Endocrine/Repro Flashcards

Question

[Hypothalamic and Pituitary Pharmacology] Describe clinical uses and adverse effects of the following GH antagonists: 3. Octreotide, lanreotide 4. Pegvisomant (Somavert) 5. Bromocriptine/cabergoline

Answer 1

GH antagonists 3. Octreotide, lanreotide - long-acting analogs of somatostatin (hormone secreted in the delta cells of pancreatic islets and the hypothalamus) --> inhibits GH and TRH + inhibits gastric secretion and gallbladder contractility A. Clinical uses - to treat smaller GH-secreting adenomas that cause acromegaly and gigantism - carcinoid tumor, VIPoma, insulinoma, glucagonoma, gastrinoma (Zollinger-Ellison), esophageal varices B. Adverse effects - GI side effects (nausea/vomiting, cramps, flatulence, gallstones, steatorrhea) - sinus bradycardia, conduction disturbances 4. Pegvisomant (Somavert) - GH receptor antagonist A. Clinical uses - normalize IGF-1 levels in patients with acromegaly 5. Bromocriptine/cabergoline - dopamine receptor agonists --> inhibit GH secretion - treat acromegaly *dopamine agonists stimulate growth hormone secretion in normal individuals, yet suppress growth hormone secretion in acromegaly patients*

Answer 2

1A. FSH - urofollitropin (uFSH), Follitropin alpha and beta (rFSH) with shorter half-lives B. LH - rLH - only for use in combo with rFSH for stimulation of follicular devlpt in infertile women with LH deficiency C. hCG - choriogonadotropin alpha (rhCG), urine extracted hCG 2. Clinical uses - for infertility to stimulate spermatogenesis in men and induce ovulation in women - reserved for anovulatory women who fail to respond to other less expensive forms of treatment (Eg clomiphene) - controlled ovarian hyperstimulation in assisted reproductive procedures eg IVF 3. Adverse effects i. ovarian hyperstimulation syndrome OHSS - ovarian enlargement, ascites, hydrothorax, hypovolemia ii. multiple pregnancies

Answer 3

1. GnRH agonists - sustained, non-pulsatile administration administration inhibits release of FSH and LH in men and women - human: gonadorelin - synthetic: goserelin, histrelin, leuprolide, nafarelin, triptorelin A. Clinical uses i. endometriosis - cyclical abdominal pain in premenopausal women caused by estrogen-sensitive endometrium-like tissue outside the uterus ii. uterine leiomyomata (fibroids) - benign, estrogen-sensitive fibrous growths in the uterus --> menorrhagia, anemia, pelvic pain iii. prostate cancer - combined anti-androgen receptor antagonist (flutamide or bicalutamide) with gnRH agonist --> reduces serum testosterone levels iv. central precocious puberty (before 7 yrs in girls, 9 yrs in boys) - for children whose final height would otherwise be compromised; or for children in whom devlpt of puberty secondary sex characteristics causes significant emotional distress B. Toxicities i. Women - sx of menopause (hot flashes, sweats) - depression, low libido, vaginal dryness, breast atrophy, ovarian cysts, ovarian cysts, reduced bone density ii. Men - hot flashes, edema, gynecomastia, low libido, low hematocrit, reduced bone density, asthenia

Answer 4

2. GnRH receptor antagonists A. Clinical uses - inhibit secretion of FSH and LH in more dose-dependent and complete manner than GnRH agonists - ganirelix and cetrorelix - controlled ovarian hyperstimulation procedures - degarelix - treatment of symptomatic, advanced androgen-dependent prostate cancer (suppresses androgens - testosterone faster than leuprolide) B. Adverse effects - ganirelix and cetrorelix - lower risk of OHSS than with GnRH agonists - degarelix - symptoms of androgen deprivation (hot flashes, edema)

Answer 5

1. Dopamine agonists - bromocriptine, cabergoline - dopamine inhibits prolactin and TSH A. Clinical use - first line treatment for hyperprolactinemia (inhibits GnRH release) --> shrink pituitary prolactin-secreting adenomas, lower circulating prolactin levels, and restore ovulation - complete success - pregnancy or 2 consecutive menses with evidence of ovulation - partial success - 2 menstrual cycles without evidence of ovulation, or 1 ovulatory cycle B. Adverse effects - nausea, headache, light headedness, orthostatic hypotension, fatigue - cabergoline causes less nausea than bromocriptine but is associated with cardiac valvulopathy (contraindicated) 2. Oxytocin - posterior pituitary hormone A. Clinical use - induce labor for conditions requiring early vaginal delivery --> increases force and frequency of uterine contractions - postpartum control of uterine hemorrhage due to uterine atony B. Adverse effects - rare, due to i. excessive contractions --> fetal distress, uterine rupture ii. inadvertent activation of ADH receptors --> fluid retention --> hyponatremia, heart failure

Answer 6

1. Sleep/wake cycle, stress, etc --> CRH (hypothalamus) --> corticotropin i.e. ACTH (pituitary) --> Cortisol (zona fasciculata of the adrenal glands) 2. Cushing's syndrome - ↑ serum cortisol * pseudo-Cushing's - high cortisol secondary to other factors (Exercise, pregnancy, uncontrolled diabetes, stress, alcoholism, sleep apnea) 3. Causes A. ACTH dependent (high ACTH) - i. Cushing's disease (ACTH secreting pituitary adenoma) ii. ectopic ACTH secretion (Small cell lung carcinoma, thymoma, pancreatic islet cell carcinomas, etc) B. ACTH independent (low ACTH) - i. iatrogenic (exogenous glucocorticoids) ii. primary adrenal adenoma/carcinoma

Answer 7

4. Diagnosis - A. Low dose overnight dexamethasone suppression test (should suppress am cortisol production) --> differentiates iatrogenic (low cortisol) vs real Cushing's (high cortisol) B. Measure ACTH levels - differentiates dependent (high plasma ACTH) vs independent (low plasma ACTH and high cortisol) C. high dose overnight dexamethasone suppression test - differentiates pituitary adenoma - Cushing's disease (low serum cortisol) vs ectopic ACTH (cortisol remains high) 5. Clinical - central obesity with buffalo hump, moon facies, but thin extremities, peripheral muscle weakness, violaceous striae *unique to Cushing's*, HTN, immune suppression 6. Treatment A. Endogenous - remove tumor producing ACTH or cortisol - radiotherapy, bilateral adrenalectomy, pharmacotherapy --> adrenal blockers - ketoconazole (steroid biosynthesis inhibitor), mifepristone(GC receptor antagonist) - or ACTH antagonists- cabergoline (dopamine receptor agonist), pasireotide (somatostatin receptor agonist) B. Exogenous (iatrogenic) - reduce corticosteroid dosage gradually to avoid acute withdrawal sx C. Pseudo-Cushing's - Treat underlying disease

Answer 8

Conn's syndrome - primary mineralocorticoid excess due to adrenal adenoma 1. 3 factors stimulate JG cells to produce renin: beta1 SNS stimulation, low NaCl delivery to macula densa, and low BP --> converts angiotensinogen to Ang I --> ACEI converts Ang I to Ang II --> zona glomerulosa in adrenal glands produces aldosterone --> salt retention --> BP increases 2. Etiology - bilateral adrenal hyperplasia (more common) or aldosterone producing adrenal adenoma 3. Clinical presentation - hypertension that cannot be cured with meds, hypokalemic metabolic alkalosis --> more suggestive of adenoma 4. Diagnosis - elevated aldosterone and high SA:PRA (plasma renin activity) - confirm via salt loading to try to suppress aldosterone (won't work) 5. Treatment - surgical - unilateral adenoma - medical therapy for bilateral hyperplasia --> spironolactone (antagonizes androgen receptors --> gynecomastia, impotence side effects in men) and eplerenone (specific for MC receptors --> free of side effects)

Answer 9

Adrenal insufficiency 1A. Primary - Addison's disease --> loss of mineralocorticoids, glucocorticoids, androgens; excess ACTH --> hyperkalemia, hyperpigmentation B. Secondary - pituitary --> loss of glucocorticoids >> loss of androgens and mineralocorticoids; RAAS (and therefore BP) intact C. Tertiary - hypothalamus 2. Causes A. Primary i. autoimmune - Addison's (MCC in USA), infectious - TB (worldwide) ii. hemorrhage (Waterhouse-Friderichsen --> adrenal hemorrhage due to Neisseria meningitidis --> rapidly progressive hypotension + DIC) iii. drugs (ketoconazole --> decreased synthesis; rifampin --> increased catabolism) B. Secondary - exogenous steroids (MCC), pituitary/hypothalamic disease, surgery, congenital 3. Diagnosis - screen via morning cortisol test --> both primary and secondary will have low cortisol - confirm via cosyntropin (synthetic ACTH) Stimulation test --> cortisol should increase - hyperkalemia and hyperpigmentation in primary

Answer 10

4. Clinical presentation: hypotension, hyponatremia, hypovolemia, weakness/fatigue, dehydration, fasting hypoglycemia, weight loss - primary deficiency: hyperkalemia (due to mineralocorticoid deficiency) + hyperpigmentation of oral mucosa/skin (high ACTH stimulates melanocytes) 5. Adrenal crisis - endocrine emergency! - shock, fever, hypotension, vomiting, anemia, renal failure, hypoglycemia, coma, death - treatment - high dose IV glucocorticoids, IV fluids 6. Treatment for primary (Addison's) A. Chronic - replacement therapy with daily oral corticosteroid (hydrocortisone) and supplementation with mineralocorticoid (fludrocortisone) B. Acute - immediate treatment - large doses of IV hydrocortisone - correct fluid electrolytes - treat precipitating cause C. Assessing adequacy of corticosteroid replacement therapy - disappearance of hyperpigmentation and resolution of electrolyte abnormalities - low early morning ACTH levels --> indicator of overtreatment (steroids suppressing ACTH)

