Professional Documents
Culture Documents
Principles of Endocrinology & Metabolism ............................................................................................................................. 2 Diabetes Mellitus .................................................................................................................................................................... 4 Carbohydrate Metabolism & Hypoglycemia ......................................................................................................................... 11 Dietary Management of Diabetes & Hyperlipidemia ........................................................................................................... 14 Thyroid Pathophysiology ...................................................................................................................................................... 17 Pituitary Gland ...................................................................................................................................................................... 26 Endocrinology of Aging ......................................................................................................................................................... 33 Adrenal Pathophysiology & Multiple Endocrine Neoplasia .................................................................................................. 35 Gender Development............................................................................................................................................................ 46 Puberty .................................................................................................................................................................................. 50 Growth .................................................................................................................................................................................. 56 Obesity .................................................................................................................................................................................. 61
Endocrine disorders are: Prevalent (mild > extreme forms) Diagnosable (often thought of as difficult)
NEWS ALERT: Theres an obesity epidemic in the USA! Metabolic syndrome, diabetes, hypercholesterolemia, too
Diagnosis
History: Exam: Lab testing is big: Imaging: Pathology: mostly pattern recognition (not too much pathognomonic stuff) test hypotheses; discovery:
o o asymptomatic thyroid nodule: 5% are cancers st absent Achilles tendon reflex can be 1 sign of diabetic peripheral neuropathy
(need context fed/fasted, time of day, etc). use selectively! Make a biochemical Dx first. check tumor prognosis
Disease Mechanisms
Congenital / hereditary Gland hypoplasia (developmental defect) Hormone biosynthetic defect (abnormal hormone or enzyme gene) Hormone resistance (abnormal hormone receptor / signaling protein gene) Acquired gland failure Physiologic atrophy: e.g. menopause / andropause Inflammatory (autoimmune e.g. type I DM, infection) Destruction (tumor, drugs, surgery radiation) Accelerated hormone metabolism Acquired hormone resistance (e.g. type II DM) Autonomous function (hyperplasia, adenoma) Abnormal gland stimulation (trophic hormone or antibody e.g. Graves) Excessive hormone action Ectopic hormone production Tissue hypersensitivity Can cause oversecretion, undersecretion, or neither Can be sporadic or hereditary (Multiple endocrine neoplasia syndromes, others) o Think hereditary if: FHx, multiple, early onset Can be benign or malignant
Primary adrenal insufficiency: adrenal gland defective ( cortisol) Secondary adrenal insufficiency: pituitary defective (also cortisol) If hypothalamus messed up: call it 3or can call it 2 if not sure where problem is (hypothalamus vs pituitary)
Secondary Hypothalamic Pituitary Hormone Releasing Hormone CRH ACTH TRH TSH GNRH LH/FSH GHRH GH
Diabetes Mellitus
Introduction / Diagnosis of Diabetes
Diabetes: need ONE of...
Fasting plasma glucose Casual plasma glucose Oral glucose tolerance test HbA1c 126 mg/dL 200 mg/dL 200 mg/dL 6.5% AND symptoms of diabetes (2 hrs post 75g oral glc load)
Pre-diabetes: need ONE of Fasting plasma glucose 100 125 mg/dL (impaired fasting glucose) Oral glucose tolerance test 140 199 mg/dL (impaired glucose tolerance) HbA1c 5.7 6.4% Pre-diabetes: the level of glucose tolerance between normal & diabetes
Note that there are 3 types of prevention most physicians end up working in 2 / 3 prevention Preventing complications is key to management
5. Blurred vision Lens stiffens (sugars not retinopathy early!) Others: poor wound healing, vaginitis, gingivitis, dental caries ( vascular flow, sugars good for infections, etc.)
HYPEROSMOLAR NONKETOTIC STATE: severely high blood glucose with dehydration but no acidosis; also fatal if untreated
Insufficient insulin (but enough to suppress ketogenesis) glc utilization, hepatic glc output Pathogenesis
massive osmotic dieresis, dehydration pre-renal azotemia ( renal blood flow) renal excretion of glucose (cant clear large endogenous glc production) Vascular collapse
Diagnosis Treatment
Management: Pay special attention to known risk factors: BP, chol, smoking, blood glucose / A1c Preventative measures (aspirin, exercise) Preventative foot care 5
Nonproliferative
Preproliferative
Proliferative
Neovascularization
Vitreous hemorrhage: If untreated, can bleed into vitreous lose vision suddenly! Pathogenesis: theories
Vasoproliferative factors (IFG, VEGF) Ischemic / intraocular pressure changes Basement membrane, mural cell leak
Management: Prevent (good glucose control) Early detection (eye screening) Laser photocoagulation (if macular edema / proliferative retinopathy detected) Vitrectomy (to replace late-stage, scarred vitreous Experimental: vasoproliferation inhibitiors (anti-VEGF) into vitreous
Management: Blood glucose, BP control o ACEi/ARB extra risk for kidney dz Dialysis / renal transplant if end-stage
Nodular glomerulosclerosis: Kimmelstiel-Wilson disease End-stage renal disease Fibrosis, inflammation, sclerosis, arterial thickening
Autonomic neuropathy
Erectile dysfunction (most common) Enteropathy (constipation / diarrhea), gastroparesis Orthostatic HTN Cardiac: can have painless myocardial ischemia (dangerous!) Pathogenesis: probably similar to peripheral neuropathy, but affecting autonomic nerves
Mononeuropathy
Peripheral or cranial Single nerve pain / palsy Rapid onset, resolves over wks / mo
Pictures: neuopathies
Long-term benefits of good diabetic control: Prevents microvascular complications (UKPDS trial: retinopathy, albuminuria, etc) Macrovascular complications too but need to look at other risk factors too (BP, lipids multifactorial) Short-term benefits: energy, polys (reverse acute symptoms)
Pathophysiology of Type 1 DM
An autoimmune disease: Circulating autoantibodies in 80% at dx; precede onset by 3-4 yrs
o o o Anti-islet-cell Anti-GAD (glutamic acid decarboxylase) Anti-insulin
Triggers: lots of hypotheses, not well proven Viral induction cells express HLA antigen? 1 islet inflammation (TNF, cytokines) immune response?
Genetics: Less hereditary than type 2, Not well worked out exception = MODY, Maturity onset diabetes of the young aut-dom, 6 specific genes IDd If hereditary, often associated with thyroid / adrenal / other endocrine abnormalities
Clinical characteristics
Onset usually < 35 yo Frequently negative FHx Thin / normal body wt Ketoacidosis is more common end-stage acute complication (complete insulin deficiency) Labile metabolic state (blood glucose bounces up and down little or no endogenous insulin see pic) 8
Treatment:
Type 1 always requires insulin therapy (multiple doses daily) Metabolic lability harder to treat New directions: window of opportunity for prevention (prior to -cell destruction)? Better insulin delivery?
Pathophysiology
No evidence for autoimmunity o no HLA associations, anti-islet Ab, link with autoimmune dz o Not inflammatory (see AMYLOID DEPOSITS in islets)
-cell defect AND peripheral insulin resistance Peripheral insulin resistance biologic effect of plasma insulin on all tissues
o Hepatic glucose output not suppressed o Peripheral glucose utilization subnormal Many hypothesis, much research, little knowledge about intracellular causes / association with abdominal obesity o Not just a change in # / affinity / configuration of insulin receptors or abnormal insulin / proinsulin o Post-receptor abnormalities that disconnect insulin receptor from downstream signal / GLUT4 insertion in PM?
Obesity is most common cause of insulin resistance (esp. abdominal obesity) o Pregnancy, corticosteroids, stress, aging, heredity, other causes also cause resistance o FFA insulin resistance? Not entirely understood
-cell secretory defect Lose 1st phase insulin secretion (see pic) insulin secretory capacity over yrs / decades
o need for pharm therapies, worse metabolic lability, even need for exogenous insulin treatment can result
Diabetes (hyperglycemia) develops when pancreatic insulin secretion is inadequate to overcome the degree of tissue insulin resistance
Need assistance from drugs over time Even if you need insulin therapy, though, theres some residual insulin secretion o Less metabolic lability than type 1 DM!
Clinical Characteristics
Onset usually > 35 yo (not always: current epidemic of childhood type 2 DM in overweight youth) FHx usually positive! (stronger heritability than type 1 DM) Usually (80%) associated with obesity Endogenous insulin reserve present; often have HYPERINSULINEMIA Can treat with diet / exercise alone or oral insulin agents exogenous insulin Relatively stable metabolic state (not prone to wide swings)
Genetics
Active field esp. with genome-wide screens ( 10 genes associated, strongest is TCF7L2 but still only risk 50%) Other associations will be found: probably polygenic + environmental
Gestational diabetes
Diabetes first diagnosed during pregnancy Pathophysiology: counter-insulin hormones in pregnancy insulin resistance If pregnant womans pancreas cant mount normal response to insulin resistance, diabetes during pregnancy Maternal hyperglycemia can transmit trans-placentally fetal pancreatic hypertrophy o Fetal hyperglycemia + hyperinsulinism large, fat baby with complications Maternal glucose metabolism usually returns to normal post-partum o But indicates a borderline pancreatic -cell function ( risk type II DM later in life!)
