Endocrine Flashcards
Corticotrophs:
- Anterior/Posterior Pituitary
- What do they produce?
- How are they stimulated?
- Anterior
- Adrenocotrophic hormone (ACTH)
- Corticotrophin Releasing Hormone (CRH)
Thyrotrophs:
- Anterior/Posterior Pituitary
- What do they produce?
- How are they stimulated?
- Anterior
- Thyroid stimulating hormone (TSH)
- Thyrotropin releasing hormone (TRH)
Gonadotrophs:
- Anterior/Posterior Pituitary
- What do they produce?
- How are they stimulated?
- Anterior
- Leutinizing hormone (LH) and Follicle stimulating hormone (FSH)
- Gonadotropin releasing hormone (GnRH)
Somatotrophs:
- Anterior/Posterior Pituitary
- What do they produce?
- How are they stimulated?
- How are they inhibited?
- Anterior
- Growth Hormone (GH)
- Growth Hormone Releasing Hormone (GHRH)
- Growth Hormone Inhibitory Hormone (GHIH) and Somatostatin
Lactotrophs:
- Anterior/Posterior Pituitary
- What do they produce?
- How are they stimulated?
- How are they inhibited?
- Anterior
- Prolactin
- Thyrotropin releasing hormone (TRH)
- Prolactin Inhibitory Hormone (PIH)
Which hormones are stored in the posterior pituitary gland (neurohypophysis)?
- Vasopressin (ADH)
2. Oxytocin
Where is ADH produced?
- Supraoptic nuclei of the hypothalamus
* Stored in the posterior pituitary for release
Where is oxytocin produced?
- Paraventricular nuclei of the hypothalamus
* Stored in the posterior pituitary for release
What are the functions of Growth Hormone?
- Increase protein synthesis
- Increase mobilization of fatty acids from adipose tissue
- Decreased utilization of glucose throughout the body
What mediates the actions of growth hormone?
- Insulin like growth factors (IGFs, aka somatomedins)
Draw the hypothalmic/pituitary/target axis for growth hormone
See notes
Axis
When does growth hormone predominate?
- During the fasted state
* Lipolysis and fatty acid oxidation (protein sparing effect) during fasting
* Insulin antagonism
What are the functions of IGH-1?
- Production increased by Growth hormone when there is sufficient nutrient intake and a high insulin concentration in the portal vein
- Antilipolytic activity
- Insulin like activity
What are the effects of growth hormone on the following?
- Insulin (CHO)
- Fat
- Protein
- Chondrocytes
- Antagonism
- Lipolysis
- Protein synthesis
- Epiphyseal growth
What are the effects of IGF-1 on the following?
- Insulin (CHO)
- Fat
- Protein
- Chondrocytes
- Insulin like activity
- Antilipolytic activity
- Protein synthesis
- Epiphyseal growth
What stimulates Growth Hormone secretion?
- Decreased BG
- Decreased FFA
- Increased amino acids
- Starvation, Fasting, Protein deficiency
- Trauma, stress, excitement
- Exercise
- Testosterone, Estrogen
- Deep sleep
- GHRH
- Ghrelin
What inhibits Growth Hormone secretion?
- Increased BG
- Increased FFH
- Aging
- Obesity
- GHIH (Somatostatin)
- Somatomedins (IGFs)
Which breeds are predisposed to pituitary dwarfism?
- German shepherd, Karelian Bear dog
What is the pathophysiology of pituitary dwarfism?
- Autosomal recessive LHX3 mutation
- Pituitary hypoplasia (pituitary cysts)
* Will have combined GH, TSH, and prolactin deficiencies
Acromegaly predominates in (males/females)
Males (88%)
What is the pathophysiology for acromegaly?
- GH-producing acidophil pituitary adenoma
- GH + IGF-1 → proliferation of bone, cartilage, soft tissues, and increase in size of organs
- Increased IGF-1 levels unable to counteract insulin resistance by excessive GH concentrations
- β cell failure → diabetes
What clinical signs are attributed to acromegaly?
