Endocrine - Anatomy/physiology Flashcards
Endocrine
What are 2 parts of fetal adrenal gland?
Inner active fetal zone and outer dormant/inactive adult zone
Endocrine
What are 2 parts of adult adrenal gland?
Inner adrenal medulla and outer adrenal cortex
Endocrine
Part of adrenal gland immature when baby born? When functional?
Zona reticularis of adrenal cortex is immature at birth and not fully developed until 3 years after birth.
Endocrine
Mechanism by which fetus produces androgens in utero?
Fetus requires PLACENTAL 3β-hydroxysteroid dehydrogenase enzyme to convert pregnenolone to progesterone for synthesis of androgens
Endocrine
What are 3 parts of adrenal cortex?
Zona glomerulosa, zona fasciculata, zona reticularis (“GFR”)
Endocrine
Zona glomerulosa secretes?Zona fasciculata secretes?Zona reticularis secretes?
Glomerulosa –> Mineralocorticoids (aldosterone)Fasciculata –> Glucocorticoids (cortisol)Reticularis –> Androgens (androstenedione)
Endocrine
Embryologic origin:Adrenal cortex?Adrenal medulla?
Cortex - MesodermMedulla - Neuroectoderm (neural crest cells)
Endocrine
Adrenal medulla is composed of what cell type? Secretory product?
Chromaffin cells - Secrete catecholamines (epinephrine, NE)Chromaffin cells are modified postganglionic sympathetic neurons that receive sympathetic input (neuroendocrine cells).
Endocrine
Adrenal tumors:MCC in adults?MCC in children?
Adults - PheochromocytomaChildren - Neuroblastoma
Endocrine
Venous drainage:Left adrenal gland?Right adrenal gland?
Left adrenal gland –> Left adrenal vein –> Left renal vein –> IVCRight adrenal gland –> Right adrenal vein –> IVCNote - Same as left/right gonadal (e.g., testicular) veins
Endocrine
Sympathetic preganglionic neurons release [?], which activates [?] receptors on postganglionic neurons.These postganglionic neurons release [?] to activate [?] receptors on target tissues.What are 2 exceptions to this principle?
Sympathetic preganglionic neurons release ACh, which activates AChR receptors on postganglionic neurons.These postganglionic neurons release NE to activate ADRENERGIC receptors on target tissues.Exceptions:1) Postganglionic neurons that innervate sweat glands release ACh, not NE.2) Chromaffin cells of adrenal medulla - Innervated by preganglionic sympathetic nerons that release ACh and bind AChRs on chromaffin cell surface. However, these cells are MODIFIED postganglionic neurons. They release catecholamines (80% epi, 20% NE) directly into blood stream to activate adrenergic receptors in target tissues.
Endocrine
Adrenal medulla releases catecholamines (epi, NE) that bind adrenergic receptors in what 4 locations in body to mediate acute stress response?
Heart, lungs, liver, and skeletal muscle
Endocrine
Precursor of all steroid hormones synthesized in adrenal cortex?
Cholesterol
Endocrine
What is 1st reaction in synthesis of all steroid hormones in adrenal cortex? Reaction catalyzed by what enzyme?
Cholesterol –> pregnenoloneReaction catalyzed by cholesterol desmolase
Endocrine
What hormone stimulates cholesterol desmolase activity, thereby increasing production of adrenal cortex steroid hormones?
ACTH
Endocrine
What drug inhibits cholesterol desmolase activity, thereby decreasing production of adrenal cortex steroid hormones?
Ketoconazole
Endocrine
What are 2 fates of pregnenolone? What enzymes catalyze these reactions?
Mineralocorticoid pathway:Pregnenolone –> progesterone via 3β-hydroxysteroid dehydrogenaseGlucocorticoid pathway:Pregnenolone –> 17-hydroxypregnenolone via 17α-hydroxylase
Endocrine
What are 2 fates of progesterone? What enzymes catalyze these reactions?
Mineralocorticoid pathway:Progesterone –> 11-deoxycorticosterone via 21β-hydroxylase*This reaction traps cholesterol metabolism in pathway that generates mineralocorticoidsGlucocorticoid pathway:Progesterone –> 17-hydroxyprogesterone via 17α-hydroxylase
Endocrine
What is 1 fate of 11-deoxycorticosterone? What enzyme catalyzes this reaction?
11-deoxycorticosterone –> corticosterone via 11β-hydroxylase
Endocrine
What is 1 fate of corticosterone? What enzyme catalyzes this reaction?
Corticosterone –> aldosterone via aldosterone synthase
Endocrine
What hormone stimulates aldosterone synthase activity, thereby increasing production of aldosterone?
Angiotensin II
Endocrine
What are 2 fates of 17-hydroxypregnenolone? What enzymes catalyze these reactions?
Glucocorticoid pathway:17-hydroxypregnenolone –> 17-hydroxyprogesterone via 3β-hydroxysteroid dehydrogenaseAndrogen pathway:17-hydroxypregnenolone –> dehydroepiandrosterone (DHEA) via 17,20-lyase
Endocrine
What are 2 fates of 17-hydroxyprogesterone? What enzymes catalyze these reactions?
Glucocorticoid pathway: 17-hydroxyprogesterone –> 11-deoxycortisol via 21β-hydroxylase*This reaction traps cholesterol metabolism in pathway that generates glucocorticoidsAndrogen pathway:17-hydroxyprogesterone –> androstenedione via 17,20-lyase
Endocrine
What is 1 fate of DHEA? What enzyme catalyzes this reaction?
DHEA –> androstenedione via 3β-hydroxysteroid dehydrogenase
Endocrine
What are 2 fates of androstenedione? What enzymes catalyze these reactions?
Androstenedione –> estrone via aromatase; estrone –> estradiolAndrostenedione –> testosterone
Endocrine
What are 2 fates of testosterone? What enzymes catalyze these reactions?
Testosterone –> estradiol via aromataseTestosterone –> dihydrotestosterone (DHT) via 5α-reductase
Endocrine
Pituitary gland, also called [?], rests in [?], a depression in [?] bone.Pituitary gland is divided into what 2 parts?
