Multiple Pituitary Deficiency

MULTIPLE PITUITARY HORMONE DEFICIENCY |

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Genetic Forms of Multiple Pituitary Hormone Deficiency. |

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Quite a few genes involved in embryonic development are candidates to explain multiple pituitary hormone deficiency (MPHD) (Chapter 550). There are several distinctive heritable forms of MPHD. Mutations of transcription factor genes that are only expressed in the anterior pituitary lead to simple phenotypes with varying combinations of anterior pituitary hormone deficiencies. Mutations of transcription factor genes that are also expressed in other embryonic tissues give rise to more complex phenotypes that include multiple congenital anomalies. |

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POU1F1 (PIT1) was originally identified as a nuclear protein that bound to the GH and PRL promoters. Mutations in POU1F1 are responsible for combined hormone deficiencies in humans. Many different types of recessive loss of function mutations have been identified in humans. Most of the dominant cases have involved a mutation causing substitution of tryptophan for arginine at position 271. The mutant protein has normal to increased promoter-binding activity but is incapable of activating transcription. Persons with POU1F1 mutations exhibit nearly normal fetal growth but experience severe growth failure in the 1st yr of life. There are complete deficiencies of GH and PRL. The severity of TSH deficiency and resultant central hypothyroidism is variable. There is no impairment of ACTH, luteinizing hormone (LH), or follicle-stimulating hormone (FSH) production. Puberty develops spontaneously, though, at a later than normal age. |

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PROP1 (Prophet of PIT-1) mutations are a very common explanation for the distinctly uncommon phenotype of MPHD. Studies from Switzerland, Poland, and Russia indicate that loss of function mutations are responsible in the majority of cases with a recessive inheritance and about half of the cases with sporadic MPHD. The proportion of sporadic cases that can be explained by PROP1 mutations is even higher when a selection is made for those who have subnormal TSH responses to thyrotropin-releasing hormone (TRH) stimulation. The most common types of mutation involve one or two base pair deletions in the second of three exons. These deletions cause frame shifts and early transcriptional termination, rendering the mutant proteins incapable of binding to promoter sites or activating transcription of target genes. Missense, nonsense, and splice site mutations have also been described. The hormonal phenotypes associated with PROP1 mutations differ in several respects from those associated with POU1F1 mutations. Although the gene defects are present from conception, the hormone deficiencies show the characteristics of an acquired disease. Growth in the 1st yr of life is considerably better than with POU1F1 defects and the median age at diagnosis of GH deficiency is around 6 yr. Recognition of TSH deficiency is delayed relative to recognition of GH deficiency. Basal and TRH-stimulated PRL levels tend to be higher than in POU1F1 mutations. PROP1 mutations cause gonadotropin deficiency and POU1F1 mutations do not. Some patients with PROP1 mutations enter puberty spontaneously and then retreat from it. Girls experience secondary amenorrhea and boys show regression of testicular size and secondary sexual characteristics. There is a loss of LH and FSH responses to luteinizing hormone-releasing hormone (LHRH) stimulation. Partial deficiency of ACTH develops over time in about one third of patients with PROP1 defects. Anterior pituitary size is small in most patients, but in others there is progressive enlargement of the pituitary. A central mass clearly originates within the sella turcica but may extend above it. The cellular content of the mass during the active phase of enlargement is not known. With time, the contents of the mass appear to degenerate, with multiple cystic areas. The mass may persist as a nonenhancing structure or it may disappear completely, leaving an empty sella turcica. At different stages, the findings on MRI can suggest a macroadenoma, a microadenoma, a craniopharyngioma, or a Rathke pouch cyst. |

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The hormonal phenotype produced by recessive loss of function mutations in the LHX3 gene located on chromosome 9q34.3 resembles that produced by PROP1 mutations. There are deficiencies of GH, PRL, TSH, LH, and FSH but not of ACTH. It is not clear whether the deficiencies are present from birth or whether they appear later in childhood. There is another similarity in that some affected individuals show enlargement of the anterior pituitary. The most important distinguishing feature is that each of the cases has had a rigid cervical spine. Imaging does not show any anatomic abnormality, but the patients are only able to rotate their necks about 90 degrees compared with a normal value of 150 to 180 degrees. |

