3

The brain participates in the endocrine system through the hypothalamus, which contains the neurosecretory system that produces releasing hormones. Some of these hormones are secreted into the hypothalamohypophysial portal system

to regulate anterior pituitary hormones, and others into the general circulation in the posterior pituitary to control water conservation and breast milk ejection. The hypo-thalamus and its connections with the anterior and posterior pituitary gland comprise the hypothalamic–pituitary unit [1,2]. The hypothalamus regulates additional vegetative and autonomic functions, including eating, drinking, and temperature. Lesions in or around the hypothalamic–pituitary unit cause various clinical syndromes in the endocrine systemassociated with decreased or increased hormonal secretions. Tumors in or around the hypothalamus also produce other vegetative symptoms and involve other neural struc-tures nearby; the optic nerves and chiasm are particularly vulnerable. At times extension into the cavernous sinus causes eye movement diffi culties. Occasionally obstruction ofthe third ventricle and its outfl ow results in hydrocephalus. Headache can be caused bytraction on the pain-sensitive dura of the diaphragm of the sella.

Lesions affecting the hypothalamus or pituitary stalk directly (parapituitary) varywith the age of the patient; craniopharyngioma is more common at younger ages and meningioma occurs later in life [1,3]. Many of these tumors are congenital. Involvement of the vasopressin system at this level frequently causes diabetes insipidus (DI), which is much less common with pituitary tumors. Prolactin may also be elevated in hypotha-lamic hypopituitarism when all other anterior pituitary secretions are diminished (growth hormone [GH], thyroid-stimulating hormone [TSH], adrenocorticotropic hormone [ACTH], lutein-izing hormone [LH], follicle-stimulating hormone [FSH]). Prolactin (PRL) secretion is mainly underinhibitory control by dopamine, which originates in the hypothalamus [1,2,4].

A diagnostic work-up includes measurements of the pituitary hormones and their target glands.In addition to an endocrine and neurologic history and examination, screening should begin with assessment of the most critical endocrine functions, especially thyroid (thyroxine [T4]) and adrenalfunction (cortisol, intravenous ACTH test), and a blood PRL determination. Visual fi eld and acuity assessments are always important. Imaging, usually MRI with gadolinium for contrast, is important to localize the lesion. Treatment is total surgical removal of the lesion if possible. Microsurgical techniques have signifi cantly improved the cure rate and reduced the morbidity in craniopharyn-gioma in the past decade. Progress in the postoperative management of DI with short-acting vaso-pressin (dDAVP) and control of the syndrome of inappropriate secretion of vasopressin (SIADH)and adrenal hypofunction has improved therapy. Similar progress has been made for other lesions.Still others, such as infi ltrating optic or hypothalamic glioma, require radiotherapy.

Pituitary tumors are either hyposecretory or hypersecretory and are associated withspecifi c endocrine syndromes. Some hypersecretory tumors are associated with diminished secretion or reduced glandular function in other systems. For example, hyperprolactinemia due to oversecretion by a pituitary prolactinoma is associated with hypogonadism, commonly seen in the amenorrhea–galactorrhea syndrome. Thyroid and adrenal defi ciency—other aspects of hypopituitarism—may be seen in prolactinoma or somatotropic adenoma owing to destructionby compression of normal pituitary tissue. Pituitary hypopituitarism due to pituitary compressionor infarction is associated with loss of all the anterior pituitary hormones, including PRL (exceptin prolactinoma). DI, which usually does not occur, responds nicely to the administration of intra-nasal dDAVP. Treatment of hypopituitarism is through the replacement of the most necessaryhormones in adults: thyroid, adrenal glucocorticoid, estrogen, and androgen. GH replacement isimportant in children, although the importance of its role in adults is still debated.

The hypersecretory pituitary syndromes include SIADH, caused by oversecretion of vasopressin,and the three most common secreting pituitary adenomas: prolactinoma, somatotropinoma, and

Earl A. Zimmerman

Neuroendocrine Disorders

CHAPTER

© Springer Science+Business Media LLC 2009R. N. Rosenberg (ed.), Atlas of Clinical Neurology

Current Medicine Group LLC, part of

74 Atlas of Clinical Neurology

basophilic adenoma, which causes Cushing’s disease [1,4]. SIADHis uncommon and transient and can be readily managed if recog-nized or even anticipated. SIADH is very dangerous, causing sei-zures and coma in the face of rapidly diminished serum sodiumlevels and osmolality; it occasionally occurs in an inpatient settingwhen intravenous solutions are given to an obtunded patient.