Answer 11

Pheochromocytoma - adrenal medulla tumor of neuroectodermal chromaffin cells --> overproduction of catecholamines esp norepinephrine 1. Causes - sporadic or familial: - VHL (Renal cell carcinoma + pheo), NF1 - MEN2A --> pheo, medullary cancer of thyroid, hyperparathroidism (Marfinoid habitus) - MEN2B --> pheo, medullary cancer of thyroid, ganglioneuromas of oral mucosa (eg tongue) 2. Rule of 10's: 10% extra-adrenal, 10% bilateral, 10% familial, 10% malignant, 10% in children, 10% calcify, 10% recur 3. Clinical presentation - paroxysms --> spontaneous episodic spells 15-20 min long, precipitated by procedures, exercise, drugs *classic triad* pain (headache), perspiration, palpitations + pressure (HTN), pallor 4. Diagnosis - plasma metanephrines, VMA, urine catecholamines 5. Treatment - surgical resection of tumor; to avoid hypertensive crisis: - give alpha blockade with alpha-adrenoreceptor antagonists first --> phenoxybenzamine, prazosin, terazosin, or doxazosin - THEN beta blockade with beta-adrenoreceptor antagonists --> atenolol, metoprolol, propranolol

Answer 12

1. Adrenal mass - i.e. incidentiloma, 25% functional but with subclinical sx A. DD - pheo, mets, benign adenoma, carcinoma B. Diagnosis - H&P, hormonal testing, imaging 2. Adrenocortical carcinoma - large mass in adrenal cortex with poor prognosis - mass effect (abdominal pain) - rapid onset hypersecretion signs and sx eg virilization (androgens), hypokalemia (aldosterone), gynecomastia (estrogen), Cushing's (Cortisol) 3A. Hirsutism - male pattern of hair distribution in a female; due to hyperandrogenemia and increased sensitivity of pilosebaceous units to androgens B. hypertrichosis - hair all over the body; due to meds (phenytoin - antiepileptic), hyperthyroidism C. lanugo - soft, villous, nonpigmented hair all over the body; due to androgens

Answer 13

1. Congenital adrenal hyperplasia (CAH) - AR inherited disorders of steroid biosynthesis - low cortisol --> ↑ ACTH levels --> adrenal hyperplasia --> overproduction of steroids that precede blockage 2. 21 hydroxylase (21-OH) deficiency (95%) --> - ↓ mineralocorticoids - ↓ cortisol / glucocorticoids - ↑ levels of 17-OH-progesterone --> ↑ androgens (DHEA, androstenedione, testosterone) A. classic (childhood) - hypotension --> presents as shock in neonates, ambiguous genitalia in females B. non-classic (adulthood) - hirsutism, oligomenorrhea, infertility 3. 11B-hydroxylase (11B-OH) deficiency - ↓ cortisol - ↑ mineralocorticoids --> hypertension, hypokalemia - ↑ androgens --> virilization (development of male physical characteristics eg increased muscle mass, voice deepening, clitoral enlargement in females)

Answer 14

4. 17alpha-hydroxylase (17OHase) deficiency - ↓ cortisol - ↑ mineralocorticoids --> hypertension, hypokalemia - ↓ androgens --> ↓ secondary sexual development (females) and pseudohermaphroditism (males) 5. CAH Treatment - - give oral dexamethasone to mother - replacement therapy with hydrocortisone - alternate day therapy with prednisone (intermediate acting) - ACTH suppression without increasing growth inhibition - oral fludrocortisone with salt to maintain PRA, BP, electrolytes

Answer 15

Glucocorticoids - cortisol/hydrocortisone, cortisone, prednisone, dexamethosone 1. Indications - oral gene expression regulators - pleiotropic --> useful but difficult to control - suppress inflammatory and immune responses - allergic reactions, asthma, IBD, lupus, arthritis, cerebral edema, sarcoidosis 2. Adverse effects with chronic use (2+ weeks therapy) - Cushingoid effects - glucose metabolism --> hyperglycemia --> diabetes - fat metabolism --> Fat redistribution --> central obesity - protein metabolism --> catabolism --> thinning, muscle wasting, poor wound healing, osteoporosis - androgenic effects --> hirsutism, acne - CNS effects --> depression, anxiety - ocular effects --> glaucoma, cataracts - GI effects --> peptic ulcers - immunosuppressive --> opportunistic infections - sleep --> insomnia - hypertensive --> glucocorticoids like cortisol that possess mineralocorticoid receptor activity

Answer 16

1. Biosynthesis A. Oxidation: Iodide (I-) comes from outside the cell and is trapped in follicular cell via Na/I symporter --> oxidized to iodine (I2) via TPO - colloid/thyroglobulin is synthesized in cell and sent to follicular lumen - backbone on which thyroid hormone is made B. Organification: Iodine + tyrosines (in colloid) combined in follicular lumen via thyroperoxidase TPO to make iodinated tyrosines DIT or MIT C. Coupling: T3 = MIT + MIT; T4 = MIT + DIT D. Exocytosis: Endocytosed into follicular cell--> T3/T4 cleaved from colloid (which is put in lysosome) --> diffuse into bloodstream 2. Anatomy - follicular cells held together by tight junctions to keep colloid (thyroglobulin) inside, surrounded by loose connective tissue

Answer 17

3. HPT axis TRH (hypothalamus) --> binds to thyrotrophs in the anterior pituitary --> secrete TSH --> stimulates T3/T4 production --> feeds back negatively on pituitary + hypothalamus 4. T4 considered prohormone, T3 is the hormone and has much higher affinity for thyroid hormone receptor - T4 is almost 100% bound (to either TBG, TBPA, or albumin); 0.03% free; t1/2 = 7 days - T3 is almost 100% bound (to TBG or albumin); 0.3% free; t1/2 = 1 day - rT3 = reverse T3, inactive metabolite formed from T4 due to 5' deiodinases D1/D3 5. Metabolism A. Iodine sufficient: Thyroid mostly makes T4 and a little bit of T3; major source of T3 is peripheral conversion from T4 --> T3 by 5' deiodinases D1/D2 B. Iodine deficient: thyroid makes both T4 and T3

Answer 18

1. Thyroid arises on floor of pharynx between first and second pharyngeal arches --> starts at base of tongue and migrates down into neck - connected to tongue by thyroglossal duct --> remnant is foramen cecum --> can get thyroglossal duct cysts (anterior neck mass that moves with swallowing) - ectopic thyroid tissue on the tongue = lingual thyroid - derived from endoderm; C cells from neural crest 2. Euthyroid sick syndrome - not a thyroid disease but response of thyroid axis to severe systemic illness - low free T3 - TSH, total T4, free T4 normal - due to defect in peripheral deiodination of T4 --> T3 because of other illness

Answer 19

1. Causes - - congenital (dysgenesis, hormone synthesis errors) - iodine deficiency (MCC worldwide) - chronic thyroiditis (MCC in USA) 2. Clinical A. Congenital (didn't receive prenatal care)- jaundice, feeding troubles, enlarged tongue, umbilical hernia B. Juvenile - mental retardation, learning disabilities, short stature (termed "Cretinism") C. Adult - - (CV) bradycardia and weakness - (CNS) delayed DTRs during relaxation phase and mental slowness - (metabolic) dry coarse skin and hair, orange skin, decreased BMR, cold intolerance/hypothermia, weight gain - (reproductive) amenorrhea (low T3/T4 stimulates TRH, which in turn stimulates prolactin, which inhibits LH/FSH and thus menstruation) - (GI) constipation - periorbital and peripheral edema - worst case is myxedema coma (due to longstanding hypothyroidism, found in elderly)--> decreased mental status, bradycardia, hyponatremia, hypotension, hypoventilation with respiratory acidosis

Answer 20

3. Classification A. Primary hypothyroidism - TSH high i. Hashimoto's i.e. Chronic Lymphocytic Thyroiditis (95%) - autoimmune lymphocytic infiltrate associated with anti-TPO and anti-thyroglobulin Abs; Type IV HSN - high prevalence in women - presents with painless thyroid enlargement (B cell lymphoma due to chronic inflammation, like gastric MALTomas and H. pylori) - histology - lymphoid infiltrate with germinal centers and Hurthle cell change ii. drug-induced iii. defects in thyroid hormone synthesis iv. thyroid development defect (lingual thyroid) v. iodine deficiency (Rare) B. Central hypothyroidism - TSH normal or low --> no stimulation for thyroid bc deficiency of TRH and/or TSH i. pituitary or hypothalamic disease (radiation, tumors, infiltrative disease) ii. normal or small thyroid gland C. Transient hypothyroidism - may become permanent i. postpartum (painless; related to Hashimoto's thyroiditis) ii. subacute "de Quervain" thyroiditis (painful referred jaw pain); viral and self-limited - can result in triphasic response --> destruction (with high T3/T4 and low TSH), repair (high TSH), normal (normal TSH)