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Mutations in the HESX1 gene also result in a complex phenotype with defects in development of the optic nerve. Septo-optic dysplasia or de Morsier syndrome is a fairly common condition that combines incomplete development of the septum pellucidum with optic nerve dysplasia. Clinical observation of nystagmus and visual impairment in infancy leads to imaging studies, which, in turn, disclose the optic nerve and brain abnormalities. It is associated with anterior and/or posterior pituitary hormone deficiencies. About 25% of cases have hypopituitarism. These patients tend to show the triad of a small anterior pituitary gland, an attenuated pituitary stalk, and an ectopic posterior pituitary bright spot. The overwhelming majority of cases are sporadic. There seems to be an association with young maternal age but no specific teratogenic agents have been identified. Studies of the HESX1 gene have disclosed abnormalities in three families. Two siblings with hypopituitarism, optic nerve dysplasia, agenesis of the corpus callosum, and a history of parental consanguinity were found to be homozygotes for an inactivating mutation. More mildly affected individuals in two other families were heterozygotes for other inactivating mutations. Homozygotes (in mice) show severe optic nerve and brain abnormalities, whereas some heterozygotes show a milder phenotype. |

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Rieger syndrome is a complex phenotype caused by mutations in the gene for a transcription factor that is expressed in multiple tissues, including the anterior pituitary gland. In addition to variable degrees of anterior pituitary hormone deficiency, the abnormalities include colobomas of the iris, a high risk of glaucoma, and abnormal development of the kidneys, gastrointestinal tract, and umbilicus. Some cases were found to have deletions or rearrangements of a region on chromosome 4q25. Further studies identified inactivating mutations of the PTX2 (pituitary homeobox 2) gene. Because of its association with Rieger syndrome, it is also known as the RIEG1 gene. The single normal gene copy in heterozygotes is inadequate to support normal development of a variety of organ systems. |

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Other Congenital Forms. |

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Pituitary hypoplasia can occur as an isolated phenomenon or in association with more extensive developmental abnormalities, such as anencephaly or holoprosencephaly (cyclopia, cebocephaly, orbital hypotelorism). Hypoplasia of the pituitary occurs with anencephaly but may have a large residuum of normal pituitary function, suggesting that hypoplasia may be secondary to a hypothalamic defect. Midfacial anomalies (cleft lip, palate) or the finding of a solitary maxillary central incisor indicate a high likelihood of GH or other anterior or posterior hormone deficiency. |

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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. |

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Acquired Forms. |

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Any lesion that damages the hypothalamus, pituitary stalk, or anterior pituitary may cause pituitary hormone deficiency. Because such lesions are not selective, multiple hormonal deficiencies are usually observed. The most common lesion is the craniopharyngioma (Chapter 489). Central nervous system germinoma, eosinophilic granuloma, tuberculosis, sarcoidosis, toxoplasmosis, and aneurysms may also cause hypothalamic-hypophyseal destruction. These lesions are frequently associated with roentgenographic changes in the skull. Besides diabetes insipidus, a deficiency of GH and other pituitary hormones may occur in children with histiocytosis. Enlargement of the sella or deformation or destruction of the clinoid processes usually indicates a tumor. Intrasellar or suprasellar calcifications usually indicate a craniopharyngioma. Trauma, including child abuse, traction at delivery, anoxia, and hemorrhagic infarction, may also damage the pituitary, its stalk, or the hypothalamus. The triad of a small anterior pituitary gland, an attenuated pituitary stalk, and an ectopic posterior pituitary bright spot on MRI has been associated with acquired as well as congenital multiple pituitary hormone deficiency. |

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CLINICAL MANIFESTATIONS |

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Congenital Hypopituitarism. |

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The child with hypopituitarism is usually of normal size and weight at birth. Children with multiple pituitary hormone deficiencies and those with genetic defects of the GH1 or GHR gene have birth length 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. Others with less severe deficiencies may have regular but slow growth in height, with the increments always less than the normal percentiles; periods of lack of growth may alternate with short spurts of growth. Delayed closure of the epiphyses permits growth beyond the age when normal persons cease to grow. Without treatment, adult heights are 4 to 12 SD below the mean. | |

