KAAP630 Test 1

What are the sections of the adrenal glands?

• Adrenal Cortex (outside)

• Adrenal Medulla (inside)

What is released from the adrenal cortex (AC)?

• corticosteroids (mineralocorticoids and glucocorticoids)

  • aldosterone (released from zona glomerulosa of AC)

  • cortisol (released from zona fasciculata and reticularis of AC)

• androgenic hormones

  • released from zona fasciculata and reticularis of AC

What is released from the adrenal medulla?

• catecholamines

What are the effects of mineralocorticoids?

• Affects electrolytes (minerals) in extracellular fluid

  • especially Potassium and Sodium

  • Aldosterone accounts for 90%; cortisol has small contribution

What are the effects of glucocorticoids?

• increase blood glucose (cortisol) and influence metabolism

Explain the synthesis, metabolism, and excretion of corticosteroids

• LDL-C (low-density-lipoproteins, cholesterol) interact with LDL receptors on surface of cells

• Brought into the cell via endosome (endocytosis) and transported to mitochondria

• LDL-C cleaved by cholesterol desmolase into pregnenolone

  • Rate-limiting step

• Pregnenolone shuttled out of mitochondria into cytoplasm, then crosses cell plasma membrane

• Bound to plasma proteins in blood

• metabolized in liver

• Excreted in urine

Function of aldosterone

• Salt regulation (absorption) and potassium secretion

  • Regulates sodium-water balance

• Regulates blood volume and pressure

  • Part of RAAS

• Two levels of control:

  • Triggered by high levels of potassium (wants to prevent hyperkalemia)

  • Triggered by decreased levels of blood volume/decrease in blood pressure; triggers Angiotensin II

Explain the simplified RAAS pathway

• Angiotensinogen cleaved by Renin (from kidney) to Angiotensin 1

• Angiotensin 1 (vasoconstrictor) converted to Aldosterone and AVP/ADH by Angiotensin-Converting-Enzyme (ACE)

• Aldosterone regulates salt and water retention

• AVP/ADH regulates water retention and vasoconstriction

Why is Renin released?

• Triggered by reduction in blood volume

• Reduced blood volume = reduced renal afferent arterial pressure, sensed by juxtaglomerulus (JG) apparatus (part of juxtaglomerulus complex)

  • Reduced blood volume = reduced glomerular filtration rate (GFR) = lower NaCl concentration in tubular fluid, stimulates JG cells

    • Sympathetic stimulation of beta receptors on JG cells causes release of Renin

Explain aldosterone stimulation pathway

• Aldosterone diffuses into principle cells of kidney

• Aldosterone bind to mineralocorticoid receptors (MR), forms hormone-receptor complex (HRC)

  • Can be blocked by presence of spironolactone (drug)

• HRC diffuses into nucleus → production of mRNA

• mRNA translated into proteins (Na/K ATPase, ENaC (epithelial sodium channel))

  • ENaC can be blocked by amiloride (drug)

• Takes at least 45 minutes for process to occur, takes hours to see full effects

Aldosterone dysregulation disorders

• Hyperaldosteronism (Conn syndrome)

  • Caused by tumors on adrenal glands

  • hypertension, hyperkalemia

• Secondary hyperaldosteronism

  • excess aldosterone production due to increased RAAS activation

• Tertiary hyperaldosteronism (Bartter and Gitleman syndrome)

  • Mutations in ion transporters in kidney, excess sodium is lost

  • stimulates aldosterone in excess via RAAS

• Hypoaldosteronism

  • Addison’s disease: destruction of adrenal glands due to infection, injury, or autoimmune disorder

  • Renal insufficiency leads to reduced RAAS

Explain cortisol stimulation pathway and its effects

• Anterior pituitary releases adrenocorticotropic hormone (ACTH)

• ACTH stimulates adrenal cortex; cortisol released

• cortisol stimulates:

  • Gluconeogenesis

  • Protein mobilization

  • Fat mobilization (lipolysis)

  • Stabilizes lysosomes

• Relieves stress, excites hypothalamus (state dependent)

• PRESENCE OF CORTISOL INHIBITS FURTHER SECRETION OF ACTH

Describe ACTH stimulation pathway

• ACTH connects to receptor, makes HRC

• Alpha subunit detaches, stimulates cAMP

• cAMP stimulates Protein Kinase A

• Protein Kinase A stimulates CEH (cholesterol ester-rich droplets) in lipid droplet to convert cholesterol esters into cholesterol

