Endocrinology Flashcards
Overview
o Intercellular communication by chemical messengers may occur by several methods: o Neural: neurotransmitters are released at synaptic cleft and act locally o Endocrine: Hormones reach the systemic circulation and influence cells some distance away (Ex. thyroid, estrogen, testosterone etc.) o Neuroendocrine: secretion from neurons reach the blood stream and influence cells some distance away (ex. ADH, epinephrine) o Paracrine: secretions from one cell type diffuse into EFC and affect neighboring cells (ex. histamine released by mast cells in the stomach area influence gastric parietal cells to increase H+ production)
Classification of Hormones according to Chemical Structure
- Proteins and peptides – 2 to 200 amino acids in length (ex. TRH, GH) - Steroids – derived from cholesterol (ex. cortisol, aldosterone, testosterone etc.) - Derivatives of the amino acid tyrosine – Epi, Norepi, thyroxine
Control of Hormone Secretion
- Control of secretion is usually by negative feedback: increased functioning of target cell results in negative feedback to the endocrine gland, resulting in a decrease rate of release of hormone - Occasionally by positive feedback: ex. Dilatation of cervix in labor stimulates the posterior pituitary to secrete oxytocin which stimulates further dilation of cervix
Mediators of Hormone Response
- Receptors on the cell surface often mediate a response to a hormone. They are usually, but not exclusively by G – protein coupling (ex. cAMP, cGMP, phospholipase C, Ca++, calmodulin) which serve to amplify hormone signal - Steroid hormones act by entering the cell and binding to intracellular receptors, which activates a specific gene, causing transcription, translation of proteins – much slower in action than cell surface receptors. (ex. treating someone with epinephrine has an immediate effect, while it will take hours to see the effect of treating an individual with prednisone for poison oak)
Laboratory Measurements
- Very small quantities make measurement challenging - Typically by Radioimmunoassay – bound/free ratio in a known solution - Lab technology generally measure immunologic amounts, not biologic activity - Expensive
Pituitary Gland and the Hypothalamus
o The pituitary is composed of 2 distinct components o Anterior pituitary (adenohypophysis) – derived from embryonic cells from the oral cavity (Rathke’s pouch) o Posterior Pituitary (neurohypophysis) – formed by down growth of cell axons from 3rd ventricle o Secretions from the pituitary are controlled by the hypothalamus
The Posterior Pituitary
Secretes two hormones o Antidiuretic hormone - ADH o Oxytocin - The neuron cell bodies which produce ADH and oxytocin are located in supra optic and paraventricular nuclei of the hypothalamus and the axons of these nerves make up the posterior pituitary; the neuropeptides produced by the posterior pituitary are secreted directly from the neurons into the systemic circulation
The Anterior Pituitary
Secretes 6 hormones o TSH – thyroid stimulating hormone o FSH – follicle stimulating hormone o LH - luteinizing hormone o GH – growth hormone o ACTH – adrenocorticotrophic hormone o Prolactin
The Anterior Pituitary
- The hypothalamus controls the cells of the anterior pituitary by so called “releasing hormones” which either stimulate or inhibit the production and release from the anterior pituitary cells of the 6 anterior pituitary hormones - The anterior pituitary is linked to hypothalamus by the hypothalamic – hypophysial portal blood vessels, which supplies the majority of the blood supply to the anterior pituitary - Arterial blood to hypothalamus delivers blood to: -> Capillary network in hypothalamus, which delivers blood to: -> Hypophysial portal vessels, which delivers blood to: -> Anterior pituitary
The Anterior Pituitary
Hypothalamic blood delivers “hypothalamic releasing hormones” to the anterior pituitary in very high concentrations (compared to levels occurring in the systemic circulation) Example: - Thyroid releasing hormone (TRH) is produced by hypothalamus o TRH enters hypothalamic – hypophysial portal system • TRH is delivered to anterior pituitary • Anterior pituitary thyroid cells (trophs) are stimulated to produce and release into the systemic circulation Thyroid stimulating hormone (aka. TSH, thyrotropin) o TSH acts on its target cells
Posterior Pituitary Hormones 1 of 2
Antidiuretic Hormone - aka. ADH; Vasopressin, Desmopressin (DDAVP, a synthetic hormone form) o Action: • Regulates osmolarity of body fluids by altering renal excretion of water • Acts on Principle Cells of distal renal tubules and collecting ducts to increase H20 re-absorption o Osmoreceptors in the hypothalamus are very sensitive to blood osmolarity. Stimulations of these receptors results in the posterior pituitary release of ADH o Baroreceptors in the left atrium, aortic arch, and carotid artery sense hypovolemia / hypervolemia signaling the hypothalamus via the vagus nerve to decrease or increase secretion of ADH o Other stimulants of ADH release: • Pain, nausea, hypoglycemia, certain drugs o Inhibitors of ADH release: • ETOH, ANP (atrial natriuretic peptide) etc.
