The pituitary is a small gland located at the base of the
brain, roughly in the space between your eyes. It is responsible
for the regulation and secretion of a number of different hormones
both in adults and in children
Slide 3
Pituitary gland development and physiology The pituitary gland,
located at the base of the brain, is composed of anterior (ie,
adenohypophysis) and posterior (ie, neurohypophysis) regions. The
anterior pituitary, an ectodermal structure that derives from the
pharynx as the Rathke pouch, produces most of the glands hormones:
Growth hormone (GH) Adrenocorticotropic hormone (ACTH)
Thyroid-stimulating hormone (TSH) Luteinizing hormone (LH)
Follicle-stimulating hormone (FSH) Prolactin (PRL)
Slide 4
The anterior pituitary is primarily regulated by neuropeptide-
releasing and release-inhibiting hormones produced in the
hypothalamus. These regulatory hormones are transported to the
anterior pituitary via the pituitary portal system circulation. The
release-stimulating hormones produced by the hypothalamus include
the following: Growth hormonereleasing hormone (GHRH)
Corticotropin-releasing hormone (CRH) Thyrotropin-releasing hormone
(TRH) Gonadotropin-releasing hormone (GnRH)
Slide 5
A negative feedback loop occurs such that the hormones produced
in the target glands feed back to inhibit the release of their
respective regulatory pituitary and hypothalamic factors. For
example, hypothalamic TRH stimulates TSH release, which in turn
stimulates the thyroid gland, resulting in increased serum levels
of thyroxine (T4) and triiodothyronine (T3). When they have reached
sufficient levels, T3 and T4 suppress TRH and TSH release
Slide 6
PRL secretion is distinct from that of the other anterior
pituitary hormones, being inhibited by hypothalamic dopamine. In
addition, antidiuretic hormone (ADH) produced in the hypothalamus
acts synergistically with CRH to promote ACTH release.
Slide 7
The posterior pituitary consists of neural tissue that descends
from the floor of the third ventricle. In contrast to the anterior
pituitary hormones, the posterior pituitary hormones (ie, ADH,
oxytocin) are synthesized by cell bodies in the hypothalamus and
transported along the neurohypophyseal tract of the pituitary
stalk. Release of these hormones occurs in response to
neurohypophyseal stimuli.
Slide 8
Causes of hypopituitarism can be divided into categories of
congenital and acquired causes. Congenital causes of
hypopituitarism : Perinatal insults (eg, traumatic delivery, birth
asphyxia) Interrupted pituitary stalk Absent or ectopic
neurohypophysis Pallister-Hall syndrome Genetic disorders causing
hypopituitarism include the following: Isolated GH deficiency types
IA, IB, II, III MPHD (eg, from PIT1 and PROP1 mutations)
Septo-optic dysplasia Isolated gonadotropin deficiency (eg, from
KAL and KISS1R mutations) Developmental central nervous system
(CNS) defects that cause hypopituitarism include the following:
Anencephaly Holoprosencephaly Pituitary aplasia or hypoplasia
Slide 9
Causes of hypopituitarism can be divided into categories of
congenital and acquired causes. Acquired etiologies Cranial
irradiation and hemochromatosis can lead to
hypopituitarism.hemochromatosis Infiltrative disorders that can
cause hypopituitarism: Histiocytosis X Tuberculosis Sarcoidosis
Lymphocytic hypophysitis Tumors: Craniopharyngioma [13]
Craniopharyngioma Germinoma [14] Glioma/astrocytoma Pituitary
adenoma (rare prior to adulthood)
Slide 10
multiple pituitary hormone deficiencies MPHD- is rare in
childhood, with a possible incidence of fewer than 3 cases per
million people per year. The most common pituitary hormone
deficiency, GHD, is much more frequent; a US study reported a
prevalence of 1 case in 3480 children.GHD A 2001 population study
in adults in Spain estimated the annual incidence of
hypopituitarism at 4.2 cases per 100,000 population. Because
hypopituitarism has congenital and acquired forms, the disease can
occur in neonates, infants, children, adolescents, and adults
Slide 11
Prognosis With appropriate treatment, the overall prognosis in
hypopituitarism is good. Sequelae from episodes of severe
hypoglycemia, hypernatremia, or adrenal crises are among potential
complications. Long-term complications include short stature,
osteoporosis, increased cardiovascular morbidity/mortality, and
infertility. Hypoglycemia - Can cause convulsions; persistent,
severe hypoglycemia can cause permanent CNS injury. Adrenal crisis
- Can occur during periods of significant stress, from ACTH or CRH
deficiency; symptoms include profound hypotension, severe shock,
and death. Short stature - Can have significant psychosocial
consequences. Hypogonadism and impaired fertility - From
gonadotropin deficiency Osteoporosis - Results in increased
fracture risk
Slide 12
The clinical presentation of hypopituitarism, which widely
varies, depends on the patient's age, the etiology, and the
specific hormone deficiencies, which may occur as isolated
deficiencies or in various combinations of MPHD. Presenting signs
and symptoms may develop insidiously and can be nonspecific,
requiring a high index of suspicion. Neonates Most neonates with
hypopituitarism have normal or even high birth weights and lengths
and no history of intrauterine growth retardation. However, they
often have histories of breech presentation, although the
explanation for this is unclear. Microgenitalia, mainly in males,
may result from a gonadotropin deficiency or from GH deficiency.
