Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
224 Cards in this Set
- Front
- Back
|
Normal menstrual cycle
|
|
|
|
Counter regulatory hormones to insulin
|
= hormones that promote the release of glucose from cells
Glucagon Cortisol Growth hormone Epinephrine |
|
|
Glucose transporters
|
= membrane-associated glycoproteins w/ 12 transmembrane domains, large extracellular loops, cytoplasmic NH2 terminus
- GLUT1: ubiquitous, placenta, brain, RBC - GLUT2: β-cells (controls insulin release from the pancreas), liver, intestine - GLUT3: ubiquitous - GLUT4 (Insulin dependent): muscle, adipose - GLUT5: jejunum |
|
|
Insulin action
|
Liver:
- ↑ glycogenesis by stimulating Glucokinase - ↓ gluconeogenesis by inhibiting PEPCK - ↓ ketogenesis by inhibiting Carintine acyl transferase Adiose tissue: - ↑ Glucose transport (activates GLUT4 transporters) - ↑ clearance of TAGs by stimulating lipoprotein lipase - ↓ Lipolysis by inhibiting triglyceride lipase Muscle - ↑AA/Glucose transport by activating GLUT4 and AA transporters |
|
|
Insulin production
|
- occurs in the β islet cells (of Langerhans) in the pancreas
- coded by INS gene, chromosome 11 - Activated when ↑ BG is detected (ingestion/digestion of protein/carbs) - Inhibited when ↓ BG is detected Forms: - preproinsulin: contains signal sequence, synthesized in rough ER - Proinsulin: contains C-peptide, delivered to golgi - Insulin: active form (hexamer), stored in secretory granules |
|
|
Insulin receptor
|
= tyrosine kinase receptor, actions mediated by GLUT4
Structure: tetramer - 2 α-subunits: extracellular, bind insulin Cys residues - 2 β-subunits: span plasma membrane, anchors receptor to cell, contains ATP-binding and tyrosine kinase domains intercellularly - α and β subunits joined by disulfide bonds Endocytosis of the receptors helps terminate insulin action (along with insulin degrading enzymes andliver cells) |
|
|
Insulin secretion
|
= biphasic release (should occur during hyperglycemia/fed state, should not occur during hypoglycemia/fasted state)
Phase 1: rapidly triggered insulin spike from pre-made vesicles in response to ↑ BG level Phase 2: sustained, slow release from newly-formed vesicles, independent of BG (usually follows phase 1 spike) Phase 1 Mechanism: - Glucose enters cell via GLUT 2 transporter, converted to G6P by glucokinase and undergoes metabolism - ↑ATP/↓Mg-ADP closes the Katp channel preventing K release and causing membrane depolarization - Voltage change opens Ca channel (L-type) increasing intracellular Ca2+ and causing insulin release from vesicles |
|
|
Type 1 diabetes mellitus
|
= inability to oxidize carbohydrates due to disturbance in insulin function. Results in hypeglycemia and glycosuria, and causes imperfect combustion of fats leading to ketonuria
Epi: 0.3% in general Caucasian (20/100000 in US, 38 in Finland/Sardinia, 2 in Pakistan/Hong Kong). Bimodal age distribution 4-6 (lots of illnesses) & 10-14 (puberty) Risk factors: family Hx (15%), DR3/4 HLA (chr 6), Caucasian, northern latitude, unknown environmental component (cow’s milk, gluten, FAs, viral) Pathophys: progressive autoimmune destruction (lymphocytic/macrophage insulitis) of β-islet cells of the pancreas leading to insulin deficiency. Both environmental and genetic triggers Clinical findings: (due to hyperglycemia, cellular malabsorption, and DKA) - polyuria (esp. nocturnal), polydipsia, polyphagia, weight loss/severe cachexia (if chronic), fatigue, blurred vision, dry mouth, poor wound healing, impotence. If DKA: fruity breath odor, compensatory tachypnea/kussmaul respirations Labs: elevated BG and HbA1c, urine ketones, positive antibodies (IAA, GAD65, ICA, IA2, ZnT-8), high urine specific gravity (excess glucose/electrolytes), ↑BUN/Cr (>20:1, pre-renal azotemia), acidosis (low pH, low bicarb) |
|
|
Complications of T1DM
|
ACUTE
DKA: massive polyuria/dehydration, potentially life threatening electrolyte shifts and metabolic acidosis. - Findings: hyperglycemia (>300 usually), ketosis, anion gap metabolic acidosis, pseudohyponatremia, K & Phos abnormalities CHRONIC Microvascular: retinopathy, nephropathy, neuropathy - Pathogenesis: hyperglycemia→ ↑intracellular glucose and metabolic products → ↑intracellular osmolarity → ↑ intracellular water → OSMOTIC INJURY Macrovascular: ischemic heart disease - Pathogenesis: glycation products (↑ arterial stiffness due to glycosylation and cross-linking w/ collagen), ↑ LDL (promotes atherogenesis), HTN (development and progression of vascular disease-and renal |
|
|
Type 2 Diabetes mellitus
|
= hyperglycemia due to increased insulin resistance and defects in the insulin pathway (rather than exclusive destruction of β-cells)
Causes: - mutation/antibodies to insulin receptor, post-receptor defects (IRS-1/2, PI-3 kinase, Akt → all decrease downstream phosphorylation & signal efficiency), activation of FOXO1 (upregulates PEPCK, G6Pase), GLUT4 sequestration, mutations interefering with β-cell function (incl. maturity onset diabetes of youth), mutations of glucokinase, HNF-1α, HNF-1 β, HNF-4α. - Most common: inability of β-cells to overcome insulin resistance (gestational diabetes, T2DM in non-pregnant adults-likely polygenic), ketosis-prone T2DM - Once in resistant state: mobilization of TAGs for energy → ↑DAG, PKC which decrease insulin effectiveness Pathogenesis: insulin resistance usually arises first (up to 20yrs), triggering compensatory increase in insulin release from the pancreas and increase in β-cell mass. Over time increased production demand results in accumulation oxidative stress (and toxic lipids from obesity) leading to improper/unfolded proteins delivered to ER causing Unfolded protein response (slow translation, increase chaperones) and synthesis of pro-apoptotic protein CHOP. Over time loss of β-cells leads to diminished insulin production and frank diabetes |
|
|
Blood glucose standards for diabetes diagnosis
|
Fasting:
- Normal <100, pre-diabetic 100-125, diabetes >126 2hr OGTT: - Normal <140, prediabetes 140-199, diabetes >200 HbA1c - Normal <5.7, high-risk 5.7-6.4, diabetes >6.5 |
|
|
Hypoglycemia
|
= clinical syndrome with diverse causes leading to ↓BG (<60mg/dL) and eventually neuroglycopenia (<50mg/dL for brain function impairment).
Symptoms: (can occur at higher BG if diabetic an normally higher basal BG rate) - Autonomic nervous system (<65): sweating, anxiety, nausea, trembling, feelings of warmth - Neuroglycopenia (<55): dizziness, fatigue, headache, confusion, difficulty speaking, inability to concentrate Tx: biochemical testing (blood/urine) and insert IV. Evaluate for ketotic vs. non-ketotic (indicates problem in lipolysis), serum glucose, serum hormones (cortisol, insulin, GH) - Acute: give glucose (oral is best—juice, soda). IV D25 or D10 (neonates) - Chronic: diazoxide TID (K channel activator), nifedipine (Ca channel blocker), octreotide (somatostatin—prepare for surgery mostly), high calorie feeds (MCT oil, corn starch) and avoidance of fasting, pancreatectomy (focal or >95%) - GH or cortisol deficiency: hormone replacement therapy |
|
|
Etiologies of hypoglycemia
|
Ketotic:
- substrate limited: insufficient calories to maintain BG. Occurs in infants (esp premies) due to poor storage therefore inability to fast for a long time - hormone deficiencies: panhypopituitarism (GH, ACTH), glucagon deficiency, epinephrine deficiency, cortisol deficiency (Addison’s disease, Congenital Adrenal Hyperplasia) - glycogen storage diseases - disorders of gluconeogenesis - others: drug induced (alcohol-increases NADH inhibiting gluconeogenesis/malate→OAA, salicylates, quinine, valproic acid, insulin), hypermetabolic systemic disorders (cancer, HIV, etc), liver disorders causing reduced synthetic function (inability to produce/utilize glucose, infectious fructose-1-phosphate aldolase deficiency) Non-Ketotic: - hyperinsulinism: congenital (PHHI) or acquired (exogenous delivery, insulinoma, retroperitoneal tumors (IGF-2), reactive hypoglycemia from high simple-sugar diet) - Disorders of FA oxidation (inability to generate ketones): acyl dehydrogenase deficiency (medium chain acyl dehydrogenase deficiency—autosomal recessive), carnitine deficiency (Akee fruit), CPT I/II deficiency (affect shuttling) |
|
|
Persistent hyperinsulinemic hypoglycemia of the infant
|
= congenital hyperinsulinism. May be transient to severe. AKA nesidioblastosis, β-cell hyperplasia, β-cell dysmaturation syndrome
Epi: usually diagnosed in 1st year of life, incidence 1/40K Gene mutations: Katp channel (persistent closure results in membrane depolarization and insulin secretion) -On chr 11: ABCC8/SUR1 gene codes for outer subunit (50-60%), KCNJ11/kir6.2 codes for inner subunit/K+ ion pore (10-15%). -severity: autosomal recessive (severe, diffuse islet cell hyperplasia→ 95-98% pancreatectomy), clonal loss of heterozygosity (moderate, paternal point mutation→ focal pancreatectomy), autosomal dominant (mild→ responds to diazoxide) Glutamate dehydrogenase: - Leucine hypersensitivity: Leu activates GDH →excess conversion of glutamate to α-ketoglutarate & ATP→ Katp channel inhibition. Milder condition: responds to diazoxide, carbo-load before protein (leu) intake - Hyperammonemia syndrome: activating mutation causes increase glutamate oxidation and depletion (↓NH3 detoxification → hyperammonemia, also ↑insulin secretion) Glucokinase: (principal control for insulin secretion) - activating mutation increases glu→ G6P which decreases insulin secretion threshold (not inhibited until <40). Very rare, autosomal dominant |
|
|
Evaluation of hyperinsulinism
|
Intra-arterial calcium gluconate infusion: (↑external Ca → ↑intracellular Ca in PHHI) measure calcium at 4 different arterial sites along the pancreas (splenic, superior mesenteric, gastroduodenal, celiac axis)
PET scan: infuse 18 fluoro DOPA, look for high uptake at high insulin concentration |
|
|
Sulphonylureas
|
First generation: chlorpropamide, tolbutamide, acetohexamide, tolazamide
Second generation: glipizide (glucotrol), glyburide (micronase) Third generation: glimepiride (Amaryl) - newer generations have greater potency, longer duration of action, fewer active metabolites, hepatic metabolism, less frequent hypoglycemia Mechanism: binds to/inhibit Katp channel on β-islet cells causing membrane depolarization, Ca2+ influx and release of store insulin from secretory granules Efficacy: monotherapy reduces A1c 1-2% and fasting glucose 60-70mg/dl. Good because cheap and have long history of use Side effects: HYPOGLYCEMIA (elderly, poor nutrition, EtOH, polypharmacy), WEIGHT GAIN, sulpha allergy, hyponatremia (chlorpropamide), caution for advanced liver disease, cardiovascular concerns (controversial) Complications: increases risks for microvascular complications, 5-10% “secondary failure” rate/yr (initial success, but over time almost everyone fails), continued exposure leads to β-cell apoptosis, not recommended for liver/renal dysfunction patients |
|
|
Glinides
|
Repaglinide (Prandin), Nateglinide (Starlix)—mainly used
Mechanism: benzoic acid derivative binds to discrete receptor on Katp inhibiting and causing membrane depolarization, Ca influx, insulin release from secretory granules. Hepatic metabolism w/ biliary excretion Kinetics (compared to sulphonylureas): faster onset (20min), shorter duration (2-3hr) Strengths: reduces A1c (0.5-2%, comparable to SUs), short duration of action, reduced hypoglycemia (compared to SUs), dosed with meal, targets post-prandial glucose Challenges: expensive, TID dosing, some hypoglycemia and weight gain w/ repaglinide |
|
|
Biguanides
|
Metformin (Glucophage)
Mechanism (not really understood, unique): decreases hepatic gluconeogenesis/glycogenolysis (increase AMPK), increases insulin-mediated muscle glucose uptake, decrease GI glucose absorption, inhibits adipose tissue lipolysis (FFA) Efficacy: ↓A1c by 1/5-2%, ↓FBG by 50-70mg/dL, promotes slight weightloss, ↓microvascular complications, ↓progression from pre to overt diabetes, advantageous lipid effects, no hypoglycemia (long record of safety), low cost Side effects: GI intolerance (dose dependent), lactic acidosis if in renal insufficiency—decreased clearance(1/40k), no hypoglycemia (no effect on pancreatic insulin secretion) Contraindications: renal insufficiency (Cr>1.5 M or 1.4 F, elderly), severe CHF (renal hypoperfusion), chronic liver disease (incl EtOH), chronic lung disease, IV contrast studies (renal effects), major surgery, severe acute illness, pregnancy (+/-) |
|
|
Thiazolidinediones (TZD)
|
Pioglitazone (Actos) [Rosiglitazone (Avandia) no longer used]
Mechanism: agonist for nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) which regulates genes involved in adipocyte differentiation and FA uptake (also in liver). Acts by transactivation (binds retinoid X receptor and PPAR response elements) and transrepression (interferes w/ signal transduction—anti-inflammatory) Effect (3-6w delay for max): enhances insulin sensitivity in muscle, liver, and adipose (↑ insulin mediated glucose uptake, ↑adipocyte differentiation, ↓lipolysis/FFA’s, ↓A1c), improved lipid profile (↓TAGs, ↑HDL), ↓ inflammatory markers, improved endothelial function Side effects: weight gain (adipose proliferation, ↑TAGs), fluid retention (peripheral edema, volume expansion), CARDIOvascular disease/MI (rosiglitazone), OSTEOporosis, BLADDER cancer (piogitazone) Contraindications: heart failure, abnormal LFT (troglitazone assoc w/ liver toxicity), bladder cancer (men) |
|
|
α-glucosidase inhibitors
|
Acarbose (precise), miglitol (glyset), voglibose
Mechanism: inhibit brush border hydrolase enzyme prevent breakdown of polysaccharides to monosaccharides, resulting in decrease/delay in postprandial carb absorption and reduced postprandial glucose level, no weight gain or hypoglycemia Effect: ↓A1c (0.5%), ↓PPBG, ↓FBG (less so) Side effects: GI (bloating, flatulence, diarrhea) → leads to poor compliance |
|
|
Insulin preparations
|
Very short (onset 15-30min, peak 1-2hr): Lispro, Aspart, Glulisine
Short (onset 0.5-1hr, peak 2-4hr): regular insulin Intermed (onset 1-4hr, peak 6-10hr): NPH Very long: Detemir (14hr), Glargine (22hr) Premixed insulins (variable time course): NPH/Reg 75/25, 70/30, 50/50 (alteration in amino acids change affinity to zinc and alter time in bound state) Ideal regimens: long acting basal (PM glargine, AM/bedtime NPH) + mealtime bolus (Lispro/aspart). Premixed are easy but limited flexibility |
|
|
Incretins
|
GLP-1 (exenatide), GIP, DPP4-inhibitors (sitagliptin, prevents incretin breakdown by DPP4)
Effect (normally reduced in T2DM patients): increase insulin release in response to glucose, decrease glucagon, decrease gastric emptying and increase satiety (less intake), promote weight loss, possibly increase islet cell neogenesis Use: GLP analogues generally more effective than DPP4-I’s. Use incombination with other therapy (metformin, insulin) to improve control |
|
|
Microvascular complications of diabetes
|
- occur in non-insulin sensitive tissues causing basement membrane damage (thickening), fibrosis, angiogenesis, coagulation, and inflammation: nephropathy, retinopathy, neuropathy (peripheral)
- risk for development is relative to high BG/A1c Path: diffuse basement membrane thickening, concentric hyaline material(collagen IV) –inappropriately glycated. Mechanism: in genetically susceptible individuals +/- independent accelerating factors (HTN, hyperlipidemia), hyperglycemia causes repeat acute changes in cellular metabolism and cumulative long-term changes in stable macro molecules, culminated in tissue damage. Possible pathways: ↑advanced glycation end-products, ↑active PKC, ↑ flux through polyol and hexosamine pathways, ↑ activation of poly- (ADP ribose) polymerase (PARP) |
|
|
Macrovascular complications of diabetes
|
- occur in insulin-sensitive tissues: atherosclerosis promotes cardiovascular (coronary artery- major cause of mortality), cerebrovascular (>2 RR), and peripheral vascular disease (non-traumatic amputation), arterioloscerlosis (synergism w/ HTN)
Path: arteriolosclerosis (classic vascular lesion of HTN), tortuosity (amorphous thickening of vessel wall (narrowed lumen) |
|
|
Diabetic Nephropathy
|
Epi: 20-40% of diabetics (> in African/Latin/Native Americans). Incidence 10-20y post diagnosis in T1DM, often at presentation of T2DM
Complications: end-stage kidney disease (assoc w/ macroalbuminuria), ↑cardiovascular mortality, proteinuria/albuminuria (reduced filtration from thickening) Tx: antihyperglycemic therapy, ACE-I, ARB Path: diffuse basement membrane thickening, mesangial sclerosis, glomerular sclerosis, arteriosclerosis (causing gross surface granularity), necrotizing papillitis (infection in collecting tubes cause gross surface pitting), Kimmelstiel-Wilson Lesions (15-30%) |
|
|
Diabetic retinopathy
|
Epi: common microvascular complication, presents 15-20y after dx in T2DM, often at diagnosis in T2DM. Leading cause of adult-onset blindness in US
Complications: blindness, glaucoma, cataracts Tx: BG control, BP control, angiogenesis inhibitors (Anti-VEGF – experimental) Types: - Non/pre-proliferative: abnormal vessels in retina (intra retinal angiogenesis), basement membrane thickening, microaneurysms, macular edema, lipid exudates - Proliferative: neoangiogenesis through internal limiting membrane (into vitreous), vitreous/preretinal hemorrhage, retinal detachment |
|
|
Diabetic neuropathy
|
Epi: deficits in >50% long-term diabetics, distinct clinical patterns (w/o overlap)
Distal symmetric sensory or sensorymotor: - ↓pain sensations and vascualopathy →ulcer risk - major cause of amputation - Axonal pathology: segmental demyelination, relative loss of small myelinated and demyelinated fiber, thick basement membrane of endoneurial arterioles Autonomic neuropathy: - GI, bladder, sexual dysfunction, risk of silent MI Focal or multifocal assymetric: - ischemic insult to peripheral nerve |
