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Pathophys: Endocrinology

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


Principles of Endocrinology & Metabolism
  Homeostasis is the key principle of endocrine physiology Endocrine glands are key nodal points in hormonal signaling pathways  

Endocrine disorders are:  Prevalent (mild > extreme forms)  Diagnosable (often thought of as difficult)

Treatable (meds ≫ surgery ≫ radiation) Personalized (therapy tailored to physiology)

NEWS ALERT: There’s an obesity epidemic in the USA! Metabolic syndrome, diabetes, hypercholesterolemia, too

     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

Deficient hormone action Acquired

Neoplasia of endocrine glands


Primary vs Secondary Hormone Deficiency
Primary deficiency: end gland is defective Secondary deficiency: defect in upstream gland in pathway Also applies to hyperfunction! Remember the hypothalamus – pituitary adrenal axis? Me neither.
 Hypothalamus makes corticotropin releasing hormone, which acts on pituitary to make adrenocorticotropic hormone, which stimulates adrenal gland to make cortisol

Primary adrenal insufficiency: adrenal gland defective (↓ cortisol) Secondary adrenal insufficiency: pituitary defective (also ↓ cortisol)  If hypothalamus messed up: call it “3°”or 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

“Primary” “End-hormone” Cortisol Thyroxine Testosterone/Estradiol IGF-1


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

Acute Complications of Uncontrolled Diabetes
  Directly due to hyperglycemia and/or insulin deficiency Can be quickly corrected by adequately controlling hyperglycemia Pathophysiology Hyperosmolarity (glucose adds 5.5 mOsm/L per 100 mg/dL) + dehydration  thirst Polydypsia  ↑ fluid intake  large urine volumes Glucose-induced osmotic diuresis Calories lost as glucosuria  negative caloric balance, wt loss Inefficient utilization of ingested calories & glucosuria. Insulin  ↑ appetite?

Symptom 1. Polydypsia 2. Polyuria 3. Weight loss 4. Polyphagia

5. Blurred vision Lens stiffens (sugars – not retinopathy early!) Others: poor wound healing, vaginitis, gingivitis, dental caries (↓ vascular flow, ↑ sugars – good for infections, etc.)


metabolic acidosis; fatal if untreated Pathogenesis Diagnosis Treatment Virtually complete lack of insulin  unrestrained lipolysis  hepatic conversion to ketone bodies  ketone bodies accumulate as organic acids  acidosis  Kussmaul respirations  Metabolic acidosis  Hyperglycemia  + ketones in blood / urine  Insulin  Electrolytes  Fluids

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 (can’t clear large ↑ endogenous glc production) Vascular collapse

Diagnosis Treatment

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PG > 1000 mg/dL Osmolarity > 340 Fluids

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Little or no acidosis or ketosis ± insulin ± electrolytes

Long-term complications of Diabetes
    Can occur in any type of diabetes (type 1/2/others) – happen over decades Macrovascular Microvascular Peripheral vascular Coronary artery Cerebrovascular   Neuropathy Retinopathy Nephropathy
  Peripheral symmetrical Mononeuropathies Autonomic neuropathies

Unifying hypothesis for complications: maybe oxidative stress?
 Activation of protein kinase C (stress response cascade)  Nonenzymatic glycation of proteins  ↑ AGEs  ↑ polyol pathway activity  ↑ sorbitol, fructose  ↑ hexosamine pathway flux

Macrovascular Disease: accelerated atherosclerosis
 Cardiovascular disease is the cause of death in 76% pts with diabetes!
o o ↑ coronary artery, cerebrovascular, peripheral vascular diseases (2 -4x) Eliminates the normal relative protection from atherosclerosis in pre-menopausal women

Pathogenesis: theories / risk factors
 Atherogenic shift: ↑LDL, shift to small-dense LDL  HyperTG, ↓ HDL-C  Hypercoagulable, pro-inflammatory; ↓ fibrinolytic activity  Hyperinsulinism  atherogenic?  HTN, smoking are risk factors too

Management:  Pay special attention to known risk factors: BP, chol, smoking, blood glucose / A1c  Preventative measures (aspirin, exercise)  Preventative foot care 5

Microvascular Disease: diabetic retinopathy
   #1 cause blindness in adults 20-74 yo Related to duration of diabetes & glycemic control ↑ risk with hyperglycemia, presence of nephropathy, ↑ BP
o Pregnancy may transiently exacerbate retinopathy in type 1 DM pts




 Microaneurysms  ↑ vascular permeability

 Cotton wool spots (soft exudates)  Beading of veins; tortuous capillaries

 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

Microvascular disease: diabetic nephropathy
Leading cause of ESRD Clinical manifestations: progressive, persistent proteinuria 1. Microalbuminuria 1st sign 30-300 μg/gm creatinine 2. Clinical proteinuria ≈ 12 yrs later (> 300mg / 24h) 3. Can progress to uremia ≈ 6-8 yrs later (↑ BUN, Cr) 4. ESRD ≈ 6-8 yrs later Can stop or slow progression with modern treatment Pathogenesis: theories  ↑ renal blood flow  hyperfilitration  ↑ intraglomerular pressure  Genetic predisposition to HTN  Thickening of glomerular capillary basement membrane 


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

Microvascular disease: diabetic neuropathies
Peripheral symmetrical polyneuropathy
 Distal, stocking-glove  progresses proximally  Symmetrical  Numbness, tingling, dysaesthesias Management: glycemic control, symptomatic relief (eg. gabapentin), preventative foot care Pathogenesis: metabolic Schwann cell defect (↑ sorbitol and/or ↓ myoinositol); 1° axonal degeneration (unclear etiology)

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


Peripheral or cranial  Single nerve pain / palsy  Rapid onset, resolves over wks / mo

Pathogenesis: ischemic (“microinfarcts” of the nerve)?

Pictures: neuopathies

Interosseal muscle wasting (diabetic peripheral symmetrical polyneuropathy)

Neuropathic ulcers (diabetic peripheral symmetrical polyneuropathy)

CN III palsy (diabetic mononeuropathy)

“The diabetic foot”
Pathogenesis: Combination of peripheral neuropathy and peripheral vascular disease  Peripheral neuropathy: lack of sensation, undetected trauma from blisters o even painless fractures (“Charcot’s foot”)  Peripheral vascular disease: relative ischemia, ↓ blood supply  ↓ healing  Infection: ↓ immune defenses  Altered biomechanics (fallen arch) Management:  Difficult combo: Immobilization, abx, revascularization, time  Goal: prevent / minimize amputations (gangrene / infection)


“Diabetic Control” & long-term diabetic complications
Diabetic control: keep blood glucose levels as close to normal as possible  Self-monitoring of blood glucose (prick finger), or  HbA1c (glycated hemoglobin): indicator of glycemic control over 2-3 months (life span of RBC ≈ 120d) In some, it’s easier; in some, it’s really hard – so individualize targets  In general: o HbA1c < 7% is very good control* o HbA1c > 9% is poor control
*DCCT – diabetes control & complications trial, 1995: HbA1c < 7% gets retinopathy, nephropathy, complications ↓↓ @ 9yrs

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)

Type 1 Diabetes Mellitus
Definition: Characterized by autoimmune beta cell deficiency, usually leading to complete insulin deficiency (after a "honeymoon" period), therefore requiring exogenous insulin administration for survival. Epidemiology: far less common than type 2 (5-10% all diabetes), ↑ in N. Europe, ↓ in Asia

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

Lymphocytic infiltration of pancreas on path (“insulitis”) Associated with other autoimmune dz
o o o Vitiligo UC Hypothyroidism o o Addison’s disease Rheumatoid arthritis

Associated with certain MHC alleles (↑ or ↓ risk)
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Triggers: lots of hypotheses, not well proven  Viral induction  β cells express HLA antigen?  1° islet inflammation (TNFα, cytokines)  immune response?

Molecular mimicry? IL-1 = β-cell toxin?

Genetics: Less hereditary than type 2, Not well worked out  exception = MODY, Maturity onset diabetes of the young – aut-dom, 6 specific genes ID’d  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

   Type 1 always requires insulin therapy (multiple doses daily) Metabolic lability  harder to treat New directions: window of opportunity for prevention (prior to β-cell destruction)? Better insulin delivery?