Pituitary gland = hypophysisRests in sella turcica, a depression in sphenoid boneAnterior (adenohypophysis) and posterior (neurohypophysis) pituitary glands
Endocrine
Relationship b/w anterior pituitary and hypothalamus?
Anterior pituitary is linked to hypothalamus via hypothalamic-hypophyseal portal systemBlood directly draining hypothalamus, which contains high concentrations of hypothalamic hormones, is delivered to anterior pituitary
Endocrine
Relationship b/w posterior pituitary and hypothalamus?
Posterior pituitary hormones are synthesized in hypothalamusNerve cell bodies that synthesis posterior pituitary hormones are located in hypothalamus. Hormones are packaged in secretory granules and transported down axons to posterior pituitary for release into circulation.Posterior pituitary is collection of UNMYELINATED axons whose cell bodies originate in hypothalamus.
Endocrine
Anterior pituitary:Another name?Embryologic origin?Hormones?
Anterior pituitary –> adenohypophysisOrigin –> UPGROWTH of oral ectoderm (Rathke’s pouch)Hormones –> FLAT PiGFSH, LH, ATCH, TSH, prolactin, GH
Endocrine
Anterior pituitary includes 5 cell types. What hormone(s) does each cell type produce?GonadotrophsCorticotrophsThyrotrophsLactotrophsSomatotrophs
Gonadotrophs –> FSH, LHCorticotrophs –> ACTHThyrotrophs –> TSHLactotrophs –> ProlactinSomatotrophs –> GH = somatotropin
Endocrine
Anterior pituitary includes 3 categories of hormones. What hormone(s) is/are included in each?Glycoprotein hormonesCorticolipotropinsSomatomammotropins
Glycoprotein hormones –> FSH, LH, TSHCorticolipotropins –> ACTHSomatomammotropins –> GH, prolactin
Endocrine
Chromophils are anterior pituitary cells that contain granules that react with acidophilic/basophilic stains.Acidophilic cells contain granules composed of what hormones? These cells stain what color?
PiG hormones –> GH, prolactinAcidophils = red/pink staining
Endocrine
Chromophils are anterior pituitary cells that contain granules that react with acidophilic/basophilic stains.Basophilic cells contain granules composed of what hormones? These cells stain what color?Basophils also stain positive for what marker?
FLAT hormones –> FSH, LH, ACTH, TSHBasophils = blue/purple stainingPAS+ “B-FLAT”
Endocrine
Chromophobes?
Anterior pituitary cells that lack granules and do not react with acidophilic/basophilic stains.Chromophobes include stromal cells and DEGRANULATED chromophils
Endocrine
Posterior pituitary:Another name?Embryologic origin?Hormones?Composition?
Posterior pituitary –> neurohypophysisOrigin –> DOWNGROWTH of neuroectodermHormones –> ADH (vasopressin) and oxytocinComposition –> unmyelinated axons that extend from cell bodies in hypothalamus
Endocrine
ADH pro-hormones:Synthesized in neuron cell bodies in which hypothalamic nuclei?Pro-hormones contain what 2 products?Pro-hormone –> Hormone?
Neuron cell bodies in hypothalamic SUPRAOPTIC NUCLEI synthesize ADH pro-hormones that contain ADH and NEUROPHYSIN II.ADH pro-hormones are packaged into secretory vesicles and transported to nerve terminals in PARS NERVOSA part of posterior pituitary.ADH pro-hormones are processed in secretory granules during transport –> Cleavage into ADH and neurophysin II.ADH has 2 names –> Antidiuretic hormone and vasopression –> NEUROPHYSIN II
Endocrine
Oxytocin pro-hormones:Synthesized in neuron cell bodies in which hypothalamic nuclei?Pro-hormones contain what 2 products?Pro-hormone –> Hormone?
Neuron cell bodies in hypothalamic PARAVENTRICULAR NUCLEI synthesize oxytocin pro-hormones that contain OXYTOCIN and NEUROPHYSIN I.Oxytocin pro-hormones are packaged into secretory vesicles and transported to nerve terminals in PARS NERVOSA part of posterior pituitary.Oxytocin pro-hormones are processed in secretory granules during transport –> Cleavage into oxytocin and neurophysin I.
Endocrine
Mechanism by which posterior pituitary hormones are released into bloodstream?
Action potential depolarizes nerve terminal causing neurosecretory vesicles to fuse w/ plasma membrane –> Releases ADH or oxytocin into perivascular space of highly fenestrated capillaries –> Entrance to systemic circulation
Endocrine
Hypothalamus hormone:Corticotropin releasing hormone (CRH)Regulatory mechanism:Stimulate/inhibit?Anterior pituitary hormone(s):?
CRH stimulates ACTH, MSH, and β-endorphinMSH = Melanocyte stimulating hormone
Endocrine
Hypothalamus hormone:Growth hormone releasing hormone (GHRH)Regulatory mechanism:Stimulate/inhibit?Anterior pituitary hormone(s):?
GHRH stimulates GH
Endocrine
Hypothalamus hormone:Gonadotropin releasing hormone (GnRH)Regulatory mechanism:Stimulate/inhibit?Anterior pituitary hormone(s):?
GnRH stimulates FSH, LH
Endocrine
Hypothalamus hormone:Thyroid releasing hormone (TRH)Regulatory mechanism:Stimulate/inhibit?Anterior pituitary hormone(s):?
TRH stimulates TSH and prolactin
Endocrine
Hypothalamus hormone:Dopamine - Another name?Regulatory mechanism:Stimulate/inhibit?Anterior pituitary hormone(s):?
Dopamine inhibits prolactin Dopamine –> prolactin inhibiting factor (PIF)
Endocrine
Hypothalamus hormone:Somatostatin - Another name?Regulatory mechanism:Stimulate/inhibit?Anterior pituitary hormone(s):?
