Endocrine/Repro Flashcards
[Diabetes]
Criteria for diabetes mellitus diagnosis
Describe the different types of diabetes - DM1
A. Cause
B. Pathogenesis
C. Clinical
Diabetes criteria
A. fasting glucose > 126 mg/dl on 2 occasions (8hr fast) *primary determinant is hepatic glucose production
B. random glucose > 200 mg/dl
C. oral glucose tolerance test > 200 mg/dl at 2 hrs (only in pregnant women)
D. HbA1c > 6.5%
DM 1 - 10%, prev known as juvenile onset diabetes
A. Cause - autoimmune; idiopathic but weak genetic predisposition
- environmental stimuli - virus but don’t know
- more common in northern european ethnic groups
B. Antibodies against insulin, pancreatic beta islet cells, or glutamic acid decarboxylase (enzyme in beta cells) –> attract inflammatory cells (eg T cells) –> destroy the tissue –> insulin deficiency
C. Clinical - Acute onset
- ketosis prone
- younger age of onset
[Diabetes] Describe the different types of diabetes - DM2 A. Cause B. Pathogenesis C. Clinical
DM2 - 85%, prev known as adult onset diabetes
A. Cause - strong genetic component –> heterogenous and polygenic - esp insulin resistance
- more common in non-Caucasian ethnic groups –> obesity enhances insulin resistance esp in South Asians
B. Pathogenesis - patients have abnormal insulin sensitivity (inherited) –> pancreas compensates by making more insulin (hyperinsulinemia) –> weight gain where it doesn’t belong (central metabolic obesity) and devlpt of insulin resistance in liver, muscle, fat –> develop metabolic syndrome (HTN, dyslipidemia, CVD, PCO)–> progressive loss of beta cells –> impaired glucose tolerance –> diabetes mellitus
- impaired aerobic exercise capacity (low V02 max) –> could be linked to mt dysfunction
- dual defect - impaired ability to make and secrete insulin (like DM1) AND impaired ability to respond to insulin (insulin resistance)
C. Clinical
- clinical evident in older patients
- central obesity - gain intracellular fat (liver/muscle/belly) which is worse than weight gain on hips/butt –> racial differences
[Diabetes] 1. Clinical manifestation of diabetes 2. Acute metabolic decompensation incl labs, clinical A. Diabetic ketoacidosis DKA B. Non-ketotic hyperglycemic coma NKHC
- 3 P’s - polyuria, polydipsia (bc glucose is osmotically active and draws fluid into urine), polyphagia (lose calories in urine –> weight loss)
- Acute metabolic compensation - ↓ insulin, ↑glucagon, ↑ catecholamines
A. Diabetic ketoacidosis DKA
- younger (<40), DM1 (bc you need almost no insulin to develop, small amounts of insulin can control FFA metabolism)
i. Pathogenesis - ↓ insulin –> ↑ fat breakdown into FFA –> ↑ ketogenesis in liver –> ↑ ketones (beta hydroxybutyrate»_space; acetoacetate)
ii. labs - glucose < 600 mg/dl, anion gap metabolic acidosis, hyperkalemia but ↓ TBK+
iii. clinical: Delirium, Kussmaul breathing, Abdominal pain/nausea/vomiting, + fruity breath odor
B. Non-ketotic hyperglycemic coma NKHC
- elderly (>40), DM2
i. Pathogenesis - hyperglycemia –> osmotic diuresis –> dehydration –> rapid onset serum hyperosmolality
ii. labs - glucose > 600 mg/dl, serum osmolality > 320 mOsm/kg, normal pH (no acidosis or ketosis)
iii. clinical: hypotension, thirst, polyuria, lethargy, seizures, strokes, coma –> high mortality
[Diabetes] Explain severe diabetic complications 1. Microvascular A. Retinopathy B. Neuropathy
Complications
- Microvascular - happens in tissues that don’t require insulin for glucose transport (GLUT1,2,3,5)
- glucose freely enters cells –> converted to sorbitol by aldose reductase –> sorbitol cannot leave the cell –> osmotic damage + consumption of NADPH (cannot regenerate GSH –> increased susceptibility to ROS)
A. Retinopathy - MCC of blindness in USA
- early lesion is ↑ blood flow due to lack of regulation –> BM thickens and ↑ permeability –> protein leaks out of bv into tissues and forms hard exudates –> proteins damage retina –> bv angiogenesis as compensation –> new bv tear, cause attachment to vitreous –> microaneurysms, retinal detachment
- can also cause glaucoma (lens swamped with glucose)
B. Neuropathy - peripheral neuropathy
- classical is stocking/glove distribution of numbness/tingling
- mononeuropathy multiplex - microinfarction of small bv to the nerves –> radiculopathy, cranial nerves
- autonomic neuropathy - ↑ resting pulse rate (lose PSNS) –> problems with orthostatic hypotension, gastric emptying –> predisposes to cardiac arrhythmias
- gastroparesis (Delayed gastric emptying), neurogenic bladder (cannot sense bladder is full, do not empty properly –> urinary stasis)
[Diabetes]
Explain severe diabetic complications
1. Microvascular
C. Nephropathy
- Macrovascular
A. Stroke
B. Heart disease
C. Peripheral vascular disease
C. Nephropathy - MCC of renal failure dialysis in USA
- non-enzymatic glycosylation of small vessels (arterioles) e.g. renal arteries (esp efferent arteriole) –> hyaline arteriosclerosis –> hyperfiltration injury –> nephrotic syndrome with Kimmelstein-Wilson nodules in the mesangial core at the end of the glomeruli (PAS positive stain)
- Macrovascular - nonenzymatic glycosylation of basement membranes in medium/large vessels –> atherosclerosis –> complications
A. Stroke - MCC of premature stroke in USA
B. Heart disease - cardiovascular disease CAD is #1 death in diabetics
