Chapter 4. Hypothalamus and Pituitary Gland

• ACTH Adrenocorticotropic hormone
• ADH Antidiuretic hormone (vasopressin)
• CLIP Corticotropin-like intermediate lobe peptide
• CRH Corticotropin-releasing hormone
• CRHBP Corticotropin-releasing hormone-binding protein
• FGF8 Fibroblast growth factor 8
• FGFR1 Fibroblast growth factor receptor 1
• FSH Follicle-stimulating hormone
• GABA Gamma-aminobutyric acid
• GH Growth hormone (somatotropin)
• GHBP Growth hormone–binding protein
• GHRH Growth hormone–releasing hormone
• GHS-R Growth hormone secretagogue receptor
• GnRH Gonadotropin-releasing hormone
• hCG Human chorionic gonadotropin
• hMG Human menopausal gonadotropin
• hPL Human placental lactogen
• ICMA Immunochemiluminescent assay
• IGF Insulin-like growth factor
• IRMA Immunoradiometric assay
• KAL1 Kallmann syndrome 1
• LH Luteinizing hormone
• β-LPH β-Lipotropin
• Met-Enk Methionine-enkephalin
• MEN Multiple endocrine neoplasia
• MSH Melanocyte-stimulating hormone
• Pit-1 Pituitary-specific positive transcription factor 1
• POMC Pro-opiomelanocortin
• PROK2 Prokineticin 2
• PROKR2 Prokineticin receptor 2
• Prop-1 Prophet of Pit-1
• PRL Prolactin
• PTTG Pituitary tumor transforming gene
• SHBG Sex hormone–binding globulin
• SIADH Syndrome of inappropriate secretion of antidiuretic hormone
• TRH Thyrotropin-releasing hormone
• TSH Thyroid-stimulating hormone (thyrotropin)
• VIP Vasoactive intestinal peptide

The hypothalamus and pituitary gland form a unit that exerts control over the function of several endocrine glands—thyroid, adrenals, and gonads—as well as a wide range of physiologic activities. This unit is highly conserved across vertebrate species and 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. 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 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 cells as a classic hormone. Examples of such multifunctional chemical messengers are shown in Table 4–1. 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 4–1). 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 9, 10, 11). 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.

Anatomy and Embryology

The anatomic relationships between the pituitary and the main nuclei of the hypothalamus are shown in Figure 4–2. 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 hypothalamic-neurohypophysial nerve tract contains approximately 100,000 nerve fibers. Repeated swellings along the nerve fibers ranging in thickness from 1 to 50 μ m constitute the nerve terminals.

The human fetal anterior pituitary anlage is initially recognizable at 4 to 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 pouch, an ectodermal evagination of the oropharynx, and migrates to join the neurohypophysis. The portion of Rathke 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 (POMC) and adrenocorticotropic hormone (ACTH). Remnants of Rathke 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 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 to 10 mm above the diaphragma sellae and anterior to the stalk (Figure 4–3).

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 to 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.

Blood Supply

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 (see Figures 4–2 and 4–3).

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 4–4). 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 4–5). 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 and Histology

Anterior pituitary cells were originally classified as acidophils, basophils, and chromophobe cells based on staining with hematoxylin and eosin. Immunocytochemical and electron microscopic techniques now permit 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 ACTH [corticotropin] 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 are controlled by a limited set of transcription factors, most notably Prop1 and Pit1 (Figure 4–6). 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.

Somatotrophs

The GH-secreting cells are acidophilic and usually located in the lateral portions of the anterior lobe. Granule size by electron microscopy is 150 to 600 nm in diameter. These cells account for about 50% of the adenohypophysial cells.

Lactotrophs

The PRL-secreting cell is a second but distinct acidophil-staining cell randomly distributed in the anterior pituitary. These cells account for 10% to 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.

Thyrotrophs

These TSH-secreting cells, because of their glycoprotein product, are basophilic and also show a positive reaction with periodic acid-Schiff 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), and 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.

Corticotrophs

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% to 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 hyaline degeneration.

Gonadotrophs

LH and FSH originate from basophil-staining cells, whose secretory granules are about 200 nm in diameter. These cells constitute 10% to 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 syndrome, and Turner 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, and others (eg, glia-like or folliculostellate cells) may 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 4–2.

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 in Table 4–3. The structures of the eight major hypothalamic hormones are shown in Table 4–4.

Hypophysiotropic Hormones

The hypophysiotropic hormones that regulate the secretion of anterior pituitary hormones include growth hormone–releasing hormone (GHRH), somatostatin, dopamine, thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), and gonadotropin-releasing hormone (GnRH). The location of the cell bodies of the hypophysiotropic hormone–secreting neurons is depicted in Figure 4–7. Most of the anterior pituitary hormones are controlled by stimulatory hormones, but GH and especially PRL 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

GHRH stimulates GH secretion by, and is trophic for, somatotrophs. GHRH-secreting neurons are located in the arcuate nuclei (see Figure 4–2), 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 GH excess (acromegaly) associated with somatotroph hyperplasia (see discussion later in the chapter). 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 to 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 (VIP), and others. The half-life of GHRH is approximately 3 to 7 minutes.

Somatostatin

Somatostatin inhibits the secretion of GH and TSH. Somatostatin-secreting cells are located in the periventricular region immediately above the optic chiasm (see Figure 4–2) 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, whereas 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 anti-somatostatin antibodies results in a rise in circulating TSH level. Somatostatin has a half-life of 2 to 3 minutes.

Dopamine

Dopamine, the primary PRL-inhibitory hormone, is found in the portal circulation and binds to dopamine receptors on lactotrophs. It has a short half-life, on the order of 1 to 2 minutes. 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 (see Figure 4–2). 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 TRH (see discussion later), 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, VIP, 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.

Thyrotropin-Releasing Hormone

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 (see Figure 4–2), and their axons terminate in the medial portion of the external layer of the median eminence. The half-life of TRH is approximately 6 minutes.

Corticotropin-Releasing Hormone

CRH, a 41-amino-acid peptide, stimulates the secretion of ACTH and other products of its precursor molecule, POMC. CRH is synthesized from a precursor of 196 amino acids. The half-life of CRH follows a biphasic pattern in plasma lasting approximately 6 to 10 minutes and 40 to 50 minutes. Both antidiuretic hormone (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 and plasma half-life of CRH. Since the 1990s, three proteins homologous to CRH, termed urocortins, and two different receptors, have been identified. In addition to the role of CRH in the physiologic response to stress, this family of peptides appears to play a significant role in energy balance.

Gonadotropin-Releasing Hormone

The secretion of LH and FSH is controlled by a single stimulatory hypothalamic hormone, GnRH. This is achieved through differences in the size and frequency of GnRH release as well as feedback from estrogens and androgens; low-frequency pulses favor FSH release while high-frequency pulses result in LH release. 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 disease (see discussion later). The precursor of GnRH—proGnRH—contains 92 amino acids. ProGnRH also contains the sequence of a 56-amino-acid polypeptide called GnRH-associated peptide. This secretory product exhibits PRL-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 terminals are found in the lateral portions of the external layer of the median eminence adjacent to the pituitary stalk (see Figure 4–2). GnRH has a half-life of 2 to 4 minutes.

