Shlomo Melmed M.D.1
1Professor and Associate Dean, UCLA School of Medicine
The author has received research support and been a scientific consultant for Eli Lilly and Co. and Novartis Pharmaceuticals Corp. for the past 12 months.
May 2004
Functional Anatomy of the Pituitary
The pituitary gland regulates the critical hormonal functions of growth, development, reproduction, stress homeostasis, and metabolic control. Because of its prominent role in these processes, the pituitary has been termed the master gland.
The pituitary is situated within the sella turcica at the base of the brain and weighs about 600 mg. It comprises functionally distinct anterior and posterior lobes. The blood supply to the anterior pituitary is predominantly derived from the hypothalamic-pituitary portal vessels. The posterior lobe is supplied directly by the systemic inferior hypophyseal arteries.
Anatomically and functionally, the pituitary is closely linked with the hypothalamus [see Figure 1 and Table 1]. Neural cell bodies in the hypothalamus synthesize releasing and inhibiting hormones that control pituitary hormone secretion. These hypothalamic hormones are secreted into the portal vessels of the pituitary stalk and are transported to the anterior pituitary cell surface receptors.
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Figure 1. Structure of Pituitary Gland The anterior pituitary and the hypothalamus are connected by the hypophyseal portal vasculature. Releasing or inhibiting hormones secreted by hypothalamic neurons enter the primary plexus of the hypophyseal portal vasculature. They flow down the long portal veins in the pituitary stalk to the secondary plexus, a capillary network that enmeshes the cells of the anterior pituitary. The anterior pituitary cells secrete their hormones in response to the releasing hormones. Because neither the hypothalamus nor the anterior pituitary is isolated by the blood-brain barrier, feedback signals have direct access to both sites of regulation. The posterior pituitary is made up of the terminal portions of neurons whose origin is the hypothalamus. (ACTH—adrenocorticotropic hormone; ADH—antidiuretic hormone; FSH—follicle-stimulating hormone; GH—growth hormone; LH—luteinizing hormone; PRL—prolactin; TSH—thyroid-stimulating hormone) |
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Table 1 Hypothalamic and Related Pituitary Hormones |
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The anterior pituitary synthesizes and secretes adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH).1,2 The posterior pituitary secretes vasopressin (also known as antidiuretic hormone [ADH]) and oxytocin, both of which are synthesized in the hypothalamus.
Pituitary tropic hormones elicit responses from their respective target glands; the latter secrete endocrine hormones that activate specific tissue receptors. Circulating levels of these peripheral hormones influence secretion of their respective pituitary tropic hormone by negative feedback [see Table 2].
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Table 2 Pituitary Hormones, Their Mediators, and Their Effects |
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Pituitary Masses
LOCAL MASS EFFECTS
Pituitary masses can cause symptoms by secreting hormones, by impinging on adjacent structures, or both. These masses may also compress adjacent normal pituitary tissue, leading to pituitary failure. Expanding intrasellar lesions can exert significant compressive effects on surrounding vascular and neurologic structures, including the cavernous sinuses, cranial nerves, and optic chiasm. Intrasellar lesions may invade contiguous local structures and may compress central structures, depending on their anatomic location [see Figure 2]. The sellar roof presents the least resistance to soft tissue expansion from within the confines of the bony sella; this accounts for the vulnerability of the optic chiasm to sellar mass expansion. Small changes in intrasellar pressure may stretch the dural plate and cause headache, the severity of which does not necessarily correlate with mass size or extension. Chiasmic pressure can result in bilateral or unilateral visual defects. Pituitary stalk compression encroaches on the portal vessels, with resultant hyperprolactinemia and concurrent failure of other pituitary tropic hormones. Cavernous sinus invasion may lead to palsies of the third, fourth, and sixth cranial nerves, as well as lesions of the ophthalmic and maxillary branches of the fifth cranial nerve. Inferior extension through the bony sellar floor involves the sphenoid sinus; further extension into the palate roof may result in nasopharyngeal invasion and, rarely, cerebrospinal fluid leakage. Tumor invasion of the temporal or frontal lobe can cause seizures and personality disorders. Hypothalamic encroachment by an invasive pituitary mass may have metabolic sequelae, including precocious puberty or hypogonadism, diabetes insipidus, dysthermia, appetite disorders, and sleep disturbances.
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Figure 2. Cross Section of Pituitary Gland Cross section of the pituitary gland and adjacent structures. |
PITUITARY TUMORS
Pituitary Adenomas
Pituitary adenomas account for about 15% of all intracranial neoplasms. They arise from one of the specific anterior pituitary cell types as benign monoclonal expansions. Loss of heterozygosity of regions of chromosome 11q13, 13, and 9 occurs in up to 20% of larger sporadic pituitary tumors, suggesting the presence of tumor suppressor genes at these loci. Other factors involved in initiation and promotion of pituitary adenoma growth include loss of negative feedback inhibition, as seen with thyroidal or gonadal failure; intrapituitary paracrine growth factors (angiogenesis factors), mainly mediated by estrogen; and activation of any of several oncogenes.
Pituitary adenomas are usually diagnosed when they hypersecrete pituitary hormones or compress adjacent structures. Tumors arising from lactotroph, somatotroph, corticotroph, and thyrotroph cells hypersecrete PRL, GH, ACTH, or TSH, respectively [see Table 3]. Functional tumors exhibit autonomous tropic hormone secretion, leading to hyperprolactinemia, acromegaly, Cushing disease, or, rarely, TSH hypersecretion. Plurihormonal tumors may produce mixed clinical features. About one third of adenomas do not actively secrete hormones and are clinically nonfunctional. On autopsy, up to one quarter of patients are found to harbor an unsuspected microadenoma (diameter < 10 mm) with no apparent clinical sequelae. Rarely, ectopic secretion of GH-releasing hormone (GHRH) or corticotropin-releasing hormone (CRH) elaborated by abdominal or chest tumors results in hyperplasia of the cells that secrete GH or ACTH; these patients may present with pituitary hyperplasia and acromegaly or Cushing syndrome.
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Table 3 Effects of Pituitary Adenomas |
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Genetic Syndromes Associated with Pituitary Adenomas
Multiple endocrine neoplasia type I
Multiple endocrine neoplasia type I (MEN I) is an autosomal dominant syndrome caused by an inactivating mutation in the coding region of menin, a tumor suppressor gene located at the q13 locus of chromosome 11. The syndrome comprises parathyroid, pancreatic, and pituitary adenomas, including prolactinomas, and may present as acromegaly or Cushing syndrome.
Carney syndrome
Carney syndrome is an autosomal dominant syndrome associated with activated protein kinase activity. It comprises spotty skin pigmentation; myxomas; and testicular, adrenal, and pituitary adenomas.
McCune-Albright syndrome
The McCune-Albright syndrome is associated with chromosome 20q13.2 mosaicism and constitutive activation of cyclic adenosine monophosphate (cAMP). This syndrome manifests as polyostotic fibrous dysplasia (cancellous bone is replaced with immature woven bone and fibrous tissue), pigmented skin patches, precocious puberty, and acromegaly.
Familial acromegaly
Affected persons with this rare syndrome have acromegaly or gigantism and exhibit loss of heterozygosity at an 11q13 chromosomal locus distinct from that of menin.
Anterior Pituitary Hormones and Associated Disorders
PROLACTIN
Synthesis
Lactotrophs comprise about 20% of the anterior pituitary cells. Estrogen causes lactotroph cell hyperplasia, which occurs transiently during pregnancy and lactation. Central inhibitory control of PRL secretion is mediated predominantly by dopamine from the hypothalamus. Physiologic, pharmacologic, or pathologic alterations in dopamine availability or action disrupt PRL regulation. For example, if the hypophyseal-portal system is disrupted by pituitary compression or pituitary stalk damage and the flow of hypothalamic dopamine to the anterior pituitary is compromised, the resulting loss of lactotroph inhibition leads to PRL hypersecretion.3
Secretion
Normal serum PRL levels are 10 to 25 µg/L. The PRL level rises approximately 10-fold during pregnancy, as does the estrogen level. The PRL level declines rapidly within 2 weeks after delivery and returns to normal during the subsequent 3 months. Basal levels remain elevated during breastfeeding, and suckling induces a transient (approximately 30 minutes) reflex rise in PRL level.
