Download Endocrinology Overview

1
INTRO
1. Definitions
a. Endocrine – hormones move through blood to act on specific R on distant cells
b. Paracrine – hormones act on adjacent cells
c. Autocrine – hormones act on the secreting cell
d. Neurocrine – neural cells release hormones into the blood
2. Chemical classification
a. Amino-acid derivatives: catecholamines, thyroid hormones
b. Simple polypeptides: releasing hormones/factors of hypothalamus, ACTH, PTH, GH, PRL, AVP, insulin, glucagon
c. Complex polypeptides (e.g. modified by glycosylation): LH, FSH, TSH, hCG
d. Lipids: steroid hormones (cortisol, aldosterone), sex hormones (testosterone, estradiol, progesterone), Vit D
3. Physical classification
a. Hydrophilic: bind to cell surface receptors
i. Catecholamines, all simple + complex polypeptides
b. Hydrophobic: bind to receptors in cytoplasm, then transport/action on nucleus
i. All lipids + thyroid hormones
4. Conversions
a. All polypeptide hormones are synthesized as pre-hormones (have signal peptide that target for secretion, removed later)
i. Insulin + PTH exist as pre-pro-hormones (have extra piece in addition to signal peptide, both removed for activity)
b. Many converted at target cell (ex) cortisol  cortisone (inactive) by mineralocorticoid cells, essentially prevents Cushings
5. Regulation via secretion (circadian, negative fb), metabolism (degraded, activated), and at target cells (amplified, downregulated)
6. MOA: hormone binding  conformation change in R  2nd messenger  ↑↓rate of txn of target genes
a. G-protein R: 7x transmembrane spanning amino acid chain w/ alpha (GTPase), beta, gamma subunits
i. Gs-adenylate cyclase: converts ATP  cAMP, which activates pkA  pCREB
1. Pseudo-hypo-parathyroidism caused by Gs mutation, hypoCa w/ normal or high PTH (PTH resistance), and
Albright hereditary osteodystrophy (short/moon face/short 4th metacarpal)
ii. Gq-PLC: converts PIP2  P3 + DAG, which activates pkC  pAP1
b. Tyrosine kinase R: autoP of R
c. Intracellular R: H-R complex acts as TF, thus directly binds promoter
7. Measurement
a. Can be affected by food/EtOH, time of day (ex) cortisol high in am, low in pm, whether hormone is free/bound
i. RIA: tracer is labeled hormone, std curve using known [ ]s unlabeled hormone w/ constant tracer, compare pt to curve
ii. IRMA (immunoradiometric): hormone is sandwiched btw 2 Ab (one immobilized on bead, other w/ tag for detection)
iii. Dynamic testing:
1. failed suppression = autonomy/overactivity (ex) Cushings
2. failed stimulation = defc’y
HYPOTHALAMIC-PITUITARY AXIS
1. Hypothalamus
a. Maintains homeostasis by initiating hormonal compensatory changes, link btw CNS and pituitary fx
b. Small paraventricular neurons release hormones into hypophyseal portal system, which supplies anterior pituitary
c. Large magnocellular neurons of supraoptic and periventricular nuclei send axons to post pit that release ADH/oxytocin
2. Sella
a. anatomic location of pituitary, bordered by cavernous sinuses
b. 1 – int carotid, 2 – CN III, 3 – CN IV, 6 – CN VI
3. Pituitary
a. Anterior (adenohypophysis) = pars distalis, pars tuberalis
i. Glandular epithelium w/ nests of cells in capillary network
1. Acidophils: somatotrophs, lactotrophs (aka mammotrophs)
2. Basophils: thyrotrophs, corticotrophs, gonadotrophs
ii. Folliculostellate cells are supporting cells; null cells are reserve cells; oncocytes ↑ w/ age
iii. Hormones: GH, TSH, ACTH, LH, FSH, PRL
HYPOTHALAMUS
TRH
CRH
GnRH
GHRH
SRIF (somatostatin)
PIF (dopamine)
b.
4.






ANT PITUITARY
secretion TSH, PRL
secretion ACTH
secretion LH, FSH
secretion GH
(-) of GH release
tonic (-) of PRL release
PERIPHERAL TARGET
 secretion thyroid hormone
 secretion cortisol
 secretion gonadal steroids, stimulates follicular devel’p/spermatogenesis
 IGF-1 production (neg fb), ↑ protein synth, ↑ overall growth
→ opposite of GHRH
PRL  lactation, inhibition of GnRH/LH/FSH
Posterior (neurohypophysis) = pars nervosa, infundibular stalk, median eminence
iv. Neuroectroderm w/ hypothalamic axons containing secretory granules of hormone (Herring bodies)
v. Pituicytes are supporting cells (modified glial cells); assoc w/ pituicytoma and granular cell tumor
vi. Hormones: oxytocin, ADH (inappropriate ADH release leads to diabetes insipidus)
Pituitary adenomas (most common pituitary tumor)
a. Most are sporadic monoclonal tumors but MEN-1 and McCune-Albright predispose to adenoma formation
b. Micro <1cm vs macro >1cm, visualize via MRI
c. Most are prolactinomas, i.e. fxn’al tumors that secrete excess PRL (see hyperpit table)
i. In females, tend to be microadenomas w/ moderate PRL elevation  oligo/amenorrhea (b/c PRL (-) GnRH)
ii. In males, tend to be macroadenomas w/ severe PRL elevation  impotence
iii. Other sx: HA, bitemporal hemianopsia (if presses on optic chiasm), CN III/IV/VI palsy (if grows into cavernous sinus)
iv. Dx: morning blood draw of all major pituitary hormones
v. Tx: dopamine agonist (ex) bromocriptine/cabergoline
d. Non-fxn’al tumors most commonly gonadotrophal (have hormones but can’t secrete)  normal levels of hormone + mass effect
e. Also invasive (usually ACTH secreting), atypical (↑ proliferation, ↑p53), carcinoma (very rare)
2
5.
6.
7.
Other sellar tumors
a. Craniopharyngioma: remnant of Rathke’s pouch, benign, common in children, HA/hypopit/diabetes insipidus, “motor oil” cyst
i. Tx via surgical excision (locally invasive); high recurrence rate, squamous epithelium
b. Chordoma: malignant tumor derived from notochord, common in young adults, HA/CN III palsy, vacuolated cells (physaliphorous)
Non-neoplastic lesions
a. Pituitary hyperplasia: response to HMS RHs, diffuse vs nodular, ectopic (due to tumor) vs orthotopic (due to end-organ failure)
i. (ex) Prolactin cell hyperplasia: physiologic w/ pregnancy, pathologic if assoc w/ other dz like Cushings, hypothyroidism
b. Also lymphocytic hypophysitis, sarcoidosis (see pituitary syndromes table)
Hypopituitarism
a. Insufficent GH in adults: osteoporosis, abnormal fat/lean muscle ratio, low self-esteem, tx aims to normalize IGF-1 levels
i. Tx adult GH defc’y w/ nightly GH injections (S/E: edema, arthralgias, ↓ glucose tolerance)
b.
Genetic defects
Dz
PATHOPHYSIOLOGY
Kallman’s Syndrome
Insufficient GnRH
Aberrant GnRH cell migration no GnRH control of ant pit
(HMS hypogonadism)
Congenital hormone defc’y
Isolated GH defc’y
PROP-1 mutation  no Pit-1 txn factor
 no somato, lacto, thryotrophs
Defect in GHRH secretion
c. Tissue resistance
GH resistance (Laron dwarfs)
GH R abnormality  IGF-1 defc’y w/ hi GH
Androgen insensitivity syndrome
AR mutation (X-linked)
8. Hyperpituitarism
Hyperprolactinemia
(normal is ˂ 29ng/mL)
Acromegaly
(Gigantism if pre-pubertal)
Cushings dz
Decelerated growth ~2yoa
Childhood: short stature, small fingers/toes
Tx with IGF-1
Geno XY, pheno female w/amenorrhea
↑ estrogens (commonly from pregnancy)
↑ TRH (1˚ hypothyroidism)
Drugs (dopamine antagonists like TCAs/neuroleptics)
Prolactinomas
Infundibular stalk compression (loss of (-) by dopa)
Galactorrhea, amenorrhea + if tumor, sx listed above
Tx: dopamine agonist (bromocriptine)
Excessive GH + high IGF-1
(ex) huge pituitary tumor w/ slow growth
CHF, colon/breast cancer  premature mortality
Excessive ACTH from pituitary tumor
Early sx: sleep apnea, carpal tunnel syndrome
Hyperglossia, enlarged hands/feet/jaw
Tx: surgery if small tumor, SRIF, GH antagonist
Obesity/HTN/osteoporosis/poor wound heal/DM
Dx by O/N dexamethasone suppression test
9. Pituitary syndromes
CNS Irradiation
Hypothalamus VERY sensitive to radiation
1˚ CSF enters sella  compression of pituitary
Empty Sella
Syndrome
2˚ due to infarction of known tumor
Pituitary Apoplexy
Hemorrhagic infarction of pituitary or pituitary
adenoma – medical emergency
Pituitary size naturally ↑ during preg  risk for outgrowing
Sheehan’s Syndrome
blood supply  post-partum infarction
Mass infiltration by lymphs/plasma cells tissue destruction
Lymphocytic
hypophysitis
Autoimmune
Sarcoidosis
CLINICAL
Anosmia + hypogonadism
Anterior pituitary is unharmed
Tx with chronic pulsatile GnRH or FSH/LH
GH, PRL, TSH defc’y (ACTH and LH/FSH spared)
Infiltration diabetes insipidus/1-OHase defc’y hyperCa
Common
Panpituitary hormone defc’y
Obese middle-aged women w/ benign intracranial HTN
Usually pituitary fxn is fine
Excruciating HA, pt collapses, stiff neck, fever
Tx: decompression, corticosteroids for stress
Inability to lactate following delivery, menses
problems, genital alopecia
Mainly occurs during pregnancy
Sx of hypopituitarism, pain 12/10
Conservative mgmt (often resolves) but may need
chronic replacement of hormones
Tx underlying dz w/ high dose steroids
Generally involves HMS and stalk
10. Laboratory testing used to differentiate hypothalamic vs pituitary disease
a. If hypothalamic d/o then other functions of hypothalamus will be impaired (ex) HR, circadian rhythm
b. IV administration of hypothalamic hormones MAY induce a pituitary response
i. If pituitary responds = hypothalamic dysfunction
ii. If pituitary does not respond =
1. Lack of priming (lack of exposure  atrophy of targets)
2. Excessive negative feedback
3. Absence of a specific cell target (mutation, destruction)
iii. Acute admin of CRH can help distinguish Cushing’s Dz (ACTH secreting tumor of pituitary) from ectopic ACTH production
1. Ectopic won’t respond, whereas Cushing’s  ↑ACTH
iv. Chronic GnRH used to tx Kallmann’s Syndrome
v. hrTSH used to dx and tx metastatic thyroid cancer (↑ uptake I131 by cancer cells)
vi. SRIF used to tx acromegaly (↓ GH and IGF-1)
vii. Dx acromegaly via glucose suppression test: failure of GH to ↓ to ˂ 0.8 ng/mL in 1h is diagnostic