- Signs related to diabetes mellitus
- PU/PD
- Plantigrade - Polyphagia
- Weight loss → stabilization → weight gain (different from diabetic cats)
- Insulin resistance
- Broadening of the head
- Prognathia infeior
- Widening of interdental spaces
- Organomegaly
- CNS signs (10-15%)
What is the diagnostic test of choice for diagnosis acromegaly?
- Measuring IGF-1
* Reflects 24 hour GH secretion
* Poorly controlled diabetes may decrease IGF-1
When could IGF-1 be normal in a cat with acromegaly? When should IGF-1 testing be done?
- If the cat is an uncontrolled diabetic
2. Recommend testing a minimum of 6-8 weeks after insulin therapy is initiated
How is acromegaly treated?
- Pituitary surgery → gold standard
- Medical therapy
- Somatostatin analogs (pasireotide, octreotide)
- Dopamine agonist (L-deprenyl)
- All showed very little effect except pasireotide - Radiation
- 2/3 will show improvement in symptoms
How is the etiology of acromegaly different in dogs?
- It is almost always induced by endogenous or exogenous progestogens giving rise to GH hypersecretion from the mammary gland
* Swedish and Norwegian Elkhounds, Border Collies, and Beagles are overrepresented
What is the precursor of ACTH?
POMC
What are the functions of cortisol?
- Increase blood glucose
- Decrease insulin sensitivity
- Decrease inflammation and immune system function
- Increase protein mobilization
- Increase mobilization of fat
What is the etiology of hyperadrenocorticism? Which is most common?
- Pituitary dependent → 85%
- Adrenal dependent → 15%
- Iatrogenic!
Hyperadrenocorticism:
Small breed dogs are more likely to have (pituitary/adrenal) dependent hyperadrenocorticism and large breed dogs are more likely to have (pituitary/adrenal)
- Pituitary
2. Adrenal
What are the clinical signs associated with Cushing’s disease?
- PU/PD → cortisol inhibits ADH’s action on V2 receptors in the collecting duct
- Polyphagia
- Muscle wasting
- Alopecia, thin skin, hyperpigmentation
- Decrease immune function
- Calcinosis cutis → Ca and P deposition increased due to secondary hyperparathyroidism
- Potbelly
- Panting
What % of Cushing’s dogs have a high PTH? Why?
- 90%
2. Secondary hyperparathyroidism
What are the characteristics of a stress leukogram?
SMILED
- Neutrophils (segs), monocytes → increased
- Lymphocytes, eosinophils → decreased
What changes can be found on a CBC in a Cushing’s patient?
- Stress leukogram
- Mild polycythemia
- Thrombocytosis (75-80%)
What changes can be found on a chemistry in a Cushing’s patient?
- ALP»>ALT
- Hypercholesterolemia (90%)
- Hypertriglyceridemia
What % of Cushing’s dogs have proteinuria?
> 50%
What % of Cushing’s dogs have UTI? What % show clinical signs?
- 50%
2. <5%
What is the effect of Cushing’s disease on thyroid function?
- Secondary hypothyroidism
- Cortisol alters thyroid hormone binding to plasma proteins
What are complications associated with Cushing’s?
- Urinary calculi
- Hypertension (31-86%)
- Gallbladder mucocele (23%)
- Pulmonary thromboembolism
The urine cortisol to creatinine ratio is very good at ruling (in/out) Cushing’s disease
- Out
2. High sens, low spec
What are you looking for in an ACTH stimulation test?
An exaggerated response to ACTH one hour post administration
- Normal <18
- Grey Zone: 18-22
- Exaggerated: >22
Low Dose Dexamethasone Suppression Test:
The 8-hour level is >1.4
This patient (is/is not) Cushinoid
Is!
What are the criteria for pituitary dependent hyperadrenocorticism on a low dose dexamethasone suppression test?