|
|
Gestational diabetes
|
= carbohydrate intolerance leading to hyperglycemia with onset (or first recognized) during pregnancy
Types: A1: abnormal OGTT, but normal fast and PP BG, diet/exercise sufficient for control A2: abnormal OGTT, abnormal FPG and/or PPBG, requires medical therapy Epi: 7% of all pregnancies (rising) Risks: fam Hx, macrosomia, obesity, mat. age >35, hx of poor obstetric outcome, previous gestational diabetes, ethnic group (African/latin/native American, pacific islander) Dx: 1hr OGTT at 24-28wks (>140 retest, >200 diagnosed), follow w/ 3hr GTT if fail (fast 105/ 1hr 180/ 2hr 155/3hr 140) Tx: diet (30% cal restriction if BMI >30), exercise (cardio), insulin/glyburide (does not cross placenta). GDMA1 (good, no follow-up), GDMA2 (antenatal surceillance 2x weekly, induce at 32wks) Prognosis: 30% have diabetes postpartum, 50% in next 10yrs (screen at 6-12wks, if normal assess every 3yrs, if impaired every year + counseling/metformin. Can use OCPs to avoid further pregnancy) |
|
|
Complications of gestational diabetes
|
Maternal:
- hypertensive disorders: preeclampsia, eclampsia - require C-section - still birth - trauma (from fat baby) Fetal - macrosomia: large babies (but not LGA), fat deposition in shoulders esp, over activation of IFG-I/II - hyperbilirubinemia - operative delivery - shoulder dystocia - birth trauma - neonatal hypoglycemia - development of diabetes later in life (due to hyperinsulinemia, obesity, and resistance) |
|
|
Factors that influence weight
|
Genetics: family hx, rare defects (leptin, leptin receptor, melanocortin 4 receptor (MC4R), POMC, cocaine-amphetamine regulated transcript, prohormone convertase, carboxypeptidase E, brain derived neurotrophic factor)
Epigenetics: neonatal environment (maternal obesity/diabetes, large birth weight) Environmental/behavioral: maternal weight (>paternal), psychological conditioning, screen time, activity, meal/eating patterns, food choiceds, pathologies, family/school/work/community environment, cultural (national advertising) Racial: AA > Hispanic > white |
|
|
Complications of obesity
|
Metabolic syndrome: diabetes, HTN, dyslipidemia, hyperandrogenemia
Muscoloskeletal: arthritis/arthropathy Cardio: venous stasis, HTN, dyslipidemia Pulm: sleep apnea, chronic lung disease Renal: glomerular disease GI: GERD, NAFLD GU: stress incontinence, hyperandrogenemia Neuro/psych: lots Immune: intertriginous (fungal) infections, cancer (breast, endometrial, colon) |
|
|
Eligibility criteria for adolescent bariatric surgery
|
BMI >40
Presence of comorbidity Skeletal maturity Participation of 6mo medical weight management: if they lose a lot surgery may not be necessary, if they lose none then they do not qualify (non-compliance) Patients and parents must be willing to make lifestyle changes before and after surgery |
|
|
Types of bariatric surgery
|
Restrictive: reduces stomach size allowing only a small amount of food to enter. Incl: sleeve (also removes ghrelin), lap band
Malabsorptive: removes part of the digestive tract responsible for absorption of food. Incl: bypass Combination: restrictive and malabsoptive. Ex: Roux-En-Y |
|
|
Pituitary
|
Posterior:
- extension of the hypothalamus (all nerves have cell bodies there at the hypothalamic nuclei) - vascular supply from the inferior hypophyseal artery from the internal carotid - secretes oxytocin and vasopressin (produced in nuclei of the hypothalamus) directly into perivascular space Anterior: - derived from Rathk’s type oral epithelium, regulated by the hypothalamus - vascular supply from the superior hypophyseal artery off the internal carotid (very close to the cavernous sinus) - secretes: LH, FSH, ACTH, TSH, GH |
|
|
Cell types of the anterior pituitary
|
Somatotrophs: growth hormone
Lactotrophs: prolactin Corticotrophs: ACTH Thyrotrophs: TSH Gonadotrophs: FSH, LH |
|
|
Pituitary Adenomas
|
(hormone secreting tumors tend to be small b/c present early w/ clinical syndrome)
Prolactinoma: 30% (most common) Non-functional adenoma: 20%, clinically non-relevant (hormone may be released but does not cause a clinical syndrome). Often present with mass effect b/c have time to grow—bitemporal hemianopsia (classic visual disturbance from impingement of optic chiasm) Corticotroph adenoma: 15%, may lead to Cushings disease Somatotroph adenoma: 15%, may give rise to gigantisim or acromegaly Gonadotroph adenoma: 5% Thyrotroph adenoma: 1% (Pituitary carcinoma are very rare <5%, and only distinguishable based on invasion—not pathology) |
|
|
ACTH producing adenoma
|
- tend to be microadenomas because they produce potent hormone
Clinical syndrome: Cushing’s Disease (central obesity w/ moon facies, stria, HTN, acne, diabetes) |
|
|
Sellar & Suprasellar neoplasia
|
Pituitary adenomas
Craniopharyngiomas: most commonly occur in adolescents but can extend to adulthood, form pituitary epithelia, can have cystic components (filled w/ oily keratin material) and calcifications, form epithelial structures on histo Rathke’s cleft cysts: benign, derived from epithelial component of the pituitary gland, bulbous lesion with a think cystic lining (single columnar ciliated epithelium), sellar or extend to suprasellar region Germ cell tumors: mostly germinomas, stain for with C-Kit and Oct4. Often has lymphocytic infiltrate and granulomatous inflammation Pituicytoma: looks more like a glial tumor (b/c arising from the posterior pituitary) Granular cell tumor: benign, arises from the posterior pituitary, with large pink, lysosome-filled cells. Cured with surgical resection Meningioma Glioma |
|
|
Hormone requirements for growth
|
Prenatal: insulin, IGF-1, adequate nutrition (not needed: pituitary GH, thyroid hormones, sex hormones)
Postnatal: all but the sex hormones Pubertal: everything, including sex hormones. Estrogens promote epiphyseal fusion |
|
|
Hormonal causes of short statures
|
(non-hormonal: Malnutrition, Systemic illness. Skeletal dysplasia, Syndromic, idiopathic)
Hormone deficiency or resistance: GH axis: - hypothalamic defect: GNRH deficiency—low basal GH, IGF-1, IGFBP-3, not indirect but direct release w/ GNRH & Ghrelin stimulation - pituitary defect: craniopharyngioma (low basal and no response to direct or indirect stimulation) - end organ defect: Laron’s syndrome (receptor mutation, low IGF-1, but high basal/stimulated GH, low basal GHBP) Thyroid axis: TRH, TSH, free T4 (deficiency can show location of defect) Prolactin axis: high Prl (hypothalamic/stalk defects-loss of dopaminergic inhibition), low Prl (pituitary defect) Cortisol axis: assess diurnal rhythm of secretion, ACTH response to insulin & CRH, cortisol response to low-dose ACTH Sex hormone axis: LH, FSH, estradiol (look for central vs. peripheral hypogonadism). LHRH to distinguish btwn hypothalamic and pituitary ADH axis: fluid history, Na levels, urine specific gravity |
|
|
Cause of panhypopituitarism
|
- tumors: carniopharyngioma, optic glioma, pituitary adenoma
- trauma: motor vehicle accident can cause pituitary stalk to severe - inflammation: histiocytosis, hypophysitis, tuberculosis, syphilis, sarcoidosis - cranial radiation - infiltrative diseases: amyloidosis, hemochromatosis, mucopolysaccharidosis - pituitary infarction: Sheehan’s - pituitary apoplexy - genetic mutations: ex: PIT1/PROP1, may be associated with septo-optic dysplasia - idiopathic |
|
|
Craniopharyngioma
|
= most common parasellar mass in childhood, 10% of all pediatric intracranial tumor
- ectopic remnants of pharyngeal epithelium with somatic cell mutations in β-catenin (staining shows β-catenin whorls, fibrosis, ghost cells) - adamantanomatous: keratin nodules, cystic and solid areas, hemorrhage, fibrosis, calcification, cholesterol deposits Difficult to resect: close to 3rd ventricle, optic nerves & chiasm, and hypothalamus. Tend to be large in size, locally invasive and at risk for recurrence Tx: combination of surgical, radiological removal, management of diabetes insipidus, hormone replacement (ACTH, TSH, GH, GRH), management of weight and somnolence |
|
|
Minerals and hormones involved in calcium regulation
|
Calcium: principal bone cation--hydroxyapatite (99% body Ca),1 % extracellular (blood, ETC space, tissues), 50% bound/complexed, 50% free (ionized/bioavailable). Labs measure total (correction for hypoalbuminemia: Serum Ca + [.8*(normal-patient albumin)])
Phosphate: principle bone anion (80% of total phos), mostly extracellular Parathyroid hormone: ↑ plasma Ca by stimulating bone resorption (↑osteoclastic activity), kidney reabsorption, ↑active vitamin D (upregs 1-α-hydroxylase), increases intestinal Ca/phos absorption Vitamin D: causes ↑intestinal absorption of Ca/Phos, sensitizes bone to resorption, ↑Ca transport and uptake by muscle Magnesium: deficiency inhibits PTH Alkaline Phosphatase: produced by osteoblasts (increases during bone turnover) Albumin: binds Ca, may adjust total Ca if abnormal |
|
|
Parathyroid hormone
|
Secreted by the parathyroid in response to low plasma Ca. Principle effect is to increase plasma Ca:
Actions: (↑serum calcium) - ↑ bone resorption: indirectly stimulate osteoclasts—PTH binds obsteoblasts leading to ↑RANKL expression which binds RANK on osteoclasts, ↑activity - ↑ kidney Ca reabsorption, ↓Phos reabsorption: ↑reabsorption in prox tubule, thick ascending limb (Ca-ATPase), Distal tubule (Na/Ca exchanger). - Upregulates 1α-hydroxylase: ↑production of 1,25-(OH)2-D, ↑intestinal absorption of Ca & Phos Signal transduction: PTH binds receptor activating G-protein, activating adenylate cyclase and producing cAMP, which increases PKA, increasing Serum Ca and urine Pho Ca-Sensing receptor (parathyroid, kidney, thyroid, brain): g-protein coupled, ↓extracellular Ca causes conformation change in receptor activating phospholipase C pathway (intracellular)→ ↑intracellular Ca → vesicle fusion and PTH release Feedback: ↑serum Ca binds parathyroid chief cell receptor, inihibts PTH release. PTHrP (related protein): domain homologous to PTH receptor binding N-terminus, can bind and activate same patheays—uncertain function, could be relatied to bone/cartilage formation |
|
|
Hypocalcemia
|
Clinical features:
- neurologic: ↑neuromuscular irritability - ocular: cataracts, papilledema, pseudotumor cerebri - cardio: ↑QT interval, non-specific T wave changes - other: soft tissue calcification, macrocytic megaloblastic anemia Symptoms: parasthesias, muscle cramping, tetany, seizures, diarrhea Signs: Chvostek’s sign, trousseau’s sign Etiologies: PTH abnormality (deficiency, resistance), Vitamin D deficiency, renal failure (↓Phos excretion), Ca-SR abnormality (gain of function, need ↓[Ca] to trigger), hypoparathyroidism (congenital, acquired), drugs (furosemide, calcitonin, anti-neoplastic agents, anti-convulsants, citrated blood products) |
|
|
Hypoparathyroidism
|
Results in: ↓(or normal) PTH, ↓Ca, ↑Phos
Congenital etiologies: - agenesis/dysgenesis: DiGeorge syndrome (defect in chr 22, pharyngeal pouch maldevelopment→ hypocalcemia, aortic arch abnormalities, abnormal thymus development, somatic/facial features) - transient (maternal hyper Ca—crosses placenta, shuts off Ca in infant) - syndromes Acquired etiologies: - autoimmune - infiltrative: iron (hemochromatosis), copper (Wilon’s), aluminum (CKD), tumor metastases (breast), granulomatous disease (sarcoid, TB) - magnesium deficiency: chronic alcoholism, malnutrition/malabsorption, TPN, chronic diuretics (thiazides, furosemide—dump Mg), familial (congenital) - iatrogenic: thyroidectomy, thyroid ablation - pseudohypoparathyroidism (biologically hypoPTH but biochemically hyperPTH): production of abnormal PTH molecule, abnormal interaction with receptor, abnormal α-subunit (G-protein). Will have abnormal biochemical findings - pseudopseudohypoparathyroidism: normal biochemical findings |
|
|
Pseudohypoparathyroidism
|
Abnormal biochemical featuers: ↓Ca, ↑Phos, ↑PTH, normal renal function, normal 25-(OH)-vitD, ↓1,25(OH2)-vitD, other hormone problems (G-protein mediated)
Etiologies: production of abnormal PTH, abnormal interaction with PTH receptor, abnormal α-subunit (G-protein) -Albrights’s hereditary osteodystophy (AHO): abnormal Gsα subunit (chr 20q13) causing short stature, obesity, brachymetaphalangia (short metacarpals), calcifications, mental retardation Pseudopseudohypoparathyroidism (PPHP): normal biochemical findings |
|
|
Vitamin D deficiency
|
Typical lab values: ↓Ca, ↓Phos, ↑AlkPhos, ↑PTH
Complications: Rickets, bony changes Symptoms: bowed legs, ricketic rosaries (rib nodules), cupping, metaohyseal flaring Etiologies: nutritional vitamin D deficiency, hypophosphatemic Rickets (x-linked or AR), 25-OHase deficiency, 1,25-OHase deficiency (receptor defect), resistance to calcitriol |
|
|
Treatment for hypocalcemia
|
First collect labs (PTH, vit D), the treat w/ Ca
Acute (symptomatic—tetany, seizure): IV calcium gluconate (to avoid cardiac issues), then Ca PO once symptoms stop Chronic (Asymptomatic): oral Ca + VitD - Ca Carbonate/Ca Glubionate: be aware of amount of elemental Ca. If milk >30min following administration to infant so Phos will bind it - Vit D: if PTH problem take active form (calcitriol), if just deficient take normal pro-form (cholecalciferol) |
|
|
Thyroid Hormone
|
T3/4 produced in the thyroid in response to TSH from the anterior pituitary
Effects: - fetal development: brain (neuroblasts →neurons & synapse formation) and skeletal - Metabolism: regulate O2 consumption (↑number/activity of mitochondria), heat production, BMR - Cardiac: heart rate, sensitivity to catecholamines (↑ cardiac output, RR) - Endocrine: stimulate carbohydrate and lipid metabolism - Skeletal: increase bone turnover (risk for osteoporosis in elderly). In youth, stimulates GH gene expression in anterior pituitary, stimulates calcification and growth plate closure Synthesis: - Iodine active transported in via Na/I symporter, diffuses into the colloidal lumen and oxidized/trapped as I2 - thyroid peroxidase (in colloid apical membrane) complexes iodide and tyrosine (generating short-lived free radicals) to form MIT and DIT - Thyroglobulin (synthesized and secreted by follicular cells) bind MIT/DIT and allow them to react together to form T3/T4. Released upon TSH stimulation - T3/4 transported to cytoplasm by pinocytosis and released in blood stream where most bind to thyroxine binding globulin (TBG) - T4 converted to active T3 by 5’-deiodinase in peripheral tissues (allows T4 to have longer half-life) |
|
|
Thyroid hormone feedback systems
|
TRH: produced in hypothalamus, stimulates TSH release from pituitary. Inhibited by T3/4
TSH: produced in anterior pituitary, promotes T3/4 synthesis (upregs iodine uptake, organification, coupling, and pinocytrosis). Stimulated by TRH, inhibitied by somatostatin, T3, T4 |
|
|
Thyroid function tests
|
Serum TSH: best indicator of thyroid function (inhibited by high T3/T4, activated by low levels of TRH, T3/4)
Free T4: best indicator of hormone levels (Total T4 strongly influenced by amount of blood proteins binding hormone) Additional Tests: - T4: total serum thyroxine - T3: triiodothyroxine - Thyroglobulin: used as a tumor maker (tumors tend to produce high levels) Ultrasonography: good way to see cysts and masses, guide fine needle aspiration Fine needle aspiration cytology: collect tissue for histologic identification I-123 scan: look for iodine uptake in the thyroid (indicative of cellular activity) |
|
|
Goiter
|
= enlargement of the thyroid gland (>80g)
Epi: sporadic or familial, can be endemic (>5% due to diet of goitrogens), most common cause is iodine deficiency Toxic goiters: (↑T3/4) - Diffuse/symmetrical: Grave’s--most common spontaneous goiter <40y, show signs of hyperthyroidism (diffuse, homogenous I-123 distribution) - Multinodular: Plummer’s disease (hyperthyroidism w/ functionally autonomous nodules), Hashimoto’s (focal discrete nodules of I-123 uptake) - Nodular: Thyroid adenoma—autonomous single nodule Others: Hashimoto’s thyroiditis, subacute thyroiditis, malignancy, genetic/familial hormone synthesis defects Non-toxic/Simple goiters: (normal T3/T4) - diffuse: hyperplasia w/o nodularity. Mostly due to goitrogens (Ca++, Fl-, vegetables) or iodine deficiency. May develop into multinodular |
|
|
Hyperthyroidism
|
= excess T3/T4 (thyrotoxicosis)
Complications: thyroid storm, goiter Causes: Grave’s disease, Plummer’s disease, subacute thyroiditis (DeQuervain thyroiditis), iatrogenic, fractious (excess ingestion), abnormal production of TSH or TSH-like hormones (stuma ovarii—thyroid teratoma, pituitary tumor, placental tumor secreting hCG) Signs/symptoms: - general: nervousness, insomnia, fatigue, heat intolerance, weight loss, increased appetite - Skin: hyperhidrosis (excessive sweating), alopecia, onycholysis (warm, moist skin) - Cardiac: tachycardia, increased risk of atrial fibrillation, high output heart failure - GI: hyperdefecation (diarrhea), abnormal LFTs - Neuromuscular: tremor, proximal myopathy, periodic paralysis, thyroid stare (beta-adrenergic stimulation/fatigue of levator palpebrae muscle) Dx: serum TSH, T3/T4 levels. Primary: ↑T3/T4 ↓TSH, Secondary: ↑T4/T4 ↑TSH Rx: beta-blocker, PTU, Methimazole, surgical resection of thyroid, radiodine ablation |
|
|
Thyroid storm
|
= life threatening thyrotoxicosis (excess T3/T4)
Symptoms: high fever, tachyarrhythmia, psychosis, confusion, diarrhea, liver dysfunction Tx: intensive care life support, anti-thyroid meds, Beta-blockers |
|
|
Subacute thyroiditis (DeQuervain Thyroiditis)
|
= inflammation of the thyroid gland causing spilling of preformed thyroid hormones and transient hyperthyroidism (pituitary inhibition then causes a transient hypothyroid state before the body returns to euthyroid state)