Somatostatin inhibits GH and TSHSomatostatin –> somatotropin release inhibiting factor (SRIF)GH –> somatotropin Recall that thyroid hormones (“TSH”) act synergistically with GH for bone development as way to remember somatostatin inhibits both GH and TSH.
Endocrine
What are 3 glycoprotein hormones synthesized by pituitary gland?Glycoprotein hormones contain what 2 subunits?Which subunit is identical in all glycoprotein hormones? Which determines hormone specificity?
Glycoprotein hormones –> FSH, LH, TSHGlycoprotein hormones contain α- and β-subunits. –> α-subunits are identical in all glycoprotein hormones–> β-subunits determine hormone specificity
Endocrine
What non-pituitary glycoprotein hormone shares homology with FSH, LH, and TSH?
hCG has identical α-subunit as glycoprotein hormones synthesized in pituitary gland
Endocrine
What are 2 functions of TSH on thyroid gland?
TSH acts on follicular cells of thyroid gland to:1) Regulate growth of gland (hypertrophy/hyperplasia)2) Secrete thyroid hormones
Endocrine
TSH binds TSH-receptors on follicular cells of thyroid and signals through what mechanism?
TSH activates Gs protein –> activates adenylyl cyclase –> produces cAMP 2nd messenger
Endocrine
What are 3 thyroid hormones?Which thyroid hormone is most active?Thyroid gland produces predominantly which thyroid hormone?
T3, T4 (thyroxine), rT3 (inactive!)T3 is 4x more active than T4. rT3 is inactive.Thyroid gland produces predominantly T4.
Endocrine
Negative feedback mechanism for TSH secretion?
Free T3 downregulates TRH receptors on thyrotrophs in anterior pituitary, thereby decreasing their sensitivity to TRH secreted by hypothalamusFree T3 induces INTERNALIZATION OF TRH RECEPTORS.
Endocrine
Thyroid gland produces predominantly T4, yet free T3 provides negative feedback for TSH secretion - Explanation?
Anterior pituitary expresses 5-deiodinase enzyme that converts free T4 to free T3
Endocrine
Thyroid stimulating immunoglobulins (TSI)?
Thyroid stimulating immunoglobulins, like TSH, bind and stimulate TSH receptors on thyroid gland –> Antibodies to TSH receptorGraves disease!
Endocrine
Mechanism by which thyroid hormones act in target cells?
Thyroid hormones diffuse across membrane of target cells and bind to steroid receptors in NUCLEUS
Endocrine
Thyroglobulin (TG)? Synthesized from what precursor?
Thyroglobulin is a glycoprotein synthesized by thyroid follicular epithelial cells. Serves as precursor for thyroid hormones.Synthesized from TYROSINE and packaged into secretory vesicles. Extruded across apical membrane into follicular lumen.
Endocrine
Transporter located on basolateral aspect of follicular epithelial cells in thyroid gland? Function?
Na+/I- cotransporter that pumps both Na+ and I- into follicular epithelial cells –> Iodide trappingI- needed for thyroid hormone synthesisPolarity of thyroid follicular epithelial cell:Basolateral membrane faces blood, apical membrane faces follicular lumen
Endocrine
What are 3 inhibitors of Na+/I- cotransporter on basolateral membrane of thyroid follicular epithelial cells?
Perchlorate, pertechnetate, and thiocyanateBlock iodide uptake and interfere with thyroid hormone synthesis
Endocrine
Once transported into thyroid follicular epithelial cells, what is fate of I-?
I- is oxidized to I2 by thyroid peroxidase and subsequently transported across apical membrane into follicular lumen
Endocrine
Once transported into follicular lumen, what is fate of I2?
I2 is enzymatically added to tyrosine residues on thyroglobulin (TG) by thyroid peroxidase to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)”Organification of I2”
Endocrine
Mechanism by which T3 and rT3 are synthesized?
Thyroid gland predominantly synthesizes T4T4 is converted to either T3 (4x more active than T4) or rT3 (inactive) in peripheral tissues by 5’-deiodinase enzyme
Endocrine
Mechanism by which thyroid hormones are cleared by body?
Glucuronidation in liver
Endocrine
How will pharmacologic treatment with exogenous T3 affect levels of following? Why?TRHTSHT3T4rT3
TRH –> T3 negatively feeds back on hypothalamus to decrease TRH synthesisTSH –> T3 negatively feeds back on hypothalamus to downregulate TSH synthesis and to cause internalization of TRH receptors (decreasing responsiveness to TRH)T3 –> Exogenous T3 will increase overall T3 levelsT4 –> T3 negative feedback on TRH/TSH will decrease thyroid gland secretion of thyroid hormones (predominantly T4), thereby causing decreased T4 levelsrT3 –> Decreased T4 levels means less T4 available to be converted to rT3 by 5’-deiodinase causing decreased rT3 levels
Endocrine
Wolff-Chaikoff effect?
High I- levels temporarily inhibit thyroid peroxidase action of organification of I2 to MIT/DIT –> Temporarily inhibits synthesis of thyroid hormones
Endocrine
S/p organification (addition of I2 to tyrosine residues on TG), how are thyroid hormones synthesized in follicular lumen?
Coupling reactions catalyzed by thyroid peroxidase:MIT + DIT –> T3DIT + DIT –> T4
Endocrine
Thyroid peroxidase:Function in thyroid follicular epithelial cell?Function in follicular lumen?
Follicular epithelial cell –> Convert I- to I2 Follicular lumen –> Organification of I2 (addition to TG), coupling reactions
Endocrine
Drug that inhibits both thyroid peroxidase and 5’-deiodinase?
Propylthiouracil (PTU)
Endocrine
Drug that inhibits only thyroid peroxidase?
Methimazole
Endocrine
Why does thyroid gland synthesize predominantly T4?
DIT + DIT coupling reaction that produces T4 proceeds at 10x greater rate than MIT + DIT coupling reaction that produces T3
Endocrine
Colloid?
Colloid –> Thyroglobulin (TG) with bound T3, T4, MIT, and DIT stored in thyroid follicles
Endocrine
Cellular mechanism by which thyroid hormones are released from gland in response to TSH stimulation?
