Chapter 10

Endocrinology

Teresa Mark, MD

I. Websites

American Diabetes Association (www.diabetes.org)
International Society for Pediatric and Adolescent Diabetes (www.ispad.org)
Pediatric Endocrine Society (www.lwpes.org)

II. Diabetes

1. Diagnostic criteria (must meet 1 of 4):
a. Symptoms for diabetes (polyuria, polydipsia, or weight loss) and random blood glucose ≥ 200 mg/dL
b. Fasting blood glucose (FPG = no caloric intake for at least 8 hours) ≥ 126 mg/dL∗
c. Oral glucose tolerance test (OGTT) with a 2-hour postload blood glucose ≥ 200 mg/dL∗
d. Hemoglobin A1c(HbA1c) ≥ 6.5%
2. Defining increased risk: FPG 100–125, 2-hour post OGTT 140–199, HbA1c 5.7%–6.4%†
3. Interpreting HbA1c: Estimates average blood glucose for the past 3 months; 6% approximately equals an average of 130 mg/dL, each additional 1% ≈ 30 mg/dL more
4. Oral glucose tolerance test:
a. Pretest preparation:
(1) Calorically adequate diet required for 3 days before the test, with 50% of total calories taken as carbohydrate.
(2) Delay test 2 weeks after illness.
(3) Discontinue all hyperglycemic and hypoglycemic agents (e.g., salicylates, diuretics, oral contraceptives, phenytoin).
b. Procedure: Give 1.75 g/kg (maximum 75 g) oral (PO) glucose after a 12-hour fast, allowing up to 5 minutes for ingestion. Mix glucose with water and lemon juice as a 20% dilution. Quiet activity is permissible during the OGTT. Draw blood samples at 0 and 120 minutes after ingestion.
1. Type I or type II (most common types, polygenic):
a. Patient characteristics (Table 10-1)
b. Laboratory characteristics:
(1) Islet cell autoantibodies: (GAD-65, insulin, islet cell antibodies) suggestive of type 1. However, ≈15% of children with type 1 diabetes will not have autoantibodies to a specific islet cell antigen and ≈5% will not have any detectable islet cell autoantibodies.
    NOTE: Some children with type 2 diabetes will have measurable islet cell autoantibodies.
(2) Ketoacidosis: Usually associated with type 1 but does not exclude type 2 (see Sections C and D). Recurrent ketosis, especially diabetic ketoacidosis (DKA), in a type 2 patient should prompt reevaluation of classification.
(3) C-peptide: In a type 1 patient, a measurable level >2 years after diagnosis should prompt reevaluation of classification.
(4) Insulin and C-peptide: Often unhelpful in initial classification. At presentation, levels usually low in type 1, but there is significant overlap with type 2.
1. Definition: Hyperglycemia, ketonemia, ketonuria, and metabolic acidosis (pH < 7.30, bicarbonate < 15 mEq/L)
2. Assessment:
a. History: In suspected diabetic, determine whether there is a history of polydipsia, polyuria, polyphagia, weight loss, vomiting, or abdominal pain, as well as history of infection or inciting event. In a known diabetic, also determine the usual insulin regimen, timing and amount of last dose.
b. Examination: Assess for dehydration, Kussmaul respirations, fruity breath, change in mental status, and current weight.
c. Laboratory tests: See Fig. 10-1. Also consider HbA1c to assess for chronic hyperglycemia (normal values are 4.5%–5.9%). In a new-onset diabetic, consider islet cell antibodies, insulin antibodies, thyroid antibodies, thyroid function tests, and celiac screen (endomesial antibody or tissue transglutaminase and total immunoglobulin [Ig]A).
3. Management: See Fig. 10-1. Because fluid and electrolyte requirements of patients in DKA vary greatly, the following guidelines are a starting point; therapy must be individualized based on patient dynamics.
a. Acidosis: pH is an indicator of insulin deficiency; if acidosis is not resolving, patient may need more insulin. NOTE: Initial insulin administration may cause transient worsening of acidosis as potassium is driven into cells in exchange for hydrogen ions.
b. Hyperglycemia: Blood glucose is an indicator of hydration status.
4. Cerebral edema: Most severe complication of DKA. Overly aggressive hydration and rapid correction of hyperglycemia may play a role in its development.
5. Insulin requirements: Once DKA is resolved, patient will need to be started on a regimen of subcutaneous (SQ) insulin. See Table 10-2 for calculations (also see Table 10-3). Insulin doses are subsequently adjusted based on actual blood sugars. Initially check blood sugars before meals (QAC), at bedtime (QHS), and at 2 AM.
D. Type II Diabetes Mellitus8-10
1. Prevalence: Increasing among children, especially among African Americans, Hispanics, and Native Americans. Increase is related to increased prevalence of childhood obesity.
2. Etiology: Abnormality in glucose levels caused by insulin resistance and insulin secretory defect.

