DEPARTMENT

Case StudyAcute & Specialty Care

Failure to Thrive in a
Neonate: A Life-Threatening
Diagnosis to Consider
Janeth Ceballos-Osorio, MD, & Irene Hong-McAtee, MD

KEY WORDS
Failure to thrive, electrolyte abnormalities, congenital
adrenal hyperplasia, 11 b-hydroxylase

A national survey suggests that as many as 10% of

children seen for primary care show signs of growth
failure (Stephens, Gentry, Michener, Kendall, &
Gauer, 2008). In most cases, comprehensive historytaking and physical examination reveals common
Section Editors
Karin Reuter-Rice, PhD, CPNP-AC, FCCM
Corresponding Editor
Duke University
Durham, North Carolina
Terea Giannetta, DNP, RN, CPNP
California State University Childrens Hospital Central
California
Fresno, California
Janeth Ceballos-Osorio, Division of General Pediatrics,
Department of Pediatrics, University of Kentucky, Lexington, KY.
Irene Hong-McAtee, Division of Pediatric Endocrinology,
Department of Pediatrics, University of Kentucky, Lexington, KY.
Conflicts of interest: None to report.
Correspondence: Janeth Ceballos-Osorio, MD, Division of
General Pediatrics, Kentucky Clinic Room J442, 740 South
Limestone, Lexington, KY 40536; e-mail: janeth.ceballos@uky.
edu.
J Pediatr Health Care. (2013) 27, 56-61.
0891-5245/$36.00
Copyright Q 2013 by the National Association of Pediatric
Nurse Practitioners. Published by Elsevier Inc. All rights
reserved.
Published online August 17, 2012.
http://dx.doi.org/10.1016/j.pedhc.2012.07.004

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Volume 27  Number 1

etiologies of failure to thrive (FTT), such as nutritional

deprivation. However, some rare cases require focused
laboratory evaluation to rule out life-threatening conditions. This case study illustrates a neonate with FTT presenting at 1 month of age, who required extensive
evaluation to diagnose congenital adrenal hyperplasia
(CAH), specifically 11 b-hydroxylase (11 b-OH)
deficiency. In addition, we review the diagnosis and
management of children with CAH.
CASE PRESENTATION
A 4-week-old Hispanic American boy presented to
clinic with poor feeding, vomiting, decreased urine output, and increased fussiness. He had been exclusively
breastfed for the first week of life. At the first postnatal
visit, the primary care provider (PCP) advised supplementation with formula due to failure to gain weight.
He refused formula feedings and began vomiting with
each feeding, tolerating only breast milk. The PCP prescribed ranitidine twice a day for gastroesophageal reflux. Four days prior to admission, the patient had
only two wet diapers a day. The mother reported listlessness but no fever. An abdominal ultrasound ordered
by his PCP was reported as negative for pyloric stenosis.
Medical History
The patient was born at term to a gravida 1, para 1
mother by spontaneous vaginal delivery with no preor postnatal complications. His birth weight was
4.05 kg. His standard 48-hour hospitalization after birth
was uneventful. He received the hepatitis B vaccine at
birth; his newborn screen was reported as normal.
The family history was negative for any childhood
diseases, including endocrine, metabolic, genetic, or
gastrointestinal diseases.
Personal/Social/Developmental History
The patient lived with his non-smoking, Spanishspeaking parents in an urban area. The family had no
Journal of Pediatric Health Care

TABLE. ACTH stimulation test results

On admission random values

On admission ACTH stimulated

a

Hormone

Value at 0 minutes (2 a.m.)