C. Peripheral vascular disease - MCC of nontraumatic amputations in USA
- arteries supplying legs/feet become stenosed –> impaired circulation –> pain, burning, ulcers, gangrene
[Diabetes Pharmacotherapy] Treatment for DM1 1. Diet 2. Pharmacotherapy - types of insulin A. Rapid acting B. Short acting
- Diet - match insulin with carbohydrate intake to avoid post-meal hyperglycemia
- Pharmacotherapy - insulin supplement; challenge is to control blood glucose in narrow range
- combine short-acting and long-acting insulin to mimic insulin profile (low basal rate and much higher rate for post-meal surge)
- different injected insulin types with same MOA but different pharmacokinetics
A. Rapid acting insulin analogues- v fast onset and short duration e.g. insulin lispro, insulin aspart, and insulin glulisine
- onset within 5 min, peak in 1 hr, duration <5 hrs
- injected right before meal, mimics endogenous prandial insulin secretion
B. Short acting (regular insulin) - rapid onset (forms monomers instantly) and short duration
- subcutaneous prep with onset in 30 min, peaks at 2-3 hrs, duration 8 hrs
- IV prep has immediate action, used in DKA (watch K+ levels), hyperkalemia (give with glucose)
[Diabetes Pharmacotherapy] 2. Pharmacotherapy - types of insulin C. Intermediate acting D. Long acting E. Inhalable insulin
C. Intermediate acting - intermediate onset and duration
- neutral protamine hagedorm NPH - combines insulin with protamine, need endogenous protease to metabolize
- onset 2 hrs, duration 12 hrs
- action is unpredictable, clinical use not recommended
D. Long acting basal insulin analogues - slow onset of action and long duration (>12 hrs)
- peakless/flat pharmacokinetic profile
- e.g. glargine, detemir, degludec (ultra long acting, up to 42 hrs)
E. Inhalable insulin - rapid acting, peak 15 min but cough, throat irritation, hypoglycemia e.g. Afrezza
Sample regiments: basal insulin + pre-meal rapid acting insulin (4 injections per day)
- NPH insulin + regular insulin (2 injections / day)
- s.c. insulin pump (bolus + basal infusion)
[Diabetes Pharmacotherapy]
- Indications for insulin supplement
- Side effects of treatment
- Indications for insulin supplement
- beta cell failure - DM1, pancreatitis, post-pancreatectomy
- DM2 when dietary control, weight reduction, oral anti-diabetic agents insufficient
- gestational (type IV) diabetes
- unstable form of diabetes - DKA, NKHC - Side effects of treatment
- hypoglycemia - most common and severe complication of DM treatment; seen with exercise, failure to eat; relieved by glucose (packets, orange juice, etc); patients can have hypoglycemic unawareness
- weight gain
- lipodystrophy - cosmetic problem, fat accumulation at injection site
[Diabetes Pharmacotherapy] Treatment for DM2: 1. Metformin A. MOA/ Effects B. Metabolism C. Indication D. Side effects
- Metformin - biguanide
A. MOA /Effects - MOA unclear - modulates mt enzymes and activates AMPK enzyme:
- ↑ insulin sensitivity –> ↓ cardiovascular events and other complications
- inhibits hepatic glucose production
- does not increase weight
- no hypoglycemia - ↓ glucose to euglycemic levels
- ↑ peripheral uptake of glucose in muscle, liver
B. Metabolism - not metabolized by liver, excreted unchanged
C. Indication - first line monotherapy for DM2 on diagnosis (+ lifestyle modification)
- prevention of DM2 in middle aged, obese
D. Side effects
- GI disturbances (nausea/vomiting, diarrhea)
- ↓ B12 absorption
- associated with formation of lactic acidosis
- contraindicated in pts with GFR < 30
[Diabetes Pharmacotherapy] Treatment for DM2: 2. Insulin secretagogues I. Sulfonylureas II. Meglitinides
A. MOA/ Effects
B. Metabolism
C. Indication
D. Side effects
- Insulin secretagogues - v inexpensive and effective in decreasing HbA1c
I. Sulfonylureas - glipizide, glimepiride, glyburide
A. MOA / Effects - inhibit the K+ ATP channel of the pancreatic beta cells –> cell depolarizes –> Ca2+ channels open –> Ca2+ influx –> stimulates insulin secretion
- chronic - ↓ glucagon in circulation
B. Metabolism - well-absorbed, protein-bound in plasma
- glyburide and glipizide inactivated by liver + kidney; contraindicated in pts with hepatic/renal insufficiency
- glimepiride inactivated by liver
C. Indication - glipizide as second agent to metformin
D. Side effects - weight gain, hypoglycemia
- effectiveness reduced by barbiturates, rifampin, glucocorticoids, OCPs, thiazides, phenytoin, beta agonists
- ↓ efficacy with chronic use over years
II. Meglitinides - repaglinide, nateglinide
A. MOA - same MOA as sulfonylureas but they are not sulfa drugs
B. Metabolism - rapid absorption, short half-lives
C. Indication - reduce postprandial hyperglycemia; take right before meal
D. Side effects - weight gain
- repaglinide contraindicated in hepatic and renal insufficiency
- nateglinide contraindicated in hepatic (Safe for renal failure pts)
[Diabetes Pharmacotherapy] Treatment for DM2: 3. SGLT2 inhibitors A. MOA/ Effects B. Metabolism C. Indication D. Side effects
- SGLT2 inhibitors - dapagliflozin, canagliflozin (invokana), empagliflozin
A. MOA/ Effects - inhibit kidney SGLT2 transporters in PCT of nephron–> reduce glucose reabsorption by the kidney and increase glucose excretion