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PRL induces and maintains puerperal lactation. It also attenuates reproductive function, thus helping to ensure that lactation is not interrupted by pregnancy. In the primed puerperal breast, integration of multihormonal signals—from PRL, placental lactogens, progesterone, and local paracrine growth factors—leads to lactation. PRL also enhances milk production by improving calcium absorption and mobilization.
Hyperprolactinemia
Etiology
Hyperprolactinemia has many possible causes; it may be physiologic, pathologic, or iatrogenic in origin [see Table 4]. Pregnancy, lactation, nipple stimulation, and chest wall lesions (including surgical incisions and herpes zoster) are associated with hyperprolactinemia. PRL-secreting pituitary adenomas (prolactinomas) produce the highest elevations of serum PRL levels (see Prolactinomas, below). Medications, compromised pituitary stalk function, hypothyroidism, and renal failure typically produce lesser elevations in PRL level [see Table 1]. Hypothalamic dopamine delivery may be disrupted by hypothalamic tumors, cysts, infiltrations, and radiation-induced damage. Plurihormonal tumors commonly hypersecrete PRL, and clinically nonfunctioning pituitary tumors may also compromise stalk integrity and cause hyperprolactinemia.
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Table 4 Causes of Hyperprolactinemia39 |
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Diagnosis
The clinical features of hyperprolactinemia vary by the sex of the patient. In males, PRL attenuates LH secretion, leading to low testosterone levels. Men with hyperprolactinemia present with diminished libido and diminished sexual potency, oligospermia, and lowered ejaculate volume; up to about 30% may have galactorrhea. In women, hyperprolactinemia leads to loss of pulsatile LH secretion, blunting of the LH peak, hypoestrogenism, and anovulation [see Figure 3]. Women with hyperprolactinemia develop oligomenorrhea and amenorrhea. Anovulation and estrogen deprivation result in vaginal dryness, dyspareunia, loss of libido, and infertility. Hyperprolactinemia is also associated with enhanced risk of bone loss, which is further exacerbated by associated hypoestrogenemia.
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Figure 3. Hyperprolactinemia in Women In women, hyperprolactinemia results in loss of pulsatile luteinizing hormone (LH) secretion and lowering of follicle-stimulating hormone (FSH) levels.39 (PRL—prolactin) |
In patients with clinical complaints consistent with hyperprolactinemia, a careful history and physical examination may reveal the source of the problem. Laboratory studies are indicated to exclude hypothyroidism, which can cause hyperprolactinemia. Alternatively, hypothyroidism and hyperprolactinemia can result from pituitary disease.
The degree of PRL elevation may offer a clue to the source of the prolactinemia. Prolactinomas account for most elevations of prolactin level higher than 100 µg/L; serum prolactin levels greater than 200 µg/L almost invariably indicate a prolactinoma.
All patients with symptoms of hyperprolactinemia and PRL levels above 30 µg/L should undergo MRI imaging of the pituitary. Small microadenomas (< 2 mm), which are undetectable on MRI scanning, may account for most cases of idiopathic hyperprolactinemia.
Treatment
Treatment of hyperprolactinemia is aimed at normalizing PRL levels, alleviating gonadal dysfunction and galactorrhea, and preserving bone mineral density. Medications known to alter PRL levels should be discontinued, if possible. Dose titration of critical neuroleptic drugs with a dopamine agonist can normalize serum PRL levels and alleviate reproductive dysfunction. Hyperprolactinemia usually resolves after thyroid hormone replacement in hypothyroid patients and after renal transplantation in patients with chronic renal failure who are on dialysis. Hypothalamic or nonadenomatous sellar mass lesions should be removed surgically. Spontaneous resolution of hyperprolactinemia occurs in up to 30% of patients, whether or not they have a visible pituitary microadenoma.
Prolactinoma
Prolactinomas arising from lactotrophs are the most common functional pituitary tumors, with an annual incidence of about three per 100,000 population. Microadenomas are less than 1 cm in diameter and do not invade the parasellar region. Macroadenomas are more than 1 cm in diameter, are locally invasive, and may compress vital structures, leading to symptoms such as headaches and visual defects. Microprolactinomas have a female preponderance (20:1). Macroadenomas occur equally in both sexes, although men usually present with larger tumors. Tumor size correlates with PRL concentrations—serum PRL values above 200 µg/L are invariably associated with larger adenomas.
Diagnosis
Prolactinoma should be suspected in patients with clinical signs of hyperprolactinemia (see above) and high random PRL levels. Men with prolactinomas tend to have relatively higher PRL levels than do women with prolactinomas. Diagnosis is confirmed by visualizing a pituitary adenoma on MRI.
Treatment
Prolactinomas can be treated medically, with cabergoline or bromocriptine [see Table 5], or, rarely, surgically.
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Table 5 Dopamine Agonists in the Treatment of Prolactinomas |
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Cabergoline is a long-acting dopamine agonist that suppresses prolactin for more than 14 days after a single oral dose and shrinks prolactinomas in most patients.4 The dosage is 0.5 to 1.0 mg twice weekly. Normal serum prolactin levels are achieved in about 80% of patients with microadenomas; normal gonadal function is restored and galactorrhea improves or resolves in 90% of patients. In patients with macroadenomas, cabergoline normalizes prolactin levels and shrinks the tumor in about 70% of cases. Cabergoline may be more effective in patients resistant to bromocriptine. Adverse effects and drug intolerance are less commonly encountered with cabergoline than with bromocriptine.
Bromocriptine mesylate is a D2 dopamine receptor agonist that normalizes prolactin secretion in up to 70% of patients with microadenomas; it decreases tumor size and restores gonadal function. Prolactin levels normalize in 70% of patients with macroadenomas, and tumor mass shrinkage of 50% or more is achieved in about 50% of patients. Headaches and visual disorders usually improve or resolve within days, and sexual function improves. Therapy is initiated with 0.625 to 1.25 mg given at bedtime with a snack, and the dosage is gradually increased. Successful control is usually achieved with a daily dose of less than 7.5 mg (i.e., 2.5 mg t.i.d.). About 20% of patients are resistant to the drug.
Side effects of dopamine agonists include transient nausea, vomiting, and postural hypotension with faintness; these symptoms occur in about 25% of patients. Other side effects include reversible constipation, nasal stuffiness, nightmares, and insomnia. For women who cannot tolerate orally administered agonists, intravaginal administration of bromocriptine tablets is often effective.
Indications for surgical resection of prolactinomas include resistance to or intolerance of pharmacologic treatment and the presence of an invasive macroadenoma that causes compromised vision and that fails to rapidly improve with dopamine agonists.5 Initial attempts at resection lead to normalization of prolactin levels in about 70% of patients with microprolactinomas but only 30% of patients with macroadenomas. Prolactinomas recur in up to 20% of patients within the first year after surgery; long-term recurrence rates for macroadenomas exceed 50%.
Therapeutic goals in patients with prolactinomas include control of hyperprolactinemia; reduction of tumor size; resolution of galactorrhea; and restoration of menses, fertility, or both [see Figure 4].6 Dopamine agonists suppress PRL secretion and synthesis and lactotroph cell proliferation. Patients are monitored with measurement of serum PRL levels, pituitary MRI scans, and visual field examinations. Once controlled, PRL levels can be measured every 6 months and MRI can be performed every 2 years. Medication doses are titrated to the lowest levels required to normalize PRL levels, restore reproductive function, and shrink the tumor mass.
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Figure 4. Management of Prolactinemia Management of prolactinoma. |
If fertility is not desired, no treatment of microprolactinoma may be needed. Such patients should be monitored through regular serial PRL measurements, pituitary MRI scans, and assessment of bone mineral density. For patients with macroadenomas, visual field testing is performed before initiating dopamine agonists. MRI results and visual fields should be assessed serially until the mass shrinks, and annually thereafter. Reduction in PRL levels invariably precedes radiographically evident tumor shrinkage, and failure to lower PRL levels usually portends lack of tumor shrinkage. Radiotherapy is reserved for the rare patients with aggressive tumors that do not respond to maximally tolerated dopamine agonists or surgery.
Prolactinomas and pregnancy
Women with prolactinomas who wish to become pregnant should receive bromocriptine and use barrier methods of contraception until they have had regular menses for 3 months; this will permit accurate conception dating. Contraception may then be discontinued. When pregnancy is confirmed, bromocriptine should be discontinued and PRL levels followed serially. The patient should be carefully monitored for headaches or visual field disturbance. Cabergoline is not approved for restoration of fertility.
