Examen Endocrino PDF

CHAPTER 4 Hypothalamus and Pituitary Gland     105 syndromes are associated with pituitary tumors or pituitary hor- intravenously) are also now available for use in some patients mone hypersecretion including multiple endocrine neoplasia (see sectio...

CHAPTER 4 Hypothalamus and Pituitary Gland     105 syndromes are associated with pituitary tumors or pituitary hor- intravenously) are also now available for use in some patients mone hypersecretion including multiple endocrine neoplasia (see section on SIADH). (MEN) type 1, McCune-Albright syndrome, Carney complex, familial acromegaly/gigantism, and X-linked acrogigantism. B. Radiotherapy Pituitary irradiation should be reserved Table 4–10 describes a number of known genetic causes of pitu- for patients who have had incomplete resection of larger itary adenomas/hormone excess. pituitary adenomas and whose tumors are not amenable to, or have failed, medical therapy. Treatment 1. Conventional irradiation—Conventional irradiation using Pituitary adenomas are treated with surgery, irradiation, or medi- high-energy sources, in total doses of 4000 to 5000 cGy given cations. The aims of therapy are to block effects of hormone in daily doses of 180 to 200 cGy, is most commonly employed. excess, correct hypersecretion of anterior pituitary hormones, to The response to radiation therapy is slow, and 5 to 10 years preserve normal secretion of other anterior pituitary hormones, may be required to achieve the full effect (see section on Acro- megaly). Treatment is ultimately successful in about 80% of and to remove or suppress the adenoma itself. These objectives are patients with acromegaly but in only about 55% to 60% of currently achievable in most patients with pituitary microadeno- patients with Cushing disease. The response rate in prolactino- mas; however, in the case of larger tumors, multiple therapies are mas is not precisely known, but tumor progression is prevented frequently required and may be less successful. in most patients. Morbidity during radiotherapy is minimal, although some patients experience malaise and nausea, and A. Surgical treatment The transsphenoidal microsurgical serous otitis media may occur. Hypopituitarism is common, approach to the sella turcica, now done endoscopically in most and the incidence increases with time following radiotherapy— about 50% to 60% at 5 to 10 years. Rare late complications centers, is the procedure of choice; transfrontal craniotomy is include damage to the optic nerves and chiasm, seizures, and required only in the rare patient with massive suprasellar exten- radionecrosis of brain tissue. Recent studies from the United sion of the adenoma. In the transsphenoidal procedure, the Kingdom have shown that conventional radiotherapy is a surgeon approaches the pituitary from the nasal cavity through major risk factor for excess mortality in acromegaly. the sphenoid sinus, removes the anterior-inferior sellar floor, 2. Gamma knife radiosurgery—This form of radiotherapy uti- and incises the dura. The adenoma is selectively removed; nor- lizes stereotactic CT-guided cobalt-60 gamma radiation to mal pituitary tissue is identified and preserved. Success rates deliver high-radiation doses to a narrowly focused area. Remis- approach 90% in patients with microadenomas. Major compli- sion rates have been reported in the range of 43% to 78%. An cations, including postoperative hemorrhage, cerebrospinal fluid adequate distance of the pituitary tumor from the optic chiasm is needed to prevent radiation-induced damage. Repeat treat- leak, meningitis, and visual impairment, occur in less than 5% ments put patients at higher risk of new visual or third, fourth, of patients and are most frequent in patients with large or mas- or sixth cranial nerve deficits. sive tumors. Transient diabetes insipidus lasting a few days to 1 to 3. Proton stereotactic radiotherapy—Experience with this 2 weeks occurs in approximately 15%; permanent diabetes modality is limited. In one study, 52% of patients with Cush- insipidus is rare. A transient form of the syndrome of inappro- ing disease had clinical remission. A similar rate of new pitu- priate secretion of antidiuretic hormone (SIADH) with symp- itary hormone deficiencies was seen, although no visual tomatic hyponatremia occurs in 10% of patients within 5 to complications or brain injury was reported. 14 days of transsphenoidal pituitary microsurgery. These abnor- malities of water balance can occur within days of each other C. Medical treatment— Medical management of pituitary making medical management difficult. A triphasic response of adenomas became feasible with the availability of bromocrip- diabetes insipidus, SIADH, and diabetes insipidus is occasion- tine, a dopamine agonist that suppresses both PRL and tumor ally encountered and thought to be due to early hypothalamic growth in patients with prolactinomas. A number of medica- dysfunction, followed by release of ADH from the degenerating tions have been used to treat hypercortisolism associated with pituitary, and then depletion of ADH stores. Surgical hypopitu- Cushing’s disease including ketoconazole, metyrapone, mito- itarism is rare in patients with microadenomas but approaches tane, etomidate, cabergoline, pasireotide, and mifepristone. 5% to 10% in patients with larger tumors. The perioperative Somatostatin analogs are useful in the therapy of acromegaly management of such patients should include glucocorticoid and some TSH-secreting adenomas. Specifics of the use of these administration in stress doses (see Chapter 9) and postoperative and other medications are discussed later. assessment of daily weight, fluid balance, and electrolyte status to look for evidence of diabetes insipidus. Mild diabetes insipi- dus is managed by giving fluids orally; in more severe cases— Posttreatment Follow-Up urine output greater than 5 to 6 L/24 h—ADH therapy in the Patients undergoing transsphenoidal microsurgery should be form of desmopressin, or DDAVP, can be administered intrana- reevaluated 4 to 8 weeks postoperatively to document that com- sally, orally, subcutaneously, or parenterally (see Chapter 5). plete removal of the adenoma and correction of endocrine hyper- SIADH is managed by fluid restriction; however, in more severe secretion has been achieved. Prolactinomas are assessed by basal cases, hypertonic saline may be required. ADH receptor antago- PRL measurements, GH-secreting tumors by glucose suppression nists (tolvaptan is given orally and conivaptan is administered testing and IGF-1 levels, and ACTH-secreting adenomas by 04-Gardner_ch04-p069-120.indd 105 09/06/17 5:31 PM  98    CHAPTER 4 Hypothalamus and Pituitary Gland Other hypothalamic tumors are usually not completely resect- The mechanism for the ischemia in such cases is not certain. able; however, biopsy is indicated to arrive at a histologic Hypotension along with vasospasm of the hypophysial arteries is diagnosis. 