Clinical Use of GnRH

(synthetic or otherwise)

• pulsatile use (pump): infertility secondary to hypothalamic disease
• Long acting analog: suppress LH/FSH -> form prostate cancer, uterine fibroids, precocious puberty

Vasopressin (ADH) Secretion Control

• Osmotic control: osmorec cells in the hypothalamus sense inc in osmolality as small as 1% above a certain set point -> inc ADH sec
• Hemodynamic control: dec blood volume/pressure activate baroreceptor cells in the circ system (less sensitive than osmorec; detect 5-10% change) -> inc ADH sec
• Both inc in osmolality and dec in effective criculating volume also leads to inc water intake and water retention (inc ADH release also causes)

Atrial Natriuretic Peptide (ANP) and 

B Type Natriuretic Peptide (BNP)

• both released from mocardial tissue in response to volume expansion, which causes stretching of the myocardium
• Lowers blood volume and pressure: direct vasodilation, inc excretion of water and Na, suppression of R-A-A
• A type - sec from atrial myocardium; Btype - sec from ventricular myocardium; C type - sec from vascular endothelium 
• Clinical Applications: Nesiritide abd B-NP

Clinical Applications of BNP

(Nesiritide)

• Nesiritide - a syn recombinant humab BNP, recently aproved by FDA for short term infusion in pts w/ congestive heart failure (CHF) to improve Sx of volume overload
• B-NP also shows to have a value in Dx of CHF
• Conc of B-NP in circ correlates w/ severity of CHF; can be measured rapidly and accurately and cost effective compared to standard diagnostic studies

Nephrogenic Diabetes Insipidus

Common Causes

• Many chronic renal diseases
• Electroly disorder: High blood Calcium (hypercalcemia) or low blood potassium (hypokalemia)
• Drugs: lithium, AMP-B, democlocycline, gentamicin, cisplatin, others
• Dietary abnormalities: dec NaCl or protein intake

Dilutional Hyponatremia

• symptom of SIADH; same Na, more H2O
• Muscle cramps, weakness
• Anorexia, N/V, irritable, confused, disoriented, seizure

Causes of SIADH

• ADH excess = water intoxication
• Physiologic: neural (stress, coitus, suckling), hypovlemia (hemorrhage, cardiac)
• Drugs: Nicotine, MS, barbiturates, acetylcholine, vincristine, clofibrate, carbamazepine
• Pathologic: pumonary, neurologic or neoplasms

Empty Sella Syndrome

• Defect in diaphragm sella, allowing subarachnoid space to extend into the sella turcica
• Pituiatry may be deformed, Sella turcica may be normal or enlarged
• CSF intensity w/i sella: dark on T1 bright on T2
• Primary: defect in diaphragm sella, regression of pituitary neoplasm, involution of pregnancy-induced pituitary enlargement, usually asymp (w/ no endocrine abalities)
• Secondary: post surgical defect in diaphragm sella; may be assoc w/ headaches/visual changes

Craniopharyngioma

• 3% of all intracranial neoplasms
• bimodal peak: 1st and 2nd decade (75%) and 5th decade (25%)
• 50% of suprasellar neoplasms in children
• neuroepithelium from craniopharyngeal duct and pirmitive buccal mucosa
• Symptoms: headaches (hydrocephalus), diabetes insipidus (pituitary compression), grawth retardation, bitemporal hemianopsia
• large complicated cystic tumor, often calcified
• Cystic cells of teeth origin involved

Pituitary Hypofunction causes

• nonfunctional tumors, traumatic brain injury, pituitary hemorrhage (apoplexy), ischemic necrosis
• Hereditary syndromes (mutation of POU1F1) results in combined GH, PRL and TSH deficiency - Histiocytosis X
• Inflammatory disorders (Sarcoid, TB meningitis)
• Surgery or irradiation
• Craniopharyngioma: rathke pouch remnant

Prader Willi Syndrome

• Hypogonadotropic hypogonadism
• OFten GH deficiency
• Morbid obesity, prone to diabetes and sleep apnea
• Reduction in volume of paraventricular nucleus (very small)
• Cognitive disability, behavioral problems
• Hypotonia, strabismus

Hypothalamic Obesity

• Most common cause is brain tumors in children
• One third of 148 kids who survived brain tumor became obese in 5 years
• Rat model: damage ot VMH results in insulin hypersecretion
• Treat with somatostatin

Sheehan's Syndrome

• called slow pituitary apoplexy
• Problems w/ something leads to infarct of pituitary
• Mother cant nurse baby because of prolactin deficiency
• Also oxytocin and FSH, LH deficiences and hypothyroidism

Common Tumors of the Sellar Region

• Anterior pituitary tumor
• Posterior pituitary tumor: very rare: pituicytoma: large, bening
• Nonpituitary origin: cranipharyngiomas, meningiomas, histiocytosis, metastases, cystic (rathke's cleft, arachnoid, dermoid)
• Inflammatory: lymphcytic hypophysitis, sarcoidosis, granulomatous hypophysitis

Empty Sella

• see big sella turcica, mainly filled w/ fluid
• Age: mean 48 (16-72)
• Female 87%; Obese 93%
• Headache 71%; hypertension 29%
• Embryologic problem: thought tobe herniation of arachnoid into pituitary fossa
• Usually normal pituitary funciton; sometimes hypoprolactinemia

TBG and Thyroid Hormone Lvls

• Increased in TBG: pregnancy, estrogen treatment: causes inc in total T4 and T3 but absence of hyperthryoidism (no inc in free)
• Decrease in TBG: cirrhosis, nephrotic syndrome: dec in total T4 and T3 but still euthyroid (no dec in free)

Clinical Features of Graves

• Apathetic hyperthyroidism: older pts often lack the common sings: flat affect, emotions labile, weight loss, muscle weakness, CHF and atrial fib
• Eye signs: lid lag, perioribital edema, conjuctival congestion, swelling, proptosis, extraocular muscle weakness, visual impairment
• Pretibial myxedema: thickening of skin over tibia, nonpitting edema, appears similar to surface of football

Thiocarbamide (anti thyroid)

Drugs

• Propylthiouracil (PTU), methimazole, carbimazole
• block thyroid hormone syn: inhibt thyroid peroxidase
• PTU: partially inhibits peripheral conversion T4-T3
• Side effects: pruritis, rash, cholestatic jaundice, acute arhtralgias, and agranulocytosis
• If pt has signs of infection discontinue and call physician. check WBC

Congenital Hypothyroidism

Presentation

• Feeding problems, hypotonia, inactivity, open posterior fontanella, edema in face and hands
• If treatment delays: retardation, short stature, delayed puberty

Myxedema Coma

Thyroid Hormone Pharmacokinetics

• T3 has 4 times the volume of distribution and also 4 times the potency 
• T4 has a 7 day half life and T3 has a 1 day half life
• T4 has 0.04% fraction unbound in the plasma andT3 has 0.4% fraction unbound in plasma 
• can be orally absorbed (T3 slightly better than T4)