Summary
Insufficient insulin causes dysmetabolism
Absolute insulin deficiency in type 1 Relative insulin deficiency + peripheral insulin resistance in type 2
Acute complications of diabetes are directly and immediately due to hyperglycemia Long term complications of diabetes are due to years/decades of dysmetabolism 10
Fall in blood glucose (between meals, overnight) Suppresses insulin secretion, which causes
hepatic glucose output ( glycogenolysis / gluconeogenesis) Lipolysis (make FFA available for oxidation as energy substrate)
Storage of excess circulating nutrients in storage forms o FFA adipose tissue TG o AA protein o Glucose liver / muscle glycogen
Proteolysis
(provides AA substrate for low-level of gluconeogenesis needed for obligate glucose-dependent organs: brain, kidney, RBC)
Post-prandial
* Cant keep glycogenolysis & gluconeogenesis going forever! Glycogen stores are limited Gluconeogenesis causes negative N balance, depletes muscle mass, and weakens the person! o For every AA trans-aminated into gluconeogenesis, nitrogen lost as urea / ammonia! 11
Counter-regulatory hormones produce the fight or flight response in response to stress, crisis, hypoglycemia blood glucose (glucose = fuel for exercise) Rapid heart beat (ready to run or fight) anxiety (mental alertness, apprehension) Sweating (dissipate excess heat) Vasodilate periphery (optimal muscle oxygenation)
Hypoglycemia
Documented Low Plasma Glucose
Lower limits of normal: 12-16h fast: 60 mg/dL Prolonged fast: as low as 30-50 mg/dL Whipples Triad
(a working definition of hypoglycemia)
Symptoms of Hypoglycemia
Adrenergic (fight or flight) see above
Diaphoresis Tremor Blurred vision Weakness Hunger Palpitations Anxiety Emotional lability Headache Pupilary dilation
Documented low plasma glucose And symptoms of hypoglycemia And response to CHO administration Neuroglucopenic
Confusion Slurred speech Somnolence Coma
Due to counter-regulatory hormones trying to bring blood glucose back up (epi, norepi, etc!) Disturbing but not as dangerous (mild/moderate hypoglycemia)
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Hepatic disease Defective gluconeogenesis Defective gluconeogenic substrate Counterregulatory hormone deficiency
Adrenal insufficiency Hypopituitarism Glucagon deficiency Growth hormone deficiency Unusual if using tons of glucose, for instance Extrapancreatic tumors Fibrosarcomas / fibromas ( glucose consumption) Hepatomas (can make insulin-like factor) *GSD are rare; at least 10 forms known, most present with fasting hypoglycemia in children
Insulinoma:
Diagnosis:
o o o Symptomatic fasting hypoglycemia (abnormal to develop Sx, even during prolonged fast!) Inappropriate hyperinsuilinism (may be subtle), or 72h diagnostic fast (look for symptomatic hypoglycemia / inappropriate hyperinsuilinism) Plasma glucose falls, but insulin doesnt insulin should drop like a rock to preserve PG, but doesnt!
Management: image to localize, surgery to remove (80% are benign & surgically cured!)
Rare specific sensitivities (usually pediatric diagnoses) Leucine sensitivity Hereditary fructose intolerance Glactosemia
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3. Blood pressure that reduces risk of vascular disease Other goals Prevent/treat chronic complications
o (obesity, dyslipidemia, CVD, HTN, nephropathy)
Targets Pre-prandial 80-120 mg/dL Post-prandial (2h) < 180 mg/dL Bedtime 100-140 mg/dL HbA1c 7% LDL Cholesterol < 100 (<70?) mg/dL Blood Pressure < 130 / 80
Encourage healthy food choices (keep pleasure of eating only limit if good scientific evidence) Address individual / cultural needs
Carbohydrates
Sugars ( blood sugar acutely) Starches (later & longer-lasting) Fiber (dont raise sugars like other complex CHOs really good!) Monosaccharides Disaccharides Polyols (sugar alcohols) Glucose, galactose, fructose Sucrose (table sugar), lactose Have alcohol moiety: sorbitol, mannitol, etc. Malto-oligosaccharides (maltodextrins) Oligosaccharides (3-9 molecules) Others: raffinose, stachyose, fructo-oligosaccharides Starch: amylose, amylpectin Polysaccharides (> 9 molecules) Fiber: cellulose, hemicelluloses, pectins, hydrocolloids Note: not just sugar!
Recommendations: CHO and monounsaturated fat should be 60-70% of energy intake Get it from whole grains (dietary fiber), fruits, vegetables, low-fat milk Total amount more important than source / type for diabetics Use other CHO sources instead of sucrose-containing foods (to help loose weight) Non-nutritive sweeteners: dont cause cancer Adjustment in intensive insulin therapy E.g. 1 unit / 15 g carbohydrates Based on CHO content of meal; pre-meal blood sugar
Fixed insulin doses possible if consistent daily CHO intake
Proteins
Should be 15-20% daily energy (no restriction if normal renal function) Does not increase plasma glucose in type 2 DM but can serum insulin response
Protein requirements may be greater than RDA in pts with uncontrolled diabetes o From protein turnover; worry about protein malnutrition in developing world
High protein low CHO diets: Atkins, South Beach Long-term effects unknown: LDL cholesterol / wt loss maintenance? Short-term results: do get weight loss & improved glycemia Better to have a sustained lifestyle change (these are hard to maintain) 14
Fats
Linoleic acid, -linoleic acid Polyunsaturated fatty acids (-3) Eicosapentoic acid (EPA) Docosohexanoic acid (DHA) Oleic acid (cis-form)* Monounsaturated fatty acids Elaidic acid (trans-form)* Lauric acid, myristic acids, palmitic Saturated fatty acids acids, stearic acids * cis forms are healthy form of monounsaturated fats trans-fats CVD risk Type of fat Saturated Monounsaturated Transunsaturated Polyunsaturated N-3 fatty acids Plant sterols* Total cholesterol LDL HDL Vegetable / plant oils Fish, plankton Plant/nut oils, nuts Margarine, hydrogenated oils Red meat, poultry, dairy products, processed grains
Triglycerides
Recommendations <7% of energy intake from saturated fat (LDL-cholesterol) Dietary cholesterol intake <200 mg/day ( LDL-cholesterol) Minimize intake of transunsaturated fatty acids Polyunsaturated fat: 2 or more servings of fish per week recommended
OK Prehypertension Hypertension
Action At goal for diabetic patient Behavior therapy alone (3mo) then add pharm therapy Behavior therapy + pharm therapy 15
potassium, magnesium, calcium (DASH diet: fruits/veggies @ 5-9 / day, low-fat dairy @ 2-4 / day) Modest weight loss Exercise
Dyslipidemia
Goal: Lower LDL-chol (prevent CVD) Limit saturated fat & transunsaturated fatty acids to < 7% energy intake
o If weight loss not desired, replace with CHO or monounsaturated fat
Improvement of metabolic syndrome dyslipidemia ( TG / LDL, HDL) Improve glycemic control (fix insulin resistance physical activity lipoprotein lipase activity) More monounsaturated fats Modest weight loss soluble fiber and plant stanols / sterols Restrict saturated fats
Calculating Carbohydrates
1 ADA CHO exchange = 1 serving = one starch / bread = 15 g CHO Calculate: total CHO (1/2 x dietary fiber) E.g. 42 g total CHO, 6 g fiber = 42-3 = 39g = 2.6 starch servings So how much CHO do I have left? E.g. on 1800 calorie diet; want ~ 50% from CHO (900g) = 11.25 servings per day So the patient has 11.25-2.6 = 8.65 servings (around 130g left)
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Thyroid Pathophysiology
Basic Anatomy
Thyroid is at the base of neck in the center, Below the thyroid cartilage, has nothing to do with thyroid gland Pyramidal lobe embryological remnant of the thryoglossal duct Easily palpable (very close to skin), can impinge on other structures
Embryology review
can get thyroglossal duct cysts or other remnants of thyroid Lingual thyroid (ectopic thyroid duct anywhere along the pathway (pics) gland) mass in back of mouth (posterior midline); can be only thyroid in body! Careful in removal!