TSH induces endocytosis of colloid (TG + T3/T4/MIT/DIT) from follicle lumen into follicular epithelial cellTG is then transported to basal membrane via microtubular transportTG fuses with lysosomal membrane and lysosomal proteases hydrolyze peptide bonds to release T3, T4, MIT, and DIT from TGT3 and T4 are transported across basal membrane into systemic circulation (bloodstream)MIT, DIT, and TG (tyrosine residues) are recycled
Endocrine
Mechanism by which MIT and DIT are recycled?
MIT and DIT deiodinized by deiodinase enzyme to salvage I- and tyrosine residues
Endocrine
Thyroid hormones:Carrier protein in blood?Physiologically active form?
Thyroxine-binding globulin (TBG) binds thyroid hormones in bloodstreamPhysiologically active form –> FREE T3 and T4Only SMALL amounts are actually unbound. TBG provides a large reservoir of circulating thyroid hormones that may be released and added to the pool of unbound, physiologically active form when needed.
Endocrine
Thyroid levels in liver failure?
Liver failure –> Decreased synthesis of TBGDecreased levels of TBG –> Transient increase in unbound/free thyroid hormones (physiologically active) –> Free T3 provides negative feedback on anterior pituitary and inhibits thyroid hormone synthesis –> Decreased thyroid hormone levels
Endocrine
Thyroid levels in pregnancy and OCP use?
High estrogen levels –> Inhibit hepatic breakdown of TBG –> Increased TBG levels –> Transient decrease in unbound/free thyroid hormones (more TBG available to bind free thyroid hormone)Decreased free T3 levels lowers negative feedback –> Activates thyroid hormone synthesisTotal T3 and T4 levels increase, but levels of unbound T3 and T4 remain same (b/c TBG levels increase)
Endocrine
Functions of thyroid hormone?
4 B’s –> Basal metabolic rate, B1 adrenergic receptor upregulation on heart, bone growth, and brain maturation
Endocrine
Mechanism by which thyroid hormone increases basal metabolic rate?
Thyroid hormone increases activity of Na/K ATPase –> Increases O2 consumption –> Heat production –> Increases BMR, RR, and body temperature
Endocrine
Mechanism by which thyroid hormone increases metabolism?
Thyroid hormone increases glucose absorption from GI tract and potentiates effects of other hormones (e.g., glucagon, GH) on gluconeogenesis, lipolysis, and proteolysisThyroid hormone induces synthesis of key metabolic enzymes
Endocrine
Mechanism by which thyroid hormone increases cardiac output?
Thyroid hormone upregulates cardiac b1-adrenergic receptors that mediate effects of sympathetic nervous system to increase HR and contractility
Endocrine
Mechanism by which thyroid hormone contributes to growth to adult stature?
Thyroid hormone works synergistically with GH to promote bone formation and to promote ossification and fusion of bone plates and bone maturation
Endocrine
Hypothyroidism in perinatal period?
Decreased thyroid hormone levels –> Irreversible mental retardation (cretinism)Thyroid hormone essential for CNS maturation
Endocrine
Cortisol:Synthesized by?Synthesized in response to?Carried in blood by (2 names)?
Synthesized by zona fasciculata of outer adrenal cortexSynthesized in response to ACTH stimulation of outer adrenal cortex (stimulates cholesterol desmolase)Cortisol carried in blood by corticosteroid binding protein (CBP) also called transcortin
Endocrine
Steroid hormone synthesis:Location of cholesterol –> pregnenolone reaction?
Mitochondria
Endocrine
Glucocorticoid (cortisol) secretion:Unique feature of secretion?Cortisol secretion highest?Cortisol secretion lowest?
Cortisol secretion oscillates with 24h periodicity (circadian rhythm)Cortisol secretion is highest just before waking –> 8AMCortisol secretion is lowest just before sleeping –> 12AM
Endocrine
Hypothalamic nuclei important in glucocorticoid (cortisol) secretory regulation?
Suprachiasmatic nuclei b/c controls circadian rhythm
Endocrine
Pro-opiomelanocortin (POMC)?
CRH stimulates anterior pituitary to synthesize POMC –> Precursor for ACTH and MSHAddison disease –> Increased ACTH levels AND increased MSH levels –> Increased pigmentation of buccal mucosa
Endocrine
Negative feedback mechanism in glucocorticoid (cortisol) secretion?
Cortisol inhibits CRH release from hypothalamus and ACTH release from anterior pituitary
Endocrine
Mechanism by which cortisol acts in target cells?
Cortisol diffuses across membrane of target cells and binds to steroid receptors in CYTOPLASM. Binding induces dissociation of cytoplasmic receptors from chaperone (heat shock protein). Cortisol-receptor complex translocates to nucleus.
Endocrine
Cortisol:Effect on blood pressure?Mechanism?
Cortisol increases BP by upregulating a1-receptors on arterioles, increasing arteriole sensitivity to effects of NE (vasoconstrictor)
Endocrine
“Cortisol is permissive for catecholamines” –> Explain
Cortisol has NO effect on vascular reactivity (vasoconstriction or vasodilation) itself, but augments/potentiates effects of catecholamines (NE) on arterioles 2/2 upregulation of a1 receptors
Endocrine
Cortisol: Effect on prostaglandins/leukotrienes?Effect on IL-2 and T cells?Effect on histamine and serotonin?Effect on neutrophils?Effect on eosinophils?
Cortisol upregulates synthesis of lipocortin (cortisol binding protein) –> Lipocortin is an inhibitor of phospholipase A2, an enzyme that liberates arachadonic acid from phospholipid membranes –> Arachadonic acids are precursors for prostaglandin and leukotriene synthesis (inflammatory mediators)Cortisol inhibits production of IL-2 and thereby inhibits proliferation of T cellsCortisol inhibits release of histamine and serotonin from mast cells and plateletsCortisol inhibits leukocyte adhesion –> Demargination of neutrophils –> Increased neutrophils in bloodCortisol reduces number of eosinophils in blood
Endocrine
Before starting treatment w/ corticosteroids always test for what infection 1st?
