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

1
 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)  Treatable (meds ≫ surgery ≫ radiation)
 Diagnosable (often thought of as difficult)  Personalized (therapy tailored to physiology)

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

Diagnosis
 History: mostly pattern recognition (not too much pathognomonic stuff)
 Exam: test hypotheses; discovery:
o asymptomatic thyroid nodule: 5% are cancers
st
o absent Achilles tendon reflex can be 1 sign of diabetic peripheral neuropathy
 Lab testing is big: (need context – fed/fasted, time of day, etc).
 Imaging: use selectively! Make a biochemical Dx first.
 Pathology: check tumor prognosis

Disease Mechanisms
 Gland hypoplasia (developmental defect)
Congenital /
 Hormone biosynthetic defect (abnormal hormone or enzyme gene)
hereditary
 Hormone resistance (abnormal hormone receptor / signaling protein gene)

Acquired gland failure

Deficient hormone action  Physiologic atrophy: e.g. menopause / andropause
 Inflammatory (autoimmune – e.g. type I DM, infection)
Acquired  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)
Neoplasia of endocrine glands
o Think hereditary if: FHx, multiple, early onset
 Can be benign or malignant

2
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” “Primary”
Hypothalamic
Pituitary Hormone “End-hormone”
Releasing Hormone
CRH ACTH Cortisol
TRH TSH Thyroxine
GNRH LH/FSH Testosterone/Estradiol
GHRH GH IGF-1

3
 Diabetes Mellitus
Introduction / Diagnosis of Diabetes
Diabetes: need ONE of...
Fasting plasma glucose ≥ 126 mg/dL
Casual plasma glucose ≥ 200 mg/dL AND symptoms of diabetes
Oral glucose tolerance test ≥ 200 mg/dL (2 hrs post 75g oral glc load)
HbA1c ≥ 6.5%

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

Symptom Pathophysiology
1. Polydypsia Hyperosmolarity (glucose adds 5.5 mOsm/L per 100 mg/dL) + dehydration  thirst
Polydypsia  ↑ fluid intake  large urine volumes
2. Polyuria
Glucose-induced osmotic diuresis
3. Weight loss Calories lost as glucosuria  negative caloric balance, wt loss
4. Polyphagia Inefficient utilization of ingested calories & glucosuria. Insulin  ↑ appetite?
5. Blurred vision Lens stiffens (sugars – not retinopathy early!)
Others: poor wound healing, vaginitis, gingivitis, dental caries (↓ vascular flow, ↑ sugars – good for infections, etc.)

4
Endstage acute complications (FATAL IF NOT TREATED)

DIABETIC KETOACIDOSIS
metabolic acidosis; fatal if untreated
Virtually complete lack of insulin  unrestrained lipolysis  hepatic conversion to ketone bodies 
Pathogenesis
ketone bodies accumulate as organic acids  acidosis
 Kussmaul respirations  Metabolic acidosis
Diagnosis
 Hyperglycemia  + ketones in blood / urine
 Insulin
Treatment  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 
 massive osmotic dieresis, dehydration ± pre-renal azotemia (↓ renal blood flow)
Pathogenesis
 ↓ renal excretion of glucose (can’t clear large ↑ endogenous glc production)
 Vascular collapse
 PG > 1000 mg/dL
Diagnosis  Little or no acidosis or ketosis
 Osmolarity > 340
 ± insulin
Treatment  Fluids
 ± electrolytes

Long-term complications of Diabetes

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

Unifying hypothesis for complications: maybe oxidative stress?

 Activation of protein kinase C (stress response cascade)  ↑ polyol pathway activity  ↑ sorbitol, fructose
 Nonenzymatic glycation of proteins  ↑ AGEs  ↑ hexosamine pathway flux

Macrovascular Disease: accelerated atherosclerosis

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

Pathogenesis: theories / risk factors

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

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

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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

Nonproliferative Preproliferative Proliferative

 Cotton wool spots (soft exudates)

 Microaneurysms
 Beading of veins; tortuous capillaries  Neovascularization
 ↑ vascular permeability

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

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Management:

 Blood glucose, BP control

o ACEi/ARB – extra ↓ risk for kidney dz

 Dialysis / renal transplant if end-stage

Nodular glomerulosclerosis: End-stage renal disease
Kimmelstiel-Wilson disease Fibrosis, inflammation,
sclerosis, arterial thickening

Microvascular disease: diabetic neuropathies

Peripheral symmetrical polyneuropathy Autonomic neuropathy Mononeuropathy
 Distal, stocking-glove 
 Erectile dysfunction (most common)
progresses proximally
 Enteropathy (constipation /
 Symmetrical Peripheral or cranial
diarrhea), gastroparesis
 Numbness, tingling, dysaesthesias  Single nerve pain / palsy
 Orthostatic HTN
 Rapid onset, resolves over wks / mo
 Cardiac: can have painless
Management: glycemic control, symptomatic
myocardial ischemia (dangerous!)
relief (eg. gabapentin), preventative foot care

Pathogenesis: metabolic Schwann cell defect Pathogenesis: probably similar to

Pathogenesis: ischemic
(↑ sorbitol and/or ↓ myoinositol); peripheral neuropathy, but affecting
(“microinfarcts” of the nerve)?
1° axonal degeneration (unclear etiology) autonomic nerves

Pictures: neuopathies

Interosseal muscle wasting (diabetic Neuropathic ulcers (diabetic

CN III palsy (diabetic mononeuropathy)
peripheral symmetrical polyneuropathy) peripheral symmetrical polyneuropathy)

“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)

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 “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 Anti-islet-cell
o Anti-GAD (glutamic acid decarboxylase)
o Anti-insulin
 Lymphocytic infiltration of pancreas on path (“insulitis”)
Associated with other autoimmune dz
o Vitiligo o Addison’s disease
o UC o Rheumatoid arthritis
o Hypothyroidism
 Associated with certain MHC alleles (↑ or ↓ risk)

Triggers: lots of hypotheses, not well proven

 Viral induction  β cells express HLA antigen?  Molecular mimicry?
 1° islet inflammation (TNFα, cytokines)  immune response?  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)

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Treatment:
 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

Pathophysiology
 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!