- usually preceded by URI by 2-3 weeks - Signs/symptoms: firm, painful tender thyroid gland +/- small goiter, fever, increased ESR, pain radiation to ears, neck, and arm. - granulomatous inflammation of histology - will see very little uptake on I-123 - usually resolves spontaneously in 4-6 weeks |
|
|
Hypothyroidism
|
= reduction in production or release of thyroid hormones
Epi: 2-4% prevalence, F>M, common disease with the elderly. Types: Primary (local in thyroid—autoimmune, post Rx, surgery, insufficiency), secondary (pituitary—low TSH), tertiary (hypothalamus, low TSHrH) Signs & symptoms: - general: lethargy, weakness - appearance: dry & thickened skin, coarse features, pasty complexion, thinning of lateral 1/3 of eyebrows, macroglossia (large tongue) - Cardiac: bradycardia - GI decreased appetite, constipation - Metabolic: weight gain, cold intolerance, hypoglycemia Tx: hormone replacement (Levothyroxine/synthroid—T4). Titrate slowly to avoid cardiac complications, increase until T4 within normal limits. Increase dosage in pregnant women by 30% immediately (otherwise kids have lower IQs). Consider resection if goiter is present |
|
|
Etiologies of hypothyroidism
|
Hashimoto’s thyroiditis: most common cause of hypothyroidism, autoimmune (lymphocyte infiltration and Hurthle cells), F>M, low T3/4 w/ high TSH and positive thyroid antibodies
Iatrogenic: previous resection or radioactive iodine ablation Postpartum thyroiditis: painless +/- goiter, develops 1-2mo postpartum and last 2-5mo, positive anti-thyroid antibodies, high recurrence in future pregnancies 2nd or 3rd hypothyroidism: Sheehan’s, sellar tumor, usually rare Juvenile hypothyroidism: thyroid insufficiency causes growth to level off while weight/BMI increase Defective thyroid hormone synthesis/iodine deficiency: defective enzyme or diet. Iodine deficiency most common hypothyroidism/goiter in developing world. ↑TSH w/ ↓T3/4 Medication: lithium, amiodarone Subacute thyroiditis: occurs following inflammatory hyperthyroidism Riedel thyroiditis: rare fibrosis of the thyroid—painless but rock hard. |
|
|
Thyroid nodules
|
- not uncommon in a healthy population: 6% in women (1/3 on US), 2% in men
- may be benign or malignant, as determined by histology after fine-needle aspiration - cysts and cold nodules on I-123 are generally benign. - Check thyroid function test to see TSH, T4 production |
|
|
Thyroid cancer
|
= most common endocrine cancer in the US (2/100K)
Risks: childhood head/neck radiation, M>F, young age, family history Presentation: typically solitary nodule, depending on growth pattern may see dyspnea, coughing/choking spells, dysphagia, hoarsness Diagnosis: usually normal TSH (but variable), >1-1.5cm on US w/ intranodular microcalcifications, significant I-123 uptake Tx: thyoidextomy (except anaplastic carcinoma--palliative) +/- radiation Types: papillary, follicular, medullary, anaplastic |
|
|
Types of thyroid carcinoma
|
= uncommon malignancy w/ increasing prevalence, possible due to ↑radioactivity. Female predominance, wide range of incidence, prognosis related to stage/histology, may have metastatic potential
Papillary: 75-85% - develops from thyroid follicles. Slow growing but can spread to lymph nodes. - risk: radiation exposure - See orphan annie nuclei and psammoma bodies Follicular: 10-20% - risks: low idiodine consumption - hematogenous rather than lymphatic spread (due to vascular invasion) Medullary: 5% - develops from parafollicular C-cells and produce calcitonin (neuroendocrine), can spread quickly - sporatic and familial types (associated w / MENIIa/b) - see amyloid deposition (positive chromagranin stains) Anaplastic (undifferentiated): 5% - develops from existing papillary or follicular cancers, usually elderly patients - Poor prognsosis: rapid growth/invasion, usually fatal—palliative care only (not thyroidectomy) - see giant cells and spindle cells on histolog |
|
|
Levothyroxine (Synthroid)
|
= synthetic T4
Mechanism: identical to human T4, allows the body to regulate active T3 depending on metabolic needs Clinical uses: and condition causing hypothyroidism |
|
|
Liothyroxine (Cytomel)
|
= synthetic T3
Mechanism: biologically the same as T3 Clinical uses: acute severe hypothyroidism, myxedema coma |
|
|
Liotrix (Euthroid)
|
= 4/1 ratio of T4/T3
Mechanism: mimics the natural ratio of circulating thyroid hormones Clinical uses: hypothyroidism (but not advantage over levothyroixine) |
|
|
Thyroid (USP) and thyroglobulin
|
= thyroid hormone isolated from dessicated extracts of animal thyroid
Mechanism: animal thyroid hormones used to increase or replace human production Clinical uses: no longer in use, but was the first therapy available |
|
|
Thioureylenes
|
Ex: Propylthiouracil (PTU), methimazole (tapazole)
= Synthetic inhibitors of iodination and conversion of T4→T3 Mechanism: competitively inhibit thyroid perioxidase and 5’ deiodinase Clinical uses: hyperthyroidism, long term management of Grave’s disease (PTU used only for the first trimester of pregnancy) Side effects (<10%): itchy rash, low grade fever, joint pain, agranulocytosis, hepatotoxicity (PTU) |
|
|
High dose iodide
|
= Lugol’s solution or tablets
Mechanism: high doses of iodine (>6mg/day) have an inhibitor effect on thyroid hormone synthesis and release Clinical uses: preoperative therapy prior to thyroidectomy (to shrink thyroid), thyroid storm/thyrotoxicosis (used w/ thioureylines) Side effects: salivation, hemorrhage (rare), induction of goiter, myxedema |
|
|
Iodie 131
|
= radioactive iodine therapy
Mechanism: iodine localizes to the thyroid and beta emissions kill surrounding cells/tissues Clinical uses (can be followed by surgery): Grave’s disease, thyroid tumor Side effects: exposure unsafe for children, pregnant women |
|
|
Propranolol (for thyroid uses)
|
= beta 1/2 antagonist
Mechanism: blocks T3/T4 activation of sympathetic nervous system (esp on the heart) Clinical uses: thyroid storm (other causes of acute thyrotoxicosis), used in combination w/ other anti-thyroid hormone treatments Side effect: exercise intolerance, impotence |
|
|
Recombinant growth hormone
|
Humatrope, Somatrem (Protropin)
Mechanism: mimics action of GH by binding to cells surface receptor and activating transcription of IGF-1 Clincial uses: dwarfism, hypopituitarism, slow growth (non-pituitary causes of delayed growth) Side effects: development of anti-GH antibodies |
|
|
Octreotide acetate (Sandostatin)
|
= synthetic somatostatin analogues
Mechanism: selectively bind SST2R to inhibit GH release (more potent than natural) Clinical uses: GH producing tumors (acromegaly) Side effects: nausea, diarrhea, stomach pain, gallstones |
|
|
Pegvisomant (Somavert)
|
= synthetic GH receptor antagonist
Mechanism: binds GH receptor and competitively inhibits GH action Clinical uses: GH secreting tumor (acromegaly/gigantism: used as an alternative or in conjunction w/ Sandostatin) Side effects: increase GH release, hypertension, increased liver function, hepatitis |
|
|
Bromocriptine (Paroldel)
|
= semi-selective synthetic domanine receptor agonist
Mechanism: semi-selectively binds D2 receptor to mimic inhibitor effects of dopamine on prolactin axis Indication: hyperprolactemia due to pituitary tumors, prolactin elevation due to pregnancy/suckling Side effects: dizziness, nausea, orthostatic hypertension |
|
|
Carbergoline (Dostinex)
|
= potent selective dopamine receptor agonist
Mechanism: bind D2 receptor to mimic the inhibitory effects of dopamine on the prolactin axis Indications: prolatinemia due to pituitary tumors, pregnancy/suckling Side effects: nausea, constipation, headache, arrhythmias, MI, heart failure (contraindicated for HTN patients) |
|
|
DDAVP (Desmopressin)
|
= stable, long lasting V2 selective analogue of arginine vasopressin (AVP)
Mechanism: selectively binds to V2 receptors to mimic the effect of ADH (increase aquaporin expression and water retention in the kidneys) Indications: diabetes insipidus, mild hemophilia A (stimulates production of factor VIII) Side effects: excessive water retention, listlessness, headache, seizures, coma |
|
|
Locations of thyroid disease
|
- Lingual thyroid: thyroid remnants at the base of the tongue
- thyroglossal duct cyst: if there is not complete closure of the duct the thyroid tissue may grow there ectopically. Will present as a midline neck mass of thyroid tissue - Lateral aberrant thyroid: typically lateral to SCM, often a metastasis of carcinoma (if midline probably misplaced normal thyroid). - Mediastinal goiter: large thyroid (usually in the neck but can extend to chest/mediastinum). Such a mass could be 4T’s: thymus, thyroid, teratoma, terrible lymphoma - Struma ovarii: teratoma with germ cell layers that have a thyroid component |
|
|
Thyroiditis
|
= inflammatory condition of thyroid, may or may not be due to infection
Acute: bacterial or fungal, usually seen in immunocompromised patients Chronic (Hashimoto’s): autoimmune thyroid destruction, characterized by Hurthle cells Subacute (DeQuervain’s): granulomatous thyroiditis (female predominance, uncertain etiology—post viral? w/ resolution in 2-6mo, giant cells seen) Fibrous (Riedel’s): inflammatory/fibrotic destruction of thyroid gland and other neck structures, causes woody/hard thyroid. Clinically resembles maglignancy Systemic (sarcoidosis) Painless or silent |
|
|
Thyroid nodules
|
- can occur in almost any thyroid disorder (benign or neoplastic), usually are euthyroid
Dx: fine needle aspiration (look for variability in colloid follicles, hyperplastic epithelium, etc), I-123 uptake (cold, non-uptake/functional regions might be neoplasm) Types: - non-neoplastic colloid nodules: 50%, no capsule present - adenoma: 30%, generally benign follicular lesions, slow growing rarely functional, have uniform follicular pattern w/ fibrous capsule - carcinoma: 10%, 4 types: papillary, follicular, undifferentiated, medullary - cysts: 5%, benign - non-epithelial tumors: malignant lymphoma |
|
|
Vitamin D
|
Sources: endogenous (ergocalciferol produced by reaction of light w/ cholesterols), exogenous (dietary-ergocalciferol, supplements-cholecalciferol)
Metabolism: vitamin D hydroxylated in the liver to 25(OH) vitamin, then in the kidney to active 1,25(OH)2 Vit D. Actions: (like a steroid hormone) - regulates genes containing vitamin D response elements (VDRE): binds cytoplasmic receptor, complex translocated to nucleus, binds retinoid X receptor, complex bind VDRE sequences altering transcription - increases Ca and Phos absorption from the GI tract |
|
|
Endocrine causes of hypercalcemia
|
Disorders of parathyroid: (causing ↑PTH secretion)
- primary hyperparathyroidism: lesion causes excess PTH and mild/asymptomatic ↑Ca (benign neoplasm 80%, nodular hyperplasia 15%, rare malignant neoplasm), F>M - secondary hyperparathyroidism: parathyroid hyperplasia due to chronic hypocalcemia (Vit D deficiency, renal failure). May be normocalcemic, result in secondary neoplasm - tertiary hyperparathyroidism: Ca-independent PTH release from parathyroid neoplasm arising due to chronic gland overstimulation (2nd ↑PT) - Others: calcium-sensing receptor defect, humoral hypercalcemia of malignancy (ectopic PTH, *PTHrP, usually symptomatic), osteolytic metastasis, medications (thiazides, lithium, antacids) Disorders of Vitamin D - vitamin D intoxication (supplement overdose), granulomatous disease (sarcoid, TB), Vit D producing tumors (lymphomas) |
|
|
Endocrine causes of hypocalcemia
|
Hypoparathyroidism: PT insufficiency/deficiency causing ↓ PTH activity
- Primary: autoimmune degradation - Iatrogenic: following surgical thyroidectomy or lymphadectomy - Congenital defect: DiGeorge, velocardiofacial syndrome - Familial: autoimmune polyendocrine syndrome type 1 Pseudohypoparathyroidism: PT gland normal & PTH normal but end organs are unresponsive, resulting in ↑PTH Vitamin D disorders: - Vit D deficiency: limited sun exposure, inadequate diet, kidney/GI disease. (Assoc w/ bone disease, cancer, CV disease, T2DM, autoimmunity) - Vit D-dependent rickets 1&2 (1-alpha-hydroxylase deficiency- no conversion to active form) - End organ resistance to vitamin D |
|
|
Physiologic manifestations of calcium dysregulation
|
Hypercalcemia:
- bone: pathologic fractures, osteoporosis, osteomalacia, osteitis fibrosis cystica (cystic lesion on Xray from excessive resoprtion→inflammation and fibrosis) - kidney: nephrolithiasis, polyuria, nephrocalcinosis - brain: depression, seizures, obtundation, neuromuscular/muscular contractions - cardio: shortened QT interval - GI: gallstones, acute pancreatitis, peptic ulcers Hypocalcemia: Neuromuscular: tetany CV: prolonged QT interval Psych: anxiety, confusion, depression, Neuro: basal ganglia calcification, parkinsonism, papilledema Dental: dental hypoplasia, failure of eruption, defective enamel |
|
|
Parathyroid neoplasia
|
Adenoma:
-sporadic, solitary lesion, less often in inherited syndromes -usually diagnosed incidentally (↑Ca on routine test), isolated by radionucleotide scan - Pathology (0.5-5g): encapsulated growth, lack of normal fat component, uniform cells w/ round nuclei and nested growth, rare mitoses Carcinoma: - difficult to distinguish from adenoma: usually larger (10g) - bland cytology: fibrosis or subtle infiltrative growth—local invasion, metastasis are only reliable malignancy criteria Genetics: (only a few from familial tumor syndromes) - Cyclin D1: promotor of cell division (60% of adenomas) - Menin: gene transcription repressor, germline mutation in MEN1, 20% of adenomas - RET: tyrosine kinase receptor , germline mutation in MEN2 |
|
|
Multiple endocrine neoplasia 1
|
Due to ch11 germline mutation in menin (gene transcription repressor), autosomal dominant
3P’s Pituitary adenomas: prolactinoma most common (+/- GH) Hyperparathyroidism: usually 4 gland hyperplasia, secondary adenomas frequent Pancreatic islet cell tumors: multiple small benign tumors (gastinomas mostly→ Zollinger-Ellison syndrome, insulinomas→hypoglycemia, VIPomas and glucgonomas rare), secondary malignancies common. Present w/ kidney stones and stomach ulcers |
|
|
Multiple endocrine neoplasia 2
|
Due to ch10 germline mutation in RET: tyrosine kinase receptor
MENIIA: Medullary thyroid carcinoma/C-cell hyperplasia (calcitonin secretion→ amyloid) Pheochromocytoma: adrenal medullary hyperplasia Parathyroid neoplasia: adenoma or hyperplasia (primary hypoparathyroidism) MENIIB: Medullary thyroid carcinoma (calcitonin secretion) Pheochromocytoma Oral/intestinal ganglioneuromatosis (mucosal neuromas)—a/w marfanoid habitus (long limbs) |
|
|
Pituitary adenomas
|
- 90% of pituitary tumors
Microadenoma: <1cm, more likely to present as a hormone secreting tumor Macroadenoma: >1cm, more likely to present as mass effect Functional adenomas: prolactinomas (35% of all, 80% of functional), GH adenomas (20%), also corticotrophs (Cushing’s), gonadotrophs (hypergonadism), thyrothrophs (hyperthyroidism) Presentations: Mass effect: headache, bitemporal hemianopsia, diplopa (CN 3,4,6 palsy), pituitary apoplexy (sudden hemorrhage), hypopituitarism (sequential loss of GH, LH/FSH, TSH, ACTH). Rarely optic atrophy, papilledema, hydrocephalus, CSF rhinorrhea Pituitary hyperfunction: |
|
|
Prolactinomas
|
35% of all pituitary tumors, 80% of all functional pituitary tumors
Presentation: - serum prolactin >200ng/ML, low FSH/LH (b/c prolactin inhibits GnRH release) - in females: galactorrhea, secondary amenorrhea, infertility - in males: decreased testosterone → loss of libido, impotence, decreased facial har. - mass effect: headache, visual disturbances (esp. men who tend to have larger tumors), hypopituitarism - immunohistochemical staining with excess secretion |
|
|
Growth hormone adenomas
|
20% of pituitary adenomas
Presentation: - in children (open epiphyses): linear and lateral bone growth →gigantism - adults (fused epiphyses): lateral bone growth → acromegaly (large hands, feet, and jaw w/ increased spacing between teeth, macroglossia, voice deepening, cardiomyopathy (usually cause of death) - general: ↑ IGF1 (synthesized and release in liver), hyperglycemia (↑gluconeogenesis), hypertension (↑Na retention), visceral organomegaly w/ dysfunction, myopathy, mass effect (headache and visual defects) |
|
|
Prolactin excess
|
Etiologes:
Primary: prolactinoma, idiopathic hyperprolactemia Secondary: - hypothalamic/pituitary stalk lesion: granulomatous or infiltrative disease (sarcoid), sellar or extracsellar lesion - chest/spinal cord lesion (enhances feedback regulation) - breast stimulation: suckling - hypothyroidism: ↑TRH → ↑PRL (VIP and TRH stim PRL release) - renal failure: mild elevations in 18% of CKD due to reduced clearance - cirrhosis: mild elevations - pregnancy: due to high estrogen levels - medications: dopamine agonists, opioids and cocaine, antidepressants, anxiolytics, verapamil, high does estrogen, H2 blockers Work-up: repeat PRL labs, exclude secondary causes (liver, kidney, thyroid function tests, pregnancy, meds), pituitary MRI, measure IGH-1, visual field testing Management: Rx (first): dopamine analogues-D2 receptor agonists (inhibitory) Surgery: transsphenoidal resection if no response to rx |
|
|
Growth hormone excess
|
Etiologies:
- Pituitary adenomas: 60% are GH only, 30% are GH/prolactin - Ectopic GH secreting tumor - MEN1 syndrome - Carcinoma - McCune Albright syndrome: autonomous endocrine hyperfunction, polyostotic fibrous dysplasia, unilateral café-au-lait spots Work-up: look elevated IGF-1, lack of GH suppression after 75g OGTT Management: Surgery (first): transsphenoidal resection (higher cure rate for microadenomas) Rx: somatostatin analogs (octreotide, lanreotide), dopamine analogs (bromocriptine, cebergoline), GH receptor antagonists (pegvisomant) |
|
|
Small intestine Ca/Phos absorption
|
Luminal TRPV6 transporters move Ca from lumen to the enterocyte.