Neuroendocrinology: The Hypothalamus as Part of a Larger System

The hypothalamus is involved in many nonendocrine functions such as regulation of body temperature, thirst, 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 1, 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 later). 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 VIP and peptides derived from POMC.

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, GABA, 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 toward 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 Hypothalamus and the Control of Appetite

With the growing appreciation of adipose tissue as an endocrine organ, as well as the increasing problem of obesity and its associated health risks, understanding how energy balance and appetite are regulated has become a major topic of study. In 1901, Frohlich observed that some tumors affecting the pituitary and hypothalamus were associated with excess subcutaneous fat and hypogonadism. Subsequent lesioning experiments by Hetherington and Ranson in the 1940s established the hypothalamus as a fundamental site in the regulation of appetite. These experiments introduced the classic dual center model of food intake where the ventromedial hypothalamic nucleus functions as a satiety center and the lateral hypothalamic area serves as a feeding center. Subsequent studies have led to refinements of this model.

Growing evidence points to the pivotal role of the arcuate nucleus in the integration of feeding signals and energy reserves. It has special access to circulating hormones via the underlying median eminence, an area rich with fenestrated capillaries, that is, it is not protected by the blood–brain barrier (see Figure 4–2). Two populations of neurons involved in the regulation of feeding are located within the arcuate nucleus: one that inhibits food intake via the expression of neuropeptides POMC and cocaine- and amphetamine-regulated transcript, and one that stimulates food intake via expression of neuropeptide Y and agouti-related peptide. The arcuate nucleus projects to second-order neuronal populations including the paraventricular nucleus, dorsomedial nucleus, ventromedial nucleus, and lateral hypothalamic area, which then activate downstream pathways controlling appetite and energy expenditure.

Circulating markers of adiposity (leptin, adiponectin, insulin), and hormones from the gastrointestinal tract (ghrelin, peptide YY, glucagon-like peptide 1, cholecystokinin, oxyntomodulin, pancreatic polypeptide) converge on the hypothalamus and brain stem to signal adequacy of short- and long-term energy stores. Alterations in the levels or tissue sensitivity of these hormones may underlie disorders of weight regulation such as obesity, and could prove useful as therapeutic targets (see also Chapter 20).

The Pineal Gland and the Circumventricular Organs

The circumventricular organs are secretory midline brain structures that arise from the ependymal cell lining of the ventricular system (Figure 4–8). 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 (see Figure 4–8). 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.

The pineal gland, considered by the 17th century French philosopher René 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 4–9). 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 appear to involve regulation of gonadal function and development and chronobiologic rhythms.

The pineal gland may be the site of origin of pineal cell tumors (pinealomas) or germ cell tumors (germinomas). Neurologic signs and symptoms are the predominant clinical manifestations; examples include increased intracranial pressure, visual abnormalities, ataxia, and Parinaud 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 (discussed later).

The six major anterior pituitary hormones—ACTH, GH, PRL, TSH, LH, and FSH—may be classified into three groups: ACTH-related peptides (ACTH itself, lipotropin [LPH], melanocyte-stimulating hormone [MSH], and endorphins); the somatomammotropin proteins (GH and PRL); and the glycoproteins (LH, FSH, and TSH). The chemical features of these hormones are set forth in Table 4–2.

Adrenocorticotropic Hormone and Related Peptides

Biosynthesis

ACTH is a 39-amino-acid peptide hormone (MW 4500) processed from a large precursor molecule, POMC (MW 28,500). Within the corticotroph, a single mRNA directs the synthesis and processing of POMC into smaller, biologically active fragments (Figure 4–10), which include β-LPH, α-MSH, β-MSH, β-endorphin, and the amino terminal fragment of POMC. 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 ACTH 1 to 13, and corticotropin-like intermediate lobe peptide (CLIP) represents ACTH 18 to 39 (see Figure 4–10). Although these fragments are found in species with developed intermediate lobes (eg, the rat), they are not secreted as separate hormones in humans. β-LPH, 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).

Function

ACTH stimulates the secretion of glucocorticoids, mineralocorticoids, and androgens—all steroids from the adrenal cortex (see Chapters 9 and 10). The amino terminal end (residues 1-18) is responsible for this biologic activity. ACTH binds to receptors on the adrenal cortex and induces steroidogenesis through a cAMP-dependent mechanism.

The hyperpigmentation observed in states of ACTH hypersecretion (eg, Addison disease, Nelson 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.

Measurement

The development of immunoradiometric and immunochemiluminescent assays (IRMAs and ICMAs, respectively) 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 to 40 pg/mL (1-4 pmol/L).

Secretion

The physiologic secretion of ACTH is mediated through neural influences by means of a complex of hormones, the most important of which is CRH (Figure 4–11).

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 4–12). 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 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, whereas slow feedback is sensitive to the absolute cortisol level. The first mechanism is probably nonnuclear; that is, this phenomenon occurs too rapidly to be explained by the influence of corticosteroids on nuclear transcription of the specific mRNA responsible for ACTH. Recent studies suggest fast feedback is mediated by a novel membrane-associated glucocorticoid receptor that stimulates a rapid synthesis and retrograde release of endocannabinoids, thereby suppressing synaptic excitation. 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).

Biosynthesis

GH or 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, pre-GH (MW 28,000), is also secreted but has no physiologic significance.

Function

The primary function of GH 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 Tables 4–5 and 4–6 (see also Chapter 6).

GH, 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.

Measurement

GH has a plasma half-life of 10 to 20 minutes. The healthy adult secretes approximately 400 μ g/d (18.6 nmol/d); in contrast, young adolescents secrete about 700 μ g/d (32.5 nmol/d). The early morning GH concentration in fasting unstressed adults is less than 2 ng/mL (90 pmol/L). There are no significant sex differences.

About half of circulating GH is bound to specific GH-binding proteins (GHBPs) that function to reduce oscillations in GH levels (due to its pulsatile secretion) and prolong plasma GH half-life. GHBPs include a high-affinity GHBP (corresponding to the extracellular portion of the GH receptor formed through proteolytic cleavage) and a low-affinity species. Measurement of serum concentrations of the high-affinity GHBP provides an index of GH receptor concentrations. For example, individuals with Laron dwarfism, a form of GH insensitivity characterized by mutations in the GH receptor, usually have abnormally low levels of GHBP.

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).

Secretion

The secretion of GH is predominantly mediated by two hypothalamic hormones: GHRH and somatostatin (GH-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 4–7 summarizes the many factors that affect GH secretion in physiologic, pharmacologic, and pathologic states.

Growth Hormone–Releasing Hormone

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 to 120 minutes.