- ↓ incidence of cardiovascular events
B. Metabolism - ?
C. Indication - 2nd/3rd line - DM2 combo; not indicated in DM1 due to DKA; contraindicated in renal failure
D. Side effects - due to increased glucose in urine
- UTI, vaginal candidiasis
- diuretic effect –> orthostatic hypotension, dizziness
[Diabetes Pharmacotherapy] Treatment for DM2: 4. GLP1 therapies I. GLP1 agonists II. DPP4 inhibitors
A. MOA/ Effects
B. Metabolism
C. Indication
D. Side effects
- Glucagon-like peptide GLP1 therapies -
I. GLP1 agonists - “-tides” - exenatide, liraglutide, dulaglutide, albuglutide
A. MOA/ Effects - stimulates gut hormone GLP1 - incretin that is released after meals and inhibits appetite, stimulates insulin secretion, and inhibits glucagon secretion, delays gastric emptying
B. Metabolism - subcutaneous injection
- metabolized by kidney
C. Indication - DM2 (Requires functional pancreatic beta cells)
D. Side effects - weight loss
- GI effects (nausea/vomiting/diarrhea)
- ↑ risk pancreatitis
- ↑ hypoglycemia when used with sulfonylureas
II. DPP4 inhibitors - “-glipins” - sitagliptin, saxagliptin, linagliptin, alogliptin
A. MOA/ Effects - inhibits enzyme DPP4 enzyme that breaks down and metabolizes GLP-1
B. Metabolism - oral; excreted renally
C. Indication - DM2 (Requires functional pancreatic beta cells)
D. Side effects - ↑ risk URTs and nasopharyngitis
[Diabetes Pharmacotherapy] Treatment for DM2: 5. Thiazolidenediones A. MOA/ Effects B. Metabolism C. Indication D. Side effects
- Thiazolidenediones - pioglitazone, rosiglitazone
A. MOA - insulin sensitizer - PPARgamma agonist –> ↑ triglyceride storage in adipocytes + ↑ transcription of proteins mediating insulin action
- upregulates GLUT4 –> ↑ glucose uptake (↓ insulin resistance) in muscle/fat/liver –> fat comes out of liver/fat/muscle and goes to butt
- improves insulin sensitivity –> ↓ cardiovascular events
B. Metabolism - need weeks to see effects
- metabolized by CYP3A4
C. Indication - DM2
D. Side effects
- modest weight gain
- fluid retention + peripheral edema
- heart failure
- ↑ risk of atypical extremity fractures in women
[Diabetes Pharmacotherapy] Treatment for DM2: 6. alpha glucosidase inhibitors A. MOA/ Effects B. Metabolism C. Indication D. Side effects
- alpha glucosidase inhibitors - acarbose, miglitol
A. MOA - competitive inhibitors of intestinal alpha glucosidases (enzymes that digest carbs to absorbable monosaccharides) –> ↓ digestion
- controls post-prandial glucose spike - no hypoglycemia
- ↓ HbA1c but not as effectively as sulfonylureas or metformin; no weight gain/loss
B. Metabolism - oral
C. Indication - DM2
D. Side effects - gas (due to carbohydrate fermentation in colon); diarrhea, abdominal pain
[Diabetes Pharmacotherapy] 7. Amylin agonists A. MOA/ Effects B. Metabolism C. Indication D. Side effects
- Bile acid binding resins
- Bromocriptine
- Amylin agonists - pramlintide
A. MOA - agonist of amylin, hormone secreted by pancreatic beta cells along with insulin –> slows gastric emptying, reduces postprandial glucagon secretion and hepatic glucose output, lowers appetite
- controls post-prandial glucose spike
- DMII results in amylin (amyloid) deposition in pancreatic islet cells
B. Metabolism - subcutaneous injection
C. Indication - treats both DMI and DMII
- contraindicated in GI motility disorders
D. Side effects - no weight gain
- GI side effects
- hypoglycemia
- Bile acid binding resins - colesevelam –> repurposed hypercholesterolemia drug
- Bromocriptine - dopamine receptor agonist –> repurposed Parkinson and hyperprolactinemia drug
[Hypoglycemia]
- What is the importance of glucose to CNS?
- Hormonal response to hypoglycemia
- CNS requires glucose and 02 to function
- brain can metabolized ketoacids (beta hydroxybutyrate and acetoacetic acid) but requires slow adaptation; rapid decline in glucose is a crisis - Major hormone players: ↓ glucose –> ↓ insulin, ↑ norepi, ↑ glucagon, ↑ epi (fastest)
- Homeostasis - almost every system responds –>
i. brain picks up ↓ glucose –> hypothalamus- pituitary response –> ↑ GH (breaks down FFA) and ACTH –> ↑ cortisol (gluconeogenic)
ii. SNS - adrenal medulla –> ↑ epi –> direct breakdown of hepatic glycogen; postganglionic neurons –> ↑ norepi and ↑ ACh
iii. pancreas –> ↑ glucagon / ↓ insulin –> ↑ glucose production in liver and kidney
- normal glucose 60-100
[Hypoglycemia]
1. Describe the signs and symptoms of hypoglycemia
A. Neurogenic
B. Neuroglycopenic
- List some of the common causes of hypoglycemia
A. Functional
B. Organic
1A. Neurogenic (adrenergic or sympathetic due to NE/E)
- anxiety, sweating, tremor, tachycardia, HTN, palpitations, nausea
B. Neuroglycopenic (brain suffering) - blurred vision, headache, drowsiness, confusion, memory loss, seizures, coma
2A. Functional (non-anatomic)
- medicated (iatrogenic, alcohol) *most common
- reactive (idiopathic, postprandial)
- factitious
- ketogenic
- pseudo
B. Organic (anatomic, fasting hypoglycemia)
- systemic illness eg liver, kidney, cardiac second most common
- bariatric surgery
- hormone deficiency - cortisol, GH, glucagon
- endogenous insulin - insulinoma (neuroendocrine tumor); nesidioblastosis (congenital beta cell hyperplasia)
- non islet cell tumors - GIST, IGF2 sarcoma
-immune - eg lupus
[Hypoglycemia] Describe the following types of functional hypoglycemia 1. Post-prandial hypoglycemia 2. Pseudo hypoglycemia A. Causes B. Clinical C. Tx
- Post-prandial hypoglycemia - insulin goes way up post meal and glucose drops precipitously
A. Causes - idiopathic, post-GI surgery, pre-diabetes (earliest sign of DM2), non-hypoglycemia
