Hypothalamus & Pituitary Gland
David C. Aron MD, MS
James W. Findling MD
- Blake Tyrrell MD
The hypothalamus and pituitary gland form a unit which exerts control over the function of several endocrine glands—thyroid, adrenals, and gonads—as well as a wide range of physiologic activities. This unit constitutes a paradigm of neuroendocrinology—brain-endocrine interactions. The actions and interactions of the endocrine and nervous systems whereby the nervous system regulates the endocrine system and endocrine activity modulates the activity of the central nervous system constitute the major regulatory mechanisms for virtually all physiologic activities. The immune system also interacts with both the endocrine and the nervous systems (see Chapter 4). These neuroendocrine interactions are also important in pathogenesis. This chapter will review the normal functions of the pituitary gland, the neuroendocrine control mechanisms of the hypothalamus, and the disorders of those mechanisms.
Nerve cells and endocrine gland cells, which are both involved in cell-to-cell communication, share certain characteristic features—secretion of chemical messengers (neurotransmitters or hormones) and electrical activity. A single chemical messenger—peptide or amine—can be secreted by neurons as a neurotransmitter or neural hormone and by endocrine gland cells as a classic hormone. Examples of such multifunctional chemical messengers are shown in Table 5-1. The cell-to-cell
communication may occur by four mechanisms: (1) autocrine communication via messengers that diffuse in the interstitial fluid and act on the cells that secreted them, (2) neural communication via synaptic junctions, (3) paracrine communication via messengers that diffuse in the interstitial fluid to adjacent target cells (without entering the bloodstream), and (4) endocrine communication via circulating hormones (Figure 5-1). The two major mechanisms of neural regulation of endocrine function are direct innervation and neurosecretion (neural secretion of hormones). The adrenal medulla, kidney, parathyroid gland, and pancreatic islets are endocrine tissues that receive direct autonomic innervation (see Chapters 8, 10, 11, and 17). An example of neurosecretory regulation is the hormonal secretion of certain hypothalamic nuclei into the portal hypophysial vessels, which regulate the hormone-secreting cells of the anterior lobe of the pituitary. Another example of neurosecretory regulation is the posterior lobe of the pituitary gland, which is made up of the endings of neurons whose cell bodies reside in hypothalamic nuclei. These neurons secrete vasopressin and oxytocin into the general circulation.
Table 5-1. Neuroendocrine messengers: Substances that function as neurotransmitters, neural hormones, and classic hormones.
Anatomy & Embryology
The anatomic relationships between the pituitary and the main nuclei of the hypothalamus are shown in Figure 5-2. The posterior lobe of the pituitary (neurohypophysis) is of neural origin, arising embryologically as an evagination of the ventral hypothalamus and the third ventricle. The neurohypophysis consists of the axons and nerve endings of neurons whose cell bodies reside in the supraoptic and paraventricular nuclei of the hypothalamus and supporting tissues. This hypothalamo-neurohypophysial nerve tract contains approximately 100,000 nerve fibers. Repeated swellings along the nerve fibers ranging in thickness from 1 ľm to 50 ľm constitute the nerve terminals.
The human fetal anterior pituitary anlage is initially recognizable at 4–5 weeks of gestation, and rapid cytologic differentiation leads to a mature hypothalamic-pituitary unit at 20 weeks. The anterior pituitary (adenohypophysis) originates from Rathke's pouch, an ectodermal evagination of the oropharynx, and migrates to join the neurohypophysis. The portion of Rathke's pouch in contact with the neurohypophysis develops less extensively and forms the intermediate lobe. This lobe remains intact in some species, but in humans its cells become interspersed with those of the anterior lobe and develop the capacity to synthesize and secrete pro-opiomelanocortin and adrenocorticotropic hormone (ACTH). Remnants of Rathke's pouch may persist at the boundary of the neurohypophysis, resulting in small colloid cysts. In addition, cells may persist in the lower portion of Rathke's pouch beneath the sphenoid bone, the pharyngeal pituitary. These cells have the potential to secrete hormones and have been reported to undergo adenomatous change.
The pituitary gland itself lies at the base of the skull in a portion of the sphenoid bone called the sella turcica (“Turkish saddle”). The anterior portion, the tuberculum sellae, is flanked by posterior projections of the sphenoid wings, the anterior clinoid processes; the dorsum sellae forms the posterior wall, and its upper corners project into the posterior clinoid processes. The gland is surrounded by dura, and the roof is formed by a reflection of the dura attached to the clinoid processes, the diaphragma sellae. The arachnoid membrane and, therefore, cerebrospinal fluid are prevented
from entering the sella turcica by the diaphragma sellae. The pituitary stalk and its blood vessels pass through an opening in this diaphragm. The lateral walls of the gland are in direct apposition to the cavernous sinuses and separated from them by dural membranes. The optic chiasm lies 5–10 mm above the diaphragma sellae and anterior to the stalk (Figure 5-3).
Figure 5-1. Intercellular communication by chemical mediators.
The size of the pituitary gland, of which the anterior lobe constitutes two-thirds, varies considerably. It measures approximately 15 × 10 × 6 mm and weighs 500–900 mg; it may double in size during pregnancy. The sella turcica tends to conform to the shape and size of the gland, and for that reason there is considerable variability in its contour.
The anterior pituitary is the most richly vascularized of all mammalian tissues, receiving 0.8 mL/g/min from a portal circulation connecting the median eminence of the hypothalamus and the anterior pituitary. Arterial blood is supplied from the internal carotid arteries via the superior, middle, and inferior hypophysial arteries. The superior hypophysial arteries form a capillary network in the median eminence of the hypothalamus that recombines in long portal veins draining down the pituitary stalk to the anterior lobe, where they break up into another capillary network and re-form into venous channels. The pituitary stalk and the posterior pituitary are supplied directly from branches of the middle and inferior hypophysial arteries (Figure 5-2 and 5-3).
Venous drainage of the pituitary, the route through which anterior pituitary hormones reach the systemic circulation, is variable, but venous channels eventually drain via the cavernous sinus posteriorly into the superior and inferior petrosal sinuses to the jugular bulb and vein (Figure 5-4). The axons of the neurohypophysis terminate on capillaries that drain via the posterior lobe veins and the cavernous sinuses to the general circulation. The hypophysial-portal system of capillaries allows control of anterior pituitary function by the hypothalamic hypophysiotropic hormones secreted into the portal hypophysial vessels. This provides a short, direct connection to the anterior pituitary from the ventral hypothalamus and the median eminence (Figure 5-5). There may also be retrograde blood flow between the pituitary and hypothalamus, providing a possible means of direct feedback between pituitary hormones and their neuroendocrine control centers.
Pituitary Development & Histology
Anterior pituitary cells were originally classified as acid-ophils, basophils, and chromophobe cells based on staining with hematoxylin and eosin. Immunocytochemical and electron microscopic techniques now per-mit classification of cells by their specific secretory products: somatotrophs (growth hormone [GH]-secreting cells), lactotrophs (prolactin [PRL]-secreting cells), thyrotrophs (cells secreting thyroid-stimulating hormone [thyrotropin; TSH]), corticotrophs (cells secreting adrenocorticotropic hormone [corticotropin; ACTH] and related peptides), and gonadotrophs (luteinizing hormone [LH]- and follicle-stimulating hormone [FSH]-secreting cells). The development of the pituitary gland and the emergence of the distinct cell types from common primordial cells is controlled by a limited set of transcription factors, most notably Prop1 and Pit1 (Figure 5-6). The individual hormone-secreting cells emerge in a specific order and from distinct lineages.
Abnormalities of pituitary and lineage-specific transcription factors have been associated with the development of hypopituitarism. Although traditionally the pituitary has been conceptualized as a gland with distinct and highly specialized cells that respond to specific hypothalamic and peripheral hormones, it has become clear that local (ie, paracrine) factors also play a role in normal pituitary physiology.
Figure 5-2. The human hypothalamus, with a superimposed diagrammatic representation of the portal hypophysial vessels. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 15th ed. McGraw-Hill, 1993.)
The GH-secreting cells are acidophilic and usually located in the lateral portions of the anterior lobe. Granule size by electron microscopy is 150–600 nm in diameter. These cells account for about 50% of the adenohypophysial cells.
The PRL-secreting cell is a second but distinct acid-ophil-staining cell randomly distributed in the anterior pituitary. These cells account for 10–25% of anterior pituitary cells. Granule size averages approximately 550 nm on electron microscopy. There are two types of lactotrophs: sparsely granulated and densely granulated. These cells proliferate during pregnancy as a result of elevated estrogen levels and account for the twofold increase in gland size.
Figure 5-3. Anatomic relationships and blood supply of the pituitary gland. (Reproduced, with permission, from Frohman LA: Diseases of the anterior pituitary. In: Endocrinology and Metabolism, 3rd ed. Felig P, Baxter JD, Frohman LA (editors). McGraw-Hill, 1995.)
These TSH-secreting cells, because of their glycoprotein product, are basophilic and also show a positive reaction with periodic acid-Schiff (PAS) stain. Thyrotrophs are the least common pituitary cell type, making up less than 10% of adenohypophysial cells. The thyrotroph granules are small (50–100 nm); these cells are usually located in the anteromedial and anterolateral portions of the gland. During states of primary thyroid failure, the cells demonstrate marked hypertrophy, increasing overall gland size.
ACTH and its related peptides (see below) are secreted by basophilic cells that are embryologically of intermediate lobe origin and usually located in the anteromedial portion of the gland. Corticotrophs represent 15–20% of adenohypophysial cells. Electron microscopy shows that these secretory granules are about 360 nm in diameter. In states of glucocorticoid excess, corticotrophs undergo degranulation and a microtubular hyalinization known as Crooke's hyaline degeneration.
LH and FSH originate from basophil-staining cells, whose secretory granules are about 200 nm in diameter. These cells constitute 10–15% of anterior pituitary cells, and they are located throughout the entire anterior lobe. They become hypertrophied and cause the gland to enlarge during states of primary gonadal failure such as menopause, Klinefelter's syndrome, and Turner's syndrome.
- OTHER CELL TYPES
Some cells, usually chromophobes, contain secretory granules but do not exhibit immunocytochemical staining for the major known anterior pituitary hormones. These cells have been called null cells; they may give rise to (apparently) nonfunctioning adenomas. Some
may represent undifferentiated primitive secretory cells; others—eg, glia-like or folliculostellate cells—produce one or more of the many paracrine factors that have been described in the pituitary. Mammosomatotrophs contain both GH and PRL; these bihormonal cells are most often seen in pituitary tumors. Human chorionic gonadotropin is also secreted by the anterior pituitary gland, but its cell of origin and physiologic significance are uncertain. The six known major anterior pituitary hormones are listed in Table 5-2.
Figure 5-4. Venous drainage of the pituitary gland—the route by which adenohypophysial hormones reach the systemic circulation. (Reproduced, with permission, from Findling JW et al: Selective venous sampling for ACTH in Cushing's syndrome: Differentiation between Cushing's disease and the ectopic ACTH syndrome. Ann Intern Med 1981;94:647.)
The hypothalamic hormones can be divided into those secreted into hypophysial portal blood vessels and those secreted by the neurohypophysis directly into the general circulation. The hypothalamic nuclei, their neurohormones, and their main functions are shown inTable 5-3. The structures of the eight major hypothalamic hormones are shown in Table 5-4.
The hypophysiotropic hormones which regulate the secretion of anterior pituitary hormones include growth hormone-releasing hormone (GHRH), somatostatin, dopamine, thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonado-tropin-releasing hormone (GnRH). The location of the cell bodies of the hypophysiotropic hormone-secreting neurons are depicted in Figure 5-7. Most of the anterior pituitary hormones are controlled by stimulatory hormones, but growth hormone and especially prolactin are also regulated by inhibitory hormones. Some hypophysiotropic hormones are multifunctional. The hormones of the hypothalamus are secreted episodically and not continuously, and in some cases there is an underlying circadian rhythm.
GHRH stimulates growth hormone (GH) secretion by and is trophic for somatotrophs. GHRH-secreting neurons are located in the arcuate nuclei (Figure 5-2), and axons terminate in the external layer of the median eminence. The major isoform of GHRH is 44 amino acids
in length. It was isolated from a pancreatic tumor in a patient with clinical manifestations of growth hormone excess (acromegaly) associated with somatotroph hyperplasia (see below). GHRH is synthesized from a larger precursor of 108 amino acids. Other secretory products derived from this precursor have also been found. Full biologic activity of these releasing factors appears to reside in the 1–29 amino acid sequence of the amino terminal portion of the molecule. Human GHRH is a member of a homologous family of peptides that includes secretin, glucagon, vasoactive intestinal peptide, and others. Like CRH, GHRH has a relatively long half-life (50 minutes).
Figure 5-5. Secretion of hypothalamic hormones. The hormones of the posterior lobe (PL) are released into the general circulation from the endings of supraoptic and paraventricular neurons, whereas hypophysiotropic hormones are secreted into the portal hypophysial circulation from the endings of arcuate and other hypothalamic neurons. (AL, anterior lobe; ARC, arcuate and other nuclei; MB, mamillary bodies; OC, optic chiasm; PV, paraventricular nucleus. SO, supraoptic nucleus.)
Somatostatin inhibits the secretion of GH and TSH. Somatostatin-secreting cells are located in the periventricular region immediately above the optic chiasm (Figure 5-2) with nerve endings found diffusely in the external layer of the median eminence.
Somatostatin, a tetradecapeptide, has been found not only in the hypothalamus but also in the D cells of the pancreatic islets, the gastrointestinal mucosa, and the C cells (parafollicular cells) of the thyroid. The somatostatin precursor has 116 amino acids. Processing of the carboxyl terminal region of preprosomatostatin results in the generation of the tetradecapeptide somatostatin 14 and an amino terminal extended form containing 28 amino acid residues (somatostatin 28). Somatostatin 14 is the major species in the hypothalamus, while somatostatin 28 is found in the gut. In addition to its profound inhibitory effect on GH secretion, somatostatin also has important inhibitory influences on many other hormones, including insulin, glucagon, gastrin, secretin, and VIP. This inhibitory hypothalamic peptide plays a role in the physiologic secretion of TSH by augmenting the direct inhibitory effect of thyroid hormone on the thyrotrophs; administration of antisomatostatin antibodies results in a rise in circulating TSH level.
Dopamine, the primary prolactin-inhibitory hormone, is found in the portal circulation and binds to dopamine receptors on lactotrophs. The hypothalamic control of PRL secretion, unlike that of the other pituitary hormones, is predominantly inhibitory. Thus, disruption of the hypothalamic-pituitary connection by stalk section, hypothalamic lesions, or pituitary autotransplantation increases PRL secretion. Dopamine-secreting neurons (tuberoinfundibular dopaminergic system) are located in the arcuate nuclei and their axons terminate in the external layer of the median eminence, primarily in the same area as the GnRH endings (laterally) and to a lesser extent medially (Figure 5-2). The neurotransmitter gamma-aminobutyric acid (GABA) and cholinergic pathways also appear to inhibit PRL release.
- PROLACTIN-RELEASING FACTORS
The best-studied factor with PRL-releasing activity is thyrotropin-releasing hormone (see below), but there is little evidence for a physiologic role; PRL increase associated with sleep, during stress, and after nipple stimulation or suckling is not accompanied by an increase in TRH or TSH. Another hypothalamic peptide, vasoactive intestinal peptide, stimulates PRL release in humans. Serotonergic pathways may also stimulate PRL secretion, as demonstrated by the increased PRL secretion after the administration of serotonin precursors and by the reduction of secretion following treatment with serotonin antagonists.
Figure 5-6. Transcription factors involved in the early development of mouse pituitary, including Tpit. *Tpit is expressed on embryonic day E 11.5, followed by expression of POMC cells by E 12.5. DAX1, dosage sensitive sex-reversal-adrenal hypoplasia congenital critical region on the X chromosome 1; GAT A2, GAT A-binding protein 2, zinc-finger transcription factor; α-GSU, α-subunit of pituitary glycoprotein hormones; Hesx1, homeobox gene expressed in embryonic stem cells 1; Isl1, islet 1 transcription factor; LH/FSH, lutenizing hormone/follicle-stimulating hormone; Lhx3/4, L1M-domain transcription factor 314; LIF, leukemia inhibiting factor; NE, neural epithelium; Neuro01, neurogenic basic helix-loop-helix transcription factor 01; OE, oral ectoderm; Pax6, pair-box containing transcription factor 6; Pit1, pituitary transcription factor 1; PRL, prolactin; Prop1, prophet of Pit1; Ptx1, pituitary homeobox 1; RP, Rathke's pouch; SF1, steroidogenic factor 1; Six3, sine oculis-like homeobox transcription factor 3; Tpit, T-box pituitary transcription factor; VH, ventral hypothalamus. (From Asteria C. T-Box and isolated ACTH deficiency. Eur J Endocrinol 2002;146:463.)
- THYROTROPIN-RELEASING HORMONE (TRH)
TRH, a tripeptide, is the major hypothalamic factor regulating TSH secretion. Human TRH is synthesized from a large precursor of 242 amino acids that contains six copies of TRH. TRH-secreting neurons are located in the medial portions of the paraventricular nuclei (Figure 5-2), and their axons terminate in the medial portion of the external layer of the median eminence.
- CORTICOTROPIN-RELEASING HORMONE (CRH)
CRH, a 41-amino-acid peptide, stimulates the secretion of adrenocorticotropic hormone (ACTH) and other products of its precursor molecule, pro-opiomel-anocortin. The structure of human CRH is identical to that of rat CRH. CRH is synthesized from a precursor of 196 amino acids. CRH has a long plasma half-life (approximately 60 minutes), and both ADH and angiotensin II potentiate CRH-mediated secretion of ACTH. In contrast, oxytocin inhibits CRH-mediated ACTH secretion. CRH-secreting neurons are found in the anterior portion of the paraventricular nuclei just lateral to the TRH-secreting neurons; their nerve endings are found in all parts of the external layer of the median eminence. CRH is also secreted from human placenta. The level of this hormone increases significantly during late pregnancy and delivery. In addition, a specific CRH-binding protein (CRHBP) has been described in both serum and in intracellular locations within a variety of cells. It is likely that CRHBPs modulate the actions of CRH.
Table 5-2. Major adenohypophysial hormones and their cellular sources.1
- GONADOTROPIN-RELEASING HORMONE (GNRH)
The secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is controlled by a single stimulatory hypothalamic hormone, gonadotropin-releasing hormone (GnRH). GnRH is a linear decapeptide that stimulates only LH and FSH; it has no effect on other pituitary hormones except in some patients with acromegaly and Cushing's disease (see below). The precursor of GnRH—proGnRH—contains 92 amino acids. ProGnRH also contains the sequence of a 56-amino-acid polypeptide called GnRH-associated peptide (GAP). This secretory product exhibits prolactin-inhibiting activity, but its physiologic role is unknown. GnRH-secreting neurons are located primarily in the preoptic area of the anterior hypothalamus and
their nerve terminal are found in the lateral portions of the external layer of the median eminence adjacent to the pituitary stalk (Figure 5-2).
Table 5-3. The hypothalamic nuclei and their main functions.1
Posterior Pituitary Hormones
The hypothalamo-neurohypophysial system secretes two nonapeptides: antidiuretic hormone (ADH) (also known as arginine vasopressin) and oxytocin. They are synthesized in large cell bodies of neurons (magnocellular neurons) in the supraoptic nuclei and the lateral and superior parts of the paraventricular nuclei (Figures 5-2 and 5-5). The genes encoding these closely related hormones reside on chromosome 20 and probably evolved by duplication and inversion of an ancestral gene. ADH is an important regulator of water balance; it also is a potent vasoconstrictor and plays a role in regulation of cardiovascular function. Oxytocin causes contraction of smooth muscle, especially of the myoepithelial cells that line the ducts of the mammary gland, thus causing milk ejection.
ADH and oxytocin are basic nonapeptides (MW 1084 and 1007, respectively) characterized by a ring structure with a disulfide linkage (seeTable 5-4). They
are synthesized by separate cells (ie, there is no cosecretion or synthesis) from prohormones that contain both the peptide and an associated binding peptide or neurophysin specific for the hormone: neurophysin II for ADH and neurophysin I for oxytocin. Since the hormone and neurophysin are synthesized from the same prohormone, defects in gene expression result in deficiency of both products. For example, the Brattleboro rat has a deficiency of ADH and neurophysin II (but not of oxytocin and neurophysin I). Following synthesis and initial processing, secretory granules containing the prohormone migrate by axoplasmic flow (2–3 mm/h) to the nerve endings of the posterior lobe. In the secretory granules, further processing produces the mature nonapeptide and its neurophysin, which are cosecreted in equimolar amounts by exocytosis. Action potentials that reach the nerve endings increase the Ca2+ influx and initiate hormone secretion.
Table 5-4. Hypothalamic hormones.
Neuroendocrinology: The Hypothalamus as Part of a Larger System
The hypothalamus is involved in many nonendocrine functions such as regulation of body temperature and food intake and is connected with many other parts of the nervous system. The brain itself is influenced by both direct and indirect hormonal effects. Steroid and thyroid hormones cross the blood-brain barrier and produce specific receptor-mediated actions (see Chapters 7 and 9). Peptides in the general circulation which do not cross the blood-brain barrier elicit their effects indirectly, eg, insulin-mediated changes in blood glucose concentration. In addition, communication between the general circulation and the brain may take place via the circumventricular organs, which are located outside the blood-brain barrier (see below). Moreover, hypothalamic hormones in extrahypothalamic brain function as neurotransmitters or neurohormones. They are also found in other tissues where they function as hormones (endocrine, paracrine, or autocrine). For example, somatostatin-containing neurons are widely distributed in the nervous system. They are also found in the pancreatic islets (D cells), the gastrointestinal mucosa, and the C cells of the thyroid gland (parafollicular cells). Somatostatin is not only secreted into the general circulation as well as locally—it is also secreted into the lumen of the gut, where it may affect gut secretion. A hormone with this activity has
been called a “lumone.” Hormones common to the brain, pituitary, and gastrointestinal tract include not only TRH and somatostatin but also vasoactive intestinal peptide and peptides derived from pro-opiomel-anocortin.
Figure 5-7. Location of cell bodies of hypophysiotropic hormone-secreting neurons projected on a ventral view of the hypothalamus and pituitary of the rat. (AL, anterior lobe; ARC, arcuate nucleus; BA, basilar artery; IC, internal carotid; IL, intermediate lobe; MC, middle cerebral; ME, median eminence; PC, posterior cerebral; Peri, periventricular nucleus; PL, posterior lobe; PVL and PVM, lateral and medial portions of the paraventricular nucleus; SO, supraoptic nucleus.) The names of the hormones are enclosed in the boxes. (SS, somatostatin; DA, dopamine.) (Courtesy of LW Swanson and ET Cunningham Jr.)
Hypothalamic function is regulated both by hormone-mediated signals—eg, negative feedback—and by neural inputs from a wide variety of sources. These nerve signals are mediated by neurotransmitters including acetylcholine, dopamine, norepinephrine, epinephrine, serotonin, gamma-aminobutyric acid, and opioids. The hypothalamus can be considered a final common pathway by which signals from multiple systems reach the anterior pituitary. For example, cytokines that play a role in the response to infection, such as the interleukins, are also involved in regulation of the hypothalamic-pituitary-adrenal axis. This system of immunoneuroendocrine interactions is important in the organism's response to a variety of stresses.
The hypothalamus also sends signals to other parts of the nervous system. For example, while the major nerve tracts of the magnocellular neurons containing vasopressin and oxytocin terminate in the posterior pituitary, nerve fibers from the paraventricular and supraoptic nuclei project to many other parts of the nervous system. In the brain stem, vasopressinergic neurons are involved in the autonomic regulation of blood pressure. Similar neurons project to the gray matter and are implicated in higher cortical functions. Fibers terminating in the median eminence permit release of ADH into the hypophysial-portal system; delivery of ADH in high concentrations to the anterior pituitary may facilitate its involvement in the regulation of ACTH secretion. Magnocellular neurons also project to the choroid plexus where they may release ADH into the cerebrospinal fluid. In addition to magnocellular neurons, the paraventricular nuclei contain cells with smaller cell bodies—parvicellular neurons. Such neurons are also found in other regions of the nervous system and may contain other peptides such as CRH and TRH.
