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Endocrine Path, 1° and 2°
(but mostly 1°), 2° and 3°, Hypo/Hyperthyroidis…
Endocrine Path
Adrenal
Congenital adrenal hyperplasias (adrenal cortical hyperplasias) 
- all are auto recessive
- most have skin hyperpigmentation because ↑ACTH also means ↑ MSH production since they're produced together)
- most also have bilateral adrenal gland enlargement (due to ↑ACTH stimulation)
- Screen using 17-hydroxyprogesterone levels:
- If ↑: 21- or 11-hydroxylase deficiency
- If ↓: 17-hydroxylase deficiency
17α-hydroxylase deficiency
- ↓ 17-hydroxyprogesterone
- can only make mineralocorticoids (aldosterone) → ↓ cortisol, ↓ androgens, ↑ weak mineralocorticoids (e.g. deoxycorticosterone/DOC) → HTN, mild ↓K+ (effects of aldosterone)
- the ↑ DOC → suppresses production of aldosterone; both renin and aldosterone are low
- in females: primary amenorrhea and lack of pubic hair
- in males: pseudohermaphroditism
- Treatment: Glucocorticoids + sex steroid replacement
21-hydroxylase deficiency (MOST COMMON)
- ↑ 17-hydroxyprogesterone, ↑ testosterone
- can't finish the process of making mineralocorticoids or glucocorticoids (↓aldosterone, ↓cortisol) → forced to make ↑ androgens/sex hormones (also because you have ↓aldosterone and ↓cortisol, your body ↑ACTH to try to fix it, but this just makes even more androgens)
- the ↓aldosterone → ↓blood pressure, ↑ serum K+, ↑ renin activity to try to ↑ aldosterone
- Treatment: low doses of exogenous corticosteroids (glucocorticoids + mineralocorticoids) to suppress excess ACTH secretion, which ↓ production of androgens by the adrenal cortex
- note that blocking testosterone wouldn't work because DHEA and androstenedione can still be converted to testosterone
Classic
Salt-wasting
- SEVERE enzyme deficiency
- In boys: presents 1-2 weeks after birth with vomiting, hyponatremia, hypotension, and hyperkalemia; genitalia are normal
- In girls: presents at birth with ambiguous genitalia (female virilization)
Non-salt wasting (simple virilizing)
- MODERATE enzyme deficiency
- In boys: presents ages 2-4 with early virilization (e.g. early pubic hair, body odor), and rapid linear growth
- In girls: presents at birth with ambiguous genitalia (female virilization)
Nonclassic form (late onset)
- MILD enzyme deficiency
- In boys: premature pubarche and rapid growth
- In girls: hirsutism, acne, oligomenorrhea
11β-hydroxylase deficiency
- ↑ 17-hydroxyprogesterone
- process of making aldosterone and cortisol is stopped a
little further on; the 11-deoxycorticosterone (11-DOC) has enough activity to → mild HTN and ↓ serum K+ → ↓ renin, thus also ↓ aldosterone
- cortisol still low, still shunted to make more sex hormones
- presents similarly to 21-hydroxylase but with ↑ DOC (↑ weak mineralocorticoids)
- Treat with glucocorticoids
Cushing syndrome
- Clarification: the adrenal atrophy is not what is causing Cushing's (even though the arrow makes it look like that); the exogenous glucocorticoids (corticosteroid) or the adrenal tumor are causing Cushing's (↑ cortisol), and because they ↑ cortisol, ACTH ↓, and that causes adrenal atrophy (the chronic suppression by ACTH causes atrophy)
- Think of the testing this way: if you've determined there is ↑ACTH, you are just trying to consider if it is a pituitary tumor or something outside the HPA axis causing problems; so if you give dexamethasone (a glucocorticoid) or CRH (both of which involved with the HPA axis), you would expect a response if the problem has to do with the HPA axis (which, of the two options, is the pituitary tumor). If there is no response, we assume the problem is outside the HPA axis (e.g. lungs)
- Pituitary adenomas secreting ACTH are one of the 3 common functional pituitary adenomas
Nelson syndrome
Adrenal insufficiency (AI) Why the hyperpigmentation?