Higher brain centers (e.g. cold exposure) can trigger TRH release E.g. when baby born: TRH TSH surge when leaving warm womb TRH acts on anterior pituitary to release TSH
TSH = thyroid stimulating hormone
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The Thyroid
Organized into spherical follicles Lined by thyrocytes Contain colloid
(which contains thyroglobulin, storage form of thyroid hormone)
Production of thyroid hormone: Iodine comes in from capillary side, gets trapped o 2Na+/I- symporter (NIS) brings it in Brush border on inside of follicle (remember, thyroglobulin in colloid) Thyroid hormone made at interface (brush border) o Iodine binds to tyrosine residues on thyroglobulin o Forms iodotyrosines linked together to iodothyrosines Pinocytosed back into thyrocytes
o Eventually released into bloodstream
two diiodotyrosines thyroxine (T4) one diiodotyrosine + one monoiodothyrosine triiodothyronine (T3)
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TBG deficit
(cirrhosis, etc)
TBG sucks up free T4 ( at first); but then pituitary senses free T4 and secretes more TSH T4, sucked up by TBG
End result: SAME FREE T4, MORE TOTAL T4 End result: SAME FREE T4, LESS TOTAL T4 Remember free T4 is what can enter cells free T4 sensed, free T4 ( T3) has biological effect
T4 T3 in peripheral tissues
E.g. liver, muscle 1,5 deiodinase removes one of the iodines
o Selenoproteins enzyme has selenium atom inside
Really complex system: there are three different iodinases T4 reverse T3, for example no biological activity D3 converts T3 to T2 (in placenta regulating T3 toxicity in utero!) Dynamic balance
100% T4 made in thyroid About 80% T3 made in periphery
If youre hungry, sick, etc. dont want to make T3 (would speed up metabolism!)
BMR with starvation (not a good way to lose weight) Very low T3 in ICU! euthyroid sick state T3 but rT3 (deiodinase enzyme levels adjusted)
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Feel OK (clinically euthyroid) free T4 / T3, or normal TSH o pituitary is also insensitive, so upregulates!
T4/T3
TSH
T4/T3
TSH
T4/T3
TSH
Measure TSH*
(unique to thyroid, more definitive but can be misleading) Central hypothyroidism** Soon after therapy of hyperthyroidism Nonthyroidal illness ( TSH with someone really sick)
*Depends on log-linear relationship between TSH & T4 Pituitary is really sensitive to TSH, so TSH by a factor of 1 T4 by a factor of 100 ** in central hypothyroidism, can have a dysfunctional TSH that is picked up by assay but not active! If someones hypothyroid, they should have a high TSH normal TSH suggests central hypothyroidism
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High TSH (right) measure T4 If low, thats garden-variety hypothyroidism If normal, suspect subclinical hypothyroid If high, suspect TSH-secreting tumor (really rare)
Thyrotoxicosis (hyperthyroidism)
Just means youre hyperthyroid (looking toxic - tachy, sweaty, like you have an infection) State of tissue exposure to concentrations of thyroid hormone Common: lifetime 2% prevalence in females
Symptoms: hypersympathetic / hypermetabolic state Fatigue, nervousness, hyperactivity, cognition Menstrual disturbances, gynecomastia Tremor Signs:
Eyelid retraction (Graves disease proptosis) Warm, moist (diaphoretic), smooth skin Tremor Goiter Tachycardia, arrhythmias, A-fib, SBP , DBP
reflexes Osteopenia, hypercalcemia, hypercalcuria Onycholysis (nails separates from nailbed, get dirt under)
Etiology of Hyperthyroidism
Graves disease is #1 Can also get toxic nodules (benign lumps in old age), subacute thyroiditis, very rare TSH tumors 21
Graves disease:
Typical patient: young woman with goiter, periorbital swelling Epidemiology: #1 cause of hyperthyroidism occurs in 2% women, has genetic influences (but only 40-70% MZ twins) Sex ratio 5-10:1 Females Males (hormonal?) Signs / symptoms: general hyperthyroid symptoms, can hear bruit over thyroid (pretty specific finding blood flow through thyroid) Diffuse goiter Ophthalmopathy: (present in 90% pts, clinically obvious): NO SPECS
o o o o o o o No findings Only stare Swelling Proptosis EOM dysfunction (inf. rectus is #1 cant look up) Corneal involvement Sight loss (ischemic optic neuropathy)
Possible triggers: smoking / stress / infection autoreactive helper T cells (APCs / suppressor cells?)
Ophthalmopathy: Fibroblasts in eye have thyroid receptors (stimulated by TSH) Diagnosis: Thyroid Stimulating Abs (can see in hashimotos thyroiditis too)
o o
only see in autoimmune thyroid disease; Hashimotos- damage is too great thyroid function
Found concurrently with other autoimmune conditions Prematurely gray hair Vitiligo
Toxic nodules
Hot thyroid nodules are more common in older people
Graves disease is a disease of younger people
Hot because they make T3 + T4 T3/4, but TSH from pituitary, so contralateral lobe atrophies (common idea in endocrinology) Some have genetic mutations
Labs in hyperthyroidism
free T4 in serum serum T3 serum TSH Radioiodine uptake in most forms of hyperthyroidism o in thyroiditis, factitious, struma ovarii
Treatment of Hyperthyroidism
Antithyroid drugs Non-ablative Side-effects: 5-20% Radioiodine > 90% cure rate, 100% hypothyroidism Simple, most cost-effective, few side effects Surgery High cure rate Serious complications Expensive
Hypothyroidism
Systemic syndrome characterized by deficiency of thyroid hormone (or, rarely, intrinsic resistance to its effects) Primary hypothyroidism Secondary (central) hypothyroidism
Due to dysfunction of thyroid gland Symptoms of hypothyroidism Fatigue, lethargy, sleepiness Mental impairment, depression, dementia Menstrual disturbances (esp menorrhagia) Cold intolerance Dry skin, perspiration Signs of hypothyroidism Goiter Slow speech, hoarseness Cool, dry skin , slow reflexes Bradycardia, pericardial effusion
body hair Dyspnea, hypoventilation, sleep apnea Multifactorial anemia Hypoosmolar state (hypoNa)
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Dermatologic manifestations Symptoms: dry, yellowed skin Signs: myxedema (nonpitting edema due to GAG deposition) o different than pretibial myxedema in Graves o Cool, dry skin with brittle nails too Growth in kids: Obesity, growth, immature body proportions Resolves with TSH administration
Etiology of hypothyroidism
Developing world: Iodine deficiency is #1!
2B in world are iodine deficient
Can see endemic goiters in some areas! Most devastating effects are in utero (cretinism) o Congenital hypothyroidism all people in pic to right are same age!
Hashimotos Thyroiditis
(a.k.a. Autoimmune thyroiditis, chronic lymphocytic thyroiditis) Epidemiology: mostly females (10:1 F>M), with age Associated with other autoimmune disorders:
o type I DM, autoimmune adenitis, vitiligo, premature gray hair
Pathogenesis: autoimmune T-cell & B-cells lymphocytic infiltrate, circulating Abs o Anti-TPO = anti-thyroid-peroxidase o Anti-TG = anti-thyroglobulin Lab findings
Total serum T4: Free serum T4: Serum T3: TSH: RadioI uptake: (but be careful of binding protein abnormalities) or nL (unless central) usually low, but overlaps with normal
Treatment of hypothyroidism
Thyroxine (T4), either brand name or generics (preparation of course) L-T3 (Cytomel): has specific indications
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Thyroiditis
Subacute thyroiditis
Self-limited, nonsuppurative inflammation of the thyroid o Infectious disease, often preceded by viral illness Systemic symptoms: malaise, fever, ESR Big, really painful thyroid(see pic to right) Mild hyperthyroidism followed by mild hypothyroidism; usually complete recovery
Thyroid gland normal or slightly enlarged; not tender Positive antithyroid Abs in most pts (autoimmune)
o Sort of a variant of hashimotos thyroiditis
Labs in Thyroiditis
T3/4 TSH uptake of radioactive iodine
Classic triphasic course: hyperthyroid euthyroid hypothyroid o TSH is normal eventually high (hypothyroid)
o Can see lots of variants in post-partum period
Examples Graves disease Toxic nodular goiter Chronic lymphocytic thyroiditis Ablation of thyroid with radioiodine Surgery Subacute thyroiditis Postpartum thyroiditis
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Pituitary Gland
Anatomy Review
Pituitary sets in sella turcica, hangs down from infundibulary stalk Forms functional unit with hypothalamus Nuclei in hypothalamus release releasing / inhibitory factors enter median eminence, cross into fenestrated capillaries to anterior pituitary (posterior has separate physiology or synthesis & secretion of certain hormones
All of these hormones are under stimulatory control (need releasing factor to be produced / released) Exception: prolactin (dopamine is an inhibitory factor) Negative feedback systems at work too: true for pretty much all of the axes Hormone can feed back on hypothalamus, anterior pituitary
Nomenclature of lesions
Microadenoma*: < 1 cm in diameter Secretory: produces hormone in excess Macroadenoma*: > 1 cm in diameter Nonfunctional: hormone production * normal height of pituitary is 9mm so > 1 cm is growing out of sella turcica!
