EndocrinologyMelena Bellin, MD

Division of Pediatric Endocrinology

Pituitary/ Hypothalamic Tract Thyroid Adrenal Ovary/ Testes and Puberty Growth and Growth Hormone Water and sodium balance Parathyroid, calcium, and bone Diabetes/ Pancreas

Content

Hypothalamus and Pituitary

Anterior Pituitary Growth Hormone (GH) Gonadotropins (FSH, LH) Adrenocorticotrophin (ACTH) Thyroid Stimulating Hormone (TSH) Prolactin

Posterior Pituitary Antidiuretic Hormone (ADH) Oxytocin

Hormones of the Pituitary Gland

THYROID DISEASE

T4/ Free T4 T3 TSH TRH

1o Hypothyroidism: Low FT4 High TSH

Thyroid Axis

Congenital Hypothyroidism• Newborns or infants• Usually diagnosed on newborn screen• Congenital abnormality of the gland

Acquired Hypothyroidism• Children, adolescents, or adults• F>M• Autoimmune

Central Hypothyroidism• Much more rare• Congenital or acquired hypothalamic or pituitary defect

Hypothyroidism

Most often ectopic or absent gland

Rarely– dyshormongenesis, maternal thyroid disease

Newborn asymptomatic

If untreated- poor growth, cognitive impairment

Newborn screen in MN– TSH

Treat with synthroid

Congenital Hypothyroidism

Untreated Congenital Hypothyroidism

Jaundice

Poor feeding

Hypotonia

Macroglossia (large tongue)

Large fontanelles, delayed closure

Course facial features

Mental retardation

Short stature

In children and young adults, usually autoimmune

HASHIMOTO’S DISEASE Presentation: Varies, asymptomatic, goiter,

fatigue, poor growth, constipation, eczema

Acquired Hypothyroidism

Diagnostic Tests:• TSH ↑• Free T4 ↓• Antibodies: thyroglobulin, thyroid

peroxidase

Treatment: Synthroid (L-thyroxine), usually lifelong. Labs monitored every 6-12 mos.

Acquired Hypothyroidism

Very rare in young children (<3 years of age)

Almost always autoimmune:• Early Hashimoto’s (before gland destruction)• Grave’s disease

LABS:• TSH ↓↓• FT4 ↑• T3 ↑

Hyperthyroidism

Hyperthyroidism

Due to antibodies that act like TSH and stimulate the thyroid gland in an uncontrolled fashion-- Thyroid Stimulating Immunoglobulin (TSI)

Always goiter

Inattention, poor sleep, palpitations, tachycardia, high systolic BP, tremors, hot intolerance, increased appetite, wt loss

Grave’s Disease

Complicated

Medications:• Atenolol/ Propanolol (symptomatic tx)• PTU• Methimazole

Radioablation

Thyroidectomy

Grave’s Disease Treatment

Benign or cancerous

Evaluation may include thyroid function tests, ultrasound or radiouptake scan, fine needle aspiration or biopsy

More likely to be cancer in children vs adults

Cancer management:• Radical thyroid dissection• High dose radioablation for residual disease• Yearly monitoring

Thyroid Nodules

Adrenal Glands

Adrenal Cortex:• Cortisol: important for cardiovascular response

to stress, maintaining BG when fasting• Aldosterone: increases blood pressure; salt

retention and potassium excretion• DHEA-S & Androstenedione: small role in

pubic hair development in puberty; in excess states- hirsutism/ virilization in girls

Adrenal Medulla:• Epinephrine: adrenaline response

Adrenal Hormones

Hypothalamic-Pituitary-Adrenal Axis:

CRH

ACTH

Cortisol

Renin-Aldosterone System:

Primary Adrenal Insufficiency Problem with the adrenal gland

“Addison’s Disease”- usually autoimmune

Cortisol +/- Aldosterone deficiency

May present with vague symptoms or with shock (low BP, tachycardia)

May have electrolyte abnormalities: Hypoglycemia, hyperkalemia, hyponatremia

Adrenal Insufficiency

Primary Adrenal Insufficiency: Diagnostic tests: • AM cortisol • ACTH (cosyntropin) stimulation test • Electrolytes and renin for aldosterone def.