Prolactinoma is the most common secretory adenoma, pro-ducing the amenorrhea–galactorrhea syndrome. In youngerpatients, most often infertile women, it is often associated with microadenoma. These small tumors may be visualized on MRI or CT. Patients have galactorrhea, hyperprolactinemia, and oth-erwise normal anterior pituitary function [1,4]. Some prolactino-mas resolve over the years and no treatment is given. If fertilityand pregnancy are important to the patient, treatment with bro-mocriptine or removal of the adenoma by transsphenoidal sur-gery provides excellent results. Larger prolactinomas tend to beassociated with hypopituitarism and visual disturbance.

The second most common secretory tumor produces GH andgigantism in children and acromegaly in adults. This is a life-threatening and debilitating condition, which fortunately is oftenassociated with adenomas that can be surgically removed, mostoften by the transsphenoidal route, resulting in a cure. Largertumors associated with hypopituitarism are more diffi cult to cure by surgery; they tend to recur but may be controlled with the

administration of bromocriptine, somatostatin analogues, and radiotherapy [1,4]. Control of the GH secretion—as in prolacti-noma—can be followed with measurement of the hormone inblood by radioimmunoassay. Half of the patients with acromegalyoversecrete PRL as well as GH.

The other hypersecretory pituitary syndrome causes Cushing’ssyndrome from basophilic cells that form ACTH. These are oftenchromophobic adenomas, as demonstrated by histochemistry.Cushing’s disease (caused by a pituitary tumor) is a common cause of Cushing’s syndrome, but other causes, such as ectopic ACTH-secreting lung tumor or an ACTH-independent adrenal tumor, mustbe considered [1,4–6]. Many Cushing’s tumors are pituitary micro-adenomas too small or diffuse to be visualized on MRI and requireinferior petrosal sinus measurements of ACTH [5] to determinewhich side of the pituitary to operate on using the transsphenoidal approach, which often results in a cure. Fortunately, aggressive ade-nomas secreting ACTH and melanocyte-stimulating hormone (withhyperpigmentation) were more common in the past after bilateraladrenalectomy (Nelson’s syndrome). Some tumors recur after sur-gery, requiring repeat urgery, drugs to suppress the adrenal gland,or radiotherapy. This serious hypersecretory state causes medicaldeterioration in a few years if untreated. Some tumors secrete morethan one of the hormones mentioned, on occasion all of them, andat times others, such as TSH, LH, or FSH.

A N T E R I O R

GH-RHBrain hormone(hypothalamus)

Pituitary hormone

Target gland

GH

Bone, liverIGF-I

Product growth,Product growthlipid, glucosemetabolism

MilkMilksecretion

EstradiolEstradiolProgesteroneTestosterone

CortisolCortisol WaterWaterreabsorption

MilkMilkejection

TT3, TT4

Breast Thyroid Gonad Adrenal Kidney Breast

PRL TSH FSH LH ACTH eriorPosteeeeeee

SOM DA TRH GnRH CRH VP VP OXY

Figure 3-1. The endocrine system. The brain participates in the endocrine system by secreting hormones known as releasing fac-tors, which act in the anterior pituitary gland to regulate the pro-duction of specifi c trophic hormones. These act on other glandsand control functions in the body: growth and metabolism, milk secretion, and thyroidal, gonadal, and adrenal functions. The target glands and their hormonal products in turn infl uence the brain, as feedback systems generally operate between endocrine organs. Thyroid hormones and adrenocortical steroids havesignifi cant feedback effects on the brain and pituitary gland.The hypothalamus region of the brain also secretes vasopressin

(VP) and oxytocin (OXY) into the general circulation through theposterior pituitary gland; these serve as an antidiuretic hormone(regulating water reabsorption by the kidney) and as a hormoneregulating breast milk ejection. ACTH—adrenocorticotropichormone; CRH—corticotropin-releasing hormone; DA—dopa-mine; FSH—follicle-stimulating hormone; GH—growth hormone; GH–RH—growth hormone–releasing hormone; GnRH—gonado-tropin-releasing hormone; IGF-I—insulin-like growth factor;LH—luteinizing hormone; PRL—prolactin; SOM—somatostatin;T3—triiodothyronine; T4—thyroxine; TRH—thyrotropin-releasing hormone; TSH—thyroid-stimulating hormone.

