169 DISORDERS OF THE ANTERIOR PITUITARY AND HYPOTHALAMUS
Harrison’s Manual of Medicine
DISORDERS OF THE ANTERIOR PITUITARY AND HYPOTHALAMUS
Pituitary Hormone Hypersecretion Syndromes
Nonfunctioning and Gonadotropin-Producing Adenomas
The anterior pituitary is often referred to as the “master gland” because, together with the hypothalamus, it orchestrates the complex regulatory functions of multiple other glands (Fig. 169-1). The anterior pituitary produces six major hormones: (1) prolactin (PRL), (2) growth hormone (GH), (3) adrenocorticotropin hormone (ACTH), (4) luteinizing hormone (LH), (5) follicle-stimulating hormone (FSH), and (6) thyroid-stimulating hormone (TSH). Pituitary hormones are secreted in a pulsatile manner, reflecting intermittent stimulation by specific hypothalamic releasing factors. Each of these pituitary hormones elicits specific responses in peripheral target glands. The hormonal products of these peripheral glands, in turn, exert feedback control at the level of the hypothalamus and pituitary to modulate pituitary function. Disorders of the pituitary include neoplasms that lead to mass effects and clinical syndromes due to excess or deficiency of one or more pituitary hormones.
FIGURE 169-1. Diagram of pituitary axes. Hypothalamic hormones regulate anterior pituitary trophic hormones that, in turn, determine target gland secretion. Peripheral hormones feedback to regulate hypothalamic and pituitary hormones. For abbreviations, see text.
Pituitary adenomas are benign monoclonal tumors that arise from one of the five anterior pituitary cell types and may cause clinical effects from either overproduction of a pituitary hormone or compressive effects on surrounding structures, including the hypothalamus, pituitary, or both. Tumors secreting prolactin are most common and have a greater prevalence in women than in men. GH- and ACTH-secreting tumors each account for about 10–15% of pituitary tumors. About one-third of all adenomas are clinically nonfunctioning and produce no distinct clinical hypersecretory syndrome. Adenomas are classified as microadenomas (<10 mm) or macroadenomas (³ 10 mm). Other entities that can present as a sellar mass include craniopharyngiomas, Rathke’s cleft cysts, sella chordomas, meningiomas, pituitary metastases, and gliomas.
Clinical Features Symptoms from mass effects include headache; visual loss through compression of the optic chiasm superiorly (classically a bitemporal hemianopia); and diplopia, ptosis, ophthalmoplegia, and decreased facial sensation from cranial nerve compression laterally. Pituitary stalk compression from the tumor may also result in mild hyperprolactinemia. Symptoms of hypopituitarism or hormonal excess may be present as well (see below).
Pituitary apoplexy is an endocrine emergency that typically presents with features that include severe headache, bilateral visual changes, ophthalmoplegia, and, in severe cases, cardiovascular collapse and loss of consciousness. It may result in hypotension, hypoglycemia, CNS hemorrhage, and death. Pts with no evident visual loss or impaired consciousness can usually be observed and managed conservatively with high-dose glucocorticoids; surgical decompression should be considered when these features are present.
Diagnosis Sagittal and coronal T1-weighted MRI images with specific pituitary cuts should be obtained before and after administration of gadolinium. In pts with lesions close to the optic chiasm, visual field assessment that uses perimetry techniques should be performed. Initial hormonal evaluation is listed in Table 169-1.
Table 169-1 Initial Hormonal Evaluation of Pituitary Adenomas
In pituitary apoplexy, CT or MRI of the pituitary may reveal signs of sellar hemorrhage, with deviation of the pituitary stalk and compression of pituitary tissue.
Pituitary surgery is indicated for mass lesions that impinge on surrounding structures or to correct hormonal hypersecretion (see below). Transsphenoidal surgery, rather than transfrontal resection, is the desired surgical approach for most pts. The goal is selective resection of the pituitary mass lesion without damage to the normal pituitary tissue, to decrease the likelihood of hypopituitarism. Transient or permanent diabetes insipidus, hypopituitarism, CSF rhinorrhea, visual loss, and oculomotor palsy may occur postoperatively. Tumor invasion outside of the sella is rarely amenable to surgical cure, but debulking procedures may relieve tumor mass effects and reduce hormonal hypersecretion. Radiation may be used as an adjunct to surgery, but >50% of pts develop hormonal deficiencies within 10 years, usually due to hypothalamic damage. Prolactin-, GH-, ACTH-, and TSH-secreting tumors may also be amenable to medical therapy.
PITUITARY HORMONE HYPERSECRETION SYNDROMES
Prolactin is unique among the pituitary hormones in that the predominant central control mechanism is inhibitory, reflecting dopamine-mediated suppression of prolactin release. Prolactin acts to induce and maintain lactation and decrease reproductive function and drive (via suppression of GnRH, gonadotropins, and gonadal steroidogenesis).
