 \212 2 If primary aldosteronism is suspected, refer to endocrinology for one of four confirmator y tests: (1) Oral sodium loading test, (2)saline infu- sion test, (3) fludrocortisone suppr ession testing, or (4) captopril chal- lenge test. 3 If primary aldosteronism is confirmed, consider targeted adrenal imaging with abdominal C T scanning, abdominal MRI scanning, or iodo-cholesterol scintigraphy scanning to identify a nd characterize adrenal abnormalities. 4 If targeted imaging is unrevealing or equivocal, consider bilateral adrenal vein sampling at an experienced center to determine whether lateraliza- tion of aldosterone secretion co nsistent with an aldosterone-producing adrenal adenoma is present. If the patient is being treated with an aldosterone receptor blocker (spironolactone, epler enone, amiloride, triamterene)or potassium-wasting diuretic, or is using products derived f rom licorice root (confections or chewing tobacco), discontinue treatment and wait at least 4 wks before testing. ** Withdraw for additional 2 wks: -blockers, central 2 -agonis ts, NSAIDs, ACE-inhibitors, ARBS, rennin inhibitors, dihydropyridine calcium channel antago nists. Pheochromocytoma Represents a rare catecholamine-secreting neoplasm (Table 9.20). 85% deve lop within the adrenal medulla, with 5 \200\22310% presenting in bilateral distri- butions and 10% eventually proving to be malignant. Catecholamine-secreting neoplasms that are iden tified in extra-adrenal locations (abdomen, thorax, head, neck) are called paragangliomas . 15 \200\22320% of pheochromocytomas are associated with familial (genetic) disorders: MEN -2 syndromes, von Hippel \200\223 Lindau (VHL) syndrome, and neurofibromatosis type 1. Over all, pheochro- mocytomas account for <0.2% of all cases of newly diagnosed hypertension. Sy mptoms Episodic paroxysms that may present with varying constella- tions of symptoms includ ing episodic headaches, sweating, and palpitations. Other symptoms may include diaphoresis, anxiety, tremulousness, fatigue, nausea, vomiting, abdominal pain, chest pain, polyuria, po lydipsia, and visual disturbances. Signs Sustained or paroxysmal hypertension is characteri stic, although 5 \200\22315% of patients present with normal BP. Peripheral vasoconstrictio n dur- ing paroxysms may produce transient pallor. Resultant increase in core body temperat ure may lead to subsequent flushing. Increased ESR, hyperg- lycemia, and stress-induced car diomyopathy have been reported. y g o o n i r c o d n E l Table 9.20 Evaluation of suspected pheochromocy toma 1 Screen for increased catecholamine secretion by checking a plasma free metanephrine level s or 24 h urine metanephrine and catecholamine levels. \212 Plasma free metanephrine levels; screening test of choice when avail- able; sensitivity is >99%, specificity is 89%. Urine metanephrine and catecholamine levels (24 h collection). La betalol, tricyclic antidepressants, levodopa, decongestants, amphet- amines, reserpine, eth anol, prochlorperazine, acetaminophen, and buspirone may artifactually increase levels. Nor mal plasma free metanephrine or urine metanephrine/cate- cholamine levels = excluded Marked ly elevated plasma free metanephrine or urine metanephrine/ catecholamine levels (2 \200 \2234 \227 >normal) = pheochromocytoma Marginally elevated plasma free metanephrine or uri ne metanephrine/ catecholamine levels = increased catecholamine secretion consistent with a possible pheochromocytoma versus other stressor (hyperten- sion, myocardial infarction, se psis, etc.) \212 \212 315 \212 \212 2 If a possible pheochromocytoma is suspected, check repeat plasma free metanephrine levels or urine metanephrine/catecholamine levels. 3 Normal repeat plasma free metanephrine or urine metanephrine/cat- echolamine levels = excluded 4 Marginally elevated repeat plasma free metanephrine or urine meta- nephrine/catecholamine levels = increased catecholamine secretion consistent with a possible pheochromocytoma.Con sider referral to an endocrinologist who may perform confirmatory tests. 5 If a pheochromocytoma is confirmed, consider targeted adrenal imag- ing with abdominal CT scanning or abdominal MRI scanning to iden- tify and characterize adrenal abnormalities; p heochromocytomas may show a characteristic bright intensity on T2-weighted MRI images. 