1. ITT (insulin tolerance test): dx adult GH deficiency (hypoglycemia should ↑ GH); IGF-1 not good screening test!
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ADRENAL CORTEX/CORTISOL
1. Steroid biosynthesis from cholesterol (into adrenal via LDL R)
a. Zona glomerulosa: mineralocorticoids (aldosterone), req CYP11B2 (11b-OHase) + 21-OHase
b. Zona fasciculata: glucocorticoids (cortisol), 17-Hydroxy Steroids, req CYP11B1 (11b-OHase) + 21-OHase
c. Zona reticularis: androgens (DHEA, androstenedione), 17-Ketone Steroids, req CYP17 (17a-OHase)
i. Androstenedione can be converted to testosterone or estrone (by aromatase)
2. Steroid actions
a. Glucocorticoids – metabolism (opposes insulin), immune response/anti-inflamm (stabilize lysosomes), stress response
i. Carbohydrates: ↑ blood glucose for GNG via inhibition of insulin  ↓glucose uptake
ii. Lipids: ↑ lipolysis
iii. Proteins: ↑ proteolysis for GNG
b. Mineralocorticoids – BP, vascular volume, electrolytes
c. Androgens – secondary sex characteristics
d. Both gluco/mineralocorticoids can bind mineralo R, ONLY glucocorticoids can bind gluco R, both = intracellular steroid R
i. Mineralo R gain specificity by inactivating cortisol (coverts to cortisone)
ii. In high [], cortisol can also activate mineralocorticoid receptor  aldosterone effects
3. Regulation of ACTH
a. Stimulated by CRH, stress, exercise, etc (ACTH itself inhibits CRH in negative fb)
b. ↓ by high plasma cortisol (negative fb)
c. Influenced by sleep-wake cycle (peak is just before waking, lowest just before sleeping), cortisol levels follow
i. Note: random cortisol level does not reflect secretion pattern, because ACTH secretion is pulsatile/diurnal rhythm
ii. Note: plasma hormone [ ] = secretory rate/metabolic clearance rate (urine free cortisol used to estimate secretion)
d. ACTH binds GPCR that ↑cAMP → ↑ cortisol via ↑LDL Rs, ↑cleavage cholesterol, ↑17-hydroxylation
e. Most of cortisol is bound to corticosteroid-binding globulin (transcortin)
4. Cushing’s Syndrome: systemic syndrome resulting from chronic excess cortisol secretion
a. Sx: CNS problems (psychosis), excessive salt retention/edema, HTN, impaired glucose tolerance, immunosuppression, stria/
ecchymoses, osteoporosis, wt gain (central obesity, moon-face, fat-pads), alopecia, hirsutism, proximal muscle atrophy
b. Etiology
i. Exogenous: pharmacologic administration of glucocorticoids (most common)
ii. Endogenous
1. ACTH from pituitary tumor aka Cushing’s Disease
2. Ectopic CRH or ACTH, as in from oat-cell carcinoma/medullary thyroid carcinoma
a.  bilateral adrenal hyperplasia
b. Abrupt onset so traditional sx not present - specifically look for hypoK alkalosis and diabetes
3. Cortisol secreting adrenal tumor
c. Adrenal function tests
i. Indicated if you suspect Cushing’s based on H&P
ii. FIRST – screening test, overnight dexamethasone suppression
1. Dexa is 30x more potent than cortisol, thus SHOULD suppress overnight cortisol secretion (via negative fb) 
LOW plasma cortisol in healthy person
2. Low dose dexa will NOT suppress Cushing’s, so morning plasma cortisol will be elevated
iii. SECOND – confirmatory test, low dose dexamethasone suppression
1. If truly Cushings, the dose is still not enough to suppress, and morning plasma cortisol will again be elevated
iv. THIRD – establish etiology, plasma ACTH
1. If low, it is an adrenal tumor, if high, it is either Cushings dz or ectopic ACTH tumor
v. FOURTH – establish etiology, high dose dexamethasone suppression
1. If cortisol release is suppressed = Cushings dz, as pituitary has R for negative fb control
2. If NOT suppressed, it is an ectopic ACTH secreting tumor, which contains no R
vi. CRH test – Cushings pt will have marked ↑ in ACTH in response to CRH (useful, but high dose dexa preferred test)
vii. ACTH test (cosyntropin) – normal pt will have ↑ cortisol w/in 1h but may see no ↑ if cortisol already overstimulated
1. Can also distinguish 1° from 2° adrenal insufficiency: both have NO ↑cortisol but 2° has ↑aldosterone
viii. Note: 3 tests to distinguish pituitary vs non-pituitary ACTH-secreting tumors: high dose dexa/metyrapone/CRH
1. See hyper-response w/Cushing’s dz (pituitary), no response w/ectopic (non-pituitary)
Disease
Cushing’s Dz (Pit Tumor)
Ectopic ACTH-Secreting Tumor
Adrenal Tumor
5.
High Dose Dexa
Suppression
YES
NO
NO
Metyrapone Response
CRH Stimulation
Plasma ACTH
YES
NO
NO
YES
NO
NO
Normal – High
High
Low
Adrenal insufficiency: hypofxn’ing adrenals fail to release sufficient gluco and/or mineralocorticoids
a. Primary (problem of adrenal dysfxn) aka Addison’s dz = autoimmune destruction of adrenals
i. Both cortisol/aldosterone low + ACTH high
b. Secondary (problem of pituitary dysfxn), usually exogenous glucocorticoids (via negative fb) or pituitary damage
i. Cortisol low + ACTH low but aldosterone normal (b/c mostly under renin control, not pituitary)
c. Sx of primary (Addison’s): hypoNa, hypoTN, hyperK, hyperpigmentation (↑ACTH  ↑MSH), vitiligo, fatigue, wt loss, salt craving
d. Sx of secondary are similar but NO hyperpigmentation (ACTH not high), NO salt craving (normal aldosterone), and NO hyperK
e. Adrenal function tests
i. Plasma ACTH: differentiates btw primary/secondary causes
ii. ACTH stimulation test: give cortrosyn – if Addison’s, NO response from adrenals
1. With long-standing secondary, there would also be no/low response due to adrenal atrophy
iii. Insulin tolerance test: induce hypoglycemia (stressful state), tests whole HPA axis
1. Normally, would see ↑ in cortisol
2. Contraindicated if Addison’s is highly suspected (Addisonian crisis), or hx of CAD, seizure disorder
iv. O/N Metyrapone test: inhibits 11β-hydroxylase so 11-deoxycortisol accumulates and ↓cortisol → ↑ ACTH (ACTH test 1st!)
1. ↑↑↑ ACTH w/ Cushing’s dz whereas adrenal tumors/ectopic ACTH syndrome show NO ↑ACTH
4
6.
Congenital adrenal hyperplasia: inherited genetic diseases w/ impaired cortisol biosynthesis due to defective enzymes in pathway
a. Tx: goal is to ↓ACTH to normal, accomplished via tx w/ cortisol/other glucocorticoids
b. 21-hydroxylase deficiency (most common, CYP21A2)
i. Blocks formation of gluco/mineralocorticoids  low cortisol/aldosterone (aldosterone defc’y is to much lesser extent)
ii. Body tries to raise cortisol by ↑ ACTH, but precursors are shunted to androgen pathway  female virilization
iii. Clinical: virilizing-salt wasting (most severe), virilizing-non salt wasting, adult onset (women only, hirsutism)
c. 17-hydroxylase deficiency (CYP17)
i. Blocks formation of sex hormones  low testosterone  ambiguous males
ii. Precursors shunted to mineralocortioid pathway  HTN, hypoK
d. 11-hydroxylase (CYP11B1 or 11-βOHase in z.fasciculata converts 11-deoxycortisol to cortisol)
i. Blocks formation of glucocorticoids  low cortisol
ii. Precursors shunted to mineralocorticoid pathway  HTN, hypoK + androgen pathway  female virilization
e. 11-hydroxylase (CYP11B2 in z.glomerulosa)
i. Blocks formation of mineralocorticoids  low aldosterone
ii. Precursors shunted to glucocorticoid pathway  hypoTN, hyperK + androgen pathway  female virilization
Defective Enzyme
21-OHase
17-OHase
11β-OHase
Salt Wasting
YES/NO
NO
NO
HTN/HypoK
NO
YES
YES
♀ Virilization
YES
YES
NO
Ambiguous ♂
NO
NO
YES
Precocious ♂
YES
YES
NO
Cholesterol
17-OHase
Pregnenolone
Sex Steroids
Progesterone
21-OHase
CYP11B2
CYP11B1
Cortisol
Aldosterone
ENDOCRINE HYPERTENSION/ALDOSTERONE
1. Endocrine HTN: state in which hormonal derangement results in clinically significant HTN
a. Suspect if sudden onset in young/old, refractory to 3+ meds, episodic HTN or HTN w/ hypoK
b. Specific findings: abdominal bruit in renal HTN, clammy hands/café au lait spot in pheo, central obesity/striae/bruising in Cushings
c. All tx aims to control BP while preserving renal fxn
TYPE
Renal Artery Stenosis
(most common)
PATHOGENESIS
>90% occlusion from AS or
fibromuscular dysplasia 
ischemia  activation of RAS
 ang II release (potent VC)
1° Aldosteronism
Hyperaldosterone  Na
retention + K excretion  ↑
intravascular volume (tho NO
edema due to aldost escape
via ANP release)
Neuroendocrine tumor of
chromaffin cells (w/in adrenal
medulla or extra-adrenal)
If ˂ 20y, bilateral→ screen for
succinate DH mutation
Pheochromocytoma
LABS/IMAGING
Unilateral, labs normal
Bilateral, ↑BUN/creatine
(indicate RF)
Angiography best (AS
looks like beads on string)
Metabolic alkalosis
↓ renin, sometimes hypoK
High aldosterone:renin
Should treat PAC/PRA > 25
CLINICAL
Upper flank
abdominal bruit
Tx
ACE (-), aldost R antag,
thiazide diuretic
Surgery if noncompliant,
young, HTN is refractory
Salt loading fails to
suppress
Muscle wasting
when K <2.5
Plasma metanephrines if
HI risk (hi sensitivity)
Urine metanephrines if
LO risk (hi specificity)
HTN + triad of HA,
sweating, palps
“10% tumor”
Need tx to prevent hi risk of
stroke, MI, afib
Surgical removal
Spironolactone/eplerenone
(aldost antag but lots S/E)
Surgical removal best
Pre-op volume expansion
Pre-op /β-blockers
Post-op β-blockers
HI recurrence rate
5
THYROID/THYROID HORMONE
1. Parafollicular C cells make calcitonin (inhibits osteoclast activity to ↓bone resorption)
2. Follicular cells: produce T3, T4 (T4 peripherally converted to T3, which binds nuclear T3Rs and feeds back on HMS/pit)
a. Synth (stimulated by TSH)
i. Uptake: I into cell via basilar 2Na/I symporter (need  50 mcg/d intake); Na back out to blood via Na/K ATPase
1. ↑ symporter activity/uptake w/ TSH and ↓uptake w/ large amts iodide or lithium
2. Much of the I taken up is stored as colloid via pendrin transporter (apical)
a. Pendred syndrome: pendrin mutation, goiter and congenital deafness
ii. Oxidation: I  I2 via TPO (thyroid peroxidase)
iii. Organification: I2 attaches to tyrosines of TG (thyroglobulin) via TPO
iv. Coupling: MITs + DITs  T3, T4 via TPO (which is inhibited by PTU(propylthiouracil)/MMI(methimazole))
v. Proteolysis: stored colloid is brought back into cell and T3, T4 is released (inhibited by excess I)
b. Transport: 99% bound to TBG, only free hormone is active, T4 in greater [] but T3 more active, converted via 5-monodeiodinase
3. Serum FT4 best in determining thyroid status b/c free levels not affected by other processes (ex) liver dz, OCP. ALWAYS check TSH too!
a. Hormone levels naturally drop when sick, pt is still considered euthyroid (sick thyroid syndrome)
b. Cancer serum biomarkers: TG for thyroid cancer and calcitonin for medullary cancer
DISORDER
1˚ hypothyroidism/Hashimoto
4.
5.
6.
7.
FREE T4
LO
TSH
HI
TRH
HI
Uptake/Scan
LO
2˚ hypothyroidism (pit)
LO
LO
HI
LO
3˚ hypothyroidism (hypothal)
LO
LO
LO
LO
1˚ hyperthyroidism/Graves
HI
LO
LO
HI
2˚ hyperthyroidism (pit)
HI
HI
LO
HI
Iodine deficiency
LO
HI
HI
HI
Iodine
a. Defc’y  ↑ TSH  compensatory thyroid enlargement + euthyroid OR hypothyroid; cretinism if fetal hypothyroid
b. Excess  Wolff-Chaikoff effect (transient hypothyroidism)  eventual escape w/resumption of normal fxn or hypothyroid
c. Excess  Jod-Basedow effect: hyperthyroidism due to excess I
Goiter: think elderly woman in I deficient area, may be hypo/hyper/euthyroid, tx w/ surgery if sx of compression
a. Diffuse: symmetric enlargement vs multi-nodular: asymmetric, heterogenous w/ necrosis, hemorrhage, cysts
b. Endemic: nutritional defc’y vs sporadic: idiopathic, enzyme defc’y
c. Papillary hyperplasia vs involution of cells
d. If impede on recurrent laryngeal n → hoarseness, parathyroids → tetany, stridor, numbness, Chvostek + Trousseau signs
Nodules
a. Hot = producing hormones so high radio-I uptake, unlikely malignant
b. Cold = not producing hormones so low/no radio-I uptake, need biopsy
c. Check TSH → if low do uptake scan and if high do biopsy
Clinical sx
SYSTEM
Metabolic
Cardiovascular
Calorigenic
Gastrointestinal
Central Nervous
Skin & Appendages
Musculoskeletal
Severe States
8.
HYPER
Hypermetabolic
Amenorrhea
↑ cholesterol metabolism
↑ insulin secretion
Wt loss
Heat intolerance
↑ HR, SV, CO, PP
↓ PVR
Atrial arrhythmias
↑ O2 consumption
↑ appetite
↑ glucose absorption
↑ bowel movements
Nervousness/tremor/insomnia
Hyperreflexia
Emotional lability
Warm sweaty skin
Fine/think hair
Exopthalmos, opthalmaplagia
Pretibial mxedema
Osteoporosis
Hyperthryoid storm
HYPO
Hypometabolic
Galactorrhea, menorrhea, hyperPRL
Hypercholesterolemia
↓ insulin secretion
Wt gain
Cold intolerance
↓ HR, SV, CO, PP
↑ PVR
↓ O2 consumption
↓ appetite
↓ glucose absorption
↓ bowel movements
Lethargy
Hyporeflexia (prolonged relaxation phase)
Depression
Cool dry/clammy skin
Dry, brittle hair/nails, allopecia
Periorbital edema
Goiter
Painful muscle cramps w/proximal myopathy
Myxedema coma and death
Pharmacology
a. Adults require 150mg/day iodine, lower in kids, higher in pregnancy
b. Amiodarone is leading cause of drug-induced hyperthryroid
c. Hypothyroid lab values: high TSH due to loss of negative feedback (low T3/T4)
d. Hyperthyroid lab values: low TSH due to negative feedback by high T3/T4
6
9.