Basolateral NCX1 (Na/Ca exchanger) and PMCA1b (ATP dependent) move Ca from enterocyte, then Ca is passively transported into the capillary. -Vitamin D: not necessary for transporter function, but enhances absorption of both Ca and Phos |
|
|
Hypophosphatemia
|
Etiologies:
- decreased absorption: Vit D deficiency, Vit D dependent rickets I/II, alcohol abuse, refeeding syndrome (after starvation) - Increased urinary losses: hyperparathyroidism, RTA’s, oncogenic osteomalacia (poor mineralized bone, FGF23 secreting tumor), X-linked hyperphosphatemic rickets (mutated PHEX gene—no FGF23 degradation), autosomal dominant hypophosphatemic rickets (mutated FGF23 resistant to cleavage), DKA (polys) - transcellular: respiratory alkalosis, leukemia *FGF23 is a peptide produced in bone, binds Klotho receptor in kidney to inhibit renal phos reabsorption and production of 1,25(OH)2 Vit D. Cleaved by PHEX |
|
|
Hyperphosphatemia
|
Etiologies:
- increased intake: TPN, phosphate, enemas - decreased excretion: chronic kidney diease (most common), genetics (pseudohypoparathyroidism, hypoPT, tumoral calcinosis) - excessive bone resorption - transcellular shift: tumor lysis, rhabdomyolysis |
|
|
Techniques for imaging the thyroid
|
I-123:
- emits γ rays with half-life of 13hrs - undergoes trapping and organificiation (can be used even if loss in organification function) - higher uptake (10-30%), slower (24hrs) - use w/ T3 suppression to check autonomy, and percholorate to check organification function (allows non-organified I to leak out) - use to differentiate follicular adenoma from carcinoma (most carinomas accumulate little iodine) TcO4 (technetium) - emits primarily γ rays w/ half-life of 6hrs - not trapped or organified - lower uptake (2-5%), but rapid (20min) I-131: - emits γ and β rays with half-life of 8 days - used for ablation therapy from β particle destruction of parenchymal cells -Cannot treat anaplastic and some medullary carcinomas (which do not accumulate iodine). Better post-resection. - At treatment should be no breast feeding, sharing utensils, frequent bladder emptying, normal diet for 3 days, away from children/pregnant women for 10 days, no pregnancy for 6mo |
|
|
Indications and complication of thyroid cancer
|
Indications:
- thyroid cancer - multinodular goiter: either symptomatic (interfere w/ swallowing) or cosmetic - nodule: indeterminate need aspiration biopsy - Grave’s disease: not usually surgical disease Complications: - hypoparathyroidism (<1%) - permanent hoarsness (<0.1%) - hematoma (<1%) - Chylothorax |
|
|
Indications for parathyroidectomy
|
Hyperparathyroidism:
- hypercalcemia - High PTH level - symptoms: bone loss, nephrolithiasis, fatigue, depression, loss of mental acuity. May also be asymptomatic - exclusion of familial hypercalcuric hypercalcemia Renal failure (~4% of patients on dialysis) - hypercalcemia - hyperphosphatemia - osteoporosis/renal osteopathy - severe bone pain, fatigue, pruritis - calciphylaxis - PTH >500 pg/mL |
|
|
Abnormal menstrual bleeding
|
= menstrual flow outside the normal volume, duration, regularity or frequency
Epi: 50% of menstruating women, common cause of seeking healthcare, most have no anatomic pathology Presentations: menstruation <2 or >7 days, recurrent bleeding between cycles, bleeding that interferes with daily activities or causes anxiety/concern, >80mL Etiologies: - pregnancy: most common, could be normal/abnormal (abortion, ectopic, implantation bleeding, normal spotting, molar pregnancy) - abnormal uterine bleeding: post-puberty, reproductive years, perimenopausal - neoplasia: vulva, vagina, cervix, uterus, fallopian tube, ovary, other - Inflammatory/Infection: vulvitis, vaginitis, cervicitis, endometritis, PID - traumatic: foreign body, direct trauma - systemic diseases: coagulopathies, blood dyscrasias, endcinopathies, drug effects - adverse effects of drugs - Iatrogenic |
|
|
Requirements for normal menstrual flow
|
- Inflow tract: endometrium, cervix, vagina, hymen
- estrogen and progesterone: theca cells (produce androgen in response to LH), granulosa cells (convert androgens to estradiol in response to TSH), after ovulation corpus luteum (produce VEGF and progesterone in response to LH) - FSH and LH: from anterior pituitary, stimulate estrogen and progesterone production in the follicle pre/post rupture - GnRH: from the hypothalamus, stimulate LH/FSH release |
|
|
PALM-COEIN classification of abnormal uterine bleeding
|
Abnormal uterine bleeding: heavy menstrual bleeding, intermenstrual bleeding
Structural causes (PALM): Polyp, Adenomyosis, Leiomyoma (submucosal, other), Malignancy & hypertrophy Non-structural causes (COEIN): Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, Not yet classified |
|
|
Structural causes of abnormal uterine bleeding
|
PALM
Polyp: benign hyperplastic lesions in reproductive age women. Cause bleeding due to abnormal vasculature: spotting or intermenstrual bleeding Adenomyosis: endometrial gland tissue growing in the myometrium. Uterus appears globular on MRI. Present w/ painful periods, enlarged uterus. Tx w/ hysterectomy, confirm dx from sample histology Leiomyomas (fibroids): benign smooth muscle tumors growing anywhere in the uterus. Rarely convert to leimyosarcoma. Cause abnormal bleeding during reproductive years (submucosal assoc. w/ sever menorrhagia). Malignancy (and hyperplasia): endometrial (must be considered in postmenopausal bleeding), ovarian (functional tumors can cause endometrial proliferation) Also Mullerian abnormalities: agenesis, bicornuate uterus, steptate uterus |
|
|
Non-structural causes of abnormal uterine bleeding
|
COEIN
Coagulopathy: underlying in 20% of AUB (often first presentation, esp in teens), Eval CBC/platelets, PT/PTT, meds Ovulatory dysfunction: spectrum of syndromes (a/oligo/polymenorrhea, menorrhagia, metrorrhagia, etc). Mechanisms: locally abnormal prostaglandins (↑systhesis/receptors), ↑ local fibrinolysis, ↑plasmin activity. Endocrinopathies: PCOS, unopposed estrogen Endometrial: endometritis (endometrial inflammation) irregular bleeding and spotting (not usually heavy), hyperplasia Iatrogenic (foreign bodies, coital laceration, trauma) and inflammatory: PID, bleeding w/o relation to menses (vulvititis, vaginitis, cervicitis, endometritis, salpingitis), assoc w/ signs of infection Not yet classified: TSH (hypo/hyper thyroidism, etiology unknown), functional deficits (in ovaries, pituitary, adrenals) |
|
|
Oligomenorrhea
|
= menstrual cycle with intervals >35 days
Typically in PCOS |
|
|
Polymenorrhea
|
= menstrual cycle with interals <24days (or 21d)
|
|
|
Menorrhagia
|
Normal menstrual intervals, excessive flow or duration (>10 days)
|
|
|
Metrorrhagia
|
Irregular menstrual intervals, normal flow and duration
|
|
|
Menometrorrhagia
|
Irregular menstrual intervals and excessive flow or duration
|
|
|
Mullerian agenesis
|
= congenital absence of shortening of the last 1/3 of the vagina
|
|
|
Ovarian cancer
|
Epi: leading mortal gyn malignancy, 30-50/100K in US, 80% benign and in young women (20-45) some found in older (45-65y). Most present at stage III (20% 5y)
Risk factors: fam hx (5-10% hereditary, BRCA1/2 assoc), null parity, North american/European descent, hx of breast/colon/uterine cancer Protective factors: decreased ovulatory cycles (multiparity, OCPs, breast feeding) Classes: germ cell (mostly adolescents , early stage), surface epithelial (>20y, often most aggressive), sex cord-stromal tumors (rare, young patients), non-specific (rare, more commom >20y) Screening: transvaginal ultrasound (not sufficient alone), CA-125 (high MW glycoprotein, general ovarian cancer marker—good sens low spec). Not cost effective, not routine Dx: imaging, symptoms (abd discomfort, dyspepsia, urinary frequency, weight loss, abd bleeding), and clinical judgement Management: tumor debulking, organ removal, IV chemo or clinical trial |
|
|
Endometrial cancer
|
Epi: most common gyn cancer, 4th most common malignancy in women,
Screening: not cost effective, only done on clinical suspicion Presentation: peri/post menopausal women w/ abnormal bleeding, leucorrhea (white/yellow vaginal discharge), pain/pressure Risks: >60y, obsess, unopposed estrogens (exogenous, cancer, hormone therapy), chronic anovulation, tamoxifen use, endometrial hyperplasia (esp. atypical), menopause, nulliparity, DM, HTN. (oddly OCP, smoking are protective) Dx (high index of suspicion): symptoms, biopsy (indicated w/ thickness >4cm w/ bleeding, post-menopausal bleeding, change in bleeding pattern, tamoxiphen w/ bleeding) Management: resection of tumor and organs/lymph nodes. Most have good prognosis and don’t require adjuvant therapy (serous <10% and clear cell <4% are more advanced and require chemo/radiation) |
|
|
Cervical cancer
|
Epi: 3rd most common gyn cancer in US (most common worldwide). 80-90% are squamous, 15% are adenocarcinomas.