NORMAL FUNCTIONAL ANATOMY

Neuroendocrine Disorders 75

stalk, an extension of the hypothalamus, connects with the posterior pituitary,which appears as a bright spot on thisMRI scan compared with the anterior pituitary gland. The anterior commissure, thalamus, and mammillary body are read-ily apparent. C, This specimen of the ante-rior pituitary gland, with trichrome stain under light microscopy, appears generally similar to other glands of the body, suchas the pancreas, and dissimilar to theposterior pituitary. Red or reddish-browncells, which take up acidic stains, are the most numerous cells of the pituitary, producing either growth hormone orprolactin. Cells that appear green here, or blue with basic stains, produce thyroid-stimulating hormone, luteinizing hor-mone, follicle-stimulating hormone, oradrenocorticotropic hormone. Cells that react with neither acidic nor basic stains are called chromophobes. D, A sagittallow-power light microscopic image of amonkey pituitary gland specimen pre-pared with immunohistochemical meth-ods. The posterior pituitary gland (PP) iscomposed primarily of nerve fi bers con-taining vasopressin and oxytocin gran-ules that descend from the hypothalamus through the internal median eminence.AP—anterior pituitary. (C, courtesy of Rich-fard Defendini, MD, College of Physicians and Surgeons, Columbia University, NewYork, NY. D, from Antunes and Zimmer-man [6]; with permission.)

Figure 3-2. The hypothalamic–pituitary unit, in which the endocrine system and the brain interact. A, Midsagittal view of an MRI of a normal human brain. This “cut” goesright through the third ventricle, which forms the midline of the paired hypothalami. The rostral border is the anterior commissure and inferior to it, the lamina terminalis(not shown). The lateral border is formed by the columns of the fornix, a major hip-pocampal output path. The pineal gland, posterior hypothalamus, and mammillarybody form the posterior region, and the thalamus forms the dorsal limit. The sphenoidsinus is separated from the pituitary gland by a thin layer of the sella turcica bone, not visualized on MRI. B, A higher magnifi cation of the same MRI reveals the optic nerveand chiasm in proximity to the pituitary stalk and hypothalamus. The thin pituitary

C DD

A

Fornix

Hypothalamus

Pineal gland

Midbrain

Pituitary gland

Sphenoid sinusB

Thalamus

Anterior commissure

Mammillary body

Optic nerve

Pituitary stalk

Posterior pituitary

Anterior pituitary

76 Atlas of Clinical Neurology

Figure 3-3. Anatomic organization of the hypothalamus. A, Sagittal MRI showing the hypothalamus has been furtherdetailed by microscopic studies. B, Nuclear groups refl ect-ing the cellular organization; some of these contain knownreleasing secretory systems (D). C, Large neurons (magnocel-lular) that form posterior pituitary hormones are concentratedin the supraoptic and paraventricular nuclei. Smaller cells(parvo cellular), located in the arcuate nucleus (infundibular), paraventricular nucleus, periventricular region, and preop-tic areas, secrete hypothalamic releasing hormones into thehypophysial portal capillaries in the external zone of the

median eminence in the lower infundibulum–upper pituitary stalk. Tanycytes are specialized ependyma typically seen in theinfundibular region lining the third ventricle; they send longprocesses to the portal capillary bed and are thought to regu-late secretory terminals. D, Hypothalamic hormones’ nucleargroup of origin. CRH—corticotropin-releasing hormone;GH–RH—growth hormone–releasing factor; GnRH—gonado-tropin-releasing factor; OXY—oxytocin; SC—suprachiasmaticnucleus; SOM—somatostatin; TRH—thyrotropin-releasing hormone; VP—vasopressin. (B, adapted from Nauta and Haymaker [7].)

Mammillothalamictract

Lateralhypothalamus

Posterior nucleus

Paraventricular nucleus

FornixAnterior commissure

Preoptic region

Dorsomedialnucleus

Ventromedialnucleus

Supraopticnucleus

Periventricularnuclei Infundibulum

B

C

Pineal

Tanycyte

Large neuron

Arcuate nucleus

Mammillary body

TThhirird ventnt iririclclclee

Paraventricular nucleusSupraoptic nucleus

Posterior pituitary

Systemic vein

Short portal vein

Anterior pituitary

Long portal vein

Portal capillariesin median eminence

Superiorhypophysial artery

Optic chiasm

Septal

Preoptic area

SC

Hypothalamic Hormones’ Nuclear Group of Origin

Hypothalamic Hormone Nuclear Group of Origin

CRH/VP Paraventricular (parvocellular)

TRH

Dopamine Infundibular (arcuate)

GH-RH

GnRH Preoptic-infundibular

SOM Periventricular

VP (to posterior pituitary) Magnocellular paraventricular and supraoptic

OXY

A

Figure 3-4. Neurosecretory neurons identifi ed by light and electron microscopy using immunoperoxidase technique. A, Cell bodies secreting oxytocin (brown) and vasopressin (blue)in rat supraoptic nucleus.