Answer 21

1. Thyrotoxic - general term for clinical evidence of excess thyroid hormone action - Hyperthyroid - thyrotoxicity due to overactive thyroid in particular 2. Clinical A. Juvenile - cranial synostosis (premature fusion of cranial sutures) B. Adult - - (CV) - ↑ systolic blood pressure (due to Ca2+ ATPase) --> angina - vasodilation --> ↓ diastolic BP + ↑ RAAS --> ↑ pulse pressure --> palpitations - beta adrenergic signaling --> tachycardia, atrial arrhythmias - (CNS) - inability to concentrate, active DTRs - (metabolic) - velvety moist skin, increased BMR, and weight loss - (GI) diarrhea - osteoporosis - myopathy (proximal muscle weakness) - Graves disease - thyroid hum (venous; arterial is called bruit) - Subacute thyroiditis - pain in neck or jaw during destruction phase

Answer 22

3A. Hyperthyroidism - TSH low / undetectable; high T3/T4 and high negative feedback i. Graves - MCC of thyrotoxicosis and hyperthyroidism - thyroid-stimulating IgG in Type 2 HSN --> triad: diffuse goiter, opthalmopathy (bulging eyes), pretibial myxedema (dermopathy with orange-peel appearance) - scalloping along edges of the colloid (due to papillary projections) and lymphoid aggregates in stroma ii. toxic multinodal goiter TMG - focal patches of hyperfunctioning follicular cells independent of TSH iii. thyroid storm - worst case; agitation, delirium, diarrhea, tachyarrhythmia B. Thyroid destruction - TSH variable i. subacute thyroiditis ii. postpartum thyroiditis iii. hashitoxicosis - transient thyrotoxicosis phase of Hashimoto's C. Atypical (rare) - TSH high, high T3/T4 i. thyrotoxicosis factitia - taking thyroid hormone (suppresses axis --> thyroid is smaller than normal) ii. TSH secreting pituitary tumor iii. struma ovarii - ovarian teratoma making thyroid hormone iv. hydatidiform mole (HCG overproduction which binds to TSH receptor)

Answer 23

1. TSH - single best test of thyroid function (but does not inform about degree of thyroid dysfunction) --> increases if thyroid levels low or decreasing if thyroid levels are high - always get a free T4 after abnormal TSH result to determine extent of hypothyroidism or thyrotoxicosis - TSH not good test if TSH/pituitary (secondary disease e.g. central hypothyroidism) is the problem 2A. Primary hypothyroidism (Hashimoto's) - low T3/T4, high TSH B. Thyrotoxicosis (Grave's) - high T3/T4, low TSH C. Atypical Thyrotoxicosis (TSH adenoma, thyroid hormone resistance)- high T3/T4, high TSH D. Central hypothyroidism (pituitary problem) - low T3/T4, low TSH

Answer 24

1. Treatment for hypothyroid - thyroid hormone - most commonly prescribed is synthetic T4 levothyroxine (e.g. Levothyroid, Levoxyl) - t1/2=7 days with 1xday dosing - synthetic T3 (Triostat, Cytomel) - t1/2=1 day, multiple daily dosings *limited use* - check ACTH levels prior to T4 therapy - give glucocorticoids if ACTH is low (raising thyroid levels will increase BMR and thus need for cortisol) 2. Side effects A. Wolff-Chaikoff Effect --> too much iodide inhibits organification (production of DIT/MIT) --> ↓ T3/T4 production - used pharmacologically via KI potassium iodide tablets --> temporary block of thyroid e.g. pre-op or for short-term tx of Grave's disease - within a week, get escape from W-C effect --> chronic high iodide inhibits Na/I symporter B. Jod-Basedow Effect --> iodide-induced thyrotoxicosis - happens if you give iodide to patient with thyroid deficiency and autonomous nodules --> they can use nodules to make thyroid hormone --> ↑ T3/T4 production * opposite of wolff-chaikoff*

Answer 25

1. Treatment for hyperthyroid (Graves, toxic nodules, thyroid cancer) A. Radioactive iodine - can give via oral pill in outpatient setting - no natural treatments B. Anti-thyroid drugs (thionamides) - propylthiouracil PTU, methimazole (Tapazole) - block thyroperoxidase TPO --> inhibit iodide oxidation and organification - PTU also inhibits peripheral T4--> T3 conversion mediated by D1/D2 - methimazole preferred since it is safer, EXCEPT in pregnancy (in which PTU is preferred) since it can cause aplasia cutis in newborn - side effects - most common --> maculopapular pruritic rash; dangerous but reversible --> hepatitis, agranulocytosis

Answer 26

1. Thyroid nodules v common - only 5% of biopsied nodules are cancer - risk factors for nodules and cancer - age, female gender 2. Approach for thyroid nodule work-up - Do TSH and free T4: A. normal TSH and low fT4 --> most nodule pts have normal thyroid function (problem is structural and not functional) --> do fine needle aspiration FNA biopsy to see if benign/malignant B. high TSH --> probably Hashimoto C. low TSH --> RAI (radioactive iodine) scan i. hot nodule - high fT4, benign - due to Grave's, multinodular goiter; do not need to biopsy ii. cold or warm - low fT4, seen in adenoma or carcinoma --> biopsy via FNA

Answer 27

1. Papillary - most common (85%) - differentiated thyroid cancer from follicular epithelium A. Histology - papillae with Orphan Annie eye nuclei and psammoma (concentric calcified) bodies B. Marker - thyroglobulin (colloid) levels C. Mets - cervical neck lymph nodes; excellent prognosis - treat with surgery, radioactive iodine, and T4 for TSH suppression 2. Follicular - differentiated thyroid cancer from follicular epithelium A. Histology - malignant proliferation of follicles with invasion of surrounding fibrous capsule B. Marker - thyroglobulin (colloid) levels C. Mets - spreads hematogenously to lung, bone

Answer 28

3. Medullary - malignant proliferation of parafollicular C cells A. Histology - sheets of malignant cells in amyloid stroma (calcitonin deposits as amyloid) that stains Congo red B. Marker - calcitonin C. Mets - multiple D. 25% cases hereditary - associated with MEN 2A and 2B (familial RET mutations) - MEN2A: medullary carcinoma, pheochromocytoma, parathyroid adenoma - MEN2B: medullary carcinoma, pheochromocytoma, ganglioneuromas of oral mucosa (eg tongue), Marfinoid body habitus 4. Anaplastic - usually seen in elderly A. Histology - undifferentiated tumor of thyroid B. Marker - none C. Mets - invades local structures, v poor prognosis --> death via dysphagia or respiratory compromise

Answer 29

1. Normal variants A. Familial short stature - normal growth rate, age of puberty, and bone age --> will always be short B. Constitutional Delay of growth - can reach normal height but temporary reduction in growth rate for age; delay in age of puberty and delayed bone age (epiphyses not fused yet, so room to grow) 2. Pathologic variants A. Disproportionate (limbs disproportionately short for the trunk or vice versa) due to genetics or bone abnormalities eg rickets, osteogenesis imperfecta B. Proportionate - growth is proportionate but there is not enough i. prenatal - intrauterine growth restriction (IUGR), genetics, defects in pituitary devlpt ii. postnatal - chronic disease, malnutrition, psychosocial dwarf, endocrine disease (growth hormone deficiency) 3. Idiopathic - diagnosis of exclusion - no short relatives - no history of puberty delay in family - all endocrine testing normal

Answer 30

Growth hormone 1. GHRH (hypothalamus) --> binds to receptor on somatotroph in anterior pituitary --> GH synthesized and secreted --> IGF-1 (liver), fat metabolism, ↑ glucose levels (↓ insulin sensitivity), ↑ muscle mass, bone growth 2. GH hypersecretion A. Cause - benign pituitary somatotroph adenoma with constitutively active Gs alpha mutation B. Diagnosis - ↑ GH after oral glucose tolerance test OGTT (glucose should suppress GH and cause levels to decrease) - present as macroadenomas C. Clinical i. before puberty - gigantism ii. after puberty - acromegaly - large hands and feet, large jaw, deep voice, goiter, soft doughy hands, glucose intolerance, cardiomegaly D. Treatment - surgical resection of tumor is first line treatment, then radiation, pharma (octreotide - somatostatin analog that suppresses GH release, pegvisomant - GH receptor antagonist)

Answer 31

3. GH deficiency A. Causes - most commonly without known cause but can have mutations in GH receptor, signaling pathway, IGF-1 B. Diagnosis - data on height curve (<2SD below mean), screening via lab values for IGF-1 and IGFB-3 - definitive testing via provocative testing with stimulation (insulin, arginine, GHRH, exercise) C. Clinical - GH stimulates liver IGF-1 for long bone growth, anabolic effects on muscle, decreases insulin sensitivity, and has catabolic effects on adipocytes i. children - present with normal birth weight and height (GH not required for in utero growth) - severe deficiency presents at birth with small phallus (boys) - mild deficiency presents after 6 mos with subnormal growth rate - children have cherubic appearance with short stature, increased body fat (central obesity), high-pitched voice, thin hair, poor nail growth, delayed dentition, and decreased muscle mass ii. adults - decreased bone density, central obesity, depression D. Treatment - growth hormone (somatropin), recombinant IGF-1 (mecasermin)

Answer 32

1. HP Axis: GnRH (hypothalamus) pulsatile secretion --> GnRH binds to receptor on gonadotrophs in anterior pituitary --> LH and FSH synthesis and secretion A. Female - LH controls production of androstenedione in ovarian theca internal cells - FSH regulates conversion of androstenedione to estradiol E2 in ovarian granulosa cells B. Male - LH controls production of testosterone in Leydig cells; FSH concentrates testosterone and regulates spermatogenesis in Sertoli cells 2. Feedback A. Female - estradiol E2 has positive feedback on pituitary and hypothalamus --> mid-cycle surge --> triggers ovulation - at other times, feedback is negative B. Male - testosterone always has negative feedback to pituitary and hypothalamus

