Tufts OpenCourseware
Author: Ronald Lechan, MD,PhD
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1. Goals

To learn the symptoms, causes and management of pituitary insufficiency

2. Learning Objectives

  • To review the physiology and anatomy of the hypothalamus/pituitary
  • To learn the definition and causes of pituitary insufficiency
  • To learn the symptoms of pituitary insufficiency due to deficiencies in specific hormones
  • To learn the difference between basal and dynamic testing
  • To become familiar with testing for the various hypohormonal states of pituitary insufficiency

3. Definition

Hypopituitarism is a term that refers to the defiiciency of one or more anterior and/or posterior pituitary hormones. The deficiency may be total (panhypopituitarism) or partial, in which one or more of the pituitary hormones may be deficient. Hypopituitarism may arise as a result of congenital defects in the development of individual anterior pituitary cell types or hypothalamic function, or from acquired disease of the pituitary or hypothalamus.

4. Review of Physiology and Anatomy

The major cell types and secretory products of the pituitary gland are shown in Table 1.

TABLE 1. Major cell types and secretory products of the pituitary gland.
Anterior Pituitary
Cell Type Secretory Products Cell Population %
Somatotroph Growth Hormone 50
Lactotroph Prolactin 15
Corticotroph Adrenocorticotrophic hormone 15
Thyrotroph Thyroid-stimulating hormone 10
Gonadotroph Luteinizing hormone/Follicle-stimulating hormone 10
Posterior Pituitary
Cell Type Secretory Products
Axon terminals of hypothalamic neurons Vasopressin and Oxytocin

Understanding the neuroanatomical relationships between the hypothalamus and pituitary gland can be very helpful in understanding the mechanisms whereby hypopituitarism can result and how disorders affecting the anterior pituitary can be distinguished from disorders affecting the hypothalamus.

4.1. Anatomy of the Pituitary Gland

The pituitary gland lies within a recess of the sphenoid bone called the sella turcica and is composed of two major subdivisions, the anterior pituitary and posterior pituitary. These structures can be readily visualized by magnetic resonance imaging (MRI) because the posterior pituitary appears as a bright spot on T1-weighted images, as shown in Figure 1.

Figure 1. Anterior pituitary and posterior pituitary
Anterior pituitary and posterior pituitary
Reprinted from Endocrin Metab Clin North Am, 16(3), Lechan RM, Neuroendocrinology of pituitary hormone regulation, pp475-501, 1987, with pemission from Elsevier.

The anterior pituitary makes up most of the pituitary gland and gives rise to most of the pituitary hormones. As the anterior pituitary embyrologically derives from Rathke's pouch, it is composed primarily of epithelial cells and does not have direct neuronal connections to the brain. In contrast, the posterior pituitary contains axon terminals of specialized neurons that arise within the hypothalamus and thereby, is a direct extension of the brain. While secretion from the posterior pituitary can occur as a result of neuronal stimulation in the hypothalmus, secretion from the anterior pituitary is dependent upon a vascular conduit, or portal plexus, that directly links the hypothalamus to the anterior pituitary gland. The portal plexus is comprised of capillaries located in a specialized structure at the base of the hypothalamus, termed the median eminence, supplied by arterial blood via a branch of the internal carotid artery, the superior hypophyseal artery (Figure 2). The portal capillaries give rise to long veins that extend along the pituitary stalk and terminate in capillary beds in the anterior pituitary. Thus, the portal plexus is a venous plexus and is the major source of blood flow to the anterior pituitary, as the anterior pituitary has little or no arterial innervation.

Figure 2. Portal plexus
Figure 2.  Blood supply to the hypothalamus-pituitary

4.2. Anatomy of the Hypothalamus

The median eminence is one of the most important structures in the hypothalamus because it is the final, common locus where axons containing all of the hypothalamic releasing and inhibiting factors terminate. Due to the high vascularity of this structure created by the portal plexus, the median eminence can be easily visualized by MRI following contrast administration (Figure 3A). As shown in the schematic image (Fig. 3B), axons containing the hypothalamic releasing and inhibiting factors terminate on the portal capillary plexus. Because these capillaries are fenestrated, the secretary products released from the axon terminals can be taken up into the portal system and transported via the long portal veins to the anterior pituitary. The median eminence also contains axons in its innermost zone en route to the posterior pituitary.