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 HYPOPITUITARISM more susceptible to the prothrombotic effects of the hyperestro- genic state. Some investigators have noted that the hypopituita- Hypopituitarism is manifested by diminished or absent secretion rism does not always correlate with the degree of hemorrhage but of one or more pituitary hormones. The development of signs and that there is good correlation between the pituitary lesion and symptoms is often slow and insidious, depending on the rate of severe disturbances of the clotting mechanism (as in patients with onset and the magnitude of hypothalamic-pituitary damage— placenta previa). Ischemic pituitary necrosis has also been reported factors that are influenced by the underlying pathogenesis. Hypo- to occur with greater frequency in patients with diabetes pituitarism is either a primary event caused by destruction of the mellitus. anterior pituitary gland or a secondary phenomenon resulting The extent of pituitary damage determines the rapidity of from deficiency of hypothalamic stimulatory factors normally act- onset as well as the magnitude of pituitary hypofunction. The ing on the pituitary. In general, acquired loss of anterior pituitary gland has a great secretory reserve, and more than 75% must be function follows the sequence of GH, LH/FSH, TSH, ACTH, destroyed before clinical manifestations are evident. The initial and PRL. Treatment and prognosis depend on the extent of hypo- clinical feature in postpartum necrosis may be failure to lactate function, the underlying cause, and the location of the lesion in after parturition; failure to resume normal menstrual periods is the hypothalamic-pituitary axis. another clue to the diagnosis. However, the clinical features of hypopituitarism are often subtle, and years may pass before pitu- Etiology itary insufficiency is recognized following an ischemic insult. Spontaneous hemorrhagic infarction of a pituitary tumor The etiologic considerations in hypopituitarism are diverse. As (pituitary apoplexy) frequently results in partial or total pituitary shown later, a helpful mnemonic device is the phrase “nine Is”: insufficiency. Pituitary apoplexy is often a fulminant clinical syn- invasive, infarction, infiltrative, injury, immunologic, iatrogenic, drome manifested by severe headache, visual impairment, oph- infectious, idiopathic, and isolated. Most of these lesions may thalmoplegias, meningismus, and an altered level of consciousness. cause pituitary or hypothalamic failure (or both). Establishing the Pituitary apoplexy is usually associated with a pituitary tumor; it precise cause of hypopituitarism is helpful in determining treat- may also be related to diabetes mellitus, radiotherapy, or open ment and prognosis. heart surgery. Acute pituitary failure with hypotension may result, and rapid mental deterioration, coma, and death may ensue. A. Invasive Space-occupying lesions cause hypopituitarism by Emergency treatment with corticosteroids (see Chapter 24) and destroying the pituitary gland or hypothalamic nuclei or by dis- transsphenoidal decompression of the intrasellar contents may be rupting the hypothalamic-hypophysial portal venous system. lifesaving and may prevent permanent visual loss. Most patients Large pituitary adenomas cause hypopituitarism by these mecha- who have survived pituitary apoplexy have developed multiple nisms, and pituitary function may improve after their removal. adenohypophysial deficits, but infarction of the tumor in some Small pituitary tumors—microadenomas (2.0 cm) are likely to recur, and long- nadism. Medical therapy with cabergoline effectively restores term dopamine agonist therapy should be continued in normal gonadal function and fertility, and pregnancy carries these patients. only a small risk of tumor expansion. Those patients who respond should be treated for 2 to 3 years, and then the drug B. Surgical treatment Transsphenoidal microsurgery is the should be withdrawn to determine if long-term remission will surgical procedure of choice in patients with prolactinomas. occur. Patients who have recurrence of hyperprolactinemia after cabergoline withdrawal may resume the drug or choose to have 1. Microadenomas—In patients with microadenomas, remis- surgical excision. In asymptomatic postmenopausal women who sion, as measured by restitution of normal PRL levels, normal decide against using medical therapy, intermittent monitoring menses, and cessation of galactorrhea, is achieved in 85% to of prolactin as a marker of tumor enlargement should be per- 90% of cases. Success is most likely in patients with basal PRL formed. Transsphenoidal adenectomy, either initially or after a levels under 200 ng/mL (9.1 nmol/L) and duration of amenor- trial of dopamine agonist therapy, carries little risk when per- rhea of less than 5 years. In these patients, the incidence of surgical complications is less than 2%, and hypopituitarism is formed by an experienced neurosurgeon and offers a high prob- a rare complication. Thus, in this group of patients with PRL- ability of long-term remission. secreting microadenomas, PRL hypersecretion can be cor- rected, gonadal function restored, and secretion of TSH and B. Macroadenomas Primary surgical therapy in these ACTH preserved. Recurrence rates vary considerably in patients usually does not result in long-term remission, so reported series. In our experience, approximately 85% of patients have had long-term remissions, and 15% have had medical therapy is the primary therapy of choice, particularly recurrent hyperprolactinemia. when the patient’s PRL levels are greater than 200 ng/mL 2. Macroadenomas—Transsphenoidal microsurgery is consider- (9.1 nmol/L) and the tumor is larger than 2 cm. Although trans- ably less successful in restoring normal PRL secretion in sphenoidal microsurgery rapidly decreases tumor size and decom- patients with macroadenomas; many clinicians would treat presses the pituitary stalk, the optic chiasm, and the cavernous these patients with dopamine agonists alone. The surgical out- sinuses, there is usually residual tumor and hyperprolactinemia. come is directly related to tumor size and the basal PRL level. Thus, these patients require additional therapy with dopamine Thus, in patients with tumors 1 to 2 cm in diameter without agonists. Although tumor growth and PRL secretion can be extrasellar extension and with basal PRL levels less than controlled by medical therapy in most patients, therapeutic 200 ng/mL (9.1 nmol/L), transsphenoidal surgery is successful in about 80% of cases. In patients with higher basal PRL levels failure can result from drug intolerance, poor compliance, or and larger or invasive tumors, the success rate—defined as resistance. Radiation therapy is reserved for postsurgical patients complete tumor resection and restoration of normal basal PRL with residual adenomas who are not controlled with dopamine secretion—is 25% to 50%. Although progressive visual loss or agonists. pituitary apoplexy is a clear indication for surgery, the great majority of these patients should be treated with dopamine agonists. 