Normal range

Cortisol
ACTH
Aldosterone
17hydroxyprogesterone
Androstenedione
11-deoxycortisol
11-deoxycorticosterone
DHEA
17-hydroxypregnenolone
Testosterone
PRA

16.7 mg/dL
169 pg/mL
12.5 ng/dL
432 ng/dL

(3-22)
(5-46)
(7-99)
(13-106)

Value at 60 minutes
18 mg/dL

227 ng/dL
644 ng/dL
2572 ng/dL
65 ng/dL
260 mg/dL
256 ng/dL
152 ng/dL
QNS

Normal rangeb
(27-50)

(85-250)
(21-114)
(101-392)
(40-158)
(67-1453)
(633-3286)
c

ACTH, adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; PRA, plasma renin activity; QNS, quantity not sufficient.
Note. Underlined values are significant values that suggest the diagnosis.
a
Normal value range from ARUP laboratories.
b
Normal value range from ESOTERIX laboratories.
c
Testosterone levels are not significantly changed by ACTH stimulation testing.

animals in the home. Despite FTT, he was achieving developmental milestones appropriate for his age.

urine electrolytes revealed a sodium level of 57

mmol/L and potassium of 19 mmol/L.

Physical Examination
This Hispanic baby boy was irritable and difficult to
console. His weight was 8 lb 2 oz (3.725 kg), temperature was 99.1 F, heart rate was 158 beats per minute, respiratory rate 48 breaths per minute, and blood
pressure was 92/60 mm Hg on his right arm. His oral
mucosa was dry, his skin turgor was poor and capillary
refill was delayed at 5 seconds. His anterior fontanel
was soft and flat, he had normal tone, and the remainder of his physical examination was within normal
limits.

Hospital Course
Due to his hyperkalemia, hyponatremia, and tachycardia, the patient was transferred to the pediatric intensive care unit for closer monitoring and
stabilization. There, he received intravenous fluids
(IVF) and wide-spectrum antibiotics. His electrocardiogram showed sinus rhythm with a rate of 173 beats
per minute and no ST wave changes. After the initial
IVF boluses, his heart rate normalized and capillary
refill time was < 2 seconds. However, he remained
hyponatremic and hyperkalemic despite fluid resuscitation. A retroperitoneal ultrasound showed normal
adrenal gland size and a small echogenic focus in
the lateral limb of right adrenal gland that could indicate a focus of hemorrhage or calcification. An adrenocorticotropin hormone (ACTH) stimulation test
revealed adrenal insufficiency due to deficiency of
11 b-OH (Table).
Corticosteroid therapy, mineralocorticoid replacement, and salt replacement were started orally. His electrolytes normalized and his blood pressures remained
normal. He started to tolerate feedings and gain weight
appropriately in the hospital. On these treatments, the
patient has thrived. No hypertension has been reported. He is growing and developing appropriately
at 2 years of age.

Diagnostic Testing
His white blood cell count was 10,100 cells/mL (52%
lymphocytes, 35% segmented neutrophils, 0% bands),
hemoglobin level was 14.6 g/dL, and platelet count
was 680,000 cells/mL. His urinalysis showed a specific
gravity of 1.006. His serum chemistry results showed sodium, 111 mmol/L; potassium, 7.1 mmol/L (non-hemolyzed sample); chloride, 77 mmol/L; bicarbonate, 20
mmol/L; blood urea nitrogen, 36 mg/dL; creatinine,
0.56 mg/dL; glucose, 77 mg/dL; calcium, 11.3 mg/dL; alanine aminotransferase, 25 U/L; aspartate aminotransferase, 41 U/L; total protein, 7.3 g/dL; albumin, 4.9 g/
dL; total bilirubin, 2.7 mg/dL; thyroid stimulating hormone, 2.89 IU/mL; and free T4, 1.5 ng/dL. Random
CASE STUDY QUESTIONS

1. Which differential diagnosis should be considered in this newborn with failure to gain weight, poor feeding,
and vomiting?
2. What causes adrenal insufficiency in infants?
3. When should CAH be suspected in the neonatal period?

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4. How can CAH be diagnosed before a life-threatening event occurs?