TABLE 10-2

SUBCUTANEOUS INSULIN DOSING

InsulinDose CalculationSample Calculation for 24-kg childDose
Total daily dose0.5–1 unit/kg/day0.75 x 24 = 18 units/day18 units
BasalGlargine1/2 daily total1/2 18 units = 99 units
OR
Detemir1/2 daily total ÷ BID
Carbohydrate coverage ratioLispro, aspart450 ÷ daily total450 ÷ 18 = 251 unit: 25 g carbohydrate
OR
Regular500 ÷ daily total
Correction factorLispro, aspart1800 ÷ daily total1800 ÷ 18 = 1001 unit: 100 mg/dL > 120
OR
Regular1500 ÷ daily total

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TABLE 10-3

CURRENTLY AVAILABLE INSULIN PRODUCTS

Insulin∗OnsetPeakEffective Duration
Rapid acting
Lispro (Humalog)
Aspart (Novo Log)
Glulisine (Apidra)		5–15 min30–90 min5 hr
Short Acting
Regular U100
Regular U500 (concentrated)
30–60 min2–3 hr5–8 hr
Intermediate acting
Isophane insulin (NPH, Humulin N/Novolin N)		2–4 hr4–10 hr10–16 hr
Long acting
Glargine (Lantus)
Detemir (Levemir)
2–4 hr†
Slow
No peak
6–8 hr
20–24 hr
6–24 hr (dose related)
Premixed
70% NPH/30% regular (Humulin 70/30)
75% NPL/25% lispro (Humalog Mix 75/25)
50% NPL/50% lispro (Humalog Mix 50/50)
70% NPA/30% aspart (Novo Log Mix 70/30)
30–60 min
5–15 min
5–15 min
5–15 min		Dual10-16 hr

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NPA, Insulin aspart protamine (neutral protamine aspart); NPH, neutral protamine Hagedom; NPL, insulin.

∗ Assuming 0.1–0.2 U/kg per injection. Onset and duration vary significantly by injection site.

† Time to steady state.

Modified from American Diabetes Association. Practical Insulin: A Handbook for Prescribing Providers, 2nd ed. Alexandria, Va: American Diabetes Association, 2007.

E. Monitoring
1. Glucose control: Daily blood glucoses; HbA1c level every 3 months
2. Other involved organ systems: Annual eye examinations and regular screening for hypertension, proteinuria, and hyperlipidemia (monitor Q2 yr with goals of low-density lipoprotein [LDL] < 100 mg/dL, high-density [HDL] > 35 mg/dL, triglycerides [TGs] < 150 mg/dL)

III. Thyroid Function11-13

1. Interpretation of thyroid function tests (Table 10-4): See reference values for age (Table 10-5). Remember that preterm infants have different ranges (Table 10-6).
2. Thyroid scan: Used to study thyroid structure and function. Localizes ectopic thyroid tissue and hyperfunctioning and nonfunctioning thyroid nodules.
3. Technetium uptake: Measures uptake of technetium by thyroid gland. Levels are increased in Grave's disease and decreased in Hashitoxicosis and hypothyroidism (except dyshormonogenesis, when levels may be increased).
B. Hypothyroidism (Table 10-7)
1. Can be congenital or acquired. See Table 10-7 for characteristics and types of hypothyroidism.
2. Hypothyroidism and obesity16: Moderate elevations in thyroid-stimulating hormone (TSH [4–10 mIU/L]), with normal or slightly elevated triiodothyronine (T3) and thyroxine (T4) are seen in 10%–23% of obese children and adolescents. In these individuals, there does not appear to be a benefit to treating with thyroxine. Values tend to normalize with weight loss, suggesting they are the result, rather than the cause, of obesity in these individuals. Could consider testing for thyroid antibodies to further clarify whether there is true thyroid dysfunction.

TABLE 10-4

THYROID FUNCTION TESTS: INTERPRETATION

DisorderTSHT4Free T4
Primary hyperthyroidismLHHigh N to H
Primary hypothyroidismHLL
Hypothalamic/pituitary hypothyroidismL, N, H∗LL
TBG deficiencyNLN
Euthyroid sick syndromeL, N, H∗LL to low N
TSH adenoma or pituitary resistanceN to HHH
Compensated hypothyroidism†HNN

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H, High; L, low; N, normal; T4, thyroxine; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone.

∗ Can be normal, low, or slightly high.

† Treatment may not be necessary.

TABLE 10-5

AGE-BASED NORMAL VALUES FOR ROUTINE THYROID FUNCTION TESTS14

AgeFree T4 (ng/dL)TSH (mIU/L)T4 (mcg/dL)T3 (ng/dL)Reverse T3 (ng/dL)TBG (mcg/mL)
Day of birth0.94–4.392.43–24.35.85–18.6819.53–266.2619.53–358.7019.17–44.7
1 wk0.96–4.080.58–5.58∗5.90–18.5820.83–265.6119.53–338.5219.16–44.68
1 mo1.00–3.440.58–5.57∗6.06–18.2725.39–264.3119.53–283.8419.12–44.59
3 mo1.04–2.860.58–5.57∗6.39–17.6636.46–259.7519.53–197.9019.02–44.35
6 mo1.07–2.440.58–5.56∗6.75–17.0451.43–252.5919.53–137.3618.87–44
1 yr1.10–2.190.57–5.547.10–16.1674.87–240.8718.23–85.9318.56–43.28
2 yr1.11–2.050.57–5.517.16–14.98103.51–228.5016.93–55.9917.94–41.82
5 yr1.08–1.930.56–5.416.39–12.94131.50–212.2313.02–35.8116–37.3
8 yr1.04–1.870.55–5.315.72–11.71130.85–202.4611.72–30.6014.2–33.09
12 yr0.99–1.810.53–5.165.08–10.58119.78–192.7011.07–27.9912.54–29.24
15 yr1.03–1.770.52–5.054.84–10.13110.02–184.8810.42–27.3411.96–27.89
18 yr0.93–1.730.51–4.93101.56–179.0310.42–26.04

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T3, Triiodothyronine; T4, thyroxine; TBG, thyroxine-binding globulin; TSH, thyroid-stimulating hormone.
NOTE: If age-specific reference ranges are provided by the laboratory running the assay, please refer to those ranges.

∗ Some labs report the reference range upper limit for TSH for children up to 12 months of age as 8.35 mU/L.

