Hypopituitarism

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Chapter 551 Hypopituitarism

Hypopituitarism denotes 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 congenital hypopituitarism is thought to be between 1 in 4,000 and 1 in 10,000 live births. With expanding knowledge of the genes that direct pituitary development or hormone production, an increasing proportion of cases can be attributed to specific genetic disorders. Mutations in 7 candidate genes account for 13% of isolated growth hormone deficiency (IGHD) and 20% of multiple pituitary hormone deficiency (MPHD) cases. The likelihood of finding mutations is increased by positive family histories and decreased in cases with adrenocorticotropin hormone (ACTH) deficiency. The genes, hormonal phenotypes, associated abnormalities and modes of transmission for such established genetic disorders are shown in Tables 551-1 and 551-2. Acquired hypopituitarism usually has a later onset and different causes (Table 551-3).

Table 551-1 ETIOLOGIC CLASSIFICATION OF MULTIPLE PITUITARY HORMONE DEFICIENCY

GENE OR LOCATION	PHENOTYPE	INHERITANCE
GENETIC FORMS
POU1F1 (PIT1)	GH, TSH, PRL	R, D
PROP1	GH, TSH, PRL, LH, FSH, ±ACTH, variable AP	R
LHX3	GH, TSH, PRL, LH, FSH, variable AP, ±short neck	R
LHX4	GH, TSH, ACTH, small AP, EPP, ±Arnold Chiari	D
TPIT	ACTH, severe neonatal form	R
HESX1	GH, variable for others, small AP, EPP	R, D
SOX3	Variable deficiencies, ±MR, EPP, small AP and stalk	XL
PTX2	Rieger syndrome	D
GLI2	Holoprosencephaly, midline defects	D
GLI3	Hall-Pallister syndrome	D
SHH (Sonic hedgehog)	GH deficiency with single central incisor	D
ACQUIRED FORMS
Idiopathic
Irradiation	GH deficiency precedes other deficiencies
Inflammation	Histiocytosis, sarcoidosis
Autoimmune	Hypophysitis
Post-surgical	Stalk section, vascular compromise
Tumor	Craniopharyngioma, glioma, pinealoma
Trauma	Battering, shaken baby, vehicular
UNCERTAIN ETIOLOGY
Idiopathic
Congenital absence of pituitary
Septo-optic dysplasia
Birth trauma

ACTH, adrenocorticotropic hormine; AP, anterior pituitary; D, dominant; EPP, ectopic posterior pituitary; FSH, follicle-stimulating hormone; GH, growth hormone; LH, luteinizing hormone; MR, mental retardation; PRL, prolactin; R, recessive; TSH, thyroid-stimulating hormone; XL, X-linked.

Table 551-2 ETIOLOGIC CLASSIFICATION OF GROWTH HORMONE DEFICIENCY OR INSENSITIVITY

Table 551-3 CAUSES OF ACQUIRED HYPOPITUITARISM

BRAIN DAMAGE*

Traumatic brain injury

Subarachnoid hemorrhage

PITUITARY TUMORS*

NON-PITUITARY TUMORS

INFECTION

INFARCTION

AUTOIMMUNE DISORDER

Lymphocytic hypophysitis

OTHER

Hemochromatosis, granulomatous diseases, histiocytosis

Empty sella

Perinatal insults

* Pituitary tumors are classically the most common cause of hypopituitarism. However, new findings imply that causes related to brain damage might outnumber pituitary adenomas in causing hypopituitarism.

From Schneider HJ, Aimaretti G, Kreitschmann-Andermahr I, et al: Hypopituitarism, Lancet 369:1461–1470, 2007.

Multiple Pituitary Hormone Deficiency

Genetic Forms

Sequentially expressed transcriptional activation factors direct the differentiation and proliferation of anterior pituitary cell types. These proteins are members of a large family of DNA-binding proteins resembling homeobox genes. Mutations produce different forms of multiple pituitary hormone deficiency. PROP1 and POU1F1 genes are expressed fairly late in pituitary development and are expressed only in cells of the anterior pituitary. Mutations produce hypopituitarism without anomalies of other organ systems. The HESX1, LHX3, LHX4, and PTX2 genes are expressed at earlier stages. They are also expressed in other organs. Mutations in these genes tend to produce phenotypes that extend beyond hypopituitarism to include abnormalities in other organs.