6 If targeted imaging is unrevealing or equivocal, consider whole-body imaging with metaiodoben zylguanidine (MIBG), 111-IN-pentetreotide scintigraphy, total body MRI or positron emission tomography (PET) scanning to attempt to localize a suspicious focus of increased cat- echo lamine secretion. Treatment Surgical resection of benign pheochromocytomas and para- gangliomas may be curati ve. Patients require preoperative treatment with -blockers started at least 2 wks (and p referably 1 month) prior to planned procedures. Agents used for this purpose include phenox ybenzamine (Dibenzyline 10 \200\223100 mg/d) and doxazosin (Cardura 2 \200\2238 mg/d). Doses should be titrated every few days to target normotensive BPs. Patient should feel ort hostatic if dosing is correct. Intraoperative hypertensive crises may require treatment wit h phentolamine or nitroprusside . Postoperatively, patients may require aggressive volume r epletion and monitoring for symp- toms and signs of incipient hypoglycemia. MEN-2a and -2b See section on Hyperparathyroidism. Von Hippel Lindau syndrome Includes pheochromocytoma (f requently bilateral), rarely paraganglioma, with retinal angiomas, cerebellar heman- giobla stoma, epididymal cystadenoma, renal and pancreatic cysts, renal cell carcinoma, and pancre atic neuroendocrine tumors.Mutations in the VHL tumor suppressor gene leading to loss of fu nction of VHL protein. Neurofibromatosis type 1 (NF1) Includes bilateral or unilateral pheo - chromocytoma, rarely paraganglioma, with neurofibromas, axillary and inguinal freckling, iris hamartomas (Lisch nodules), and caf au lait spots. Genetic testing for autosomal do minant mutations in NF1, although not always necessary if clinical phenotype is clear. Gene tic screening Referral to an endocrinologist for genetic testing for familial types of pheo chromocytoma and paraganglioma should be made in the following cases: \212 \212 \212 Paraganglioma at any site Bilateral adrenal pheochromocytoma Unilateral pheochromocytoma with family history of pheochromocytoma/ paraganglioma \212 \212 Unilateral pheochromocytoma at a young age (<30 years) Other clinical findings suggesting g enetic syndromes (MEN-2a or -2b, VHL, NF1) 316 Hirsutism Defined as new or increased abnormal growth of thick, coarse, pigmented terminal hair in females. May be distributed in regions commonly associated with male secondary sexu al characteristics including the face, chest, back, lower abdomen, and inner thighs. May be caused by (a) increased secre- tion of androgens from the ovaries, (b) increased secretion of androgens from the adrenal cortex, or (c) increased 5 -reductase activity leading to increased conversion of testosterone to dihydrotestosterone at target tis- sues.Hirsutism may be idiopathic in nature or based on ethnic heritage. Hyperprolactinemia is a rare cause of hirsutism. Increased secretion of androgens from the ovaries Most common cause is polyc ystic ovary syndrome (see below). May also be associated with ovarian hyperthecosis or, rar ely, the growth of androgen-secreting ovarian neoplasms. Increased secretion of androgens f rom the adrenal cortex Most common cause is nonclassic (late-onset) congenital adrenal hype rplasia (CAH) associated with 21-hydroxylase deficiency. May also be caused by Cushing \200 \231s syndrome, growth of androgen-secreting adrenal adenomas, or growth of adrenal carcino mas. Evaluation Should initially focus on identification and quantification of abnormal ter minal hair growth using a Ferriman- Gallwey score. Patients may need to limit cosmetic treatment for a period to allow for accurate assessment. Reprodu ctive history should focus on identification of sig- nificant menstrual irregularities and problems with infertility. Biochemical evaluation of hirsutism should be performed in women (1) with moderate or severe hirsutism, (2) when hirsutism is of rapid and progressive onse t to exclude tumor, or (3) if the hirsutism is associated with obesity, irregular menses, o r frank virilization (see Table 9.21). Polycystic ovary syndrome Clinical diagnosis based o n identification of a history of significant menstrual irregularities in conjunction with f indings consistent with hyperandrogenism (hirsutism, comedonal acne, male pat- tern balding , etc.). National Institute of Health consensus criteria for the diagnosis of PCOS include: (1) menstrual irregularities due to oligo- or anovulation, (2) clinical (hirsutism, acne, etc.) or biochemical (high serum androgens) evidence of hyperandrogenism, and (3) exclusion of other causes of hyperandrogenism. Only the Rotterdam criteria 12 indicate that polycyst ic ovaries by ultrasound are necessary for a PCOS diagnosis. Pathophysiology A complex synd rome in which both genetics and envi- ronmental factors contribute to the onset and severit y of the condition.In part, may be caused by relative increase in secretion of luteinizing hormone (LH) leading to increased production and secretion of androgens from the ovaries. M ay lead to enlargement and polycystic thickening of the ovar- ian capsule. Subsequent conve rsion of androgens to estrogen may lead to endometrial hyperplasia. Insulin resistance with resultant hyperinsulinemia is frequently found in PCOS, which may also promote androgen se cre- tion by theca cells. Women with PCOS my have genetic predisposition to hyperandrogenis m. Groups at risk for PCOS include women with (a) T1DM, T2DM, or gestational diabetes; (b) obesity or insulin resistance; (c) history of premature adrenarche; (d)first-degree relativ es with