The hypoglycemia risk is higher in neonates with hypopituitarism,
with various manifesting symptoms, such as lethargy, jitteriness,
pallor, cyanosis, apnea, or convulsions. Jaundice may be secondary
to indirect hyperbilirubinemia (as occurs in TSH axis deficiency)
or to direct hyperbilirubinemia (as occurs in GH or ACTH axis
deficiencies).
Slide 13
Older infants and children Common presenting features include
growth failure, disorders of pubertal development, and diabetes
insipidus. Growth failure may be the most common presenting symptom
in this age group, possibly with an associated delay in tooth
development. Hypoglycemia, although less frequent, can also be a
presenting sign of hypopituitarism in older infants and children.
Patients with acquired or milder forms of gonadotropin deficiency
who do not present with microgenitalia in infancy may present later
with absent or delayed puberty.diabetes insipidusGrowth failure
Central diabetes insipidus secondary to ADH deficiency can be
difficult to recognize in infancy, because patients often present
with nonspecific signs (eg, irritability, unexplained fever).
Symptoms of polyuria and polydipsia are more readily obvious in
older children. Patients with hypothyroidism secondary to a TSH
axis deficiency present with signs and symptoms identical to those
of primary hypothyroidism, although typically less severe. These
include fatigue, cold intolerance, constipation, dry skin, slow
growth, and weight gain.
Slide 14
Older infants and children: Depending on the etiology of the
hypopituitarism, associated findings in the neonate, infant, or
child may include developmental delay, various visual and
neurologic symptoms, seizure disorder, and a number of congenital
malformation syndromes. Optic nerve hypoplasia has been associated
with a spectrum of endocrine abnormalities, from isolated GHD to
MPHD. Patients with acquired hypopituitarism, caused by a
suprasellar tumor, often present with headaches, visual
disturbances, and other neurologic symptoms. Anencephaly is
associated with variable pituitary hypoplasia and complete absence
of the hypothalamus. Various forms of holoprosencephaly particular
associated with HESX1 mutations may be associated with
hypopituitarism.
Slide 15
Physical Examination Neonates Birth weights and lengths are
typically within the reference range in neonates with
hypopituitarism. Important physical signs in the neonate that may
suggest a diagnosis of hypopituitarism include microgenitalia,
jaundice, and physical evidence of possible hypoglycemia (ie,
jitteriness, pallor). [19] Microgenitalia includes micropenis
(which has a well-documented association with hypopituitarism) and
an underdeveloped clitoris. Micropenis is defined as stretched
penile length less than 2.5 cm (reference range mean length is 4
cm). Data on normal clitoral size, including that for different
gestational ages, are also available. [20] Cryptorchidism is often
associated with micropenis. Optic nerve hypoplasia is associated
with hypopituitarism; the presence of small, pale optic disks or
nystagmus should prompt consideration of hypopituitarism
Slide 16
Physical Examination Older infants and children Growth failure
(see the image below) is the most important sign to recognize in
hypopituitarism. Growth failure may often exist for a considerable
period of time before it is recognized. In addition to short
stature and abnormal growth rate, the affected child may show
evidence of delayed skeletal maturation (eg, delayed dental
development During the physical examination, pay particular
attention to pubertal development, because patients with
hypopituitarism may present with microgenitalia in infancy or with
delayed or absent puberty. Anosmia, particularly in a patient with
delayed or absent puberty, should prompt consideration of Kallmann
syndrome (KS). Weight gain typically is out of proportion to
growth, resulting in relative obesity. This obesity is truncal in
distribution; skull and head circumference growth are typically
preserved, producing the impression of a large head. Craniofacial
features of pituitary GHD include craniofacial disproportion (ie,
normal head circumference, small facies, prominent forehead,
frontal bossing). The presence of a central incisor is an
important, finding because it may represent hypopituitarism in a
midline CNS abnormality.obesity Visual and neurologic abnormalities
may represent important features associated with hypopituitarism.
When not recognized in infancy, optic nerve hypoplasia may be noted
in childhood as decreased visual acuity. Signs that may indicate
the potential presence of a suprasellar mass include decreased
visual acuity, visual field defects, papilledema, and/or optic
atrophy.