- due to GI disturbance –> altered GI tone as a result of altered PSNS activity in the gut
- non-specific sx following eating incl anxiety, lethargy (not hypoglycemia but rather anxiety associated with eating)
B. Clinical - avoid foods that cause sx, usually goes away over time
C. Tx - replicate meal which causes sx and study glucose/hormone every 30 min
- acarbose (glucosidase inhibitor to reduce carb absorption) - Pseudo hypoglycemia - normally draw blood in red test tube –> red cells in test tube eat the glucose in plasma/serum –> laboratory artifact (esp with CML, polycythemia vera with ↑ Hb)
- daw blood in grey test tube with fluoride to prevent glycolysis
[Hypoglycemia] Describe the following types of functional hypoglycemia 3. Ketotic hypoglycemia 4. Alcoholic hypoglycemia A. Causes B. Clinical C. Tx
- Ketotic hypoglycemia
A. Causes - in children –> Active child who exhausts glucose stores / oxidizes stored glycogen in muscle and liver –> insulin decline –> shifts to ketone metabolism –> lipolysis and ketogenesis
*insulin is anti-lipolytic
B. Clinical - child is lethargic or hysterical with low glucose levels and ketones
C. Tx - feed the kid so they don’t burn up all the glucose; goes away as child increases and glycogen stores increase - Alcoholic hypoglycemia
A. Cause - alcohol blocks gluconeogenesis by depleting NAD (energy producing substrate) –> ↑ SNS and glucagon, suppress insulin –> develop ketotic state to protect against hypoglycemic insults –> alcoholic ketoacidosis
- brain metabolism adjusts to tolerate hypoglycemic –> like DKA but without hyperglycemia
B. Clinical - can present in any phase - hypoglycemic (from not eating/adapting), or mildly ketotic (with low sugar), or markedly ketotic (low pH)
[Hypoglycemia]
- Tests for fasting (organic) hypoglycemia
- Evaluation of fasting hypoglycemia
- Tests: glucose, ↑ insulin, ↑ C-peptide or proinsulin (ensure it is endogenous insulin)
- ↓ beta hydroxybutyrate bc insulin will turn off lipolysis and prevent ketosis
- ↓ sulfonylurea - insulin secretagogues
- ↓ anti-insulin Ab or anti-insulin receptor Ab - Exclude systemic disorders (liver or renal disease, sepsis, stromal tumors, endocrine deficiency disorders)
- provoke hypoglycemia with fasting; get tests above
- exclude factitious hypoglycemia; consider insulin/glucose ratio: > 0.3 suspicious for inappropriate insulin secretion
[Hypoglycemia]
Describe the following types of organic hypoglycemia
1. Pancreatic-endocrine tumors e.g. insulinoma
A. Causes
B. Clinical
C. Tx
- Pancreatic endocrine tumors - rare neuroendocrine carcinoid tumors that involve islet cells
- most common is insulinoma - tumor of pancreatic beta cells
- other islet cell tumors - Zollinger-Ellison (due to gastrinoma), VIPoma (prolonged water diarrhea, hypokalemia, dehydration), glucagonoma (dermatitis, DVT, declining weight, depression), somatostatinoma (steatorrhea, gallstones)
A. Causes - usually sporadic - solitary and benign
- could be part of familial MEN1 (Pituitary tumors, Pancreatic endocrine tumors, Parathyroid adenoma) - more likely to be multiple, malignant
B. Clinical - fasting hypoglycemia, ↑ insulin levels, ↑ C-peptide levels + amyloid deposition
- Whipple’s triad - clinical presentation of pancreatic insulinomas:
I. Sx and signs c/w hypoglycemia (as opposed to non-specific SNS activation caused by anxiety, GI distress)
II. Glucose < 50 mg/dl *with rapid decline, sx can occur even above normal range bc brain cannot acclimate
III. Sx resolve with interventions that raise glucose level (e.g. IV glucose)
C. Tx - surgical resection
[Hypothalamic and Pituitary Disorders] Disorders or prolactin 1. Regulation of secretion of prolactin 2. Causes of hyperprolactinemia 3. Clinical 4. Treatment
- Prolactin is secreted from lactotrophs in anterior pituitary, is tonically inhibited by dopamine from hypothalamus (constantly secreted under normal conditions); prolactin secreted when you block dopamine signal
* all other anterior pituitary hormones are stimulated - Causes of hyperprolactinemia:
A. Physiologic - pregnancy (hCG), stress, orgasm, exercise, hypoglycemia
B. Pharmacologic - dopamine antagonists/antipsychotics (eg haloperidol, risperidone, methyldopa)
C. Pathologic - cranipharyngioma (pituitary stalk compression –> ↓ dopamine –> ↓ prolactin inhibition)
- primary hypothyroidism (↑ TRH stimulates TSH and prolactin), prolactinoma (most common pituitary tumor) - Clinical:
- ↑ prolactin –> inhibits GnRH release –> ↓ LH, FSH
- galactorrhea (breast milk production) + sx of secondary hypogonadism –> infertility, amenorrhea (due to inhibition of GnRH), gynecomastia, osteoporosis - Treatment: First-line tx is pharmacologic (for other tumors its surgical) for prolactin-secreting adenomas –> dopamine agonists
- bromocriptine - short-acting
- cabergoline - long-acting, fewer side effects (D2 receptor specificity)
[Hypothalamic and Pituitary Disorders]
- Define secondary adrenocortical insufficiency
- Causes
- Diagnosis
- Clinical
- Differentiate from primary adrenocortical insufficiency
- Treatment
- Secondary adrenocortical insufficiency - decreased ACTH production from anterior pituitary –> ↓ cortisol
- Causes
A. Medications (most common) - due to withdrawal of glucocorticoids (need to do steroid taper)
B. Anatomic lesions - Diagnosis - stimulation tests (ACTH, insulin); adrenal insufficiency test (hypoglycemia leads to ↑ cortisol)
- Clinical - nausea/vomiting, fatigue/weakness, hypotension + hyponatremia, confusion, fever, hypoglycemia (cortisol stimulates gluconeogenesis)