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Small macroadenoma: hypodense lesion, see deviation of pituitary stalk (S), displacing pituitary
Macroadenoma: has eroded bony floor of sella turcica sphenoid sinus; grown up through top of sella compressing optic chiasm, touching hypothalamus!
Huge macroadenoma: invaded cavernous sinuses on both sides; also invading temporal lobe
Massive pituitary tumor, occupying entire sphenoid sinus, obliterating sella tucica, necrosis cyst formation
Neurological defects
When tumor macroadenoma Compresses optic chiasm, other adjacent structures
Hypersecretion
Tumor can start secreting!
Hypopituitarism
Gonadotrophin deficiency Women Men
Amenorrhea Infertility 2 sex characteristics Infertility libido / impotency Small testes (no FSH) 2 sex characteristics
TSH deficiency
Fatigue Cold intolerance Dry skin Constipation Weight gain
ACTH deficiency
Weakness Orthostasis Dizziness Pallor Hypoglycemia
GH deficiency
fat, lean body mass exercise capacity, performance muscle strength HDL chol, bone mineral density Impaired cardiac fxn
These are secondary deficiencies nothing wrong with the end organ! Can get these singly, in combo, or all (panhypopituitarism) How to tell 1 from 2 deficiencies? Primary hypothyroidism: see TSH
(trying to get more out of the thyroid pituitary OK)
Neurological deficits
Lesion is growing in a confined space Floor of sella turcica is all around it (saddle)
Cavernous sinuses separated by thick dura (less common involvement) Above (optic chiasm) thin dura (more common involvement) 1. Tension-type headache is early sign: tumor grows up, stretches diaphragmatic sella (has nerves in it) 2. Optic chiasm compression is next: inferior posterior portion compromised (SUPERIOR TEMPORAL FIELDS) a. Can be one or both sides eventually bitemporal hemianopsias 3. cavernous sinus invasion (less common) a. Contains CN 3, 4, V1/V2, 6 b. CN 3/4/6 EOMs c. CN 3 papillary constriction (parasymps)
Failure of L eye abduction: L cavernous sinus invasion (L CN 6) Failure of R. eye abduction; not constricting R. pupil: R cavernous sinus (R CN 3)
Secretory adenomas
See below for more detail Secretory adenomas (in order of prevalence) 1. Prolactin Galactorrhea / amenorrhea 2. Growth hormone Acromegaly 3. ACTH Cushings syndrome 4. TSH Hyperthyroidism
Secretory Adenomas
Prolactinoma
#1 for secretory pituitary adenomas Clinical manifestations: either biochemical or mechanical Mechanical origin: physical effects (as discussed above): gonadatroph function, visual field defects, CN palsies, H/A Biochemical origin: due to prolactin level
infertility abnormal menstrual cycles galactorrhea libido osteopenia 2 to associated estrogen insufficiency gonadotroph function dyspareunia impotence gynecomastia Population: women with Amenorrhea Galactorrhea Infertility Galactorrhea + oligoamenorrhea % with prolactinoma 20% 30% 35% 70-75%
When prolactin is high, it feeds back to the hypothalamus and shuts off gonadotrophin releasing hormone function LH, FSH (2 form of hypogonadism) 28
Galactorrhea: can be present in males or females! DDx of hyperprolactinemia is large! Physiological causes: exercise (even a little), stress, post-prandial (get fasting level), post-coitus, pregnancy, suckling, slow-wave sleep Pathological causes: o prolactin-secreting tumors (prolactinomas) o 1/3 of growth-hormone secreting tumors too! (check GH with prolactin) o Large sellar masses / hypothalalmic masses Dopamine is inhibitory: if dopamine, prolactin (but coming from normal pituitary)
o o o
If normal pituitary is making prolactin, treatment is surgical! (prolactin usually > 200) If tumor is making prolactin (prolactinoma), treatment is medical!
IF PROLACTIN > 250, it HAS to be a PROLACTINOMA! (small prolactinoma can be < 250)
Primary hypothyroidism, polycystic ovary, renal failure can prolactin Drugs: dopamine receptor blockers, catecholamine depletors Chest wall trauma (suckling reflex from nipple to brain disrupt prolactin uncommon)
Diagnosis Elevated fasting prolactin R/O pregnancy, hypothyroidism, renal failure Drug history (no D2 receptor antagonists?) MRI if everything else ruled out
Clinical features of acromegaly (distinctive think Jaws from Bond movies) Enlargement of hands, feet, other organs (e.g. heart) Facies: distinctive
coarsening of facial features soft tissues grow (tip of nose, etc) bony abnormalities (hypertrophy of frontal sinuses look like neanderthal) o mandible sticks out (underbite) - prognathism Vision defects, headache, Galactorrhea prognathism perspiration CARDIOMEGALY HTN Thyroid can grow & be nodular Splenomegaly Frontal bossing Polyps, enlarged colon Enlarged nose, tongue, lips Carpal tunnel syndrome Deformed sella turcica Osteoarthritis Skin tags Sleep apnea o o o
Takes about ten years to develop these features but changes are insidious changes (dont notice!)
Want to make early dx: better chance of reversal, prevent side effects; soft tissues reverse, bone changes dont Compare to older pictures look for coarsening!
Acromegaly + gigantism: excess GH while growth plates are still open can get vertical growth (gigantism) 29
Diagnosis of acromegaly Growth hormone releasing hormone (GHRH) stimulates GH release Somatostatin is inhibitory (SRIF) Most of the effects of GH are due to generation of IGF-1 (insulin-like growth factor 1) ACROMEGALICS have IGF-1 used for diagnosis If theres a mild in IGF-1 and you suspect acromegaly do a glucose tolerance test but look for growth hormone
o o Normal patients: growth hormone after a meal Acromegaly: growth hormone doesnt respond to glucose
TSH-secreting tumors
Least common TSH stimulates thyroid to make too much thyroid hormone hyperthyroidism Like Graves w/o eye findings (tremor, SOB, wt loss, weakness, tachycardia, insomnia) Primary treatment: surgical
Craniopharyngioma
Squamous epithelial tumor arising from stalk (or hypothalamus, or 3rd ventricle) Has solid & cystic components Peak incidence in childhood Significant headaches panhypopituitarism; also diabetes insipidus Surgical excision if small; destructive when they get large Recurrence: try surgery again, radiation
Pituitary Apoplexy
Spontaneous hemorrhage into pituitary tumor (2-5% of all untreated pituitary tumors) Severe H/A, N/V, fever, stiff neck pts usually go right to ED
o o o worst headache of my life usually misdiagnosed as subarachnoid hemorrhage, meningitis Visual loss, diplopia, ptosis too (expansion of blood) Meningismus sx from necrotic tissue exploding into CSF
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Treatment of Hypopituitarism
Secondary Hypothyroidism Sex hormone deficiency Cause TSH GRH Treatment cant rely on TSH like in 1 (TSH messed up!) need to rely only on free T4 & symptoms Testosterone (patch, gel, injections) estrogen / progesterone (OCP) Prednisone / dexamethasone (potencies different; all replace glucocorticoids) Maintenance dose + extra dose for stress
o o
Glucocorticoid deficiency
ACTH
Extra maintenance if just a little sick 10x dose if severe illness, surgery, etc Wear medical alert tag
Vasopressin: brings in free water back from renal tubules into plasma
Binds V2 receptors translocates aquaporins via cAMP into apical membrane Plasma osmolarity is #1 regulator of [vasopressin] in the blood
vasopressin when were dehydrated o > 280 osmolarity = osmotic threshold release vasopressin; autonomic process o Thirst threshold is about 292 (start to drink more water to take advantage of vasopressin) Vasopressin also concentrates urine ( urine osmolarity, plasma osmolarity)
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Pathophysiology: Cant get aquaporins in to concentrate urine very dilute urine, polyuria dehydration / hypotension if cant get to water! Etiology:
Post-operative (e.g. transsphenoidal) most common Head trauma (#2) Idiopathic (#3) CNS tumor (e.g. craniopharyngioma) Metastatic tumor Infiltrative disorder (e.g. sarcoid) Aneurysm Pituitary adenoma
Signs / symptoms: polyuria, polydipsia, dehydration, dilute urine, hyperNa DDx of polyuria: hyperosmolar states (hyperglycemia - DM), neurogenic DI, nephrogenic DI, 1 polydipsia (psych pts) Dx of DI Serum osmolarity > 295 (hyperosmolar) Urine osmolarity < 800 should have tons of vasopressin; should be around 1200! Not diluting! Water deprivation test: deprive pt of fluids, then get these values (keep from compensating by drinking)
Keep making & secreting vasopressin even when osmolarity is low! These are euvolemic patients with hypoNa Check plasma osmolarity (mostly sodium) and see its low But urine is inappropriately concentrated Shouldnt have ADH around! Causes: many! Meds, tumors, pulmonary disorders, CNS disorders, etc.