The Pineal Gland & the Circumventricular Organs
The circumventricular organs are secretory midline brain structures that arise from the ependymal cell lining of the ventricular system (Figure 5-8). These organs are located adjacent to the third ventricle—subfornical organ, subcommissural organ, organum vasculosum of the lamina terminalis, pineal, and part of the median eminence—and at the roof of the fourth ventricle—area postrema (Figure 5-8). The tissues of these organs have relatively large interstitial spaces and have fenestrated capillaries which, being highly permeable, permit diffusion of large molecules from the general circulation; elsewhere in the brain tight capillary endothelial junctions prevent such diffusion—the blood-brain barrier. For example, angiotensin II (see Chapter 10) is involved in the regulation of water intake, blood pressure, and secretion of vasopressin. In addition to its peripheral effects, circulating angiotensin II acts on the
subfornical organ resulting in an increase in water intake.
Figure 5-8. Circumventricular organs. The neurohypophysis (NH) and adjacent median eminence, the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO), and the area postrema (AP) are shown projected on a sagittal section of the human brain. The pineal (PI) and the subcommissural organ (SCO) are also shown but probably do not function as circumventricular organs. (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 15th ed. McGraw-Hill, 1993.)
The pineal gland, considered by the 17th century French philosopher Renž Descartes to be the seat of the soul, is located at the roof of the posterior portion of the third ventricle. The pineal gland in humans and other mammals has no direct neural connections with the brain except for sympathetic innervation via the superior cervical ganglion. The pineal gland secretes melatonin, an indole synthesized from serotonin by 5-methoxylation and N-acetylation (Figure 5-9). The pineal releases melatonin into the general circulation and into the cerebrospinal fluid. Melatonin secretion is regulated by the sympathetic nervous system and is increased in response to hypoglycemia and darkness. The pineal also contains other bioactive peptides and amines including TRH, somatostatin, GnRH, and norepinephrine. The physiologic roles of the pineal remain to be elucidated, but they involve regulation of gonadal function and development and chronobiologic rhythms.
Figure 5-9. Formation and metabolism of melatonin. (HIOMT, hydroxyindole-O-methyltransferase.) (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 15th ed. McGraw-Hill, 1993.)
The pineal gland may be the site of pineal cell tumors (pinealomas) or germ cell tumors (germinomas). Neurologic signs and symptoms are the predominant clinical manifestations, eg, increased intracranial pressure, visual abnormalities, ataxia, and Parinaud's syndrome—upward gaze palsy, absent pupillary light reflex, paralysis of convergence, and wide based gait. Endocrine manifestations result primarily from deficiency of hypothalamic hormones (diabetes insipidus, hypopituitarism, or disorders of gonadal development). Treatment involves surgical removal or decompression, radiation therapy, and hormone replacement (see below).
ANTERIOR PITUITARY HORMONES
The six major anterior pituitary hormones—ACTH, GH, PRL, TSH, LH, and FSH —may be classified into three groups: corticotropin-related peptides (ACTH, LPH, melanocyte-stimulating hormone [MSH], and endorphins); the somatomammotropins (GH and PRL), which are also peptides; and the glycoproteins (LH, FSH, and TSH). The chemical features of these hormones are set forth in Table 5-2.
ACTH & RELATED PEPTIDES
ACTH is a 39-amino-acid peptide hormone (MW 4500) processed from a large precursor molecule, pro-opiomelanocortin (POMC) (MW 28,500). Within the corticotroph, a single mRNA directs the synthesis and processing of POMC into smaller biologically active fragments (Figure 5-10) which include β-LPH, α-MSH, β-MSH, β-endorphin, and the amino terminal fragment of pro-opiomelanocortin. Most of these peptides are glycosylated, which accounts for differences in the reporting of molecular weights. These carbohydrate moieties are responsible for the basophilic staining of corticotrophs.
Two of these fragments are contained within the structure of ACTH: α-MSH is identical to ACTH1–13, and corticotropin-like intermediate lobe peptide (CLIP) represents ACTH18–39 (Figure 5-10). Although these fragments are found in species with developed intermediate lobes (eg, the rat), they are not secreted as separate hormones in humans. β-Lipotropin, a fragment with 91 amino acids (1–91), is secreted by the corticotroph in equimolar quantities with ACTH. Within the β-LPH molecule exists the amino acid sequence for β-MSH (41–58), γ-LPH (1–58), and β-endorphin (61–91).
ACTH stimulates the secretion of glucocorticoids, mineralocorticoids, and androgenic steroids from the adrenal cortex (see Chapters 9 and10). The amino terminal end (residues 1-18) is responsible for this biologic activity. ACTH binds to receptors on the adrenal cortex and induces steroidogenesis using cAMP.
The hyperpigmentation observed in states of ACTH hypersecretion (eg, Addison's disease, Nelson's syndrome) appears to be primarily due to ACTH binding to the MSH receptor, because α-MSH and β-MSH do not exist as separate hormones in humans.
The physiologic function of β-LPH and its family of peptide hormones, including β-endorphin, is not completely understood. However, both β-LPH and β-endorphin have the same secretory dynamics as ACTH.
Figure 5-10. The processing of pro-opiomelanocortin (MW 28,500) into its biologically active peptide hormones. Abbreviations are expanded in the text.
The development of an immunoradiometric assay using monoclonal antibodies has provided a sensitive and practical clinical ACTH assay for the evaluation of pituitary-adrenal disorders. The basal morning concentration ranges from 9 to 52 pg/mL (2–11 pmol/L). Its short plasma half-life (7–12 minutes) and episodic secretion cause wide and rapid fluctuations both in its plasma concentration and in that of cortisol.
Although β-LPH has a longer half-life than ACTH and is more stable in plasma, its measurement has not been extensively utilized. Current data suggest that the normal concentration of β-LPH is 10–40 pg/mL (1–4 pmol/L).
The physiologic secretion of ACTH is mediated through neural influences by means of a complex of hormones, the most important of which is corticotropin-releasing hormone (CRH) (Figure 5-5, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11).
CRH stimulates ACTH in a pulsatile manner: Diurnal rhythmicity causes a peak before awakening and a decline as the day progresses. The diurnal rhythm is a reflection of neural control and provokes concordant diurnal secretion of cortisol from the adrenal cortex (Figure 5-12). This episodic release of ACTH is independent of circulating cortisol levels—ie, the magnitude of an ACTH impulse is not related to preceding plasma cortisol levels. An example is the persistence of diurnal rhythm in patients with primary adrenal failure (Addison's disease). ACTH secretion also increases in response to feeding in both humans and animals.
Many stresses stimulate ACTH, often superseding the normal diurnal rhythmicity. Physical, emotional, and chemical stresses such as pain, trauma, hypoxia, acute hypoglycemia, cold exposure, surgery, depression, and interleukin-1 and vasopressin administration have all been shown to stimulate ACTH and cortisol secretion. The increase in ACTH levels during stress is mediated by vasopressin as well as CRH. Although physiologic cortisol levels do not blunt the ACTH response to stress, exogenous corticosteroids in high doses suppress it.
Negative feedback of cortisol and synthetic glucocorticoids on ACTH secretion occurs at both the hypothalamic and pituitary levels via two mechanisms: “Fast feedback” is sensitive to the rate of change in cortisol levels, while “slow feedback” is sensitive to the absolute cortisol level. The first mechanism is probably nonnuclear; ie, this phenomenon occurs too rapidly to be explained by the influence of corticosteroids on nuclear transcription of the specific mRNA responsible for ACTH. “Slow feedback,” occurring later, may be explained by a nuclear-mediated mechanism and a subsequent decrease in synthesis of ACTH. This latter form of negative feedback is the type probed by the clinical dexamethasone suppression test. In addition to the negative feedback of corticoids, ACTH also inhibits its own secretion (short loop feedback).
Figure 5-11. The hypothalamic-pituitary-adrenal axis, illustrating negative feedback by cortisol (“F”) at the hypothalamic and pituitary levels. A short negative feedback loop of ACTH on the secretion of corticotropin-releasing hormone (CRH) also exists. (Reproduced, with permission, from Gwinup G, Johnson B: Clinical testing of the hypothalamic-pituitary-adrenocortical system in states of hypo- and hypercortisolism. Metabolism 1975;24:777.)
Growth hormone (GH; somatotropin) is a 191-amino-acid polypeptide hormone (MW 21,500) synthesized and secreted by the somatotrophs of the anterior pituitary. Its larger precursor peptide, preGH (MW 28,000), is also secreted but has no physiologic significance.
Figure 5-12. The episodic, pulsatile pattern of ACTH secretion and its concordance with cortisol secretion in a healthy human subject during the early morning. (Reproduced, with permission, from Gallagher TF et al: ACTH and cortisol secretory patterns in man. J Clin Endocrinol Metab 1973;36:1058.)
The primary function of growth hormone (somatotropin) is promotion of linear growth. Its basic metabolic effects serve to achieve this result, but most of the growth-promoting effects are mediated by insulin-like growth factor 1 (IGF-I; previously known as somatomedin C). The metabolic and biologic effects of GH and IGF-I are shown in Table 5-5 and 5-6 (see also Chapter 6).
Growth hormone, via IGF-I, increases protein synthesis by enhancing amino acid uptake and directly accelerating the transcription and translation of mRNA. In addition, GH tends to decrease protein catabolism by mobilizing fat as a more efficient fuel source: It directly causes the release of fatty acids from adipose tissue and enhances their conversion to acetyl-CoA, from which energy is derived. This protein-sparing effect is an important mechanism by which GH promotes growth and development.
GH also affects carbohydrate metabolism. In excess, it decreases carbohydrate utilization and impairs glucose uptake into cells. This GH-induced insulin resistance appears to be due to a postreceptor impairment in insulin action. These events result in glucose intolerance and secondary hyperinsulinism.
GH has a plasma half-life of 20–50 minutes. The healthy adult secretes approximately 400 ľg/d (18.6 nmol/d); in contrast, young adolescents secrete about 700 ľg/d (32.5 nmol/d). There are specific GH-binding proteins in plasma.
The early morning GH concentration in fasting unstressed adults is less than 2 ng/mL (90 pmol/L). There are no significant sex differences.
Concentrations of IGF-I are determined by radioreceptor assays or radioimmunoassays. Determining the levels of these mediators of GH action may result in more accurate assessment of the biologic activity of GH (see Chapter 6). Growth hormone-binding proteins (GHBPs) include a high-affinity GHBP that represents the extracellular portion of the GH receptor and a low-affinity species. About half of circulating GH is bound to GHBPs. Measurement of serum concentrations of the high-affinity GHBP provides an index of GH receptor concentrations.
Table 5-5. Metabolic effects of GH and IGF-1 in vivo.1
Table 5-6. Main biologic effect of the GH-IGF-1 axis.1
The secretion of GH is mediated by two hypothalamic hormones: growth hormone-releasing hormone (GHRH) and somatostatin (growth hormone-inhibiting hormone), both of which contribute to the episodic pattern of GH secretion. These hypothalamic influences are tightly regulated by an integrated system of neural, metabolic, and hormonal factors. Table 5-7 summarizes the many factors that affect GH secretion in physiologic, pharmacologic, and pathologic states.
GHRH binds to specific receptors, stimulating cAMP production by somatotrophs and stimulating both GH synthesis and secretion. The effects of GHRH are partially blocked by somatostatin. The administration of GHRH to normal humans leads to rapid release of GH (within minutes); levels peak at 30 minutes and are sustained for 60–120 minutes.
Other peptide hormones such as ADH, ACTH, and α-MSH may act as GH-releasing factors when present in pharmacologic amounts. Even thyrotropin- and gonadotropin-releasing hormones (TRH and GnRH) often cause GH secretion in patients with acromegaly; however, it is not certain whether any of these effects are mediated by the hypothalamus or represent direct effects on the somatotroph. Regulation of GHRH is primarily under neural control (see below), but there is also short-loop negative feedback by GHRH itself.
Somatostatin, a tetradecapeptide, is a potent inhibitor of GH secretion. It decreases cAMP production in GH-secreting cells and inhibits both basal and stimulated GH secretion. Somatostatin secretion is increased by elevated levels of GH and IGF-I. Long-acting analogs of somatostatin have been used therapeutically in the management of GH excess and in conditions such as pancreatic and carcinoid tumors that cause diarrhea.
- GROWTH HORMONE SECRETAGOGUES
Non-GHRH secretagogues act to release GH, not through the GHRH receptor but through an orphan receptor, the growth hormone secretagogue receptor (GHS-R). A number of synthetic secretagogues, both peptides and nonpeptides, have been described. Ghrelin, an endogenous ligand for GHS-R, has recently been identified. Its location in the stomach suggests a new mechanism for regulation of GH secretion.
- NEURAL CONTROL
The neural control of basal GH secretion results in irregular and intermittent release associated with sleep and varying with age. Peak levels occur 1–4 hours after the onset of sleep (during stages 3 and 4) (Figure 5-13).
These nocturnal sleep bursts, which account for nearly 70% of daily GH secretion, are greater in children and tend to decrease with age. Glucose infusion will not suppress this episodic release. Emotional, physical, and chemical stress, including surgery, trauma, exercise, electroshock therapy, and pyrogen administration, provoke GH release; and impairment of secretion, leading to growth failure, has been well documented in children with severe emotional deprivation (see Chapter 6).
Table 5-7. Factors affecting growth hormone secretion.1
Figure 5-13. Sleep-associated changes in prolactin (PRL) and growth hormone (GH) secretion in humans. Peak levels of GH occur during sleep stages 3 or 4; the increase in PRL is observed 1–2 hours after sleep begins and is not associated with a specific sleep phase. (Reproduced, with permission, from Sassin JF et al: Human prolactin: 24-hour pattern with increased release during sleep. Science 1972;177:1205.)
- METABOLIC CONTROL
The metabolic factors affecting GH secretion include all fuel substrates: carbohydrate, protein, and fat. Glucose administration, orally or intravenously, lowers GH in healthy subjects and provides a simple physiologic maneuver useful in the diagnosis of acromegaly (see below). In contrast, hypoglycemia stimulates GH release. This effect depends on intracellular glycopenia, since the administration of 2-deoxyglucose (a glucose analog that causes intracellular glucose deficiency) also increases GH. This response to hypoglycemia depends on both the rate of change in blood glucose and the absolute level attained.
A protein meal or intravenous infusion of amino acids (eg, arginine) causes GH release. Paradoxically, states of protein-calorie malnutrition also increase GH, possibly as a result of decreased IGF-I production and lack of inhibitory feedback.
Fatty acids suppress GH responses to certain stimuli, including arginine and hypoglycemia. Fasting stimulates GH secretion, possibly as a means of mobilizing fat as an energy source and preventing protein loss.
- EFFECTS OF OTHER HORMONES
Responses to stimuli are blunted in states of cortisol excess and during hypo- and hyperthyroidism. Estrogen enhances GH secretion in response to stimulation.
- EFFECTS OF NEUROPHARMACOLOGIC AGENTS
Many neurotransmitters and neuropharmacologic agents affect GH secretion. Biogenic amine agonists and antagonists act at the hypothalamic level and alter GHRH or somatostatin release. Dopaminergic, alpha-adrenergic, and serotonergic agents all stimulate GH release.
Dopamine agonists such as levodopa, apomorphine, and bromocriptine increase GH secretion, whereas dopaminergic antagonists such as phenothiazines inhibit GH. The effect of levodopa, a precursor of both norepinephrine and dopamine, may be mediated by its conversion to norepinephrine, since its effect is blocked by the alpha-adrenergic antagonist phentolamine. Moreover, phentolamine suppresses GH release in response
to other stimuli such as hypoglycemia, exercise, and arginine, emphasizing the importance of alpha-adrenergic mechanisms in modulating GH secretion.
Beta-adrenergic agonists inhibit GH, and beta-adrenergic antagonists such as propranolol enhance secretion in response to provocative stimuli.
Prolactin (PRL) is a 198-amino-acid polypeptide hormone (MW 22,000) synthesized and secreted from the lactotrophs of the anterior pituitary. Despite evolution from an ancestral hormone common to GH and human placental lactogen (hPL), PRL shares only 16% of its residues with the former and 13% with hPL. A precursor molecule (MW 40,000–50,000) is also secreted and may constitute 8–20% of the PRL plasma immunoreactivity in healthy persons and in patients with PRL-secreting pituitary tumors. PRL and GH are structurally related to members of the cytokine-hematopoietin family that include erythropoietin, granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukins IL-2 to IL-7.
PRL stimulates lactation in the postpartum period (see Chapter 16). During pregnancy, PRL secretion increases and, in concert with many other hormones (estrogen, progesterone, hPL, insulin, and cortisol), promotes additional breast development in preparation for milk production. Despite its importance during pregnancy, PRL has not been demonstrated to play a role in the development of normal breast tissue in humans. During pregnancy, estrogen enhances breast development but blunts the effect of PRL on lactation; the decrease in both estrogen and progesterone after parturition allows initiation of lactation. Accordingly, galactorrhea may accompany the discontinuance of oral contraceptives or estrogen therapy. Although basal PRL secretion falls in the postpartum period, lactation is maintained by persistent breast suckling.
PRL levels are very high in the fetus and in newborn infants, declining during the first few months of life.
Although PRL does not appear to play a physiologic role in the regulation of gonadal function, hyperprolactinemia in humans leads to hypogonadism. In women, initially there is a shortening of the luteal phase; subsequently, anovulation, oligomenorrhea or amenorrhea, and infertility occur. In men, PRL excess leads to decreased testosterone synthesis and decreased spermatogenesis, which clinically present as decreased libido, impotence, and infertility. The exact mechanisms of PRL inhibition of gonadal function are unclear, but the principal one appears to be alteration of hypothalamic-pituitary control of gonadotropin secretion. Basal LH and FSH levels are usually normal; however, their pulsatile secretion is decreased and the midcycle LH surge is suppressed in women. Gonadotropin reserve, as assessed with GnRH, is usually normal or even exaggerated. Prolactin also has a role in immunomodulation; extrapituitary synthesis of PRL occurs in T lymphocytes (among other sites), and prolactin receptors are present on T and B lymphocytes and macrophages. PRL modulates and stimulates both immune cell proliferation and survival.
The PRL secretory rate is approximately 400 ľg/d (18.6 nmol/d). The hormone is cleared by the liver (75%) and the kidney (25%), and its half-time of disappearance from plasma is about 50 minutes.
Basal levels of PRL in adults vary considerably, with a mean of 13 ng/mL (0.6 nmol/L) in women and 5 ng/mL (0.23 nmol/L) in men. The upper range of normal in most laboratories is 15–20 ng/mL (0.7–0.9 nmol/L).
The hypothalamic control of PRL secretion is predominantly inhibitory, and dopamine is the most important inhibitory factor. The physiologic, pathologic, and pharmacologic factors influencing PRL secretion are listed in Table 5-8.
- PROLACTIN-RELEASING FACTORS
TRH is a potent prolactin-releasing factor that evokes release of PRL at a threshold dose similar to that which stimulates release of TSH. An exaggerated response of both TSH and PRL to TRH is observed in primary hypothyroidism, and their responses are blunted in hyperthyroidism. In addition, PRL secretion is also stimulated by vasoactive intestinal peptide and serotonergic pathways.
- EPISODIC AND SLEEP-RELATED SECRETION
PRL secretion is episodic. An increase is observed 60–90 minutes after sleep begins but—in contrast to GH—is not associated with a specific sleep phase. Peak levels are usually attained between 4 and 7 am (Figure 5-13). This sleep-associated augmentation of PRL release is not part of a circadian rhythm, like that of ACTH; it is related strictly to the sleeping period regardless of when it occurs during the day.
- OTHER STIMULI
Stresses, including surgery, exercise, hypoglycemia, and acute myocardial infarction, cause significant elevation
of PRL levels. Nipple stimulation in nonpregnant women also increases PRL. This neurogenic reflex may also occur from chest wall injury such as mechanical trauma, burns, surgery, and herpes zoster of thoracic dermatomes. This reflex discharge of PRL is abolished by denervation of the nipple or by spinal cord or brain stem lesions.
Table 5-8. Factors affecting prolactin secretion.
- EFFECTS OF OTHER HORMONES
Many hormones influence PRL release. Estrogens augment basal and stimulated PRL secretion after 2–3 days of use (an effect that is of special clinical importance in patients with PRL-secreting pituitary adenomas); glucocorticoids tend to suppress TRH-induced PRL secretion; and thyroid hormone administration may blunt the PRL response to TRH.
- EFFECTS OF PHARMACOLOGIC AGENTS
(Table 5-8.) Many pharmacologic agents alter PRL secretion. Dopamine agonists (eg, bromocriptine) decrease secretion, forming the basis for their use in states of PRL excess. Dopamine antagonists (eg, receptor blockers such as phenothiazines and metoclopramide) and dopamine depletors (eg, reserpine) augment PRL release. Serotonin agonists will enhance PRL secretion; serotonin receptor blockers suppress PRL release associated with stress and with nursing.
Thyrotropin (thyroid-stimulating hormone, TSH) is a glycoprotein (MW 28,000) composed of two noncovalently linked alpha and beta subunits. The structure of the alpha subunit of TSH is identical to that of the other glycoprotein molecules—FSH, LH, and human chorionic gonadotropin (hCG)—but the beta subunit differs in these glycoproteins and is responsible for their biologic and immunologic specificity. The peptides of these subunits appear to be synthesized separately and united before the carbohydrate groups are attached. The intact molecule is then secreted, as are small amounts of nonlinked subunits.
The beta subunit of TSH attaches to high-affinity receptors in the thyroid, stimulating iodide uptake, hormonogenesis, and release of T4 and T3. This occurs through activation of adenylyl cyclase and the generation of cAMP. TSH secretion also causes an increase in gland size and vascularity by promoting mRNA and protein synthesis. (For a more detailed description, see Chapter 7.)
TSH circulates unbound in the blood with a half-life of 50–60 minutes. With ultrasensitive immunoradiometric assays for measuring TSH concentration, the normal range is usually 0.5–4.7 ľU/mL (0.5–4.7 mU/L). These new assays are helpful in the diagnosis of primary hypothyroidism and hyperthyroidism; however, TSH levels alone cannot be used to evaluate pituitary or hypothalamic hypothyroidism.
The alpha subunit can be detected in about 80% of normals, with a range of 0.5–2 ng/mL. Plasma alpha subunit levels increase after administration of TRH in
normal subjects, and basal levels are elevated in primary hypothyroidism, primary hypogonadism, and in patients with TSH-secreting, gonadotropin-secreting, or pure alpha subunit-secreting pituitary adenomas.
The secretion of TSH is controlled by both stimulatory (TRH) and inhibitory (somatostatin) influences from the hypothalamus and in addition is modulated by the feedback inhibition of thyroid hormone on the hypothalamic-pituitary axis (Table 7-6 and Figure 7-22).
The response of TSH to TRH is modulated by the circulating concentration of thyroid hormones. Small changes in serum levels (even within the physiologic range) cause substantial alterations in the TSH response to TRH. As shown in Figure 5-14, the administration of T3 (15 ľg) and T4 (60 ľg) to healthy persons for 3–4 weeks suppresses the TSH response to TRH despite only small increases in circulating T3 and T4levels. Thus, the secretion of TSH is inversely proportionate to the concentration of thyroid hormone.
The set point (the level at which TSH secretion is maintained) is determined by TRH. Deviations from this set point result in appropriate changes in TSH release. Administration of TRH increases TSH within 2 minutes, and this response is blocked by previous T3 administration; however, larger doses of TRH may overcome this blockade—suggesting that both T3 and TRH act at the pituitary level to influence TSH secretion. In addition, T3 and T4 inhibit mRNA for TRH synthesis in the hypothalamus, indicating that a negative feedback mechanism operates at this level also.
This inhibitory hypothalamic peptide augments the direct inhibitory effect of thyroid hormone on the thyrotrophs. Infusion of somatostatin blunts the early morning TSH surge and will suppress high levels of TSH in primary hypothyroidism. Octreotide acetate, a somatostatin analog, has been used successfully to inhibit TSH secretion in some patients with TSH-secreting pituitary tumors.
Figure 5-14. Administration of small doses of T3 (15 ľg) and T4 (60 ľg) to healthy subjects inhibits the TSH response to 2 doses (400 ľg, left; 25 ľg, right) of TRH (protirelin). (Reproduced, with permission, from Snyder PJ, Utiger RD: Inhibition of thyrotropin-releasing hormone by small quantities of thyroid hormones. J Clin Invest 1972;51:2077.)
- NEURAL CONTROL
In addition to these hypothalamic influences on TSH secretion, neurally mediated factors may be important. Dopamine physiologically inhibits TSH secretion. Intravenous dopamine administration will decrease TSH in both healthy and hypothyroid subjects as well as blunt the TSH response to TRH. Thus, as expected, dopaminergic agonists such as bromocriptine inhibit TSH secretion and dopaminergic antagonists such as metaclopramide increase TSH secretion in euthyroid subjects. Bromocriptine has also been effective in the management of some TSH-secreting pituitary tumors.