2. ACROMEGALY AND GIGANTISM GH-secreting pituitary adenomas are second in frequency to pro- C. Radiotherapy Conventional radiation therapy is reserved lactinomas for functioning pituitary tumors and cause the classic for patients with PRL-secreting macroadenomas who have per- clinical syndromes of acromegaly and gigantism. sistent hyperprolactinemia and who have not responded to The characteristic clinical manifestations are the consequence attempts to control their pituitary adenomas with surgery or of chronic GH hypersecretion, which in turn leads to excessive dopamine agonists. In this group of patients, radiotherapy with generation of IGF-1, the mediator of most of the effects of GH 4000 to 5000 cGy prevents further tumor expansion, although (see Chapter 6). Although overgrowth of bone is the classic 04-Gardner_ch04-p069-120.indd 109 09/06/17 5:31 PM  110    CHAPTER 4 Hypothalamus and Pituitary Gland feature, GH excess causes a generalized systemic disorder with Pathophysiology deleterious effects and an increased mortality rate, although deaths In acromegaly, GH secretion is increased and its dynamic control are rarely due to the space-occupying or destructive effects of is abnormal. Secretion remains episodic; however, the number, pituitary adenoma per se. duration, and amplitude of secretory episodes are increased, and Acromegaly and gigantism are virtually always secondary to a they occur randomly throughout the 24-hour period. The charac- pituitary adenoma. Ectopic GHRH secretion has been identified teristic nocturnal surge is absent, and there are abnormal responses as another cause of GH hypersecretion and acromegaly in a few to suppression and stimulation. Thus, glucose suppressibility is patients with carcinoid or islet cell tumors. Reports of intrapitu- lost (see Diagnosis, later), and GH stimulation by hypoglycemia itary GHRH-secreting gangliocytomas in direct contiguity with is usually absent. TRH and GnRH may cause GH release, whereas GH-secreting somatotroph adenomas and a report of a GHRH- these substances do not normally stimulate GH secretion. Dopa- secreting hypothalamic hamartoma in a patient with acromegaly mine and dopamine agonists such as bromocriptine and apomor- provide a link between ectopic and eutopic GHRH production. phine, which normally stimulate GH secretion, paradoxically Ectopic secretion of GH per se is very rare but has been docu- cause GH suppression in about 70% to 80% of patients with mented in a few lung tumors. acromegaly. In adults, GH excess leads to acromegaly, the syndrome char- Most of the deleterious effects of chronic GH hypersecretion acterized by local overgrowth of bone, particularly of the skull and are caused by its stimulation of excessive amounts of IGF-1 (see mandible. Linear growth does not occur, because of prior fusion Chapter 6), and plasma levels of this protein are increased in acro- of the epiphyses of long bones. In childhood and adolescence, the megaly. The growth-promoting effects of IGF-1 (DNA, RNA, onset of chronic GH excess leads to gigantism. Most of these and protein synthesis) lead to the characteristic proliferation of patients have associated hypogonadism, which delays epiphysial bone, cartilage, and soft tissues and increase in size of other organs closure and the combination of IGF-1 excess and hypogonadism to produce the classic clinical manifestations of acromegaly. The leads to a striking acceleration of linear growth. Most patients insulin resistance and carbohydrate intolerance seen in acromegaly with gigantism also have features of acromegaly if GH hypersecre- appear to be direct effects of GH and not due to IGF-1 excess. tion persists through adolescence and into adulthood. Pathology Clinical Features Pituitary adenomas causing acromegaly are usually more than 1 The sex incidence of acromegaly is approximately equal; the mean cm in diameter when the diagnosis is established. These tumors age at diagnosis is approximately 40 years; and the duration of arise from the lateral wings of the anterior pituitary; less than 10% symptoms is usually 5 to 10 years before the diagnosis is are diagnosed as microadenomas. established. GH-secreting adenomas are of two histologic types: densely Acromegaly is a chronic disabling and disfiguring disorder with and sparsely granulated. However, there appears to be no differ- increased late morbidity and mortality if untreated. Although ence in the degree of GH secretion or clinical manifestations in spontaneous remissions have been described, the course is slowly these patients. About 15% of GH-secreting tumors also contain progressive in the great majority of cases. lactotrophs, and these tumors thus hypersecrete both GH and PRL. A. Symptoms and signs Early manifestations (Table 4–13) include soft tissue proliferation, with enlargement of the hands and feet and coarsening of the facial features. This is usually Etiology and Pathogenesis accompanied by increased sweating, heat intolerance, oiliness of In most cases, excessive pituitary GH secretion is a primary pitu- the skin, fatigue, and weight gain. itary disorder. A somatic mutation in the Gs protein leading to At diagnosis, most patients have classic manifestations, and excessive cAMP production has been identified in 40% of GH- acral and soft tissue changes are always present. Bone and cartilage secreting adenomas. Familial isolated pituitary adenomas (FIPA) changes affect chiefly the face and skull. These changes include is characterized by genetic defects in the aryl hydrocarbon receptor thickening of the calvarium; increased size of the frontal sinuses, interacting protein (AIP) gene, which probably acts as a tumor which leads to prominence of the supraorbital ridges; enlargement suppressor. A recently described syndrome of pituitary gigantism of the nose; and downward and forward growth of the mandible, termed X-linked acrogigantism (X-LAG) appears to be due to which leads to prognathism and widely spaced teeth. Soft tissue genomic duplication of Xq26.3 (which includes the GPR101 growth also contributes to the facial appearance, with coarsening of gene) (see Table 4–10). Pituitary adenomas are present in virtually the features and facial and infraorbital puffiness. The hands and all patients and are usually greater than 1 cm in diameter; hyper- feet are predominantly affected by soft tissue growth; they are large, plasia alone is rare, and nonadenomatous anterior pituitary tissue thickened, and bulky, with blunt, spade-like fingers (Figure 4–19) does not exhibit somatotroph hyperplasia when examined histo- and toes. A bulky, sweaty handshake frequently suggests the diag- logically. In addition, there is a return of normal GH levels and nosis, and there are increases in ring, glove, and shoe sizes. There is dynamic control of GH secretion following selective removal of generalized thickening of the skin, with increased oiliness and the pituitary adenoma. sweating. Acne, sebaceous cysts, and fibromata mollusca (skin tags 04-Gardner_ch04-p069-120.indd 110 09/06/17 5:31 PM  CHAPTER 4 Hypothalamus and Pituitary Gland     111 TABLE 4–13 Clinical manifestations of acromegaly intolerance, lethargy, fatigue, and increased sleep requirement. in 100 patients. Sleep apnea, both obstructive and central, is very common in patients with acromegaly. This has particular importance for the Manifestations of GH excess anesthesiologist who must take special precautions to protect the Acral enlargement 100a Soft tissue overgrowth 100 airway during surgery. Moderate weight gain usually occurs. Par- Hyperhidrosis 88 esthesias, usually due to carpal tunnel compression, occur in 70%; Lethargy or fatigue 87 sensorimotor neuropathies occur uncommonly. Bone and carti- Weight gain 73 Paresthesias 70 lage overgrowth leads to arthralgias and in longstanding cases to Joint pain 69 degenerative arthritis of the spine, hips, and knees. Photophobia Photophobia 46 