- Primary adrenocortical insufficiency (Addison’s) - problem with the adrenal glands –> hyponatremia AND hyperkalemia + hyperpigmentation
- Treatment - glucocorticoid replacement
[Hypothalamic and Pituitary Pharmacology]
Describe clinical uses and adverse effects of the following Growth hormone drugs:
1. recombinant GH (somatropin)
2. recombinant IGF-1 (mecasermin)
- recombinant GH - somatropin (Nutropin, Omnitrope); subQ 1xday
A. Clinical uses
i. GH deficiency - used in kids to achieve normal adult height, used in adults to reverse obesity, asthenia (abnormal muscle weakness)
ii. pediatric patients with short stature unrelated to GH deficiency - e.g. Prader-Willi, Turner, Noonan, idiopathic; effects not as pronounced
B. Adverse effects *patients should be checked for deficiencies in other anterior pituitary hormones
i. Children - rare, pseudotumor cerebri (intracranial pressure), scoliosis, edema, hyperglycemia (peripheral insulin resistance)
ii. Adults - more adverse effects incl peripheral edema, myalgias, arthralgias; remit with dose reduction
- recombinant IGF-1 - mecasermin (Increlex); subQ 2x day
A. Clinical uses - children with growth failure and severe IGF-1 deficiency that is not responsive to exogenous GH
B. Adverse effect - hypoglycemia (IGF-1 activates insulin receptor)
- carbo load 20min before/after administration
[Hypothalamic and Pituitary Pharmacology]
Describe clinical uses and adverse effects of the following GH antagonists:
3. Octreotide, lanreotide
4. Pegvisomant (Somavert)
5. Bromocriptine/cabergoline
GH antagonists
- Octreotide, lanreotide - long-acting analogs of somatostatin (hormone secreted in the delta cells of pancreatic islets and the hypothalamus) –> inhibits GH and TRH + inhibits gastric secretion and gallbladder contractility
A. Clinical uses - to treat smaller GH-secreting adenomas that cause acromegaly and gigantism
- carcinoid tumor, VIPoma, insulinoma, glucagonoma, gastrinoma (Zollinger-Ellison), esophageal varices
B. Adverse effects - GI side effects (nausea/vomiting, cramps, flatulence, gallstones, steatorrhea)
- sinus bradycardia, conduction disturbances - Pegvisomant (Somavert) - GH receptor antagonist
A. Clinical uses - normalize IGF-1 levels in patients with acromegaly - Bromocriptine/cabergoline - dopamine receptor agonists –> inhibit GH secretion
- treat acromegaly dopamine agonists stimulate growth hormone secretion in normal individuals, yet suppress growth hormone secretion in acromegaly patients
[Hypothalamic and Pituitary Pharmacology]
1. Describe the pharmacologic forms of the following
A. FSH
B. LH
C. hCG
2. Clinical uses
3. Adverse effects
1A. FSH - urofollitropin (uFSH), Follitropin alpha and beta (rFSH) with shorter half-lives
B. LH - rLH - only for use in combo with rFSH for stimulation of follicular devlpt in infertile women with LH deficiency
C. hCG - choriogonadotropin alpha (rhCG), urine extracted hCG
- Clinical uses - for infertility to stimulate spermatogenesis in men and induce ovulation in women
- reserved for anovulatory women who fail to respond to other less expensive forms of treatment (Eg clomiphene)
- controlled ovarian hyperstimulation in assisted reproductive procedures eg IVF - Adverse effects
i. ovarian hyperstimulation syndrome OHSS - ovarian enlargement, ascites, hydrothorax, hypovolemia
ii. multiple pregnancies
[Hypothalamic and Pituitary Pharmacology]
Describe clinical use and adverse effects of the following GnRH drugs:
1. GnRH agonists
- GnRH agonists - sustained, non-pulsatile administration administration inhibits release of FSH and LH in men and women
- human: gonadorelin
- synthetic: goserelin, histrelin, leuprolide, nafarelin, triptorelin
A. Clinical uses
i. endometriosis - cyclical abdominal pain in premenopausal women caused by estrogen-sensitive endometrium-like tissue outside the uterus
ii. uterine leiomyomata (fibroids) - benign, estrogen-sensitive fibrous growths in the uterus –> menorrhagia, anemia, pelvic pain
iii. prostate cancer - combined anti-androgen receptor antagonist (flutamide or bicalutamide) with gnRH agonist –> reduces serum testosterone levels
iv. central precocious puberty (before 7 yrs in girls, 9 yrs in boys) - for children whose final height would otherwise be compromised; or for children in whom devlpt of puberty secondary sex characteristics causes significant emotional distress
B. Toxicities
i. Women - sx of menopause (hot flashes, sweats)
- depression, low libido, vaginal dryness, breast atrophy, ovarian cysts, ovarian cysts, reduced bone density
ii. Men - hot flashes, edema, gynecomastia, low libido, low hematocrit, reduced bone density, asthenia
[Hypothalamic and Pituitary Pharmacology]
Describe clinical use and adverse effects of the following GnRH drugs:
2. GnRH receptor antagonists
- GnRH receptor antagonists
A. Clinical uses - inhibit secretion of FSH and LH in more dose-dependent and complete manner than GnRH agonists
- ganirelix and cetrorelix - controlled ovarian hyperstimulation procedures
- degarelix - treatment of symptomatic, advanced androgen-dependent prostate cancer (suppresses androgens - testosterone faster than leuprolide)
B. Adverse effects
- ganirelix and cetrorelix - lower risk of OHSS than with GnRH agonists
- degarelix - symptoms of androgen deprivation (hot flashes, edema)
[Hypothalamic and Pituitary Pharmacology]
Describe clinical use and adverse effects of the following:
1. Dopamine agonists
2. Oxytocin
- Dopamine agonists - bromocriptine, cabergoline - dopamine inhibits prolactin and TSH
A. Clinical use - first line treatment for hyperprolactinemia (inhibits GnRH release) –> shrink pituitary prolactin-secreting adenomas, lower circulating prolactin levels, and restore ovulation
