PEDIATRICS

ENDOCRINOLOGY LECTURE
SERIES
 OBJECTIVES AND TIMELINE
Objective
To discuss Pediatric Endocrinology and common diseases related to it in the
pediatric ages groups
Discuss the Endocrinology system, the organs involved and its function
Common endocrinology diseases, its etiology, pathophysiology, diagnosis
and treatment
Schedule
 LECTURE OUTLINE AND REFERENCES

Topics
Endocrine system and the organs involved
Disorders of the Hypothalamus and the pituitary
Disorders of the thyroid gland and parathyroid Gland
Disorder of the Adrenal Gland
Disorders of the Gonads
Diabetes Mellitus
References
Nelson Textbook of Pediatrics 21st Edition
ENDOCRINE SYSTEM
Endocrine Organs in the Head and
Neck
Pituitary gland
Hypothalamus
Thyroid gland
Parathyroid Gland
Endocrine Organs in the abdomen
and pelvis
Adrenal Gland
Pancreas
*Gonads
 PHYSIOLOGY OF PUBERTY
Prepubertal Stage
- At childhood to 8-9 years old, HPG axis is dormant with undetectable levels of LH and
Sex Hormones
- 1-3 years before onset of puberty, nocturnal pulses of GnRH allow levels of LH to be
detectable which continues to increased and is responsible for enlargement and
maturation of the gonads and the secretion of sex hormones
Early Puberty
- Appearance of secondary sex characteristics is the visible culmination of the
peripubertal period
Midpuberty
- LH pulses become evident and occur at approximately 90-120 min intervals.
- A second critical event in girls which is cyclicity and ovulation, occur
 PHYSIOLOGY OF PUBERTY
Onset of Puberty
- The age of onset of puberty varies and is more closely correlated with osseous
maturation than with chronological age
- Females: breast bud (thelarche) is first sign of puberty (10-11 yr of age),
followed by appearance of pubic hair (pubarche) 6-12 mo later. The onset of
menstrual activity (menarche) is usually after 2-2.5 yr(max 6yrs) at 12.75yrs
- Males: growth of testes (≥4 mL vol or 2.5 cm dm) and thinning of the scrotum
are the first signs of puberty (11-12 yr). Followed by pigmentation of the
scrotum and growth of the penis and by pubarche
- . Appearance of axillary hair usually occurs in midpuberty
PHYSIOLOGY OF PUBERTY: FEMALES
PHYSIOLOGY OF PUBERTY: MALES
 DISORDERS OF PUBERTAL DEVELOPMENT
Precocious Puberty
- onset of secondary sexual characteristics before 8 yr in girls and 9 yr in boys
- Classification
Central (aka gonadotropin dependent, or true) -always isosexual and
stems from hypothalamic-pituitary-gonadal activation with ensuing sex
hormone secretion and progressive sexual maturation
Peripheral (aka gonadotropin independent or precocious
pseudopuberty) -some of the secondary sex characteristics appear, but
there is no activation of the normal hypothalamic-pituitary-gonadal interplay
- mixed type occurs in congenital adrenal hyperplasia, McCune-Albright
syndrome, and familial male-limited precocious puberty
 CENTRAL PRECOCIOUS PUBERTY
- Onset of breast development before the age of 8 yr in girls and onset of
testicular development (volume ≥4 mL) before age of 9 yr in boys,
- as a result of the early activation of HPG axis
Clinical Manifestation
- Progression follows that of normal
Females: menstruation may be irregular with initial cycle as unovulatory
Males: spermatogenesis may exist as early as 5-6 years old
- Height, weight, and osseous maturation are advanced resulting in early
closure of the epiphyses, with ultimate stature less than it would have been
otherwise
- Without treatment: Mental development equals chronological age.
Emotional behavior & mood swings are common, serious psychologic
problems are rare
 CENTRAL PRECOCIOUS PUBERTY
Laboratory Findings
- Sex hormone concentrations are usually appropriate for the stage of puberty
in both sexes
-
Serum LH, estradiol and testosterone determination: using highly sensitive
immunofluorometric and chemiluminescent assays yields 50-75% in girls
and higher in males. With moderate sensitivity, serial blood samples obtained
during sleep has greater diagnostic power than measurement in a single
random sample
-
IV GnRH agonist (leuprolide stimulation test) is a helpful diagnostic tool
-
Osseous maturation is variably advanced, often by more than 2-3 SD
-