Risk factors: HPV 16/18 (most), low socioeconomic status, young age of first intercourse, multiple sexual partners, smoking, high risk male partner, HIV infection. Screening: Pap smear (cancer preceded by long-stand precursor lesions) once every 3 years after age 21, every 5 years after 30 if all negative, discontinued after 10 years normal or 65 Symptoms: discharge, bleeding (esp. post-coital), back/flank pain, hematuria, dysuria Diagnosis: Pap smear, colposcopy, biopsy, physical exam, chemistries. Also for metastasis: CXR, IV pyelogram, barium enema, sigmoidoscopy, cystoscopy Staging (clinical): (1) cervix only, (2) beyond cervix but not pelvic wall, (3) pelvic wall and lower vaginal 1/3 (3b may involve other organs) Tx: radical hysterectomy, chemo, radiatino |
|
|
Maternal adaptations to pregnancy
|
Maternal adaptations to pregnancy Metabolic: insulin resistant (from human placental lactogen-> glycosuria), increased lyposis & sensitivity to ketosis (from hPL)
Uterine: muscle fiber hypertrophy (at term 1100g, 5L, norm 70g), increased blood flow (vasodilation via estrogen/progesterone) Cervix: softening and ↑glandular activity (mucous plug/bloody show) Vagina & perineum: increased vascularity and hyperemia (chadwick sign –violet color), thick discharge (acidic pH), ↑ mucosal thickness, loosening of connective tissue, hypertrophy of smooth muscles Bone: relaxation of pelvic joints (pubic symphasis & sacroiliac) GI: normal motility until labor (then ↓--constipation), ↓ L. Eso sphincter tone (heartburn), hyperemic/soft gums (bleed), appendix displaced upwards, 20-40% ↑Fe absorption, nausea (hyperemesis gravidarum, “morning sickness”) Liver: size normal, double AlkPhos, ↓serum albumin, ↓LFTs, cholestasis (gallstones) Renal: ↑kidney size (dilation of pelvices, calyces, ureters nocturia, UTI/pyelonephritis, incontinence), 50% ↑RBF/GRF (↓srCr and BUN), water retention (↓pOsm—resetting of thirst/ADH thresholds, Pica) Heme: increased volume, dilutional anemia, hypercoagulability Endocrine: pituitary hypertrophy, thyroid gland enlargment (euthyroids), PTH increase in 2/3 trimesters, increase ACTH/aldosterone, hyperpigmentation Immune: suppression of T-helper and cytotoxic cells (improved autoimmune diseases, sensitivity to infection), increased IgA/G in cervical mucous, ↑CRP/SED Other: progressive lower back lordosis (pain), carpal tunnel, ↑corneal thickness, mental status changes (attention, concentration, memory, depression, sleep) |
|
|
Maternal steady states
|
Hypervolemic: 40-45% increase near term (1600-2500cc), dilutional anemia (↓HCT b/c more plasma than RBC increase—protective for labor blood losses), ↓viscosity, increased iron requirements. ↑RBF/GFR (↑urine production, renal dilation)
Hyperdynamic: ↑10bpm resting pulse, ↑CO (30-50%), ↑S1 splitting, systolic murmur, ↓PVR, ↓BP mid pregnancy (dizziness, syncope; increased in 3rd most HTN disorders), pelvic veins/IVC occluded by uterus (edema, varicose veins, hemorrhoids, DVT, supine hypotension), heart displaced Hypermetabolic: weight gain (300kcal/d, ↑central fat storage), ↑protein needs, insulin resistance (fasting hypoglycemia, postprandial hyperGly/Insulin), ↑lipolysis (LDL, HDL, cholesterol, sensitive to ketogenesis), increased temp, salt cravings/Pica, postpartum hairloss Hypercoagulable: ↑all clotting factors except II, V, XII (50% ↑fibrinogen), ↓platelets, ↓protein C/S. DVT/PE risk (esp. postpartum), DIC w/ bleeding Hyperventilation: normal RR, ↑tidal volume (minute respiration), ↓pulm resistance, respiratory alkalosis (transports CO2 from fetus to mother), ↑upper respiratory vascularization (stuffiness, nosebleeds, voice change, impaired hearing/ear fullness) Hyperpigmentation (from hormonal increase): linea nigra, melisma, stretch marks, angiomas/vascular spiders, palmar erythema |
|
|
Malignant ovarian neoplasms
|
By origin cell type 2/ tumor marker
Germ cell (oocytes): dysgerminoma (LDH) Extra embryonic tissue (from germ cell): trophoblast (choriocarcinoma, hCG), yolk sack (endodermal sinus tumor, AFP) Somatic tissue: embryonic (embryomal teratoma), adult (adult teratoma) Sex cord stroma: granulosa and theca cells (granulosa-theca cell tumor, estrogens), sertoli and leydig cells (sertioli-leydig cell tumor, androgens), fibroblasts (fibroma) |
|
|
Ovarian tumors associated w/ hormone secretion
|
Stuma ovarii: thyroid hormone
Ovarian carcinoid in a teratoma: serotonin-like substance (bilateral may be metastases from ileal carcinoid) Granulosa cell tumor: estrogens (rarely androgens), cause feminization Theca cell tumor: estrogens Sertoli-leydig cell tumor: sometimes androgens (from leydig cells), cause masculinization |
|
|
Meig’s syndrome
|
= acites + ipsilateral hydrothorax
- results from benign ovarian fibromas |
|
|
Struma ovarii
- cystic teratomas - resemble thyroid tissue, can secrete T4 |
|
|
Reinke crystals
3-20μm, no known function - a/w leydig cell tumor (or sertoli-leydig cell tumor) |
|
|
Call-exner body
- monotonous cells forming small rosettes - a/w granulosa cell tumor (germ cell tumor of the granulosa cells) |
|
|
Schiller-Duval body
- tumor cells arranged in a circle (glomerulus-like structures), forming papillae and a central empty space - a/w endodermal sinus tumor (germ cell tumor of the yolk sac, a/w AFP) |
|
|
Sertoli-Leydig cell tumor
= germ cell tumor of the stertoli/leydig cells of the testes - secrete androgens, so are masculinization (virilization, clitoromegaly, hirsutism) Micro: leydig cells are large w/ abundant cytoplasm and small nucleoli. Sertoli cells are elongated and luminal |
|
|
Theca cell tumor
= germ cell tumor of the theca cells - mostly benign, usually produce estrogens Gross: solid, yellow, not hemorrhagic or necrotic Micro: uniform cells |
|
|
Granulosa cell tumor
= germ cell tumor of the granulosa cells - usually produces estrogens (and rarely androgens), which may lead to endometrial cancer - malignancy shown by recurrence (>15y later, patients should be followed) Gross: solid, yellow, hemorrhagic Micro: contains call-exner bodies |
|
|
Fibroma
= germ cell tumor of the sex chord stroma fibroblasts - benign - a/w pleural effusions and ascites (Meig’s syndrome) - solid white, firm mass |
|
|
Teratoma
|
= germ cell tumor of somatic cells within the adult (after birth)
Types: Immature (solid, cystic or both) - neuroepithelial rosettes: embryonal brain tissue, hallmark of malignant immature teratoma - solid immature teratoma: high risk of malignancy, esp if necrotic Mature: - solid - cystic: mature cystic teratoma (usually benign/neural but some malignant/squamous). Most common germ cell tumor in females (10% bilateral) Composed of fetal tissue derived for 2 or 3 germ layers (can form skin, hair, bone, cartilage, gut, thyroid, etc). Torsion can cause vascular strangulation/infarction/necrosis - monodermal or high specialized: struma ovarii (mainly thyroid), carcinoid, both, others |
|
|
Embryonal cell carcinoma
|
= germ cell tumor of embryonal somatic cells
- aggressive, malignant tumor w/ early metastasis - seen in men in the early 20’s, prognosis better in recent years - not-radiosensitive, usually favorable response to chemo after orchiectomy - alpha feto-protein may be used as a tumor marker Macro: may appear hemorrhagic Micro: large primitive or epithelial cells, can be anaplastic (gland or sheet forming) |
|
|
Choriocarcinoma
|
= germ cell tumor of the trophoblasts
Types: both markedly hemorrhagic and can be monitored by hCG Gestational (a/w pregnancy): good prognosis, methotrexate sensitive Nongestational (a/w germ cells): worse prognosis, not methotrexate sensitive - malignany tumor composed of trophoblasts and syncytiotrophoblasts; mimics placental tissue but villi are absent - has early hematogenous spread |
|
|
Choriocarcinoma
|
= germ cell tumor of the trophoblasts
Types: both markedly hemorrhagic and can be monitored by hCG Gestational (a/w pregnancy): good prognosis, methotrexate sensitive Nongestational (a/w germ cells): worse prognosis, not methotrexate sensitive - malignany tumor composed of trophoblasts and syncytiotrophoblasts; mimics placental tissue but villi are absent - has early hematogenous spread |
|
|
Endodermal sinus tumor
|
= tumor of the yolk sac (germ cell)
- most common germ cell tumor in children, common in young women, common testicular tumor in young men - monitored by serum AFP - malignant tumor controlled by surgery, radiation, chemo Gross: soft, yellow, hemorrhagic and necrotic tumor (mimics the yolk sac) Micro: schiller-duval bodies, globules containing AFP |
|
|
Dysgerminoma
|
= cancer of the germ cell (oocytes –testicular counterpart is the seminoma)
- most common malignant germ cell tumor, <1% of all ovarian tumors (most are epithelial) - present in young adulthood/adolescence, good prognosis, responds to radio therapy - serum LDH may be elevated (tumor marker) Gross: solid, yellow, lobular tumor Micro: big, hypercrhomatic nuclei, clear cytoplasm |
|
|
Medullary thyroid carcinoma
|
= neuroendocrine neoplasm arising from parafollicular C-cells
Epi: sporadic and familial (assoc. w/ MEN2a/b syndromes) Manifestations: ectopic hormone production (calcitonin, others) Histo: see amyloid deposition, positive chromagranin stain, hyperplasia of follicular cells, neurosecretory granules on EM |
|
|
Follicular thyroid carcinoma
|
= second most common thyroid carcinoma (10-20%)
Epi: F>M, occurs in middle aged adults - favorable prognosis (91% at 5ys), slightly more aggressive than papillary but usually minimally invasive - typically involves progression from adenoma involving Ras mutation, can progress to anaplastic carcinoma w/ p53 mutations Histology: transcapsular blood vessel invasion (allows for hematogenous metastasis) |
|
|
Papillary thyroid carcinoma
|
= most common thyroid carcinoma (75-80%)
Epi: F>M, usually young-middle aged adults, occurs sporadically w/ history of radiation exposure - slow growing w/ good prognosis 95-7% 5y survival - typically involves RER mutations in normal follicular cells, can progress to anaplastic lesion w/ p53 mutations Histology: finger-like projections (malignant fibrovascular cores lined w/ epithelial cells), orphan annie eye nuclear inclusions (appear empty), psammoma bodies (calcified structures in infarcted papillae), lymph node infiltration (lateral aberrant thyroid). May have follicular variant |
|
|
Hashimoto’s Thyroiditis
|
= autoimmune/lymphoctic thyroiditis causing destruction of thyroid tissue, most common cause of hypothyroidism in adults (prevalence <1%)
Risks: F>M, family history, other autoimmune history (RA, connective tissue diseases). May predispose thyroid carcinoma or lymphoma Presentation: hypothyroidism (↑TSH), goiter or in late stages atrophic thyroiditis Pathogenesis: thought o involve deficiency in suppressor T cells leading to immunological abnormalities and autoimmune stimulation of B cells Autobodies: antimicrosomal Ab, antithyroglobulin Ab, anti-TSH receptor Ab, blocking Abs. Gross: bumpy thyroid (early) with white/yellow/cream appearance due to lymphocytic/inflammatory infiltrate Micro: lymphocytic & plasma cell infiltration, reactive follicular centers, destruction of thyroid follicles, germinal centers develop into fibrotic Hurthle cells (eosinophilic, granualar, lots of mitochondira--indicate advanced disease or rare subtype of follicular adenoma and carcinoma) |
|
|
Normal thyroid tissue: cuboidal or flat epithelium surround colloid reservoirs of thyroid hormone (bound to thyroglobulin). Scoops out go the colloid represent phagocytosis.
The normal thyroid begins that the thyroid cartilage and extends to the 5th or 6th tracheal rings |
|
|
Grave’s Disease
|
= autoimmune hyperthyroidism
Epi: most common cause of spontaneous hyperthyroidism in people <40y (80%), F>M, familial clustering Pathogenesis: TSIgG (thyroid stimulating IgG) is produced, activating TSH receptor and causing over production of T3/T4 (TSH will be low to compensate, and measure high TSIgG directly) Symptoms: exophthalmos (due to fullness of retro-orbital tissue), diffuse goiter, pretibial myxedema (rare dermal infiltration w/ mucopolysaccharides), onycholysis (fragile nails→ decresed protein turnover) Rx: anti-thyroid drugs (PTU, methimazole), surgical resection, radioiodine ablation |
|
|
Pituitary Apoplexy
|
= pituitary adenoma infarction
- slowly growing, asymptomatic adenoma gets large and bulky and occludes its blood supply causing infarction and death. It then expands rapidly Causes very severe headache, visual disturbance/loss (if impinging the optic chiasm) Medical emergency, will usually find sellar/suprasellar mass and associated symptoms on evaluation |
|
|
Patterns of adenomatous growth
|
A. Sheet: pink cytoplasmic coloration, loss of glandular structure
B. Neurocytic rosettes: form around vessels C. Papillary: columnar or cuboidal cells grow on a fine fibrovascularstalk D. Ribbon: grows around vessels Cannot determine type of adenoma based on growth pattern, have to use immunohistochemistry |
|
|
Pituitary Pathology
|
Posterior:
- neutrophil: meshwork of axonal processes - pituicytes: glial cells involved in regulation and release of neurohormones to the perivascular space. Envelope the nerve terminals from the hypothalamus - herring bodies: storage compartments along the axon filled with neurosecretory granules (look like pinks smudges) Anterior - acinar/glandular structure w/ multiple types of secretory cells (different funtions/color) over basement membrane - highly vascularized to carry hormones to systemic circulation Intermediate lobe: - cystic structures with mucinous secretions (not forming glandular structures). If get larger and displaced can give rise to Rathke’s cleft cysts. Can undergo neoplastic conversion to craniopharyngeoma |
|
|
OCP mechanism
|
= hormonal regulation of the menstrual cycle that takes advantage of the inhibitor effects of E2/P on the H/P/O axis to prevent theLH/FSH surge required for ovulation
Progestin: - thickens cervical mucus (impedes sperm), prevents LH surge and ovulation, endometrial changes (more difficult to implant), decreased fallopian tube motility (↓movement of egg to sperm) - variable half-life as medication (endogenous progesterone has T1/2 of 5min) - side effects: can stimulate glucocorticoid and androgen/estrogen receptors (help w/ acne), can stimualte mineralocorticoid receptor (↓Na retention), depressive/hypnotic effect on the brain Dosing: excess (increased appetite, weight gain, acne, depression), deficiency (late breakthrough bleeding) Estrogen/Estradiol: - inhibits FSH (prevents ovulation, potentiates P inhibition of LH but also enhances LH), stabilizes endometrium to minimize irregular shedding, - Side effects: stimulates development of secondary sex characteristics (altered fat distribution, axillary/pubic hair), continuous used can cause endometrial hyperplasia and abnormal bleeding, ↓ bone resorption (osteo-protective), improved lipid profile (↑HDL, ↓LDL), ↑TAG synthesis and ↓oxidation of adipose (weight gain), hypercoagulability (↑ factors II,VII,IX,X), altered libido (neural receptors), fluid shifts (edema) Dosing: excess (nausea, HTN, migrane, breast tenderness, edema), deficiency (early or midcycle breakthrough bleeding) |
|
|
Contraceptive options
|
E/P
Monophasic: most common, >50 versions on the market w/ different estrogen/progesterone ratios Biphasics: 5 versions, 2 E/P ratios Triphasics: 10 versiosn, 3 E/P ratios, can also vary in dose lengths Seasonal “Seasonque”: monophasic w/ fixed E/P ratio, menstruation every 84 days Lybrel: continuous use, fixed E/P, no regular menstruation (many women have breakthrough) Progestin only: continuous use (multiple progestins used), lower dose than OCP, slightly higher rates of failure and menstrual disturbances Uterine IUD: changes environment to inhibit sperm and implantation, may also have hormones, can be used as emergency contraceptive Estrogen only: not used b/c a/w endometrial caner |
|
|
Risks/Benefits of hormonal OCPs
|
Risks:
↑ risk of DVT & PE (estrogen ↑ coagulability) ↑ risk of stroke & MI, esp in patients >35 who smoke heavily (clotting increases these risks) Facilitate growth of hormone sensitive tumors Can shut off lactation after pregnancy (P has negative feedback on PRL) Small risk of pregnancy (estimated 99% efficacy, in practice 92%) Benefits ↓risk of endometrial, ovarian, and colorectal cancer (ovulatory rest—less chance to accumulate mutations) Improvements in dysmenorrhea (regular cycles), anemia (less blood loss), acne (interaction w/ androgen receptors) ↓ PID (mechanism unknown) ↓ breast and ovarian cysts (reduced ovulation) Improved lipid profile |
|
|
Post-coital birth control
|
Plan B:
- high dose of progestin delays or prevents ovulation, induces endometrial changes - bust be taken ASAP, but w/in 72hrs - not effective if already pregnant reduces pregnancy by 89% - available OTC for >17yo Ella: - progesterone receptor modulator delays or prevents ovulation/follicle rupture for 5 days. Also induces endometrial changes - single dose within 5 days (not effective if egg implanted) - Rx only (approved 2010) |
|
|
Mifepristone
|
= competitive antagonist of progesterone and glucocorticoid receptors
Indications: contraceptive (blocks ovulation), abortive/induction of labor (causes endometrial shedding), anti-cancer Mechanism: inhibits progesterone binding, which is necessary to maintain pregnancy. If given <49 days after LMP (w/ prostaglandin analog/Misoprostol) causes endometrial shedding |
|
|
Clomophene
|
= estrogen receptor antagonist