PCOS; or (e) y g o o n i r c o d n E l Table 9.21 Evaluation of hirsutism 10 317 1 Check early morning total and free testosterone levels* and dehydroepiandrosterone-sulfat e (DHEA-S) levels. If menses are irregu- lar, also check a serum prolactin level. \212 Elevated serum prolactin level = consider prolactin-producing pitu- itary tumor; pituitary MRI may be warranted for further evaluation. Total testosterone > upper limit of reference range for females but <150 ng/dL = likely polycystic ovarian syndrome Total testosterone >1 50 ng/dL + DHEA-S <700 mcg/dL = possible androgen-secreting ovarian neoplasm; consider targ eted imaging with transvaginal pelvic ultrasonography. \212 \212 2 Total testosterone >150 ng/dL + DHEA-S >700 mcg/dL = possible Cushing \200\231s syndrome, androgen-secreting adrenal adenoma, or adre- nal carcinoma; consider formal evaluation for hypercortisolemia (see Cushing \200\231s syndrome) or targeted imaging of adrenal glands w ith abdom- inal CT or MRI scanning. If nonclassic (late-onset) CAH is suspected, check a ba se-line 17-hydroxyprogesterone level, administer 250 mcg of cosyntropin (Cortrosyn ) IV, t hen checkrepeat 17-hydroxyprogesterone levels at 30 and 60 min. Baseline 17-hydroxyprogeste rone >200 ng/dL + 17-hydroxy-progesterone >1,500 ng/dL = nonclassic CAH \212 stimulated Free testosterone should be checked in a specialty lab wher e assays are more accurate. 10 Evaluation and treatment of hirsutism in premenopausal women: An Endocrine Society clini - cal practice guideline. J Clin Endolcrinol Metabol . 2008. oligo-ovulatory fertility. Women with suspected PCOS should be screened for insulin resista nce and other components of the metabolic syndrome. PCOS and infertility Oligo- or anovulat ion associated with hyperan- drogenism and PCOS often complicates conception.In overweight women, weight loss should be encouraged to lower androgen levels and, often, restore normal ovulation. Pharmacotherapeutic interventions include clo- miphene citrate (Clomid 50 \200\223100 mg/d \227 5 d starting on the fifth day of the menstrual cycle) or metformin ( Glucophage 500 \200\2231,000 mg bid, Glucophage XR 1,000 \200\2232,000 mg qpm). Some st udies show that these agents may be used in combination to help to induce ovulation. Exogen ous gonadotropin (LH and follicle-stimulating hormone [FSH]) therapy may also induce ovu- l ation. Patients who do not desire fertility may be treated with oral contra- ceptives that combine 30 \200\22335 mcg of ethinyl estradiol with progestins known to demonstrate minimal androgenic activity (desogestrel, norethindrone). Metformin may also help to manage oligom enorrhea, promote weight loss, and prevent T2DM. Nonclassic (late-onset) CAH Condition asso ciated with decreased production and secretion of glucocor- ticoids due to 21-hydroxylase d eficiency that leads to increased secretion of ACTH. 13 Increased ACTH levels stimulate sec retion of androgens from the adrenal cortex. Findings consistent with exposure to increased levels of circulating androgens may first become evident at the onset of puberty with prem ature pubarche, acne, hirsutism, and menstrual irregularities.More com- mon in women of His panic, Eastern European Jewish, or Yugoslav descent. Confirmation of CAH based on measureme nt of baseline and stimulated 17-hydroxyprogesterone levels (see Table 9.21). Treatment for nonclassic CAH aimed at management of hirsutism and oligo- or anovulation. Antiandrogen th erapy Spironolactone (Aldactone 50 \200\223200 mg/d) acts to inhibit binding of dihydrotest osterone to target receptors. It may be used as a first-line agent or in conjunction with o ther therapies. Continuous treat- ment for up to 6 months may be necessary before efficacy can be deter- mined. Cosmetic treatments involving shaving, plucking, waxing, bleaching, el ectrolysis, or use of depilatories may still be required to achieve desired appearances. Or al contraceptives In women who do not desire fertility, oral contra- ceptives may be used a lone (or in combination with antiandrogens) for menstrual cycle management and suppression of ACTH and ovarian/adre- nal androgens. Glucocorticoid therapy Given the potential risks a nd side effects of long-term glucocorticoid therapy, this treatment is usually reserved for women with anovulatory infertility. Treatment usually involves use of dex- amethasone (Dec adron 0.25 \200\2230.75 mg qhs) at doses targeted to suppress ACTH levels.If glucocortico ids are ineffective, other assisted reproduction techniques may be needed to induce ovulati on. Glucocorticoid treatment should be discontinued when fertility is no longer desired. Vi rilization Constellation of findings that reflect exposure to markedly elevated levels of c irculating androgens. Patients may present with frontal (male pattern) balding, deepening o f the voice, clitoral enlargement, and increased muscle mass. Presence or rapid onset of si gns should raise