Other peptide hormones such as ADH, ACTH, and α-MSH may act as GH-releasing factors when present in pharmacologic amounts. Even TSH 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 discussion later), but there is also short-loop negative feedback by GHRH itself.

Somatostatin

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 a separate receptor, the growth hormone secretagogue receptor (GHS-R). A number of synthetic secretagogues, both peptides and nonpeptides, have been described. Ghrelin, a circulating peptide made by endocrine cells in the stomach, was identified in 1999 as the endogenous ligand for GHS-R. 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 to 4 hours after the onset of sleep (during stages 3 and 4) (Figure 4–13). 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 does not suppress this episodic release. Emotional, physical, and chemical stress, including surgery, trauma, exercise, electroshock therapy, and pyrogen administration, provoke GH release. In addition, impairment of secretion leading to growth failure has been well documented in children with severe emotional deprivation (see Chapter 6).

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 discussed below). In contrast, hypoglycemia stimulates GH release. This effect depends on intracellular glycopenia, because 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, because 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

Biosynthesis

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% to 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.

Function

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 by administration of exogenous GnRH, is usually normal. PRL also has a role in immunomodulation; extrapituitary synthesis of PRL occurs in T lymphocytes (among other sites), and PRL receptors are present on T and B lymphocytes and macrophages. PRL modulates and stimulates both immune cell proliferation and survival.

Measurement

The PRL secretory rate is approximately 400 μ g/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 25 to 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 to 20 ng/mL (0.7-0.9 nmol/L).

PRL is measured using a highly specific immunoradiometric assay. However, when PRL levels are extremely high, which can occur with some PRL-secreting tumors, this assay may be susceptible to the “hook effect.” PRL levels are erroneously reported as normal or modestly elevated due to saturation of available assay antibodies. Appropriate sample dilutions (ie, 1:100) will avoid this artifact.

In some patients a form of PRL with molecular mass greater than 150 kDa predominates. This is termed macroprolactinemia and consists of aggregates of monomeric PRL as well as PRL-immunoglobulin G complexes. These complexes may have reduced biological activity and can be measured using polyethylene glycol precipitation of serum samples.

Secretion

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 4–8.

Prolactin-Releasing Factors

TRH is a potent PRL-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 VIP and serotonergic pathways.

Episodic and Sleep-Related Secretion

PRL secretion is episodic. An increase is observed 60 to 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 (see Figure 4–13). 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.

Effects of Other Hormones

Many hormones influence PRL release. Estrogens augment basal and stimulated PRL secretion after 2 to 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 4–8)

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 enhance PRL secretion; serotonin receptor blockers suppress PRL release associated with stress and with nursing.

Thyrotropin

Biosynthesis

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 subunits differ 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.

Function

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.)

Measurement

TSH circulates unbound in the blood with a half-life of 35 to 50 minutes. With ultrasensitive IRMAs for measuring TSH concentration, the normal range is usually 0.5 to 4.7 μ U/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 to 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.

Secretion

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.

TRH

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 4–14, the administration of T3 (15 μ g) and T4 (60 μ g) to healthy persons for 3 to 4 weeks suppresses the TSH response to TRH despite only small increases in circulating T3 and T4 levels. Thus, the secretion of TSH is inversely proportional 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.

Somatostatin

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 suppresses high levels of TSH in primary hypothyroidism. Octreotide acetate, a somatostatin analog, has been used successfully to inhibit TSH secretion in patients with TSH-secreting pituitary tumors.

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 decreases TSH in both healthy and hypothyroid subjects as well as blunts the TSH response to TRH. Thus, as expected, dopaminergic agonists such as bromocriptine inhibit TSH secretion and dopaminergic antagonists such as metoclopramide increase TSH secretion in euthyroid subjects.

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 increases their TRH-induced TSH response. (See also Chapter 7.)

Gonadotropins: Luteinizing Hormone and Follicle-Stimulating Hormone

Biosynthesis

LH and 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 hCG are used clinically for induction of spermatogenesis or ovulation (see Chapters 12 and 13).

Function

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 midmenstrual 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.

Measurement

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 (see Chapter 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.

Secretion

The secretion of LH and FSH is controlled by GnRH, which maintains basal gonadotropin secretion, generates the phasic release of gonadotropins for ovulation, and determines the onset of puberty. As noted above, the size and frequency of GnRH pulses determine the ratio of gonadotropin secretion: low-frequency pulses favor FSH release while high-frequency pulses result in LH release. 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 hormone made in adipocytes in proportion to fat stores, 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 downregulation 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.

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 to 12 hours after the LH peak and 24 to 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 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, provocative testing using synthetic or purified hormones (eg, ACTH, ovine CRH, glucagon, insulin) can be used to assess hypothalamic-pituitary reserve and excess.

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 4–9. The clinical manifestations of either hypo- or hypersecretion of anterior pituitary hormones are discussed in subsequent sections.

Evaluation of Adrenocorticotropic Hormone

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 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, because its short plasma half-life and episodic secretion result in wide fluctuations in plasma levels (see Figure 4–12). 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 syndrome (see the later section on Cushing disease and also Chapter 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 μ g/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 μ g/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.

Adrenal Stimulation

Because 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 μ g) causes a rapid increase (within 30 minutes) of cortisol to at least 18 to 20 μ g/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 μ g ACTH test is designed to improve its sensitivity in detection of secondary adrenal insufficiency. The cortisol response to 1 μ g of synthetic ACTH correlates better with the cortisol response to insulin-induced hypoglycemia in patients with complete chronic secondary adrenal insufficiency. However, the results in partial secondary adrenal insufficiency are less reliable and technical difficulties make the test impractical for routine use. Thus, the standard 250 μ g ACTH test remains the procedure of choice (see discussion later and Chapter 9).

Pituitary Stimulation

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 to 20 μ g/dL (496-552 nmol/L), indicating normal ACTH reserve. Although plasma ACTH also rises, its determination has not proved to be as useful, because 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, because 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, because 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 μ g/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 discussion earlier). 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. It 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 μ g/kg) provokes a peak ACTH response within 15 minutes and a peak cortisol response within 30 to 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

ACTH hypersecretion is manifested by adrenocortical hyperfunction (Cushing syndrome). The diagnosis and differential diagnosis of ACTH hypersecretion and hypercortisolism are outlined in a later section on Cushing disease and also in Chapter 9. The low-dose dexamethasone suppression test is used to establish the presence of hypercortisolism regardless of its cause. Dexamethasone 1 mg is taken orally between 11 PM and midnight. The following morning at 8 AM, a blood sample is obtained for cortisol (and dexamethasone level if available or cortisol does not suppress). Cortisol values less than 1.8 μ g/dL are normal. Sensitivity using this cutoff is good though specificity is compromised. Patient compliance, individual differences in dexamethasone metabolism, drugs that affect metabolism of dexamethasone, and medical conditions that alter cortisol secretion (acute illness, anxiety, depression, alcoholism) may influence the accuracy of this test.

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 IRMAs give results that are 30% to 50% lower than older radioimmunoassays.