Treatment: • Cortisol replacement: hydrocortisone,

prednisone, or decadron• Need higher doses for illness- “stress dose”• Florinef if aldosterone deficiency present

Adrenal Insufficiency

Central adrenal insufficiency:

Problem with the pituitary gland or hypothalamus

Also called secondary or tertiary AI

By far most common cause: treatment with prednisone or other glucocorticoid for inflammatory condition

Diagnosis: AM cortisol or ACTH stimulation (“low dose”)

Treatment: Slowly wean hydrocortisone

Adrenal Insufficiency

State of cortisol excess

Etiology:• Exogenous prednisone• Adrenal disease (tumor)• Pituitary adenoma (ACTH-

secreting)• Para-neoplastic (non-pituitary

ACTH production)

Symptoms: obesity, poor stature growth, bruising, stria

Cushing’s Syndrome

Diagnostic Tests:• 24 hour urine– free cortisol• Dexamethasone suppression test– pt takes

decadron, which should shut down endogenous cortisol production

• Imaging

Treatment depends on location of problem (pituitary, adrenal, vs cancer elsewhere)

Cushing’s Syndrome

Unregulated aldosterone excess

Very rare

Results in:• Hypertension• Low potassium level

Primary Hyperaldosteronism

Usually ovarian androgen overproduction, but need to rule out adrenal androgen

Polycystic Ovarian Syndrome is characterized by presence of:• Symptoms of androgen excess: hirsutism (excess

hair growth), acne• Biochemical abnormalities: elevated androgens,

abnormal LH:FSH ratio• Irregular menses (anovulatory cycles)• Polycystic ovaries on ultrasound

Is frequently associated with insulin resistance and obesity in 2/3rds of pts

Androgen Excess- PCOS

Diagnostic Tests:• Clinical History• Labs: LH, FSH, testosterone, adrenal androgens• +/- Ultrasound

Treatment:• Oral Contraceptives: Yasmin• Spironolactone– diuretic with anti-androgen

effect• Metformin- if associated insulin resistance

Androgen Excess- PCOS

Life-threatening enzyme block in cortisol synthesis

If a defect in aldosterone synthesis also is present, also get salt wasting and hypotension---Emergency!

Androgen pathway not blocked---high ACTH levels stimulate androgen production in utero & after birth

Female fetus: virilization (female should not see any androgen)

Male fetus: normal genitalia (plenty of testicular androgen

present)

Adrenal Androgen Excess- Congenital Adrenal Hyperplasia

Most common cause of ambiguous genitalia of the newborn

21-hydroxylase enzyme deficiency in more than 90% of cases

Diagnostic test: high 17-OH-progesterone level

Treatment: Cortisol +/- Florinef replacement

Some female infants undergo surgery for virilized genitalia

Adrenal Androgen Excess- CAH

Gonads- Testes & Ovary

Hypogonadism- 1o or 2o

Tanner staging= description of breast and pubic hair development

Prader beads= used to estimate testicular size (1-3 mL= prepubertal)

Adrenarche or Pubarche= onset of pubic hair development

Thelarche= onset of breast development

Menarche= onset of menses

Assessing Puberty in Children

Girls > 13.0 years Boys> 14.0 years Can be due to:• Constitutional delay of growth and puberty=

normal variant. Family hx of “late bloomers”• Hypothalamic/pituitary problem- often in context

of anorexia or systemic illness. Sometimes specific genetic defects (Kallman’s syndrome)

• Ovarian or testicular failure

Delayed Puberty in Children

Kallman’s Syndrome: Specific genetic defects that result in failure of

the GnRH-producing neurons of the hypothalamus

Pubertal delay

Often also have anosmia (lack sense of smell)

Will need lifelong replacement of testosterone (boys) or estrogen (females)

Delayed Puberty in Children

Ovarian or Testicular Failure: Radiation Chemotherapy (cytoxan) Autoimmune (rare in children but cause of

premature menopause in adult woman) Aneuploidy of sex chromosomes:• Turner’s syndrome (XO)• Klinefelter’s syndrome (XXY)

Delayed Puberty in Children

Abnormal X chromosome– XO or mosaic XX/XO female

Short stature

Streak ovaries- pubertal delay

Other physical features

Cardiac disease

Structural Renal Anomalies

Normal cognition (struggle w/math)