Levothyroxine (T4)

• preparation of choice: stable, inexpensive, free of antigenicity, and has uniform potency
• half life of 7 days: means not huge impact if pts miss dose
• Drug interactions: dec absorption: sprue, diabetic diarrhea, ileal bypass surgery, polyvalent cations, acid suppression
• also liothryonine (T3) and  Liotrix (T4:T3; 4:1)

Thioamides

• Propylthiouracil(PTU), methimazole, carbimazole
• MOA: block peroxidase, iodide organification, PTU inhibits peripheral conversion of T4 to T3
• noninvasive, low initial cost, low risk of permanent hypothyroidism, possible remission (immune effects)
• adv effects: rash (fever), hepatitis, transient leukopenia, agranulocytosis (more severe WBC<250), can cross placenta (PTU les than methimazole)
• transient leukopenia does not predict who will develop agranulocytosis
• Tehimazole preferred to PTU: lower risk of liver injury, given once daily; PTU preffered in pregnancy and thyroid storm; monitor for adv effects

Anion Inhibitors

• monovalent anions: Perchlorate, pertechnetate and thiocynate
• Block uptake of iodide by thryoid by competitive inhibition of iodide transport
• Major clinical use: block thyroidal reuptake of iodide in iodide induced hyperthyroidsim (ie amiodarone); rarely used

Iodide Salts

• Rapidly suppresses hormone relase, control Sx, but can screw up the efficacy of RAI
• Superseded by beta blockers
• can block uptake of RAI if given w/i several months
• can delay onset of thioamide therapy
• used to prepare for surgery (x7-14) and to block thyroid release after the use of RAI (x3-7 days)

Adjuncts in Hyperthyroid Treatment

• beta blockers w/o ISA: propranolol 20-40 mg 
• Diltiazem if beta blockers contraindicated
• barbiturates accelerate T4 breakdown
• Bile acid sequestraints

Thyroglossal Duct Cyst

• persistence of a tract along the migratory path of the thyroid 
• usual midline anterior neck
• Most oftenasymptomatic, usually discovered in childhood
• can develop daining sinus w/ infection of trauma: entire lining may be replaced w/ granulation tissue if the cyst has been infected
• Classic histology: pseudostratified columnar resp type epithelium w/ thyroid tissue in wall
• thyroid tissue present in 2/3
• Very rarely develop CA of the thyroid tissue; usually pappilary type
• Squamous metaplasia very common (pseudostratified ciliated ep to stratified squamous epi

Hashimoto's Thyroiditis

• chronic lymphocytic thyroiditis; autoimmune disorder
• non tender diffuse enlargement, usually nodular or lobular
• white tan cut surface resembles a lymph node
• diffuse , dense, lymphoplastic infiltrate; gemrinal centers
• Nearly 80 fold inc for development of thyroid lymphoma
• can also cause atrophy of follicles w/ dec colloid
• Often show oxyphilic (Hurthle cell) metaplasia)
• abundant eosinophilic cytoplsam, nuc enlargement and clearing of chromatin, prominent nucleoli

Papillary Thyroid Carcinoma

• 80% of thyroid mallignances; strong assoc w/ rads
• usually presents at a palpable mass or as cervical lymphadenopathy (mets through lymph)
• Grossly may be solid or cystic mass, typically circumscribed: often gritty cut surface (calcifications)
• classic growth pattern of complex branching fibrovascular cores lined by malignant cells
• Psammoma bodies highly suggestive of pappilarry CA
• nuclear features are the key to diagnosis of papillary thyroid CA: nuc corwding and overlap of polarity
• little orphan annie nuc: clearing of nuc chromatin; looks like a pearl w/ a purple border and white inside
• Incranucular cytoplasmic inclusions: not true inclusion; invagination of the cytoplasm into nuc

Variants of Papillary Thyroid CA

• Folicular Variant:
• Composed of smal, tightly packed folicles w/ scant colloid, classic nuc features of papillar CA
• Nuc features and lack of distinct capsule separate from follicular adenoma/CA
• prognosis identical to classic papillary thyroid CA
• Tall Cell Variant and Columnar Cell Variant
• tend ot have worse prognosis, occur in older pts w/ large tumors, often w/ extrathyroid extensions

Medullary Thyroid Carcinoma

• malignant tumor derived form C-Cells; 5th decade
• serum calcitonin lvls are almost invariably elevated
• MEN2A, familialy medullary thyroid CA, MEN2B: autosomal dominant
• Cellular tumor w/ irregular infiltrative borders
• Often assoc w/ amorphous eosinophilc amyloid deposition - congo red stain and bifringence
• Cells from small ness w/ delicate fibrovascular backgorund (tpical growth pattenr)
• Round ovoid nuc w/ finely dispersed salt and pepper chromatin

Reidel Thyroiditis

• rare chronic inflammatory disease, benign and self limited
• 1/3 of pts have or dvelop another fibroising disorder (retroperitoneal fibrosis, sclerosing cholangitis, mediastinal fibrosis, etc)
• Exact etiology unclear, autoimmune postulated: possibly related to IgG4 related system dz
• unique in that fibrosis replaces the gland also extends into adjacent soft tissue
• diffusely enlarged thyroid w/ ragged surgical margins (ddificult dissection) and densely fibrotic whit tan cut surface
• Extensive amount of fibrosis predominates over the inflammatory infiltrate, primarily lymphocytes and plasma cells w/ occasional neutrophils, histiocytes and eosinophils
• will find rare entrapped thyroid follicles at periphery

Ca and blood pH

• Acidosis: inc ionized calcium (dec protein binding)
• Alkalosis - dec ionized calcium (inc protein binding)

Signs and Symptoms of 

Moderate and Severe Hyperclacemia

• fatigue, polyuria, polydipsia, weakness, anorexi, nausea, vomiting, constipation
• Abdominal pain, hyporeflexia, proximal muscle weakness, change in mental status, lethargy, coma, pancreatitis, nephrolithiasis, nephrocalcinosis, HTN, bradycardia

Bisphosphonates

• Zoleronate and and pamidronate
• used for hypercalcemia; particularly effective for hypercalcemia of malignancy
• inhibits osteoblastic bone resoprtion
• Zoledronate - long acting: higher complete response (10days) and longer duration of action (30-40 days) before relapse than pamidronate

Medications for Acute Hypercalcemia

• bisphosphonates - on anotehr card; inhibit osteoclasts
• Calcitonin: rapid fall in serum Ca; intermediate while waiting for response to a bisphosphonate, relatively short duration of action, tachyphylaxis
• Corticosteroids/glucocorticoids: most effect when mech is due to inc produciton of 1,25 Vit D; lymphoma or granulomatous disease (sarcoidosis, TB)

Benign Familial Hypercalcemia

• benign familial hypocalciuric hypercalcemia
• Autosomal Dom inactivating mutation of Ca sensing rec
• higher than normal SCa req to suppress PTH and the renal tubules conserve Ca inappropriately
• Homozygoes: severe neonatal hypercalcemia
• Heterozygotes: lifelong, asymp modest hyperclacemia, relative hypocalcuria, normal PTH, high normal or elevated SMg, surgical treatment Contraindicated