• Cholesterol converted to pregnanolone, shuttled into mitochondrion

• Pregnanolone converted to 17-OH pregnanolone; 17-OH preg converted to 11-deoxy-cortisol; 11-deoxy-cortisol converted to cortisol

  • Conversion steps occur in smooth endoplasmic reticulum which works with mitochondria

• Cortisol released from mitochondria, diffuses across cell membrane, bound to plasma protein and circulates in blood

Example stimulation path for cortisol

• broken bone/stress/burns/exercise → positive stimulation of higher brain centers

• higher brain centers → positive stimulation of hypothalamus

• hypothalamus releases CRH → stimulates anterior pituitary gland to release ACTH

• ACTH → positive stimulation of adrenal cortex

• cortisol released from adrenal cortex

Physiological effects of cortisol

• Mobilizes tissue amino acids (muscle breakdown)

• blocks entry of glucose into tissue (Blocks GLUT 4 transporters)

• stimulates gluconeogenesis

  • antagonizes insulin in liver, stops inhibition of gluconeogenesis

• mobilizes free fatty acids (lipolysis)

• Decrease growth hormone (GH) and IGF-1; can impair bone and muscle growth

Anti-inflammatory effects of cortisol

• stabilizes lysosomal proteins

• decreases capillary permeability

• decreases WBC mobilization and phagocytosis of damaged cells

• suppresses immune system → decline in lymphocyte reproduction

• lowers fever by reducing release of interleukin-1 from WBCs

Prednisone (drug) used to treat inflammatory conditions; mimics cortisol

Glucocorticoid dysregulation disorders

• Cushing’s disease

  • excess cortisol production

  • usually results from tumor, can be ACTH independent or dependent

  • excess weight gain, round/moon face, fat deposition, hypertension, muscle loss, osteoporosis

• Addison’s disease

  • glucocorticoid deficiency

  • auto-immune disease, destroys adrenal gland/interferes with steroid hormone synthesis

  • weakness/fatigue, low BP/hypotension, decreased appetite, weight loss, hyperkalemia

  • Can be life-threatening

Name the relevant catecholamines and their receptor types

• acetylcholine (ACh, nicotinic)

• epinephrine (E, adrenergic)

• norepinephrine (NE, adrenergic)

Name the two types of adrenergic receptors and their effects once stimulated

• alpha

  • GPCR

  • vasoconstriction/increased peripheral resistance

  • reduced mucosal edema (in airway, makes it easier to breathe)

  • decreased cAMP

  • inhibition of NT release

  • autoreceptor feedback regulation

• beta

  • GPCR

  • increased HR/CO

  • increased contractility

  • bronchodilation

  • vasodilation

  • reduced inflammatory mediator disease

  • lipolysis

  • metabolic regulation

Explain and understand the GPCR pathway

What is the function of the pancreas?

• glucose homeostasis, digestion aid

• alpha cells secrete glucagon

• beta cells secrete insulin

Structure of insulin?

Glucose stimulates insulin release when it passes through the _____ channel of beta-cells in pancreas

GLUT 2

Steps of insulin release

• Glucose enters beta cell via GLUT 2 channel

• Glucose undergoes glycolysis, generates ATP

• ATP closes ATP-sensitive K+ channels

• Plasma membrane depolarizes, Ca++ voltage-gated channels open, Ca++ flows in

• Influx of Ca++ → insulin vesicles mobilize + fuse with cell membrane

  • Translocation via GLUT 4 vesicle

• Insulin released into circulation

Insulin effect on carbohydrate metabolism

• stimulates:

  • glucose transport in fat tissue and muscle

  • rate of glycolysis in fat tissue and muscle

  • glycogen synthesis in fat tissue, muscle, and liver

• inhibits:

  • glycogen breakdown in liver and muscle

  • rate of glycogenolysis and gluconeogenesis in liver

Insulin effects on lipid metabolism

• stimulates:

  • fatty acid and triacylglycerol synthesis in tissues

  • uptake of triglycerides from blood into fat tissue and muscle

  • rate of cholesterol synthesis in liver

• inhibits:

  • lipolysis in fat tissue (lower fatty acid level in plasma)

  • fatty acid oxidation in muscle and liver

  • ketogenesis

Insulin effects on protein metabolism

• stimulates:

  • amino acid transport into tissue

  • protein synthesis in muscle, fat tissue, liver, etc.