Answer 33

1. GnRH - neurons originate in nasal placode, migrate through cribriform plate / olfactory bulb to get to hypothalamus - GnRH synthesized in preoptic nuclei of hypothalamus --> goes through portal vessel to pituitary - pulsatile secretion - increased GH receptor expression/sensitization associated with the pulse --> leads to pulsatile secretion of LH and FSH; any disruption leads to hypogonadism - continuous GnRH --> low levels of LH and FSH 2. Kallman syndrome (congenital- XLR) - mutated KAL1 protein --> defective migration of GnRH neurons through olfactory bulb --> hypothalamic hypogonadotropic hypogonadism + anosmia - enuchoidal proportions (arm span >> height), color blindness, midline defects (Eg cleft palate) - undetectable testosterone, LH, FSH - pituitary function normal

Answer 34

1A. Primary hypogonadism - ↓ production of sex hormones due to problem with gonads; ↑ LH, FSH B. Secondary - ↓ LH, FSH C. Tertiary - ↓ GnRH 2. Causes: A. Secondary - pituitary adenoma (rare, acquired), low body weight due to anorexia, exercise (functional), ectopic --> increase CRH and ACTH --> inhibit GnRH --> inhibit LH and FSH secretion B. Tertiary - Kallman syndrome 3. Clinical - amenorrhea, gynecomastia, infertility, decreased libido, absence of secondary sexual characteristics (eg body hair), osteoporosis (gonadal hormones required for proper bone density), reduced libido, increased BMI and body fat %, depression, sleeplessness, hot flashes 4. Treatment - estrogen/testosterone replacement A. Congenital/Kallman's - pulsatile GnRH from pump B. Acquired - pituitary surgery C. Functional - increase body weight, long-acting GnRH agonist (eg leuprolide, gonadorelin) to decrease body secretion of GnRH

Answer 35

1. Normal puberty - Hypothalamic GnRH --> LH and FSH --> - stimulate testosterone in males --> gonadarche (increased testes) - stimulate estradiol in females --> thelarche (onset of breast development), menarche is late event in pubertal devlpt (after maximum growth velocity); occurs at 12 years - stimulates adrenal glands --> adrenal androgens --> adrenarche (Tanner pubic hair); occurs at 15 years 2. Tanner stages for breast, genitalia, and pubic hair Stage 1 - no sexual hair, no breast tissue Stage 2 - public hair appears, breast bud, testicular enlargement --> heralds onset of puberty Stage 3 - pubic hair coarsens, breast enlarges, penis enlarges Stage 4 - adult pubic hair but less in quantity, breast enlarges, penis and length width increases Stage 5 - adult pubic hair in inverted triangle, adult penis and testes, adult breasts

Answer 36

1. Delayed puberty - Hypogonadism (Females) no breast devlpt by 13 or menses by 16 (Males) no testicular devlpt by 14 A. Central (85%) - hypogonadotropic --> inability to make GnRH, LH, FSH (hypothalamic/pituitary dysfunction) - constitutional delay of puberty *more common in boys - functional hypogonadotropic hypogonadism - stress, exercise, hyperprolactinemia - permanent hypogonadotropic hypogonadism - genetic, tumors, vascular B. Peripheral/primary (15%) - hypergonadotropic --> high GnRH, LH, FSH (due to loss of negative feedback by estradiol, testosterone) - gonadal dysgenesis - Turner XO, Klinefelter XXY - gonadal failure (eg ovarian/testicular dysfunction) - e.g. premature ovarian failure (associated with Fragile X syndrome), autoimmune, chemo, radiation, torsion C. Treatment i. Girls - ethinyl estradiol; begin prostagen when menstruation starts ii. Boys - testosterone - can give pulsatile GnRH or combo FSH/hCG to induce fertility

Answer 37

1. Precocious puberty - (Females) breast devlpt before 8; (Males) increase in testicular size before 9 A. Central (90%) - gonadotropin (LH/FSH) dependent --> high GnRH, LH, FSH, sex steroids - idiopathic central precocious puberty - MCC *more common in girls - general CNS insult (radiation, trauma) - CNS tumors (hamartomas) B. Peripheral (10%) - gonadotropin (LH/FSH) independent --> high estradiol/testosterone and low LH/FSH - sex steroid secreting tumor in gonad - sex steroid secreting tumor of adrenal, CAH - exogenous estrogen or androgen - McCune-Albright syndrome (activating Gs alpha mutation) --> cafe au lait spots - (Females) ovarian cysts - (Males) - hCG secreting tumor, familial testotoxicosis (LH receptor mutation) C. Treatment - - GnRH agonists (eg leuprolide, gonadorelin) - continuous GnRH secretion induces pituitary desensitization --> lowers levels of LH and FSH

Answer 38

Menstrual cycle - 28 days: 1. Follicular (proliferative) phase - Days 0-13 A. Starts with menses from previous cycle (shedding of endometrium) B. E2 levels low and steady --> negative feedback on LH secretion - inhibin B from pre-ovulatory follicle --> negative feedback on anterior pituitary --> low FSH + non-selected follicles undergo atresia without FSH C. before ovulation, E2 levels spike due to selected follicle --> stimulates FSH secretion (switches to positive feedback) D. in response to high E2, inhibin B production stops and activin is produced by gonadotropes (anterior pituitary) --> activin stimulates FSH secretion --> E2 production and LH receptor expression within granulosa cells of selected follicle *E2 stimulates proliferation/thickening of endometrium 2. Ovulation - Day 14 - preovulatory gonadotropin surge (LH>> FSH) --> LH triggers ovulation (completes meiosis I) 3. Luteal (secretory) phase - Days 15-28 - elevated inhibin A produced by corpus luteum --> negative feedback on FSH - elevated P4 and E2 (P4>>E2) --> affects GnRH pulse frequency --> negative feedback (P4 mostly affects LH and E2 mostly affects FSH) * P4 targets endometrium + myometrium --> development of blood supply 4. Menstruation - Day 28 - P4 and E2 levels decline at end of cycle --> withdrawal bleed (menses) --> shed upper 2/3 of functional layer of endometrium * rise in basal body temperature during luteal phase due to thermogenic P4--> BBT can provide info about ovulation/endocrine functioning * very little variation in luteal phase in women; variation is in follicular phase

Answer 39

Folliculogenesis 1. Primordial - non-growing reserve of immature follicles contain oocyte + one layer of pre-granulosa cells 2. Primary - growing cohort that begin differentiating after recruitment; oocyte + granulosa cells 3. Preentral --> Antral - one follicle selected to further differentiate as the dominant / Graffian follicle - granulosa cells in follicle pregulate FSH receptors 4. Pre-ovulatory - steroidogenic differentiation with granulosa + theca cells --> steroidogenesis starts with RLS - cleavage of C27 side chain to go from cholesterol --> pregnenolone - theca cells have LH receptors; make androgens (androstenedione >>> testosterone) via CYP17 - granulosa cells have FSH receptors; use androgens to make estrogens (estradiol E2 >> E1) via CYP19 - one follicle 4. Ovulation - oocyte released from pre-ovulatory follicle; all hormone levels drop 5. Corpus luteum - formed from pre-ovulatory follicle - theca cells make progesterone P4 - granulosa cells make P4 and E2

Answer 40

Folliculogenesis cycle takes place over 3-4 months with multiple overlapping cycles --> at a given time there are follicles in different growth stages 1. Recruitment - some primordial (Resting) follicles are brought from reserve into growth pool; one recruitment occurs every month - independent of gonadotropins (FSH, LH) ``` #2-4 are gonadotropin-dependent: 2. Selection - one follicle selected from the pool that goes on to mature ``` 3. Luteinization - pre- and post- ovulatory differentiation of the selected follicle (i.e. dominant follicle = Graffian follicle) --> selected follicle drives serum hormone level changes 4. Luteolysis - corpus luteum degenerates Atresia - apoptotic death of non-selected follicles, can happen at any time

Answer 41

1A. Primary amenorrhea - never had a period; by age 16 with secondary sexual characteristics or by age 14 without secondary sexual characteristics (breasts, pubic hair) B. Secondary amenorrhea - has had a period previously but 6+ mos without menses C. Oligomenorrhea - menstrual interval between 1-6 mos 2. MCC is etiologies secondary to abnormal ovarian function A. Progestin challenge (progestin withdrawal test) - pts with normal physiological levels of estrogen will have a withdrawal bleed within 1 week --> - bleed --> problem due to PCOS, anovulation - no bleed --> do estrogen + progestin test B. Estrogen + Progestin test --> - no bleed --> utero-vaginal obstruction - bleed --> problem with estrogen --> check FSH C. FSH levels - high --> ovarian failure - low --> hypothalamic-pituitary dysfunction

Answer 42

1. PCOS - dysfunction at level of correlating folliculogenesis with menstrual cycle luteal phase A. Causes: unknown; correlated with diabetes: ↑ insulin --> ↑ GnRH pulsatility --> ↑ LH levels --> ↑ androgen production in theca cells --> ↑ peripheral conversion to estrogens --> negative feedback --> ↓ FSH --> cystic degeneration of follicles B. Labs: - ↑ LH/FSH ratio (normal ratio is FSH >> LH) - ↑ AMH - ↑ androgens - ↓ sex hormone binding globulin SHBG (more free testosterone) C. Clinical: obese young woman with infertility, oligomenorrhea, and hirsutism - hirsutism - androgens stimulate pilosebaceous units to form terminal hairs - acne - excess secretion from sebaceous glands; inflammatory on face, chest, back - male-pattern alopecia - "string of pearls" on ultrasound due to multiple follicles but no dominant follicle ovulated (bc no LH surge) D. SHBG binds tighter to testosterone than estrogens - Increased SHBG --> estrogens, hyperthyroidism, hepatitis, anticonvulsants - Decreased SHBG --> androgens, hypothyroidism, obesity, insulin resistance