Hypoparathyroidism Causes

• post surgical hypoparathyroidism: hypocalcemia usually only lasts a few wks to months; irreversible post surg dz is unlikely unless all four glands removed or damaged
• Autoimmune destruction - in assoc w/ Hashimoto's thyroiditis or addison's dz
• Infiltrative dz: ex hemochromatosis
• Pseudohypoparathyroidism: congenital, dysmorphic features, hypocalcemia, resistance to PTH (PTH lvs very high)

Rickets

• VitD dependent Rickets Type I (VDDR-I): genetic defect in activity of renal 1 α hydroxylase activity
• VitD Dependent Rickets Type II (VDDR-II): large number of loss of func mutations in VitD rec gene (hereditary resistance to action of 1,25D)
• Vitamin D resistant Rickets (VDRR): x linged hypophosphatemic rickets (PHEX mutation)
• Clinical manifestation: skeletal pain and deformity, fractures of abnormal bones, slippage of epihyses, listlessness/weakness/hypotonia - if concomitant vit D def, delayed dental eruption and enamel defects

Vit D Resistant Rickets (VDRR)

• X linked hypophosphatemic rickets
• Loss of function mutation in gene on X chrom which encodes PHEX
• PHEX normally func to limit renal phosphate excretion
• PHEX mutation - defective rneal tubular phosphate reabsorption, hypophosphatemia, inappropriately normal 1,25 D, low normal serum clacium, high normal or slightly elevated intact PTH

Radio and Labs for Osteomalacia

• looser zones (pseudofractures) - pathognomionic
• Radiolucent bands perpendicular to bone surface
• Most common - femur, pubic rami, edges of scapula)
• Rugger-jersey spine sign adn bowed long bones
• labs: hypocalcemia, hypophosphatase (except in renal osteodystrophy), alkaline phosphatase (usually elevated)
• Bone biopsy may be necessary for Dx

Paget's Disease

• Focal disorder of bone remodeling leading to greatly acc rates of bone turnover and disruption of normal bone architecture
• presents: radio abnormalities; elevated alkaline phosphate
• bone pain, deformity, spinal stenosis, hearing loss, cranial nerve plasies, obs hydrocephalus, CV complications
• inc blood flow to invovled bone, inc CO, vascular and aortic valve calcifications
• fracture, malignant transformation, immobilization hypercalcemia
• OSteolytic phase, mixed phase (cototn wool appearance of skull), less active period (marked sclerosis)

Osteoporosis 

• risks: age, female, premature or surgical menopause, smoking, escessive alcohol, eating disorders, excessive exercise causing amenorrhea, glucocorticoids, anticonvulsants, heparin
• Causes of secondary osteoporosis: hyperparathyr, cushings, hyperthyroidism, sickle cell, lymphoma, osteogenesis imperfecta, homocysteinuria, chronic renal failure, primary biliary cirrhosis, celiac disease, turners and klinefelters
• Dual energy xray absorptiometry (DEXA scan) gold standard for measuring bone mass

WHO Definition of Bone Mass

• Normal Bone mass: T score > -1
• Low bone mass: T score -1 to -2.5
• Osteoporosis: T score < -2.5
• Established severe osteoporosis: T score < -2.5 and one or more osteoporotic fractures

Medications for Postmenopausal Osteoporosis

• Bisphosphonates - alendronate, risedronate, ibandronate, zoledronate
• Selective Estrogen Rec Modulator (SERM) - Raloxifene: antiresorptive estrogen like effects in bone, but not in breast or uterus
• Calcitonin nasal spray
• Teriparatide - recombinant human PTH, only anabolic agent, inc risk of osteosarcoma in animal studies

Steroid Effects on bone

• dec calcium absopriton, 
• inc urinary Ca excretion
• inc bone resorption
• Significantly dec osteoblastic func,
•  net effect of dec bone formation
• RANKL activation
• give bisphosphonate therapy if expect prednisone >5mg for > 3 months

Parathyroid Adenoma

• solitary mass, benign, well encapsulated
• Tan fleshy cut surface, may have areas of cystic degeneration
• May be composed of chief or oxyphil cells
• A chief adenoma can demonstrate an encapsulated nodule lacking adipose tissue w/ a compressed rim of normal parathyroid tissue peripherally (slight nuc pleomorphisim)
• Water Clear cell adenoma: seen vary rarely, cells larger w/ smaller nuc and abundant clear cytoplasm (glycogen), cell borders well defined and is a variety of chief cell

Brown Tumor

• focal cystic hemorrhagic lesion
• Histologically shows an area of bone resorption replaced by fibrous tissue
• fibroblastic tissue w/ numerous osteoclast like giant cells throughout
• shoulds dark spot in middle of white bone on imaging (not from outside like before?)
• more common in rimary Hyperparathryoidism

Adrenocortical Carcinoma

• much larger, more atypical cellular appearance and necrosis
• Atypical bizarre giant cells
• most are functional: so inc produciton
• in children difficult to tell btw large adenoma and carcinoma
• Only therapy is romve it regardless of adenoma or carcinoma

Neuroblastoma

• malignant tumor of primitive neural cerst cells
• 3 most common malignanc in infancy (leukemia and CNS tumors) and 2nd most common abdominal tumor (wilms)
• 50% by 2 yrs, 80% by 4 yrs, and 100% by 10 yrs
• palpable abd mass, pain and fever, bone pain, difficulty ambulating, inc catecholamine production
• adrenal medulla (40%), abdomen (paravertebral; 25%), posterior mediastinum, neck, pelvis
• CXR shows soft tissue mass (mediastinal epicenter
• Clacifications: up to 85% on CT
• characteristic rosettes - NSE and neurosec granules by EM
• infants have better prognosis than older
• often encounter disseminated, diagnose in marrow: cluser of tumor cells showing rosettes in marrow

Lab diagnosis of Adrenal Insufficiency

• Morning Cortisol: high specificity, low sensitivity
• Standard dose cortrosyn stimulaiton: 30-60 mins after adm normal chol should be >18
• ACTH level: better done before initiation of therapy: elevation implies primary AI

Autoimmune Polyglandular Syndrome

• Assoc w/ adrenal insufficiency
• Type 1: recessive AIRE mutaiton: autoimmune regulator, chromosome 21
• Mucocutaneous candidiases, hypothyroidism, Addison;s Disease (Primary AI)
• associates: hepatitis, vitligo, hypogonadism, hypothyroidism
• Type 2: Peak age 30, HLA DR3 or DR4, antibodies 21 hydroxylase: hypothyroidism DM 1 and Primary adrenal insufficiency
• Assoc: alopecia, viligo, celiac sprue

17 Alpha Hydroxylase Deficiency 

(17 alpha OH)