The above ranges are modified from Lem AJ, de Rijke YB, van Toor H, et al. Serum thyroid hormone levels in healthy children from birth to adulthood and in short children born small for gestational age. J Clin Endocrinol Metab. 2012;97:3170-3178.

TABLE 10-6

MEAN TSH AND T4 OF PRETERM AND TERM INFANTS 0–28 DAYS15

Age ± SDCord (Day 0)Day 7Day 14Day 28
T4 (mcg/dL)
23–27∗5.44 ± 2.024.04 ± 1.794.74 ± 2.566.14 ± 2.33
28–306.29 ± 2.026.29 ± 2.106.60 ± 2.257.46 ± 2.33
31–347.61 ± 2.259.40 ± 3.429.09 ± 3.578.94 ± 2.95
>379.17 ± 1.9412.67 ± 2.8710.72 ± 1.409.71 ± 2.18
fT4 (ng/dL)
23–271.28 ± 0.411.47 ± 0.561.45 ± 0.511.50 ± 0.43
28–301.45 ± 0.431.82 ± 0.661.65 ± 0.441.71 ± 0.43
31–341.49 ± 0.332.14 ± 0.571.96 ± 0.431.88 ± 0.46
>371.41 ± 0.392.70 ± 0.572.03 ± 0.281.65 ± 0.34
TSH (mIU/L)
23–276.80 ± 2.903.50 ± 2.603.90 ± 2.703.80 ± 4.70
28–307.00 ± 3.703.60 ± 2.504.90 ± 11.23.60 ± 2.50
31–347.90 ± 5.203.60 ± 4.803.80 ± 9.303.50 ± 3.40
>376.70 ± 4.802.60 ± 1.802.50 ± 2.001.80 ± 0.90

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FT4, Free thyroxine; T4, thyroxine; TSH, thyroid-stimulating hormone.

∗ Weeks gestational age.

Data modified from Williams FL, Simpson J, Delahunty C, et al. Collaboration from The Scottish Preterm Thyroid Group: Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab. 2004;89:5314-5320.

TABLE 10-7

HYPOTHYROIDISM

Disease and Clinical SymptomsOnsetEtiologyManagementFollow-up
Primary/Congenital
Large fontanelles, lethargy, constipation, hoarse cry, hypotonia, hypothermia, jaundiceSymptoms usually develop within first 2 weeks of life; almost always present by 6 weeks.
Some infants may be relatively asymptomatic if the cause is other than absence of the thyroid gland.
Treated patients are still at risk for developmental delay.		Primary hypothyroidism: Most common cause is defect of fetal thyroid development. Other causes include TSH receptor mutation or thyroid dyshormonogenesis.
OR
Central hypothyroidism: Deficiency of thyrotropin-releasing hormone (TRH)or thyrotropin (TSH).		Goal is to achieve T4 in the upper half of normal range. In primary hypothyroidism, TSH should be kept <5. A minority of infants maintain persistently high TSH despite correction of T4. Replacement with L-thyroxine as soon as diagnosis is confirmed.Monitor T4 and TSH at the end of weeks 1 and 2 of therapy and 3–4 weeks after any dose change.
If levels are adequate, follow every 1–3 months during the first 12 months.
Acquired
Growth deceleration; other signs may include coarse, brittle hair, dry, scaly skin, delayed tooth eruption, cold intoleranceCan occur as early as the first 2 years of life.Hashimoto thyroiditis (diagnosis supported by presence of antithyroglobulin or antimicrosomal antibodies).
Head/neck radiation.
Central hypothyroidism (pituitary/hypothalamic insult).		Replacement with L-thyroxine.As for primary/congenital.
After 2 years, monitor levels every 6–12 months as dose changes become less frequent.

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NOTE: Thyroid hormone levels in premature infants are lower than those seen in full-term infants. Further, the TSH surge seen at approximately 24 hours of age in full-term babies does not appear in preterm infants. In this population, lower levels are associated with increased illness, but the effect of replacement therapy remains controversial.
L-thyroxine, Levothyroxine; TSH, thyroid-stimulating hormone.

3. Newborn screening for hypothyroidism13,17: Mandated in all 50 states. Measures a combination of TSH and T4, based on the particular state's algorithm; 1:25 abnormal tests are confirmed. Congenital hypothyroidism has prevalance of 1:3000–4000 U.S. infants. If abnormal results are found, clinicians should follow recommendations of American College of Medical Genetics—ACT sheets and Algorithm for confirmation testing. See Chapter 13 for further resources on newborn screening.
    NOTE: Because of the risk of inducing adrenal crisis if adrenocorticotropic hormone (ACTH) deficiency is present, do not begin treatment of central hypothyroidism until normal ACTH/cortisol functionis documented.
C. Hyperthyroidism
1. General:
a. Symptoms: Hyperactivity, irritability, altered mood, insomnia, heat intolerance, increased sweating, pruritus, tachycardia, palpitations, fatigue, weakness, weight loss despite increased appetite (or weight gain), increased stool frequency, oligomenorrhea or amenorrhea, fine tremor, hyperreflexia, hair loss.
b. Epidemiology: Prevalence increases with age, beginning in adolescence; 4:1 female-to-male predominance.
c. Etiology: Most common cause in childhood is Graves disease (see later). Other causes: Subacute thyroiditis, factitious hyperthyroidism (intake of exogenous hormone), TSH-secreting pituitary tumor (rare). Pituitary resistance to thyroid hormone (compensatory rise in T4, but TSH remains within normal range).
d. Laboratory findings: ↑ T4, ↑ T3, usually ↓ TSH. Further tests include TSH receptor–stimulating antibody, thyroid-stimulating immunoglobulin (TSI), antithyroglobulin and antimicrosomal antibodies, free T4, and free T3.
2. Graves disease:
a. Physical examination: Diffuse goiter, a feeling of grittiness and discomfort in the eye, retrobulbar pressure or pain, eyelid lag or retraction, periorbital edema, chemosis, scleral injection, exophthalmos, extraocular muscle dysfunction, localized dermopathy, and lymphoid hyperplasia.
b. Epidemiology: Peak incidence, age 11–15 years; 5:1 female-to-male ratio. Family history of autoimmune thyroid disease.
c. Etiology: Autoimmune (positive TSI; may also have low titers of thyroglobulin ± microsomal antibodies).
d. Laboratory findings: ↑ T4, ↑ T3, ↓ TSH (↑ iodine 123 [123I] uptake distinguishes from Hashimoto thyroiditis).
e. Treatment and monitoring: Methimazole (inhibits formation of thyroid hormone). Propylthiouracil (PTU) should not be used as first-line treatment in children, owing to higher risk of liver dysfunction than with methimazole. PTU can be considered for those with mild reactions to methimazole. Radioactive iodine (131I) or surgical thyroidectomy are options for initial treatment or refractory cases. Follow symptoms and T4 and TSH levels.