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Endocrinology of Aging
Thyroid Hormone
Overt or subclinical hypothyroidism affect 7-15% of people > age 60 (esp women) Overt hypothyroidism hyperlipidemia, risk CHD. MUST TREAT Subclinical hypothyroidism: common; TSH but no symptoms o risk of overt hypothyroidism o So: check TSH levels, follow treat (?) subclinical hypothyroidism in the elderly
Consequences of Aging
Muscle mass
o Strength o Balance
Intra-abdominal fat
o o o o o Glucose intolerance Hyperlipidemia Hypertension Diabetes CVD
Bone mass
o Fracture risk
Growth Hormone
Note lower levels, smaller peaks with age somatostatin C (like IGF-1) with age, too (gradual)
Aging looks like growth hormone deficiency in adults Maybe we should be replacing GH?
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Effects of GH deficiency
muscle mass intra-abdominal fat bone mass fracture risk SBP Hyperlipidemia
Hard to interpret results of replacement of GH in elderly: limited #, variable duration / doses, short-lived vs decades of decline Essential and valuable in those who have GH deficiency (congenital or post-surgical) but not clear in aging
Life extension / aging prevention industry just straight up wrong to take advantage of old folks Illegal to sell GH to avoid aging or boost athletic performance
DHEA (dehydroepiandrosterone)
DHEA and DHEAS (DHEA sulfate) are readily interchangeable Synthesized in zona reticularis of the adrenal gland Secretion mediated by ACTH but no feedback on pituitary/adrenal axis (no way to ACTH) A small amount of DHEA can eventually be converted to testosterone
Way more DHEA than T in the body o most prevalent of gonadal steroids DHEAS > DHEA in serum DHEA/S are pretty inactive as an androgen, though
In aging: marked DHEA levels with time (both men & women) Variable amount of decline from one to another DHEA often marked as a super-pill to prevent all sorts of aging stuff o No evidence whatsoever to support these claims (not a fountain of youth, miracle pill, antidote for aging) Major effect of taking DHEA (even by mouth): raises DHEA / DHEAS blood levels At least you can take it by mouth!
A little ability to increase estrogen / T levels? Maybe IGF-1? LDL cholesterol lowering? Not well proven. Maybe body fat, body mass. Probably does increase skin status
RCT in elderly: NO physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, QOL Only should be used for adrenal insufficiency (not for healthy old folks)
Testosterone
age slow testosterone, male sexual function: But no evidence that those two things are related or causal Risks of testosterone replacement: BPH, worse prostate cancer, sleep apnea, Hct, HDL-chol, Sleep apnea Take-home: dont give T unless the patient is severely T deficient (from another cause) 34
Anatomy
Note that : Cortex / medulla have separate arterial supplies Medulla exposed to cortical venous effluent
Right adrenal drains directly into IVC Left adrenal drains into left renal vein
Nerve supply:
Cortex: efferent symps / parasymps regulate blood flow Medulla: symps catecholamine release
Cardiovascular Actions
Goal: maintain blood pressure Cortisol (glucocorticoid) Aldosterone (mineralocorticoid) Generally works faster Generally works on longer time scale myocardial contractility, SV, CO renal Na retention, K excretion vascular sensitivity to pressor effects of intravascular volume catecholamines Some direct effects on myocardium too Chronic glucocorticoids / aldosterone hypertension 35
Effect in chronic cortisol excess (Cushings Syndrome) protein wasting, skeletal myopathy insulin-resistant diabetes mellitus body fat redistribution (trunk, mesentery, mediastinum)
Activates lipolysis
Immune function
Goal: limit inflammatory response to infection a check to keep immune system from getting out of control Lymphyocytes
Redistribute T & B cells (away from circulation) T cell apoptosis T / B cell, NK function inhibited
Granulocytes
Redistribute to circulation granulocytosis Chemotaxis, phagocytosis
Other
Eos, M, monocytes histamine, prostaglandin, TNF vascular permeability
Chronic glucocorticoid excess excess immune suppression susceptibility to infection (bacterial / viral / fungal)
adrenal growth 36
Clinical significance Resistance to negative feedback is the hallmark of glucocorticoid excess (Cushings Syndrome) Withdrawing exogenous glucocorticoids (e.g. post therapy) may suppress HPA axis
o Already CRH, ACTH from exogenous glucocorticoids
Mineralocorticoids: Regulation
Produced in zona glomerulosa (e.g. aldosterone: salt)
Clinical significance: ACTH deficiency doesnt usually produce mineralocorticoid deficiency, but ACTH excess can lead to mineralocorticoid excess
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Adrenocortical Insufficiency
Primary AI: indicates damage to adrenal cortex (Addisons disease) Adrenals knocked out so aldo, cortisol
CRH, ACTH (negative feedback from cortisol removed) renin, AT I/II ( aldosterone renal blood flow)
Symptoms
Weakness Sleepiness / fatigue Anorexia Nausea / vomiting Abdominal pain Postural light-headedness* Salt craving Weight loss Hyperpigmentation* Hypotension*
Signs
Dehydration* Loss of pubic / axillary hair
* especially in primary adrenal insufficiency Addisons Disease = autoimmune 1 adrenal insufficiency Hyperpigmentation: CRH ACTH production. ACTH and MSH (melanocyte stimulating hormone) are both made from POMC (precursor protein) stimulation of ACTH production MSH too hyperpigmentation! Loss of pubic / axillary hair: androgens (in post-menopausal women adrenals are source of most androgens)
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Lab findings
HypoNa* HyperKa* Hypoglycemia BUN/Creatinine* HyperCa (rare) Anemia *mostly primary (vs secondary) Eosinophilia Lymphocytosis
Mild block (e.g. heterozygote): ACTH can drive a little more through the pathway Severe block (e.g. homozygote) cant drive through to make cortisol / aldosterone at all In both cases, block leads to precursors andro, T Attenuated form Partial block of enzymatic activity (e.g. heterozygote) Common cause of hirsuitism & irregular menses Only apparent in females Mild excess of testosterone & androstenedione Salt-losing form Complete block of enzymes (e.g. homozygote) Life-threatening cortisol & aldosterone deficiency Defect present at birth Androgen excess in females
Very characteristic appearance: Note abdominal obesity with thigh wasting Moon-like, full, reddish facies
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Etiologies of Hypercortisolism
ACTH-dependent Cushings disease: pituitary ACTH-secreting tumor Ectopic: o small cell lung cancer o Carcinoid, medullary thyroid, pheochromocytoma Exogenous glucocorticoid treatment (#1 iatrogenic) Adrenal adenoma or carcinoma Mostly in severe alcoholics (can resolve if stop EtOH) Also possible in major depression can get central activation of axis
ACTH-independent Pseudo-Cushings
Diagnosis of hypercortisolism
INITIAL STUDIES Urinary free cortisol 24 h urine collection measure cortisol (24h: integrates circadian variation) Cushings syndrome: (3x nL)
Milder elevations: Cushings, pseudo-Cushings, or stress (repeat test)
INITIAL STUDY OF CHOICE Midnight Salivary Cortisol Get saliva sample at midnight ( plasma free cortisol Normal: should be really low (lowest circadian level) Cushings: inappropriately normal or high Alternative initial study CONFIRMING HYPERCORTISOLISM LOW-DOSE dexamethasone suppression test Give dexamethasone 0.5mg po q6h x 2d Collect plasma cortisol Normal: should suppress plasma cortisol (< 1.8mcg/dL) Cushings: have impaired feedback suppression by low doses of exogenous corticosteroid (> 1.8 mcg/dL) Doesnt distinguish Cushings disease vs other causes of hypercortisolism 41
BIOCHEMICAL LOCALIZATION Plasma ACTH Method: Collect ACTH from plasma Low ACTH (<5 pg/mL) and cortisol:
ACTH-independent (exogenous vs. adrenal tumor)
Comments:
If massive elevations, likely ectopic ACTH If elevations modest, need more testing HIGH-DOSE dexamethasone suppression test Dexamethasone 2mg po q6h x 2d or 8mg overnight Collect plasma cortisol or 24h UFC Pituitary Cushings disease: most cases suppress > 90%
Method:
Results: Ectopic ACTH / adrenal tumors: rarely suppress > 90% Comments: Pituitary tumors often retain partial feedback suppression; adrenal tumors & ectopic-ACTH tumors rarely do Test unreliable by itself (lots of false positives / negatives) Petrosal venous sinus sampling Cath petrosal venous sinuses draining each pituitary hemisphere. Give CRH, then measure ACTH from drainage & periphery Calculate central:peripheral ACTH gradient Pituitary tumors: gradient >3 (often >10) Ectopic ACTH: no central:peripheral ACTH gradient GOLD STANDARD for localizing ACTH-DEPENDENT CUSHINGS Specialized, not available in all hospitals
Method:
Results:
Comments:
After these steps: Radiography: MRI of pituitary, occasionally chest/abdomen Summary of Glucocorticoid Function Tests Test 24 hour urinary free cortisol Midnight salivary cortisol Basal plasma ACTH Basal plasma cortisol Low dose dexamethasone suppression High dose dexamethasone suppression ACTH stimulation (of adrenal) CRH stimulation (of pituitary) Metyrapone stimulation (of hypo/pituitary) Useful in Glucocorticoid insufficiency Glucocorticoid excess