Type 2 Diabetes Mellitus
Definition: diabetes characterized by insulin resistance and a relative (rather than absolute) insulin deficiency Epidemiology: most common form by far (90% cases), prevalence in population proportional to (abdominal) obesity  Disease of prosperity: too many nutrients!  ↑ in AA, Hispanics, Native Americans vs Caucasians

 No evidence for autoimmunity o no HLA associations, anti-islet Ab, link with autoimmune dz o Not inflammatory (see AMYLOID DEPOSITS in islets)

β-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

β-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

Natural history is for progression of secretory defect over the years!
   Initially ↑ secretion to match ↑ resistance , but can’t keep it up β-cell secretion starts to fail If insulin resistance stays the same (obesity), but secretory defect ↑, then you get a gradual increase in blood glucose

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, there’s 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)


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

Type 1 vs Type 2 Diabetes Mellitus Type 1 Type 2
Formerly known as Without Insulin Rx Age of Onset Obesity Family History HLA Association Endogenous Insulin Insulin Resistance Metabolic Course Response to Pills Etiology IDDM, Juvenile Onset Ketoacidosis, death Usually <35 Unusual Usually Negative Yes Usually Absent Usually Absent Labile No Autoimmune NIDDM, Adult Onset Usually, no ketosis Usually >35 Common Usually Positive No Usually Present Usually Present Usually Stable Yes Non-Autoimmune

Other Types of Diabetes
Secondary diabetes
Diabetes with well defined cause:
    Loss of pancreatic tissue Excess counterregulatory hormones Drug-induced Rare insulin receptor abnormalities (pancreatectomy, chronic pancreatitis) (e.g. acromegaly, hyperadrenocorticism); (e.g. thiazides)

Gestational diabetes
Diabetes first diagnosed during pregnancy Pathophysiology: ↑ counter-insulin hormones in pregnancy  insulin resistance  If pregnant woman’s pancreas can’t 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 β-cell function (↑ risk type II DM later in life!)

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

Carbohydrate Metabolism & Hypoglycemia
Overview of Carbohydrate Metabolism
Rise in blood glucose (after CHO containing meal) Stimulates insulin secretion, which causes…
 Utilization of circulating glucose as energy substrate (↑ glycolysis)  Suppression of new glucose formation (↓ gluconeogenesis

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)

Role of Insulin: “metabolic traffic cop”
  If you’ve just eaten carbs: use it for energy; don’t store it o And if you’re going to store, do it efficiently (fat = 9 cal/g; CHO = 4 cal/g because you need to solubilize in H2O) o If you weigh 80 kg; 25% body fat, you can fast for 90 days: 25% x 80 kg @ 9cal / gm, figure 2000 cal/day If you’re fasting: protect your blood glucose level (keep brain going); use stored calories for energy Liver High Insulin (Anabolic) Low Insulin (Catabolic) Glycolysis (use of ingested glucose) Glycogenesis (carb storage) Gluconeogenesis Glycogenolysis (glucose release) Adipose Lipogenesis (lipid storage) Lipolysis (FFA release) Muscle Protein Synthesis (protein storage) Proteolysis (AA release)

Three States of Metabolism
for ≈ 3 hrs after eating (“fed state”, “absorptive”)

Metabolic changes ↑ insulin secretion
  Dietary CHO enters cells  main food source FA synthesis  FAs stored in adipose tissue Glycogen synthesis  excess CHO stored in liver, muscle


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↓ insulin, ↑ glucagon Post-absorptive
4-24 hrs after eating (“overnight fast”) Glycogenolysis, hepatic gluconeogenesis (support blood glucose without dietary CHO around) Lipolysis activated (freeing FA from adipose tissue) Fatty acids become main source for glucose fuel Hepatic glycogen largely used up ↓ glucagon  ↓ gluconeogenesis Lipolysis takes over, lipid becomes main fuel source

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↓↓↓ insulin and ↓ glucagon Prolonged fast*
> 24 hrs after eating

* Can’t 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

Normal Blood Glucose Homeostasis
Normally blood glucose is tightly controlled between 65-140 by…   “closed-loop” regulation of insulin secretion Counter-regulatory hormones (act in opposition to insulin: “insulin against the world!”) o Glucagon, epinephrine, corticosteroids, growth hormone, norepi o Protect glucose if it falls too low

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)

Documented Low Plasma Glucose
Lower limits of normal:  12-16h fast: ≈ 60 mg/dL  Prolonged fast: as low as 30-50 mg/dL Whipple’s 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

Neuro signs: from focal seizure to psych

Due to ↑ counter-regulatory hormones trying to bring blood glucose back up (epi, norepi, etc!) Disturbing but not as dangerous (mild/moderate hypoglycemia)

Not enough glucose for brain metabolism!


Response to CHO administration
 Carbohydrate (oral or IV) will specifically ameliorate the symptoms (adrenergic or as severe as coma!) o See dramatic response in 10-20 minutes – even waking up from coma o E.g. give orange juice to someone hypoglycemic  feel a lot better!

Fasting vs. Post-prandial (“reactive”) Hypoglycemia
Fasting hypoglycemia
 Occurs post-absorptively (> 10hrs after a meal)  Unusual and definitely abnormal o Requires an explanation!  Must be documented by plasma glucose + objective symptomatology

Post-prandial (“reactive”) hypoglycemia
 Occurs after absorptive phase (≈ 2-4h after meal)  Thought to be common o not often due to a defined disease  Hard to document


Fasting hypoglycemia: partial DDx
Excess exogenous insulin      Diabetes treatment (certain oral agents or insulin) Factitious / foul play Insulinoma (insulin-secreting pancreatic adenoma) – see below Sulfonylurea ingestion (diabetes treatment or factitious) Nesidioblastosis (islet cell hyperplasia in newborns)
      fulminant hepatic failure alcoholic hypoglycemia CHF Glycogen storage diseases* Cachexia Uremia

Excess endogenous insulin

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

 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 doesn’t – insulin should drop like a rock to preserve PG, but doesn’t!

Management: image to localize, surgery to remove (80% are benign & surgically cured!)

Postprandial (“reactive”) hypoglycemia: partial DDx
Controversial diagnosis – rarely proven but commonly diagnosed Post-oral glucose  Alimentary hypoglycemia (rapid gastric emptying, after gastric bypass surgery, for instance?) o Maybe excess GLP-1 stimulation from rapid gastric emptying?  Possible early diabetes? “Functional” reactive hypoglycemia? Questionable.
o o o Maybe mild hypoglycemia  feel sx  counterregulation brings glucose back Maybe too high / late of an insulin spike? Is it a disease? Does it cause symptoms? Malingering? Controversial.

Rare specific sensitivities (usually pediatric diagnoses)  Leucine sensitivity  Hereditary fructose intolerance  Glactosemia


Dietary Management of Diabetes & Hyperlipidemia
Glycemic Goals of diabetes management 1. Try to get blood glucose in normal range (as close as possible) 2. Lipid / lipoprotein profile that ↓ risk macrovascular disease
o DM is a cardiovascular risk equivalent (= previous MI)

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

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Encourage healthy food choices (keep pleasure of eating – only limit if good scientific evidence) Address individual / cultural needs

   Sugars (↑ blood sugar acutely) Starches (later & longer-lasting) Fiber (don’t 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”!

Simple CHOs (1-2 molecules) Complex CHOs (3+ molecules)

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: don’t 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

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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

Linoleic acid, α-linoleic acid Polyunsaturated fatty acids (Ω-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


    
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  

* corn, soy, vegetable / plant oils
   Saturated fat just does pretty much everything bad Monounsaturated fats (here cis) help lower LDLs Trans-unsaturated fats raise LDLs Polyunsaturated fats help lower LDL a little Fish oils (omega-3) lowers TGs Plant sterols help lower LDL / total cholesterol

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

General Energy Intake & Obesity
 Insert mental recreation of fat maps; make joke about Mississippi Recommendations: ↓ energy intake   drop 500-1000 calories vs maintenance shoot for 5-7% weight loss to start (manageable)    Lifestyle changes education (food labels) reduce fat (< 40% daily energy) regular physical activity

Pedometer with goal (e.g. 10k steps/day) can be useful

Exercise and behavior modification are adjuncts

Dietary Management of Chronic Diabetic Complications
HTN + diabetes:
  ↑ risk of CVD (coronary heart disease, stroke, peripheral vascular disease), ↑ risk of other vascular complications (nephropathy / ESRD, retinopathy)

OK Prehypertension Hypertension

Systolic < 130 130-139 ≥ 140

Diastolic <80 80-89 ≥90

Action At goal for diabetic patient Behavior therapy alone (3mo) then add pharm therapy Behavior therapy + pharm therapy 15

Behavior modification  ↓ sodium (2300 mg/day, or 6000 mg sodium chloride)
o o o Can use salt substitute (replace half of Na with K) – careful in chronic renal failure / on diuretics High salt: smoked meat / fish / hot dogs, lunch meats / canned soups, frozen foods, cheese, processed snacks, condiments (mustard, relish, pickles, soy sauce, ketchup) If sodium per serving size is more than 10% of RDA, don’t buy it!