Continued on the next page

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

D

Neuroendocrine Disorders 77

Figure 3-4. (Continued) B, Dark fi eld photomicrograph of vaso-pressin-containing axons leaving paraventricular magnocellular neurons laterally and coursing through and around the fornix ontheir ventral pathway to the pituitary stalk. Massive numbers offi bers provide the hormone to the posterior pituitary gland forthe minute-to-minute regulation of tightly controlled osmolal-ity. C, Vasopressin-containing granules in nerve terminals in thezona externa of the median eminence coexist with corticotropin-releasing hormone–containing granules and serve to stimulate adrenocorticotropic hormone secretion. D, These granules and others containing releasing hormones for the anterior pituitary targets are smaller than the vasopressin granules in the posterior pituitary gland. (A, courtesy ofA E.A. Zimmerman, MD, and H. Sokol,fMD, Albany Medical College, Albany, NY. B, from Zimmerman et al. [8]; with permission. C and D, courtesy of A.J. Silverman, MD, fCollege of Physicians and Surgeons, Columbia University, NewYork, NY; and E.A. Zimmerman, MD)

CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCB

DDDDDDDDDDDDDDDDDDDDDDDDDDDD

PATHOPHYSIOLOGIC STATES

Figure 3-5. Clinical presentations of pituitary and parapituitary lesions. Hydrocephalus is caused by the tumor blocking theforamen of Monro (A). There is a loss of visual acuity due tothe optic nerve being affected or a visual fi eld defect due to adisturbance of the optic chiasm (B). Cavernous sinus syndrome affecting cranial nerves VI, III, IV, and VI due to bleeding into the adenoma (pituitary apoplexy) (C). Cerebrospinal fl uid rhi-norrhea and possibly the tumor extending into the nose due toerosion of the fl oor of the sella into the sphenoidal sinus (D). Hypothalamic symptoms: hypopituitarism, hyperprolactinemia,and diabetes insipidus (E). Hypopituitarism due to disruption of the pituitary stalk by trauma, surgery, or tumor (F). Retro-orbital headache due to pressure on the diaphragm sella (G). Anterior pituitary failure (H).

78 Atlas of Clinical Neurology

Figure 3-6. Midsagittal MRI showing a large pituitary adenomaextending upward to involve the pituitary stalk, optic chiasm,and inferior hypothalamus. (From Abrams and Zimmerman [4];with permission.)

Figure 3-7. Hypothalamic lesions and symptoms. DI—diabetes insipidus; MBH—medial basal hypothalamus; OVLT—organumvasculosum of the lamina terminalis; PVN—paraventricular nucleus; SFO—subformical organ; SIADH—syndrome of inap-propriate secretion of vasopressin; SON—supraoptic nucleus;VMN—ventromedial nucleus.

Hypothalamic Lesions and SymptomsLesions Symptoms

VMN, medial hypothalamus Obesity, excitability

Lateral hypothalamus Aphagia, placidity

Anterior hypothalamus Hyperthermia

Posterior hypothalamus Hypothermia in cold

Preoptic area, OVLT, SFO Abnormal thirst (adipsia)

PVN, SON, tract DI or SIADH if stimulated

MBH Hypopituitarism

Figure 3-8. Some lesions affecting thehypothalamus. Craniopharyngioma and optic glioma are more common in chil-dren, and pituitary adenoma and menin-gioma are more often seen in adults.

Some Lesions Affecting the HypothalamusCraniopharyngioma—arises from the pituitary stalk, most commonly presents in childhood with visual changes, diabetes insipidus

Pituitary adenoma by upward extension, causing bitemporal hemianopia

Optic glioma—begins in optic nerve or chiasm, causing visual loss

Occurs in neurofi bromatosis type 1

Dermoid, teratoma, colloid cyst of the third ventricle—congenital tumors

Pinealoma—choriocarcinoma and germ cell type may secrete -human chorionicgonadotropin causing precocious pseudopuberty in boys

Meningioma in adults

Granulomatous lesions—sarcoidosis, histiocytosis X, tuberculosis

Metastatic—lung, breast, most often to the pituitary gland

Neuroendocrine Disorders 79

Figure 3-9. A, Midsagittal MRI from a patient with a cranio-pharyngioma involving the pituitary stalk and hypothalamus. B, MRI from the same patient with gadolinium enhancement

outlining the cystic portion in the hypothalamus. (Courtesy of David Hojnacki, MD, Jacobs Neurological Institute,fBuffalo, NY.)

BA

Hypothalamic lesion

Lactation, occasional( prolactin < 100 ng/dL)

Adrenal insufficiency( ACTH)

Diabetes insipidus( vasopressin,

water reabsorption)

Hypothyroidism ( TSH)

Ovarian failure withamenorrhea( FSH,LH)

GH in childrenHypoglycemia—decreasedinsulin-like factors from theliver and insulin from thepancreas when associatedwith adrenal failure

Failure to grow inheight—loss of epiphyseallong bone growth

Figure 3-10. Clinical manifestations ofhypothalamic hypopituitarism. ACTH—adrenocorticotropic hormone; FSH—fol-licle-stimulating hormone; GH—growth hormone; LH—luteinizing hormone;TSH—thyroid-stimulating hormone.

