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
[Thyroid] 3. Causes of each type of thyrotoxicosis incl TSH levels A. Hyperthyroidism B. Thyroid destruction C. Atypical
3A. Hyperthyroidism - TSH low / undetectable; high T3/T4 and high negative feedback
i. Graves - MCC of thyrotoxicosis and hyperthyroidism - thyroid-stimulating IgG in Type 2 HSN –> triad: diffuse goiter, opthalmopathy (bulging eyes), pretibial myxedema (dermopathy with orange-peel appearance)
- scalloping along edges of the colloid (due to papillary projections) and lymphoid aggregates in stroma
ii. toxic multinodal goiter TMG - focal patches of hyperfunctioning follicular cells independent of TSH
iii. thyroid storm - worst case; agitation, delirium, diarrhea, tachyarrhythmia
B. Thyroid destruction - TSH variable
i. subacute thyroiditis
ii. postpartum thyroiditis
iii. hashitoxicosis - transient thyrotoxicosis phase of Hashimoto’s
C. Atypical (rare) - TSH high, high T3/T4
i. thyrotoxicosis factitia - taking thyroid hormone (suppresses axis –> thyroid is smaller than normal)
ii. TSH secreting pituitary tumor
iii. struma ovarii - ovarian teratoma making thyroid hormone
iv. hydatidiform mole (HCG overproduction which binds to TSH receptor)
[Thyroid] 1. Thyroid hormone testing principles 2. Describe thyroid hormone testing results for the following: A. Primary hypothyroidism B. Thyrotoxicosis C. Atypical Thyrotoxicosis D. Central hypothyroidism
- TSH - single best test of thyroid function (but does not inform about degree of thyroid dysfunction) –> increases if thyroid levels low or decreasing if thyroid levels are high
- always get a free T4 after abnormal TSH result to determine extent of hypothyroidism or thyrotoxicosis
- TSH not good test if TSH/pituitary (secondary disease e.g. central hypothyroidism) is the problem
2A. Primary hypothyroidism (Hashimoto’s) - low T3/T4, high TSH
B. Thyrotoxicosis (Grave’s) - high T3/T4, low TSH
C. Atypical Thyrotoxicosis (TSH adenoma, thyroid hormone resistance)- high T3/T4, high TSH
D. Central hypothyroidism (pituitary problem) - low T3/T4, low TSH
[Thyroid] 1. Treatment for hypothyroid 2. Side effects A. Wolff-Chaikoff Effect B. Jod-Basedow Effect
- Treatment for hypothyroid - thyroid hormone
- most commonly prescribed is synthetic T4 levothyroxine (e.g. Levothyroid, Levoxyl) - t1/2=7 days with 1xday dosing
- synthetic T3 (Triostat, Cytomel) - t1/2=1 day, multiple daily dosings limited use
- check ACTH levels prior to T4 therapy - give glucocorticoids if ACTH is low (raising thyroid levels will increase BMR and thus need for cortisol) - Side effects
A. Wolff-Chaikoff Effect –> too much iodide inhibits organification (production of DIT/MIT) –> ↓ T3/T4 production
- used pharmacologically via KI potassium iodide tablets –> temporary block of thyroid e.g. pre-op or for short-term tx of Grave’s disease
- within a week, get escape from W-C effect –> chronic high iodide inhibits Na/I symporter
B. Jod-Basedow Effect –> iodide-induced thyrotoxicosis
- happens if you give iodide to patient with thyroid deficiency and autonomous nodules –> they can use nodules to make thyroid hormone –> ↑ T3/T4 production
- opposite of wolff-chaikoff*
[Thyroid]
1. Treatment for hyperthyroid
A. Radioactive iodine
B. Anti-thyroid drugs
- Treatment for hyperthyroid (Graves, toxic nodules, thyroid cancer)
A. Radioactive iodine
- can give via oral pill in outpatient setting
- no natural treatments
B. Anti-thyroid drugs (thionamides)
- propylthiouracil PTU, methimazole (Tapazole) - block thyroperoxidase TPO –> inhibit iodide oxidation and organification
- PTU also inhibits peripheral T4–> T3 conversion mediated by D1/D2
- methimazole preferred since it is safer, EXCEPT in pregnancy (in which PTU is preferred) since it can cause aplasia cutis in newborn
- side effects - most common –> maculopapular pruritic rash; dangerous but reversible –> hepatitis, agranulocytosis
[Thyroid]
- Why are most thyroid nodules benign?
- Approach for thyroid nodule work-up
- Thyroid nodules v common - only 5% of biopsied nodules are cancer
- risk factors for nodules and cancer - age, female gender - Approach for thyroid nodule work-up
- Do TSH and free T4:
A. normal TSH and low fT4 –> most nodule pts have normal thyroid function (problem is structural and not functional) –> do fine needle aspiration FNA biopsy to see if benign/malignant
B. high TSH –> probably Hashimoto
C. low TSH –> RAI (radioactive iodine) scan
i. hot nodule - high fT4, benign - due to Grave’s, multinodular goiter; do not need to biopsy
ii. cold or warm - low fT4, seen in adenoma or carcinoma –> biopsy via FNA
[Thyroid]
Describe the types of thyroid carcinoma incl histology, markers, mets
1. Papillary
2. Follicular
- Papillary - most common (85%) - differentiated thyroid cancer from follicular epithelium
A. Histology - papillae with Orphan Annie eye nuclei and psammoma (concentric calcified) bodies
B. Marker - thyroglobulin (colloid) levels
C. Mets - cervical neck lymph nodes; excellent prognosis - treat with surgery, radioactive iodine, and T4 for TSH suppression - Follicular - differentiated thyroid cancer from follicular epithelium
A. Histology - malignant proliferation of follicles with invasion of surrounding fibrous capsule
B. Marker - thyroglobulin (colloid) levels
C. Mets - spreads hematogenously to lung, bone
[Thyroid]
Describe the types of thyroid carcinoma incl histology, markers, mets
3. Medullary
4. Anaplastic
- Medullary - malignant proliferation of parafollicular C cells
A. Histology - sheets of malignant cells in amyloid stroma (calcitonin deposits as amyloid) that stains Congo red
B. Marker - calcitonin
C. Mets - multiple
D. 25% cases hereditary - associated with MEN 2A and 2B (familial RET mutations)
- MEN2A: medullary carcinoma, pheochromocytoma, parathyroid adenoma
- MEN2B: medullary carcinoma, pheochromocytoma, ganglioneuromas of oral mucosa (eg tongue), Marfinoid body habitus - Anaplastic - usually seen in elderly
A. Histology - undifferentiated tumor of thyroid
B. Marker - none
C. Mets - invades local structures, v poor prognosis –> death via dysphagia or respiratory compromise
[Growth Disorders] Describe the following types of short stature 1. Normal variants A. Familial B. Constitutional Delay of growth
- Pathologic variants
A. Disproportionate
B. Proportionate - Idiopathic
- Normal variants
A. Familial short stature - normal growth rate, age of puberty, and bone age –> will always be short
B. Constitutional Delay of growth - can reach normal height but temporary reduction in growth rate for age; delay in age of puberty and delayed bone age (epiphyses not fused yet, so room to grow) - Pathologic variants
A. Disproportionate (limbs disproportionately short for the trunk or vice versa) due to genetics or bone abnormalities eg rickets, osteogenesis imperfecta
B. Proportionate - growth is proportionate but there is not enough
i. prenatal - intrauterine growth restriction (IUGR), genetics, defects in pituitary devlpt
ii. postnatal - chronic disease, malnutrition, psychosocial dwarf, endocrine disease (growth hormone deficiency) - Idiopathic - diagnosis of exclusion
- no short relatives
- no history of puberty delay in family
- all endocrine testing normal
[Growth Disorders]
1. Regulation of GH secretion
2. GH hypersecretion A. Cause B. Diagnosis C. Clinical D. Treatment
Growth hormone
1. GHRH (hypothalamus) –> binds to receptor on somatotroph in anterior pituitary –> GH synthesized and secreted –> IGF-1 (liver), fat metabolism, ↑ glucose levels (↓ insulin sensitivity), ↑ muscle mass, bone growth
- GH hypersecretion
A. Cause - benign pituitary somatotroph adenoma with constitutively active Gs alpha mutation
B. Diagnosis - ↑ GH after oral glucose tolerance test OGTT (glucose should suppress GH and cause levels to decrease)
- present as macroadenomas
C. Clinical
i. before puberty - gigantism
ii. after puberty - acromegaly
- large hands and feet, large jaw, deep voice, goiter, soft doughy hands, glucose intolerance, cardiomegaly
