Objectives of this lecture Hypopituitarism Objectives of this lecture Definition Causes Clinical features: congenital and acquired Diagnosis Treatment and adverse effects

Hypopituitarism Hypopituitarism : underproduction of growth hormone (GH) alone or in combination with deficiencies of other pituitary hormones. Affected children have postnatal growth impairment that is specifically corrected by replacement of GH. The incidence of hypopituitarism is between 1 in 4,000 and 1 in 10,000 live births.

Aetiology MULTIPLE PITUITARY HORMONE DEFICIENCY Genetic Forms Acquired Forms The most common lesion is the craniopharyngioma. CNS germinoma, eosinophilic granuloma (histiocytosis), tuberculosis, sarcoidosis, toxoplasmosis, meningitis, and aneurysms may also cause hypothalamic-hypophyseal destruction. Trauma, including shaken child syndrome, motor vehicle crash, traction at delivery, anoxia, and hemorrhagic infarction, may also damage the pituitary, its stalk, or the hypothalamus.

Genetic forms of GH deficiency ISOLATED GROWTH HORMONE DEFICIENCY AND INSENSITIVITY Genetic forms of GH deficiency Acquired Forms: the use of radiotherapy for malignancy, meningitis, histiocytosis, and trauma. GH insensitivity: Abnormalities of GH receptor Post – receptor forms of GH insensitivity

CLINICAL MANIFESTATIONS: Congenital hypopitutarism: The child with hypopituitarism is usually of normal size and weight at birth . *Children with severe defects in GH production or action are more than 4 SD below the mean by 1 yr of age.. *Infants present with neonatal emergencies such as apnea, cyanosis, or severe hypoglycemia with or without seizures. *Microphallus in boys provides an additional diagnostic clue. *Prolonged neonatal jaundice is common. *special faces: *The head of the toddler is round, and the face is short and *The nose is small, and the nasolabial folds are well developed. *The eyes are somewhat bulging.

The neck is short, and the larynx is small *The neck is short, and the larynx is small. The voice is high- pitched and remains high after puberty. *The extremities are well proportioned, with small hands and feet. *Weight for height is usually normal, *The genitalia are usually small for age, and sexual maturation may be delayed or absent. *Facial, axillary, and pubic hair usually is lacking, and the scalp hair is fine. *Symptomatic hypoglycemia, usually after fasting, occurs in 10–15% of children with panhypopituitarism and those with IGHD. *Intelligence is usually normal.

Acquired hypopitutarism: The child initially is normal; manifestations similar to those seen in idiopathic pituitary growth failure gradually appear and progress. When complete or almost complete destruction of the pituitary gland occurs, signs of pituitary insufficiency are present. Atrophy of the adrenal cortex, thyroid, and gonads results in loss of weight, asthenia, sensitivity to cold, and absence of sweating. Sexual maturation fails to take place or regresses if already present. There is a tendency to hypoglycemia. Growth slows dramatically.

*If the lesion is an expanding tumor, symptoms such as headache, vomiting, visual disturbances, pathologic sleep patterns, decreased school performance, seizures, polyuria, and growth failure may occur. *Slowing of growth may antedate neurologic signs and symptoms, especially with craniopharyngiomas, but symptoms of hormonal deficit account for only 10% of presenting complaints.Evidence of pituitary insufficiency may first appear after surgical intervention. *In children with craniopharyngiomas, visual field defects, optic atrophy, papilledema, and cranial nerve palsy are common.

LABORATORY FINDINGS: The diagnosis of GH deficiency is suspected in children with moderate to severe postnatal growth failure. Criteria for growth failure include height below the 1% for age and sex, or height more than 2 SD below sex-adjusted mid-parent height. Acquired GH deficiency can occur at any age; when it is of acute onset, height may be within the normal range but growth velocity decline. A strong clinical suspicion is important in establishing the diagnosis because laboratory measures of GH sufficiency lack specificity. Definitive diagnosis of GH deficiency traditionally requires demonstration of absent or low levels of GH in response to stimulation. A variety of provocative tests have been devised that rapidly increase the level of GH in normal children. These include administration of insulin, arginine, clonidine, or glucagon.

In chronic GH deficiency, the demonstration of poor linear growth, delayed skeletal age, and peak levels of GH (<10 ng/mL) in each of 2 provocative tests, are compatible with GH deficiency. In acute GH deficiency, a high clinical suspicion of GH deficiency and low peak levels of GH (<10 ng/mL) in each of 2 provocative tests are compatible with GH deficiency. A majority of normal prepubertal children fail to achieve GH values >10 ng/mL with 2 pharmacologic tests. Three days of estrogen priming may be needed prior to GH testing to achieve greater diagnostic specificity. *In addition to establishing the diagnosis of GH deficiency, it is necessary to examine other pituitary functions. Levels of TSH, thyroxine (T4), ACTH, cortisol, gonadotropins, and gonadal steroids may provide evidence of other pituitary hormonal deficiencies.