Indications: treatment of infertility due to anovulation (induction of ovulation), Mechanism: blocking estrogen receptor at higher brain levels inhibits negative feedback, inducing LH surge and ovulation, increasing chance of pregnancy Dosing: 2-6 days at beginning of cycle (LH surge will occur 5-10 days later) Success: 60-75% in first 6mo, after that prognosis of pregnancy decreases Side effects: multiple births, ovarian cysts (affects follicular development), can effect cervical mucus at higher doses (affecting ability to get pregnant) |
|
|
DECISION model for pregnancy counseling
|
Determine reason for the visit
Evaluate feelings about test result Confirm the result Identify personal circumstances discuss Support services address Immediate questions Offer a timeline Next steps |
|
|
Medical abortion
|
Medications: mifepristone (competitive progesterone/glucocorticoid receptor antagonist) and misoprostol (prostaglandin E1 analog)
Mechanism: together cause desidual necrosis and detachment of trophoblast from the uterus and induction of uterine contraction (misoprostol) and cervical ripening. Net is detachment and expulsion of the placenta from the uterus. Dosing regimens: - FDA approved: 600 Mife/400miso, up to 49 days, follow up 14 days - Evidence based: 200 mife/800miso, up to 63 days, follow up 4-8 days Benefits: non-invasive, occurs at home, seems more natural, avoids anesthesia Disadvantages: may have prolonged bleeding and cramps, requires 2+ visits, must be done sooner, requires active patient participation |
|
|
Aspiration abortion
|
Procedure: local anesthesia, cervical dilation to open the os, a cannula is attached to a syringe and advanced into the surgical fundus. When the uterus is reached the suction is turned on and the cannula moved back and forth and rotated to ensure evacuation of the uterus (until there is no more tissue entering the syringe)
Benefits: 1 visit (complete on the same day), available in second trimester, follow-up usually unnecessary, passive participation Disadvantages: invasive, must be done in medical setting |
|
|
HPV
|
Epi: most common STI in the US, most common cause of gyn cancer worldwide. Lifetime risk of cervical cancer w/o screening is 2-4%
Strains: - non-oncogenic/low risk (HPV 6,11): cause benign or low-grade abnormalities of cervical cells, anogentital warts, and recurrent respiratory papillomatosis - oncogenic/high-risk (HPV 16,18): can cause intraepithelial neoplasia of the agonetial region, including cervical, vulvar, vaginal, penile, and anal cancers as well as oropharyngeal cancers. Genome: 8-10 genes (E: early viral cycle, L: late viral cycle). E6 and E7 (HPV16), encode oncoproteins that bind and degrade p53 and retinoblastoma (pRb) tumor suppressor (respectively) resulting in cell immortalization and resistance to terminal differentiation Pathogenesis: HPV infects epithelial cells in transformation zone (junction of squamous/columnar epithelium—cervix, anus, tonsils). Does not spread hematogenously between sites Progression: Initial infection (18-24mo)→ clearance, carcinoma insitu grade 1 (→clearance or continuing infection), continuing infection (0-5y) → CIN 2/3 (→may clear) 1-20y → invasive cervical cancer Vaccinate at age 11-26 (HPV2—not in boys or HPV4), pap smear every 3 years at 21, cannot r/o cancer |
|
|
HTN in pregnancy
|
Normal BP in pregnancy: declines until about 18wks due to decreasing peripheral vascular resistance (increased venous capacitance and vascular size) while blood volume and CO increase
HTN pregnancy is abnormal but common (12-22%) Preeclampsia: HTN during pregnancy w/ proteinuria, 6-8% in all live births, 17.6% of maternal deaths in US. Risk factors: young/old maternal age, first delivery, chronic HTN (20-50% risk), vascular disease, diabetes, history of HTN in pregnancy, minority status (Hispanic, AA) |
|
|
Categories of hypertensive disorders in pregnancy
|
Chronic hypertension:
- BP >140/90 predating pregnancy (>20wk before gestation—complications of HTN in pregnancy don’t usually present then) or HTN that develops in second 20wks of pregnancy and persists >12wks post gestation Gestational Hypertension - gestational HTN: BP >140/90 occurring after 20wks w/o proteinuria (determined on 24h urine) Preeclampsia: - gestational HTN and proteinuria - Mild: >140/90 & >300mg/24hrs. Severe: >160/110 AND >5g (or >3+ in 2 random). Chronic HTN + preeclampsia superimposed Atypical preeclampsia: presents as eclampsia w/o progression from gestational HTN (20% of the time), Just vague RUQ or epigastric discomfort, fatigue and slight headache. May have thrombocytopenia |
|
|
Preeclampsia
|
= gestational hypertension and proteinuria
Pathogenesis: unknown but placental etiology. When placenta forms inadequate trophoblast invasion →insufficient spiral arteries of the uterus. Also/or immunologic, circulating toxins, DIC, endothelial damage can occur causing vasoconstriction/spasim. Findings include loss of angiotensin resistance: increased sFlt1 receptor and VEGF – PlatGF Types: - mild: BP >140/90 and >300mg/24hr - severe: one or more: >160 sys or >110 diasys x2 while on bedrest, OR proteinuria >5g/24hrs or >3+ at 2 random samples - HELLP Syndrome: hemolysis + elevated LFTs + low platelets. Risk for DIC, liver hematoma, and liver failure - other severity criteria: oligouria (<500mL/24hrs), cerebral or visual disturbance, headache, pulmonary edema or cyanosis, epigastric to RUQ pain, N/V, impaired liver fx, thrombocytopenia (platelets <100K), fetal growth restriction Signs: swollen face and nose, edema (not specific), sudden weight gain, seizures Fetal risks: growth restriction, oligohydramnios (↓amniotic fluid, ↓urine from ↓fRBF), placental infarction and abruption, consequences of premature delivery (50% survival @ 24wks), uteroplacental insufficiency (small babies), perinatal death/stillbirth Maternal risks: CNS problems (seizure/stroke), DIC, thrombocytopenia and hemolysis, renal failure, hepatic failure and rupture (hematomas), eclampsia (preeclampsia + grand mal seizure –treat w/ MgSO4, antiHTNs), death Management: manage as appropriate, if severe preterm cesarean/placental removal. If <32 wks, prepare fetus with antenatal steroids and stabilize mother for 48hrs then deliver. For HELLP syndrome mother must be delivered—only treatment |
|
|
GP000 nomenclature
|
G: # of gestations
P1: full term deliveries P2: preterm deliveries (<37w) P3: any loss <20w P4: children currently alive |
|
|
Miscarriage
|
= “spontaneous abortion”
- 50% of first trimester bleeding, marked by absent hCG - causes: any significant fetal defect leading to spontaneous termination (mostly chromosomal: aneuploidy, monoploidy) - don’t require treatment - Types: threatened (blood + closed cervix), inevitable (blood + open cervix), missed (no fetal heartbeat but no symptoms), incomplete (some tissue remains), complete (empty uterus) |
|
|
Causes of bleeding during pregnancy
|
First trimester (25% of pregnancies)
- miscarriage (50%) - ectopic pregnancy Second trimester - cervical insufficiency (short cervix, can’t hold pregnancy in) - miscarriage - preterm labor Third trimester (6% of pregnancies) - preterm labor (50%) - placental abruption (15%) – detachment from uterine wall - placental previa (10%) – attachment close to or touching the cervix - vasa previa (fetal vessel across the os, at risk for rupture) - uterine rupture Postpartum: (5%) - normal vaginal losses 500cc, normal C-section losses 1000cc, mostly due to separation of placenta (occurs prior to uterine involution and coagulation/thrombus formation) - uterine atony (lack of uterine involution/clamping down, will feel boggy): usually high parity, over distention, long or rapid labor, prolonged use of induction agents, chorioamnionitis, obstructed labor - genital lacerations: large baby, compound presentation, episiotomy, operative delivery, rapid/uncontrolled labor - retained placental fragments (prevent uterine involution): prior C-section, prior surgery - coagulation disorders |
|
|
Ectopic pregnancy
|
= implantation of the embryo outside of the uterus (
- Locations: tubal 95-96% (isthmus is least favorable b/c least distensible, most occur in ampulla—70%), ovaries (3%), abdominal (1%), cervical (<1%), cesarean scar (<1%) Prevelance: 1-2% of pregnancies Risk factors: prior ectopic pregnancy, PID (damages lining of tube), IUD, prior surgery (causing adhesions), endometriosis (implantation in tissue outside the uterus), chlamydia Complications: desidual cast (necrotic, membranous uterine tissue w/o chorionic villi expelled from vagina), Arias-stella reaction (enlargement of endometrial glands), hematosalpinx (ruptured/hemorrhagic fallopian tube), placenta and products of conception outside uterus - Rupture of the tube/uterus can lead to 10% mortality due to hypotensive shock and bleeding into the abdomen. Usually around 4-6w. Can cause infertility and chronic pain Dx: r/o with hCG and transvaginal ultrasound. If hGC>1500 a gestational sac should be visible indicating normal pregnancy. If hCG is 1400, wait 48hrs and hCG should rise by 66% (and sac should be visible). If ectopic hCG will not increase as expected Treatment: - unstable (tachycardic, hypotensive, blood inabdomen) → laproscopy - stable and hCG <5000, treat with methotrexate to abort pregnancy |
|
|
Placental abruption
|
= detachment of the placenta from the uterine wall, blood then collects behind the placenta
Incidence: 1:120 deliveries, causes 15% of 3rd trimester bleeding Complications: abnormal fetal heart sound and death (if insufficient O2 is transfused through placenta), maternal pain and bleeding (30% occult/within uterus, cervical blood is dark), induction of contractions (blood is irritant) Risk factors: trauma, smoking, cocaine (↑BP can cause it), multiparity, HTN/preeclampsia, prior abruption, advanced maternal age Diagnosis: usually clinical, US not helpful as cannot r/o abruption but occasionally can show blood clots |
|
|
Placental previa
|
= attachment of the placenta is close to or obstructing the internal cervical os
Incidence: 0.5% of pregnancies, cause 10% of 3rd trimester bleeding Symptoms: bleeding is painless, initially w/o contractions, blood is fresh/bright red, fetal heart sounds are normal (placenta still intact) Risk factors: multiparity (twins = large placenta), prior cesarean, prior D&C, smoking, prior previa, advanced age Dx: use US to r/o previa, do not do cervical exam |
|
|
Chronic pelvic pain
|
= non-cyclical pain for >6mo
Epi: >15% of reproductive age women, 40% of laparoscopies and 18% of hysterectomies are for this, these women have higher rates of abuse (screen for mental health), 70% are multi-causal Etiologies: IBS, endometriosis, internal cystitis, pelvic adhesions, vulvodynia, chronic constipation, myofasical pain Workup: description of pain quality, menstrual/sexual/STD/gestational hx, pap w/ cultures, bimanual and rectovaginal exams (pinpoint source of pain). Treatment: (little guiding evidence): NSAIDs, tricyclic antidepressants, OCPs or GnRH agonists, surgical procedures |
|
|
Dysmenorrhea
|
= painful menstruation
Epi: 50% of menstruating women, 5-10% severe enough to interfere w/ daily activities Risk factors: young age, low BMI, smoking, early menarche, longer/heavier menstrual cycles, nulliparity Symptoms: lower abdominal cramping and pain radiation to back and legs, may have GI and neuro symptoms (malaise) Primary: - no pelvic pathology, more common, usually appears 1-2mo after menarche. - Due to increase endometrial prostaglandin (PGF2, PGE2) production in luteal phase, which increases uterine tone and decreases blood flow (vasoconstriction) causing ischemic pain. - Pain begins just prior to cycle, lasts 48-72hrs, is colicky and may radiate. May be a/w N/V, diarrhea, and syncope - Tx: prostaglandin synthase inhibitors or NSAIDs prior to onset of pain, OCPs (suppress endometrial proliferation), if failed then narcotics and surgery (nerve stimulation/ablation/excision) Secondary: - underlying pelvic pathology (dx by PE + US/Lapar/hyster), occurs years after menarche, pain occurs 3-5d before cycle, may also have dyspareunia, menorrhagia, fever - Etiologies: endometriosis, adenomyosis, fibroid uterus, congenital uterine anomalies trapping flow, cervical stones, endometrial polyp, PID, IUD, pelvic adhesions Tx: NSAIDs/OCPs unhelpful, treat underlying cause |
|
|
Endometriosis
|
= non-neoplastic endometrial outgrowth (containing both glands and stroma) found outside the uterus. Most commonly ovaries, uterine ligaments, rectovaginal septum, and cul-de sac, but also outside pelvis or in myometrium (adenomyosis)
Risks: FHx (8x increase), retrograde menstruation, flow obstruction, obesity, decreased peripheral estrogen (exercise, smoking) Pathogenesis (unclear): retrograde menstruation through fallopian tubes spreads endometrial tissue to the peritoneal cavity Complications: dysmenorrhea, dyspareunia, pelvic pain, periuterine adhesions, infertility, blood clots and “chocolate cysts” (from bleeding). If in the brain—seizures, if in the lung—collapse and pain Dx: PE, laparoscopy (gold standard), US, Ca-125 (not specific) Tx: OCPs, depot medroxyperogesterone acetate, NSAIDs, GnRH analogs (Lupron, expensive, can cause menopausal state--osteoporosis), surgical destruction of lesions, presacral neurectomy, and hysterectomy |
|
|
Gonococcal infection
|
Etiologies
Vaginal: bartholinitis (bartholin gland infection), purulent discharge Skin: septic vasculitis, gonococcal pustules Minor salivary glands: oral pharyngitis (manifests by swelling and redness of the glands of the mouth) Joint synovium: monoarticular arthritis (always suspect in young, sexually active patients with single joint arthritis) Neonate conjunctiva: conjunctivitis, can lead to blindness if not treated Diagnosis: - smear: purulent exudate from infected site, look for intracellular gram negative diplococci - Culture: blood agar plate, sensitivity testing |
|
|
Pelvic inflammatory disease
|
= infection of the upper reproductive tract organs (also called acute salpingitis—fallopian infection). Many organs may be involved (w/ or w/o abscess formation), but fallopian tube most important
Epi: difficult to diagnosis to true incidence is unknown, chlamydia is most common cause of tubal factor infertility - most common organsims: gonococci (Neisseria gonorrhoeae), chlamydia (chlamydia trachomatis), bacterial vaginosis, others: mycoplasma, anaerobes, herpes, actinomyces, mycobacteria (TB) Presentation: asymptomatic or mild, lower abdrominal pain, uterine or adnexal or cervical motion tenderness Complications: - pelvic abscesses: pus between uterus and rectum causing generalized inflammation that can lead to adhesions to nearby organs - tubo-ovarian abscesses: usually polymicrobial (or post actinomyces or mycoplasma infection), present w/ lower abdominal pain w/ unilateral or bilateral adnexal masses - pyosalpinx: dilated fallopian tube filled with pus - hydrosalpinx: dilated fallopian tube with fluid filled cyst which compresses normal papillary folds into broad, thickened papillary structures. - infertility or extopic pregnancy |
|
|
Selective estrogen and progesterone receptor modifiers
|
= agents that selectively mimic the effect of estrogen/progesterone in different tissues, depending the inducible conformation of receptors, the different receptors available in tissues, the availability of co-regulators
Tamoxifen: (SERM) - used in breast cancer treatment and prevention of ER positive breast tumors. - antagonizes breast tissue, agonizes vessels, bone, and uterine tissue: lowers circulating cholesterol, helps maintain bone density, can cause endometrial cancer Raloxifene: (SERM) - used to prevent post-menopausal osteoporosis, - antagonizes beast and endometrial tissue, agonizes bone and vessels: reduces cancer risk, maintains bone density (reduces fractures), lowers circulating cholesterol Ella (ulipristal acetate): (SPRM) - used as an emergency contraceptive for up to 5 days after unprotected sex - antagonizes progesterone in ovaries and endometrium: prevents follicle rupture, delays endometrial maturation |
|
|
Factors contributing to teratogenesis
|
1. Ability to get across placental barrier: high lipid solubility, low molecular weight, low plasma protein binding, placental metabolism (activating)
2. developmental stage of the fetus: cells undergoing division and differentiation, key steps in morphogenesis (varies by organ system), generally weeks 3-8 3. Dose of agent: amount taken by mother and delivered to fetus, metabolism/excretion rates, generally prolonged is worse (hits more susceptible periods of morphogenesis) 4. individual target by the teratogen: species (different organogenesis, placental transport, drug metabolism), genetic of mother and fetus 5. action of agent: ex: thalidomide causes loss of immature blood vessels in limbs IN breast milk: basically the same except for ion trapping in the alveolar spaces (weak bases are worse), lipophilic can bind milk fats, low protein binding, long t1/2 or sustained release, anti-proliferative are universally bad |
|
|
Use-in-Pregnancy rating
|
Category A: controlled studies show no risk—no risk in 1st trimester, no evidence of later risk
Category B: No evidence of risk in humans – animal reproduction studies show no risk Category C: Risk cannot be ruled out—animal studies show risk, but potential benefits outweigh Category D: Positive evidence of risk—human studies show risk, but benefits outweigh Category X: Contraindicated in pregnancy—human and animal studies show risk which clearly outweighs benefit |
|
|
Tubular carcinoma
|
= carcinoma of the terminal ductules
- result in increased incidence in cancer in the opposite breast (10-40%) - tend to ER/PR positive, HER2/neu negative Histo: small, resemble tubes |
|
|
Infectious causes of genital ulcers
|
Syphilis: typically painless. medium, superficial, well demarcated, elevated edge, circular/oval. Firm induration.