Antidiuretic Hormone - Pathophysiology
Abnormalities of ADH secretion: o Diabetes insipidus (aka. D.I.) - Central DI - Nephrogenic DI o SIADH (syndrome of inappropriate ADH secretion) - Characterized by a decrease plasma osmolarity, decreased serum Na+ (Total body Na+ is normal; too much total body free water) - Associated with Oat cell CA of the lung and many other conditions
Posterior Pituitary Hormones 2 of 2
Oxytocin (aka. Pitocin and Syntocinon) - Actions: o Uterine contraction, helps in parturition o “Let down of milk” (milk moves from production areas to traveling down the ductal system) o Milk ejection - Secretion stimulated by: o Suckling of breast; stimulation of nipple o Conditioned response to sight, sound, smell of infant o Secreted in response to cervical dilation during labor and during orgasm - Clinically useful in: o Induction / and maintenance of labor of (originally administered as a nasal spray, today by IV administration) o Reduction of postpartum bleeding (uterus “clamps down” on bleeding vessels) o ? Potential psychiatric treatment – makes people more trusting? There is resurgence in interest in the nasal administration of oxytocin as treatment for behavioral issues
Anterior Pituitary Hormones
6 hormones produced by 5 cell types. Cells types sometimes referred to as –trophes: thyrotrophes, corticotrophes, lactotrophes, somatotrophes, gonadotrophes
GH – Growth Hormone (aka. Somatotropin; rhGH)
Multiple physiological effects (vs. targeting of specific glands) - Pulsatile release – largest burst within the first hour of falling asleep - Action mediated through generation of locally produced and circulating somatomedins or insulin-like growth factors (IGFs). Effects may be tempered by generation of somatostatins - Actions: o Increase in linear growth (before bone growth plates close) o Increase protein synthesis, increased lean body mass o Promotes utilization of fats for energy source o Diabetogenic – increases insulin resistance - Secretion stimulated by: o Fasting, starvation, increased plasma levels of amino acids, exercise,
GH – Growth Hormone : Pathophysiology
o Excess growth hormone causes: - Acromegaly (in adults whose bone growth plates have closed) - Gigantism (in teens/children with “open growth plates”) o Deficiently: - Failure to grow, short stature, mild obesity
Prolactin
- Release is tonically inhibited by dopamine (the default is release of prolactin; dopamine inhibits the release) - Pregnancy and suckling are stimuli for production and release - Actions: o Lactogenesis – stimulation of milk production and secretion in response to suckling (prolactin’s action is inhibited by high levels of estrogen/progesterone during pregnancy. With delivery, the existing high levels of prolactin are able to act because of the rapid fall of estrogen/progesterone after delivery). Pregnancy is not need for mild production. Sufficient stimulation of nipple can produce milk o Inhibits ovulation by inhibiting GnRH (gonadotropin-releasing hormone). o Breast development at puberty (with estrogen/progesterone) and pregnancy
Prolactin : Pathophysiology
- Excess Prolactin: o Galactorrhea (milk production unassociated with pregnancy or nursing) 1) Destruction of dopamine source “dis-inhibits” production 2) Hypothalamic-hypophysial portal tract interruption may result in galactorrhea (pituitary tumor, trauma etc.) 3) Treated with bromocriptine (dopamine agonist) o Infertility in males secondary to impaired spermatogenesis - Prolactin deficiency: o Failure to lactate o “Empty sella syndrome” - Headache and galactorrhea as presenting symptoms of pituitary adenoma (30% of cases of hyperprolactinemia). - Often no etiology is found for hyperprolactinemia
TSH - Thyroid Stimulating Hormone (aka. Thyrotropin)
- Secreted in response to thyroid releasing hormone (TRH) made by hypothalamus; carried by the portal systems to anterior pituitary which stimulates release of TSH - Actions of TSH: o Regulates growth of thyroid gland o Regulates secretion of thyroid hormones, T3 & T4 - Negative feedback loop of T3 produces a “steady state” of secretion of thyroid hormones (vs. pulsatile secretion)