of unknown cause occurs in about half of cases and is most trou- Papillomas 45 blesome in bright sunlight and during night driving. Hypertrichosis 33 Goiter 32 GH excess leads to generalized visceromegaly, clinically evident Acanthosis nigricans 29 as thyromegaly and enlargement of the salivary glands. Enlarge- Hypertension 24 ment of other organs is usually not clinically detectable. Cardiomegaly 16 Hypertension occurs in about 25% of patients and cardio- Renal calculi 11 megaly in about 15%. Cardiac enlargement may be secondary to Disturbance of other endocrine functions hypertension, atherosclerotic disease, or, rarely, to acromegalic Hyperinsulinemia 70 Glucose intolerance 50 cardiomyopathy. Renal calculi occur in 11% secondary to the Irregular or absent menses 60 hypercalciuria induced by GH excess. Decreased libido or impotence 46 Other endocrine and metabolic abnormalities are common Hypothyroidism 13 and may be due either to GH excess or to mechanical effects of the Galactorrhea 13 Gynecomastia 8 pituitary adenoma. Glucose intolerance and hyperinsulinism Hypoadrenalism 4 occur in 50% and 70% of patients, respectively, owing to Local manifestations GH-induced insulin resistance. Overt clinical diabetes occurs in a Enlarged sella 90 minority, and diabetic ketoacidosis is rare. Hypogonadism occurs Headache 65 in 60% of female and 46% of male patients and is of multifacto- Visual deficit 20 rial origin; tumor growth and compression may impair pituitary a Percentage of patients in whom these features were present. gonadotropin secretion, and associated hyperprolactinemia (see Adapted with permission from Friesen SR. Surgical Endocrinology: Clinical Syndromes. later) or the PRL-like effect of excessive GH secretion may impair Philadelphia: Lippincott Williams & Wilkins; 1978. gonadotropin and gonadal function. In men, low total plasma testosterone levels may be due to GH suppression of sex hormone– and papillomas) are common, as is acanthosis nigricans of the axil- binding globulin (SHBG) levels; in these cases, plasma-free lae and neck and hypertrichosis in women. testosterone levels may be normal, with normal gonadal function. These bony and soft tissue changes are accompanied by With earlier diagnosis, hypothyroidism and hypoadrenalism due systemic manifestations, which include hyperhidrosis, heat to destruction of the normal anterior pituitary are unusual and are FIGURE 4–19 Markedly increased soft tissue bulk and blunt fingers in a middle-aged man with acromegaly. 04-Gardner_ch04-p069-120.indd 111 09/06/17 5:31 PM  112    CHAPTER 4 Hypothalamus and Pituitary Gland present in only 13% and 4% of patients, respectively. Galactor- A rhea occurs in about 15% and is usually caused by hyperprolac- tinemia 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 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 com- plications 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 cardio- vascular and cerebrovascular atherosclerosis, respiratory diseases, and colon cancer is two to four times that of the normal popula- tion. Death rates tend to be higher in patients with hypertension, cardiovascular disease, or clinical diabetes mellitus. C 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 B now occurs in only 15% to 20%, because most patients are now diagnosed because of the manifestations of GH excess. B. Laboratory findings In addition to elevations in IGF-1 and GH, postprandial plasma glucose may be elevated, and serum insulin is increased in 70% of cases. Elevated serum phos- phate (due to increased renal tubular resorption) and hypercal- ciuria appear to be due to direct effects of GH or IGF-1. C. Imaging studies Plain films (Figure 4–20) show sellar enlargement in 90% of cases. Thickening of the calvarium, enlargement of the frontal and maxillary sinuses, and enlarge- ment of the jaw can also be seen. Radiographs of the hand show increased soft tissue bulk, “arrowhead” tufting of the distal pha- langes, increased width of intra-articular cartilages, and cystic FIGURE 4–20 Radiologic signs in acromegaly. A: Skull with changes of the carpal bones. Radiographs of the feet show simi- enlarged sella turcica and frontal sinuses, thickening of the calvar- lar changes, and there is increased thickness of the heel pad ium, and enlargement of the mandible. B: Hand with enlarged sesa- (normal, 52 pg/mL [11 pmol/L]) and usually (3) Taper to maintenance therapy on day 3-5 and add mineralocorti- exceed 200 pg/mL (44 pmol/L). Plasma ACTH concentrations coid therapy as required are inappropriately normal or less than 10 pg/mL (2.2 pmol/L) in General and Supportive Measures patients with secondary adrenal insufficiency (see Figure 9–9). (1) Correct volume depletion, dehydration, and hypoglycemia with However, basal ACTH levels must always be interpreted in light intravenous saline and glucose of the clinical situation, especially because of the episodic nature (2) Evaluate and correct infection and other precipitating factors of ACTH secretion and its short plasma half-life. For example, ACTH levels frequently exceed the normal range during the recovery of the HPA axis from secondary adrenal insufficiency and confirmed. Therapy includes administration of glucocorticoids; may be confused with levels seen in primary adrenal insufficiency. correction of dehydration, hypovolemia, and electrolyte abnor- Patients with primary adrenal insufficiency consistently have ele- malities; general supportive measures; and treatment of coexisting vated ACTH levels. In fact, the ACTH concentration is elevated or precipitating disorders. early in the course of adrenal insufficiency even before a signifi- cant reduction in the basal cortisol level or its response to exoge- A. Cortisol (Hydrocortisone) Parenteral cortisol in soluble nous ACTH occurs. Therefore, plasma ACTH measurements form (hydrocortisone hemisuccinate or phosphate) is the gluco- serve as a valuable screening study for primary adrenal corticoid preparation most commonly used. When administered insufficiency. in supraphysiologic doses, hydrocortisone has sufficient sodium- retaining potency so that additional mineralocorticoid therapy is Partial ACTH Deficiency not required in patients with primary adrenocortical insufficiency. When partial ACTH deficiency and decreased pituitary reserve Cortisol in intravenous doses of 50 to 100 mg is given every 6 are suspected despite normal responsiveness to the rapid ACTH to 12 hours for the first 24 hours. The response to therapy is usu- stimulation test, the following procedures may be used for more ally rapid, with improvement occurring within 12 hours or less. If direct assessment of hypothalamic-pituitary function. improvement occurs and the patient is stable, doses can be weaned by 50% on the second day, and in most patients the dosage may A. Methods of testing The overnight metyrapone test is then be gradually reduced to maintenance dose thereafter (see sec- used in patients with suspected hypothalamic or pituitary disor- tion “Maintenance Therapy,” later). ders when hypoglycemia is contraindicated and in those with prior glucocorticoid therapy. Insulin-induced hypoglycemia is 1. In severely ill patients, especially in those with additional major used in patients with suspected hypothalamic or pituitary complications (eg, sepsis), higher cortisol doses (100 mg intra- tumors, because both ACTH and GH responsiveness can be venously every 6-8 hours) are maintained until the patient is assessed (see Chapter 4). stable. 