Hypothyroidism
a. Developmental delays
i. Earliest hypothyroidism results in worst results: cretinoid appearance, skeletal delays, mental retardation
1. Puffy hands/face, deaf mutism, jaundice, cyanosis, hoarse cry
ii. Juvenile form spares mental retardation but delayed sexual maturation and ↓ school performance
iii. Adult form, developmental delays do not occur, sx listed in clinical sx chart
b. Tx: thyroxine (T4) replacement
i. Myxedema coma: endstage untx’ed hypo, poor px  mental status Δs, hypo-thermia/ventilation/glycemia/Na
1. 3 major features: CO2 retention/hypoxia, fluid/electrolyte imbalance, and hypothermia
2. Adrenal insufficiency likely to occur, automatically tx w/ glucocorticoids (hydrocortrisone) before replace T4 in ER
TYPE
Hashimoto’s
thyroiditis
1° (inc. Hashimoto)
Pituitary (2°)
HMS (3°)
Nutritional
Medication-induced
CAUSE
Anti-TPO/TG Ab  gradual
destruction of thyroid gland
Assoc w/ other autoimmune dz
No T4
No TSH
No TRH
Iodine deficiency
PTU/MMI, amiodarone, lithium
CLINICAL
Diffuse, firm, non-tender enlargement
Hurthle cells (eosinophilic inclusions in lymphos)
F>M (20:1)
See clinical sx chart; most common
Same
Same
Same + likely goiter due to HI TSH levels
Usually resolves quickly following w/d
10. Hypothyroid tx
a. Levothyroxine dosing
i. Normal maintenance: 100-150 microg/d
ii. Starting dose if young w/o longstanding dz OR >45y w/o cardiac dz: 50 mcg/d + titrate by 25-50 mcg/d
iii. Starting dose if elderly OR have hx of cardiac dz: 12.5-25 mcg/d + titrate by 12.5-25 mcg/d
DRUG
Levothyroxine
MOA
Synthetic T4 replacement
INDICATION
DOC for hypothyroidism
(can  hyperthyroidism)
Synthetic T3
Replacement
When faster onset necessary
SE/CONTRAINDICATION
CV S/E (angina, arrhythmia) are dose limiting
Steady state ~2mo, ↓ if thyrotoxicosis occurs
Malabsorption (take in am on empty stomach)
DDI: resin binders, E2
CV S/E
11. Hyperthyroidism
a. Use uptake/scan to help differentiate
i. HI uptake = excess hormone from thyroid vs LO uptake = ectopic hormone production or thyroiditis
ii. Diffuse scan = Graves dz vs nodular scan = adenoma (hot nodule = functional/unlikely to be malignant)
b. Tx: PTU/MMI, iodides, lithium, β-blockers, ablation (surgical or radio-iodine)
c. Thyroid storm: extreme thyrotoxicosis (delirium, severe tachycardia, N/V/D, fever, dehydrat), poor px, medical emergency
i. Tx w/ hydrocortisone, PTU/MMI, iodide (1h later!), propranolol
TYPE
Graves Disease
CAUSE
Anti-TSH R Ab  mimic TSH &
cause stimulation of thyroid
(can cross placenta)
Toxic Nodular Goiter
Infxn  inflamm, destruction of
cells  release of hormone
Viral infxn → host tissue damage
→ auto-immune destruction in
HLA-B35 individuals
Autonomous nodule
Subclinical hyperthyroidism
Euthyroid but TSH depressed
Ectopic thyrotoxicosis
Ectopic hormone production via
drugs, struma ovarii (teratoma)
Acute thyroiditis
Subacute Granulomatous Thyroiditis
12. Hyperthyroid tx
Thioamide
PTU, MMI
Iodides
Radioactive Iodide
(RAI, I131)
β-blockers
CLINICAL
Exopthalmos, pretibial myxedema, acropachy
(clubbing due to new subperiosteal bone formation)
Assoc with other autoimmune dz
High uptake, diffuse scan, often goiter w/ bruit
Painful thyroid, fever, eventual recovery
Initially hyperthyroid, but once depleted, hypothyroid
Acutely VERY painful thyroid (diffusely enlarged)
Will spontaneously resolve, don’t need to Tx
Low radioiodine uptake
Goiter w/nodule(s) that are hyperactive (hot)
Usually in elderly, no optho pathology
Risk of atrial fibrillation and osteoporosis
Amiodarone rich in I  hyperthryroidism
(-) TPO, coupling, T4T3 periph
DOC kids/teens, preg, Graves
(-) T3/T4 release, synth
 necrosis of hyperactive
thyroid portions
Controls cardiac sx
Pre-op tx
DOC old, heart dz, toxic nodules
Maculopapular rash (try alternate)
Hepatotox/agranulocytosis (do NOT try alt)
Hypersensitivity, salivary/breast gland swelling
Hypothyroidism can occur → monitor levels
Give β-blockers to all pts 1st
↓ tremor, palps, anxiety
13. Neoplasms (papillary and follicular respond to tx w/ radioactive iodine, anaplastic does not)
TYPE
CLINCAL
Follicular adenoma
Benign, encapsulated, differentiated, very common middle aged euthyroid woman
Papillary carcinoma
Branching growth pattern, clear nuclei (orphan annie eyes), psammoma bodies
Behavior/staging depends on age (generally good px even w/ local LN mets if ˂ 45y)
(most common)
Assoc w/ RET oncogene
Follicular carcinoma
Min invasive vs widely invasive, px better w/ former
Insular carcinoma
Nests of poorly differentiated tumor cells
Anaplastic carcinoma
Worst px, undiff tumor replaces gland, rare (see in elderly)
Medullary carcinoma
Neoplasm of para-follicular C cells w/ salt & pepper chromatin +/- amyloid (calcitonin)
Strong assoc w/ RET oncogene (and MEN-2 syndrome)
7
PARATHRYOID/Ca HOMEOSTASIS
1. Parathyroid hormone (PTH; important for minute-to-minute Ca regulation)
a. Stimulation: low Ca, high P, low VitD
i. Calcium Sensing Receptor (CaSR) on parathyroid cells sense [], G-protein w/ multiple signaling ptwy (↑cAMP)
b. Inhibition: high VitD via negative fb
c. Effects
i. Kidneys: ↑ Ca reabsorption, ↑ P excretion, activates 1-OHase (25-VitD  1,25VitD)
ii. Intestines: active VitD  ↑ absorption of Ca
iii. Bone: ↑ osteoclast activity  bone resorption, Ca release  ↑ serum Ca
d. Serum Ca levels can be ↑ by:
i. ↑ intestinal absorption (via 1,25hydroxyVitD)
ii. ↑ bone resorption (via PTH)
iii. Inhibiting Ca renal excretion (via PTH)
iv. ↑ pH (hyperventilation/metabolic alkalosis is associated with hypoCa)
e. Serum Ca measurement via total Ca, which is dependent on albumin levels (since 80% bound)
i. Corrected calcium (used if albumin abnormal) = measured total Ca + 0.8(4.2 – measured serum albumin)
2. Parathyroid also produces a compound PTHrP
a. PTH-related peptide has sequence homology with PTH
b. It is found physiologically in developing bone, in placenta, and in fetal tissues and acts as a paracrine factor
c. Unlike PTH, it is NOT physiologically important in adult Ca homeostasis (only works in the fetus)
d. However, it is secreted by various cancers pathologically and can lead to hyperCa
3. VitD (important for long-term Ca homeostasis)
a. Stimulation: low Ca, low P, high PTH
i. Defc’y due to low intake, low absorption, low UV exposure, PTH resistance
b. Synth: 7-dehydrocholecalciferol + UV  VitD3, which is constitutively hydroxylated by liver to 25-VitD3 (storage form, test of
choice for defc’y), then kidney converts 25  1,25 VitD via PTH stimulation
c. Effects: ↑ intestinal absorption of calcium, suppress PTH gene transcription
4. HyperCa
a. Most commonly subclinical, but important to tx to prevent rare complications
b. Sx: fatigue, depression, thirst, polyuria (osmotic diuresis), constipation
c. Complications: osteoporosis/pathologic fx, kidney stones, life-threatening dehydration
Dz
Primary hyperPTH
Familial hypocalciuric
hyperCa
PTHrP cancers
Malignancy
Vit D intoxication
5.
PATHOGENESIS
Adenoma/genetic  high PTH  ↑bone resorption  ↑ Ca
CaSR mutation makes receptor less sensitive to Ca
PEARLS
Most common cause
Takes higher Ca to shut off PTH secretion
PTHrP shares bone resorp fxn of PTH  high Ca/low PTH
Osteolytic mets (kidney, lung, thyroid, MM) resorb bone 
high Ca  neg fb  low PTH
Excessive Ca intake/absorption  ↑Ca  neg fb  low PTH
Suspect if hyperCa in cancer pt
Most common cause of non-PTH mediated hyperCa
Measure 1,25vitD for dx of tox (vs 25vitD for defc’y)
HypoCa
a. Chronic well-tolerated vs acute assoc w/ parasthesias, spasms, tetany (partial depol of resting Vm  hyperexcitability)
b. Chvostek’s sign: twitch of upper lip toward side of tapped cheek
c. Trousseau’s sign: acute pain/muscle clenching in arm/fingers following inflation of BP cuff for 3min
Chronic Kidney Disease
Autoimmune (most common), post-op, infiltrative (ex: malignancy)  no/low
PTH  low Ca
Renal failure  no response despite high PTH  low 1-OHase  low VitD/low Ca
Vit D deficiency
PTH resistance
Inability to absorb Ca despite high PTH
Target tissue R mutation  no response despite high PTH
Gland destruction
6.
7.
Most common cause
 hyperplasia of PTH gland
Genetic disorder
HypoP and HyperP
a. Acute hypoP (due to VitD defc’y/resistance or alkalosis): muscle weakness (↓ATP), paralysis, rhabdomyolysis, hemolysis
b. Chronic hypoP: bone pain/osteomalacia
c. HyperP: ectopic calcification, pruritis, 1OHase suppression (→hypoCa), usually due to renal failure
FGF23: hormone from osteocytes that ↑P excretion and inhibits 1OHase synthesis in kidney so excess causes hypoP/osteomalacia
a. Degraded by PHEX, endopeptidase from gene on X chromosome
8
METABOLIC BONE DISEASE
1. 1°/2° hyperPTH  bone loss (see ↑ telopeptides NTx/CTx, ends of type 1 collagen)  subperiosteal erosions/cystic lesions on xray
2. Hyperthyroidism  ↑ bone turnover
RICKETS / OSTEOMALACIA
Lack VitD  defective bone mineralization
(gene mutations exist, ex: 1-OHase defc’y)
Can be hyperPTH w/↑osteoid/alk phos
Can be excess FGF23 from tumor (TIO)
PAGETS Dz
Viral infxn of osteoclast  localized
disorder of bone remodeling
Disorganized woven bone replaces
lamellar bone, very fragile
OSTEOPOROSIS
Uncoupled bone remodeling
Low bone mass  risk for fx
1° forms= idiopathic in young,
postmenopausal, senile
Clinical
Features
“Soft” bone, bone/muscle pain + weakness
Physical
Findings
Bone deformities (bowing w/ waddling gait)
Delayed/absent calcification in zone of
maturation, unmineralized osteoid
Fragility fx, Dowager’s hump
Tx: wt-bear exercise, bisphos,
teriparatide, QUIT smoking!