Answer 43

2. Sheehan's syndrome - postpartum hypopituitarism or postpartum pituitary necrosis - postpartum hemorrhage + hypovolemic shock --> acute infarction, ischemia - affects all hormones produced by pituitary (GH, FSH LH, ACTH, TRH) - but #1 symptom is failure of lactation 3. Premature ovarian failure - high FSH levels but low estrogen A. causes: i. idiopathic ii. genetic - Y chromosome, abnormality of X, fragile X pre-mutation (CGG repeat expansion) iii. autoimmune *MCC* - hypothyroidism, hypoparathyroidism, hypoadrenalism B. Treatment - prevent osteoporosis 4. Uterovaginal obstruction - Asherman's syndrome - result of overaggressive dilation and curettage --> loss of basalis and scarring (intrauterine adhesions) - pelvic radiation

Answer 44

Sexual development: gonads indifferent up until 7 weeks in development; differentiation based on SRY gene on Y chromosome A. Male: Y chromosome --> SRY --> testis determining factor TDF --> SOX9 --> A. Sertoli cells: anti-Mullerian hormone AMH --> Mullerian (paramesonephric) duct regression --> absent uterus and fallopian tubes B. Leydig cells i. testosterone --> testicular descent, conversion to DHT, Wolffian (mesonephric) duct devlpt --> ejaculatory ducts, epididymis, seminal vesicles, vas deferens - DHT (from action of 5-alpha reductase on testosterone) external genitalia differentiation --> penis, scrotum, prostate * testosterone is a prohormone --> DHT via 5alpha reductase - -> estradiol E2 via CYP19 aromatase B. Female: No AMH --> - Mullerian (paramesonephric) duct --> fallopian tubes, uterus, upper 2/3 vagina - urogenital sinus - lower 1/3 vagina

Answer 45

2. Breasts present, uterus absent --> high estrogen + AMH A. MKRH/Mullerian agenesis - 46XX but congenital abnormality --> failure of mullerian duct development (uterus, fallopian tubes) - normal female with ovaries and testosterone levels --> normal secondary sexual characteristics (e.g. pubic hair) with primary amenorrhea - correlated with renal and skeletal anomalies B. Androgen insensitivity syndrome - 46XY - inability to respond to androgens or receptor defect - XL-R with Xq12 deletion - clinical manifestation varies depending on severity of insensitivity (can be female or male phenotype) - complete insensitivity: female phenotype, presents at puberty with primary amenorrhea, short blind-end vagina, no cervix/uterus, large breasts, tall stature, no pubic hair - male levels of testosterone; can have testes in inguinal canal (remove testicles i.e. gonadectomy) to reduce risk of germ cell tumor Differences: Mullerian agenesis has female (lower testosterone levels) and normal pubic hair; AIS has male testosterone levels and no pubic hair

Answer 46

3. Breasts absent, uterus present --> low estrogen, no AMH A. Gonadal dysgenesis --> high FSH - Turner's syndrome (XO) - MCC; short, streak gonads, aortic coarctation, horseshoe kidneys - 46XX - 17Ohase deficiency - type of congenital adrenal hyperplasia with ↑ mineralocorticoids and ↓ androgens - 46XY - SRY gene mutation i.e. Swyer's Syndrome B. Hypothalamic/pituitary failure e.g. Kallman's --> low FSH 4. Breasts absent, uterus absent --> low estrogen, AMH present A. 46XY - 17Ohase deficiency B. Testicular regression syndrome 5. Breasts present, uterus present --> congenital outflow obstruction A. imperforate hymen (no hymenal ring) B. transverse vaginal septum (horizontal wall of tissue that blocks vagina)

Answer 47

1. Maternal recognition of pregnancy in weeks 3-4 - placenta makes GnRH --> stimulates syncytiotrophoblasts in placenta --> produce hCG (potent LH analog), peaks at 12 weeks --> binds LH receptors on corpus luteum --> progesterone P4 produced --> negative feedback on hypothalamus + pituitary (HPA axis control removed) --> no menstrual cycles in pregnancy - progesterone production shifts from corpus luteum to placenta in late 1st trimester (corpus luteum degenerates) 2A. Fetus: - fetal pituitary gland produces ACTH --> stimulates fetal adrenal glands to produce DHEAS --> placenta converts DHEAS to estriol E3 B. Maternal progesterone P4 used by: - fetal adrenal glands to make DHEAS and cortisol - placenta to make E3

Answer 48

3A. Progesterone - highest levels of all the hormones - made by corpus luteum in 1st trimester - made by placenta in 2nd and 3rd and peaks before labor B. E2 estradiol = E3 estriol throughout most of pregnancy - activation of uterine ER --> E3 production --> ↑ E3>>E2 induces contractions 4. hCG (peaks in week 12) can stimulate TSH receptor (beta subunit homology) --> drives thyroid function independent of TSH --> ↑ free T4 and ↓ TSH but then reverts to normal by second semester - ↑ TBG (thyroxine-binding globulin) and ↑ total T4 throughout pregnancy - placenta makes Type 3 iodothyronine deiodinase --> metabolizes free T4 into rT3 *keeps T4 levels appropriate for fetus* 5. Gestational diabetes due to ↑ placental growth hormone

Answer 49

1. Mother needs to increase body fluid levels due to additional circulation A. placental E2 + vascular underfilling (due to shunt-like placental circulation) --> activate RAAS --> Ang II - AII-induced vasoconstriction overridden by relaxin (from corpus luteum, placenta) and P4 - but AII and aldosterone do work in kidney for Na+ and H20 reabsorption B. AVP - progesterone + E2 stimulate AVP release from posterior pituitary, which acts at 3 receptors: i. V1R - vasoconstriction overridden by relaxin, P4, E2 ii. V2R for distal H20 reabsorption iii. V3R (anterior pituitary) --> ACTH --> glucocorticoids Overall result - ↑ in body fluid not vasoconstriction --> no ↑ in BP during pregnancy

Answer 50

2. Renal function - ↑ perfusion, ↓ vascular resistance --> ↑ GFR --> SGLT can saturate --> glucosuria and ↑FEIodine - overall result: ↓ plasma creatinine and BUN 3. Cardiac/hemodynamic function A. first trimester: ↑ intravascular volume, ↑ RBC (due to ↑ P4), ↑ vasodilation --> facilitates placental perfusion (↑Q and ↓P) B. second and third trimesters: ↑ maternal HR, ↑ CO (bc CO=HR*SV) 4. Cardiac/pulmonary function - ↑ plasma volume --> ↑ venous return --> but central venous pressure normal due to ↑ CO - ↓ pulmonary vascular resistance --> but pulmonary arterial pressure normal due to ↑ CO 5. BP = CO * TPR --> stays constant during pregnancy ↑CO (due to ↑ HR) and ↓TPR (due to relaxin, estrogen, P4, NO) --> ↓ diastolic pressure and ↑ pulse pressure

Answer 51

1. Chest and lungs - rib cage expands (relaxin softens rib ligaments) - ↓ chest diameter and diaphragm pushed upwards --> ↓ ERV and thus functional residual capacity FRC (ERV+RV), ↓ chest wall compliance 2. Respiration - pregnant women more sensitive to changes in P02 and C02 - placental progesterone P4 --> lowers C02 sensitivity threshold in medullary respiratory centers --> ↑ minute ventilation --> ↑ respiratory rate --> ↑ tidal volume TV - P4 also ↑ sensitivity of peripheral chemoreceptors to hypoxia - ↑ metabolism --> ↑ C02 --> stimulates chemoreceptors in carotid bodies 3. ↑ ventilation --> ↓ PAC02 --> ↑ PA02 and ↓ PaC02 (respiratory alkalosis) --> ↑ Pa02 + kidneys excrete bicarb to maintain homeostasis - creates gradient favoring maternal --> fetal 02 transfer and fetal C02 offloading 4. Maternal Hb curve shifts right (↓ 02 binding affinity) Fetal Hb curve shifts left (↑ 02 binding affinity) - volume increase can lead to maternal physiologic anemia but 02 delivery maintained bc of ↑ CO

Answer 52

Highest susceptibility to teratogens at 3-8 weeks (organogenesis) 1. ACE inhibitors ("prils")- renal damage 2. Aminoglycosides (Streptomycin, gentamicin, etc) - absent digits, ear and facial anomalies 3. Carbamezapine (anticonvulsant) - craniofacial defects, fingernail hypoplasia, Intrauterine growth restriction IUGR, neural tube defects 4. Folate antagonists (methotrexate, trimethoprim) - neural tube defects 5. Lithium - Ebstein anomaly (downward displacement of tricuspid valve --> Tricuspid regurg)

Answer 53

6. Methimazole (antithyroid) - aplasia cutis congenita (focal absence of skin) 7. Iodine - too little --> cretinism; too much --> goiter 8. Maternal diabetes - caudal regression syndrome (mermaid) , congenital heart defects, neural tube defects 9. Vitamin A excess - spontaneous abortions, cleft palate, cardiac abnormalities 10. Alcohol - fetal alcohol syndrome (low nasal bridge, epicanthal folds, missing philtrum, low set ears, thin upper lip)