• type of Congenital Adrenal Hyperplasia
• block is in pahtway to androgens, therefore males have ambiguous genitalia
• shunted metabolism towards MC, GC - therefore hypertensive

21 Hydroxylase Deficiency

Non-Classic Form 

• 20-60% normal enzyme activity
• symptoms: hirsutism, oligomenorrhea or amenorrhea, polycystic ovaries, infertility
• Ethnic Groups: far east, middle east, 1-2% caucasians
• Cortrosyn stimulation w/ 250 mcg 17 OHP > 1,500
• Presents later in life w/ androgen exces leading to precocoious puberty (males) or hirsutism w/ menstrual irregularities (females)

I-123 MIBG Testing

• Good for suspicion of malignant disease
• Negative MRI/CT w/ biochemically proven dz
• False positives: TC antidepressents, Ca Channel blockers, Antipsychotics, labetolol

Neurofibromatosis Type 1

• Autosomal Dominant mutaiton NF-1 Gene
• Neurofibromas, skin fold thickenings, iris hamartomas
• Pheochromocytoma

Praganglioma (PGL) Syndromes

• autosomal dominant, four types
• Defects in succinate dehydrogenase genes
• Some types assoc w/ other malignancies
• often preent w/ space occupying lesions

Primary Aldoseronemia test

Aldosterone Renin Ratio

• positive screen if >20
• If on ACE inhibitor positive screen > 10
• Renin should be suppressed
• Adlosterone should be at least 15 ng/dl
• Can also do adrenal venous sampling: bilateral comparison of aldosterone/cortisol ratios; done w/ CRH stimulation, step up indicates presence of aldosterone sec tumor

Insulin Resistance Syndrome

• AKA: Metabolic Syndrome, Syndrome X, Dismetabolic Syndrome
• Assoc w/ endothelial dysfunction
• Inc risk of diabetes, heart disease
• Metabolic syndrome diagnosis: any three of the following:
• Impaired fasting glucose >100
• HTN >135/80
• TG > 150
• HDL < 40 in males and < 50 in females
• Waist circ > 35 in females and > 40 in males

Types of Insulin

• Rapid acting - lispro, apsart, glulisine, inhaled
• Short Acting - regular (R), inhlaed human insulin
• Intermediate Acting - NPH (N)
• Long Acting - glargine, detemir
• Mixed insulin: 70/30, 75/25, 50/50
• U-500 insulin - rarely used by non endocrinologist

Fasting Blood Sugar Phenomena

• Overnight hypoglycemia, asmyp
• Resultant counterregulatory effects drive fasting blood sugar above normal
• solution - less insulin dosed overnight

Dawn Phenomen

• lack of insulin near dawn (diurnal rise in cortisol, GH) leads to fasting hyperglycemia
• solution - more insulin dosed overnight

Gestational Diabetes

• Develops during pregnancy, usually resolves after delivery
• 2-5% of pregnancies; up to 14% in some ethnic groups
• inc risk fo future type II diabetes if weight gained during pregnancy is not lost post partum (50% at 20 years)
• Diabetes may persist postpartum; retest for diabetes at 6 wks postpartum
• Screen at 24-48 wks if: older than 25, 1st degree w/ diabetes, high risk ethnic, history of previous >9lb baby, history of uneqplained perinatal death, prior history of GDM
• 100 gram 3 hour OGTT positive (2): fasting >95, 1 hour > 180, 2 hour > 155, 3 hour > 140

Diabetic Nephropathy

Macroalbuminuria

• >400 mg/24 hrs or > 300 mg/gram creatinine
• usually occurs at about 15 yrs of diabetes
• aka overt diabetic nephropathy
• inexorable progression to ESRD w/i 5-10 yrs
• progression can be slowed, but not reversed
• assoc w/ macrovascular complications

Whipples Triad

• for hypoglycemia; satisfy all three
• Signs/symptoms
• LOW glucose (<50mg/dl)
• Symptoms relieved by administration of glucose

Diabetes Ketoacidosis(DKA)

• occurs primarily in type 1 DM, absolue insulin def
• unchecked counterregulatory hormones (glucagon, epinephrine) promotes ketosis
• Dx: hyperglycemia (>250), ketosis(ketonuria), acidosis (blood pH < 7.3 or bicarb < 15)
• Sx: nausea, vomiting, polyuria/dypsia, abd pain, anorexia, shortness of breath, altered mental func, tachycardia, kussmaul resp, tachypnea, ketonic breath, fever, coma
• correct w/ IV fluids and insulin, monitor electrolytes (K replacement usually needed), use bicarb only if very severe

Sulfonylureas

• Glipizide, Glyburide, Gimepiride
• MOA: inc release of insulin from beta cells by inh ATP sens K channels; inc bolus release of insulin w/ little effect on basal release
• Adv: hypoglycemia, weight gain, dermatologic, hepatotoxicity, alcohol intolerance, ischemic pre cond
• Glyburide and gimepiride: caution in elderly and renal dysfunction

Meglitinides

• repaglinide and nateglinide
• MOA: close ATP sens k channels in beta cells but more dependent on presence of D-gluc to exert their effect
• Indication: more effectively lowers PPG than FBG; people w/ varying meal schedules
• adv: hypoglycemia like sufonylureas

Biguanides

• Metoformin - first line drug in TIIDM
• MOA: dec hepatic glucose output, inc insulin sens in skel muscle and adipose tissue
• Indicaitnos: esp useful in obesity and hyperlipidemia
• ADv effects: nausea, diarrhea, hypoglycemia and Lactic acidosis
• Risk factors for Lactic acidosis: renal failure, hepatic insuf, severe cardiac or pulmonary insuff.

Thiazolidinediones

• Rosiglitazone, pioglitazone
• MOA: inc the # of GLUT 4 gluc transporters in cell membranes of muslce and adipose tissue 
• Adv effects:: hepatotoxicity, weight gain, plasma volume expansion, NO hypoglycemia, cardiovasc toxicity, osteoporosis, bladder cancer

Alpha Glucosidase Inhibitors

• Acarbose, Miglitol
• MOA: inh of brush border enzymes
• Indic: type 2 DM, adm w/ the first bite of each meal
• Adv: flatulence and bloating, does not not cause hypoglycemia alone but if in combo must treat w/ glucose

Amylin Analogue

• Pramlintide
• TIDM or TIIDM that req insulin: reduces postprandial hyperglycemia, mean reduciton in wieght
• Amylin dec glucagon, dec glucose release from liver, delayed gastric emptying, inc satiety
• dec prandial insulin by 50% at initiation
• Adv: hypoglycemia, mild nausea

GLP-1 Agonist

• liraglutide, exanatide
• stim glucose dependent insulin release, delays gastric emptying, postprandial glucagon suppression, and inc satiety
• Adv: hypoglycemia, nausea, pancreatitis
• extended release causes thyroid CCell tumors in animals