During pregnancy, the pituitary swells and there is an increased risk of prolactinoma growth; in particular, up to 30% of macroadenomas may grow during pregnancy. In women harboring macroadenomas, bromocriptine is restarted if visual field defects develop. Although pituitary MRI is considered safe during pregnancy, it is reserved for patients who develop severe headache or documented visual field defects. In the rare cases in which vision is threatened during the third trimester, surgical decompression may be indicated. Bromocriptine can be safely restarted during pregnancy. Comprehensive surveillance data do not indicate an adverse impact on the fetus; nevertheless, this approach should be undertaken cautiously, and only with the patient's informed consent.
GROWTH HORMONE
Synthesis and Secretion
GH is the most abundant anterior pituitary hormone; GH-secreting somatotroph cells constitute about 50% of the pituitary cell population. GH is encoded by five distinct genes situated on chromosome 17q22. The pituitary GH gene gives rise to a circulating form of GH that is 22 kilodaltons in size, and to a less abundant, cleaved 20-kd GH molecule. Placental syncytiotrophoblast cells express a GH variant, as well as chorionic somatotrophin. Somatotroph development and pituitary GH expression are largely determined by the Pit-1 nuclear transcription factor, whose mutations may also account for rare cases of hereditary pituitary failure.
GH secretion is controlled by complex hypothalamic and peripheral factors. Hypothalamic GHRH and somatostatin release-inhibitor factor (SRIF) stimulate and inhibit GH secretion, respectively. Ghrelin is synthesized predominantly in the gastrointestinal tract and stimulates GH secretion by binding to a specific pituitary GH secretagogue receptor.7 SRIF is also expressed in extrahypothalamic tissues, including the GI tract and the pancreas. SRIF binds to five distinct receptor subtypes (SSTR1 to SSTR5), of which SSTR2 and SSTR5 are expressed on the surface membranes of pituitary cells. Signaling through the SSTR2 and SSTR5 subtypes preferentially suppresses secretion of GH (and also TSH). Insulinlike growth factor-1 (IGF-1), the peripheral target hormone for GH, inhibits GH via negative feedback.
GH secretion occurs in pulsatile peaks, interspersed by periods during which GH may be undetectable.8 GH secretion peaks during puberty and declines by middle age, in parallel with age-related decline in muscle mass. Mean integrated nocturnal GH levels are at least twice that of daytime levels. GH levels rise within 1 hour after onset of deep sleep, as well as after exercise and trauma. GH secretion is low in the elderly and the obese and is higher in women; GH secretion is enhanced by estrogen replacement therapy. Increased GH pulse frequency and peak amplitudes occur with chronic malnutrition and prolonged fasting. Glucose loading suppresses GH to below 0.7 µg/L in women and below 0.07 µg/L in men. A complex interaction of nutritional factors and hypothalamic appetite-regulating peptides, including leptin, mediate GH secretion. Therefore, random measurements of GH levels do not readily identify adult patients with GH deficiency.9 Differences in linear growth patterns in males and females may reflect differences in GH pulsatility. Higher GH pulses observed in males, as compared with the relatively continuous GH secretion patterns in females, may determine liver enzyme induction and postreceptor activity levels of GH-signaling molecules.
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Peripheral GH receptors are most abundant in the liver. The extracellular domain of GH receptors is a soluble form—GH binding protein (GHBP)—which circulates in the blood. Binding of GH to its receptor induces intracellular signaling that is mediated by a phosphorylation cascade involving the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway.10
In children and adolescents, GH stimulates the differentiation of epiphyseal prechondrocytes into IGF-1-responsive cells. GH also induces local IGF-1 and chondrocyte expansion. Linear growth is maintained by complex endocrine and paracrine mechanisms. In persons of all ages, GH antagonizes insulin action, impairs glucose tolerance, induces protein synthesis, enhances lipolysis, and increases lipid oxidation.
Insulinlike growth factors
The IGF family of polypeptide growth factors comprises IGF-1, IGF-2, and proinsulin. IGF-1 in peripheral tissue exerts local paracrine actions, which are both GH dependent and independent. GH induces increases in circulating levels and tissue levels of IGF-1. Both IGF-1 and IGF-2 are bound to one of six high-affinity circulating IGF binding proteins (IGFBPs) that also regulate IGF bioactivity. IGFBP3 is GH dependent and is the major carrier protein for circulating IGF-1. GH deficiency, GH insensitivity, and malnutrition are associated with low IGFBP3 levels. Serum IGF-1 levels increase throughout puberty, peak at 16 years of age, and decline thereafter. Concentrations are higher in female subjects, especially during puberty. IGF-1 levels are lower in patients with GH deficiency, cachexia, malnutrition, or sepsis; they are invariably high in patients with acromegaly.
Adult GH Deficiency
Somatotroph damage and the subsequent development of pituitary tropic hormone deficiency follows a sequential pattern in which loss of adequate GH reserve usually foreshadows subsequent deficits of other pituitary hormones. The presence of central hypogonadism, hypothyroidism, or hypoadrenalism invariably implies concomitant GH deficiency. About half of all patients with pituitary insufficiency will already manifest GH deficiency if specifically tested.
Diagnosis
Clinically, GH deficiency in adults is marked by impaired quality of life, body composition changes, and decreased exercise capacity [seeTable 6]. Cardiovascular risk factors increase in patients with GH deficiency; indeed, the increase in mortality associated with adult hypopituitarism, and, possibly, GH deficiency in particular, is primarily from cardiovascular and cerebrovascular disease.11 Because adult GH deficiency is rare and its symptoms are largely nonspecific, patients should be carefully selected for evaluation on the basis of well-defined risk criteria. These criteria include a history of pituitary surgery; pituitary or hypothalamic mass lesions; cranial irradiation; the need for GH replacement therapy in childhood, or the finding of a low IGF-1 level, as compared to the age- and sex-matched population.12 A subnormal evoked GH response (i.e., < 3 µg/ml) to a standard GH stimulation test establishes the diagnosis of adult GH deficiency. If other pituitary tropic hormone deficits are present, GH deficiency will be an inevitable concomitant finding; for that reason, some experts have recommended that GH testing not be required in this setting.13 About 25% of GH-deficient adults have normal IGF-1 levels.
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Table 6 Findings in Adult Growth Hormone Deficiency39 |
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Treatment
GH replacement is indicated for adult patients with unequivocal GH deficiency.14 The decision to treat is also determined by informed patient perception of therapeutic benefits, including prevention of future ischemic heart disease and skeletal fractures, improved exercise capacity and energy levels, and enriched quality of life. For replacement therapy, GH is started at a dosage of 0.15 to 0.2 mg/day and titrated to a maximum of 1.25 mg/day, to maintain midrange age- and sex-matched IGF-1 levels. Women require higher GH doses than men, and elderly patients require lower doses.15
Contraindications to therapy include the presence of an active neoplasm or both uncontrolled diabetes and retinopathy. The risks of pituitary tumor regrowth are currently being assessed in long-term surveillance studies.
The side effects of GH replacement include reversible dose-related fluid retention, joint pain, and myalgia and parethesia associated with carpal tunnel syndrome. These side effects occur in up to 30% of patients.16 Patients with type 2 (non-insulin-dependent) diabetes mellitus will initially experience increased insulin resistance. However, glycemic control may improve in association with sustained loss of abdominal fat during long-term GH replacement.
If after 6 months there is no clinical response to GH replacement, treatment should be discontinued. In patients who show a response, GH replacement is continued in conjunction with regular monitoring of IGF-1 levels, lipids, and bone density.
GH is not indicated for adults with intact pituitary function, except for those with AIDS-related cachexia. The hormone should not be used for nonapproved indications, because the risk of side effects—especially glucose intolerance and fluid retention—outweigh potential benefits ascribed to improved muscle energy and anti-aging properties. Results of prospective controlled trials for these potential indications are not yet at hand.
Acromegaly
Etiology
GH hypersecretion usually results from a GH-secreting pituitary adenoma [see Table 7]. Occasionally, patients with partially empty sella may harbor a small GH-secreting adenoma within the compressed rim of pituitary tissue. Rarely, GH is secreted ectopically by abdominal or chest tumors. GHRH may be elaborated by hypothalamic tumors or carcinoid tumors in the chest or abdomen, causing acromegaly through chronic somatotroph overstimulation.