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Clinical Characteristics
 Onset usually > 35 yo (not always: current epidemic of childhood type 2 DM in overweight youth)
 FHx usually positive! (stronger heritability than type 1 DM)
 Usually (80%) associated with obesity
 Endogenous insulin reserve present; often have HYPERINSULINEMIA
 Can treat with diet / exercise alone or ± oral insulin agents ± exogenous insulin
 Relatively stable metabolic state (not prone to wide swings)

Genetics
 Active field – esp. with genome-wide screens (≈ 10 genes associated, strongest is TCF7L2 but still only ↑ risk 50%)
 Other associations will be found: probably polygenic + environmental
Type 1 vs Type 2 Diabetes Mellitus
Type 1 Type 2
Formerly known as IDDM, Juvenile Onset NIDDM, Adult Onset
Without Insulin Rx Ketoacidosis, death Usually, no ketosis
Age of Onset Usually <35 Usually >35
Obesity Unusual Common
Family History Usually Negative Usually Positive
HLA Association Yes No
Endogenous Insulin Usually Absent Usually Present
Insulin Resistance Usually Absent Usually Present
Metabolic Course Labile Usually Stable
Response to Pills No Yes
Etiology Autoimmune Non-Autoimmune

Other Types of Diabetes

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

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!)
Summary
Insufficient insulin causes dysmetabolism
 Absolute insulin deficiency in type 1
 Relative insulin deficiency + peripheral insulin resistance in type 2
Acute complications of diabetes are directly and immediately due to hyperglycemia
Long term complications of diabetes are due to years/decades of dysmetabolism
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 Carbohydrate Metabolism & Hypoglycemia
Overview of Carbohydrate Metabolism
Rise in blood glucose (after CHO containing meal) Fall in blood glucose (between meals, overnight)
Stimulates insulin secretion, which causes… Suppresses insulin secretion, which causes…

 Utilization of circulating glucose as energy substrate  ↑ hepatic glucose output

(↑ glycolysis) (↑ glycogenolysis / gluconeogenesis)
 Suppression of new glucose formation  ↑ Lipolysis
(↓ gluconeogenesis (make FFA available for oxidation as energy substrate)
 Storage of excess circulating nutrients in storage forms  ↑ Proteolysis
o FFA  adipose tissue TG (provides AA substrate for low-level of gluconeogenesis
o AA  protein needed for obligate glucose-dependent organs: brain,
o Glucose  liver / muscle glycogen 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 Adipose Muscle

High Insulin Glycolysis (use of ingested glucose)
Lipogenesis (lipid storage) Protein Synthesis (protein storage)
(Anabolic) Glycogenesis (carb storage)
Low Insulin Gluconeogenesis
Lipolysis (FFA release) Proteolysis (AA release)
(Catabolic) Glycogenolysis (glucose release)

Three States of Metabolism

Timing Metabolic changes

↑ insulin secretion
for ≈ 3 hrs after eating  Dietary CHO enters cells  main food source
Post-prandial
(“fed state”, “absorptive”)  FA synthesis  FAs stored in adipose tissue
 Glycogen synthesis  excess CHO stored in liver, muscle

↓ insulin, ↑ glucagon
 Glycogenolysis, hepatic gluconeogenesis (support blood
4-24 hrs after eating
Post-absorptive glucose without dietary CHO around)
(“overnight fast”)
 Lipolysis activated (freeing FA from adipose tissue)
 Fatty acids become main source for glucose fuel

↓↓↓ insulin and ↓ glucagon

 Hepatic glycogen largely used up
Prolonged fast* > 24 hrs after eating
 ↓ glucagon  ↓ gluconeogenesis
 Lipolysis takes over, lipid becomes main fuel source
* 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!

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 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)

Hypoglycemia

Documented Low Plasma Glucose Whipple’s Triad

Lower limits of normal: (a working definition of hypoglycemia)
 12-16h fast: ≈ 60 mg/dL  Documented low plasma glucose
 Prolonged fast: as low as 30-50 mg/dL  And symptoms of hypoglycemia
 And response to CHO administration
Symptoms of Hypoglycemia

Adrenergic (fight or flight) – see above Neuroglucopenic

 Diaphoresis  Confusion
 Hunger  Emotional lability
 Tremor  Slurred speech Neuro signs: from focal
 Palpitations  Headache
 Blurred vision  Somnolence seizure to psych
 Anxiety  Pupilary dilation
 Weakness  Coma
Due to ↑ counter-regulatory hormones trying to bring blood
Not enough glucose for brain metabolism!
glucose back up (epi, norepi, etc!)

Disturbing but not as dangerous (mild/moderate hypoglycemia) VERY DANGEROUS – SEVERE HYPOGLYCEMIA – TREAT‼

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 Post-prandial (“reactive”) hypoglycemia

 Occurs post-absorptively (> 10hrs after a meal)  Occurs after absorptive phase (≈ 2-4h after meal)
 Unusual and definitely abnormal  Thought to be common
o Requires an explanation! o not often due to a defined disease
 Must be documented by plasma glucose + objective symptomatology  Hard to document

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Fasting hypoglycemia: partial DDx

 Diabetes treatment (certain oral agents or insulin)

Excess exogenous insulin
 Factitious / foul play

 Insulinoma (insulin-secreting pancreatic adenoma) – see below

Excess endogenous insulin  Sulfonylurea ingestion (diabetes treatment or factitious)
 Nesidioblastosis (islet cell hyperplasia in newborns)
 fulminant hepatic failure
 alcoholic hypoglycemia
Hepatic disease
 CHF
Defective gluconeogenesis
 Glycogen storage diseases*
 Cachexia
Defective gluconeogenic substrate
 Uremia
 Adrenal insufficiency
Counterregulatory  Hypopituitarism
hormone deficiency  Glucagon deficiency
 Growth hormone deficiency
Unusual – if using tons of glucose, for instance
Extrapancreatic tumors  Fibrosarcomas / fibromas (↑ glucose consumption)
 Hepatomas (can make insulin-like factor)
*GSD are rare; at least 10 forms known, most present with fasting hypoglycemia in children

Insulinoma:
 Diagnosis:
o Symptomatic fasting hypoglycemia (abnormal to develop Sx, even during prolonged fast!)
o Inappropriate hyperinsuilinism (may be subtle), or
o 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 Maybe mild hypoglycemia  feel sx  counterregulation brings glucose back
o Maybe too high / late of an insulin spike?
o Is it a disease? Does it cause symptoms? Malingering? Controversial.

Rare specific sensitivities (usually pediatric diagnoses)

 Leucine sensitivity
 Hereditary fructose intolerance
 Glactosemia

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 Dietary Management of Diabetes & Hyperlipidemia
Goals of diabetes management
Targets
1. Try to get blood glucose in normal range (as close as possible)
Pre-prandial 80-120 mg/dL

Glycemic
2. Lipid / lipoprotein profile that ↓ risk macrovascular disease
o DM is a cardiovascular risk equivalent (= previous MI) Post-prandial (2h) < 180 mg/dL
3. Blood pressure that reduces risk of vascular disease Bedtime 100-140 mg/dL
HbA1c 7%
Other goals LDL Cholesterol < 100 (<70?) mg/dL
 Prevent/treat chronic complications Blood Pressure < 130 / 80
o (obesity, dyslipidemia, CVD, HTN, nephropathy)
 Encourage healthy food choices (keep pleasure of eating – only limit if good scientific evidence)
 Address individual / cultural needs

Carbohydrates
 Sugars (↑ blood sugar acutely)
 Starches (later & longer-lasting)
 Fiber (don’t raise sugars like other complex CHOs – really good!)