- Suppress below 1.4 at the 4 hour mark and then are above 1.4 at the 8 hour
- Are at 50% of baseline at either the 4 hour or the 8 hour
ACTH Stim vs Low Dose Dex
- More sensitive
Low Dose Dex
*Less specific → can get a false positive from stressed dogs in the hospital
ACTH Stim vs Low Dose Dex
- More specific
ACTH Stim
- Can trust a positive test
- Less sens → if neg, need to do a low dose dex
ACTH Stim vs Low Dose Dex
- Can separate PDH from ADH
Low dose dex
What is the purpose of the HIGH dose dex suppression test? What is it NOT able to do?
- Differentiating test
2. Will NOT tell you if a dog has Cushing’s disease
What are the treatments for Cushing’s disease?
- Adrenalectomy → esp. if tumor >2 cm
- Hypophysectomy
- Medical Management
- Trilostane
- Mitotane
- Ketoconazole - Radiation not effective
What is the MOA of triolostane?
Competitive inhibitor of 3β-hydroxysteroid dehydrogenase
What are the adverse effects of trilostane?
- Vomiting
- Lethargy
- Electrolyte shifts (iatrogenic Addison’s, less common)
What are the monitoring recommendations for dogs on trilostane?
- ACTH stim 10-14 days post dose change (4-6 hours post pill)
What is the MOA of mitotane?
- Selective necrosis of the zona fasciculata and reticularis
* Non-reversible
* Zona glomerulosa is resistant - Also inhibits steroid biosynthesis
- 11β-hydroxylase
- Cholesterol desmolase
What are the adverse effects for mitotane?
- Anorexia
- Lethargy
- Weakness
- Diarrhea
- Hepatotoxicity
What is a unique clinical presentation for cats with Cushing’s disease?
- Skin fragility
2. High ALP is not a consistent finding
Why does the body need cortisol?
- Hepatic gluconeogenesis and glycogenesis
- Protein and fat catabolism
- Maintain vascular reactivity to catecholamines
- Maintain endothelial integrity
- Maintain GI mucosa
What are regulators of Aldosterone secretion?
- RAAS
- Increased Angiotensin II - Increased plasma K concentration
Minor players
- Increased plasma Na
- Increased plasma ACTH
Hypophysectomy (will/will not) result in a mineralocorticoid deficiency
- Will not
- ACTH is only a minor player in aldosterone regulation
What are the consequences of hypocortisolemia?
- Hypoglycemia
- Muscular weakness
- Hypotension
- Increased vascular permeability
- Vomiting, diarrhea, weight loss
- Hypoalbuminemia
- Hypoglobulinemia
- Hypocholesterolemia
What % of dogs have primary hypoadrenocorticism? Secondary?
- 95%
2. 5%
What is the difference between primary and secondary hypoadrenocorticism?
- Primary has glucocorticoid and mineralocorticoid deficiency whereas secondary only has glucocorticoid deficiency
What % of dogs are reported to have atypical Addison’s?
- 30%
* Normal electrolytes at diagnosis
What % of the adrenal glands must be destroyed to have primary Addison’s?
- Bilateral >90% destruction
* Immune mediated adrenalitis is suspected in the majority
Addison’s is more common in (males/females)
Females
Addison’s disease most commonly has what type of inheritance?
- Autosomal recessive
* Poodles are common breed
What is the median age of onset for Addison’s?
4 years
What changes can be seen on a CBC for dogs with Addison’s?
- Non-regenerative anemia (27%)
2. Lack of a stress leukogram
What changes can be seen on a chemistry for dogs with Addison’s?
- Hyperkalemia (96%)
- Hyponatremia (81%)
* 30% have normal electrolytes - Hypercalcemia (31%)
- Azotemia (88%) and Hyperphosphatemia (68%)
- Hypoglycemia (17%)
- Hypoalbuminemia (39%)
- Reduced cardiac output
- Reduced renal perfusion
What parasite can cause Addison like changes?
Whipworms
What does a baseline cortisol >2 indicate? <= 2?
- Ruled out Addison’s
2. Needs further testing
What result on an ACTH stimulation test would indicate Addison’s disease?
Flat-line
Dexamethasone (does/does not) cross react with the cortisol assay
Does not
*One benefit for giving it in an acute setting for a suspect addison’s
What is used for treatment of Addison’s?