suspi- cion of an underlying androgen-secreting ovarian or adrenal neoplas m. 318 Gynecomastia Defined as enlargement of breast tissue in males. Transient, self-limited gyne comastia may be evident in up to 70% of males during puberty. Enlargement that persists or presents as a new development in adult males may be considered abnormal. May develop as a r esult of a range of different underlying disorders that promote relative imbalances between circulating levels of estrogens and androgens (see Table 9.22). Continued exposure to rela tively increased circulating levels of estrogens may promote growth of ductal and stromal e lements in breast tissue. Usually bilateral. Discernible as a firm concentric ridge of tiss ue that extends beyond the perimeter of the areola. May be painful, with associated tendern ess to palpation. Evaluation Should focus on (a) quantification of extent of breast tissue, (b) documentation of any history of exposure to possible offending agents, and (c) measure ment of total and free testosterone, estradiol, LH, HCG, liver function tests, and TSH leve ls. If findings consistent with undetected Klinefelter \200\231s are evident on exam (tall stature, widened arm span, small testicular size), a karyotype may be performed to confirm a suspected diag- nosis. If a suspiciously firm or enlarged breast mass is detected on exam , a mammogram may be considered to check for possible male breast cancer. Elevated serum HC G should prompt testicular ultrasound and urologic referral. Treatment Should be centered o n identification and treatment of underly- ing disorders. Gynecomastia may persist long aft er relative balance between circulating levels of estrogens and androgens has been restored . In cases presenting with significant pain, tenderness, or cosmetic deformity, surgical bi lateral reduction mammoplasty may be indicated. y g o o n i r c o d n E l Table 9.22 Mechanisms of disorders associated with gynecomastia \212 Increased production of sex hormone-binding globulin leads to increased binding of testoste rone that decreases circulating free tes- tosterone levels; this may occur in the setting o f thyrotoxicosis or chronic liver disease. Excessive stimulation of Leydig cells due to exp osure to elevated LH levels; leads to increased secretion of estrogens; this condition may develop as a complication of primary hypogonadism associated with Klinefelter \200\231s syn drome or adult Leydig cell failure. This may also occur as part of the refeeding syndrome. Excessive stimulation of Leydig cells due to exposure to elevated human chorionic gonadotro pin (HCG) levels; leads to increased secre- tion of estrogens; this may be associated with the growth of germ cell testicular neoplasms that secrete excessive amounts of HCG. Also se en in body-builders abusing HCG as a part of an anabolic steroid regimen. Inhibition of bin ding of dihydrotestosterone to target receptors; may be associated with treatment with spir onolactone or cimetidine. Direct binding of estrogen receptors; may be associated with trea tment with digoxin; it may also occur as a result of exposure to phytoestro- gens present i n marijuana. 319 \212 \212 \212 \212 Pituitary adenomas The incidence of detection of sellar masses has increased with more wide - spread use of neuroradiographic imaging to evaluate neurologic symptoms. Dedicated pituit ary MRI scanning with gadolinium provides the most accu- rate assessment of the size and lo cation of a suspected pituitary adenoma. The maximum diameter may be used to classify a sus pected pituitary adenoma as a microadenoma (<10 mm) or a macroadenoma (<10 mm). Evaluation requires determining whether a suspected pituitary adenoma is (1) functional (secreting sti mulating hormones that may lead to develop- ment of characteristic clinical syndromes) or ( 2) nonfunctional but impair- ing the normal secretion of hormones by adjacent pituitary tis sue. 14 Some functional pituitary adenomas may be treated medically, whereas others require surgery. See Table 9.23. Evaluation Comprehensive functional evaluation of a suspected pit uitary adenoma may incorporate (a) static testing based on measurement of TSH, free T4, pro lactin, and IGF-1 levels, and (b) dynamic testing based on per- formance of an overnight lo w-dose dexamethasone stimulation test and a GH suppression test. 24 h urine free cortisol l evels or salivary cortisol levels may be measured as well. Nonfunctional pituitary adenomas If a suspected pituitary adenoma proves to be nonfunctional, further evaluation should foc us on determin- ing whether its growth may be associated with (a) hypopituitarism, (b) hype rprolactinemia, (c) visual field deficits caused by upward growth with compression of the o ptic chiasm, (d) cranial nerve palsies caused by lateral extension into the cavernous sinus es, or (e) severe headaches caused by pressure and traction on meningeal structures. Sympto matic nonfunctional