Hypopituitarism and Growth Hormone Deficiency

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Chapter 6

Hypopituitarism and Growth Hormone Deficiency

Hypopituitarism refers to the deficiency of one or more pituitary hormones. It is seen commonly in endocrine practice and, it is important to note, is associated with increased morbidity and mortality. Clinical manifestations are influenced by the cause, severity, and rate of onset of pituitary hormone deficiency.

Adult patients with hypopituitarism receive substitutive hormone treatment for secondary glucocorticoid, sex steroid, and thyroid hormone deficiency. Until recently, growth hormone (GH) deficiency was not regarded as clinically important, as it was assumed that GH had no physiologic relevance after cessation of childhood growth. The advent of genetic engineering resulting in abundant supplies of recombinant GH has led to a major reappraisal of its physiologic role in adult life. GH continues to be produced throughout adult life and is the most abundant hormone in the adult pituitary gland. Many countries, including the United States, the United Kingdom, member countries of the European Union, and Australia, have approved the use of GH for replacement therapy in adults with GH deficiency.

Epidemiology

Limited information is available on the epidemiology of hypopituitarism. A Swedish survey estimates the prevalence of hypopituitarism to be 175 cases per million.1 A Spanish study has reported a prevalence of hypopituitarism of 290 and 450 cases per million from two cross-sectional surveys in 1992 and 1999, respectively, and a corresponding incidence of 60 per million per year.2 Sixty percent of the patients were GH deficient, giving a prevalence of GH deficiency of 114 to 270 cases per million and an incidence of 24 per million per year. A recent nationwide study in Denmark of GH deficiency identified an average incidence of approximately 20 million per year.3

Mortality

Mortality is increased in hypopituitarism. Data from six epidemiologic studies,4–9 comprising patients aged between 46 and 52 years who were followed for 10 to 13 years, report increased mortality with standardized mortality rates (SMRs) from 1.2 to 2.2. The higher mortality arises from cardiovascular and cerebrovascular disease and appears to be greater in women10 (Fig. 6-1).5–8,11,12 Risk ratios for malignancies and respiratory disease varied. Comparison of these studies is difficult because of different definitions, causes, and degrees of hypopituitarism. For example, patients with craniopharyngioma and/or patients treated with radiotherapy were included in some4,6,8,9 but not all studies.5,7 Craniopharyngiomas carry a worse prognosis than pituitary adenomas,13 and radiotherapy has been identified as a factor that increases mortality.8 However, it is unclear whether it is radiotherapy or the result of more aggressive disease requiring radiotherapy that reduces survival.8 A recent study, which included only postoperative hypopituitarism from pituitary adenoma followed for a mean duration of 12.4 years, demonstrated increased mortality only in women, with an SMR of 1.97.14

GH deficiency has been implicated as a major contributor to excess mortality in hypopituitarism because it is the only defect not replaced in the studies of hypopituitarism. However, the contribution to overall mortality of other risk factors, such as radiotherapy and suboptimal replacement therapies for other hormone deficits, is the subject of ongoing investigation.

Causes

Major causes of hypopituitarism are shown in Table 6-1. The most common cause is a pituitary adenoma or treatment with pituitary surgery or radiotherapy.

Pituitary and Hypothalamic Mass Lesions

Pituitary adenomas account for the vast majority of pituitary mass lesions, although secondary tumors do occur, from metastases to the pituitary gland from carcinomas of the breast, lung, colon, and prostate. Pituitary microadenomas are surprisingly common and are found in between 1.5% and 27% of patients at autopsy15; these tumors are very rarely, if at all, associated with hypopituitarism and tend to run a benign course. Macroadenomas are less common but are more frequently associated with pituitary hormone deficiencies; some 30% of patients with pituitary macroadenomas have one or more anterior pituitary hormone deficiencies. The causative mechanism of hypopituitarism is compression of the portal vessels in the pituitary stalk, secondary to the expanding tumor mass directly or to increased intrasellar pressure,16 which explains the potential reversibility of pituitary dysfunction after surgery in some patients.

Many hypothalamic mass lesions arise from developmental abnormalities such as craniopharyngiomas, Rathke’s cleft cysts, and arachnoid cysts. Craniopharyngiomas, the third most common intracranial tumor, account for most parapituitary tumors that occur. A bimodal peak in incidence occurs at 5 to 14 years and again after the age of 50. Their development origin is uncertain. They frequently have large cystic components and may be intrasellar, extrasellar, or both. Rathke’s cleft cysts are cystic sellar and suprasellar lesions lined by a single epithelial layer. Arachnoid cysts present at a later age and are less common than both craniopharyngiomas and Rathke’s cleft cysts.

Derangement of central endocrine regulation also occurs with other parapituitary space-occupying lesions such as chondromas, chordomas, suprasellar meningiomas, astrocytomas of the optic nerve, and primary tumors of the third ventricle.

Pituitary Surgery

The incidence and degree of hypopituitarism after surgery depend on the size of the original tumor, the degree of infiltration, and the experience of the surgeon. About 50% of patients already had evidence of GH, gonadotropin, or cortisol deficiency17 before surgery. The patient should also be warned of a possible deterioration of postoperative pituitary function, and assessment of pituitary function should be performed promptly after surgery. However, a postoperative decline in pituitary function is not universal. After surgery, about 80% had evidence of GH or gonadotropin deficiency. In patients who received postoperative radiotherapy, evaluation after 5 years revealed that all patients were GH deficient.17 On the other hand, surgery for pituitary adenomas may be associated with significant recovery of pituitary function. About half of the patients recover at least one pituitary insufficiency after transsphenoidal surgery. Postoperative improvement is more likely if no tumor is found on postoperative imaging, or if the tumor is not invasive.18 The pituitary hormone most likely to recover is thyroid-stimulating hormone (TSH), followed in order by adrenocorticotropic hormone (ACTH), gonadotropins, and GH.19 Recovery of pituitary function occurs early, within 8 weeks after surgery.20

Radiotherapy

Deficiency of one or more anterior pituitary hormones is almost invariable when the hypothalamic-pituitary axis lies within the fields of radiation. Hypopituitarism also develops in patients who received radiation therapy for nasopharyngeal carcinomas, parasellar tumors, and primary brain tumors, as well as in children who underwent prophylactic cranial irradiation for acute lymphoblastic leukemia or total body irradiation (TBI) for a variety of tumors and other diseases.21

The radiobiological impact of an irradiation schedule is dependent on the total dose, the number of fractions, and the duration and length of follow-up. Somatotrophs are the most sensitive to radiation damage, and thus, after lower radiation doses (<30 Gy), isolated GH deficiency ensues, whereas higher doses (30 to 50 Gy) increase the frequency of GH deficiency to 50% to 100% and may produce panhypopituitarism (Fig. 6-2). Radiation dose also determines the speed of onset of hormonal deficiency. The greater the dose, the earlier is the occurrence of GH deficiency, so that between 2 and 5 years after irradiation, 100% of children receiving more than 30 Gy (over a 3-week period) to the hypothalamic-pituitary axis developed subnormal GH responses to an insulin tolerance test (ITT), whereas 35% of those receiving less than 30 Gy (over a 3-week period) still showed a normal GH response22 (Fig. 6-3). However, interpretation of the impact of radiation-induced damage to the hypothalamic-pituitary axis on GH status is complicated in the early years after irradiation. Discordant results to different GH-provocative agents may be seen, such that up to 50% of patients classified as severely GH deficient with use of the ITT showed normal or mildly insufficient GH response during the combined GH-releasing hormone (GHRH) plus arginine stimulation test.23,24 The discordant response to dynamic testing in patients with GH deficiency is discussed in greater detail later in the chapter, under Diagnosis in Growth Hormone Deficiency.