. ACTH - Adrenocorticotrophic Hormone
- Actually a family of hormones of which ACTH is the most important - Derived from a precursor: pro-opiomelanocortin - The “ACTH family” includes: o ACTH o MSH – melanocyte stimulating hormone o Beta – endorphin o Alpha & beta lipotropin - Control of release of ACTH by corticotrophin-releasing hormone (CRH) - Actions of ACTH: o Modulates cortisol secretion from the zona fasciculate of the adrenal cortex
FSH – Follicle Stimulation Hormone
- Under control of GnRH – gonadotropin releasing hormone - Action: o Stimulates development of follicles in the ovary o Stimulates spermatogenesis
LH – Luteinizing Hormone
- Under control of GnRH - Actions: o Stimulates development of corpus luteum in the ovaries o Stimulates testosterone secretions from the Leydig cells of testis
Estrogen and Progesterone
Are steroid hormones secreted by the follicle and corpus luteum of the ovary. These hormones feedback to hypothalamus influencing release of FSH and LH (as does testosterone). Topic covered in detail in Women’s Health Module
Thyroid Hormones
- Affects every organ system in the body - Thyroid hormones are the mediators of cellular metabolic rate - Two forms: o T3 – triodothyronine •The physiologically more active form o T4 – thyroxine, •Less active form •Dominate form of secretion and in circulation •Target tissues convert T4 to T3
Thyroid Hormones : Anatomy
- Butterfly shaped gland in the anterior neck - The thyroid gland is composed of a large number of follicles - The follicles are filled with a colloid material - The coloid material is made up primarily of thyroglobulin which contains the thyroid hormone
Thyroid Hormones : Synthesis and Transport of Thyroid Hormones
- Multistep process in synthesis and secretion into blood - Iodide trapping by the thyroid’s iodide pump concentrates iodide in gland (30 X greater than in blood; what are the implications for those living in the area of Fukushima Japan?) - T3 and T4 are “highly protein bound” in the serum by thyroxine-binding globulin (TGB) o Less than 1% is “ free” o Very long half lives T4- 7 days; T3 – 1 day
Thyroid Hormones : Actions
- Via intracellular hormone – receptor complex that binds to DNA, increasing transcription o Slower in onset o Influence lasts several days - Increases cellular metabolic rate (basal metabolic rate) o Increase number, size of mitochondria, mitochondrial crystae o Physiologic effects • Increased thermogenesis, sweating • Increase rate/depth respiration (increased 02 consumption/ C02 production) • Increase cardiac output, arrhythmias • Increased pulse pressure (positive inotropic effects) • Increased utilization of nutrients, increased food intake, weight loss o Essential to normal growth and development beginning in utero o Excitatory effect on nervous system – wakefulness, alertness
Pathophysiology: Diseases of the Thyroid : Hyperthyroidism
Graves’ Disease: Most commonly by an autoimmune process; antibodies (thyroid stimulating immunoglobulins – TSI) directed against TSH receptors on the thyroid gland, activate the TSH receptors promoting release of T3 / T4 - Symptoms: Heat intolerance, sweating, increased appetite and weight loss, palpitation, tachycardia, nervousness, emotional labiality, muscle weakness, tiredness, but unable to sleep, exophthalmus - TSH levels are decreased because of negative feedback exerted by high plasma levels of hormones T3 / T4 - Rx’d with methimazole, propythiouracil (PTU) particularly if pregnant; radioactive iodine is sometimes used to “burn out the gland”
Pathophysiology: Diseases of the Thyroid : Hypothyroidism
Decrease metabolic rate results in: • Cold intolerance • Weight gain • Slowness in movement, speech, and thought • Lethargy • Myxedema – puffiness of skin, non-pitting edema, pleural, cardiac effusions
Pathophysiology: Diseases of the Thyroid : Goiter
