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PITUITARY DISORDERS
Gülay ÇİLER ERDAĞ
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
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 gland’s hormones:
 Growth hormone (GH)
 Adrenocorticotropic hormone (ACTH)
 Thyroid-stimulating hormone (TSH)
 Luteinizing hormone (LH)
 Follicle-stimulating hormone (FSH)
 Prolactin (PRL)
The anterior pituitary is primarily regulated by neuropeptidereleasing 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 hormone–releasing hormone (GHRH)
Corticotropin-releasing hormone (CRH)
Thyrotropin-releasing hormone (TRH)
Gonadotropin-releasing hormone (GnRH)
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
 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.
The posterior pituitary consists of neural tissue that
descends from the floor of the third ventricle.
In contrast to the anterior pituitary hormones,
posterior pituitary hormones (ie, ADH, oxytocin)
synthesized by cell bodies in the hypothalamus
transported along the neurohypophyseal tract of
pituitary stalk.
the
are
and
the
Release of these hormones occurs in response to
neurohypophyseal stimuli.
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
Causes of hypopituitarism can be divided into categories
of congenital and acquired causes.
Acquired etiologies
 Cranial irradiation and hemochromatosis can lead to hypopituitarism.
 Infiltrative disorders that can cause hypopituitarism:
 Histiocytosis X
 Tuberculosis
 Sarcoidosis
 Lymphocytic hypophysitis
 Tumors:
 Craniopharyngioma[13]
 Germinoma[14]
 Glioma/astrocytoma
 Pituitary adenoma (rare prior to adulthood)
 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.
 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
 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
 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).
 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.
 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.
 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.
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
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.
 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.
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
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 pre–gadolinium contrast
and post–gadolinium contrast, which can be helpful in the
delineation of the posterior pituitary and some pituitary tumors.
Laboratory Studies
Screening for GHD using insulinlike growth factor-I (IGF-I) and
insulinlike growth factor–binding 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.
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.
 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.
 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.
 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 patient’s need for stress hydrocortisone
 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
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).
 Pathophysiology
 Hypothalamic dysfunction clearly may promote tumor growth, but
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overwhelming evidence indicates intrinsic pituicyte genetic disruption
leads to pituitary tumorigenesis.
The monoclonal nature of most pituitary adenomas, confirmed by Xinactivation 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.
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.
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.
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
hydroxycorticosteroids (17-OHCS)
of
free
cortisol
and
17-
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.
•Pubertal arrest, failure, or delay may occur.
•Amenorrhea may be noted.
•Hypertension may be present.
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).
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.