Monosaccharides Glucose, galactose, fructose

Simple CHOs
Disaccharides Sucrose (table sugar), lactose
(1-2 molecules)
Polyols (sugar alcohols) Have alcohol moiety: sorbitol, mannitol, etc.
Malto-oligosaccharides (maltodextrins)
Oligosaccharides (3-9 molecules)
Complex CHOs Others: raffinose, stachyose, fructo-oligosaccharides
(3+ molecules) Starch: amylose, amylpectin
Polysaccharides (> 9 molecules)
Fiber: cellulose, hemicelluloses, pectins, hydrocolloids
Note: not just “sugar”!

Recommendations:
 CHO and monounsaturated fat should be 60-70% of energy intake
 Get it from whole grains (dietary fiber), fruits, vegetables, low-fat milk
 Total amount more important than source / type for diabetics
 Use other CHO sources instead of sucrose-containing foods (to help loose weight)
 Non-nutritive sweeteners: 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

Proteins
 Should be 15-20% daily energy (no restriction if normal renal function)
 Does not increase plasma glucose in type 2 DM but can ↑ serum insulin response
 Protein requirements may be greater than RDA in pts with uncontrolled diabetes
o From ↑ protein turnover; worry about protein malnutrition in developing world

High protein low CHO diets: Atkins, South Beach

 Long-term effects unknown: LDL cholesterol / wt loss maintenance?
 Short-term results: do get weight loss & improved glycemia
 Better to have a sustained lifestyle change (these are hard to maintain)

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Fats
Polyunsaturated fatty acids (Ω-3)
Monounsaturated fatty acids
Saturated fatty acids
* cis forms are “healthy” form of monounsaturated fats – trans-fats ↑ CVD risk
Linoleic acid, α-linoleic acid Vegetable / plant oils
Eicosapentoic acid (EPA)
Fish, plankton
Docosohexanoic acid (DHA)
Oleic acid (cis-form)* Plant/nut oils, nuts
Elaidic acid (trans-form)* Margarine, hydrogenated oils
Lauric acid, myristic acids, palmitic Red meat, poultry, dairy products,
acids, stearic acids processed grains

Type of fat Total cholesterol LDL HDL Triglycerides

Saturated    
Monounsaturated  
Transunsaturated 
Polyunsaturated 
N-3 fatty acids 
Plant sterols*  
* corn, soy, vegetable / plant oils

 Saturated fat just does pretty much everything bad  Polyunsaturated fats help lower LDL a little
 Monounsaturated fats (here cis) help lower LDLs  Fish oils (omega-3) lowers TGs
 Trans-unsaturated fats raise LDLs  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 Lifestyle changes
 education (food labels)
 drop 500-1000 calories vs maintenance  reduce fat (< 40% daily energy)
 shoot for 5-7% weight loss to start (manageable)  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

Hypertension
HTN + diabetes:
 ↑ risk of CVD (coronary heart disease, stroke, peripheral vascular disease),
 ↑ risk of other vascular complications (nephropathy / ESRD, retinopathy)
Systolic Diastolic Action
OK < 130 <80 At goal for diabetic patient
Prehypertension 130-139 80-89 Behavior therapy alone (3mo) then add pharm therapy
Hypertension ≥ 140 ≥90 Behavior therapy + pharm therapy
15
Behavior modification
 ↓ sodium (2300 mg/day, or 6000 mg sodium chloride)
o Can use salt substitute (replace half of Na with K) – careful in chronic renal failure / on diuretics
o High salt: smoked meat / fish / hot dogs, lunch meats / canned soups, frozen foods, cheese, processed snacks,
condiments (mustard, relish, pickles, soy sauce, ketchup)
o If sodium per serving size is more than 10% of RDA, don’t buy it!
 ↑ potassium, magnesium, calcium (DASH diet: fruits/veggies @ 5-9 / day, low-fat dairy @ 2-4 / day)
 Modest weight loss
 Exercise

Dyslipidemia
Goal: Lower LDL-chol (prevent CVD)
 Limit saturated fat & transunsaturated fatty acids to < 7% energy intake
o If weight loss not desired, replace with CHO or monounsaturated fat
 ↑ 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)

16
 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 can get thyroglossal duct cysts or other remnants of thyroid Lingual thyroid (ectopic thyroid
down front of neck, duct anywhere along the pathway (pics) gland) – mass in back of mouth
ends up at base (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 All are glycoprotein hormones made by pituitary (except hCG – from placenta)
o 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!

17
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: two diiodotyrosines  thyroxine (T4)

 T3 can also form: 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

18
What happens when TBG levels change?

TBG excess TBG deficit

(e.g. pregnancy: estrogen  ↑ TBG) (cirrhosis, etc)

TBG sucks up free T4 (↓ at first); but then pituitary senses ↓ TBG excess  more free T4  downregulate TSH, T4
free T4 and secretes more TSH  ↑ T4, sucked up by TBG
End result: SAME FREE T4, MORE TOTAL T4 End result: SAME FREE T4, LESS TOTAL T4
Remember free T4 is what can enter cells – free T4 sensed, free T4 ( T3) has biological effect

T4  T3 in peripheral tissues
 E.g. liver, muscle  1,5’ deiodinase removes one of the iodines
o “Selenoproteins” – enzyme has selenium atom inside

 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)

19
Thyroid hormone receptor family
 Nuclear receptor superfamily
 Constitutively bound to chromatin
 Involved in DNA binding / transcription
o to upregulate / downregulate gene expression
o E.g. ↓ TSH, ↑ hepatic proteins
o 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 ↑ TSH ↑ T4/T3 ↓ TSH ↓ T4/T3 ↓ TSH

Thyroid smaller, so ↓ T4/T3, Thyroid bigger, so ↑ T4/T3, Thyroid normal, pituitary messed up , so
pituitary upregulates TSH pituitary downregs TSH ↓ 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

20
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  Heat intolerance, ↑ perspiration
 Menstrual disturbances, gynecomastia  Weight loss, ↑ appetite, diarrhea
 Tremor  Weakness

Signs:
 Eyelid retraction (Graves’ disease  proptosis)  ↑ reflexes
 Warm, moist (diaphoretic), smooth skin  Osteopenia, hypercalcemia, hypercalcuria
 Tremor  Onycholysis (nails separates from nailbed, get
 Goiter dirt under)
 Tachycardia, arrhythmias, A-fib, SBP ↑, DBP ↓