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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, and clinical manifestations of hypopituitarism evolve more rapidly than in the usual child with hypopituitarism. Prolonged neonatal jaundice is common. It involves elevation of conjugated and unconjugated bilirubin and may be mistaken for neonatal hepatitis. |

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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 infantile, and the teeth, which erupt late, are frequently 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. The genitals are usually underdeveloped for the child's 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. Affected children may become shy and retiring. |

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Acquired Hypopituitarism. |

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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 may be present early but tends to improve spontaneously as the anterior pituitary is progressively destroyed. |

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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. In other patients, the neurologic manifestations may precede the endocrinologic, or 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. |

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Laboratory Findings. |

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The diagnosis of classic GH deficiency is suspected in cases of profound postnatal growth failure, with heights more than 3 SD below the mean for age and gender. Acquired GH deficiency can occur at any age. When the disorder is of short duration, height may still 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-I and the GH-dependent IGF-BP3 can be helpful. Values that are in the upper part of the normal range for age effectively exclude GH deficiency. Values for normally growing and children with hypopituitarism overlap during infancy and childhood. |

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Definitive diagnosis rests on 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 l-dopa, insulin, arginine, clonidine, or glucagon. Peak levels of GH less than 10 μg/L in each of two provocative tests are compatible with GH deficiency. Stimulation with GHRH or synthetic ghrelin agonists generally produces greater responses in children with GH deficiency secondary to hypothalamic disorders and fails to elicit a response in those with GHRH receptor, GH1, POU1F1, PROP1, and LHX3 mutations. The frequency of false-negative responses to a single standard test in normally growing children is approximately 20%. One study suggests that a majority of normal prepubertal children fail to achieve GH values greater than 10 μg/L with two pharmacologic tests. The researchers suggest that 3 days of estrogen priming should be used before GH testing to achieve greater diagnostic specificity. |

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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. 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. |

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In addition to establishing the diagnosis of GH deficiency, it is necessary to examine other pituitary functions. Levels of TSH, thyroxine (T4), ACTH, cortisol, dehydroepiandrosterone sulfate, 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. 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 craniopharyngioma 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. |

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Roentgenographic Examination. |

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Roentgenograms of the skull are most helpful when there is a destructive or space-occupying lesion causing hypopituitarism. Evidence of increased intracranial pressure may be found in patients with nausea, vomiting, loss of vision, headache, or an increase in circumference of the head. Enlargement of the sella, especially ballooning with erosion and calcifications within or above the sella, may be detected. MRI is indicated in all patients with hypopituitarism. In addition to providing detail about space-occupying lesions, it can define the size of the anterior and posterior pituitary lobes and the pituitary stalk. It is superior to CT in differentiating a full from an empty sella turcica. The posterior pituitary is readily recognized as a bright spot. In many cases of idiopathic MPHD with prenatal or perinatal onset, the posterior pituitary bright spot is ectopic. It appears at the base of the hypothalamus rather than in the pituitary fossa. MRI can provide timely confirmation of suspected hypopituitarism in a newborn with hypoglycemia and micropenis. MRI may also reveal pituitary gland hypoplasia or aplasia, septo-optic dysplasia, holoprosencephaly, or absence of the septum pellucidum. |

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Skeletal maturation is markedly delayed in patients with long-standing GH deficiency. The bone age tends to be approximately 75% of chronologic age. It may be even more delayed for patients with TSH and GH deficiency. The fontanels may remain open beyond the 2nd yr, and intersutural wormian bones may be found. Long bones are slender and osteopenic. Dual photon x-ray absorptiometry shows deficient bone mineralization, deficiencies in lean body mass, and a corresponding increase in adiposity. |

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Differential Diagnosis. |

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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-I 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 as adults as a result of GH treatment and which will have compromised adult height. Such treatment of short children without proven hypopituitarism is still undergoing experimental trials. |