Figure 3 A&B - Median eminence
Figure 3.  Panel A: Imaging (MRI) of median eminence, Panel B: Schematic representation of median eminence

The origin of the hypothalamic releasing and inhibitory factors is primarily from nuclear groups that are organized in medial regions of the hypothalamus that underlie the third ventricle, including the preoptic nucleus, paraventricular nucleus periventricular nucleus and arcuate nucleus. The location of these important hypothalamic nuclear groups is shown in Figure 4 on coronal MRI images of the human hypothalamus. The specific hypothalamic releasing and inhibitory hormones produced by the hypothalamus, their origin in the hypothalamus, and the anterior pituitary hormones they regulate are listed in Table 2.

Figure 4. Coronal MRI images of the human hypothalamus
Coronal MRI images
Reprinted from Endocrin Metab Clin North Am, 16(3), Lechan RM, Neuroendocrinology of pituitary hormone regulation, pp475-501, 1987, with pemission from Elsevier.
TABLE 2. Hypothalamic releasing and inhibitory factors.
Releasing/Inhibiting Factor Hypothalamic Origin Function
Corticotropin-releasing hormone (CRH) Paraventricular Nucleus Stimulate ACTH
Dopamine Arcuate Nucleus Inhibit Prolactin
Growth hormone-releasing hormone (GHRH) Arcuate Nucleus Stimulate GH
Gonadotropin-releasing hormone (GnRH) Preoptic Nucleus Stimulate LH/FSH
Somatostatin (SRIF) Periventricular Nucleus Inhibit GH/TSH
Thyrotropin-releasing hormone (TRH) Paraventricular Nucleus Stimulate TSH/Prol.

In contrast, neuronal cell groups giving rise to the posterior pituitary hormones, vasopressin (or antidiuretic hormone, ADH) and oxytocin, are located more laterally in the hypothalamus in lateral portions of the paraventricular nucleus and the supraoptic nucleus.

5. Hypopituitarism

5.1. Etiology of Hypopituitarism

There are many disorders that can cause hypopituitarism, either by affecting the hypothalamus or the pituitary gland. Congenital disorders are a cause for hypopituitarism presenting in children. Formation of the pituitary during embryonic development depends upon the juxtaposition of cells of neurectodermal origin, which form the posterior pituitary, and endodermal cells which form the anterior pituitary. Defects in the transcription factors HESX-1, PROP-1, and PIT-1 are known to result in various degrees of hypopituitarism. HESX-1 mutations are associated with septo-optic dysplasia, characterized by the triad of optic nerve hypoplasia, midline neuroradiological abnormalities such as agenesis of the corpus callosum, and pituitary hypoplasia with hypopituitarism. PROP-1 mutations have deficiencies in the gonadotrophs (LH and FSH), growth hormone, prolactin and TSH. PIT-1 mutations result in combined deficiencies of growth hormone, prolactin and TSH. Mutations may also selectively affect posterior pituitary function including point mutations in the vasopressin-neurophysin II gene. Most involve the neurophysin II region of the vasopressin gene, resulting in abnormal processing, transport or cleavage of the vasopressin precursor, or cytotoxicity to vasospressin-producing cells in the hypothalamus. Wolfram syndrome (DIDMOAD syndrome) is an inherited autosomal recessive disorder due to a mutation in the transmembrane protein, wolframin, and characterized by DI, Diabetes Mellitus, Optic Atrophy and Deafness. Pituitary adenomas are the most common cause for hypopituitarism in adults. Causes of hypopituitarism are listed in Table 3.

TABLE 3. Causes of hypopituitarism
Congenital Disorders
HESX-1, PIT-1, and PROP-1 mutations, KAL and DAX-1 mutations, GnRH and GHRH receptor mutations, Kallmann, Prader Willi and Bardet-Beidl Syndromes, Vasopressin-Neurophysin gene mutations, DIDMOAD
Benign Neoplasms Malignant Neoplasms Cysts
Pituitary Adenoma Germ Cell Tumors (Germinoma) Arachnoid
Craniopharyngioma Lymphoma Dermoid
Meningioma Plasmacytoma Epidermoid
Optic Nerve Glioma Metastatic Disease (breast, lung) Rathke's Cleft
Granulomatous Disease Vascular Disorders Infections
Eosiniphilic Granuloma Aneurysm Abscess
Histiocytosis X Cavernous Angioma Cysticercosis
Sarcoidosis Infarction (Postpartum, D.M.) Tuberculosis
Autoimmune Traumatic Other
Lymphocytic Hypophysitis Pituitary Stalk Transection Cerebral Edema
Vasculitis Pituitary Apoplexy
Radiation Therap