- 2-4w incubation, bilateral nontender lymphadenopathy - test ulcer exudate, serum: darkfield microscopy, treponemal test Herpes: circular, small, superficial, smooth. No induration, exquisite pain - 2-7d, bilateral tender lymphadenopathy, - test scrapings from ulcer base: tissue culture/PCR/antigen (HSV1/2) Chlamydia/lymphogranuloma venereum: elevated edge, variable depth, sm/med, round/oval. +/-pain. Occasionally firm induration - 3-42d, unilateral large, tender lymphadenopathy - test aspirate from bubo or ulcer base swap: culture, genotyping Chancroid: irregular/ragged edge, deep, sm/lrg. Soft induration +/- pain - 1-14d, unilateral tender (can suppurate) lymphadenopathy - test ulcer base swab, aspirate from bubo: semiselective growth media Granulama inguinale: irregular shape, elevated edge w/ beefy base, sm/lrg. Firm induration, painless - 8-80d, pseudobuboes, regional lymph w/ superinfection - teset crush preparation from lesion: giemsa or wright stain for Donovan bodies |
|
|
Adrenal glands
|
Adrenal cortex:
- mesodermal origin, 90% 0f adrenal weight, yellow/tan color (cholesterols for steroid synthesis) - Zones: glomerulosa (mineralcoricoids), fasciculate (glucocorticoids), reticularis (sex hormones) Adrenal medulla: - neural crest origin (sympathetic paraganglia), 10% of weight, central, grey - secretes: catecholamines (Epi, NE→ metabolized to metanephrine and vanillylmandelic acid (VMA) |
|
|
Etiologies of primary adrenal insufficiency
|
= impaired function of the adrenals due to local defect/damage (chronic insufficiency is Addison’s)
Autoimmune disease (most common, 65%): polyendocrinopathies, isolated autoimmune adrenalitis: see lymphocytosis and neutropenia on histology Tuberculosis (20%): M>F, disease severity correlates to involvement Adrenoleukodystrophy (10%): metabolic disorder of peroxisomes (ABCD1 gene) causing v. long chain FA accumulation Hereditary or idiopathic causes (5%): - Congenital adrenal hyperplasia (Adrenogenital syndrome): Autorecessive, enzyme deficiency causes hypocortisolism, lack of feedback → ↑ACTH → adrenocortical hyperplasia and diffuse skin pigmentation - Waterhouse-Friderichen syndrome: acute hemorrhagic necrosis of the adrenal glands - ACTH resistance Other infection: fungal, HIV/AIDS, MAI, CMV Metastasis: lead to thrombosis Infiltrative: amyloidosis, sarcoidosis, hemochromatosis Iatrogenic: adrenalectomy, inhibitors of steroid synthesis, stimulators of cortisol catabolism, repeated use of Mifepristone (GC receptor blocker) Secondary: iatrogenic (glucocorticoids), hypothalamic/pituitary diseases (tumor, infarction), infiltrative diseases, trauma, rare hereditary diseases |
|
|
Clinical findings of Cushing syndrome
|
= hypercortisolism of any etiology
Clinical findings: - metabolic: weight gain (due to hyperinsulinism: ↑fat storage, ↑Na retention)—moon facies, buffalo hump, truncal/central visceral obesity - endocrine: hirsuitism (↑androgens), glucose intolerance/ T2DM (hyperinsulinism), also ↑LH/FSH/TSH can occur in response to ↑GCC - cardio/renal: diastolic HTN (↑GCCs bind ald receptor, NOT aldosterone), glaucoma, cardiomegaly, atherosclerosis, renal stones (hypercalcuria) - SMBJ: muscle weakness (cortisol → protein catabolism), purple abdominal stria (cortisol weakens collagen →blood vessel rupture), osteoporosis (↓bone formation), acne (GCC excess, hyperandrogenism), reduced linear growth - GI: peptic ulcers, increased appetite - immune: suppression, anti-inflammatory action - Neuro/psych: depression, psychosis Dx: w/ labs, urine, saliary cortisol, symptoms, radiology Tx: excision/ablsatoin, steroid synthesis inhibitors, GCC receptor antagnonists,CRF inhibtors (prevent ACTH release) |
|
|
Etiologies of Cushing syndrome
|
Iatrogenic (most common): prolonged corticosteroid therapy
Anterior pituitary adenoma (2nd most common): produces ACTH, classic Cushing’s Disease (still susceptible to feedback inhibition—dexamethasone test) Primary adrenal: markedly ↓ACTH (gland atrophy) and ↑cortisol, cause Cushing Syndrome (won’t suppress from dexamethasone) - adrenocortical adenoma (adults) - adrenocortical carcinoma (children) - micronodular hyperplasia: hyperpigmented, bilateral nodules. Young/adolescent women - familial hypersecretion of gastric inhibitory peptide (GIP) (and other regulatory hormones): excess food-dependent release of cortisol Ectopic ACTH: paraneoplastic ACTH secretion, markedly ↑ACTH and cortisol - SCC of lung (50%) - bronchial carcinoid - ovarian, thymus or thyroid tumors |
|
|
Clinical features of adrenal insufficiency
|
Primary: adrenal origin, ↑ACTH, not responsive to shor or long cosyntropin stimulation test
- general: weakness, fatigue, weight loss - renal: *hyperkalemia (no aldosterone production), hyponatremia, hypercalcemia - GI: nausea, anorexia, diarrhea, weight loss - cardio: postural hypotension - SMBJ: *hyperpigmentation (ACTH stimulation of melanocytes), *vitiligo (autoimmune), myalgia, arthralgia - *adrenal calcification (TB, fungal) Secondary: pituitary, ↓ACTH, small response to short cosyntropin test (<18mg/dL cortisol, due to gland atrophy), high response to long cosyntropin test (>3d) - general: weakness, fatigue, anorexia, weight loss - renal: hyponatremia, hypercalcemia - GI: nausea, diarrhea - SMBJ: myalgia, arthralgia Dx: short/long cosyntropin test, Tx: hormone replacement (GCC and MCC if primary) w/ stress doses (surgery, fever, Addisonian crisis) |
|
|
Cushing’s Disease
|
= anterior pituitary adenoma secreting ACTH causing adrenal hyperfunction (Cushing syndrome)
Epi: most common non-iatrogenic cause of Cushing syndrome (60%), F:M 5:1 - mostly microadenomas (85%) because are picked up early due to clinical syndromes - Will be sensitive to dexamethasone suppression test, because tumor is still susceptible to feedback—just has a new high set point (requires more cortisol to shut off) |
|
|
Autoimmune polyglandular syndrome
|
Type 1:
- autosomal recessive, childhood onset, no HLA association - genetics/antibodies: AIRE gene mutation, anti- 17α hydroxylase and L-amino acid decarboxylase - glands involved: mucocutaneous candidiasis (75%, due to immune deficiency), adrenal insufficiency/Addison's (60%), parathyroid insufficiency (89%, low Ca). Others: gonad (45%), thyroid (12%), pancreas (diabetes, 1%), pituitary (rare) - Assoc. AI conditions: pernicious anemia (16%), vitiligo (4%), alopecia (20%), malabsorption (25%), chronic active hepatitis (9%) Type II: - autosomal dominant (50% familial), adult onset, HLA B8 (DW3), DR3 and DR4 associations - Genetics: unknown gene, some linkage to 2q33 - Glands involved: adrenal is requisite for dx, otherwise no particular sequence, but adults don’t get candidiasis or parathyroid involvement. Other glands: thyroid (70%), pancreas/diabetes (50%), gonad (5-50%), pituitary (rare) - Assoc. AI conditions: vitiligo (5%), others rare |
|
|
Antidiuretic hormone/vasopressin
|
- synthesized in hypothalamus, transported along axons with neurophysins, stored in pituitary
- actions: controls rate of free water excretion (renal) by increasing H20 permeability of cortical and medullary collecting ducts. Net: ↑H2O reabsorption, ↑plasma volume, ↓serum Osm - receptors: V1 (vasoconstriction and ↑prostaglandin production), V2 (antidiuresis, ↑factor VIII and vWF from vascular endothelium), V3/1b (pituitary release of ACTH) - regulation: SrOsm >295mOsm/kg, also >10% decrease in plasma volume Disorders: - deficiency/resistance: Diabetes insipidus (free water loss >2.5-3L/d), maybe central (ADH responsive) or nephrogenic (not ADH responsive) or primary polydipsia - overproduction: SIADH (H2O retention and hyponatremia/hypoosmolality despite euvolemia) |
|
|
Etiologies of Secondary hypertension
|
= hypertension caused by an underlying condition
Etiologies: Pheochromocytoma: excessive cateholamine secretion stimulates α/β receptors throughout the body, increasing BP, HR, contractility. Can ultimately cause heart disease, stroke Hyperaldosteronism: (most common) ↑aldosterone results in salt/water retention and renin suppression causing hypervolemia and hypertension - Conn’s syndrome: aldosterone producing adenoma - deoxycorticosterone (DOC) excesses: increased in 11β-hydroxylase deficiency (minor MCC but effective in excess) - Liddle’s syndrome (“pseudohyperaldosteronism”): constitutive opening of amilioride sensitive Na channels increasing Na resorption - glucocorticoid-remediable aldosteronism (familial hyperaldosteronism type1): autodom activation of aldosterone synthase (promoter region translocation) resulting in continued synthesis Syndrome of apparent mineralocorticiod excess (AME): autorecess mutation of 11β-HSD2 converting cortisol →cortisone, excess cortisol can bind MCC receptors Licorice ingestion: glycyrrhizinic acid inhibits 11β-HSD2 resulting in excess cortisol → HTN |
|
|
Diagnosis and management of secondary hypertension
|
Clinical clues:
- HTN is resistant: BP> 140/90 (130/80 in DM or renal disease) despite regimen of 3 antihypertensives, incl diuretic - onset is sudden usually age <30 or >55 Etiology specific clues: - pheochromocytoma: <30 onset, labile or paroxysmal HTN, triad of headache, perspiration, and palpitations (also retinopathy, fine tremors, fever, polyuria, polydipsia, abdominal and chest pain). Labs: high urinary/plasma catecholamines and metabolites, elevated BG, renin, pancreatic liver and cardiac enzymes, lactic acidosis - Conn’s: high aldosterone/renin ratio (normal <20, >40 suggestive, >100 diagnostic). Labs: hypokalemia, alkalosis, kaliuresis. Check salt suppression of aldosterone secretion, adrenal vein sampling, CT - Familial hyperaldosteronism: relatively Asx, profound hypokalemia w/ thiazides, fam hx of hemorrhagic stroke - AME: childhood onset (low birth weight, FtT, short stature), Labs: hypokalemia, alkalosis - Licorice: history of large intake Tx: aldosterone receptor blockers (spironolactone, epleronone, triamterene, amiloride), surgical resection, ACTH suppression (dexamethasone, prednisone), renal transplant (for AME), stop eating the damn licorice. |
|
|
Congenital adrenal hyperplasia
|
= enzyme defects in steroid synthesis pathways causing varying deficiencies in GCCs, MCCs, sex hormones, and ACTH stimulation/excess and gland hypertrophy.
Deficiencies: - 21-hydroxylase (most common, lose aldos, cort): ambiguous genitalia, hirsutism, +/- salt wasting hypotension - 3β-hydroxysteroid dehydrogenase II (lose aldos, cort, SxH): ambiguous genitalia, premature pubarche, hirsutism, +/- salt wasting hypotension - 11β-hydroxylase (lose Ald, cort, gain Doxycort): virilization, endocrine hypertension (excess deoxycorticosterone binds aldosterone receptor) - 17α-hydroxylase (lose cort, SxH): endocrine hypertension, sexual infantilism, primary amenorrhea |
|
|
Pheochromocytoma
= adrenal medullary neoplasm (neuroendocrine) derived from chromaffin cells (neural crest) and produces catecholamines (Epi, NE, D2). Usually unilateral, benign Clinical features: - rule of 10’s: 10% malignant, 10% extra-adrenal (bladder, organ of Zuckerandl, posterior mediastinum), 10% calficy, 10% in children, 10% familial - 5 P’s (hyperadrenergic): pressure (↑BP), pain (headache), perspiration (hyperhidrosis), pallor, palpitations (tachycardia) Genetics associations: - Familial: MEN2 A/B (mutated RET oncogene), neurofibromatosis, von Hippel-Lindau disease (often bilateral, VHL mutation) - non-familial: Struge-weber syndrome, tuberous sclerosis, Carney’s triad Diagnosis: ↑urinary catecholamine metabolites (metanephrine, vanillylmandelix acid), biopsy Macro: brown, hemorrhagic, often necrotic, bilateral in some familial Micro: polygonal spindle cells, often nested (Zellballen), extensive vascular network, not features to distinguish benign/malignant |
|
|
Adrenocortical carcinoma
Epi: F>M, children ~4y, adults ~45y, usually functional in children, variable in adults (Cushings + virilization more common than hyperaldosteronism) - Presentation: "OH DAMN IT": obesity/osteoporosis, hypertension/hirsuitism, diabetes/depression, acne/amenorrhea, muscular weakness, neurologic symptoms, integument changes - a/w Beckwith Wiedermann syndrome, Li Fraumeni syndrome (p53), hemihypertrophy - poor prognosis (median survival 2y) Gross: large, yellow/tan mass (15-20cm) w/ hemorrhage and necrosis Micro: sheets of eosinophilic clear cells, nuclear polymorphism, atypical mitotic figures **adrenals also common site for metastases, usually bilateral, common: lungs, breast, kidneys, GI |
|
|
Adrenocortical adenoma
= Benign lesions of the adrenal cortex, usually non-functional Epi: F>M, usually in children <5y, mostly functional in children (cortisol, androgens → Cushings + virilization), in adults Cushings> hyperaldosteronism (Conn’s) > virilization Gross: solitary, encapsulated, yellow/tan (cholesterol), >1.0cm Micro: lipid rich, resemble normal adrenocortical cells, nuclearpleomorphism |
|
|
Waterhouse-Friderichsen syndrome
= acute hemorrhagic necrosis of the adrenal glands causing primary adrenal insufficiency - more common in children - a/w DIC, septicemia (Neisseria meningitides, pseudomonas), endotoxic shoc |
|
|
Mucinous (colloid carcinoma)
= rare, mucin producing invasive ductal carcinoma - usually occur in elderly women - on mammography looks rounded, no spiculations Gross: rounded, expansile, wet/sticky looking Micro: cells surrounded by mucin (islands), remnants of DCIS with cribiform (colander) pattern |
|
|
Infiltrating medullary carcinoma
|
= less aggressive type of infiltrating ductal carcinoma
- a/w BRCA1 mutations, most are ER/PR negative Gross: rounded/discrete, expansile (bulky), soft tumor Micro: large cells, lymphoid infiltrate |
|
|
Infiltrating Ductal carcinoma
|
= invasive progression of DCIS
- firm, fixed lesion Gross: indurated, gray-white tumor, stellate morphology - mammogram can visualize calcifications which look spiculated (needle-like) Micro: remnants of DCIS/duct-like structure persist, invasive component pervades, matrix deposition allows for neovascularization |
|
|
Infiltrating lobular carcinoma
|
= invasive progression of LCIS
- no calcifications so not visible on mammogram - micro: neoplastic cells arranged in linear fashion or in concentric circles (bulls-eye) |
|
|
Paget’s disease (of the breast)
= extension on DCIS along the lactiferous ducts to the nipple - causes inflammation and rash/erosion around the areola, +/- nipple retraction Micro: cells are pale, mucinous cytoplasm, large nuclei |
|
|
Lobular carcinoma in situ
|
Progression:
- lobules (ductules) → - 16q32 (e-cadherin, others) → atypical lobular hyperplasia → lobular carcinoma in situ → (25% over many years) infiltrating lobular carcinoma, usually low grade ALH: cells spread diffusely through lobules but do not calcify—cannot be identified on mammogram LCIS: usually ER/PR positive, but 1/3 does usually invade. Characterized by e-cadherin mutation (universal) causing loss of cell adhesion allow diffuse spread |
|
|
Ductal carcinoma in situ
|
Low grade DCIS:
- Usual ductal hyperplasia → -16q -17p→ atypical ductal hyperplasia →no progression OR low grade DCIS → infiltrating ductal carcinoma grade 1 - has myoepithelial cells at the periphery (lost in invasive sections), central has clonal proliferation and “roman bridge” formation - calcifications form pattern that is usually detectable by mamography High grade DCIS: - normal duct epithelia → HER2/neu amplification (surface receptor, sensitive to growth factors) → high grade DCIS (may have necrotic center)→ infiltrating ductal carcinoma grade 3 (usually ER/PR negative, poorly differentiated) - no punched out spaces/bridges, grows fast causing central/lumenal necrosis which then forms calcifications - linear calcifications w/ branching identifiable on mamography - greater risk of invasion than low grade, will recur |
|
|
Non-Atypical lesions of the terminal duct lobule unit
|
= proliferative lesions of the ductal epithelium and stroma without characteric changes of carcinoma in situ (and low risk of progression)
Adenosis = hyperplasia of the lobules (increase in # and size of lobules), may becom calcified - usually women in 30’s/40’s, most likely in response to cyclic hormonal change, causes lumpy breasts in women with fibrocystic change Sclerosing adenosis= benign sclerotic proliferation of the lobules - lesions will feel hard/firm (due to sclerotic material) and calcify and give suspicious mammography results - slightly higher risk of malignant transformation than adenosis, but still low |
|
|
Fibroadenoma
= firm, small, mobile circumscribed masses arising from the terminal duct lobule unit of the breast. Non-malignant -usually in the upper quadrant of the breast, can grow as large as 2cm Epi: 8-10% of US women throughout life, commonly in teens/20’s, more common in AA women Pathogenesis: hypertrophy of a single or group of lobules to perceived hormonal growth stimulus, resulting in hypertrophy (cells and stroma) and with age sclerosis and calcifications |
|
|
Mammary cysts
|
= non-proliferative lesions of the terminal duct lobular units
Epi: fibrocystic changes are common (~50% of US women at midlife), Pathogenesis: exaggerated response of breast stroma & epithelium to hormones and growth factors cause edema and swelling Symptoms: dense, palpable lumps or plaques in the breast, may cause tenderness before menstruation Micro: cells in the lobule undergo apocrine metaplasia (become similar to sweat glands) and produce foul smelling liquid |
|
|
Turner’s syndrome
|
= 45X phenotype due to either complete or partial absence or defect of the second sex chromosome. May have universal or mosaic distribution (depending on when non-disjunction occurred)
Epi: mostly due to paternal non-disjunction, effects 1/2500 live female births, found in 10% of all spontaneous abortions, most diagnosed late 15yo (subtle signs overlooked), 6-11% have Y chromosome mosacism (increases risk for gonadoblastoma) Systems involved: (overall premature death) - orthopedic: short stature (missing SHOX gene copy), cervical hypoplasia, congenital hip dislocation, shield chest, cubitus valgus, increase risk for osteoporosis and fracture - OMF: high arch palate (feeding & speech problems, shorter/horizontal Eustachian tube—otitis media, dental crowding/malocclusion), micrognathia, low set ears - lymphatic: cystic hygroma, acral lymphedema (non-pitting edema) - cardio: aortic coarctation (HTN, CHF, cardiomegaly, pulm vascularity/edema), bicuspid aortic valve, aortic dissection, increased risk for ischemic heart disease atherosclerosis, HTN, cerebrovascular disease - endocrine: hypothyroidism, hypogonadism (amenorrhea), premature ovarian failure (infertility), risk for T1/2DM and obesity - renal: horseshoe kidney (5-10%), upper urinary tract duplications (significant if can cause UTI, obstruction, HTN) - integument: pterygium colli (neck webbing), nail dysplasia, low hairline - neuro/psych: learning disabilities, difficulty w/ language, visual-spacial, memory, facial/social cues, executve function - audiologic: ear shape anomalies, sensorineural/conductive deafness - ophthalmologic: strabismus - hepatic: elevated LFTs, structural abnormalities (regenerative nodular hyperplasia, portal hypertension, steatosis hepatis) - immunologic: autoimmunity (thyroid, T1DM, Graves, Celiac, IBD, RA) Tx: systems as needed, GH early (age 2), estrogen at puberty if delayed start progesterone when menstrual cycle occurs |
|
|
Etiologies of precocious puberty
|
Central: gonadotrophin excess (↑FSH/LH → ↑testosterone/estradiol), will progress bone age
- idiopathic (90% females, 45% males) - hypothalamic/pituitary masses - cerebral malformations -trauma Non-central: gonadotrophin independent (↓FSH/LH, but ↑testosterone/estradiol) - McCune-Albright Syndome: GNAS mutation receptor leads to cyclical formation and involution of estrogen-releasing cysts→ early puberty (often relapsing), café-au-lait patches, hyperostosis fibrous dysplasia (smoked out appearance on long bones). Tx: aromatase inhibitors, SERMs, no treatment - Congenital adrenal hyperplasia or adrenal tumors: small testes b/c of overproduction of testosterone outside the testes. Tx: surgical removal of tumor - Van Wyk-Grumback syndrome: primary hypothyroidism→ ↑TSH which shares α subunit w/ FSH → ↑FSH → ↑estrodiol . Does not accelerate bone age or growth (low thyroid inhibits it) - exogenous sex hormone exposure: parent has hormone creams - endocrine tumor: ovarian, testicular, liver (hCG → ↑testosterone) |
|
|
Treatment of precocious puberty
|
- treat if there are psychological concerns or compromises to full development/height
Non-central: - resolve primary cause (remove exposures, resect tumors, treat hormone imbalance) - ketoconazole: androgen synthesis inhibitor Central: - Lupron: GnRH agonist (intramuscular, implant, intranasal spray). Discontinue when psychologically ready, maximal height reached, no older than 12 |
|
|
Hydrocele
|
= congenital or acquired accumulation of fluid in the tunica vaginalis surrounding the testis.