Latent TB infection b/c corticosteroids inhibit IL-2 which is necessary for maintenance of granulomas.Decreased IL-2 may lead to decomposition of granulomas and release of latent TB infection –> Reactivation of TB.
Endocrine
Cortisol:Effect on gluconeogenesis?Mechanism?
Cortisol stimulates gluconeogenesis by:1) Increasing protein catabolism (proteolysis) in muscle and decreasing protein synthesis to provide more amino acids to liver for gluconeogenesis2) Decreasing glucose utilization and insulin sensitivity of adipose tissue –> Diabetogenic3) Increasing lipolysis to provide more glycerol to liver for gluconeogenesis
Endocrine
Cortisol:Effect on fibroblasts?Clinical correlate?
Cortisol inhibits fibroblasts –> Abdominal striae in Cushing disease
Endocrine
Cortisol:Effect on bone?Mechanism?
Cortisol decreases bone formation and increases bone resorption by decreasing activity of osteoblasts
Endocrine
Unique feature of mineralocorticoid synthesis in zona glomerulosa of adrenal cortex?
Mineralocorticoid (aldosterone) synthesis regulated by renin-angiotensin-aldosteron system (ATII) and by K+ levelsZona fasciculata and reticularis regulated by ACTH ACTH receptor deficiency –> Aldosterone synthesis NORMAL
Endocrine
Stimulation of aldosterone synthesis (x2)?
1) Decrease in mean arterial pressure (MAP) –> Decrease in renal perfusion pressure –> Renin production –> Renin catalyzes conversion of angiotensinogen to angiotensin I –> ACE in lungs catalyzes ATI to ATII –> ATII stimulates aldosterone synthase in zona glomerulosa to increase synthesis of aldosterone2) Hyperkalemia –> Increased K+ depolarizes cells in zona glomerulosa –> Opens voltage-gated Ca2+ channels –> Increased Ca2+ stimulates synthesis of aldosterone
Endocrine
Aldosterone:Compensatory mechanism in response to decreased renal perfusion pressure?
Aldosterone acts on principal cells in late distal tubule and collecting duct to increase renal Na+ reabsorption –> H2O follows –> Restores volume
Endocrine
Aldosterone:Compensatory mechanism in response to hyperkalemia?
Aldosterone acts on principal cells in late distal tubule and collecting duct to increase renal K+ wasting –> Decreases serum K+ levels to normal
Endocrine
Growth hormone (GH) secretion:Unique feature of secretion?2 stimulators of secretion?3 inhibitors of secretion?
GH secretion is pulsatile with secretory bursts every 2 hoursGH secretion increased by –> Exercise and sleepGH secretion decreased by –> Hyperglycemia (high glucose), somatostatin, and somatomedins
Endocrine
What are somatomedins and when are they produced?
Somatomedins –> Insulin-like growth factors (IGFs)IGFs are produced when GH acts on target tissues
Endocrine
GH secretion:Feedback mechanisms (x4)?
1) GHRH released by hypothalamus feeds back on hypothalamus itself and inhibits further GHRH secretion2) GH released by anterior pituitary feeds back on hypothalamus and stimulates secretion of somatostatin –> Somatostatin = somatotropin release inhibiting factor (SRIF) –> Somatostatin inhibits GH (somatotropin) synthesis in anterior pituitary3) Somatomedins (IGFs) produced in target tissues feed back on anterior pituitary and inhibit GH secretion4) Somatomedins (IGFs) produced in target tissues feed back on hypothalamus and stimulates secretion of somatostatin –> GH inhibition
Endocrine
Only direct function of GH?
GH increases blood glucose levels by decreases glucose uptake and utilization (insulin resistance) –> Diabetogenic Cortisol –> Also diabetogenic
Endocrine
Somatomedins:Function?Act on what 3 tissue types?
Somatomedins increase protein synthesis –> Chondrocytes, muscle, most other organs
Endocrine
Somatomedins:Chondrocytes?Muscle?Most other organs?
Chondrocytes –> Increased protein synthesis –> Increased linear growth –> PUBERTAL GROWTH SPURTMuscle –> Increased protein synthesis –> Increased lean body massMost other organs –> Increased protein synthesis –> Increased organ size
Endocrine
GH deficiency before puberty:Clinical presentation?Treatment?
Failure to grow, short stature, mild obesity, delayed pubertyFailure to grow and short stature –> Decreased protein synthesis in chondrocytesMild obesity –> Decreased protein synthesis in muscleTx –> GH replacement therapy
Endocrine
GH excess before puberty:Clinical presentation?Treatment?
Gigantism –> Increased linear growth –> Epiphyseal plates have yet to fuse pre-pubertyTx –> Somatostatin analog (octreotide)
Endocrine
GH excess after puberty (adult):Clinical presentation?Treatment?
Acromegaly –> Increased organ size, increased hand/foot size, enlargement of tongue, coarsening of facial featuresEpiphyseal plates have already fused –> Increased protein synthesis in organs only (not chondrocytes)Insulin resistance, glucose intoleranceTx –> Somatostatin analog (octreotide)
Endocrine
Negative feedback mechanism in prolactin secretion?
Prolactin feeds back on hypothalamus to stimulate dopamine (prolactin inhibiting factor) secretion, which inhibits prolactin secretion
Endocrine
What are 3 functions of prolactin?
Stimulation of milk production (lactogenesis) in breastPotentiates breast development with estrogenInhibits ovulation/spermatogenesis by inhibiting synthesis/secretion of GnRH in hypothalamus –> Amenorrhea in women, decreased libido in men
Endocrine
What are 2 milk products in breast milk?
Casein, lactalbumin
Endocrine
Suckling stimulates sensory nerves that carry suckling signal from breast to [?] to promote what 3 effects?