Turner’s syndrome

XXY karyotype

Start puberty but then have testicular failure

Tall

Small testes

Lack body hair

Elevated FSH, low testosterone level

Klinefelter’s Syndrome

Girls < 8 years of age (controversial) Boys <9 years of age Most often idiopathic central precocious

puberty Other causes: tumors, excess adrenal or

gonadal steroid production “Benign” variants:• Premature Thelarche: isolated breast

development• Premature Adrenache: isolated pubic hair

Precocious Puberty

Often includes labs: FSH, LH, testosterone, estradiol, DHEA-S

Lupron stimulation test: pituitary FSH and LH secretion have classic pubertal or prepubertal patterns

Bone age

Puberty Evaluation

Delayed Puberty, often need T or E2: Testosterone- most common is IM injection;

other options include patch, gel Estrogen- Premarin or ethinyl estradiol alone

initially. Later estrogen + progesterone (OCP) for menstrual cycles

Precocious Puberty: Depends on cause of puberty Most common is central puberty, treated with

Depot Lupron (IM injection) or Supprelin implant

Treatments

Treatments

Growth and Growth Hormone

GH Axis

Endocrinological reasons for poor growth: Growth Hormone Deficiency Hypothyroidism Cushing’s syndrome (very rare)

Most children with poor growth will not have an endocrine problem. Consider also:

Occult systemic disease- renal disease, CF Malabsorption- inflammatory bowel, celiac Poor nutrition

Assessing Growth

It’s complicated! GH is secreted in pulses from the pituitary

gland. A random GH is never helpful for poor growth.

First step: Check IGF-1 and IGF-BP3 (growth factors)

Second step: GH stimulation testing• Clonidine• Arginine• GH >10 is considered normal

Diagnosing GH Deficiency

First, rule out tumor– Brain MRI

Growth Hormone Treatment• Daily SQ injections• Very expensive– prior authorization from

insurance

Treating GH Deficiency

Very Rare Due to pituitary adenoma secreting GH Gigantism in children Acromegaly in adults

Growth Hormone Excess

Water and Sodium Balance

Largely regulated by ADH from posterior pituitary gland:

ADH acts on the collecting ducts in the kidney to allow water absorption

• lack ADH- loose too much water> High urine output> Dehydration> Hypernatremia

• too much ADH- absorb too much water> Low urine output> Retain free water hyponatremia

Water and Sodium Balance

Condition in which the body cannot produce or cannot respond to ADH

Cannot produce ADH= Central DI Cannot respond to ADH= Nephrogenic DI Presents with:• Polyuria (excess urination)• Polydipsia (excess thirst)• Hypernatremia

Diabetes Insipidus

Causes of central DI include:• Tumors• Trauma• Neurosurgery

Treatment= ddAVP (synthetic ADH)• Comes as oral tablets, nasal spray, or SQ

injection

Treatment of nephrogenic DI is more complex

Diabetes Insipidus

Condition of excess ADH

Presents as low urine output, concentrated urine, and hyponatermia

Often transient, in response to:• Neurosurgery• Meningitis• Pneumonia or other pulmonary infection

SIADH

Parathyroid, Calcium, Vitamin D, and Bone

Parathyroid Hormone (PTH):• Secreted by parathyroid gland in response to low

calcium levels• Retains calcium at the level of the kidney, activates

vitamin D, and has some direct effect on bone

Vitamin D:• Necessary to absorb calcium normally from the gut

Bone:• Where most of our body’s calcium is stored; • in the absence of dietary calcium intake, we leach

calcium from bone to maintain blood levels

Factors Regulating Calcium:

Tumor or hyperplasia of parathyroid glands

Excess secretion of PTH

Characteristic findings:• Hypercalcemia• Low phosphorus• Bone pain• Risk of kidney stones and kidney damage

Treatment: increase fluid intake, often need surgery to remove abnormal parathyroid tissue

Hyperparathyroidism

Congenital underdevelopment of parathyroid glands

Acquired deficiency– autoimmune destruction

Characteristic features:• Low calcium- may present as tetany or seizure• High phosphorus

Treatment: Calcium and calcitriol (vitamin D) supplementation

Hypoparathyroidism

Congenital hypoplasia of parathyroid glands

Associated with characteristic facial features, cardiac defects, thymic aplasia

DiGeorge Syndrome (chrom 22q11 del)

In very young children, causes rickets.

Rickets= bone deformities from calcium/ vitamin D deficiency.