Ca/VitD for peak bone mass
Low bone density on DEXA
(T score <-2.5 = osteoporosis)
(T score -2.5 to -1 = osteopenia)
Radiology
Tests
Widened growth plate, concave metaphysis
Looser zones: pseudofractures (tender)
Affects adults, middle aged men
Enlarged, painful, brittle bone
Can cause hearing loss, heart failure
Tx: bisphos, calcitonin
Vascular steal syndrome
Osteosarcomas (30x ↑ risk)
↑ alk phosph
Cranial nerve palsys, frontal bossing
Sclerotic bone w/ shaggy lytic areas
Definition
OSTEOGENESIS IMPERFECTA
Defective Type 1 collagen production → weak
bone w/ ↓ mass → fx, deformity
OSTEOPETROSIS
Osteoclast defc’y → overgrowth/sclerosis
of cortical bone
Clinical
Features
fx, blue sclera, brittle teeth, hearing loss
Tx: bisphos
Pathologic fx, poor tooth eruption,
anemia (↓ marrow cavity),
vision/hearing loss (CN compression)
CKD MINERAL/BONE DISORDER
↑PTH → osteitis fibrosa cystica
↓VitD → osteomalacia
Together → mixed uremic osteodyst
2° to dialysis (β2 microglob amyloid)
Abnormal Ca homeostasis
Biopsy for definitive dx
Definition
Radiolucent porous bone
OBESITY
1. Definition: excessive body weight assoc w/ adverse health
a. Central obesity: ↑ waist circumference – M >40in, F >35in (best indicator)
i. ↑ visceral fat  release of hormones/cytokines that ↑ insulin resistance
b. BMI: ratio of height and weight (kg/m2) or [(lbs/2.2)/(ft*0.3)2]
i. 18.5-25 normal
ii. 25-30 overweight
iii. 30-35 obese type I
iv. 35-40 obese type II
v. >40 morbidly obese
2. Epidemiology: >20% of adults are obese, esp AA
3. Consequences
a. ↑ morbidity & mortality – @ risk for metabolic syndrome, arthritis, gall bladder disease, endocrine cancers, HTN, CAD, DM
i. Metabolic syndrome: excessive intake of food + thrifty genes, which try to conserve energy  obesity, insulin resistance
ii. Adipocyte secretions: ↑ IL-6/TNF- (pro-inflamm) + ↓ adiponectin release (→ insulin resistance)
iii. Dx: 3/5 of:
1. Central obesity
2. TG >160
3. HDL <40 (M), >50 (F)
4. HTN
5. Hyperglycemia
4. Weight regulation
a. Complicated by genetics, biological predispositions
b. Energy expenditure
i. BMR: energy cost of homeostasis (65%)
ii. Physical activity (30%) – low activity is biggest cause of obesity
iii. TEF (thermal effect of food): energy cost of digestion (5%)
c. Hormones
i. ↑ appetite/↓ energy expenditure: Neuropeptide Y (NpY R in HMS), Orexins, Ghrelin (from stomach, modulates NpY)
ii. ↓ appetite/↑ energy expenditure: Leptin (from adipose to HMS), POMC/MSH (bind melanocortin4 R or MC4 R)
1. Note: most obese have paradoxically ↑ leptin → suggests leptin resistance
d. Drugs can lead to weight gain (diabetes meds, corticosteroids, OCP)
5. Management
a. Lifestyle changes (moderately overweight)
i. 500cal/day reduction + exercise, esp important for T2DM
b. Pharmacologic changes (overweight with risk factors, or obese)
i. Sibutramine (5-HT, NE reuptake inhibitor or SNRI); S/E: ↑HR/BP
ii. Phentermine (NE agonist)
iii. Orlistat (inhibit pancreatic lipase to ↓ fat absorption); S/E: soft stool/anal leakage/↓ fat-soluble vitamin absorption
c. Surgical Management (BMI 35-40 w/ risk factors or morbid obesity)
i. Roux-en-Y gastric bypass (gold std), very effective in weight loss/elimination of DM/asthma/HTN/sleep apnea
1. Basically cut off fundus of stomach (esophagus attached) and attached directly to s. intestine
2. Pt must understand procedure and commit to long-term F/U
3. Watch for vitamin deficiencies (esp. Fe/Ca/thiamine/VitD/VitB12)
ii. Liposuction can be dangerous and has not been shown to improve metabolic/CV risk
9
HYPERLIPIDEMIA
1. Lipoproteins
a. Enable transport of insoluble lipids via complexing w/ proteins
b. Cores of hydrophobic lipids (TG, cholesterol) + surface layer of hydrophilic proteins/phospholipids
2. Apolipoproteins
a. Protein moiety on lipoprotein surface that (1) helps solublize lipids + (2) acts as R ligands that direct to specific target cell
b. Responsible for LDL R-mediated clearance of LDL particles
i. LDL R recognizes Apo-B100, Apo-E ONLY; thus, mutation  no uptake  very high serum chol levels
c. Lp(a) – an LDL particle linked to apoprotein (a); is an independent risk factor for AS and CAD
LIPOPROTEIN
Chylomicron
VLDL
IDL
LDL
HDL
3.
4.
5.
6.
TRANSPORTS
TG
TG
cholesterol
cholesterol
APOLIPOPROTEIN
Apo-B48, Apo-E, Apo-C2
Apo-B100, Apo-E, Apo-C2
Apo-B100, Apo-E
Apo-B100 only
Apo-A
NOTES
Exogenous pathway (intestine), degraded LPL
Endogenous pathway (liver), degraded LPL
VLDL  IDL  LDL
Carries chol to tissues
Carries chol from tissues back to liver
Exogenous pathway: fat in intestine  chylomicrons  lympatics to peripheral tissue (energy), liver (as remnants)
Endogenous pathway: liver converts lipids into VLDL for energy for body  IDL/LDL via LPL in adipocytes/myocytes/MΦ
a. LPL mutation  inability to extract TG from chylomicrons for use in tissues  very high serum TG levels
b. LCAT (formation of cholesterol esters) and CETP (removes cholesterol from HDL) enzymes convert chol into various forms
Atherosclerosis : lipid deposition  cellular proliferation and inflammation  reduces blood flow/ischemia
a. High calorie/fat intake  high VLDL production from liver
b. High VLDL  high LDL in circulation both by more production and down-regulation of LDL receptor (thus, less removal)
c. High LDL  deposition into intima, where oxidized/taken up by scavenger R of MΦ
d. Foam cells (MΦ filled w/ cholesterol) release inflammatory cytokines  more MΦ + prolif of smooth muscle cells
e. Tunica media becomes filled w/ foam cells and hypertrophied/hyperplastic smooth muscle  vessel narrowing
f.
Thrombogenic surface  clot formation
Pancreatitis: due to severe hyperTG (>1000 mg/dL)  membrane breakdown, leakage of enzymes  inflamm + autolysis
7.
Primary lipoproteinemias
Dz
MOA
AutoD LDL R mutation  high LDL
Familial
family hx
hypercholesterolemi
a
Familial combined
hyperlipidemia
Type III
hyperlipoproteinemia
LPL defc’y
AutoD unknown  high TG + LDL
family hx
AutoR Apo-E mutation  defective
binding CM/VLDL/IDL remnants to LDL R
AutoR LPL mutation ↓ clearance of
chylomicrons (thus, HIGH TGs)
Apo CII defc’y
Familial hyperTG
AutoR Apo-CII mutation (LPL cofactor)
AutoD unknown  very high VLDL/TG
8. Secondary lipoproteinemias
Insulin defc’y  impaired LPL
Uncontrolled DM
activity  impaired removal of
circulating lipoprots
Hypothyroidism
Impaired clearance of LDL
↑ VLDL synth in liver
Alcoholism and
estrogen therapy
Proteinuria  liver produces more of
Nephrotic syndrome
everything, including VLDL/LDL
Drugs
9.
Tx
a.
b.
CLINICAL
Heterozygote: common, premature CHD, xanthelesmas (near eye),
tendon xanthomas, arcus corneae, LDL <500mg/dL
Homozygote: rare, CHD early childhood, planar xanthoma in addition to
sx for heterozygote, LDL 500-1000mg/dL
Premature CHD but NO xanthomas/xanthelesmas
High [] of cholesterol remnants  cholesterol ~300mg/dL
Premature CHD, palmar xanthomas
Heterozygote: resembles 2° lipoproteinemia
Homozygote: early childhood, pancreatitis, hepatosplenomegaly,
lipemia retinalis, eruptive xanthomas
Resembles LPL defc’y
Assoc w/ obesity, insulin resistance
High TG, LDL
Low HDL
High LDL (screen pts for hypo), but responds well to thyroid HRT
Both also ↑ HDL
Protease inhibitors, glucocorticoids, androgens
Screening: fasting lipid profile for all adults >20y, if normal, repeat every 5y
Diet: esp for those w/ CHD → ≤30% of total calories from fat (<7% saturated fat) + <200mg/d cholesterol
DRUG
HMG-CoA reductase
inhibitors (statins)
Bile acid seq
Fibric acid derivs
Niacin
MOA
(-) rate-limiting step in chol synth +
 up-regulation of LDL R
Resins exchange Cl for bile acids
Bile acid loss to feces causes liver to
use chol to make more (↑LDL R)
Unknown, assoc w/PPAR activation
Unknown
Ezetimibe
Ileal Bypass Surgery
(-) chol absorption @ brush border
(-) chol absorption
INDICATION
DOC to ↓ LDL
SE / CONTRAINDICATION
Myalgias, myopathy
Adjunct to statins to ↓ LDL
Bloating, constipation
↓ TG
↓ LDL/TG/Lp(a)
ONLY one that ↑ HDL
Adjunct to statins to ↓ LDL
Severe hyperchol and failed other tx
Myalgias, myopathy, rare hepatotox
Flushing syndrome, rare hepatotox
10
DIABETES
1. Definition: abnormalities in CHO/protein/fat metabolism due to lack of/resistance to insulin  hyperglycemia + microvascular dz
(retinopathy, neuropathy, nephropathy) + macrovascular dz(accelerated AS) + freq HTN/dyslipidemia
2. Epidemiology: >21 million in US (95% of which is type II), more prevalent in minorities
3. Insulin
a. Synthesis: via β-cells in central portion of Islet of Langerhaans in 1:1 ratio of insulin + C-peptide
b. Secretion: in response to ↑ blood glucose
i. Glucose enters β-cell via GLUT-2 (glucose independent)
1. First phase due to release of preformed insulin, thus immediate
2. Second phase due to preformed insulin AND de novo synthesis, thus slower
ii. Inhibition: GGCC (Glucagon from -cells, GH, Cortisol, Catecholamines)
c. Effects: major anabolic hormone in the body
i. Stimulates synthesis (+ inhibits degradation) of glycogen, proteins, and lipids
1. Liver - ↓ GNG, ↑ glycogen synthesis/lipogenesis
2. Fat - ↑ fat uptake/lipogenesis
3. Muscle - ↑ glucose uptake/glycogen synthesis/protein synthesis
4. Brain/RBCs - use glucose but uptake is not insulin-dependent GLUT-4, i.e. glucose level independent
ii. MOA
1. Binding of insulin to -subunit of insulin R  autoP of β-subunits  tyrosine kinase activation  cascade
a. Insulin R is NOT a GPCR
b. PIP3 pathway: translocation of GLUT-4 to cell membrane  ↑ glucose uptake in muscle/fat
c. MAP Kinase pathway: cell growth, proliferation, altered DNA activity
d. Leprechaunism: due to homozygous mutation in insulin R gene (rare)
4. Dx
a. 1/4 criteria needed
i. Random glucose >200mg/dL + classical sx (polyuria, polydypsia, nocturia, wt loss)
ii. Fasting glucose >126mg/dL on two separate occasions (normal is ˂100mg/dL)
iii. OGTT >200mg/dL @ 2hrs post-prandial (normal is ˂140mg/dL)
iv. HbA1c ˃6.5%
5.
Classification of Diabetes
Genetic assoc
Key sx
Type of destruction
°of insulin deficiency
Req exogenous insulin?
DKA common?
Obesity common?
Age of onset?
a.
6.
Type 1
i.
ii.
Type 2
i.
ii.
Type 1
Weak, assoc with HLA-DR3/4
Micro/macrovascular, polyuria/dypsia, wt loss
Autoimmune (T cell mediated)
Absolute
Completely dependent on exogenous insulin
Yes
Rarely obese, weight loss is common
Often younger, quick presentation
Type 2
Very strong, family hx common
Insidious onset, mainly MACROvascular (ex) AS
Amyloid deposition/degeneration of β-cells
Relative
May be necessary in late stages/uncontrolled
Rare, HHNKC is more common
Usually obese
Often older, insidious presentation
Diabetes
Anti-insulin Ab, anti-islet Ab, anti-GAD Ab are MARKERS of dz, not the cause
Sx begin with >90% β-cell destruction (i.e. years after hypersensitivity has begun)
b.
Diabetes
No 1st response (the one where preformed insulin released), but normal 2nd response
Body tries to compensate by ↑ endogenous insulin synth/secretion, eventually, β-cell failure  low insulin
1. Basal level of insulin remains – enough to prevent ketosis but not enough to prevent hyperglycemia
iii. In early stages, if glucose is effectively lowered, insulin sensitivity returns (cure glucose toxicity)
c. Impaired Glucose Tolerance (pre-diabetes)
i. Dx via meet 1/3 criteria:
1. Fasting glucose 100-125mg/dL
2. 2hour OGTT 140-200mg/dL
3. HbA1c 5.7-6.4%
d. Gestational DM: 3hour OGTT results with at least 2 of: 1 hour (>180), 2 hours (>155), 3 hours (>140), fasting (>95)
Acute complications
a. DKA
i. Rare, but an emergency medical condition seen in type 1 DM, often precipitated by infxn
ii. Absolute insulin deficiency + high glucagon  catabolic state
1. Muscle releases AA (substrate for GNG), fat releases FFA (substrate for ketogenesis)
a. Marked ↑ GNG  extreme hyperglycemia
i. ↑ sugar  high filtered load that exceeds resorptive capacity of kidney  unreabsorbed
glucose acts as osmotic diuretic in urine  polyuria  vol depletion
ii. Low volume  ↓ renal blood flow  acute renal failure
b. Excess FFA  ketones, which are acidic, thus  acidosis
i. Body ↑ respirations to blow off excess CO2 (from excess H) = Kussmauls breathing
2. Sx: polyuria, N/V, fruity breath odor (acetone)
3. PE: low BP, high HR, high RR, dry mucous membranes/soft eyes due to dehydration
4. Labs: high Hb (hemo[]ed), high BUN/Cr, low arterial pH
b. Hyperglycemic Hyperosmolar Non-Ketotic Coma (HHNKC)
i. Seen in type II DM due to relative insulin defc’y
ii. Low insulin levels sufficient to prevent ketone body production but insufficient to prevent hyperglycemia
iii. Ppt factor (drank gallons of Coke to satisfy polydipsia)  extreme hyperglycemia  osmotic diuresis  extreme
dehydration but NO KETOSIS  coma  predictable sx, lab values
1. Liver thinks glucose is low (b/c intracellular glucose IS low)  GNG/glycogenolysis which exacerbates problem
c. Hypoglycemia (due to excessive insulin)
11
7.