5.2. Clinical Presentation of Hypopituitarism

Disorders that affect the hypothalamus may be distinguished from those affecting the pituitary by using both clinical and biochemical parameters. Since prolactin secretion from the anterior pituitary is primarily under inhibitory regulation by the hypothalamus, any destructive process of the hypothalamus often results in elevation of prolactin levels in the bloodstream (hyperprolactinemia). The combination of a modestly elevated prolactin and deficiency of one or more anterior pituitary hormones, therefore, suggests involvement of either the hypothalamus or pituitary stalk. In contrast, destruction of the anterior pituitary would be expected to result in low prolactin levels. An exception to this rule, however, occurs when prolactin is abnormally secreted from a prolactinoma. In addition, disorders affecting the hypothalamus are more commonly associated with abnormalities of posterior pituitary function such as diabetes insipidus (see below), and a variety of other hypothalamic syndromes listed in Table 4. A lesion centered in the median eminence due to metastatic breast carcinoma, for example, might be expected to result in deficiencies of ACTH, TSH, GH, LH/FSH, and vasopressin, and a modest elevation in prolactin. Destruction of the anterior pituitary, such as may occur in the postpartum period due to bleeding into the anterior pituitary (Sheehan's Syndrome), might result in deficiencies of ACTH, TSH, GH, LH/FSH, as well as prolactin, but usually not vasopressin.

TABLE 4. Neurologic manifestations of hypothalamic disease.
Disorders of Temperature Regulation Disorders of Food Intake
Hyperthermia Anorexia
Hypothermia Hyperphasia
Disorders of Water Intake Disorders of Sleep and Consciousness
Adipsia, Hypodipsia Somnolence
Compulsive Water Drinking Coma
Disorders of Autonomic Function Disorders of Psychic Function
Cardiac Arrhythmias Rage
Diencephalic Epilepsy Hallucinations
Pulmonary Edema

Since the pituitary gland lies adjacent to the cavernous sinus, temporal lobes and sphenoid sinus (Figure 5), other clinical symptoms such as palsies of extraoccular muscles, sensory disturbances in the first and second branches of cranial nerve, temporal lobe seizures, and CSF rhinorrhea can occur with disorders affecting the pituitary gland.

Figure 5. Pituitary gland
Pituitary gland
Reprinted from Endocrin Metab Clin North Am, 16(3), Lechan RM, Neuroendocrinology of pituitary hormone regulation, pp475-501, 1987, with pemission from Elsevier.

Disorders of both the hypothalamus and pituitary can also compress or infiltrate the optic chasm, resulting in a variety of visual field abnormalities affecting peripheral vision (hemanopia). Specific symptoms associated with the loss of each pituitary hormone are listed in Table 5 and more fully discussed below. GH is often the first hormone to be affected during hypopituitarism, followed by LH/FSH, ACTH, TSH and prolactin. Nevertheless, any of the anterior pituitary hormones can be affected in any order. In childhood, the dominant clinical picture of hypopituitarism is often failure of normal linear growth, while in the adult it is hypogonadism. Depending upon the underlying cause, however, pituitary deficiencies may be gradual and progressive (as with an enlarging pituitary adenoma) or acute (as with pituitary apoplexy). As a result, the presenting manifestations of hypopituitarism can vary enormously.

TABLE 5. Symptoms associated with hypopituitarism due to deficiency of specific hormones
Growth Hormone (GH) Gonadotrophins (LH/FSH)
Weight Gain (abdominal adiposity) Amenorrhea/oligomenorrhea
Decreased Muscle Strength Infertility
Decreased Exercise Capacity Dyspareunia
Increased Cardiovascular Risk Breast Atrophy
Impaired Psychological Well-being Loss of Secondary Sexual Hair
Growth Retardation (children) Decreased Libido
Small, Soft Testes
Decreased Muscle Mass and Strength
Decreased Erythropoiesis
Thyroid Stimulating Hormone (TSH) Adrenocorticotropin (ACTH)
Sensitivity to Cold Weight Loss
Dry Skin Fatigue
Constipation Pallor
Decreased Energy Hypoglycemia
Circulatory Collapse
Prolactin Vasopressin (Antidiuretic Hormone)
Poor or Absent Lactation Urinary Frequency