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 No findings
o Only stare
o Swelling
o Proptosis
o EOM dysfunction (inf. rectus is #1 – can’t look up)
o Corneal involvement
o 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 Against TSH receptor but stimulate growth / function
o 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 only see in autoimmune thyroid disease;
o 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 Radioiodine Surgery
 High cure rate
 Non-ablative  > 90% cure rate, 100% hypothyroidism
 Serious complications
 Side-effects: 5-20%  Simple, most cost-effective, few side effects
 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)

Hypothyroidism
Systemic syndrome characterized by deficiency of thyroid hormone (or, rarely, intrinsic resistance to its effects)

Primary hypothyroidism Secondary (central) hypothyroidism

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

Symptoms of hypothyroidism
 Fatigue, lethargy, sleepiness  Slight weight gain, ↓
 Mental impairment, depression, dementia appetite
 Menstrual disturbances (esp menorrhagia)  Constipation
 Cold intolerance  Arthralgias
 Dry skin, ↓ perspiration  Paresthesias

Signs of hypothyroidism
 Goiter  ↓ body hair
 Slow speech, hoarseness  Dyspnea, hypoventilation,
 Cool, dry skin sleep apnea
 ↓, slow reflexes  Multifactorial anemia
 Bradycardia, pericardial effusion  Hypoosmolar state (hypoNa)

23
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 congenital absence of thyroid / enzyme defect
o postablative (RAI / surgery)
o 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: ↓ (but be careful of binding protein abnormalities)
 Free serum T4: ↓
 Serum T3: ↓ or nL
 TSH: ↑ (unless central)
 RadioI uptake: 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

24
 Thyroiditis
Subacute thyroiditis
 Self-limited, nonsuppurative inflammation of the thyroid
o Infectious disease, often preceded by viral illness
 Systemic symptoms: malaise, fever, ↑↑↑ ESR
 Big, really painful thyroid(see pic to right)
 Mild hyperthyroidism followed by mild hypothyroidism; usually complete recovery

Painless / postpartum / lymphocytic thyroiditis

 Transient hyperthyroidism (2-3mo) followed by transient hypothyroidism (2-3 mo)
o May be recurrent, hypothyroidism may be permanent (20%)
 Often in postpartum women (5% post-partum women, ↑ with DM type 1)
o Can also get Graves’, transient / permanent hypothyroidism post-partum

 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 Examples
can make too much thyroid hormone  Graves’ disease
 (overactive thyroid, hyperthyroidism)  Toxic nodular goiter
 Chronic lymphocytic thyroiditis
can make too little thyroid hormone
 Ablation of thyroid with radioiodine
 (underactive thyroid, hypothyroidism)
 Surgery
 Subacute thyroiditis
can become inflamed
 Postpartum thyroiditis
can become enlarged (goiter) or develop one or more lumps (nodules)

25
 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

26
Lesions: radiographic appearance

Microadenoma: Small macroadenoma:

Macroadenoma: has pushed normal
Hypodense lesion(arrow). ≈4cm hypodense lesion, see deviation of
pituitary to top of sella turcica
(pituitary 9 cm tall) pituitary stalk (S), displacing pituitary

Macroadenoma: has eroded bony floor of

Huge macroadenoma: invaded cavernous Massive pituitary tumor, occupying entire
sella turcica  sphenoid sinus; grown up
sinuses on both sides; also invading sphenoid sinus, obliterating sella tucica,
through top of sella  compressing optic
temporal lobe necrosis  cyst formation
chiasm, touching hypothalamus!

Clinical Manifestations of Pituitary Lesions growing in Sella Turcica

HPI should have three main focuses:
Hypopituitarism Neurological defects Hypersecretion
First “innocent bystander” for growth – When tumor  macroadenoma
lesion can grow, compress, destroy cell population.  Compresses optic chiasm, other Tumor can start secreting!
 ↓ TSH / LSH /FSH  ↓ peripheral hormone levels adjacent structures

Hypopituitarism
Gonadotrophin deficiency
TSH deficiency ACTH deficiency GH deficiency
Women Men
 ↑ fat, ↓ lean body mass
 Fatigue  Weakness  ↓ exercise capacity,
 Amenorrhea  Infertility
 Cold intolerance  Orthostasis performance
 Infertility  ↓ libido / impotency
 Dry skin  Dizziness  ↓ muscle strength
 ↓ 2° sex  Small testes (no FSH)
 Constipation  Pallor  ↓ HDL chol,
characteristics  ↓ 2° sex characteristics  Weight gain  Hypoglycemia  ↓ 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: Failure of R. eye abduction;

L cavernous sinus invasion (L CN 6) 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  Hypogonadism  Adrenal dysfunction
 Visual abnormalities  Hypothyroidism  Secretory syndrome

Secretory Adenomas
Prolactinoma Population: women with % with prolactinoma
 #1 for secretory pituitary adenomas Amenorrhea 20%
Galactorrhea 30%
Clinical manifestations: either biochemical or mechanical Infertility 35%
Galactorrhea + oligoamenorrhea 70-75%
Mechanical origin: physical effects (as discussed above):
↓ gonadatroph function, visual field defects, CN palsies, H/A

Biochemical origin: due to ↑ prolactin level

 infertility  ↓ libido  dyspareunia
 abnormal menstrual cycles  osteopenia 2° to associated estrogen insufficiency  impotence
 galactorrhea  ↓ gonadotroph function  gynecomastia

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)
 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)
o Primary hypothyroidism, polycystic ovary, renal failure can ↑ prolactin
o Drugs: dopamine receptor blockers, catecholamine depletors
o 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
o coarsening of facial features
o soft tissues grow (tip of nose, etc)
o 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

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 Normal patients: growth hormone ↓ after a meal
o 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

Craniopharyngioma
Squamous epithelial tumor arising from stalk (or hypothalamus, or 3rd ventricle)
 Has solid & cystic components
 Peak incidence in childhood
 Significant headaches  panhypopituitarism; also diabetes insipidus
 Surgical excision if small; destructive when they get large
 Recurrence: try surgery again, ± radiation

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 “worst headache of my life” – usually misdiagnosed as subarachnoid hemorrhage, meningitis
o Visual loss, diplopia, ptosis too (expansion of blood)
o Meningismus sx from necrotic tissue exploding into CSF
 Panhypopituitarism (hemorrhage)  acute cortisol deficiency (can be life threatening!)