- EFFECTS OF CORTISOL AND ESTROGENS
Glucocorticoid excess has been shown to impair the sensitivity of the pituitary to TRH and may lower serum TSH to undetectable levels. However, estrogens increase the sensitivity of the thyrotroph to TRH; women have a greater TSH response to TRH than men do, and pretreatment of men with estradiol will increase their TRH-induced TSH response. (See also Chapter 7 and Table 7-6.)
GONADOTROPINS: LUTEINIZING HORMONE, FOLLICLE-STIMULATING HORMONE
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are glycoprotein gonadotropins composed of alpha and beta subunits and secreted by the same cell. The specific beta subunit confers on these hormones their unique biologic activity, as it does with TSH and hCG. The biologic activity of hCG, a placental glycoprotein, closely resembles that of LH. Human menopausal gonadotropin (hMG, menotropins)—an altered mixture of pituitary gonadotropins recovered from the urine of postmenopausal women—is a preparation with FSH-like activity. Menotropins and chorionic gonadotropin are used clinically for induction of spermatogenesis or ovulation (see Chapters 12 and 13).
LH and FSH bind to receptors in the ovary and testis and regulate gonadal function by promoting sex steroid production and gametogenesis.
In men, LH stimulates testosterone production from the interstitial cells of the testes (Leydig cells). Maturation of spermatozoa, however, requires both LH and FSH. FSH stimulates testicular growth and enhances the production of an androgen-binding protein by the Sertoli cells, which are a component of the testicular tubule necessary for sustaining the maturing sperm cell. This androgen-binding protein promotes high local concentrations of testosterone within the testis, an essential factor in the development of normal spermatogenesis (see Chapter 12).
In women, LH stimulates estrogen and progesterone production from the ovary. A surge of LH in the mid menstrual cycle is responsible for ovulation, and continued LH secretion subsequently stimulates the corpus luteum to produce progesterone by enhancing the conversion of cholesterol to pregnenolone. Development of the ovarian follicle is largely under FSH control, and the secretion of estrogen from this follicle is dependent on both FSH and LH.
The normal levels of LH and FSH vary with the age of the subject (see Appendix). They are low before puberty and elevated in postmenopausal women. A nocturnal rise of LH in boys and the cyclic secretion of FSH and LH in girls usually herald the onset of puberty before clinical signs are apparent. In women, LH and FSH vary during the menstrual cycle; during the initial phase of the cycle (follicular), LH steadily increases, with a midcycle surge that initiates ovulation. FSH, on the other hand, initially rises and then decreases during the later follicular phase until the midcycle surge, which is concordant with LH. Both LH and FSH levels fall steadily after ovulation. (SeeChapter 13.)
LH and FSH levels in men are similar to those in women during the follicular phase. The alpha subunit, shared by all the pituitary glycoprotein hormones, can also be measured (see TSH) and will rise following GnRH administration. The normal responses of LH and FSH to GnRH are shown in Table 5-9.
The secretion of LH and FSH is controlled by gonadotropin-releasing hormone (GnRH), which maintains basal gonadotropin secretion, generates the phasic release of gonadotropins for ovulation, and determines the onset of puberty. Many other factors are involved in regulation of this axis. For example, activins and follistatins are paracrine factors that exert opposing effects on gonadotrophs. Leptin, a recently described hormone made in adipocytes, is involved in regulation of this axis and may help to explain the suppression of gonadotropin secretion that accompanies caloric restriction.
- EPISODIC SECRETION
In both males and females, secretion of LH and FSH is episodic, with secretory bursts that occur each hour and are mediated by a concordant episodic release of
GnRH. The amplitude of these secretory surges is greater in patients with primary hypogonadism. The pulsatile nature of GnRH release is critical for sustaining gonadotropin secretion. A continuous, prolonged infusion of GnRH in women evokes an initial increase in LH and FSH followed by prolonged suppression of gonadotropin secretion. This phenomenon may be explained by down-regulation of GnRH receptors on the pituitary gonadotrophs. Consequently, long-acting synthetic analogs of GnRH may be used clinically to suppress LH and FSH secretion in conditions such as precocious puberty.
Table 5-9. Normal gonadotropin responses (ą SD) to GnRH (100 ľg).
- POSITIVE FEEDBACK
Circulating sex steroids affect GnRH secretion and thus LH and FSH secretion by both positive and negative (inhibitory) feedback mechanisms. During the menstrual cycle, estrogens provide a positive influence on GnRH effects on LH and FSH secretion, and the rise in estrogen during the follicular phase is the stimulus for the LH and FSH ovulatory surge. This phenomenon suggests that the secretion of estrogen is to some extent influenced by an intrinsic ovarian cycle. Progesterone amplifies the duration of the LH and FSH surge and augments the effect of estrogen. After this midcycle surge, the developed egg leaves the ovary. Ovulation occurs approximately 10–12 hours after the LH peak and 24–36 hours after the estradiol peak. The remaining follicular cells in the ovary are converted, under the influence of LH, to a progesterone-secreting structure, the corpus luteum. After about 12 days, the corpus luteum involutes, resulting in decreased estrogen and progesterone levels and then uterine bleeding. (See Chapter 13.)
- NEGATIVE FEEDBACK
Negative feedback effects of sex steroids on gonadotropin secretion also occur. In women, primary gonadal failure or menopause results in elevations of LH and FSH, which can be suppressed with long-term, high-dose estrogen therapy. However, a shorter duration of low-dose estrogen may enhance the LH response to GnRH. In men, primary gonadal failure with low circulating testosterone levels is also associated with elevated gonadotropins. However, testosterone is not the sole inhibitor of gonadotropin secretion in men, since selective destruction of the tubules (eg, by cyclophosphamide therapy) results in azoospermia and elevation of only FSH.
Inhibin, a polypeptide (MW 32,000) secreted by the Sertoli cells of the seminiferous tubules, is the major factor that inhibits FSH secretion by negative feedback. Inhibin, which has been purified and sequenced by analysis of its complementary DNA, consists of separate alpha and beta subunits connected by a disulfide bridge. Androgens stimulate inhibin production; this peptide may help to locally regulate spermatogenesis. (See Chapter 12.)
ENDOCRINOLOGIC EVALUATION OF THE HYPOTHALAMIC-PITUITARY AXIS
The precise assessment of the hypothalamic-pituitary axis has been made possible by radioimmunoassays of the major anterior pituitary hormones and their specific target gland hormones. In addition, four synthetic hypothalamic hormones—TRH (protirelin), GnRH (gonadorelin), ovine CRH, and human GHRH—which are available commercially, can be used to assess hypothalamic-pituitary reserve.
This section describes the principles involved in testing each pituitary hormone as well as special situations (eg, drugs, obesity) that may interfere with pituitary function or pituitary testing. Specific protocols for performing and interpreting diagnostic procedures are outlined at the end of this section and in Table 5-11. The clinical manifestations of either hypo- or hypersecretion of anterior pituitary hormones are discussed in subsequent sections.
EVALUATION OF ACTH
ACTH deficiency leads to secondary adrenocortical insufficiency, characterized by decreased secretion of cortisol and the adrenal androgens; aldosterone secretion,
controlled primarily by the renin-angiotensin axis, is usually maintained. In contrast, excessive ACTH secretion leads to adrenal hyperfunction (Cushing's syndrome, discussed in a later section of this chapter and in Chapter 9).
Plasma ACTH Levels
Basal ACTH measurements are usually unreliable indicators of pituitary function, since its short plasma half-life and episodic secretion result in wide fluctuations in plasma levels (Figure 5-12). Therefore, the interpretation of plasma ACTH levels requires the simultaneous assessment of cortisol secretion by the adrenal cortex. These measurements are of greatest utility in differentiating primary and secondary adrenocortical insufficiency and in establishing the etiology of Cushing's syndrome (see the later section on Cushing's disease and alsoChapter 9).
Evaluation of ACTH Deficiency
In evaluating ACTH deficiency, measurement of basal cortisol levels is also generally unreliable. Because plasma cortisol levels are usually low in the late afternoon and evening, reflecting the normal diurnal rhythm, samples drawn at these times are of virtually no value for this diagnosis. Plasma cortisol levels are usually highest in the early morning; however, there is considerable overlap between adrenal insufficiency and normal subjects. A plasma cortisol level less than 5 ľg/dL (138 nmol/L) at 8 am strongly suggests the diagnosis—and the lower the level, the more likely the diagnosis. Conversely, a plasma cortisol greater than 20 ľg/dL (552 nmol/L) virtually excludes the diagnosis. Similarly, salivary cortisol levels less than 1.8 ng/mL (5 nmol/L) at 8 am strongly suggest adrenal insufficiency, while levels in excess of 5.8 ng/mL (16 nmol/L) greatly reduce the probability of the diagnosis. Consequently, the diagnosis of ACTH hyposecretion (secondary adrenal insufficiency) must be established by provocative testing of the reserve capacity of the hypothalamic-pituitary axis.
Since adrenal atrophy develops as a consequence of prolonged ACTH deficiency, the initial and most convenient approach to evaluation of the hypothalamic-pituitary-adrenal axis is assessment of the plasma cortisol response to synthetic ACTH (cosyntropin). In normal individuals, injection of cosyntropin (250 ľg) causes a rapid increase (within 30 minutes) of cortisol to at least 18–20 ľg/dL (496–552 nmol/L), and this response usually correlates with the cortisol response to insulin-induced hypoglycemia. A subnormal cortisol response to ACTH confirms adrenocortical insufficiency. However, a normal response does not directly evaluate the ability of the hypothalamic-pituitary axis to respond to stress (see Chapter 9). Thus, patients withdrawn from long-term glucocorticoid therapy may have an adequate increase in cortisol following exogenous ACTH that precedes complete recovery of the hypothalamic-pituitary-adrenal axis. Therefore, such patients should receive glucocorticoids during periods of stress for at least 1 year after steroids are discontinued, unless the hypothalamic-pituitary axis is shown to be responsive to stress as described below.
The more physiologic dose administered in the 1 ľg ACTH test is designed to improve its sensitivity in detection of secondary adrenal insufficiency. The cortisol response to 1 ľg of synthetic ACTH correlates better with the cortisol response to insulin-induced hypoglycemia in patients with chronic secondary adrenal insufficiency. However, the results in secondary adrenal insufficiency of recent onset are less reliable. Performance of the 1 ľg test is also associated with some technical problems: there are no ready-to-use vials containing 1 ľg, and there is controversy about the diagnostic criteria used for the 1 ľg test. Even if this latter issue is resolved, clinicians must be wary about comparisons of different cortisol assays (see above). These problems notwithstanding, the low-dose (1 ľg) ACTH stimulation test is gaining greater acceptance and may emerge as the diagnostic procedure of choice in suspected secondary adrenal insufficiency.
Direct evaluation of pituitary ACTH reserve can be performed by means of insulin-induced hypoglycemia, metyrapone administration, or CRH stimulation. These studies are unnecessary if the cortisol response to rapid ACTH stimulation is subnormal.
- INSULIN-INDUCED HYPOGLYCEMIA
The stimulus of neuroglycopenia associated with hypoglycemia (blood glucose < 40 mg/dL) evokes a stress-mediated activation of the hypothalamic-pituitary-adrenal axis. Subjects should experience adrenergic symptoms (diaphoresis, tachycardia, weakness, headache) associated with the fall in blood sugar. In normal persons, plasma cortisol increases to more than 18–20ľg/dL (496–552 nmol/L), indicating normal ACTH reserve. Although plasma ACTH also rises, its determination has not proved to be as useful, since pulsatile secretion requires frequent sampling, and the normal response is not well standardized. Although insulin-induced hypoglycemia most reliably predicts ACTH secretory capacity in times of stress, it is rarely performed at present since the
procedure requires a physician's presence and is contraindicated in elderly patients, patients with cerebrovascular or cardiovascular disease, and those with seizure disorders. It should be used with caution in patients in whom diminished adrenal reserve is suspected, since severe hypoglycemia may occur; in these patients, the test should always be preceded by the ACTH adrenal stimulation test.
- METYRAPONE STIMULATION
Metyrapone administration is an alternative method for assessing ACTH secretory reserve. Metyrapone inhibits P450c11 (11β-hydroxylase), the enzyme that catalyzes the final step in cortisol biosynthesis (see Chapter 9). The inhibition of cortisol secretion interrupts negative feedback on the hypothalamic-pituitary axis, resulting in a compensatory increase in ACTH. The increase in ACTH secretion stimulates increased steroid biosynthesis proximal to P450c11, and the increase can be detected as an increase in the precursor steroid (11-deoxycortisol) in plasma. The overnight test is preferred because of its simplicity; it is performed by administering 30 mg/kg of metyrapone orally at midnight. Plasma 11-deoxycortisol is determined the following morning and rises to more than 7 ľg/dL (0.2 nmol/L) in healthy individuals. Again the test should be used cautiously in patients with suspected adrenal insufficiency and should be preceded by a rapid ACTH stimulation test (see above). The traditional 3-day metyrapone test should not be used at present because of the risk of precipitating adrenal insufficiency. The overnight metyrapone test is most useful in patients with partial secondary adrenal insufficiency in whom the rapid ACTH stimulation test is normal or borderline and has been shown to correlate well with the response to insulin-induced hypoglycemia. Metyrapone may be obtained directly from the Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
- CRH STIMULATION
Ovine CRH administered intravenously is used to assess ACTH secretory dynamics. In healthy subjects, CRH (1 ľg/kg) provokes a peak ACTH response within 15 minutes and a peak cortisol response within 30–60 minutes. This dose may be associated with mild flushing, occasional shortness of breath, tachycardia, and hypotension. Patients with primary adrenal insufficiency have elevated basal ACTH levels and exaggerated ACTH responses to CRH. Secondary adrenal insufficiency results in an absent ACTH response to CRH in patients with pituitary corticotroph destruction; however, in patients with hypothalamic dysfunction, there is a prolonged and augmented ACTH response to CRH with a delayed peak. Because of overlap between the responses of normal individuals and those with partial secondary adrenal insufficiency, the CRH test is less useful than the procedures described above.
ACTH hypersecretion is manifested by adrenocortical hyperfunction (Cushing's syndrome). The diagnosis and differential diagnosis of ACTH hypersecretion are outlined in a later section on Cushing's disease and also in Chapter 9.
EVALUATION OF GROWTH HORMONE
The evaluation of GH secretory reserve is important in the assessment of children with short stature and in adults with suspected hypopituitarism. Provocative tests are necessary because basal levels of GH are usually low and therefore do not distinguish between normal and GH-deficient patients. Special attention must be given to the methodology and the laboratory standards of GH measurement. Newer immunometric assays give results that are 30–50% lower than older radioimmunoassays.
The most reliable stimulus of GH secretion is insulin-induced hypoglycemia. In normal individuals, GH levels will increase to more than 10 ng/mL (460 pmol/L) after adequate hypoglycemia is achieved. Since 10% of normal individuals fail to respond to hypoglycemia, other stimulatory tests may be necessary.
Both forms of human GHRH (GHRH-40 and GHRH-44) have been used to evaluate GH secretory capacity. A dose of GHRH (1 ľg/kg) combined with a 30-minute infusion of arginine (0.5 g/kg to a maximum of 20 g) promptly stimulates GH; the mean peak is 10–15 ng/mL (460–700 pmol/L) at 30–60 minutes in healthy subjects. The results are comparable to those achieved with insulin-induced hypoglycemia.
Tests With Levodopa, Arginine, & Other Stimuli
Stimulation testing with levodopa, arginine infusion alone, propranolol, or glucagon is less reliable in the diagnosis of GH deficiency.
The evaluation of GH hypersecretion is discussed in the section on acromegaly and is most conveniently assessed by GH suppression testing with oral glucose and measurement of IGF-I levels.
EVALUATION OF PROLACTIN
PRL secretion by the pituitary is the most resistant to local damage, and decreased PRL secretory reserve indicates severe intrinsic pituitary disease.
The administration of TRH is the simplest and most reliable means of assessing PRL reserve. Although the response of PRL to TRH varies somewhat according to sex and age (Table 5-10), PRL levels usually increase twofold 15–30 minutes after TRH administration. In addition, insulin-induced hypoglycemia will evoke a stress-related increase in PRL.
PRL hypersecretion is a common endocrine problem. Its evaluation is discussed in the section on prolactinomas.
EVALUATION OF TSH
The laboratory evaluation of TSH secretory reserve begins with an assessment of target gland secretion; thyroid function tests (free thyroxine [FT4]) should be obtained. Normal thyroid function studies in a clinically euthyroid patient indicate adequate TSH secretion, and no further studies are warranted. Laboratory evidence of hypothyroidism requires measurement of a TSH level. With primary thyroid gland failure, the TSH level will be elevated; low or normal TSH in the presence of hypothyroidism suggests hypothalamic-pituitary dysfunction (see Chapter 7).
Table 5-10. Normal responses of TSH and prolactin to TRH (500 ľg).1
Since accurate methods for determining TSH and FT4 readily establish the diagnosis of hypothyroidism in virtually all patients, the TRH test is rarely indicated today.
EVALUATION OF LH & FSH
Testosterone & Estrogen Levels
The evaluation of gonadotropin function also requires assessment of target gland secretory function, and measurement of gonadal steroids (testosterone in men, estradiol in women) is useful in the diagnosis of hypogonadism. In women, the presence of regular menstrual cycles is strong evidence that the hypothalamic-pituitary-gonadal axis is intact. Estradiol levels rarely fall below 50 pg/mL (180 pmol/L), even during the early follicular phase. A level of less than 30 pg/mL (110 pmol/L) in the presence of oligomenorrhea or amenorrhea is indicative of gonadal failure. In men, serum testosterone (normal range, 300–1000 ng/dL; (10–35 nmol/L) is a sensitive index of gonadal function. (SeeChapters 12 and 13.)
LH & FSH Levels
In the presence of gonadal insufficiency, high LH and FSH levels are a sign of primary gonadal failure; low or normal LH and FSH suggest hypothalamic-pituitary dysfunction (hypogonadotropic hypogonadism).
LH and FSH secretory reserves may be assessed with the use of synthetic GnRH (gonadorelin). Administration of GnRH causes a prompt increase in plasma LH and a lesser and slower increase in FSH (for normal responses, see Table 5-9). However, in most patients the GnRH test provides no more useful information than is obtained by measurement of basal gonadotropin and gonadal steroid levels. Thus, this test is uncommonly performed.
PROBLEMS IN EVALUATION OF THE HYPOTHALAMIC-PITUITARY AXIS
This section briefly outlines some of the disorders and conditions that may cause confusion and lead to misinterpretation of pituitary function tests. The effects of drugs are described in the next section.
GH dynamics are impaired in many severely obese patients; all provocative stimuli, including insulin-induced hypoglycemia, arginine, levodopa, and glucagon plus propranolol, often fail to provoke GH secretion. The GH response to GHRH is also impaired in obesity and improves with weight loss.
Although glucose normally suppresses GH secretion, most type I diabetic individuals have normal or elevated GH levels that often do not rise further in response to hypoglycemia or arginine. Levodopa will increase GH in some diabetic patients, and even a dopamine infusion (which produces no GH change in nondiabetic subjects, since it does not cross the blood-brain barrier) will stimulate GH in diabetic patients. Despite the increased GH secretion in patients with inadequately controlled diabetes, the GH response to GHRH in insulin-dependent diabetic patients is similar to that of nondiabetic subjects. IGF-I levels are low in insulin-deficient diabetes despite the elevated GH levels.
Basal levels of GH, PRL, LH, FSH, TSH, and free cortisol tend to be elevated, for the most part owing to prolongation of their plasma half-life. GH may paradoxically increase following glucose administration and is often hyperresponsive to a hypoglycemic stimulus. Although the administration of TRH (protirelin) has no effect on GH secretion in healthy subjects, the drug may increase GH in patients with chronic renal failure. The response of PRL to TRH is blunted and prolonged. Gonadotropin response to synthetic GnRH usually remains intact. Dexamethasone suppression of cortisol may be impaired.
Starvation & Anorexia Nervosa
GH secretion increases with fasting and malnutrition, and such conditions may cause a paradoxical increase in GH following glucose administration. Severe starvation, such as occurs in patients with anorexia nervosa, may result in low levels of gonadal steroids. LH and FSH responses to GnRH may be intact despite a state of functional hypogonadotropic hypogonadism. Cortisol levels may be increased and fail to suppress adequately with dexamethasone. PRL and TSH dynamics are usually normal despite a marked decrease in circulating total thyroid hormones (see Chapter 7).
Depression may alter the ability of dexamethasone to suppress plasma cortisol and may elevate cortisol secretion; the response to insulin-induced hypoglycemia usually remains intact. In addition, late-evening salivary cortisol levels usually remain normal and are not elevated as seen in patients with Cushing's syndrome. The ACTH response to CRH is blunted in endogenous depression. Some depressed patients also have abnormal GH dynamics: TRH may increase GH, and hypoglycemia or levodopa may fail to increase GH. These patients may also show blunted TSH responses to TRH.
EFFECTS OF PHARMACOLOGIC AGENTS ON HYPOTHALAMIC-PITUITARY FUNCTION
Glucocorticoid excess impairs the GH response to hypoglycemia, the TSH response to TRH, and the LH response to GnRH. Estrogens tend to augment GH dynamics as well as the PRL and TSH response to TRH. Estrogens increase plasma cortisol secondary to a rise in corticosteroid-binding globulin and may result in inadequate suppression with dexamethasone.
Phenytoin enhances the metabolism of dexamethasone, making studies with this agent difficult to interpret. Phenothiazines may blunt the GH response to hypoglycemia and levodopa and frequently cause hyper prolactinemia. The many other pharmacologic agents that increase PRL secretion are listed in Table 5-8.
Narcotics, including heroin, morphine, and methadone, may all raise PRL levels and suppress GH and cortisol response to hypoglycemia.
In chronic alcoholics, alcohol excess or withdrawal may increase cortisol levels and cause inadequate dexamethasone suppression and an impaired cortisol increase after hypoglycemia.
ENDOCRINE TESTS OF HYPOTHALAMIC-PITUITARY FUNCTION
Methods for performing endocrine tests and their normal responses are summarized in Table 5-11. The indications for and the clinical utility of these procedures are described in the preceding section and will be mentioned again in the section on pituitary and hypothalamic disorders.
Table 5-11. Endocrine tests of hypothalamic-pituitary function.
Symptoms of pituitary hormone excess or deficiency, headache, or visual disturbance lead the clinician to consider a hypothalamic-pituitary disorder. In this setting, accurate neuroradiologic assessment of the hypothalamus and pituitary is essential in confirming the existence and defining the extent of hypothalamic-pituitary lesions; however, the diagnosis of such lesions should be based on both endocrine and radiologic criteria. This is because variability of pituitary anatomy in the normal population may lead to false-positive interpretations. Furthermore, patients with pituitary microadenomas may have normal neuroradiologic studies. Imaging studies must be interpreted in light of the fact that 10–20% of the general population harbor nonfunctional and asymptomatic pituitary microadenomas.
Magnetic Resonance Imaging (MRI)
MRI is the current procedure of choice for imaging the hypothalamus and pituitary. It has superseded the use of CT since it allows better definition of normal structures and has better resolution in defining tumors. Arteriography is rarely utilized at present except in patients with intrasellar or parasellar aneurysms.
Imaging is performed in sagittal and coronal planes at 1.5–2 mm intervals. This allows clear definition of hypothalamic and pituitary anatomy and can accurately visualize lesions as small as 3–5 mm. The use of the heavy-metal contrast agent gadolinium allows even more precise differentiation of small pituitary adenomas from normal anterior pituitary tissue and other adjacent structures as shown in Figure 5-15.
- NORMAL ANATOMY
The normal anterior pituitary is 5–7 mm in height and approximately 10 mm in its lateral dimensions. The superior margin is flat or concave but may be upwardly convex with a height of 10–12 mm in healthy menstruating young women. The floor of the sella turcica is formed by the bony roof of the sphenoid sinus, and its lateral margins are formed by the dural membranes of the cavernous sinuses, which contain the carotid arteries and the third, fourth, and sixth cranial nerves. The posterior pituitary appears on MRI as a high-signal-intensity structure, the “posterior pituitary bright spot,” which is absent in patients with diabetes insipidus. The pituitary stalk, which is normally in the midline, is 2–3 mm in diameter and 5–7 mm in length. The pituitary stalk joins the inferior hypothalamus below the third ventricle and posterior to the optic chiasm. All of these normal structures are readily visualized with MRI; the normal pituitary and the pituitary stalk show increased signal intensity with gadolinium.