8.
Chronic complications
a. Elevated HbA1C (marker of long-term glucose status, good way to determine if pt is compliant w/ therapy)
b. Macrovascular (main complications)
i. Begin early, with start of insulin resistance
ii. Ex: AS  CAD (#1 killer complication of diabetes) + PVD
c. Microvascular
i. Begin later, with hyperglycemia
ii. Most likely caused by non-enzymatic glycosylation due to all the excess glucose (formation of AGEs)
iii. Ex
1. Retinopathy: capillary hemorrhage  ischemia  neovascularization prone to bleeding  blindness
2. Nephropathy: thickening of glomerular caps  destruction of membrane  micro/macroalbuminuria  RF
3. Neuropathy: esp in distal hands/feet
4. Poor wound healing
Pharmacology – hypoglycemia is always a potential SE!
a. Type 1 has absolute requirement for exogenous insulin
i. Types of insulin
1. Rapid acting for use before meals: Aspart, Lispro, Glulisine
2. Short acting: regular insulin
3. Intermediate acting: NPH, Lente
4. Long acting to maintain basal level (prevents ketosis): Ultralente (small peak), Glargine, Detemir
Ultralente
/Detemir
b.
ii.
iii.
Type 2
i.
ii.
MOA: replaces non-existent insulin, suppresses hepatic GNG, ↑ glucose uptake by GLUT4 tissues
Indication: DOC for type 1, may be necessary in late stage type 2
Non-pharmacological tx is first (lifestyle changes)
Oral hypoglycemics
DRUG
IV Fluids
Sulfonylureas
Glipizide
Glyburide
Glimepiride
Biguanides
Metformin
MOA
Replacement of fluid and electrolytes
↑ insulin secretion by triggering pre-form insulin
release (SU R, K-channel), “secretagogue”
INDICATION
Esp w/ DKA, HHNKC
Type 2 DM
Lean pts ( wt gain)
↓ hepatic GNG
Obese + insulin resistance
Hx of hypoglycemia
PCOS
Thiazolidinediones
-glitazones
↓ insulin resistance (bind PPAR  ↑ GLUT4)
↓FFAs
Meglitinides
-glinides
-Glucosidase (-)
Acarbose
Miglitol
Incretins
Pramlintide
↑ insulin when glucose exceeds a threshold
(so effect is glucose [ ]-dependent)
Slows GI breakdown/absorption of complex CHO
Insulin resistance
Hx of hypoglycemia
PCOS
Type 2 DM
Sitagliptin
(-) DPP-4, the enzyme which deactivates GLP-1
(an incretin)
GLP-1 analog, resistant to DPP-4
Exenatide
Amylin analog, a normal gut protein 
delayed emptying, satiety, ↓ glucagons, ↓ GNG
Postprandial hyperglycemia
Severe hypoglycemia due to
tx w/SUs
Type 2 DM
Type 1 DM - add to insulin
SE / CONTRAINDICATION
Type 1 DM (no β-cells to respond)
Glyburide contra: renal insufficiency
(↑ risk of hypoglycemia)
DDI: EtOH, NSAIDs, E2, β-block, etc
Contra: renal/hepatic dz, CHF
(↑ risk lactic acidosis)
GI effects
DDI: furosemide, cimetidine, digoxin
Contra: CHF (↑ plasma vol)
↑LFTs, wt gain, ovulation, edema
Hypoglycemia/HA
DDIs: erythromycin, rifampin, ketocon
GI effects, flatulence
Glucose tablets for hypoglycemia
(complex carbs not absorbed!)
Nausea
Take immediately before meals and
lower insulin dose by 50%
Type 2 DM
Type 2 DM
Combo w/ SU, metformin
Nausea
Take 60min prior to meals
Contra: severe kidney dz
12
FEMALE REPRODUCTIVE
1. Pubertal Development
a. Thelarche (breast budding/glandular development), starts ~8y
b. Adrenarche (pubic/axillary hair) and growth spurt
c. Menarche (as growth spurt decelerates), starts ~12y and first 1.5y may be anovulatory
2. Review
a. Hypothalamus releases pulsatile GnRH  FSH/LH release from pituitary  E/P/A from ovary
b. Ovarian follicular phase is correlated with endometrial proliferative phase; ovarian luteal assoc with endometrial secretory phase
c. Rising estrogen/progesterone lead to LH surge, and ovulation follows ~24h later
d. During luteal phase, high estrogen/progesterone (PG) prepare endometrium (secretory phase)
i. w/o implantation (w/o hCG to replace LH, which is ↓ due to ↓ GnRH pulses)  luteal degeneration (↓PG)  menses
e. Follicle anatomy: w/in are granulosa cells (FSH receptors), outside are theca cells (LH receptors)
f.
FSH roles
i. Stimulates granulosa cell proliferation and E2 formation (via aromatase, from testosterone produced by theca cells)
ii. Upregulates FSH + LH receptors
g. LH roles
i. Stimulates testosterone formation in theca cells
ii. LH surge: midcycle, causes follicle to undergo meiotic change
Amenorrhea
Primary Amenorrhea, high FSH
Turner Syndrome (45, XO)
Testicular feminization
syndrome (46, XY)
Anatomic Problems
HMS/Pituitary Problems
2° Amenorrhea w/↑ FSH
2° Amenorrhea w/o ↑ FSH
3.
4.
5.
6.
Pathogenesis
Ovary does not respond to FSH
Pre-pubertal destruction (chemo), chromosomal dysfxn
Accelerated postnatal follicular atresia  nonfxn ovary
High FSH/LH
XY male w/ AR mutation  make androgen but can’t
respond to it, female external phenotype
Have internal testes, blind-end vagina
Various anatomic problems that prevent normal
menstruation, dx by estrogen/progestin challenge
Lifestyle: excessive exercise, stress, morbid obesity
Organic: Kallman’s, pituitary tumor
Ovary destruction (ex chemo)  acquired ovary failure
Anatomic (scarring)/HMS/pituitary problem acquired
ovarian failure, dx by estrogen/progestin challenge
Clinical
Amenorrhea and lack of 2° sex-characteristics
first via history, then order a karyotype
No secondary sex characteristics
Webbed neck, wide-spaced nipples, low hairline
Undergo thelarche but NO adrenarche/menarche
Testes still secrete Müllerian inhibit substance
Testes must be removed to prevent cancer
Ovarys make estrogen  normal 2° sex
Tx by surgery
Endocrine imbalance  lack normal 2° sex
Tx by hormonal supplementation
Estrogen HRT can be used
Tx by surgery for anatomic
Tx by hormonal replacement for HMS/pituitary
Menstrual disorders
a. Amenorrhea
i. Normal mensturation: 4 weeks plus/minus 1 week (poly/oligo-mennorrhea)
1. Menorrhagia – excessive bleeding
2. Menometrorrhagia – chaotic non-periodic bleeding
ii. Primary amenorrhea: a woman who has never menstruated (age 18, or by 16 if sex-characteristics are lacking)
iii. Secondary amenorrhea: a women who has menstruated but now does not (6 cycles or 3 intervals)
iv. Dx: primary or secondary? check FSH → if high, the problem is w/ the ovary not responding
b. Dysfunctional Uterine Bleeding – endometrium is responding normally to abnormal endocrine signals
i. Functional Problems
1. Anovulatory cycles – most common cause of DUB during reproductive years
a. failure of ovulation  loss of progesterone, thus unopposed estrogen stimulation
2. Endometrial atrophy is most common cause in postmenopausal women
ii. Organic Problems such as polyps
Hyperandrogenic Disorders
a. Women secrete androgens from two sites: adrenals (zona reticularis) and ovary
b. Circulating androgens – free form is active form, levels ↑ with high estrogens (which also bind SHBG)
c. Types of androgens that can be over-produced
i. DHEAS – made by adrenals, so elevations point toward adrenal overproduction
ii. Testosterone – most potent, elevations w/o DHEA elevations point toward ovarian problem
d. Dx
i. Elevations of DHEAS = adrenal overproduction: adrenocortical carcinoma, Cushings, CAH (congenital adrenal
hyperplasias) – late onset form is very common and usually involves 21-hydroxylase defc’y (tx w/ glucocorticoids)
ii. Elevations of testosterone w/o elevation of DHEAS = ovarian problem
1. Ovarian neoplasm (very high testosterone levels)
2. Polycystic Ovarian Disease
a. Overstimulation of theca and under-aromatization  hyper GnRH release from hypothalamus
b. Abnormal LH/FSH is key  ↑ androgens, ↓ estrogen  hormonal and metabolic imbalance
c. US shows multiple cysts
e. Sx of excess androgens: oligo or amenorrhea, hirsutism (irreversible conversion vellus→terminal hair), obesity, insulin resistance
f.
Tx: treat source of hyperandrogenism w/ 5-reductase inhibitors (finasteride), AR antag (spironolactone, ketoconazole), flutamide
Pathophysiology of hyperprolactinemia /galactorrhea
a. Prolactin = pituitary hormone that regulates lactation, tonically inhibited by dopamine (prolactin inhibitory factor)
b. Prolactin ↑ during pregnancy involved in milk production not milk let-down (that’s oxytocin)
c. Galactorrhea is an inappropriate bilateral discharge of milk (unassoc w/ childbirth or nursing)
d. Causes of hyperprolactinemia: ↓ dopamine in CNS (neuroleptics), hypothyroidism, pituitary tumors (may be removed → transspenoidal resection), stalk compression such that PIF doesn’t reach target, chest wall trauma, nipple stimulation
e. Tx: dopamine agonists (ex) bromocriptine, cabergoline
Infertility Medicine
a. Infertility: 1 year of regular unprotected intercourse not resulting in conception (normal monthly probability of fertilization ~20%)
b. Male problems – central (pre-testicular), testicular, post-testicular
c. Female problems – dysfunction vs failure, anatomical obstruction
13
FEMALE PATHOLOGY
1. Infections
a. Chlamydia – gram neg intracellular, most common STD, neonatal conjunctivitis, can  infertility
b. Gonorrhea – gram neg diplococcus, ascending infxn leads to scarring
c. Herpes – must delivery babies of herpes+ mothers by C-sxn to prevent transmission (often fatal), ulcerated vesicles
d. Trichomonas – large flagellated protozoan easily seen in wet mount, see “strawberry cervix”
e. Candida – exacerbated by pregnancy, OCP (oral contraceptive pill), and diabetes, hyphae/pseudohypae, curd-like discharge
f.
Gardnerella vaginalis – very common, gram (-) bacillus, fishy odor
2. Vulva
a. Epithelium is stratified squamous
b. Lichen Sclerosus – dermal sclerosis, may be autoimmune, often older women, little inflammation, no rete ridges
c. Lichen Simplex Chronicus – epithelial hyperplasia and hyperkeratosis → white patches, may have inflamm infiltrate
d. Vulvar Intraepithelial Neoplasia (VIN) = HPV
i. Mild dysplasia: squamous, assoc with low risk HPV (6,8,11)→ condyloma acuminatum (warts)
ii. Severe Dysplasia: assoc with Paget’s disease (owl eye cells) or melanoma (non-squamous)
1. Don’t know where malignant cells in vulvar Paget’s come from (vs from DCIS in nipple Paget’s)
3. Cervix
a. Ectocervix = stratified squamous while Endocervix = columnar (mucin secreting)
b. Squamous epithelium meets glandular epithelium at squamocolumnar junction (SCJ)
c. Cervical Intraepithelial Neoplasia (CIN) = HPV (CIN much more common than VIN)
i. Squamous metaplasia of columnar cells at SCJ
ii. Due to high risk HPV (16,18,31) and can result in transformation to invasive cancer
1. Can  adenocarcinoma in situ or invasive adenocarcinoma
iii. Risk factors: multiple sex partners!!
iv. Classification (Bethesda System building on CIN system)
1. LSIL (low grade squamous intraepithelial lesion) = CIN 1 = mild dysplasia
2. HSIL (high grade SIL) = CIN 2,3 = moderate or severe dysplasia including carcinoma in situ
v. Pathology: koilocytes
vi. Screening: Pap smears
4. Uterus
a. 3 layers: serosa, myometrium (muscular layer), endometrium
b. Menstrual cycle
i. Days 1-4: Menstrual Phase
ii. Days 4-14: Proliferative Phase – REQ ESTROGEN, prolif of stroma
iii. Days 15-28: Secretory Phase – REQ PROGESTERONE, spiral arteries
c. Endometritis (inflammation)
i. Acute is usually due to ascending infxn thru cervix, see PMNs
ii. Chronic assoc w/ PID (esp chronic gonorrhea), see fibrosis and mononuclear cells, must see plasma cells
d. Dysfunctional Uterine Bleeding – endometrium is responding normally to abnormal endocrine signals
i. Functional
1. Anovulatory cycles – most common cause during reproductive years
a. Failure of ovulation  don’t get progesterone, thus unopposed estrogen stimulation
2. Inadequate luteal phase – corpus luteum forms but is wimpy
3. Endometrial atrophy – most common cause in postmenopausal women
ii. Organic
1. Polyps, leiomyoma, hyperplasia, carcinoma
e. Endometrial Hyperplasia
i. ↑ gland:stroma ratio
ii. ↑ risk of developing into carcinoma
iii. Pathology (+/- atypia)
1. Simple – cystic, large bubbles
2. Complex – papillary projections of glands, carcinoma-in-situ  risk of progression to carcinoma
iv. Causes (extra estrogen stimulation): anovulation, PCOS, granulosa cell tumors, obesity
f.