• inhibits:

  • protein degradation in muscle

  • urea formation (urea made when amino acids are broken down)

What are the types of diabetes and what defines them?

• Type 1: no insulin

  • autoimmune, system attacks and destroys insulin/beta cells

• Type 2: less insulin and increased insulin resistance

  • 95% of cases, often lifestyle influenced

What are the diagnostic criteria for diabetes?

• fasting plasma glucose (FPG) > 126 mg/dL

• 2 hr plasma glucose > 200 mg/dL during Oral Glucose Tolerance Test (OGTT)

  • test measures ability of body to store glucose and return glucose to normal after glucose load (ie: eating)

• hemoglobin A1C (hemoglobin with glucose attached) > 6.5%

• symptoms of hyperglycemia & plasma glucose (p[GI]) > 200 mg/dL

  • Frequent urination/excretion of large amounts of dilute urine

  • Excessive thirst

  • Blurred vision

  • Fatigue

• *Pre-Diabetes: FPG 100-125 mg/dL

What are the treatments for diabetes?

• control and monitor blood glucose

  • exercise

  • medication

    • sulfonylureas: close K+ ATP channels in beta cells of pancreas; stimulate insulin release

    • metformin: inhibits gluconeogenesis; enhances insulin receptor tyrosine kinase activity —> stimulates glucose transport

Diabetes can lead to renal (kidney) failure, cardiovascular disease, autonomic disease, and blindness

Function of glucagon

• make glucose/free up glucose

  • glycogenolysis: breakdown of glycogen into glucose

  • gluconeogenesis: make glucose from amino acids, glycerol, and lactate

• released by alpha cells of pancreas

• inhibits:

  • glycolysis: breaking glucose down to pyruvate

  • glycogenesis: converting glucose to glycogen for storage

What are normal blood glucose levels in a healthy individual?

4-6 mM of glucose in blood

Describe the pathway for hormonal stimulation of the ovaries

• Hypothalamus secretes gonadotropin-releasing hormone (GnRH) → anterior pituitary stimulated to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH)

• LH and FSH (through different mechanism) stimulate ovaries → ovaries are stimulated; release estradiol and progesterone

on god just know this slide

What is the purpose of the female reproductive cycle?

• Grow 1 follicle

• Prepare endometrium for egg implantation

What happens during the follicular/proliferative phase of the female reproductive cell?

• FSH and LH make 6-12 primary follicles to grow

• Granulosa cells secrete fluid (antrum) that has LOTS of estrogen

• Upregulation of FSH and LH receptors → more estrogen made → explosive growth of ovum and follicle

  • Only 1 lives/out grows the others; other follicles become atretic (degraded)

• Remaining follicle released during ovulation

• surge in LH

  • needed for ovulation; causes progesterone release

What happens during the luteal/secretory phase of the female reproductive cell?

• after ovulation → LH causes granulosa/thecal cells to become lutein cells = corpus luteum → secretes estrogen & progesterone (and inhibin)

  • Estradiol (E2) and Progesterone (P4) inhibit further FSH and LH production

  • Causes proliferation, enlargement, and secretion (goal of fertilization)

  • If no fertilization, corpus luteum degrades; fall in E2 and P4; FSH and LH begin to rise for next cycle

• menstruation begins

Properties of estradiol and progesterone

• Derived from cholesterol (steroid hormone)

• Bound loosely to plasma proteins

• Metabolized and degraded in liver

Functions of estrogen

• Cell proliferation and growth

  • ovaries, fallopian tubes, uterus, breasts

• sodium and water retention

  • chemical similarity to ACTH

• temperature regulation

What is the primary function of progesterone?

• promote secretory changes in uterine endometrium → prepare for inflammation

What characterizes menopause?

• little to no primary follicles left

  • estrogen levels fall

• Rise in FSH and LH

• Symptoms:

  • hot flashes

  • anxiety/depression

  • trouble sleeping

  • vaginal dryness

  • fatigue

• Controversy around treating menopause with HRT

What were the findings of the study done by the Women’s Health Initiative?