D. Treatment - surgical resection of tumor is first line treatment, then radiation, pharma (octreotide - somatostatin analog that suppresses GH release, pegvisomant - GH receptor antagonist)
[Growth Disorders] 3. GH deficiency A. Causes B. Diagnosis C. Clinical in children vs adults D. Treatment
- GH deficiency
A. Causes - most commonly without known cause but can have mutations in GH receptor, signaling pathway, IGF-1
B. Diagnosis - data on height curve (<2SD below mean), screening via lab values for IGF-1 and IGFB-3
- definitive testing via provocative testing with stimulation (insulin, arginine, GHRH, exercise)
C. Clinical - GH stimulates liver IGF-1 for long bone growth, anabolic effects on muscle, decreases insulin sensitivity, and has catabolic effects on adipocytes
i. children - present with normal birth weight and height (GH not required for in utero growth)
- severe deficiency presents at birth with small phallus (boys)
- mild deficiency presents after 6 mos with subnormal growth rate
- children have cherubic appearance with short stature, increased body fat (central obesity), high-pitched voice, thin hair, poor nail growth, delayed dentition, and decreased muscle mass
ii. adults - decreased bone density, central obesity, depression
D. Treatment - growth hormone (somatropin), recombinant IGF-1 (mecasermin)
[Sexual development disorders]
1. Describe hypothalamic-pituitary axis control of reproductive function
A. Female
B. Male
- Sex steroid hormone feedback on reproductive axis
A. Female
B. Male
- HP Axis: GnRH (hypothalamus) pulsatile secretion –> GnRH binds to receptor on gonadotrophs in anterior pituitary –> LH and FSH synthesis and secretion
A. Female - LH controls production of androstenedione in ovarian theca internal cells
- FSH regulates conversion of androstenedione to estradiol E2 in ovarian granulosa cells
B. Male - LH controls production of testosterone in Leydig cells; FSH concentrates testosterone and regulates spermatogenesis in Sertoli cells - Feedback
A. Female - estradiol E2 has positive feedback on pituitary and hypothalamus –> mid-cycle surge –> triggers ovulation
- at other times, feedback is negative
B. Male - testosterone always has negative feedback to pituitary and hypothalamus
[Sexual development disorders]
- Development of GnRH neurons
- Describe Kallman syndrome
- GnRH - neurons originate in nasal placode, migrate through cribriform plate / olfactory bulb to get to hypothalamus
- GnRH synthesized in preoptic nuclei of hypothalamus –> goes through portal vessel to pituitary
- pulsatile secretion - increased GH receptor expression/sensitization associated with the pulse –> leads to pulsatile secretion of LH and FSH; any disruption leads to hypogonadism
- continuous GnRH –> low levels of LH and FSH - Kallman syndrome (congenital- XLR) - mutated KAL1 protein –> defective migration of GnRH neurons through olfactory bulb –> hypothalamic hypogonadotropic hypogonadism + anosmia
- enuchoidal proportions (arm span»_space; height), color blindness, midline defects (Eg cleft palate)
- undetectable testosterone, LH, FSH
- pituitary function normal
[Hypothalamic and Pituitary Disorders]
Disorders of FSH and LH
1. Differentiate Primary vs secondary vs tertiary hypogonadism
2. Causes of secondary vs tertiary hypogonadism
3. Clinical manifestations of hypogonadism
4. Treatment
1A. Primary hypogonadism - ↓ production of sex hormones due to problem with gonads; ↑ LH, FSH
B. Secondary - ↓ LH, FSH
C. Tertiary - ↓ GnRH
- Causes:
A. Secondary - pituitary adenoma (rare, acquired), low body weight due to anorexia, exercise (functional), ectopic –> increase CRH and ACTH –> inhibit GnRH –> inhibit LH and FSH secretion
B. Tertiary - Kallman syndrome - Clinical - amenorrhea, gynecomastia, infertility, decreased libido, absence of secondary sexual characteristics (eg body hair), osteoporosis (gonadal hormones required for proper bone density), reduced libido, increased BMI and body fat %, depression, sleeplessness, hot flashes
- Treatment - estrogen/testosterone replacement
A. Congenital/Kallman’s - pulsatile GnRH from pump
B. Acquired - pituitary surgery
C. Functional - increase body weight, long-acting GnRH agonist (eg leuprolide, gonadorelin) to decrease body secretion of GnRH
[Sexual development disorders]
- Describe normal puberty
- Describe Tanner stages of sexual development
- Normal puberty -
Hypothalamic GnRH –> LH and FSH –>
- stimulate testosterone in males –> gonadarche (increased testes)
- stimulate estradiol in females –> thelarche (onset of breast development), menarche is late event in pubertal devlpt (after maximum growth velocity); occurs at 12 years
- stimulates adrenal glands –> adrenal androgens –> adrenarche (Tanner pubic hair); occurs at 15 years - Tanner stages for breast, genitalia, and pubic hair
Stage 1 - no sexual hair, no breast tissue
Stage 2 - public hair appears, breast bud, testicular enlargement –> heralds onset of puberty
Stage 3 - pubic hair coarsens, breast enlarges, penis enlarges
Stage 4 - adult pubic hair but less in quantity, breast enlarges, penis and length width increases
Stage 5 - adult pubic hair in inverted triangle, adult penis and testes, adult breasts
[Sexual development disorders] Describe abnormalities in puberty: 1. Delayed puberty A. Central B. Peripheral C. Treatment
- Delayed puberty - Hypogonadism
(Females) no breast devlpt by 13 or menses by 16
(Males) no testicular devlpt by 14
A. Central (85%) - hypogonadotropic –> inability to make GnRH, LH, FSH (hypothalamic/pituitary dysfunction)
- constitutional delay of puberty *more common in boys
- functional hypogonadotropic hypogonadism - stress, exercise, hyperprolactinemia
- permanent hypogonadotropic hypogonadism - genetic, tumors, vascular
B. Peripheral/primary (15%) - hypergonadotropic –> high GnRH, LH, FSH (due to loss of negative feedback by estradiol, testosterone)
- gonadal dysgenesis - Turner XO, Klinefelter XXY
- gonadal failure (eg ovarian/testicular dysfunction) - e.g. premature ovarian failure (associated with Fragile X syndrome), autoimmune, chemo, radiation, torsion
C. Treatment
i. Girls - ethinyl estradiol; begin prostagen when menstruation starts
ii. Boys - testosterone
- can give pulsatile GnRH or combo FSH/hCG to induce fertility
[Sexual development disorders] Describe abnormalities in puberty: 1. Precocious puberty A. Central B. Peripheral C. Treatment
- Precocious puberty - (Females) breast devlpt before 8; (Males) increase in testicular size before 9
A. Central (90%) - gonadotropin (LH/FSH) dependent –> high GnRH, LH, FSH, sex steroids
- idiopathic central precocious puberty - MCC *more common in girls
- general CNS insult (radiation, trauma)
- CNS tumors (hamartomas)
B. Peripheral (10%) - gonadotropin (LH/FSH) independent –> high estradiol/testosterone and low LH/FSH
- sex steroid secreting tumor in gonad
- sex steroid secreting tumor of adrenal, CAH
- exogenous estrogen or androgen
- McCune-Albright syndrome (activating Gs alpha mutation) –> cafe au lait spots
- (Females) ovarian cysts
- (Males) - hCG secreting tumor, familial testotoxicosis (LH receptor mutation)
C. Treatment -
- GnRH agonists (eg leuprolide, gonadorelin) - continuous GnRH secretion induces pituitary desensitization –> lowers levels of LH and FSH
[Female repro] Describe menstrual cycle and relative levels of hormones - FSH, LH, estrogen, progesterone 1. Follicular 2. Ovulation 3. Luteal 4. Menstruation
Menstrual cycle - 28 days:
1. Follicular (proliferative) phase - Days 0-13
A. Starts with menses from previous cycle (shedding of endometrium)
B. E2 levels low and steady –> negative feedback on LH secretion
- inhibin B from pre-ovulatory follicle –> negative feedback on anterior pituitary –> low FSH + non-selected follicles undergo atresia without FSH
C. before ovulation, E2 levels spike due to selected follicle –> stimulates FSH secretion (switches to positive feedback)
D. in response to high E2, inhibin B production stops and activin is produced by gonadotropes (anterior pituitary) –> activin stimulates FSH secretion –> E2 production and LH receptor expression within granulosa cells of selected follicle