Suckling signal inputs to ARCUATE NUCLEUS of hypothalamus to inhibit dopamine, thereby promoting prolactin releaseSuckling –> Prolactin and oxytocin release
Endocrine
Prolactin:Causes of deficiency (x1)?Causes of excess (x2)?Manifestations of deficiency?Manifestations of excess?Drug(s) that stimulate(s) prolactin release?Drug(s) that inhibit(s) prolactin release?
Deficiency –> Destruction of anterior pituitary–> Failure to lactate –> Dopamine antagonists (estrogens/OCPs, antipsychotics) stimulate prolactin secretionExcess –> Hypothalamic destruction (loss of tonic inhibitory control by dopamine) or prolactin-secreting tumor (prolactinoma)–> Galactorrhea, amenorrhea in females or decreased libido in males, impaired ovulation/spermatogenesis (prolactin inhibits GnRH)–> Dopamine agonists (bromocriptine) inhibit prolactin secretion –> Treat prolactinoma
Endocrine
Parathyroid hormone (PTH):Site of synthesis?Function?
PTH synthesized in chief cells of parathyroid glandsFunctions to regulate serum Ca2+ levels
Endocrine
Parathyroid hormone (PTH):2 triggers that stimulate PTH?2 triggers that inhibit PTH?
Decreases in serum Ca2+ and MILD decreases in serum Mg2+ stimulate PTH secretionIncreases in serum Ca2+ and SEVERE decreases in serum Mg2+ inhibit PTH secretion
Endocrine
Mechanism by which serum Ca2+ levels control PTH secretion?
Increased serum Ca2+ –> Ca2+ binds Ca2+-sensing receptors on chief cell membrane –> Inhibits PTH secretionDecreased serum Ca2+ –> Less Ca2+ available to bind Ca2+-sensing receptors on chief cell membrane –> Triggers PTH secretion
Endocrine
What are 2 causes of hypomagnesemia?
Decreased absorption or intake of Mg2+ –> Chronic diarrhea, alcoholism Increased renal loss of Mg2+–> Diuretics (loop, thiazide)–> Drugs (aminoglycosides)
Endocrine
PTH functions to increase [?] and decrease [?] serum levels
Increase Ca2+, decrease phosphate
Endocrine
Vitamin D:Cutaneous precursor?Vitamin D2 = ?Vitamin D3 = ?
Cutaneous precursor –> 7-dehydrocholesterolVitamin D2 –> Ergocalciferol (dietary plant sources)Vitamin D3 –> Cholecalciferol (dietary animal sources)
Endocrine
Cutaneous source of vitamin D?
On exposure to ultraviolet light, cutaneous precursor of vitamin D (7-dehydrocholesterol) undergoes photochemical cleavage to form vitamin D3 (cholecalciferol)
Endocrine
Cholecalciferol (vitD3) processing?
Liver –> Cholecalciferol undergoes 25-hydroxylation to form 25-hydroxycholecalciferol 25-OH-cholecalciferol
Endocrine
25-OH-cholecalciferol processing (x2)?
25-OH-cholecalciferol –> 1,25-(OH)2-cholecalciferol via 1α-hydroxylase in kidney25-OH-cholecalciferol –> 24,25-(OH)2-cholecalciferol via 24α-hydroxylase in kidney1,25-(OH)2-cholecalciferol –> Calcitrol –> ACTIVE vitamin D24,25-(OH)2-cholecalciferol –> INACTIVE vitamin D
Endocrine
What 3 factors increase production of active vitamin D (calcitrol)? Mechanism?
Decreased Ca2+, decreased phosphate, increased PTH–> Increase activity of renal 1α-hydroxylase and decrease activity of 24α-hydroxylase
Endocrine
Vitamin D deficiency:In adults –> ?In children –> ?4 causes of deficiency?
Adults –> OsteomalaciaChildren –> Rickets Deficiency:–> Malabsorption–> Poor diet–> Decreased sunlight (decreased photochemical cleavage of 7-dehydrocholesterol to cholecalciferol)–> Chronic renal failure –> Impaired 1α-hydroxylase activity responsible for calcitrol production
Endocrine
Mechanism by which vitamin D (calcitrol) acts in target tissues?
Vitamin D diffuses across membrane of target cells and binds to steroid receptors in NUCLEUS
Endocrine
What are 3 functions of vitamin D?
1) Increase Ca2+ reabsorption in duodenum2) Increase phosphate reabsorption in jejunum and ileum3) Increases bone resorption –> Provides Ca2+ and phosphate from “old” bone to mineralize “new” bone
Endocrine
Vitamin D increases Ca2+ reabsorption in gut: Site?Mechanism?
Increased Ca2+ reabsorption in duodenum Vitamin D increases production of vitamin D-depending Ca2+-binding protein –> CALBINDIN D
Endocrine
Vitamin D increases bone resorption: Mechanism?
Vitamin D stimulates monocytic stem cells to become osteoclasts –> Bone-resorbing cells
Endocrine
PTH functions to increase serum Ca2+ and decrease serum phosphate levels by coordinating what 4 independent actions?
1) Increases bone resorption –> Brings both Ca2+ and phosphate from bone mineral into serumAlone, this effect would not increase serum ionized (free) Ca2+ b/c increased phosphate complexes with increased Ca2+2) Inhibits renal phosphate reabsorption –> Increases phosphate excretion (phosphaturic effect) –> Decreases serum phosphate levels3) Increases renal Ca2+ reabsorption –> Increases serum Ca2+ levels4) Increases intestinal Ca2+ reabsorption INDIRECTLY by stimulating 1α-hydroxylase activity in kidney and increasing production of active vitamin D
Endocrine
PTH increases Ca2+ reabsorption in [?] of kidneyPTH decreases phosphate reabsorption in [?] of kidney
Increased Ca2+ reabsorption –> Distal convoluted tubuleDecreased phosphate reabsorption –> Proximal convoluted tubule (phosphate –> proximal)
Endocrine
PTH –> Increased bone resorption:PTH acts on PTH-receptors on what cell type?Receptor binding triggers what 2 processes?2 downstream effects of these processes?