Paradoxically, whereas high doses of cranial irradiation may render a child gonadotropin-deficient, lesser doses of irradiation may be associated with early puberty. The mechanism for early puberty after irradiation is likely to be related to disinhibition of cortical influences on the hypothalamus.

Fractionated stereotactic conformal radiotherapy (SCRT) is a more precise technique of localized irradiation that may reduce radiation damage to normal structures in the brain. However, despite this theoretical advantage of normal-tissue sparing, hypopituitarism remains a common complication. At a median follow-up of 32 months, 22% of patients with previously normal pituitary function or partial hypopituitarism developed new hormonal deficit, and 18% developed panhypopituitarism.25 The incidence of hypopituitarism was not different between conventional radiotherapy and SCRT,25 and it may occur as late as 10 years after therapy, reaching as high as 66% after a median follow-up of 17 years.26,27 Therefore, with increased survival, follow-up evaluation of patients irradiated for tumors of the brain and surrounding structures must focus equally on the possibility of tumor recurrence and on the delayed effects of therapy, including the endocrine effects. Endocrine testing should be performed on a yearly basis for at least 10 years and again at 15 years.

Genetic Causes

Major advances in our understanding of the developmental biology of the pituitary in recent years have provided insights into the molecular pathology of genetic causes of hypopituitarism. During embryonic development, the pituitary gland is formed by the association of neural ectodermal cells from the ventral diencephalons with ectodermal cells from the oral cavity. The former give rise to the posterior pituitary, and the latter give rise to the anterior pituitary. The formation and differentiation of Rathke’s pouch, the primordial anterior pituitary lobe structure, into the mature pituitary gland are regulated by the actions of specific transcription factors in a spatial and temporal fashion. These include KAL, HESX-1, Prop-1, and Pit-1. Mutations in genes encoding for these transcription factors result in deficiency of one or more anterior pituitary hormones.

Combined Pituitary Hormone Deficit

A cascade of pituitary transcription factors regulates the differentiation of cells of Rathke’s pouch into somatotrophs, lactotrophs, thyrotrophs, gonadotrophs, and corticotrophs. Mutations in early appearing transcription factors tend to cause more extensive hormone deficiencies (Table 6-2).

Pit-1 (pituitary-specific transcription factor-1) is a pituitary-specific transcription factor that is responsible for the development of somatotrophs, lactotrophs, and thyrotrophs in mammals. Pit-1 abnormalities account for only a small minority of the total number of worldwide cases of hypopituitarism. Pit-1 gene mutations also have been discovered in patients with idiopathic GH deficiency associated with preserved basal prolactin and TSH secretion, illustrating the variability of phenotypic presentation among these patients.

PROP1 (Prophet of Pit-1) is a novel pituitary paired-like homeodomain factor, which regulates the expression of Pit-1. Several multicenter studies of patients have reported that PROP1 mutations are the most common genetic cause of multiple pituitary hormone deficiencies, accounting for up to 40% to 50% of cases. PROP1 abnormalities result in similar phenotypic abnormalities to Pit-1 mutations but with associated gonadotropin deficiency. The degree of gonadotropin deficiency is variable, even among individuals within the same family with identical mutations. In individuals with a mutation of the PROP1 gene, progressive hypopituitarism develops, with GH, TSH, and gonadotropin deficiency typically present by the end of the second decade.28 The pituitary gland may pass through a hyperplastic phase before undergoing a phase of degeneration and late appearance of partial ACTH deficiency.

Other genetic causes of combined pituitary hormone deficiencies include mutations of HESX1, LHX3/LHX4, and Pitx1/Pitx2, which are transcription factors engaged in early pituitary cell development before the appearance of Pit-1 and PROP1.29–31 For example, HESX-1 is a homeobox gene expressed early in the ectoderm, which is the precursor of Rathke’s pouch. It plays an important role in optic nerve and anterior pituitary development. HESX-1 mutations in humans are associated with septo-optic dysplasia and GH deficiency. Other genes (e.g., LHX3) bind to Pit-1 and can enhance Pit-1 activity, or synergistically activate prolactin and TSH genes (e.g., Pitx1).

Isolated Pituitary Hormone Deficiency

Isolated Growth Hormone Deficiency: Isolated GH deficiency (IGHD) can arise from mutations of the GH gene and of the GH-releasing hormone (GHRH) receptor gene.32 The human GH (hGH) gene is located on chromosome 17 in a cluster of five genes: hGH-N encodes the gene for pituitary GH, hGH-V encodes the gene for placental GH, and three genes encode for human chorionic somatotropin (hCS). There are four types of Mendelian disorders of the GH gene that are due to deletion of these genes: IGHD IA and IB are both inherited in an autosomal recessive manner, resulting in absent or low GH levels. In patients with absent GH (IGHD IA), anti-GH antibodies often develop when they are treated with GH. IGHD II has an autosomal dominant mode of inheritance with variable clinical severity. IGHD III is an X-linked disorder that often is associated with hypogammaglobulinemia. Mutations of the gene encoding the GHRH receptor have been identified in a number of kindreds with severe GH deficiency in Pakistan and in Brazil.33,34

Isolated Gonadotropin Deficiency: Several gene mutations have been identified as causes of idiopathic hypogonadotropic hypogonadism (IHH) in humans.35 Gonadotropin-releasing hormone (GnRH) neurons originate in the olfactory placode and migrate during embryogenesis with the olfactory nerves to the hypothalamus. The KAL protein is necessary for this process to occur. Kallmann’s syndrome is characterized by the combination of IHH and anosmia or hyposmia, which usually is caused by defective GHRH secretion. It is a heterogeneous condition that manifests in an X chromosome–linked or autosomal dominant form. The X-linked form of the disorder is due to mutations in the KAL gene. Recently, several growth factors, including fibroblast growth factors (FGFs) and adhesion molecules, have been identified to play important regulatory roles in the development and migration of GHRH neurons. Mutation of the FGF receptor 1 (FGFR1) gene causes the autosomal dominant form of Kallmann’s syndrome.36 Additional clinical features associated with KAL mutations include bimanual synkinesia and renal agenesis; FGFR1 mutations typically lead to cleft lip palate and dental agenesis.

Another important protein is DAX1, which is a transcription factor involved in development of pituitary gonadotrophs and the adrenal cortex. Mutations in the DAX1 gene give rise to X-linked recessive hypogonadotropic hypogonadism and adrenal hypoplasia. Other genes implicated in IHH are PC1 (prohormone convertase, associated with defects in prohormone processing), OB, and DB (leptin and leptin receptor, associated with obesity), whereas inactivating mutations of luteinizing hormone (LH)-β and follicle-stimulating hormone (FSH)-β genes can cause isolated deficiencies of LH and FSH, respectively.