- Extreme excess of ACTH production (no negative feedback) induces melanocytes (remember when ACTH is made, MSH is also made as a byproduct of POMC cleavage)
Primary
(chronic primary = Addison's)
- HLA DR3 + DR4
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Acute adrenal insufficiency (adrenal/Addisonian crisis)
- Illness/injury/surgery in patient with chronic AI (they are not able to increase glucocorticoid production in response to acute stress) OR adrenal hemorrhage or infarction OR pituitary apoplexy → adrenal crisis → hypotension, shock, nausea, vomiting, abdominal pain (acute abdomen), fever, generalized weakness
- history of other autoimmune conditions (e.g. hypothyroidism) puts someone at higher risk for adrenal crisis
- treat immediately (without waiting for diagnostic study results) with hydrocortisone or dexamethasone (give them the glucocorticoids they are missing) and rapid IV volume repletion
Waterhouse-Friderichsen syndrome
- N. meningitidis meningococcemia (sepsis) → DIC → hemorrhagic necrosis of adrenal glands → acute onset adrenal insufficiency
- lack of cortisol worsens the hypotension → death
- in addition to DIC and AI, symptoms can also include:
- fever
- myalgias
- HYPOtension
- signs of N. meningitidis infection e.g. petechial/ecchymotic rash
Hyperaldosteronism TYPO IN DIAGRAM; ↑ Na+ reabsorption will lead to INCREASED blood volume)
- ↑BP because aldosterone increases BP (sodium and water retention)
- ↓ K+ because aldosterone loses K+
- alkalosis because aldosterone loses H+ (also, the hypokalemia makes this worse, because the alpha-intercalated cells ramp up the K+/H+ ATPase to try to correct the hypokalemia, which worsens the alkalosis)
- Note the aldosterone escape mechanism; the increased plasma volume (due to aldosterone's fluid retention effects) → "pressure natriuresis" that forces some fluid loss/sodium loss
Thus, ↑ ECF, ↑ MAP, ↔ [Na+]pl
- Note the differences between this and Liddle syndrome (Liddle syndrome would have ↓ aldosterone)
Primary (adrenal problem)
- ↑ aldosterone → ↓ renin → increased juxtaglomerular apparatus (JGA) perfusion (? from duke)
- No edema due to aldosterone escape
- causes:
- Bilateral adrenal hyperplasia (most common)
- Adrenal adenoma (Conn syndrome)
- 3) Adrenal carcinoma (rare)
Secondary (RAAS activation, e.g. renovascular HTN or CHF)
- overactivation of RAAS → ↑ aldosterone
- e.g. renal artery stenosis
- edema often present
Adrenal neoplasms
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Pheochromocytoma
- neoplasm arising from the chromaffin cells of the adrenal medulla
- secretes catecholamines (can cause catecholamine hypertensive crisis)
- in patients with undiagnosed pheochromocytoma, induction of anesthesia (e.g. preparation for thyroidectomy) can precipitate a catecholamine surge → hypertensive crisis, flash pulmonary edema, atrial fibrillation
- diagnosed by ↑ metanephrines (in serum and in urine) and ↑ vanillylmandelic acid (VMA)
- part of MEN2 syndromes (MEN2A and MEN2B); up to 50% of patients with MEN2 get pheochromocytoma
- also associated with von Hippel-Lindau disease (VHL) and neurofibromatosis type 1 (NF1)
- "Rule of 10s"…
- 10% bilateral
- 10% familial
- 10% malignant
- 10% located outside the adrenal medulla
Thyroid
Hypothyroidism (↓ T3/T4)
Primary (↑ TSH but not necessarily)
Subacute granulomatous thyroiditis
(de Quervain thyroiditis)
- viral illness → release of stored thyroid hormone → transient hypERthyroid symptoms (↑ T4, ↓ TSH), painFUL thyroid enlargement ("tender to palpation")
- Self-limited; only about 15% of cases progress to a hypothyroidism
- Labs: ↑ ESR & CRP, ↓ Radioiodine uptake
- Histo: Inflammatory infiltrate with macrophages & giant cells; granulomatous
Hashimoto thyroiditis
(chronic autoimmune thyroiditis, chronic lymphocytic thyroiditis)
- Autoimmune (HLA DR3) → follicles damaged and release thyroid hormone → transient HYPERthyroidism → progresses to hypothyroidism (e.g. fatigue, cold intolerance), painLESS thyroid enlargement
- can cause smooth/diffuse goiter
- Labs: + TPO (anti-thyroid peroxidase) antibody and + Tg (anti-thyroglobulin) antibody, variable radioiodine uptake
- once progresses to hypothyroid state: ↓ T4, ↑ TSH