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↑ potassium, magnesium, calcium (DASH diet: fruits/veggies @ 5-9 / day, low-fat dairy @ 2-4 / day) Modest weight loss Exercise

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

↑ plant stanols / sterols, soluble fiber

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)


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

Thyroid descends down front of neck, ends up at base

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!

Hypothalamic – Pituitary axis
Hypothalamus secretes TRH
 TRH = thyrotropin releasing hormone (thyrotropin = TSH)

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

TSH stimulates thyroid to make T4 (and a little T3)
  Goes to target cells throughout body Negative feedback too (onto hypothalamus, anterior pituitary)

Pituitary Hormones, TSH, and the TSH receptor
 LH, FSH, β-hCG, and TSH all have common α-subunits with different β-subunits
o o All are glycoprotein hormones made by pituitary (except hCG – from placenta) β-subunits confer biological specificity

TSH binds to TSH receptor in thyroid
   GCPR, α/β subunits of receptor, etc Mediates iodine uptake, Tg biosynthesis, Tg T3 / T4 All the steps needed for thyroid hormone synthesis!


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

Pendrin: transports iodine across brush border
  Also in endolymphatic sacs in ear Pendrin’s syndrome: no enzyme, congenital deafness & hypothyroid

TPO: Thyroid peroxidase  Mediates binding of iodine to thyroglobulin
o Iodine must be oxidized with locally produced peroxide first!

 

T4 formed from coupling: T3 can also form:

two diiodotyrosines  thyroxine (T4) one diiodotyrosine + one monoiodothyrosine  triiodothyronine (T3)

Much more T4 is formed & released than T3 (ratio is 20:1)
Thyroid Binding Proteins
In the bloodstream, T4 / T3 bound to proteins  99.97% bound, only 0.03% free T4    Thyroxine-binding Globulin (TBG) is main one Thyroxine-binding prealbumin (binds vitamin A too) Albumin binds a bit


What happens when TBG levels change?
TBG excess
(e.g. pregnancy: estrogen  ↑ TBG)

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

TBG excess  more free T4  downregulate TSH, T4

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

T3 is the main thyroid hormone that mediates action o T4 is like a prohormone!

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

Regulated pathway: deiodination inhibited by
      Fasting Illness Glucocorticoids Iodine contrast agents drugs (propylthiouracil, propranalol, amiodarone) selenium deficiency

If you’re hungry, sick, etc. – don’t 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)


Thyroid hormone receptor family
   Nuclear receptor superfamily Constitutively bound to chromatin Involved in DNA binding / transcription
o o o to upregulate / downregulate gene expression E.g. ↓ TSH, ↑ hepatic proteins Often complexes with retinoic acid receptor (RxR)

Thyroid hormone resistance: Defect in receptor:
 target tissue receptors can’t bind or translate activity into signals

 

Feel OK (clinically euthyroid) ↑ free T4 / T3, ↑ or normal TSH o pituitary is also insensitive, so upregulates!

The Thyroid in Disease States
Primary hypothyroidism Primary hyperthyroidism Central hypothyroidism

↓ T4/T3


↑ T4/T3


↓ T4/T3


Thyroid smaller, so ↓ T4/T3, pituitary upregulates TSH

Thyroid bigger, so ↑ T4/T3, pituitary downregs TSH

Thyroid normal, pituitary messed up , so ↓ TSH  ↓ T4/T3

Thyroid Function Testing
Two main strategies Measure thyroid hormone itself
(but can be misleading)  Protein binding alterations can’t be detected  nonthyroidal illness different conversions (rT3, etc)  Can’t ID subclinical thyroid dz

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 someone’s hypothyroid, they should have a high TSH – normal TSH suggests central hypothyroidism


Algorithm for Thyroid Testing
Down the middle: normal! No more testing Low TSH (left) – measure T4
   If low, suspect severe illness / central hypothyroidism If normal, suspect subclinical hyperthyroidism If high, suspect garden-variety hyperthyroidism

High TSH (right) – measure T4  If low, that’s garden-variety hypothyroidism  If normal, suspect subclinical hypothyroid  If high, suspect TSH-secreting tumor (really rare)

Subclinical (“mild”) hypothyroidism
   Really common, may develop after inflammation of thyroid, etc. T3/4 are just a little low (for that person), TSH keeps climbing to keep up After years, T3/T4 exit “normal” range

Subclinical (“mild”) hyperthyroidism
   T3/4 are just a little above normal for that person TSH is really sensitive, keeps dropping to ↓ T3/T4 Eventually hit overt hyperthyroidism

Radioactive Iodine Uptake
Pt ingests radioactive thyroid, measure with Geiger counter the next day @ neck  ↑ uptake in Graves’ disease (overactive)  ↓ uptake in thyroiditis (thyroid is “sick” – not taking iodine in, although TSH levels high)

Thyrotoxicosis (hyperthyroidism)
   Just means you’re 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:     

Heat intolerance, ↑ perspiration Weight loss, ↑ appetite, diarrhea Weakness

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 – can’t look up) Corneal involvement Sight loss (ischemic optic neuropathy)

 

Dermopathy: pretibial myxedema
o Usually in front of shins; Myxedema – usually in hypothyroidism

Thyroid acropachy = clubbing

Etiology:  Autoimmune disease: thyroid stimulating antibodies (TSAb)
o o Against TSH receptor but stimulate growth / function Bypassing TSH  stimulating thyroid receptors!

 

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 hashimoto’s thyroiditis too)
o o

only see in autoimmune thyroid disease; Hashimoto’s- damage is too great  ↓ thyroid function

Radioactive iodine  check thyroid uptake (should ↑ enhancement)

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

Treat with radioactive iodine (taken up  kills nodule) 22

Toxic Multinodular goiter
  Just a more extreme case of the solitary toxic nodules Goiter just means big thyroid

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

Rare causes of hyperthyroidism
  Pituitary adenoma: making TSH (TSH↑  T3/4 ↑ too) Factitious thyrotoxicosis: patient is surreptitiously iodine (form of Munchausen syndrome) o RaI uptake is low – already full of iodine (mimics thyroiditis)

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

Due to dysfunction of hypothalamus / pituitary gland    

Slight weight gain, ↓ appetite Constipation Arthralgias Paresthesias

   

↓ body hair Dyspnea, hypoventilation, sleep apnea Multifactorial anemia Hypoosmolar state (hypoNa)


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!

Developed world:  Hasimoto’s thyroiditis (autoimmune) is #1  Also:
o o o congenital absence of thyroid / enzyme defect postablative (RAI / surgery) drugs (lithium, amiodarone / other I-containing drugs)

Hashimoto’s 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


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

Painless / postpartum / lymphocytic thyroiditis
    Transient hyperthyroidism (2-3mo) followed by transient hypothyroidism (2-3 mo)
o o May be recurrent, hypothyroidism may be permanent (20%) Can also get Graves’, transient / permanent hypothyroidism post-partum

Often in postpartum women (5% post-partum women, ↑ with DM type 1)

Thyroid gland normal or slightly enlarged; not tender Positive antithyroid Abs in most pts (autoimmune)
o Sort of a variant of hashimoto’s 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

Thyroid for Dummies: what can go wrong with the thyroid?
Problem can make too much thyroid hormone
 (overactive thyroid, hyperthyroidism)

Examples        Graves’ disease Toxic nodular goiter Chronic lymphocytic thyroiditis Ablation of thyroid with radioiodine Surgery Subacute thyroiditis Postpartum thyroiditis

can make too little thyroid hormone
 (underactive thyroid, hypothyroidism)

can become inflamed

can become enlarged (goiter) or develop one or more lumps (nodules)


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!