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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 first 4-12 mo of life. Growth then decelerates to near or below the 3rd percentile for height and weight. By 2-3 yr of age, growth resumes at a normal rate of 5 cm/yr or more. Studies of GH secretion and other studies are within normal limits. Bone age is closer to height age than to chronologic age. Detailed questioning often reveals other family members (frequently one or both parents) with histories of short stature in childhood, delayed puberty, and eventual normal stature. The prognosis for these children to achieve normal adult height is good. Boys with unusual degrees of delayed puberty 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 (Chapter 14). Constitutional growth delay can be differentiated from genetic short stature by the level of skeletal maturation, which is consistent with chronologic age in the latter condition. Genetic short stature is usually found in other family members. Results of studies of hormones related to growth, however, are normal. |

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Primary hypothyroidism is usually easily diagnosed on clinical grounds. Responses to GH provocative tests may be subnormal, and enlargement of the sella may be present. Low T4 and elevated TSH levels clearly establish the diagnosis. Pituitary hyperplasia recedes during treatment with thyroid hormone. Because thyroid hormone is a necessary prerequisite for normal GH synthesis, its levels must always be assessed before GH studies. |

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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. The mechanisms by which sensory and emotional deprivation interfere with growth are not fully understood. 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 (Chapter 35.2). Proof may be difficult to establish because the adults responsible often hide the true family situation from professionals, and the children rarely divulge their plight. Emotionally deprived children frequently have perverted or voracious appetites, enuresis, encopresis, insomnia, crying spasms, and sudden tantrums. The subgroup of children with hyperphagia and a normal body mass index tends to show catch-up growth when placed in a less stressful environment. |

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The Silver-Russell syndrome is characterized by short stature, frontal bossing, small triangular facies, sparse subcutaneous tissue, shortened and incurved 5th fingers, and in many cases, asymmetry (i.e., hemihypertrophy). Affected children have low birthweight for gestational age. There is some degree of GH secretory deficiency in very short children with intrauterine growth retardation, whether or not they have Silver-Russell syndrome. Short-term treatment with GH often results in increased rates of growth, particularly when higher than usual doses are used. The impact on adult height of different dosage regimens is still unknown. |

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Treatment. |

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The Lawson Wilkins Pediatric Endocrine Society, Academy of Pediatrics, and the GH Research Society have published guidelines for hGH 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 classmates during childhood and to have the greatest effect on mature height. The recommended dose of hGH is 0.18-0.3 mg/kg/wk. It is administered subcutaneously in six or seven divided doses. If the effect of therapy wanes, compliance should be evaluated before the dose is increased. Concurrent treatment with GH and an LHRH agonist has been used in the hope that interruption of puberty will delay epiphyseal fusion and prolong growth. This strategy may augment final height, but it can also increase the discrepancy in physical maturity between GH-deficient children and their age peers and may impair bone mineralization. Therapy should be continuous until near final height is achieved. Criteria for stopping treatment include a growth rate less than 1 inch per yr and a bone age of greater than 14 yr in girls and greater that 16 yr in boys. | |

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Some patients treated with GH have subsequently acquired leukemia. The risk of leukemia in treated patients may be double that in the general population. There is conflicting evidence about whether GH treatment confers an increase in risk or whether the increased incidence reflects the consequences of therapeutic radiation for craniopharyngiomas and brain tumors. 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 1-2 wk of treatment. Fasting and postprandial insulin levels are characteristically low before treatment, and they normalize during GH replacement. Development of diabetes mellitus is rare. Older GH-deficient patients treated with cadaver pituitary extracts are at risk for Creutzfeldt-Jakob disease for at least 10-15 yr after therapy. Use of recombinant GH has eliminated this risk. |

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Maximal response to GH occurs in the 1st yr of treatment. With each successive year of treatment, the response tends to decrease. Some patients receiving GH acquire reversible hypothyroidism. Periodic evaluation of thyroid function is indicated for all patients treated with GH. GHRH is nearly as effective as GH in the treatment of children with hypothalamic causes of hypopituitarism with a deficiency of GHRH, but daily subcutaneous injections are required. Recombinant IGF-I may prove useful in the treatment of children with Laron syndrome and possibly those with GH1 gene deletions and high titers of antibodies. |