- Histo: Lymphocytic infiltrate with well-developed germinal centers, Hürthle cells (eosinophilic epithelial cells), chronic inflammation
- ↑ risk for B-cell (marginal zone) lymphoma
- Most common cause of hypothyroidism in developed nations
Postpartum thyroiditis
- mild, self-limited variant of Hashimoto thyroiditis arising < 1yr (within 12 mo) after delivery
- autoimmune destruction of thyroid follicles → release of preformed thyroid hormone → hyperthyroid phase (↑T3/4, ↓TSH)→ depletion of thyroid stores → hypothyroid phase → eventual return to a euthyroid state
- Thyroid metabolic activity during the hyperthyroid phase is suppressed (because preformed thyroid hormone is being released) and glandular blood flow (↓blood flow on Doppler ultrasound) and radioiodine uptake are low (important)
Riedel thyroiditis (invasive fibrous thyroiditis)
- chronic inflammation and extensive fibrosis of the thyroid gland that extends into surrounding tissues
- thyroid gland is hard and nontender
- Clinically mimics anaplastic carcinoma, but patients are younger and malignant cells are absent
Congenital hypothyroidism (formerly cretinism)
- occurs in infants/young children
Other causes
Multinodular goiter
- Iodine deficiency → ↓ T3/T4 → TSH ↑ to compensate → follicular cell hypertrophy/hyperplasia
- Recurrent episodes result in irregular enlargement, i.e. multinodular goiter
- can cause smooth/diffuse goiter (verify)
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Secondary/Central (↓ TSH or inappropriately normal)
- ↓TSH, ↓T4 (focus on T4 more than T3)
- due to problem with hypothalamus and/or pituitary
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Thyroid neoplasms Three basic principles of diagnosing/treating thyroid neoplasia:
1) Presents as a distinct, solitary nodule which is more likely to be benign than malignant
2) Iodine radiotracer studies are useful for initial workup: low activity/uptake indicates neoplasm (in contrast to a "hot nodule" characteristic of multinodular goiter)
3) Biopsy performed by fine needle aspiration
Benign
Thyroid adenoma/follicular adenoma
• can cause nodular goiter NOTE: If trying to distinguish follicular adenoma from carcinoma, a fine needle aspiration cannot be used to differentiate between the two, since FNA cannot assess penetration through surrounding fibrous capsule. Therefore, the whole capsule must be examined to make the diagnosis.
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Parathyroid
- PTH secreted from chief cells
- 3 actions of PTH:
1) Increases osteoclast activity to release Ca2+ and PO43- (note that it achieves this by acting on osteoblasts; PTH ↑ the expression of RANKL on osteoblasts → RANKL binds the osteoclastic RANK receptor → ↑ osteoclast activity → increased bone resorption (breakdown) and calcium release)
2) Increases small bowel absorption of Ca2+ and PO43- by activating vitamin D (↑ 1α-OHase activity)
3) Increases renal Ca2+ reabsorption (DCT), decreases renal PO43- reabsorption (PCT)
Hypoparathyroidism
Primary (↓PTH)
- see sheet
- 2 signs seen in in hypoparathyroid-induced hypocalcemia:
- Trousseau sign (filling of BP cuff induces muscle spasm in arm)
- Chvostek sign (tapping on the facial nerve elicits facial muscle spasm)
Secondary (pseudohypoparathyroidism; ↑ PTH)
- End-organ (e.g. renal) resistance to PTH
- Labs reveal hypocalcemia but with ↑ PTH
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Familial hypocalciuric hypercalcemia (FHH; ↑ Ca2+)
- defective GPCR Ca2+-sensing receptors (CaSR) in multiple tissues (e.g. parathyroids, kidneys) → body thinks there is less calcium then there is, so PTH stays high (and higher than normal Ca2+ levels are required to suppress PTH) → increased effects of PTH (↑ renal calcium absorption, etc.) → mild hypercalcemia and hypocalciuria
- PTH can be ↑ but can also be normal
ADH problems
SIADH
- 2 clinical features:
1) Hyponatremia (↓ Na+) and ↓ serum osmolality (contrast to diabetes insipidus, which has hypernatremia (↑Na+) and ↑ serum osmolality)
2) Mental status changes and seizures (hyponatremia induces neuronal swelling/cerebral edema; remember "low to high the pons will die, high to low the brain will blow"; thus low sodium can cause cerebral edema or brain herniation