pituitary adenomas may require surgery to preserve eyesight or alleviat e headaches. Asymptomatic nonfunctional pituitary adenomas may often be followed with seria l imaging and visual field testing. Pituitary apoplexy Hemorrhage into an undetected or pre viously identified pituitary adenoma may cause sudden pituitary expansion lead- ing to a se vere headache. Upward expansion may precipitate compres- sion of the optic chiasm with loss of visual acuity. Lateral expansion may lead to compression of cranial blood vessels and h erniation. Expansion within the constrained space of the sella may lead to rapid developmen t 320 Table 9.23 Clinical syndromes associated with functional pituitary adenomas \212 Prolactin-secreting pituitary adenoma (prolactinoma) = hyperpro- lactinemia (high serum pro lactin) disease) = adenoma ACTH-secreting ACTH-dependent Cushing \200\231s syndrome (high s erum ACTH and cortisol) Growth hormone (GH)-secreting pituitary adenoma = acromegaly (high serum IGF-1) TSH-secreting pituitary adenoma = hyperthyroidism (high serum TSH and free T4) \212 pituitary (Cushing \200\231s \212 \212 FSH and LH-secreting pituitary adenomas do not appear to correlate with specific clinical s yndromes 14 Freda PU, et al. Pituitary incidentaloma: An Endocrine Society clinical practice guideli ne. J Clin Endocrinol Metabol . 2011. 96(4):894 \200\223904. of central (secondary) adrenal insufficiency that may provoke an adrenal crisis. Suspected cases of apoplexy require (a) treatment with stress-dose glucocorticoids, (b) urgent assess ment of visual acuity, and (c) urgent neu- rosurgical decompression versus high-dose steroi d administration. y g o o n i r c o d n E l Hypopituitarism Condition characterized by deficiency of one or more of the stimulating or trophic hormones secreted by the anterior pituitary. May be caused by (1) disorders that di srupt the function of the anterior pituitary itself or (2) disorders that disrupt hypothala mic regulation of the anterior pituitary. The principal stimulating and trophic hormones se creted by clusters of cells in the anterior pituitary include ACTH, TSH, GH, FSH, and LH. C auses of hypopituitarism Common acquired causes include pituitary surgery, cranial irradiat ion, head trauma, compression due to growth of pituitary adenomas, or other cranial tumors that impinge upon the sella. Rare causes include hypovolemic pituitary infarction (Sheehan \200\231s syndrome), hemochromatosis, disseminated tuberculosis, pituitary abscess, pituita ry metastases, lymphocytic hypophysitis, and trauma.There are also inherited, genetic disor ders that cause hypopituitarism (POU1F1 defects, PROP1 mutations, etc.). Evaluation Compreh ensive evaluation of suspected hypopituitarism may incorporate (a) targeted imaging with de dicated pituitary MRI scanning; (b) static early morning testing based on measurement of AC TH, TSH, free T4, FSH, LH, testosterone, cortisol, and insulin-like growth factor 1 (IGF-1) lev- els; and (c) dynamic testing based on performance of a cosyntropin stimula- tion test and a GH stimulation test. Central pituitary disorders Deficiencies of pituitary hormones (TSH, LH, FSH, GH, AND ACTH) present clinically in different ways. Clinical presentation wi ll depend on how deficiency of the stimulating and trophic hormones affect target tissues a nd glands. These disorders are referred to as central or \200\234secondary \200\235 forms of clinical syndromes and result from either pituitary or, rarely, hypothalamic dysfunction . Central adrenal insufficiency Presentation may vary, depending on the acuity of the under lying cause. With rapid deficiency of ACTH (apoplexy, ischemia, trauma), patients may prese nt in adrenal crisis (see above).With more prolonged deficiency of ACTH (tumor, infection, infiltration), the pre- sentation may be insidious and include nonspecific weight loss, fat igue, and weakness. Diagnosis based on confirmation of a cosyntropin-stimulated plasma cort isol <18 mcg/dL in conjunction with a plasma ACTH <30 pg/mL. Condition is treated with gluc ocorticoid replacement therapy. Mineralocorticoid replacement therapy is usually not necess ary, given that aldosterone secretion by adrenals (not controlled centrally) remains intact . Central hypothyroidism Patients may present with characteristic symp- toms and signs refl ecting deficiency of thyroid hormone (fatigue, weight gain, dry skin, etc.). Diagnosis base d on confirmation of a low or inappro- priately normal TSH level in conjunction with a low free T4 level. In some cases, it may be prudent to check a free T4 level measured by equili brium dialysis to provide verification. Treatment with thyroid hormone replace- ment requir ed. TSH levels do not provide an accurate index of replacement in this setting. Doses of le vothyroxine should be adjusted to target normal free T4 levels Central hypogonadism Often c lassified as hypogonadotropic hypogo- nadism. Manifestations