• use of HRT with estrogen and progesterone led to:

  • increased risk of stroke

  • increased risk of heart attack

  • increased risk of blood clots

  • increased risk of breast cancer

  • decreased risk of colorectal cancer

  • fewer bone fractures

• use of HRT with estrogen alone led to:

  • no difference in heart attack risk

  • increased risk for stroke

  • increased risk of blood clots

  • uncertain effect on breast cancer risk

  • no difference in colorectal cancer risk

  • reduced risk of bone fractures

What are the limitations of the Women’s Health Initiative’s study?

• Low participant adherence

• High dropout rate

• Not truly representative sample:

  • overweight participants

  • smokers

  • primarily Caucasian

  • older participants** (very important)

Why was the age of participants in the WHI study such an issue?

• timing hypothesis: the principle that the when of an intervention is as important as the what, because the outcome depends on the physiological state of the system at that moment

What is CEE?

• Conjugated Equine Estrogens (CEE): mixture of estrogens derived from pregnant horse urine

• used in post-menopausal HRT

What is tE2?

• 17-B estradiol (transdermal, tE2): biochemical estradiol from body, used in post-menopausal HRT

• Preferred HRT method because it’s endogenous to the body and it’s not synthetic

When (roughly) do testosterone levels in men begin to decline after puberty?

• around age 70

Explain the pathway for testosterone stimulation

What are the functions of testosterone?

• promotes growth of hair, bones, protein formation/muscle, basal metabolic rate

• skin health

• voice

What are the symptoms of “manopause”?

What are the main functions of the parathyroid gland?

• bone resorption (breaking down) and releasing Ca++ into blood

• Ca++ reabsorption in the kidneys

• Phosphate excretion

• Activation of Vitamin D (calcitriol)

What are the characteristics of blood calcium control?

• blood calcium is very finely controlled (small amount in blood)

• Ca++ needed for:

  • Muscle contraction, neural transmission, bone development, etc.

• Hypercalcemia depresses CNS, hypocalcemia causes tetany

• Inverse relationship with inorganic phosphate in blood

Understand this graph for homeostatic regulation of blood calcium

What do high Ca++ blood levels stimulate the parathyroid gland to do?

• Ca++ interacts with GPCR → Phospholipase A₂ → Arachidonic acid → Leukotrienes

• Leukotrienes degrade PTH and inhibit its release

What do low Ca++ blood levels stimulate the parathyroid gland to do?

• Blood Ca++ doesn’t interact much with GPCR, so GPCR relaxes

• GPCR relaxation allows PTH release

What is a biphasic response (in terms of PTH)?

• pre-formed PTH can be released to acute changes in Ca++ in blood

• Chronic low Ca++ → increased PTH synthesis (long-term)

What is Phosphate’s relationship with Calcium the in blood?

• Positive correlation

• Phosphate increases PTH by removing inhibitory effect stopping formation of Arachidonic acid from Phospholipase

• In renal disease, elevated Phosphate can → hyperparathyroidism and bone loss

Know this diagram for how PTH releases calcium from the bone

Understand the target organs and effects of PTH

What does PTH do to the kidneys?

• Increase Ca++ reabsorption by increasing # of Ca++ channels in membrane to draw more Ca++ back in

• Excrete phosphate and reduce intake (reduced gene expression of Na+/PO4 cotransporter)

• Activation of enzyme 1-alpha-hydroxylase which activates Vitamin D (calciferol → calcitriol)

How does active Vitamin D (calcitriol) impact blood Ca++?

• function: Ca++ reabsorption in gut; deposition and resorption of bone

• How:

  • Calcitriol binds Vitamin D receptors (VDRs) on nuclei of gut cells (enterocytes) → stimulates transcription of Ca++ transport proteins (Calbindin, TRPV6, etc.)

What does PTH do to Vitamin D?

• PTH causes conversion of calciferol (inactive Vitamin D) to calcitriol (active Vitamin D) in proximal tubule of kidneys

What is CaSR?

• GPCR on parathyroid chief cells, kidney tubules, bone cells, etc.

• monitors extracellular Ca++ concentrations

  • high Ca++ concentration → activates CaSR → fall in expression of hormones/mechanisms that increase Ca++ concentration in blood (ie: PTH, Vitamin D)

True or false: hypoparathyroidism is more common than hyperparathyroidism

False

What are the causes, symptoms, treatments, and complications of hyperparathyroidism?