Insulin-Induced Hypoglycemia

The most reliable stimulus of GH secretion is insulin-induced hypoglycemia. In normal individuals, GH levels increase to more than 5 ng/mL after adequate hypoglycemia is achieved. Because 10% of normal individuals fail to respond to hypoglycemia, other stimulatory tests may be necessary.

GHRH-Arginine Test

Both forms of human GHRH (GHRH-40 and GHRH-44) have been used to evaluate GH secretory capacity. A dose of GHRH (1 μ g/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 to 15 ng/mL (460-700 pmol/L) at 30 to 60 minutes in healthy subjects. The results are comparable to those achieved with insulin-induced hypoglycemia. Unfortunately, GHRH is no longer available in the United States.

Glucagon Stimulation Test

Glucagon can also be used to evaluate GH secretory capacity. A dose of glucagon (1 mg) is given intramuscularly and GH levels are measured every 30 minutes for 3 to 4 hours. In adults with GH deficiency, peak GH levels fail to rise above 3 ng/mL.

Tests with Levodopa, Arginine, and Other Stimuli

Stimulation testing with levodopa, arginine infusion alone, or propranolol, is less reliable in the diagnosis of GH deficiency.

GH Hypersecretion

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.

PRL hypersecretion is a common endocrine problem. Macroprolactinemia can be assessed using polyethylene glycol precipitation of serum samples. Additional evaluation of hyperprolactinemia is discussed in the section on prolactinomas.

Evaluation of Thyroid-Stimulating Hormone

Basal Measurements

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 is elevated; low or normal TSH in the presence of hypothyroidism suggests hypothalamic-pituitary dysfunction (see Chapter 7).

TRH Test

Because accurate methods for determining TSH and FT4 readily establish the diagnosis of hypothyroidism in virtually all patients, the TRH test is rarely indicated today (TRH is also not currently commercially available).

Evaluation of LH and FSH

Testosterone and 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 (see Chapters 12 and 13).

LH and 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).

GnRH Test

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. 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.

Obesity

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. Obesity is also a common cause of hypogonadotropic hypogonadism in adult men.

Diabetes Mellitus

Although glucose normally suppresses GH secretion, most individuals with type 1 diabetes have normal or elevated GH levels that often do not rise further in response to hypoglycemia or arginine. Levodopa increases GH in some diabetic patients, and even a dopamine infusion (which produces no GH change in nondiabetic subjects, because it does not cross the blood–brain barrier), stimulates 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.

Uremia

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 and 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

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 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 clinical testing in patients of this agent difficult to interpret. Phenothiazines may blunt the GH response to hypoglycemia and levodopa and frequently cause hyperprolactinemia. The many other pharmacologic agents that increase PRL secretion are listed in Table 4–8.

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.

Methods for performing endocrine tests and their normal responses are summarized in Table 4–9. 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.

Neuroradiologic Evaluation

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, 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% to 20% of the general population harbor nonfunctional and asymptomatic pituitary microadenomas.

Magnetic Resonance Imaging

MRI is the current procedure of choice for imaging the hypothalamus and pituitary. It has superseded the use of computed tomography (CT) because 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 to 2 mm intervals. This allows clear definition of hypothalamic and pituitary anatomy and can accurately visualize lesions as small as 3 to 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 4–15.

Normal Anatomy

The normal anterior pituitary is 5 to 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 to 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 to 3 mm in diameter and 5 to 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.

Microadenomas

These lesions, which range from 2 to 10 mm in diameter, appear as low-signal-intensity lesions on 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, because minor abnormalities occur in 10% of patients who have had incidental high-resolution scans but no clinical pituitary disease. These abnormalities may represent the clinically insignificant pituitary abnormalities that occur in 10% to 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.

Macroadenomas

Pituitary adenomas greater than 10 mm in diameter are readily visualized with MRI scans, and the scan also defines 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 and 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.

Etiology and Early Manifestations

In adults, the most common 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 and 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 disease (see discussion later).

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.

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 and, if present, usually indicates panhypopituitarism. Thus, patients with secondary hypothyroidism or hypoadrenalism should undergo a complete assessment of pituitary function and neuroradiologic studies, because panhypopituitarism and large pituitary tumors are common in this setting. PRL measurement is again essential, because 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 proven 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 and metastases to the pituitary, but is rare in primary pituitary lesions. Diagnostic evaluation is described in Chapter 5. In addition, all patients should undergo radiologic evaluation and assessment of anterior pituitary function.

Empty Sella Syndrome

Etiology and Incidence

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 4–16) 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 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.

Clinical Features

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, although some patients have hyperprolactinemia. Endocrine function studies should be performed to exclude pituitary hormone insufficiency or a hypersecretory pituitary microadenoma.

Diagnosis

The diagnosis of 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

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.

Clinical Features

Craniopharyngioma

Craniopharyngiomas are thought to originate from metaplasia of remnant epithelial cell rests in Rathke pouch and the craniopharyngeal duct during development. The differential diagnosis includes Rathke cleft cysts and arachnoid cysts. Rathke cleft cysts are a common incidental finding within the pituitary, but may present with symptoms similar to craniopharyngiomas. Although Rathke cleft cysts and craniopharyngiomas are both thought to arise from Rathke pouch during development, craniopharyngiomas tend to be more aggressive and are more likely to recur after resection.

The initial symptoms of craniopharyngioma in children and adolescents are predominantly endocrinologic; however, these manifestations are frequently unrecognized, and at diagnosis more than 80% of patients have hypothalamic-pituitary endocrine deficiencies. These endocrine 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%.

Symptoms leading to the diagnosis are 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% of patients; 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; that is, 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. The appearance is typically of a heterogeneous, cystic mass that enhances with contrast. Calcifications may also be present.

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. Frohlich syndrome, or adiposogenital dystrophy, is characterized by obesity, growth retardation, and delayed development of sexual organs. 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.

Diagnosis

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, because deficiencies are present in the great majority (see section on Hypopituitarism below), and the evaluation will establish the requirements for replacement therapy. PRL levels should also be determined, because most hypothalamic lesions cause hyperprolactinemia either by hypothalamic injury or by damage to the pituitary stalk.

Treatment

Treatment depends on the type of tumor. Because 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 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

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. In general, acquired loss of anterior pituitary function follows the sequence of GH, LH/FSH, TSH, ACTH, and PRL. Treatment and prognosis depend on the extent of hypofunction, the underlying cause, and the location of the lesion in the hypothalamic-pituitary axis.

Etiology

The etiologic considerations in hypopituitarism are diverse. As shown below, a helpful mnemonic device is the phrase “nine Is”: 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.

Invasive

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.

Infarction

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 the prothrombotic effects of the hyperestrogenic state. Some 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.

Infiltrative

Hypopituitarism may be the initial clinical manifestation of infiltrative disease processes such as sarcoidosis, hemochromatosis, and Langerhan histiocytosis.

1. 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.

2. Hemochromatosis— Hypopituitarism, particularly hypogonadotropic hypogonadism, is a prominent manifestation of iron storage disease—either primary (hereditary) 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 considered in any 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.