Other Congenital Forms

Severe, early-onset MPHD including deficiency of ACTH is often associated with the triad of anterior pituitary hypoplasia, absence or attenuation of the pituitary stalk, and an ectopic posterior pituitary bright spot on MRI. Most cases are sporadic and there is a male predominance. Some are due to abnormalities of the SOX3 gene, located on the X chromosome. As with septo-optic dysplasia, the majority of cases have not been explained at the genetic level.

Pituitary hypoplasia can occur as an isolated phenomenon or in association with more extensive developmental abnormalities such as anencephaly or holoprosencephaly. Midfacial anomalies (cleft lip, palate; Chapter 302) or the finding of a solitary maxillary central incisor indicate a high likelihood of GH or other anterior or posterior hormone deficiency. At least 12 genes have been implicated in the complex genetic etiology of holoprosencephaly (Chapter 585.7). In the Hall-Pallister syndrome, absence of the pituitary gland is associated with hypothalamic hamartoblastoma, postaxial polydactyly, nail dysplasia, bifid epiglottis, imperforate anus, and anomalies of the heart, lungs, and kidneys. The combination of anophthalmia and hypopituitarism has been associated with mutations in the SIX6, SOX2, and OTX2 genes.

Acquired Forms

Any lesion that damages the hypothalamus, pituitary stalk, or anterior pituitary can cause pituitary hormone deficiency (see Table 551-3). Because such lesions are not selective, multiple hormonal deficiencies are usually observed. The most common lesion is the craniopharyngioma (Chapter 491). Central nervous system germinoma, eosinophilic granuloma (histiocytosis), tuberculosis, sarcoidosis, toxoplasmosis, meningitis, and aneurysms can also cause hypothalamic-hypophyseal destruction. Trauma, including shaken child syndrome (Chapter 37), motor vehicle accidents, traction at delivery, anoxia, and hemorrhagic infarction, can also damage the pituitary, its stalk, or the hypothalamus.

Isolated Growth Hormone Deficiency and Insensitivity

Genetic Forms of Growth Hormone Deficiency

Isolated GH deficiency (IGHD) is caused by abnormalities of the GH-releasing hormone (GHRH) receptor, growth hormone genes and by genes located on the X chromosome.

GHRH Receptor

Recessive loss-of-function mutations in the receptor for GHRH interfere with proliferation of somatotropes during pituitary development and disrupt the most important signals for release of GH. The anterior pituitary is small, in keeping with the observation that somatotropes normally account for >50% of pituitary volume. There is some compromise of fetal growth followed by severe compromise of postnatal growth.

GH1

The GH1 gene is one of a cluster of five genes on chromosome 17q22-24. This cluster arose through successive duplications of an ancestral GH gene. Unequal crossing over at meiosis has produced a variety of gene deletions. Small deletions (<10 kb) remove only the GH1 gene, whereas large deletions (45 kb) remove ≥1 of the adjacent genes (CSL, CS1, GH2, and CS2). The growth phenotype is identical with deletion of GH1 alone or GH1 together with one or more of the adjacent genes. Loss of the CS1, GH2, and CS2 genes without loss of GH1 causes deficiency of chorionic somatomammotropin and placental GH in the maternal circulation, but it does not result in fetal or postnatal growth retardation. Children who are homozygous for GH1 gene deletions respond very well to GH therapy.

Recessively transmitted mutations in the GH1 gene produce a similar phenotype. Missense, nonsense, and frameshift mutations have been described. The most common involve the 4th and final intron of the gene. These mutations eliminate the normal splice donor site and foster use of an alternative site. The abnormal mRNA encodes a protein that is longer than normal and has no biologic activity.

Autosomal dominant IGHD is also caused by mutations in GH1. The mutations usually involve splice site errors in intron 3. There is overproduction of a 20-kd protein that lacks the amino acids normally encoded by exon 3. Accumulation of this protein interferes with the processing, storage, and secretion of the normal 22-kd GH protein. Additional deficiencies of TSH and/or ACTH have been recognized as late complications in patients with dominant mutations in GH1.

The existence of short stature owing to biologically inactive GH was proposed in 1978. Some patients with normal to high levels of circulating GH by immunoassay have lower levels of GH when assessed by cell-proliferation, receptor-binding, and receptor-activation assays. The best-documented example involves a child with homozygosity for a missense mutation of the GH1 gene. Substitution of a glycine for the normal serine at position 53 prevents formation of a disulfide bridge between residues 53 and 165. The mutant molecule has subnormal activities in immunofunction, receptor binding, and activation of the Jak2/Stat5 signaling pathway. GH treatment produced increases in insulin-like growth factor–1 (IGF-1) levels and growth rate, and the patient attained a normal adult height.