Isolated ACTH and TSH Deficiencies: Isolated deficiencies of TSH or ACTH are very rare; however, in a number of cases, a genetic abnormality has been described or proposed. Mutations of the coding region of the TSH-β subunit gene37 and the thyrotropin-releasing hormone (TRH)-receptor gene38 have been found in a number of families to be the cause of hereditary isolated TSH deficiency.

Recently, a pituitary transcription factor causing isolated ACTH deficiency was identified. TBX19 (the human T-box pituitary transcription factor, analogous to Tpit in the mouse) plays an essential role in differentiation of pro-opiomelanocortin (POMC) cells in the pituitary. At least two TBX19 gene mutations causing isolated ACTH deficiency have been described,39,40 and this may underlie the cause of a neonatal-onset form of congenital isolated ACTH deficiency,41 which is fatal unless diagnosed early and replaced with glucocorticoid.

Traumatic Brain Injury

Traumatic brain injury (TBI) is an under-appreciated cause of hypopituitarism. It was first reported in 1918. Meta-analysis of 19 studies, which included more than 1000 patients, demonstrated a pooled prevalence of hypopituitarism following TBI of 27.5% (1 pituitary hormone deficiency), and 7.7% of patients had multiple deficiencies. GH deficiency was the most common with a prevalence of 12.4%, followed by secondary hypogonadism (12.5%), hypoadrenalism (8.2%), and hypothyroidism (4.1%). Prevalence of diabetes insipidus is 26% in the acute phase and is decreased to 6.9% among long-term survivors.42

Risk factors of traumatic hypopituitarism include basal skull fracture, diffuse axonal injury, raised intracranial pressure, and prolonged stay in the intensive care unit.

TBI is common, with an overall incidence of 235 per 100,000 persons per year.43 Traumatic hypopituitarism therefore is a major public health issue with significant clinical implications. The incidence of hypopituitarism following TBI is more than 30 patients per 100,000 population per year.44 Patients therefore should be screened for hypopituitarism following TBI. Early (<3 months) hormonal dysfunction, including central hypothyroidism and hypogonadism, was not predictive of long-term development of hypopituitarism.45 Assessment for GH deficiency, hypogonadism, and hypothyroidism is not necessary in the acute phase, but adrenal insufficiency should not be missed, as it can be fatal if untreated. All patients should undergo screening for hypopituitarism between 3 and 6 months after injury.

Lymphocytic Hypophysitis

Lymphocytic hypophysitis, an immune-mediated diffuse infiltration of the anterior pituitary with lymphocytes and plasma cells, occurs predominantly in women and often is first evident in pregnancy or after delivery. The classic presentation is peripartum hypopituitarism, often with a pituitary mass and visual failure. ACTH deficiency is an almost universal feature that, when undiagnosed, has proved fatal. At an early stage, the pituitary gland is enlarged and cannot be distinguished from a pituitary tumor by computed tomography (CT) or magnetic resonance imaging (MRI), whereas in later stages, the gland may atrophy, leaving an empty sella. Lymphocytic hypophysitis is more common in patients with other autoimmune endocrine diseases. Cytosolic autoantigens against the pituitary can be demonstrated in some cases but also are present in normal patients; thus the definitive diagnosis of this condition remains difficult without pituitary biopsy. Recently, identification of more specific autoantigens, such as chorionic somatomammotropin, may allow noninvasive diagnosis of hypophysitis in the future, with a sensitivity of 64% and a specificity of 86% by immunoblotting.46 Spontaneous resolution of both the mass and the hypopituitarism has been reported, and in some cases, neurosurgical intervention has led to irreversible pituitary failure. Therefore, conservative management is appropriate in most patients. Spontaneous recovery with physiologic hydrocortisone replacement can happen,47 and high-dose methylprednisolone pulse therapy may improve adrenopituitary function and shrinkage of the sellar mass.48

Hypopituitarism

Clinical Features

Presentation of hypopituitarism can be nonspecific. It is affected by degree, type, and rate of onset of the pituitary hormone deficiency. Local pressure effects or hormonal hypersecretion may complicate the clinical picture. Hypopituitarism arising from an expanding mass lesion or from irradiation produces a characteristic evolution of pituitary failure caused by an initial loss of GH secretion, followed by LH and FSH, and finally by failure of ACTH and TSH secretion.

In cases arising from loss of function caused by an expanding silent mass lesion, the onset of symptoms is insidious, typically occurring with mild headaches, lethargy, fatigue, disinterest, weight gain, low mood, and declining libido—symptoms mimicking depression. Rarely, anorexia and weight loss may arise from ACTH deficiency and may be mistaken for and lead to extensive investigations for occult malignancy. Progressive mass expansion causing increasingly severe headaches or visual symptoms from chiasmal compression usually leads to radiologic investigations that clinch the diagnosis. A high index of suspicion is required to diagnose hypopituitarism. The symptoms and signs of individual hormone deficiency are listed in Table 6-3. The features of isolated deficiencies of each axis are described below. GH deficiency is addressed separately in the section dedicated to GH deficiency in adults.

Gonadotropin Deficiency

In male patients, the clinical features of gonadotropin deficiency differ according to whether the deficiency was acquired before or after pubertal age. If acquired before pubertal age, clinical examination reveals a small penis, small testes, and eunuchoid proportions (span exceeds a height of 5 cm). Hypogonadism acquired postpubertally is associated with a reduction in testicular size, loss of facial and body hair, and thinning of the skin, leading to the characteristic finely wrinkled facial skin of the “aging youth.” Other effects include a decrease in skeletal muscle mass, bone mineral density, sexual function, libido, and general well-being. Azoospermia is an almost inevitable consequence of hypogonadotropic hypogonadism. Partial LH deficiency may result in low circulating testosterone levels and gynecomastia with preserved testicular size and fertility, as intratesticular testosterone levels remain high enough to maintain spermatogenesis.

In a teenage girl, hypogonadotropic hypogonadism is associated with primary amenorrhea and absent breast development. In the adult woman, amenorrhea or oligomenorrhea, infertility, breast atrophy, vaginal dryness, and dyspareunia occur; pubic and axillary hair remains unless ACTH deficiency also is present.

Adrenocorticotropic Hormone Deficiency

ACTH deficiency is the most life-threatening component of hypopituitarism. If the onset is abrupt, as in pituitary apoplexy, the clinical picture may be dominated by profound shock in the most serious form. Patients with chronic ACTH deficiency usually present with chronic progressive symptoms of chronic fatigue, anorexia, and weight loss, sometimes mimicking anorexia nervosa or an occult malignancy. Patients on long-term glucocorticoid therapy can develop adrenal atrophy secondary to ACTH suppression.49,50 Examination may reveal pallor of the skin, in contrast to the hyperpigmentation of Addison’s disease, and in female patients particularly, loss of secondary sexual hair occurs. In severe ACTH deficiency, particularly in childhood, hypoglycemia can occur: Cortisol deficiency results in increased insulin sensitivity and a decrease in hepatic glycogen reserves. Hyponatremia, although less commonly seen than in Addison’s disease because of preservation of aldosterone secretion, may be the presenting feature of ACTH deficiency, particularly in the elderly.