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Table 7 Causes of Acromegaly |
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Diagnosis
The manifestations of GH and IGF-1 hypersecretion are protean and develop slowly; they are often not diagnosed for 10 years or more [seeTable 8]. Acral bony overgrowth results in frontal bossing, increased hand and foot size, and mandibular enlargement with prognathism and a widening of incisor spaces. GH hypersecretion that occurs before epiphyseal long-bone closure causes pituitary gigantism. Soft tissue swelling results in coarse facial features; increased heel pad thickness; and enlargement of the feet and hands, evidenced by increased shoe or glove size and ring tightening. Hyperhidrosis; oily skin; a deepening of the voice; arthropathy; kyphosis; carpal tunnel syndrome; proximal muscle weakness and fatigue; skin tags; and visceromegaly, including macroglossia, cardiomegaly, thyroid, and salivary gland enlargement, may be encountered. About 30% of patients develop coronary artery disease, cardiomyopathy with arrhythmias, left ventricular hypertrophy, decreased diastolic function, or hypertension. Sleep apnea, caused by soft tissue laryngeal airway obstruction or central sleep dysfunction, is an important comorbidity. Diabetes develops in 25% of patients, because GH is a potent insulin antagonist; most patients with elevated GH levels are intolerant of glucose. Colon polyps are present in up to one third of patients. Overall mortality is enhanced about threefold, primarily as a result of cardiovascular and cerebrovascular disorders and respiratory disease. Unless GH levels are tightly controlled, survival is reduced by an average of 10 years compared with an age-matched control population.
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Table 8 Features of Acromegaly |
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Measurement of serum IGF-1 can be used for case finding in patients with possible acromegaly; in patients with GH hypersecretion, IGF-1 levels are invariably elevated, as compared with the levels in the age- and sex-matched population. Single random GH measurements are not useful for diagnosis. Instead, diagnosis is confirmed by demonstrating a failure to suppress GH levels to below 1 µg/L within 1 to 2 hours after an oral glucose load (75 g); about 20% of patients exhibit a paradoxical glucose-induced rise in GH. PRL levels are elevated in about 25% of patients. Thyroid function studies and assays of gonadotropin and sex steroid levels may show attenuation, which is the result of the compressive effects of an expanding pituitary mass.
Treatment
Control of acromegaly can be achieved by a judicious application of multimodal therapeutic approaches.17,18 Therapeutic interventions include surgery, somatostatin analogues, and dopamine agonists. Transsphenoidal surgical resection by an experienced surgeon is indicated for both microadenomas and macroadenomas. Resection results in control of disease in about 70% of patients with microadenomas but in less than 50% of patients with macroadenomas. GH levels fall rapidly after tumor resection, and IGF-1 levels return to normal within 3 to 4 days. The disorder recurs in about 10% of patients, and pituitary failure develops in up to 15% of patients after surgery. Persistent postoperative GH hypersecretion necessitates adjuvant therapy, typically with somatostatin analogues.
Octreotide acetate is an 8-amino acid synthetic somatostatin analogue that binds mainly to SSTR2 receptors and effectively controls GH hypersecretion.19 Octreotide is given in a dosage of 50 to 400 µg subcutaneously every 8 hours. Within an hour of receiving an injection, most patients experience an 80% reduction in GH level. About 10% of patients show no response. Rapid relief of headache and soft tissue swelling occurs, with amelioration of excessive perspiration, obstructive apnea, and cardiac failure. Significant pituitary tumor shrinkage occurs in about 40% of patients.20 A long-acting octreotide formulation, Sandostatin LAR Depot, provides sustained GH suppression, with effects lasting for up to 6 weeks after a 30 mg intramuscular injection. Long-term treatment with monthly injections of 20 to 40 mg maintains GH and IGF-1 suppression in about 70% of patients, and pituitary tumor size is controlled. Because it is effective, and well tolerated and is less inconvenient for the patient than subcutaneous preparations, the long-acting formulation is the medical treatment choice for these patients.21,22
Side effects of somatostatin analogues are typically minor and transient; they are mostly related to suppression of GI motility and secretion. Nausea, abdominal discomfort, diarrhea, and flatulence occur in one third of patients but usually remit within 2 weeks. In the United States, up to 30% of patients receiving long-term treatment develop echogenic gallbladder sludge or asymptomatic cholesterol gallstones. Mild glucose intolerance, hypothyroxinemia, asymptomatic bradycardia, and local pain at the injection site have been reported.
Bromocriptine may suppress GH secretion in some patients. High doses (i.e., 20 mg/day or more) are usually required. About 10% of patients receiving bromocriptine have normalized IGF-1 levels. Cabergoline suppresses GH when given at a relatively high dosage (i.e., 0.5 mg/day). Combination treatment with octreotide plus cabergoline offers additive biochemical control compared with either drug alone.
GH antagonists have been developed. These new GH analogues antagonize GH action by blocking peripheral GH receptor binding. Pegvisomant, administered in daily subcutaneous injections, lowers serum IGF-1 levels and so may block the deleterious peripheral effects of GH. GH levels may remain elevated, but the excess hormone is effectively inactive. Long-term monitoring of pituitary adenoma size and liver function testing are suggested. The drug is particularly useful in those patients with persistently elevated IGF-1 levels and controlled GH levels.
External radiation therapy or high-energy radiosurgery suppresses GH levels to below 5 µg/L, although 50% of patients require at least 8 years of therapy for this outcome.23 Interim medical therapy is required in the years before patients attain maximal radiation benefits. Most patients also develop gonadotropin, ACTH, or TSH deficiency within 10 years of therapy. Rarely, visual deficits, brain necrosis, or new tumor formation are encountered. Stereotactic ablation of GH-secreting adenomas by gamma-knife radiosurgery is promising, but compelling long-term results are not yet available, and long-term side-effect profiles have not been established.
The initial treatment option for well-circumscribed GH-secreting tumors is surgical resection. Somatostatin analogues reduce GH hypersecretion and are used for preoperative shrinkage of large, invasive macroadenomas; for immediate relief of debilitating symptoms in frail patients experiencing morbidity; for patients who decline surgery; and for patients in whom surgery fails to result in biochemical control, as is inevitable in cases of invasive adenoma.24 Irradiation or repeat surgery is indicated for patients for whom medical therapy fails. The main disadvantages of radiotherapy are the slow rate of biochemical response (i.e., 5 to 15 years) and the high rate of hypopituitarism. Comorbid features of acromegaly, including cardiovascular disease, diabetes, and arthritis, should be aggressively treated. Maxillofacial surgery may be indicated for mandibular repair.
Adrenocorticotropic Hormone Synthesis
Up to 20% of the pituitary consists of ACTH-secreting corticotroph cells. These cells express products of the POMC (pro-opiomelanocortin) gene, which include 1-39 ACTH, β-lipotropin, and endorphins. β-Lipotropin gives rise to α-lipotropin and β-endorphin; the latter contains the sequence for met-enkephalin. The POMC gene, located on chromosome 2, possesses different promoter regions that determine pituitary-specific and peripheral tissue-specific POMC expression, respectively. Ectopic ACTH/POMC transcripts are expressed in gonads, placenta, GI tissues, kidney, adrenal medulla, lung, and lymphocytes; POMC products also arise from peripheral neuroendocrine tumors.
Secretion
ACTH synthesis and release are stimulated by CRH. In addition, ACTH release is induced by vasopressin, cytokines, physical stress, exercise, acute illness, and hypoglycemia.
ACTH secretion is pulsatile and follows a circadian rhythm that is highest in early morning and declines at night. This rhythm is paralleled by a diurnal pattern of adrenal glucocorticoid secretion. ACTH levels peak at 6 A.M., with values ranging from 8 to 25 pg/ml; peak values are approximately fourfold higher than the nadir levels measured between 11 P.M. and 3 A.M. Glucocorticoids suppress CRH and ACTH release. The loss of cortisol inhibition that occurs with primary adrenal failure results in extremely high compensatory ACTH levels.
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The hypothalamic-pituitary-adrenal (HPA) axis maintains metabolic homeostasis and mediates the neuroendocrine stress response. The pituitary affects the pattern and quantity of adrenal cortisol secretion by integrating peripheral and central signals. The neuroendocrine stress response reflects the net result of sensitively integrated hypothalamic, intrapituitary, and peripheral hormone and cytokine signals, resulting in cortisol production. The HPA axis is triggered by acute inflammatory or septic insults that mediate release of inflammatory cytokines, bacterial toxins, and neural signals. ACTH stimulates steroidogenesis by maintaining adrenal cell proliferation and function. Cortisol elevation curtails the inflammatory response and provides host protection.