DDP-4 Inhibitors 

• sitagliptin; saxagliptin, linagliptin
• Clinical effects: similar to GLP-1 agonist (dec A1C about 0.5-1.5%), effective in combo w/ metformin and TZD, lack weight loss effect, did not reduce glucose in nodiabetic pts
• Sitagliptin adv effects: pancreatitis
• Saxagliptin and Sitagliptin need dosage adj in moderate, severe and end stage renal dz
• Linagliptin:  no dosage adj needed in renal or hepatic dz

SGLT-2 Inhibitors

• Canagliflozin, dapagliflozin, empagliflozen
• SGLT2 is upregulated in TIIDM and is at proximal end of PCT, responsible for 90% of glucose reabs
• SGLT-2 inh block this Na-gluc cotransporter: dec serum glucose and inc urinary glucose
• clinical effects: lowers FPG, PPG, A1C and BP, weight loss
• Cautions: caution in renal insuffic, genital yeast inf (women > men), postural hypotension, hypoglycemia, hyperkalemia, inc LDL-C and osteoporosis
• Canagliflozen: drug interactions w/ antihypertensives, k sparing or anti RAS drugs, digoxin (inc digoxin lvls), UGT1A0 and 2B4 induces (phytoin, phenobarbital, ritonavire: dec efficacy of canagliflozin)

MEN Type 1

Wermer Syndrome

• pituitary adenoma, parathyroid hyperplasia, pancreatic tumors (3 Ps)
• Autosmal Dom mutation of MEN1; prod menin
• hypercalcemia from parathyroid hyperplasia (adenoa is rare) is usually presenting Sx, 95% have have elvevated PTH by 20-25yrs
• prolactinoma is most common pituitary adenoma
• 70% develop islet cell tumor - gastrinoma or insulinoma

MEN Type 2

• new mutation accounts for 5% of MEN2A and 50% of MEN 2B
• MEN2A - Sipple Syndrome (80%): parathyroid hyperplasia, medullary thyroid carcinoma (1st develop and 100% get), pheochromocytoma
• Familial Medullary Carcinoma
• MEN2B (5%): meddulary thyroid CA, pheo, marfanoid habitus, mucosal neuroma and intestinal gangliomatosis

Autoimmune Polyendocrine Syndromes

(APS)

• APS I: AIRE gene mut, auto rec; asplenism; candidiasis, hypoparathryoidism, addison's dz
• APS II: Prevalence is common and time of onset infancy thru adulthood, no immunodef but assoc w/ diabetes (20%), Addison's, Chronic Thyroiditis
• Xlinked Polyendocrineopathy, immune dysfunction and diarrhea: x lined mutation in FOXP3 genes; loss of Treg cells, common presents as neonatal diabetes and malabsorption

Apolipoproteins

• regulatory proteins for particle delivery
• Apo A-1 - found on all HDL particles
• Apo B: chylomicrons, VLDL, IDL, LDL; one apo B per lipoprotein; intestine erived particles (B-48), liver derived particles (B100)

LDL

(low density lipoprotein)

• end product of hepatic triglyceride lipase (HTGL) action on IDL
• smaller, more dense than IDL
• Carries 70% of total serum cholesterol
• 70% of LDL cleared by LDL rec in the liver
• Apoprotein B-100 is its only Apoprotein necessary for LDL rec mediated clearance
• 35% of LDL can be cleared from the blood by subendothelial macrophages, which eventually become foam cells
• This scavenger pathway allows development of atherosclerotic plaque

lipoprotein "Little a" - lp(a)

• abnormal apoprotein (a) bound to LDL apoprotein B-100 
• Apoprotein homologous to plasminogen
• Autoomal dominant
• Interferes w/ normal activation of plasmin, accelerating clot fomration
• High levels confer an inc risk of atherosclerosis and early coronary disease

HDL

(High density Lipoprotein)

• smallest, most dense lipoprotein
• Produced in liver and intestine
• Apoprotein A-1 is HDL-defining, and a necessary cofactor for plasma enzyme lecithin-cholesterol acyltransferase (LCAT)
• LCAT converts cholesterol into its ester form (CE): CE is more hydrophobic, forces cholesterol to stay in lipoprotiens, easier to transport
• Factors which inc HDL lvls: female, african american, exercise, alcohol, phenytoin, niacin(nicotinic acid)
• Factors which dec HDL levels: male, caucasian, sedentary lifestyle, obesity, smoking, anabolic steroids

Abetalipoproteinemia

• autosomal rec (bassen-kornzweig synd)
• extremely low chol levels (<50)
• defective microsomal transfer protein (MTP)
• cannot syn apo B containg lipoprotein; causes malabsorption (cant make chylomicrons)
• Retinitis pigmentosa (poor night/color vision), spinocerebellar degeneration (ataxia) acanthosis, hemolytic anemia
• Treatment: low fat diet, fat soluble vit supplements, essentialy FAs

Familial Hypobetalipoproteinemia

• autosmal codominant mutaiton in B100 production
• LDL generally half of normal
• clinically similar to abetalipoproteinima (poor night/color vision, spinocerebellar degen etc)
• Lower risk of ASCVD

Lipoprotein Lipase and Apo C-II deficiency

• cannot release TG from TG rich particles 
• Severe Hypertriglyceridemia (>1000 mg/dl)
• Autosomal rec, rare
• Pancreatitis, lipemia retinalis
• Eruptive xanthomas
• Treatment: low fat diet, plasmapheresis

Familial Dybetalipoproteinemia (FDBL)

• type III Hyperlipoproteinemia; autosomal recessive
• Abnormal apoprotein E, not recognized wlel by hepatic rec
• IDL accumulates
• cholesterol elevation = TG elevation
• Tuboeruptive xanthomas
• Palmar xanthomas pathognomonic
• Inc ASCAD risk

Familial Hypercholesterolemia (FH)

• Autosomal codominant lack of LDL rec
• Very high LDL levels
• premature ahterosclerosis
• tendinous and tuberous xanthomas
• milder forms much more common (polygenic hypercholesterolemia)

Sitosterolemia

• rare autosomal recessive disorder
• abnormal ATP binding cassetes transporters (ABCG5 or ABCG8) in intestine and liver
• Abnormally high sterol absorption
• Tendon xanthomas w/ normal cholesterol lvl
• Treatment: bile acid binders, absorption inhibitors

Other Apoprotein B disorders

• familial hypertriglyceridemia (FHTG): elevated VLDL, moderately high LDL, TG, inc risk of pancreatitis; treat fibrates and nicotinic acid
• Familial Combined Hperlipidemia (FCH): overproduction of apoprotien B100, premature ASCAD, phenotype can change over time (High TG or LDL or both)
• Mided hperlipidemia (elevated TG and LDL): secondary causes , dietary indiscretion, very common

Disorders of HDL

• Apo A-1 Deficiency or Apo A1 Mutations: absence or very low HDL: corneal opacities, planar xanthomas, elevated risk of ASCAD
• Tangier Disease: Defective ABCA1 (cant transport chol out of cell); low HDL; orange tonsils
• LCAT deficiency: complete (kidney dz, hemolytic anemia), partial def (fish eye dz, cornal opacities)
• CETP deficiency: high HDL
• Familial hypoalphalipoproteinemia: low HDL, normal chol and TG lvls, inc risk  ASCAD
• Familial hyperalphalipoproteinemia: HDL>80 women and 70 men, dec risk ASCAD