X-Linked Isolated Growth Hormone Deficiency

Two loci on the X chromosome have been associated with hypopituitarism. The 1st lies at Xq21.3-q22 in the region of the Bruton thymidine kinase (BTK) gene. Mutations in this region produce hypogammaglobulinemia as well as IGHD. The second locus maps farther out on the long arm, at Xq24-q27.1, a region containing the SOX2 transcription factor gene. Abnormalities in this locus have been linked to IGHD with mental retardation as well as to MPHD with the triad of pituitary hypoplasia, missing pituitary stalk, and ectopic posterior pituitary gland.

Acquired Forms

The GH axis is more susceptible to disruption by acquired conditions than are other hypothalamic-pituitary axes. Recognized causes of acquired GH deficiency include the use of radiotherapy for malignancy, meningitis, histiocytosis, and trauma.

Children who receive radiotherapy for CNS tumors or prevention of CNS malignancies (i.e., leukemia) are at risk for developing GH deficiency. Spinal irradiation contributes to disproportionately poor growth of the trunk. Growth typically slows during radiation therapy or chemotherapy, improves for 1-2 yr, and then declines with the development of GH deficiency. The dose and frequency of radiotherapy are important determinants of hypopituitarism. GH deficiency is almost universal 5 yr after therapy with a total dose ≥35 Gy. More subtle defects are seen with doses around 20 Gy. Deficiency of GH is the most common defect, but deficiencies of TSH and ACTH can also occur. In contrast to other forms of hypopituitarism, puberty tends to be early rather than delayed. The clinician is likely to encounter children in the 8-10 yr age range who are growing at rates that are normal for chronological age but subnormal for stage of pubertal development.

Growth Hormone Insensitivity

Abnormalities of the Growth Hormone Receptor

Growth hormone insensitivity is caused by disruption of pathways distal to production of GH. Laron syndrome involves mutations of the GH receptor. Children with this condition clinically resemble those with severe IGHD. Birth length tends to be about 1 standard deviation (SD) below the mean, and severe short stature with lengths >4 SD below the mean is present by 1 yr of age. Resting and stimulated GH levels tend to be high and IGF-1 levels are low. The GH receptor has an extracellular GH-binding domain, a transmembrane domain, and an intracellular signaling domain. Mutations in the extracellular domain interfere with binding of GH. Serum GH-binding protein (GHBP) activity, representing the circulating form of the membrane receptor for GH, is generally low. Mutations in the transmembrane domain can interfere with anchoring of the receptor to the plasma membrane. In these cases, circulating GHBP activity is normal or high. Mutations in the intracellular domain interfere with JAK/STAT signaling.

Post-Receptor Forms of Growth Hormone Insensitivity

Some children with severe growth failure, high GH and low IGF-1 levels, and normal GHBP levels have abnormalities distal to the GH binding and activation of the GH receptor. Several have been found to have mutations in the gene encoding signal transducer and activator of transcription 5b (STAT5b). Disruption of this key intermediate connecting receptor activation to gene transcription produces growth failure similar to that seen in Laron syndrome. These patients also suffer from chronic pulmonary infections, consistent with important roles for STAT5b in interleukin cytokine signaling.

IGF-1 Gene Abnormalities

Abnormalities of the IGF-1 gene produce severe prenatal and postnatal growth impairment. Microcephaly, mental retardation, and deafness are present in patients with exon deletion and a missense mutation. These patients can be expected to respond to recombinant IGF-1 treatment.

IGF Binding Protein Abnormalities

Mutation of the gene encoding the acid-labile subunit of the circulating 165-kd IGF-1, IGFBP3, ALS complex has been associated with short stature. Total IGF-1 levels were very low. The index case, with homozygosity for an ALS mutation, did not show an increase in IGF-1 levels or an increase in growth rate during GH treatment.

IGF-1 Receptor Gene Abnormalities

Mutations of the IGF-1 receptor also compromise prenatal and postnatal growth. The phenotype does not appear to be as severe as that seen with absence of IGF-1. Adult heights are closer to the normal range, and affected patients do not have mental retardation or deafness.