Diagnosis and Endocrine Evaluation

Radiologic Phenotype of GH Deficiency

GH deficiency can be divided broadly into either genetic GH deficiency, when proven genetic mutations, such as GH-1, GHRH-R, and PROP-1, are identified, or idiopathic GH deficiency, when a genetic abnormality cannot be identified. On MRI, cases of genetic GH deficiency typically reveal a pituitary gland that is small or of normal size. The pituitary stalk is intact, and the location of the posterior lobe is normal. In contrast, idiopathic GH deficiency frequently is associated with a small pituitary gland, with evidence of stalk hypoplasia or interruption and an ectopic posterior lobe (Fig. 6-4). It has been suggested that perinatal trauma may be responsible for these abnormalities on MRI, resulting in idiopathic GH deficiency.51,52 This is supported by the observed higher frequency of breech delivery and birth hypoxemia with idiopathic GH deficiency than in genetic cases.53

The stalk provides vascular communication, and its presence is significant in relation to the evaluation of diagnostic testing for GH deficiency. Maghnie and colleagues have reported that integrity of the hypothalamic-pituitary connection is necessary for GHRH-arginine to stimulate GH release, as the GH response is markedly impaired in patients with stalk agenesis.54

Endocrine Evaluation

The endocrine assessment of a patient with suspected hypopituitarism usually involves measurement of both baseline and stimulated hormone levels. Evaluation of baseline function involves prolactin, TSH, thyroxine (T4), cortisol, LH, FSH, and testosterone in men, and estradiol in women. Baseline blood testing reliably identifies hypothyroidism, hypogonadism, and severe hypoadrenalism due to pituitary insufficiency.

Dynamic Testing:

Adrenocorticotropic Hormone Deficiency.: A high index of clinical suspicion is most important in establishing the diagnosis. In normal people, the highest plasma cortisol levels are found between 6:00 am and 8:00 am, and the lowest before midnight. Plasma cortisol and ACTH concentrations are elevated during physical and emotional stress, including acute illness, trauma, surgery, infection, and starvation.

If a 9:00 am cortisol level is less than 100 nmol/L, particularly in an unwell patient, cortisol deficiency is highly likely, whereas a baseline level greater than 500 nmol/L indicates normality; many authors suggest that dynamic assessment of the hypothalamic-pituitary-adrenal (HPA) axis is not necessary under these circumstances.55 Unless the patient is known to have pituitary disease, a paired plasma ACTH level will help distinguish between primary and secondary glucocorticoid deficiency: In primary cortisol deficiency (Addison’s disease), the ACTH level will be high, whereas in secondary glucocorticoid deficiency, the ACTH level will be low or inappropriately normal.

If cortisol deficiency is suspected in an unwell patient, baseline cortisol and ACTH samples should be taken, and replacement therapy should be commenced immediately. Provocative testing can be performed at a later date.

The insulin tolerance test (ITT) is the test of choice in those suspected of secondary adrenal failure. The ITT evaluates the response of the HPA axis to the potent stressor of hypoglycemia, and it is generally the “gold standard” in the confirmation of secondary adrenal failure. It has the advantage of also being a test of growth hormone reserve in patients with pituitary disease.56 Following injection of a standard dose of intravenous insulin (0.1 unit/kg),57 cortisol concentrations are measured serially. Upon achievement of adequate hypoglycemia (<2.2 mmol/L), a peak cortisol response of between 500 and 600 nmol/L generally is accepted as adequate.58

The short Synacthen (tetracosactrin) test sometimes is used as a surrogate test of ACTH deficiency on the basis that the adrenal gland will respond to an exogenous bolus of synthetic ACTH when there is a normal endogenous ACTH reserve and the gland is not atrophic. Although it is a good test of adrenal reserve, it does not directly test pituitary ACTH reserve. In a patient with organic pituitary disease, a normal response to Synacthen does not exclude mild or recent ACTH deficiency.

Antidiuretic Hormone Deficiency.: The diagnosis of ADH deficiency first requires confirmation of polyuria, which is defined as the excretion of more than 3 L of urine per 24 hours (40 mL/kg/24 hours). Any patient with normal serum sodium and plasma osmolality who has a fluid output of <2 L/24 hours is likely to be normal and does not warrant further investigation.

Once excess urine output has been confirmed, the usual first-line investigation is an 8-hour fluid deprivation test. The test should be performed under strict observation because severe fluid and electrolyte depletion can occur. Plasma osmolality, urine volume, and osmolarity are measured hourly for 8 hours, after which a synthetic analogue of ADH (desmopressin) is given intramuscularly (IM). The urine osmolality then is remeasured. In a normal subject, ADH is secreted throughout the test, water is absorbed normally, and a subsequent elevation of urine osmolality occurs. In diabetes insipidus, the urine fails to concentrate (normal subjects achieve a urine osmolality at least twice the plasma osmolality) because of a lack of ADH; hence, plasma osmolality increases. Urine concentrates adequately only after administration of desmopressin. Sometimes in cases with long-standing polyuria, failure of urine concentration in response to desmopressin occurs not because of nephrogenic diabetes insipidus but because of a washout of interstitial solutes, including urea. This may lead to diagnostic difficulties. In cases in which the results of a water deprivation test are inconclusive, ADH measurement is helpful. A definitive diagnosis of ADH deficiency can be established by infusing hypertonic saline for 2 hours to increase plasma osmolality to more than 300 mOsm/kg, with regular 20 to 30 minute blood sampling to estimate plasma osmolality and ADH. In nephrogenic diabetes insipidus, ADH values are above the normal reference range, whereas in cranial diabetes insipidus, values are at the lower end of or below the normal reference range.

Management

Treatment for hypopituitarism can be separated into those therapies directed at the underlying disease process and endocrine replacement therapy (Table 6-4). Management of the underlying condition is particularly challenging for craniopharyngiomas because randomized studies are lacking and their growth pattern is often unpredictable.60 Surgical excision in combination with external beam irradiation forms the mainstay of treatment. A recent trial demonstrated no recurrence of tumors during an average follow-up of 6.5 years in patients who received combined surgery with radiotherapy at diagnosis. Sixty percent of patients who received surgery alone had tumor recurrence.61

Hormone Replacement in Hypopituitarism

Endocrine replacement therapy should aim to mimic the normal hormonal milieu as far as possible, thus improving symptoms while avoiding overtreatment. GH replacement therapy is discussed separately under the section on adult GH deficiency.

Gonadotropin Deficiency: In both sexes, sex steroid replacement therapy is important for the maintenance of normal body composition, skeletal health, and sexual function, and it is the most appropriate form of replacement therapy in patients not desirous of fertility.

Estrogen Replacement.: In women, this can be provided by many standard hormone replacement therapy preparations. Progesterone must be given (cyclically or continuously) in all women with an intact uterus to prevent the possible effect of unopposed estrogen on the endometrium, that is, dysfunctional bleeding or endometrial cancer. The dose of estrogen should not be supraphysiologic (as in the oral contraceptive pill) unless a clear indication, such as strong patient preference, exists, or a patient with partial gonadotropin deficiency still has occasional menstrual cycles, along with a desire for contraception. Although estrogen can be delivered as a tablet, patch, gel, or implant, a nonoral route is recommended because of reduction of insulin-like growth factor (IGF)-1 and fat oxidation by oral estrogen. The pathophysiology of the interaction of oral estrogen with the GH axis is discussed separately under the section on adult GH deficiency. However, an international surveillance study on 315 hypopituitary women taking estrogen replacement demonstrated significant predominance of oral versus transdermal estrogen use (86% vs. 14%). Women on oral estrogen had a significantly greater waist/hip ratio after GH treatment, with lower IGF-1 levels at the end of the study period on twice the GH dose received by women on transdermal estrogen.62 Therefore a nonoral route is highly recommended.