Pelvic UTZ in girls reveals enlargement of the ovaries, fundus, uterus
-
MRI scan usually demonstrates physiologic enlargement of the pituitary
gland, as seen in normal puberty; it may also reveal CNS pathology
 CENTRAL PRECOCIOUS PUBERTY
Differential Diagnosis
 CENTRAL PRECOCIOUS PUBERTY
Differential Diagnosis
 CENTRAL PRECOCIOUS PUBERTY
Treatment
- Regardless of the cause, therapy with GnRH agonists is as effective in children
with organic brain lesions causing central precocious puberty, and these
analogs are the therapy of choice to halt premature sexual development.
- Combined growth hormone therapy should be considered for patients with
associated growth hormone deficiency.
 OTHER CAUSES OF PRECOCIOUS PUBERTY
Precocious Puberty Following Irradiation of the Brain
Radiation Therapy – for leukemia and Intracranial tumors
Low-dose radiation (18-24 Gy) hastens onset set of puberty almost girls.
High-dose radiation (25-47 Gy), conversely, appears to trigger in both sexes,
and the risk is inversely proportional to the age of the child at the time
TX: GnRH analogs. concomitant GH deficiency should be diagnosed & treated
Precocious Puberty Following Irradiation of the Brain
Untreated hypothyroidism, onset of puberty is usually delayed until epiphyseal
maturation reaches 12-13 yr of age Precocious puberty in a child with untreated
hypothyroidism and a prepubertal bone is common and may occur in as many as
50% of children with severe hypothyroidism of long duration.and
Hypothyroidism
 OTHER CAUSES OF PRECOCIOUS PUBERTY
Chorionic Gonadotropin-Secreting Tumors
HEPATIC TUMORS: Cases of hepatoblastoma causing isosexual precocious
puberty have been in boys, with average age of 2 yr (range: 4 mo to 8 yr)
INTRACRANIAL TUMORS: Nongerminomatous or mixed germ cell tumors,
choriocarcinomas, teratomas, teratocarcinomas, and others account for <5% of
intracranial tumors may cause precocious puberty in boys if they secrete hCG,
and rarely in girls because of mass effect
TUMORS IN OTHER LOCATIONS: Very rare locations include the
mediastinum, gonads, or even adrenal glands. Mediastinal tumors have been
reported to cause precocious puberty in boys with Klinefelter syndrome
 OTHER CAUSES OF PRECOCIOUS PUBERTY
McCune-Albright Syndrome
(Precocious Puberty with Polyostotic Fibrous Dysplasia and
Abnormal Pigmentation)
- Syndrome of endocrine dysfunction is associated with patchy cutaneous pigmentation
and fibrous dysplasia of the skeletal system].
- It is a rare, prevalence between 1 in 100,000 and 1 in 1,000,000
- Classic cause of peripheral precocious puberty, it can also induce pituitary, thyroid, and
adrenal aberration
- caused by a missense mutation in the gene encoding α-subunit of GS, the G protein that
stimulates CAMP formation
- Treatment For girls, Aromatase inhibitors, letrozole (1.25-2.5 mg/day orally) or
antiestrogens (such as tamoxifen 5-20 mg/day orally)
- for boys, those, plus antiandrogens (spironolactone 50-100 mg bid, flutamide 125-250
mg bid, or bicalutamide 25-50 mg daily)
ENDOCRINE SYSTEM
Endocrine Organs in the Head and
Neck
Pituitary gland
Hypothalamus
Thyroid gland
Parathyroid Gland
Endocrine Organs in the abdomen
and pelvis
*Adrenal Gland
Pancreas
Gonads
ADRENAL GLAND
 ADRENAL GLAND
composed of 2 endocrine tissues: the medulla and the cortex
The adrenal cortex consists of 3 zones: the zona glomerulosa, the outermost
zone; the zona fasciculata, the middle zone; and the zona reticularis, the
innermost zone
zona glomerulosa: aldosterone (most potent natural mineralocorticoid)
zona fasciculata: cortisol (most potent natural glucocorticoid)
zona reticularis synthesize the adrenal androgens
The adrenal medulla consists mainly of neuroendocrine (chromaffin) cells and
glial (sustentacular) cells with some connective tissue and vascular cells.It
produces catecholamine, epinephrine and norepinephrine
ADRENAL GLAND
 CONGENITAL ADRENAL HYPERPLASIA
Family of autosomal recessive disorders affecting adrenal steroidogenesis
21-Hydroxylase deficiency
11β-Hydroxylase deficiency
17α-Hydroxylase deficiency
3β-Hydroxysteroid dehydrogenase deficiency
Lipoid/StAR CAH
U.S. Occurrences – 1:15,500 Caucasian births, 1:42,000 African American
births
HYPOTHALAMIC–PITUITARY-ADRENAL (HPA) AXIS