Acute
1. Fluid therapy
2. Glucocorticoid supplementation (dexamethasone)
3. DOCP
Chronic
1. Glucocorticoid supplementation → double during times of stress
2. DOCP
What is the most common adrenal disease in cats?
- Hyperaldosteronism
* Many have concurrent CKD, is likely underdiagnosed
What are the clinical signs of hyperaldosteronism?
- Weakness (may be episodic)
- Lethargy
- PU/PD
- Neck ventroflexion
- Blindness
When should primary hyperaldosteronism be strongly considered in cats?
- Adrenal nodule and unexplained hypokalemia or hypertension
- Hypertension or hypokalemia refractory to therapy
What is the gold standard test for feline hyperaldosteronism?
Aldosterone:Renin Ratio
*Is not very easy to do
What is the most clinically useful diagnostic for hyperaldosteronism?
- Plasma aldosterone concentration
How is hyperaldosteronism treated?
Surgery - Treatment of choice Medical Mangement 1. Hypokalemia - Mineralocorticoid receptor blockers → spironolactone - K supplementation 2. Hypertension - Calcium channel blockers → amlodipine - +/- ACEi
How many transmembrane segments do G protein linked receptors have? Enzyme linked hormone receptors?
- 7 transmembrane segments
2. 1 transmembrane segment
How does the adenylyl cyclase-cAMP second messenger system function?
- Converts ATP → cAMP → activates cAMP dependent protein kinase → phosphorylation of specific proteins in the cell
- cAMP also activates protein kinase A → downstream causes increased or decreased activity of RNA polymerases and transcription of target genes
How does the phospholipase C second messenger system function?
- Attached to the inside projections of receptors and catalyzes the breakdown of the phospholipids in the cell membrane → PIP2 → IP3 + DAG
- Activates protein kinase C → phosphorylates other proteins
Adenylyl Cyclase vs Phospholipase C
- Angiotensin II (epithelial cell of proximal tubule, thick ascending LoH, distal tubule, and collecting duct)
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- Catecholamines (β receptor)
Adenylyl cyclase
Adenylyl Cyclase vs Phospholipase C
- Vasopressin (V2 receptors)
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- Calcitonin/PT
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- ACTH
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- FSH
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- TSH (on Thyroid)
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- LH
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- CRH
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- Glucagon
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- Secretin
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- Somatostatin
Adenylyl Cyclase
Adenylyl Cyclase vs Phospholipase C
- Angiotensin II (vascular smooth muscle)
Phospholipase C
Adenylyl Cyclase vs Phospholipase C
- Catecholamines (α receptors)
Phospholipase C
Adenylyl Cyclase vs Phospholipase C
- Vasopressin (V1 receptor on vessels, vascular smooth muscle)
Phospholipase C
Adenylyl Cyclase vs Phospholipase C
- Oxytocin
Phospholipase C
Adenylyl Cyclase vs Phospholipase C
- GnRH
Phospholipase C
Adenylyl Cyclase vs Phospholipase C
- GHRH
Phospholipase C
Adenylyl Cyclase vs Phospholipase C
- TRH
Phospholipase C
Adrenocortical hormones are synthesized from what?
Cholesterol
What is the primary source of cholesterol?
LDL
How is LDL converted to cholesterol?
- ACTH stimulates uptake of LDL by the adrenal gland (as well as enzymes needed to liberate cholesterol from LDL)
What is the rate limiting step in steroid synthesis? What is this step stimulated by?
- Cholesterol desmolase: Conversion of cholesterol to pregnenalone
* Occurs in the mitochondria - Stimulated by ACTH and Angiotensin II
How do glucocorticoids stimulate gluconeogenesis in the liver?
- Stimulates enzymes to convert amino acids into glucose
- Mobilizes amino acids from the peripheral tissues
- Insulin antagonist
What are the primary substrates for gluconeogenesis?
- Amino acids
- Glycerol
- Lactate
How do glucocorticoids stimulate protein metabolism?
- Stimulates protein catabolism in peripheral tissues to mobilize amino acids to the liver for gluconeogenesis
- While peripheral protein stores are decreased, plasma proteins and liver proteins are increased