may vary depending on age of o nset. Sex steroid deficiency that develops during childhood may lead to delayed or absent 321 onset of puberty. Premenopausal adult females may present with oligom- enorrhea or amenorrh ea. Diagnosis in females is based on confirmation of low or inappropriately normal FSH and LH levels in conjunction with a previously normal menstrual and reproductive history. Treat ment usually involves estrogen and progesterone replacement with oral contraceptives. Conce ption may require successive courses of ovulation induction and in vitro fertilization. Adu lt males with hypogonadotrophic hypogonadism may present with variable symptoms that may in clude a diminished libido, erec- tile dysfunction, impotence, and an appreciable decline in muscle strength. Examination may reveal diminished growth of facial hair and body hair, de creased muscle mass, low BMD, and fine wrinkles at the corners of the eyes and mouth. Diagn osis in males is based on confirmation of a low or inappropriately normal LH level in conju nction with a low testosterone level. Treatment involves androgen replacement therapy with testosterone administered as a 1% topical gel (AndroGel 5 \200\22310 g qam, Testim 5 \200\22310 g qam), a transdermal patch (Androderm 2.5 \200\22310 mg qhs), or an intramus- cular depot injection (testosterone cypionate 50 \200\223400 mg IM every 2 \200\2234 wks). Doses may be adjusted to target testosterone levels in the normal range. Blood counts shou ld be monitored for polycythemia, and prostate-specific antigen (PSA) should be followed. C entral growth hormone deficiency Manifestations may vary depend- ing on age of onset. Growt h hormone deficiency that develops during child- hood may lead to short stature. Adults may present with low BMD and changes in body composition discernible as an increase in fat mas s and decrease in lean body mass. Diagnosis is based on confirmation of a low serum IGF-1 l evel by itself or in conjunction with an abnormal growth hor- mone stimulation test. Serum GH should not be measured to screen for GH deficiency and should only be assessed during fo rmal GH stimulation testing. Growth hormone stimulation tests are performed by measuring GH levels before and after administration of glucagon, a provocative agent thought to stimula te GH indirectly via insulin release.A peak GH level <3 ng/mL may be consistent with growth hormone deficiency. Insulin toler- ance tests (ITT) also stimulate GH secretion.Both gluca gon and ITT testing require careful monitoring of blood glucose levels, as hypoglycemia can occur.Treatment of GH deficiency involves daily administration of subcu- taneous injection s of recombinant human growth hormone . Doses may be adjusted to target normal IGF-1 levels . 15 322 Hyperprolactinemia Physiology Prolactin is constitutively secreted by lactotroph cells in t he anterior pituitary. Dopamine secreted by the hypothalamus travels along the pituitary st alk through the hypophyseal portal circulation to bind to dopamine receptors on lactotroph cells. This binding of dopamine inhib- its the secretion of prolactin. Several different un derlying mechanisms may lead to increased secretion of prolactin with resultant hyperprolac tinemia (Table 9.24). Symptoms Hyperprolactinemia may suppress secretion of gonadotro- pin releasing hormone (GnRH), effectively inhibiting secretion of FSH and LH. This may lead to development of hypogonadotropic hypogonadism. Premenopausal adult females may present with oligomenorrhea, amenor- rhea, or infertility. Elevated prolactin levels in premenopausal fe males may also stimulate abnormal secretion of milk from one or both breasts, a con- dition known as galactorrhea . Adult males may present with a diminished libido, erectile dysfunc tion, or impotence. 15 Moltich ME, et al. Evaluation and management of adult growth hormone deficiency: An Endo crine Society clinical practice guideline. J Clin Endocrinol Metabol . 2011.96(6):1587 \200 \2231609. y g o o n i r c o d n E Table 9.24 Mechanisms of disorders associated with hyperprolactinemia l \212 Proliferation of lactotroph cells in the form of a prolactin-secreting pituitary adenoma (p rolactinoma) leads to increased constitutive secretion of prolactin Exposure to agents that inhibit binding of dopamine to dopamine receptors; most commonly implicated agents are tho se used to treat psychosis (haloperidol, risperidone, chlorpromazine, olanzapine), GI drugs (metoclopramide, cimetidine), opiates (codeine, morphine), and antihypertensive agents (me thyldopa, verapamil, reserpine). Compression of the pituitary stalk may interrupt passage o f dopamine through the hypophyseal portal system; stalk compression may be associated with growth of nonfunctional pituitary adenomas or other sellar and suprasellar masses. Increase d secretion of prolactin caused byincreased secretion of TRH; precise mechanism is unclear; hyperprolactinemia may develop in