*The defect can be localized to the hypothalamus if there is a normal response to the administration of hypothalamic-releasing hormones for TSH, ACTH, or gonadotropins. RADIOLOGICAL FINDINGS: Skeletal maturation (bone age) is delayed in patients with IGHD and may be even more delayed when there is combined GH and TSH deficiency. CT is appropriate for recognizing suprasellar calcification associated with craniopharyngiomas and bony erosions accompanying histiocytosis. MRI provides a much more detailed view of hypothalamic and pituitary anatomy.

DIFFERENTIAL DIAGNOSIS: There are many causes of growth disorders : Genetic short stature: one or both parents are short, with normal bone age. 2. Systemic conditions: such as inflammatory bowel disease, celiac disease, occult renal disease, and anemia must be considered. Patients with systemic conditions often have greater loss of weight than length. 3.idiopathic short stature: A few otherwise normal children are short (>3 SD below the mean for age) and grow 5 cm/yr or less but have normal levels of GH in response to provocative tests and normal spontaneous episodic secretion. Most of these children show increased rates of growth when treated with GH in doses comparable to those used to treat children with hypopituitarism. Plasma levels of IGF-I in these patients may be normal or low.

4. Constitutional growth delay: a common variant of normal growth. Length and weight measurements of affected children are normal at birth, and growth is normal for the first 4–12 mo of life. Height is sustained at a lower percentile during childhood. The pubertal growth spurt is delayed, so their growth rates continue to decline after their friends have begun to accelerate. Detailed questioning often reveals other family members (frequently 1 or both parents) with histories of short stature in childhood, delayed puberty, and eventual normal stature. IGF-I levels tend to be low for chronological age but within the normal range for bone age. Growth hormone responses to provocative testing tend to be lower than in children with a more typical timing of puberty.

The prognosis for normal adult height in these children is good The prognosis for normal adult height in these children is good. Boys with more than 2 yr of pubertal delay may benefit from a short course of testosterone therapy to hasten puberty after 14 yr of age. The cause of this variant of normal growth is thought to be persistence of the relatively hypogonadotropic state of childhood . 5. Primary hypothyroidism: is more common than GH deficiency. Low total or free T4 and elevated TSH levels establish the diagnosis. Responses to GH provocative tests may be subnormal. Because thyroid hormone is a necessary for normal GH synthesis, it must always be assessed before GH evaluation.

6. Psychosocial dwarfism: Emotional deprivation is an important cause of retardation of growth and mimics hypopituitarism. The condition is known as psychosocial dwarfism, maternal deprivation dwarfism, or hyperphagic short stature. Functional hypopituitarism is indicated by low levels of IGF-I and by inadequate responses of GH to provocative stimuli. Puberty may be normal or even premature in its appearance. Appropriate history and careful observations reveal disturbed mother-child or family relations and provide clues to the diagnosis Proof may be difficult to establish because the parents often hide the true family situation from professionals, and the children rarely can talk. Emotionally deprived children frequently have abnormal or voracious appetites, enuresis, encopresis, insomnia, crying spasms.

TREATMENT: In children with classic GH deficiency, treatment should be started as soon as possible to narrow the gap in height between patients and their peers during childhood and to have the greatest effect on mature height. The recommended dose of hGH is 0.18–0.3 mg/kg/wk during childhood. Higher doses have been used during puberty. Recombinant GH is administered subcutaneously in 6 or 7 divided doses. Growth hormone therapy should be continued until near final height is achieved. Some patients develop either primary or central hypothyroidism while under treatment with GH. Similarly, there is a risk of developing adrenal insufficiency, If unrecognized, this can be fatal. Periodic evaluation of thyroid and adrenal function is indicated for all patients treated with GH.

Recombinant IGF-I is approved for use in the United States *Recombinant IGF-I is approved for use in the United States. It is given subcutaneously twice a day. The risk of hypoglycemia is reduced by giving the injections concurrently with a meal or snack. In certain situations, its use will be more effective than use of GH. GH is currently approved in the United States for treatment of children with growth failure as a result of Turner syndrome, end-stage renal failure before kidney transplantation, Prader-Willi syndrome, intrauterine growth retardation, and idiopathic short stature. In children with MPHD, replacement should also be directed at other hormonal deficiencies.

ADVERSE EFFECTS OF hGH TREATMENT: ADVERSE EFFECTS OF hGH TREATMENT: *Some patients treated with GH have developed leukemia. Growth hormone treatment does not increase the risk for recurrence of brain tumors or leukemia. *Other reported side effects include pseudotumor cerebri, slipped capital femoral epiphysis, gynecomastia, and worsening of scoliosis. *There is an increase in total body water during the first 2 wk of treatment. *Fasting and postprandial insulin levels are characteristically low before treatment, and they normalize during GH replacement. Treatment does not increase risk of type 1 diabetes, but it may increase the risk of type 2 diabetes.