Endocrine Review Flashcards
What are Pheochromocytomas?
-Tumor of chromaffin cells of the adrenal medulla
-cells synthesize, store, and secrete catecholamines in response to sympathetic stimulation
-can occur alone or as part of a multiple endocrine neoplasia syndrome
-can be locally invasive or metastatic
Clinical signs of Pheochromocytomas
-hypertension, weakness, syncope, tachypnea, abdominal distension, tachyarrhythmias, bradyarrhythmias, abdominal pain
-30-50% of dogs have clinical sign
-sustained or paroxysmal
-cats: lethargy, PU/PD, aggression, systemic hypertension, weight gain, vomiting
Diagnosis of pheochromocytoma
-CT/MRI best for determining size of tumor and extent of invasion
-Rads show mineralization in the area of adrenal glands, retroperitoneal effusion, or mass effect
-65-83% seen on AUS
-if >20 mm, thought to be malignant
Labwork abnormalities seen with Pheochromocytomas
-can have ELE
-hypercalcemic from elevated PTH or parathyroid hormone related peptide
-hyperglycemia from catecholamine stimulation of hepatic gluconeogenesis, refractory catecholamine-induced insulin receptors, decreased insulin release from alpha receptor stimulation
-25% dogs have hypercholesterolemia from increased fat mobilization from catecholamine secretion or concurrent Cushing’s
-50% dogs have proteinuria from hypertensive glomerulopathy
Treatment of pheo
-Sx excision is definitive tx
-phenoxybenzamine (non-competitive alpha adrenergic blockade) to reduce hypertensive episodes during SX, start tx 1 week prior to sx
-sx often requires vena cava venotomy and nephrectomy
-medical management: phenoxybenzamine, beta-blockers, anti-arrhythmics
-beta blockers should not be administered without concurrent alphablockades because the loss of the beta-2 receptor mediated vasodilation may exacerbate hypertension
Prognosis of Pheochromocytomas
-Survival times from 18 months to 4 years with successful surgical resection and uneventful post-operative course
-poor prognosis associated with neurological deficits, weight loss, abdominal dissension, acute hemorrhage, larger tumors with invasion of neighboring structures, metastasis, and Venus thrombosis
Synthesis of peptide/protein hormones
In the nucleus, the gene for the hormone is transcribed into mRNA mRNA transferred to the cytoplasm and translated on the ribosomes to the first protein product (preprohormone) translation of the mRNA begins with a signal peptide at the N terminus that signal peptide attaches to receptors on the endoplasmic reticulum via “docking proteins” translation continues until preprohormone produced Signal peptide is removed from the endoplasmic reticulum preprohormone converted to prohormone Prohormone contains complete hormone sequence plus other peptide sequences which will be removed in a final step (some of the other peptide sequences are necessary for proper folding of the hormone) prohormone transferred to golgi apparatus where it is packaged into secretory vesicles. Inside the vesicles, proteolytic enzymes cleave the peptide sequences from the prohormone to the final hormone. Golgi also allows for glycosylation and phosphorylation of the hormone final hormone stored in secretory vesicles until the endocrine cell is stimulated
What are steroid hormones and how are they synthesized?
-Synthesized and secreted by the adrenal cortex, gonads, corpus luteum, and placenta.
-Steroid hormones include cortisol, aldosterone, estradiol, estriol, progesterone, testosterone, 1,25-dihydroxycholecalciferol.
-All steroid hormones are derivatives of cholesterol, modified by removal or addition of side chains, hydroxylation, or aromatization of the steroid nucleus.
What is the mechanism of action of Gs activation?
- G proteins are a family of membrane bound proteins that couple hormone receptors to effector enzymes (adenylyl cyclase) -> G proteins serve as molecular switches that decide whether the hormone can proceed
- G proteins have 3 subunits – alpha, beta, gamma
- Alpha subunit can bind GDP (inactive) or GTP (active)
- Once active, the alpha-GTP complex binds to adenylyl cyclase
- AC catalyzes the conversion of ATP to cAMP
- cAMP works via a series of steps involving activation of protein kinase A, which allows for phosphorylation of proteins
- cAMP is degraded by phosphodiesterase into 5’AMP turns off action of the second messenger
What is the mechanism of Gq activation?