- hence need to correct SIADH slowly to prevent osmotic demyelination syndrome/central pontine myelinolysis
3) Adjustment to what is on sheet:
- In addition to free water restriction:
- 1st line: V2 ADH receptor antagonists ("-vaptans")
- 2nd line: demeclocycline (reduces response of collecting tubules to ADH)
Diabetes insipidus
• compare to primary polydipsia 3 main clinical features:
1) Polyuria and polydipsia with life-threatening dehydration
2) Hypernatremia (↑Na+)
3) ↓ urine osmolality (↑ serum osmolality) and specific gravity
Central DI
- langerhans cell histiocytosis can cause
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Pituitary
Hypopituitarism
- over 75% of the pituitary parenchyma must be rendered nonfunctional before signs of hypopituitarism manifest
Sheehan syndrome
- systemic hypotension during delivery → ischemic necrosis of the pituitary gland → central/2° hypothyroidism
- patients may also develop deficiencies of other pituitary hormones (eg, ACTH, prolactin, gonadotropins)
- presents with:
- poor lactation
- loss of pubic hair (pubic hair arises due to LH from anterior pituitary)
- Fatigue
Empty sella syndrome
- Herniation of the arachnoid/CSF into the sella → compresses and destroys the pituitary gland
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Other causes (Brain injury, radiation)
Nonsecreting/nonfunctional pituitary adenoma
- present with "mass effect" symptoms:
- Bitemporal hemianopsia
- Hypopituitarism
- Headache
- Pressure on pituitary stalk → mild hyperprolactinemia:
- dopamine usually inhibits prolactin; pressure can cause disruption of dopaminergic pathways or blockade of dopamine D2 receptors → release of inhibition → mild hyperprolactinemia → gallactorrhea
- But should be able to distinguish from prolactinoma due to presence of mass effect symptoms
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Hyperpituitarism
Various types of pituitary adenoma (e.g. prolactinoma, corticotropinoma, etc.)
Growth hormone (GH) adenoma
- pituitary adenoma secreting GH (somatotroph adenoma because somatotrophs make GH; remember GH is also called somatotropin)
- one of the 3 most common functional pituitary adenomas
Acromegaly
- Signs/symptoms:
- enlarged bones of the hands, feet, jaw
- growth of visceral organs leading to dysfunction (LV hypertrophy is common; may → HF)
- enlarged tongue (macroglossia)
- "hypertrophy of articular cartilage": ↑GH and IGF-1 → hyperplasia of articular chondrocytes and synovial hypertrophy → later degeneration of articular cartilage and periarticular bone; can affect the joints in both the axial and the appendicular skeleton (e.g. pain in lower back, knees, + joints)
- MSK: bony hypertrophy (e.g. frontal bossing, enlarged jaw, hands, and feet) and osteoarthritis
- 2° diabetes mellitus (GH induces liver gluconeogenesis)
- Diagnosis:
- ↑ serum GH
- ↑ serum IGF-1
- Lack of GH suppression by oral glucose
- Treatment:
- Octreotide (somatostatin analogue)
- GH receptor antagonists (pegvisomant)
- Surgery
Gigantism
- increased linear bone growth
- tumor seen in children (in adults would be acromegaly)
Zollinger-Ellison syndrome/gastrinoma
- can be part of MEN1
- remember gastrin doesn't only cause HCl secretion, it also has a trophic effect on parietal cells; thus the ↑ gastrin → parietal cell hyperplasia → visible enlargement of gastric folds on endoscopy (don't confuse this with Ménétrier's disease! which would have ↓ acid)
Prolactinoma
- pituitary adenoma secreting prolactin (one of the 3 common functional pituitary adenomas)
- ↑ prolactin inhibits LH (and FSH to a lesser extent) → ↓ estrogen → estrogen maintains bone mass (in premenopausal women), so low estrogen → ↑ RANKL, ↑ osteoclast activity → osteoporosis (loss of bone mass)
- presents in males: ↓ libido and headache
- presents in femaless: galactorrhea and amenorrhea
- Treatment: dopamine agonists (bromocriptine or cabergoline; these ↑ dopamine → ↓ prolactin production → shrinks the tumor (but larger lesions may need to be surgically excised)
Pancreatic
Diabetes mellitus Pathogenesis of neuropathy in patient with T2DM?