These lesions, which range from 2 mm to 10 mm in diameter, appear as low-signal-intensity lesions with MRI and do not usually enhance with gadolinium. Adenomas less than 5 mm in diameter may not be visualized and do not usually alter the normal pituitary contour. Lesions greater than 5 mm in diameter create a unilateral convex superior gland margin and usually cause deviation of the pituitary stalk toward the side opposite the adenoma.
MRI scans must be interpreted with caution, since minor abnormalities occur in 10% of patients who have had incidental high-resolution scans but no clinical pituitary disease. These abnormalities may of course represent the clinically insignificant pituitary abnormalities which occur in 10–20% of the general population, and they may also be due to small intrapituitary cysts, which usually occur in the pars intermedia. Artifacts within the sella turcica associated with the bones of the skull base may also result in misinterpretation of imaging studies. Finally, many patients with pituitary microadenomas have normal high-resolution MRI scans. Therefore, despite increased accuracy of neuroradiologic diagnosis, the presence or absence of a small pituitary tumor and the decision concerning its treatment must be based on the entire clinical picture.
Pituitary adenomas greater than 10 mm in diameter are readily visualized with MRI scans, and the scan will also define the adjacent structures and degree of extension of the lesion. Thus, larger tumors show compression of the normal pituitary and distortion of the pituitary stalk. Adenomas larger than 1.5 cm frequently have suprasellar extension, and MRI scans show compression and upward displacement of the optic chiasm. Less commonly, there is lateral extension and invasion of the cavernous sinus.
- OTHER USES
High-resolution MRI scanning is also a valuable tool in the diagnosis of empty sella syndrome, hypothalamic tumors, and other parasellar lesions.
PITUITARY & HYPOTHALAMIC DISORDERS
Hypothalamic-pituitary lesions present with a variety of manifestations, including pituitary hormone hypersecretion and hyposecretion, sellar enlargement, and visual loss. The approach to evaluation should be designed to ensure early diagnosis at a stage when the lesions are amenable to therapy.
Figure 5-15. Upper Panel: A: The coronal magnetic resonance (MR) image shows a large nonfunctioning pituitary adenoma (arrows) with pronounced suprasellar extension and chiasmal compression. B: A sagittal MR image of another large pituitary adenoma shows spontaneous hemorrhage within the suprasellar portion of the adenoma (arrows). (Photographs courtesy of David Norman, MD.) (Reproduced, with permission, from West J Med 1995;162:342, 350.)Lower Panel: Gadolinium-enhanced magnetic resonance images are shown of the pituitary gland. A and B: Coronal and sagittal images show the normal, uniformly enhancing pituitary stalk and pituitary gland. C: A pituitary microadenoma appears as a low-intensity lesion in the inferior aspect of the right lobe of the gland (arrow). D: The pituitary microadenoma appears as a low-intensity lesion between the left lobe of the pituitary and the left cavernous sinus (arrow). (Photographs courtesy of David Norman, MD.)
Etiology & Early Manifestations
In adults, the commonest cause of hypothalamic-pituitary dysfunction is a pituitary adenoma, of which the great majority are hypersecreting. Thus, the earliest symptoms of such tumors are due to endocrinologic abnormalities—hypogonadism is the most frequent manifestation— and these precede sellar enlargement and local manifestations such as headache and visual loss, which are late manifestations seen only in patients with larger tumors or suprasellar extension.
In children, pituitary adenomas are uncommon; the most frequent structural lesions causing hypothalamic-pituitary dysfunction are craniopharyngiomas and other hypothalamic tumors. These also usually manifest as endocrine disturbances (low GH levels, delayed puberty, diabetes insipidus) prior to the development of headache, visual loss, or other central nervous system symptoms.
Common & Later Manifestations
- PITUITARY HYPERSECRETION
PRL is the hormone most commonly secreted in excess amounts by pituitary adenomas, and it is usually elevated in patients with hypothalamic disorders and pituitary stalk compression as well. Thus, PRL measurement is essential in evaluating patients with suspected pituitary disorders and should be performed in patients presenting with galactorrhea, gonadal dysfunction, secondary gonadotropin deficiency, or enlargement of the sella turcica. Hypersecretion of GH or ACTH leads to the more characteristic syndromes of acromegaly and Cushing's disease (see below).
- PITUITARY INSUFFICIENCY
Although panhypopituitarism is a classic manifestation of pituitary adenomas, it is present in less than 20% of patients in current large series because of earlier diagnosis of these lesions.
At present, the earliest clinical manifestation of a pituitary adenoma in adults is hypogonadism secondary to elevated levels of PRL, GH, or ACTH and cortisol. The hypogonadism in these patients is due to interference with the secretion of GnRH rather than to destruction of anterior pituitary tissue. Thus, patients with hypogonadism should first be screened with FSH and LH measurements to exclude primary gonadal failure (elevated FSH or LH) and those with hypogonadotropic hypogonadism should have serum PRL levels measured and be examined for clinical evidence of GH or ACTH and cortisol excess.
In children, short stature is the most frequent clinical presentation of hypothalamic-pituitary dysfunction; in these patients, GH deficiency should be considered. (See Chapter 6.)
TSH or ACTH deficiency is relatively unusual in current series of patients and usually indicates panhypopituitarism. Thus, patients with secondary hypothyroidism or hypoadrenalism should undergo a complete assessment of pituitary function and neuroradiologic studies, since panhypopituitarism and large pituitary tumors are common in this setting. PRL measurement is again essential, since prolactinomas are the most frequent pituitary tumors in adults.
- ENLARGED SELLA TURCICA
Patients may present with enlargement of the sella turcica, which may be noted on radiographs performed for head trauma or on sinus series. These patients usually have either a pituitary adenoma or empty sella syndrome. Other less common causes include craniopharyngioma, lymphocytic hypophysitis, and carotid artery aneurysm. Evaluation should include clinical assessment of pituitary dysfunction and measurements of PRL and thyroid and adrenal function. Pituitary function is usually normal in the empty sella syndrome; this diagnosis can be confirmed by MRI. Patients with clinical or laboratory evidence of pituitary dysfunction usually have a pituitary adenoma.
- VISUAL FIELD DEFECTS
Patients presenting with bitemporal hemianopsia or unexplained visual field defects or visual loss should be considered to have a pituitary or hypothalamic disorder until proved otherwise. The initial steps in diagnosis should be neuro-ophthalmologic evaluation and neuroradiologic studies with MRI, which will reveal the tumor if one is present. These patients should also have PRL measurements and be assessed for anterior pituitary insufficiency, which is especially common with large pituitary adenomas.
In addition to causing visual field defects, large pituitary lesions may extend laterally into the cavernous sinus, compromising the function of the third, fourth, or sixth cranial nerve, leading to diplopia.
- DIABETES INSIPIDUS
Diabetes insipidus is a common manifestation of hypothalamic lesions but is rare in primary pituitary lesions. Diagnostic evaluation is described later. In addition, all patients should undergo radiologic evaluation and assessment of anterior pituitary function.
EMPTY SELLA SYNDROME
Etiology & Incidence
The empty sella syndrome occurs when the subarachnoid space extends into the sella turcica, partially filling
it with cerebrospinal fluid. This process causes remodeling and enlargement of the sella turcica and flattening of the pituitary gland.
Primary empty sella syndrome resulting from congenital incompetence of the diaphragma sellae (Figure 5-16) is common, with an incidence in autopsy series ranging from 5% to 23%. It is the most frequent cause of enlarged sella turcica. An empty sella is also commonly seen after pituitary surgery or radiation therapy and may also occur following postpartum pituitary infarction (Sheehan's syndrome). In addition, both PRL-secreting and GH-secreting pituitary adenomas may undergo subclinical hemorrhagic infarction and cause contraction of the overlying suprasellar cistern downward into the sella. Therefore, the presence of an empty sella does not exclude the possibility of a coexisting pituitary tumor.
- SYMPTOMS AND SIGNS
Most patients are middle-aged obese women. Many have systemic hypertension; benign intracranial hypertension may also occur. Although 48% of patients complain of headache, this feature may have only initiated the evaluation (ie, skull x-rays), and its relationship to the empty sella is probably coincidental. Serious clinical manifestations are uncommon. Spontaneous cerebrospinal fluid rhinorrhea and visual field impairment may occur rarely.
- LABORATORY FINDINGS
Tests of anterior pituitary function are almost always normal, though some patients have hyperprolactinemia. Endocrine function studies should be performed to exclude pituitary hormone insufficiency or a hypersecretory pituitary microadenoma.
The diagnosis of the empty sella syndrome can be readily confirmed by MRI, which demonstrates the herniation of the diaphragma sellae and the presence of cerebrospinal fluid in the sella turcica.
Hypothalamic dysfunction is most often caused by tumors, of which craniopharyngioma is the most common in children, adolescents, and young adults. In older adults, primary central nervous system tumors and those arising from hypothalamic (epidermoid and dermoid tumors) and pineal structures (pinealomas) are more common. Other causes of hypothalamic-pituitary dysfunction are discussed below in the section on hypopituitarism.
The initial symptoms of craniopharyngioma in children and adolescents are predominantly endocrinologic;
however, these manifestations are frequently unrecognized, and at diagnosis over 80% of patients have hypothalamic-pituitary endocrine deficiencies. These endo-crine abnormalities may precede presenting symptoms by months or years; GH deficiency is most common, with about 50% of patients having growth retardation and approximately 70% decreased GH responses to stimulation at diagnosis. Gonadotropin deficiency leading to absent or arrested puberty is usual in older children and adolescents; TSH and ACTH deficiencies are less common, and diabetes insipidus is present in about 15%.
Figure 5-16. Representation of the normal relationship of the meninges to the pituitary gland (left) and the findings in the empty sella(right) as the arachnoid membrane herniates through the incompetent diaphragma sellae. (Reproduced, with permission, from Jordan RM, Kendall JW, Kerber CW: The primary empty sella syndrome: Analysis of the clinical characteristics, radiographic features, pituitary function, and cerebrospinal fluid adenohypophysial hormone concentrations. Am J Med 1977;62:569.)
Symptoms leading to the diagnosis are, unfortunately, frequently neurologic and due to the mass effect of the expanding tumor. Symptoms of increased intracranial pressure such as headache and vomiting are present in about 40%; decreased visual acuity or visual field defects are the presenting symptoms in another 35%. MRI confirms the tumor in virtually all patients; in 95%, the tumor is suprasellar.
In adults, craniopharyngiomas have similar presentations; ie, the diagnosis is usually reached as a result of investigation of complaints of headache or visual loss. However, endocrine manifestations—especially hypogonadism, diabetes insipidus, or other deficiencies of anterior pituitary hormones—usually precede these late manifestations. MRI readily demonstrates the tumors, which in adults are almost always both intrasellar and suprasellar.
- OTHER TUMORS
Other hypothalamic or pineal tumors and primary central nervous system tumors involving the hypothalamus have variable presentations in both children and adults. Thus, presentation is with headache, visual loss, symptoms of increased intracranial pressure, growth failure, various degrees of hypopituitarism, or diabetes insipidus. Endocrine deficiencies usually precede neurologic manifestations. Hypothalamic tumors in childhood may present with precocious puberty.
- OTHER MANIFESTATIONS OF HYPOTHALAMIC DYSFUNCTION
Lesions in the hypothalamus can cause many other abnormalities, including disorders of consciousness, behavior, thirst, appetite, and temperature regulation. These abnormalities are usually accompanied by hypopituitarism and diabetes insipidus.
Somnolence can occur with hypothalamic lesions, as can a variety of changes in emotional behavior. Decreased or absent thirst may occur and predispose these patients to dehydration. When diminished thirst accompanies diabetes insipidus, fluid balance is difficult to control. Hypothalamic dysfunction may also cause increased thirst, leading to polydipsia and polyuria that may mimic diabetes insipidus. Obesity is common in patients with hypothalamic tumors because of hyperphagia, decreased satiety, and decreased activity. Anorexia and weight loss are unusual manifestations of these tumors.
Temperature regulation can also be disordered in these patients. Sustained or, less commonly, paroxysmal hyperthermia can occur following acute injury due to trauma, hemorrhage, or craniotomy. This problem usually lasts less than 2 weeks. Poikilothermia, the inability to adjust to changes in ambient temperature, can occur in patients with bilateral hypothalamic lesions. These patients most frequently exhibit hypothermia but can also develop hyperthermia during hot weather. A few patients manifest sustained hypothermia due to anterior hypothalamic lesions.
Patients with suspected hypothalamic tumors should undergo MRI to determine the extent and nature of the tumor. Complete assessment of anterior pituitary function is necessary in these patients, since deficiencies are present in the great majority (see section on hypopituitarismbelow) and the evaluation will establish the requirements for replacement therapy. PRL levels should also be determined, since most hypothalamic lesions cause hyperprolactinemia either by hypothalamic injury or by damage to the pituitary stalk.
Treatment depends upon the type of tumor. Since complete resection of craniopharyngioma is usually not feasible, this tumor is best managed by limited neurosurgical removal of accessible tumor and decompression of cysts, followed by conventional radiotherapy. Patients treated by this method have a recurrence rate of approximately 20%; with surgery alone, the recurrence rate approximates 80%.
Other hypothalamic tumors are usually not completely resectable; however, biopsy is indicated to arrive at a histologic diagnosis.
Hypopituitarism is manifested by diminished or absent secretion of one or more pituitary hormones. The development of signs and symptoms is often slow and insidious, depending on the rate of onset and the magnitude of hypothalamic-pituitary damage—factors that are influenced by the underlying pathogenesis. Hypopituitarism is either a primary event caused by destruction of the anterior pituitary gland or a secondary phenomenon resulting from deficiency of hypothalamic stimulatory factors normally acting on the pituitary.
Treatment and prognosis depend on the extent of hypofunction, the underlying cause, and the location of the lesion in the hypothalamic-pituitary axis.
The etiologic considerations in hypopituitarism are diverse. As shown below, a helpful mnemonic device is the phrase “nine I's”: Invasive, Infarction, Infiltrative, Injury, Immunologic, Iatrogenic, Infectious, Idiopathic, and Isolated. Most of these lesions may cause pituitary or hypothalamic failure (or both). Establishing the precise cause of hypopituitarism is helpful in determining treatment and prognosis.
Space-occupying lesions cause hypopituitarism by destroying the pituitary gland or hypothalamic nuclei or by disrupting the hypothalamic-hypophysial portal venous system. Large pituitary adenomas cause hypopituitarism by these mechanisms, and pituitary function may improve after their removal. Small pituitary tumors—microadenomas (< 10 mm in diameter)—characteristically seen in the hypersecretory states (excess PRL, GH, ACTH) do not directly cause pituitary insufficiency. Craniopharyngioma, the most common tumor of the hypothalamic-pituitary region in children, frequently impairs pituitary function by its compressive effects. Primary central nervous system tumors, including meningioma, chordoma, optic glioma, epidermoid tumors, and dermoid tumors, may decrease hypothalamic-pituitary secretion by their mass effects. Metastatic lesions to this area are common (especially breast carcinoma) but rarely result in clinically obvious hypopituitarism. Anatomic malformations such as basal encephalocele and parasellar aneurysms cause hypothalamic-pituitary dysfunction and may enlarge the sella turcica and mimic pituitary tumors.
Ischemic damage to the pituitary has long been recognized as a cause of hypopituitarism. In 1914, Simmonds reported pituitary necrosis in a woman with severe puerperal sepsis, and in 1937 Sheehan published his classic description of its occurrence following postpartum hemorrhage and vascular collapse. The mechanism for the ischemia in such cases is not certain. Hypotension along with vasospasm of the hypophysial arteries is currently believed to compromise arterial perfusion of the anterior pituitary. During pregnancy, the pituitary gland may be more sensitive to hypoxemia because of its increased metabolic needs or more susceptible to vasoconstrictive influences because of the hyperestrogenic state. Some degree of hypopituitarism has been reported in 32% of women with severe postpartum hemorrhage. Other investigators have noted that the hypopituitarism does not always correlate with the degree of hemorrhage but that there is good correlation between the pituitary lesion and severe disturbances of the clotting mechanism (as in patients with placenta previa). Ischemic pituitary necrosis has also been reported to occur with greater frequency in patients with diabetes mellitus.
The extent of pituitary damage determines the rapidity of onset as well as the magnitude of pituitary hypofunction. The gland has a great secretory reserve, and more than 75% must be destroyed before clinical manifestations are evident. The initial clinical feature in postpartum necrosis may be failure to lactate after parturition; failure to resume normal menstrual periods is another clue to the diagnosis. However, the clinical features of hypopituitarism are often subtle, and years may pass before pituitary insufficiency is recognized following an ischemic insult.
Spontaneous hemorrhagic infarction of a pituitary tumor (pituitary apoplexy) frequently results in partial or total pituitary insufficiency. Pituitary apoplexy is often a fulminant clinical syndrome manifested by severe headache, visual impairment, ophthalmoplegias, meningismus, and an altered level of consciousness. Pituitary apoplexy is usually associated with a pituitary tumor; it may also be related to diabetes mellitus, radiotherapy, or open heart surgery. Acute pituitary failure with hypotension may result, and rapid mental deterioration, coma, and death may ensue. Emergency treatment with corticosteroids (see Chapter 24) and transsphenoidal decompression of the intrasellar contents may be lifesaving and may prevent permanent visual loss. Most patients who have survived pituitary apoplexy have developed multiple adenohypophysial deficits, but infarction of the tumor in some patients may cure the hypersecretory pituitary adenoma and its accompanying endocrinopathy. Pituitary infarction may also be a subclinical event (silent pituitary apoplexy), resulting in improvement of pituitary hormone hypersecretion without impairing the secretion of other anterior pituitary hormones.
Hypopituitarism may be the initial clinical manifestation of infiltrative disease processes such as sarcoidosis, hemochromatosis, and histiocytosis X.
- Sarcoidosis—The most common intracranial sites of involvement of sarcoidosis are the hypothalamus and pituitary gland. At one time, the most common endocrine abnormality in patients with sarcoidosis was thought to be diabetes insipidus; however, many of these patients actually have centrally mediated disordered control of thirst that results in polydipsia and polyuria, which in some cases explains the abnormal
water metabolism. Deficiencies of multiple anterior pituitary hormones have been well documented in sarcoidosis and are usually secondary to hypothalamic insufficiency. Granulomatous involvement of the hypothalamic-pituitary unit is occasionally extensive, resulting in visual impairment, and therefore may simulate the clinical presentation of a pituitary or hypothalamic tumor.
- Hemochromatosis—Hypopituitarism, particularly hypogonadotropic hypogonadism, is a prominent manifestation of iron storage disease—either idiopathic hemochromatosis or transfusional iron overload. Hypogonadism occurs in most such cases and is often the initial clinical feature of iron excess; complete iron studies should be obtained in any male patient presenting with unexplained hypogonadotropic hypogonadism. If the diagnosis is established early, hypogonadism in hemochromatosis may be reversible with iron depletion. Pituitary deficiencies of TSH, GH, and ACTH may occur later in the course of the disease and are not reversible by iron chelation therapy.
- Histiocytosis X—Histiocytosis X, the infiltration of multiple organs by well-differentiated histiocytes, is often heralded by the onset of diabetes insipidus and anterior pituitary hormone deficiencies. Most histologic and biochemical studies have indicated that this infiltrative process involves chiefly the hypothalamus, and hypopituitarism occurs only as a result of hypothalamic damage.
Severe head trauma may cause anterior pituitary insufficiency and diabetes insipidus. Posttraumatic anterior hypopituitarism may be due to injury to the anterior pituitary, the pituitary stalk, or the hypothalamus. Pituitary insufficiency with growth retardation has been described in battered children who suffer closed head trauma with subdural hematoma.
Lymphocytic hypophysitis resulting in anterior hypopituitarism is a distinct entity, occurring most often in women during pregnancy or in the postpartum period. It may present as a mass lesion of the sella turcica with visual field disturbances simulating pituitary adenoma. An autoimmune process with extensive infiltration of the gland by lymphocytes and plasma cells destroys the anterior pituitary cells. These morphologic features are similar to those of other autoimmune endocrinopathies, eg, thyroiditis, adrenalitis, and oophoritis. About 50% of patients with lymphocytic hypophysitis have other endocrine autoimmune disease, and circulating pituitary autoantibodies have been found in several cases. It is presently uncertain how this disorder should be diagnosed and treated. It must be considered in the differential diagnosis of women with pituitary gland enlargement and hypopituitarism during pregnancy or the postpartum period.
Lymphocytic hypophysitis may result in isolated hormone deficiencies (especially ACTH or prolactin). Consequently, women with this type of hypopituitarism may continue to menstruate while suffering from secondary hypothyroidism or hypoadrenalism.
Both surgical and radiation therapy to the pituitary gland may compromise its function. The anterior pituitary is quite resilient during transsphenoidal microsurgery, and despite extensive manipulation during the search for microadenomas, anterior pituitary function is usually preserved. The dose of conventional radiation therapy presently employed to treat pituitary tumors is 4500–5000 cGy and results in a 50–60% incidence of hypothalamic and pituitary insufficiency. Such patients most frequently have modest hyperprolactinemia (PRL 30–100 ng/mL [1.3–4.5 nmol/L]) with GH and gonadotropin failure; TSH and ACTH deficiencies are less common. Heavy particle (proton beam) irradiation for pituitary tumors results in a 20–50% incidence of hypopituitarism. Irradiation of tumors of the head and neck (nasopharyngeal cancer, brain tumors) and prophylactic cranial irradiation in leukemia may also cause hypopituitarism. The clinical onset of pituitary failure in such patients is usually insidious and results from both pituitary and hypothalamic injury.
Although many infectious diseases, including tuberculosis, syphilis, and mycotic infections, have been implicated as causative agents in pituitary hypofunction, anti-infective drugs have now made them rare causes of hypopituitarism.
In some patients with hypopituitarism, no underlying cause is found. These may be isolated (see below) or multiple deficiencies. Familial forms of hypopituitarism characterized by a small, normal, or enlarged sella turcica have been described. Both autosomal recessive and X-linked recessive inheritance patterns have been reported. A variety of complex congenital disorders may include deficiency of one or more pituitary hormones, eg, Prader-Willi syndrome and septo-optic dysplasia. The pathogenesis of these familial disorders is uncertain.
Isolated (monotropic) deficiencies of the anterior pituitary hormones have been described. Some of these have been associated with mutations in the genes coding for the specific hormones. Others, particularly GH
deficiency, have been associated with mutations in genes necessary for normal pituitary development as noted.
- GH deficiency—In children, congenital mono-tropic GH deficiency may be sporadic or familial. These children, who may experience fasting hypoglycemia, have a gradual deceleration in growth velocity after 6–12 months of age. Diagnosis must be based on failure of GH responsiveness to provocative stimuli and the demonstration of normal responsiveness of other anterior pituitary hormones. Monotropic GH deficiency and growth retardation have also been observed in children suffering severe emotional deprivation. This disorder is reversed by placing the child in a supportive psychosocial milieu. A more detailed description of GH deficiency and growth failure is provided in Chapter 6.
- ACTH deficiency—Monotropic ACTH deficiency is rare and is manifested by the signs and symptoms of adrenocortical insufficiency. Lipotropin (LPH) deficiency has also been noted in such patients. The defect in these patients may be due to primary failure of the corticotrophs to release ACTH and its related peptide hormones or may be secondary to impaired secretion of CRH by the hypothalamus. Most acquired cases of monotropic ACTH deficiency are due to lymphocytic hypophysitis.
- Gonadotropin deficiency—Isolated deficiency of gonadotropins is not uncommon. Kallman's syndrome, an X-linked dominant disorder with incomplete penetrance, is characterized by an isolated defect in GnRH secretion associated with maldevelopment of the olfactory center with hyposmia or anosmia; a deletion in a gene on the short arm of the X chromosome (Xp22.3) results in decreased expression of the cell adhesion molecule KALIG-1. This in turn interferes with the normal embryonic development and migration of GnRH-secreting neurons. Sporadic cases occur, and other neurologic defects such as color blindness and nerve deafness have been seen. Since anterior pituitary function is otherwise intact, young men with isolated hypogonadotropic hypogonadism develop a eunuchoid appearance, since testosterone deficiency results in failure of epiphysial closure (see Chapter 12). In women, a state of hypogonadotropic hypogonadism manifested by oligomenorrhea or amenorrhea often accompanies weight loss, emotional or physical stress, and athletic training. Anorexia nervosa and marked obesity both result in hypothalamic dysfunction and impaired gonadotropin secretion. Hypothalamic hypogonadism has also been observed in overtrained male athletes. Sickle cell anemia also causes hypogonadotropic hypogonadism due to hypothalamic dysfunction and results in delayed puberty. Clomiphene treatment has been effective in some cases. Isolated gonadotropin deficiency may also be seen in the polyglandular autoimmune syndrome; this deficiency is related to selective pituitary gonadotrope failure from autoimmune hypophysitis. Other chronic illnesses, eg, poorly controlled diabetes and malnutrition, may result in gonadotropin deficiency. Isolated deficiencies of both LH and FSH without an obvious cause such as those described have been reported but are rare.