ACC/AHA Guideline for Statins

• four groups need statins
• Existing cardiovascular dz: clinical ASCVD
• LDL -c >190
• Diabetes (40-75, LDL-C 70-189)
• 10 yr ASCVD risk > 7.5%: recalc every 4-6 yrs

CETP Inhibitor

• Evacetrapib
• CETP normally allows transfer of chol from HDL to apoB containing lipoproteins
• monotherapy inc HDL by 115% and dec LDL by 23%
• monotherapy not likely to be assoc w/ any sig change in BP and did not have any adverse effects on mineralocorticoid or glucocorticoid measures

HMG CoA Reductase inhibitors

• statins: lovastatin and simvastatin, rosuvastatin, atorvastatin (last two have longer half life and are more potent)
• comp inh of HMG Coa reductase, the rate limiting stem in cholesterol biosynthesis
• reduc chol content in liver results in inc LDL rec expression in hepatocytes; reduces LDL lvls
• reduction of oxidative stress and vascular inflam, plaque stabilization
• Anti inflammatory effects: inh of HMG CoA red prevents syn of FPP and GGPP which reduces inflam; also induces eNOS accum in endothelial cells
• adv: hepatotoxic, rhabdomyolisis, mopathy (esp w/ niacin, fibrates, erythromycin)

Nicotinic Acid (Niacin)

• inhibits VLDL syn and sec (dec LDL); 
• only durg to reduce Lp(a)
• inc HDL: due to inc the half life of ApoA1, most effect drug in inc HDL
• activates liprotein lipase-> inc VLDL, chylomicron clearance
• adv effects: flushing, pruritis, dec glucose tolerance (hyperglycemia), digestive upset, inc AST/ALT (inc levels of liver enzymes), skin disorders
• CI: in pregnancy, ulcers, caution in diabetes and gout

Fibrates

• Gemfibrozil, fenofibrate
• ligands for PPAR-α (activate); inc LPL to promote TG clearance
• dec VLDL, modest dec in LDL, inc HDL
• therapeutic uses: hyper TG w/ inc VLDL or low HDL, dysbetalipoproteinemia, can be used w/ sttins
• Adv: GI symp, rash, arrhtyhmias, hypokalemia, rhabdomyolysis, myopathy (gemfibrozil) thats worse w/ statins, inc in liver transaminase, inc risk of chol gallstones
• CI: hepatic or rneal dz, pregnnacy or gemfibrozil and statins (myopathy and rhabdomyolysis)

Ezetimibe (Zetia)

• inhibit intestinal absorptioin of dietary/biliar chol: binds to and inh NPC1L1 chol transporter
• reduce chol in chylomicron, thus reduces delivery of dietary chol to liver (leads to red chol incorporated to VLDL in liver)
• low liver chol leads to inc LDLr expression
• effective as monotherapy
• Adv: co adm w/ bile acid resins is contraindicated (dec absorption), hypersensitivitya nd rare hepatic impairment

Male Sexual Determination

• testis determ begins at 6 wks gestation: sertoli cell proliferation, seminiferous cords
• SRY gene on the y chrom is trigger for testis determ
• WT-1 Plays major role in SRY expression
• SRY and SF-1 act cooporivively to inc SOX9 (this alone is sufficient for testis development)
• Normal male differentiation and functino requires: Test, Anit mullerian hormone, 5 alpha reductase, DHT, androgen rec

Fetal Aclohol Syndrome

• no safe threshold defined; inc risk if chronic large quantities or binge drinking
• duraiton of exposure may relate to severity
• behavior disturbances, irritability, poor coordination, mental retardation, learing disorders, ADHD
• Brain, cardiac and spinal defects
• craniofacial abnormalities: flat philtrum, broad, thin upper lip, flattened nasal bridge, short nose, small eyes, small lower jaw

ACE inhibitors

(teratogen)

• enalapril, also captopril and lisinopril
• fetal renal ischemia, renal tubular dysgenesis, anuria
• oligohydramnios -> abnormal lung dev and limb contractures
• growth restriction,, relative limb shortening, amd maldevelopment of skull
• unkown if ACE inh are problematic during embryonic period

Retionic Acid

• Vit A, isotretnoin
• First trimester exposure can lead to pregnancy loss, small or missing ear, narrow or missing ear canal, small lower jaw, cleft palate, retinal/optc nerve abnormalities, congenital hearing lesions, hydrocephalus

Fetal Warfarin Syndrome

• exposure during 6th and 9th week: defect of CNS and skeletal and facial defects (nasal and midface hypoplasia, stippled vertebra, and femoral epiphyses), still births, spontaneous abortions
• Exposure dure 2nd or 3rd trimester: malformations of brain, small eyes, optic atrophy and blindness, impairment in physical growth, developmental delay and mental retardation

Herbal Medicine

(teratogens)

• echinacea: allergic reactions, immune system effects
• Ephedra, yohimbe: HTN
• Garlic, ginger: inc bleeding risk
• Kava, valerian: sedation, withdrawal
• Glucosamine and chondroitin: worsening of diabetes
• St john wort: many drug interactions

Eclampsia

• complication of pregnancy - vascular injury
• primary cause results in alered placentation and organic or functional obstruction of spiral arterioles
• possible problems in trophoblastic invasion and can run in familes
• vicious cycle that dec perfusion causes relase of factors to stimulate perfusion and cause vasoconstriction in others areas so you get HTN
• Activates intravasc coag and leads to DIC/deosion of fiber in orgers
• Kidneys = dec GFR and proteinuria; CNS - seizures and coma; liver - abnormal liver func tests and other organs = ischemia and fibrin thrombi

Endometrial Polyp

• pedunculated into cavity, covered by endometrial epithelium; can be cancerous
• locate them w/ scope
• usually neoplasms of the stroma, storma outgrows and drags glands along w/ it
• potential risk is prolapse out through the surface which leads to torsion and necrosis
• consist of round and tubular glands and stroma and blood vessels: stroma is a little more cellular and denser
• glands and stroma in polyps dont typically cycle so they will often be out of sync w/ rest of endometrium
• cancer can develop only w/i polyp or polyp and surrounding endometrium

Serous Adenocarcinoma of Ovary

• invasion of ovarian stroma by glands, papillary structures, solid areas
• markedly atypical serous looking cells
• often caller serous papillary carcinoma beacuse forms papillary structures
• can lose gland formation, so if there is only solid areas and papillary structures can still be serous adenocarcinoma

Mucinous Adenocarcinoma

• more ramifying glands: saw tooth, irregular appearance
• Mucin w/i apex of cells; often look like intestinal epithelium w/ goblet cells
• can also represent endocervical epithelium w/ nongoblet like mucin vacuoles
• must suspect mtastatic colon carcinoma b4 you think of primary mucin adenocarcinoma: many tumors mets to ovary and some mimic primary mucinous