IV. Parathyroid Gland Function and Vitamin D

A. Parathyroid Gland
1. Parathyroid hormone (PTH) function: Increases serum calcium by increasing bone resorption, increasing calcium and magnesium reuptake in the kidney, increasing phosphorus excretion in the kidney, and increasing 25-hydroxyvitamin D conversion to 1,25-dihydroxyvitamin D in order to increase calcium absorption in the intestine.
c. Laboratory findings, primary: ↑ PTH, ↑ serum Ca2+; ↓ serum phosphorus; normal/↑ alkaline phosphatase. In secondary hyperparathyroidism, Ca2+ normal/↓.
d. Treatment for hypercalcemia associated with primary hyperparathyroidism: Hydration is mainstay of treatment; enhances calciuria. Furosemide may be used with caution with adequate hydration. Hydrocortisone (1 mg/kg Q6 hr), reduces intestinal absorption of calcium. Calcitonin transiently opposes bone resorption. In severe hypercalcemia, bisphosphates may be considered. Surgical removal of parathyroid glands (may result in hypoparathyroidism).
B. Vitamin D Deficiency (Table 10-8)18-20
1. Current recommendations suggest 600 IU/day in children >12 months of age to meet daily requirements.

TABLE 10-8

VITAMIN D DEFICIENCY

Disease, Clinical Symptoms, and OnsetEtiologyEvaluationManagement
Rickets (infancy/childhood): Failure of adequate bone mineralization, leading to soft bones/skeletal deformities
Osteomalacia (adults): Bone pain and muscle weakness		Decreased dietary intake
Inadequate exposure to sunlight
Increased melanin
Impaired renal function
Fat malabsorption (celiac disease, cystic fibrosis, Crohn’s disease)		↓ 25-OH vitamin D

Supplementation for:

• Breast-fed infants

• Those with celiac disease, cystic fibrosis, Crohn’s disease, pancreatic deficiency

Repletion per Formulary

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BOX EC 10-A MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROMES

V. Adrenal Function21-23

A. Adrenal Insufficiency
1. Etiology:
a. Common causes: Congenital adrenal hyperplasia (CAH) and chronic glucocorticoid treatment (suppression of ACTH secretion)
b. Other causes: Addison disease and hypothalamic or pituitary disease secondary to tumors, surgery, radiation therapy, or congenital defects
2. Evaluation:
b. ACTH stimulation test:
(1) Purpose: Measures ability of the adrenal gland to produce cortisol in response to ACTH. Most useful in diagnosis of adrenal insufficiency.
(2) Interpretation: Normally, a rise in serum cortisol follows ACTH administration. With ACTH deficiency or prolonged adrenal suppression, there is no rise in cortisol after a single ACTH dose. Blunted cortisol response can be indicative of CAH. Lack of response after 3 consecutive days of ACTH stimulation is pathognomonic of Addison disease.
(3) Standard-dose ACTH stimulation test (250 mcg intravenously; cortisol measured at 30 minutes. Used to evaluate for primary adrenal insufficiency, although may be used to evaluate for central adrenal insufficiency:
(a) For evaluation of primary adrenal insufficiency:
    <18 mcg/dL: Highly suggestive of adrenal insufficiency
    >18 mcg/dL: Normal (rules out adrenal insufficiency)
(b) For evaluation of central adrenal insufficiency:
    <16 mcg/dL: Highly suggestive of adrenal insufficiency
    16–30 mcg/dL: Adrenal insufficiency less likely but not excluded
    >30 mcg/dL: Normal (rules out adrenal insufficiency)
a. Group of autosomal recessive disorders characterized by a defect in one of the enzymes required in the synthesis of cortisol from cholesterol (Fig. 10-3). Cortisol deficiency results in oversecretion of ACTH and hyperplasia of the adrenal cortex.

TABLE 10-10

CORTISOL, 8AM

InterpretationCortisol (mcg/dL)
Suggestive of adrenal insufficiency<5 mcg/dL
Indeterminate5–14 mcg/dL
Adrenal insufficiency unlikely>14 mcg/dL
(2) Nonclassic or simple virilizing form (partial enzyme deficiency):
(a) Adrenal insufficiency tends to occur only under stress; manifests as androgen excess after infancy (precocious pubarche, irregular menses, hirsutism, acne, advanced bone age).