Androgen Replacement.: The choice of preparation of androgen replacement depends on local availability and patient preference. IM injection of testosterone can be associated with disturbing fluctuations in sexual function, energy level, and mood, mirroring the changes in testosterone concentrations. Transdermal testosterone systems, which are an alternative, are available as patch systems (nonscrotal or scrotal) or as the recently introduced testosterone gel. Both formulations are able to maintain physiologic testosterone profiles in most patients, but skin irritation, the need for scrotal shaving, and drying time after gel application are some of the potential drawbacks of both transdermal systems. Testosterone undecanoate has become available as an intramuscular injection, which achieves stable serum testosterone levels over a 10- to 14-week period. This new preparation has essentially replaced testosterone implants as replacement therapy.63

Androgen replacement therapy should always be monitored to ensure physiologic mean testosterone levels. Suboptimal replacement doses result in low trough levels, whereas supraphysiologic doses can promote secondary polycythemia and progression of prostate cancer; therefore, regular monitoring of hemoglobin and prostate-specific antigen is recommended.

An area of investigative concern now is the therapeutic use of testosterone in women. In postmenopausal women, particularly those who have undergone bilateral oophorectomy, evidence exists that combined estrogen and testosterone replacement improves libido and sexual function. The rationale behind such therapy is that after bilateral oophorectomy, circulating testosterone levels decrease by 50%. This reduction tends to be even greater in women with hypopituitarism, who are likely to be more severely androgen deficient from loss of adrenal androgen production. Thus symptomatic patients may benefit from androgen supplementation. Such patients demonstrate improvement in sense of well-being, libido, lean body mass, and bone mineral density with androgen supplementation with dehydroepiandrosterone64 or low-dose testosterone.65

Gonadotropin and Gonadotropin-Releasing Hormone Therapy.: In the hypogonadotropic hypogonadal patient, fertility can be achieved with gonadotropin therapy in both men and women. The choice of therapy lies between gonadotropin replacement and GnRH. The former is the traditional therapeutic approach; initially, LH “activity” is provided by human chorionic gonadotropin (hCG) administered subcutaneously (SC) or IM at a dose of between 1000 and 2000 IU, two to three times weekly. Spermatogenesis is unlikely within the first 3 months of therapy. Treatment with hCG alone is continued for 6 months, with regular sperm counts to monitor progress. If adequate spermatogenesis is not achieved, then FSH in the form of human menopausal gonadotropin (hMG) or a recombinant FSH is added. The dose of FSH is increased if adequate spermatogenesis is not achieved after 6 months of combination therapy. The alternative regimen in patients with idiopathic hypogonadotropic hypogonadism and Kallmann’s syndrome is pulsatile GnRH therapy. GnRH is administered SC via a catheter attached to a minipump. This regimen appears to offer few advantages over gonadotropin therapy in men but may cause less gynecomastia. Both regimens may take up to 2 years to achieve adequate spermatogenesis; thus once effective, consideration should be given to storing several samples of frozen sperm for any future attempts at pregnancy.

In women with hypogonadotropic hypogonadism, pregnancy rates up to 80% are reported after therapy with pulsatile GnRH or gonadotropins. These are better than rates achieved in women undergoing ovulation induction for other pathologic conditions. Again, the choice of therapy lies between gonadotropin therapy and pulsatile GnRH, but obvious advantages accrue to GnRH therapy if the patient has enough residual gonadotroph function.

Pulsatile GnRH therapy is more likely than hMG to result in development and ovulation of a single follicle, thereby reducing the risks for ovarian hyperstimulation and multiple gestation. However, in practice, GnRH therapy may not be practicable, and in more than 50% of women with organic pituitary disease, residual gonadotroph function is not sufficient to support this method.

Adrenocorticotropic Hormone Replacement.: Different forms of glucocorticoids are available for replacement, and each has its merits and disadvantages. The modern approach to glucocorticoid replacement is to mimic physiologic levels, ensuring sufficiency during times of acute illness, and to prevent over-replacement, which is associated with adverse metabolic outcomes.

Any patient identified as having ACTH deficiency should be educated about its clinical implications. It is crucial for the patient to understand the need to increase the replacement dose twofold to threefold in case of an intercurrent illness or when undergoing surgery. Patients should wear an appropriate Medic-alert bracelet or necklace and should be issued an IM hydrocortisone pack and taught how to self-administer in the event of protracted vomiting.

Hydrocortisone directly replaces the missing hormone. Cortisone acetate is metabolized to cortisol and has a slower onset of action with longer biological activity. Both prednisolone and dexamethasone have longer half-lives, thus allowing daily administration. Recent estimation of a cortisol production rate of 9 mg/m2/day demonstrated by the isotope dilution method is lower than previously shown, and the traditional cortisol replacement dose of 30 mg/day is supraphysiologic and may lead to adverse metabolic outcomes.66,67 Generally, the lowest replacement dose tolerated by the patient is preferred (10 to 20 mg/day). Indeed higher serum concentrations of total cholesterol, low-density lipoprotein, triglycerides, and waist circumference were observed with increasing doses of glucocorticoid levels in a study comparing the metabolic phenotypes of patients with growth hormone deficiency treated with different formulations and doses of glucocorticoids. Metabolic end points were not worsened compared with ACTH-sufficient patients only in those treated with hydrocortisone-equivalent doses <20 mg/day.68 Doses should be divided to suit individual needs.

Growth Hormone Deficiency in Adults

The critical role of GH in stimulating childhood growth is well recognized, and its use in treating dwarfism due to GH deficiency is an unchallenged indication worldwide. Body growth represents the result of the stimulation by GH of a complex and integrated series of metabolic processes that are readily demonstrable in adults, even after cessation of body growth. Growth stops at the end of puberty as a result of fusion of the growth plates in long bones. However, GH continues to be produced throughout adult life and is the most abundant hormone in the adult pituitary gland. Hormones exert their actions by binding to specific receptors on tissues. All body tissues examined to date contain receptors for GH. This observation suggests that effects of GH are widespread, and that the hormone plays a general role in maintaining the metabolic process and the integrity of many tissues.

Causes

The causes of adult GH deficiency from four series totaling 1798 patients are shown in Table 6-5.69–72 Approximately 50% arise from pituitary tumors, 18% from extrapituitary tumors, and 5% from inflammatory or infiltrative lesions; up to 15% are idiopathic. Treatment for pituitary and extrapituitary tumors is the most common cause of deficiency, accounting for nearly two thirds of cases. The frequency of causes differs between patients with childhood-onset and adult-onset GH deficiency.70 Idiopathic causes, representing the largest group in childhood disease, are likely to represent a heterogeneous collection of congenital developmental abnormalities, including mutations of pit-1 and PROP genes, which cause multiple pituitary hormone deficiencies.

Clinical Features

Adults with GH deficiency, whether dating from childhood or acquired in later adult life, have a range of metabolic, body compositional, and functional abnormalities. These patients have a recognizable clinical syndrome, associated with a characteristic history, symptoms, signs, and investigative findings (Table 6-6).