Normal radiographic appearance
C=chiasm I = infundibulum (L) or internal carotid artery (R) SS = sphenoid sinus (out to nasal area) CS = cavernous sinus (contains CNs AP = anterior pituitary PP = posterior pituitary


Lesions: radiographic appearance

Microadenoma: Hypodense lesion(arrow). ≈4cm (pituitary 9 cm tall)

Small macroadenoma: hypodense lesion, see deviation of pituitary stalk (S), displacing pituitary

Macroadenoma: has pushed normal pituitary to top of sella turcica

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

Clinical Manifestations of Pituitary Lesions growing in Sella Turcica
HPI should have three main focuses: Hypopituitarism
First “innocent bystander” for growth – lesion can grow, compress, destroy cell population.  ↓ TSH / LSH /FSH  ↓ peripheral hormone levels

Neurological defects
When tumor  macroadenoma  Compresses optic chiasm, other adjacent structures

Tumor can start secreting!

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)

Secondary hypothyroidism: see ↓ TSH
(TSH is the problem!)

Same thing for gonadal, other axes 27

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 Cushing’s syndrome 4. TSH Hyperthyroidism

Presenting Symptoms of a pituitary adenoma
Putting it all together:  Headache  Visual abnormalities   Hypogonadism Hypothyroidism   Adrenal dysfunction Secretory syndrome

Secretory Adenomas
 #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

Acromegaly (growth hormone secreting tumors)
   #2 most common but still uncommon (3-4/million) Tend to be diagnosed in 40s Mean age of death in 60s if untreated (cardiac disorders)

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 (don’t notice!)
  Want to make early dx: better chance of reversal, prevent side effects; soft tissues reverse, bone changes don’t 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 there’s 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 doesn’t respond to glucose

ACTH-secreting tumors & Cushing Syndrome
   Various causes, complex Dx: not just ACTH-secreting tumors Complex syndrome, really nasty moon facies, plethora (redness), violaceous stretch marks, abdominal obesity, easy bruising, buffalo hump, acne, etc.etc.etc.,

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

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

Empty Sella Syndrome
Invagination of diaphragm sella (stretched piece of dura above) by CSF  Starts to pancake pituitary across floor of sella
 Pic: see little crescent shaped pituitary being pushed down by CSF

Normal function in 95% of cases
 Remarkable compression, but slow  can adapt!

no intervention needed if function ok
Need to DDx from cyst (cyst can progress!)

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

Panhypopituitarism (hemorrhage)  acute cortisol deficiency (can be life threatening!)


Hypopituitarism: monohormonal failures
   Usually inherited (can be acquired) Kallman syndrome: failure to elaborate gonadotrophin releasing hormone (↓ LH/FSH) – 2° hypogonadism Isolated ACTH / TSH / GH possible too

Treatment of Hypopituitarism
Secondary… Hypothyroidism Sex hormone deficiency Cause ↓ TSH ↓ GRH Treatment  can’t 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



Extra maintenance if just a little sick 10x dose if severe illness, surgery, etc Wear medical alert tag

Disorders of the Posterior Pituitary
Neurogenic Diabetes Insipidus Deficiency of vasopressin Syndrome of Inappropriate ADH Excess vasopressin Release Remember ADH = vasopressin Posterior pituitary: just a storage depot for vasopressin & oxytocin  two hypothalalmic nuclei (supraocular, paraventricular) synthesize vasopressin, oxytocin  Axons run down to posterior pituitary, terminals in posterior pituitary  Signal  release into circulation

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 we’re 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)

Neurogenic diabetes insipidus
Deficiency of vasopressin  Less commonly from vasopression receptor inactivation (renal; very rare)  Central diabetes insipidus: when posterior lobe of pituitary fails to secrete enough vasopression
o o NOT from tumor – can actually remove part of posterior lobe and not have DI (axons run above) Can if lesion is in upper stalk or higher (larger lesions or lesions higher up in stalk)


Pathophysiology:  Can’t get aquaporins in to concentrate urine  very dilute urine, polyuria   dehydration / hypotension if can’t 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)

SIADH: Syndrome of inappropriate secretion of ADH
   Excessive secretion of vasopressin (opposite of DI) Leads to excessive water retention, hypoNa Most common cause of non-iatrogenic hyponatremia

Keep making & secreting vasopressin even when osmolarity is low! These are euvolemic patients with hypoNa Check plasma osmolarity (mostly sodium) and see it’s low  But urine is inappropriately concentrated  Shouldn’t have ADH around! Causes: many! Meds, tumors, pulmonary disorders, CNS disorders, etc.


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 ↑

 Exercise capacity ↓  Cognitive skills ↓  Sexual desire / function ↓

From graphs: ↓ muscle strength Body composition:  ↓ muscle  ↑ fat

Hormones that Decline with Age
  Normally if ↓ GH, give GH Open question: should these declining hormones be prescribed for healthy elderly pts? Hormone Estrogen, progesterone Growth hormone DHEA Testosterone Name Menopause Somatopause Adrenopause Andropause, “male climacteric”

Estrogen & Progesterone Replacement
   Benefits of replacement ↓ menopausal vasoactive Sx Slow bone loss ↓ risk CAD (?)    Risks of replacement ↑ risk of breast cancer (long-term) ↑ uterine cancer with unopposed estrogen ↑ venous thrombosis

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?


Effects of GH deficiency
      ↓ muscle mass ↑ intra-abdominal fat ↓ bone mass ↑ fracture risk ↑ SBP Hyperlipidemia

GH replacement in healthy elderly Effects Potential Risks
 ↑ lean body mass (good)  ↓ total body, abdominal fat  NO CHANGE in FUNCTIONAL STATUS  Total / HDL chol = inconsistent       Joint pain Carpal tunnel Fluid retention HTN Diabetes Cancers? Accelerated aging?

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

GH: Hucksters, Scam Artists, & Other Scallywags
   ORAL GH JUST DOESN’T WORK – need to inject (high discomfort, high costs)
o Can’t “enhance” GH releasing hormone with oral supplements either

“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)

↑ 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: don’t give T unless the patient is severely T deficient (from another cause) 34

Adrenal Pathophysiology & Multiple Endocrine Neoplasia
Overview of Adrenal Pathophysiology
Glucocorticoid & mineralocorticoid deficiency Glutocorticoid excess Mineralocorticoid excess Catecholamine excess Multiple Endocrine Neoplasia syndromes Addison’s disease, Congenital Adrenal Hyperplasia Cushing’s syndrome Hyperaldosteronism Pheochromocytoma

Normal Embryology, Anatomy, & Physiology
Adrenal cortex / medulla are functionally separate organs
  Cortex: Medulla: mesynchemal origin; invaded by neural crest cells (2 mo gestation) NCC  chromaffin cells (secrete catecholamines) under ↑ local *glucocorticoid+

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

Histology & Function: out in = salt  sugar  sex  violence
Cortex Medulla Zona glomerulosa Zona fasiculata Zona reticularis Aldosterone Glucocorticoids Androgens Catecholamines “salt” “sugar” “sex” “fight / flight”

Corticosteroids:  glucocorticoids (e.g. cortisol)  mineralocorticoids (e.g. aldosterone)

Glucocorticoids: Physical Function
From zona fasiculata (“sugar”) In stress situations (sepsis, hemorrhage, surgery), glucocorticoid secretion can ↑ 10x
  ↑ survival: affects cardiovascular system, CHO / lipid metabolism, immune system In adrenal insufficiency  can have life-threatening adrenal crisis if stressed w/o glucocorticoid replacement

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

CHO / Lipid metabolism
Goal: maintain fuel to brain (↑ blood glucose) Effect of glucocorticoids (cortisol) ↑ appetite, gut absorption ↑ hepatic gluconeogenesis  (substrates from glycogen, protein, lipid) ↓ peripheral glucose uptake: insulin resistance
  (↓ glucose transporter function) (abdominal fat retained, peripheral fat eliminated)

Effect in chronic cortisol excess (Cushing’s 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

 Redistribute to circulation  granulocytosis  ↓ Chemotaxis, phagocytosis

 ↓ Eos, Mϕ, monocytes  ↓ histamine, prostaglandin, TNF  ↓ vascular permeability

Chronic glucocorticoid excess  excess immune suppression  ↑ susceptibility to infection (bacterial / viral / fungal)

Glucocorticoids: Regulation (cellular level)
Nuclear receptor binds DNA  affects gene transcription, etc. Cortisol is active, Cortisone is inactive  11HSD: 11-β hydroxysteroid dehydrogenase (conversion)  11HSD2 inactivates at tissues Activity of glucocorticoids regulated locally by:  11HSD activity  Nuclear receptor protein presence/absence

Glucocorticoids: Regulation (H-P-A axis / negative feedback)
Remember: CRH (hypothalamus)  ACTH (pituitary)  cortisol (adrenal)  ↑ cortisol inhibits CRH & ACTH synthesis & release (negative feedback)  CRH / ATCH release is pulsatile CRH pulses:  Stimulate ACTH synthesis & secretion
o Important for daily-type stresses, diurnal variation, etc.