Classically: deficient dietary iodine resulting in decreased T3 /T4 secretion, high TSH levels, and stimulation growth of gland; Goiters may also occur in Graves’ disease
The Adrenal Gland and Adrenal Hormones - Anatomy
- The Adrenal Medulla is responsible for “catecholamine” production (epinephrine/norepinephrine) - The Adrenal Cortex is responsible for “steroid hormones” based on a cholesterol backbone. The three cortical adrenal layers and their products: o Zona reticularis – Androgens o Zona fasciculata – Glucocorticoids (cortisol) o Zona glomerulosa – Mineralocorticoids (aldosterone)
Control of Secretions of Adrenocortical Steroid Hormones
- Corticotrophin releasing hormone (CRH) (a hypothalamic hormone) stimulates secretion of ACTH from the anterior pituitary - ACTH stimulates the steps in the synthetic pathway to produce the adrenocortical hormones derived from cholesterol (cholesterol desmolase) - Production and secretion from the Zona fasciculate, and zona reticularis are under direct control of ACTH - Secretion from Zona glomerulosa is dependent on this first step (production), but the actual control of release of aldosterone is controlled by the rennin – angiotensin-aldosterone system
Glucocorticoids/androgens secretion
- Pulsatile and diurnal – peak release in early morning - Controlled by negative feedback of cortisol to the pituitary - Dexamethasone suppression test is a method of evaluating the functioning of the pituitary –adrenal axis
Aldosterone Secretion
- Angiotensin II – stimulates secretion of aldosterone - Kidney senses “volume depletion” and secretes Renin 1) Renin converts angiotensinogen to angiotensin I; angiotensin converting enzyme converts angiotensin I to angiotensin II 2) Angiotensin II stimulates aldosterone secretion
Actions of Adrenocortical Steroids : Glucocorticoids
Cortisol is essential for life; the “stress hormone” - Stimulates gluconeogenesis and storage of glycogen • Catabolic - Antiinflammatory – inhibits inflammatory responses of prostaglandins/leukotrienes/ histamines/serotonin - Suppresses immune response – especially cellular mediated immunity (T cell) - Maintains vascular response to catecholamines - Inhibits bone formation - Increases GFR - CNS effects: limbic system/sleep alterations
Actions of Adrenocortical Steroids: Mineralocorticoids (aldosterone)
- Increases Na+ resorption resulting in ECF volume expansion, hypertension - Increases renal K+ secretion - hypokalemia - Increases renal H+ secretion – metabolic alkalosis
Actions of Adrenocortical Steroids: Adrenal Androgens
- DHEA (dehydro-epiandrosterone) and androstenedione - Adrenal derived DHE plays a minor role in males - Adrenal derived DHE is the major androgen in females - Abnormal function in females may cause “masculinization”
Abnormal function of the Adrenal Cortex : Addison’s disease
aka. adrenal insufficiency - Causes 1) Primary - failure of gland; causes include: • Autoimmune destruction of gland; • Metastatic lung cancer destroys gland • Symptoms: Hypoglycemia, anorexia, weakness, hyperpigmentation (high ACTH levels, high MSH) 2) Secondary – failure to stimulate the gland (insufficient CRH or ACTH); causes include: • Iatrogenic (sudden withdrawal of exogenous steroids) • Pituitary tumor • Hypothalamic disorders • Symptoms: Hypoglycemia, anorexia, weakness, No hyperpigmentation - RX: replacement steroids
Abnormal function of the Adrenal Cortex : Cushing’s Syndrome
- Causes: • Iatrogenic (the most common cause in developed countries) • Pituitary adenoma with increased secretion ACTH • Adrenal adenoma (cortisol secreting tumor) - Clinical picture: Hyperglycemia, HTN, muscle wasting, round face, buffalo hump, abdominal striae, hyperpigmentation (if excess ACTH), virilization - RX: depends on cause - adrenalectomy, pituitary surgery, ketoconazole
Abnormal function of the Adrenal Cortex : Conn’s syndrome
Primary Hyperaldosteronism - Cause: aldosterone secreting tumor • Increases ECF volume • Clinical picture: hypertension, hypokalemia, metabolic alkalosis - RX: spironolactone (an aldosterone antagonist); tumor removal