Pro-opiomelanocortin peptides and appetite control
Several lines of experimental and clinical evidence implicate the POMC system in appetite control. The melanocortin receptor family comprises important regulators of central appetite control. Inactivation of MC-2 receptors leads to obesity, hypoadrenalism, and red hair pigmentation. Disruption of MC4 receptors is associated with childhood obesity and elevations in the level of circulating leptins; disruption is also genetically linked to the POMC gene locus [see 3:X Obesity].
HPA Axis Testing
Insulin-induced hypoglycemia and cortisol levels
Intravenous administration of insulin (0.05 to 0.3 U/kg) lowers blood glucose levels to 50% of baseline within 30 minutes. This evokes plasma cortisol increases of 7 mg/dl or greater; peak cortisol levels of at least 20 µg/dl are evoked within 30 to 45 minutes of nadir blood glucose levels and indicate intact pituitary ACTH reserve production.
Metyrapone
The pituitary response to a decrease in the serum cortisol level can be assessed with metyrapone testing. A 3 g oral dose of metyrapone administered at 11 P.M. with a snack blocks conversion of the cortisol precursor 11-deoxycortisol (compound S) to cortisol. The resulting fall in serum cortisol level normally stimulates ACTH secretion, raising the compound S level to above 8 µg/dl at 8 A.M. the next morning. Cortisol inhibition by metyrapone can be confirmed by finding that the plasma cortisol level is less than 5 µg/dl.
Synthetic ACTH
Injection of synthetic ACTH (Cortrosyn) at a dose of 250 µg intravenously or intramuscularly evokes adrenal cortisol reserve after 30 and 60 minutes. Cortisol levels should rise to at least twice the baseline value, rise at least 7 µg/dl, or peak at above 20 µg/dl; any one of those three reactions indicates normal reserve. Blunted cortisol responses to ACTH reflect compromised pituitary ACTH reserve, primary adrenal failure, or steroid ingestion.
CRH
Intravenous CRH, 1 µg/kg, directly stimulates ACTH secretion during the 60 minutes after injection. Pituitary damage prevents an evoked response. Patients with Cushing disease associated with an ACTH-secreting corticotroph cell adenoma often have exaggerated ACTH responses to CRH. CRH injection does not stimulate a further rise in ACTH secretion by ectopic ACTH-secreting tumors.
ACTH Deficiency
Diagnosis
Clinically, pituitary ACTH deficiency results in secondary hypocortisolism with tiredness, weakness, anorexia, nausea, and vomiting; occasionally, hypoglycemia results from diminished counterregulation of insulin. Stressful acute illness may unmask the presence of partial ACTH deficiency and cause life-threatening hypocortisolism.
On laboratory testing, ACTH deficiency is characterized by inappropriately low ACTH levels in conjunction with low cortisol levels. Low basal serum cortisol levels or blunted cortisol responses to provocative ACTH stimulation reflect diminished adrenal reserve caused by prolonged insufficient ACTH tropic action on the adrenal cortex.
Treatment
Hydrocortisone replacement reverses most clinical and biochemical features of cortisol deficiency. Hydrocortisone is given two or three times daily. The total daily dose should usually not exceed 20 mg. Doses should be increased severalfold during periods of acute illness or stress.
ACTH-Secreting Adenoma (Cushing Disease)
ACTH-producing adenomas account for about 10% to 15% of all pituitary adenomas and are usually well-differentiated microadenomas. Cushing syndrome is also caused by ectopic ACTH production by tumors, including small-cell lung carcinomas and bronchial and thymic carcinoids. In contrast to ACTH secretion by pituitary tumors, which can be suppressed by high-dose glucocorticoids, ectopic ACTH secretion by neoplasms is usually not suppressible, a fact that highlights the unrestrained malignant gene expression.
Diagnosis
Unrestrained ACTH secretion causes hypercortisolemia, which results in thin, brittle skin; central obesity; hypertension; plethoric moon facies; purple striae and susceptibility to bruising; glucose intolerance or diabetes; gonadal dysfunction; osteoporosis; proximal muscle weakness; acne; hirsutism; and labile depression, mania, or psychosis [see Table 9]. Leukocytosis, lymphopenia, and eosinopenia also may develop. In young women, osteoporosis may be particularly prominent. Cardiovascular disease is the primary cause of death.
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Table 9 Clinical Features of Cushing Syndrome40 |
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The differential diagnosis of ACTH-secreting pituitary tumor includes other causes of hypercortisolism: iatrogenic glucocorticoid administration, ectopic ACTH-secreting tumor, and cortisol-secreting adrenal tumor. In ectopic Cushing syndrome, manifestations usually develop acutely: patients present with florid skin hyperpigmentation, severe myopathy, hypertension, hypokalemic alkalosis, glucose intolerance, and edema. Serum potassium levels are below 3.3 mmol/L in most patients with ectopic ACTH secretion.
The diagnosis of pituitary Cushing disease requires documentation of hypercortisolism in the presence of pituitary-derived ACTH elevation. Reproducible markers for hypercortisolism include the failure to experience suppression of the cortisol level after a dose of dexamethasone and an elevation in 24-hour urinary free cortisol level. Urinary cortisol levels greater than 300 µg/day indicate the presence of Cushing syndrome. Urinary 17-hydroxysteroid levels reflect secretion of cortisol metabolites.
In general, ACTH-secreting pituitary tumors retain feedback responsiveness to circulating glucocorticoids. Basal ACTH levels are usually about eightfold higher in patients with ectopic ACTH secretion, but considerable overlap with pituitary adenoma-derived ACTH may preclude an accurate biochemical distinction of the two disorders. In patients with endogenous (adrenal) or exogenous (iatrogenic) Cushing syndrome, ACTH levels are suppressed. Elevated concentrations of circulating ACTH and cortisol measured at midnight usually indicate the presence of Cushing syndrome.
Dynamic testing should be undertaken when hypercortisolemia has been rigorously documented.25 Dexamethasone suppression of ACTH and ultimately of cortisol levels is the standard test for diagnosis of ACTH-dependent Cushing disease. Ingestion of 1 mg oral dexamethasone at 11 P.M. should result in suppression of serum cortisol levels to below 7 µg/dl at 8 A.M. the next morning, unless obesity, chronic depression, or alcoholism is present. In patients with ACTH-secreting pituitary adenomas or ectopic tumors, overnight dexamethasone does not suppress plasma ACTH or serum cortisol levels, and longer-term dexamethasone suppression testing is required. Baseline pretesting of 24-hour urinary free cortisol and 17-ketosteroids or 17-hydroxysteroid values is followed by administration of low-dose dexamethasone (0.5 mg every 6 hours) for 2 days. Plasma ACTH, serum cortisol, and 24-hour urinary free cortisol levels remain elevated in patients with Cushing disease. High-dose dexamethasone (2 mg every 6 hours) for the subsequent 2 days will usually suppress 17-hydroxysteroid levels by 50% or less and suppress urinary free cortisol to less than 90% of baseline in patients with pituitary ACTH-secreting tumors, but this result will be seen in only 10% of those patients with ectopic ACTH secretion.
MRI scanning is indicated for patients with documented hypercortisolemia and nonsuppressed ACTH levels. If a pituitary mass is clearly visible on MRI, transsphenoidal surgical resection should be undertaken after rigorous biochemical confirmation of pituitary-derived ACTH hypersecretion. However, most ACTH-secreting tumors are less than 5 mm in diameter; about half are less than 2 mm in diameter, and so are undetectable even by sensitive MRI. Therefore, MRI has only limited ability to visualize ACTH-secreting pituitary tumors. Bilateral inferior petrosal sinus ACTH sampling before and after CRH administration may distinguish pituitary from ectopic ACTH hypersecretion.26Because most ectopic ACTH-secreting tumors are located in the chest or abdomen, imaging studies of those areas are indicated for diagnosis. The diagnosis of ectopic ACTH secretion is ultimately confirmed by four measures: (1) rigorous exclusion of a pituitary lesion; (2) demonstration of an arteriovenous ACTH gradient over the tumor bed; (3) resolution of hypercortisolism with excision of the tumor; and (4) confirmation of POMC gene expression in excised tumor tissue.