5. What is the plan of care for a newborn with CAH?
CASE STUDY ANSWERS
1. Which differential diagnosis should be considered
in this newborn with failure to gain weight, poor feeding, and vomiting?
Although non-accidental trauma or psychosocial FTT
is an important part of the differential, underlying systemic disease should be suspected due to the presence
of vomiting, poor feeding, alteration in mental status,
and electrolyte abnormalities.
The most common cause of hyponatremia in infants
is gastrointestinal loss, but can also occur due to
salt-losing nephritis, glucocorticoid deficiency and/or
mineralocorticoid deficiency (Box 1; Halberthal,
Halperin, & Bohn, 2001; Russo, Davis, Betts, &
Davies, 2007). Hyperkalemia can also have multiple
causes (Box 2). However, this patient presented with
the combination of hypovolemia, severe hyponatremia, urine sodium loss (random urine sodium > 20
mmol/L), and hyperkalemia indicating mineralocorticoid loss of action or deficiency. Of note, the patients
initial aldosterone level appeared to be within normal
reference range. However, hypovolemia and hyponatremia should stimulate the renin-angiotensinaldosterone axis to increase aldosterone levels. Thus,
this normal level indicated relative aldosterone deficiency, due to adrenal insufficiency.
2. What causes adrenal insufficiency in infants?
Acute adrenal insufficiency in infants can occur with
serious illnesses like septicemia, trauma, or surgical

BOX 1. Major causes of hyponatremia

according to volume status
Euvolemia
Syndrome of inappropriate ADH secretion
Glucocorticoid deficiency
Hypothyroidism
Water intoxication
Drugs (e.g., diuretics, barbiturates, opioids)
Pseudohyponatremia (hyperglycemia,
hypertriglyceridemia)
Hypovolemia
With urine sodium > 20 mmol/L
Mineralocorticoid loss of action or deficiency
Diuretics (thiazides)
Salt-losing nephropathy
Cerebral salt wasting
With urine sodium < 20 mmol/L
Gastrointestinal losses (e.g., vomiting or diarrhea)
Dermal loss (extensive burns)
Hypervolemia
Heart failure, cirrhosis, chronic renal failure, and
nephrotic syndrome

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procedures. Once the diagnosis is established, it is important to consider whether the etiology is primary or
secondary (Russo et al., 2007; Shulman, Palmert, &
Kemp, 2007). Primary adrenal insufficiency is a rare disorder with a prevalence of 90-140 per million in
developed countries (Hsieh & White, 2011). It is caused
by destruction or dysfunction of the adrenal cortex
gland producing impaired production or release of
mineralocorticoids and glucocorticoids. It has multiple
etiologies, including autoimmune, bilateral adrenalectomies, ACTH resistance, adrenoleukodystrophy, adrenal hypoplasia congenital, as well as CAH, adrenal
hemorrhages, and idiopathic causes (Hsieh & White,
2011).
Secondary adrenal insufficiency is produced by atrophy of the adrenal cortex due to decreased production
of ACTH by the pituitary gland. Any pathology or injury
that involves the hypothalamus or pituitary gland and
interferes with ACTH secretion, such as septo-optic
dysplasia, can produce this (Santhanam, Saleem, &
Saleem, 2010).
As seen in this case, the PCP must have a high index of
suspicion to diagnose CAH, especially when the newborn screen is negative.
3. When should CAH be suspected in the neonatal period and how is the specific type elucidated?
The diagnosis of CAH should be suspected in any
baby with shock, dehydration, electrolyte abnormalities, ambiguous genitalia or signs of inappropriate virilization (Collett-Solberg, 2001b; Merke & Bornstein,
2005; Shulman et al., 2007). Females with classical
forms usually have ambiguous genitalia. Genital findings include clitoromegaly, partially-fused labia majora
with rugae, and a urogenital sinus in place of a separate
urethra and vagina. Females with salt-losing CAH are
typically identified due to genital ambiguity prior to developing any electrolyte abnormalities. Some with minimal clitoromegaly may not be detected at birth but may
develop progressive clitoromegaly during the first year
of life (Witchel & Azziz, 2011).