Clinical Manifestations

Congenital Hypopituitarism

The child with hypopituitarism is usually of normal size and weight at birth, although those with MPHD and genetic defects of the GH1 or GHR gene have birth lengths that average 1 SD below the mean. Children with severe defects in GH production or action are more than 4 SD below the mean by 1 yr of age. Those with less-severe deficiencies grow at rates below the 25th percentile for age and gradually diverge from normal height percentiles. Delayed closure of the epiphyses permits growth beyond the normal age when growth should be complete.

Infants with congenital defects of the pituitary or hypothalamus usually present with neonatal emergencies such as apnea, cyanosis, or severe hypoglycemia with or without seizures. Microphallus in boys provides an additional diagnostic clue. Deficiency of GH may be accompanied by hypoadrenalism and hypothyroidism. Prolonged neonatal jaundice is common. It involves elevation of conjugated and unconjugated bilirubin and may be mistaken for neonatal hepatitis.

The head is round, and the face is short and broad. The frontal bone is prominent, and the bridge of the nose is depressed and saddle-shaped. The nose is small, and the nasolabial folds are well developed. The eyes are somewhat bulging. The mandible and the chin are underdeveloped, and the teeth, which erupt late, are often crowded. 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, but an excess of body fat and a deficiency of muscle mass contributes to a pudgy appearance. The genitals 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. Length is mainly affected, giving toddlers a pudgy appearance. Symptomatic hypoglycemia, usually after fasting, occurs in 10-15% of children with panhypopituitarism and those with IGHD. Intelligence is usually normal.

Acquired Hypopituitarism

The child is normal initially, and 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, mental torpor, and absence of sweating. Sexual maturation fails to take place or regresses if already present. There may be atrophy of the gonads and genital tract with amenorrhea and loss of pubic and axillary hair. There is a tendency to hypoglycemia. Growth slows dramatically. Diabetes insipidus (Chapter 552) may be present early but tends to improve spontaneously as the anterior pituitary is progressively destroyed.

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 can occur (Chapter 491). Slowing of growth can antedate neurologic signs and symptoms, especially with craniopharyngiomas, but symptoms of hormonal deficit account for only 10% of presenting complaints. Evidence of pituitary insufficiency might first appear after surgical intervention. In children with craniopharyngiomas, visual field defects, optic atrophy, papilledema, and cranial nerve palsy are common.

Laboratory Findings

GH deficiency is suspected in children with moderate to severe postnatal growth failure. Criteria for growth failure include height below the 1st percentile for age and sex or height >2 SD below sex-adjusted mid-parent height. Acquired GH deficiency can occur at any age, and when it is of acute onset, height may be within the normal range. A strong clinical suspicion is important in establishing the diagnosis because laboratory measures of GH sufficiency lack specificity. Observation of low serum levels of IGF-1 and the GH-dependent IGF-BP3 can be helpful, but IGF-1 and IGF-BP3 levels should be matched to normal values for skeletal age rather than chronological age. Values in the upper part of the normal range for age effectively exclude GH deficiency. IGF-1 values in normally growing children and those with hypopituitarism overlap during infancy and early childhood.

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, a delayed skeletal age, and peak levels of GH (<10 ng/mL) in each of two 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 two provocative tests are compatible with GH deficiency. This rather arbitrary cutoff point is higher than the 3 or 5 ng/mL criteria used for diagnosis of adult GH deficiency. The frequency of negative GH responses to a single standard test in normally growing children is usually considered to approach 20%. Monoclonal antibody assays generally underestimate GH concentration compared to the earlier polyclonal antibody assays. There is no consensus regarding adoption of criteria that take into account age, sex, and GH assay characteristics. Stimulation with GHRH generally produces greater responses in children with GH deficiency caused by hypothalamic disorders and fails to elicit a response in those with GHRH receptor, GH1, POU1F1, PROP1, and LHX3 mutations. One study suggests that a majority of normal prepubertal children fail to achieve GH values >10 ng/mL with two pharmacologic tests. The researchers suggest that 3 days of estrogen priming should be used before GH testing to achieve greater diagnostic specificity.