Etiology Physiologic elevation of prolactin occurs in pregnancy and lactation. Otherwise, prolactin-secreting pituitary adenomas (prolactinomas) are the most common cause of prolactin levels >100 µg/L. Less pronounced hyperprolactinemia is commonly caused by medications (chlorpromazine, perphenazine, haloperidol, metoclopramide, opiates, H2 antagonists, amitriptyline, SSRIs, calcium channel blockers, estrogens), pituitary stalk damage (tumors, lymphocytic hypophysitis, granulomas, trauma, irradiation), primary hypothyroidism, or renal failure. Nipple stimulation may also cause acute prolactin increases.
Clinical Features In women, amenorrhea, galactorrhea, and infertility are the hallmarks of hyperprolactinemia. In men, symptoms of hypogonadism or mass effects are the usual presenting symptoms, and galactorrhea is uncommon.
Diagnosis Fasting, morning prolactin levels should be measured; when clinical suspicion is high, measurement of levels on several different occasions may be required. If hyperprolactinemia is present, nonneoplastic causes should be excluded (e.g., pregnancy test, hypothyroidism, medications).
If pt is taking a medication that is known to cause hyperprolactinemia, the drug should be withdrawn, if possible. A pituitary MRI should be performed if the underlying cause of prolactin elevation is unknown. Resection of hypothalamic or sellar mass lesions can reverse hyperprolactinemia due to stalk compression. Medical therapy with a dopamine agonist is indicated in microprolactinomas for control of symptomatic galactorrhea, restoration of gonadal function, or when fertility is desired. Alternatively, estrogen replacement may be indicated if fertility is not desired. Dopamine agonist therapy for macroprolactinomas generally results in both adenoma shrinkage and reduction of prolactin levels. Cabergoline (initial dose 0.5 mg q week, usual dose 0.5–1 mg twice a week) or bromocriptine (initial dose 1.25 mg qhs, usual dose 2.5–5 mg po tid) are the two most frequently used dopamine agonists. These medications should initially be taken at bedtime with food, followed by gradual dose increases, to reduce the side effects of nausea and postural hypotension. Other side effects include constipation, nasal stuffiness, dry mouth, nightmares, insomnia, or vertigo; decreasing the dose usually alleviates these symptoms. Dopamine agonists may also precipitate or worsen underlying psychiatric conditions. Spontaneous remission of microadenomas, presumably caused by infarction, occurs in up to 30% of pts. Surgical debulking may be required for macroprolactinomas that do not respond to medical therapy.
Women with microprolactinomas who become pregnant should discontinue bromocriptine therapy, as the risk for significant tumor growth during pregnancy is low. In those with macroprolactinomas, visual field testing should be performed at each trimester. A pituitary MRI should be performed if severe headache and/or visual defects occur.
Etiology GH hypersecretion is usually the result of pituitary adenomas, but can rarely be due to extrapituitary production of GH or hypothalamic or peripheral GHRH secreting tumors.
Clinical Features In children, GH hypersecretion prior to long bone epiphyseal closure results in gigantism. The presentation of acromegaly in adults is usually indolent. Pts may note a change in facial features, widened teeth spacing, deepening of the voice, snoring, increased shoe or glove size, ring tightening, hyperhidrosis, oily skin, arthropathy, and carpal tunnel syndrome. Frontal bossing, mandibular enlargement with prognathism, macroglossia, an enlarged thyroid, skin tags, thick heel pads, and hypertension may be present on examination. Associated conditions include cardiomyopathy, left ventricular hypertrophy, diastolic dysfunction, sleep apnea, diabetes mellitus, colon polyps, and colonic malignancy. Overall mortality is increased approximately three- fold.
Diagnosis Insulin-like growth factor (IGF) 1 levels are a useful screening measure, with elevation suggesting acromegaly. Due to the pulsatility of GH, measurement of a single random GH level is not useful for screening. The diagnosis of acromegaly is confirmed by demonstrating the failure of GH suppression to <1 µg/L within 1–2 h of a 75-g oral glucose load.
GH levels are not normalized by surgery alone in many pts with macroadenomas; somatostatin analogues provide adjunctive medical therapy that suppresses GH secretion with modest effects on tumor size. Octreotide (50 µg SC tid) is used for initial therapy. Once tolerance of side effects (nausea, abdominal discomfort, diarrhea, flatulence) is established, pts may be changed to long-acting depot formulations (20–30 mg IM q2–4 weeks). Pituitary irradiation may also be required as adjuvant therapy but has a high rate of late hypopituitarism.
Etiology Pituitary adenomas account for 70% of pts with endogenous causes of Cushing’s syndrome. Iatrogenic hypercortisolism, ectopic ACTH production by tumors, adrenal adenomas, carcinomas, and hyperplasia are other causes of hypercortisolism.