TABLE 10-11

17-HYDROXYPROGESTERONE, SERUM

AgeBaseline (ng/dL)
Premature (31–35 weeks)≤360
Term infants (3 days)≤420
1–12 mo11–170
1–4 yr4–115
5-9 yr≤90
10-13 yr≤169
14-17 yr16–283
Males, Tanner II–III12–130
Females, Tanner II–III18–220
Male, Tanner IV–V51–190
Females, Tanner IV–V36–200
Male (18–30 yr)32–307
Adult female
 Follicular phase≤185
 Midcycle phase≤225
 Luteal phase≤285

Reference ranges from Quest Diagnostics LC/MS assay (liquid chromatography/tandem mass spectroscopy). For preterm infants or infants born small for gestational age, see Olgemöller B, Roscher AA, Liebl B, et al. Screening for congenital adrenal hyperplasia: adjustment of 17-hydroxyprogesterone cut-off values to both age and birth weight markedly improves the predictive value. J Clin Endocrinol Metab. 2003;88:5790-5794.

a. Syndrome of weakness, fatigue, and hyperpigmentation due to insufficient mineralocorticoid and glucocorticoid production, with compensatory ACTH overproduction. Because of its nonspecific presentation, can be missed in older children.
b. Autoimmune destruction of adrenal glands is the most common cause outside of infancy. In children, it may be part of autoimmune polyendocrine syndrome type 1 (APS-1), which also includes hypoparathyroidism and chronic mucocutaneous candidiasis. Individuals with autoimmune Addison disease should also be screened for other endocrinopathies.
5. Management of adrenal insufficiency (for relative potency of steroids see Table 10-12)

TABLE 10-12

POTENCY OF VARIOUS THERAPEUTIC STEROIDS
(Set Relative to Potency of Cortisol)

SteroidGlucocorticoid Effect∗ (in mg of cortisol per mg of steroid)Mineralocorticoid Effect† (in mg of cortisol per mg of steroid)
Cortisol (hydrocortisone)11
Cortisone acetate (oral)0.80.8
Cortisone acetate (intramuscular)0.80.8
Prednisone40.25
Prednisolone40.25
Methyl prednisolone50.4
Betamethasone250
Triamcinolone50
Dexamethasone300
9α–fluorocortisone (fludrocortisone)15200
Deoxycorticosterone (DOC) acetate020
Aldosterone0.3200–1,000

∗ To determine cortisol equivalent of a given steroid dose, multiply dose of steroid by corresponding number in column for glucocorticoid or mineralocorticoid effect. To determine dose of a given steroid based on desired cortisol dose, divide desired hydrocortisone dose by corresponding number in the column.

† Total physiologic replacement for salt retention is usually 0.1 mg Florinef, regardless of patient size.

Modified from Sperling MA. Pediatric Endocrinology, 3rd ed. Philadelphia: Saunders, 2008:476.

a. Signs and symptoms (including rapid weight gain with central obesity, buffalo hump, moon face, striae, thinning of skin and other membranes, hypertension) associated with elevated cortisol levels and overexposure to glucocorticoids (either endogenous or exogenous). Relatively rare in children, with most cases resulting from iatrogenic causes.
b. Cushing evaluation:
(1) 24-hour urine collection for excess cortisol (normal value range by mass spectrometry: ≤27–30 ng/mL).
(2) Salivary cortisol level: Measured at 11 PM (spit in a tube); levels are akin to free serum cortisol. Normal range is <0.2 mcg/dL.
(3) Dexamethasone suppression test:
(a) Dexamethasone suppresses secretion of ACTH by the normal pituitary, decreasing endogenous production of cortisol. Useful in determining the etiology of glucocorticoid or androgen overproduction.
(b) Overnight dexamethasone suppression test: Measure serum cortisol at 8 AM; preceded by 1 mg of dexamethasone PO given at 11 PM the night before. Level <1.8 mcg/dL (50 nmol/L) is within normal range of suppression.
    NOTE: Random cortisol is not useful in evaluation for Cushing syndrome.
B. Adrenal Medulla—Pheochromocytoma26-28
1. Pheochromocytoma only accounts for ≈1% of pediatric hypertension. Often associated with syndromes: MEN IIa and IIb, Von Hippel-Lindau, neurofibromatosis (NF)1, familial paraganglioma syndrome.
2. Evaluation for pheochromocytoma should involve imaging and laboratory workup. See Expert Consult, Chapter 10, for additional information about plasma concentrations of free, fractionated metanephrines.
3. Measurement of free, fractionated metanephrines in plasma:
a. Use: Detection of pheochromocytoma
b. Upper limits of normal: Somewhat assay dependent
(1) One study suggests upper normal limits to be metanephrines, 0.3 nmol/L; normetanephrines, 0.6 nmol/L.27
(2) A pediatric study suggests metanephrines for boys, 0.52; girls, 0.37 nmol/L; normetanephrines for boys, 0.53; girls, 0.42 nmol/L.28

VI. Posterior Pituitary Gland—Vasopressin29

VII. Growth and Sexual Development29-38

A. Growth
1. Target height range: Calculated as midparental stature ± 2 SD (1 SD = 2 inches)
a. Midparental stature for boys: (Paternal height + maternal height + 5 inches)/2
b. Midparental stature for girls: (Paternal height + maternal height − 5 inches)/2
3. Tall stature: Most common cause is familial tall stature or precocious puberty. Bone age may be helpful.
4. Obesity: A growing problem in pediatric population. Although the majority do not have endocrine etiology, two disease categories may be addressed when approaching the obese patient:
a. Hypothyroidism: May be evaluated with serum thyroid function tests

TABLE 10-13

INSULIN-LIKE GROWTH FACTOR 1 (IGF-1)

Age (years)Male (ng/mL)Females (ng/mL)
<1≤142≤185
1–1.9≤134≤175
2–2.9≤135≤178
3–3.930–15538–214
4–4.928–18134–238
5–5.931–21437–272
6–6.938–25345–316
7–7.948–29858–367
8–8.962–34776–424
9–9.980–39899–483
10–10.9100–449125–541
11–11.9123–497152–593
12–12.9146–541178–636
13–13.9168–576200–664
14–14.9187–599214–673
15–15.9201–609218–659
16–16.9209–602208–619
17–17.9207–576185–551

NOTE: A clearly normal IGF-1 level argues against growth hormone (GH) deficiency, except in young children, where there is considerable overlap between normals and those with GH deficiency.