- Hormone binds to receptor (Gq)
- Alpha subunit binds to GTP and migrates/binds to phospholipase C
- Activated phospholopase C catalyzes the liberation of DAG an IP3 from PIP2
- IP3 causes release of Ca2+ from intracellular stores in ER and SR
- Results in increased Ca2+ concentration
- Ca2+ and DAG activate protein kinase C -> phosphorylates proteins to produce the final physiologic actions
Tyrosine kinase activation
a. Receptor tyrosine kinase have intrinsic tyrosine kinase activity within the receptor molecule. Tyrosine kinase associated receptors do not have intrinsic tyrosine kinase activity, but associate noncovalently with proteins that do.
b. Receptor tyrosine kinases have an extracellular binding domain that binds the hormone or ligand, and an intracellular domain that contains tyrosine kinase activity. Once activated, the intrinsic tyrosine kinase phosphorylates itself and other proteins.
c. Tyrosine kinase-associated receptors do mot tyrosine kinase activity, but are noncovalently associated with tyrosine kinase (ie: JAK). Hormone binds to extracellular domain activation of tyrosine kinase phosphorylates tyrosine moieties on itself, hormone receptor, and other proteins
Steroid hormone mechanism of action
a. Steroid hormones and thyroid hormones have the same mechanism of action. It involves binding to cytosolic (nuclear) receptors that initiate DNA transcription and synthesis of new proteins.
b. Steroid hormone mechanism: Hormone diffuses across the cell membrane and enters target cell -> binds to specific receptor protein in cytosol or nucleus. Each rceptor has 6 domains -> steroid hormone binds to E domain located near C terminus -> Once bound, receptor undergoes conformational change and activated hormone-receptor complex enters nucleus of target cell -> complex dimerizes and binds via zinc fingers to specific DNA sequences (steroid-responsive elements) located in the target gene -> complex is now a transcription factor -> new mRNA is transcribed -> leaves nucleus and is translate to new proteins
ADH production and secretion
-ADH acts on kidneys and arterioles
- The connections between the hypothalamus and the posterior lobe of the pituitary are neural. Hormones are secreted by the posterior lobe. The cell bodies of ADH-secreting neurons are located in the supraoptic and paraventricular nuclei within the hypothalamus. Once synthesized in the cell bodies, the hormones are transported down the axons in neurosecretory vesicles and stored in bulbous nerve terminals in the posterior pituitary. When cell body is stimulated, neurosecretory vesicles are released from the nerve terminals by exocytosis and secreted hormone enters nearby fenestrated capillaries. Venous blood from the posterior pituitary enters the systemic circulation, which delivers hormones to target tissues.
CIRCI
-Critical illness-related corticosteroid insufficiency
-Due to a combination of alternations in the production, plasma protein binding, metabolism, and target tissue effects of cortisol
Pathophysiology of CIRCI
o Pathophysiology of CIRCI appears to be a complex combination of alternations in the production, plasma carriage, metabolism of, and tissue responsiveness to cortisol. Direct trauma, infarction or hemorrhage, cytokine influence may impair HPA axis function and there by decrease circulating cortisol. Medications in the ICU can decrease cortisol production (ketoconazole, etomidate, propofol, opiates)
o There is evidence that molecules other than ACTH can drive adrenal cortisol production and release independent of ACTH (cytokines, lipopolysaccharide-bound TLR, endothelin)
o Fraction of total cortisol that circulates as free is increased in critical illness -> may inhibit hypothalamus and pituitary leading to lower ACTH concentration
-> Free cortisol is increased because systemic inflammation decreases hepatic synthesis of cortisol’s carrier proteins and albumin
o During critical illness, there is impaired cortisol metabolism by kidney and liver
o GR structure may be altered in sepsis, making them resistant to cortisol
Clinical signs of CIRCI
Pressor-resistant hypotension
Normal cortisol physiology
o Hypothalamus produces corticotropin releasing hormone (CRH) which stimulates that anterior pituitary to release ACTH. Hypothalamus derived arginine vasopressin works synergistically with CRH to enhance ACTH secretion. ACTH stimulates zona fasciculata and zona reticularis of the adrenal gland to produce and release cortisol. Cortisol has negative feedback action on the hypothalamus and pituitary release. When cortisol is low, CRH and ACTH increase to stimulate cortisol production.
o Once in circulation, most cortisol is bound to corticosteroid-binding globulin and a small fraction is bound to albumin
o Cortisol that is not protein-bound is free cortisol and is biologically active fraction. Free cortisol exerts systemic effects though genomic and nongenomic pathways in nearly every cell type in the body
o Free cortisol enters target cells and binds to glucocorticoid receptor in the cytoplasm. The GR-cortisol complex translocates to the nucleus where it affects the transcription of numerous genes and alters cell function.
Cortisol function and release
Cortisol is released by adrenal glands in small amounts in circadian rhythm and larger amounts during times of physiologic stress.
-Important homeostatic functions- regulation of carbohydrate, lipid, and protein metabolism
-Immune system modulation
-Proper production of catecholamines and function of adrenergic receptors
-Stabilizing cell membranes