• causes:

  • adenoma (tumor of parathyroid gland); causes overproduction of PTH

  • kidney disease

• symptoms:

  • high blood Ca++

  • bone loss/pain/fracture

  • increased urination (more Ca++ filtered and reabsorbed)

  • kidney stones

  • muscles weakness/twitches

  • heart palpitations

• treatments: surgery to remove adenoma or medication

• Complication: “hungry bones”; post-op, bones can overcorrect due to the sudden shift in metabolism → hypocalcemia as bones take in too much Ca++ from blood

What does hypoparathyroidism do to levels of Ca++ and Phosphate in blood?

• decreases Ca++, raises Phosphate (less excreted)

What are the alternative names for the pituitary gland, the anterior pituitary gland, and the posterior pituitary gland?

• pituitary gland: hypophysis

• anterior pituitary gland: adenohypophysis

  • communicates with hypothalamus via hypothalamic-hypophysial portal vessels

• posterior pituitary gland: neurohypophysis

  • neural tissue extending down from hypothalamus

Describe the basic stimulation pathway for the anterior pituitary gland

• hypothalamic stimulating or releasing hormones → median eminence → hypothalamic-hypophysial portal vessels system → anterior pituitary

Name the hypothalamic hormones that stimulate the anterior pituitary gland and their effects

• thyrotropin-releasing hormone (TRH) → causes release of thyroid-stimulating hormone (TSH)

• corticotropin-releasing hormone (CRH) → causes release of adrenocorticotropic hormone (ACTH)

• growth hormone-releasing hormone (GHRH) → causes release of growth hormone (GH) and growth hormone inhibitory hormone (GHIH)/somatostatin

• gonadotropin-releasing hormone (GnRH) → causes release of two gonadotropic hormones (FSH, LH)

• prolactin-inhibiting hormone (PIH) → causes inhibition of prolactin secretion (lactation hormone)

Stimulation pathways of the hypothalamic hormones

• Phospholipase C = PLC

• Adenyl Cyclase = AC

What are the functions and effects of growth hormone (GH)?

• causes growth in tissues

• increases size of cells, mitosis, cell differentiation

• Target organs:

  • Skeleton/bones: increase amino acid uptake, protein and collagen synthesis, chondrocyte (cartilage cell) proliferation, longitudinal growth of bones

  • Adipose tissue: increases lipolysis → raises free fatty acids in blood, lowers fat storage

  • Muscle: increases amino acid uptake, protein synthesis → bigger muscles

  • Liver: increases IGF secretion, IGFBP synthesis, and glucose output → rise in blood sugar

Describe the stimulation pathway from GHRH to GH

• GHRH → GPCR → Adenylate cyclase/cAMP → Protein kinase A → GH

True or false: IGF-1 from the liver can inhibit GH; this is an example of negative feedback

• True

True or False: IGF-1 is necessary for linear growth

• True

Fill in the blanks

Most GHs in circulation are bound to ____________ ______. GH binds to _______ _______ ________ and activate downstream signaling proteins for target-organ-specific effects.

• GH-binding proteins

• surface cytokine receptors

What are the metabolic effects of GH?

• increase rate of protein synthesis

  • enhances transport of AA through the cell

  • increased transcription

  • increased translation/protein synthesis

  • decreased protein breakdown in cell

• enhances fat utilization for energy (makes body more dependent on fat energy by raising adipose tissue insulin resistance)

• decreases rate of glucose utilization (protects blood glucose for brain)

GH disorders

• dwarfism: too little GH

• giantism/acromegaly: too much GH

What hormones are released by the thyroid gland?

• Calcitonin (reduce blood Ca++)

• T3

  • Less common than T4, but more potent

• T4

  • More common than T3, but less potent

  • T4 → T3 in tissues

What makes up the thyroid?

• follicles lined with cuboidal epithelial cells that secrete colloid

• C cells that secrete calcitonin

What is colloid?