PTH acts on PTH-receptors on osteoblast precursors (bone-forming cells)–> Increases synthesis/secretion of macrophage colony-stimulating factor (M-CSF)–> Increases expression on cell surface of “receptor activator for nuclear factor kB ligand” –> RANK-L–> M-CSF and RANK-L bind receptors on osteoclast precursors (bone-resorbing cells) to stimulate production of mature osteoclasts –> RANK-L binds receptors on mature osteoclasts to increase their bone-resorbing activity
Endocrine
Laboratory finding that correlates with PTH actions on proximal convoluted tubule (decreased phosphate reabsorption) and distal convoluted tubule (increased Ca2+ reabsorption)?
Increased urinary cAMP b/c PTH signals through cAMP 2nd messenger
Endocrine
Laboratory finding that correlates with PTH (and vitamin D) action on bone to increase matrix reabsorption?
Increased urinary hydroxyproline, which correlates with resorption of bone organic matrix
Endocrine
PTH leads to ___ (increased/decreased) reabsorption of Ca2+ and ___ (increased/decreased) reabsorption of phosphate where?Vitamin D to ___ (increased/decreased) reabsorption of Ca2+ and ___ (increased/decreased) reabsorption of phosphate where?
PTH –> Increased reabsorption of Ca2+ and decreased reabsorption of phosphate in kidneysVitamin D –> Increased Ca2+ AND phosphate reabsorption in gut
Endocrine
What are 3 forms of Ca2+ in serum?
Ionized/free Ca2+ (45%)Ca2+ bound to albumin (40%)Ca2+ bound to anions, e.g., phosphate (15%)
Endocrine
Increased pH –> Affect on Ca2+ levels in serum?
Increased pH –> Increased affinity of negatively-charged albumin for Ca2+ –> Decreased free/ionized Ca2+ levels”Hypocalcemia” –> Cramps, pain, paresthesias, carpopedal spasm
Endocrine
Negative feedback mechanism for PTH secretion?
Increased serum Ca2+ and vitamin D (calcitrol) levels feed back on chief cells of parathyroid glands and decrease PTH release
Endocrine
Calcitonin:Site of synthesis?Function?
Calcitonin synthesized in parafollicular C cells of thyroid glandFunctions to counter actions mediated by PTH and thereby regulate “tone” or level of Ca2+–> Does NOT appear to function in normal Ca2+ homeostasis
Endocrine
Calcitonin:Trigger of secretion?
Increased serum Ca2+ stimulates calcitonin release Calcitonin “tones” down Ca2+ levels by opposing actions of PTH
Endocrine
Mechanism by which calcitonin opposes PTH action to “tone” Ca2+ levels?
Calcitonin inhibits osteoclast bone resorption
Endocrine
PTH –> Increases bone resorption by acting on [?]Calcitonin –> Decreases bone resorption by acting on [?]
PTH –> Acts on OSTEOBLASTS–> Indirectly activates osteoclast activityCalcitonin –> Acts on OSTEOCLASTS–> Directly inhibits osteoclast activity
Endocrine
Pancreatic islets, α cells:Location in islet?Secretory product?
Located peripherallySecrete glucagon
Endocrine
Pancreatic islets, β cells:Location in islet?Secretory product?
Located centrallySecrete insulinINSulin cells –> INSide islet
Endocrine
Pancreatic islets, δ cells:Location in islet?Secretory product?
Intermixed throughout isletSecrete somatostatin
Endocrine
Proinsulin: Site of processing?Mechanism of processing?
Proinsulin is deposited in rER and transported within membrane-enclosed organelles to sacs of Golgi apparatus Within Golgi, convertases cleave proinsulin –> insulin + C peptide
Endocrine
Structure of insulin?
Insulin –> 2 peptide chains (A and B chains) linked by 2 disulfide linkages
Endocrine
Insulin secretion:- Glucose uptake into β cell via what transporter?- Fate of glucose in β cell?- 1st channel to close s/p glucose uptake?- Trigger for this channel to close?- Mechanism by which β cell membrane depolarizes?- Depolarization opens what channel?- Final trigger for insulin release?
- Glucose into β cell via GLUT2 transporter- Glucose undergoes glycolysis, which raises intracellular ATP - K(ATP) channels - Increased ATP closes ATP-dependent K+ channels (K+ accumulates inside cell)- Decreased K+ conductance depolarizes β cell membrane (potential is less negative)- Depolarization opens voltage-gated Ca2+ channels - Ca2+ influx triggers Ca2+-dependent Ca2+ release –> Significantly elevated Ca2+ levels trigger exocytosis of insulin granules –> Release of insulin + C peptide
Endocrine
Mechanism by which α- and β-cells communicate?
Gap junctions
Endocrine
Insulin receptor structure?
α2β2 heterotetrameric complex2 insulin-binding α subunits2 catalytically-active β subunits –> Intracellular tyrosine kinase activity
Endocrine
Binding of insulin to α-subunits of insulin receptor triggers?
Binding of insulin to extracellular α-subunits of insulin receptor triggers tyrosine kinase activity of intracellular β-subunits1 β-subunit phosphorylates other (autophosphorylation) –> Initiates signal cascade
Endocrine
1st phosphorylation event triggered by activation of insulin receptor?
Phosphorylation of insulin receptor substrates (IRS-1, IRS-2)
Endocrine
IRS-1 and IRS-2 phosphorylation triggers what 2 signaling pathways?
Metabolic pathway Mitogenic pathway
Endocrine
Metabolic pathway of insulin signaling:Signaling mechanism?Functions (x2)?
Metabolic signaling –> PI3K/Akt/mTOR1) Drives GLUT-4 containing vesicles to cell membrane in adipocytes and muscle cells 2) Increases glycogen synthesis, lipid synthesis, and protein sysnthesis
Endocrine
Mitogenic pathway of insulin signaling:Signaling mechanism?Function?
Mitogenic signaling –>RAS, Raf kinase, MAPKCell growth and DNA synthesis
Endocrine
Mechanism by which glucagon mediates insulin resistance?