During the 3 decades in which hGH was obtained by extraction from human pituitary glands culled at autopsy, its supply was sharply limited and only patients with classic GH deficiency were treated. In addition, the question was raised whether rare patients treated with cadaveric hGH contracted Creutzfeldt-Jakob disease from this preparation. With the advent of an unlimited supply of recombinant GH, there has been a marked interest in redefining the criteria for GH deficiency to include children with lesser degrees of deficiency. It has become popular to evaluate the spontaneous secretion of GH by measuring its level every 20 min during a 24- or 12-hr (8 PM-8 AM) period. Some short children with normal levels of GH, when studied by provocative tests, show little spontaneous GH secretion. Such children are considered to have GH neurosecretory dysfunction. With the collection of more normative data, it is clear that frequent GH sampling also lacks diagnostic specificity. There is a wide range of spontaneous GH secretion in normally growing prepubertal children and considerable overlap with the values observed in children with classic GH deficiency. Although the clinical and laboratory criteria for GH deficiency in patients with severe (classic) hypopituitarism are well established, the diagnostic criteria are unsettled for short children with lesser degrees of GH deficiency.

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 might 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. When there is a deficiency of TSH, serum levels of T₄ and TSH are low. A normal increase in TSH and PRL after stimulation with TRH places the defect in the hypothalamus, and absence of such a response localizes the defect to the pituitary. An elevated level of plasma PRL taken at random in the patient with hypopituitarism is also strong evidence that the defect is in the hypothalamus rather than in the pituitary. Some children with craniopharyngiomas have elevated PRL levels before surgery, but after surgery, PRL deficiency occurs because of pituitary damage. Antidiuretic hormone deficiency may be established by appropriate studies.

Radiologic Findings

Conventional x-ray films of the skull have been replaced by CT and, increasingly, by MRI. CT is appropriate for recognizing suprasellar calcification associated with craniopharyngiomas and bony changes accompanying histiocytosis. MRI provides a much more detailed view of hypothalamic and pituitary anatomy. Many cases of severe early-onset MPHD show the triad of a small anterior pituitary gland, a missing or attenuated pituitary stalk, and an ectopic posterior pituitary bright spot at the base of the hypothalamus. Subnormal anterior pituitary height, implying a small anterior pituitary, is common in genetic and idiopathic causes of IGHD. Craniopharyngiomas are common and pituitary adenomas are rare in children with hypopituitarism. Both hypoplastic and markedly enlarged anterior pituitary glands are seen in patients with PROP1 or LHX3 mutations.

Skeletal maturation is delayed in patients with IGHD and may be even more delayed when there is combined GH and TSH deficiency. Dual photon x-ray absorptiometry shows deficient bone mineralization, deficiencies in lean body mass, and a corresponding increase in adiposity.

Differential Diagnosis

The causes of growth disorders are legion. 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. A few otherwise normal children are short (i.e., >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-1 in these patients may be normal or low. Several groups of treated children have achieved final or near-final adult heights. Different studies have found changes in adult height that range from −2.5 to +7.5 cm compared with pretreatment predictions. There are no methods that can reliably predict which of these children will become taller in adulthood as a result of GH treatment and which will have compromised adult height.

Diagnostic strategies for distinguishing between permanent GH deficiency and other causes of impaired growth are imperfect. Children with a combination of genetic short stature and constitutional delay of growth have short stature, below-average growth rates, and delayed bone ages. Many of these children exhibit minimal GH secretory responses to provocative stimuli. When children in whom idiopathic or acquired GH deficiency is diagnosed are treated with hGH and are retested as adults, the majority have peak GH levels within the normal range.

Constitutional Growth Delay

Constitutional growth delay is one of the variants of normal growth commonly encountered by the pediatrician. Length and weight measurements of affected children are normal at birth, and growth is normal for the 1st 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 classmates have begun to accelerate. Detailed questioning often reveals other family members (often one or both parents) with histories of short stature in childhood, delayed puberty, and eventual normal stature. IGF-1 levels tend to be low for chronological age but within the normal range for bone age. GH responses to provocative testing tend to be lower than in children with a more typical timing of puberty. The prognosis for these children to achieve normal adult height is guarded. Predictions based on height and bone age tend to overestimate eventual height to a greater extent in boys than in girls. Boys with >2 yr of pubertal delay can 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 (Chapter 13).

Primary Hypothyroidism

Primary hypothyroidism (Chapter 559) 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 and the sella may be enlarged. Pituitary hyperplasia recedes during treatment with thyroid hormone. Because thyroid hormone is a necessary prerequisite for normal GH synthesis, it must always be assessed before GH evaluation.