2. In primary Addison disease, mineralocorticoid replacement, in B. Interpretation A normal response to either metyrapone the form of fludrocortisone (see later), is usually added when hydrocortisone replacement is reduced to near physiological or hypoglycemia excludes secondary adrenocortical insufficiency levels. (see section “Laboratory Evaluation”). Subnormal responses, 3. In secondary adrenocortical insufficiency with acute crisis, the even in the presence of a normal response to ACTH administra- primary requirement is glucocorticoid replacement and is sat- tion, establish the diagnosis of secondary adrenal insufficiency. isfactorily supplied by the administration of cortisol, as out- lined earlier. If the possibility of excessive fluid and sodium retention in such patients is of concern, equivalent parenteral TREATMENT OF ADRENOCORTICAL doses of synthetic steroids such as prednisolone or dexametha- sone may be substituted. INSUFFICIENCY The aim of treatment of adrenocortical insufficiency is to produce levels of glucocorticoids and mineralocorticoids equivalent to B. Intravenous fluids Intravenous glucose and saline are those achieved in an individual with normal HPA function under administered to correct volume depletion, hypotension, and similar circumstances. hypoglycemia. Volume deficits may be severe in Addison dis- ease, and hypotension and shock may not respond to vasopres- sors unless glucocorticoids are administered. Hyperkalemia and Acute Addisonian Crisis (Table 9–8) acidosis are usually corrected with cortisol and volume replace- Treatment for acute Addisonian crisis should be instituted as soon ment; however, an occasional patient may require specific ther- as the diagnosis is suspected and not delayed until the diagnosis is apy for these abnormalities (see also Chapter 24). 09-Gardner_ch09-p299-342.indd 324 09/06/17 4:12 PM  CHAPTER 9 Glucocorticoids and Adrenal Androgens     325 TABLE 9–9 Regimen for maintenance therapy of management with stress dosing of glucocorticoids should be re- primary adrenocortical insufficiency. enforced frequently. Patients receiving excessive doses of gluco- corticoids are also at risk for increased bone loss and clinically (1) Hydrocortisone, 10-15 mg in am, 5-10 mg in the afternoon significant osteoporosis. Therefore, the replacement dose of (4-5 pm) (2) Fludrocortisone, 0.05-0.1 mg orally in am glucocorticoid should be maintained at the lowest amount (3) Clinical follow-up: maintenance of normal weight, blood pressure, needed to provide the patient with a proper sense of well-being. and electrolytes with regression of clinical features Two major factors have prompted a reassessment of the issue of (4) Patient education plus identification card, medical alert bracelet or necklace (dog tag). Useful patient education materials are avail- appropriateness and possible excess glucocorticoid replacement able from the National Institutes of Health. http://www.cc.nih.gov/ for patients with adrenal insufficiency. First, there is a greater ccc/patient_education/pepubs/mngadrins.pdf appreciation of the potential risks of overtreatment or under- (5) Increase hydrocortisone dosage during stress. Double or triple the treatment. Recent evidence suggests that subclinical Cushing oral dose for mild illness. Provide patient with injectable form of glucocorticoid for emergency use syndrome associated with adrenal incidentaloma contributes to elevated blood sugar and blood pressure, decreased bone mineral density, increased cardiovascular disease, and even increased mortality. The levels of cortisol secretion by many incidentalo- Maintenance Therapy (Table 9–9) mas are similar to those observed in patients with adrenal insuf- Patients with Addison disease require life-long glucocorticoid and ficiency receiving mild cortisol overreplacement. In addition, mineralocorticoid therapy. Cortisol (hydrocortisone) is the gluco- studies in patients receiving glucocorticoid replacement therapy corticoid preparation of choice. The basal production rate of cor- demonstrate an inverse relationship between dose and bone min- tisol is approximately 8 to 12 mg/m2/d. The maintenance dose of eral density and a positive correlation between dose and markers hydrocortisone is usually 15 to 25 mg daily in adults. The oral of bone resorption. Second, there is recognition that there is dose is usually divided into 10 to 15 mg in the morning on arising considerable variation among individuals in terms of the plasma and 5 to 10 mg later in the day. Cortisol in twice-daily doses gives levels of cortisol achieved with orally administered hydrocorti- satisfactory responses in most patients; however, some patients sone or cortisol. may require only a single morning dose, and others may require The measurement of urine free cortisol does not provide a reli- three doses daily (eg, 10-5-5) to maintain well-being and normal able index for appropriate glucocorticoid replacement. Similarly, energy levels. Insomnia is a side-effect of glucocorticoid adminis- ACTH measurements are not a good indication of the adequacy tration and can usually be prevented by administering the last dose of glucocorticoid replacement; marked elevations of plasma in the early afternoon. ACTH in patients with chronic adrenal insufficiency are often not Fludrocortisone (9α-fluorocortisol) is used for mineralocorti- suppressed into the normal range despite adequate hydrocortisone coid therapy; the usual doses are 0.05 to 0.2 mg/d orally in the replacement. In fact, plasma ACTH values that fall to low normal morning. Because of the long half-life of this agent, divided doses or low levels suggest overreplacement with glucocorticoids. Plasma are not required. About 10% of addisonian patients can be man- cortisol day curves—multiple samples for plasma cortisol concen- aged with cortisol and adequate dietary sodium intake alone and tration—have been proposed but not yet widely adopted. There- do not require fludrocortisone. fore, it is prudent to use clinical assessment of the patient’s Secondary adrenocortical insufficiency is treated with the cor- response to therapy, rather than biochemical criteria, to gauge the tisol dosages described earlier for the primary form. Fludrocorti- adequacy of steroid replacement. sone is rarely required. The recovery of normal function of the Adequate treatment results in the disappearance of weakness, HPA axis following suppression by exogenous glucocorticoids malaise, and fatigue. Anorexia and other gastrointestinal symp- may take weeks to years, and its duration is not readily predictable. toms resolve, and weight returns to normal. The hyperpigmenta- Consequently, prolonged replacement therapy may be required. tion invariably improves but may not entirely disappear. Several studies in women have suggested potential benefits of Inadequate cortisol administration leads to persistence of these DHEA in doses of 50 mg/d in terms of improvement in well- symptoms of adrenal insufficiency, and excessive pigmentation being, although this remains controversial. remains. Adequate mineralocorticoid replacement may be determined by assessment of blood pressure and electrolyte