Slide 17
Diagnostic Considerations Conditions to consider in the
differential diagnosis of hypopituitarism include the following:
Delayed puberty Psychosocial deprivation Hyposomatotropism
Hypothyroidism Neonatal jaundice Differential Diagnoses Adrenal
Insufficiency Ambiguous Genitalia and Intersexuality Diabetes
Insipidus Growth Failure Growth Hormone Deficiency Hypernatremia
Hypoglycemia Hypogonadism Hyponatremia Microphallus
Slide 18
Approach Considerations Laboratory tests are essential in the
diagnosis and assessment of patients with hypopituitarism. However,
any patient with hypopituitarism must also have a magnetic
resonance imaging (MRI) examination to exclude a brain tumor. A
brain MRI with specific cuts of the pituitary is the preferred
imaging study for hypopituitarism. [23] This may be obtained
pregadolinium contrast and postgadolinium contrast, which can be
helpful in the delineation of the posterior pituitary and some
pituitary tumors.
Slide 19
Laboratory Studies Screening for GHD using insulinlike growth
factor-I (IGF-I) and insulinlike growth factorbinding protein 3
(IGFBP-3) may be useful, except in cases of brain tumors. Random
measurement of GH levels has no diagnostic value except during
early infancy, when GH levels are usually tonically elevated. If
abnormal growth patterns are seen, and GHD is strongly suspected,
further provocative testing of GH secretion is typically performed
under the supervision of a pediatric endocrinologist.
Insulin-induced hypoglycemia is the most reliable provocative test
for GHD and has the added advantage of accurately assessing the
CRH-ACTH-cortisol axis. Measurement of morning serum cortisol
levels can help to exclude a CRH-ACTH-cortisol axis deficiency; a
level of 20 mcg/dL virtually excludes this diagnosis.
Slide 20
To assess central hypothyroidism (ie, TSH or TRH deficiency),
low free thyroxine (FT4) levels assayed by dialysis and reference
range or low serum TSH levels are diagnostic. Elevated serum sodium
and serum osmolality levels, when combined with low or low-normal
urine osmolality, suggest diabetes insipidus. A low serum ADH level
in this context can be diagnostic for central diabetes insipidus
(ie, pituitary vasopressin deficiency). A water deprivation test is
definitive; this test is performed under the supervision of a
pediatric endocrinologist. In patients with diabetes insipidus,
serum sodium and serum osmolality levels rise during water
deprivation, while urine fails to concentrate properly. A normal
response to administered vasopressin differentiates central
diabetes insipidus from nephrogenic diabetes insipidus.
Slide 21
TREATMENT Treatment for hypopituitarism primarily involves
appropriate hormone replacement. The presence of 1 or more hormone
deficiencies determines medication choice. Conduct appropriate
stress dosing of corticosteroid replacement. Surgical intervention
can be employed in tumor-associated hypopituitarism, with the tumor
location and type dictating the choice of surgical procedure. Diet
and activity are typically unrestricted in patients with
hypopituitarism, but special situations do apply that can impact
these areas, depending on the underlying cause of
hypopituitarism.
Slide 22
Diet Special considerations may apply in dietary management for
children with hypopituitarism. Children with diabetes insipidus and
hypopituitarism may require close monitoring of water and fluid
intake to prevent excessive fluctuations in blood sodium and
osmolality. Children with hypothalamic damage in association with
their hypopituitarism may be predisposed to hypothalamic obesity,
with risk for rapid weight gain with morbid obesity. This
subpopulation of children with hypopituitarism require close
monitoring of their daily food intake.