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The doses of GH used to treat children with classic GH deficiency usually enhance the growth of many non-GH-deficient children as well. Intensive investigation is in progress to determine the full spectrum of short children who may benefit from treatment with 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, or intrauterine growth retardation. In children with all other causes of short stature, it is unknown whether GH treatment increases their final height, and treatment of such patients should be confined to prospective clinical trials until further data establish the validity of this expensive, long-term form of therapy. |

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Replacement should also be directed at other hormonal deficiencies. In TSH-deficient subjects, thyroid hormone is given in full replacement doses. In ACTH-deficient patients, the optimal dose of hydrocortisone should not exceed 10 mg/m2/24 hr. Increases are made during illness or in anticipation of surgical procedures. Therapy can often be deferred until growth has been completed if the deficiency is partial. In patients with a deficiency of gonadotropins, gonadal steroids are given when bone age reaches the age at which puberty usually takes place. For infants with microphallus, one or two 3-mo courses of monthly intramuscular injections of 25 mg of testosterone cypionate or testosterone enanthate may bring the penis to normal size without an inordinate effect on osseous maturation. |

550 Hormones of the Hypothalamus and Pituitary |

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John S. Parks |

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The anterior pituitary gland originates from the Rathke pouch as an invagination of the oral ectoderm. It then detaches from the oral epithelium and becomes an individual structure of rapidly proliferating cells. Persistent remnants of the original connection between the Rathke pouch and the oral cavity can develop into craniopharyngiomas, which are the most common type of tumor in this area. Five cell types in the anterior pituitary produce six peptide hormones. Somatotropes produce growth hormone (GH), lactotropes produce prolactin (PRL), thyrotropes make thyroid-stimulating hormone (TSH), corticotropes express pro-opiomelanocortin (POMC), the precursor of corticotropin (adrenocorticotropic hormone [ACTH]), and gonadotropes express both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). |

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A series of sequentially expressed transcriptional activation factors directs the differentiation and proliferation of anterior pituitary cell types. These proteins are members of a large family of DNA-binding proteins resembling homeobox genes. The consequences of mutations in several of these genes are evident in human forms of multiple pituitary hormone deficiency. |

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The HESX1 gene is expressed in precursors of all five cell types early in development, at embryonic day 8.5 (e8.5) in the mouse. It is not expressed after day e13.5. Pituitary OTX or Ptx-1 is also expressed early. This protein is capable of activating transcription from the POMC, GH, and PRL promoters as well as from the promoter of the α-glycoprotein subunit (α-GSU) that is common to LH, FSH, and TSH. In vitro, it can also activate the β-LH and β-FSH subunits. It acts cooperatively with the transcription factor POU1F1 (formerly termed PIT1) in activation of transcription from the GH and PRL promoters. Ptx-1 appears to be necessary for expression of the next transcription factor in the cascade, termed LHX3. The protein encoded by LHX3 appears by day e9.5. It activates the α-GSU promoter and acts synergistically with POU1F1 to increase transcription from the PRL, β-TSH, and POU1F1 promoters. Targeted disruption of this gene in the mouse produces a phenotype of hypopituitarism in which the Rathke pouch develops normally, but the anterior and intermediate lobes of the pituitary fail to develop. The Ptx-2 gene, also known as the Rieg1 gene, is expressed from day e11 into adult life. Its DNA-binding domain differs from that of Ptx-1 by only 2 of 60 amino acids. The Ptx-2 protein is also found in developing eye, tongue, kidney, testis, and umbilicus. Expression of the "Prophet of Pit-1" or PROP1 gene begins at day e10.5 and is downregulated by day e14.5. This protein is found in the nuclei of somatotropes, lactotropes, and thyrotropes. Its role includes turning off HESX3 and turning on POU1F1. The POU1F1 (POU-homeodomain factor 1) appears at day e14.5 and is necessary for emergence of somatotropes, lactotropes, and a definitive population of thyrotropes. This protein persists in the mature pituitary and is involved in activation of GH, PRL, and β-TSH expression. |