Glucagon –> Activates serine kinases that phosphorylate insulin receptor substrates (IRS-1, IRS-2) such that they’re not available to be phosphorylated by insulin receptor –> Inhibits insulin signaling pathway
Endocrine
Mechanism by which TNFα mediates insulin resistance?
TNFα –> Activates serine kinases that phosphorylate insulin receptor substrates (IRS-1, IRS-2) such that they’re not available to be phosphorylated by insulin receptor –> Inhibits insulin signaling pathwaySame as glucagon
Endocrine
Mechanisms by which insulin decreases blood glucose levels (x3)?
1) Upregulates expression of GLUT4 receptor on adipocytes and muscle cells –> Increases glucose uptake into these cells2) Promotes formation of glycogen from glucose and inhibits glycogenolysis (breakdown of glycogen) in muscle and liver cells 3) Decreases gluconeogenesis –> Increases production of fructose-2,6-bisphosphate thereby increasing phosphofructokinase (PFK) activity –> Substrate is shunted toward glucose breakdown and away from glucose formation
Endocrine
Effect of insulin on fats?
Insulin decreases fatty acid levels in blood –> Stimulates fat deposition in adipose tissue and inhibits lipolysis
Endocrine
Effect of insulin on proteins?
Insulin decreases amino acid levels in blood –> Stimulates amino acid uptake into cells –> Increases protein synthesisSimultaneously, insulin inhibits protein degradation*Insulin is anabolic
Endocrine
Effect of insulin on K+ levels?
Insulin promotes K+ uptake into cells –> Decreases K+ levels in blood –> Hypokalemia
Endocrine
Effect of insulin on Na+ levels?
Insulin increases Na+ reabsorption in kidneys –> Increases Na+ levels in blood –> Hypernatremia
Endocrine
Glucose - Cross placenta?Insulin - Cross placenta?
Glucose crosses placenta Insulin does NOT cross placenta
Endocrine
Stimulators of insulin secretion (x3)?
1) Hyperglycemia 2) Growth hormone (GH)3) β2-agonists (Gs protein –> Epinephrine)
Endocrine
Inhibitors of insulin secretion (x4)?
1) Hypoglycemia 2) Somatostatin3) α2-agonists (Gi protein –> Norepinephrine)4) Glucagon
Endocrine
Mechanism by which GH stimulates insulin secretion?
GH decreases glucose uptake into cells and increases insulin resistance –> Stimulates increased insulin secretionGH does NOT stimulate insulin directly
Endocrine
Only insulin-dependent glucose transporter?
GLUT4GLUT1, GLUT2, GLUT3, GLUT5 –> Insulin-INDEPENDENT transporters
Endocrine
GLUT1:Present on what cell type(s)?Distinctive feature(s)/function(s)?
CNS, RBCsGLUT1 mediates basal glucose uptake b/c it has a very high affinity for glucose (low Km) –> Can therefore transport glucose into cells at relatively low concentrations, such as those found in fasting statesEnsures adequate transport of glucose into CNS and RBCs–> RBCs lack mitochondria –> Rely on glucose for all energy
Endocrine
GLUT2:Present on what cell type(s)?Distinctive feature(s)/function(s)?
Hepatocytes and pancreatic β cells GLUT2 regulates insulin release –> low affinity for glucose (high Km) Low affinity for glucose reduces hepatic uptake of glucose during fastingBi-directional transporter –> Assists in export of glucose from hepatocytes when needed
Endocrine
GLUT3:Present on what cell type(s)?Distinctive feature(s)/function(s)?
Neurons, placentaGLUT3 has a very high affinity for glucose (low Km) –> Responsible for glucose uptake into neurons even in fasting states GLUT3 mediates placental transport of glucose –> High affinity for glucose permits glucose uptake by placenta to provide developing embryo/fetus with glucose
Endocrine
GLUT4:Present on what cell type(s)?Distinctive feature(s)/function(s)?
Adipocytes, muscle cellsGLUT4 –> Insulin-dependent transporter –> Sequestered within intracellular vesicles until insulin stimulation induces its expression on cell surface
Endocrine
GLUT5:Present on what cell type(s)?Distinctive feature(s)/function(s)?
GI tract, spermatocytesGLUT5 responsible for fructose uptake from GI tract–> Fructose important in spermatocyte function
Endocrine
Stimulator of glucagon secretion (x1)?
Hypoglycemia
Endocrine
Inhibitors of glucagon secretion (x3)?
HyperglycemiaSomatostatinInsulin
Endocrine
Mechanisms by which glucagon decreases blood glucose levels (x2)?
1) Increases glycogenolysis (glycogen breakdown into glucose) in muscle and liver cells 2) Increases gluconeogenesis (production of glucose in liver)–> Decreases production of fructose-2,6-bisphosphate thereby decreasing phosphofructokinase (PFK) activity –> Substrate is shunted toward glucose formation and away from glucose breakdown
Endocrine
Effect on lipids:Insulin?Glucagon?
Insulin –> Decreases blood fatty acid levels b/c stimulates fat deposition in adipose tissue and inhibits lipolysis (fat breakdown)Glucagon –> Increases fatty acid levels b/c stimulates lipolysis (fat breakdown) in adipose tissue
Endocrine
Effect on ketoacids:Insulin?Glucagon?
Insulin –> Inhibits ketoacid formation in liver b/c insulin decreases fatty acid production –> Less acetyl CoA substrate available for ketoacid formationGlucagon –> Increases ketoacid formation in liver b/c glucagon increases fatty acid production–> More acetyl CoA substrate available for ketoacid formation–> Glucagon senses hypoglycemia and responds to increase glucose levels in blood to provide tissues with substrate for energy production–> Glucagon stimulates ketoacid production to be used as energy as well
Endocrine
Ketoacids:Synthesized from what precursor?What are 2 ketoacids?
Ketoacids via acetyl CoA precursor2 ketoacids –> Acetoacetate and β-hydroxybutyrate