Most often occurs in purely breastfed infants in northern latitudes

Reason for recommending vitamin D supplement in breast feeding infants

Treat with high dose vitamin D

Vitamin D Deficiency

PANCREAS, ISLETS, AND BETA-CELLS:

DIABETES MELLITUS

Diabetes Mellitus Type 1 Diabetes

◦ Autoimmune destruction of beta-cells with eventual complete inability to secrete insulin

Type 2 Diabetes◦ Insulin resistance (need more insulin) ◦ Plus insulin insufficiency

2009 ADA Diagnostic Criteria For Diabetes Mellitus

Casual (Random) Glucose Test > 200 mg/dL + symptoms◦Polyuria, polydipsia,hyperphagia, weight loss

Fasting blood glucose > 126 mg/dL*◦< 100 mg/dl: Normal◦100-125 mg/dl: Impaired Fasting Glucose

2 Hour OGTT glucose > 200 mg/dL*◦< 140 mg/dl: Normal◦140-199 mg/dl: Impaired Glucose Tolerance

*In absence of unequivocal hyperglycemia, requires confirmation on separate day*

History of Diabetes Mellitus• 1552 BC earliest written record of DM (Egyptian

physician)

• 1st Breakthrough in understanding: 1889– The problem is within the pancreas

• “Cure” for diabetes (type 1) – insulin: 1922

insulin

1970

1980

1990

2000

Not much change for the next 50 years!

Islet Cell Antibodies

Genetic Studies: HLA Association

Pathology Studies: Insulitis

Insulin Autoantibodies

GAD65 antibodies, IA-2

Type 1 diabetes is immune mediated

Human Insulin

Home Glucose Monitoring

DCCT

Insulin pumps

Rapid-acting Insulin

Basal InsulinMarked changes in Therapy

An islet in type 1 diabetes

ISLET

IMMUNE CELLS

Exocrine Pancreas

Natural History of Type 1 Diabetes

CELLULAR (T CELL) AUTOIMMUNITY

LOSS OF FPIR (IVGTT)

GLUCOSE INTOLERANCE (OGTT)

HUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD65, IA2Ab, etc.)

TIME

BETA

CEL

L M

ASS

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

GENETICALLY AT RISK

UNKNOWN TRIGGER

CLINICAL ONSET

Pediatric Type 2 Diabetes Mellitus

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Acanthosis Nigricans

Honeymoon Period: refers to period of time early after diagnosis of type 1 diabetes mellitus when blood sugars are easier to control.

Basal or Background Insulin Bolus Insulin Glucagon: Used for hypoglycemic

emergency to raise blood sugar

Other Terminology in DM

Common Brands: One Touch (Ultra, Link, Mini) Bayer (Contour) Accucheck (Aviva) Freestyle (Lite)

Blood Glucose Meters

Insulin Types: Lantus (glargine) Levimir (detrimir) Novolog (aspart) Humalog (lispro) Apidra (glulisine) NPH (“N”) Regular (“R”)

Insulin- Vial and Syringe

Easy to carry and use “Dial up” dose in 0.5

or 1 unit increments

Insulin Pens

Features: Basal Rates Bolus “wizard” Alarms Temp basal & patterns

Insulin Pumps

Components: Pump Catheter “site” Insulin Cartridge

Measure interstitial glucose Requires calibration with blood glucose Readings every 2-5 minutes

Continuous Glucose Monitors

Used for type 2 DM, rarely adjuvant to insulin in type 1 DM

METFORMIN

ROSIGLITAZONE/ PIOGLITIZONE (TZDs)

GLIPIZIDE, GLYBURIDE (sulfonylureas)

Oral Medications

Acute Complications of DM Diabetic Ketoacidosis

◦ T1DM and new onset T2DM◦ #1 cause of hospitalization in children with DM◦ Cerebral edema occurs in 0.7-3% of DKA- 20%

mortality

Non-ketotic hyperosmolar coma

Hypoglycemia

MICROvascular disease Retinopathy

Nephropathy/ Microalbuminuria

Neuropathy

MACROvascular disease Coronary artery disease

LOWER hemoglobin A1c = LOWER risk of complications

Chronic Complications of DM

Associated Conditions

Type 1 DM (autoimmunity) Thyroid disease (10-15%) Celiac disease (~5%) Adrenal insufficiency (<1%)

T2 DM (metabolic syndrome) Obesity Dyslipidemia Hypertension PCOS Fatty liver