Metabolism

Hypopituitary patients in whom GH has not been replaced display biochemical abnormalities that are linked strongly to the development of vascular disease. These patients have higher concentrations of total and low-density lipoprotein (LDL) cholesterol, as well as apolipoprotein B.73–75 Evidence is available from ultrasonographic studies of intima and media thickening and premature atherosclerosis of large vessels.76,77 These patients also have a higher level of plasminogen inhibitory activity and a higher concentration of fibrinogen,78 both of which are markers of increased atherothrombotic propensity. Fibrinogen also is a risk factor for stroke and myocardial infarction. Circulating levels of proinflammatory factors linked to the development of vascular disease, such as C-reactive protein (CRP), also are increased.79

Body Composition

Marked abnormality of body composition is characterized by increased proportion of body fat and reduced lean mass.80,81 These changes are a consequence of the loss of lipolytic and anabolic actions of GH. The effects of GH on body fat and muscle can be seen in Fig. 6-5, which shows striking changes in body physique in a man before and 5 years after acquisition of GH deficiency after surgery for a pituitary tumor.

These patients are more obese and display a disproportionate increase in central abdominal fat.81 The tendency toward central fat deposition is important because visceral obesity is linked to the development of insulin resistance, diabetes, and cardiovascular disease.82 Adults with GH deficiency have evidence of insulin resistance83 and a higher prevalence of impaired glucose tolerance.84

The reduction of lean body mass in adult GH deficiency arises from the combined reduction of bone, muscle and visceral mass, and extracellular fluid volume. Bone mass at different skeletal sites is reduced in patients with childhood-onset and adult-onset GH deficiency.85,86 The risk for fracture is increased between twofold and threefold.87,88

Physical Performance

Patients show significant impairment of physical performance and muscle strength.89,90 Physical fitness, as determined by cycle ergometry, has been shown to be reduced consistently in adult GH deficiency, with rates of maximal oxygen uptake reduced on average by about 30%.91 Exercise performance is a complex parameter that is dependent on numerous factors, including cardiorespiratory and neuromuscular muscle function. These patients have impaired cardiac function with reduced ventricular muscle mass, reduced ejection fraction, impaired ventricular filling,92–94 and reduced lung size, all of which contribute to reduced exercise capacity. As the skin is a target tissue of GH action, another likely contributing factor to reduced exercise endurance is impairment of sweating, which arises from hypoplasia of the eccrine sweat glands. The skin of GH-deficient subjects is atrophic and dry.73 Reduced sweating increases susceptibility to hyperthermia during exercise and may limit exercise performance.95

Quality of Life

Metabolic, body compositional, and functional abnormities in adult GH deficiency are accompanied by significant impairment of psychological well-being and reduced quality of life. Fatigue, easy exhaustion, and lack of vitality are common symptoms. Early studies using generic questionnaires revealed lower self-perception of quality of life, with patients regarding themselves as having reduced health, self-control, and vitality, and experiencing increased anxiety.96,97 A Dutch survey of social integration reported that GH-deficient adults had impaired social status.98 These patients were on a lower professional scale, had lower income, and generally were without partners and were living at home with their parents. Recent studies based on disease-specific questionnaires evaluating life satisfaction revealed marked impairment in quality of life, regardless of country and cultural background.99 On average, scores from GH-deficient patients were approximately half those of the normal population.100 A recent study demonstrated significantly increased morbidity in patients with GHD, with hazard ratios approximately three times higher than in the normal population.101

Thus, the collective evidence indicates that adults who lack GH are not normal but suffer from metabolic abnormalities, disordered body composition, reduced physical fitness, impaired psychological well-being, and reduced quality of life.

Diagnosis

Although the features of GH deficiency are recognizable, they are not particularly distinct and mimic body compositional and biochemical changes of the aging process.102 GH secretion itself decreases progressively with aging, associated with a progressive increase in adiposity, which itself reduces GH secretion.103,104 Thus, clinical suspicion must be confirmed by accurate biochemical diagnosis to ensure that GH-deficient patients are accurately identified and treated.

Who to Treat

GH deficiency should be defined biochemically within an appropriate clinical context. Biochemical testing for GH deficiency should be considered in patients with a high probability of hypothalamic-pituitary disease who manifest clinical features of the syndrome.105 This includes patients with a history of organic hypothalamic-pituitary dysfunction, cranial irradiation, known childhood-onset GH deficiency, and TBI. Patients with childhood-onset GH deficiency should be retested as adults before they are committed to long-term GH replacement.105

Biochemical Diagnosis

Three widely accepted approaches for assessing GH secretory status include measuring (1) peak GH response to a provocative test, (2) spontaneous GH secretion, and (3) serum concentrations of GH-regulated proteins such as insulin-like growth factor 1 (IGF-1) and IGF-binding protein-3 (IGFBP-3).

Provocative Test

The diagnosis of adult GH deficiency is established by provocative testing of GH secretion. Patients should be receiving adequate and stable hormone replacement for other hormonal deficits before they undergo testing.105 Provocative tests include the insulin tolerance test (ITT); arginine, glucagon, clonidine, and growth hormone-releasing hormone (GHRH) alone or in combination with arginine or pyridostigmine are available for testing.

In 1997, the Growth Hormone Research Society recommended the ITT as the diagnostic test of choice.106 It is superior to measuring integrated 24 hour GH concentration or IGF-157 (Fig. 6-6). Provided adequate hypoglycemia (<2.2 mmol/L or 40 mg/dL) is achieved, the ITT distinguishes GH deficiency from the reduced GH secretion that accompanies normal aging and obesity. The ITT should be performed in experienced endocrine units under supervision. The test is contraindicated in patients with electrocardiographic evidence or history of ischemic heart disease, and in those with seizure disorder. Given these precautions, the ITT is safe, with a risk for adverse events of less than 1 in 450.107 Normal subjects respond to insulin-induced hypoglycemia with a peak GH concentration greater than 5 mg/L.107,108 Severe GH deficiency is defined by a peak GH response to hypoglycemia of less than 3 mg/L. These cutoff values were defined in GH assays in which polyclonal competitive radioimmunoassays were use.56 However, GH immunoassay results vary between different methods; therefore the cutoff value may require appropriate adjustment.