BOX 2. Major causes of hyperkalemia

Hemolyzed sample
Metabolic acidosis
Renal failure
Mineralocorticoid deficiency or resistance
Pseudohyperkalemia
Insulin deficiency, hyperglycemia, and hyperosmolality
Increased tissue catabolism
Drugs (beta blockers, digitalis overdose, succinylcholine)

Journal of Pediatric Health Care

In males, the diagnosis of CAH is more difficult because external genital development is normal. Most
male neonates are not diagnosed until they present in
adrenal crisis, between 5 and 30 days of life, as in this
case. Hyperpigmentation of the external genitalia can
be a subtle physical finding in male newborns
(Collett-Solberg, 2001b; Shulman et al., 2007; Witchel
& Azziz, 2011). Around 75% of classic CAH is associated
with aldosterone deficiency, leading to salt wasting,
FTT, hypovolemia, and shock, but the remainder does
not have salt wasting. However, there is a mild nonclassic form of CAH (NCAH) which may show variable
degrees of postnatal androgen excess or may be asymptomatic (Speiser et al., 2010).
To review, CAH is a group of autosomal recessive
disorders (Collett-Solberg, 2001a). More than 90% of
cases of CAH are caused by a defect in the enzyme
21-hydroxylase (21-OH) deficiency. However, at least
four other enzyme deficiencies, along with one cholesterol transport protein defect, account for the remaining cases (Antal & Zhou, 2009). The general
world-wide incidence of severe 21-OH deficiency is
1/15,000 and more mild defects may affect more
than 1/1,000 with variation among different ethnic
backgrounds (Merke & Bornstein, 2005; Witchel &
Azziz, 2011).
The patients hormonal work-up revealed elevated
ACTH values suggesting CAH (Table). The specific defect was elucidated by drawing hormonal precursors in
the steroid synthesis pathway before and after administration of intravenous ACTH (Figure). In CAH secondary to 11 b-OH deficiency, high basal or ACTH
stimulated plasma levels of 11-deoxycorticosterone
and/or 11-deoxycortisol are elevated (Peter, Dubuis,
& Sippell, 1999; Zachmann, Tassinari, & Prader, 1983),
as shown in this patient (Table).

11 b-OH deficiency is caused by mutations in the

CYP11B1 gene (Peter et al., 1999). Data regarding the
frequency in the general population is scarce but since
defects that cause 11 b-OH deficiency account for 5%8% of patients with CAH in the general population, an
incidence of 1/250,000 can be assumed (CollettSolberg, 2001a; Merke et al., 1998; Peter et al., 1999).
Some studies report an incidence of 1/100,000 among
Caucasians, and of 1/5,000 to 1/7,000 in Israeli Moroccan Jews (Paperna, Gershoni-Baruch, Badarneh, Kasinetz, & Hochberg, 2005).
In the classic form of CAH secondary to 11 b-OH
deficiency, there are elevated mineralocorticoid precursors that can suppress the renin-angiotensinaldosterone axis and cause low renin, low aldosterone,
and hypertension. However, many of the affected neonates, like this patient, do not have hypertension and
suppressed plasma renin activity (PRA). Hypertension
often develops within the first years of life. Patients
with non-classic 11 b-OH deficiency have normal blood
pressure (Peter et al., 1999) and rare cases of classic 11
b-OH deficiency which present with signs of mineralocorticoid deficiency before treatment, have been reported (Zachmann et al., 1983).
4. How can CAH be diagnosed before a lifethreatening event occurs?
To diagnose a child with CAH before a lifethreatening event occurs, serum concentrations of
17-hydroxyprogesterone progesterone (17-OHP) are
measured as part of state newborn screening programs.
17-OHP levels are normally high at birth and decrease
rapidly during the first few postnatal days. In patients
with CAH, 17-OHP levels increase over time (Speiser
et al., 2010). However, a normal newborn screen does
not eliminate the diagnosis of CAH due to different factors. First, state screens test for the most common cause

FIGURE. Pathways of adrenal steroid. This schematic shows the pathways of adrenal steroid
synthesis. The highlighted gray boxes represent the four enzymes which deficiencies that can
produce CAH: 21-hydroxylase (21-OH), 11-beta hydroxylase (11-OH), 17-alpha-hydroxylase (17-OH),
and 3-beta-hydroxysteroid dehydrogenase (3b HSD). The large arrows (outlined in black) represent
the patients hormonal values supporting the diagnosis.