Reference ranges from Quest Diagnostics LC/MS (liquid chromatography/tandem mass spectrometry) assay.

5. Polycystic ovarian syndrome (PCOS):
a. Syndrome of hyperandrogenism and menstrual dysfunction
b. Diagnostic criteria:
(1) Hyperandrogenism: Clinical characteristics are hirsutism, acne, and female pattern alopecia. Biochemical characteristic is elevated free testosterone, calculated from total serum testosterone and sex hormone binding protein (SHBG).
(2) Menstrual dysfunction: Amenorrhea or oligomenorrhea.
(3) Polycystic ovaries: Ultrasound (US) characteristics are increased ovarian volume (reliable in adolescents via transabdominal US) or follicular phase with ≥12 follicles measuring 2–9 mm (reliable via transvaginal US only).
c. Management:
(1) Weight reduction and other lifestyle changes increase SHBG (thus decreasing free testosterone) can restore ovulation, and increase insulin sensitivity.
(2) Treatment of hirsutism/acne: Hormonal contraceptives.
(3) Insulin-sensitizing agents (e.g., metformin) may help mitigate metabolic consequences.
(4) Prevention of endometrial hyperplasia (increased risk of endometrial cancer) by intermittent induction of menstruation or prevention of endometrial proliferation by hormonal contraception.
B. Sexual Development
1. Delayed puberty: For girls, no pubertal development by age 14 years, or >5 years between thelarche and adrenarche. Primary amenorrhea: no menarche by age 16 years in the presence of secondary sexual characteristics, or no menarche and no secondary sexual characteristics by age 14 years. For boys, no testicular enlargement by age 14 years, or >5 year for genital development.
a. Delayed puberty may be divided according to luteinizing hormone (LH)(Table 10-14) and follicle-stimulating hormone (FSH) levels (Table 10-15):
(1) Hypergonadotropic hypogonadism (high LH and FSH): Primary gonadal failure, possibly due to Turner or Klinefelter syndromes, androgen insensitivity, tumor, chemotherapy.
(2) Hypogonadotropic hypogonadism (low or normal LH/FSH): May be due to constitutional delay or central gonadotropin deficiency. Of the latter cause, etiologies include Kallman syndrome (most common cause of isolated gonadotropin deficiency), CNS tumors, hypopituitarism.
b. Evaluation of delayed puberty may also be divided into the following categories (Fig. 10-5):
(1) Constitutional delay
(2) Hypopituitarism
(3) Chromosomal abnormality

TABLE 10-14

LUTEINIZING HORMONE

AgeMales (mIU/mL)Females (mIU/mL)
0–2 yrNot establishedNot established
3–7 yr≤0.26≤0.26
8–9 yr≤0.46≤0.69
10–11 yr≤3.13≤4.38
12–14 yr0.23–4.410.04–10.80
15–17 yr0.29–4.770.97–14.70
Tanner StagesMales (mIU/mL)Females (mIU/mL)
I≤0.52≤0.15
II≤1.76≤2.91
III≤4.06≤7.01
IV–V0.06–4.770.10–14.70

Reference values are from Quest Diagnostics immunoassay. For more information visit www.questdiagnostics.com.

TABLE 10-15

FOLLICLE-STIMULATING HORMONE

AgeMale (mIU/mL)Female (mIU/mL)
0–4 yrNot establishedNot established
5–9 yr0.21–4.330.72–5.33
10–13 yr0.53–4.920.87–9.16
14–17 yr0.85–8.740.64–10.98

Reference values are from Quest Diagnostics immunoassay. For more information visit www.questdiagnostics.com.

c. Initial evaluation: LH and FSH, bone age, and thyroid studies. A gonadotropin-releasing hormone (GnRH) stimulation test can be obtained to rule out hypogonadotropic hypogonadism.
d. GnRH stimulation test:39
(1) Measures pituitary luteinizing hormone (LH) and FSH reserve: Helpful in the differential diagnosis of precocious or delayed sexual development.
(2) Method: Give 20 mcg/kg GnRH analog (Leuprolide) SQ, and measure LH and FSH levels at 0 and 60 minutes.
(3) Interpretation: Prepubertal children should show no or minimal increase in LH and FSH in response to GnRH. A rise of LH to > 3.3–5.0 IU/L is evidence of central puberty.
2. Precocious puberty: Traditionally defined as any sign of secondary sexual maturation before age 8 years in girls and age 9 years in boys. More recent data suggest early puberty may not warrant extensive evaluation or intervention if it occurs after age 6 years in African-American girls or after age 7 years in Caucasian girls.
(3) Imaging: Magnetic resonance imaging (MRI) of the brain may help identify a CNS lesion. In girls, pelvic ultrasonography may identify ovarian cysts, whereas in boys it may detect nonpalpable Leydig-cell tumors and should be considered in cases of asymmetric testicular volume or peripheral precocious puberty. For normal testicular size and volume see Table 10-21.
3. Ambiguous genitalia:
a. Clinical findings in a neonate suspicious for ambiguous genitalia: Anogenital ratio > 0.5 (distance between anus and posterior fourchette divided by distance between anus and base of clitoris), phallus length < 1.9 cm (mean newborn length: 2.5 SD), clitoromegaly (length > 1 cm), nonpalpable gonads in an apparent male, and hypospadias associated with separation of scrotal sacs or undescended testis.