Clinical Features Typical features include thin, brittle skin, central obesity, hypertension, plethoric moon facies, purple striae, easy bruisability, glucose intolerance, osteoporosis, proximal muscle weakness, hypogonadism, acne, hirsutism, and psychological disturbances (depression, mania, and psychoses).
Diagnosis Elevated measurement of 24-h urine free cortisol and failure to suppress plasma cortisol after an overnight 1-mg dexamethasone suppression test can be used to screen pts for hypercortisolism. Measurement of an ACTH level, dynamic testing, and inferior petrosal sinus sampling may be used for localization (Table 328-13, p. 2049 in HPIM-15). Once biochemical localization confirms a pituitary source of Cushing’s, pituitary MRI should be performed.
Transsphenoidal resection is the initial therapy for Cushing’s disease and is successful in most pts with microadenomas. Repeat surgery or pituitary irradiation and steroidogenic inhibitors (ketoconazole, metyrapone, mitotane) may be required to suppress cortisol hypersecretion. Bilateral adrenalectomy may ultimately be required, though this necessitates permanent glucocorticoid and mineralocorticoid replacement and predisposes to Nelson’s syndrome (pituitary adenoma enlargement).
Nonfunctioning and Gonadotropin-Producing Adenomas
These tumors usually present with symptoms of one or more hormonal deficiencies or mass effect. They typically produce small amounts of intact gonadotropins (usually FSH) as well as uncombined a and LHb and FSHb subunits. Surgery is indicated for mass effects or hypopituitarism; asymptomatic small adenomas may be followed with regular MRI and visual field testing. Diagnosis is based on immunohistochemical analysis of resected tumor tissue.
TSH-producing adenomas are rare but often large and locally invasive when they occur. Pts present with goiter and hyperthyroidism and/or sella mass effects. Diagnosis is based on elevated serum free T4 levels in the setting of inappropriately normal or high TSH secretion and MRI evidence of pituitary adenoma. Surgery is indicated and is usually followed by somatostatin therapy to treat residual tumor. Thyroid ablation or antithyroid drugs can be used to reduce thyroid hormone levels.
Etiology A variety of disorders may cause deficiencies of one or more pituitary hormones. These disorders may be congenital, traumatic (pituitary surgery, cranial irradiation, head injury), neoplastic (large pituitary adenoma, parasellar mass, craniopharyngioma, metastases, meningioma), infiltrative (hemochromatosis, lymphycytic hypophysitis, sarcoidosis, histiocytosis X), vascular (pituitary apoplexy, postpartum necrosis, sickle cell disease), or infectious (tuberculous, fungal, parasitic).
Clinical Features Hormonal abnormalities after cranial irradiation may occur 5 to 15 years later, with GH deficiency occurring first, followed sequentially by gonadotropin, TSH, and ACTH deficiency.
Each hormone deficiency is associated with specific findings:
Prolactin: failure of lactation
GH: growth disorders in children; increased intraabdominal fat, reduced lean body mass, hyperlipidemia, reduced bone mineral density, and social isolation in adults
FSH/LH: menstrual disorders and infertility in women; hypogonadism in men
ACTH: features of hypocortisolism without mineralocorticoid deficiency
TSH: growth retardation in children, features of hypothyroidism in children and adults
Diagnosis Biochemical diagnosis of pituitary insufficiency is made by demonstrating low or inappropriately normal levels of pituitary hormones in the setting of low target hormone levels. Initial testing should include an 8 A.M. cortisol level, TSH and free T4, IGF-1, testosterone in men, and assessment of menstrual cycles in women. Provocative tests may be required to assess pituitary reserve for individual hormones. Adult GH deficiency is diagnosed by demonstrating a subnormal GH response to a standard provocative test (insulin tolerance test, L-dopa, arginine, GHRH). Acute ACTH deficiency may be diagnosed by a subnormal response in an insulin tolerance test, metyrapone test, or CRH stimulation test. Standard ACTH (cosyntropin) stimulation tests may be normal in acute ACTH deficiency; with adrenal atrophy, the cortisol response to cosyntropin is blunted.
Hormonal replacement should aim to mimic physiologic hormone production. Effective dose schedules are outlined in Table 169-2. GH therapy, particularly when excessive, may be associated with fluid retention, joint pain, and carpal tunnel syndrome. Glucocorticoid replacement should always precede levothyroxine therapy to avoid precipitation of adrenal crisis. Pts requiring glucocorticoid replacement should wear a medical alert bracelet and should be instructed to take additional doses during stressful events such as acute illness, dental procedures, trauma, and acute hospitalization.
Table 169-2 Hormone Replacement Therapy for Adult Hypopituitarisma
For a more detailed discussion, see Melmed S: Disorders of the Anterior Pituitary and Hypothalamus, Chap. 328, p. 2029, in HPIM-15.