In extreme stress: vasopressin can also cause ACTH release

ACTH pulses:  Stimulate secretion of:
cortisol (principal glucocorticoid) aldosterone (mineralocorticoid) DHEAS / androstenedione (weak androgens) ↑ steroid hormone biosynthesis (↑cholesterol  pregenolone conversion – rate limiting step, + other steps) o o o

↑ adrenal growth 36

Clinical significance  Resistance to negative feedback is the hallmark of glucocorticoid excess (Cushing’s Syndrome)  Withdrawing exogenous glucocorticoids (e.g. post therapy) may suppress HPA axis
o Already ↓ CRH, ACTH from ↑ exogenous glucocorticoids

Circadian variation in cortisol secretion
  Plasma cortisol peaks in the morning, lowest ≈ midnight o small, decreasing peaks through the rest of the day (tapering down) Cortisol deficiency  really really tired all the time

Mineralocorticoids: Regulation
Produced in zona glomerulosa (e.g. aldosterone: “salt”)

Under dual regulation Angiotensin II
primary stimulus for mineralocorticoid synthesis & secretion

High levels of ACTH
can be a secondary stimulus for mineralocorticoid release

Clinical significance:  ACTH deficiency doesn’t usually produce mineralocorticoid deficiency, but  ACTH excess can lead to mineralocorticoid excess

Adrenal / Immune Systems: Negative Feedback
Net effect is to dampen immune response  part of negative feedback to keep immune processes in check Immune stimulus  ↑ TNF / IL-1, IL-6 from mononuclear cells  triggers ↑ CRH, ↑ ACTH, ↑ cortisol  ↑ cortisol has immunosuppressive effects o Also triggers negative feedback (as shown above) Ends up trying to achieve a sort of “balanced” immune response


Adrenocortical Insufficiency

Primary AI: indicates damage to adrenal cortex (Addison’s disease)  Adrenals knocked out so ↓ aldo, ↓ cortisol
  ↑ CRH, ACTH (negative feedback from cortisol removed) ↑ renin, ↑ AT I/II (↓ aldosterone  ↓ renal blood flow)

ACTH Cortisol Aldosterone

Primary High Low Low

Secondary Low Low Normal

Secondary AI: indicates damage to hypothalamus / pituitary (↓ ACTH production)
   Aldo still produced – although adrenals are small (↓ ACTH), they can still make some Patients can partially compensate with aldosterone: don’t have as many vascular issues (partial compensation) ↓ cortisol but ↓ ACTH too (pituitary is damaged!

Clinical manifestations of adrenocortical insuficiency
Severity depends on
   Rate, degree of loss of adrenal function Whether aldosterone secretion is preserved Level of concurrent physiological stress

    Weakness Sleepiness / fatigue Anorexia Nausea / vomiting  Abdominal pain  Postural light-headedness*  Salt craving  Weight loss  Hyperpigmentation*  Hypotension*

 Dehydration*  Loss of pubic / axillary hair

* especially in primary adrenal insufficiency Addison’s 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)


Acute adrenal crisis
   Muscle, joint, abdominal pain  Clouded sensorium Intractable vomiting, severe dehydration  Electrolyte disorders Hypotension resistant to pressors Give EMPIRIC GLUCOCORTICOID TREATMENT!

Lab findings
   HypoNa* HyperKa* Hypoglycemia  ↑ BUN/Creatinine*  HyperCa (rare)  Anemia *mostly primary (vs secondary)   Eosinophilia Lymphocytosis

Etiologies of primary adrenal insufficiency
    Autoimmune destruction Adrenal hemorrhage Metastatic carcinoma Infections (can be isolated or polyglandular) = Addison’s disease (associated with anticoagulant Rx, meningococcemia) (need > 90% replacement by tumor) (TB, fungal, CMV)

Etiologies of secondary adrenal insufficiency
o o o After glucocorticoid treatment > 2/3 wks, therapy should be tapered down HPA axis needs to recover: have been suppressing higher levels (ACTH, CRH) If patient is stressed while axis suppressed, they’ve basically got functional adrenal insufficiency

Tumors (hypothalamic / pituitary) – less common

Diagnosis of adrenal insufficieny
Short ACTH (cortrosyn) stimulation test: Best initial study of choice for adrenal insufficiency of any cause  Give ACTH, check cortisol (adrenals should produce cortisol > 18 mcg/dL)  But won’t work in recent onset 2° AI (adrenals haven’t atrophied yet) Plasma ACTH level: to differentiate 1° vs 2° (ACTH ↑ in primary, ↓ in secondary) CRH, metyrapone tests  Used to detect recent onset secondary AI; stimulate the H-P-A axis centrally, rarely used now  CRH: stimulates pituitary  Metyrapone: entire H-P-A axis (cortisol synthesis inhibitor) but can therefore exacerbate AI!

Treatment of AI: Basic Principles
1. Individualize for primary vs secondary a. Secondary: hydrocortisone (= cortisol) alone b. Primary: hydrocortisone + mineralocorticoid (cortisol + fludrocortisones) 2. Mimic normal diurnal changes (avoid overtreatment) a. Normal basal production 10-12 mg/m2/day 3. Anticipate ↑ requirements during stress a. Fevers, other mild illness: 3x dose b. Surgery / severe illness: 10x dose (“stress dose steroids”) 39

Congenital Adrenal Hyperplasia
Family of disorders with specific defects in steroid biosynthetic enzymes
   Relative ↓ in cortical secretion  ↓ feedback suppression of CRH, ACTH  ↑↑ ACTH secretion  ↑ production of cortisol precursors (upstream of enzymatic block  ↑ androgens) Long term ↑↑ ACTH  overgrowth of adrenal glands (hyperplasia)

21-hydroxylase deficiency: Example of CAH
Most common example of CAH
 varying degrees of cortisol/aldosterone deficiency & androgen excess

Mild block (e.g. heterozygote):  ↑ ACTH can drive a little more through the pathway Severe block (e.g. homozygote)  can’t 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

Hypercortisolism (Cushing’s Syndrome)
Cushing’s Syndrome Generic hypercortisolism regardless of cause Cushing’s Disease Hypercortisolism from an ACTH-secreting pituitary tumor

Clinical Manifestations of Hypercortisolism
System General Skin Cardiovascular Muscle Bone Reproductive Metabolic Immune Psychiatric Manifestations truncal obesity with peripheral wasting, moon facies, cervicodorsal fat cutaneous atrophy, abdominal striae (purplish, not silvery like post-pregnancy), acne hypertension, edema, cardiomyopathy (rare) proximal myopathy (often severe) osteoporosis, aseptic hip necrosis amenorrhea, hirsuitism, virulization insulin resistant DM, hyperlipidemia broad immunodeficiency, esp T-cell mood swings, depression, mania (esp. on very short time scale) psychosis

Very characteristic appearance:  Note abdominal obesity with thigh wasting  Moon-like, full, reddish facies


Etiologies of Hypercortisolism
ACTH-dependent   Cushing’s 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-Cushing’s

   

ACTH-dependence stems from etiology:
   Cushing’s disease: very high doses of cortisol can sometimes counteract high ACTH levels Ectopic ACTH: no matter how much cortisol you jack up, you can’t ↓ ACTH levels Adrenal tumor: too much cortisol being produced, but hypothal / pituitary negative feedback working OK (ACTH suppressed)

Diagnosis of hypercortisolism
INITIAL STUDIES Urinary free cortisol 24 h urine collection  measure cortisol (24h: integrates circadian variation) Cushing’s syndrome: ↑↑ (3x nL)
Milder elevations: Cushing’s, pseudo-Cushing’s, or stress (repeat test)