TABLE 10-17

TESTOSTERONE, TOTAL SERUM

AgeMale (ng/dL)Female (ng/dL)
Cord blood17–6116–44
1–10 days≤187≤24
1–3 mo72–344≤17
3–5 mo≤201≤12
5–7 mo≤59≤13
7–12 mo≤16≤11
1–5.9 yr≤5≤8
6–7.9 yr≤25≤20
8–10.9 yr≤42≤35
11–11.9 yr≤260≤40
12–13.9 yr≤420≤40
14–17.9 yr≤1000≤40
≥18 (adult)250–11002–45
Tanner Stage
Stage I≤5≤8
Stage II≤167≤24
Stage III21–719≤28
Stage IV25–912≤31
Stage V110–975≤33

NOTE: Normal testosterone/dihydrotestosterone (T/DHT) ratio is <18 in adults and older children, <10 in neonates. T/DHT ratio >20 suggests 5-alpha-reductase deficiency or androgen insensitivity syndrome.

Reference ranges from Quest Diagnostics LC/MS (liquid chromatography/tandem mass spectrometry) assay.

TABLE 10-18

TESTOSTERONE, FREE

AgeMale (pg/mL)Female (pg/mL)
5.9–9 yr≤5.30.2–5.0
10–13.9 yr0.7–520.1–7.4
14–17.9 yr18–1110.5–3.9
18–69 yr35–1550.1–6.4

Reference ranges from Quest Diagnostics LC/MS (liquid chromatography/tandem mass spectrometry) assay.

TABLE 10-19

DEHYDROEPIANDROSTERONE (DHEA), UNCONJUGATED

Ageng/dL
1–5 yr≤377
6–9 yr19–592
10–13 yr42–1067
14–17 yr137–1489
Adult male61–1636
Adult female102–1185

Reference ranges from Quest Diagnostics LC/MS (liquid chromatography/tandem mass spectrometry) assay.

TABLE 10-20

DEHYDROEPIANDROSTERONE SULFATE (DHEA-S)

AgeMale (mcg/dL)Female (mcg/dL)
<1 mo≤31615–261
1–6 mo≤58≤74
7–11 mo≤26≤26
1–3 yr≤15≤22
4–6 yr≤27≤34
7–9 yr≤91≤92
10–13 yr≤138≤148
14–17 yr38–34037–307
Tanner Stages (ages 7–17)
I≤49≤46
II≤8115–133
III22–12642–126
IV33–17742–241
V110–37045–320

Reference values from Quest Diagnostics assay. For more information see www.questdiagnostics.com.

TABLE 10-21

TESTICULAR SIZE

Tanner Stage (Genital)Length (cm) (Mean ± SD)Volume (mL)
I2.0 ± 0.52
II2.7 ± 0.75
III3.4 ± 0.810
IV4.1 ± 1.020
V5.0 ± 0.529

NOTE: Testicular volume of >4 mL or a long axis >2.5 cm is evidence that pubertal testicular growth has begun.
SD, Standard deviation.

b. Etiology: Most common cause is CAH (see Section IV.A.3). Other causes: testicular regression syndrome, androgen insensitivity, testosterone biosynthesis disorders, and chromosomal abnormalities.
c. Diagnosis: Based on karyotype, measurement of gonadotropins (LH, FSH), adrenal steroids (cortisol, 17-OHP, and ACTH stimulation test), testosterone precursors (DHEA, androstenedione), testosterone, dihydrotestosterone (DHT), and hCG stimulation test (see hCG stimulation test on Expert Consult). NOTE: Best test for 5-alpha-reductase deficiency is the testosterone-to-DHT ratio.

VIII. Neonatal hypoglycemia evaluation40

1. Definition of hypoglycemia: Serum glucose level insufficient to meet metabolic requirements; can vary with perinatal stress, birth weight, and maternal factors. For practical purposes, value is defined as <45 mg/dL.
    NOTE: Bedside glucometer is inaccurate at levels <40 mg/dL; stat serum glucose must be sent.
2. Symptoms: Abnormal cry, seizures, apnea, hypotonia, bradycardia, hypothermia.
3. Treatment: Do not delay while awaiting serum glucose results:
a. Plasma glucose 25–45 mg/dL (1.4–2.5 mM), asymptomatic: breast feed or nipple/gavage with formula
b. Plasma glucose level <25 mg/dL (<1.4 mM) ± symptoms, asymptomatic infants who do not tolerate enteral feeding, or symptomatic infants:
(1) Give IV bolus of glucose 0.25 g/kg (2.5 mL/kg of 10% glucose, or 1 mL/kg of 25% glucose) over 1–2 minutes.
(2) Continue IV glucose at a rate of 6–8 mg/kg/min (3.6–4.8 mL/kg/hr of 10% glucose).
(3) Monitor blood glucose Q30–60 min, and increase glucose delivery by 1–2 mg/kg/min if blood glucose is consistently <50 mg/dL.
4. If serum glucose is consistently <45 mg/dL: Further endocrine workup warranted. At the time of hypoglycemia (serum glucose <45 mg/dL), obtain serum levels of glucose, insulin, growth hormone, free fatty acids, and β-hydroxybutyrate.
5. Glucagon stimulation test: At the time of hypoglycemia, obtain above laboratory tests, administer glucagon, and obtain serum glucose levels Q10 min × 4. Repeat growth hormone and cortisol levels 30 minutes after documented hypoglycemia.
a. A rise in glucose secondary to glucagon ≥30 mg/dL along with elevated insulin levels, low serum levels of free fatty acids and β-hydroxybutyrate, and a glucose requirement >8 mg/kg/min suggests a diagnosis of hyperinsulinemia.