- TSH deficiency—Monotropic TSH deficiency is rare and is caused by a reduction in hypothalamic TRH secretion (tertiary hypothyroidism). Some patients with chronic renal failure appear to have impaired TSH secretion.
- Prolactin deficiency—PRL deficiency almost always indicates severe intrinsic pituitary damage, and panhypopituitarism is usually present. However, isolated PRL deficiency has been reported after lymphocytic hypophysitis. Deficiencies of TSH and PRL have been noted in patients with pseudohypoparathyroidism.
- Multiple hormone deficiencies isolated from other pituitary damage—Multiple hormone deficiencies result from abnormal pituitary development related to abnormalities of the genes encoding the transcription factors, PIT-1 and PROP-1.
The onset of pituitary insufficiency is usually gradual, and the classic course of progressive hypopituitarism is an initial loss of GH and gonadotropin secretion followed by deficiencies of TSH, then ACTH, and finally PRL.
Impairment of GH secretion causes decreased growth in children but may be clinically occult in adult patients. GH deficiency is associated with a decreased sense of well-being and a lower health-related quality of life. Hypogonadism, manifested by amenorrhea in women and decreased libido or erectile dysfunction in men, may antedate the clinical appearance of a hypothalamic-pituitary lesion.
Hypothyroidism caused by TSH deficiency generally simulates the clinical changes observed in primary thyroid failure; however, it is usually less severe, and goiter is absent. Cold intolerance, dry skin, mental dullness, bradycardia, constipation, hoarseness, and anemia have all been observed; gross myxedematous changes are uncommon.
ACTH deficiency causes adrenocortical insufficiency, and its clinical features resemble those of primary adrenal failure. Weakness, nausea, vomiting,
anorexia, weight loss, fever, and hypotension may occur. Since the zona glomerulosa and the renin-angiotensin system are usually intact, the dehydration and sodium depletion seen in Addison's disease are uncommon. However, these patients are susceptible to hypotension, shock, and cardiovascular collapse since glucocorticoids are necessary to maintain vascular reactivity, especially during stress. Because of their gradual onset, the symptoms of secondary adrenal insufficiency may go undetected for prolonged periods, becoming manifest only during periods of stress. Hypoglycemia aggravated by GH deficiency may occur with fasting and has been the initial presenting feature of some patients with isolated ACTH deficiency. In contrast to the hyperpigmentation that occurs during states of ACTH excess (Addison's disease, Nelson's syndrome), depigmentation and diminished tanning have been described as a result of ACTH insufficiency. In addition, lack of ACTH-stimulated adrenal androgen secretion will cause a decrease in body hair if gonadotropin deficiency is also present.
GH deficiency is associated with decreased muscle mass and increased fat mass, though this may be difficult to discern in any given individual. The only symptom of PRL deficiency is failure of postpartum lactation.
Abnormal findings on physical examination may be subtle and require careful observation. Patients with hypopituitarism are not cachectic. A photograph of a cachectic patient with “Simmonds' syndrome” that appeared in some older textbooks of endocrinology caused confusion. That particular patient probably suffered from anorexia nervosa and was found to have a normal pituitary gland at postmortem examination.
Patients with pituitary failure are usually slightly overweight. The skin is fine, pale, and smooth, with fine wrinkling of the face. Body and pubic hair may be deficient or absent, and atrophy of the genitalia may occur. Postural hypotension, bradycardia, decreased muscle strength, and delayed deep tendon reflexes occur in more severe cases. Neuro-ophthalmologic abnormalities depend on the presence of a large intrasellar or parasellar lesion.
- LABORATORY AND OTHER FINDINGS
These may include anemia (related to thyroid and androgen deficiency and chronic disease), hypoglycemia, hyponatremia (related to hypothyroidism and hypoadrenalism, which cause inappropriate water retention, not sodium loss), and low-voltage bradycardia on electrocardiographic testing. Hyperkalemia, which is common in primary adrenal failure, is not present. Adult GH deficiency is associated with decreased red blood cell mass, increased LDL cholesterol, and decreased bone mass.
- ASSESSMENT OF TARGET GLAND FUNCTION
(Figure 5-17.) If endocrine hypofunction is suspected, pituitary hormone deficiencies must be distinguished from primary failure of the thyroid, adrenals, or gonads. Basal determinations of each anterior pituitary hormone are useful only if compared to target gland secretion. Baseline laboratory studies should include thyroid function tests (free T4) and determination of serum testosterone levels. Testosterone is a sensitive indicator of hypopituitarism in women as well as in men. In women, a substantial decrease in testosterone is commonly observed in pituitary failure related to hypofunction of the two endocrine glands responsible for its production—the ovary and the adrenal. Adrenocortical reserve should initially be evaluated by a rapid ACTH stimulation test.
- EVALUATION OF PROLACTIN
Since hyperprolactinemia (discussed later), regardless of its cause, leads to gonadal dysfunction, serum PRL should be measured early in the evaluation of hypogonadism.
- DIFFERENTIATION OF PRIMARY AND SECONDARY HYPOFUNCTION
Subnormal thyroid function as shown by appropriate tests, a low serum testosterone level, or an impaired cortisol response to the rapid ACTH stimulation test requires measurement of basal levels of specific pituitary hormones. In primary target gland hypofunction (such as polyglandular failure syndrome), TSH, LH, FSH, or ACTH will be elevated. Low or normal values for these pituitary hormones suggest hypothalamic-pituitary dysfunction.
- STIMULATION TESTS
Provocative endocrine testing may then be employed to confirm the diagnosis and to assess the extent of hypofunction. At present, these tests are not required in most patients.
Treatment of secondary adrenal insufficiency, like that of primary adrenal failure, must include glucocorticoid support (see Chapter 9). Hydrocortisone (20–30 mg/d
orally) or prednisone (5–7.5 mg/d orally) in two or three divided doses provides adequate glucocorticoid replacement for most patients. The minimum effective dosage should be given in order to avoid iatrogenic hypercortisolism. Increased dosage is required during periods of stress such as illness, surgery, or trauma. Patients with only partial ACTH deficiency may need steroid treatment only during stress. A two- to threefold increase in steroid dosage during the stressful situation should be recommended, followed by gradual tapering as the stress resolves. Unlike primary adrenal insufficiency, ACTH deficiency does not usually require mineralocorticoid therapy. Patients with adrenal insufficiency should wear medical alert bracelets so they may receive prompt treatment in case of emergency.
Figure 5-17. VDiagnostic evaluation of hypothalamic-pituitary-target gland hypofunction.
The management of patients with secondary hypothyroidism must be based on clinical grounds and the circulating concentration of serum thyroxine (see Chapter 7). The treatment of secondary and tertiary hypothyroidism is identical to that for primary thyroid failure. Levothyroxine sodium, 0.1–0.15 mg/d orally, is usually adequate. Response to therapy is monitored clinically and with measurement of serum free thyroxine levels, which should be maintained in the mid to upper range of normal. Measurement of TSH levels is obviously of no value in the management of these patients.
Caution: Since thyroid hormone replacement in patients with hypopituitarism may aggravate even partial adrenal insufficiency, the adrenal disorder should be treated first.
The object of treatment of secondary hypogonadism is to replace sex steroids and restore fertility (see Chapters 12 and 13).
- Estrogens and progesterone—In women, estrogen replacement is essential. Adequate estrogen treatment will maintain secondary sex characteristics (eg, vulvar and vaginal lubrication), prevent osteoporosis, and abolish vasomotor symptoms, with an improvement in sense of well-being. Many estrogen preparations are available, eg, oral estradiol, 1–2 mg daily; conjugated estrogens, 0.3–1.25 mg orally daily; or transdermal estradiol, 0.05–0.1 mg daily. Estrogens should be cycled with a progestin compound (eg, medroxyprogesterone, 5–10 mg orally daily during the last 10 days of estrogen therapy each month) to induce withdrawal bleeding and prevent endometrial hyperplasia.
- Ovulation induction—Ovulation can often be restored in women with hypothalamic-pituitary dysfunction (see Chapter 13). In patients with gonadal failure of hypothalamic origin, clomiphene citrate may cause a surge of gonadotropin secretion resulting in ovulation. Pulsatile subcutaneous injections of GnRH with an infusion pump can also be used to induce ovulation and fertility in women with hypothalamic dysfunction. Combined treatment with FSH (human menopausal gonadotropins; menotropins) and LH (chorionic gonadotropin) can be utilized to provoke ovulation in women with intrinsic pituitary failure. This form of therapy is expensive, and multiple births are a risk. (See Chapter 13.)
- Androgens in women—Because of a deficiency of both ovarian and adrenal androgens, some women with hypopituitarism have diminished libido despite adequate estrogen therapy. Although experience is limited, small doses of long-acting androgens (testosterone enanthate, 25–50 mg intramuscularly every 4–8 weeks) may be helpful in restoring sexual activity without causing hirsutism. In addition, some reports have suggested that oral DHEA in doses of 25–50 mg/d may restore plasma testosterone levels to normal. A transdermal delivery system is being evaluated for use in women but is not currently available for routine use.
- Androgens in men—The treatment of male hypogonadism is discussed in Chapter 12.
Available therapeutic preparations include intramuscular testosterone enanthate or cypionate in doses of 100 mg every week or 200 mg every 2 weeks. Transdermal testosterone patches in doses of 2.5 or 5 mg are also available but require daily application. The most recent product is a testosterone gel in doses of 2.5 or 5 mg which is also applied daily. (See Chapter 12).
- Spermatogenesis—Spermatogenesis can be achieved in many patients with the combined use of chorionic gonadotropin and menotropins. If pituitary insufficiency is of recent onset, therapy with chorionic gonadotropin alone may restore both fertility and adequate gonadal steroid production. Pulsatile GnRH infusion pumps have also been used to restore fertility in male patients with secondary hypogonadism.
- GROWTH HORMONE
(See Chapter 6.) Human growth hormone (hGH) produced by recombinant DNA technology is available for use in children with hypopituitarism and for adults with GH deficiency and known pituitary disease. Therapeutic use of human growth hormone in adults with GH deficiency due to other causes, eg, reduced secretion associated with aging, is under investigation. Some studies indicate improvement in body composition, bone density, psychologic well-being, and functional status with GH therapy. However, the long-term benefits and risks remain to be established. In adults, GH is usually administered subcutaneously, once per day in a
dosage of 2–5 ľg/kg. Monitoring of effectiveness is accomplished by measurement of IGF-I, and the dosage of GH is adjusted accordingly (up to about 10 ľg/kg/d). Side effects should be assessed, eg, edema, paresthesias, arrhythmias, and glucose intolerance.
Advances in endocrinologic and neuroradiologic research in recent years have allowed earlier recognition and more successful therapy of pituitary adenomas. Prolactinomas are the most common type, accounting for about 60% of primary pituitary tumors; GH hypersecretion occurs in approximately 20% and ACTH excess in 10%. Hypersecretion of TSH, the gonadotropins, or alpha subunits is unusual. Nonfunctional tumors currently represent only 10% of all pituitary adenomas, and some of these may in fact be gonadotropin-secreting or alpha subunit-secreting adenomas.
Early clinical recognition of the endocrine effects of excessive pituitary secretion, especially the observation that PRL excess causes secondary hypogonadism, has led to early diagnosis of pituitary tumors before the appearance of late manifestations such as sellar enlargement, panhypopituitarism, and suprasellar extension with visual impairment.
Pituitary microadenomas are defined as intrasellar adenomas less than 1 cm in diameter that present with manifestations of hormonal excess without sellar enlargement or extrasellar extension. Panhypopituitarism does not occur, and such tumors can usually be treated successfully.
Pituitary macroadenomas are those larger than 1 cm in diameter and cause generalized sellar enlargement. Tumors 1–2 cm in diameter confined to the sella turcica can usually be successfully treated; however, larger tumors—and especially those with suprasellar, sphenoid sinus, or lateral extensions—are much more difficult to manage. Panhypopituitarism and visual loss increase in frequency with tumor size and suprasellar extension.
Insights into the pathogenesis and biologic behavior of pituitary tumors have been gained from studies of pituitary tumor clonality and somatic mutations. Analyses of allelic X inactivation of specific genes has shown that most pituitary adenomas are monoclonal, a finding most consistent with a somatic mutation model of tumorigenesis; polyclonality of tumors would be expected if tonic stimulation by hypothalamic releasing factors were the mechanism underlying neoplastic transformation. In fact, transgenic animals expressing GHRH have exhibited pituitary hyperplasia but not pituitary adenomas. Recently, an animal model system for ACTH-secreting pituitary tumors has been developed involving transgenic mice. One somatic mutation has been found in 30–40% of growth hormone-secreting tumors (but not in leukocytes from the same patients). Point mutations in the alpha subunit of the GTP binding protein responsible for activation of adenylyl cyclase results in constitutive stimulation of pituitary cell growth and function. In studies of anterior pituitary cell ontogeny, PIT-1 has been identified as a transcription factor important in pituitary differentiation. The restriction of its expression to somatotrophs, lactotrophs, and thyrotrophs may account for the plurihormonal expression seen in some tumors. A pituitary tumor transforming gene (PTTG) has also been described.
Pituitary adenomas are treated with surgery, irradiation, or drugs to suppress hypersecretion by the adenoma or its growth. The aims of therapy are to correct hypersecretion of anterior pituitary hormones, to preserve normal secretion of other anterior pituitary hormones, and to remove or suppress the adenoma itself. These objectives are currently achievable in most patients with pituitary microadenomas; however, in the case of larger tumors, multiple therapies are frequently required and may be less successful.
- SURGICAL TREATMENT
The transsphenoidal microsurgical approach to the sella turcica is the procedure of choice; transfrontal craniotomy is required only in the rare patient with massive suprasellar extension of the adenoma. In the transsphenoidal procedure, the surgeon approaches the pituitary from the nasal cavity through the sphenoid sinus, removes the anterior-inferior sellar floor, and incises the dura. The adenoma is selectively removed; normal pituitary tissue is identified and preserved. Success rates approach 90% in patients with microadenomas. Major complications, including postoperative hemorrhage, cerebrospinal fluid leak, meningitis, and visual impairment, occur in less than 5% of patients and are most frequent in patients with large or massive tumors. Transient diabetes insipidus lasting a few days to 1–2 weeks occurs in approximately 15%; permanent diabetes insipidus is rare. A transient form of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) with symptomatic hyponatremia occurs in 10% of patients within 5–14 days of transsphenoidal pituitary microsurgery. Surgical hypopituitarism is rare in patients with microadenomas but approaches 5–10% in patients with larger tumors. The perioperative management of such patients should include glucocorticoid administration in stress doses
(see Chapter 9) and postoperative assessment of daily weight, fluid balance, and electrolyte status. Mild diabetes insipidus is managed by giving fluids orally; in more severe cases—urine output greater than 5–6 L/24 h—ADH therapy in the form of desmopressin acetate should be administered (see section on diabetes insipidus). SIADH is managed by fluid restriction; however, in more severe cases, hypertonic saline may be required. (See section on SIADH.)
Pituitary irradiation is usually reserved for patients with larger tumors who have had incomplete resection of large pituitary adenomas.
- Conventional irradiation—Conventional irradiation using high energy sources, in total doses of 4000–5000 cGy given in daily doses of 180–200 cGy, is most commonly employed. The response to radiation therapy is slow, and 5–10 years may be required to achieve the full effect (see section on acromegaly). Treatment is ultimately successful in about 80% of acromegalics but only about 55–60% of patients with Cushing's disease. The response rate in prolactinomas is not precisely known, but tumor progression is prevented in most patients. Morbidity during radiotherapy is minimal, though some patients experience malaise and nausea, and serous otitis media may occur. Hypopituitarism is common, and the incidence increases with time following radiotherapy—about 50–60% at 5–10 years. Rare late complications include damage to the optic nerves and chiasm, seizures, and radionecrosis of brain tissue.
- Gamma knife radiosurgery—This form of radiotherapy utilizes stereotactic CT-guided cobalt-60 gamma radiation to deliver high radiation doses to a narrowly focused area. Limited experience to date has been obtained in patients with acromegaly and Cushing's disease. (See sections following.)
- MEDICAL TREATMENT
Medical management of pituitary adenomas became feasible with the availability of bromocriptine, a dopamine agonist that suppresses both prolactin and tumor growth in patients with prolactinomas. Somatostatin analogs are useful in the therapy of acromegaly and TSH-secreting adenomas. Specifics of the use of these and other medications are discussed below.
Patients undergoing transsphenoidal microsurgery should be reevaluated 4–6 weeks postoperatively to document that complete removal of the adenoma and correction of endocrine hypersecretion have been achieved. Prolactinomas are assessed by basal PRL measurements, GH-secreting tumors by glucose suppression testing and IGF-I levels, and ACTH-secreting adenomas by measurement of urine free cortisol and the response to low-dose dexamethasone suppression (see below). Other anterior pituitary hormones—TSH, ACTH, and LH/FSH —should also be assessed as described above in the section on endocrine evaluation. In patients with successful responses, yearly evaluation should be done to watch for late recurrence; late hypopituitarism does not occur after microsurgery. MRI is not necessary in patients with normal postoperative pituitary function but should be utilized in patients with persistent or recurrent disease.
Follow-up of patients treated by pituitary irradiation is also essential, since the response to therapy may be delayed and the incidence of hypopituitarism increases with time. Yearly endocrinologic assessment of both the hypersecreted hormone and the other pituitary hormones is recommended.
PRL hypersecretion is the most common endocrine abnormality due to hypothalamic-pituitary disorders, and PRL is the hormone most commonly secreted in excess by pituitary adenomas.
The understanding that PRL hypersecretion causes not only galactorrhea but also gonadal dysfunction and the use of PRL measurements in screening such patients have permitted recognition of these PRL-secreting tumors before the development of sellar enlargement, hypopituitarism, or visual impairment.
Thus, plasma PRL should be measured in patients with galactorrhea, suspected hypothalamic-pituitary dysfunction, or sellar enlargement and in those with unexplained gonadal dysfunction, including amenorrhea, infertility, decreased libido, or impotence (Table 5-12).
PRL-secreting pituitary adenomas arise most commonly from the lateral wings of the anterior pituitary, but with progression they fill the sella turcica and compress
the normal anterior and posterior lobes. Tumor size varies greatly from microadenomas to large invasive tumors with extrasellar extension. Most patients have microadenomas, ie, tumors less than 1 cm in diameter at diagnosis.
Table 5-12. Indications for prolactin measurement.
Prolactinomas usually appear chromophobic on routine histologic study, reflecting the inadequacy of the techniques used. The cells are small and uniform, with round or oval nuclei and scanty cytoplasm, and secretory granules are usually not visible with routine stains. The stroma contains a diffuse capillary network.
Electron microscopic examination shows that prolactinoma cells characteristically contain secretory granules that usually range from 100 nm to 500 nm in diameter and are spherical. Larger granules (400–500 nm), which are irregular or crescent-shaped, are less commonly seen. The cells show evidence of secretory activity, with a large Golgi area, nucleolar enlargement, and a prominent endoplasmic reticulum. Immunocytochemical studies of these tumors have confirmed that the secretory granules indeed contain PRL.
The clinical manifestations of PRL excess are the same regardless of the cause (see below). The classic features are galactorrhea and amenorrhea in women and galactorrhea and decreased libido or impotence in men. Although the sex distribution of prolactinomas is approximately equal, microadenomas are much more common in women, presumably because of earlier recognition of the endocrine consequences of PRL excess.
Galactorrhea occurs in the majority of women with prolactinomas and is much less common in men. It is usually not spontaneous, or may be present only transiently or intermittently; careful breast examination is required in most patients to demonstrate galactorrhea. The absence of galactorrhea despite markedly elevated PRL levels is probably due to concomitant deficiency of the gonadal hormones required to initiate lactation (see Chapter 16).
- GONADAL DYSFUNCTION
- In women—Amenorrhea, oligomenorrhea with anovulation, or infertility is present in approximately 90% of women with prolactinomas. These menstrual disorders usually present concurrently with galactorrhea if it is present but may either precede or follow it. The amenorrhea is usually secondary and may follow pregnancy or oral contraceptive use. Primary amenorrhea occurs in the minority of patients who have onset of hyperprolactinemia during adolescence. The necessity of measuring PRL in patients with unexplained primary or secondary amenorrhea is emphasized by several studies showing that hyperprolactinemia occurs in as many as 20% of patients with neither galactorrhea nor other manifestations of pituitary dysfunction. A number of these patients have been shown to have prolactinomas.
Gonadal dysfunction in these women is due to interference with the hypothalamic-pituitary-gonadal axis by the hyperprolactinemia and except in patients with large or invasive adenomas is not due to destruction of the gonadotropin-secreting cells. This has been documented by the return of menstrual function following reduction of PRL levels to normal by drug treatment or surgical removal of the tumor. Although basal gonadotropin levels are frequently within the normal range despite reduction of sex steroid levels in hyperprolactinemic patients, PRL inhibits both the normal pulsatile secretion of LH and FSH and the midcycle LH surge, resulting in anovulation. The positive feedback effect of estrogen on gonadotropin secretion is also inhibited; in fact, patients with hyperprolactinemia are usually estrogen-deficient.
Estrogen deficiency in women with prolactinomas may be accompanied by decreased vaginal lubrication, other symptoms of estrogen deficiency, and osteopenia as assessed by bone densitometry. Other symptoms may include weight gain, fluid retention, and irritability. Hirsutism may also occur, accompanied by elevated plasma levels of dehydroepiandrosterone (DHEA) sulfate. Patients with hyperprolactinemia may also suffer from anxiety and depression. Treatment with dopamine agonists has been shown to improve psychologic distress in such patients.
- In men—In men, PRL excess may also occasionally cause galactorrhea; however, the usual manifestations are those of hypogonadism. The initial symptom is decreased libido, which may be dismissed by both the patient and physician as due to psychosocial factors; thus, the recognition of prolactinomas in men is frequently delayed, and marked hyperprolactinemia (PRL > 200 ng/mL [9.1 nmol/L]) and sellar enlargement are usual. Unfortunately, prolactinomas in men are often not diagnosed until late manifestations such as headache, visual impairment, or hypopituitarism appear; virtually all such patients have a history of sexual or gonadal dysfunction. Serum testosterone levels are low, and in the presence of normal or subnormal gonadotropin levels, PRL excess should be suspected as well as other causes of hypothalamic-pituitary-gonadal dysfunction (see section on hypopituitarism). Impotence also occurs in hyperprolactinemic males. Its cause is unclear, since testosterone replacement may not reverse it if hyperprolactinemia is not corrected. Male infertility accompanied by reduction in sperm count is a less common initial complaint.
- TUMOR PROGRESSION
In general, the growth of prolactinomas is slow, and several studies have shown that most microadenomas do not progress.
The many conditions associated with hyperprolactinemia are listed in Table 5-8. Pregnancy, hypothalamic-pituitary disorders, primary hypothyroidism, and drug ingestion are the most common causes.
Hypothalamic lesions frequently cause PRL hypersecretion by decreasing the secretion of dopamine that tonically inhibits PRL release; the lesions may be accompanied by panhypopituitarism. Similarly, traumatic or surgical section of the pituitary stalk leads to hyperprolactinemia and hypopituitarism. Nonfunctional pituitary macroadenomas frequently cause mild hyperprolactinemia by compression of the pituitary stalk or hypothalamus.
Pregnancy leads to a physiologic increase in PRL secretion; the levels increase as pregnancy continues and may reach 200 ng/mL (9.1 nmol/L) during the third trimester. Following delivery, basal PRL levels gradually fall to normal over several weeks but increase in response to breast feeding. Hyperprolactinemia persisting for 6–12 months or longer following delivery is an indication for evaluation. PRL levels are also high in normal neonates.
