THE ENDOCRINE SYSTEM

Purpose: Communication

Nature: Slow, not specific

Regulates: growth, metabolism, reproduction, autonomic functions

hormonehormone receptor

Cell A Cell B

blood

Cell A Cell B

HORMONE

PARACRINE AGENT

Cell A

AUTOCRINE AGENT

DEFINITIONS

CHEMICAL NATURE OF HORMONES

Amines: epinephrine, norepinephrine, dopamine, T3, T4

Peptides and proteins: insulin, glucagon, TSH, TRH, (many others)

Steroids: testosterone, estrogen, progesterone, cortisol, aldosterone

Amines, proteins and peptides (except T3, T4): •Water soluble•Can’t cross cell membranes•Bind to receptors on cell surface•Effects usually rapid and transient•Not effective when ingested

Steroids and T3, T4:•Not water soluble (need a carrier in blood)•Can cross cell membranes•Bind to receptors in the cytoplasm or on DNA•Act primarily by initiating gene transcription•Effects usually slow and sustained•Effective when ingested, can also be applied topically

Regulation of ThyroidHormone release

TSH causes:

•Uptake of iodine•Synthesis of thyroglobulin•Iodination of thyroglobulin•Uptake of colloid into thyroid cell•Secretion of T3/T4 from thyroid cell•Increase in the size and number of thyroid cells

Cell membrane

cytoplasm

Nuclear membrane

T3

T3

T3 receptor

gene

EFFECTS OF THYROID HORMONES

•Increased O2 consumption/metabolic rate- Increased size of mitocondria- Increased expression of respiratory enzymes- Increase Na+/K+ ATPase- Increased proteins for growth and maturation

•Increased expression of -adrenergic receptors•Required for brain development

Iodine Deficiency

IODINE REQUIREMENTS (mg/kg/day)

Infants (10-12 mo) 15Children (1-6 yr) 6School children (6-12 yr) 4Adults (12+ yr) 2Pregnant and 3.5lactating women

DIETARY SOURCES OF IODINE (ug/g)

Fish (fresh water) 17-40Fish (marine) 163-3180Shellfish 308-1300Meat 27-97Milk 35-56Eggs 93Grain 22-72Fruits 10-29Legumes 23-36Vegetables 12-201

IODINE DEFICIENCY

•Leading cause of brain damage worldwide (13% of world population)

•Another 39% at risk

•130 developing countries affected

•particularly problematic in pregnant women (iodine required for fetal development)

•even mild cases with no symptoms can result in a decrement of 15 IQ points

How do you know if someone is iodine deficient?

How do you know if someone is iodine deficient?

•Increased thyroid size•Increased serum TSH levels

Regulation of ThyroidHormone release

Insufficient dietary iodine

Inability of thyroid to make T3/T4

Reduced serum T3/T4

Less T3/T4 inhibition of anterior pituitary TSH synthesis

Increased serum TSH

Increased thyroid growth (goiter)

Increases efficiency of the thyroid for T3/T4 production

CONSEQUENCES OF IODINE DEFICIENCY

Fetus Abortions/stillbirthsCongenital abnormalitiesIncreased perinatal mortalityNeurological deficits (cretinism)Mental and growth retardationPsychomotor defects

Neonates GoiterHypothyroidism

Children GoiterHypothyroidismImpaired mental functionRetarded growth

Adults GoiterHypothyroidismImpaired mental function

A Public Health Story

Early 1900’s goiter was highly prevalent in the Great Lakesand Northwest regions of the US

1924: Michigan department of Health does survey in 4 counties.39% of children have goiter. Begins campaign for iodized salt.

1928: Same counties resurveyed. Goiter down by 75%

1951: Goiter prevalence less than 0.5%

1993: Universal Salt Iodization Program started (WHO).Global rates of goiter, cretinism and mental retardation aredeclining rapidly.

Why salt?