Benign Polyps - most common endometrial tumor, usually solitary, more common post-menopause, usually present w/ bleeding
g. Endometrial Carcinomas
i. Type 1 (endometrial type)
1. Obese, assoc w/ high estrogen, low grade/good px
ii. Type 2 (serous & clear-cell type)
1. Older women, skinny, no association with estrogen, high grade/poor px, see Hobnail cells
iii. DES medication use in mother  clear cell VAGINAL carcinoma in daughter
iv. Other factors: cervical invasion ↑ the stage, vascular invasion ↑ metastatic risk (NO effect on stage tho)
1. Stage is most important indication of px
a. 1= confined to uterus
b. 2= involves cervix
c. 3= outside uterus, but not outside pelvis
d. 4 = outside pelvis
h. Myometrium
i. Leiomyoma
1. most common benign uterine tumor, very common in reproductive women
2. Location is intramural, submucosal, sub-serosal
ii. Leiomyosarcoma
1. Does not arise from pre-existing leiomyomas
2. Aggressive w/ mets to lung and often recur after removal
3. Best predictors of malignant behavior: mitotic activity/necrosis/nuclear atypia
iii. Adenomyosis
1. Endometrium glands and stroma inappropriately located w/in myometrium, very painful
14
5.
Ovary
a.
b.
c.
Polycystic Ovary Syndrome
i. Triad: obesity/insulin resistance, hirsutism, amenorrhea/oligomenorrhea
ii. Common cause of infertility
iii. Due to excessive secretion of GnRH  excessive LH (but not FSH) → excessive androgen secretion
iv. Ovaries have sclerotic capsules (“great white ovaries”) and cysts lined by thick theca interna
Endometriosis
i. Ovary is the most common site, very painful, “chocolate cyst”
Ovarian Tumors
i. Ovarian cancers have highest mortality rate of any female genital cancers due to late detection
ii. Predisposing risk factors: many, none of which is more harmful than the other
1. Pts with BRCA1/2 mutations will likely get breast/ovarian cancers, but have better chemo-sensitivity
iii. Surface Epithelial-Stromal Tumors
1. Most common tumors of ovary
2. Assoc with BRCA1 ovarian tumors
3. Types
a. serous tumors: most common type, huge cyst, psammoma bodies (calcified lamellar concretion)
b. mucinous tumors: multiloculated cysts
c. clear cell carcinomas are epithelial tumors assoc with endometriosis, hobnailing
d. Brenner tumor: dense fibrous stroma w/ nests of urothelial cells w/ coffee bean nuclei
4. Grades
a. Benign: serous cystadenoma most common
b. Borderline tumor: proliferative but good px, no invasion into stroma
i. Pseudomyxoma peritonei – enlarged abdomen filled w/ gelatinous goo, tumor of appendix
c. Malignant: poor px, invasion into stroma
i. Serous carcinoma most common, psammoma bodies
iv. Sex Cord-Stromal Tumors
1. Granulosa Cell Tumors
a. ↑ estrogen  endometrial hyperplasia (or carcinoma)
b. Postmenopausal women
c. Call-Exner bodies – granulosa cells haphazardly surrounding cyst filled with eosinophilic fluid
d. Coffee bean nuclei
2. Thecoma-Fibroma
a. Usually benign and unilateral in older women
b. Thecomas are stromal cells w/ lipid droplets (functional)
c. Fibromas are hard fibrous tissue (non-functional)
d. Meig’s syndrome: ovarian tumor + hydrothorax (often R side only) + ascites
v.
vi.
vii.
6.
Sertoli/Leydig Cell Tumors
1. Homologous to testicular cancer
2. Usually low malignant potential, usually unilateral
3. See in young virilized women
4. Secrete androgens
Germ Cell Tumors
1. Children, very aggressive, but chemo-sensitive
2. Teratoma: mature type are benign; immature type are malignant, dermoid cysts most common (tissue from all 3
germ layers including things like hair/teeth)
3. Yolk sac tumors: Schiller-Duval bodies, elevated -fetoprotein
Metastatic carcinoma
1. Breast, lung, stomach, GI
2. Bilateral
3. Krukenberg tumors: from stomach, aka “signet-ring” tumor cells filled w/ mucin
Placenta
a. Clinical problems assoc with placenta: IUGR, congenital abnormalities, maternal/fetal morbidity, maternal/fetal/infant death
b. Disorders of placenta
i. Abnormalities of placentation
1. Placenta accreta
a. Abnormally deep adherence of placenta to myometrium due to no decidua basalis
b. risk is rupture, hemorrhage when placenta detaches→ need surgery
c. Accreta is superficial myometrium, incerta is intermediate, and percreta is extension thru uterine wall
2. Placenta previa
a. Implantation near region of cervix prevents normal separation
b. Results in postpartum hemorrhage/uterine rupture
3. Abruptio placenta
a. Premature separation of placenta (which was normally situated)
b. May result in retroplacental hematoma (a complication seen w/ pre-eclampsia)
ii. Ascending infections (bacterial, can  chorioamnionitis and funisitis (umb. cord)) vs hematogenous (viral)
1. Complications: premature rupture of membranes or preterm labor
iii. Gestational trophoblastic disease = hydatidiform moles (risk higher if ˂15y or ˃40y, and for asians
1. Complete: no fetus, all villi involved (hydropic changes so villi look like grapes, trophoblastic prolif/atypia),
Karyotype is diploid (XX, both from father), can  choriocarcinoma (check hCG)
2. Partial: fetus is present, only some villi are affected, karyotype is triploidy (XXY, 1 mom and 2 dad)
a. Less trophoblast prolif and no atypia, less hCG and choriocarcinoma rare
3. Choriocarcinoma spreads hematogenously to brain/GI/lung/liver, produces hCG, responds to chemo
15
7.
Fallopian Tubes
a. Salpingitis (inflammation)
i. Acute due to ascending infxn (E.coli, N.gonorrhea, Chlamydia, Mycoplasma)
1. N.gonorrhea causes pus formation (pyosalpinx) and can lead to PID
ii. Chronic due to repeat episodes of acute (esp subclinical Chlamydia)
1. Complications include obstruction → infertility/ectopic pregnancy/hydrosalpinx/PID
b. Salpingitis Isthmica Nodosa
i. Isthmus of tube has diverticula
ii. May result in infertility/ectopic pregnancy
c. Ectopic Pregnancy (1/200 live conceptions)
i. 95% in fallopian tubes and ½ of these due to impedance of flow thru tube
ii. Trophoblasts permeate wall leading to hematosalpinx and potentially dangerous intraperitoneal hemorrhage
d. Malignant Tumors
i. Usually mets from ovary/uterus
ii. Primary tubal carcinoma is rare and asymptomatic, so dx late w/ poor px
BREAST PATHOLOGY
1. Drainage & Supply
a. Lymphatic drainage 85% to axillary lymph nodes, rest to internal mammary; important for metastasis
i. Level 1 = lateral to pec minor
ii. Level 2 = deep to pec minor insertion on coracoid process
iii. Level 3 = medial to pec minor
b. Arterial supply: internal mammary (from subclavian), axillary artery perfuses lateral periphery, least perfused is lateral inferior
c. Innervation: intercostal n (nipple is by 4th intercostal nerve), intercostobrachial most often damaged during axillary node removal
d. Cyclic menstrual changes due to E/P: ↑ cellular proliferation, ↑ acini #, “premenstrual fullness”
e. Changes due to pregnancy: dramatic hyperplasia of all cell types
f.
Changes due to menopause: atrophy
2. Terminal Duct Lobular Unit (TDLU) – functional unit, structure from which most breast diseases arise
3. Characterization of breast masses:
a. 5Cs: count/consistency/contour/character/clock (to assess masses/lumps)
b. 4Ds: dominant/discrete/dense/different (to determine true lumps from lumpy areas)
4. Benign dz
a. Mastalgia – breast pain
i. Usually cyclical, hormonal, high caffeine
ii. Tx is conservative (↓caffeine, take VitE/primrose oil)
b. Fibrocystic Change
i. Breast pain, swelling, tenderness
ii. Usually nothing but need to rule out breast cancer
c. Nipple Discharge
i. Bloody discharge – usually need to excise the duct, rule out Pagets
d. Mastitis
i. Backed up milk → staph infection
ii. Think: Could this be an inflammatory breast cancer? biopsy after 1 wk of symptoms/no improve w/ABx
e. Duct Ectasia
i. Subareolar ductal dilatation w/ fibrosis and inflammation, may respond to ABx but often need excision of duct
5. Benign epithelial lesions
a. Presenting w/ nodules (size, tenderness?) and nipple discharge
i. Discharge color:
1. Milky-white (galactorrhea)
2. Sanguineous (intra-ductal papilloma)
3. Green (bilateral, reassure pt could just be an infxn)
ii. Most worrisome: unilateral, spontaneous, single-duct, bloody discharge
b. Types
i. Risk is elevated with family hx of breast cancer and ↑ age of pt
ii. Non-proliferative fibroblastic change (1% ↑ risk)
1. By far the most commonly detected lesions in the breast
a. Fibrosis
b. Adenosis
c. Apocrine metaplasia: change in cell type, repro age women, normal response to abnormal stimuli
d. Fibroadenoma
e. Simple cysts: dilated ducts
iii. Proliferative Fibrocystic Changes w/o Atypia (2% ↑ risk)
1. Typical ductal hyperplasia – cells look normal, just hyperplastic
2. Papillomas – intraductal papilloma, a core of vessels surrounded by proliferation
3. Sclerosing adenosis – extra tissue in lobules
4. Radial scar/complex sclerosing lesion (same except scar is ˂1cm)
5. Mondor’s dz – thromboplebitis of superficial thoracoepigastric vein → painful palpable cord (give NSAIDs)
6. Fat necrosis – can mimic cancer, assoc w/ recent trauma, tx w/ NSAIDs
iv. Proliferative Fibrocystic Changes w/ Atypia (5% ↑ risk)
1. Atypical ductal hyperplasia - duct is lined by abnormal cells
16
6.
Breast Carcinoma
a. 1/8 of women, ↑ by late age 1st childbirth, obesity, family hx, HRT, early menarche (˂11y), late menopause (˃55y)
b. BRCA1 (Ch17) > BRCA2 (Ch13) (both DNA repair enzymes), assoc with pre-menopausal breast/ovarian cancer
i. Carriers have 85% of developing cancer
c. Carcinoma in situ (general)
i. No invasion to stroma, vasculature
ii. Ductal carcinoma in situ (DCIS)
1. Most common presentation is mammographic calcification
2. Can have central necrosis
3. Paget’s disease (inflammation, erosion of the nipple)
a. Malignant cells travel along collecting ducts to epidermis, unilateral
b. Paget’s cells: abundant clear cytoplasm, atypical nuclei w/ prominent nucleoli
iii. Lobule carcinoma in situ (LCIS) – much less common, not seen on mammography
iv. Tx: local excisions plus irradiation, unless entire portion of breast is involved, then mastectomy
d. Invasive Carcinoma
i. Invasive ductal carcinoma (much more common)
1. Malignant cells arranged in cords/tubules in background of desmoplasia
ii. Invasive lobular carcinoma (not seen on mammogram)
1. No desmoplasia
2. Complete excision NOT indicated b/c does not ↓ future breast cancer risk
iii. Inflammatory breast cancer
1. IS NOT INFLAMMATION, it is terminology for the most advanced aggressive stage carcinoma
2. Dermal lymphatic invasion w/malignant cells
3. Skin has orange peel appearance (thick/erythematous/rough)
iv. Tx: sentinel lymph node biopsy followed by radiation therapy, if nodes are involved, then node dissection
e. Prognostic / Predictive Factors
i. Stage
1. Axillary lymph node status – most significant px
2. Tumor size – correlates with Px (˂ 1cm best)
3. Stage 0 – carcinoma in situ or Paget dz of nipple (100% 5 year life-expectancy)
a. Tx: Pt can choose between excision/radiation or mastectomy, no need to check lymph nodes
4. Stage 1 – small tumor (˂ 2cm) w/o axillary lymph node involvement
a. Tx for invasive breast cancer: first check lymph nodes, radiation to ↓ local recurrence
5. Stage 4 – metastasis (20% 5 year life-expectancy)
a. Surgery only for palliation
ii. Grade: 1 (well differentiated) – 3 (poorly differentiated) based on tubule formation, pleomorphic nuclei, mitoses
iii. Hormonal Receptors: HER-2 Neu positive is worse Px (Hercep test), estrogen R negative is worse Px
iv. Gail Model for breast cancer risk: age, age of menarche/first live birth, # family affected, atypia in previous biopsy, race
7. Benign Stromal Tumors
a. Fibroadenoma
i. Most common stromal tumor
ii. Well circumscribed, benign proliferation w/ NO ↑ risk of cancer
iii. Reproductive age group (esp. ♀ ˂ 30y)
b. Phyllodes tumor: malignant form of fibroadenoma
8. Gynecomastia: in males, only due to ductal proliferation, NOT lobular involvement
9. Recommendations for Breast Maintenance
a. Self Breast Exam: start at age 20
b. Clinical exam every 3yrs, then annually at 40
c. Mammogram: annually in women age 40 and older, or 10y prior to when a family member had an early onset breast cancer
i. Digital pic better than film for ˂ 50y, dense breasts, pre-menopausal
ii. Must biopsy new calcifications in cluster pattern – use stereotactic biopsy
d. Breast MRI – is more sensitive but more $, only indicated in pts w/ high lifetime risk (ie BRCA, Cowden (PTEN), Li-Fraumeni (p53))
e. Needle (fine needle, or core biopsy) is the way to go normally
f.