Several systemic disorders lead to hyperprolactinemia. Primary hypothyroidism is a common cause, and measurement of thyroid function, and especially TSH, should be part of the evaluation. In primary hypothyroidism, there is hyperplasia of both thyrotrophs and lactotrophs, presumably due to TRH hypersecretion. This may result in significant pituitary gland enlargement, which may be mistaken for a PRL-secreting pituitary tumor. The PRL response to TRH is usually exaggerated in these patients. PRL may also be increased in liver disease, particularly in patients with severe cirrhosis, and in patients with chronic renal failure.
PRL excess and galactorrhea may also be caused by breast disease, nipple stimulation, disease or injury to the chest wall, and spinal cord lesions. These disorders increase PRL secretion by stimulation of afferent neural pathways. Artifactual elevations in prolactin level may be observed in the presence of anti-prolactin antibodies or of macroprolactinemia. In the latter, a high-molecular-weight complex of prolactin molecules maintains immunologic activity but not bioactivity.
The most common cause of hyperprolactinemia is drug ingestion, and a careful history of drug intake must be obtained. Elevated PRL levels, galactorrhea, and amenorrhea may occur following estrogen therapy or oral contraceptive use, but their persistence should suggest prolactinoma. Many other drugs also cause increased PRL secretion and elevated plasma levels (Table 5-8). PRL levels are usually less than 200 ng/mL (9 nmol/L), and the evaluation is primarily by discontinuing the drug or medication and reevaluating the patient after several weeks. In patients in whom drug withdrawal is not feasible, neuroradiologic studies, if normal, will usually exclude prolactinoma.
- GENERAL EVALUATION
The evaluation of patients with galactorrhea or unexplained gonadal dysfunction with normal or low plasma gonadotropin levels should first include a history regarding menstrual status, pregnancy, fertility, sexual function, and symptoms of hypothyroidism or hypopituitarism. Current or previous use of medication, drugs, or estrogen therapy should be documented. Basal PRL levels, gonadotropins, thyroid function tests, and TSH levels should be established, as well as serum testosterone in men. Liver and kidney function should be assessed. A pregnancy test should be performed in women with amenorrhea.
Patients with galactorrhea but normal menses may not have hyperprolactinemia and usually do not have prolactinomas. If the PRL level is normal, they may be reassured and followed with sequential PRL measurements. Those with elevated levels require further evaluation as described below.
- SPECIFIC DIAGNOSIS
When other causes of hyperprolactinemia have been excluded, the most likely cause of persistent hyperprolactinemia is a prolactinoma, especially if there is associated hypogonadism. Since currently available suppression and stimulation tests do not distinguish PRL-secreting tumors from other causes of hyperprolactinemia, the diagnosis must be established by the assessment of both basal PRL levels and neuroradiologic studies. Patients with large tumors and marked hyperprolactinemia usually present little difficulty. With very rare exceptions, basal PRL levels greater than 200 ng/mL (9.1 nmol/L) are virtually diagnostic of prolactinoma. In addition, since there is a general correlation between the PRL elevation and the size of the pituitary adenoma, these patients usually have sellar enlargement and obvious macroadenomas. Similarly, if the basal PRL level is between 100 and 200 ng/mL (4.5 and 9.1 nmol/L), the cause is usually prolactinoma. These patients may have either micro- or macroadenomas; however, with basal levels of PRL greater than 100 ng/mL (4.5 nmol/L), the PRL-secreting tumor is usually
radiologically evident, and again the diagnosis is generally straightforward. Patients with mild to moderate hyperprolactinemia (20–100 ng/mL [0.9–4.5 nmol/L]) present the greatest difficulty in diagnosis, since both PRL-secreting microadenomas and the many other conditions causing hyperprolactinemia (Table 5-8) cause PRL hypersecretion of this degree. In such patients, MRI should be performed and will frequently demonstrate a definite pituitary microadenoma. Scans showing only minor or equivocal abnormalities should be interpreted with caution, because of the high incidence of false-positive scans in the normal population (see neuroradiologic evaluation, above). Since the diagnosis cannot be either established or excluded in patients with normal or equivocal neuroradiologic studies, they require further evaluation or serial assessment (see below).
Satisfactory control of PRL hypersecretion, cessation of galactorrhea, and return of normal gonadal function can be achieved in most patients with PRL-secreting microadenomas. In patients with hyperprolactinemia, ovulation should not be induced without careful assessment of pituitary anatomy, since pregnancy may cause further expansion of these tumors as discussed below.
Although most microadenomas do not progress, treatment of these patients is recommended to restore normal estrogen levels and fertility and to prevent early osteoporosis secondary to persistent hypogonadism. In addition, medical or surgical therapy is more successful in these patients than in those with larger tumors. Therefore, all patients with PRL-secreting macroadenomas should be treated, because of the risks of further tumor expansion, hypopituitarism, and visual impairment.
Patients with persistent hyperprolactinemia and hypogonadism and normal neuroradiologic studies—ie, those in whom prolactinoma cannot be definitely established—may be managed by observation if hypogonadism is of short duration. However, in patients whose hypogonadism has persisted for more than 6–12 months, dopamine agonists should be used to suppress PRL secretion and restore normal gonadal function. In women with suspected or proved prolactinomas, replacement estrogen therapy is contraindicated because of the risk of tumor growth.
- SURGICAL TREATMENT
Transsphenoidal microsurgery is the surgical procedure of choice in patients with prolactinomas.
- Microadenomas—In patients with microadenomas, remission, as measured by restitution of normal PRL levels, normal menses, and cessation of galactorrhea, is achieved in 85–90% of cases. Success is most likely in patients with basal PRL levels under 200 ng/mL (9.1 nmol/L) and a duration of amenorrhea of less than 5 years. In these patients, the incidence of surgical complications is less than 2%, and hypopituitarism is a rare complication. Thus, in this group of patients with PRL-secreting microadenomas, PRL hypersecretion can be corrected, gonadal function restored, and secretion of TSH and ACTH preserved. Recurrence rates vary considerably in reported series. In our experience, approximately 85% of patients have had long-term remissions, and 15% have had recurrent hyperprolactinemia.
- Macroadenomas—Transsphenoidal microsurgery is considerably less successful in restoring normal PRL secretion in patients with macroadenomas; many clinicians would treat these patients with dopamine agonists alone. The surgical outcome is directly related to tumor size and the basal PRL level. Thus, in patients with tumors 1–2 cm in diameter without extrasellar extension and with basal PRL levels under 200 ng/mL (9.1 nmol/L), transsphenoidal surgery is successful in about 80% of cases. In patients with higher basal PRL levels and larger or invasive tumors, the success rate—defined as complete tumor resection and restoration of normal basal PRL secretion—is 25–50%. Although progressive visual loss or pituitary apoplexy are clear indications for surgery, the great majority of these patients should be treated with dopamine agonists.
- DOPAMINE AGONISTS
Bromocriptine became available in the US more than 20 years ago and was the first effective medical therapy for pituitary adenomas; however, cabergoline is more potent, much longer-acting, and better-tolerated. Cabergoline has therefore become the dopamine agonist of choice in the therapy of prolactinomas.
- Bromocriptine—Bromocriptine, the first available dopamine agonist, stimulates dopamine receptors and has effects at both the hypothalamic and pituitary levels. It is effective therapy for a PRL-secreting pituitary adenoma and directly inhibits PRL secretion by the tumor. The dosage is 2.5–10 mg/d orally in divided doses. Side effects consisting of dizziness, postural hypotension, nausea, and occasionally vomiting are common at onset of therapy but usually resolve with continuation of the medication. They can usually be avoided by starting with a low dose and gradually increasing the dose over days to weeks until the PRL level is suppressed to the normal range. Most patients tolerate doses of 2.5–10 mg without difficulty; however, in about 10%, persistent postural hypotension and gastrointestinal side effects necessitate discontinuance of therapy.
- Cabergoline—Cabergoline, a newer nonergot dopamine agonist, is administered once or twice a week and has a better side effect profile than bromocriptine. It is as effective as bromocriptine in reducing macroadenoma size and is more effective in reducing prolactin levels. It has been used successfully in most patients previously intolerant or resistant to bromocriptine. Cabergoline should be started at a dosage of 0.25 mg twice per week and increased if necessary to 0.5 mg twice per week.
- a. Microadenomas—In patients with microadenomas, bromocriptine successfully reduces PRL levels to normal in about 80% of cases. About 10% of patients cannot tolerate the drug long-term because of persistent side effects, and another 10% are resistant to the effects of bromocriptine. Cabergoline, now the drug of choice, is successful in about 90% of patients and very few are intolerant or resistant. Correction of hyperprolactinemia allows recovery of normal gonadal function; ovulation and fertility are restored, so that mechanical contraception should be advised if pregnancy is not desired. Bromocriptine induces ovulation in most female patients who wish to become pregnant. There is less current experience with cabergoline. In these patients with microadenomas, the risk of major expansion of adenoma during the pregnancy appears to be less than 5%; however, both the patient and the physician must be aware of this potential complication. Current data do not indicate an increased risk of multiple pregnancy, abortion, or fetal malformations in pregnancies occurring in women taking bromocriptine; however, the patient should be instructed to discontinue bromocriptine at the first missed menstrual period and obtain a pregnancy test.
At present, there is no evidence that dopamine agonists cause permanent resolution of PRL-secreting microadenomas, and virtually all patients have resumption of hyperprolactinemia following discontinuation of therapy even when it has been continued for several years. Although no late toxicity has yet been reported other than the side effects noted above, questions about possible long-term risk and the indicated duration of therapy in such patients with microadenomas are currently unanswered.
- Macroadenomas—Dopamine agonists are effective in controlling hyperprolactinemia in patients with PRL-secreting macroadenomas even when basal PRL levels are markedly elevated. Dopamine agonists may be used either as initial therapy or to control residual hyperprolactinemia in patients unsuccessfully treated with surgery or radiotherapy. Dopamine agonists should not be used to induce ovulation and pregnancy in women with untreated macroadenomas, since the risk of tumor expansion and visual deficits in the later part of pregnancy is approximately 15–25%. These patients should be treated with surgery prior to induction of ovulation.
Dopamine agonists normalize PRL secretion in about 60–70% of patients with macroadenomas and also reduces tumor size in about the same number. Reduction of tumor size may occur within days to weeks following institution of therapy. The drugs have been used to restore vision in patients with major suprasellar extension and chiasmal compression. Tumor reduction in response to dopamine agonists is sustained only as long as the medication is continued, and reexpansion of the tumor and recurrence of hyperprolactinemia may occur rapidly following discontinuation of therapy.
Conventional radiation therapy is reserved for patients with PRL-secreting macroadenomas who have persistent hyperprolactinemia and who have not responded to attempts to control their pituitary adenomas with surgery or dopamine agonists. In this group of patients, radiotherapy with 4000–5000 cGy prevents further tumor expansion, though PRL levels usually do not fall into the normal range. Impairment of anterior pituitary function occurs in approximately 50–60% of patients.
Experience with gamma knife radiosurgery in prolactinomas is limited.
Selection of Therapy for Prolactinomas
The selection of therapy for prolactinomas depends on the wishes of the patient, the patient's plans for pregnancy and tolerance of medical therapy, and the availability of a skilled neurosurgeon.
All patients should be treated to prevent the occasional tumor progression, osteopenia, and the other effects of prolonged hypogonadism. Medical therapy with dopamine agonists effectively restores normal gonadal function and fertility, and pregnancy carries only a small risk of tumor expansion. The major disadvantage is the need for chronic therapy. Transsphenoidal adenectomy, either initially or after a trial of dopamine agonist therapy, carries little risk when performed by an experienced neurosurgeon and offers a high probability of long-term remission.
Primary surgical therapy in these patients usually does not result in long-term remission, so medical therapy is the primary therapy of choice, particularly when the patient's prolactin levels are greater than 200 ng/mL (9.1 nmol/L) and the tumor is larger than 2 cm. Although
transsphenoidal microsurgery will rapidly decrease tumor size and decompress the pituitary stalk, the optic chiasm, and the cavernous sinuses, there is usually residual tumor and hyperprolactinemia. Thus, these patients will require additional therapy with dopamine agonists. Although tumor growth and prolactin secretion can be controlled by medical therapy in most patients, therapeutic failure can result from drug intolerance, poor compliance, or resistance. Radiation therapy is reserved for postsurgical patients with residual adenomas who are not controlled with dopamine agonists.
- Acromegaly & Gigantism
GH-secreting pituitary adenomas are second in frequency to prolactinomas and cause the classic clinical syndromes of acromegaly and gigantism.
The characteristic clinical manifestations are the consequence of chronic GH hypersecretion, which in turn leads to excessive generation of IGF-I, the mediator of most of the effects of GH (see Chapter 6). Although overgrowth of bone is the classic feature, GH excess causes a generalized systemic disorder with deleterious effects and an increased mortality rate, though deaths are rarely due to the space-occupying or destructive effects of pituitary adenoma per se.
Acromegaly and gigantism are virtually always secondary to a pituitary adenoma. Ectopic GHRH secretion has been identified as another cause of GH hypersecretion and acromegaly in a few patients with carcinoid or islet cell tumors. Reports of intrapituitary GHRH-secreting gangliocytomas in direct contiguity with GH-secreting somatotroph adenomas and a report of a GHRH-secreting hypothalamic hamartoma in a patient with acromegaly provide a link between ectopic and eutopic GHRH production. Ectopic secretion of GH per se is very rare but has been documented in a few lung tumors.
In adults, GH excess leads to acromegaly, the syndrome characterized by local overgrowth of bone, particularly of the skull and mandible. Linear growth does not occur, because of prior fusion of the epiphyses of long bones. In childhood and adolescence, the onset of chronic GH excess leads to gigantism. Most of these patients have associated hypogonadism, which delays epiphysial closure, and the combination of IGF-I excess and hypogonadism leads to a striking acceleration of linear growth. Most patients with gigantism also have features of acromegaly if GH hypersecretion persists through adolescence and into adulthood.
Pituitary adenomas causing acromegaly are usually over 1 cm in diameter when the diagnosis is established. These tumors arise from the lateral wings of the anterior pituitary; less than 20% are diagnosed as microadenomas.
GH-secreting adenomas are of two histologic types: densely and sparsely granulated. However, there appears to be no difference in the degree of GH secretion or clinical manifestations in these patients. About 15% of GH-secreting tumors also contain lactotrophs, and these tumors thus hypersecrete both GH and PRL.
Etiology & Pathogenesism
Excessive pituitary GH secretion could be secondary to abnormal hypothalamic function, but in most cases it is a primary pituitary disorder. A mutation in the Gs protein leading to excessive cAMP production has been identified in 40% of GH-secreting adenomas. Pituitary adenomas are present in virtually all patients and are usually greater than 1 cm in diameter; hyperplasia alone is rare, and nonadenomatous anterior pituitary tissue does not exhibit somatotroph hyperplasia when examined histologically. In addition, there is a return of normal GH levels and dynamic control of GH secretion following selective removal of the pituitary adenoma.
In acromegaly, GH secretion is increased and its dynamic control is abnormal. Secretion remains episodic; however, the number, duration, and amplitude of secretory episodes are increased, and they occur randomly throughout the 24-hour period. The characteristic nocturnal surge is absent, and there are abnormal responses to suppression and stimulation. Thus, glucose suppressibility is lost (see diagnosis, below), and GH stimulation by hypoglycemia is usually absent. TRH and GnRH may cause GH release, whereas these substances do not normally stimulate GH secretion. Dopamine and dopamine agonists such as bromocriptine and apomorphine, which normally stimulate GH secretion, paradoxically cause GH suppression in about 70–80% of patients with acromegaly.
Most of the deleterious effects of chronic GH hypersecretion are caused by its stimulation of excessive amounts of IGF-I (see Chapter 6), and plasma levels of this compound are increased in acromegaly. The growth-promoting effects of IGF-I (DNA, RNA, and protein synthesis) lead to the characteristic proliferation of bone, cartilage, and soft tissues and increase in size of other organs to produce the classic clinical manifestations of acromegaly. The insulin resistance and carbohydrate intolerance seen in acromegaly appear to be direct effects of GH and not due to IGF-I excess.
The sex incidence of acromegaly is approximately equal; the mean age at diagnosis is approximately 40 years; and the duration of symptoms is usually 5–10 years before the diagnosis is established.
Acromegaly is a chronic disabling and disfiguring disorder with increased late morbidity and mortality if untreated. Although spontaneous remissions have been described, the course is slowly progressive in the great majority of cases—patients once thought to be “burned out” can almost invariably be shown to have continuing clinical manifestations and GH hypersecretion.
- SYMPTOMS AND SIGNS
Early manifestations (Table 5-13) include soft tissue proliferation, with enlargement of the hands and feet and coarsening of the facial features. This is usually accompanied by increased sweating, heat intolerance, oiliness of the skin, fatigue, and weight gain.
At diagnosis, virtually all patients have classic manifestations; acral and soft tissue changes are always present. Bone and cartilage changes affect chiefly the face and skull (Figure 5-18). These changes include thickening of the calvarium; increased size of the frontal sinuses, which leads to prominence of the supraorbital ridges; enlargement of the nose; and downward and forward growth of the mandible, which leads to prognathism and widely spaced teeth. Soft tissue growth also contributes to the facial appearance, with coarsening of the features and facial and infraorbital puffiness. The hands and feet are predominantly affected by soft tissue growth; they are large, thickened, and bulky, with blunt, spade-like fingers (Figure 5-19) and toes. A bulky, sweaty handshake frequently suggests the diagnosis, and there are increases in ring, glove, and shoe sizes. There is generalized thickening of the skin, with increased oiliness and sweating. Acne, sebaceous cysts, and fibromata mollusca (skin tags and papillomas) are common, as is acanthosis nigricans of the axillae and neck and hypertrichosis in women.
These bony and soft tissue changes are accompanied by systemic manifestations, which include hyperhidrosis, heat intolerance, lethargy, fatigue, and increased sleep requirement. Moderate weight gain usually occurs. Paresthesias, usually due to carpal tunnel compression, occur in 70%; sensorimotor neuropathies occur uncommonly. Bone and cartilage overgrowth leads to arthralgias and in long-standing cases to degenerative arthritis of the spine, hips, and knees. Photophobia of unknown cause occurs in about half of cases and is most troublesome in bright sunlight and during night driving.
GH excess leads to generalized visceromegaly, clinically evident as thyromegaly and enlargement of the salivary glands. Enlargement of other organs is usually not clinically detectable.
Table 5-13. Clinical manifestations of acromegaly in 100 patients.1
Hypertension occurs in about 25% of patients and cardiomegaly in about 15%. Cardiac enlargement may be secondary to hypertension, atherosclerotic disease, or, rarely, to “acromegalic cardiomyopathy.” Renal calculi occur in 11% secondary to the hypercalciuria induced by GH excess.
Other endocrine and metabolic abnormalities are common and may be due either to GH excess or to mechanical effects of the pituitary adenoma. Glucose intolerance and hyperinsulinism occur in 50% and 70%, respectively, owing to GH-induced insulin resistance. Overt clinical diabetes occurs in a minority, and diabetic ketoacidosis is rare. Hypogonadism occurs in 60% of female and 46% of male patients and is of multifactorial origin; tumor growth and compression may impair pituitary gonadotropin secretion, and associated
hyperprolactinemia (see below) or the PRL-like effect of excessive GH secretion may impair gonadotropin and gonadal function. In men, low total plasma testosterone levels may be due to GH suppression of sex hormone-binding globulin (SHBG) levels; in these cases, plasma free testosterone levels may be normal, with normal gonadal function. With earlier diagnosis, hypothyroidism and hypoadrenalism due to destruction of the normal anterior pituitary are unusual and are present in only 13% and 4% of patients, respectively. Galactorrhea occurs in about 15% and is usually caused by hyperprolactinemia from a pituitary adenoma with a mixed cell population of somatotrophs and lactotrophs. Gynecomastia of unknown cause occurs in about 10% of men. Although acromegaly may be a component of multiple endocrine neoplasia (MEN) type 1 syndrome, it is distinctly unusual, and concomitant parathyroid hyperfunction or pancreatic islet cell tumors are rare.
Figure 5-18. Serial photographs of an acromegalic patient at the ages indicated. Note the gradual increase in size of the nose, lips, and skin folds. (Reproduced, with permission, from Reichlin SR: Acromegaly. Med Grand Rounds 1982;1:9.)
Figure 5-19. Markedly increased soft tissue bulk and blunt fingers in a middle-aged man with acromegaly.
When GH hypersecretion is present for many years, late complications occur, including progressive cosmetic deformity and disabling degenerative arthritis. In addition, the mortality rate is increased; after age 45, the death rate in acromegaly from cardiovascular and cerebrovascular atherosclerosis, respiratory diseases, and colon cancer is two to four times that of the normal population. Death rates tend to be higher in patients with hypertension, cardiovascular disease, or clinical diabetes mellitus.
Manifestations of the pituitary adenoma are also common in acromegaly; eg, 65% of patients have headache. Although visual impairment was usually present in older series, it now occurs in only 15–20%, since most patients are now diagnosed because of the manifestations of GH excess.
- LABORATORY FINDINGS
Postprandial plasma glucose may be elevated, and serum insulin is increased in 70%. Elevated serum phosphorus (due to increased renal tubular resorption of phosphate) and hypercalciuria appear to be due to direct effects of GH or IGF-I.
- IMAGING STUDIES
Plain films (Figure 5-20) show sellar enlargement in 90% of cases. Thickening of the calvarium, enlargement of the frontal and maxillary sinuses, and enlargement of the jaw can also be seen. Radiographs of the
hand show increased soft tissue bulk, “arrowhead” tufting of the distal phalanges, increased width of intra-articular cartilages, and cystic changes of the carpal bones. Radiographs of the feet show similar changes, and there is increased thickness of the heel pad (normal, < 22 mm).
Figure 5-20. Radiologic signs in acromegaly: Left: Skull with enlarged sella turcica and frontal sinuses, thickening of the calvarium, and enlargement of the mandible. Center: Hand with enlarged sesamoid bone and increased soft tissue shadows. Right: Thickened heel pad. (Reproduced, with permission, from Levin SR: Manifestations and treatment of acromegaly. Calif Med [March] 1972;116:57.)
Acromegaly is usually clinically obvious and can be readily confirmed by assessment of GH secretion; basal fasting GH levels (normal, 1–5 ng/mL [46–232 pmol/L]) are > 10 ng/mL (465 pmol/L) in over 90% of patients and range from 5 ng/mL (232 pmol/L) to over 500 ng/mL (23,000 pmol/L), with a mean of approximately 50 ng/mL (2300 pmol/L). However, single measurements are not entirely reliable, because GH secretion is episodic in acromegaly and because other conditions may increase GH secretion (see below).
- GLUCOSE SUPPRESSION
Suppression with oral glucose is the simplest and most specific dynamic test for acromegaly. In healthy subjects, oral administration of 100 g of glucose causes a reduction of the GH level to less than 2 ng/mL (93 pmol/L) at 60 minutes. In acromegaly, GH levels may decrease, increase, or show no change; however, they do not decrease to less than 2 ng/mL (93 pmol/L), and this lack of response establishes the diagnosis.
Supersensitive GH assays have been developed and are becoming commercially available. With these assays, normal individuals may suppress GH levels to less than 0.1 ng/mL. Thus, the criteria expressed above may need to be adjusted in the near future.
- IGF-I MEASUREMENT
Measurement of IGF-I (see Chapter 6) is a useful means of establishing the diagnosis of GH hypersecretion. IGF-I results must be interpreted according to the patient's age and sex. IGF-I levels directly reflect GH activity. IGF-I has a long half-life, so that IGF-I levels fluctuate much less than GH levels. IGF-I levels are elevated in virtually all patients with acromegaly (normal ranges vary widely in different laboratories, and some commercial assays are not reliable). Since IGF-I levels decline with age, a level that is in the normal range for a 45-year-old person might be abnormally high in a 65-year-old person (see Appendix).
- TUMOR LOCALIZATION
Radiographic localization of the pituitary adenoma causing acromegaly is usually straightforward (see Neuroradiologic Evaluation, above). In virtually all patients,
tumor location and size can be shown by MRI; 90% have tumors over 1 cm in diameter that are readily visualized. In the rare patient with normal neuroradiologic studies, an extrapituitary ectopic source of GH or GHRH should be considered. If the scans suggest diffuse pituitary enlargement or hyperplasia, ectopic GHRH should also be suspected.