30
 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

Secondary…
Hypothyroidism
Sex hormone deficiency
Glucocorticoid deficiency
Treatment of Hypopituitarism
Cause Treatment
 can’t rely on TSH like in 1° (TSH messed up!)
↓ TSH
 need to rely only on free T4 & symptoms
 Testosterone (patch, gel, injections)
↓ GRH
 estrogen / progesterone (OCP)
 Prednisone / dexamethasone (potencies different; all replace glucocorticoids)
 Maintenance dose + extra dose for stress
↓ ACTH o Extra maintenance if just a little sick
o 10x dose if severe illness, surgery, etc
o 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 NOT from tumor – can actually remove part of posterior lobe and not have DI (axons run above)
o Can if lesion is in upper stalk or higher (larger lesions or lesions higher up in stalk)

31
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 • Metastatic tumor
• Head trauma (#2) • Infiltrative disorder (e.g. sarcoid)
• Idiopathic (#3) • Aneurysm
• CNS tumor (e.g. craniopharyngioma) • 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.

32
 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 ↓  Intra-abdominal fat ↑  Bone mass ↓

o Strength ↓ o Glucose intolerance o Fracture risk ↑
o Balance ↓ o Hyperlipidemia
o Hypertension  Exercise capacity ↓
o Diabetes  Cognitive skills ↓
o CVD
 Sexual desire / function ↓

From graphs:

↓ muscle strength

Body composition:
 ↓ muscle
 ↑ fat

Hormones that Decline with Age

Hormone Name
 Normally if ↓ GH, give GH
Estrogen, progesterone Menopause
 Open question: should these declining Growth hormone Somatopause
hormones be prescribed for healthy elderly pts? DHEA Adrenopause
Testosterone Andropause, “male climacteric”
Estrogen & Progesterone Replacement
Benefits of replacement Risks of replacement
 ↓ menopausal vasoactive Sx  ↑ risk of breast cancer (long-term)
 Slow bone loss  ↑ uterine cancer with unopposed estrogen
 ↓ risk CAD (?)  ↑ 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?

33
 GH replacement in healthy elderly
Effects of GH deficiency
Effects Potential Risks
 ↓ muscle mass  Joint pain
 ↑ lean body mass (good)
 ↑ intra-abdominal fat  Carpal tunnel
 ↓ total body, abdominal fat
 ↓ bone mass  Fluid retention
 ↑ fracture risk  HTN
 NO CHANGE in FUNCTIONAL STATUS
 ↑ SBP  Diabetes
 Total / HDL chol = inconsistent
 Hyperlipidemia  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)

Testosterone
↑ age  slow ↓ testosterone, ↓ male sexual function: But no evidence that those two things are related or causal

Risks of testosterone replacement: ↑ BPH, worse prostate cancer, sleep apnea, ↑ Hct, ↓ HDL-chol, Sleep apnea

Take-home: 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 Addison’s disease, Congenital Adrenal Hyperplasia
Glutocorticoid excess Cushing’s syndrome
Mineralocorticoid excess Hyperaldosteronism
Catecholamine excess Pheochromocytoma
Multiple Endocrine Neoplasia syndromes
Normal Embryology, Anatomy, & Physiology
Embryology
Adrenal cortex / medulla are functionally separate organs
 Cortex: mesynchemal origin; invaded by neural crest cells (2 mo gestation)
 Medulla: NCC  chromaffin cells (secrete catecholamines) under ↑ local *glucocorticoid+

Anatomy
Note that :
 Cortex / medulla have separate arterial supplies
 Medulla exposed to cortical venous effluent

 Right adrenal drains directly into IVC

 Left adrenal drains into left renal vein

Nerve supply:
 Cortex: efferent symps / parasymps regulate blood flow
 Medulla: symps  catecholamine release

Histology & Function: out in = salt  sugar  sex  violence

Zona glomerulosa Aldosterone “salt”
Cortex Zona fasiculata Glucocorticoids “sugar”
Zona reticularis Androgens “sex”
Medulla Catecholamines “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) Effect in chronic cortisol excess (Cushing’s Syndrome)

↑ appetite, gut absorption
↑ hepatic gluconeogenesis
protein wasting, skeletal myopathy
 (substrates from glycogen, protein, lipid)
↓ peripheral glucose uptake: insulin resistance
insulin-resistant diabetes mellitus
 (↓ glucose transporter function)
Activates lipolysis
body fat redistribution (trunk, mesentery, mediastinum)
 (abdominal fat retained, peripheral fat eliminated)

Immune function
Goal: limit inflammatory response to infection – a “check” to keep immune system from getting out of control

Lymphyocytes Granulocytes Other

 Redistribute T & B cells (away from circulation)  Redistribute to circulation   ↓ Eos, Mϕ, monocytes
 T cell apoptosis granulocytosis  ↓ histamine, prostaglandin, TNF
 T / B cell, NK function inhibited  ↓ Chemotaxis, phagocytosis  ↓ 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:
o cortisol (principal glucocorticoid)
o aldosterone (mineralocorticoid)
o DHEAS / androstenedione (weak androgens)
 ↑ steroid hormone biosynthesis (↑cholesterol  pregenolone conversion – rate limiting step, + other steps)
 ↑ 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 High levels of ACTH
primary stimulus for mineralocorticoid synthesis & secretion 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

37
 Adrenocortical Insufficiency

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

Symptoms Signs
 Weakness  Abdominal pain  Weight loss  Dehydration*
 Sleepiness / fatigue  Postural light-headedness*  Hyperpigmentation*  Loss of pubic / axillary hair
 Anorexia  Salt craving  Hypotension*
 Nausea / vomiting
* 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)
38
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*  ↑ BUN/Creatinine*  Eosinophilia
 HyperKa*  HyperCa (rare)  Lymphocytosis
 Hypoglycemia  Anemia
*mostly primary (vs secondary)

Etiologies of primary adrenal insufficiency

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

Etiologies of secondary adrenal insufficiency

 STEROID HORMONE WITHDRAWAL (#1 most common)
o After glucocorticoid treatment > 2/3 wks, therapy should be tapered down
o HPA axis needs to recover: have been suppressing higher levels (ACTH, CRH)
o 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 Salt-losing form

Partial block of enzymatic activity (e.g. heterozygote) Complete block of enzymes (e.g. homozygote)
 Common cause of hirsuitism & irregular menses  Life-threatening cortisol & aldosterone deficiency
 Only apparent in females  Defect present at birth
 Mild excess of testosterone & androstenedione  Androgen excess in females

Hypercortisolism (Cushing’s Syndrome)

Cushing’s Syndrome Cushing’s Disease

Generic hypercortisolism regardless of cause Hypercortisolism from an ACTH-secreting pituitary tumor

Clinical Manifestations of Hypercortisolism

System Manifestations
General truncal obesity with peripheral wasting, moon facies, cervicodorsal fat
Skin cutaneous atrophy, abdominal striae (purplish, not silvery like post-pregnancy), acne
Cardiovascular hypertension, edema, cardiomyopathy (rare)
Muscle proximal myopathy (often severe)
Bone osteoporosis, aseptic hip necrosis
Reproductive amenorrhea, hirsuitism, virulization
Metabolic insulin resistant DM, hyperlipidemia
Immune broad immunodeficiency, esp T-cell
Psychiatric 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