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of CAH, 21-hydroxylase deficiency, and not for other

less common forms of CAH (American Academy of Pediatrics, 2000). Second, 17-OHP concentration in NCAH
is usually lower than in classical CAH. Third, preterm infants, heterozygotic carriers, and stressed infants have
17-OHP concentrations similar to infants with NCAH.
Fourth, there are no universally accepted standards
for 17-OHP levels, however most U.S. laboratories use
a birth weight-adjusted and gender-specific cutoff. In
practice, states screens attempt to maintain balance between excessive numbers of false positive results while
trying to maintain adequate sensitivity and specificity to
detect classical CAH (Speiser et al., 2010; Witchel &
Azziz, 2011). To note, false negative results are uncommon but are more often in females (Varness, Allen, &
Hoffman, 2005).
Any newborn with ambiguous genitalia should undergo diagnostic studies including karyotype, abdominal/pelvic ultrasound, and serum 17-OHP. CAH should
be considered in newborns with undescended testes.
Serum electrolytes and PRA are also important to assess
mineralocorticoid deficiency, especially in males suspected to have CAH. In general, any sign of systemic illness should warrant laboratory work-up including
serum electrolytes (Witchel & Azziz, 2011). Adrenal insufficiency is a life-threatening disorder and it should be
in the clinicians differential with any neonate presenting with vomiting and FTT as demonstrated by this case.
5. What is the plan of care for a newborn with CAH?
The plan of care of a patient and family with CAH is
interdisciplinary, including the PCP, endocrinologist,
geneticist, surgeon, and a counselor. For high-risk
pregnancies due to maternal history of CAH or
a previous child with CAH, prenatal testing and treatment is available. Classic 11 b-OH deficiency can be
diagnosed by measuring 11-deoxycorticosterone and
11-deoxycortisol in the amniotic fluid (Peter et al.,
1999). However, prenatal therapy is currently experimental and there are no recommended treatment
protocols (Speiser et al., 2010).
In the neonatal period, any newborn with ambiguous
genitalia should be monitored closely for salt-wasting
signs and symptoms while the after diagnosis is
established. Neonates with a possible salt-wasting
form of CAH should be hospitalized for initial stabilization. Treatment includes electrolyte stabilization,
rehydration, replacement of glucocorticoids and mineralocorticoids, and sodium supplementation. It is particularly crucial to treat the cortisol deficiency by giving
glucocorticoids (GC), which reduce ACTH secretion
and adrenal androgen production (Peter et al., 1999;
Witchel & Azziz, 2011). Current practice guidelines recommend GC maintenance therapy with hydrocortisone
tablets in growing patients with classic CAH; if the baby
is salt wasting, then fludrocortisone and sodium chloride supplements are required, often even beyond the
newborn period (Speiser et al., 2010). Stress dosing
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is recommended (tripling the GC dosage of CAH patients) in situations such as febrile illness (> 38.5 C), gastroenteritis with dehydration, surgery, and major
trauma. However, pediatric endocrinologists do not
recommend stress GC doses in emotional stress, minor
illness, or before physical exercise (Claahsen-van der
Grinten, Stikkelbroeck, Otten, & Hermus, 2011;
Speiser et al., 2010).
Surgical reconstruction is usually recommended in
severely virilized girls, though timing and number of
surgical stages vary by practice. Endocrinologists recommend that this surgery be performed only by experienced centers (Speiser et al., 2010).
The long-term goal for the management of children
with CAH is the attainment of normal growth, achievement of normal sexual development and minimization
of the side effects from medications (Trapp, Speiser, &
Oberfield, 2011). Monitoring of infants and children
with CAH includes measurement of hormone levels,
regular follow-up of height, weight, and physical examination; and annual bone age assessment after age 2
years (Martin et al., 2011; Speiser et al., 2010).
CONCLUSION
Any infant with persistent FTT should receive not only
serial weight checks but also laboratory evaluation. A
high index of suspicion is required to diagnose rare
but life-threatening diseases, such as CAH in a newborn.
Care of the infant with CAH requires interdisciplinary
care, including the PCP, pediatric endocrinologist,
counselors, and surgeons.
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