3. Langerhan histiocytosis— In this disorder, 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.

Injury

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.

Immunologic

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.

Iatrogenic

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 to 5000 cGy and results in a 50% to 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 and gamma knife radiosurgery for pituitary tumors results in a 15% to 55% 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.

Infectious

Although many infectious diseases, including tuberculosis, syphilis, and mycotic infections, have been implicated as causative agents in pituitary hypofunction, antimicrobial drugs have now made them rare causes of hypopituitarism.

Idiopathic

In some patients with hypopituitarism, no underlying cause is found. These may be isolated (see discussion later) 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, septo-optic dysplasia). Although progress has been made into understanding the genetic basis for some of these disorders, the pathogenesis remains uncertain.

Isolated

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.

1. GH deficiency—In children, congenital monotropic GH deficiency may be sporadic or familial. These children, who may experience fasting hypoglycemia, have a gradual deceleration in growth velocity after 6 to 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.

2. ACTH deficiency—Monotropic ACTH deficiency is rare and is manifested by the signs and symptoms of adrenocortical insufficiency. 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 presumed to be due to lymphocytic hypophysitis.

3. Gonadotropin deficiency—Isolated deficiency of gonadotropins is not uncommon. Kallmann syndrome initially described in the 1940s, is characterized by an isolated defect in GnRH secretion associated with maldevelopment of the olfactory center with hyposmia or anosmia; X-linked recessive, autosomal dominant, and autosomal recessive patterns of inheritance are seen. Sporadic cases occur, and other neurologic defects such as color blindness and nerve deafness have been reported. At least five Kallmann syndrome genes have been identified: KAL1, FGFR1, FGF8, PROKR2, and PROK2. KAL1 mutations are responsible for the X-linked form of the disease and result in decreased expression of the extracellular glycoprotein anosmin-1. This in turn interferes with the normal embryonic development and migration of GnRH-secreting neurons. Because 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, 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. In addition, acquired partial gonadotropin deficiency may occur in middle-aged men. The cause and exact frequency of this disorder are unknown.

4. TSH deficiency—Monotropic TSH deficiency is rare and can be caused by a reduction in either hypothalamic TRH secretion (tertiary hypothyroidism) or pituitary TSH secretion (secondary hypothyroidism). These defects have reported in association with gene mutations, empty sella, lymphocytic hypophysitis, and pituitary tumors. Some patients with chronic renal failure also appear to have impaired TSH secretion.

5. 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.

6. 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 (TSH, GH, and PRL) and PROP-1 (TSH, GH, PRL, LH, FSH, and ACTH).

Clinical Features

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.

Symptoms

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. Decreased muscle mass and increased fat mass can also be seen, although this may be difficult to discern in any given individual.

Hypogonadism, manifested by amenorrhea in women and decreased libido or erectile dysfunction in men, may antedate the clinical appearance of a hypothalamic-pituitary lesion. The only symptom of PRL deficiency is failure of postpartum lactation.

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. The zona glomerulosa and the renin-angiotensin system are usually intact; therefore, the dehydration and sodium depletion seen in Addison disease are uncommon. However, these patients are susceptible to hypotension, shock, and cardiovascular collapse, because glucocorticoids are necessary to maintain vascular reactivity, especially during stress. In addition, 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 disease, Nelson 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.

Signs

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.

Diagnosis

Assessment of Target Gland Function (Figure 4–17)

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

Because 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 autoimmune polyglandular syndromes types 1 and 2 (APS 1 and 2), 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

ACTH

Treatment of secondary adrenal insufficiency, like that of primary adrenal failure, must include glucocorticoid support (see Chapter 9). Hydrocortisone (15-25 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.

TSH

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. Full oral replacement dose of levothyroxine sodium is 1.6 μ g/kg daily (0.1-0.15 mg/d 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: Because thyroid hormone replacement in patients with hypopituitarism may aggravate even partial adrenal insufficiency, the adrenal hormone deficiency should be treated first.

Gonadotropins

The object of treatment of secondary hypogonadism is to replace sex steroids and restore fertility (see Chapters 12 and 13).

1. Estrogens and progesterone—In premenopausal women, estrogen replacement is essential. Adequate estrogen treatment maintains secondary sex characteristics (eg, vulvar and vaginal lubrication), prevents osteoporosis, and abolishes 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. Many oral contraceptive pill combinations are also clinically available.

2. 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).

3. 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 dehydroepiandrosterone (DHEA) in doses of 25 to 50 mg/d may restore plasma testosterone levels to normal. A transdermal delivery system is being evaluated for use in women, but efficacy appears to be modest and the long-term safety is unknown.

4. Androgens in men—The treatment of male hypogonadism is discussed in Chapter 12. Testosterone gels (available in packets in doses of 2.5, 5, or 10 g, or from a metered-dose pump in 1.25 g increments) and testosterone patches (in doses of 2.5 or 5 mg) are applied daily. A transbuccal formulation is administered at a dose of 30 mg twice daily. Other therapeutic preparations include intramuscular testosterone enanthate or cypionate in doses of 100 mg every week or 200 mg every 2 weeks. Testosterone undecanoate is an intramuscular preparation available in several countries that can be given every 3 months. Oral testosterone preparations available in the United States are rarely used out of concern for hepatic side effects.

5. Spermatogenesis—Spermatogenesis can be achieved in many patients with the combined use of hCG and recombinant FSH. If pituitary insufficiency is of recent onset, therapy with hCG 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 (Also See Chapter 6)

Human GH (hGH) produced by recombinant DNA technology is available for use in children with hypopituitarism and for adults with GH deficiency and known pituitary disease. 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 to 5 μ g/kg. Monitoring of effectiveness is accomplished by measurement of IGF-I, and the dosage of GH is adjusted accordingly (up to about 10 μ g/kg/d). Side effects (eg, edema, paresthesias, arrhythmias, glucose intolerance, diabetes) should be assessed. Contraindications to GH therapy include the presence of diabetic retinopathy, active malignancy, intracranial hypertension, or airway obstruction in individuals with Prader-Willi syndrome.

Pituitary Adenomas

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. The differential diagnosis of nonpituitary sellar and parasellar masses is listed in Table 4–10.

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 to 2 cm in diameter confined to the sella turcica can usually be successfully treated; however, larger tumors—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. One somatic mutation has been found in 30% to 40% of GH-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 result 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 host of other candidate genes have been described, including the pituitary tumor transforming gene (PTTG). Overexpression of this gene has been found in all pituitary tumor types and may promote tumorigenesis through cell cycle disruption, stimulation of fibroblast growth factor secretion, and abnormal chromatid separation. Several genetic syndromes are associated with pituitary tumors including multiple endocrine neoplasia type 1, McCune-Albright syndrome, Carney syndrome, and familial acromegaly.