*E2 stimulates proliferation/thickening of endometrium
- Ovulation - Day 14
- preovulatory gonadotropin surge (LH» FSH) –> LH triggers ovulation (completes meiosis I) - Luteal (secretory) phase - Days 15-28
- elevated inhibin A produced by corpus luteum –> negative feedback on FSH
- elevated P4 and E2 (P4»E2) –> affects GnRH pulse frequency –> negative feedback (P4 mostly affects LH and E2 mostly affects FSH)
* P4 targets endometrium + myometrium –> development of blood supply - Menstruation - Day 28
- P4 and E2 levels decline at end of cycle –> withdrawal bleed (menses) –> shed upper 2/3 of functional layer of endometrium
- rise in basal body temperature during luteal phase due to thermogenic P4–> BBT can provide info about ovulation/endocrine functioning
- very little variation in luteal phase in women; variation is in follicular phase
[Female repro]
Explain process of ovarian folliculogenesis, incl steroidogenesis and contrasting theca vs granulosa cells
Folliculogenesis
1. Primordial - non-growing reserve of immature follicles contain oocyte + one layer of pre-granulosa cells
- Primary - growing cohort that begin differentiating after recruitment; oocyte + granulosa cells
- Preentral –> Antral - one follicle selected to further differentiate as the dominant / Graffian follicle
- granulosa cells in follicle pregulate FSH receptors - Pre-ovulatory
- steroidogenic differentiation with granulosa + theca cells –> steroidogenesis starts with RLS - cleavage of C27 side chain to go from cholesterol –> pregnenolone
- theca cells have LH receptors; make androgens (androstenedione»_space;> testosterone) via CYP17
- granulosa cells have FSH receptors; use androgens to make estrogens (estradiol E2»_space; E1) via CYP19
- one follicle - Ovulation - oocyte released from pre-ovulatory follicle; all hormone levels drop
- Corpus luteum - formed from pre-ovulatory follicle
- theca cells make progesterone P4
- granulosa cells make P4 and E2
[Female repro]
Folliculogenesis timeline incl recruitment, selection
Folliculogenesis cycle takes place over 3-4 months with multiple overlapping cycles –> at a given time there are follicles in different growth stages
- Recruitment - some primordial (Resting) follicles are brought from reserve into growth pool; one recruitment occurs every month
- independent of gonadotropins (FSH, LH)
#2-4 are gonadotropin-dependent: 2. Selection - one follicle selected from the pool that goes on to mature
- Luteinization - pre- and post- ovulatory differentiation of the selected follicle (i.e. dominant follicle = Graffian follicle) –> selected follicle drives serum hormone level changes
- Luteolysis - corpus luteum degenerates
Atresia - apoptotic death of non-selected follicles, can happen at any time
[Amenorrhea] 1. Define: A. Primary amenorrhea B. Secondary amenorrhea C. Oligomenorrhea
- MCC of amenorrhea and how to work up
1A. Primary amenorrhea - never had a period; by age 16 with secondary sexual characteristics or by age 14 without secondary sexual characteristics (breasts, pubic hair)
B. Secondary amenorrhea - has had a period previously but 6+ mos without menses
C. Oligomenorrhea - menstrual interval between 1-6 mos
- MCC is etiologies secondary to abnormal ovarian function
A. Progestin challenge (progestin withdrawal test) - pts with normal physiological levels of estrogen will have a withdrawal bleed within 1 week –>
- bleed –> problem due to PCOS, anovulation
- no bleed –> do estrogen + progestin test
B. Estrogen + Progestin test –>
- no bleed –> utero-vaginal obstruction
- bleed –> problem with estrogen –> check FSH
C. FSH levels
- high –> ovarian failure
- low –> hypothalamic-pituitary dysfunction
[Amenorrhea] Describe the following causes of secondary amenorrhea: 1. Polycystic ovarian syndrome PCOS A. Causes B. Labs C. Clinical D. Factors that increase/decrease SHBG
- PCOS - dysfunction at level of correlating folliculogenesis with menstrual cycle luteal phase
A. Causes: unknown; correlated with diabetes: ↑ insulin –> ↑ GnRH pulsatility –> ↑ LH levels –> ↑ androgen production in theca cells –> ↑ peripheral conversion to estrogens –> negative feedback –> ↓ FSH –> cystic degeneration of follicles
B. Labs:
- ↑ LH/FSH ratio (normal ratio is FSH»_space; LH)
- ↑ AMH
- ↑ androgens
- ↓ sex hormone binding globulin SHBG (more free testosterone)
C. Clinical: obese young woman with infertility, oligomenorrhea, and hirsutism
- hirsutism - androgens stimulate pilosebaceous units to form terminal hairs
- acne - excess secretion from sebaceous glands; inflammatory on face, chest, back
- male-pattern alopecia
- “string of pearls” on ultrasound due to multiple follicles but no dominant follicle ovulated (bc no LH surge)
D. SHBG binds tighter to testosterone than estrogens
- Increased SHBG –> estrogens, hyperthyroidism, hepatitis, anticonvulsants
- Decreased SHBG –> androgens, hypothyroidism, obesity, insulin resistance
[Amenorrhea] Describe the following causes of secondary amenorrhea: 2. Sheehan's syndrome 3. Premature ovarian failure 4. Uterovaginal obstruction
- Sheehan’s syndrome - postpartum hypopituitarism or postpartum pituitary necrosis
- postpartum hemorrhage + hypovolemic shock –> acute infarction, ischemia
- affects all hormones produced by pituitary (GH, FSH LH, ACTH, TRH)
- but #1 symptom is failure of lactation - Premature ovarian failure - high FSH levels but low estrogen
A. causes:
i. idiopathic
ii. genetic - Y chromosome, abnormality of X, fragile X pre-mutation (CGG repeat expansion)
iii. autoimmune MCC - hypothyroidism, hypoparathyroidism, hypoadrenalism
B. Treatment - prevent osteoporosis - Uterovaginal obstruction
- Asherman’s syndrome - result of overaggressive dilation and curettage –> loss of basalis and scarring (intrauterine adhesions)
- pelvic radiation
[Amenorrhea]
Describe sexual development in males and females
Sexual development: gonads indifferent up until 7 weeks in development; differentiation based on SRY gene on Y chromosome
A. Male: Y chromosome –> SRY –> testis determining factor TDF –> SOX9 –>
A. Sertoli cells: anti-Mullerian hormone AMH –> Mullerian (paramesonephric) duct regression –> absent uterus and fallopian tubes
B. Leydig cells
i. testosterone –> testicular descent, conversion to DHT, Wolffian (mesonephric) duct devlpt –> ejaculatory ducts, epididymis, seminal vesicles, vas deferens
- DHT (from action of 5-alpha reductase on testosterone) external genitalia differentiation –> penis, scrotum, prostate
- testosterone is a prohormone –> DHT via 5alpha reductase
- -> estradiol E2 via CYP19 aromatase
B. Female: No AMH –>
- Mullerian (paramesonephric) duct –> fallopian tubes, uterus, upper 2/3 vagina
- urogenital sinus - lower 1/3 vagina
[Amenorrhea]
Describe causes of primary amenorrhea with the following features:
2. Breasts present, uterus absent
- Breasts present, uterus absent –> high estrogen + AMH
A. MKRH/Mullerian agenesis - 46XX but congenital abnormality –> failure of mullerian duct development (uterus, fallopian tubes)
- normal female with ovaries and testosterone levels –> normal secondary sexual characteristics (e.g. pubic hair) with primary amenorrhea
- correlated with renal and skeletal anomalies
B. Androgen insensitivity syndrome - 46XY
- inability to respond to androgens or receptor defect
- XL-R with Xq12 deletion
- clinical manifestation varies depending on severity of insensitivity (can be female or male phenotype)
- complete insensitivity: female phenotype, presents at puberty with primary amenorrhea, short blind-end vagina, no cervix/uterus, large breasts, tall stature, no pubic hair
- male levels of testosterone; can have testes in inguinal canal (remove testicles i.e. gonadectomy) to reduce risk of germ cell tumor
Differences: Mullerian agenesis has female (lower testosterone levels) and normal pubic hair; AIS has male testosterone levels and no pubic hair