- complete success - pregnancy or 2 consecutive menses with evidence of ovulation
- partial success - 2 menstrual cycles without evidence of ovulation, or 1 ovulatory cycle
B. Adverse effects - nausea, headache, light headedness, orthostatic hypotension, fatigue
- cabergoline causes less nausea than bromocriptine but is associated with cardiac valvulopathy (contraindicated) - Oxytocin - posterior pituitary hormone
A. Clinical use - induce labor for conditions requiring early vaginal delivery –> increases force and frequency of uterine contractions
- postpartum control of uterine hemorrhage due to uterine atony
B. Adverse effects - rare, due to
i. excessive contractions –> fetal distress, uterine rupture
ii. inadvertent activation of ADH receptors –> fluid retention –> hyponatremia, heart failure
[Adrenal Disorders] - Cushing’s
- Regulation of ACTH secretion
- Define Cushing’s syndrome and differentiate from pseudo-Cushing’s
- Causes
- Sleep/wake cycle, stress, etc –> CRH (hypothalamus) –> corticotropin i.e. ACTH (pituitary) –> Cortisol (zona fasciculata of the adrenal glands)
- Cushing’s syndrome - ↑ serum cortisol
* pseudo-Cushing’s - high cortisol secondary to other factors (Exercise, pregnancy, uncontrolled diabetes, stress, alcoholism, sleep apnea) - Causes
A. ACTH dependent (high ACTH) -
i. Cushing’s disease (ACTH secreting pituitary adenoma)
ii. ectopic ACTH secretion (Small cell lung carcinoma, thymoma, pancreatic islet cell carcinomas, etc)
B. ACTH independent (low ACTH) -
i. iatrogenic (exogenous glucocorticoids)
ii. primary adrenal adenoma/carcinoma
[Adrenal Disorders] - Cushing's 4. Diagnosis 5. Clinical 6. Treatment A. Endogenous B. Exogenous C. Pseudo-Cushing's
- Diagnosis -
A. Low dose overnight dexamethasone suppression test (should suppress am cortisol production) –> differentiates iatrogenic (low cortisol) vs real Cushing’s (high cortisol)
B. Measure ACTH levels - differentiates dependent (high plasma ACTH) vs independent (low plasma ACTH and high cortisol)
C. high dose overnight dexamethasone suppression test - differentiates pituitary adenoma - Cushing’s disease (low serum cortisol) vs ectopic ACTH (cortisol remains high) - Clinical - central obesity with buffalo hump, moon facies, but thin extremities, peripheral muscle weakness, violaceous striae unique to Cushing’s, HTN, immune suppression
- Treatment
A. Endogenous - remove tumor producing ACTH or cortisol
- radiotherapy, bilateral adrenalectomy, pharmacotherapy –> adrenal blockers - ketoconazole (steroid biosynthesis inhibitor), mifepristone(GC receptor antagonist)
- or ACTH antagonists- cabergoline (dopamine receptor agonist), pasireotide (somatostatin receptor agonist)
B. Exogenous (iatrogenic) - reduce corticosteroid dosage gradually to avoid acute withdrawal sx
C. Pseudo-Cushing’s - Treat underlying disease
[Adrenal Disorders] - Conn’s
- Describe RAAS system
- Etiology
- Clinical presentation
- Diagnosis
- Treatment
Conn’s syndrome - primary mineralocorticoid excess due to adrenal adenoma
- 3 factors stimulate JG cells to produce renin: beta1 SNS stimulation, low NaCl delivery to macula densa, and low BP –> converts angiotensinogen to Ang I –> ACEI converts Ang I to Ang II –> zona glomerulosa in adrenal glands produces aldosterone –> salt retention –> BP increases
- Etiology - bilateral adrenal hyperplasia (more common) or aldosterone producing adrenal adenoma
- Clinical presentation - hypertension that cannot be cured with meds, hypokalemic metabolic alkalosis –> more suggestive of adenoma
- Diagnosis - elevated aldosterone and high SA:PRA (plasma renin activity)
- confirm via salt loading to try to suppress aldosterone (won’t work) - Treatment - surgical - unilateral adenoma
- medical therapy for bilateral hyperplasia –> spironolactone (antagonizes androgen receptors –> gynecomastia, impotence side effects in men) and eplerenone (specific for MC receptors –> free of side effects)
[Adrenal Disorders] - Adrenal insufficiency
- Differentiate primary vs secondary vs tertiary
- Causes
- Diagnosis
Adrenal insufficiency
1A. Primary - Addison’s disease –> loss of mineralocorticoids, glucocorticoids, androgens; excess ACTH –> hyperkalemia, hyperpigmentation
B. Secondary - pituitary –> loss of glucocorticoids»_space; loss of androgens and mineralocorticoids; RAAS (and therefore BP) intact
C. Tertiary - hypothalamus
- Causes
A. Primary
i. autoimmune - Addison’s (MCC in USA), infectious - TB (worldwide)
ii. hemorrhage (Waterhouse-Friderichsen –> adrenal hemorrhage due to Neisseria meningitidis –> rapidly progressive hypotension + DIC)
iii. drugs (ketoconazole –> decreased synthesis; rifampin –> increased catabolism)
B. Secondary - exogenous steroids (MCC), pituitary/hypothalamic disease, surgery, congenital - Diagnosis - screen via morning cortisol test –> both primary and secondary will have low cortisol
- confirm via cosyntropin (synthetic ACTH) Stimulation test –> cortisol should increase
- hyperkalemia and hyperpigmentation in primary
[Adrenal Disorders] - Adrenal insufficiency
4. Clinical presentation
- Adrenal crisis
- Treatment for primary
A. Chronic
B. Acute
C. Assessing adequacy of corticosteroid replacement therapy
- Clinical presentation: hypotension, hyponatremia, hypovolemia, weakness/fatigue, dehydration, fasting hypoglycemia, weight loss
- primary deficiency: hyperkalemia (due to mineralocorticoid deficiency) + hyperpigmentation of oral mucosa/skin (high ACTH stimulates melanocytes) - Adrenal crisis - endocrine emergency!