Treatment

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, now done endoscopically in most centers, 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 to 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 to 14 days of transsphenoidal pituitary microsurgery. These abnormalities of water balance can occur within days of each other making medical management difficult. A triphasic response of diabetes insipidus, SIADH, and diabetes insipidus is occasionally encountered and thought to be due to early hypothalamic dysfunction, followed by release of ADH from the degenerating pituitary, and then depletion of ADH stores. Surgical hypopituitarism is rare in patients with microadenomas but approaches 5% to 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 to look for evidence of diabetes insipidus. Mild diabetes insipidus is managed by giving fluids orally; in more severe cases—urine output greater than 5 to 6 L/24 h—ADH therapy in the form of desmopressin, or DDAVP, can be administered intranasally, orally, subcutaneously, or parenterally (see Chapter 5). SIADH is managed by fluid restriction; however, in more severe cases, hypertonic saline may be required. ADH receptor antagonists (tolvaptan is given orally and conivaptan is administered intravenously) are also now available for use in some patients (see section on SIADH).

Radiotherapy

Pituitary irradiation should be reserved for patients who have had incomplete resection of larger pituitary adenomas and whose tumors are not amenable to, or have failed, medical therapy.

1. Conventional irradiation—Conventional irradiation using high-energy sources, in total doses of 4000 to 5000 cGy given in daily doses of 180 to 200 cGy, is most commonly employed. The response to radiation therapy is slow, and 5 to 10 years may be required to achieve the full effect (see section on Acromegaly). Treatment is ultimately successful in about 80% of patients with acromegaly but in only about 55% to 60% of patients with Cushing disease. The response rate in prolactinomas is not precisely known, but tumor progression is prevented in most patients. Morbidity during radiotherapy is minimal, although 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% to 60% at 5 to 10 years. Rare late complications include damage to the optic nerves and chiasm, seizures, and radionecrosis of brain tissue. Recent studies from the United Kingdom have shown that conventional radiotherapy is a major risk factor for excess mortality in acromegaly.

2. 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. Remission rates have been reported in the range of 43% to 78%. An adequate distance of the pituitary tumor from the optic chiasm is needed to prevent radiation-induced damage. Repeat treatments put patients at higher risk of new visual or third, fourth, or sixth cranial nerve deficits.

3. Proton stereotactic radiotherapy—Experience with this modality is limited. In one study, 52% of patients with Cushing disease had clinical remission. A similar rate of new pituitary hormone deficiencies was seen, although no visual complications or brain injury was reported.

Medical Treatment

Medical management of pituitary adenomas became feasible with the availability of bromocriptine, a dopamine agonist that suppresses both PRL and tumor growth in patients with prolactinomas. Somatostatin analogs are useful in the therapy of acromegaly and some TSH-secreting adenomas. Specifics of the use of these and other medications are discussed later.

Posttreatment Follow-Up

Patients undergoing transsphenoidal microsurgery should be reevaluated 4 to 8 weeks postoperatively to document that complete removal of the adenoma and correction of endocrine hypersecretion has 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 later). Other anterior pituitary hormones—TSH, ACTH, and LH/FSH—should also be assessed as described earlier in the section on endocrine evaluation. In patients with successful responses, yearly evaluation should be performed 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, because 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.

Prolactinomas

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 is that PRL hypersecretion causes not only galactorrhea but also gonadal dysfunction, and the use of PRL measurements in screening such patients has 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 4–11).

Pathology

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 <1 cm in diameter at diagnosis).

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 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.

Clinical Features

The clinical manifestations of PRL excess are the same regardless of the cause (see later). The classic features are galactorrhea and amenorrhea in women 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

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. 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

1. 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 low bone mass 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. In small clinical trials, treatment with dopamine agonists has been shown to improve psychologic well-being in such patients.

2. 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 should other causes of hypothalamic-pituitary-gonadal dysfunction (see section on Hypopituitarism). Impotence also occurs in hyperprolactinemic males. Its cause is unclear, because 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; several studies have shown that most microadenomas do not change significantly in size, and macroadenomas tend to grow very slowly.

Differential Diagnosis

The many conditions associated with hyperprolactinemia are listed in Table 4–8. 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 to 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 PRL levels may be observed in the presence of anti-PRL antibodies or of macroprolactinemia. In the latter, a high-molecular-weight complex of PRL molecules maintains immunologic activity, but minimal or no bioactivity. Macroprolactinemia can be assessed with polyethylene glycol precipitation of serum samples.

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 (see Table 4–8). PRL levels are usually less than 200 ng/mL (9 nmol/L), and the evaluation should focus on discontinuation of the drug or medication and reevaluation of the patient after several weeks. In patients in whom drug withdrawal is not feasible, neuroradiologic studies, if normal, usually exclude prolactinoma.

Diagnosis

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 later.

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. Because 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 to 300 ng/mL (9.1-13.7 nmol/L) are virtually diagnostic of prolactinoma. In addition, because 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, because both PRL-secreting microadenomas and the many other conditions causing hyperprolactinemia (see Table 4–8) cause PRL hypersecretion of this degree. In such patients, MRI frequently demonstrates 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). Because the diagnosis cannot be either established or excluded in patients with normal or equivocal neuroradiologic studies, they require further evaluation or serial assessment (see later). Dilutions of prolactin samples can be performed in patients with modest prolactin elevation or macroadenomas to rule out interference from the high-dose hook effect; large quantities of antigen can impair antigen-antibody binding, resulting in erroneously low prolactin measurements in some immunoassays.

Treatment

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, because pregnancy may cause further expansion of these tumors as discussed later.

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. 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—that is, 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 to 12 months, dopamine agonists should be used to suppress PRL secretion and restore normal gonadal function. In women with macroprolactinomas, replacement estrogen therapy should be initiated only after PRL hypersecretion has been controlled by dopamine agonist therapy since estrogen stimulates lactotroph hyperplasia and may increase tumor size. In this regard, periodic measurement of serum PRL should be performed in women with microadenomas on estrogen therapy who are not also receiving dopamine agonist therapy.

Dopamine Agonists

Bromocriptine became available in the United States more than 30 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.

1. Bromocriptine—Bromocriptine 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. Doses of 2.5 to 5 mg daily are often effective. However, at present, cabergoline is the therapy of choice

2. 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 PRL 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. Although several recent studies have demonstrated associations between cabergoline and cardiac valve disease in patients treated for Parkinson disease, clinically relevant valve disease in patients treated for prolactinoma appears to be rare, likely because doses used to manage symptoms of Parkinsonism are often 20 to 30 times higher and administered daily rather than twice weekly. The risk also appears to be related to the affinity of different dopamine agonists for valvular serotonin (5-HT2B) receptors. Until larger, prospective safety studies are available, some authorities recommend echocardiographic evaluation in patients who are expected to need long-term treatment, especially at high doses.