[Amenorrhea] Describe causes of primary amenorrhea with the following features: 3. Breasts absent, uterus present 4. Breasts absent, uterus absent 5. Breasts present, uterus present
- Breasts absent, uterus present –> low estrogen, no AMH
A. Gonadal dysgenesis –> high FSH
- Turner’s syndrome (XO) - MCC; short, streak gonads, aortic coarctation, horseshoe kidneys
- 46XX - 17Ohase deficiency - type of congenital adrenal hyperplasia with ↑ mineralocorticoids and ↓ androgens
- 46XY - SRY gene mutation i.e. Swyer’s Syndrome
B. Hypothalamic/pituitary failure e.g. Kallman’s –> low FSH - Breasts absent, uterus absent –> low estrogen, AMH present
A. 46XY - 17Ohase deficiency
B. Testicular regression syndrome - Breasts present, uterus present –> congenital outflow obstruction
A. imperforate hymen (no hymenal ring)
B. transverse vaginal septum (horizontal wall of tissue that blocks vagina)
[Pregnancy]
1. Describe maternal hormonal recognition of pregnancy
- Maternal-fetal steroidogenesis
- Maternal recognition of pregnancy in weeks 3-4
- placenta makes GnRH –> stimulates syncytiotrophoblasts in placenta –> produce hCG (potent LH analog), peaks at 12 weeks –> binds LH receptors on corpus luteum –> progesterone P4 produced –> negative feedback on hypothalamus + pituitary (HPA axis control removed) –> no menstrual cycles in pregnancy
- progesterone production shifts from corpus luteum to placenta in late 1st trimester (corpus luteum degenerates)
2A. Fetus:
- fetal pituitary gland produces ACTH –> stimulates fetal adrenal glands to produce DHEAS –> placenta converts DHEAS to estriol E3
B. Maternal progesterone P4 used by:
- fetal adrenal glands to make DHEAS and cortisol
- placenta to make E3
[Pregnancy]
3. Relative levels of the following maternal serum hormones during pregnancy:
A. Progesterone
B. Estrogens - E2 and E3
- Physiologic alterations in thyroid function
- Sugar levels
3A. Progesterone - highest levels of all the hormones
- made by corpus luteum in 1st trimester
- made by placenta in 2nd and 3rd and peaks before labor
B. E2 estradiol = E3 estriol throughout most of pregnancy
- activation of uterine ER –> E3 production –> ↑ E3»E2 induces contractions
- hCG (peaks in week 12) can stimulate TSH receptor (beta subunit homology) –> drives thyroid function independent of TSH –> ↑ free T4 and ↓ TSH but then reverts to normal by second semester
- ↑ TBG (thyroxine-binding globulin) and ↑ total T4 throughout pregnancy
- placenta makes Type 3 iodothyronine deiodinase –> metabolizes free T4 into rT3 keeps T4 levels appropriate for fetus - Gestational diabetes due to ↑ placental growth hormone
[Pregnancy]
Describe physiologic rationale for changes in:
1. Fluid status
- Mother needs to increase body fluid levels due to additional circulation
A. placental E2 + vascular underfilling (due to shunt-like placental circulation) –> activate RAAS –> Ang II
- AII-induced vasoconstriction overridden by relaxin (from corpus luteum, placenta) and P4
- but AII and aldosterone do work in kidney for Na+ and H20 reabsorption
B. AVP - progesterone + E2 stimulate AVP release from posterior pituitary, which acts at 3 receptors:
i. V1R - vasoconstriction overridden by relaxin, P4, E2
ii. V2R for distal H20 reabsorption
iii. V3R (anterior pituitary) –> ACTH –> glucocorticoids
Overall result - ↑ in body fluid not vasoconstriction –> no ↑ in BP during pregnancy
[Pregnancy] Describe physiologic rationale for changes in: 2. Renal function 3. Cardiac/hemodynamic function 4. Cardiac/pulmonary pressure 5. BP
- Renal function
- ↑ perfusion, ↓ vascular resistance –> ↑ GFR –> SGLT can saturate –> glucosuria and ↑FEIodine
- overall result: ↓ plasma creatinine and BUN - Cardiac/hemodynamic function
A. first trimester: ↑ intravascular volume, ↑ RBC (due to ↑ P4), ↑ vasodilation –> facilitates placental perfusion (↑Q and ↓P)
B. second and third trimesters: ↑ maternal HR, ↑ CO (bc CO=HR*SV) - Cardiac/pulmonary function
- ↑ plasma volume –> ↑ venous return –> but central venous pressure normal due to ↑ CO
- ↓ pulmonary vascular resistance –> but pulmonary arterial pressure normal due to ↑ CO - BP = CO * TPR –> stays constant during pregnancy
↑CO (due to ↑ HR) and ↓TPR (due to relaxin, estrogen, P4, NO) –> ↓ diastolic pressure and ↑ pulse pressure
[Pregnancy]
Describe physiologic rationale for changes in:
1. Chest and lungs
2. Respiration
3. Acid-base and ABG (PA02, PAC02, Pa02, and PaC02)
4. Maternal and fetal Hb curves
- Chest and lungs
- rib cage expands (relaxin softens rib ligaments)
- ↓ chest diameter and diaphragm pushed upwards –> ↓ ERV and thus functional residual capacity FRC (ERV+RV), ↓ chest wall compliance - Respiration - pregnant women more sensitive to changes in P02 and C02
- placental progesterone P4 –> lowers C02 sensitivity threshold in medullary respiratory centers –> ↑ minute ventilation –> ↑ respiratory rate –> ↑ tidal volume TV
- P4 also ↑ sensitivity of peripheral chemoreceptors to hypoxia
- ↑ metabolism –> ↑ C02 –> stimulates chemoreceptors in carotid bodies - ↑ ventilation –> ↓ PAC02 –> ↑ PA02
and ↓ PaC02 (respiratory alkalosis) –> ↑ Pa02 + kidneys excrete bicarb to maintain homeostasis
- creates gradient favoring maternal –> fetal 02 transfer and fetal C02 offloading - Maternal Hb curve shifts right (↓ 02 binding affinity)
Fetal Hb curve shifts left (↑ 02 binding affinity)
- volume increase can lead to maternal physiologic anemia but 02 delivery maintained bc of ↑ CO
[Prenatal Care] Describe effects of the following teratogenic agents: 1. ACE inhibitors 2. Aminoglycosides 3. Carbamezapine 4. Folate antagonists 5. Lithium
Highest susceptibility to teratogens at 3-8 weeks (organogenesis)
1. ACE inhibitors (“prils”)- renal damage
- Aminoglycosides (Streptomycin, gentamicin, etc) - absent digits, ear and facial anomalies
- Carbamezapine (anticonvulsant) - craniofacial defects, fingernail hypoplasia, Intrauterine growth restriction IUGR, neural tube defects
- Folate antagonists (methotrexate, trimethoprim) - neural tube defects
- Lithium - Ebstein anomaly (downward displacement of tricuspid valve –> Tricuspid regurg)
[Prenatal Care] Describe effects of the following teratogenic agents: 6. Methimazole 7. Iodine 8. Maternal diabetes 9. Vitamin A excess 10. Alcohol
- Methimazole (antithyroid) - aplasia cutis congenita (focal absence of skin)
- Iodine - too little –> cretinism; too much –> goiter
- Maternal diabetes - caudal regression syndrome
(mermaid) , congenital heart defects, neural tube defects - Vitamin A excess - spontaneous abortions, cleft palate, cardiac abnormalities
- Alcohol - fetal alcohol syndrome (low nasal bridge, epicanthal folds, missing philtrum, low set ears, thin upper lip)
[Gestational Pathology]
Describe pathophysiology, risk factors, clinical presentation, diagnosis, and treatment of:
- Ectopic pregnancies
- Ectopic pregnancies
A. Pathophysiology - fetus implants outside of the uterus, most commonly in fallopian tube
- MCC of maternal mortality in 1st semester (internal hemorrhage)
B. Risk factors - scarring due to salpingitis (PID) or endometriosis, infertility, assisted reproductive techniques, tubal surgery, smoking
C. Clinical - lower quadrant abdominal pain and vaginal bleeding a few weeks after missed period
D. Diagnosis - trans-vaginal ultrasound, beta hCG
E. Treatment - methotrexate (early on in unruptured ectopics); surgical (laparoscopy)
[Gestational Pathology]
Describe pathophysiology, risk factors, clinical presentation, diagnosis, and treatment of:
- Gestational trophoblastic diseases
i. complete hydatidiform mole
ii. partial hydatidiform mole
- Gestational trophoblastic diseases
A. Pathophys - abnormal proliferation of placental tissue, usually manifest before 20 weeks
- non-cancerous = hydatidiform mole
i. complete - 2 sperm fertilize empty egg with no nucleus/chromosomes –> 46 chromosomes no maternal DNA –> all placental tissue and no fetus
- diffuse proliferation of syncytiotrophoblasts (higher hCG) with theca-lutein cysts around hydropic villi
- increased chance of malignancy (choriocarcinoma)
ii. partial - 2 sperm fertilize single egg –> too much paternal DNA –> may have unviable fetus