80 Atlas of Clinical Neurology

Figure 3-11. MRI changes in hypothalamic hypopituitarism. The“bright spot” (arrow) appearance of the posterior pituitary gland is missing from its normal location in the sella turcica. Instead it is located in the lower hypothalamus and upper pituitary stalkin this child with congenital growth hormone and thyroid-stim-ulating hormone deficiency. Damage to the stalk interrupts the hypophysial portal system and vasopressin fibers. These fibersregenerate, forming a new, usually smaller posterior pituitary in this location (ectopic). Such patients may recover from or havepartial diabetes insipidus. More proximal hypothalamic nucleiand tracts to the vasopressin system do not regenerate. Inter-ruption of the releasing factor pathways and the portal systemresults in anterior pituitary deficiencies.

Figure 3-12. Causes of diabetes insipidus. The appearance of diabetes insipidus is important to investigate, as it suggests abrain lesion [10].

Causes of Diabetes InsipidusPrimary: hereditary, idiopathic

Secondary

Trauma: accident, surgery

Neoplasm

Large pituitary adenoma with upward growth to involve hypothalamus

Craniopharyngioma

Meningioma

Epidermoid

Dermoid

Teratoma

Chordoma

Optic glioma

Metastatic carcinoma

Infection: meningitis, encephalitis

Systemic: sarcoidosis, lymphoma, histiocytosis X

Autoantibodies [9]

Figure 3-13. Clinical features of diabetes insipidus. No disease other than hypothalamic diabetes insipidus, when fully devel-oped, produces such a great need for drinking very large vol-umes in 24 hours (eg, amounts associated with kidney disease and psychogenic water drinking usually do not exceed a quart or two at most). The patient may be hypernatremic due to free water loss [11,12].

Clincial Features of Diabetes InsipidusPolyuria—volumes, often 5–8 quarts when severe

Polydypsia—often a craving for cold water

Hypernatremia and dehydration

Dilute urine (low specific gravity, low osmolality)

Rapid response to intranasal or subcutaneous administration of vasopressin

Neuroendocrine Disorders 81

Figure 3-14. Causes, clinical manifestations, diagnostic procedures, and management of syndrome ofinappropriate secretion of vasopressin [12]. SSRIs—selective serotonin reuptake inhibitors.

Syndrome of Inappropriate Secretion of VasopressinSome of Many Causes

Iatrogenic Ectopic hormone production

Parenteral administration of fluids in patients not regulating their own fluid intake, in a clinical setting in which vasopressin is oversecreted(eg, postoperative patients, especially following thoracic or neurologic surgery)

Carcinoma of the lung

Other cancers

Metabolic conditions

Central nervous system (overstimulation of vasopressin secretion) Acute intermittent porphyria

Head trauma Myxedema

Basilar skull fracture Drugs

Damage to hypothalamus and pituitary stalk Carbamazepine

Neurosurgery Chlorpropamide

Craniopharyngioma Clofibrate

Subarachnoid hemorrhage Cyclophosphamide

Meningitis Vincristine

Suprahypothalamic lesions Chlorthiazide

Stroke Cyclophosphamide

Subdural hematoma SSRIs

Pulmonary disease (lung afferents stimulate the central nervous system) Narcotics

Pneumonia Diagnostic Procedures

Pulmonary tuberculosis Rule out thyroid, kidney, and adrenal failure

Clinical Manifestations Management

Hyponatremia and low serum osmolality due to excessive vasopressin secretion Eliminate the cause

Slow lowering of sodium (eg, ectopic vasopressin secretion by lung carcinoma) Restrict fluid intake

May have no clinical signs Replace sodium chloride (carefully—too rapidly may cause central demyelination)

Rapid lowering of sodium (eg, obtunded postoperative patient receivingintravenous fluids)

Prescribe diuretics (furosemide)

Prescribe diuretics (furosemide)

Seizures Prescribe diuretics (furosemide)

Obtundation

Coma

Death (very low sodium levels, eg, 110 mEq/dL)