Answer 54

1. Ectopic pregnancies A. Pathophysiology - fetus implants outside of the uterus, most commonly in fallopian tube - MCC of maternal mortality in 1st semester (internal hemorrhage) B. Risk factors - scarring due to salpingitis (PID) or endometriosis, infertility, assisted reproductive techniques, tubal surgery, smoking C. Clinical - lower quadrant abdominal pain and vaginal bleeding a few weeks after missed period D. Diagnosis - trans-vaginal ultrasound, beta hCG E. Treatment - methotrexate (early on in unruptured ectopics); surgical (laparoscopy)

Answer 55

2. Gestational trophoblastic diseases A. Pathophys - abnormal proliferation of placental tissue, usually manifest before 20 weeks - non-cancerous = hydatidiform mole i. complete - 2 sperm fertilize empty egg with no nucleus/chromosomes --> 46 chromosomes no maternal DNA --> all placental tissue and no fetus - diffuse proliferation of syncytiotrophoblasts (higher hCG) with theca-lutein cysts around hydropic villi - increased chance of malignancy (choriocarcinoma) ii. partial - 2 sperm fertilize single egg --> too much paternal DNA --> may have unviable fetus - focal proliferation of cytotrophoblasts B. Risk factors - asian, maternal age, previous moles C. Clinical - uterine bleeding, no fetal heart tones, preeclampsia <20 weeks - passage of grape-like masses if woman doesn't receive prenatal care D. Diagnosis - "snowstorm" appearance on ultrasound - uterus much larger and beta hCG much higher than expected for gestational age E. Treatment - surgical evacuation, follow up for detection of malignant change

Answer 56

3. Preeclampsia A. Pathophysiology - - placental dysfunction (failure of trophoblasts to adequately invade uterine spiral arteries and dilate them) --> reduced placental blood flow --> uteroplacental ischemia --> oxidative/inflammatory stress on maternal circulation --> vasospasms, endothelial dysfunction, coagulation --> vasoconstriction --> maternal systemic organ ischemia B. Risk factors - nulliparous (first pregnancy), multiple pregnancies, chronic HTN, 35+ yo, obesity, African, autoimmune C. Clinical - non-pitting edema, headaches, vision problems, SOB, nausea/vomiting, abdominal pain (RUQ) - HELLP syndrome - severe form of preeclampsia with Hemolysis, Elevated Liver enzymes, and Low Platelets - Eclampsia - preeclampsia + seizures D. Diagnosis - BP > 140/90 at 20+ weeks, proteinuria E. Treatment - delivery (usually resolves after delivery) - use IV magnesium sulfate (Ca2+ antagonist) to prevent seizures *reverse with IV calcium gluconate if needed*

Answer 57

4. Placental abruption A. Pathophysiology - premature separation of normally implanted placenta and wall of uterus B. Risk factors - trauma, maternal hypertension, icigarette smoking, prior abruption C. Clinical - PAINFUL contractions and vaginal bleeding 5. Placenta previa A. Pathophysiology - placenta is located over/near the internal cervical os --> baby cannot be delivered vaginally B. Risk factors - increased age and parity, prior C-section, smoking C. Clinical - PAINLESS vaginal bleeding; do NOT perform pelvic exam (you will rupture the placenta) 6. Placenta accreta/increta/percreta A. Pathophysiology - placenta does not separate after delivery; should separate within 30 min of delivery i. accreta - invades decidua ii. increta - invades muscle wall of uterus iii. percreta - invades serosal lining of uterus, can growth through the wall of the uterus B. Clinical - life threatening bleeding

Answer 58

1. mass, positive screening test (asymptomatic), nipple discharge, skin changes, pain (common problem but infrequently cause of cancer) 2A. Inspection - symmetry, size, scars - skin changes (erythema, dimpling) - nipple position (usually everted) B. Palpation - systemic, nipple-areola, axillary/supra-clavicular lymph nodes 3. Mammary ridge forms "milk streak" from budding of ectoderm into surrounding mesenchyme - failure to completely regress --> accessory nipple (usually on thorax below breasts) or accessory mammary tissue (usually in axilla)

Answer 59

1. Acute mastitis A. Cause - MCC is Staph aureus B. Pathopys - bacterial invasion through fissures in nipple (esp associated with breastfeeding) C. Clinical - erythematous (red) breast with prurulent nipple discharge *clinical symptoms without breastfeeding --> think inflammatory breast cancer D. Treatment - drainage (continue breastfeeding) and antibiotics (dicloxacillin) 2. Periductal mastitis A. Cause - smoking B. Pathophys - relative Vitamin A deficiency --> squamous metaplasia of lactiferous ducts --> keratin blocks ducts --> inflammation C. Clinical - subareolar mass with nipple retraction

Answer 60

3. Duct ectasia A. Cause - - in multiparous postmenopausal women B. Pathophys - inflammation with dilation (ectasia) of subareolar ducts C. Clinical - periareolar mass with green-brown nipple discharge (inflammatory debris) * cancer should be on differential 4. Fat necrosis A. Cause - trauma B. Pathophys - trauma --> bleeding --> inflammation --> incomplete resolution with saponification, skin thickening C. Clinical - palpable mass; calcification on mammography

Answer 61

1. Fibrocystic changes - most common benign breast condition A. Causes - consequence of cyclical breast changes with menstrual cycle B. Pathophys - non-proliferative changes (fibrosis, cysts, "adenosis" - ↑ in acini per lobule) in terminal duct-lobular unit with no increased risk of invasive carcinoma C. Clinical - vague irregularity of breast tissue - "lumpy breast" in upper outer quadrant - can undergo apocrine metaplasia (resemble sweat glands with eosinophilic cytoplasm) 2. Breast cysts - benign, common in 40-50 yo A. Pathophys - due to lobule dilatation and coalescence B. Clinical - blue-dome appearance, mobile and firm, can be v large --> no increased cancer risk - histology: flattened epithelium - US: anechoic - cyst rupture can lead to inflammatory changes and fibrosis --> palpable firmness

Answer 62

3. Gynecomastia - benign enlargement of glandular breast tissue in men A. Causes i. physiologic: in adolescence (↑ estrogen) and older men (obesity) ii. certain drugs (e.g. spironolactone, ketoconazole) - interferes with binding of hormones to sex hormone binding globulin SHBG --> E2 not bound tightly so kicked off --> ↑ in free estrogen iii. pathologic: endocrine abnormalities, neoplasms B. Pathophys - estrogen stimulates duct epithelial hyperplasia, duct elongation, and stroma proliferation C. Clinical - subareolar fat/tissue

Answer 63

4. Sclerosing adenosis A. Cause - most common change in premenopausal breast; hormone mediated B. Pathophys - increased acini, stromal proliferation and fibrosis C. Clinical - pain, lump (masses of small glands in fibrous stroma) - 2x overall increased breast cancer risk - mammographic calcifications 5. Atypical hyperplasia - A. Cause - proliferative change, pathologic diagnosis B. Pathophys - ducts or lobules filled with monomorphic proliferation of regularly spaced cells C. Clinical - 5x overal increased breast cancer risk 6. Intraductal papilloma A. Cause - proliferative change B. Pathophys - papillary growth into a large duct; fibrovascular stalk with projections lined by epithelial (luminal) and myoepithelial cells C. Clinical - bloody nipple discharge in premenopausal women; solitary and located beneath areola - must distinguish from papillary breast carcinoma - also has bloody nipple discharge but more common in postmenopausal women

Answer 64

7. Fibroadenoma - A. Cause - most common benign neoplasm; seen in younger / premenopausal women B. Pathophys - tumor of fibrous tissue and glands - proliferation of lobular stroma --> compresses epithelium C. Clinical - well-circumscribed, mobile, marble-like mass - estrogen sensitive - grows during pregnancy/menstruation - benign; no increased risk of breast cancer 8. Phylloides tumor A. Cause - in postmenopausal women B. Pathophys - fibroadenoma-like tumor with overgrowth of fibrosis - leaf-like projections on biopsy C. Clinical - mostly benign; large, rapidly-growing mass probably phylloides tumor

Answer 65

1. Ductal carcinoma in situ (DCIS) A. Pathophys - malignant clonal proliferation of epithelial cells in ducts and lobules with no invasion of basement membrane - disease can travel in the duct system B. Imaging - small, clustered, pleiomorphic calcifications on mammography --> need to biopsy C. Histology i. Comedo - tumor cells with high grade nuclei and areas of central necrosis; worst prognosis D. Clinical - Paget disease (Atypical presentation) --> DCIS that extends up lactiferous ducts and involves skin of the nipple --> disrupts keratinocytes --> nipple ulceration, erythema, itching, scaling - cytokeratin 7 (CK7) marker, PAS stain positive * Paget's disease is associated with underlying ductal adenocarcinoma

Answer 66

2. Lobular carcinoma in situ (LCIS) - malignant proliferation of cells in lobule - not considered to be a true breast cancer but instead a marker of risk --> increased risk for invasive carcinoma in either breast A. Pathophys - cells lack E-cadherin adhesion protein B. Imaging - incidental finding, not found on mammography or physical exam (no mass or calcifications) C. Histology - atypical lobular cells proliferating with no invasion of basement membrane - treat with tamoxifen to reduce risk of carcinoma 3. Invasive lobular carcinoma - cells grow in single file pattern --> no duct formation due to lack of E-cadherin - spreads via lymphatics - presents as mass - need to biopsy for diagnosis