IX. Additional Normal Values

Please note that normal values may differ among laboratories because of variation in technique and type of assay used.
See Expert Consult, Chapter 10, for normal values of:
Table EC 10-A, Dihydrotestosterone (DHT)
Table EC 10-B, Catecholamines, urine
Table EC 10-C, Catecholamines, plasma
Table EC 10-D, Insulin-like growth factor binding protein
Table EC 10-E, Mean stretched penile length
Table EC 10-F, Androstenedione, serum

TABLE EC 10-A

DIHYDROTESTOSTERONE (DHT)

AgeMales (ng/dL)Females (ng/dL)
Cord blood<2–8<2–5
1–6 mo12–85<5
Prepubertal<5<5
Tanner stage II–III3–335–19
Tanner stage IV–V22–753–30

Reference ranges from Quest Diagnostics RIA (radioimmunoassay).

TABLE EC 10-B

CATECHOLAMINES, URINE

Compound3–8 years9–12 years13–17 yearsAdults
Dopamine (mcg/24 hr)80–37851–47451–64552–480
Epinephrine (mcg/24 hr)1–7≤8≤112–14
Norepinephrine (mcg/24 hr)5–415–5012–8815–100
Homovanillic acid (mg/24 hr)0.5–6.71.1–6.81.4–7.21.6–7.5
Vanillyl mandelic acid (g/24 hr)≤2.3≤3.4≤3.9≤6.0
3 mo–4 yr5–9 years10–13 years14–17 years18–29 years
Metanephrines (mcg/24 hr)25–11711–13951–27540–18925–222
Normetanephrines (mcg/24 hr)54–24931–39867–50369–53140–412

image

NOTE: Catecholamines are elevated in a variety of tumors, including neuroblastoma, ganglioneuroma, ganglioblastoma, and pheochromocytoma.

Reference ranges from JHH laboratories.

TABLE EC 10-C

CATECHOLAMINES, PLASMA

Supine (pg/mL)Sitting (pg/mL)
Epinephrine
3–15 yr≤464Not determined
Adult≤50≤95
Norepinephrine
3–15 yr≤1251Not determined
Adult112–658217–1109
Dopamine
3–15 yr≤60Not determined
Adult≤30≤30

image

From Blondell R, Foster MB, Dave KC. Disorders of puberty. Am Family Phys. 1999;60:209-218.Reference ranges from JHH Laboratories.

TABLE EC 10-D

INSULIN-LIKE GROWTH FACTOR–BINDING PROTEIN (IGF-BP3)

Agemg/LTanner StageFemale mg/LMale mg/L
0–7 days≤0.7Tanner I1.2–6.41.4–5.2
8–15 days0.5–1.4Tanner II2.8–6.92.3–6.3
16 days–1 yr0.7–3.6Tanner III3.9–9.43.2–8.9
2 yr0.8–3.9Tanner IV3.3–8.13.7–8.7
3 yr0.9–4.3Tanner V2.7–9.12.6–8.6
4 yr1.0–4.7
5 yr1.1–5.2
6 yr1.3–5.6
7 yr1.4–6.1
8 yr1.6–6.5
9 yr1.8–7.1
10 yr2.1–7.7
11 yr2.4–8.4
12 yr2.7–8.9
13 yr3.1–9.5
14 yr3.3–10.0
15 yr3.5–10.0
16 yr3.4–9.5
17 yr3.2–8.7
18 yr3.1–7.9
19 yr2.9–7.3
Adults continue to vary by age

image

NOTE: Levels below 5th percentile suggest growth hormone deficiency. This test may have greater discrimination than the IGF-1 test in younger patients.

Reference values from Quest Diagnostics immunochemiluminometric assay (ICMA).

TABLE EC 10-E

MEAN STRETCHED PENILE LENGTH (cm)

AgeMean ± SD−2.5 SD
Birth
30 wk gestation2.5 ± 0.41.5
34 wk gestation3.0 ± 0.42.0
Full term3.5 ± 0.42.5
0–5 mo3.9 ± 0.81.9
6–12 mo4.3 ± 0.82.3
1–2 yr4.7 ± 0.82.6
2–3 yr5.1 ± 0.92.9
3–4 yr5.5 ± 0.93.3
4–5 yr5.7 ± 0.93.5
5–6 yr6.0 ± 0.93.8
6–7 yr6.1 ± 0.93.9
7–8 yr6.2 ± 1.03.7
8–9 yr6.3 ± 1.03.8
9–10 yr6.3 ± 1.03.8
10–11 yr6.4 ± 1.13.7
Adult13.3 ± 1.69.3

NOTE: Measured from the pubic ramus to the tip of the glans while traction is applied along the length of the phallus to the point of increased resistance.
SD, Standard deviation.

From Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr. 1975;86:395.

TABLE EC 10-F

ANDROSTENEDIONE, SERUM

AgeMales (ng/dL)Females (ng/dL)
Premature (31–35 wk)≤480≤480
Full-term infants≤290≤290
1–12 mo6–786–78
1–4 yr5–515–51
5–9 yr6–1156–115
10–13 yr12–22112–221
14–17 yr22–22522–225
Tanner stage II–III17–8243–180
Tanner stage IV–V57–15073–220
Adult male (18–30 yr)50–220
Female follicular phase35–250
Female luteal phase30–235

Values from Quest Diagnostics LC/MS (liquid chromatography/tandem mass spectrometry) analysis.