- Glucose freely enters Schwann cells, aldose reductase converts glucose to sorbitol → causes osmotic damage
- Nonenzymatic glycosylation (NEG) of endoneural vasculature
- NEG of large and medium vessels → atherosclerosis
- NEG of small vessels (arterioles) → hyaline arteriolosclerosis
- arteriolosclerosis in kidney → glomerulosclerosis (scarred kidneys with granular surface) and diabetic glomerulonephropathy (see renal entry)
- NEG of Hemoglobin → Hemoglobin A1C testing
- Coronary heart disease most common cause of death; in fact, diabetes mellitus is considered a coronary heart disease equivalent (meaning risk of a cardiovascular event is similar to having proven/known CHD)
- Long-standing diabetes (i.e. > 5 years) → pancreatic alpha cell failure → ↓ glucagon → ↑ risk of hypoglycemic episodes
- see "diabetic glomerulonephropathy" in renal, "diabetic neuropathy" and "diabetic retinopathy" in neuro, "diabetic gastroparesis" in GI (type of diabetic neuropathy)
Type 1
- Decreased insulin production due to pancreatic islet cell autoantibodies (reaction mediated by T cells; type 4 hypersensitivity)
- HLA DR3 + DR4 ("4 - 3 = type 1")
- Unmanaged → leads to DKA
- autoantibodies against insulin (sign of islet damage) appear in serum long before clinically apparent disease
Diabetic Ketoacidosis (DKA)
- Stress (e.g. infection, which can ↑ insulin requirements) or insulin noncompliance → ↑ epinephrine → ↑ glucagon secretion → ↑ lipolysis → ↑ free fatty acids → liver breaks these down by fatty acid beta oxidation) → ↑ acetyl-CoA made → diverted to ketogenesis rather than TCA (because not enough glucose to do TCA and meet metabolic demands) → ketones made (β-hydroxybutyrate > acetoacetate)
- symptoms include:
- mental status changes (e.g. delirium/psychosis; due to acid-base imbalance)
- Kussmaul respirations (rapid, deep breathing as a respiratory compensation for metabolic acidosis)
- abdominal pain/nausea/vomiting (response to acidosis)
- dehydration (hyperglycemia → diuresis)
- fruity breath odor (due to exhaled acetone, a type of ketone)
- Labs: hyperglycemia, ↑H+, ↓bicarb (high anion gap metabolic acidosis), ↑urine and blood ketones, normal/↑ serum K+ (BUT ↓ intracellular K+ because the lack of insulin means the K+ isn't going into the cells); also osmotic diuresis (due to loss of glucose in urine) →↑ K+ lost in urine → total body K+ depletion
- complications include: Life-threatening mucormycosis, cerebral edema, cardiac arrhythmias
- Treatment: IV fluids, IV insulin, replacement of K+ to replete intracellular stores. Glucose may be required to prevent hypoglycemia from insulin therapy
IPEX syndrome
- associated with type 1 diabetes in male infants; see immune entry
Type 2
- Unmanaged → leads to HHS
- Diagnostic cutoffs:
- Random glucose measurement > 200 mg/dL
- Fasting glucose measurement > 126 mg/dL
- Glucose tolerance test measurement > 200 mg/dL two hours after glucose loading
Hyperosmolar hyperglycemic state (HHS)
- Profound hyperglycemia → excessive osmotic diuresis → dehydration and ↑ serum osmolality → HHS
- Classically seen in elderly patients with type 2 DM and limited ability to drink
- symptoms:
- thirst
- polyuria
- lethargy
- focal neurologic deficits
- seizures
- untreated → can lead to hyperosmolar non-ketotic coma (life-threatening diuresis with hypotension and coma → death)
- Labs: Hyperglycemia (often > 500-600 mg/dL), ↑ serum osmolality (> 320 mOsm/kg), normal pH (no acidosis), no ketones; Normal/ ↑ serum K+, ↓ intracellular K+
- treat the same way you'd treat DKA
CF-related diabetes
- pancreatic fibrosis and fat infiltration → progressive destruction of pancreatic islet cells → ↓ insulin production
- initially glucose is normal when fasting (they can produce some insulin), but ↑ after eating (e.g. after an oral glucose tolerance test)
- as the disease progresses → fasting hyperglycemia and ↑ HbA1c levels
- see biochem entry for cystic fibrosis
Pancreatogenic diabetes