composition. With Response to Therapy adequate treatment, the blood pressure is normal without ortho- General clinical signs, such as good appetite and sense of well- static change, and serum sodium and potassium remain within the being, are the guides to the adequacy of replacement. Obviously, normal range. Some endocrinologists monitor plasma renin activ- signs of Cushing syndrome indicate overtreatment. It is generally ity (PRA) as an objective measure of fludrocortisone replacement. expected that the daily dose of hydrocortisone should be dou- Upright PRA levels are usually less than 5 ng/mL/h in adequately bled or tripled during periods of minor stress, and the dose needs replaced patients. Hypertension and hypokalemia result if the to be increased to as much as 200 to 300 mg/d during periods fludrocortisone dose is excessive. Conversely, undertreatment may of major stress, such as a surgical procedure. Acute adrenal crisis lead to fatigue and malaise, orthostatic symptoms, and subnormal is a common problem in patients with established adrenal insuf- supine or upright blood pressure, with hyperkalemia and ficiency (8%-10% per year); accordingly, appropriate sick day hyponatremia. 09-Gardner_ch09-p299-342.indd 325 09/06/17 4:12 PM  326    CHAPTER 9 Glucocorticoids and Adrenal Androgens Prevention of Adrenal Crisis now depends on the underlying cause of the adrenal insufficiency. In patients with autoimmune Addison disease, survival approaches The development of acute adrenal insufficiency in previously that of the normal population, and most patients lead normal diagnosed and treated patients is almost entirely preventable in lives. In general, death from adrenal insufficiency now occurs only compliant individuals. The essential elements are patient educa- in patients with rapid onset of disease who may die before the tion and increased glucocorticoid dosages during illness. diagnosis is established and appropriate therapy started. The patient should be informed about the necessity for lifelong Secondary adrenal insufficiency has an excellent prognosis with therapy, the possible consequences of acute illness, and the neces- glucocorticoid therapy. Adrenal insufficiency due to bilateral adre- sity for increased therapy and medical assistance during acute ill- nal hemorrhage may be fatal, with some cases being recognized ness. An identification card or bracelet should be carried or worn only at autopsy. at all times. The cortisol dose should be increased by the patient to 60 to 80 mg/d with the development of minor illnesses; the usual main- tenance dosage may be resumed in 24 to 48 hours if improvement CUSHING SYNDROME occurs. Increased mineralocorticoid therapy is not required. Chronic glucocorticoid excess, whatever its cause, leads to the If symptoms persist or become worse, the patient should con- constellation of symptoms and physical features known as Cush- tinue increased cortisol doses and call the physician. ing syndrome. It is most commonly iatrogenic, resulting from Vomiting may result in inability to ingest or absorb oral cortisol, chronic glucocorticoid therapy. Spontaneous Cushing syndrome is and diarrhea in addisonian patients may precipitate a crisis because caused by abnormalities of the pituitary or adrenal gland or may of rapid fluid and electrolyte losses. Patients must understand that occur as a consequence of ACTH or CRH secretion by nonpitu- if these symptoms occur, they should seek immediate medical assis- itary tumors (ectopic ACTH syndrome; ectopic CRH syn- tance so that parenteral glucocorticoid therapy can be given. drome) (Figure 9–10). Cushing disease is defined as the specific type of Cushing syndrome due to excessive pituitary ACTH secre- Steroid Coverage for Surgery (Table 9–10) tion from a pituitary tumor. This section reviews the various types The normal physiologic response to surgical stress involves an of endogenous Cushing syndrome and discuss their diagnosis and increase in cortisol secretion. The increased glucocorticoid activity therapy (see also Chapter 4). may serve primarily to modulate the immunologic response to stress. Thus, patients with primary or secondary adrenocortical insufficiency scheduled for elective surgery require increased glu- Classification and Incidence cocorticoid coverage. This problem is most frequently encoun- Cushing syndrome is classified as either ACTH dependent or tered in patients with pituitary-adrenal suppression due to ACTH independent (Table 9–11). The ACTH-dependent types exogenous glucocorticoid therapy. The principles of management of Cushing syndrome—ectopic ACTH syndrome and Cushing are outlined in Table 9–10. disease—are characterized by chronic ACTH hypersecretion, which results in hyperplasia of the adrenal zonae fasciculata and reticularis and, therefore, increased secretion of cortisol, andro- PROGNOSIS OF ADRENOCORTICAL gens, and DOC. INSUFFICIENCY ACTH-independent Cushing syndrome may be caused by a primary adrenal neoplasm (adenoma or carcinoma) or bilateral Before glucocorticoid and mineralocorticoid therapy became nodular adrenal hyperplasia. In these cases, the cortisol excess sup- available, primary adrenocortical insufficiency was invariably fatal, presses pituitary ACTH secretion. with death usually occurring within 2 years after onset. Survival A. Cushing disease Traditionally this has been the most frequent type of Cushing syndrome and most studies attribute TABLE 9–10 Steroid coverage for surgery. 80% of reported cases to Cushing disease. It is much more com- (1) Correct electrolytes, blood pressure, and hydration if necessary mon in women than in men (female-male ratio of about 5:1) (2) Give hydrocortisone sodium phosphate or sodium succinate, and the age at diagnosis is usually 20 to 40 years but may range 100 mg intramuscularly, on call to operating room from childhood to 70 years. (3) Give 50 mg intramuscularly or intravenously in the recovery room and then every 6-8 h for the first 24 h (4) If progress is satisfactory, reduce dosage to 25 mg every 6-8 h for B. Ectopic ACTH hypersecretion This disorder accounts 24 h and then taper to maintenance dosage over 2-5 d. Resume for approximately 10% of patients with ACTH-dependent previous fludrocortisone dose when the patient is taking oral medications Cushing syndrome. The production of ACTH from a tumor of (5) Maintain or increase hydrocortisone dosage to 200-400 mg/d if nonpituitary origin may result in severe hypercortisolism, but fever, hypotension, or other complications occur many of these patients lack the classic features of glucocorticoid Reproduced with permission from Felig P, Baxter JD, Frohman LA. Endocrinology and excess. This presumably reflects the acuteness of the clinical Metabolism. 