High urine osmolality, inappropriate with low serum osmolality

82 Atlas of Clinical Neurology

Uri

ne

ou

tpu

t,L/

d

Weig

ht, lb

15

Pitressine

0

1

2

3

4

5

6

7

8

9

10

11

12

13

142311

221

211

201

191

181

171

161

151

141

131

121

111

Postoperative day

000 11 22 33 44 55 66

Highest specific gravity of urine

1.024 1.009 1.007 1.016 1.022 1.022 1.0071.011 1.018 1.022 1.010 1.008

77 88 99 1010 1111 1212 1313 1414 1515

Daily urinary outputo uaua

Body weightgwo

Figure 3-15. Diabetes insipidus alternating with syndrome ofinappropriate secretion of antidiuretic hormone—triphasic diabetes insipidus. Triphasic diabetes insipidus (DI) was fi rst demonstrated in experimental animals with lesions in thepituitary stalk; it is now anticipated in patients who have had surgery in the region of the pituitary stalk [13]. It is especially seen in relation to surgery for craniopharyngioma, whichoften arises from and is attached to the pituitary stalk, as in the patient associated with this graph. In this patient the dailyurinary output rose signifi cantly to 10 to 12 L and body weightfell by the 4th postoperative day, indicating DI and failure ofvasopressin secretion (antidiuretic hormone) by damaged nerve fi bers in the pituitary stalk. This was treated by a long-acting (24-hour) preparation of vasopressin such as Pitressin (Parke-Davis, Morris Plains, NJ) administered by injection.While the patient was receiving intravenous (IV) fl uids, on day 6 the situation reversed, with marked weight gain and a great decrease in urinary output, which hit its lowest point on day 8. Pitressin was discontinued by day 7, but urinary spe-cifi c gravity continued to rise due to excessive secretion of vasopressin by degenerating nerve terminals in the posterior

pituitary gland distal to the damage to the pituitary stalk; thissecond phase was due to syndrome of inappropriate secretion of vasopressin. By day 10 the situation again reversed, withmarked diuresis of 15 L per 24 hours and a 10-lb weight loss by postoperative day 11. Urinary specifi c gravity fell and remainedlow. This phase of DI was due to elimination of the vasopres-sin released from degenerating nerve terminals. Partial DI appeared to persist. Regeneration of the proximal vasopres-sin-secreting nerve terminals, beginning about 2 weeks post-operatively, may result in partial or complete recovery from DI.Interruption of the hypophysial portal system is likely to cause failure of anterior pituitary function (Fig. 3-11).

The phenomenon of triphasic DI still occurs in patients, butthe risk of major swings in water and electrolyte balance have been eliminated from practice by anticipating it; administrating short-acting preparations of vasopressin for DI, including theintranasal form when appropriate; and especially monitoring IVfl uid intake and urinary output when patients are not regulat-ing their fl uid intake by their own thirst mechanisms. Removing patients earlier from IV fl uids permits them to regulate their own fl uid intake needs sooner and makes management easier.

Neuroendocrine Disorders 83

Pituitarydestruction

Failure oflactation( prolactin)

Adrenalinsufficiency( ACTH)

Usually nodiabetes insipidus

Hypothyroidism( TSH)

Ovarian failurewith amenorrhea( FSH,LH)

Pallor ( MSH)

Testicular failure,loss of beard

Figure 3-16. Clinical manifestations of pituitary hypopituitarism.The causes of pituitary hypopituitarism include pituitary adeno-ma hypophysitis [14], metastatic carcinoma, postpartum pitu-itary necrosis (which is sometimes called Sheehan’s syndrome), and hemorrhage into an adenoma, or pituitary apoplexy.ACTH—adrenocorticotropic hormone; FSH—follicle-stimulating hormone; LH—luteinizing hormone; MSH—melanocyte-stimu-lating hormone; TSH—thyroid-stimulating hormone.

Pituitaryprolactinoma

Galactorrhea(lactation)

Prolactin(often > 100 ng/dL)

Adrenalinsufficiency( ACTH)

No diabetesinsipidus

Hypothyroidism( TSH)

Ovarian failurewith amenorrhea( FSH,LH)

Figure 3-17. Clinical features and management of a prolactin-secreting pituitary adenoma. A prolactin microadenoma is lessthan 1 cm in diameter. Primary treatment is generally adminis-tration of a dopamine agonist for 1 to 3 years [15] rather thantranssphenoidal surgery [16]. The only presenting symptoms may be an amenorrhea–galactorrhea syndrome. A larger tumormay cause intracranial symptoms such as bitemporal hemiano-pia, retro-orbital headaches, and possible pituitary failure withthyroidal, gonadal, and adrenal insuffi ciency. ACTH—adreno-corticotropic hormone; FSH—follicle-stimulating hormone; LH—luteinizing hormone; TSH—thyroid-stimulating hormone.