5.3. Biochemical Diagnosis of Hypopituitarism

Although one can infer some pituitary deficiencies based on history and clinical findings, demonstrating hormone deficiencies by biochemical testing is essential to establish the diagnosis of hypopituitarism. A variety of tests can be performed to evaluate the reserve of each of the pituitary hormones and are described below under each hormone. It is extremely important to make the diagnosis of ACTH and/or TSH deficiency, since these anterior pituitary hormones are essential for life. Some tests are also helpful in differentiating whether the cause for hypopituitarism is of pituitary or hypothalamic origin.

6. Hypocortisolism (ACTH)

Cortisol and adrenal androgen secretion are ACTH dependent and can be decreased in hypopituitarism. Because aldosterone secretion is dependent primarily on the rennin-angiotensin system, however, hypopituitarism is not associated with aldosterone deficiency. Major symptoms of ACTH deficiency include fatigue, weakness, anorexia, weight loss, nausea, vomiting, abdominal pain, and myalgia. Pallor of the skin and decreased tanning are observed contrary to the characteristic manifestations of Addison's Disease due to autoimmune adrenalitis. Because of impaired gluconeogenesis, hypoglycemia may be present particularly with fasting or alcohol ingestion, and hyponatremia is common due to inappropriate secretion of vasopressin (SIADH) and inability to secrete a water load. Loss of adrenal androgens is of little consequence for males if testicular androgen production is normal, but can result in decreased libido and loss of axillary and pubic hair in women. Circulatory collapse can occur in association with acute stressful situations. Several tests are available to assess ACTH reserve. Measurement of basal levels of serum cortisol are generally not very helpful except when extremely low since cortisol does undergo a diurnal variation (higher in the AM and lower in the PM) and does not necessarily reflect adequate reserves of ACTH required during stress. Thus, provocative tests of the adrenal axis are necessary.

6.1. Cortrosyn Stimulation Test

Cortrosyn is synthetic ACTH 1-24 and is administered im or iv to induce cortisol secretion from the adrenal gland. Individuals with long-standing hypopituitarism develop atrophy of the adrenal cortex and as a result, show blunted peak cortisol responses to cortisol (Fig. 6).

Figure 6. Cortrosyn Stimulation Test
Figure 6.  Cortrosyn Stimulation Test

6.2. Overnight Metyrapone Test

Metyrapone inhibits 11-beta hydroxylase in the adrenal cortex, thereby reducing the conversion of 11-deoxycortisol to cortisol. The reduction in cortisol in the circulation increases ACTH secretion through direct effects on anterior pituitary corticotrophs (negative feedback regulation). This results in a secondary increase in 11-deoxycortisol (compound S) in the circulation. ACTH and 11-deoxycortisol are measured in the blood the morning following a single dose of metyrapone the preceding evening. In hypopituitarism, both ACTH and 11-deoxycortisol levels are blunted.

6.3. Insulin Tolerance Test

The insulin tolerance test (ITT) is the "gold standard" for assessing adequate adrenal reserve. However, the test is potentially hazardous since hypoglycemia (blood glucose less than 40 mg/dl) is a necessary endpoint to allow activation of the adrenal axis. Accordingly, the ITT is contraindicated in anyone with a history of heart disease or seizures and should be avoided in the elderly. The stress of the hypoglycemia increases the secretion of ACTH through effects on the release of CRH and vasopressin from the hypothalamus. Both ACTH and cortisol are measured after achieving hypoglycemia. In hypopituitarism, both ACTH and cortisol levels are blunted.

6.4. CRH Stimulation Test

Both human and bovine synthetic CRH are available. The hormone is administered in a single bolus iv and ACTH and cortisol levels are measured over 2 hrs.

7. Hypothyroidism (TSH)

TSH insufficiency results in reduced thyroid hormone secretion from the thyroid gland resulting in symptoms of hypothyroidism. Classical features include cold intolerance, fatigue, dry skin and constipation. Speech may be slowed, and there may be slowing of mental and physical function. Hyponatremia and a normochromic normocytic anemia may be present. As opposed to ACTH, the best test to assess TSH reserve is measurement of basal thyroid hormone levels. Low thyroxine (T4) and triiodothyronine (T3) levels simultaneously with an inappropriately low TSH, establishes the diagnosis of central hypothyroidism.