1. Microadenomas—Cabergoline 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. In these patients with microadenomas, the risk of major expansion of adenoma during the pregnancy is less than 2%; 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 dopamine agonists; however, patients should be instructed to discontinue these drugs at the first missed menstrual period and obtain a pregnancy test. Although no late toxicity has yet been reported other than the side effects noted above, questions about possible long-term risk are currently unanswered. Maternal hyperprolactinemia should not be harmful to the developing fetus; prolactin increases normally during pregnancy and does not appear to cross the placenta.

2. 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, because the risk of tumor expansion and visual deficits in the later part of pregnancy is approximately 15% to 25%. These patients should first have tumor volume decreased with medical therapy or be treated with surgery prior to induction of ovulation.

   Dopamine agonists normalize PRL secretion in about 60% to 70% of patients with macroadenomas and also reduce tumor size in about the same percentage of patients. 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.

3. Long-Term Remission—Current studies suggest that 30% to 40% of patients with micro- and macroadenomas will remain in long-term remission after withdrawal of cabergoline therapy of 2 to 3 years duration provided that they have normalization of PRL levels and tumor shrinkage. Larger macroadenomas (> 2.0 cm) are likely to recur, and long-term dopamine agonist therapy should be continued in these patients.

Surgical Treatment

Transsphenoidal microsurgery is the surgical procedure of choice in patients with prolactinomas.

1. Microadenomas—In patients with microadenomas, remission, as measured by restitution of normal PRL levels, normal menses, and cessation of galactorrhea, is achieved in 85% to 90% of cases. Success is most likely in patients with basal PRL levels under 200 ng/mL (9.1 nmol/L) and 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.

2. 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 to 2 cm in diameter without extrasellar extension and with basal PRL levels less than 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% to 50%. Although progressive visual loss or pituitary apoplexy is a clear indication for surgery, the great majority of these patients should be treated with dopamine agonists.

Radiotherapy

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 to 5000 cGy prevents further tumor expansion, although PRL levels usually do not fall into the normal range. Impairment of anterior pituitary function occurs in approximately 50% to 60% of patients. Experience with gamma knife radiosurgery in prolactinomas is limited and rates of remission and reduction in tumor volume have been reported with varying degrees of success.

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.

Microadenomas

All patients should be treated to prevent the occasional tumor progression, loss of bone mass, and the other effects of prolonged hypogonadism. Medical therapy with cabergoline effectively restores normal gonadal function and fertility, and pregnancy carries only a small risk of tumor expansion. Those patients who respond should be treated for 2 to 3 years, and then the drug should be withdrawn to determine if long-term remission will occur. Patients who have recurrence of hyperprolactinemia after cabergoline withdrawal may resume the drug or choose to have surgical excision. 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.

Macroadenomas

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 PRL levels are greater than 200 ng/mL (9.1 nmol/L) and the tumor is larger than 2 cm. Although transsphenoidal microsurgery rapidly decreases tumor size and decompresses the pituitary stalk, the optic chiasm, and the cavernous sinuses, there is usually residual tumor and hyperprolactinemia. Thus, these patients require additional therapy with dopamine agonists. Although tumor growth and PRL 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 and 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, although 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.

Pathology

Pituitary adenomas causing acromegaly are usually more than 1 cm in diameter when the diagnosis is established. These tumors arise from the lateral wings of the anterior pituitary; less than 10% 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 and Pathogenesis

In most cases, excessive pituitary GH secretion is a primary pituitary disorder. A somatic 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.

Pathophysiology

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, later), 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% to 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 protein 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.

Clinical Features

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 to 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.

Symptoms and Signs

Early manifestations (Table 4–12) 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, most patients have classic manifestations, and acral and soft tissue changes are always present. Bone and cartilage changes affect chiefly the face and skull. 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 4–18) 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. Sleep apnea, both obstructive and central, is very common in patients with acromegaly. This has particular importance for the anesthesiologist who must take special precautions to protect the airway during surgery. 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 longstanding 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.

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% of patients, 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 later) 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.

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.

Space-occupying 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% to 20%, because most patients are now diagnosed because of the manifestations of GH excess.

Laboratory Findings

In addition to elevations in IGF-I and GH, postprandial plasma glucose may be elevated, and serum insulin is increased in 70% of cases. Elevated serum phosphate (due to increased renal tubular resorption) and hypercalciuria appear to be due to direct effects of GH or IGF-I.

Imaging Studies

Plain films (Figure 4–19) 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).

Diagnosis

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 greater than 10 ng/mL (465 pmol/L) in more than 90% of patients and range from 5 ng/mL (232 pmol/L) to greater than 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 discussed later).

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 1 ng/mL (47 pmol/L) at 60 minutes. In acromegaly, GH levels may decrease, increase, or show no change; however, they do not decrease to less than 1 ng/mL (47 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 age- and sex-adjusted normative data. 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).

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 greater than 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 scans suggest diffuse pituitary enlargement or hyperplasia, ectopic GHRH should also be suspected.

Differential Diagnosis

Other Causes of GH or IGF-I 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. Use of testosterone or the contraceptive depot medroxyprogesterone acetate has been associated with modest elevations in IGF-I.

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.

Treatment

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. Recent reports described increased late mortality in patients with GH levels by radioimmunoassay greater than 2.5 ng/mL (116 pmol/L) after therapy. Therefore, current guidelines for remission are a fasting GH of 1 ng/mL (47 pmol/L) or less and a glucose-suppressed GH of 1 ng/mL (47 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 medically with somatostatin analogs, dopamine agonists, or a GH receptor antagonist. 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% to 80% of patients. In those with small or moderate-sized tumors (<2 cm), success is achieved in more than 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% to 60%. Recurrence rates in those with a successful initial response are low (about 5% of patients at our institution). Surgical complications (discussed earlier) 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 μ g) given subcutaneously three times daily. Its use in acromegaly has been superseded by sustained-release somatostatin analogs with activities lasting up to 1 month. Preparations include octreotide LAR and lanreotide acetate given by injection every 4 weeks. Octreotide LAR normalizes GH and IGF-I levels in 75% of patients when used at doses of 20 to 40 mg/mo; however, tumor reduction occurs in a much smaller percentage. These long-acting agents have 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. Impaired glucose tolerance has been reported in some studies. The dopamine agonist cabergoline normalizes IGF-I levels in about 30% of acromegalic patients when used at doses of 1 to 2 mg/wk. However, it has not been commonly used as sole therapy. When cabergoline is added to somatostatin analog therapy, the number of patients with normalization of GH and IGF-I levels is increased.

Pegvisomant, the latest medical therapy for acromegaly, is a GH receptor antagonist. In doses of 10 to 20 mg/d given by subcutaneous injection, it reduces IGF-I levels to normal in more than 90% of patients. Although there are concerns regarding the continued excess GH secretion and possible tumor progression, serious problems have not arisen to date. Pegvisomant is effective, but its use is limited by cost and the need for daily injection. Therefore, it is currently used mainly in those patients who have failed therapy with surgery and somatostatin analogs.