Non-palpable masses are done by ultra-sound guided stereotactic core biopsy (note that USound doesn’t see Ca)
g. Genetic counseling – 1+ close family members affected, male family member affected, Jewish family with hx young dx
h. Follow-up for high risk: surveillance, chemoprevention (tamoxifen), prophylactic bilateral simple mastectomy or oophorectemy
10. Tx
a. SERM: Tamoxifen blocks estrogen receptor to ↓ growth of breast cancer cells that have ERs
b. Aromatase inhibitors (anastrozole, exemestame) – block estrogen formation from androgens, better survival than SERMS
c. Trastuzumab (Herceptin) – go after cells over-expressing HER2/NEU
d. Bevacizumab (Avastin) – prevents angiogenesis feeding metastatic dz; S/E: delays wound healing, damages kidney, and ↑BP
e. ER(–) or HER2/Neu –chemotherapy
f.
If nodes are involved – chemotherapy
g. Chemotherapy combos:
i. CMF = cyclophosphamide, MTX, 5-FU
ii. CAF = cyclophosphamide, adriamycin/doxorubicin, 5-FU
iii. AC = adriamycin/cyclophosphamide (may be followed by taxane)
11. High yield
a. Invasive Carcinoma – most common carcinoma presenting as breast mass
b. DCIS – highest likelihood to be multicentric ipsilateral disease (remember it follows the milk ducts)
c. Lobular carcinoma in situ – highest likelihood to be bilateral
d. Phyllodes – often large but mobile
e. Inflammatory carcinoma – dermal lymphatic invasion
f.
Metastases go to: bone ˃ lung ˃ liver ˃ brain
g. Breast cancer rarely assoc w/ pregnancy but note that therapeutic abortion does NOT improve maternal survival
h. Male breast cancer dx/tx similar to female but no indication for aromatase inhibitors (give SERM)
17
FEMALE PHARM
1. Estrogens (have phenolic A ring)
a. E1 = Estrone, 10X less bioactive than E2
b. E2 = 17β-estradiol, most potent and most abundant, made from androstenedione and adrenal DHEA by aromatase
c. E3 = Estriol, made in high [ ] by placenta
d. DES = potent synthetic that does not bind SHBG and is not rapidly metabolized, can be palliative tx in prostate cancer
e. Phytoestrogens (ie genistein) found in soy/clover/hops/flax are weak estrogens
f.
Must use C17 synthetic derivatives in oral contraceptives to avoid 1st pass effect, avoid SHBG binding, prolong t½
i. Ethinyl Estradiol
ii. Mestranol
2. HRT
a. Relieves menopausal sx, slows osteoporosis (↓ fractures but doesn’t build bone), but has risks and many DDIs
b. Must add progestin to estrogen replacement if uterus is still intact due to risk of endometrial/breast cancer
c. Do not start HRT for osteoporosis w/o menopausal sx, the risks (thromboemboli, endometrial/breast cancer) outweigh the benefit
d. DDIs: Effects are ↑ by VitC, acetaminophen, protease inhibitors/NNRTIs and ↓ by antibiotics/anticonvulsants
3. PCOS (polycystic ovarian syndrome)
a. Lifestyle changes (diet, wt loss, smoking cessation)
b. Pharmacotherapy
i. Reduce androgenic sx (hirsutism/acne/male pattern baldness)
1. Estrogens/non-androgenic OCPs (norgestimate, desogestrel, drospirenone): ↓LH to ↓ androgen synth, ↑SHBG
2. Antiandrogens: flutamide (R antag), finasteride (5-red inhibitor), glucocorticoids (suppress HPA axis)
3. Eflornithine cream retards hair growth by inhibiting ornithine carboxylase
ii. Reduce insulin levels (assume all PCOS pts to have some degree of insulin resistance)
1. Wt loss, which also helps restore ovulation
2. Metformin – ↑ insulin sensitivity, improves ovulation, wt loss, less androgen synth, tx BP/lipids
iii. Address fertility
1. Induce ovulation by wt loss, Metformin
2. Beware endometrial hyperplasia (& cancer) risk from chronic anovulation (use combined oral contraceptives)
4. Infertility
a. Method is manipulation of FSH/LH via various mechanisms (see chart)
DRUG
Estrogens
MOA
PCOS: ↑ E2  fb inhibition  ↓
GnRH/LH  ↓ androgen production
INDICATION
↓ menopause sx + osteoporosis
PCOS
Progestins
PCOS: endometrial protection via
withdrawal bleeding
Part of HRT if intact uterus
PCOS (esp medroxyprogesterone,
though no effect on
acne/hirsutism/birth control
PCOS, hirsutism
Infertility
Given early in cycle (dy 3-8)
Restore menstrual cycle/ovulation
Used +/- Clomiphene
PCOS, oligomenorrhea
Stimulate ovulation
Used +/- Clomiphene
Stimulate ovulation
Used in combo w/ hCG
Given during follicular phase
Used in combo w/ gonadotropins
Given ~day 12-15
Progesterone
Norethindrone
Medroxyprogesterone
Spironolactone
Clomiphene (SERM)
Metformin
AR antag + androgen synth (-)
ER antag in HMS  ↓ neg fb 
↑GnRH/FSH+LH/E2  ovulation
Insulin sensitizer (biguanide)
↓ liver glucose synth
Thiazolidinediones
Rosiglitazone
Gonadotropins
Insulin sensitizer
hCG
Elicits LH surge necessary for
ovulation
Directly ↑FSH levels
(exogenous supplementation)
SE / CONTRAINDICATION
Post-menopausal bleeding, nausea,
breast tenderness, HTN, ↑pigment
Contra: hx of E2-dependent
neoplasm, TE, prego (category X),
undx genital bleed, hepatic dz
Vaginal bleeding, hyperK
Hot flashes
Risk of multiple gestations
Potential weight gain
Risk for multiple gestation
OHSS (ovarian hyperstimulation
syndrome): excess VGEF 
↑capillary permeability 
ascites/hypovolemia
18
MALE REPRODUCTIVE
1. Normal Physiology
a. Pulsatile GnRH stimulates pituitary FSH/LH
i. FSH acts on Sertoli cells to enhance spermatogenesis (seminiferous tubules), release is ↓ by inhibin-B (negative fb)
ii. LH stimulates Leydig cells to produce testosterone, release is ↓ by testosterone (negative fb)
b. Vast majority of testosterone in serum is bound to albumin/SHBG
i. Bioactive testosterone = free testosterone
ii. Bioavailable testosterone = free testosterone + albumin-bound testosterone (this fraction larger in ♂)
c. Testosterone 
i. DHT via 5-reductase  external virilization during embryogenesis + devl’p of male 2˚ characteristics during puberty
ii. Estradiol via aromatase  bone metabolism effects + gynecomastia
2. Hypogonadism  problems in spermatogenesis (infertility & ↓ testicular volume) and/or testosterone production
a. Primary: defect in testes
i. Klinefelter syndrome (47XXY or 48 XXXY) is most common
1. Damage to seminiferous tubules and Leydig cells  no spermatogenesis (infertility) + low testosterone
2. Sx: small/firm testes, eunuchoid proportions (long arms/legs), gynecomastia ( breast cancer)
b. Secondary: defect in hypothalamus or pituitary
i. Kallmann’s syndrome
1. X-linked KALIG gene mutation  isolated GnRH defc’y
2. Sx: anosmia, sx of low testosterone, color blindness/hearing loss can also occur
ii. Idiopathic w/ mental retardation: Prader-Willi and Laurence-Moon-Bardet-Biedl
iii. Hyperprolactinemia: Elevated PRL suppresses GnRH and FSH/LH
3. Clinical manifestations
a. 1st trimester defc’y in primary hypogonadism results in female/ambiguous genitalia + hypospadias
b. 1st trimester defc’y in secondary hypogonadism results in micropenis (b/c testosterone production under control of hCG, not LH)
c. 3rd trimester defc’y in either results in micropenis
d. Pre-pubertal hypogonadism: small/soft testes, small external genitalia, never 2˚ sex characteristics, eunuchoid proportions
e. Post-puberty hypogonadism (most common): infertility, regression of 2˚ characteristics, ↓ libido, ED, ↓ muscle mass/↑fat
f.
Primary is most likely associated with ↓ in sperm production and gynecomastia
4. Dx
a. Genital exam, look for: eunuchoid proportions, size of testes, masses in testes, hair distribution, muscle mass, gynecomastia
b. Measure testosterone
i. Free testosterone is most reliable measure
ii. Total testosterone levels drawn in morning and must take into account SHBG levels
c. High FSH/LH indicate primary hypogonadism
d. High prolactin levels indicate GnRH suppression
e. Semen analysis – concentration, motility, morphology (dx abnormality if 3 abnormal samples in 3mo period)
i. Normal →  20 million/mL w/  50% motility
5. Tx
a. Testosterone HRT: reverses all the features of impaired sexual characteristics; improves libido/performance, ↑ bone density
i. S/E: polycythemia/hyperviscosity syndrome, sleep apnea, acne, gynecomastia, testicular atrophy w/ prolonged tx
ii. Contra: known prostate cancer (though does not ↑ risk in those w/o hx), breast cancer, Hct >55%
iii. Caution: untx sleep apnea, severe BPH, CHF, Hct ˃50%
19
MALE PATHOLOGY
1. Anatomy of prostate
a. Retroperitoneal, surrounds bladder neck/urethra
b. Two zones – peripheral zone (prostate cancer) + transition zone (BPH)
c. Fibromuscular stroma + secretory glands
2. PSA produced by both benign and malignant epithelium but prostate cancer is dx based on elevated PSA levels
a. Higher levels often indicate more advanced tumor
b. Levels drop with treatment, rise in re-activation
3. Testicular biopsy determines
a. Whether there is an abnormality in spermatogenesis and whether or not it can be corrected
i. Endocrine causes: hypogonadism, Klinefelters, testicular aplasia
b. Whether there is a germ cell tumor (seminoma vs non-seminoma) or sex cord tumor
i. Testicular tumors rare, but most common in young men 15-40, present w/ painless enlarged testis
ii. Stages: pTis (in situ), pT1 (epididymis), pT2 (epididymis + vasc/lymph invasion), pT3 (spermatic cord), pT4 (scrotum)
4. Prostate disorders
Dz
NOTES
UTI (E Coli)  reflux into gland  purulent inflamm w/ PMNs  tissue destruction  healing w/ fibrosis
Acute prostatitis
Destruction of epithelium  ↑ PSA
Chronic prostatitis
Sequelea of acute w/ lymphocytes in prostatic secretions, manifests as low back pain
Assoc w/ development/conversion to cancer over time
Granulomatous prostatitis
Idiopathic, TB, iatrogenic
Mimics carcinoma on prostate exam
↑ age  hyperplasia of transition zone surrounding urethra  urethral obstruction  dys/poly/noct-uria
BPH
(aka nodular hyperplasia)
Somewhat hormonally driven since anti-androgens alleviate
Enlarged gland  ↑ PSA
Pressure atrophy of peripheral zone
Prostatic carcinoma
Precursor lesion = PIN (prostatic intraepithelial neoplasia): crowded cells w/ macronucleoli, basophilic
↑ w/ age, race disparity (blacks ˃ whites ˃ asians)
Very slow growing – more men die with prostate cancer than from it
Dx by PSA, rectal exam, transrectal US-guided tissue biopsy
Gleason score: grade 2-10 (add 2 most common scores), 10 being the worst px/poorest glandular differentiation
Stage: T1 (incidental), T1c (elevated PSA), T2 (palpable but confined), T3 (invades seminal v), T4 (invades out)
5. Testicular disorders
Cryptorchidism
Undescended testis due to hormones, mechanical, idiopathic
Eventually atrophies – if bilateral, infertility
50x ↑ risk seminoma
Acute torsion
Emergency due to venous obstruction
Inflammation/Infxn
Testicular: mumps orchitis (heals w/o infertility), granulomatous (sudden tender mass)
Epididymis: gonorrhea (inflamm destroys)
Both: malakoplakia, fungal infxn
Germ Cell Tumors
Staging: pTis (in situ), pT1 (confined to epididymis), pT2 (to lymph/blood/t.vaginalis), pT3 (invades sperm cord)
NSGCT (non-seminoma
Metastatic (via lymphatics and blood), usually present at stage pT3+, ave age 30y
germ cell tumors)
Radioresistant but chemosensitive
Elevated -fetoprotein
Aka mixed GC tumor
Seminoma
Confined to testis, but can metastasize via lymph nodes, usually present at stage pT2, ave age 40y
(most common)
Very radiosensitive, excellent Px
Smooth, homogenous tumor, usually not assoc w/ elevated serum markers
High -fetoprotein and hCG
Embryonal Carcinoma
More aggressive, worse px, most common in 20-30y age grp
Variegated, areas of hemorrhage/necrosis
Yolk Sac Tumor
Scaller-Duval cells
Areas of hemorrhage/necrosis common, reticular pattern, PAS/diastase-resistant hyaline globules
(most common in kids)
Elevated -fetoprotein
Choriocarcinoma
Highly malignant, poor px (high propensity for lymph/blood spread)
Elevated hCG
IGCN (intratubular germ
Carcinoma in situ
cell neoplasia)
Usually seen in aria surrounding invasive tumors or in contralateral testis from invasive tumor
Teratoma
Contains cells from all 3 germ lines (mature)
Prepubertal: diploid DNA, do not metastasize, not assoc w/ IGCN unclassified
Postpubertal: hypo-triploid DNA, does metastasize, assoc w/ IGCN unclassified
6. External genitalia disorders
Syphilis
Warthin-starry stain for spirochete, sharply demarcated chancre (vs chanchroid)
Chancroid
H.ducreyi, shallow ulcer w/ undermined edges
Granuloma Inguinale
Calymmatobacterium granulomatis, bipolar Donovan bodies, large histiocytes
Multinucleated viral infection  painful, ulcerated vesicles
Genital Herpes (HSV II)
Condyloma Acuminata
HPV infection, see koilocytes
Molluscum Contagiosum
DNA pox virus
Bowenoid Papulosis
Koilocytes, full-thickness atypia, assoc w/ HPV (btw genital wart and SCC in situ (aka Bowen dz))
Squamous Cell Carcinoma
Minority of male cancers
Hypo/epispadias  infxn, obstruction
Congenital
20
MALE PHARM
1. Hypogonadal tx
a. ↓ androgens cause:
i. ↓ spermatogenesis & fertility (via LH/FSH defc’y)
ii. ↓ libido/ED
iii. ↓ muscle mass (↓ nitrogen retention), body hair
iv. Osteoporosis, anemia
v. Depression
vi. Gynecomastia
b. HRT should reverse all complications caused by low testosterone
i. After 1mo: normal testosterone levels, ↑ energy, ↑ libido/sexual fxn’ing, better mood
ii. After 3mo: ↑ muscle mass, ↓ body fat
iii. After 6mo: ↑ bone mass
DRUG
17-OH T esters
T enanthate
T cypionate
T propionate
T undecanoate
17- alkylated
Methyltestosterone
Fluoxymesterone
Patch & Gel forms
Andro-derm/gel
Buccal forms
Striant
Anabolic Steroids
19-Nortestosterone
Oxandrolone
Oxymetholone
Stanozolol
Danazol
2.