Slide 23
Long-Term Monitoring Routinely monitor growth and development
at 3-month intervals in patients with hypopituitarism. If a patient
is receiving recombinant human growth hormone (rhGH) therapy,
monitor for adverse effects and monitor insulinlike growth factor
(IGF)-I and insulinlike growth factor binding protein-3 (IGFBP3)
levels at least annually. Also, consider monitoring for impaired
glucose tolerance with a fasting morning blood sugar or hemoglobin
A1c (HgbA1c), particularly in the patient with risk factors for
diabetes mellitus (eg, family history, obesity). Monitor thyroid
functions routinely in hypopituitarism (FT4) or as part of
scheduled monitoring in isolated GHD, when appropriate. Consider
repeat low-dose ACTH stimulation testing in high-risk patients or
if clinical symptoms of cortisol deficiency are apparent. Home
blood glucose monitoring to screen for hypoglycemia in very young
patients and/or patients with central adrenal insufficiency should
be strongly considered. In those patients with hypopituitarism that
includes adrenal insufficiency, a medical alert bracelet should be
worn, alerting first-responders of the patients need for stress
hydrocortisone therapyblood glucose monitoring
Slide 24
Consultations Consultations are dependent on the etiology of
hypopituitarism. Some of the consultants that may be involved in
the care of patients with hypopituitarism come from the following
specialties: Ophthalmology - Optic nerve hypoplasia, septo-optic
dysplasia, pituitary tumors Neurology - Septo-optic dysplasia,
holoprosencephaly, traumatic brain injury, pituitary tumors or
other CNS tumors Genetics - Congenital hypopituitarism, septo-optic
dysplasia, holoprosencephaly Oncology - CNS tumors (including
pituitary tumors), other malignancies Rehabilitation medicine
Psychology services for neurodevelopmental and educational
monitoring
Slide 25
Slide 26
Hyperpituitarism Hyperpituitarism, or primary hypersecretion of
pituitary hormones, is rare in children. It typically results from
a pituitary microadenoma. The most frequently encountered adenoma
in children is the prolactinoma,and corticotropinoma &
somatotropinoma. Hypersecretion of pituitary hormones secondary to
macroadenomas can interfere with other pituitary hormone functions,
resulting in target organ hormone deficiencies (hypogonadism,
hypoadrenalism, hypothyroidism).hypogonadismhypothyroidism
Slide 27
Pathophysiology Hypothalamic dysfunction clearly may promote
tumor growth, but overwhelming evidence indicates intrinsic
pituicyte genetic disruption leads to pituitary tumorigenesis. The
monoclonal nature of most pituitary adenomas, confirmed by X-
inactivation studies, implies their usual origin from a clonal
event in a single cell. Most pituitary adenomas are functional and
secrete a hormone that produces a characteristic clinical
presentation. Nonfunctioning pituitary adenomas are rare in
children, whereas they comprise 30% of adenomas in adults. In
children, disruption of growth regulation and/or sexual maturation
is common, either because of hormone hypersecretion or because of
manifestations caused by local compression by the tumor.
Slide 28
Prolactinoma Overall, prolactinoma is the most common pituitary
adenoma encountered in childhood. Most pediatric cases occur in
adolescence, more commonly in females than males. Boys tend to have
larger tumors and higher serum prolactin (PRL) levels than girls.
Females with these tumors present with amenorrhea, and males
present with gynecomastia and hypogonadism. Prolactinomas arise
from acidophilic cells that are derived from the same lineage as
the somatotropes and thyrotropes. Hence, PRL-secreting adenomas may
also stain for and secrete growth hormone (GH) and, occasionally,
TSH.amenorrhea
Slide 29
Corticotropinoma (Cushing disease) In children,
corticotropinomas are the most common adenomas observed before
puberty, although they occur in people of all ages. They increase
in frequency in pubescent and postpubescent children, with a female
preponderance. First described by Harvey Cushing in the early
1900s, Cushing disease specifically refers to an
adrenocorticotropic hormone (ACTH) producing pituitary adenoma that
stimulates excess cortisol secretion.Cushing disease
Slide 30
Adenomas that cause Cushing disease are significantly smaller
than all other types of adenomas at presentation. Children have
clinical courses somewhat different from adults. They most commonly
present with weight gain (usually not centripetal) and growth
failure. As in adults, most patients display an absence of the
physiologic diurnal rhythm of plasma cortisol and ACTH with
increased urinary excretion of free cortisol and 17-
hydroxycorticosteroids (17-OHCS)
Slide 31
Slide 32
Slide 33
Cushingoid appearance includes a dorsal cervical fat pad, moon
facies, bruising, and striae. These features are only observed in
patients with advanced long-standing disease. Growth failure and
short stature may be observed. Weight gain and obesity in children
with Cushing disease tends to be generalized rather than
centripetal.obesity Pubertal arrest, failure, or delay may occur.
Amenorrhea may be noted. Hypertension may be
present.Hypertension
Slide 34
Somatotropinoma (gigantism) GH-secreting adenomas are rare in
childhood. Gigantism refers to GH excess in childhood when open
epiphysial plates allow for excessive longitudinal growth. Most
cases of gigantism result from GH-secreting pituitary adenomas or
hyperplasia. Although gigantism typically occurs as an isolated
disorder, it occasionally represents one feature of other
conditions (eg, multiple endocrine neoplasia [MEN] type 1,
McCune-Albright syndrome [MAS], neurofibromatosis, tuberous
sclerosis, Carney complex).Gigantismmultiple endocrine neoplasia
[MEN] type 1McCune-Albright syndrome [MAS]neurofibromatosistuberous
sclerosis
Slide 35
Thyrotropinoma Very few cases of thyrotropinoma have been
reported in children. These adenomas may secrete excess PRL, GH,
and alpha subunit in addition to TSH. They are usually large
because of their aggressive features and because their diagnosis is
often delayed. The clinical presentation consists of signs and
symptoms of hyperthyroidism, visual symptoms, and headaches.
Biochemical features include the elevation of circulating free
thyroxine (T4) and total triiodothyronine (T3) levels but
inappropriately unsuppressed TSH.headaches