Adrenal imaging is indicated when suppressed ACTH levels point to an adrenal origin of hypercorticolism. Bilateral adrenal hyperplasia with cortical thickening usually indicates tropic effects of ACTH hypersecretion. Adrenal adenomas causing Cushing syndrome are usually clearly visible, and adrenal carcinomas are larger than adenomas (> 2 cm). The contralateral gland may be normal or atrophic. Adrenal nodularity may occur unilaterally or bilaterally, with approximately 50% of glands appearing normal [see 3:IV The Adrenal].
Treatment
Selective transsphenoidal resection after careful preoperative localization is the preferred treatment for ACTH-secreting pituitary adenomas.27 Remission rates are about 80% for microadenomas but less than 50% for the less common ACTH-secreting macroadenomas. After successful surgery, patients may experience a period of compensatory adrenal insufficiency for up to 6 months and may require low-dose cortisol replacement during that time. Within 5 years of the operation, approximately 5% of patients in whom surgery was initially successful will experience biochemical recurrence.
Patients with ACTH hypersecretion that is not controlled by surgery require pituitary irradiation. Cortisol-lowering agents (i.e., mitotane, ketoconozole, or aminoglutethimide) are administered after irradiation to achieve earlier biochemical remission. Rarely, all these measures fail, and bilateral adrenalectomy is required.
FOLLICLE-STIMULATING HORMONE AND LUTEINIZING HORMONE
Synthesis
Gonadotroph cells comprise up to 10% of anterior pituitary cells. The gonadotropins FSH and LH (along with TSH and human chorionic gonadotropin) are glycoprotein hormones comprising a common α and a specific β subunit. Gonadotroph cells exhibit cytoplasmic immunostaining for both FSH and LH β subunits, as well as for the common α subunit. Primary gonadal failure, resulting from gonadal damage, is associated with hyperplastic gonadotroph cells with accumulation of hormone secretory granules, reflecting loss of negative feedback by peripheral sex steroids.
Hypothalamic gonadotropin-releasing hormone (GnRH) regulates both LH and FSH secretion. GnRH, under positive feedback control by peripheral estrogens, is secreted in a pulsatile fashion every 60 to 120 minutes; it regulates the complex reproductive cycles. Activins also induce gonadotropins, whereas inhibins suppress their secretion.
ACTIONS
Gonadotropins interact with their respective cell surface receptors on the ovary and testis, thereby controlling the development and maturation of germ cells and the synthesis of steroid hormones. In women, LH mediates ovulation and the maintenance of the corpus luteum, and FSH mediates ovarian follicle development and induces ovarian estrogen production. In men, LH induces testosterone secretion by the Leydig cells, and FSH regulates seminiferous tubule development and stimulates spermatogenesis.
Gonadotropin Deficiency
Gonadotropin secretion is sensitive to pituitary damage, and hypogonadism is the most common presenting feature of adult hypopituitarism. Congenital or acquired central hypogonadotropic hypogonadism results from a pituitary or hypothalamic disorder that disrupts GnRH availability. Hypothalamic defects causing hypogonadism include Kallmann syndrome and a mutation in the DAX-1 gene that is associated with deficient GnRH and pituitary gonadotropin synthesis. Inactivating mutations in the LH and FSH β-subunit gene cause hypogonadism by disrupting gonadotropin formation and function.
Diagnosis
Clinical features of hypogonadism depend on the age at onset of the disorder. Primary amenorrhea, immature internal and external genitalia, absent secondary sex characteristics, and eunuchoidal body proportions occur in adolescent girls. In premenopausal women, decreased ovarian function presents as oligomenorrhea or amenorrhea, infertility, decreased vaginal secretions, decreased libido, breast atrophy, and hot flushes. The onset of hypogonadotropism during male adolescence results in sexual infantilism, with a smooth scrotum and small penis, diminished or absent postpubertal sex drive, absent secondary sexual characteracteristics, central obesity, eunuchoid proportions, delayed epiphyseal closure, and a characteristic high-pitched prepubertal voice. In men, testicular failure is associated with decreased libido and potency, infertility, decreased muscle mass with weakness, attenuated beard and body hair growth, soft testes, and fine facial wrinkles [see 3:II Testes and Testicular Disorders]. Prolonged hypogonadism results in osteoporosis in both females and males.
Central hypogonadism is diagnosed by a finding of low-normal or low serum gonadotropin levels and low sex hormone concentrations (testosterone in males, estradiol in females). Male patients have abnormal results on semen analysis. Normal values for circulating FSH and LH in menstruating women are 4 to 20 mIU/ml, depending on the menstrual phase; levels rise considerably with menopause. FSH and LH levels in men are 1 to 12 mIU/ml. Normal total testosterone levels in men are above 280 ng/100 ml; the serum testosterone concentration should be measured at about 8 A.M., when it is at its peak [see 3:II Testes and Testicular Disorders]. In women, circulating estradiol levels vary with the menstrual cycle.
Pituitary gonadotropin deficiency can sometimes be confirmed with GnRH stimulation testing. Gonadotrophs are stimulated by intravenous injection of 100 µg GnRH; evoked LH levels peak within 30 minutes, and FSH plateaus during the subsequent 60 minutes. Normal responses vary with the age and sex of the subject and, in women, the menstrual cycle stage. However, a robust gonadotropin response does not necessarily exclude pituitary gonadotroph damage, and the absence of a response does not reliably distinguish pituitary from hypothalamic causes of hypogonadism. In patients with documented central hypogonadism, pituitary MRI and pituitary function testing are required.
Treatment
In premenopausal women, estrogen and progesterone replacement therapy results in the maintaining of secondary sexual characteristics and genitourinary tract integrity and prevents osteoporosis. Gonadotropin therapy is used for ovulation induction. Pulsatile GnRH is effective for treating hypothalamic hypogonadism. In women who exercise vigorously and maintain a low body mass index (e.g., athletes and ballet dancers), caloric replacement may restore menses. In males, testosterone replacement therapy will result in the attaining and maintaining of growth and development of the external genitalia and secondary sexual characteristics, and patients will maintain libido, muscle mass, and bone density [see 3:II Testes and Testicular Disorders].
Nonfunctioning Pituitary Adenomas
So-called nonsecreting adenomas arising from gonadotroph cells are the most common pituitary adenomas. Because these adenomas are clinically nonfunctional, they usually produce no distinct hypersecretory syndrome.28 Some adenomas express gonadotropin α-subunits but not intact FSH or LH molecules, and administration of thyrotropin-releasing hormone (TRH) may inappropriately evoke gonadotropins or subunit secretion. Clinically inactive, asymptomatic pituitary microadenomas are commonly encountered as incidental findings on MRI; these are termed pituitary incidentalomas.
Diagnosis
Nonsecreting adenomas may be incidentally discovered on an MRI performed for another indication. Mass effects, including optic chiasm pressure and other neurologic symptoms, are the usual initial presenting symptoms of large tumors. Gradual onset of visual defects with progressive bitemporal field defects, scotoma, or impaired acuity may occur. Compression of surrounding pituitary tissue by an adenoma may disrupt gonadotropin secretion, resulting in hypogonadism. Amenorrhea and infertility occur in women, whereas men present with progressively decreased potency and low testosterone levels. Rarely, excess FSH or LH secretion results in ovarian hyperstimulation or the downregulation of the reproductive axis.
On laboratory testing, circulating gonadotropin α-subunit levels are elevated in about 15% of male patients. TRH administration evokes LH β-subunit levels in most patients of both sexes. The serum prolactin level should be measured: an elevation suggests a prolactinoma; a PRL level below 100 µg/L in a hypogonadal patient harboring a pituitary mass suggests pituitary stalk compression by a nonfunctioning adenoma. In postmenopausal women, physiologic elevations of FSH concentrations may be difficult to distinguish from tumor-derived FSH elevations. Primary ovarian or testicular failure may lead to compensatory gonadotroph cell hyperplasia and uniformly elevated LH and FSH levels.