•Cheap (0.05 US$ per person per year)•Widely available•Consumed throughout the year

Hyperthyroidism – Grave’s Disease

• most common cause of hyperthyroidism• autoimmune disorder

– Antibodies that stimulate TSH receptor

• increased T3/T4 levels• goiter (enlargement of the thyroid)

Regulation of ThyroidHormone release

Antibodies that stimulate TSH receptor

Grave’s Disease - Symptoms

• Hypermetabolic state• Excess sympathetic nervous activity• Psychological symptoms• Overactivity of muscles retracting eyelids:

increased staring, decreased blinking• Exopthalmus (protruding eyes)• Increased gut motility (diarrhea)

Grave’s Disease - Treatment

• Destroy gland– Surgery– Radioactive Iodine

• Block T3/T4 synthesis– Thiouricil: inhibits peroxidation of thyroglobulin– Lithium (blocks TSH signal transduction

pathway)

Hypothyroidism

• inadequate production of thyroid hormone• Primary

– Ablation of thyroid by surgery/radioisotopes– Hashimoto’s thyroiditis

• Autoimmune

– idiopathic• Secondary

– Lack of TSH

Hypothyroidism – Symptoms (adult onset)

• Decreased metabolic state– Cold intolerance, fatigue, hypothermia, weight gain

• Decreased sympathetic activation– bradycardia

• Slowing of intellectual and motor activity– Forgetfulness, apathy, even dementia

• Decreased gut motility (constipation)• Myxedema

• Myxedema– Accumulation of mucopolysaccharides and

fluid in tissues– Facial puffiness– Edema– Hoarseness– Joint stiffness– Nerve compressions/parathesias– Pleural, cardiac, and peritoneal effusions

•Cretinism (lack of T3/T4 in childhood)–impaired development of skeletal, nervous system

–mental retardation

–historically, dietary; iodine supplementation eliminates

Hypothyroidism – Symptoms (childhood onset)

Disorders of growth hormone

Effects of growth hormone

•Bone growth

•Protein synthesis

•Anti-insulin effects

Results in:

•Decreased adiposity•Increased lean body mass•Increased organ size and mass•Increased plasma glucose concentrations

•Lengthening occurs at epiphyseal plates

•At puberty, epiphyseal plates close

•After puberty, bones can get wider, butnot longer

Acromegaly

•Caused by increased growth hormone secretion

•Usual cause is a tumor of the GH secreting cellsof the anterior pituitary

Alterations in GH secretion

•Oral glucose challenge usually decreases GH levels to undetectable, but not in acromegaly (used in diagnosis)

•Response to GHRH is increased

•Hypoglycemia and arginine both increase GH (same as normal)

•Somatostatin lowers GH but not to normal

Effects

• Increased bone muscle and connective tissue growth

• Increased incidence of diabetes

• Effects of tumor mass• Headaches• Vision impairment, particularly peripheral vision (optic nerve runs near the anterior pituitary)

• Effects resulting from loss of anterior pituitaryhormones due to compression of the pituitaryby tumor mass (loss of FSH and LH: amennorhea in women, impotence in men and reduced secondary sex characteristics in men)

Effects on bone and tissue mass

•Increased size of hands and feet (first sign may be increase in shoesize)•Changes in facial features

orbital ridgingunderbitecoarsening of features

•Spaces between teeth due to enlargement of mandible•Thickening of vocal cords deepens voice•Thickening of skin•Increased sweating and decreased heat tolerance•Increased size of internal organs•Increased sleep problems (obstructive sleep apnea)•Muscle weakness, pain, loss of sensation (compression of nerves bysoft tissue)•Congestive heart failure

Acromegaly - hands

Acromegaly – facial features

Acromegaly – facial features

Treatment:

•Surgery to remove tumor (replacement therapy for otherhormones may be required)

•Long acting analog of somatostatin

•GH receptor antagonist, pegvisomant

Gigantism

Etiology is the same as acromegaly, but the tumor occursbefore epiphyseal plate fusion

GH deficiency, GH insensitivity, or IGF-1 deficiency, results inDwarfism, a condition of short stature, but otherwise normaldevelopment in children

Achondroplasia: •short stature with disproportionally short arms and legsand an enlarged head•autosomal dominant defect caused by mutations in the FGFR3