One stimulation test is sufficient for the diagnosis of adult GH deficiency. A 2007 workshop of the Growth Hormone Society has endorsed the GHRH plus arginine test, the GHRH plus GH-releasing peptide (GHRP) test, and the glucagon stimulation test as validated alternatives to the ITT.105 The ITT evaluates the integrity of the hypothalamic-pituitary axis and has the added advantage of stimulating ACTH. Diagnostic tests employing GHRH and/or GHRP, both of which directly stimulate GH release from the pituitary gland, may miss GH deficiency due to hypothalamic disease.109 This is exemplified by studies in those treated with cranial irradiation, in which the ITT shows the greatest sensitivity and specificity within the first 5 years after irradiation. If the peak GH level during a GHRH plus arginine test is normal in those who have received irradiation, then an ITT should also be performed. In irradiated patients and in those with inflammatory and infiltrative lesions, GH deficiency may develop many years after the initial insult. Therefore, this group should be followed over the longer term with repeat testing as clinically indicated.24

Biochemical Markers of GH Action

These markers include IGF-1, IGFBP-3, and the acid-labile subunit of the IGF-1-BP complex. Of the three biochemical markers, the merit of IGF-1 has been the most intensively studied. Serum IGF-1 concentrations are useful only when age-adjusted normal ranges are used. Although IGF-1 levels are reduced in adult GH deficiency, a normal concentration does not exclude the diagnosis (see Fig. 6-6). A subnormal IGF-1 level in an adult patient with coexisting pituitary hormone deficits is strongly suggestive of GH deficiency, particularly in the absence of conditions known to reduce IGF-1 levels, such as malnutrition, liver disease, poorly controlled diabetes mellitus, and hypothyroidism. The separation of IGF-1 values between GH-deficient and normal subjects is greatest in the young. As IGF-1 levels decline in normal subjects with aging, IGF-1 becomes less reliable as a biochemical marker of GH deficiency in patients older than 50 years, when the values are merged with those of normal subjects.110 Measurement of IGFBP-3 or the acid-labile subunit does not offer any advantage over IGF-1.111

In patients with organic hypothalamic-pituitary disease, the prevalence of GH deficiency is strongly linked to the number of pituitary hormone deficits, ranging from approximately 25% to 40% with no deficit to virtually 95% to 100% when more than three pituitary hormone deficiencies are present112 (Fig. 6-7). Patients with three or more pituitary hormone deficiencies and an IGF-1 level below the reference range have a >97% chance of being GH deficient and therefore do not need a GH stimulation test.105

Growth Hormone Replacement

The benefit effects of GH replacement in adults with hypopituitarism were first reported in 1989.81,113 Since then, the impact of GH replacement has been studied extensively, and long-term experience of up to 10 years indicates sustained benefits.114

Metabolism

GH treatment induces profound effects on protein and fat metabolism, which result in significant changes in body composition. The anabolic effects arise from direct stimulation of protein synthesis and reduction of protein oxidation. GH stimulates lipolysis and fat oxidation, enhancing the utilization of fat for energy metabolism. The marked effects of GH on substrate metabolism are accompanied by significant stimulation of resting energy expenditure.81

In addition to exerting effects on the oxidative metabolism of fat, GH reduces a significant shift in lipoprotein metabolism to a less atherogenic profile. Most studies report a decrease in total cholesterol.75 Less consistently reported are effects on increasing high-density lipoprotein (HDL) cholesterol and reducing levels of LDL cholesterol and apolipoprotein.115–117 The favorable effects of improving the lipoprotein profile are more evident after treatment is provided for longer than a year.117,118 Most studies report little effect on triglyceride levels.75 Mechanisms that account for a less atherogenic profile include GH induction of hepatic LDL receptors and reduction in central adiposity, accompanied by an improvement in insulin sensitivity.

GH treatment reduces intima-media thickness of the carotid arteries and improves flow-mediated endothelium-dependent dilatation.15,119 The mean intima-media thickness of the carotid vessels was significantly less after 10 years of GH treatment when compared with that of an untreated GH-deficient group.114 The changes are not correlated to the reductions in plasma lipids. Proinflammatory factors such as CRP and interleukin (IL)-6, strongly implicated in the pathogenesis of vascular disease, decrease significantly with GH treatment.120 It is yet to be established that improvement in these risk markers translates to a reduction in cardiovascular mortality.

Body Composition

GH replacement induces striking changes in body composition.75,81,113,116 One of the first studies of adult replacement reported a significant reduction in body fat of 18% and a corresponding increase in lean body mass of 10% over a 6-month treatment period (Fig. 6-8). These changes in body composition occurred without a significant change in body weight. The greatest reduction in body fat occurs in abdominal and visceral fat.121 Restoration of body composition is largely completed within the first 12 months of treatment. Significant increases in extracellular water also occur as a consequence of the antinatriuretic properties of GH, which are dose dependent and involve activation of the renin-angiotensin system, as well as a direct renal tubular effect.122 Renal plasma flow and glomerular filtration rate are increased.

Bone remodeling is activated by GH. Markers of bone formation such as osteocalcin, alkaline phosphatase, and bone Gla protein, along with markers of resorption such as urinary hydroxyproline, are increased by GH treatment.75 Initial studies reporting changes in BMD over 6 to 12 months of treatment yielded conflicting results. However, more recent studies reporting long-term data show a progressive increase in BMD beyond 12 to 18 months of treatment123–125 (Fig. 6-9), with a plateau reached after 3 years.118,126 Markers of bone turnover increase over the first 12 months but return to baseline after 3 to 4 years.127

Physical Performance

Several studies reported that the increase in lean body and muscle mass during GH treatment is accompanied by an improvement in muscle strength. Quadriceps or hip muscle strength improves significantly after 6 months of treatment.90,113 Muscle strength is normalized after 2 years, without further significant change at 5 years.128,129

Many studies reported improvement in exercise capacity and performance in parallel with an increase in maximal oxygen uptake90,130 (Fig. 6-10). Exercise training alone significantly improves the aerobic capacity of GH-deficient adults, and this is not additive to the effects of GH treatment alone.131

In patients with GH deficiency, submaximal exercise performance, estimated as anaerobic threshold, increases significantly during GH treatment, suggesting that physical activities of daily living may be accomplished with less metabolic stress and subjective perception of effort.132 Maximal workload and oxygen consumption increased progressively over a 5 year period of GH treatment.125 In addition to increases in muscle strength, many factors may contribute to an improvement in exercise performance. These include enhanced cardiac function and improved heat dissipation through increased sweating. The data supporting a positive effect of GH on cardiac function are strong. Stroke volume, cardiac output, and diastolic function improve during GH treatment.90,133,134

Quality of Life

Several double-blind, placebo-controlled studies have reported improvement in mood, energy, sleep, and vitality scores with GH treatment,96,116,121 with continued improvement in these domains noted during the open phase. In general, GH replacement improved perceived health status and subjective well-being in the domains of health-related quality of life within 6 months. These findings were confirmed in a large randomized placebo-controlled blinded trial based on partner evaluation by questionnaire. According to the partners, patients were more alert, active, and industrious and had greater vitality and endurance during GH treatment.135 Disease-specific tools have reported unequivocal improvement in measures of life satisfaction after GH treatment.100 A large survey of 304 patients showed not only an improvement in quality of life, but also significant reduction in the numbers of sick leave and doctor visits during 12 months of GH therapy136 (Fig. 6-11).