Basal
Potentially misleading
Suppression
Stimulation
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Treatment of hypercortisolism
Etiology Cushings disease Adrenal tumors Ectopic ACTH Refractory / inoperable disease Treatment options
Trans-sphenoidal pituitary surgery Post-operative pituitary irradiation Adrenal surgery Surgery (if possible) Cortisol synthesis inhibitors (ketoconazole, metyrapone, mitotane) Rarely: bilateral adrenalectomy
Hyperaldosteronism
Endocrine causes of hypertension: Cushings syndrome, Hyperaldosteronism, or pheochromocytoma Clinical features: hypoK: urinary potassium wasting hyperNa: suppressed plasma renin (in 1 hyperaldosteronism)
Etiologies
Primary
due to adrenal cause (adenoma / hyperplasia), or idiopathic Diuretics, CHF, renal artery stenosis
Secondary
Diagnostic evaluation
1. Identify primary vs. secondary hyeraldosteronism
a. b. c. After repletion of Na / K, check plasma renin / aldosterone If renin and aldosterone, think primary If renin and aldosterone, think secondary
2. Confirm non-suppressible hyperaldosteronism with salt-loading test (salt tabs or IV normal saline 3. If primary hyperaldosteronism, identify etiology (adrenal tumor vs. hyperplasia) a. Adrenal CT b. Adrenal vein sampling (aldosterone / cortisol) c. Aldosterone-producing adenoma will lateralize; idiopathic hyperaldosteronism wont
Treatment
Adenoma: Idiopathic: surgery aldosterone receptor inhibitors (spironolactone . eplerenone) 43
Pheochromocytomas
Rare catecholamine-producing tumor of medulla 10% extra-adrenal (paragangliomas) 20% familial, 20% malignant NEED TO DX (can provoke life-threatening hypertensive crisis)
The metabolites (metanephrines / VMA) are more stable (good for diagnostic measurement)
Clinical manifestations
More frequently paroxysmal than static (come in waves minutes to hours) Usually spontaneous; occasionally in response to abdominal manipulations / strenuous exertion
o not in response to emotional distress like anxiety
Can resemble hypoglycemia (activation of sympathetic pathways) Nausea Tremor Nervousness Chest pain Dyspnea Pallor > flushing (vasoconstriction) Light-headedness HTN (often severe)
Locations of pheochromocytomas Solitary adrenal Bilateral adrenal 80% 10% Hereditary disease associations
Multiple Endocrine Neoplasia Type 2 Von-Hippel Lindau Disease (VHL) Neurofibromatosis (NF-1) Succinate Dehydrogenase B and D
Extra-adrenal 10%
Malignant 15-20%
(Medullary thyroid cancer, pheo, hyperparathyroidism) (CNS and retinal hemangiomas, renal carcinoma, pheo, paraganglioma) (Caf au lait spots,cutaneous neurofibromas, pheo) (Paraganglioma and pheo)
Biochemical test of choice: 24h metanephrines / plasma metanephrines Stable catecholamine metabolites, usually > 2x ULN in pheochromocytoma
Interference possible (certain antiHTN meds, drug/alcohol withdrawal) Urinary catecholamines, VMN have lower sensitivity
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Treatment
1. Pre-op preparation a. Anesthesia, other major procedure w/o -blocade could induce hypertensive crisis b. -adrenergic blockade (phenoxybenzamine usually used) c. AVOID ISOLATED -BLOCKER USE (can worsen HTN by inhibiting -2 adrenergic receptors) 2. Adrenalectomy (laparoscopic)
Treatment Parathyroid: 4 gland resection with forearm re-implantation Pituitary: similar indications for surgery / DA agonists as in sporadic disease GI: o PPI for gastrinoma
o o others have similar indications for surgery, somatostatin analogues to control hypersecretion in inoperable tumors
3 characteristic syndromes MEN 2A MTC (>90% by age 30), pheo (50%), hyperparathyroidism (15%) MEN 2B MTC (early onset, often aggressive), frequent pheo, mucosal ganglioneuromas, marfanoid FMTC Isolated MTC, often later onset / less penetrant Diagnosis: Need DNA testing (RET gene mutation) test known MEN2 families & MTC pts, even w/o obvious FHx If test positive in asymptomatic person (e.g. relative) prophylactic childhood thyroidectomy (prevent MTC) Surveillance for pheochromocytoma & hyperparathyroidism
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Gender Development
Introduction
Original theories of gender development: learning influenced psychosexual development Current model: androgen exposure, genes on Y chromosome Novel predictors: parent attitudes may play a role Importance of studying: influences how we understand sex and gender
Definitions
Gender Identity (GI): f Gender role (GR): Sexual orientation: DSD: undamental sense of belonging to one sex behavior designated as masculine or feminine attraction to sexual partners disorders of sexual development o (sensitive to patients: replace intersex, pseudohermaphrodites, sex reversal, etc)
Embryology
Sex ducts: all embryos start out with em; may or may not continue Mullerian ducts internal female reproductive structures
(upper vagina, cervix, uterus, etc.)
Starting point: Undifferentiated gonadal tissue (all embryos) Male development If embryo is 46XY and SRY+, develops into testis; makes: Makes Mullerian ducts disappear Mullerian inhibiting factor (MIF) peptide hormone Testosterone DHT (dihydrotestosterone) (5- reductase: T DHT) androgen more potent androgen
Promotes masculinization of external genital structures (embryo will have male bits)
Female development (not as well understood) If theres no Y chromosome and no SRY, get ovaries (quiescent: make no hormones) Mullerian ducts develop No MIF No Testosterone No DHT (dihydrotestosterone) Wolffian ducts regress
(embryo will have female internal reproductive structures) (embryo wont have male internal reproductive structures)
No masculinization of external genital structures (embryo wont have male bits - female by default)
Example: 46XY with 5- reductase deficiency: cant convert T to DHT No masculinization (female external genitalia!) 50+ types of DSD: so what do you do?
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Optimal Gender Theory (Money) If GI is learned, DSD newborns should be reared according to sex that genital phenotype most resembles o Problem: limited long-term follow-up Easier to surgically construct female genitalia than male genitalia o Problem: it may look right, but maybe it doesnt work right (cosmetic vs function) Criticism of optimal gender theory (90s):
Paper published on XY kids raised as females; noted that they often assign themselves back John/Joan had male identical twin; circumcision mistake; reassigned / surgery female, reassigned self to male in teens Intersex society of North America started to criticize
Cant make cortisol so cortisol precursors ( androgens) external masculinization Full penis Labia completely fused (empty scrotum no testes! Ovaries!) Spectrum (Prader 0-5; femalemale)
Prader 0
Prader 1
Prader 2
Prader 3
Prader 4
Prader 5
Simple virilizers ( prader 0-2) or salt-losers (prader 3-5 tend to lose salt)
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Raised female (external) but have had lots of androgen exposure Should have both Mullerian & Wolffian ducts (no MIF but yes T) Totally functional as females, but with Wolffian ducts too o Cant ethically take away childs fertility potential to raise as a boy Research question: If prenatal androgen exposure is important, should have more masculinization with androgens Salt-losers have more androgen exposure than simple virilizers; compare to sisters / controls Question
Satisfaction with female rearing (better off as male?) Have you questioned your female rearing? Sexual orientation (Kinsey scale) Vs. friends, etc.: how masculine are you? Past life: How feminine? How masculine?
Result
No differences between groups (GENDER IDENTITY) Dose-response with androgen exposure (Im hirstute, I have menstrual problems, etc.) Salt users more towards bisexual end of scale Dose-response with masculinity (GENDER ROLE) Everybody says they femininity with time (Learning? Puberty? Combo?) Salt-losers: masculinity early, but with time
Conclusion: genetically female but exposed to lots of androgen: Gender role and sexual orientation can be changed, but NOT GENDER IDENTITY
Research question: whats the influence of the Y chromosome alone? All really female-typical; just about all female heterosexual (n=3 for this study) Y chromosome alone has no influence on sexuality in humans Raise these babies as girls
Study: various conditions; all 46,XY DSD with the same external genital appearance Reared female Reared male Gender identity 75% satisfied 75% satisfied (satisfaction with rearing) 25% dissatisfied 25% dissatisfied
(intersex, homosexual orientation) (intersex, gender change)
Sexual orientation 39% exclusively female heterosexual 95% exclusively male heterosexual Gender role More feminine ( with time) More masculine ( with time) Early androgen exposure might have role in sexual orientation or maybe other factors at play?
Parental factors?