Treatment
Nonfunctioning microadenomas have a benign natural history. They are slow-growing and can safely be followed with annual imaging and visual testing, as long as the patient remains asymptomatic. Nonfunctioning pituitary masses greater than 1 cm in diameter should be resected. These larger masses should be distinguished from nonadenomatous lesions by MRI characteristics and histologic evaluation of resected tissue.29 After resection, the tissue diagnosis of a clinically nonsecreting gonadotroph adenoma should be confirmed.30 Visual improvement occurs in 70% of patients with preoperative visual field defects. Hypopituitarism resulting from compression of normal pituitary tissue improves and may resolve completely. Early complications of surgery include diabetes insipidus, inappropriate antidiuretic hormone secretion, or both. Approximately 15% of tumors recur within 5 to 6 years after initially successful surgical resection.31 Adjuvant pituitary radiotherapy after transsphenoidal surgery has been advocated to prevent future tumor regrowth in patients with residual adenoma tissue.32
THYROID-STIMULATING HORMONE
Synthesis
TSH-secreting thyrotroph cells constitute 5% of the anterior pituitary cell population. Hypothalamic TRH stimulates TSH synthesis and secretion. TRH also stimulates lactotroph cells to secrete PRL. Thyroid hormones, dopamine, SRIF, and glucocorticoids suppress TSH and override TRH induction. Thyroid damage, including surgical thyroidectomy, radiation-induced hypothyroidism, chronic thyroiditis, or prolonged goitrogen exposure are associated with reversible thyrotroph hypertrophy and hyperplasia with prominent TSH secretory granules and sellar enlargement. Thyrotroph cells regress with thyroid hormone treatment and hormone-mediated TSH suppression.
TSH Deficiency
Hypothyroidism from TSH deficiency has the same clinical features as primary hypothyroidism [see 3:I Thyroid]. On thyroid function testing, however, patients with pituitary hypothyroidism have low levels of both TSH and thyroxine (T4). Patients with hypothyroidism of hypothalamic origin have normal, low, or slightly elevated TSH levels and low T4 values.
Testing of TSH reserve is used to confirm the diagnosis of central hypothyroidism. Twofold to threefold increases in TSH levels occur within 30 minutes of an intravenous injection of TRH (200 µg) in normal patients. Primary hypothyroidism is associated with an exaggerated TSH response to TRH because of release of the thyrotroph from negative feedback inhibition. Hyperthyroidism, exogenously administered thyroid hormone, and pituitary damage result in blunted TSH responses to TRH.
Thyrotropin-Secreting Adenomas
TSH-producing pituitary adenomas are very rare. Patients with these tumors usually present with a goiter and mild or frank hyperthyroidism.33 The diagnosis is made by demonstrating elevated serum T4 levels, inappropriately high TSH or α-subunit secretion, and evidence of a pituitary adenoma on MRI. These tumors are usually large and locally invasive. Administration of thyroid hormone fails to suppress TSH secretion, wheras administration of TRH evokes a blunted TSH response. In such cases, it is important to exclude thyroid hormone resistance, which can produce abnormalities in TSH and T4 levels identical to those seen with TSH-producing adenomas.
Treatment
TSH-producing pituitary adenomas are debulked surgically. Total resection is often not achieved because most of these tumors are large and locally invasive. Postoperative treatment with a somatostatin analogue controls residual TSH and α-subunit hypersecretion, shrinks the tumor mass in approximately 50% of patients, and improves visual fields in about 75% of patients.
Posterior Pituitary Hormones and Associated Disorders
Vasopressin and oxytocin are stored in the posterior pituitary and released in response to appropriate stimuli. Serum vasopressin levels (and, thus, urinary concentrations) vary in response to changes in serum osmolality. The sensitivity and, to a lesser extent, the threshold of vasopressin response to a change in tonicity show considerable variability from one person to another; at least part of this variation is hereditary. Chronic heart failure lowers the osmotic threshold for vasopressin release, whereas aging and other factors reduce sensitivity of vasopressin release (i.e., the rate of vasopressin release per unit change in osmolality). Shifts in blood volume and pressure of greater than 10% affect vasopressin release significantly. Hypotension and hypovolemia stimulate vasopressin release by lowering the osmotic threshold; hypertension and hypervolemia inhibit release by raising the threshold. These influences are mediated by baroreceptor pathways that have left atrial afferents.
Nausea, but not vomiting, is a powerful stimulus to vasopressin release; it raises the serum vasopressin up to 1,000 times the level required for maximal antidiuresis. Pain, however, is not an important stimulant of vasopressin release. Many neural pathways influence vasopressin release in response to nonosmotic stimuli. In general, alpha-adrenergic pathways stimulate and beta-adrenergic pathways inhibit vasopressin release.
The principal disorders of vasopressin secretion consist of partial or complete deficiency (diabetes insipidus) and the syndrome of inappropriate antidiuretic hormone (SIADH) excess [see 10:I Renal Function and Disorders of Water and Sodium Balance].
DIABETES INSIPIDUS
Polyuria is a common clinical problem. A patient passing large quantities of urine generally has one of three abnormalities: an osmotic diuresis (e.g., from glycosuria), resistance to vasopressin, or deficient vasopressin secretion. Resistance to vasopressin (i.e., nephrogenic diabetes insipidus) is discussed elsewhere [see 10:I Renal Function and Disorders of Water and Sodium Balance]. Deficiency of vasopressin (i.e., neurogenic diabetes insipidus) reflects either functional or structural disease of the supraoptic hypothalamic neurons that secrete the hormone. Brain tumors, craniopharyngiomas, metastatic cancer, hypothalamic-pituitary surgery or trauma, pituitary stalk damage, histiocytosis, and lymphocytic hypophysitis account for most cases. Rare familial polyuric syndromes may also present as hypothalamic diabetes insipidus.
Diagnosis
Two clinical clues suggest vasopressin deficiency: sudden onset of polyuria and a preference for iced beverages. However, neurogenic diabetes insipidus must be distinguished from primary polydipsia, because overdrinking also results in polyuria and suppressed vasopressin secretion.
Neurogenic and nephrogenic diabetes insipidus can usually be differentiated by means of clinical testing. After confirmation that the blood glucose level is normal, the patient is deprived of water until 3% to 5% of body weight is lost and the serum tonicity is higher than 295 mOsm/kg. If polyuria disappears and the urine concentration rises above 500 mOsm/kg, vasopressin secretion is adequate. If polyuria and dilute urine (< 300 mOsm/kg) persist, then 20 mg desmopressin acetate (DDAVP), a synthetic vasopressin analogue, is given intranasally; alternatively, 300 µU of DDAVP can be administered intravenously. If urine flow decreases and urine concentration rises, vasopressin deficiency can be inferred. If, however, the serum becomes concentrated and the urine remains dilute despite administration of DDAVP, the patient has nephrogenic diabetes insipidus.
Some cautions should be kept in mind when conducting dehydration tests. First, the term partial diabetes insipidus describes a patient who, when deprived of water, achieves a urine concentration greater than the serum osmolality but less than that obtained after administration of vasopressin. Functional testing can be misleading in patients with neurogenic or nephrogenic partial diabetes insipidus. In such patients, who have a urine concentration between 300 and 500 mOsm/kg, measurement of the serum vasopressin level can be extremely helpful. A high vasopressin level in the presence of concentrated serum and relatively dilute urine points to nephrogenic diabetes insipidus; a low value points to hormone deficiency. Conversely, partial resistance to vasopressin can result from chronic overdrinking, with secondary dilution of the medullary concentration in the kidney. If such patients control their excess water intake, they recover a normal renal medullary concentration and, at the same rate, a normal response to vasopressin. Finally, water deprivation appears to produce less thirst in older men than in younger men. Men older than 80 years must be watched carefully after testing to ensure that they resume appropriate water intake.
Granulomas, trauma, infection, and other infiltrations can all produce diabetes insipidus. Metastatic tumor seldom produces insufficiency in other endocrine glands, but secondary tumors arising from lung, breast, and other organs can all produce insufficiency in the posterior pituitary. The sensitivity of MRI has considerably refined the approach to the diagnosis of diabetes insipidus.
Diabetes insipidus can develop suddenly after neurosurgery or external trauma. Cases that develop after neurosurgery may be marked by a triphasic sequence of vasopressin deficiency, vasopressin excess, and vasopressin deficiency. In postoperative or posttraumatic diabetes insipidus, a dilute polyuria with a serum sodium level greater than 145 mEq/L allows a presumptive diagnosis, and parenteral DDAVP should be given immediately. Conversely, hyponatremia from increased vasopressin secretion after transsphenoidal surgery should also be anticipated by following serum sodium levels. Explosive and fatal central diabetes mellitus and diabetes insipidus have been reported in young women with postoperative hyponatremia that was not aggressively treated. The pathogenesis of the disorder is not understood, but the pathologic sequence included cerebral edema and herniation, compression of the third cranial nerve, hypoxic infarction of the pituitary and hypothalamus, respiratory arrest, and coma. The rapidity of deterioration in these patients indicates that the hyponatremia in such cases should be promptly corrected, even though fixed pupillary dilatation, secondary to compression of the oculomotor nerve, may suggest brain death.