cases of untreated primary hypothyroidism. Macroprolacti n is a benign cause of elevated serum prolactin levels. \200\234Big prolactin \200\235 for ms when 23-kD molecules become glycosylated. Diagnose with serum macroprolactin measurement s in patients with- out symptoms of hyperprolactinemia. Rare causes of hyperprolactinemia: Nipple stimulation/chest wall injury, chronic kidney disease, excessive estrogen intake. \212 \212 \212 \212 \212 Evaluation Initial evaluation should focus on (a) documenting a recent medication history t o check for exposure to specific agents and (b) mea- suring a TSH level to check for primar y hypothyroidism.Prolactin >200 ng/ mL should raise suspicion for prolactinoma.Further eval uation may require dedicated pituitary MRI scanning with gadolinium to check for the presen ce of a sellar mass that may represent a prolactin-secreting pituitary adenoma or a nonfunc tional pituitary adenoma with stalk compression. Treatment of prolactin-secreting pituitary adenomas Many prolactin-secreting pituitary adenomas are very responsive to treatment with dopamine agonists alone. 16 Reduction in size with diminished secretion of prolactin may b e confirmed in up to 90% of successfully treated patients. Cabergoline (Dostinex 0.5 mg) is preferred as a first-line agent. Usual start- ing dose is 0.25 mg twice a week. May be a dvanced as tolerated to 1 mg twice a week. Dose-limiting side effects may include nausea, o rthostasis, and cognitive impairment. Bromocriptine (Parlodel 2.5 mg bid \200\223tid) may also be considered as an alternative agent when cost, availability, or intol- erance of ca bergoline side effects present difficulties. Prolactin levels may be checked 2 \200\2233 wk s after starting treatment or after adjusting a dose of a dopamine agonist to gauge efficac y. Changes in prolactinoma size may be detected on pituitary MRI scans checked 6 \200\2238 wks after starting treatment. In cases where patients require treatment but (1) cannot tole rate therapeutic doses of dopamine agonists or (2) tumor is unresponsive to medical ther- a py, surgery may be considered. Microadenomas can usually be removed via transsphenoidal app roaches. Removal of larger macroadenomas may require craniotomy. Success rates following in itial surgery vary. Persistent disease may require repeat surgery and/or treatment with ext ernal beam radiation. 323 16 Melmed S, et al. Diagnosis and treatment of hyperprolactinemia: An Endocrine Society cli nical practice guideline. J Clin Endocrinol Metabol. 2011. 96(2):273 \200\223288. Treatment of prolactin-secreting pituitary adenomas during pregnancy Increased production a nd secretion of estrogen during preg- nancy may promote growth and expansion of prolactin-s ecreting pituitary adenomas. Macroadenomas may expand and cause visual field deficits or se vere headaches. Women who require treatment of hyperprolactinemia to become pregnant should be placed on bromocriptine due to the greater certainty that it does not cause birth defec ts.If possible, dopamine agonists should be discontinued in pregnancy. Clinical monitoring every 3 months during pregnancy should include questioning about headaches and visual chang es.If the location or size of the prolactinoma requires continued medical management during pregnancy, treatment with bromocriptine can be continued or reinitiated.In cases of known macroadenomas, particu- larly those that abut the optic chiasm, expectant management may fo cus on considering surgery prior to conception to prevent potential complica- tions.Should visual acuity decline or neurologic symptoms progress during pregnancy, dedicated pituitary MRI scanning and visual field testing may be required to assess tumor growth.If necessary, surgery may be considered during the second trimester. Acromegaly A rare systemic syndrome resulting from exposure to excessive levels of GH. The most common cause is proliferation of somatotroph cells in the form of a GH-secreting pitui tary adenoma. GH stimulates increased pro- duction and secretion of IGF-1 in the liver. Ove r time, excessive circulating levels of IGF-1 may lead to growth and enlargement of somatic tissues. Signs Changes in appearance may be insidious, developing gradually over the cours e of several years (Table 9.25). Review of older photographs may help to establish timing a nd extent of changes. Overgrowth of soft tissues may lead to coarsening of facial features. Patients and observers may note bossing of the frontal bones, expansion of the nose, enlar gement of the tongue (macroglossia), deepening of the voice, and increased prominence of th e jaw with resultant spacing of the teeth. Spade-like enlargement of the hands and feet may prompt successive changes in ring and shoe sizes. Carpal tunnel syndrome, skin tag formati on, excessive sweating (hyper- hidrosis), and hirsutism are also associated with acromegaly . Bone density may be increased in men and premenopausal women. Findings consistent with le ft ventricular hypertrophy may be evident. Complications Untreated acromegaly may be associ ated with the devel- opment of hypertension, cardiomyopathy, heart failure, T2DM, hypertro- phic cardiomyopathy, colonic neoplasia, and obstructive sleep apnea. 