Parental support purported to be primary factor that promotes well-being (not studied much)
Hypothesis:
Maybe parents of children with life-threatening DSD at greatest risk for stress, overprotection, perceived child vulnerability Maybe parents reading children discordant with genetic sex at greatest risk for stress, overprotection, etc. Maybe parents of children with ambiguous genitalia at greatest risk for stress/overprotection / perceived child vulnerability
Turns out that ambiguous genitalia and raising girls will parental stress
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Puberty
Puberty: physiological process causing development of 2 sexual characteristics and leading to reproductive maturity.
What do sex steroids do in puberty? Cause secondary sexual characteristics Accelerate growth; contribute to pubertal growth spurt Accelerate closing of growth plates (stop growing after puberty) Steroid Androgens Estrogen Testosterone From Adrenals Ovary Testes Effects Sexual hair (M/F) Virilization if Breast development (F) Pubic hair, virilization (M)
Where do sex steroids come from in puberty? Pituitary kicks things off LH testis testosterone LH/FSH ovary androstenedione estradiol ACTH adrenal DHEA/DHEAS androgens
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Theca cells LH hits GCPR AC cAMP androgen synthesis androstendione steroid crosses to follicular cells Follicular cells FSH hits GCPR AC cAMP conversion of o Testosterone to estradiol (aromatase) o Androstenedione (from theca cells) to estrone
Leydig cells LH hits GCPR AC cAMP production of testosterone (FSH acts on Sertoli cells to promote somatogenesis) Not involved in steroid production
Female
Ovary develops, E2 secreted in nd 2 trimester
Note: gonadal development is separate from pituitary / hypothalamic development NO GnrRH / LH / FSH NEEDED!
Infancy
Pulsatile secretion of GnRH at delivery! T production in males GnRH Secretion of LH / FSH E2 production in females Gonads continue to develop for 1 year (peaks at 3 mo) (peaks at 6 mo)
3-8 yrs
GnRH not released (so serum LH, FSH, T, E2 low axis quiescent) 6-7yrs: start secreting adrenal androgens (DHEA / DHEAS)
Boys vs Girls
Why are men taller than women? Peak height velocity is earlier & lower in girls than boys Growth spurt lasts longer in males
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Definitions
Females Males Breast development < 8 yrs and/or Testicular enlargement < 9 yrs and/or Precicious puberty* Pubic hair development < 8 yrs Pubic hair development < 9 yrs Secondary characteristics 13yrs Delayed puberty Testicular enlargement 14 yrs Menarche 16yrs Proposed (controversial): breast development <7 in whites, <6 in AA unless rapid progression
Precocious Puberty
Basic approach: Isosexual Central: premature activation of hypothalamus / pituitary
all gonadotropin levels (LH/FSH/T/E2)
Etiology: what could activate this axis? Tumors (GnRH-secreting; LH/FSH-secreting have never been described; other hypothal tumors) Idiopathic (most common) Diagnostic Criteria
Tanner 2 breast < 8 or enlarged testes < 9 Accelerated growth velocity Accelerated bone age (degree of maturation of bones of left hand - with sex steroids) Pubertal LH/FSH or pubertal response of LH/FSH to GnRH stimulation Exclude pathologic etiologies of CPP before you call it idiopathic (imaging)
Treatment: GnRH analogues (agonists) e.g. Depot Luprolide (Lupron) Seems counterintuitive! Induce pituitary desensitization
o o o Give GnRH at a constant level Gonadotrophs reg amt of GnRH receptors! LH pulse at first, then LH secretion /synthesis with time
Effects:
o o o growth velocity ( sex steroids), bone age advancement Final height improved (may not reach target height Fertility maintained
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Adrenal gland can be turned on o (estrogen-secreting adrenal tumors are rare though) Estrogen creams / gels or consumption of OCPs
McCune Albright syndrome Autosomal-recessive; causes precocious puberty in both boys & girls Activating mutation in Gs proteins downstream of LH/FSH receptors
o Constitutive activation unregulated steroid production
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Mechanism
Aromatase inhibitors Estrogen antagonist Blocks steroid production by P-450 enzymes Competitive inhibition of androgen receptor
Idea behind Rx
E production estrogen effects steroids androgen effects
If E2 increased If T increased
Ketoconazole Spironolactone
Delayed Puberty
Females Males Secondary characteristics 13yrs Testicular enlargement 14 yrs Menarche 16yrs Classification
Hypergonadotropic hypogonadism
LH/FSH but gonads not working aka primary hypogonadism, gonadal failure
Hypogonadotropic Hypogonadism
LH/FSH (pituitary or hypothalamic dysfunction) gonadal failure Secondary hypogonadism
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Growth
Any serious illness can affect a childs growth: an important vital sign in pediatrics o normal growth in a kid doesnt r/o serious illness, but abnormal growth concern for significant illness
Normal growth
Height / length most affected by hormones Growth curves: the importance is in both: o the absolute value (e.g. way over / under normal) o the trajectory (e.g. from 75th to 10th %ile rapidly)
Normal growth: Height between the 3rd and 97th percentiles Track along a percentile line on the growth curves: mostly true from 2 to 8-10 yo Growth velocity > 2 inches/yr (5 cm/yr): mostly true after 4 yo Height appropriate for genetic potential Normal growth may not follow all of the characteristics of normal growth: atypical isnt always abnormal But evaluate these kids (e.g. look at growth & compare to normal growth variants)
Calculating genetic height potential: Average parents height after correcting for sex difference in mean adult height (5in = 13 cm M>F)
o MPH =
o
Can also just average percentile th th o (e.g. if mom in 20 %ile, dad in 20 %ile kid too)
Crossing %iles can still be abnormal in infancy! But look at it in context of parents
Growth after 8-10 yrs of age highly dependent in timing of puberty Earlier puberty = can cross up Later puberty = can cross down
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Note that 50% of all boys will have 5cm/yr growth in early adolescence
Nadir of 50 %ile hits the cutoff Sensitivity / specificity of 5cm/yr changes with age! Not very specific in early adolescence.
Note too that later puberty means your growth velocity nadir occurs later & lower
> 50% of these kids will have growth 5cm / yr th o Graph (lower) only 50 %ile lines
Constitutional delay of growth & development Often cross percentiles early in life Delayed puberty (boys normally 9-14, girls normally 8-13; menarche 12.5)
o o o Delayed bone age Often have FHx of delayed puberty Growth velocity often dips below 5 cm/ yr
Hormones involved Stimulate growth Thyroid hormone Growth hormone Sex hormones (androgens, estrogens) Impair growth Glucocorticoids (cortisol) slow linear growth & stimulate appetite ( weight gain)
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Hypothyroidism
Example: girl starts to cross %iles , TSH is really high and T4 low: primary hypothyroidism. o Treat with L-thyroxine; growth jumps back up
Etiology in peds: Congenital Primary Central Most from aplasia (1:3k, most sporadic) / dysplasia of thyroid Dyshormonogenesis too (aut-recessive, enzymes affected more rare) Often with other pituitary hormone defects Acquired Autoimmune (Hashimotos mostly adolescents) Worry about tumor, etc.
Evaluation: get TSH + Free T4 (1 & central hypothyroidism need thyroxine for central) Both are possible in kids! Congenital hypothyroidism Used to be leading cause of mental retardation; now have uniform newborn screening If hypothyroidism is a possibility in children < 2-3 yrs old, test early (preserve brain development) o Compare results to age-specific normal ranges!
Normal T4 range is higher than infants than adults (reported normal range often adult normal!)
IGF-1 levels are stable throughout the day (random samples are informative)
o Vs. growth hormone random samples useless (varies throughout day)
Growth is stimulated by: o IGF-1 (locally produced > circulating) o Growth hormone itself (IGF-1-independent actions)
IGFBP-3 ( in GH deficiency)
IGF-binding protein Production stimulated by GH
Lack of appropriate rise of GH suggests deficiency Sensitivity: poor Specificity: good* actual cut-off is pretty arbitrary *IGF-1 (good sensitivity) and IGFBP-3 (good specificity) are pretty good in combo for older kids Tests are imperfect (tricky Dx to make)
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Congenital Hypopituitarism
Suggestive findings:
Midline defects (cleft lip/palate, single central incisor) Micropenis in male infant (< 2.0cm at birth) from gonadotropin and/or GH deficiency Hypoglycemia (from cortisol / GH deficiency) Prolonged jaundice / hepatitis (hypothyroidism) Visual problems o Septo-optic-dysplasia: optic nerve atrophy, abnormality of corpus callosum, hypopituitarism st o Nystagmus in an infant may be 1 clue of visual impairment
Acquired hypopuitarism
GH especially for relevance of this talk Etiology: Brain tumors, other malignancies , Histiocytosis X Radiation Trauma (MVA)
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Sex hormones involved in pubertal growth spurt PP Growth acceleration in childhood, but SHORT FINAL HEIGHT Growing too early & closing growth plates too soon! Central precocious puberty More common in girls than boys Boys Girls Normal age of puberty onset 9-14 yo 8-13 yo* First sign of central puberty Enlargement of testes (< 2.5 cm) Thelarche (breast development) *Puberty beginning in girls between 6-8 yo may be normal! Peripheral precocious puberty (non-gonadotropin-dependent sex hormone production) Adrenal: present with androgen effect in both girls & boys o Congenital adrenal hyperplasia or tumor Gonadal: generally present with androgen effect in boys and estrogen androgen effect in girls o Tumor o McCune Albright Syndrome o Testotoxicosis in boys (activating mutation of LH receptor o Exogenous / environmental sources
Sample cases
Note that testes are small probably not central! T coming from andro (adrenal gland)
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Obesity
Definition of obesity: an accumulation of adipose tissue that is of sufficient magnitude to impair health Clinically: estimate using BMI o o BMI =
weight (kg) height in m
Has limitations (Ray Lewis = 33 kg/m2) Not good in muscular, fluid weight needs to be fat!