Method: Results: Comments:

INITIAL STUDY OF CHOICE Midnight Salivary Cortisol Get saliva sample at midnight (≈ plasma free cortisol Normal: should be really low (lowest circadian level) Cushing’s: 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) Cushing’s: have impaired feedback suppression by low doses of exogenous corticosteroid (> 1.8 mcg/dL) Doesn’t distinguish Cushing’s disease vs other causes of hypercortisolism 41

Method: Results: Comments:

Method: Results: Comments:

BIOCHEMICAL LOCALIZATION Plasma ACTH Method: Collect ACTH from plasma Low ACTH (<5 pg/mL) and ↑ cortisol:
 ACTH-independent (exogenous vs. adrenal tumor)

Results: Normal / high ACTH (> 15mcg) and ↑ cortisol
 ACTH-dependent (pituitary Cushing’s dz vs ectopic ACTH)


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 Cushing’s disease: most cases suppress > 90%


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 CUSHING’S Specialized, not available in all hospitals




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


 Potentially misleading

    



  

Treatment of hypercortisolism
Etiology Cushing’s 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

Endocrine causes of hypertension: Cushing’s syndrome, Hyperaldosteronism, or pheochromocytoma Clinical features:  hypoK: urinary potassium wasting  hyperNa: suppressed plasma renin (in 1° hyperaldosteronism)



 

due to adrenal cause (adenoma / hyperplasia), or idiopathic Diuretics, CHF, renal artery stenosis



renin-dependent (multiple etiologies  ↓ renal blood flow)

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 won’t

  Adenoma: Idiopathic: surgery aldosterone receptor inhibitors (spironolactone . eplerenone) 43

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)

Symptoms / signs  Headache  Diaphoresis  Palpitation

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) (Café au lait spots,cutaneous neurofibromas, pheo) (Paraganglioma and pheo)

  Recognize distinctive symptom complex or HTN that’s really severe Then: confirm biochemically, then localize

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

Optional follow-up test: clonidine suppression test
  Indicated if metanephrine ↑ is modest (1.5-3x); get plasma metanephrines before / after clonidine Metanephrines suppressed by clonidine in normal individuals; stable/↑ in pheo


Anatomic localization: with CT/MRI, 123I-MIBG, FDG-PET

1. Pre-op preparation a. Anesthesia, other major procedure w/o α-blocade could induce hypertensive crisis b. α-adrenergic blockade (phenoxybenzamine usually used) c. AVOID ISOLATED β-BLOCKER USE (can worsen HTN by inhibiting β-2 adrenergic receptors) 2. Adrenalectomy (laparoscopic)

Multiple Endocrine Neoplasia Syndromes
Two distinct syndromes: MEN1 / MEN2  Both aut dom inheritance of multiple endocrine tumors  DNA-based diagnosis of pre-symptomatic patients possible

MEN1: Parathyroid, Pancreas, Pituitary
 Inactivating mutations of the Menin gene (function obscure)  Clinical manifestations: 3P’s (Parathyroid, pancreas, pituitary)  Cardinal lesion is parathyroid adenomas (>90% penetrance by age 30)  GI tumors (40%) incl. gastrinoma, carcinoid (serotoinin), insulinomas  Pituitary tumors (30%) incl. prolactinoma, non-secretory, ACTH, GH Diagnosis:  Ionized calcium, PTH, FHx  

Gene testing difficult

Prolactin, gastrin, others

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

MEN2: MTC, Pheo, Parathyroid
  Activating mutations of RET tyrosine kinase receptor Cardinal lesion is medullary thyroid cancer (25% MTC hereditary; 75% sporadic)

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


Gender Development
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

    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)

Sex ducts: all embryos start out with ‘em; may or may not continue   Mullerian ducts  internal female reproductive structures
(upper vagina, cervix, uterus, etc.)

Wolffian ducts internal male reproductive structures
(seminal vesicles, epididymes, vas deferens, prostate)

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-α reductase: T  DHT) androgen more potent androgen

(embryo won’t have female internal reproductive structures)

Promotes Wolffian duct development
(embryo will have male internal reproductive structures)

Promotes masculinization of external genital structures (embryo will have male bits)

Female development (not as well understood)  If there’s 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 won’t have male internal reproductive structures)

No masculinization of external genital structures (embryo won’t have male bits - female by default)

Example: 46XY with 5-α reductase deficiency: can’t convert T to DHT  No masculinization (female external genitalia!) 50+ types of DSD: so what do you do?


Optimal Gender Theory (John Money)
John Money (Hopkins PhD – gender identity clinic)
  Identified gender identity vs gender role Believed that GI is learned, GR is in part hormonally programmed

“ 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 doesn’t 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

“Biology is Destiny” Theory of Gender
Replacement for optimal gender theory Different takes:  Early androgen exposure masculinizes the brain and subsequent behavior in humans  Genes encoded on the Y chromosome masculinize the brain and behavior in humans  Both masculinize the brain and behavior in humans in an additive or synergistic manner Frank Beach: 1st behavioral endocrinologist; looked at guinea pigs
 Castrated male rats o gave T  start mounting stuff o gave E show lordosis (submission) Similar for female rats – estrogen / testosterone seems to control behavior

Congenital Adrenal Hyperplasia (CAH) – 21-hydroxylase deficiency
   Most common cause of XX-DSD Formerly called “female pseudohermaphrotism” Life-threatening condition (often fatal in 1st 10 days of life if not caught!)
o o o Easier to pick up in genetic females Genetic males – harder (supposed to look like this!) – often die Now: newborn screening in all states in USA

Can’t make cortisol so ↑ cortisol precursors (↑ androgens)  external masculinization  Full penis  Labia completely fused (empty scrotum – no testes! Ovaries!)  Spectrum (Prader 0-5; femalemale)

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)


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 Can’t ethically take away child’s 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?

No differences between groups (GENDER IDENTITY) Dose-response with androgen exposure (I’m 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

Congenital Androgen Insensitivity Syndrome (CAIS, AIS)
   46XY DSD with female genitalia Have testes in abdomen Testes work fine (making T, made MIF) o So internal male structures (Wolffian) o but no internal female structures (Mullerian) o Converts T to DHT just fine, but no external masculinization  No androgen receptor  no pubic hair, etc. either
Has lots of T  can convert to estrogen with aromatase (breast development)

Clinical presentation: no menses, no pubic hair, normal breasts
 Question: does rodent model apply to humans? Exposed to lots of T in utero (should masculinize brain?)  All CAIS females were heterosexual, satisfied with gender identity role  Really feminine! Maybe because the T is being converted to E(not best population to study)

46,XY Complete Gonadal Dysgenesis (CGD)
Really rare; a.k.a. “Swyer syndrome” XY but can’t differentiate into testes (no SRY, etc.)
  Gonadal streaks instead of testes No T, no MIF (female external genitalia, Mullerian ducts  female)

Research question: what’s 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

46, XY DSD with ambiguous genitalia
  What do you do if you don’t know what fertility potential is? Almost always reared female 48

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?

“Biology is Destiny” theory – evidence
“Early androgen exposure masculinizes the brain, subsequent behavior in humans”  Not true for GI (think CAH, 46,XY with ambiguous genitalia)  May be true for GR and sexual orientation (CAH-SL and 46,XY with ambiguous genitalia) o Take into consideration in assigning gender roles “Genes encoded on the Y chromosome masculinize the brain and behavior in humans”  Not true for GI, GR, or sexual orientation (CAIS and CGD) “Both early androgens / Y-chromosome masculinize brain / behavior in an additive / synergistic way)  Not true for GI (46,XY with ambiguous genitalia reared female)  May be true for GR (46,XY with ambiguous genitalia reared female)  Not true for sexual orientation (only 39% of 46,XY with ambiguous genitalia reared female are heterosexual)

What to do with these babies?
46,XY DSD with Quigley 3/4 (pretty ambiguous) – what to do?  Appearance of genitalia alone can’t predict long-term gender development (25% chance of dissatisfaction)  Look for other predictors

Parental factors?

   

Parental support purported to be primary factor that promotes well-being (not studied much)

Parents of kids with chronic diseases
Parent stress  ↓ behavior / social / emotional outcomes of kids with cancer Stress in parents  ↑ depression in type 1 DM kids More overprotective  ↑ adjustment difficulties in kids Moms > Dads for getting stressed out

   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


Puberty: physiological process causing development of 2° sexual characteristics and leading to reproductive maturity.

