Gülay Ç İ LER ERDA Ğ PITUITARY DISORDERS. The pituitary is a small gland located at the base of...

Glay LER ERDA PITUITARY DISORDERS

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 glands 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 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)

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, 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.

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.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)

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

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.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.

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.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.

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 pregadolinium contrast and postgadolinium 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 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.

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 patients need for stress hydrocortisone therapyblood glucose monitoring

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).hypogonadismhypothyroidism

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.

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

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

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)

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

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

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

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