- secondary to chronic pancreatitis
- also typically have inadequate alpha cell reserve and can experience frequent hypoglycemia
Maturity onset diabetes of the young (MODY)
- Various types; Glucokinase (GK) deficiency, HNF mutations
- GK is the liver hexokinase (but GK has higher Km and Vmax); allows for the liver to take in glucose when it is high and store it
- Acts more like type 2 diabetes than type 1 (although some websites say that MODY caused by GK deficiency is asymptomatic and found on routine testing)
Gestational diabetes
- Glucokinase deficiency is a potential cause
- Human placental lactogen (chorionic somatomammotropin) is released by the syncytiotrophoblast of placenta during pregnancy, it stimulates insulin production; the ↑ insulin can lead to insulin resistance, and if pancreatic function cannot overcome the insulin resistance → gestational diabetes
- Diabetes during pregnancy (either gestational or a mother with T1D/T2D, other diabetes) causes ↑ fetal insulin → ↑ risk of neonatal respiratory distress syndrome
- Babies born to mothers with diabetes also have ↑ risk of:
- being larger than expected for gestational age (LGA) or macrosomia
- caudal regression syndrome
- cardiac defects (eg, VSD)
- neural tube defects,
- neonatal hypoglycemia (due to islet cell hyperplasia)
- polycythemia
- Treatment: nutrition and exercise alone; if this fails, insulin replacement
Pancreatic islet cell tumors
Insulinoma
- Tumor of pancreatic β cells → overproduction of insulin → hypoglycemia
- clinical presentation is called Whipple triad:
a. Symptoms consistent with hypoglycemia (eg, tremor, diaphoresis, confusion, lethargy, syncope, diplopia)
b. Low blood glucose level
c. Relief of hypoglycemic symptoms when the blood glucose level is corrected
- ↓ blood glucose and ↑ C-peptide levels (vs exogenous insulin users, which would have ↓ blood glucose and ↓ C-peptide since exogenous insulin does not contain C-peptide)
- note that ↓ blood glucose and ↑ C-peptide levels can also be seen in patients taking insulin secretagogues (e.g. sulfonylureas); this can be used by patients with factitious disorder using family member's drugs
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Neuroendocrine tumors
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Carcinoid tumors
- see sheet
- often derived from neuroendocrine cells in GI tract
- carcinoid tumors are the most common tumors of the appendix; they are usually benign, but can cause:
- tumor at the base of appendix → appendicitis
- appendiceal tumor that metastasizes → carcinoid syndrome
- Histo:
- islands or sheets of uniform cells with eosinophilic cytoplasm
- oval-to-round stippled nuclei
° Note that serotonin cannot cross the BBB (and anyway serotonin is metabolized by the liver or the lungs before it can get to the CNS); thus all of the symptoms of carcinoid syndrome are due to serotonin's peripheral effects. In contrast, serotonin syndrome is due to excess serotonin within the CNS caused by overdose/multiple serotonergic drugs
Overview of endocrine hormones: Note that ADH is released from the supraoptic nucleus of the hypothalamus and oxytocin from the paraventricular nucleus of the hypothalamusProlactin: produces milk
Oxytocin: ejects milk
Adrenal steroids: Note that these are all made in the adrenal CORTEX (besides estrone, estradiol, and DHT, which are made in peripheral tissue)Adrenal MEDULLA makes epinephrine and norepinephrine
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Hypo/Hyperthyroidism Clinical Overview Generally, hyperthyroidism causes:
1) ↑ basal metabolic rate (due to ↑ synthesis of Na+/K+ ATPase)
2) ↑ sympathetic nervous system activity (due to ↑ expression of β1-adrenergic receptors)
Thyroid hormone production
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Note that ACTH may be listed as "high-normal" or "low-normal" - interpret that as high or low. Don't let them trick you!
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