels:

  • lower levels stimulate synthesis

  • higher levels stimulate degradation

SYMPATHOMIMETIC EFFECT & THE CARDIOVASCULAR SYSTEM

• Up-regulates beta-adrenergic receptors, esp. in heart & nervous system – this is a permissive action of TH wrt catecholamines – increased TH can cause individuals with normal catecholamine levels to display signs of excessive sympathetic nervous system activity

  • anxiety and nervousness

  • racing heart

GROWTH & DEVELOPMENT OF NERVOUS & MSK SYSTEMS

• TH needed for normal production of GH and also IGF-1 by liver

• TH critical for normal development of nervous system in fetus (formation of axonal terminals, dendrites, myelin sheathes, synapses)

• TH supports muscle growth (protein synthesis) and proper muscle functioning (calcium uptake by SR, increased max shortening velocity)

• TH needed in adult life needed for proper nerve/muscle reflexes & normal cognition

What is congenital iodine deficiency syndrome? Is this still a concern today, despite iodized salt?

mom cant make enough TH during pregnancy

Pregnancy (and especially in other species, prolonged exposure to cold) stimulate secretion of what? which does what?

TRH → overrides negative feedback effect of thyroid hormone

Hypothyroidism in adults

Causes: autoimmune thyroiditis (e.g. Hashimoto’s disease), deficits in TSH or TRH secretion, inadequate intake of dietary iodine, thyroidectomy

Symptoms: low BMR, feel chilled, constipation, thick & dry skin, puffy eyes, edema (TSH stimulates fibroblast synthesis of glycosaminoglycans in CT), lethargy & mental sluggishness

Result: Goiter (follicle cells continue to produce thyroglobulin but cannot iodinate it; TSH continues to stimulate gland; goiter is reversible with iodine supplementation)

Treatment: give iodine or TSH/T4 supplements, depending on cause of disease

Hypothyroidism in fetus/infant

Congenital Iodine Deficiency Syndrome

Causes: can be due to genetic deficiency in fetal thyroid gland or inadequate intake of iodine by mother during pregnancy

Symptoms: thyroid hormones essential for development of nervous and skeletal systems; if lacking, don’t get proper body growth or development of CNS

Result: affected individuals are short, body is disproportionate & there are levels of intellectual disability

Treatment: during childhood, TH essential for myelination of axons, dendritic arborization and formation of synapses

Hyperthyroidism

most common & puzzling form is Grave’s Disease (autoimmune disease)

Causes: patient has developed antibodies that mimic TSH (LATS = long-acting thyroid stimulator) - bind to follicle cells & continuously stimulate output of thyroid hormones

Symptoms: elevated BMR, sweating, rapid & irregular heartbeat, nervousness, weight loss, exophthalmos (accumulation of fatty tissue, fluid and inflammation behind the orbit)

Result: exophthalmos (protruding eyes), goiter

Treatment: removal of thyroid (take T4 for the rest of life) or ingestion of radioactive iodine

Major function of HYPOTHYROIDISM

• Mentally & physically sluggish

• Cold sensitive (intolerant)

• Decreased appetite

• Decreased O2 consumption

• Reduced CO

• Myxedema (deposition of mucopolysaccharides [e.g. hyaluronic acid] in skin; their synthesis by fibroblasts enhanced by

• TSH

• dry, course, sparse hair

• lateral eyebrows thin

• periorbital edema

• puffy dull face with dry skin

Major function of HYPERTHYROIDISM

• Restless, mentally quick & wakeful

• Heat sensitive (intolerant)

• Increased appetite (and/or weight loss)

• Increased O2 consumption

• Increased CO (can be dangerous)

• Bulging eyes (exophthalmos)

• anxiety

• insomnia

• eyelid retraction

• diarrhea

• excessive sweating

• hand tremors

• weight loss

• goiter