Normal Puberty: Physiology
Hypothalamus: neurons that make GnRH (peptide hormone)  Travels via pituitary portal system to… Anterior Pituitary: gonadotrophs stimulated by GnRH  Secrete LH / FSH  travel through systemic circ to… Gonads: Stimulated by LH/FSH  produce testosterone and/or estrogen

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

Pulsatile GnRH Secretion
Hypothalamus releases pulses of GnRH  GnRH & LH: “in a relationship”
o o GnRH pulses are very synchronized to subsequent LH pulses If GnRH↓, LH↓

GnRH & FSH: “it’s complicated”
o FSH is also coupled to GnRH but not as tightly


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

Normal Maturation of the Reproductive Axis
Fetal development
Hypothalamus GnRH neurons migrate down (1st trimester) Pituitary ↑ LH, ↑ FSH (2nd trimester) Gonad* Male
 Testes develop (if testes-determining factors around)  Testosterone secretion starts (1st trimester); increases to mid-pubertal levels at birth!

 Ovary develops, E2 secreted in nd 2 trimester

Note: gonadal development is separate from pituitary / hypothalamic development – NO GnrRH / LH / FSH NEEDED!

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)

8-10 yo: Female puberty begins
Pulsatile secretion of GnRH  pulsatile secretion of LH / FSH  LH to theca cells  androstenedione (AD)  FSH to follicular cells  AD  T  E2  E2 production  breast development, skeletal growth Adrenals produce androgens  pubic hair  “adrenarche” – separate process 51

11-14 yo: Male puberty begins
Pulsatile secretion of GnRH  pulsatile secretion of LH / FSH  LH to Leydig cells  testicular enlargement, T production (some E2 too) o T  ↑ penile length, male pattern hair o T + E2  skeletal growth, close growth plates  FSH to Sertoli cells  spermatogenesis

Puberty: Clinical Assessment
Tanner Stages
   Describe the 2° sex characteristics during different times of puberty Five stages (1=infantile, 5=adult) Specific stages for:
o o o Breast development Pubic hair Male external genitalia (contour of breast / areola) (distribution / quality) (testes size / penis length / changes in scrotal skin)

Girls: pubertal events
Whole thing takes around 5 yrs    Breast development Pubic hair Menarche Begins ≈ 10.5 yrs, takes ≈ 4yrs After breast, takes ≈ 3 yrs Stage 4 (≈ 12.5 yrs) o after maximal growth velocity
o Age of menarche ↓ slightly over last century

Boys: pubertal events
Starts later than girls; takes ≈ 4-5 yrs      Testicular enlargement Spermarche Growth spurt Axillary / facial hair Voice changes First (≈ 11 yrs) ≈13 yrs after stage 5 (later than girls) ≈ 14 yrs ≈ 14.5 yrs

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

Abnormal Puberty (pathophysiology)
Criteria for puberty
Criteria for puberty Development of secondary sex characteristics Accelerated growth rate Evidence of premature fusing of growth plates on hand X-ray Sex steroid functions Cause secondary sex characteristics Accelerate growth / contribute to pubertal growth spurt Accelerate closing of growth plates


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)

Contrasexual (always peripheral origin) Males  breast development Females  virilization

Peripheral: gonadotropin-independent (gonads alone)
 ↑ T/E2 but ↓LH/FSH (neg feedback)

“Gonadotrophin dependent” (central) precocious puberty (isosexual)
Activating hypothalamus / pituitary (↑ GnRH)
 ↑ 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

o o o ↓ growth velocity (↓ sex steroids), ↓ bone age advancement Final height improved (may not reach target height Fertility maintained


Isosexual gonadotrophin-independent (peripheral) precocious puberty
2° sex characteristics appropriate for sex; ↑ T/E2 but ↓LH/FSH (neg feedback)

Males: some process is causing testosterone / androgen production!
  Not coming from ovaries or pituitary LH/FSH pathway! Testis can be doing their own thing (unregulated)
o o o Tumors making T Mutations in LH signaling pathway (FMPP – see below) McCune – Albright syndrome (aut-recessive) (G-proteins downstream of LH receptor tonically on)

Adrenal gland can be turned on
o o o Adrenal tumors Congenital adrenal hyperplasia (CAH) Premature adrenarche (idiopathic)

Testosterone cream / spray gels (kid gets inadvertent exposure)

Familial Male-limited Precocious Puberty (FMPP)
    Mutations in LH signaling pathway X-linked (not in females) LH receptor tonically ON  Leydig cells make T even without LH Precocious puberty as young as 4-5 yo

Females: some process is causing estrogen production!
  Not coming from testes or pituitary LH/FSH pathway Ovaries can be doing their own thing (unregulated) o Tumors making andro  estradiol o McCune – Albright syndrome (aut-recessive)
o  (G-proteins downstream of LH receptor tonically on) McCune-Albright present in F, not FMPP (X-linked)

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

Can enter puberty as young as 2-3 yo


Contrasexual gonadotrophin-independent (peripheral) precocious puberty
2° characteristics not appropriate for one’s sex Males: estrogen-producing processes
 Adrenal tumors  Gonadal tumors, feminizing  Drugs: digoxin, spironolactone (antagonizes androgen receptors), THC (lots of pot ↑ E2), methadone, E2  Liver disease (can’t metabolize steroids  ↑ E2 – last stop in pathway)

Females: androgen-producing processes
     CAH (most common) Adrenal tumors (adrenal cortical carcinoma) Gonadal tumors Exogenous androgens Premature adrenarche

Treatment of gonadotrophin-independent precocious puberty
Challenging: if you can’t take tumor out, try to ↓ steroids / effects (stop production or block binding) Drugs Testolactone / anastrozole
Tamoxifen with ± success

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

Primary hypogonadism (hypergonadotropic)
Why aren’t the gonads working? Gonadal dysgenesis (gonads not formed well)  XXY (Klinefelter’s syndrome)  XO (Turner’s syndrome)   Insult / injury to gonads Chemo, radiation, tumor Autoimmune destruction, infection

Secondary hypogonadism (hypogonadotropic)
Why no LH/FSH production?     CNS disorders (disorders of pituitary, hypothalamus) Chronic systemic disease (adaptive mechanism – shut down reproductive capacity; mechanism not understood) Isolated gonadotropin deficiency (rare – can’t make GnRH, LH, etc.) Constitutional delay of puberty (most common cause – “late bloomers” – just start puberty later) o Rule out other causes – pituitary imaging, etc.


 Any serious illness can affect a child’s growth: an important “vital sign” in pediatrics o normal growth in a kid doesn’t 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 isn’t always abnormal  But evaluate these kids (e.g. look at growth & compare to normal growth variants)

Normal variant growth patterns
Outside of 3 /97 %iles
  By statistical definition, 6% normal, healthy kids fall outside this range No specific evaluation needed as long as growth o/w normal o normal velocity, not diverging further, consistent with genetic potential
rd th

Calculating genetic height potential:  Average parents’ height after correcting for sex difference in mean adult height (5in = 13 cm M>F)

o MPH =
o 

Father's height+ Mother's height± 5in 2

Add 5 in for a boy / subtract 5 in for a girl

Can also just average percentile th th o (e.g. if mom in 20 %ile, dad in 20 %ile  kid too)

Target range = MPH (mid-parental height) ± 4 in (10 cm)

Not tracking along %ile line (between 2 and 8-10 yo)
Why between 2 and 8-10 years? “crossing linear percentiles of infancy”  Only about 1/3 of infants won’t cross percentiles during infancy (1/3 up, 1/3 down) o Birth size really depends on in utero factors > genetics
o o Cross %ile up = small infant of tall parents Cross %ile down = large infant of small parents

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


Not growing ≥ 2 in/yr (5 cm/yr) after 4yo
  Growth velocity higher in kids < 4yo Growth velocity ↓ until adolescent growth spurt starts

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

Interpret growth velocity in context of pubertal development
o Kids in middle of puberty should be growing faster

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

Growth curve appearance:
o o o o Start growing along %ile but then diverge further from curve in adolescence (peers growing, they’re not) Ultimately catch up (normal final height) Only really detect when kid reaches final height

Abnormal Growth Patterns: Short stature: height < 3rd %ile
       Normal variants of growth Chronic systemic disease IUGR Chromosomal abnormalities Genetic syndromes Skeletal abnormalities HORMONAL ABNORMALITIES (genetic short stature, constitutional delay of growth & development) (may be only manifestation of dz, e.g. IBD) (intrauterine growth retardation – 50% cases have poor catch-up growth) (Turner, Down) (Prader Willi, Russel-Silver) (chondrodysplasias, rickets)

Hormones involved    Stimulate growth Thyroid hormone Growth hormone Sex hormones (androgens, estrogens) Impair growth  Glucocorticoids (cortisol) – slow linear growth & stimulate appetite (↑ weight gain)


 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 (Hashimoto’s – 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!)