- focal proliferation of cytotrophoblasts
B. Risk factors - asian, maternal age, previous moles
C. Clinical - uterine bleeding, no fetal heart tones, preeclampsia <20 weeks
- passage of grape-like masses if woman doesn’t receive prenatal care
D. Diagnosis - “snowstorm” appearance on ultrasound
- uterus much larger and beta hCG much higher than expected for gestational age
E. Treatment - surgical evacuation, follow up for detection of malignant change
[Gestational Pathology]
Describe pathophysiology, risk factors, clinical presentation, diagnosis, and treatment of:
- Preeclampsia incl eclampsia + HELLP
- Preeclampsia
A. Pathophysiology -
- placental dysfunction (failure of trophoblasts to adequately invade uterine spiral arteries and dilate them) –> reduced placental blood flow –> uteroplacental ischemia –> oxidative/inflammatory stress on maternal circulation –> vasospasms, endothelial dysfunction, coagulation –> vasoconstriction –> maternal systemic organ ischemia
B. Risk factors - nulliparous (first pregnancy), multiple pregnancies, chronic HTN, 35+ yo, obesity, African, autoimmune
C. Clinical - non-pitting edema, headaches, vision problems, SOB, nausea/vomiting, abdominal pain (RUQ)
- HELLP syndrome - severe form of preeclampsia with Hemolysis, Elevated Liver enzymes, and Low Platelets
- Eclampsia - preeclampsia + seizures
D. Diagnosis - BP > 140/90 at 20+ weeks, proteinuria
E. Treatment - delivery (usually resolves after delivery)
- use IV magnesium sulfate (Ca2+ antagonist) to prevent seizures reverse with IV calcium gluconate if needed
[Gestational Pathology]
Describe pathophysiology, risk factors, clinical presentation, diagnosis, and treatment of:
- Placental abruption
- Placenta previa
- Placenta accreta/increta/percreta
- Placental abruption
A. Pathophysiology - premature separation of normally implanted placenta and wall of uterus
B. Risk factors - trauma, maternal hypertension, icigarette smoking, prior abruption
C. Clinical - PAINFUL contractions and vaginal bleeding - Placenta previa
A. Pathophysiology - placenta is located over/near the internal cervical os –> baby cannot be delivered vaginally
B. Risk factors - increased age and parity, prior C-section, smoking
C. Clinical - PAINLESS vaginal bleeding; do NOT perform pelvic exam (you will rupture the placenta) - Placenta accreta/increta/percreta
A. Pathophysiology - placenta does not separate after delivery; should separate within 30 min of delivery
i. accreta - invades decidua
ii. increta - invades muscle wall of uterus
iii. percreta - invades serosal lining of uterus, can growth through the wall of the uterus
B. Clinical - life threatening bleeding
[Breast disorders]
- Common clinical manifestations of breast disease
- Clinical breast exam
- Describe breast development
- mass, positive screening test (asymptomatic), nipple discharge, skin changes, pain (common problem but infrequently cause of cancer)
2A. Inspection - symmetry, size, scars
- skin changes (erythema, dimpling)
- nipple position (usually everted)
B. Palpation - systemic, nipple-areola, axillary/supra-clavicular lymph nodes
- Mammary ridge forms “milk streak” from budding of ectoderm into surrounding mesenchyme
- failure to completely regress –> accessory nipple (usually on thorax below breasts) or accessory mammary tissue (usually in axilla)
[Breast disorders] - Breast infection
Describe the following incl causes, pathophysiology, clinical sx:
1. Acute mastitis
2. Periductal mastitis
- Acute mastitis
A. Cause - MCC is Staph aureus
B. Pathopys - bacterial invasion through fissures in nipple (esp associated with breastfeeding)
C. Clinical - erythematous (red) breast with prurulent nipple discharge
*clinical symptoms without breastfeeding –> think inflammatory breast cancer
D. Treatment - drainage (continue breastfeeding) and antibiotics (dicloxacillin) - Periductal mastitis
A. Cause - smoking
B. Pathophys - relative Vitamin A deficiency –> squamous metaplasia of lactiferous ducts –> keratin blocks ducts –> inflammation
C. Clinical - subareolar mass with nipple retraction
[Breast disorders] - Breast infection
Describe the following incl causes, pathophysiology, clinical sx:
3. Duct ectasia
4. Fat necrosis
- Duct ectasia
A. Cause - - in multiparous postmenopausal women
B. Pathophys - inflammation with dilation (ectasia) of subareolar ducts
C. Clinical - periareolar mass with green-brown nipple discharge (inflammatory debris)
* cancer should be on differential - Fat necrosis
A. Cause - trauma
B. Pathophys - trauma –> bleeding –> inflammation –> incomplete resolution with saponification, skin thickening
C. Clinical - palpable mass; calcification on mammography
[Breast disorders] - Benign breast disorders
Describe the following incl causes, pathophysiology, clinical sx:
1. Fibrocystic changes
2. Breast cysts
- Fibrocystic changes - most common benign breast condition
A. Causes - consequence of cyclical breast changes with menstrual cycle
B. Pathophys - non-proliferative changes (fibrosis, cysts, “adenosis” - ↑ in acini per lobule) in terminal duct-lobular unit with no increased risk of invasive carcinoma
C. Clinical - vague irregularity of breast tissue - “lumpy breast” in upper outer quadrant
- can undergo apocrine metaplasia (resemble sweat glands with eosinophilic cytoplasm) - Breast cysts - benign, common in 40-50 yo
A. Pathophys - due to lobule dilatation and coalescence
B. Clinical - blue-dome appearance, mobile and firm, can be v large –> no increased cancer risk
- histology: flattened epithelium
- US: anechoic
- cyst rupture can lead to inflammatory changes and fibrosis –> palpable firmness
[Breast disorders] - Benign breast disorders
Describe the following incl causes, pathophysiology, clinical sx:
3. Gynecomastia
- Gynecomastia - benign enlargement of glandular breast tissue in men
A. Causes
i. physiologic: in adolescence (↑ estrogen) and older men (obesity)
ii. certain drugs (e.g. spironolactone, ketoconazole) - interferes with binding of hormones to sex hormone binding globulin SHBG –> E2 not bound tightly so kicked off –> ↑ in free estrogen
iii. pathologic: endocrine abnormalities, neoplasms
B. Pathophys - estrogen stimulates duct epithelial hyperplasia, duct elongation, and stroma proliferation
C. Clinical - subareolar fat/tissue
[Breast disorders] - Benign breast disorders
Describe the following incl causes, pathophysiology, clinical sx:
4. Sclerosing adenosis
5. Atypical hyperplasia
6. Intraductal papilloma
- Sclerosing adenosis
A. Cause - most common change in premenopausal breast; hormone mediated
B. Pathophys - increased acini, stromal proliferation and fibrosis
C. Clinical - pain, lump (masses of small glands in fibrous stroma)
- 2x overall increased breast cancer risk
- mammographic calcifications - Atypical hyperplasia -
A. Cause - proliferative change, pathologic diagnosis
B. Pathophys - ducts or lobules filled with monomorphic proliferation of regularly spaced cells
C. Clinical - 5x overal increased breast cancer risk - Intraductal papilloma
A. Cause - proliferative change
B. Pathophys - papillary growth into a large duct; fibrovascular stalk with projections lined by epithelial (luminal) and myoepithelial cells
C. Clinical - bloody nipple discharge in premenopausal women; solitary and located beneath areola
- must distinguish from papillary breast carcinoma - also has bloody nipple discharge but more common in postmenopausal women
[Breast disorders] - Benign breast disorders
Describe the following incl causes, pathophysiology, clinical sx:
7. Fibroadenoma
8. Phyllodes tumor
- Fibroadenoma -
A. Cause - most common benign neoplasm; seen in younger / premenopausal women
B. Pathophys - tumor of fibrous tissue and glands - proliferation of lobular stroma –> compresses epithelium
C. Clinical - well-circumscribed, mobile, marble-like mass
- estrogen sensitive - grows during pregnancy/menstruation
- benign; no increased risk of breast cancer - Phylloides tumor
A. Cause - in postmenopausal women