ABNORMAL HPA FEEDBACK (CAH)

NORMAL HPA FEEDBACK
Hypothalamus Hypothalamus

CRH CRH

Anterior Pituitary Anterior Pituitary

ACTH ACTH

Adrenal Cortex Adrenal Cortex

Cortisol Cortisol
 21-HYDROXYLASE DEFICIENCY

CRH, ACTH

21-Hydroxylase
 21-HYDROXYLASE DEFICIENCY
>90% of CAH cases
CYP21 gene on chromosome 6
Classic Phenotype Non-classic Phenotype

Severe form Mild/late-onset form

1:15,000 live births 1:1,000 live births

Salt-losing (67%) or Simple virilizing (33%)

 21-HYDROXYLASE DEFICIENCY
FEMALES MALES
Enlarged clitoris Subtle hyperpigmentation
Partly-fused, rugose labia majora Possible penile enlargement
Common urogenital sinus in place Salt-losing presents DOL 7-14 with
of urethra and vagina emesis, weight loss, lethargy,
Salt-losing present soon after dehydration, shock, hyponatremia,
birth, given ambigious genitalia hyperkalemia
Normal internal female organs Non-salt-losing present with early
virilization at 2-4yrs
Normal male internal organs, but
can have small testes if untreated
SALT-WASTING 21-HYDROXYLASE DEFICIENCY
67% patients with classic 21-hydroxylase deficiency
Secondary to aldosterone deficiency
Associated lab abnormalities: hyponatremia, hyperkalemia
Early signs: frequent feedings
Present with salt-wasting and acute adrenal crisis within weeks after birth
CLINICAL MANIFESTATION: ADRENAL CRISIS
DECREASED ACTIVITY/FATIGUE
ALTERED MENTAL STATUS
POOR FEEDING/WEAK SUCK
DRY MUCOUS MEMBRANES
HYPERPIGMENTATION
ABDOMINAL PAIN AND VOMITING
HYPONATREMIA, HYPERKALEMIA, HYPOGLYCEMIA
METABOLIC ACIDOSIS
HYPOTHERMIA, HYPOTENSION, DEHYDRATION
LACK OF WEIGHT GAIN
CONGENITAL ADRENAL HYPERPLASIA: LABORATORY WORKUP

POC GLUCOSE
CMP (NEED NON-HEMOLYZED SAMPLE)
ABG
CORTISOL LEVEL
ACTH
17-HYDROXYPROGESTERONE LEVEL
PELVIC/SCROTAL ULTRASOUND
KARYOTYPE
NON-CLASSIC 21-HYDROXYLASE DEFICIENCY EXAM FINDINGS