Figure 3-18. Light microscopic photomicrographs of sections through a pituitary adenoma associated with excessive prolac-tin secretion. A, Section stained with routine hematoxylin and eosin demonstrating uniform tumor cells that are not react-ing with either basic or acid stains, indicating a chromophobeadenoma. B, Adjacent section immunoreacted for prolactin by peroxidase technique, causing a brown reaction productin most of the tumor cells. The pituitary gland is the source of very high blood levels of prolactin in many patients with pro-

lactinoma. Blood concentrations greater than 100 or 200 ng/dLare nearly diagnostic of prolactinoma. Levels can be as high asseveral thousand. However, patients with proven prolactinoma and amenorrhea–galactorrhea syndrome may have only slightlyelevated concentrations, often less than 100 ng/dL. These tendto be microadenomas. (Courtesy of R.F. Defendini, MD, and A.G. fFrantz, MD, College of Physicians and Surgeons, Columbia Uni-versity, New York, NY; and E.A. Zimmerman, MD, Albany MedicalCollege, Albany, NY.)

BA

84 Atlas of Clinical Neurology

BA

C

A

Figure 3-19. Radiographic tomograms showing changes in the sella that indicate skull changes in pituitary adenoma. Prior to advanced CT and MRI, radiographic tomography was an important tool fordetecting pituitary adenoma by showing changes in the sella.

A, Sagittal tomographic view of a small prolactinoma in a 35-year-old woman with amenorrhea–galactorrhea syndrome, demonstrating the normal right side of the sella. B, A depres-sion of the fl oor on the left side by the tumor into the sphe-noid sinus in the same patient. More aggressive tumors canerode through the fl oor, causing cerebrospinal fl uid (CSF)to leak into the sphenoid sinus and, rarely, forming a portal for sinus infection to enter the brain and cause meningitisor brain abscess. These tumors can also grow into the nasalcavity, so that the patient presents with epistaxis. Aggressiveadenomas, prolactin secreting or not, may also grow upward, affecting the visual apparatus and eventually blocking the thirdventricle and its outfl ow, causing hydrocephalus. C, Midsagit-tal tomogram showing a generally enlarged sella (“ballooned sella”), characteristic of a large pituitary adenoma expandingthe sella. This particular tomogram was taken from a patient with “empty sella syndrome” (ESS): a large sella with a smallamount of pituitary tissue usually plastered on the fl oor, withmost of the intrasellar space fi lled with CSF. Pituitary func-tion was normal in this patient, but some patients with ESS have pituitary insuffi ciency and, on rare occasions, visual fi eldabnormalities. In these cases, it is suspected that a pituitary adenoma had been present but shrank due to spontaneous

Figure 3-20. CTs showing the treatment of prolactinoma withbromocriptine. A, Frontal view of the brain and sella turcica with a prolactinoma before treatment. Arrows point to the top of theadenoma extending above the sella.

Continued on the next page

small hemorrhage and infarction that went unrecognized.Larger hemorrhages result in the syndrome of pituitary apo-plexy with acute pituitary failure and a neurologic syndrome:headache, cavernous sinus syndrome. Radiotherapy could alsoshrink a pituitary adenoma, as could bromocriptine therapy administered for prolactinoma.

Neuroendocrine Disorders 85

Figure 3-20. (Continued) B, Frontal view 1 year after treatmentof the prolactinoma with bromocriptine, showing shrinkage of the tumor into the sella (arrows). Dopamine agonists suchas bromocriptine have been the preferred therapy for manypatients with prolactin microadenomas; menses and fertil-ity are restored in most. Prolactin microadenomas frequently shrink signifi cantly in response to the drug [ 17 ], but they oftenrecur after it is discontinued. Tumor response may be partial,requiring additional therapy such as surgical debulking orradiotherapy. Transsphenoidal surgery is usually safe and suc-cessful for patients who plan a pregnancy but do not toleratebromo criptine. (From Molitch et al. [17]; with permission.)

B

Somatotropic adenomaof pituitary

Acromegalicfacies Hyperostosis

(thoracic vertebrae)

Cardiomegaly

Barrel chest

Abnormal glucosetolerance

secondary toinsulin resistance

Hypogonadism

Carpal tunnelCsyndrome

Increased size(hands, feet)

Degenerativearthritis

Thickened skin(hypertrophyof sebaceous

and sweat glands)

Growth of long bones(children)

Figure 3-21. Clinical features of growth hormone–secretingadenoma. Growth hormone–secreting adenoma causes acro-megaly in adults and gigantism in children. The pituitary isusually enlarged on brain imaging. Hypersecretion is detectedin blood by radioimmunoassay after a glucose suppression test. Insulin-like growth factor I is also elevated. Surgery is the fi rst-line treatment. Radiation or radiosurgery [ 18] is used if tumorremoval is not complete. Somatostatin analogues can be used to suppress persistent hypersecretion [ 19].

Figure 3-22. Facial features of a woman with acromegaly.Note the thickened skin and large nose and lips. Serialphotographs over several years can be very helpful inappreciating these changes.