B. Pathophys - fibroadenoma-like tumor with overgrowth of fibrosis
- leaf-like projections on biopsy
C. Clinical - mostly benign; large, rapidly-growing mass probably phylloides tumor
[Breast disorders] - Breast cancers
Describe breast cancers incl causes, pathophys, imaging, histology, clinical:
1. Ductal carcinoma in situ
- Ductal carcinoma in situ (DCIS)
A. Pathophys - malignant clonal proliferation of epithelial cells in ducts and lobules with no invasion of basement membrane
- disease can travel in the duct system
B. Imaging - small, clustered, pleiomorphic calcifications on mammography –> need to biopsy
C. Histology
i. Comedo - tumor cells with high grade nuclei and areas of central necrosis; worst prognosis
D. Clinical - Paget disease (Atypical presentation) –> DCIS that extends up lactiferous ducts and involves skin of the nipple –> disrupts keratinocytes –> nipple ulceration, erythema, itching, scaling
- cytokeratin 7 (CK7) marker, PAS stain positive
- Paget’s disease is associated with underlying ductal adenocarcinoma
[Breast disorders] - Breast cancers
Describe breast cancers incl causes, pathophys, imaging, histology, clinical:
2. Lobular carcinoma in situ
3. Invasive lobular carcinoma
- Lobular carcinoma in situ (LCIS) - malignant proliferation of cells in lobule
- not considered to be a true breast cancer but instead a marker of risk –> increased risk for invasive carcinoma in either breast
A. Pathophys - cells lack E-cadherin adhesion protein
B. Imaging - incidental finding, not found on mammography or physical exam (no mass or calcifications)
C. Histology - atypical lobular cells proliferating with no invasion of basement membrane
- treat with tamoxifen to reduce risk of carcinoma - Invasive lobular carcinoma
- cells grow in single file pattern –> no duct formation due to lack of E-cadherin
- spreads via lymphatics
- presents as mass - need to biopsy for diagnosis
[Breast disorders] - Breast cancers
Describe invasive breast cancers incl causes, pathophys, imaging, histology, clinical:
1. Invasive ductal carcinoma
2. Inflammatory breast cancer
- Describe three different classifications of breast cancers based on markers
- Describe breast cancers based on genetics
- Invasive ductal carcinoma - 80% of all invasive breast cancer cases
- histology: duct-like structures in desmoplastic stroma
- prsets as mass on exam or mammography
- subtypes: tubular, mucinous, medullary, inflammatory, papillary - Inflammatory breast cancer - marker of aggressive disease; subtype of invasive ductal carcinoma
- invasive ductal carcinoma cells block dermal lymphatic vessels –> blockage leads to inflammation –> rapid onset of inflamed, swollen breast
- presentation is similar to acute mastitis
- treated differently - chemo (tamoxifen) prior to any surgical mgmt
3A. ER+/PR+/HER2- (60%) - most common
- treat with tamoxifen (selective estrogen receptor modulator SERM) - antagonist at breast ERs
- other treatment option is anastrozole (aromatase inhibitor)
B. HER2+ (20%) - can treat with trastuzumab
C. ER-/HER2- (20%) - “triple negative” when progesterone receptor PR -
- seen in young women, BRCA (+), and African descent
- worst prognosis
- Most common familial BC is due to BRCA mutation (tumor suppressor gene)
- BRCA1 - breast (medullary invasive ductal carcinoma) and ovarian (Serous cystadenocarcinoma)
- BRCA2 - male breast cancer
[Gynecologic Cancer] Cervical carcinoma 1. Risk factors 2. Connection to HPV A. High risk B. Low risk 3. Clinical
- Risk factors - #1 is multiple sexual partners; started having sex young, smoking
- immunocompromised eg. HIV
- most commonly in middle aged women 40-50 yo (takes decades to go from HPV infection –> CIN –> carcinoma) - Cause - HPV (Sexually transmitted DNA virus) - necessary but not sufficient
- HPV infects basal layer of the epithelium - at the transition zone between stratified squamous of ectocervix and simple columnar epithelium of endocervix
- 90% infected will clear virus on their own; those who don’t / have chronic infection can develop cervical dysplasia
A. High-risk: HPV16, 18, 31, 33 –> produce E6 and E7 proteins –> E6 binds p53 and E7 binds Rb for degradation; cause cervical and oral cancers
B. Low risk: HPV6, 11; cause genital warts (condyloma) - Clinical - most women asymptomatic, have abnormal PAP smear
- post-coital vaginal bleeding
- advanced tumor – invades anterior uterine wall into bladder –> obstructs ureters –> hydronephrosis, leg edema, pain
[Gynecologic Cancer] Cervical intraepithelial neoplasia 1. Histology 2. Classification 3. Histology
Cervical intraepithelial neoplasia
1. Histology - koilocytes, disordered cellular maturation, nuclear atypia, increased mitotic activity within cervical epithelium
- Classification - based on thickness of epithelium due to immature dysplastic cells
Stage I - <1/3 of thickness
Stage II - <2/3 of thickness
Stage III - almost entire thickness
In situ - entire thickness of epithelium –> invasive squamous cell carcinoma - Histology - koilocytes (collapsed nucleus surrounded by a halo) pathognomonic for HPV infection
[Gynecologic Cancer] Leiomyoma vs Leiomyosarcoma A. Risk factors B. Pathology C. Clinical
- Leiomyoma (fibroids) - benign smooth muscle neoplasms arising from myometrium; most common tumor in women
A. Risk factors -
i. related to estrogen exposure - premenopausal, low parity, obesity
ii. race (African American)
iii. family hx
- leiomyomas are NOT precursor lesions to leimyosarcoma
B. Pathology - multiple, well-defined, white, whorled round masses found in myometrium
- bundles of homogenous smooth muscle cells with oval nuclei
C. Clinical - commonly asymptomatic but pelvic pain, urinary sx, abnormal uterine bleeding, infertility - Leiomyosarcoma - malifnant proliferation of smooth muscle arising from myometrium
A. Risk factors - rare, usually arises de novo in postmenopausal women
B. Pathology - unclear but pathologically distinct from leiomyoma –> nuclear atypia and high mitotic index
- single lesion with areas of necrosis and hemorrhage
C. Clinical - presents similarly to leiomyoma with bleeding, pelvic pain, pelvic mass
[Gynecologic Cancer] Endometrial cancer 1. Type I 2. Type II 3. Clinical 4. Treatment
Endometrial cancer - incidence increases with age; most common invasive carcinoma of female genital tract
- Type I (80%) - hyperplasia type; more common
A. Risk factors - unopposed estrogen exposure e.g. tamoxifen; obesity, chronic anovulation, nulliparity
- genetics - PTEN, KRAS, Lynch syndrome
B. Pathology - arises from endometrial hyperplasia that mimics proliferative endometrial glands
- invades basement membrane, spreads via direct myometrial invasion and can metastasize via lymphatics - Type II (20%) - serous type
A. Risk factors - older women (endometrial atrophy), p53 mutation
B. Pathology - sporadic; poorly differentiated with no evident precursor lesion; clear cells (in basal layer); atrophic endometrium
- serous histology - resembles serous carcinoma of ovary with papillary architecture, nuclear atypia, and psammoma bodies
- all high grade - exhibit aggressive behavior - intraperitoneal and lymphatic spread - Clinical - most common sx is abnormal (postmenopausal) bleeding –> need to do endometrial biopsy
- Treatment - platinum compounds (cisplatin), paclitaxel, doxorubicin
[Gynecologic Cancer] Ovarian cancer 1. Risk factors 2. Clinical sx 3. Physical findings 4. Types of ovarian cancers
Ovarian cancer
- Risk factors - nulliparity, delayed menopause (continued estrogen exposure)
- genetics - BRCA1 (mucinous ovarian cancer), Lynch Syndrome - Clinical - sx vague until disease advanced
- triad: bloating, increasing abdominal girth, urinary symptoms (urgency, frequency) - Physical findings - ovarian mass, ascites (due to diffuse peritoneal seeding of malignant serous tumors), pleural effusion, abdominal mass, bowel obstruction
- Ca-125 is serum marker for monitoring response and recurrence - Types - based on cell of origin
A. Surface epithelium - most common, worst prognosis
B. Germ cells
C. Sex cord-stroma