Significant differences are noted in clinical and biochemical presentation and responses to GH therapy between patients with childhood-onset and those with adult-onset GH deficiency.70,129 Height, body weight, and lean body mass are lower in those with childhood-onset GH deficiency. The quality of life appears to be less disrupted in childhood-onset disease. During GH treatment, this group displays greater changes in body composition and greater increases in BMD and muscle strength, but lesser improvement in lipid profiles and quality-of-life measures, when compared with their adult-onset counterparts. The interesting differences at baseline and in responses to GH are likely to reflect the biological roles of GH at difference phases of life, as well as the psychological impact of GH injections given to the developing child. A patient with adult-onset disease is likely to recognize the restoration of quality of life to a level experienced before GH deficiency was acquired. In contrast, adults who received GH as a developing child have grown up with and adapted to the condition and are likely to harbor negative recollections of enforced daily injections. As GH therapy is terminated on epiphyseal closure, which occurs before somatic maturation, conventionally GH-treated children may not reach their physical and developmental potential on termination of GH treatment for dwarfism.137 The data suggest the existence of two clinical entities, developmental and metabolic, which reflect the function of GH at different stages of life.70

Transition Age Patients

GH treatment of the GH-deficient child normally is terminated when final height and epiphyseal closure are reached. Strong evidence indicates that biological maturity is attained after the postpubertal period during the early years of adulthood. Muscle mass and strength continue to increase in normal subjects after puberty; this does not occur in GH-deficient subjects.137,138 The bone mineral content of GH-treated subjects doubled that of unreplaced GH-deficient subjects after 2 years in the postpubertal period.139

A significant proportion of patients with childhood-onset GH deficiency exhibit normal GH response when retested at the end of completion of GH treatment. The requirement for continued GH treatment should be evaluated carefully, as proposed by the European Society for Paediatric Endocrinology140 (Fig. 6-12). GH testing is not required for those with a transcription factor mutation (e.g., Pit-1, PROP-1), those with more than three pituitary hormone deficits, and those with isolated GH deficiency associated with an identified mutation (e.g., GH-1, GHRH-R). All other patients should undergo GH testing after at least 1 month off GH treatment. Compelling reasons exist for GH-deficient children to continue GH treatment after puberty, to optimize not only physical maturation but also cardiovascular health and quality of life.

Treatment

Dosage

GH secretion is greater in younger individuals than in older ones, and in women than in men. It therefore is recommended that the starting dose of GH in young men and women be 0.2 and 0.3 mg/day, respectively, and in older individuals 0.1 mg/day.105 Dose determination based on body weight is not recommended because of large interindividual variation in absorption and in sensitivity to GH, as well as the lack of evidence that a larger replacement is required for heavier individuals in adults. It is recommended that GH be administered in the evening to mimic the greater secretion of GH at night. Dose escalation should be gradual, individualized, and guided by clinical and biochemical response. Long-acting preparations of human GH are under evaluation for long-term safety and efficacy.

A physical examination, including anthropometric measurements such as waist circumference and skin folds, and careful history, with particular attention to quality-of-life questions, are of great value in monitoring treatment; where possible, the partner’s input should be sought. Serum IGF-1 is the most useful biochemical marker of GH response, the level of which should be maintained within an age-adjusted normal range. Clinical monitoring should include assessment of body composition with dual x-ray absorptiometry and lipid measurements.

Interaction

GH may influence the metabolism of many substances, including hormones and medications. GH stimulates the activity of the hepatic cytochrome P-450 system, a major pathway of the oxidative metabolism of several drugs, including anticonvulsants. It is likely that dosage adjustments may be necessary in patients commencing GH treatment. Cortisol also is metabolized by the hepatic cytochrome P-450 system. Biochemical evidence indicates that GH increases the metabolic disposition of cortisol and may increase the risk for adrenal insufficiency,141 which has been reported in some studies.142 Although a causal relation remains unproved, GH-deficient patients receiving GH therapy should be strongly advised to increase the dosage of glucocorticoids when unwell, as is generally recommended.

Recently, the importance of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in determining tissue exposure to glucocorticoids has been recognized increasingly.66,143 Hepatic 11β-HSD1 converts cortisone to cortisol. Its activity is inhibited by GH and therefore is increased in GHD individuals. Some studies demonstrated supraphysiologic tissue cortisol exposure in hydrocortisone-treated GHD subjects. This may explain the observation in one study of higher waist circumference and glycated hemoglobin (HbA1c) in hydrocortisone-treated GHD patients, compared with GHD patients on cortisone.66

GH stimulates the peripheral conversion of T4 to triiodothyronine (T3). This effect may be seen frequently as a decrease in circulating T4 levels, particularly in patients taking thyroid hormone replacement for hypopituitarism.144 If T3 is not monitored during GH replacement, a decrease in T4 may be misinterpreted as inadequate substitution, and this may lead to an unnecessary increase in the dosage of thyroid hormone replacement.

Sex steroids exert significant modulatory effects on GH action. Estrogen exerts significant effects on hepatic function that are dependent on the route of administration. When compared with estrogen given by the transdermal route, oral estrogen reduces IGF-1 and fat oxidation—effects that are opposite to those of GH.145 GH-deficient women who are also hypogonadal should receive estrogen by a nonoral route during GH replacement, because oral but not transdermal estrogen attenuates the biological effects of GH.146 Fifty percent more GH was required during oral estrogen treatment than during transdermal administration to maintain an equivalent IGF-1 level (Fig. 6-13). In contrast, androgens enhance the metabolic effects of GH. The divergent effects of estrogens and androgens on GH action provide a likely explanation for the observation that women are less responsive than men to GH118,147 (Fig. 6-14). Over a 5-year treatment period, the average weight-adjusted dose for women was 30% higher than for men, whose IGF-1 was one standard deviation higher than that in women118 (Fig. 6-14). Thus, women require a larger dose of GH than is required by men.

Safety

The experience from several large multicenter clinical trials indicates that GH treatment is safe and well tolerated.116,148,149 The most common side effects arise from the antinatriuretic action of GH, which causes fluid retention (Table 6-7). These manifest as dependent edema, paresthesia, and carpal tunnel syndrome and occur with greater frequency in older patients. However, the symptoms are mild and dose related and resolve in most patients either spontaneously or with dosage reduction.150

Although GH antagonizes insulin action, the risk for developing hyperglycemia is very low. Only two case of reversible diabetes were reported from two European multicenter trials with a combined total of 400 patients,148,149 whereas diabetes developed in none of 166 patients in an Australian study.88 Insulin sensitivity did not change after 7 years of GH treatment.151

Because GH promotes the growth of tissues, concern has been expressed that GH therapy may increase the risk for pituitary tumor recurrence or the development of neoplasia. Analysis of the extensive pediatric experience shows no convincing evidence for a causal link between GH treatment and tumor recurrence or the development of neoplasia,152 including leukemia.153 In a retrospective comparison between hypopituitary adults with or without GH replacement and the normal population, an increased rate of malignancy, with colorectal cancer being the most common, was observed in hypopituitary adults without GH replacement. The rate of malignancy in patients on GH replacement was not different from that seen in the normal population.13 In addition, overall cancer incidence rates were lower in acromegalic patients than in the general population.154 These data on acromegaly provide the strongest evidence against a causal association between IGF-1 and malignancy.

Conclusions

Hypopituitarism increases morbidity and mortality in affected patients. The extent to which GH deficiency contributes to such excess morbidity and mortality awaits confirmation from longer-term studies. Adequate and appropriate hormone replacement is mandatory in the treatment of hypopituitary patients. Based on global evidence of efficacy and safety, adults with GH deficiency should also have replacement with GH, a principle consistent with the tenet of hormone replacement for hormone deficiency in the practice of endocrinology. Because GH remains expensive, it is important that its use in adults be restricted to patients with proven GH deficiency.

The modern management of hypopituitarism and GH deficiency should also focus on their prevention. By restriction of surgery to experienced centers and replacement of conventional radiotherapy with stereotactic surgery, the incidence of long-term hypopituitarism will be significantly reduced. Furthermore, greater use of medical therapy for acromegaly with somatostatin analogues and a GH receptor antagonist should mean fewer hypopituitary patients in the future.

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