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Anterior Lobe Hormones. |

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The protein hormones produced by the anterior pituitary act on other endocrine glands and on certain body cells to affect almost every organ. Anterior pituitary cells are themselves controlled by neuropeptide-releasing and release-inhibiting hormones that are produced by hypothalamic neurons, secreted into the capillaries of the median eminence, and carried by portal veins to the anterior pituitary. Many conditions formerly classified as pituitary in origin are caused by hypothalamic defects. |

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Human GH is a protein with 191 amino acids. Its gene (GH1) is the first in a cluster of five closely related genes on the long arm of chromosome 17 (q22-24). The four other genes have greater than 90% sequence identity with the GH1 gene. They consist of the CS1 and CS2 genes, which encode the same human chorionic somatomammotropin (hCS) protein, a placental growth hormone gene (GH2), and a pseudogene (CSP). Syncytiotrophoblastic cells of the fetal placenta produce large quantities of hCS, and placental GH replaces pituitary GH in the maternal circulation after 20 wk of gestation. When the fetal genome lacks the CS1, CS2, GH2, and CSP genes, hCS and placental GH are absent, but fetal growth and postpartum lactation are normal. |

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The GH1 gene is expressed in pituitary somatotropes under the control of three hypothalamic hormones. Growth hormone-releasing hormone (GHRH) stimulates and somatostatin inhibits GH release. Alternating secretion of GHRH and somatostatin accounts for the rhythmic secretion of GH. Peaks of GH occur when peaks of GHRH coincide with troughs of somatostatin. The secretion of GH is pulsatile, with the highest peaks occurring with sleep. A second stimulatory system, parallel to that involving the GHRH receptor, is activated by ghrelin. Ghrelin is produced in the arcuate nucleus of the hypothalamus and in much greater quantities by the stomach. GH secretion may be influenced by ghrelin levels in the hypothalamic-pituitary portal circulation and the systemic circulation. Fasting stimulates and feeding inhibits ghrelin release into the systemic circulation. Intraventricular injection of ghrelin increases feeding and weight gain in rats. |

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The three molecular species of GHRH contain 37, 40, or 44 amino acids. A fully active 29-amino acid synthetic GHRH is available as a diagnostic agent and for treatment of GH deficiency secondary to GHRH deficiency. Somatostatin exists in 14- and 28-amino acid forms. Somatostatin production is not limited to the hypothalamus. It also acts through autocrine and paracrine mechanisms in the islets of Langerhans and in the gastrointestinal tract. Somatostatin inhibits secretion of insulin, glucagon, secretin, gastrin, vasoactive intestinal peptide (VIP), GH, and thyrotropin. In the pancreatic islets, it is localized to the D cells. Somatostatin-secreting pancreatic tumors (somatostatinomas) occur in adults. A potent, long-acting somatostatin analog, octreotide, which inhibits GH preferentially over insulin, is available to treat patients with GH-secreting tumors. It is also useful in managing patients with gastrinomas, insulinomas, glucagonomas, VIPomas, and carcinoid tumors (see Chapters 81 and 326). 123I-labeled octreotide appears to be useful in localizing somatostatin receptor-positive tumors and their metastases. Ghrelin has an unusual structure. It consists of 28 amino acids and the third amino acid, a serine, is octanoylated. This octanoyl group is essential for physiologic activity. |

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GH acts through binding to receptor molecules on the surface of target cells. The GH receptor is a single-chain molecule of 620 amino acids. It has an extracellular domain, a single membrane-spanning domain, and a cytoplasmic domain. Proteolytically cleaved fragments of the extracellular domain circulate in plasma and act as a GH-binding protein. As in other members of the cytokine receptor family, the cytoplasmic domain of the GH receptor lacks intrinsic kinase activity; instead, GH binding induces receptor dimerization and activation of a receptor-associated Janus kinase (Jak2). Phosphorylation of the kinase and other protein substrates initiates a series of events that leads to alterations in nuclear gene transcription. |