th
Classification Underweight Normal Overweight Class I Obesity Class II Obesity Class III Obesity
Fat Distribution
Abdominal fat: visceral fat is really important clinically (vs. subcutaneous fat) Measure by proxy: Men Women Waist Circumference > 40 in (102cm) > 35 in (88 cm) Waist / Hip Ratio > 1.0 > 0.8 Can measure by imaging too (x-sectional MRI)
Epidemiology of Obesity
Hey, did you know theres this series of maps that shows obesity trends over time in the US? obesity with: Black > Hispanic > White; Bigger disparities in women, growing (ha!) in men Living in states with a country radio station : NPR affiliate ratio of > 5:1 (especially Mississippi)
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Calories in: pretty much just what you eat. Can be measured accurately, although its tedious. Calories out: 24 hr energy expenditure Resting BMR ( 50%) Activity expenditure (spontaneous, e.g. fidgeting, and unrestricted, exercise) o Really variable across patients Thermic effect of food (moving across the food) o Varies a bit with type of food, etc.
Regulation
Hypothalamus involved a lot (CNS side) o regulates satiety / appetite Fat cells produce Leptin, Ghrelin, etc. GI system produces CCK, ghrelin, etc. Feedback systems energy balance regulation o Hungry? Rest? Be active?
Polygenic Obesity
Probably explains susceptibility to obesity; may have multiple variants
o Previous evolutionary advantage? thrifty metabolically?
Consider genetic syndrome if: Obesity onset > 6 mo (leptin signaling pathway defect?) Other abnormal physical findings / developmental delay (Prader Willi, Bardet-Biedel, others?) Consider endocrine syndrome if growth velocity decreases (r/o hypothyroidism, GH deficiency think Cushings?)
physical activity (labor-saving devices, community planning dont walk, do laundry, take stairs, etc).
Consequences of Obesity
Medical Consequences of Obesity
Whole huge list of conditions across every system
GI: incontinence, impotence, kidney stones, NASH Repro: fertility, polycystic ovary syndrome, impotence Derm: chronic skin infections, acanthosis nigrans Vascular: venous insufficiency, DVT Cardiovascular: cerebrovascular disease, CAD, cor pulmonale, HTN Oncology: cancer Pulm: Asthma, sleep apnea, Pickwickian syndromes Many, many more
End result: mortality, years of life lost (BMI 45 @ age 20: lose 11 yrs of life!) J-shaped curve: with underweight & overweight; Asians morbidity with lower BMI (different genes!) 63
Treatment of Obesity
Lifestyle, medical, or surgical
Lifestyle modification
Combo of low calorie diet, physical activity, behavior modification Realistic goals: aim for healthier weight, NOT ideal weight
o o o Slow, incremental process to goal
o Short-term goal:
5 TO 10 % LOSS, 1 TO 2 LBS / WK
Interim goal: maintenance Long-term goal: additional wt loss, if desired, + long-term maintenance
Lifestyle: Diet
Diet: look for 500-1000 kcal deficit / day,
Women: Men, women > 165 lbs: 1000-1200 kcal/day 1200-1600 kcal/day
3500 kcal = 1 lb
Low-carb diets (15-20 carbs / piece of bread) Atkins diet: induction phase (20g/day carbs) gradual carbs South beach: low carb, but more allowance for fruits / veggies Protein power: 75 gm protein / kg IBW, < 30g carbs Carbohydrate addicts diet: 2 complementary meals + 1 reward meal Low fat diets: e.g. Ornish, < 10% cal from fat Meal replacements: e.g. SlimFast, may be better than traditional diets Effects of different diets: Whenever you lose weight: HDL, LDL / TGs / glucose / insulin / CRP No clinically important differences across diets Key points on weight-loss diets Its the calories that count Compliance, perserverence key Tailored diet may be more effective
(low carb more wt loss @ 6mo, but similar @ 12-24 mo) (stick to it longer = lose more weight) (studies limited by high attrition)
Want 30-60 min of moderate intensity physical activity on most / all days of week!
You need to exercise a lot to burn significant amounts of calories (obese = need less exercise to burn same amt) Exercise alone - not really good for weight loss
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Pharmacotherapy of Obesity
Two FDA-approved drugs for long-term (2yr) use; to be used with comprehensive program BMI 30 or BMI 27 with risk factors / diseases (HTN, dyslipidemia, CVD, type 2 DM, sleep apnea)
Orlistat (Xenical)
Dose Action Adverse effects Cost 120 mg po tid before meals Inhibits pancreatic lipase fat absorption absorption of ADEK (fat-soluble vits) Soft stools, anal leakage $170 / mo More CVD risk factors
Lose about 5.7 lbs more than placebo @ 6mo Lose about 6.4 lbs more than placebo @ 12mo chol, BP, insulin, glucose
Sibutramine (Meridia)
10 mg po qd to start, can to 10 mg or to 5 mg Norepi, serotonin, dopamine reuptake inhibitor HR / BP $104 / mo More weight loss
Lose about 9.5lbs more than placebo @ 12mo glucose but no change in lipids, BP, HR
Efficacy
Dont induce more weight loss after 6mo treatment More effective than placebo in maintaining wt loss up to 2 yrs
Short-term use: all sympathomimetics (stimulants) dont use longer than 12 weeks - risk of primary pulmonary HTN Side effects (what youd expect with sympathomimetics Generic Name Brand Name Usual Dose
Phentermine resin Phentermine Diethylproprion Benzphetamine Phendimetrazine Ionamin Adipex-P, Fastin, Oby-Cap Tenuate, Tepanil Didrex Bontril, Plegine, Prelu-2, Xtrozine 15-30 mg per day 18.75-37.5 mg per day 25 mg 3x per day (75 mg SR) 25-50 mg 1-3x per day 17.5-70 mg 2-3x per day
Other drugs: FDA approved for other indications (but if you can kill 2 birds with one stone) Fluoxetine, sertraline (Prozac, Zoloft) Metformin (Glucophage) Buproprion (Wellbutrin) Byetta Topirimate (Topamax) Investigational drugs
3 -adrenergic receptors Cholecystokinin-A receptors
Cannabinoid-1 receptor blocker (rimonabant) was promising but FDA didnt approve (psych side effects)
Supplement: billions of dollars / yr, but generally unsafe: either toxic or actual drug used in unregulated way 65
Bariatric Surgery
Indicated for patients with class III obesity BMI 40 kg/m2 or BMI 35 with comorbid conditions AND failure of prior therapy
o Most insurers require period of medically supervised wt loss before approving surgery
Contraindicated if Reversible condition causing the obesity Current drug or alcohol abuse Uncontrolled, severe psychiatric illness
Roux-en-Y is most common - malabsorptive Make a small stomach pouch (limit food intake) Bypass duodenum and some of ileum (cause malabsorption) Most common, but lap-band in popularity Most other surgeries are restrictive Gastric banding (e.g. lap band) put a band around the stomach to restrict! Sleeve gastrectomy turn stomach into small tube
Results: lose 20-30% of body weight; avg 20 kg loss in 8 yrs It works! Bypass > banding for long-term results, but both effective Clinical outcomes: see resolution of DM, HTN, dyslipidemia, sleep apnea (60-80%ish) o improvements with more wt loss (BPD / RYGB > banding) o mortality too (12% controls vs 8% surgery @ 12 yrs) only therapy to mortality Mechanism of changes: calorie absorption ( intake + malabsorption, improvements from wt loss) Neuroendocrine GI axis involved? May see improvements in glucose homeostasis before wt loss in RYGB Complications: both GI related and from doing surgery in obese pts Use nutritional supplements & follow-up to prevent! Mortality 0.3 2.2% ( with medicare, being older) VOLUME OF SURGERY performed by SURGEON is KEY (like any surgery)
Prevention of Obesity
Approach like cigarettes: Multi-pronged City planning: sidewalks, parks Buildings: stairwell access Unhealthy food advertising Access to healthy, affordable foods Schools : Lunch programs, Physical Education, Vending machines
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