Growth hormone deficiency
  Pulsatile secretion, stimulated by GHRH, inhibited by somatostatin GH stimulates IGF-1 production
o o liver  circulating IGF-1 local sites too – e.g. chondrocytes (IGF-1 for bone growth)

 

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)

Lab tests for GH deficiency IGF-1 level (↓ in GH deficiency)
Sensitivity:  poor in young kids  good* in older kids Specificity: poor

IGFBP-3 (↓ in GH deficiency)
IGF-binding protein Production stimulated by GH

Provocative GH stimulation tests
Stimulate GH release with: GHRH, arginine, L-DOPA, clonidine, hypoglycemia, propanolol, exercise, sleep.

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)


Congenital Hypopituitarism

    

↓ GH especially for relevance of this talk

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)

 

Vascular disturbances (strokes) Inflammatory disease (or autoimmune)

A couple of case examples

Glucocorticoid-associated growth failure
   Growth very sensitive to exposure to excess glucocorticoids Most cases of excess in children are IATROGENIC Cushing’s syndrome is rare in peds, but does occur o would have ↑ weight with ↓ linear growth (bottom line)
o vs. obesity due to caloric excess, growth velocity is normal (or accelerated) – top line

Abnormal Growth Patterns: Accelerated Growth
Much less common complaint in pediatrics than growth failure DDx of accelerated growth:  Genetic syndromes (Marfan’s, Sotos)  Excess calories  Constitutional or genetic tall stature, early puberty, etc.  ENDOCRINE DISORDERS (this talk)


Growth Hormone Excess
   Exceedingly rare Marked by ↑ IGF-1 level Results in o abnormally tall adult stature (gigantism) if in kids o Acromegaly if onset in adulthood

Sex Hormone Excess (androgens and/or estrogens)
  Central precocious puberty (H-P-gonad axis turned on at pathologically early age) Peripheral precocious puberty (non-gonadotropen-dependent sex hormone production)

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)


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 𝟐

Has limitations (Ray Lewis = 33 kg/m2) Not good in muscular, ↑ fluid – weight needs to be fat!

In children: usually use percentiles
o o > 85 %ile for age / sex = at risk for overweight th > 95 %ile for age / sex = overweight

BMI < 18.5 18.5- 24.9 25-29.9 30-34.9 35-39.9 40

Classification Underweight Normal Overweight Class I Obesity Class II Obesity Class III Obesity

Other measures of obesity (accurate; get % body fat - mostly research)
   Measure with calipers o 7 skin fold sites or 3 skin fold sites; do calculations / sum / etc DEXA scans (dual-photon densitometry; tell lean body mass from fat) Densitometry by underwater weighing (completely submerge) o Compare wt in water, out of water o Fat-free mass is more dense than less dense; compute % body fat Densitometry by ADP (air displacement plethysmography) o put in chamber, raise pressure – compute % body fat o Limited size – not everybody can fit in! Bioelectrical Impedance Analysis o Electricity goes slower through fat than muscle! Compute % body fat o Measure resistance, reactance, etc.

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 there’s 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)


Pathophysiology of Obesity: Energy Balance
Calories in = calories out.  If intake > expenditure, you gain weight. Details unknown.
 Genetics, social / cultural issues, psychological issues, cytokines / hormones (leptin, adiponectin, etc) probably involved.

Calories in: pretty much just what you eat.  Can be measured accurately, although it’s 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.

    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?

Disruption of Energy Balance
    Genetic Environment Gene/environment interactions Other causes Probably 40-80% of variance Probably causing recent rapid rise Genetically “at risk”  respond differently to environment

Monogenic Obesity (all very to extremely rare)
     Leptin deficiency (e.g. ob/ob mouse) Leptin receptor deficiency (e.g. db/db mouse) POMC deficiency (proopiomelanocortin) PC 1/3 (prohormone convertase 1/3) Melanocortin-4 receptor (MC4R) deficiency

Polygenic Obesity
  Probably explains “susceptibility” to obesity; may have multiple variants
o Previous evolutionary advantage? “thrifty” metabolically?

Common “known” genetic variants: slight susceptibility to obesity; no treatment implications
o o Fat mass and obesity associated (FTO) gene Peroxisome proliferator-activated receptors (PPAR-γ) o o Beta-2 adrenergic receptor Perilipin

Probably many unknown variants too 62

Genetic syndromes associated with obesity
  Bardet-Biedl  Prader-Willi  Weaver Fragile X  Turner More in notes – most have other characteristics associated with them – often mental retardation

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 Cushing’s?)

The (Toxic) Environment
  Food available, abundant: cheap, high fat, calorie-dense
o Portions getting bigger (e.g. bagels get larger, soda, etc.)

↓ physical activity (labor-saving devices, community planning – don’t walk, do laundry, take stairs, etc).

Other reasons for energy imbalance
  We don’t only eat when hungry (celebrations, comfort, social gatherings – e.g. churches, ‘because it’s there’) We choose inactivity over activity (TV, computers, video games)

Iatrogenic weight gain
• • • Insulin or insulin secretagogues Glucocorticoids Psychotropic medications (e.g. olanzapine) • • • Mood stabilizers (e.g. lithium) Antidepressants (e.g. tricyclics) Anticonvulsants (e.g. valproate)

Other (Novel) risk factors for weight gain
Risk factors Fetal origins (unfavorable uterine environment) Breast feeding (protective) Environmental toxins Sleep deprivation Viral infections Notes
Low birth weight  obesity later (“programmed” to conserve energy?) 4% ↓ risk obesity with each month of breast feeding Bisphenol A, phytoestrogen-like compounds < 7-8 hrs associated with obesity Adenovirus 36? obesity in animals, ↑ prevalence in obese humans

Other causes of weight gain / obesity
• • • Really uncommonly the cause – but check if sx / hx suggestive Hypothyroidism • Insulinoma Growth hormone deficiency • Hypothalamic disorders (injury or congenital malformation) Cushing syndrome

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

Other consequences of obesity
   Discrimination (housing, employment, socially) ↓ QOL   Disability $$$ ($78.5B in 1998, ≈9% total expenditure)

Why is obesity so bad?
Fat isn’t just an inert storage tissue: adipose tissue is an endocrine organ o Adipokines (Leptin, IL-6, TNF-α, adiponectin, etc) have many effects o ↑ monocytes, lymphocytes – inflammatory state o + feedback loops set up  downward spiral

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

Balanced deficit diet
CHO (55%) Protein (15%) Total fat (< 30%) high fiber (↑ satiety) lean sources “Low fat” useful – if ↓cal too!

 try to lose 1-2 lbs / wk

3500 kcal = 1 lb

Low-carb diets (15-20 carbs / piece of bread)  Atkin’s 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 addict’s 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  It’s 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)

Lifestyle: Physical Activity
  Modestly contributes to weight loss May decrease abdominal fat   ↑ cardiorespiratory fitness May be most important in weight maintenance

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


Lifestyle: behavior modification
   Self monitoring is most effective tool (write down what you eat & when you exercise) Stimulus control, meal planning, contingency management can be used too ± Cognitive restructuring, problem-solving stress-management training

Lifestyle modification: Summary of Results
  Most studies: 5-10% initial body wt loss Without maintenance strategies, most or all weight regained by 12 mo!

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


Don’t 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)  don’t use longer than 12 weeks - ↑ risk of primary pulmonary HTN  Side effects (what you’d 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

Leptin Ciliary neurotrophic factor (rhvCNTF)

Cannabinoid-1 receptor blocker (rimonabant) – was promising but FDA didn’t 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

Lack of comprehension of (or ability to comprehend)
risks, benefits, outcomes, alternatives and/or lifestyle changes required with surgery

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