D. Metastasis - eg Krukenberg tumor - bilateral ovarian mucinous tumors with signet ring cells; due to metastatic gastric carcinoma
[Gynecologic Cancer] Ovarian cancer - Surface epithelial cell tumors 1. Serous 2. Mucinous 3. Endometrioid 4. Transitional cell
REVIEW TABLE on slide 93
Surface epithelial cell tumors = cystadenocarcinoma; most common; malignant tumors cause diffuse peritoneal seeding –> ascites and omental caking
- Serous (epithelial lining of fallopian tube) - filled with watery fluid
A. Benign (70%) - usually cysts lined with cuboidal epithelium; in younger women - low grade
B. Malignant (30%) - cyst lining is thick and shaggy; in older women; bilateral + psammoma bodies (dystrophic calcification) - aggressive - Mucinous (epithelial lining of endocervix)
- 90% benign; unilateral; well-circumscribed, large and multiloculated, filled with gelatinous mucus-like fluid
- solid areas of growth indicates malignancy
- differentiated from mucinous Krukenberg tumor due to metastatic gastric carcinoma – which are bilateral - Endometrioid - tubular glands resembling endometrium; association with endometrial carcinoma and endometriosis in young women
- Transitional cell i.e. Brenner tumors - rare; mostly benign
- solid, encapsulated, unilateral tumor
- stroma with nests of transitional-type (bladder-like) epithelium
[Gynecologic Cancer] Ovarian cancer - Germ cell tumors 1. Teratoma A. Mature B. Immature 2. Dysgerminoma 3. Yolk sac tumors
REVIEW TABLE on slide 105
Germ cell tumor (GCT) - usually occur in women of reproductive age
- Teratoma i.e. dermoid cysts
A. Mature- most common ovarian tumor in 20-30 yo women
- almost all are benign, unilateral
- contain mature tissue from all three germ layers and lined by epidermis
- lined by skin, can contain hair, teeth
- specialized: struma ovarii –> epithelium is mature thyroid tissue –> hyperthyroid
B. Immature - also in younger women
- bulky and solid
- contain immature elements e.g. foci of neuroepithelial differentiation
- Dysgerminoma - unilateral; composed of immature germ cells (resemble oocytes); occurs with gonadal dysgenesis
- all malignant (30% aggressive and spread), all radiosensitive (good cure rate)
- male counterpart is testicular seminoma
- serum LDH elevated - Yolk sac tumors - unilateral, more common in children
- Schiller-duval bodies (glomerular-like structures)
- serum AFP (alpha feto protein) elevated
[Gynecologic Cancer]
Ovarian cancer - Sex cord stromal tumors
1. Granulosa-theca cell
2. Sertoli-Leydig
REVIEW TABLE on slide 105
Sex cord stromal tumors - from ovarian stroma
- Granulosa cell - malignant neoplastic proliferation of granulosa and theca cells; unilateral
A. Cause - FOXL2 gene mutation
B. Pathology - Call-Exner bodies (nests of cells forming primitive follicles with “coffee-bean” nuclei)
C. Clinical - produce large amounts of estrogen –> sx depend on cancer onset
i. prior to puberty –> precocious puberty
ii. reproductive age –> menorrhagia
iii. postmenopause (most common) –> endometrial hyperplasia with postmenopausal uterine bleeding - Sertoli-Leydig - proliferation of Sertoli cells (form tubules) and Leydig cells (between tubules) with Reinke crystals
A. Cause - DICER1 mutation (microRNA processing)
B. Pathology - androgen-secreting; unilateral
C. Clinical - virilization (breast atrophy, hair loss, amenorrhea, infertility) and hirsutism (male hair pattern)
[Women’s Health Pharmacology]
I. Hormonal contraceptives - MOA
- Non-oral contraceptives
A. Combination estrogen and progestin
B. Progestin only
C. Postcoital
I. Hormonal contraceptives - MOA
- suppress release of FSH and LH from anterior pituitary –> inhibit follicular development and ovulation
- progestin thickens cervical mucus and decreases ovum motility in uterine tubes
- Non-oral contraceptives
A. Combination estrogen and progestin - transdermal patch (Ortho Evra), vaginal ring (NuvaRing)
B. Progestin only - subdermal implant (Implanon), injectable (Depo Provera)
C. Postcoital - levonorgestrel (Plan B) - progestin, take within 72 hours
- Non-oral contraceptives
[Women's Health Pharmacology] 2. Oral contraceptives A. Preparation B. Adverse effects C. Contraindications D. Beneficial effects
Oral contraceptives
A. Preparation - progestin alone or combination of estrogen (ethinyl estradiol) and progestin (various names)
B. Adverse effects -
i. mild adverse effects common - headache/nausea, breakthrough bleeding (insufficient estrogen to maintain endometrial stability)
ii. moderate - weight gain, acne and hirsutism (androgen-like progestins), amenorrhea with cessation
iii. severe (rare) - thromboembolic disease, MI, cerebrovascular disease i.e. stroke (>35 yo), GI disorders, depression
C. Any cardiovascular, cerebrovascular, or thromboembolic disorders
- do not take with anything that affects CYP3A4 (metabolizes OCPs)
D. Beneficial effects - reduced risk of cysts, ovarian and endometrial cancer, ectopic pregnancy
[Women’s Health Pharmacology]
Ovulation-inducing agents
1. Clomiphene
2. Leuprolide
A. MOA
B. Indication
C. Adverse effects
- Clomiphene (Clomid)
A. MOA - selective estrogen receptor modulator (SERM) - partial agonist at ER and inhibits action of stronger estrogens –> inhibits estradiol negative feedback –> increased release of gonadotropins (LH and FSH) from pituitary
B. Indication - stimulates ovulation in women with oligomenorhea, amenorrhea, ovulatory dysfunction
C. Adverse effects - hot flashes
- breast soreness, heavy menses, nausea/vomiting, weight gain
- not due to drug but to hormonal changes with ovulatory cycle - Leuprolide (Lupron)
A. MOA - GnRH agonist
B. Indication - anovulatory women who do not respond to clomiphene
- inhibits LH/FSH release –> suppresses spontaneous ovulation as part of controlled ovarian hyperstimulation in assistive reproductive procedures eg IVF
[Women’s Health Pharmacology]
Describe the disease and drugs to treat:
1. Pelvic inflammatory disease (PID) Drugs
A. Cause
B. Clinical
C. Treatment
- PID
A. Cause - exposure to Neisseria gonorrhea, Chlamydia trachomatis (Chlamydia more common)
B. Clinical - cervical motion tenderness (chandelier sign)
- prurulent white cervical discharge
- can lead to Fitz-Hugh-Curtis syndrome (infection of liver capsule with violin string adhesions)
C. Treatment:
- Neisseria - ceftriaxone (intramuscular) –> 3rd generation cephalosporin; beta lactam antibiotic that inhibits cell wall synthesis –> bactericidal
- most people have concomitant chlamydia infection - give oral antibiotics –> protein synthesis inhibitors –> bacteriostatic
i. macrolide (azithromycin) - targets 50s rb subunit
ii. tetracycline (doxycycline) - targets 30S rb subunit
[Women's Health Pharmacology] Drugs to treat the following: 2. Trichomoniasis A. Cause B. Clinical C. Treatment + MOA D. Adverse effects
- Trichomoniasis
A. Cause - Trichomonas vaginalis - flagellated protozoan parasite –> motile trophozoite on wet mount
- sexually transmitted (only STI caused by a protozoa)
- more common in women
B. Clinical
- vaginitis: foul-smelling, yellow-green vaginal discharge, burning, vulvovaginal itching
- cervicitis: strawberry-red cervix
C. Treatment - oral metronidazole (Flagyl)
- MOA- activated by PFOR enzyme found in bacteria –> turns into toxic radical that damages microbial DNA –> cell death
- single oral dose; treat partners as well
D. Adverse effects - GI issues (eg diarrhea) bc kills gut flora so take with meals
- nausea, headache, dry mouth
- contraindicated with alcohol, first semester pregnancy
[Women's Health Pharmacology] Drugs to treat the following: 3. Herpes A. Cause B. MOA C. Adverse effects
- Herpes - epithelial cells with intranuclear inclusion bodies
A. Cause - HSV-2
- genital herpes - painful, shallow ulcers with vaginal pain, itching, dysuria + fever, headache, malaise
B. Treatment - “vir” antivirals eg acyclovir, valacyclovir, famciclovir
- MOA - is first phosphorylated by a viral thymidine kinase –> then competitive inhibits viral DNA polymerase –> blocks viral DNA synthesis