324 Table 9.25 Evaluation of suspected acromegaly 1 Screen for elevated GH secretion by checking a serum IGF-1 level. 2 If the IGF-1 level is elevated, check a GH suppression test. \212 GH suppression test is performed by measuring a baseline GH level, administering a 75 g ora l glucose tolerance test load, then measuring GH levels at 30, 60, 90, and 120 min marks. \212 Peak GH <1 ng/mL = normal response \212 Peak GH >2 ng/mL = acromegaly 3 Consider dedicated pituitary MRI scanning with gadolinium to check for the presence of a sellar mass that may represent a GH-secreting pituitary adenoma. Note that, at the time of diagnosis, many tumors are macroadenomas (>10 mm in size). Treatment Principal treatment is surgical resection. Smaller macroad- enomas can usually be removed via transsphenoidal approaches. Removal of larger macroadenomas may require cranio tomy. Success rates following initial surgery vary. Documentation of cure may depend on dem onstrating (a) normal postsurgical IGF-1 levels, (b) postsurgical serum GH concentra- tion <2.5 ng/mL, and (c) a postsurgical GH suppression test with a peak GH <1 ng/mL. Persistent disease may require repeat surgery, treatment with external beam radiation, and/or initiati on of medical therapy targeted to inhibit secretion of GH from residual pituitary tissue or antagonize growth hormone receptors to inhibit production and secretion of IGF-1. Medical therapy targeted to inhibit secretion of GH Somatostatin analogs act by binding to somatost atin receptors on target tissues and inhibiting GH secretion. Octreotide and lanreotide are commercially available somatostatin analogs. Octreotide is available in a short-acting sub cutaneous preparation (Sandostatin ) and a long-acting IM preparation (Sandostatin LAR ). Lanreotide is only available as a long-acting analog (Somatuline Depot). Limiting side e ffects of both agents may include nausea, abdomi- nal discomfort, hyperglycemia, and cholel ithiasis. Patients who tolerate test doses may be continued on escalating doses of the shor t-acting preparation or may be switched to the long-acting preparations. Doses may be adjus ted every 6 \200\2238 wks to target normalization of IGF-1 levels. In some cases, dop- amin e agonists may also inhibit secretion of GH from residual tissue and may be used alone or i n concert with somatostatin analogs. Cabergoline (Dostinex 0.5 mg, usual starting dose 0. 25 mg twice a week) has proven to be more effective than other agents when used for this pu rpose. May be advanced as tolerated to 1 mg twice a week. Dose-limiting side effects may in clude nausea, orthostasis, and cognitive impairment. Medical therapy targeted to inhibit pr oduction and secretion of IGF-1 Pegvisomant (Somavert ) is a modified form of GH that acts by competitively binding to GH receptors, inhibiting the production and secre- tion of IGF -1 in the liver. Clinical trials have shown that it may effectively normalize IGF-1 levels in patients who have failed to respond to treatment with somatostatin analogs. Can also be used in combination with soma- tostatin analogs. Side effects of this GH receptor antagonis t include nausea, diarrhea, chest pain, and transaminitis that may require discontinuation of the drug. y g o o n i r c o d n E l 325 Diabetes insipidus Physiology of water balance Increased serum osmolality and decreased eff ective circulating volume stimulate release of antidiuretic hormone (ADH) from the supraopt ic and paraventricular nuclei in the hypothala- mus. Circulating ADH binds to receptors in the collecting tubules of the kidney, activating aquaporin channels that mediate increased reabsorption of free water (see figure). Diabetes insipidus is a disorder characterized by decreased reabsorption of free water in the collecting tubules. It may be precipitated by d isorders that (1) interrupt the release of ADH from the hypothalamus (central diabetes insi pidus) or (2) inhibit the action of ADH in the collecting tubules (nephrogenic diabetes ins ipidus). See Figure 9.2. Patients present with severe polyuria (urine output >3,000 mL/day) and compensatory polydipsia associated with the excretion of large volumes of dilute urine . Primary polydipsia Also known as psychogenic polydipsia, is caused by excessive intake of water. Commonly seen in patients with psychiatric ill- ness, although may be induced by hy pothalamic injury or infiltration affect- ing thirst center. Table 9.26 Water deprivation test 1 Starting after breakfast, hold all intake of fluids. Check the patient \200\231s baseline weight, pulse, and BP, and measure a baseline serum osmo- lality and serum sodium level. \212 \212 \212