- shock, fever, hypotension, vomiting, anemia, renal failure, hypoglycemia, coma, death
- treatment - high dose IV glucocorticoids, IV fluids - Treatment for primary (Addison’s)
A. Chronic - replacement therapy with daily oral corticosteroid (hydrocortisone) and supplementation with mineralocorticoid (fludrocortisone)
B. Acute - immediate treatment
- large doses of IV hydrocortisone
- correct fluid electrolytes
- treat precipitating cause
C. Assessing adequacy of corticosteroid replacement therapy
- disappearance of hyperpigmentation and resolution of electrolyte abnormalities
- low early morning ACTH levels –> indicator of overtreatment (steroids suppressing ACTH)
[Adrenal Disorders] - Pheochromocytoma
- Causes
- Rule of 10’s
- Clinical presentation
- Diagnosis
- Treatment
Pheochromocytoma - adrenal medulla tumor of neuroectodermal chromaffin cells –> overproduction of catecholamines esp norepinephrine
- Causes - sporadic or familial:
- VHL (Renal cell carcinoma + pheo), NF1
- MEN2A –> pheo, medullary cancer of thyroid, hyperparathroidism (Marfinoid habitus)
- MEN2B –> pheo, medullary cancer of thyroid, ganglioneuromas of oral mucosa (eg tongue) - Rule of 10’s: 10% extra-adrenal, 10% bilateral, 10% familial, 10% malignant, 10% in children, 10% calcify, 10% recur
- Clinical presentation - paroxysms –> spontaneous episodic spells 15-20 min long, precipitated by procedures, exercise, drugs
classic triad pain (headache), perspiration, palpitations
+ pressure (HTN), pallor - Diagnosis - plasma metanephrines, VMA, urine catecholamines
- Treatment - surgical resection of tumor; to avoid hypertensive crisis:
- give alpha blockade with alpha-adrenoreceptor antagonists first –> phenoxybenzamine, prazosin, terazosin, or doxazosin
- THEN beta blockade with beta-adrenoreceptor antagonists –> atenolol, metoprolol, propranolol
[Adrenal Disorders]
1. Adrenal mass
A. DD
B. Diagnosis
- Adrenocortical carcinoma
- Distinguish hirsutism vs hypertrichosis vs lanugo
- Adrenal mass - i.e. incidentiloma, 25% functional but with subclinical sx
A. DD - pheo, mets, benign adenoma, carcinoma
B. Diagnosis - H&P, hormonal testing, imaging - Adrenocortical carcinoma - large mass in adrenal cortex with poor prognosis
- mass effect (abdominal pain)
- rapid onset hypersecretion signs and sx eg virilization (androgens), hypokalemia (aldosterone), gynecomastia (estrogen), Cushing’s (Cortisol)
3A. Hirsutism - male pattern of hair distribution in a female; due to hyperandrogenemia and increased sensitivity of pilosebaceous units to androgens
B. hypertrichosis - hair all over the body; due to meds (phenytoin - antiepileptic), hyperthyroidism
C. lanugo - soft, villous, nonpigmented hair all over the body; due to androgens
[Adrenal Disorders]
- Congenital adrenal hyperplasia
- 21-OH deficiency
- 11B-hydroxylase deficiency
- Congenital adrenal hyperplasia (CAH) - AR inherited disorders of steroid biosynthesis
- low cortisol –> ↑ ACTH levels –> adrenal hyperplasia –> overproduction of steroids that precede blockage - 21 hydroxylase (21-OH) deficiency (95%) –>
- ↓ mineralocorticoids
- ↓ cortisol / glucocorticoids
- ↑ levels of 17-OH-progesterone –> ↑ androgens (DHEA, androstenedione, testosterone)
A. classic (childhood) - hypotension –> presents as shock in neonates, ambiguous genitalia in females
B. non-classic (adulthood) - hirsutism, oligomenorrhea, infertility - 11B-hydroxylase (11B-OH) deficiency
- ↓ cortisol
- ↑ mineralocorticoids –> hypertension, hypokalemia
- ↑ androgens –> virilization (development of male physical characteristics eg increased muscle mass, voice deepening, clitoral enlargement in females)
[Adrenal Disorders]
- 17alpha-hydroxylase deficiency
- CAH Treatment
- 17alpha-hydroxylase (17OHase) deficiency
- ↓ cortisol
- ↑ mineralocorticoids –> hypertension, hypokalemia
- ↓ androgens –> ↓ secondary sexual development (females) and pseudohermaphroditism (males) - CAH Treatment -
- give oral dexamethasone to mother
- replacement therapy with hydrocortisone
- alternate day therapy with prednisone (intermediate acting) - ACTH suppression without increasing growth inhibition
- oral fludrocortisone with salt to maintain PRA, BP, electrolytes
[Adrenal Disorder Pharmacology]
Glucocorticoids
1. Indications
2. Adverse effects with chronic use
Glucocorticoids - cortisol/hydrocortisone, cortisone, prednisone, dexamethosone
- Indications - oral gene expression regulators
- pleiotropic –> useful but difficult to control
- suppress inflammatory and immune responses - allergic reactions, asthma, IBD, lupus, arthritis, cerebral edema, sarcoidosis - Adverse effects with chronic use (2+ weeks therapy) - Cushingoid effects
- glucose metabolism –> hyperglycemia –> diabetes
- fat metabolism –> Fat redistribution –> central obesity
- protein metabolism –> catabolism –> thinning, muscle wasting, poor wound healing, osteoporosis
- androgenic effects –> hirsutism, acne
- CNS effects –> depression, anxiety
- ocular effects –> glaucoma, cataracts
- GI effects –> peptic ulcers
- immunosuppressive –> opportunistic infections
- sleep –> insomnia
- hypertensive –> glucocorticoids like cortisol that possess mineralocorticoid receptor activity
[Thyroid]
- Describe thyroid hormone synthesis
- Describe anatomy of thyroid incl organization of follicle
- Biosynthesis
A. Oxidation: Iodide (I-) comes from outside the cell and is trapped in follicular cell via Na/I symporter –> oxidized to iodine (I2) via TPO