- oral regimen –> reduced viral shedding, shorter duration of sx, and reduced time for ulcers to heal
C. Adverse effects - well tolerated; occasional GI effects (nausea, vomiting, diarrhea) - take with food
- rare neurological issues with valacyclovir high dose
[Male hypogonadism] Describe defects in androgen action incl hormone levels and clinical manifestation 1. Complete androgen insensitivity 2. Partial androgen insensitivity 3. 5-alpha reductase deficiency
- Complete androgen insensitivity - dysfunctional androgen receptor; XY with female phenotype
A. Hormones:
- ↑ testosterone (male range)
- ↑ estrogen
- ↑ LH/FSH
B. Clinical - female phenotype (normal breasts) but
- primary amenorrhea
- blind vaginal pouch
- absent uterus
- absent pubic and axillary hair
- testes absent or in abdomen, inguinal canal, labial folds - Partial androgen insensitivity - can be female or male phenotype
- 5-alpha reductase deficiency - AR mutation in enzyme for testosterone –> dihydrotestostone (DHT)
A. Hormone - elevated testosterone:DHT ratio
- androgens, estrogens in normal range
B. Clinical - 46XY
- hypospadias - urethral opening on underside of penis
- virilization at puberty (muscle and phallic growth)
[Male hypogonadism]
- Describe eunochoidism
- Ddx of gynecomastia
- eunochoidism
- eunuchoid proportions/habitus - legs longer than upper body OR arm span longer than height (due to excessive long bone growth)
- no pubertal growth sport
- high pitched voice
- microgenitalia (small testes)
* implies that hypogonadism arose before puberty
- eg Klinefelter XXY - eunochoidal with decreased testosterone, elevated FSH/LH –> hypergonadotropic hypogonadism - Ddx of gynecomastia -
A. circulating estrogen»_space; testosterone
- aging
- hyperthyroidism and liver disease (↑ SHBG, which binds tighter to testosterone than estrogen)
- increased body fat (adipose aromatization)
B. Hypogonadism
C. Medications that block male hormones or androgen receptors or raise prolactin eg spironolactone
D. tumors of gonads, adrenals, pituitary gland
[Male hypogonadism] 1. Symptoms of male hypogonadism 2. Testosterone replacement A. Indications B. Benefits C. Side effects D. Contraindications
- Symptoms of male hypogonadism
- decreased energy
- poor libido
- decreased erectile function, strength and endurance, secondary hair growth
- infertility
- hot flashes - Testosterone replacement
A. Indication - symptomatic hypogonadism only
B. Benefits - prevents gynecomastia, improved sexual function, prevents premature CAD + osteoporosis
C. Side effects - dyslipidemia, HTN, polycythemia, acne, gynecomastia (aromatization), sleep apnea, prostate growth, decreased fertility (negative feedback on FSH and LH)
D. Contraindications - prostate cancer, sleep apnea, breast cancer
[Male hypogonadism]
Differentiate the following incl hormone levels and causes:
1. hypogonadotropic hypogonadism
2. hypergonadotropic hypogonadism
- hypogonadotropic hypogonadism
- ↓ testosterone
- ↓ FSH/LH
A. genetic - Kallman, Prader-Willi
B. Pituitary dysfunction - hyperprolactinemia, pituitary tumor, sarcoidosis, hemachromatosis
C. Other causes
- isolated LH deficiency
- opiate and steroid use
- anorexia/stress
- aging/obesity - hypergonadotropic hypogonadism
- ↓ testosterone
- ↑ FSH/LH
A. genetic - Klinefelter 47 XXY (↑ breast cancer risk), myotonic dystrophy
B. congenital - bilateral anorchia
C. orchitis - mumps, HIV
D. gonadal damage - trauma, radiation, chemo, alcohol inhibits testosterone synthesis)
[Male reproductive cancers] Testicular tumors 1. Risk factors 2. Clinical 3. Etiology based on age 4. Precursor lesion 5. Treatment
Testicular tumors - most common tumor of 15-34 yo
- Risk factors - familial risk, congenital (cryptorchidism, Klineflelter), race (higher in whites)
- Clinical - nodule or painless swelling
- can be ache in lower abdomen/scrotum, gynecomastia - Etiology - 95% tumors are germ cell origin (germ cell tumor GCT) - aggressive but curable
- 60% single histological subtype
- most common is seminoma; most common in men 50+ is lymphoma - Precursor lesion = testicular germ cell neoplasia in situ
- seen adjacent to germ cell tumor in almost all cases - Treatment - go through groin (inguinally) - do NOT biopsy or excise testicle through the scrotum**
- -> leaves inguinal portion of spermatic cord intact and may alter lymphatic drainage of testes; increases risk of local recurrence, can have pelvic/inguinal lymph node metastasis
[Male reproductive cancers] Describe types of testicular germ cell tumors GCTs: 1. Seminoma 2. Non-seminoma A. Embryonal carcinoma B. Yolk sac tumor C. Choriocarcinoma
- Seminoma - most common type of germ cell tumor, peak in 30s; large, fleshy mass
- often Stage I and confined to testicle (if it does metastasize, goes via lymphatics)
- uniform tumor cells with abundant clear cytoplasm, distinct cell borders, large central nuclei
- PLAP+ and CD117+
- 95% cure rate
- analogous to female dysgerminoma - Non-seminoma - usually Stage II or III; early mets and more hematogenous spread
A. Embryonal carcinoma - 2nd most common GCT
- extend through tunica albuiginea, poorly demarcated
- seen with other GCTs
- more aggressive – poorest prognosis
B. Yolk sac tumor - most common testicular tumor in infants and young children
- elevated serum AFP levels
- Schiller-Duval bodies (glomerular-like with central vessel encircled by tumor cells) pathognomonic
C. Choriocarcinoma - very rare and most aggressive
- presents as small nodule; hematogenous spread to liver and lungs
- usually mixed with other GCT tumors
- elevated hCG (contains syncytiotrophoblasts)
[Male reproductive cancers]
Describe the following testicular pathologies:
1. Cryptorchidism
2. Testicular torsion
- Leydig cell
- Sertoli cell
- Cryptorchidism - incomplete descent of testis from abdomen to scrotum
- ↑ risk for testicular cancer
- associated with tubular atrophy and sterility
- tx - orchiopexy (Surgery) - Testicular torsion - testis turns and occludes blood supply
- younger patients - acute onset nausea and vomiting
- older patients - abdominal pain and fever
- scrotal swelling, pain with palpation, loss of cremasteric reflex
Non-germ cell tumors
- Leydig cell tumors - most common sex cord tumor
- hormonally active –> androgens (precocious puberty) and estrogens (gynecomastia)
- pathology = crystalloids of Reinke - Sertoli cell tumors - most benign
- hormonally silent
[Male reproductive cancers] 1. Benign prostatic hypertrophy A. Pathogenesis B. Histology C. Clinical D. Management
- Benign prostatic hypertrophy BPH
A. Pathogenesis - stromal cells make DHT –> binds to androgen receptor (more potently than testosterone) –> stromal proliferation –> discrete, smooth nodular enlargement –> compresses urethra
- most commonly occurs in transition zone
B. Histology - nodular hyperplasia of both layers of cells in prostate (basal layer of cuboidal epithelial cells and secretory layer of columnar stromal cells)
C. Clinical - frequency, nocturia, difficulty starting and stopping urine stream, dysuria
- may lead to distention and hypertrophy of bladder, hydronephrosis, UTIs
- not premalignant
D. Management - avoid caffeine and alcohol
- alpha1 antagonists (terazosin, tamsulosin) –> relaxation of smooth muscle
- 5alpha-reductase inhibitors (finasteride)
[Male reproductive cancers] 2. Prostate adenocarcinoma A. Risk factors B. Histology C. Clinical D. Treatment
- Prostate adenocarcinoma - most common form of cancer in men
A. Risk factors - FH, age (50+), race (more common in blacks)
B. Histology - pleomorphic cells with no secretions
- single layer of glands (only secretory layer; basal endothelial layer gone)
- perineural invasion pathognomonic for invasive cancer
C. Clinical - nodule on digital rectal exam
- diagnosed via ↑ PSA (prostate specific antigen) *problems that affect use of PSA as screening tool
- most commonly occurs in peripheral zone –> cancer arises away from urethra –> urinary symptoms are late (As opposed to BPH)
- metastases to bone are osteoblastic
D. Treatment - surgery, radiation, hormonal