7.1. TRH Stimulation Test

Synthetic TRH is available for iv administration and acts directly on the anterior pituitary. In normal individuals, TSH rises abruptly (within 15-30 min) and then falls to baseline values. Pituitary disease may result in an absent or blunted TSH response, whereas hypothalamic disease may result in a delayed peak response of TSH (Figure 7). Significant overlap exists in the TSH response to TRH in patients with disorders that affect the pituitary and hypothalamus, respectively, such that this test cannot reliably differentiate between pituitary and hypothalamic disease.

Figure 7. TRH Stimulation Test
Figure 7.  TRH Stimulation Test

7.2. Prolactin

The only clinical manifestation of prolactin deficiency known is failure of lactation in the postpartum period. Basal levels of prolactin are generally sufficient to assess prolactin reserve. Serum prolactin may be low with pituitary lesions (unless due to a prolactinoma) and high with hypothalamic disorders or disorders that prevent the flow of portal blood from the hypothalamus to the anterior pituitary such as stalk compression. A number of provocative tests are available that are very effective in stimulating the secretion of prolactin, including the TRH stimulation test and the ITT, but are rarely needed.

7.3. Hypogonadism

LH and FSH are necessary for secondary sexual development, maintenance of secondary sexual characteristics and fertility. In men, gonadotrophin deficiency results in loss of libido, erectile dysfunction, oligospermia, reduced erythropoiesis, decreased body mass and osteoporosis. In women, LH and FSH deficiency are manifest by oligo/amenorrhea, breast atrophy, decreased secondary sexual hair and osteoporosis. Low plasma estradiol (women) or testosterone (men) levels simultaneous with inappropriately low LH and FSH levels, establishes the diagnosis of hypogonadotropic hypogonadism. Provocative tests are available including the GnRH stimulation test, in which synthetic GnRH acts directly on the anterior pituitary, and the clomiphene stimulation test, in which clomiphene acts on the hypothalamus as an anti-estrogen, but also are not very effective in differentiating pituitary from hypothalamic disease.

7.4. Growth Hormone Deficiency (GH)

Assessment of GH reserve is particularly important in children who have not yet reached their full growth potential. However, as it is becoming increasingly apparent that GH deficiency may be associated with significant physical and psychological abnormalities in adults and could contribute to the 2-3-fold increased mortality in individuals with hypopituitarism primarily due to cardiovascular complications, assessment of GH reserve in adults is also important. Adults with growth hormone deficiency exhibit a higher body mass index and waist-to-hip ratio due to an approximately 8% increase in subcutaneous and visceral adipose tissue and approximately 8% decrease in lean body mass. There is a tendency for the increased atherothrombotic propensity due to higher PA-1 activity and increased fibrinogen, and abnormal lipid profiles are also commonly seen including elevated total cholesterol, LDL cholesterol, ApoB, and triglycerides. Elevated serum insulin and impaired glucose metabolism also may also contribute to the increased risk of cardiovascular disease. Since GH is secreted episodically (one pulse every 2-4 h), measurement of a random GH level is not useful. In addition, unless the insulin like growth factor-1 (IGF-1) level is extremely low (IGF-1 is produced primarily by the liver and mediates many of the actions of GH), it also is not a reliable index of GH reserve. Thus, provocative tests are necessary to establish normal GH reserve.

7.4.1. Insulin Tolerance Test

The ITT is the "gold standard" for assessing GH reserve. GH rises in response to the hypoglycemia induced by a blous of insulin. Constant medical monitoring is required throughout the procedure as a blood glucose less than 40 mg/dl is required for an adequate GH response in normal individuals. The ITT can also be used to assess ACTH reserve as described above. Figure 8 shows the normal response for GH and ACTH following insulin hypoglycemia.

Figure 8. Insulin Tolerance Test
Figure 8.  Insulin Tolerance Test

7.4.2. Argenine Stimulation Test

Argenine produces a rise in blood glucose, followed by a secondary fall. When the blood glucose falls, there is a rise in GH. Argenine is infused iv over 30 min and the GH response measured over 2 h. The test is not as reliable as the ITT.