Mullerian Agenesis

• Rokitansky-kuster- hauser syndrome
• agenesis of uterus, cervix and vagina
• 2nd most common cause of primary amenorrhea
• normal growth, development (normal ovarian func)
• renal and skeletal anomalies common
• surgical/nonsurgical creation of neo-vagina

Progestin Challenge

• Bio assay for presence of estrogen
• Positive progestin challenge (bleeding) confirms: adequate estrogen functioning outflow tract (chronic anovulation)
• Negative PRogestin Challenge (no bleeding) - due to: inadequate estrogen or nonfunc outflow tract (uterine dysfunction/obstruction
• if negative progestin test, start estrogen therapya nd repeat test: if menses after 2nd progestin, problem is inadequate estrogen; if no menses after progestin problem is uterine dysfunction/obstruction)

Ovarian Failure vs Chronic Anovulation

• Ovarian failure: irrevesible inability of ovaries to respond to gonadotropin stimulation; complete absence of estrogen and progeterone production
• Chronic Anovulation: temporary, reversible state of abnormal ovarian func (either due to intrinsic ovarian dysfunction or extrinsic dysfunction of the H/P axis
• Estrogen prod is variable in chronic anovulation: hypothalamic dys (estrogen low), PCOD (estrogen high/normal)

Pathophysiology of

Polycystic Ovarian Syndrome

• excessive ovarian androgen production; overreactivity of CYP17a
• Insulin resistance -> inc insulin -> dec IGF BP1 -> inc IGF-1 activity -> in LH rec -> inc activity of CYP17a -> androgen production
• benefits of Oral Contraceptives: prevention of abnormal bleeding, endometrial hyperplasia and cancer; supresioon of LH dpeendent hperandrogenism; elevates SHBG, reducing free Testosterone

Hypothalamic Amenorrhea

• etiologies: psychogenic, extreme exercise, eating disorder/malnutrition
• abormal slowing of the arcuate nuc pulse generator: normal FSH/LH ratio reveres (FSH>LH), reduced leptin lvls (from adipose)
• mutliple variables: body fat conent, stress, energy output, diet, photoperiod (pineal sec of melatonin)
• Hypoestrogenism and bone loss:even streneous exercise does not compensate for the effect of low estrogen on bones (esp in adolescents; amenorrheic exerciser has an inc risk of fractures
• Female athelete triad: eating disorder, amenorrhea, and osteoporosis (stress fractures)

Endocervical Adenocarcinoma In Situ

• becoming more common; type of endocervical hyperplasia
• Aslo assoc w/ high risk HP infection; like squamous cell carcinoma
• precedes endocervical adenocarcinoma
• difficult to recognize on pap smear andbiopsy - about 50% false negatives on pap
• not a slowly progressive process to endocervical adenocarcinoma (only a couple years) compared to squamous hyperplasia and squamous CA

Progestin (contraception)

• norethindrone or norgestrel: only take p only if you cant be on combo; ex is breastfeeding women
• also has negative feedback to GnRH; also inc cervical mucus viscosity (doesnt let sperm in) and induces thinning of endometrial lining (atrophy)
• only 2 hour window to take pill daily; quickly reversible and risk of ovulation though still protect
• dec blood clots and cramps
• P only contraindications: thormboembolic disorders, CVD or CAD, estrogen dependent cancers, acute hepatitis, jaundice, hepatic failure

E+P contraindications

• Absolute: breastfeeding, < 6 wks postpartum, smoker, > 35 yrs, cardiovasc dz, blood pressure > 160/100, stroke
• relative:complicated DM, liver tumors, cirrhosis, active hepatitis, prolonged immobilization/thromboembolic mutations, migraine headache, current breast cancer

Emergency Contraception

• levonorgestrel one step, ulipristal
• about 57-85% effective; quicker you use it better chance it works; have 120 hours
• Side effects: nausea and cramping; less effective in >165lb womena nd not effective in >175lb
• trys to stop ovulation or implantation but not abortive drug

Abortifacients

• Mifeprisone RU486- anti progestin; 7 wks max; heavy bleeding, cramps, nausea, and vomiting for 80 hours; misoprostol can be added
• Dinoprostone(prostin E2, Cervidil: supository 12-20th week gestation: anitprogestin (prostin) and cervical ripening (cervidil)

Selective Estrogen Receptor Modulators

(SERMs)

• Tamoxifen - antiestrogen at breast and estrogen agonist at uterus
• Raloxifene: - anti estrogen at breast and uterus, agonist at bone (used for osteoporosis)
• Uesd for breast cancer prevention and second line for hormone repleacement
• Risk of DVT, causes hot flashes and vaginal dryness

First Trimester Ultrasound

• 1/7/11 rule
• document intrauterine locaiton and locate gestational sac - 1k
• document yolk sac (5 wks) -7k; and document and measure fetal pole - 11k
• evaluate embryo cardiac activity
• determine presence of multiple gestations and survery pelvis/adnexal structures
• other structures in 1st trimester: placenta, amnion, maniotic space, limb buds, rhombencephalon, physiologic herniation of bowel (10wks)

Amniotic Fluid Evaluation

• normal
• polyhydramnios (inc) causes: mother -DM; Fetal - neural tube defects or GI obstruction causes
• Oligohydramnios (dec) causes - mother -premature rupture of membranes/leakage; Fetal - renal problems

Ultrasound of Male Repro

Differential

• Pain: think of torsion, inflammation, trauma
• Mass: intratesticular (tumor), extratesticular (epididymis inflammation, hydrocele, varicocele
• Differential: inflammation (48%), hydrocele (24%), torsion (9%), varicocele, spermatocele, cysts, malignant tumors, benign tumors

Papilloma

• generally neoplasm of lactiferous ducts; proliferation of stroma that carries ducts w/ it
• Expands into duct lumen itself
• Papillary cores containing small blood vessles surrounded by normal 2 cell layer of duct epithelium
• acts as ball valve causing obstruction of outflow; leads to cystic expansion of duct: can result in bloody nipple discharge
• Usually excised, usually benign (histo benign and not premalignant)
• fist sample ususally obtained by needle core biopsy

Ductal Carcinoma In Situ

• similar in appearance to invasive breast cancer except there is no invasion
• lumen of duct of TDLU are filled and expanded w/ malgnant looking cells
• excisional biopsy shows a myoepithelial layer; which separates it from invasive cancer
• calcifications often present w/i secondary lumens
• Comedocarcinoma: highest grade; still contains myoepithel and BM; lesions edges are blue because of high cellularity, pink center is necrotic material (dead tumor cells), 
• tend form large, granular coarse calcificatinos on mamograms

Lobular Carcinoma In Situ

• In every way similar to ductal carcinoma in situ; distinguish by cell appearance
• same filling and expansion of TDLU except cells are smaller and blander; stil high nuc activity (blue) but all cells about same size (no pleomorphism)
• tend to not form calcificatinos
• LCIS being diangosed from atypical lobular hyperplasia when entire thing is involved