Answer 67

1. Invasive ductal carcinoma - 80% of all invasive breast cancer cases - histology: duct-like structures in desmoplastic stroma - prsets as mass on exam or mammography - subtypes: tubular, mucinous, medullary, inflammatory, papillary 2. Inflammatory breast cancer - marker of aggressive disease; subtype of invasive ductal carcinoma - invasive ductal carcinoma cells block dermal lymphatic vessels --> blockage leads to inflammation --> rapid onset of inflamed, swollen breast - presentation is similar to acute mastitis - treated differently - chemo (tamoxifen) prior to any surgical mgmt 3A. ER+/PR+/HER2- (60%) - most common - treat with tamoxifen (selective estrogen receptor modulator SERM) - antagonist at breast ERs - other treatment option is anastrozole (aromatase inhibitor) B. HER2+ (20%) - can treat with trastuzumab C. ER-/HER2- (20%) - "triple negative" when progesterone receptor PR - - seen in young women, BRCA (+), and African descent - worst prognosis 4. Most common familial BC is due to BRCA mutation (tumor suppressor gene) - BRCA1 - breast (medullary invasive ductal carcinoma) and ovarian (Serous cystadenocarcinoma) - BRCA2 - male breast cancer

Answer 68

1. Risk factors - #1 is multiple sexual partners; started having sex young, smoking - immunocompromised eg. HIV - most commonly in middle aged women 40-50 yo (takes decades to go from HPV infection --> CIN --> carcinoma) 2. Cause - HPV (Sexually transmitted DNA virus) - necessary but not sufficient - HPV infects basal layer of the epithelium - at the transition zone between stratified squamous of ectocervix and simple columnar epithelium of endocervix - 90% infected will clear virus on their own; those who don't / have chronic infection can develop cervical dysplasia A. High-risk: HPV16, 18, 31, 33 --> produce E6 and E7 proteins --> E6 binds p53 and E7 binds Rb for degradation; cause cervical and oral cancers B. Low risk: HPV6, 11; cause genital warts (condyloma) 3. Clinical - most women asymptomatic, have abnormal PAP smear - post-coital vaginal bleeding - advanced tumor -- invades anterior uterine wall into bladder --> obstructs ureters --> hydronephrosis, leg edema, pain

Answer 69

Cervical intraepithelial neoplasia 1. Histology - koilocytes, disordered cellular maturation, nuclear atypia, increased mitotic activity within cervical epithelium 2. Classification - based on thickness of epithelium due to immature dysplastic cells Stage I - <1/3 of thickness Stage II - <2/3 of thickness Stage III - almost entire thickness In situ - entire thickness of epithelium --> invasive squamous cell carcinoma 3. Histology - koilocytes (collapsed nucleus surrounded by a halo) *pathognomonic for HPV infection*

Answer 70

1. Leiomyoma (fibroids) - benign smooth muscle neoplasms arising from myometrium; most common tumor in women A. Risk factors - i. related to estrogen exposure - premenopausal, low parity, obesity ii. race (African American) iii. family hx - leiomyomas are NOT precursor lesions to leimyosarcoma B. Pathology - multiple, well-defined, white, whorled round masses found in myometrium - bundles of homogenous smooth muscle cells with oval nuclei C. Clinical - commonly asymptomatic but pelvic pain, urinary sx, abnormal uterine bleeding, infertility 2. Leiomyosarcoma - malifnant proliferation of smooth muscle arising from myometrium A. Risk factors - rare, usually arises de novo in postmenopausal women B. Pathology - unclear but pathologically distinct from leiomyoma --> nuclear atypia and high mitotic index - single lesion with areas of necrosis and hemorrhage C. Clinical - presents similarly to leiomyoma with bleeding, pelvic pain, pelvic mass

Answer 71

Endometrial cancer - incidence increases with age; most common invasive carcinoma of female genital tract 1. Type I (80%) - hyperplasia type; more common A. Risk factors - unopposed estrogen exposure e.g. tamoxifen; obesity, chronic anovulation, nulliparity - genetics - PTEN, KRAS, Lynch syndrome B. Pathology - arises from endometrial hyperplasia that mimics proliferative endometrial glands - invades basement membrane, spreads via direct myometrial invasion and can metastasize via lymphatics 2. Type II (20%) - serous type A. Risk factors - older women (endometrial atrophy), p53 mutation B. Pathology - sporadic; poorly differentiated with no evident precursor lesion; clear cells (in basal layer); atrophic endometrium - serous histology - resembles serous carcinoma of ovary with papillary architecture, nuclear atypia, and psammoma bodies - all high grade - exhibit aggressive behavior - intraperitoneal and lymphatic spread 3. Clinical - most common sx is abnormal (postmenopausal) bleeding --> need to do endometrial biopsy 4. Treatment - platinum compounds (cisplatin), paclitaxel, doxorubicin

Answer 72

Ovarian cancer 1. Risk factors - nulliparity, delayed menopause (continued estrogen exposure) - genetics - BRCA1 (mucinous ovarian cancer), Lynch Syndrome 2. Clinical - sx vague until disease advanced - triad: bloating, increasing abdominal girth, urinary symptoms (urgency, frequency) 3. Physical findings - ovarian mass, ascites (due to diffuse peritoneal seeding of malignant serous tumors), pleural effusion, abdominal mass, bowel obstruction - Ca-125 is serum marker for monitoring response and recurrence 4. Types - based on cell of origin A. Surface epithelium - most common, worst prognosis B. Germ cells C. Sex cord-stroma D. Metastasis - eg Krukenberg tumor - bilateral ovarian mucinous tumors with signet ring cells; due to metastatic gastric carcinoma

Answer 73

Surface epithelial cell tumors = cystadenocarcinoma; most common; malignant tumors cause diffuse peritoneal seeding --> ascites and omental caking 1. Serous (epithelial lining of fallopian tube) - filled with watery fluid A. Benign (70%) - usually cysts lined with cuboidal epithelium; in younger women - low grade B. Malignant (30%) - cyst lining is thick and shaggy; in older women; bilateral + psammoma bodies (dystrophic calcification) - aggressive 2. Mucinous (epithelial lining of endocervix) - 90% benign; unilateral; well-circumscribed, large and multiloculated, filled with gelatinous mucus-like fluid - solid areas of growth indicates malignancy - differentiated from mucinous Krukenberg tumor due to metastatic gastric carcinoma -- which are bilateral 3. Endometrioid - tubular glands resembling endometrium; association with endometrial carcinoma and endometriosis in young women 4. Transitional cell i.e. Brenner tumors - rare; mostly benign - solid, encapsulated, unilateral tumor - stroma with nests of transitional-type (bladder-like) epithelium

Answer 74

Germ cell tumor (GCT) - usually occur in women of reproductive age 1. Teratoma i.e. dermoid cysts A. Mature- most common ovarian tumor in 20-30 yo women - almost all are benign, unilateral - contain mature tissue from all three germ layers and lined by epidermis - lined by skin, can contain hair, teeth - specialized: struma ovarii --> epithelium is mature thyroid tissue --> hyperthyroid B. Immature - also in younger women - bulky and solid - contain immature elements e.g. foci of neuroepithelial differentiation 2. Dysgerminoma - unilateral; composed of immature germ cells (resemble oocytes); occurs with gonadal dysgenesis - all malignant (30% aggressive and spread), all radiosensitive (good cure rate) - male counterpart is testicular seminoma - serum LDH elevated 3. Yolk sac tumors - unilateral, more common in children - Schiller-duval bodies (glomerular-like structures) - serum AFP (alpha feto protein) elevated

Answer 75

Sex cord stromal tumors - from ovarian stroma 1. Granulosa cell - malignant neoplastic proliferation of granulosa and theca cells; unilateral A. Cause - FOXL2 gene mutation B. Pathology - Call-Exner bodies (nests of cells forming primitive follicles with "coffee-bean" nuclei) C. Clinical - produce large amounts of estrogen --> sx depend on cancer onset i. prior to puberty --> precocious puberty ii. reproductive age --> menorrhagia iii. postmenopause (most common) --> endometrial hyperplasia with postmenopausal uterine bleeding 2. Sertoli-Leydig - proliferation of Sertoli cells (form tubules) and Leydig cells (between tubules) with Reinke crystals A. Cause - DICER1 mutation (microRNA processing) B. Pathology - androgen-secreting; unilateral C. Clinical - virilization (breast atrophy, hair loss, amenorrhea, infertility) and hirsutism (male hair pattern)

Answer 76

I. Hormonal contraceptives - MOA - suppress release of FSH and LH from anterior pituitary --> inhibit follicular development and ovulation - progestin thickens cervical mucus and decreases ovum motility in uterine tubes 1. 2. Non-oral contraceptives A. Combination estrogen and progestin - transdermal patch (Ortho Evra), vaginal ring (NuvaRing) B. Progestin only - subdermal implant (Implanon), injectable (Depo Provera) C. Postcoital - levonorgestrel (Plan B) - progestin, take within 72 hours

Answer 77

Oral contraceptives A. Preparation - progestin alone or combination of estrogen (ethinyl estradiol) and progestin (various names) B. Adverse effects - i. mild adverse effects common - headache/nausea, breakthrough bleeding (insufficient estrogen to maintain endometrial stability) ii. moderate - weight gain, acne and hirsutism (androgen-like progestins), amenorrhea with cessation iii. severe (rare) - thromboembolic disease, MI, cerebrovascular disease i.e. stroke (>35 yo), GI disorders, depression C. Any cardiovascular, cerebrovascular, or thromboembolic disorders - do not take with anything that affects CYP3A4 (metabolizes OCPs) D. Beneficial effects - reduced risk of cysts, ovarian and endometrial cancer, ectopic pregnancy