Hormones of the Endocrine Pancreas : Anatomy
- Islets of Langerhans • Beta cells – insulin production • Alpha cells – glucagon • Delta cells – somatostatin (think of GH & somatomedins) • Others - pancreatic polypeptide
Hormones of the Endocrine Pancreas : Insulin
“The Hormone of Abundance” - Derived from precursors: o Preproinsulin ›› Proinsulin ›› Insulin - Regulated by: o Plasma glucose concentration is the most important regulator of secretion o GIP (gastric inhibitory peptide; aka. Glucose-Dependant Insulinotropic Peptide) stimulates secretion of insulin o Glucagon like Peptide (GLP-1) promotes secretion o Sulfonylureas (tolbutamide; glyburide) stimulate secretion
Hormones of the Endocrine Pancreas : Insulin Actions
- Decreases blood glucose concentration by: • Increasing glucose transport into cells • Promotes formation of glycogen in liver and muscle • Inhibits gluconeogenesis - Decreases blood lipid levels • Stimulates fat deposition • Inhibits lipolysis - Decreases serum amino acid concentration • Stimulates uptake by tissues • Increase protein synthesis • Inhibits protein degradation - Promotes K+ uptake into cells
Type I diabetes mellitus (aka. “Insulin dependent diabetes mellitus” IDDM; “Juvenile onset diabetes mellitus”)
- Caused by inadequate insulin secretion, secondary to destruction of beta cells of the pancreas, often by autoimmune processes - Characterized by: o Hyperglycemia – decreased uptake/utilization of glucose o Ketoacidosis – increased use of fats/amino acid for energy, decreased uptake o Polyuria, nocturia – osmotic diuresis with high serum glucose levels o Polydipsia – increase thirst/water intake o Polyphagia – cellular starvation, wasting, hunger o Hyperkalemia o Diabetic ketoacidosis, diabetic coma, dehydration - Rx: Insulin replacement, correction of dehydration and metabolic abnormalities
Type II Diabetes mellitus (aka “Non-insulin dependent diabetes mellitus” NIDDM; “Adult onset diabetes mellitus”; “Insulin resistant diabetes mellitus”)
- Adequate insulin secretion; tissues are unable to properly utilize the insulin – “insulin resistance”; etiology is unclear; we know that there is an “intracellular post receptor deficit” - Characterized by: o Abnormal fasting/postpranial serum glucose levels o Exhibits some of metabolic derangements of Type I,(ie. increased risks of diabetic complications) but is generally not prone to ketosis - Rx: o Weight reduction, diet modification o Sulfonylureas – increase insulin production o Metformin – improves tissue usage of insulin o GIP / GLP-1 analogs increases insulin secretion; opposes actions of glucagon
Hormones of the Endocrine Pancreas : Glucagon
- “Hormone of starvation” - Production stimulated by decreased blood glucose concentration - Inhibited by GLP - Actions: the opposite of insulin o Increases blood glucose concentration • Glycogenolysis (break down of glycogen) • Gluconeogenesis • Increased lipolysis
Hormones of the Endocrine Pancreas : Somatostatin
- Also known as growth hormone inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF)) - Produced and released from cells of the hypothalamus into the portal venous system and from cells of the GI tract (stimulated by ingestion of all forms of food) - Modulates responses of glucose/glucagon to food ingestion - Affects many other hormone systems in an inhibitory manner
Overview of Calcium
Calcium in blood exists in several forms: - Protein bound 40%; - Complexed with ions 10% - Ionized 50% - this is the active form
Hypocalcemia causes:
- Hyperreflexia - Muscle cramping - Spontaneous twitching - Tingling and numbness - Chvostek sign: twitching of facial muscle caused by tapping on facial nerve - Trosseau sign: carpopedal spasm with inflation of BP cuff
Hypercalcemia causes:
- Polyuria - Polydipsia - Hyporeflexia - Constipation - Lethargy, coma, death
Changes in ionized Calcium may result from other physiologic processes:
- Acid – base changes; o Both Ca++ and H+ ion binds to albumin. Increasing or decreasing H+ concentration alters Ca++ binding site availability. Acute respiratory alkalosis may cause hypocalcemia symptoms - Changes in anion concentrations; o Increased phosphate concentration increases complexed Ca++, decreasing free Ca++ concentration o Decreased phosphate concentration decreases complexed Ca++, increasing free Ca++ concentration
Parathyroid Hormone
- Secretion stimulated by decreased serum Ca++ concentration - Actions: 1. Bone – promotes resorption, increasing Ca++ and phosphate in EFC 2. Kidney • Stimulates Ca++ reabsorption • Inhibits phosphate reabsorption 3. Small intestine – indirectly stimulates absorption of Ca++ via vitamin D
Pathophysiology: Hyperparathyriodism
- Primary – ex. parathyroid adenoma (tumor producing parathyroid hormone) o Clinically one see: • Hypercalcemia • Kidney stones – Calcium oxalate/ phosphate • Hypophosphatemia 2. Secondary – the gland is normal; excessive PTH secretion secondary to hypocalcemia from: o Vitamin D deficiency (can’t absorb dietary Ca++) o Chronic renal failure (can’t get rid of phosphorus which pushes serum Ca++ down) o PTH secreting tumors (other than parathyroid tumors)
Pathophysiology: Hypoparathyriodism
Usually caused by treatment of thyroid gland which destroying or damages the parathyroid glands - Clinically ones sees: o Hypocalcemia – decreased bone and kidney reabsorption o Hyperphosphatemia – increased phosphate reabsorption
Vitamin D - Cholecalciferol
- The second major regulatory hormone for Calcium and phosphate - Synthesized in skin, or ingested in diet; inactive in this form - Liver modifies Vitamin D to 25-hydroxycholecalciferol (inactive form) - Kidney modifies 25- hydroxycholecalciferol, depending on the body’s needs into: o An active form 1,25-dihydroxycholecalciferol, or o An inactive form 24,25 dihydroxycholecalciferol
Vitamin D - Cholecalciferol : Actions
- Promotes mineralization of new bone (therefore there is a need to increase both Ca ++ and phosphorus levels) - Intestine – increases Ca++ and phosphate absorption – major action* - Kidney – increased reabsorption of Ca++ and phosphate - Bone – Stimulates bone “remodeling” through resorption and mineralization
Pathophysiology: Deficiency of Vitamin D
- In children – causes rickets – growth failure and skeletal deformities because of insufficient Ca++ and phosphate to mineralize growing bones. - In adults – osteomalacia; osteoporosis - Chronic renal failure – kidneys are unable to form active metabolite, no matter how much vitamin D is present.
Calcitonin
Calcium Deprivation
Calcium Loading
Parathyroid hormone
Secretion stimulated
Secretion inhibited
Vitamin D
Production stimulated by increased parathyroid hormone secretion
Synthesis suppressed due to low parathyroid hormone secretion
Calcitonin
Very low level secretion
Secretion stimulated by high blood calcium
Intestinal absorption of calcium
Enhanced due to activity of vitamin D on intestinal epithelial cells
Low basal uptake
Release of calcium and phosphate from bone
Stimulated by increased parathyroid hormone and vitamin D
Decreased due to low parathyroid hormone and vitamin D
Renal excretion of calcium
Decreased due to enhanced tubular reabsorption stimulated by elevated parathyroid hormone and vitamin D; hypocalcemia also activates calcium sensors in loop of Henle to directly facilitate calcium reabsorption
Elevated due to decreased parathyroid hormone-stimulated reabsorption.
Renal excretion of phosphate
Strongly stimulated by parathyroid hormone; this phosphaturic activity prevents adverse effects of elevated phosphate from bone resorption
Decreased due to hypoparathyroidism
General Response
Typically see near normal serum concentrations of calcium and phosphate due to compensatory mechanisms. Long term deprivation leads to bone thining (osteopenia).
Low intestinal absorption and enhanced renal excretion guard against development of hypercalcemia.
Calcitonin
- Produced by the thyroid - Opposes action of PTH by lowering serum free Ca++
- Stimulates deposition of bone which serum Ca levels are high