40
Etiologies of Hypercortisolism
 Cushing’s disease: pituitary ACTH-secreting tumor
 Ectopic:
ACTH-dependent
o small cell lung cancer
o Carcinoid, medullary thyroid, pheochromocytoma
 Exogenous glucocorticoid treatment (#1 – iatrogenic)
ACTH-independent
 Adrenal adenoma or carcinoma
 Mostly in severe alcoholics (can resolve if stop EtOH)
Pseudo-Cushing’s
 Also possible in major depression  can get central activation of axis

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
Method:
(24h: integrates circadian variation)
Cushing’s syndrome: ↑↑ (3x nL)
Results: Milder elevations: Cushing’s, pseudo-Cushing’s, or
stress (repeat test)
Comments: INITIAL STUDY OF CHOICE

Midnight Salivary Cortisol

Method: Get saliva sample at midnight (≈ plasma free cortisol
Normal: should be really low (lowest circadian level)
Results:
Cushing’s: inappropriately “normal” or “high”
Comments: Alternative initial study

CONFIRMING HYPERCORTISOLISM
LOW-DOSE dexamethasone suppression test
Give dexamethasone 0.5mg po q6h x 2d
Method:
Collect plasma cortisol
Normal: should suppress plasma cortisol (< 1.8mcg/dL)
Results:
Cushing’s: have impaired feedback suppression by low doses of exogenous corticosteroid (> 1.8 mcg/dL)
Comments: Doesn’t distinguish Cushing’s disease vs other causes of hypercortisolism

41
 BIOCHEMICAL LOCALIZATION
Plasma ACTH
Method: Collect ACTH from plasma

Low ACTH (<5 pg/mL) and ↑ cortisol:

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

If massive elevations, likely ectopic ACTH

Comments:
If elevations modest, need more testing

HIGH-DOSE dexamethasone suppression test

Dexamethasone 2mg po q6h x 2d or 8mg overnight
Method:
Collect plasma cortisol or 24h UFC
Pituitary Cushing’s disease: most cases suppress > 90%
Results:
Ectopic ACTH / adrenal tumors: rarely suppress > 90%

Pituitary tumors often retain partial feedback suppression;

Comments: 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.
Method:
Give CRH, then measure ACTH from drainage & periphery
Calculate central:peripheral ACTH gradient
Results:  Pituitary tumors: gradient >3 (often >10)
 Ectopic ACTH: no central:peripheral ACTH gradient

GOLD STANDARD for localizing ACTH-DEPENDENT CUSHING’S

Comments:
Specialized, not available in all hospitals

After these steps:

 Radiography: MRI of pituitary, occasionally chest/abdomen
Summary of Glucocorticoid Function Tests
Useful in…
Test
Glucocorticoid insufficiency Glucocorticoid excess
24 hour urinary free cortisol 
Midnight salivary cortisol 
Basal
Basal plasma ACTH  
Basal plasma cortisol Potentially misleading
Low dose dexamethasone suppression 
Suppression
High dose dexamethasone suppression 
ACTH stimulation (of adrenal) 
Stimulation CRH stimulation (of pituitary) 
Metyrapone stimulation (of hypo/pituitary) 

42
Treatment of hypercortisolism
Etiology Treatment options
 Trans-sphenoidal pituitary surgery
Cushing’s disease
 Post-operative pituitary irradiation
Adrenal tumors Adrenal surgery
Ectopic ACTH Surgery (if possible)
 Cortisol synthesis inhibitors (ketoconazole, metyrapone, mitotane)
Refractory / inoperable disease
 Rarely: bilateral adrenalectomy

Hyperaldosteronism
Endocrine causes of hypertension: Cushing’s syndrome, Hyperaldosteronism, or pheochromocytoma
Clinical features:
 hypoK: urinary potassium wasting
 hyperNa: suppressed plasma renin (in 1° hyperaldosteronism)
Etiologies
 due to adrenal cause (adenoma / hyperplasia), or idiopathic
Primary  Diuretics, CHF, renal artery stenosis

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

Diagnostic evaluation
1. Identify primary vs. secondary hyeraldosteronism
a. After repletion of Na / K, check plasma renin / aldosterone
b. If ↓ renin and ↑ aldosterone, think primary
c. 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
Treatment
 Adenoma: surgery
 Idiopathic: aldosterone receptor inhibitors (spironolactone . eplerenone)

43
 Pheochromocytomas
Rare catecholamine-producing tumor of medulla
 ≈10% extra-adrenal (paragangliomas)
 20% familial, 20% malignant
 NEED TO DX (can provoke life-threatening hypertensive crisis)

 The metabolites (metanephrines / VMA) are more stable (good for diagnostic measurement)

Clinical manifestations
 More frequently paroxysmal than static (come in waves – minutes to hours)
 Usually spontaneous; occasionally in response to abdominal manipulations / strenuous exertion
o not in response to emotional distress like anxiety
 Can resemble hypoglycemia (activation of sympathetic pathways)

Symptoms / signs
 Headache  Nausea  Chest pain  Light-headedness
 Diaphoresis  Tremor  Dyspnea  HTN (often severe)
 Palpitation  Nervousness  Pallor > flushing (vasoconstriction)

Locations of pheochromocytomas
Solitary adrenal Bilateral adrenal Extra-adrenal Malignant
80% 10% 10% 15-20%

Hereditary disease associations

Multiple Endocrine Neoplasia Type 2 (Medullary thyroid cancer, pheo, hyperparathyroidism)
Von-Hippel Lindau Disease (VHL) (CNS and retinal hemangiomas, renal carcinoma, pheo, paraganglioma)
Neurofibromatosis (NF-1) (Café au lait spots,cutaneous neurofibromas, pheo)
Succinate Dehydrogenase B and D (Paraganglioma and pheo)
SUSPECT if tumors are EARLY ONSET, BILATERAL, OR EXTRA-ADRENAL‼

Diagnosis
 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

44
Anatomic localization: with CT/MRI, 123I-MIBG, FDG-PET

Treatment
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 others have similar indications for surgery,
o 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

45
 Gender Development
Introduction
Original theories of gender development: learning influenced psychosexual development
Current model: androgen exposure, genes on Y chromosome
Novel predictors: parent attitudes may play a role
Importance of studying: influences how we understand sex and gender

Definitions
 Gender Identity (GI): f
 Gender role (GR):
 Sexual orientation:
 DSD:
undamental sense of belonging to one sex
behavior designated as masculine or feminine
attraction to sexual partners
disorders of sexual development
o (sensitive to patients: replace intersex, pseudohermaphrodites, sex reversal, etc)

Embryology

Sex ducts: all embryos start out with ‘em; may or may not continue

 Mullerian ducts  internal female reproductive structures

(upper vagina, cervix, uterus, etc.)