3rd ed. New York: McGraw-Hill Education; 1995. course in the ectopic ACTH syndrome. The clinical 09-Gardner_ch09-p299-342.indd 326 09/06/17 4:12 PM  CHAPTER 9 Glucocorticoids and Adrenal Androgens     327 Hypothalamus – – CRH CRH – – Pituitary ACTH ACTH Adrenal cortex Cortisol Cortisol Normal state Pituitary ACTH-dependent Cushing syndrome – – – CRH CRH CRH – – – ACTH ACTH ACTH Cortisol Cortisol Cortisol Adrenal adenoma with Ectopic ACTH Ectopic CRH ACTH-independent syndrome syndrome Cushing syndrome FIGURE 9–10 Hypothalamic-pituitary axis in Cushing syndrome of different causes. These panels illustrate hormone secretion in the nor- mal state (upper left), and four types of cortisol excess: Pituitary ACTH-dependent (with an ACTH-secreting pituitary tumor) (upper right), adre- nal tumor (lower left), ectopic ACTH syndrome due to an ACTH-secreting lung cancer (lower middle), and ectopic CRH syndrome due to a CRH-secreting lung tumor. In contrast to normal secretion and hormone levels, decreased hormonal secretion is indicated by a dotted line and increased secretion by a dark solid line. presentation of ectopic ACTH secretion is most frequently seen variety of tumors has been reported to produce ectopic ACTH in patients with tumors of a thoracic origin. Bronchial carci- and may be radiologically inapparent at the time of the presenta- noid, small cell and non-small cell lung carcinoma are respon- tion. The ectopic ACTH syndrome is more common in men, sible for over 50% of cases of this syndrome. The prognosis in and the peak age incidence is 40 to 60 years. patients with the ectopic ACTH syndrome is generally poor and largely a function of the primary tumor. Individuals with ecto- C. Primary adrenal tumors Primary adrenal tumors are pic ACTH syndrome from small cell lung carcinoma have a increasingly being recognized as a common cause of Cushing mean survival of less than 12 months. The ectopic ACTH syn- syndrome. Most of these patients have benign adrenocortical drome may also present in a fashion identical to classic Cushing adenomas. Adrenocortical carcinomas are uncommon, with an disease and pose a challenging diagnostic dilemma. A wide incidence of approximately 2 per million per year. Adrenal 09-Gardner_ch09-p299-342.indd 327 09/06/17 4:12 PM  328    CHAPTER 9 Glucocorticoids and Adrenal Androgens TABLE 9–11 Cushing syndrome: differential surrounding the nucleus; these are responsible for Crooke hya- diagnosis. line changes visible on light microscopy. 2. Hyperplasia—Diffuse hyperplasia of corticotroph cells has ACTH-Dependent been reported rarely in patients with Cushing disease. Pituitary adenoma (Cushing disease) Nonpituitary neoplasm (ectopic ACTH) 3. Other conditions—In patients with adrenal tumors or ectopic ACTH syndrome, the pituitary corticotrophs show prominent ACTH-Independent Crooke hyaline changes and perinuclear microfilaments. The Iatrogenic (glucocorticoid, megestrol acetate) ACTH content of corticotroph cells is reduced consistent with Adrenal carcinoma their suppression by excessive cortisol secretion present in these Unilateral adrenal neoplasm/adenoma Bilateral adrenal hyperplasia/neoplasm conditions. Bilateral macronodular adrenal hyperplasia McCune Albright syndrome Primary pigmented nodular adrenal disease B. Adrenocortical hyperplasia Chronic ACTH hyperse- Isolated micronodular adrenocortical disease cretion, usually due to Cushing disease, can lead to bilateral enlargement and hyperplasia of the adrenal cortex. Combined adrenal weight (normal, 8-10 g) is modestly increased, ranging carcinomas are more common in women. Autonomous cortisol from 12 to 24 g. On histologic study, there is equal hyperplasia secretion without the classic features of Cushing syndrome of the compact cells of the zona reticularis and the clear cells of occurs in up to 20% to 25% of patients with adrenal inciden- the zona fasciculata; consequently, the width of the cortex is talomas (see later). increased. Electron microscopy reveals normal ultrastructural features. When ACTH levels are very high as in the ectopic D. Childhood Cushing syndrome Childhood Cushing ACTH syndrome, the adrenals are frequently larger, with com- disease is rare, but is more common in the adolescent popula- bined weights up to or more than 50 g. The characteristic tion than in younger children. Most pediatric cases occur in microscopic feature is marked hyperplasia of the zona reticularis; patients over 10 years of age with an equal distribution between columns of compact reticularis cells expand throughout the the sexes. Cushing disease remains the most common cause of zona fasciculata and into the zona glomerulosa. The zona fas- Cushing syndrome accounting for more than 80% of cases. ciculata clear cells are markedly reduced. Primary adrenal disease accounts for an additional 10% to 15% of all pediatric cases. A hallmark of childhood Cushing syn- C. Nodular adrenal disease Adrenal nodules that hyperse- drome is significant weight gain without accompanying linear crete cortisol can be unilateral or bilateral, and their pathology growth. varies depending on the etiology. 1. Unilateral cortisol-secreting adrenal adenomas—These ade- Pathology nomas are encapsulated, usually weigh 10 to 70 g, and range in A. Anterior pituitary gland size from 1 to 6 cm. Microscopically, clear cells of the zona 1. Pituitary adenomas—Pituitary adenomas are present in over fasciculata type predominate, although cells typical of the zona 90% of patients with Cushing disease. These tumors are typi- reticularis are also seen. The uninvolved adrenal cortex con- cally smaller than those secreting GH or PRL; 80% to 90% are tiguous to the tumor and that of the contralateral gland are less than 10 mm in diameter. A small group of patients have atrophic in the presence of functioning adrenal adenomas and larger tumors (>10 mm); these macroadenomas are frequently carcinomas (see later). The cortex is markedly thinned, whereas invasive, leading to extension outside the sella turcica. Malig- the capsule is thickened. Histologically, the zona reticularis is nant pituitary tumors occur very rarely. virtually absent; the remaining cortex is composed of clear Microadenomas are located within the anterior pituitary; fasciculata cells. The architecture of the zona glomerulosa is they are not encapsulated but surrounded by a rim of com- normal. pressed normal anterior pituitary cells. With routine histologic 2. Adrenal carcinomas—Adrenal carcinomas are usually greater stains, these tumors are composed of compact sheets of well- than 4 cm when diagnosed and often weigh more than 100 g, granulated basophilic cells in a sinusoidal arrangement. ACTH, occasionally exceeding 1 kg. They may be palpable as abdomi- β-lipotropin, and β-endorphin have been demonstrated in nal masses. Grossly, they are encapsulated and highly vascular; these tumor cells by immunocytochemical methods. Larger necrosis, hemorrhage, and cystic degeneration are common, tumors may appear chromophobic on routine histologic study; and areas of calcification may be present. The histologic however, they also contain ACTH and its related peptides. appearance of these carcinomas varies considerably; they may These ACTH-secreting adenomas typically show Crooke appear to be benign or may exhibit considerable pleomor- changes (a zone of perinuclear hyalinization that is the result of phism. Vascular or capsular invasion is predictive of malignant chronic exposure of corticotroph cells to hypercortisolism). behavior, as is local extension. These carcinomas invade local Electron microscopy demonstrates secretory granules that structures (kidney, liver, and retroperitoneum) and metastasize vary in size from 200 to 700 nm. The number of granules hematogenously to liver and lung. As in unilateral glucocorti- varies in individual cells; they may be dispersed throughout coid-secreting adenomas, the surrounding adrenal cortex is the cytoplasm or