Treatment
There are several approaches to the treatment of diabetes insipidus. If the polyuria is mild and does not interfere with sleep, no treatment may be needed. Chlorpropamide potentiates the effect of vasopressin on renal concentrating ability and can be used to treat partial diabetes insipidus. It is given in a dosage of 250 to 375 mg once a day and usually does not produce hypoglycemia in normal persons. However, if patients do not eat regularly or if they have unsuspected anterior pituitary insufficiency, chlorpropamide can be hazardous.
For patients with severe diabetes insipidus, intranasal or oral DDAVP provides excellent control of polyuria and polydipsia. Intranasal DDAVP is effective, nontoxic, and nonirritating. Tablets of DDAVP are given in a dose of 0.1 or 0.2 mg, taken one to three times daily. All patients with diabetes insipidus should be warned that in circumstances of extreme water loss or unconsciousness, they are exposed to added risk unless they are under the care of a physician who is aware of the diagnosis.
Pituitary Failure
Attenuated pituitary secretory reserve can develop as a result of impingement and compression of an expanding mass on adjacent functioning pituitary cells or because of acquired or inherited pituitary cell damage.34 Tropic hormone failure associated with pituitary compression or destruction usually occurs sequentially, with GH; then FSH, LH, and TSH; and finally ACTH. In childhood, growth retardation is often the presenting feature; in adults, hypogonadism is the earliest symptom. Pressure effects may impair synthesis or secretion of hypothalamic hormones, with pituitary failure [see Table 10].
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Table 10 Causes of Pituitary Failure39 |
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DEVELOPMENTAL PITUITARY DYSFUNCTION
Developmental pituitary dysfunction occurs with aplastic, hypoplastic, or ectopic pituitary gland development. Midline craniofacial disorders may be associated with structural pituitary dysplasia. Birth trauma—including cranial hemorrhage, asphyxia, and breech delivery—can cause acquired pituitary failure in the newborn.
Transcription Factor Mutations
Tissue-specific transcription factors, including Pit-1 and PROP-1, determine tissue-specific development and expression of pituitary hormones and are critical for maintaining anterior pituitary cell function. Hereditary transcription factor mutations may result in disruption of pituitary function, which may manifest during infancy, childhood, puberty, or early adulthood. Autosomal dominant or recessive Pit-1 mutations result in combined deficiency of GH, PRL, and TSH. Pituitary imaging may reveal a normal or hypoplastic gland. PROP-1 is an early transcription factor that appears to be necessary for Pit-1 function. PROP-1 mutations result in combined deficiency of GH, TSH, gonadotropins, and sometimes ACTH. Most afflicted patients have growth retardation and do not enter puberty spontaneously. By adulthood, most patients are deficient in TSH and gonadotropins, and some have an enlarged pituitary gland. T-Pit mutations result in isolated ACTH deficiency.
Dysgenesis of the septum pellucidum or corpus callosum may lead to hypothalamic dysfunction and hypopituitarism, with manifestations that include diabetes insipidus, GH deficiency, and, occasionally, TSH deficiency. Affected children harbor a mutation in the HESX-1 gene. Clinical features include cleft palate, syndactyly, ear deformities, and hypertelorism.
ACQUIRED PITUITARY FAILURE
Rarely, infiltration of the hypothalamus by diseases such as sarcoidosis, histiocytosis X, amyloidosis, or hemachromatosis may disrupt hypothalamic and pituitary function.35 This hypothalamic infiltration may result in diabetes insipidus and, if GH attenuation occurs before pubertal bone closure, in growth retardation. Hypogonadotropic hypogonadism and, rarely, hyperprolactinemia occur with disrupted gonadotropin secretion. Pituitary damage may be directly caused by accidental or neurosurgical trauma; pituitary or hypothalamic neoplasms, including pituitary adenomas, craniopharyngioma, Rathke cysts, chordomas, or metastatic deposits; inflammatory disease, such as lymphocytic hypophysitis; or pituitary irradiation. Tuberculosis, opportunistic fungal infections associated with HIV infection, and tertiary syphilis may destroy pituitary tissue.
Cranial Irradiation
Cranial irradiation results in long-term compromise of hypothalamic and pituitary function. Children and adolescents who have undergone therapeutic irradiation of the brain or head and neck are at especially high risk. The resulting hormonal abnormalities correlate strongly with radiation dosage, as well as the time elapsed since completion of radiotherapy. By 10 to 15 years after therapy, GH deficiency invariably occurs, whereas central hypogonadism and ACTH deficiency less commonly occur. Anterior pituitary function should be tested in previously irradiated patients, and replacement therapy instituted when required.
Lymphocytic Hypophysitis
Lymphocytic hypophysitis usually occurs in pregnant or postpartum women. It presents as hyperprolactinemia and a pituitary mass resembling an adenoma on MRI; PRL levels are often mildly elevated.36 Transient pituitary failure and symptoms of progressive sellar compression, such as headache and visual disturbance, may occur, and the erythrocyte sedimentation rate may be elevated. Because its appearance on MRI may be indistinguishable from that of a pituitary adenoma, lymphocytic hypophysitis should be excluded in a postpartum woman with a newly diagnosed pituitary mass. Pituitary surgery is unnecessary in such cases: glucocorticoid treatment usually restores pituitary function within 6 months, and the mass invariably resolves.
Pituitary Apoplexy
Acute intrapituitary hemorrhage may result in catastrophic vascular compression of parasellar structures.37 Hemorrhage may occur in a preexisting adenoma, often in association with diabetes or hypertension, or in the postpartum period (Sheehan syndrome). During pregnancy, swelling of the pituitary increases the risk of intrapituitary hemorrhage and infarction. Hypoglycemia, hypotension, shock, apoplexy, and death may follow. Severe headache with signs of meningeal irritation, visual loss, dynamically changing ophthalmoplegia, cardiovascular collapse, and loss of consciousness portend acutely progressive intrasellar bleeding. Pituitary imaging may reveal signs of intratumoral or sellar hemorrhage, with deviation of vital structures, including compression of noninvolved pituitary tissue. If vision is intact and consciousness is unimpaired, patients can be treated conservatively with observation and high-dose steroid infusions. Visual loss or decreased consciousness is an indication for urgent surgical decompression. Subsequent pituitary hormone replacement will be required for the inevitable pituitary damage.
Empty Sella Syndrome
Clinically silent pituitary mass infarction may result in development of a partially or totally empty sella. CSF fills the dural herniation. Pituitary function often remains intact, because the surrounding tissue is fully functional. Hypopituitarism may develop insidiously, however. A partially or apparently totally empty sella is usually an incidental MRI finding. Rarely, small functional pituitary adenomas may arise within the rim.
DIAGNOSIS
Pituitary failure is characterized by the clinical impact of single or multiple tropic hormone loss. Growth disorders and abnormal body composition result from GH loss in children and adults, respectively; menstrual disorders and infertility in women and decreased sexual function, infertility, and loss of secondary sexual characteristics in men are caused by gonadotropin deficits; hypothyroidism is caused by TSH loss; hypocortisolism with hypoglycemia is caused by ACTH loss; and failed lactation is caused by PRL loss. Polyuria and polydipsia reflect loss of ADH secretion. These features may occur selectively or may be sequential and ultimately result in panhypopituitarism. Enhanced mortality in patients with long-standing pituitary damage is caused mainly by increased cardiovascular and cerebrovascular disease.38
On laboratory tests, patients with pituitary insufficiency demonstrate lack of normal hormonal feedback responses, with low tropic hormone levels in conjunction with low target hormone concentrations. Provocative tests confirm lack of pituitary hormone reserve.
TREATMENT
Replacement of pituitary hormones or their respective target hormones usually results in clinical homeostasis with few side effects [seeTable 11]. Hormone replacement therapy for pituitary failure includes glucocorticoids, thyroid hormone, sex steroids, GH, and vasopressin. Rational replacement regimens ensure a normal and safe quality of life. Patients receiving glucocorticoid replacement require dose increases during stressful events, including dental procedures, trauma, and hospitalizations for acute illness.
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Table 11 Replacement Therapy for Hypopituitarism in Adults |
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Acknowledgment
Figures 1 and 2 Alice Y. Chen.
References
Editors: Dale, David C.; Federman, Daniel D.