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The mitogenic actions of GH are mediated through increases in the synthesis of insulin-like growth factor-I (IGF-I), formerly named somatomedin C, a single-chain peptide with 70 amino acids coded for by a gene on the long arm of chromosome 12. IGF-I has considerable homology to insulin. Circulating IGF-I is synthesized primarily in the liver and formed locally in mesodermal and ectodermal cells, particularly in the growth plate of children, where its effect is exerted by paracrine or autocrine mechanisms. Circulating levels of IGF-I are related to blood levels of GH to a large extent, except in the fetus and during the neonatal period. IGF-I circulates bound to several different binding proteins; the major one is a 150-kd complex (IGF-BP3), which is decreased in GH-deficient children but is in the normal range in children who are short for other reasons. Human recombinant IGF-I may have therapeutic potential in conditions characterized by end organ resistance to GH. Examples include Laron syndrome, a state of resistance to GH caused by mutations in the GH receptor, and resistance caused by the development of antibodies to administered GH. IGF-II is a single-chain protein with 67 amino acids that is coded for by a gene on the short arm of chromosome 11. It has homology to IGF-I, but much less is known about its physiologic roles, although it appears to be an important mitogen in bone cells, where it occurs in a concentration many times higher than that of IGF-I. |

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Several disorders of growth are caused by abnormalities of the genes that code for the GHRH receptor, HESX1, POU1F1, PROP1, LHX3, GH1, the GH receptor, and IGF-I. |

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Prolactin is composed of 199 amino acids, and its gene is located on chromosome 6. The major prolactin-inhibiting factor is dopamine; medications that disrupt hypothalamic dopaminergic pathways result in increased serum levels of prolactin. Serum levels of prolactin are increased after administration of thyrotropin-releasing hormone (TRH), in states of primary hypothyroidism, and after disruption of the pituitary stalk, as may occur in children with craniopharyngioma. Levels are decreased by destruction of the pituitary and by mutations in PROP1 and POU1F1, which interfere with the embryonic development of lactotropes. |

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The main established role for prolactin is the initiation and maintenance of lactation. Concentrations in amniotic fluid are 10-100 times the levels in maternal or fetal serum. The major source of amniotic prolactin appears to be the decidua. Mean serum levels in children and in fasting adults of both sexes are about 5-20 μg/L, but levels in the fetus and in neonates during the 1st wk of life are usually higher than 200 μg/L. |

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TSH consists of two glycoprotein chains linked by hydrogen bonding. The α-chain is identical to that found in FSH, LH, and chorionic gonadotropin (hCG). The β-chain is unique in each of these hormones and confers specificity. The gene for the α-chain has been mapped on chromosome 6, that for the α-chain of TSH on chromosome 1, and those for the β-chains for LH and hCG on chromosome 19. TSH increases iodine uptake, iodide clearance from the plasma, iodotyrosine and iodothyronine formation, thyroglobulin proteolysis, and release of thyroxine (T4) and triiodothyronine (T3) from the thyroid. Most of the effects of TSH are mediated by cyclic adenosine monophosphate. Deficiency of TSH results in inactivity and atrophy of the thyroid, and excess results in hypertrophy and hyperplasia. |

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TRH is a tripeptide ([pyro] Glu-His-Pro-NH2). Thyroxine and triiodothyronine inhibit TSH secretion by blocking the action of TRH on the pituitary cell. TRH also stimulates the release of prolactin in both sexes. Synthetic TRH is useful for testing pituitary reserves of TSH and prolactin. |

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ACTH is derived by proteolytic cleavage from a large precursor glycoprotein product of the pituitary gland called POMC. Cleavage of POMC yields ACTH, a single chain of 39 amino acids, and β-lipotropin (β-LPH), a 91-amino acid glycoprotein. Further cleavage of ACTH and β-LPH in the pituitary yields yet other hormonal products. The α-melanocyte-stimulating hormone is identical to the first 13 amino acids of ACTH but has no corticotropin activity. Cleavage of β-LPH results in neurotropic peptides with morphinomimetic activity (fragment 61-91 is β-endorphin), and β-melanocyte-stimulating hormone consists of a 17-amino acid fragment of β-LPH. |

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ACTH acts primarily on the adrenal cortex. It produces changes in structure, chemical composition, enzymatic activity, and release of corticosteroid hormones. ACTH release has a diurnal rhythm. The level is lowest between 10 pm and 2 am, with peak levels reached about 8 am. Levels of β-LPH and β-endorphin are elevated in patients with increased levels of ACTH. It appears that ACTH rather than MSH is the principal pigmentary hormone in humans. |