7.4.3. GHRH Stimulation Test

Synthetic GHRH 1-29 is administered iv and the GH response measured over 2 h. Its action is exerted directly on the anterior pituitary. The biochemical diagnosis of GH deficiency is enhanced when the GHRH stimulation test is combined with the Arginine Stimulation Test.

A number of other provocative stimuli are available for stimulating GH including clonidine, glucagon, L-DOPA, and exercise, but these tests are not as reliable in inducing a GH rise in normal individuals as the above tests, and therefore, are difficult to interpret.

7.5. Diabetes Insipidus (Vasopressin)

Deficiency of vasopressin is manifest by urinary frequency and large urine volumes (greater than 3 L/d but may reach 20 L/d) due to the inability to concentrate the urine, a condition referred to as diabetes insipidus (DI). DI has a second cause, however, called nephrogenic DI which is due to renal insensitivity to the actions of vasopressin. Characteristic of central DI is a high serum osmolality (usually 290-300 mOsm/kg), inappropriately low urine osmolality and specific gravity (usually <200 mOsm/kg with urine sp. gr < 1.010), and inappropriately low plasma vasopressin level. These individuals are generally very thirsty, unless they have simultaneous damage to thirst centers in the hypothalamus. If the plasma osmolality is not greater than 295 mosmol/kg, a water deprivation test is performed. The individual is deprived of all food and drink until the plasma osmolality rises above 295, at which time the urine osmolality and plasma vasopressin level are simultaneously measured. Individuals with central DI will have serum osmolality levels that are high, urine osmolality levels that are inappropriately low, and will continue to have a high urine output. The normal rise in plasma vasopressin with dehydration (rise in plasma osmolality) is shown in Figure 9. The shaded area and + correspond to normal, expected values. Filled squares represent individuals with nephrogenic DI, filled diamonds represent individuals with complete central DI, and closed triangles represent individuals with partial central DI. During a water deprivation test, no individual should be allowed to lose more than 3% of body weight. Following the administration of the synthetic vasopressin analogue, desmopressin or DDAVP, individuals with central DI show an increase in urine osmolality of >50% 60 min later.

Figure 9. Normal response of vasopressin to dehydration
Figure 9.  Normal response of vasopressin to dehydration

7.6. Management of Hypopituitarism

The aim of treatment is to replace those deficiencies needed for normal function and to treat the underlying disease process. In most instances, replacement of hormone deficiencies can be accomplished by the oral, cutaneous (skin patch, gels or creams), subcutaneous or nasal administration of the deficient hormones. The dose is usually the same from day to day with exception of glucocorticoid replacement, which must be increased at times of stress. Individuals with ACTH deficiency must wear an ID bracelet or necklace indicating their dependence on exogenous glucocorticoids. They should also be instructed in the administration of intramuscular glucocorticoids should they be unable to take their medication orally due to vomiting. Table 6 lists the common drugs used for hormone replacement therapy in hypopituitarism. As a general rule, glucocorticoid replacement therapy should be given first. Thyroid hormone replacement therapy should never be given before glucocorticoids have been replaced to prevent precipitating an Addisonian crisis.

TABLE 6. Hormone replacement therapy in hypopituitarism
Deficient Hormone Replacement
ACTH glucocorticoids (hydrocortisone, prednisone, dexamethasone)
TSH thyroxine (T4)
Prolactin Not replaced
LH/FSH estradiol + progesterone (women)
testosterone (men)
Pulsatile synthetic GnRH (if anterior pituitary intact) or HCG/human recombinant FSH if fertility desired to induce ovulation/spermatogenesis
GH Human recombinant growth hormone (hGH)
Vasopressin (ADH) desmopressin (DDAVP)

8. References

  • Abboun CF, Anterior Pituitary Failure, in The Pituitary, S. Melmed, ed, 341-410, 1995.
  • Lechan RM, Functional microanatomy of the hypophysial-pituitary axis, Front Horm Res 20, 2-40, 1996.
  • Robertson GL, Antidiuretic Hormone, Normal and Disordered Function, Endocrinologyb and Metabolism. Clinics of North America 30: 671- 694, 2001.
  • Vance ML, Mauras N, Growth hormone therapy in adults and children, NEJM 341, 1206-1216, 1999.