 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
(embryo won’t have female internal reproductive structures)
Promotes Wolffian duct development
Testosterone androgen
(embryo will have male internal reproductive structures)
DHT (dihydrotestosterone) Promotes masculinization of external genital structures
more potent androgen
(5-α reductase: T  DHT) (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
(embryo will have female internal reproductive structures)
Wolffian ducts regress
No Testosterone
(embryo won’t have male internal reproductive structures)
No masculinization of external genital structures
No DHT (dihydrotestosterone)
(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?

46
 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 Easier to pick up in genetic females
o Genetic males – harder (supposed to look like this!) – often die
o 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)

47
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?
Result
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

Clinical presentation: no menses, no pubic hair, normal breasts

 Has lots of T  can convert to estrogen with aromatase (breast development)

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

Hypothesis:
 Maybe parents of children with life-threatening DSD at greatest risk for stress, overprotection, perceived child vulnerability
 Maybe parents reading children discordant with genetic sex at greatest risk for stress, overprotection, etc.
 Maybe parents of children with ambiguous genitalia at greatest risk for stress/overprotection / perceived child vulnerability

Turns out that ambiguous genitalia and raising girls will ↑ parental stress

49
 Puberty
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 From… Effects

Androgens Adrenals Sexual hair (M/F)
Virilization if ↑↑
Estrogen Ovary Breast development (F)
Testosterone Testes 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 GnRH pulses are very synchronized to subsequent LH pulses
o If GnRH↓, LH↓

 GnRH & FSH: “it’s complicated”

o FSH is also coupled to GnRH but not as tightly

50
Theca cells
 LH hits GCPR  AC  ↑ cAMP  ↑ androgen synthesis Leydig cells
 ↑ androstendione  steroid  crosses to follicular cells  LH hits GCPR  ↑ AC  ↑ cAMP 
 ↑ production of testosterone
Follicular cells
 FSH hits GCPR  ↑ AC  ↑ cAMP → ↑ conversion of (FSH acts on Sertoli cells to promote somatogenesis)
o Testosterone to estradiol (aromatase)  Not involved in steroid production
o Androstenedione (from theca cells) to estrone

Normal Maturation of the Reproductive Axis

Fetal development
Gonad*
Hypothalamus Pituitary
Male Female
 Testes develop
GnRH neurons
↑ LH, ↑ FSH (if testes-determining factors around)  Ovary develops, E2 secreted in
migrate down
 Testosterone secretion starts (1st trimester);
nd
(2nd trimester) 2 trimester
(1st trimester)
increases to mid-pubertal levels at birth!
Note: gonadal development is separate from pituitary / hypothalamic development – NO GnrRH / LH / FSH NEEDED!

Infancy
Pulsatile secretion of GnRH at delivery!
T production in males (peaks at 3 mo)
GnRH  Secretion of LH / FSH
E2 production in females (peaks at 6 mo)

 Gonads continue to develop for ≈ 1 year

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 Breast development (contour of breast / areola)
o Pubic hair (distribution / quality)
o Male external genitalia (testes size / penis length / changes in scrotal skin)

Girls: pubertal events

Whole thing takes around 5 yrs

 Breast development Begins ≈ 10.5 yrs, takes ≈ 4yrs

 Pubic hair After breast, takes ≈ 3 yrs
 Menarche 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 First (≈ 11 yrs)

 Spermarche ≈13 yrs
 Growth spurt after stage 5 (later than girls)
 Axillary / facial hair ≈ 14 yrs
 Voice changes ≈ 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 Sex steroid functions
Development of secondary sex characteristics Cause secondary sex characteristics
Accelerated growth rate Accelerate growth / contribute to pubertal growth spurt
Evidence of premature fusing of growth plates on hand X-ray Accelerate closing of growth plates

52
Definitions
Females Males
Breast development < 8 yrs and/or Testicular enlargement < 9 yrs and/or
Precicious puberty*
Pubic hair development < 8 yrs Pubic hair development < 9 yrs
Secondary characteristics ≥ 13yrs
Delayed puberty Testicular enlargement ≥ 14 yrs
Menarche ≥ 16yrs
Proposed (controversial): breast development <7 in whites, <6 in AA unless rapid progression

Precocious Puberty

Basic approach:
Isosexual Contrasexual (always peripheral origin)
Central: premature activation of hypothalamus / pituitary
 ↑ all gonadotropin levels (LH/FSH/T/E2) Males  breast development

Peripheral: gonadotropin-independent (gonads alone) Females  virilization

 ↑ 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 Give GnRH at a constant level
o Gonadotrophs  ↓reg amt of GnRH receptors!
o LH pulse at first, then ↓ LH secretion /synthesis with time

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

53
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 Tumors making T
o Mutations in LH signaling pathway (FMPP – see below)
o McCune – Albright syndrome (aut-recessive)
(G-proteins downstream of LH receptor tonically on)

 Adrenal gland can be turned on

o Adrenal tumors
o Congenital adrenal hyperplasia (CAH)
o 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)
(G-proteins downstream of LH receptor tonically on)
o 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

54
Contrasexual gonadotrophin-independent (peripheral) precocious puberty
2° characteristics not appropriate for one’s sex

Males: estrogen-producing processes Females: androgen-producing processes

 Adrenal tumors  CAH (most common)
 Gonadal tumors, feminizing  Adrenal tumors (adrenal cortical carcinoma)
 Drugs: digoxin, spironolactone (antagonizes androgen receptors),  Gonadal tumors
THC (lots of pot ↑ E2), methadone, E2  Exogenous androgens
 Liver disease (can’t metabolize steroids  ↑ E2 – last stop in pathway)  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 Mechanism Idea behind Rx

Testolactone / anastrozole Aromatase inhibitors ↓ E production
If E2 increased
Tamoxifen with ± success Estrogen antagonist ↓ estrogen effects
Ketoconazole Blocks steroid production by P-450 enzymes ↓ steroids
If T increased
Spironolactone Competitive inhibition of androgen receptor ↓ androgen effects

Delayed Puberty
Females Males
Secondary characteristics ≥ 13yrs
Testicular enlargement ≥ 14 yrs
Menarche ≥ 16yrs
Classification
Hypergonadotropic hypogonadism Hypogonadotropic Hypogonadism
↑ LH/FSH but gonads not working ↓ LH/FSH (pituitary or hypothalamic dysfunction)  gonadal failure
aka primary hypogonadism, gonadal failure Secondary hypogonadism

Primary hypogonadism (hypergonadotropic)

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

55
 Growth
 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

rd th
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

Calculating genetic height potential:

 Average parents’ height after correcting for sex difference in mean adult height (5in = 13 cm M>F)
Father's height+ Mother's height± 5in
o MPH = 2
o 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 Cross %ile up = small infant of tall parents
o 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

56
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

th
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 Delayed bone age
o Often have FHx of delayed puberty
o Growth velocity often dips below 5 cm/ yr

 Growth curve appearance:

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

Abnormal Growth Patterns: Short stature: height < 3rd %ile

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

57
Hypothyroidism
 Example: girl starts to cross %iles ↓, TSH is really high and T4 low: primary hypothyroidism.
o Treat with L-thyroxine; growth jumps back up

Etiology in peds:
Congenital Acquired
Autoimmune
Most from aplasia (1:3k, most sporadic) / dysplasia of thyroid
Primary (Hashimoto’s – mostly
Dyshormonogenesis too (aut-recessive, enzymes affected more rare)
adolescents)
Central Often with other pituitary hormone defects 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 liver  circulating IGF-1
o 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
*IGF-1 (good sensitivity) and IGFBP-3 (good specificity) are pretty good in combo for older kids
IGFBP-3
Provocative GH stimulation tests
(↓ in GH deficiency)
IGF-binding protein Stimulate GH release with: GHRH, arginine, L-DOPA,
Production stimulated by GH clonidine, hypoglycemia, propanolol, exercise, sleep.
Sensitivity: poor Lack of appropriate rise of GH suggests deficiency
Specificity: good*  actual “cut-off” is pretty arbitrary
Tests are imperfect (tricky Dx to make)

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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  Vascular disturbances (strokes)
 Trauma (MVA)  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)

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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)

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 Obesity
Definition of obesity: an accumulation of adipose tissue that is of sufficient magnitude to impair health

weight (kg)
 Clinically: estimate using BMI BMI = BMI Classification
height in m 𝟐
< 18.5 Underweight
o Has limitations (Ray Lewis = 33 kg/m2) 18.5- 24.9 Normal
o Not good in muscular, ↑ fluid – weight needs to be fat! 25-29.9 Overweight
30-34.9 Class I Obesity
 In children: usually use percentiles 35-39.9 Class II Obesity
th
o > 85 %ile for age / sex = at risk for overweight 40 Class III Obesity
th
o > 95 %ile for age / sex = overweight

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)

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 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.

Regulation
 Hypothalamus involved a lot (CNS side)
o regulates satiety / appetite
 Fat cells produce Leptin, Ghrelin, etc.
 GI system produces CCK, ghrelin, etc.

 Feedback systems  energy balance regulation

o Hungry? Rest? Be active?

Disruption of Energy Balance

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

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 Fat mass and obesity associated (FTO) gene o Beta-2 adrenergic receptor
o Peroxisome proliferator-activated receptors (PPAR-γ) o Perilipin

 Probably many unknown variants too

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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 • Mood stabilizers (e.g. lithium)
• Glucocorticoids • Antidepressants (e.g. tricyclics)
• Psychotropic medications (e.g. olanzapine) • Anticonvulsants (e.g. valproate)

Other (Novel) risk factors for weight gain

Risk factors Notes
Fetal origins (unfavorable uterine environment) Low birth weight  obesity later (“programmed” to conserve energy?)
Breast feeding (protective) 4% ↓ risk obesity with each month of breast feeding
Environmental toxins Bisphenol A, phytoestrogen-like compounds
Sleep deprivation < 7-8 hrs associated with obesity
Viral infections 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
• Cushing syndrome (injury or congenital malformation)
Consequences of Obesity
Medical Consequences of Obesity
Whole huge list of conditions across every system

 GI: incontinence, impotence, kidney stones, NASH  Cardiovascular: cerebrovascular disease, CAD, cor
 Repro: ↓ fertility, polycystic ovary syndrome, impotence pulmonale, HTN
 Derm: chronic skin infections, acanthosis nigrans  Oncology: ↑↑ cancer
 Vascular: venous insufficiency, DVT  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!)
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Other consequences of obesity
 Discrimination (housing, employment, socially)  Disability
 ↓ QOL  $$$ ($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 Slow, incremental process to goal
o Short-term goal: 5 TO 10 % LOSS, 1 TO 2 LBS / WK
o Interim goal: maintenance
o Long-term goal: additional wt loss, if desired, + long-term maintenance

Lifestyle: Diet
Diet: look for 500-1000 kcal deficit / day,
 Women: 1000-1200 kcal/day Balanced deficit diet
 Men, women > 165 lbs: 1200-1600 kcal/day CHO (55%) high fiber (↑ satiety)
 try to lose 1-2 lbs / wk 3500 kcal = 1 lb Protein (15%) lean sources
Total fat (< 30%) “Low fat” useful – if ↓cal too!
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 (low carb – more wt loss @ 6mo, but similar @ 12-24 mo)
 Compliance, perserverence key (stick to it longer = lose more weight)
 Tailored diet may be more effective (studies limited by high attrition)

Lifestyle: Physical Activity

 Modestly contributes to weight loss  ↑ cardiorespiratory fitness
 May decrease abdominal fat  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

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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) Sibutramine (Meridia)

Dose 120 mg po tid before meals 10 mg po qd to start, can ↑ to 10 mg or ↓ to 5 mg
Action Inhibits pancreatic lipase  ↓ fat absorption Norepi, serotonin, dopamine reuptake inhibitor
↓ absorption of ADEK (fat-soluble vits)
Adverse effects ↑ HR / BP
Soft stools, anal leakage
Cost $170 / mo $104 / mo
More ↓ CVD risk factors More weight loss
Lose about 5.7 lbs more than placebo @ 6mo Lose about 9.5lbs more than placebo @ 12mo
Lose about 6.4 lbs more than placebo @ 12mo ↓ glucose but no change in lipids, BP, ↑ HR
Efficacy ↓ chol, BP, insulin, glucose
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 Ionamin 15-30 mg per day
Phentermine Adipex-P, Fastin, Oby-Cap 18.75-37.5 mg per day
Diethylproprion Tenuate, Tepanil 25 mg 3x per day (75 mg SR)
Benzphetamine Didrex 25-50 mg 1-3x per day
Phendimetrazine Bontril, Plegine, Prelu-2, Xtrozine 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
 Leptin  3 -adrenergic receptors
 Ciliary neurotrophic factor (rhvCNTF)  Cholecystokinin-A receptors
 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

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 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 • Lack of comprehension of (or ability to comprehend)
• Current drug or alcohol abuse risks, benefits, outcomes, alternatives and/or lifestyle
• Uncontrolled, severe psychiatric illness 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 • Access to healthy, affordable foods

• City planning: sidewalks, parks • Schools : Lunch programs, Physical Education,
• Buildings: stairwell access Vending machines
• Unhealthy food advertising

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