• secreted by cuboidal epithelial cells in follicle

• rich in thyroglobulin, which has a lot of thyroid hormones

Describe the production of T3 and T4 in a thyroid follicle, beginning with Iodide

• iodide is co-transported into cuboidal cell with sodium (Na+); ‘iodine trapping’

• Pendrin (counter transport molecule) transports iodide into the follicle

• Thyroglobulin secreted by ER and Golgi into follicle

• Iodide oxidized to by iodine by thyroid peroxidase (TPO)

  • Iodide → iodine by TPO lets TPO attach iodine to the tyrosine AAs on thyroglobulin

  • Iodine-tyrosine AAs coupled → thyroid hormones

• Colloid droplet taken into cuboidal cell via endocytosis

• Proteases cleave thyroglobulin → T3 and T4

• Thyroid hormones stored for months until secreted into blood

How does TSH (from anterior pituitary gland) increase T3 and T4?

• increases:

  • TG cleavage

  • activity of iodine pump

  • iodination

  • number of cells

  • cell size and secretory activity

• stimulates cells via adenylate cyclase/cAMP (2nd messenger system)

Describe T3 and T4 transport and activity

• circulate bound to plasma proteins; released slowly and used slowly to and by the target cells

• T4 → T3 via iodinase before entering nucleus

• T3 acts on thyroid hormone receptor in nucleus

• Upregulation of gene expression → mRNA transcription → increases protein synthesis

• Revs up body’s functional activity (higher cardiac output, increased glycogenesis, etc.)

What are the effects of thyroid hormone?

• bone growth and development

• increases cardiac output (CO)

• increases lipolysis

• cholesterol metabolism in the liver

• axon myelination in brain

• stimulates GH; inhibits TSH (negative feedback)

True or false: disorders of the thyroid do not involve resistance to TH at the level of the tissues

• False

What are hyperthyroidism and hypothyroidism?

• hypothyroidism: usually disease of the thyroid gland; low metabolic state (→ weight gain), low hormone levels

  • thyroid gland can be enlarged (goiter caused by too little iodine)

    • myxedema: swelling of face/eyes; bags under eyes

    • atherosclerosis: lack of TH → buildup of cholesterol (bc TH stimulates cholesterol metabolism in liver)

  • Hashimoto’s: autoimmune; immune system destroys the thyroid gland

  • treated with TH

• hyperthyroidism: excessive thyroid function; increased BMR, cardiac and ANS dysfunction

  • Grave’s disease (autoimmune): immune system attacks the thyroid gland → too much TH produced → hyperthyroidism in blood

    • characterized by bulging eyes

What can cause goiter?

• hyperthyroidism

• hypothyroidism

• too little iodine

• tumors

• autoimmune condition

What hormones are released from the posterior pituitary gland (hypophysis)?

• Oxytocin: stimulate smooth muscle contraction

  • childbirth, lactation

  • pitocin (synthetic oxytocin) given to induce labor

• ADH/AVP: reduce body water loss to maintain plasma volume

  • reabsorbs water in the kidneys (acts on V2 receptors) via tubules; water moved to capillaries → body fluid maintained

  • main trigger: osmolality of blood, NOT LOW BLOOD VOLUME but that does still trigger it

• hormones are secreted from nerve endings in the hypothalamus via exocytosis into adjacent capillaries

Describe the mechanism of activation, function, and effect of ADH/AVP

• Osmoreceptors in hypothalamus sense blood osmolality and water concentration

  • high osmolality/low water concentration → osmoreceptors shrink → neural reflex in hypothalamus → ADH released

  • ADH released → kidneys retain water

  • If osmolality normal but plasma volume low (ie: in cases of hemorrhage) → stretch receptors in heart (aorta and carotid arteries) initiate reflex → ADH released and vasoconstriction is triggered

Understand the ADH stimulation pathway in the collecting duct of the kidneys

Understand the ADH/AVP stimulation pathway in response to normal osmolality and low plasma volume

Know PLC (phospholipase-C) vs AC (adenylate cyclase)

ADH/AVP disorders

• hyper: causes body to hold too much fluid

  • can happen in heart failure or nephrotic syndrome

• hypo: causes excess excretion

  • diabetes insipidus: caused by ADH/AVP deficiency instead of insulin

    • neurogenic: most common; AVP can’t be released due to trauma, inflammation, cancer, etc.

    • nephrotic/renal: mutations in receptors or aquaporin-2 channels (AQP2) → water can’t be reabsorbed