- OTHER CAUSES OF GH HYPERSECRETION
The presence of clinical features of GH excess, elevated GH and IGF-I secretion, and abnormal GH dynamics, together with the demonstration of a pituitary tumor by neuroradiologic studies, are diagnostic of acromegaly. However, other conditions associated with GH hypersecretion must be considered in the differential diagnosis. These include anxiety, exercise, acute illness, chronic renal failure, cirrhosis, starvation, protein-calorie malnutrition, anorexia nervosa, and type I (insulin-dependent) diabetes mellitus. Estrogen therapy may increase GH responsiveness to various stimuli. These conditions may be associated with abnormal GH suppressibility by glucose and by abnormal GH responsiveness to TRH; however, patients with these conditions do not have clinical manifestations of GH excess and are thus readily differentiated from patients with acromegaly. In addition, the conditions listed above do not lead to elevation of IGF-I concentrations.
- ECTOPIC GH OR GHRH SECRETION
These rare patients with acromegaly due to ectopic secretion of GH or GHRH have typical clinical manifestations of acromegaly. This may occur in lung carcinoma, carcinoid tumors, and pancreatic islet cell tumors. These syndromes should be suspected in patients with a known extrapituitary tumor who have GH excess or in those with clinical and biochemical features of acromegaly who have radiologic procedures that show normal pituitary glands or that suggest diffuse pituitary enlargement or hyperplasia.
All patients with acromegaly should undergo therapy to halt progression of the disorder and to prevent late complications and excess mortality. The objectives of therapy are removal or destruction of the pituitary tumor, reversal of GH hypersecretion, and maintenance of normal anterior and posterior pituitary function. These objectives are currently attainable in most patients, especially those with smaller tumors and only moderate GH hypersecretion. In patients with large tumors who have marked GH hypersecretion, several therapies are usually required to achieve normal GH secretion.
The criteria for an adequate response to therapy continue to evolve. Until recently, many authors used a basal GH level of 5 ng/mL (232 pmol/L) or less to define remission. However, some of these patients continue to have elevated IGF-I levels, and recent reports describe increased late mortality in patients with GH levels greater than 2.5 ng/mL (116 pmol/L) after therapy. Current guidelines for remission are a fasting GH of 2 ng/mL (93 pmol/L) or less and a glucose-suppressed GH of 2 ng/mL (93 pmol/L) or less accompanied by a normal level of IGF-I.
The initial therapy of choice is transsphenoidal microsurgery because of its high success rate, rapid reduction of GH levels, the low incidence of postoperative hypopituitarism, and the low surgical morbidity rate. Patients with persisting GH hypersecretion after surgery should currently be treated with a sustained-release form of somatostatin analog (octreotide LAR or lanreotide). Radiation therapy should be reserved for those patients with inadequate responses to surgery and medical therapy.
- SURGICAL TREATMENT
Transsphenoidal selective adenoma removal is the procedure of choice; craniotomy is necessary in the rare patient in whom major suprasellar extension precludes the transsphenoidal approach. Successful reduction of GH levels is achieved in approximately 60–80% of patients. In those with small or moderate-sized tumors (< 2 cm), success is achieved in over 80%, whereas in those with larger tumors and basal GH levels greater than 50 ng/mL (2325 pmol/L)—and particularly in those with major extrasellar extension of the adenoma—successful responses occur in only 30–60%. Recurrence rates in those with a successful initial response are low (about 5% of patients at our institution). Surgical complications (discussed above) occur in less than 2%.
- MEDICAL TREATMENT
Octreotide acetate, a somatostatin analog was the first effective medical therapy for patients with acromegaly; however, the drug required high doses (100–500 ľg) given by subcutaneous injection three times daily. Its use in acromegaly has been superseded by sustained-release somatostatin analogs with activities lasting up to one month. Preparations include octreotide LAR given by injection every four weeks and lanreotide given every two weeks. Octreotide LAR, which is available in the US, normalizes GH and IGF-I levels in 75% of patients; however, tumor reduction occurs in a much smaller percentage. Octreotide LAR has become the therapy of choice for patients with residual GH hypersecretion following surgery. Side effects of this class of agents consist mainly of gastrointestinal symptoms and the development of gallstones. Medical therapy with
bromocriptine or other dopamine agonists is successful in only a few patients.
Conventional supervoltage irradiation in doses of 4500–5000 cGy is successful in 60–80% of patients, though GH levels may not return to normal until years after therapy. Thus, in one series, GH levels were under 10 ng/mL (460 pmol/L) in only 38% of patients at 2 years posttreatment; however, at 5 and 10 years, 73% and 81% had achieved such levels. The incidence of hypopituitarism is appreciable, and in this series hypothyroidism occurred in 19%, hypoadrenalism in 38%, and hypogonadism in approximately 50–60% of patients as a consequence of radiotherapy. Because of the prolonged delay in achieving reduction in GH levels, conventional radiotherapy is generally reserved for patients with persistent GH secretion following pituitary microsurgery and medical therapy. Gamma knife radiosurgery has also been used for tumors confined to the sella. Current series, although limited, suggest remission rates of about 70% at two years following therapy.
Response to Treatment
In patients with successful reduction in GH hypersecretion, there is cessation of bone overgrowth. In addition, these patients experience considerable clinical improvement, including reduction in soft tissue bulk of the extremities, decreased facial puffiness, increased energy, and cessation of hyperhidrosis, heat intolerance, and oily skin. Headache, carpal tunnel syndrome, arthralgias, and photophobia are also reversible with successful therapy. Glucose intolerance and hyperinsulinemia as well as hypercalciuria are also reversed in most cases.
Recent studies have also shown that the excess mortality is reversed if GH levels are normalized.
Posttreatment assessment includes evaluation of GH secretion, anterior pituitary function, and tumor size. Patients undergoing surgery should be seen 4–6 weeks after the operation for assessment of GH secretion and pituitary function. Those with persistent GH hypersecretion (>2 ng/dL [93 pmol/L]) should receive further therapy with somatostatin analogs. Patients with postoperative GH levels under 2 ng/mL (93 pmol/L) should have follow-up GH and IGF-I determinations at 6-month intervals for 2 years and yearly thereafter to rule out recurrences. Late hypopituitarism after surgery alone does not occur.
Patients treated with radiotherapy should have biannual assessment of GH secretion and annual assessment of anterior pituitary function, since the incidence of late hypopituitarism is appreciable and increases with time following irradiation.
- ACTH-Secreting Pituitary Adenomas: Cushing's Disease
In 1932, Harvey Cushing documented the presence of small basophilic pituitary adenomas in six of eight patients with clinical features of adrenocortical hyperfunction. Years later, ACTH hypersecretion was identified from such tumors and found to be the cause of bilateral adrenal hyperplasia. Pituitary ACTH hypersecretion (Cushing's disease) is now recognized as the most common cause of spontaneous hypercortisolism (Cushing's syndrome) and must be distinguished from the other forms of adrenocorticosteroid excess—ectopic ACTH syndrome and adrenal tumors (see Chapter 9).
ACTH-secreting pituitary tumors exist in virtually all patients with Cushing's disease. These tumors are usually benign microadenomas under 10 mm in diameter; 50% are 5 mm or less in diameter, and microadenomas as small as 1 mm have been described. These tumors in Cushing's disease are either basophilic or chromophobe adenomas and may be found anywhere within the anterior pituitary. Rarely, ACTH-secreting tumors are large, with invasive tendencies, and malignant tumors have rarely been reported.
Histologically, the tumors are composed of compact sheets of uniform, well-granulated cells (granule size, 200–700 nm by electron microscopy) with a sinusoidal arrangement and a high content of ACTH and its related peptides (β-LPH, β-endorphin). A zone of perinuclear hyalinization (Crooke's changes) is frequently observed as a result of exposure of the corticotroph cells to prolonged hypercortisolism. A specific ultrastructural finding in these adenomas is the deposition of bundles of perinuclear microfilaments that encircle the nucleus; these are the ultrastructural equivalent of Crooke's hyaline changes seen on light microscopy. In contrast to the adenoma's cells, ACTH content in the portion of the anterior pituitary not involved with the tumor is decreased.
Diffuse hyperplasia of anterior pituitary corticotrophs or adenomatous hyperplasia, presumed to result from hypersecretion of corticotropin-releasing hormone (CRH), occurs rarely.
The adrenal glands in Cushing's disease are enlarged, weighing 12–24 g (normal, 8–10 g). Microscopic examination shows a thickened cortex due to hyperplasia of both the zona reticularis and zona fasciculata; the zona glomerulosa is normal. In some
cases, ACTH-secreting pituitary adenomas cause bilateral nodular hyperplasia; the adrenals show diffuse bilateral cortical hyperplasia and the presence of one or more nodules that vary from microscopic to several centimeters in diameter, with multiple small nodules being the most common.
The weight of current evidence is that Cushing's disease is a primary pituitary disorder and that hypothalamic abnormalities are secondary to hypercortisolism. The endocrine abnormalities in Cushing's disease are as follows: (1) hypersecretion of ACTH, with bilateral adrenocortical hyperplasia and hypercortisolism; (2) absent circadian periodicity of ACTH and cortisol secretion; (3) absent responsiveness of ACTH and cortisol to stress (hypoglycemia or surgery); (4) abnormal negative feedback of ACTH secretion by glucocorticoids; and (5) subnormal responsiveness of GH, TSH, and gonadotropins to stimulation.
Evidence that Cushing's disease is a primary pituitary disorder is based on the high frequency of pituitary adenomas, the response to their removal, and the interpretation of hypothalamic abnormalities as being secondary to hypercortisolism. In addition, molecular studies have found that nearly all corticotroph adenomas are monoclonal. These findings suggest that ACTH hypersecretion arises from a spontaneously developing pituitary adenoma and that the resulting hypercortisolism suppresses the normal hypothalamic-pituitary axis and CRH release and thereby abolishes the hypothalamic regulation of circadian variability and stress responsiveness.
Analysis of the response to therapy by pituitary microsurgery sheds some light on the pathogenesis of Cushing's disease. Selective removal of pituitary microadenomas by transsphenoidal microsurgery corrects ACTH hypersecretion and hypercortisolism in most patients. After selective removal of the pituitary adenoma, the following return to normal: the circadian rhythmicity of ACTH and cortisol, the responsiveness of the hypothalamic-pituitary axis to hypoglycemic stress, and the dexamethasone suppressibility of cortisol secretion.
Cushing's disease presents with the signs and symptoms of hypercortisolism and adrenal androgen excess (see Chapter 9). The onset of these features is usually insidious, developing over months or years. Obesity (with predominantly central fat distribution), hypertension, glucose intolerance, and gonadal dysfunction (amenorrhea or impotence) are common features. Other common manifestations include moon facies, plethora, osteopenia, proximal muscle weakness, easy bruisability, psychologic disturbances, violaceous striae, hirsutism, acne, poor wound healing, and superficial fungal infections. Unlike patients with the classic form of ectopic ACTH syndrome, patients with Cushing's disease rarely have hypokalemia, weight loss, anemia, or hyperpigmentation. Virilization, observed occasionally in patients with adrenal carcinoma, is unusual in Cushing's disease. Clinical symptoms related to the ACTH-secreting primary tumor itself, such as headache or visual impairment, are rare because of the small size of these adenomas.
The usual age range is 20–40 years, but Cushing's disease has been reported in infants and in patients over 70. There is a female:male ratio of approximately 8:1. In contrast, the ectopic ACTH syndrome occurs more commonly in men (male:female ratio of 3:1).
The initial step in the diagnosis of an ACTH-secreting pituitary adenoma is the documentation of endogenous hypercortisolism, which is confirmed by increased urine free cortisol secretion and abnormal cortisol suppressibility to low-dose dexamethasone. The differentiation of an ACTH-secreting pituitary tumor from other causes of hypercortisolism must be based on biochemical studies, including the measurement of basal plasma ACTH levels and central venous sampling, to detect a central to peripheral gradient of ACTH levels (see Chapter 9). The diagnosis and differential diagnosis of Cushing's syndrome are presented in Chapter 9.
Transsphenoidal microsurgery is the procedure of choice in Cushing's disease. A variety of other therapies—operative, radiologic, pharmacologic—are discussed below.
- SURGICAL TREATMENT
Selective transsphenoidal resection of ACTH-secreting pituitary adenomas is the initial treatment of choice. At operation, meticulous exploration of the intrasellar contents by an experienced neurosurgeon is required. The tumor, which is usually found within the anterior lobe tissue, is selectively removed, and normal gland is left intact. If the tumor is too small to locate at surgery, total hypophysectomy may be performed in adult patients who are past the age of reproduction and whose biochemical diagnosis has been confirmed with selective venous ACTH sampling.
In about 85% of patients with microadenomas, selective microsurgery is successful in correcting hypercortisolism.
Surgical damage to anterior pituitary function is rare, but most patients develop transient secondary adrenocortical insufficiency requiring postoperative glucocorticoid support until the hypothalamic- pituitary-adrenal axis recovers, usually in 6–18 months. Total hypophysectomy is necessary to correct hypercortisolism in another 10% of patients. In the remaining 5% of patients with microadenomas, selective tumor removal is unsuccessful. By contrast, transsphenoidal surgery is successful in only 25% of the 10–15% of patients with Cushing's disease with pituitary macroadenomas or in those with extrasellar extension of tumor.
Transient diabetes insipidus occurs in about 10% of patients, but other surgical complications (eg, hemorrhage, cerebrospinal fluid rhinorrhea, infection, visual impairment, permanent diabetes insipidus) are rare. Hypopituitarism occurs only in patients who undergo total hypophysectomy.
Before the introduction of pituitary microsurgery, bilateral total adrenalectomy was the preferred treatment of Cushing's disease and may still be employed in patients in whom other therapies are unsuccessful. Total adrenalectomy, which can now be performed laparoscopically, corrects hypercortisolism but produces permanent hypoadrenalism, requiring lifelong glucocorticoid and mineralocorticoid therapy. The ACTH-secreting pituitary adenoma persists and may progress, causing hyperpigmentation and invasive complications (Nelson's syndrome; see below). Persistent hypercortisolism may occasionally follow total adrenalectomy as ACTH hypersecretion stimulates adrenal remnants or congenital rests.
Conventional radiotherapy of the pituitary is of benefit in patients who have persistent or recurrent disease following pituitary microsurgery. In these patients, reported remission rates are 55–70% at 1–3 years after radiotherapy.
Gamma knife radiosurgery has been reported from one center with remission rates of 75% in adults and 80% in children. However, 55% of the adults developed panhypopituitarism, and each of the children and adolescents were growth hormone-deficient. Therefore, gamma knife radiosurgery may be best suited for postoperative radiotherapy in patients with unsuccessful responses to pituitary microsurgery.
- MEDICAL TREATMENT
Drugs that inhibit adrenal cortisol secretion are useful in Cushing's disease, often as adjunctive therapy (see Chapter 9). No drug currently available successfully suppresses pituitary ACTH secretion.
Ketoconazole, an imidazole derivative, has been found to inhibit adrenal steroid biosynthesis. It inhibits the cytochrome P450 enzymes P450scc and P450c11. In daily doses of 600–1200 mg, ketoconazole has been effective in the management of Cushing's syndrome. Hepatotoxicity is common, however, but may be transient. Metyrapone, which inhibits P450c11, and aminoglutethimide, which inhibits P450scc, have also been utilized to reduce cortisol hypersecretion.
These drugs are expensive; their use is accompanied by increased ACTH levels that may overcome the enzyme inhibition; and they cause gastrointestinal side effects that may limit their effectiveness. More effective control of hypercortisolism with fewer side effects is obtained by combined use of these agents. Adequate data are not available on the long-term use of these drugs as the sole treatment of Cushing's disease. Thus, ketoconazole and aminoglutethimide ordinarily are used while awaiting a response to therapy or in the preparation of patients for surgery.
The adrenolytic drug mitotane results in adrenal atrophy predominantly of the zonae fasciculata and reticularis. Remission of hypercortisolism is achieved in approximately 80% of patients with Cushing's disease, but most relapse after therapy is discontinued. Mitotane therapy is limited by the delayed response, which may take weeks or months, and by the frequent side effects, including severe nausea, vomiting, diarrhea, somnolence, and skin rash.
Pharmacologic inhibition of ACTH secretion in Cushing's disease has also been attempted with cyproheptadine and bromocriptine. However, only a very few patients have had successful responses, and the use of these agents is not recommended.
- Nelson's Syndrome
The clinical appearance of an ACTH-secreting pituitary adenoma following bilateral adrenalectomy as initial therapy for Cushing's disease was first described by Nelson and coworkers in 1958. However, with the evolution of pituitary microsurgery as the initial therapy for Cushing's disease, Nelson's syndrome is now a rare occurrence.
It now seems likely that Nelson's syndrome represents the clinical progression of a preexisting adenoma after the restraint of hypercortisolism on ACTH secretion and tumor growth is removed. Thus, following adrenalectomy, the suppressive effect of cortisol is no longer present, ACTH secretion increases, and the pituitary adenoma may progress.
Prior to the development of transsphenoidal surgery, when bilateral adrenalectomy was the initial therapy for Cushing's disease, the incidence of Nelson's syndrome ranged from 10% to 78% depending on what criteria were used for diagnosis (see Chapter 9). Approximately 30% of patients adrenalectomized for Cushing's disease developed classic Nelson's syndrome with progressive hyperpigmentation and an obvious ACTH-secreting tumor; another 50% developed evidence of a microadenoma without marked progression; and about 20% never developed a progressive tumor. The reasons for these differences in clinical behavior are uncertain. At present, when adrenalectomy is utilized only in those patients who fail pituitary microsurgery, the incidence of Nelson's syndrome is less than 10%. Nevertheless, continued examination, including plasma ACTH levels and MRI, is required following bilateral adrenalectomy in patients with Cushing's disease.
The pituitary tumors in patients with classic Nelson's syndrome are among the most aggressive and rapidly growing of all pituitary tumors. These patients present with hyperpigmentation and with manifestations of an expanding intrasellar mass lesion. Visual field defects, headache, cavernous sinus invasion with extraocular muscle palsies, and even malignant changes with local or distant metastases may occur. Pituitary apoplexy may also complicate the course of these tumors.
Plasma ACTH levels are markedly elevated, usually over 1000 pg/mL (222 pmol/L) and often as high as 10,000 pg/mL (2220 pmol/L). MRI defines the extent of the tumor.
Pituitary surgery by the transsphenoidal approach is the initial mode of treatment. Complete resection is usually not possible, because of the large size of these tumors. Conventional radiotherapy is employed postoperatively in patients with residual tumor or extrasellar extension. Experience with gamma knife radiosurgery is limited.
- Thyrotropin-Secreting Pituitary Adenomas
Thyrotropin-secreting pituitary adenomas are rare tumors manifested as hyperthyroidism with goiter in the presence of elevated TSH. Patients with TSH-secreting tumors are often resistant to routine ablative thyroid therapy, requiring large, often multiple doses of 131I and several operations for control of thyrotoxicosis. Histologically, the tumors are chromophobe adenomas. They are often very large and cause visual impairment, which alerts the physician to a pituitary abnormality. Patients with these tumors do not have extrathyroidal systemic manifestations of Graves' disease such as ophthalmopathy or dermopathy. Pituitary TSH hypersecretion in the absence of a demonstrable pituitary tumor has also been reported to cause hyperthyroidism in a few patients.
The diagnosis is based on findings of hyperthyroidism with elevated serum TSH and alpha subunit, and neuroradiologic studies consistent with pituitary tumor. Differential diagnosis includes those patients with primary hypothyroidism (thyroid failure) who develop major hyperplasia of pituitary thyrotrophs and lactotrophs with sellar enlargement and occasional suprasellar extension.
Treatment should be directed initially at the adenoma via the transsphenoidal microsurgical approach. However, additional therapy is usually required because of the large size of these adenomas.
Somatostatin analogs normalize TSH and T4 levels in more than 70% of these patients when given subcutaneously in doses similar to those used for the treatment of acromegaly (see above). Shrinkage of the tumor has been observed in about 40% of patients.
If tumor growth and TSH hypersecretion cannot be controlled by surgery and somatostatin analogs, the next step would be to undertake pituitary irradiation. In addition, such patients may also require ablative therapy of the thyroid with either 131I or surgery to control their thyrotoxicosis.
- Gonadotropin-Secreting Pituitary Adenomas
Although many pituitary adenomas synthesize gonadotropins (especially FSH) and their subunits, only a minority of these patients have elevated serum levels of FSH or LH. The majority of these tumors produce FSH and the alpha subunit, but tumors secreting both FSH and LH and a tumor secreting only LH have been described.
Gonadotropin-secreting pituitary adenomas are usually large chromophobe adenomas presenting with visual impairment. Most patients have hypogonadism and many have panhypopituitarism. Hormonal evaluation reveals elevated FSH in some patients accompanied by normal LH values. Basal levels of the alpha subunit may also be elevated. The presence of elevation of both FSH and LH should suggest primary hypogonadism. TRH stimulation leads to an increase in FSH
secretion in 33% and an increase in LHβ in 66% of patients.
Therapy for gonadotropin-secreting adenomas has been directed at surgical removal. Because of their large size, adequate control of the tumor has not been achieved, and radiotherapy is usually required.
- Alpha Subunit-Secreting Pituitary Adenomas
Excessive quantities of the alpha subunit of the glycoprotein pituitary hormones have been observed in association with the hypersecretion of many anterior pituitary hormones (TSH, GH, PRL, LH, FSH). Recently, however, pure alpha subunit hypersecretion has been identified in several patients with large invasive chromophobe adenomas and partial panhypopituitarism. Thus, the determination of the alpha subunit may be a useful marker in patients with presumed“nonfunctioning” pituitary adenomas.
- Nonfunctional Pituitary Adenomas
“Nonfunctional” chromophobe adenomas once represented approximately 80% of all primary pituitary tumors; however, with clinical application of radioimmunoassay of anterior pituitary hormones, these tumors currently account for only about 10% of all pituitary adenomas. Thus, the great majority of these chromophobe adenomas have now been documented to be PRL-secreting; a smaller number secrete TSH or the gonadotropins.
Nonfunctional tumors are usually large when the diagnosis is established; headache and visual field defects are the usual presenting symptoms. However, endocrine manifestations are usually present for months to years before the diagnosis is made, with gonadotropin deficiency being the most common initial symptom. Hypothyroidism and hypoadrenalism are also common, but the symptoms are subtle and may be missed.
Evaluation should include MRI and visual field testing; endocrine studies should include assessment of pituitary hormones and end-organ function to determine whether the adenoma is hypersecreting or whether hormonal replacement is needed.
Since these tumors are generally large, both surgery and radiation therapy are usually required to prevent tumor progression or recurrence. In the absence of an endocrine index of tumor hypersecretion such as PRL excess, serial scans at yearly intervals are required to assess the response to therapy and to detect possible recurrence.
ANTIDIURETIC HORMONE(ADH; Vasopressin)
ADH is metabolized rapidly in the liver and kidney and has a half life of 15–20 minutes. It acts through three receptors, termed V1, V2, and V3 (Table 5-14). The V1 receptors mediate vascular smooth muscle contraction and stimulate prostaglandin synthesis and liver glycogenolysis. Activation of these receptors increases phosphatidylinositol breakdown, thus causing cellular calcium mobilization. The V2receptors, which produce the renal actions of vasopressin, activate Gs proteins and
stimulate the generation of cAMP (see Chapter 3). The V3 receptors in the pituitary contribute to ACTH release by potentiating the action of CRH.
Table 5-14. ADH receptors in humans.
The major renal effect of ADH is to increase the water permeability of the luminal membrane of the collecting duct epithelium via the ADH-sensitive water channels, aquaporin-2 (one of a family of aquaporins). In the absence of ADH, permeability of the epithelium is very low and reabsorption of water decreases, leading to polyuria. When ADH is present, epithelial permeability increases markedly, and water is reabsorbed. This ADH effect is caused by ADH binding to the V2 receptor. Acutely, ADH mobilizes aquaporin-2 in a manner analogous to insulin's effect on glucose disposal via mobilization of GLUT 4. Water permeability of the luminal membrane is increased by increasing the number of narrow aqueous channels at the luminal surface (radii of about 0.2 nm). Thus, diffusion of water through the membrane is enhanced, as is transcellular flow.
As the collecting ducts traverse the renal medulla, the urine passes regions of ever-increasing osmolality up to a maximum of 1200 mosm/kg of water at the tip of the papilla. In the presence of ADH, collecting duct fluid equilibrates with this hyperosmotic environment, and urine osmolality approaches that of medullary interstitial fluid. Thus, maximal ADH effect results in low urine flow, and urine osmolality may approximate 1200 mosm/kg; with ADH deficiency, urine flow may be as high as 15–20 mL/min, and urine osmolality is less than 100 mosm/kg. The ability to vary urine osmolality over a tenfold range allows maintenance of homeostasis over a wide range of water intake. ADH also stimulates urea absorption in the inner medullary collecting ducts via urea transporters 1.