Answer 78

1. Clomiphene (Clomid) A. MOA - selective estrogen receptor modulator (SERM) - partial agonist at ER and inhibits action of stronger estrogens --> inhibits estradiol negative feedback --> increased release of gonadotropins (LH and FSH) from pituitary B. Indication - stimulates ovulation in women with oligomenorhea, amenorrhea, ovulatory dysfunction C. Adverse effects - hot flashes - breast soreness, heavy menses, nausea/vomiting, weight gain - not due to drug but to hormonal changes with ovulatory cycle 2. Leuprolide (Lupron) A. MOA - GnRH agonist B. Indication - anovulatory women who do not respond to clomiphene - inhibits LH/FSH release --> suppresses spontaneous ovulation as part of controlled ovarian hyperstimulation in assistive reproductive procedures eg IVF

Answer 79

1. PID A. Cause - exposure to Neisseria gonorrhea, Chlamydia trachomatis (Chlamydia more common) B. Clinical - cervical motion tenderness (chandelier sign) - prurulent white cervical discharge - can lead to Fitz-Hugh-Curtis syndrome (infection of liver capsule with violin string adhesions) C. Treatment: - Neisseria - ceftriaxone (intramuscular) --> 3rd generation cephalosporin; beta lactam antibiotic that inhibits cell wall synthesis --> bactericidal - most people have concomitant chlamydia infection - give oral antibiotics --> protein synthesis inhibitors --> bacteriostatic i. macrolide (azithromycin) - targets 50s rb subunit ii. tetracycline (doxycycline) - targets 30S rb subunit

Answer 80

2. Trichomoniasis A. Cause - Trichomonas vaginalis - flagellated protozoan parasite --> motile trophozoite on wet mount - sexually transmitted (only STI caused by a protozoa) - more common in women B. Clinical - vaginitis: foul-smelling, yellow-green vaginal discharge, burning, vulvovaginal itching - cervicitis: strawberry-red cervix C. Treatment - oral metronidazole (Flagyl) - MOA- activated by PFOR enzyme found in bacteria --> turns into toxic radical that damages microbial DNA --> cell death - single oral dose; treat partners as well D. Adverse effects - GI issues (eg diarrhea) bc kills gut flora so take with meals - nausea, headache, dry mouth - contraindicated with alcohol, first semester pregnancy

Answer 81

3. Herpes - epithelial cells with intranuclear inclusion bodies A. Cause - HSV-2 - genital herpes - painful, shallow ulcers with vaginal pain, itching, dysuria + fever, headache, malaise B. Treatment - "vir" antivirals eg acyclovir, valacyclovir, famciclovir - MOA - is first phosphorylated by a viral thymidine kinase --> then competitive inhibits viral DNA polymerase --> blocks viral DNA synthesis - oral regimen --> reduced viral shedding, shorter duration of sx, and reduced time for ulcers to heal C. Adverse effects - well tolerated; occasional GI effects (nausea, vomiting, diarrhea) - take with food - rare neurological issues with valacyclovir high dose

Answer 82

1. Complete androgen insensitivity - dysfunctional androgen receptor; XY with female phenotype A. Hormones: - ↑ testosterone (male range) - ↑ estrogen - ↑ LH/FSH B. Clinical - female phenotype (normal breasts) but - primary amenorrhea - blind vaginal pouch - absent uterus - absent pubic and axillary hair - testes absent or in abdomen, inguinal canal, labial folds 2. Partial androgen insensitivity - can be female or male phenotype 3. 5-alpha reductase deficiency - AR mutation in enzyme for testosterone --> dihydrotestostone (DHT) A. Hormone - elevated testosterone:DHT ratio - androgens, estrogens in normal range B. Clinical - 46XY - hypospadias - urethral opening on underside of penis - virilization at puberty (muscle and phallic growth)

Answer 83

1. eunochoidism - eunuchoid proportions/habitus - legs longer than upper body OR arm span longer than height (due to excessive long bone growth) - no pubertal growth sport - high pitched voice - microgenitalia (small testes) * implies that hypogonadism arose before puberty - eg Klinefelter XXY - eunochoidal with decreased testosterone, elevated FSH/LH --> hypergonadotropic hypogonadism 2. Ddx of gynecomastia - A. circulating estrogen >> testosterone - aging - hyperthyroidism and liver disease (↑ SHBG, which binds tighter to testosterone than estrogen) - increased body fat (adipose aromatization) B. Hypogonadism C. Medications that block male hormones or androgen receptors or raise prolactin eg spironolactone D. tumors of gonads, adrenals, pituitary gland

Answer 84

1. Symptoms of male hypogonadism - decreased energy - poor libido - decreased erectile function, strength and endurance, secondary hair growth - infertility - hot flashes 2. Testosterone replacement A. Indication - symptomatic hypogonadism only B. Benefits - prevents gynecomastia, improved sexual function, prevents premature CAD + osteoporosis C. Side effects - dyslipidemia, HTN, polycythemia, acne, gynecomastia (aromatization), sleep apnea, prostate growth, decreased fertility (negative feedback on FSH and LH) D. Contraindications - prostate cancer, sleep apnea, breast cancer

Answer 85

1. hypogonadotropic hypogonadism - ↓ testosterone - ↓ FSH/LH A. genetic - Kallman, Prader-Willi B. Pituitary dysfunction - hyperprolactinemia, pituitary tumor, sarcoidosis, hemachromatosis C. Other causes - isolated LH deficiency - opiate and steroid use - anorexia/stress - aging/obesity 2. hypergonadotropic hypogonadism - ↓ testosterone - ↑ FSH/LH A. genetic - Klinefelter 47 XXY (↑ breast cancer risk), myotonic dystrophy B. congenital - bilateral anorchia C. orchitis - mumps, HIV D. gonadal damage - trauma, radiation, chemo, alcohol inhibits testosterone synthesis)

Answer 86

Testicular tumors - most common tumor of 15-34 yo 1. Risk factors - familial risk, congenital (cryptorchidism, Klineflelter), race (higher in whites) 2. Clinical - nodule or painless swelling - can be ache in lower abdomen/scrotum, gynecomastia 3. Etiology - 95% tumors are germ cell origin (germ cell tumor GCT) - aggressive but curable - 60% single histological subtype - most common is seminoma; most common in men 50+ is lymphoma 4. Precursor lesion = testicular germ cell neoplasia in situ - seen adjacent to germ cell tumor in almost all cases 5. Treatment - go through groin (inguinally) - do NOT biopsy or excise testicle through the scrotum** - -> leaves inguinal portion of spermatic cord intact and may alter lymphatic drainage of testes; increases risk of local recurrence, can have pelvic/inguinal lymph node metastasis

Answer 87

1. Seminoma - most common type of germ cell tumor, peak in 30s; large, fleshy mass - often Stage I and confined to testicle (if it does metastasize, goes via lymphatics) - uniform tumor cells with abundant clear cytoplasm, distinct cell borders, large central nuclei - PLAP+ and CD117+ - 95% cure rate - analogous to female dysgerminoma 2. Non-seminoma - usually Stage II or III; early mets and more hematogenous spread A. Embryonal carcinoma - 2nd most common GCT - extend through tunica albuiginea, poorly demarcated - seen with other GCTs - more aggressive -- poorest prognosis B. Yolk sac tumor - most common testicular tumor in infants and young children - elevated serum AFP levels - Schiller-Duval bodies (glomerular-like with central vessel encircled by tumor cells) *pathognomonic* C. Choriocarcinoma - very rare and most aggressive - presents as small nodule; hematogenous spread to liver and lungs - usually mixed with other GCT tumors - elevated hCG (contains syncytiotrophoblasts)

Answer 88

1. Cryptorchidism - incomplete descent of testis from abdomen to scrotum - ↑ risk for testicular cancer - associated with tubular atrophy and sterility - tx - orchiopexy (Surgery) 2. Testicular torsion - testis turns and occludes blood supply - younger patients - acute onset nausea and vomiting - older patients - abdominal pain and fever - scrotal swelling, pain with palpation, loss of cremasteric reflex Non-germ cell tumors 3. Leydig cell tumors - most common sex cord tumor - hormonally active --> androgens (precocious puberty) and estrogens (gynecomastia) - pathology = crystalloids of Reinke 4. Sertoli cell tumors - most benign - hormonally silent

Answer 89

1. Benign prostatic hypertrophy BPH A. Pathogenesis - stromal cells make DHT --> binds to androgen receptor (more potently than testosterone) --> stromal proliferation --> discrete, smooth nodular enlargement --> compresses urethra - most commonly occurs in transition zone B. Histology - nodular hyperplasia of both layers of cells in prostate (basal layer of cuboidal epithelial cells and secretory layer of columnar stromal cells) C. Clinical - frequency, nocturia, difficulty starting and stopping urine stream, dysuria - may lead to distention and hypertrophy of bladder, hydronephrosis, UTIs - not premalignant D. Management - avoid caffeine and alcohol - alpha1 antagonists (terazosin, tamsulosin) --> relaxation of smooth muscle - 5alpha-reductase inhibitors (finasteride)

Answer 90

2. Prostate adenocarcinoma - most common form of cancer in men A. Risk factors - FH, age (50+), race (more common in blacks) B. Histology - pleomorphic cells with no secretions - single layer of glands (only secretory layer; basal endothelial layer gone) - perineural invasion pathognomonic for invasive cancer C. Clinical - nodule on digital rectal exam - diagnosed via ↑ PSA (prostate specific antigen) *problems that affect use of PSA as screening tool - most commonly occurs in peripheral zone --> cancer arises away from urethra --> urinary symptoms are late (As opposed to BPH) - metastases to bone are osteoblastic D. Treatment - surgery, radiation, hormonal