MOA
Replenishes low levels
INDICATION
Hypogonadism
SE / CONTRAINDICATION
Given IM (in oil) every few weeks
T prop has short t ½
T undec is oral
Replenishes low levels
Post-pubertal hypogonadism
Replenishes low levels, absorbed
readily thru skin
Replenishes low levels, absorbed
readily thru oral mucosa
↑ anabolic effects > sexual
Hypogonadism
Given orally 1x/d
Hepatotoxicity (rarely used now)
-cholestatic hepatitis, adenocarcinoma
Avoid skin contact w/ women/kids
Difficult to titrate dose of patch
Weak progestin/androgen activity
Suppress ovulation by (-) LH surge
endometriosis
Hypogonadism
Avoids 1st pass metabolism
If you desire a cell w/ Bonds + ARod
Long term  CV risk, atherosclerosis
(altered lipid profile), hepatotoxicity,
aggressiveness, infertility
Excessive androgen tx
a. ↑ androgens cause:
i. ↓ spermatogenesis & fertility (via fb inhibition of LH/FSH)
ii. Acne, esp in women (via androgenic stimulation of sebaceous glands)
iii. Virilization in women
iv. Premature physis closure in children
v. Erythrocytosis
vi. Na/water retention (can exacerbate CHF)
DRUG
GnRH R Agonists
Leuprolide
Goserelin
Triptorelin
GnRH R Antag
Plenaxis
Non-steroid AR antag
Flutamide
Bicalutamide
5-reductase (-)
Finasteride
Ketoconazole
Spironolactone
MOA
Downregulates GnRH R
INDICATION
Prostate cancer (w/ AR antag)
Triptorelin is long-acting;being
evaluated for paraphilia/sex deviant
SE / CONTRINDICATION
Initial surge of testosterone before
downregulating R
Block GnRH R to block LH release
Prostate cancer
No initial surge of testosterone
Blocks action testosterone
Prostate cancer (w/ GnRH agonist)
Flut: hepatox, gynecomastia, 3x/d dose
Bical: low hepatotox, 1x/d dose
Blocks testosterone  DHT
BPH
Alopecia
Teratogenic (don’t use in women)
↓ libido/sexual dysfunction
Antifungal
(-) androgen/glucocorticoid synth
AR antagonist
Female hirsutism
Polycystic ovary syndrome (PCOS)
21
GENETICS IN ENDOCRINOLOGY
1. MEN1/2 (multiple endocrine neoplasia type 1/2)
2. FHH (familial hypocalciuric hypercalcemia)
3. PHP (pseudo-hypoparathyroidism)
4. PPHP (pseudo-pseudo-hypoparathyroidism)
5. PDD I/II/III (polyglandular deficiency disorder type I/II/III): all female predominant (suspect w/ premature ovarian failure)
6. MODY (maturity onset diabetes of the young)
Disease
MEN1
MEN2
Inheritance
AutoD
AutoD
MOA
Inactivation of MENIN tumor suppressor gene
Activation of RET oncogene
FHH
PHP1a
AutoD
AutoD
imprinted
Inactivation of CaSR
Inactivation of Gs gene (if mutant allele maternal)
PHP1b
AutoD
imprinted
AutoD
imprinted
AutoD
Inactivation of Gs gene (if mutant allele paternal)
PPHP
MODY
Altered imprinting of Gs gene
Results in ↓ renal expression
5 txn factor genes regulating insulin secretion
6th gene is glucokinase (MODY2)
Heterozygous → DM
Homozygous → incompatible w/ life
PHP2
Type of PDD
PDD I
PDD II
PDD III
Onset
3-5y
Peak ~30y
Middle-age
Genetics
AutoR AIRE mutation
Polygenic dominant
Unkwn but may be polygenicD
Features
Hyperparathyroidism, pituitary tumor, pancreatic tumor
Medullary thyroid carcinoma, pheochromocytoma
MEN2a: also have Hirshsprung dz, upper back pruritis
MEN2b: also have tongue/GI neuromas, thick lips/eyelids
Benign hyperCa, hyperparathyroidism, no tx needed
HypoCa (PTH-resistant), Albright Hereditary
Osteodystrophy (moon face, short stature, mental
retard)
HypoCa (PTH-resistant) only
Albright Hereditary Osteodystrophy only
MODY3 (HNF1) most commonly affected, then MODY2
Most DM is T2DM (may be 40+ risk alleles)
T1DM shows strong assoc w/ HLA 6p21
↓ phosphaturic response to PTH
Effects
Adrenal insufficiency, hypoparathyroid, chronic
mucocutaneous candidiasis, alopecia, pernicious anemia,
celiac dz/malabsorption, thyroid disorders
Adrenal insufficiency, T1DM, vitiligo, thyroid disorders
Thyroid disorders
22
HIGH YIELD
1. Signet ring tumor
2. Schiller-Duval bodies
3. Hoarseness
4. Meigs Syndome
5. Hobnailing histopathology
6. Pseudomyxoma peritonei
7. Koilocyte
8. Condyloma acuminate
9. When to worry about the peripheral zone?
10. When to worry about transition zone?
11. KALIG gene mutation
12. RET oncogene
13. Anti-thyroglobulin/TPO Ab
14. Anti-TSH Ab
15. Hurthle cells
16. Pre-tibial myxedema & exopthalmos
17. Psammoma bodies
18. Upper flank abdominal bruit
19. Dysphagia, SOB
20. Hyperpigmentation
21. Vitiligo
22. ACTH stimulation test
23. CRH stimulation test
24. Dexamethasone low/high dose testing
25. Plasma ACTH
26. HPV low risk
27. HPV high risk
28. Laron Dwarfs
29. Inability to lactate following delivery
30. Xanthelesmas, xanthomas, arcus corneae
31. Palmar xanthomas
32. Pancreatitis in childhood
33. Galactorrhea
34. Diff Dx for hirsutism
35. Bitemporal hemianopsia
36. Malignant HTN + HA + sweating + palps
37. Salt and pepper chromatin
38. Test for VitD defc’y
39. Test for VitD tox
40. Most common cause hypocalcemia
41. ↓ adiponectin causes
42. Only drug that significantly ↑ HDL
43. Apo-B100
44. Renal insufficiency contraindication for?
45. Opposes insulin
46. SERM used in infertility
47. Contraindications for testosterone HRT
48. Hyperprolactinemia in men 
49. Hyperprolactinemia in women 
50. Most common testicular cancer
Krukenberg tumors (metastatic carcinoma to ovary; stomach origin)
Hallmark of yolk sac tumors, look for -fetoprotein
Recurrent laryngeal n damage due to thyroid
Ovarian fibroma, pleural effusion, ascites
Clear cell carcinoma (malignant epithelial tumor assoc with endometriosis)
Tumor of appendix that results in ovarian mucinous borderline tumor
Hallmark of HPV (HSIL)
HPV infection
Prostate cancer
Cervical cancer
Failure of GnRH cell migration  Kallmans (anosmia, hypogonadism)
Medullary thyroid carcinoma
Hashimoto’s
Grave’s
Hashimotos thyroditis, eosinophilic inclusions
Grave’s
Papillary thyroid carcinoma
Renal vascular hypertension
Compression of esophagus/trachea due to enlarged thryoid
Adison’s (primary adrenal insufficiency)
Assoc with autoimmune diseases, esp Grave’s & Addison’s
For hypocortisolism (Addisons)
For pituitary hypofunction (Cushings dz vs ectopic ACTH)
For hypercortisolism (Cushings)
Ectopic (very high), Cushings dz (normal), adrenal tumor (low)
6, 11
16, 18, 31
GH R problem  small, pudgy kids
Sheehans (post-partum pituitary infarction)
FH, heterozygote
Type 3 hyperlipoporteinemia/dysbetalipoproteinemia (apoE mutation)
LPL defc’y
Hyperprolactinemia
Cushings, PCOS, 21hydroxylase severe defects, Anabolic steroid usage
Mass on optic chiasm, think pituitary adenoma
Pheochromocytoma
Medullary thyroid carcinoma
25-VitD
1,25-VitD
Chronic kidney disease
↑ insulin resistance (adiponectin secreted by visceral adipocytes)
Niacin
Expressed on VLDL, IDL, LDL (ONLY one on LDL)
Metformin, glyburide
glucagons, GH, cortisol, catecholamines
Clomiphene
Prostate cancer, breast cancer, Hct >50%
Secondary hypogonadism (neg fb on GnRH  low LH/FSH)
Amenorrhea, galactorrhea (same MOA as above)
Seminoma
Hyperadrenals (Exogenous glucocort, Cushings)
CNS problems (psychosis)
Salt / Water Imbalance, Excessive Salt Retension->Edema, HTN
HTN
Impaired Glucose Tolerance
Immunosuppresion and Osteoporosis
Skin Thinning (Purpura, Stria, Echymoses)
Weight Gain (moon face, fat pads, buffalo hump)
Alopecia, Hursuitism
Gluconeogenesis (req aa, proteolysis  weakness)
Enzyme defect
21 OHase
17 OHase
11β OHase (CYPB1)
11β OHase (CYPB2)
Na wasting
+/+
HTN
+
+
-
Hypoadrenals (Addisons, 21β-hydroxylase)
Excessive salt loss, hypoK -> dehydration, Hypotension
Hypotension, orthopnea
Hyperpigmentation (high ACTH -> high MSH), vitiligo
Weight Loss
21hydroxy: precocious puberty, ambiguous female genitalia
Electrolyte disturbances  weakeness
Female Virilization
+
+
+
Pure chol ↑
Congenital
FH
Acquired
Hypothyroidism
Nephrotic syndrome
Ambiguous Male
+
-
Mixed
Type III
Combined FH
Hypothyroidism
Nephrotic syndrome
Uncontrolled DM
Precocious Male
+
+
+
Pure TG ↑
LPL defc’y
Apo-C2 defc’y
EtOH
Estrogen
Uncontrolled DM