Cardiovascular & Other Actions
ADH effects on V1 receptors in peripheral arterioles increase blood pressure. However, these effects are usually blunted by efferent mechanisms such as bradycardia and inhibition of sympathetic nerve activity that result from baroreceptor activation. ADH pressor effects may be important during hypovolemia when plasma ADH levels are very high and maintenance of tissue perfusion is critical. ADH, through V2 receptors, stimulates release of clotting factor VIII and von Willebrand factor from vascular endothelium. The physiologic significance of these actions in unknown. However, pharmacotherapy with ADH analogs has been useful in treatment of some disorders associated with bleeding diatheses. ADH is also involved in the regulation of the CRH ACTH-cortisol axis (see above).
Oxytocin primarily affects uterine smooth muscle. It increases both the frequency and the duration of action potentials during uterine contractions. Thus, administration of oxytocin initiates contractions in a quiescent uterus and increases the strength and frequency of muscle contractions in an active uterus. Estrogen enhances the action of oxytocin by reducing the membrane potential of smooth muscle cells, thus lowering the threshold of excitation. Toward the end of pregnancy, as estrogen levels become higher, the membrane potential of uterine smooth muscle cells becomes less negative, rendering the uterus more sensitive to oxytocin. The number of oxytocin receptors in the uterus also increases at this time, and their activation causes cellular calcium to be mobilized through polyphosphatidylinositol hydrolysis.
Actions Affecting the Female Reproductive System
As the fetus enters the birth canal, the lower segment of the uterus, the cervix, and then the vagina are dilated, and this causes reflex release of oxytocin. Strong uterine contractions cause further descent of the fetus, further distention, and further release of oxytocin.
Oxytocin is also involved in lactation. Stimulation of the nipple produces a neurohumoral reflex that causes secretion of oxytocin. In turn, oxytocin causes contraction of the myoepithelial cells of the mammary ducts and the ejection of milk.
A number of stimuli that also release ADH such as increased plasma osmolality and hypovolemia cause oxytocin secretion. Since oxytocin is an effective natriuretic agent—particularly at low rates of urine flow—it may be involved in the regulation of sodium balance.
CONTROL OF WATER BALANCE
Water balance is precisely controlled by an integrated system that balances water intake via thirst mechanism with water output controlled by ADH. The average individual loses 2.5–3 L of water per day (Table 5-15) and must take in that amount in order to maintain balance. Given free access to water, total human body water rarely varies by more than 1–2%. Approximately
1.2 L of water is taken in food or is provided by oxidative metabolism. The remainder is ingested as water or other fluids.
Table 5-15. Routes of loss of water in an average adult human.
Concentration of Urine
Renal concentrating mechanisms are essential to the maintenance of water balance in order for the kidney to excrete osmotically active solutes derived from the diet.
The average human excretes 1.5 L of urine per day at an osmolality of approximately 600 mosm/kg of water, ie, twice the concentration of plasma. Without the capacity to concentrate urine, 3 L of water at a concentration of 300 mosm/kg would be excreted and the extra water would have to be ingested. During negative water balance, the urine volume may be reduced to 600 mL/d at a maximum urinary concentration of 1200 mosm/kg. This fourfold capacity (versus plasma) to concentrate the urine is of extreme importance in protection against dehydration and hypovolemia.
Urinary concentration mechanisms can reduce but not completely prevent loss of water in the urine. Even if an individual is maximally concentrating urine, obligatory fluid loss is still considerable. This situation is exacerbated in a warm environment, where many liters of fluid may be lost to maintain a constant temperature via sweating. The only way to bring body fluid levels back to normal is by increasing water intake. It is not surprising that many similarities exist between mechanisms involved in the control of thirst and ADH secretion.
Control of Thirst & ADH Secretion
Cellular and extracellular dehydration are the two major mechanisms involved in the control of thirst and ADH secretion.
- CELLULAR DEHYDRATION
Cellular dehydration occurs when extracellular fluid osmolality is increased relative to that of intracellular fluids, leading to the efflux of water from cells. When extracellular fluid osmolality increases, all cells, including the hypothalamic osmoreceptors, become dehydrated, thus providing the signal for secretion of ADH. Hypothalamic osmoreceptor cells that sense the effective plasma-intracellular osmotic gradient contain a unique aquaporin H2O channel. In the presence of plasma hyperosmolality (usually related to increased serum Na+), these channels open and allow water migration out of the cell, resulting in a reduction in osmoreceptor cell volume. Stretch-inactivated cation channels become activated, and this in turn leads to depolarization of the cell and subsequently stimulation of ADH secretion and synthesis. In humans, an increase of only 1% in plasma osmolality stimulates thirst, water intake, and simultaneously ADH (Figures 5-21and 5-22).
The relationship between plasma ADH concentration and plasma osmolality in humans is presented in Figure 5-22. The exquisite sensitivity of ADH release to changing plasma osmolality is obvious.
- EXTRACELLULAR FLUID DEHYDRATION
Extracellular fluid dehydration—ie, decreased extracellular fluid volume without a change in osmolality—stimulates thirst and ADH secretion. Thus, hemorrhage reduces extracellular fluid volume and results in both thirst and ADH secretion (Figure 5-23). Small
decreases in volume have minimal effects on ADH secretion, but reductions larger than 10% cause a marked stimulation of ADH to values > 100 pg/mL (92.5 pmol/L). These high circulating levels of ADH do not further increase water conservation, since maximum urinary concentration is reached at much lower levels. However, the high levels of ADH may support blood pressure via V1 receptors.
Figure 5-21. Relationship between water intake and jugular vein plasma osmolality. Central osmolality was increased selectively by infusing hypertonic sodium chloride into carotid loops in trained conscious dogs (•). Infusion of hypertonic sucrose was equally effective (□), whereas hypertonic urea (Δ) did not stimulate drinking. (Data from Wood RJ, Rolls BJ, Ramsay DJ: Am J Physiol 1977;323:88.)
Figure 5-22. Relationship between plasma vasopressin concentration and plasma osmolality in humans during dehydration. (Reproduced, with permission, from Hammer M, Ladefoged J, Olgaard K: Am J Physiol 1980;238:313.)
- INTERACTION OF OSMOLALITY AND VOLUME
Two major mechanisms are involved in hypovolemic stimulation of thirst and ADH secretion. Moderate reductions in blood volume stimulate low-pressure receptors in the left and right atria and in the pulmonary circulation. With more severe hypovolemia, which reduces blood pressure, the arterial baroreceptors are activated. Responses from these baroreceptor areas in the circulation are then transmitted to magnocellular cells in the hypothalamus. In addition, the renin-angiotensin system may be involved, since hypovolemia stimulates renin secretion and angiotensin formation. Angiotensin II also stimulates thirst and ADH secretion. The relative roles of the direct baroreceptor input and angiotensin mechanisms in the responses to extracellular dehydration have yet to be determined.
Figure 5-23. Relationship of plasma vasopressin to isosmotic reductions in blood volume in rats. (Reproduced, with permission, from Dunn FL et al: J Clin Invest 1973;52:3212.)
Thus, regulation of water balance involves interaction between osmotic and volume stimuli. In the case of ADH secretion, the fall in extracellular fluid volume sensitizes the release of ADH to a given osmotic stimulus. Thus, for a given increase in plasma osmolality, the increase in plasma ADH will be greater in hypovolemic than in normovolemic states.
In dehydration, increased plasma osmolality results in withdrawal of fluid from cells. Thus, the reduction in total body water is shared equally between intracellular and extracellular fluid compartments. The increase in plasma osmolality and the reduction of extracellular fluid volume act synergistically to stimulate ADH release. In salt depletion, however, plasma ADH concentrations remain constant or even slightly elevated in spite of a fall in plasma osmolality. Hypovolemia in this situation appears to dominate ADH secretory control.
Thirst mechanisms also involve interactions between extracellular fluid volume and osmolality. During periods of dehydration, increased plasma osmolality provides approximately 70% of the increased thirst drive, and the remaining 30% is due to hypovolemia. In salt depletion, the situation is less clear, but the normal or
increased drinking that has been observed in experimental animals has been attributed to the associated hypovolemia.
Other factors that affect circulating ADH levels include nausea, pain, and surgery, all of which stimulate ADH secretion. Pregnancy is associated with a reduction in the osmoregulatory threshold for ADH release.
Diabetes insipidus is a disorder resulting from deficient ADH action and is characterized by the passage of copious amounts of very dilute urine. This disorder must be distinguished from other polyuric states such as primary polydipsia (see below) and osmotic diuresis. Central (or neurogenic) diabetes insipidus is due to failure of the posterior pituitary to secrete adequate quantities of ADH; nephrogenic diabetes insipidus results when the kidney fails to respond to circulating ADH. The resulting renal concentrating defect leads to the loss of large volumes of dilute urine, ie, free water. This causes cellular and extracellular dehydration, which stimulate thirst and cause polydipsia.
- CENTRAL DIABETES INSIPIDUS
The major causes of central diabetes insipidus are shown in Table 5-16.
Many of the disorders discussed above in the section on pituitary and hypothalamic disorders which cause hypopituitarism may also cause diabetes insipidus. Primary pituitary adenomas—even those which are large—rarely cause diabetes insipidus, but hypothalamic tumors such as craniopharyngiomas or other primary central nervous system lesions and infiltrative and invasive lesions cause diabetes insipidus more frequently. These lesions cause diabetes insipidus by damage to the pituitary stalk, which interrupts the hypothalamic-neurohypophysial nerve tracts, or by direct damage to the hypothalamic neurons that synthesize ADH. These disorders cause varying degrees of ADH deficiency.
Table 5-16. Causes of central diabetes insipidus.
Diabetes insipidus can also be caused by trauma and is common following surgery for hypothalamic or pituitary tumors. Central diabetes insipidus resulting from head trauma frequently follows a triphasic course. The initial phase is followed by a phase of antidiuresis (as ADH is released from damaged axons) and then by persistent diabetes insipidus. How complete the diabetes insipidus is depends upon the extent of the damage. Resection of hypothalamic tumors via craniotomy frequently results in permanent diabetes insipidus, which may be complicated by disorders of thirst. Transsphenoidal pituitary microsurgery causes transient postoperative diabetes insipidus in as many as 20% of patients; however, the diabetes insipidus lasts only a few days and rarely longer than 2–3 weeks.
Familial central diabetes insipidus, which is inherited in both recessive or dominant patterns, is rare and has its onset in infancy. The number of ADH-containing fibers in the supraoptic and paraventricular nuclei, nerve tracts, and posterior pituitary is reduced. Idiopathic diabetes insipidus presents in later childhood or adolescence and in adulthood. It is also associated with a decrease in the number of ADH-containing fibers. As many as 30–40% of these patients have antibodies directed against ADH-secreting hypothalamic neurons. The “posterior pituitary bright spot,” which is normally visualized by MRI, is absent in patients with familial or idiopathic diabetes insipidus. An autosomal dominant form of central diabetes insipidus occurs in association with diabetes mellitus, optic atrophy, and deafness (DIDMOAD; Wolfram's syndrome). Diabetes insipidus due to enzymatic destruction of circulating ADH by increased plasma levels of vasopressinase may occur during pregnancy.
- NEPHROGENIC DIABETES INSIPIDUS
This group of diseases (Table 5-17) is caused by renal unresponsiveness to the physiologic actions of ADH; thus, ADH levels are normal or elevated. Chronic renal diseases, particularly those affecting the medulla and collecting ducts, can cause nephrogenic diabetes insipidus. Thus, if medullary disease (eg, from pyelonephritis, polycystic disease or medullary cystic disease) prevents formation of a medullary concentration gradient, and urine passing through the collecting duct system cannot become concentrated.
The electrolyte disorders hypokalemia and hypercalcemia reduce urinary concentrating capacity. Many drugs have been implicated in the development of nephrogenic diabetes insipidus. For example, lithium carbonate reduces the sensitivity of the renal tubule to ADH by reducing V2 receptor density or aquaporin-2
expression. The ability of demeclocycline to cause nephrogenic diabetes insipidus has been used to advantage in the management of states of ADH excess (see below). Hereditary nephrogenic diabetes insipidus is a rare condition caused by a defect in the response of the renal tubule to ADH, one type is associated with defects in the V2 receptor gene, which leads to impairment of medullary adenylyl cyclase activity. It is most common in males with a family history of transmission through apparently healthy females, suggesting X-linked inheritance. However, several cases have recently been reported in females. Another form of nephrogenic diabetes insipidus involves a postreceptor defect with abnormalities of the aquaporin-2 gene.
Table 5-17. Causes of nephrogenic diabetes insipidus.
Primary polydipsia (psychogenic polydipsia, compulsive water drinking) is a disorder of thirst that is either due to psychogenic causes or to altered osmotic and nonosmotic regulation of thirst. It involves greatly increased drinking, usually in excess of 5 L of water per day, leading to dilution of the extracellular fluid, inhibition of vasopressin secretion, and water diuresis.
It is important to distinguish both types of diabetes insipidus and primary polydipsia from other common causes of polyuria. In general, other forms of polyuria involve osmotic or solute diuresis. For example, in diabetes mellitus, increased excretion of glucose and other solutes requires excretion of increased volumes of water. In osmotic diuresis, the osmolality of the urine tends toward that of plasma. In sharp contrast, the osmolality of the urine in diabetes insipidus and psychogenic polydipsia is very low when compared with that of plasma. Thus, a urine specific gravity less than 1.005 (osmolality < 200 mosm/kg of water) will generally rule out polyuria due to osmotic diuresis. After a careful history has been taken, focusing on patterns of drinking and urination behavior and the family history, a series of investigations should be instituted to distinguish between the two types of diabetes insipidus and primary polydipsia. For unknown reasons patients with idiopathic central diabetes insipidus have a predilection for cold beverages. The physiologic principles are set forth in Table 5-18, and the actual procedures are summarized in Table 5-19.
- PLASMA AND URINE OSMOLALITY
The first test involves simultaneous estimation of osmolality and sodium in plasma and urine. Since in both forms of diabetes insipidus the primary problem is inappropriate water diuresis, the urine will be less concentrated than plasma, whereas the plasma osmolality may be higher than normal depending upon the state of hydration. In primary polydipsia, however, dilute plasma and hyponatremia are usually associated with the production of dilute urine. The poor sensitivity of these randomly drawn levels necessitates dynamic testing.
Occasionally, even the tests outlined below do not produce a definitive diagnosis, so that a therapeutic trial of desmopressin may be warranted.
Table 5-18. Results of diagnostic studies in various types of polyuria.
Table 5-19. Differential diagnosis of polyuria.
- WATER DEPRIVATION
The next step is to examine the effect of water deprivation on urine osmolality under supervision. Supervision is necessary both because the patient with primary polydipsia will go to great lengths to obtain water and because the patient with complete diabetes insipidus may become dangerously dehydrated very rapidly. The patient should be weighed and denied access to water and each voided urine sample measured for specific gravity or osmolality (or both). Whereas the healthy individual will soon reduce urine flow to 0.5 mL/min at a concentration greater than that of plasma, the patient with complete diabetes insipidus will maintain a high urine flow at a specific gravity less than 1.005 (200 mosm/kg of water). The test is continued until urinary osmolality plateaus (an hourly increase of < 30 mosm/kg for 3 successive hours). A period of 18 hours is usually ample to confirm the diagnosis. The test should be terminated if the body weight falls by more than 3%, since serious consequences of dehydration may ensue. Patients with primary polydipsia will always increase urine osmolality to values greater than those of plasma. However, it may be difficult to distinguish these patients from patients with partial central diabetes insipidus.
- VASOPRESSIN TEST
Once the diagnosis of diabetes insipidus is established, the ADH-insensitive (nephrogenic) disease must be distinguished from the ADH-sensitive (central) form. This is done following water deprivation by injection of aqueous vasopressin or desmopressin acetate. Give 5 units of aqueous vasopressin subcutaneously or 1 ľg of desmopressin acetate intravenously, intramuscularly, or subcutaneously, and measure urine osmolality after 1 hour; patients with complete central diabetes insipidus will show an increase of > 50% in urine osmolality, while patients with nephrogenic diabetes insipidus do not respond. Patients with partial central diabetes insipidus show increases of 10–50% after vasopressin administration, whereas patients with primary polydipsia have responses of < 9%. In these cases, measurement of ADH levels is particularly helpful.
- ADH RADIOIMMUNOASSAYS
Sensitive radioimmunoassays for ADH are available. Random plasma samples are of little value; levels should be measured as part of dynamic testing, either during water deprivation test or with infusions of hyperosmotic saline. Plasma levels should be interpreted based upon nomograms of their relationship to plasma osmolality. Patients with nephrogenic diabetes insipidus have normal or increased levels of vasopressin following water deprivation, allowing a clear distinction to be made from central forms of diabetes insipidus (Figure 5-24). Patients with partial central diabetes insipidus show a smaller than normal increase in plasma vasopressin concentration following dehydration or infusion of hypertonic saline.
- CENTRAL DIABETES INSIPIDUS
Desmopressin acetate, a synthetic analog of vasopressin prepared in aqueous solution containing 100 ľg/mL, is administered intranasally as a metered-dose nasal spray that delivers 10 ľg (0.1 mL) per spray or via a calibrated plastic catheter in doses of 5–20 ľg (0.05–0.2 mL). The frequency of administration varies; patients with mild to moderate diabetes insipidus require one or two doses of 10 ľg per 24 hours; Patients with severe diabetes insipidus may require 10–20 ľg two or three
times daily. This agent provides excellent control of polyuria and polydipsia in patients with central diabetes insipidus. Serum osmolality and sodium must be monitored at regular intervals (initially every 1–2 weeks, later every 3 months) to be certain that the dose is appropriate. For patients who cannot tolerate intranasal therapy, desmopressin acetate can be given subcutaneously in single doses of 1–2 ľg once or twice daily.
Figure 5-24. Effect of dehydration on plasma vasopressin concentration in normal subjects and patients with polyuria. Note that patients with neurogenic (pituitary) diabetes insipidus cannot increase plasma vasopressin concentration with dehydration, in contrast to patients with psychogenic polydipsia and nephrogenic diabetes insipidus. (Reproduced, with permission, from Robertson GL et al: J Clin Invest 1973;52:2346.)
More recently, desmopressin acetate has become available in an oral form as tablets containing 0.1 or 0.2 mg. The usual dose ranges from 0.1 mg twice daily to 0.2 mg three times daily. However, many patients do not find this preparation as effective as the nasal spray.
- NEPHROGENIC DIABETES INSIPIDUS
The underlying disorder should be treated if possible. It is important to recognize familial disease early, since infants are particularly susceptible to neurologic damage due to dehydration. Diuretics are helpful, along with dietary salt restriction if necessary. Prostaglandin synthesis inhibitors may also be useful. The objective is to maintain the patient in a state of mild sodium depletion and reduce the solute load on the kidney, thus enhancing proximal tubular reabsorption. Reduction in distal tubular flow allows some sodium concentration to take place and minimizes loss of water. Patients with partial sensitivity to vasopressin may be treated with large doses of desmopressin acetate (up to 40 ľg/4 h intranasally).
SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE (SIADH)
A variety of disorders are associated with plasma ADH concentrations that are inappropriately high for the plasma osmolality. Thus, water retention accompanies normal water intake, leading to hyponatremia and hypo-osmolality. The urine is usually more concentrated than plasma but in any case is inappropriately concentrated. Overall sodium balance is essentially normal. It is important to rule out renal and endocrine disorders and drug effects that diminish the kidney's capacity to dilute the urine. The syndrome is termed the syndrome of inappropriate secretion of antidiuretic hormone, or SIADH. The clinical picture can be produced experimentally by giving high doses of vasopressin to a healthy subject receiving normal to high fluid intake. Water restriction in patients suspected of having SIADH will result in plasma osmolality and sodium concentration returning to normal.
The diagnostic criteria for SIADH include (1) hyponatremia with corresponding plasma hypo-osmolality (< 280 mosm/kg); (2) urine less than maximally dilute, ie, inappropriately concentrated (> 100 mosm/kg); (3) euvolemia (including absence of congestive heart failure, cirrhosis, and nephrotic syndrome); and (4) absence of renal, adrenal or thyroid insufficiency. Urinary sodium is usually > 20 mmol/d, probably a consequence of increased atrial natriuretic factor. Dynamic testing and plasma ADH levels are usually unnecessary in diagnosis.
Causes of SIADH
The causes of SIADH are outlined in Table 5-20. A number of malignant neoplasms are associated with ectopic production of vasopressin, leading to high plasma vasopressin levels. Bronchogenic carcinomas are particularly apt to be associated with SIADH. Tumors at other sites such as the pancreas and duodenum have also been shown to produce vasopressin. A number of nonmalignant pulmonary diseases such as tuberculosis and pneumonias are associated with high plasma vasopressin concentrations. Tuberculous lung tissue has
been shown to contain assayable levels of vasopressin. However, it is not known whether all types of lung disease causing SIADH do so by producing ectopic vasopressin or by stimulation of pituitary vasopressin.
Table 5-20. Conditions associated with SIADH.
Many central nervous system disorders are associated with increased vasopressin secretion, leading to the clinical picture of SIADH. Temporary causes of SIADH include surgical trauma, anesthesia, pain, opiates and anxiety. A number of drugs implicated in vasopressin release are listed in Table 5-20. Endocrine disorders such as adrenal insufficiency, myxedema, and anterior pituitary insufficiency may be associated with increased ADH levels and impaired renal excretion of free water. All of these factors—particularly with fluid loading—can lead to hyponatremia and hypo-osmolality. In fact, the majority of hospitalized patients with euvolemic hyponatremia have inappropriately increased ADH levels. The hyponatremia observed in patients with psychosis may reflect a combination of several factors, including inappropriate ADH release and compulsive water drinking.
Types of Osmoregulatory Defects
Serial measurements of serum ADH in patients with SIADH delineate four patterns of osmoregulatory defects in this syndrome. Type A, found in 20% of patients, is characterized by large irregular changes in plasma ADH completely unrelated to serum osmolality. This erratic and irregular secretion of ADH can be associated with both malignant and nonmalignant disease. Type B is found in about 35% of patients and is associated with secretion of ADH that is excessive but proportionate to osmolality. In these patients, the osmotic control of ADH secretion appears to be either set at a low level or abnormally sensitive to changes in serum osmolality. Type C, found in 35% of patients, is characterized by a high basal level of ADH that rises even higher with a rise in serum osmolality. Type D, found in only 10% of patients, represents a different type of problem. ADH is normally suppressed in hypovolemic states and rises normally with increase in osmolality. Thus, the SIADH in these patients may be associated with a change in renal sensitivity to serum arginine vasopressin.
The treatment of SIADH depends upon the underlying cause. A patient with drug-induced SIADH is treated by withholding the drug. The treatment of SIADH in a patient with bronchogenic carcinoma is more complicated, however, and the prognosis is poor. Treatment aims to return plasma osmolality to normal without causing further expansion of the extracellular fluid compartment, as would occur following infusion of hyperosmotic solutions.
- FLUID RESTRICTION
The simplest form of treatment is fluid restriction, although in the long term the excessive thirst associated with this treatment may be difficult to manage.
If plasma osmolality is low and rapid correction is required, loop diuretics such as furosemide can be employed. These agents limit free water generation in the loop of Henle and reduce the concentration gradient in the renal medulla, thereby decreasing the effectiveness of vasopressin. Because diuresis is accompanied by significant urinary losses of potassium, calcium, and magnesium, these electrolytes should be replaced by intravenous infusion.
- OTHER METHODS
In an emergency situation with severe hyponatremia, hypertonic saline, ie, 3% saline, administered intravenously at a rate of 0.1 mL/kg/min, will increase plasma sodium and osmolarity. However, this must be done with caution, since fluid overload may precipitate heart failure or circulatory collapse, and overly rapid correction may lead to central pontine myelinolysis. Drugs (mentioned earlier in this chapter) that reduce the effect of vasopressin on the kidney may be useful. Demeclocycline, 1–2 g/d orally, causes a reversible form of nephrogenic diabetes insipidus, countering the effect of SIADH. However, it is nephrotoxic, and renal function (blood urea nitrogen and serum creatinine) must be monitored carefully. Lithium carbonate has a
similar effect, but therapeutic doses are so close to the toxic dose that this drug is rarely useful.
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