Radiotherapy

Conventional supervoltage irradiation in doses of 4500 to 5000 cGy, although ultimately successful in 60% to 80% of patients, should not be used, because GH levels may not return to normal until 10 to 15 years after therapy. 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% to 60% of patients as a consequence of radiotherapy. Gamma knife radiosurgery has also been used for tumors confined to the sella. Current series, although limited, suggest remission rates of about 50% to 70% at 2 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. Bony changes typically do not regress. Headache, carpal tunnel syndrome, arthralgias, sleep apnea, 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 associated with acromegaly can be reversed if GH levels are normalized.

Posttreatment Follow-Up

Posttreatment assessment includes evaluation of GH secretion, anterior pituitary function, and tumor size. Patients undergoing surgery should be seen 4 to 8 weeks after the operation for assessment of GH secretion and pituitary function. Those with persistent GH hypersecretion (> 1 ng/dL [47 pmol/L]) should receive further therapy with somatostatin analogs. Patients with postoperative GH levels under 1 ng/mL (47 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. Recurrent elevations in IGF-I should prompt a repeat MRI of the sella. Late hypopituitarism after surgery alone does not occur. GH replacement therapy in patients with history of acromegaly and hypopituitarism is controversial and further studies are needed.

ACTH-Secreting Pituitary Adenomas: Cushing 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 disease) is now recognized as the most common cause of spontaneous hypercortisolism (Cushing syndrome) and must be distinguished from the other forms of adrenocorticosteroid excess—ectopic ACTH syndrome and adrenal tumors (see Chapter 9).

Pathology

ACTH-secreting pituitary tumors exist in virtually all patients with Cushing 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 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 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 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 CRH, occurs rarely.

The adrenal glands in Cushing disease are enlarged, weighing 12 to 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.

Pathogenesis

The weight of current evidence is that Cushing disease is a primary pituitary disorder and that hypothalamic abnormalities are secondary to hypercortisolism. The endocrine abnormalities in Cushing 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 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, thereby abolishing 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 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.

Clinical Features

Cushing 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 (rounded) 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 disease rarely have hypokalemia, weight loss, anemia, or hyperpigmentation. Virilization, observed occasionally in patients with adrenal carcinoma, is unusual in Cushing 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 to 40 years, but Cushing 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).

Diagnosis

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, abnormal cortisol suppressibility to low-dose dexamethasone, and/or abnormal late night salivary cortisol measurement. 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 syndrome are presented in Chapter 9.

Treatment

Transsphenoidal microsurgery is the procedure of choice in Cushing 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.

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 2 to 18 months. The role of total hypophysectomy is currently unclear, however; hemihypophysectomy based on central venous sampling lateralization is successful in only about 50% to 70% of patients.

By contrast, transsphenoidal surgery is successful in only 25% of the 10% to 15% of patients with Cushing 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 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 syndrome; see below). Persistent hypercortisolism may occasionally follow total adrenalectomy as ACTH hypersecretion stimulates adrenal remnants or congenital rests.

Radiotherapy

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% to 70% at 1 to 3 years after radiotherapy.

Gamma knife radiosurgery achieves remission rates of 65% to 75%. However, as noted above, both forms of radiotherapy cause late loss of pituitary function in more than 50% of patients and visual deficits can occur with damage to the optic chiasm or cranial nerves.

Medical Treatment

Drugs that inhibit adrenal cortisol secretion are useful in Cushing 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 to 1200 mg, ketoconazole has been effective in the management of Cushing 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. Metyrapone is only available directly through the manufacturer and aminoglutethimide is no longer manufactured in the United States.

The use of these drugs is accompanied by increased ACTH levels that may overcome the enzyme inhibition. In addition, 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 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 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.

The anesthesia induction agent etomidate inhibits P450c11. It must be given intravenously and is generally reserved for life-threatening cases of hypercortisolism resistant to conventional therapy or when oral medications are contraindicated.

Pharmacologic inhibition of ACTH secretion in Cushing disease has also been attempted with cyproheptadine, bromocriptine, and cabergoline. However, few patients have had successful responses, and the use of these agents is not recommended.

Nelson Syndrome

The clinical appearance of an ACTH-secreting pituitary adenoma following bilateral adrenalectomy as initial therapy for Cushing disease was first described by Nelson and coworkers in 1958. However, with the evolution of pituitary microsurgery as the initial therapy for Cushing disease, the Nelson syndrome is now a rare occurrence.

Pathogenesis

It now seems likely that Nelson 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.

Incidence

Prior to the development of transsphenoidal surgery, when bilateral adrenalectomy was the initial therapy for Cushing disease, the incidence of Nelson syndrome ranged from 10% to 78% depending on what criteria were used for diagnosis (see Chapter 9). In one series, approximately 30% of patients adrenalectomized for Cushing disease developed classic Nelson 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. Prophylactic pituitary radiotherapy is controversial. At present, when adrenalectomy is utilized only in those patients who fail pituitary microsurgery, the incidence of Nelson syndrome is less than 10%. Nevertheless, continued examination, including plasma ACTH levels and MRI, is required following bilateral adrenalectomy in patients with Cushing disease.

Clinical Features

The pituitary tumors in patients with classic Nelson syndrome can be 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.

Diagnosis

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.

Treatment

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 or gamma knife radiosurgery is employed postoperatively in patients with residual tumor or extrasellar extension.

Thyrotropin-Secreting Pituitary Adenomas

TSH-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.

The diagnosis is based on findings of hyperthyroidism (elevated T4 or T3) with elevated serum TSH and alpha subunit, and neuroradiologic studies consistent with pituitary tumor. The differential diagnosis includes those patients with primary hypothyroidism (thyroid failure) that develops major hyperplasia of pituitary thyrotrophs and lactotrophs with sellar enlargement and occasional suprasellar extension. These patients can be identified by symptoms of hypothyroidism and low thyroid hormone levels. Thyroid hormone resistance may be more difficult to exclude as T4 and T3 levels can also be elevated. These patients, however, tend to be clinically euthyroid or hypothyroid, have a family history of thyroid hormone resistance, and generally do not present with sellar masses. Alpha subunit levels in these patients are usually not elevated.

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 in doses similar to those used for the treatment of acromegaly (see discussion earlier). 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 is 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 LH-β 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 is difficult to achieve, 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). 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.

Because 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.

Pituitary Carcinoma

Pituitary carcinomas are extremely rare with fewer than 200 cases reported and defined by the distant metastases of a pituitary tumor. Most present as hormone-producing invasive macroadenomas with symptoms of mass effect. ACTH- and PRL-secreting tumors are most common. Metastases may present many years after diagnosis of the primary pituitary tumor. Survival rates are low and treatment may include additional surgery, radiotherapy, or chemotherapy.

Neuroendocrinology

Pituitary Function Testing and Neuroradiology

Pituitary Adenomas: General

ACTH: Cushing Disease

Growth Hormone: Acromegaly

PRL: Prolactinoma

Gonadotropins (LH/FSH): Gonadotropin-Secreting Pituitary Tumors

TSH-Secreting Pituitary Tumors

Hypopituitarism and Other Hypothalamic-Pituitary Disorders