PRESENT IN LATE CHILDHOOD OR EARLY ADULTHOOD

HYPERANDROGENISM MANIFESTATIONS
PREMATURE ADRENARCHE
ADVANCED BONE AGE, SHORT ADULT STATURE
FEMALE HIRSUTISM (60%) OR MALE-PATTERN BALDNESS
OLIGOMENORRHEA/AMENORRHEA (54%)
POLYCYSTIC OVARIES
INSULIN RESISTANCE
ACNE (33%)
5-10% CHILDREN WITH PREMATURE ADRENARCHE HAVE AN
UNDERLYING DIAGNOSIS OF NON-CLASSIC CAH
Other Forms of CAH
 11-β Hydroxylase Deficiency

CRH, ACTH

11-β Hydroxylase
17-α Hydroxylase/ 17,20 Lyase Deficiency

CRH, ACTH

17,20 Lyase
17-α Hydroxylase
 3-β Hydroxysteroid Dehydrogenase Deficiency

CRH, ACTH

3-β
Hydroxysteroid
Dehydrogenase
StAR (Congenital Lipoid Hyperplasia)

CRH, ACTH

StA
R
CONGENITAL ADRENAL HYPERPLASIA: DIAGNOSIS

17-OHP Screen Obtained

Normal Elevated 17-OHP

Compare to
normals for birth
weight and EGA

Borderline Elevated

Repeat 17-OHP Physical exam

ACTH stim test
Endocrine referral
DNA analysis
 CONGENITAL ADRENAL HYPERPLASIA: DIAGNOSIS

NEWBORN SCREENS
HIGH 17-HYDROXYPROGESTERONE (17-OHP) LEVEL >242
NMOL/L ON DAY OF LIFE 3
INCREASED FALSE-POSITIVE RISK WITH PREMATURE INFANTS
NEED FOR AGE-ADJUSTED LEVELS
PRENATAL TREATMENT WITH GLUCOCORTICOIDS
CORTICOTROPIN STIMULATION TEST
17-OHP > 45NMOL/L (1400 NG/DL) IS DIAGNOSTIC.
PLASMA RENIN ACTIVITY (PRA) TO ALDOSTERONE RATIO
EVALUATE AMBIGUOUS GENITALIA WITH KARYOTYPE AND
PELVIC/ABDOMINAL ULTRASOUND
 CONGENITAL ADRENAL HYPERPLASIA: TREATMENT

SUPPLEMENTAL GLUCOCORTICOIDS
HYDROCORTISONE 12-20MG/M2 PER DAY DIVIDED TID
DEXAMETHASONE Q DAY
CONTINUOUS SUBCUTANEOUS THERAPY?
STRESS-DOSE WHEN ILL OR UNDERGOING SURGERY
SUPPLEMENTAL MINERALOCORTICOIDS
FLUDROCORTISONE 0.1-0.2MG, UP TO 0.4MG, PER DAY
SODIUM CHLORIDE 1-2G (1G = 17 MEQ SODIUM)
REGULAR LABS
17-OHP, ANDROSTENEDIONE
WATCH FOR CUSHING’S SYNDROME
ANNUAL BONE AGE
CONGENITAL ADRENAL HYPERPLASIA: LABORATORY TREATMENT

Glucocorticoid Potency
Hydrocortisone (Cortef, Solu-cortef) 1
Prednisone 4
Prednisolone (Orapred, Prelone) 4
Methylprednisone (Solu-Medrol) 5
Dexamethasone (Decadron) 20-25

Maintenance Adrenal Gland Production of Cortisol: 6

mg/m2/day
Maintenance Oral Hydrocortisone Dose: 12 mg/m2/day

Emergency Glucocorticoid Dosing (IM or

IV)
Infant Child Adult
Methylprednisone 25 mg 50 mg 100 mg
Dexamethasone 1 mg 2 mg 4-5 mg
Thank
you!