- tunica vaginalis creates a potentioal space, lines the surface of the testes and is a derivation of the peritoneum of the abdominal wall. Presentation: painless enlargement of the scrotum, may transilluminate(light passes through cystic fluid) Congenital: occur in first year of life as patent processus vaginalis fails to close (retains passage from abdominal wall), often associated with inguinal hernia Acquired: lymphatic obstruction from trauma, neoplasms or infection of the epididymis/testis. In tropical areas parasites (filariasis) inhabit inguinal lymphatic and cause testicular obstruction as well as non-pitting leg edema |
|
|
Varicocele
|
= relatively painful dilation of the venous plexus in the sprematic cord
- 10% of young males, more common on left side due to greater angle of drainage into the renal vein (vs. IVC, so column of fluid accumulates) - occasionally associated with infertility due to increased temperatures in the scrotum causing decreased spermatogenesis and sperm motility - repaired through open surgery or embolization |
|
|
Spermatocele
|
= small cyst (hard, pea sized nodule) arising from the efferent ductal system of the testes, particular the epididymis
- often palpable mass located ABOVE (not in) the testis - usually insignificant and harmless: if you can determine that they come from the epididymis not the testis you don’t have to remove it (less likely to be testicular tumor, unlike mass in the testis) |
|
|
Etiologies of Orchiditis
|
Bacterial: usually do to retrograde extension of bacterial infection from the epididymis to the testes
Syphilitic: infiltration of lymphocytes and plasma cells may cause obliteration of small blood vessels resulting in tubular atrophy and fibrosis, very much like the manifestations of cryptorchidism Mumps: uncommon in childhood mumps (that usually is just salivary gland swelling), in adulthood there is a 30% chance: very painful swelling, permanent focal atrophy and scaring can develop in 50% of involved testes (but fertility usually preserved) |
|
|
Epididymitis
|
- most common intrascrotal inflammatory disorder
- arises from direct extension of UTI from the prostate or prostatic urethra - inflammation and swelling can potentially lead to scaring - Fibrosis and chronic obstruction due to purulent exudate may result leading to infertility - In older patients: chlamydia and gonococcal disease, in older patients mostly E. coli, sometimes M. tuberculosis |
|
|
Sertoli cell only syndrome
|
= idiopathic cause of infertility characterized by seminiferous tubules line only by sertoli cells (no germ cells are present).
Etiologies: - failure of embryologic migration of germ cells from the yolk sac to the gonads. Untreatable - Chemo/radiation or estrogen treatment: germ cells are highly sensitive to these therapies, but should regenerate after exposure is removed—potentially reversible |
|
|
Male hypogonadism
|
= ↓ of the gonads either due to ↓testosterone or resistance to it
Symptoms: - impotence: ↓libido (failure to sustain errection, not from sympathetics) - loss of secondary male sex characteristics: Pre-pubertal (small testes, high voice, ↓ muscle mass, ↓ body hair, delayed bone age). Post-pubertal (soft testes, ↓strength/muscle mass, ↓body hair, gynecomastia-unopposed estrogen) - osteoporosis: T normally inhibits osteoclasts - infertility: ↓spermatogenesis Dx: history (incl birth), Labs (8am T and LH/FSH, SxHBG), imaging, bone age Tx: T replacement |
|
|
Etiologies of male hypogonadism
|
Hypergonadotrophic: primary testicular defect, ↑FSH/LH, ↓T
- Congenital: gonadal dysgenesis (Klinefelter’s, tx factor deficiency), leydig cell hypoplasia (→male psuedohermaphrotism), sertoli cell only syndrome (germ cell aplasia), congenital adrenal hyperplasia, vanishing testes syndrome (anorchia from prenatal torsion or tx factor deficiency) - acquired: infectious (mumps, Coxsackie, echovirus, arborvirus), drugs (spironolactone, cyproterene, ketoconazole), iatrogenic (surgical resection, chemo, radiation), trauma Hypogonadotrophic: secondary central defect (pituitary ↓FSH/LH, hypothalamus ↓GnRH) - Congenital: gene mutations (PROP1), central midline deficiencies (cleft palate, septo-optic dyplasia), genetic syndromes (Kallman’s, Prader-Willi) -Acquired: brain abnormality (trauma, infection, tumor—craniopharyngioma, macroadenoma), systemic illness (also anorexia, malnutrition), ↑prolactin (inhibits GnRH), hemochromatosis, obstructive sleep apnea |
|
|
Germ cell tumor
|
= neoplasm derived from the germs cells, may be cancerous or non-cancerous
Epi: peak incidence age 15-34, Risks: race (Caucasian, European descent), cryptorchidism (10%), familial (10x if sibling), testicular dysgenesis, Ch12 abnormality - normally arise in the gonads, may arise outside due to errors in during embryogenesis: mediastinal tumor in Klinefelter’s , sacrococcygeal teratoma (most common tumor diagnosed at birth) - in males: most prepubertal are benign (mature teratomas) or low grade malignant (yolk sac—most common), those in seminiferous tubules are usually malignant - in females: ovarian germ cell tumors usually benign, especially cystic teratomas |
|
|
Invasive Germ cell tumors
|
Seminomas: have potential to become multiple different tissue in the body
- most common, - good prognosis: very sensitive to radiation, don’t require additional treatment Non-seminomatous germ cells: differentiate into specific tissues - aggressive, not sensitive to radiation, require chemo - types: embryonal carcinoma, teratoma, yolk sac tumor, choriocarcinoma (makes trophoblasts), mixtures of the above (most) |
|
|
Sex cord stromal tumors
|
= malignant tumors of the ovaries and testes
- 5% of testicular cancers, 8% of ovarian cancers - 70% are stage 1, good prognosis Types: granulosa cell & sertoli-leydig cell (most common), thecoma, sertoli cell, leydig cell, fibroma, fibrosarcoma, sclerosing stromal |
|
|
Carcinoma of the penis
|
Epi: <1% male cancers in US (more common in Asia, Africa, S. America), usually uncircumscised males >40y
Risks: poor genital hygience in uncircumsized men (chronic infections of foreskin glands), phimosis (forskin not retractable), HPV 16/18 infection (other HPV leads to condyloma acuminatum but not carcinoma) Precursor lesions: both associated w/ HPV 16 - Bowen disease (squamous cell carcinoma in situ): neoplastic skin disease w/ 10% risk invasion. Gradually enlarging, well demarcated erythematous plaque w/ irregular border, crusting or scale - Bowenoid papulosis: verrucous papules on the body of the penis, Clinical course: slow growing, locally invasive, metastases to inguinal and iliac nodes, widespread dissemination is uncommon (topical exposure to coal/tars can cause carcinoma off the scrotum) |
|
|
Seminoma
|
= most common pure-type male germ cell tumor
- arise as a large mass in testes, asymptomatic or pain/discomfort - hCG is a tumor marker Micro: mass of thousands of spermatogonia, giant cells and lymphocytes also seen Tx: radiation (very sensitive, good prognosis—paraaortic lymph nodes ), no biopsy (fear of spreading tumor), radical inguinal orchiectomy (entire spermatic cord, epididymis also take out) |
|
|
Seminoma
|
= most common pure-type male germ cell tumor
- arise as a large mass in testes, asymptomatic or pain/discomfort - hCG is a tumor marker Micro: mass of thousands of spermatogonia, giant cells and lymphocytes also seen Tx: radiation (very sensitive, good prognosis—paraaortic lymph nodes ), no biopsy (fear of spreading tumor), radical inguinal orchiectomy (entire spermatic cord, epididymis also take out) |
|
|
Intra-tubular germ cell neoplasia (ITGCN)
|
= pre-invasive form of male germ cell tumors (testicular carcinoma in situ)
- 50% of men w/ ITCGN will progress to invasive tumor w/in 5 years - occurs in 5% of contralateral testes of men w/ orchiectomy for germ cell neoplasia - found in 2% of cryptorchid testes and in biopsies for infertility - widespread ITGCN is found adjacent to almost all invasive germ cell tumors - Irregular nuclei, large germ cells |
|
|
3 main etiologies of male infertility
|
Supratesticular causes:
- disorders of the hypothalamus/pituitary gland causing deficiencies in gonadotropin release (GnRH, FSH/LH): adenomas, trauma, transection of the stalk, congenital anomalies. (result I immature development of seminiferous tubules and no spermatogenesis) - systemic illnesses, malnutrition - endocrine anomalies - particular illnesses w/ longstanding fever: heat impairs fertility Testicular infertility: - cryptorchid testes: atrophy and peritubular fibrosis - varicocele: hypospermatogenesis - genetic disease: Klinefelter’s syndrome - idiopathic: characteristic histolo;gy of germ cell maturation arrest and germ cell aplasia (Sertoli Cell only syndrome) Post-testicular: - anatomical anomalies obstructing ejaculation, retrograde ejaculation - Epididymitis: inflammation causing obstruction of the tube (incl. TB) - trauma: damage to vas deferens or epididymis - vasectomy: procedure ties off vas deferens (most common!) |
|
|
Testicular torsion
|
= twisting of the testis around the spermatocord
- compresses the vessels: inhibits venous drainage → vascular engorgement, infarction → death - very painful, must be corrected surgically within 6 hours to save the testis - mostly 2nd decade, may be related to minor injury, or occur spontaneously Etiology: due to some anomaly in testicular suspension—“horizontal lie” within the tunica vaginalis resulting in increased mobility. Both sides at risk and must be fixed to avoid total infertility |
|
|
Cryptorchidism
|
= one or both testes has not descended to normal position in the scrotal sac.
- 3% of males at birth, 1% after 1y. 20% are in abdominal cavity and never descend (must be surgically moved), 80% are arrested along the path of the inguinal canal (prone to injury) - complications: low sperm count (infertility), increased risk of germ cell tumors (5-10x, maybe due to increased temps?), atrophy and fibrosis of the seminiferous tubular membrane after 2 years if not brought down Tx: orchiopexy (surgical retrieval and attachment to scrotum) |
|
|
Grading of adenocarcinoma of the endometrium
|
Grade 1: no more than 5% of the tumor is solid growth (choice A is correct).
Grade 2: 6-50% solid growth pattern (choice B is incorrect) Grade 3: > 50% solid growth pattern (choice C is incorrect) Stage Ia- Limited to endometrium Stage Ib- invasion of only inner ½ of myometrium Stage Ic- invasion of outer ½ of myometrium Stage II- cervical invasion Stage III- serosal, adnexal or vaginal invasion (adjacent structures) Stage IV- bladder or bowel invasion, distant metastasis Types: Endometrioid (Type I): villoglandular, secretory, or ciliated Serous (Type II): Clear cell, Mucinous, Squamous, or Mixed |
|
|
Lymphogranuloma venereum
|
= caused by Chlamydia
Three stages: - primary stage: erythema and hyperemia in the vulva. - secondary stage: inguinal lymph nodes become infected and form buboes (large and painful, and they may burst) - tertiary stage: resolution by fibrosis--fibrosis obliterates the lymphatics, leading to atrophy of the vulva, loss of pigmentation, leukoplakia, and elephantiasis of the vulva (hugely enlarged vulva). Some patients develop rectal strictures (LGV is the third most common cause of rectal strictures after carcinoma and endometriosis) |
|
|
Serous cystadenocarcinoma of the ovary
|
= very common ovarian tumor of the epithelium (resembles fallopian tube--ciliated and columnar)
Benign cystadenoma: single layer of epithelium, will look smooth and shiny grossly, 20% bilateral Borderline cystadenoma: malignant but with good prognosis (100% 5y, 76% 10y), have papillary tufts (from proliferation of serous epithelium), pleomorphism, atypia, mitoses, often bilateral (30%), Ca-125 may indicate presence, cannot differentiate grade (better for monitoring treatment) Malignant cystadenocarcinoma: all the above PLUS invasion of the ovarian stroma also may have psammoma bodies, papillary tufts may be on outside wall of cyst, may be solid, papillary, necrotic, hemorrhagic. Poor prognosis (50% 5y, 13%10y), 66% bilateral. May cause ascites due to peritoneal seeding (omentum metastasis, iatrogenic rupturing of cyst) |
|
|
Condyloma accuminatum
|
= genital warts caused by HPV
-no good treatment |
|
|
Malignant mixed mullerian tumor
|
= tumor of the uterus, fallopian tubes, cervix, and/or upper 1/3 of vagina (all Mullerian tissue)
- occurs in 7-9th decades - very necrotic and malignant (grows rapidly and kills itself), poor prognosis - mixture of adenocarcinoma (glands) and sarcoma (connective tissue) = "carcino-sarcoma". May also be heterologous element not normally seen in uterus (ex: cartilage) - Tx: radical surgery, chemo, radiation |
|
|
11 β-HSD2 (hydroxysteroid dehydrogenase)
|
= enzyme that converts to cortisol to corticosterone
- if deficient, excess cortisol can bind mineralocorticoid receptors and cause hypertension - Inhibited by glycyrrhetinic acid found in licorice and tobacco |
|
|
Congenital Adrenal hyperplasia
|
= defects in 21-hydroxylase, 17α-hydroxylase, or 11β-hydroxylase which are involved in cortisol production
Defects cause decreased cortisol, increased ACTH, gland hypertrophy and increased adrenal androgens. - CAH presents as virilization of the female at birth, but it is more difficult to detect in males. |
|
|
Albright's Hereditary Osteodystrophy
|
= pseudohypoparathyroidism
- caused by a mutation in the stimulatory subunit of a G-protein, which causes PTH resistance despite high PTH levels |
|
|
Apparent Mineralcorticoid excess
|
= deficiency in 11- β-hydroxysteroid dehyrogenase which converts cortisol to corticosterone so that it will not bind to mineralcorticoid receptors
- if deficient, free cortisol can bind to mineralcorticoid receptors and lead to hypertension. - Acquired deficiencies result from licorice or chewing tobacco (glycyrrhetinic acid) |
|
|
McCune-Albright syndrome
|
= abnormality in the G-as subunit of a G protein.
Classic triad: - Non-central precocious puberty: so estradiol/testosterone is high while FSH and LH are at low, pre-pubertal levels - Irregular café-au-lait spots that are different from those seen in neurofibromatosis - Hyperostosis fibrous dysplasia: a smoked out appearance in the long and facial bones |
|
|
Conn syndrome
|
hyperaldosteronism caused by aldosterone secreting tumor
- will have low renin |