- colloid/thyroglobulin is synthesized in cell and sent to follicular lumen - backbone on which thyroid hormone is made
B. Organification: Iodine + tyrosines (in colloid) combined in follicular lumen via thyroperoxidase TPO to make iodinated tyrosines DIT or MIT
C. Coupling: T3 = MIT + MIT; T4 = MIT + DIT
D. Exocytosis: Endocytosed into follicular cell–> T3/T4 cleaved from colloid (which is put in lysosome) –> diffuse into bloodstream - Anatomy - follicular cells held together by tight junctions to keep colloid (thyroglobulin) inside, surrounded by loose connective tissue
[Thyroid]
- Describe HPT axis
- Compare T3 and T4
- Peripheral metabolism of thyroid hormones
- HPT axis
TRH (hypothalamus) –> binds to thyrotrophs in the anterior pituitary –> secrete TSH –> stimulates T3/T4 production –> feeds back negatively on pituitary + hypothalamus - T4 considered prohormone, T3 is the hormone and has much higher affinity for thyroid hormone receptor
- T4 is almost 100% bound (to either TBG, TBPA, or albumin); 0.03% free; t1/2 = 7 days
- T3 is almost 100% bound (to TBG or albumin); 0.3% free; t1/2 = 1 day
- rT3 = reverse T3, inactive metabolite formed from T4 due to 5’ deiodinases D1/D3 - Metabolism
A. Iodine sufficient: Thyroid mostly makes T4 and a little bit of T3; major source of T3 is peripheral conversion from T4 –> T3 by 5’ deiodinases D1/D2
B. Iodine deficient: thyroid makes both T4 and T3
[Thyroid]
- Describe embryonic development of the thyroid and pathology
- Describe euthyroid sick syndrome
- Thyroid arises on floor of pharynx between first and second pharyngeal arches –> starts at base of tongue and migrates down into neck
- connected to tongue by thyroglossal duct –> remnant is foramen cecum –> can get thyroglossal duct cysts (anterior neck mass that moves with swallowing)
- ectopic thyroid tissue on the tongue = lingual thyroid
- derived from endoderm; C cells from neural crest - Euthyroid sick syndrome - not a thyroid disease but response of thyroid axis to severe systemic illness
- low free T3
- TSH, total T4, free T4 normal
- due to defect in peripheral deiodination of T4 –> T3 because of other illness
[Thyroid] Hypothyroidism 1. Causes 2. Clinical A. Congenital B. Juvenile C. Adult
- Causes -
- congenital (dysgenesis, hormone synthesis errors)
- iodine deficiency (MCC worldwide)
- chronic thyroiditis (MCC in USA) - Clinical
A. Congenital (didn’t receive prenatal care)- jaundice, feeding troubles, enlarged tongue, umbilical hernia
B. Juvenile - mental retardation, learning disabilities, short stature (termed “Cretinism”)
C. Adult -
- (CV) bradycardia and weakness
- (CNS) delayed DTRs during relaxation phase and mental slowness
- (metabolic) dry coarse skin and hair, orange skin, decreased BMR, cold intolerance/hypothermia, weight gain
- (reproductive) amenorrhea (low T3/T4 stimulates TRH, which in turn stimulates prolactin, which inhibits LH/FSH and thus menstruation)
- (GI) constipation
- periorbital and peripheral edema
- worst case is myxedema coma (due to longstanding hypothyroidism, found in elderly)–> decreased mental status, bradycardia, hyponatremia, hypotension, hypoventilation with respiratory acidosis
[Thyroid] 3. Causes of each type of hypothyroidism incl TSH levels A. Primary hypothyroidism B. Central hypothyroidism C. Transient hypothyroidism
- Classification
A. Primary hypothyroidism - TSH high
i. Hashimoto’s i.e. Chronic Lymphocytic Thyroiditis (95%) - autoimmune lymphocytic infiltrate associated with anti-TPO and anti-thyroglobulin Abs; Type IV HSN
- high prevalence in women
- presents with painless thyroid enlargement (B cell lymphoma due to chronic inflammation, like gastric MALTomas and H. pylori)
- histology - lymphoid infiltrate with germinal centers and Hurthle cell change
ii. drug-induced
iii. defects in thyroid hormone synthesis
iv. thyroid development defect (lingual thyroid)
v. iodine deficiency (Rare)
B. Central hypothyroidism - TSH normal or low –> no stimulation for thyroid bc deficiency of TRH and/or TSH
i. pituitary or hypothalamic disease (radiation, tumors, infiltrative disease)
ii. normal or small thyroid gland
C. Transient hypothyroidism - may become permanent
i. postpartum (painless; related to Hashimoto’s thyroiditis)
ii. subacute “de Quervain” thyroiditis (painful referred jaw pain); viral and self-limited
- can result in triphasic response –> destruction (with high T3/T4 and low TSH), repair (high TSH), normal (normal TSH)
[Thyroid] Thyrotoxicosis 1. Define and differentiate from hyperthyroid 2. Clinical manifestations A. Juvenile B. Adult
- Thyrotoxic - general term for clinical evidence of excess thyroid hormone action
- Hyperthyroid - thyrotoxicity due to overactive thyroid in particular - Clinical
A. Juvenile - cranial synostosis (premature fusion of cranial sutures)
B. Adult -
- (CV) - ↑ systolic blood pressure (due to Ca2+ ATPase) –> angina
- vasodilation –> ↓ diastolic BP + ↑ RAAS –> ↑ pulse pressure –> palpitations
- beta adrenergic signaling –> tachycardia, atrial arrhythmias
- (CNS) - inability to concentrate, active DTRs
- (metabolic) - velvety moist skin, increased BMR, and weight loss
- (GI) diarrhea
- osteoporosis
- myopathy (proximal muscle weakness)
- Graves disease - thyroid hum (venous; arterial is called bruit)
- Subacute thyroiditis - pain in neck or jaw during destruction phase