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POMC peptides are also produced in nonpituitary tissues. In the testis, some peptides act as autocrine regulators of androgen-secreting Leydig cells, and others may potentiate or oppose the action of FSH on Sertoli cells. |

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Secretion of ACTH, β-endorphin, and other POMC-related peptides is regulated by corticotropin-releasing hormone (CRH). CRH is a 41-amino acid peptide found predominantly in the median eminence but also in other areas of the brain and in tissues outside the brain, particularly the placenta. During pregnancy, levels of CRH increase several hundred-fold, increase further during labor and delivery, and then decrease to nonpregnant levels within 24 hr. Its source is probably the placenta, which contains the peptide and its mRNA. Synthetic CRH is available for diagnostic use and it is particularly useful in differentiating the different forms of Cushing syndrome. |

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Gonadotropic hormones include two glycoproteins, LH and FSH. They contain the same α subunit as TSH and distinct β subunits. Receptors for FSH on the ovarian granulosa cells and on testicular Sertoli cells mediate FSH stimulation of follicular development in the ovary and of gametogenesis in the testis. On binding to specific receptors on ovarian theca cells and testicular Leydig cells, LH promotes luteinization of the ovary and Leydig cell function of the testis. The receptors for LH and FSH belong to a class of receptors with seven membrane-spanning protein domains. Receptor occupancy activates adenylyl cyclase through mediation of G proteins. |

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Luteinizing hormone-releasing hormone, a decapeptide, has been isolated, synthesized, and widely used in clinical studies. Because it leads to the release of LH and FSH from the same gonadotropic cells, it appears that there is only one gonadotropin- releasing hormone. |

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Secretion of LH is inhibited by androgens and estrogens, and secretion of FSH is suppressed by gonadal production of inhibin, a 31-kd glycoprotein produced by the Sertoli cells. Inhibin consists of α and β subunits joined by disulfide bonds. The β-β dimer (activin) also occurs, but its biologic effect is to stimulate FSH secretion. The biologic features of these newer hormones are being delineated. In addition to its endocrine effect, activin has paracrine effects in the testis. It facilitates LH-induced testosterone production, indicating a direct effect of Sertoli cells on Leydig cells analogous to the interaction of these cells through the paracrine effects of POMC. |

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The posterior lobe of the pituitary is part of a functional unit, the neurohypophysis, that consists of the neurons of the supraoptic and paraventricular nuclei of the hypothalamus; neuronal axons, which form the pituitary stalk; and neuronal terminals in the median eminence or in the posterior lobe. |

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Hormones of the Neurohypophysis. |

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The neurohypophysis is the source of arginine vasopressin (AVP; antidiuretic hormone) and of oxytocin. Both are octapeptides, differing in only two amino acids. These hormones are produced by neurosecretion in the hypothalamic nuclei. Vasopressin derives its name from early observations of its pressor and antidiuretic activities but the latter is its physiologically important function. At levels 50-1,000 times those found in blood, it affects blood pressure, intestinal contractility, hepatic glycogenolysis, platelet aggregation, and release of factor VIII. |

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Vasopressin and its accompanying protein, called neurophysin II, are encoded by the same gene. A single preprohormone is cleaved and the two are transported to neurosecretory vesicles in the posterior pituitary. The two are released in equimolar amounts. Oxytocin and neurophysin I have a similar relationship. |

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AVP has a short half-life and responds quickly to changes in hydration. The stimuli for AVP release are increased plasma osmolality, perceived by osmoreceptors in the hypothalamus, and decreased blood volume, perceived by baroreceptors in the carotid sinus of the aortic arch. AVP changes the permeability of the renal tubular cell membrane through cyclic adenosine monophosphate. A synthetic analog, desmopressin combines high potency, selectivity for antidiuretic hormone receptors, and resistance to degradation by proteases. Desmopressin may be given by injection, by intranasal spray, or by mouth. The amount that is required for management of diabetes insipidus depends on the mode of administration. A typical dose is on the order of 1 μg for the injected, 10 μg for the intranasal, and 100 μg for the oral form. |