concentrated along the cell membrane. A atrophic. typical feature of these adenomas is the presence of bundles 3. Bilateral nodular adrenal hyperplasia—This can be due to of perinuclear microfilaments (average 7 nm in diameter) ACTH stimulation (ACTH-dependent) or from several unique 09-Gardner_ch09-p299-342.indd 328 09/06/17 4:12 PM  CHAPTER 9 Glucocorticoids and Adrenal Androgens     329 ACTH-independent pathophysiologic disorders. Longstand- hyperplasia; these may be secondary to excessive CRH secretion ing ACTH hypersecretion—either pituitary or nonpituitary— by rare, benign hypothalamic gangliocytoma. may result in nodular enlargement of the adrenal gland. The cortex between the nodules is not atrophic as there is ACTH B. Ectopic ACTH syndrome and ectopic CRH syndrome stimulation to the entire gland. These focal nodules are often mistaken for adrenal neoplasms and may lead to unnecessary as Ectopic ACTH syndrome arises when nonpituitary tumors syn- well as unsuccessful unilateral adrenal surgery. In occasional thesize and secrete biologically active ACTH. The related pep- cases these nodules may, over a period of time, even become tides a-lipotropin and β-endorphin are also synthesized and autonomous or semiautonomous. Removal of the ACTH- secreted, as are inactive ACTH fragments. Production of CRH secreting neoplasm results in regression of the adrenal nodules has also been demonstrated in ectopic tumors secreting ACTH, as well as resolution of hypercortisolism unless the nodules but whether CRH plays a role in pathogenesis is unclear. A few have already developed significant autonomy. cases in which nonpituitary tumors produced only CRH have ACTH-independent bilateral nodular adrenal hyperplasia been reported. can be divided based on nodular size, diameter less than 1 cm (micronodular) or more than 1 cm (macronodular). Primary Ectopic ACTH syndrome occurs predominantly in selected pigmented nodular adrenocortical disease (PPNAD) is a tumor types (Figure 9–11); carcinoid tumors of lung, non-small micronodular condition that has small to normal sized adrenal cell, and small cell carcinoma of the lung account for most of the glands with multiple black and brown nodules with intranodu- cases. Other tumors causing the syndrome are of neuroendocrine lar cortical atrophy. The pathology of nodules in bilateral origin from cells in the thymus, gut, ovary, pancreatic islet, or macronodular adrenal hyperplasia (BMAH) is similar to uni- thyroid (ie, C-cells). Multiple other tumor types have also been lateral disease, but the internodular cortex can be hyperplastic (commonly) or can be atrophic. reported to cause the ectopic ACTH syndrome, but are very rare causes for it (see Chapter 21). Pathogenesis and Genetics (Table 9–12) C. Nodular adrenal disease Recent discoveries have A. Cushing disease The causes, natural history, and allowed a better understanding of the genetics responsible for genetics of Cushing disease are reviewed in Chapter 4. Cur- nodular adrenal disease. rent evidence is consistent with the view that spontaneously 1. Unilateral cortisol-secreting adrenal adenomas—In 2013, arising corticotroph-cell pituitary adenomas are the primary four separate groups from around the world reported a muta- cause and that the consequent ACTH hypersecretion and tion in the gene for the protein kinase A catalytic subunit, hypercortisolism lead to the characteristic endocrine abnor- PRKACA. Together, these groups investigated more than 200 malities and hypothalamic dysfunction. This is supported by cortisol-secreting adrenal adenomas. They found mutations in evidence showing that selective removal of these adenomas by the gene for PRKACA leading to constitutive activation of pituitary microsurgery reverses the abnormalities and is fol- protein kinase A in more than 40% of the adenomas. The lowed by return of the HPA axis to normal. In addition, mutations were largely (95%) found in a single hotspot. These mutations were not found to surrounding normal adrenal tis- molecular studies have shown that nearly all corticotroph sue, in non-functional adenomas, adrenal cortical carcinomas, adenomas are monoclonal. or in adrenal nodules with subtle cortisol hypersecretion (sub- Although these primary pituitary adenomas are responsible for clinical Cushing syndrome). the great majority of cases, a few patients have been described in 2. Bilateral micronodular adrenal hyperplasia—Primary pig- whom pituitary disease has been limited to corticotroph-cell mented nodular adrenocortical disease is an uncommon TABLE 9–12 Genetic causes of adrenal dependent cushing syndrome. Condition/Gene/Chromosome Related Conditions Nodular Disease McCune Albright syndrome/GNAS1/20q13.3 Fibrous dysplasia of bone, café-au-lait skin pigmenta- Unilateral or bilateral, micro- or tion, precocious puberty macronodularity Primary pigmented nodular adrenal disease/ Carney Complex (myxomas, testicular tumors, thyroid Bilateral, micronodular PRKAR1A/17q22-24 nodules, growth hormone producing pituitary adenomas Cortisol producing adenomas/PRKACA/19p13.1 No associated syndrome Unilateral, usually macronodular Familial adenomatous polyposis/APC/5q22.2 Multiple colon polyps and colon cancer Unilateral or bilateral, macronodular Multiple endocrine neoplasia type 1/MENIN/11q13 Primary hyperparathyroidism, pancreatic endocrine Unilateral or bilateral, macronodular tumors, pituitary adenomas Hereditary leiomyomatosis and renal cell cancer Hereditary leiomyomatosis, renal cell cancer, uterine Bilateral, macromodular syndrome/fumarate hydratase/1q42.1 fibroids Hereditary bilateral adrenal adenomas/ Hereditary adrenal adenomas, often cortisol- Bilateral, macronodular ARMC5/16q11.2 producing (may be subclinical cortisol excess) 09-Gardner_ch09-p299-342.indd 329 09/06/17 4:12 PM  330    CHAPTER 9 Glucocorticoids and Adrenal Androgens 60 Total n = 383 50 Thoracic tumors 40 Percentage (%) 30 Abdominal tumors 20 10 0 ids ok ors K ors s s as T ET ors nd ma oid NE id en om u ino dN um tum tum r-fo ro n yto /ad ted rci n hy arc ic t lize rci ve oc ell us ca LC yt na t. c ym ca Ne rom tc ca eo llar Gl mi SC no ias Th Isle Lo llan se ch du de ng ed Dis eo sce Me a Lu /m Ph Gl Mi ng Lu FIGURE 9–11 Prevalence of the most common tumors causing ectopic ACTH secretion. (K, carcinoma; NET, neuroendocrine tumor; SCLC, small cell lung carcinoma). (Reproduced with permission from Isidori AM, Lenzi A. Ectopic ACTH syndrome. Arq Bras Endocrinol Metabol. 2007 Nov;51(8):1217-1225.) familial cause of adrenal-dependent Cushing syndrome. It is decrease steroidogenesis in vitro and may explain why very associated with myxomas (cardiac, cutaneous, and mammary), large nodules are required to produce cortisol excess. Several spotty skin pigmentation, endocrine overactivity, sexual pre- studies have looked at relatives of patients with BMAH and cocity, acromegaly, and schwannomas—referred to as the Car- found germline mutations in over half of the studied relatives. ney complex. Germline inactivating mutations in the regulatory In these individuals without any symptoms of Cushing syn- subunit of protein kinase A have been shown to cause constitu- drome, adrenal nodular hyperplasia was frequently discovered. tive activation of a pathway critical for cortisol production. It has also been reported that ACTH may be produced in the