Invasive Ductal Carcinoma

• breast cancer, prototypical carcinoma
• has spiculated radiating appearance on radiology and grossly
• lesion dense and has calcifications; center firm, dense and grity
• radiating edges not circumscribed; pushing out in irregular fashion
• Grade 1 - well differentiated: have gland lumens but invading into stroma in halphazard distribution, stroma has become desmoplastic; dense and fibroplastic
• Grade 3 - poorly differentiated - no recognition of glandular structures at all, covered in blue, degree of desmplasia may be less (may be yellowisha nd tan but is softer than grade 1)

Invasive Lobular Carcinoma

• cells smaller, blander and harder to make out at same power as invasive ductal CA
• see linear blue cords of cells, sometimes single linear cells
• spray of cells invading into stroma (can look like lymphocytes)
• tend to circum ring benign structures (onion ringing)
• variable to less degrees of desmoplasia; not very dense, can have palpable mass not visible on radiograph
• cells lack intracellular adhesion molecules and mitotic count low

Aromatase Inhibitors

• Anastrazole, letrozole, exemestane
• these are oral agents used in the treatment of postmenopausal women w/ hormone rec positive breast cancer
• arthralgias and myalgias, bone loss, hypercholesterolemia, capral tunnel/tendinitis, HTN, Dry skin, and mucus membranes

Mucinous Breast Carcinoma

• special subtype of invasive ductal carcinoma
• Tumor cells forming small islands, solid, sitting in background of clear space (mucin)
• can see some septation but mostly clear stuff
• very well circumscribed and homogenous and can mimic fibroadenoma
• has better prognosis than typical breast carcinoma

Inflammatory Breast Cancer

• IBC is an aggressive form of locally adv breast cancer
• almost all women have lymph node involvement and a htird have distant mets
• rapidly progessive
• highly angiogenic and angioinvasive
• majority are hormone rec negative
• chemotherapy first: anthrycycline, taxane (only type of breast cancer where you start w/ chemo)
• surgery usually masectomy; regardless radiation in all cases
• long term survival usually 50%

Familail Breast Cancer

• autosomal dominant BRCA1/2 mutaitons
• high cumulative lifetime risk of breast cancer
• BRCA1 usually ounger age, high risk features, triplenegative more common
• ovarian cancer risk 30-60% (BRCA1) and 27% (BRCA2)
• Multiple relatives w/ breast/ovarian cancer
• vertical transmission/male breast cancer,/ 2 generations

Li Fraumeni Syndrome

• rare autosmal dominant mutaiton of p53
• soft issue sarcomas, osteosarcomas, leukemias, brain tumors, adrenocortical tumors, early onset breast cancer
• 50% develop cancer by age 30, 90% by age 70

Basal Like Breast Cancer

• expession pattern mimics normal braest myoepithelial cells
• more likely to have aggressive features
• triple negative; african american premenopausal women
• chemotherapy sensitive
• BRCA1 mutation carriers

Prostatic Carcinoma

• peak incidence in 65-75 yrs of age
• hereditary factors: first degree relatives, american blacks, prostatic CA genes
• environmental - high animal fat, geogrpahy
• bound PSA (>4ng)
• Adenocarcinoma are the majority; mainly in the peripheral (outer) zones; hence lack of voiding sx in early stages
• treatment: prostate gland removal, radiation, hormanal adjuvant, PSA-NOW as tumor marker

Gleason's Score

• pathologists assign a grade for the most common tumor pattern as primary grade
• grade for the 2nd most common tumor pattern as secondary grade
• score of primary grade + secondary grade (4+3=7)
• score inc as degree of differentiatino dec: 4+3 worse than 3+4
• well differentiated to poorly differentiated
• scale 1: small, uniform glands
• scale 2: more space btw glands
• Scale 3: infiltratinos of cells from glands at margins
• Scale 4: irregular masses of cells w/ few glands
• Scale 5: lack of glands, sheets of cells

Testicular Inflammatory Lesions

• more common in epididymis than testis proper
• Non specific epididymitis and orchitis: may be assoc w/ urinary tract infectino; swollen, tender; neutrophilic infiltrate
• Orchitis: complication of mumps virus infection (20% in adult infection); lymphocytes and plasma cells; enlarged and painful testis, loss of seminiferous tubules and resultant testicular atrophy, fibrosis and sterility
• can see granulomatous orchitis (TB)

Sex Cord/Stromal Tumors

• Leydig Cell - benign; testosterone producing; any age (20-60 yr); testicular swelling; sexual precocity; gynecomastia; may elaborate androgens or estrogens or corticosteroids; 10% malignancy
• Sertoli Cell tumors - uncommon; may purssue a benign course; estrogens or androgens; infrequently produces precocious masculinizaitno or feminization or gynecomastia

Clinical Presentation of Testicular Tumors

• Painless enlargeent; beware widespreasd mets as presenting signs/Sx
• Seminomas - often confied to testis
• Lymph nodes - pelvic, obturator, para-aortic, iliac
• Hematogenous mets - lung, liver, brain (choriocarcinoma)
• Non-seminomatous - tend to mets earlier (blood and lymphatics)
• Mets may contain different maturation

Seminoma

• Classic in younger men (85%), anaplastic (5-10%) and spermatocytic in older men (5%)
• homogenous tumors, gray white cut surface
• seminoma cells - large round cells w/ clear cytoplasm
• intratubular germ cell neoplasia (precursor -equivalent to in situ germ cell neoplasia)
• rare giant cells (HCG) are seen
• never in infacnts, spermatocytic - better prognosis
• Pure = good prognosis
• tumors spread via lymphatics or hematogenous (lungs, liver, brain and bone)

Embryonal Carcinoma

• more aggressive thans eminomas
• may be small primary lesions w/ mets already
• hemorrhagic cut surface
• may invade the cord and epididymis
• growth pattern may be in sold sheets of primitive epithelial/epithelioid cells
• usually part of a mixed germ cell tumor
• AFP may be seen
• glandular, alveolar or tubular gorwth patterns or undiff (sheets of cells) growth pattern

Mixed Germ Cell Tumors

• 40-50% testicular tumors
• combinations of any of the above tumors may be seen/present
• most common-teratoma, embryonal and yolk sac
• Yolk sac ALONE is rare (usually mixed; unless children)
• Embryonal ALONE is also rare

GnRH Antagonists and Agonists

• Agonists: leuproide, goserelin, buserelin, Gonadorelin
• antagonists: Ganirelix, cetrorelix

Vitiligo

• depigmentation of parts of the skin when skin pigment cells die or are unable to function
• think about mostly thyroid disease, but also pernicious anemia, rhematoid arthritis, psoriasis, lupus, addisons disase and LADA (adult onset autoimmune diabetes)
• May precede the disease or the disease may not develop, but it at least should make you think about other problems