86 Atlas of Clinical Neurology

Figure 3-23. Histologic features of growth hormone(GH)–secreting tumors. A, Light photomicrograph of a routine his-tologic specimen stained with hematoxylin and eosin, from asection through a pituitary adenoma from a patient with acro-megaly. The specimen demonstrates eosinophilia (acid stain) inmany cells concentrated in the adenoma; normal compressedtissue on the left margin also contains normal eosinophils. Clas-sic eosinophilic adenoma is associated with growth hormone hypersecretion. B, Another section from the same patient. This specimen was prepared with an immunoperoxidase techniqueusing antiserum to GH. The brown reaction product demon-strated even more GH concentrated in the tumor. Immunologicstains are more sensitive than histologic stains. About 50% of these tumors produce prolactin, which is also normally located in eosinophils, but most prolactinomas are not eosinophilic(Fig. 3-18). Many GH-secreting tumors appear chromophobic on tinctorial staining. (Courtesy of R. Defendini, MD, College of fPhysicians and Surgeons, Columbia University, New York, NY; and E.A. Zimmerman, MD, Albany Medical College, Albany, NY.)

BBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBBB

AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

Emotionaldisturbance

Memory deficiency,insomnia

Pituitary basophilicadenoma

Buffalo hump

Osteoporosis

Moon facies

Cardiachypertrophy

(hypertension)

Glucose intolerance

Obesity

Gastric ulcer

Skin ulcers(poor wound

healing)

Purpura

Muscle weakness

Amenorrhea

Abdominal striae Thin, wrinkled skin

Adrenal tumor orhyperplasia

Figure 3-24. Clinical aspects of Cushing’s syndrome. The causes of Cushing’s syndrome include pituitary adenomas that secreteadrenocorticotropic hormone (ACTH), adrenal tumors that secrete cortisol, ectopic tumors (eg, lung tumors) that secrete ACTH, and the administration of glucocorticoids (iatrogenic).

Neuroendocrine Disorders 87

Figure 3-25. The etiology of spontaneous Cushing’s syndrome in 225 patients seen at St. Bartholomew’s Hospital, London,England, 1969 to 1991. ACTH—adrenocorticotropic hormone. (Adapted from Trainer and Besser [5].)

Etiology of SpontaneousCushing’s Syndrome

Etiology Proportion of All Causes, %

ACTH-dependent 83

Pituitary Cushing’s syndrome (79%)

66

Ectopic ACTH (14%) 12

ACTH source unknown (6%) 4

Macronodular hyperplasia (1%) 1

ACTH-independent 17

Adrenal adenoma (58%) 10

Adrenal carcinoma (42%) 7

Workup for Differential Diagnosis of Cushing’s Syndrome

Clinical Features

Cortisol Suppressionwith High-doseDexamethasone

ACTH BloodLevels Imaging

ACTH-dependent tumors

Pituitary Cushing’s syndrome Headache (large tumor) Partial response Some elevation; to CRH

MRI—small adenomas present, but few visualized*

Pigmentation (Nelson’s syndrome)

Ectopic ACTH-producing tumors Wasting No suppression Often very high; no to CRH

CT and MRI of lung and thymus

Clinical diabetes mellitus

Pigmentation

Marked hypokalemia

ACTH-independent tumors

Adrenal tumor Carcinoma in children No suppression Very low CT and MRI of adrenal gland

*See Figure 3-27.

Figure 3-26. Work-up for differential diagnosis of Cushing’s syndrome after initial screening with a dexamethasone suppres-sion test: urinary free cortisol levels were not suppressed in the

morning following the administration of 1 mg of dexametha-sone at midnight [20]. ACTH—adrenocorticotropic hormone;CRH—corticotropin-releasing hormone.

Inferior Petrosal Sinus Sampling for ACTHPlasma ACTH (ng/L) After IV CRH 100 mg

0 Min 5 Min 10 Min 15 Min

Left inferior petrosal sinus 14 477 280 123

Right inferior petrosal sinus 16 23 28 54

Simultaneous peripheral vein 17 19 25 32

Figure 3-27. Inferior petrosal sinus venous sampling for adrenocorticotropic hormone (ACTH) on both sides of thepituitary gland, compared with peripheral venous sampling, both before and after stimulation with corticotropin-releasinghormone (CRH). Many pituitary adenomas cannot presently bevisualized with imaging methods, including MRI with gadolin-ium enhancement. This procedure may indicate on which side

of the gland the microadenoma is located in preparation fortrans sphenoidal surgery, which is the defi nitive treatment forCushing’s disease. The recent addition of vasopressin (desmo-pressin) to corticotropin-releasing hormone as the stimulanthas increased sensitivity of this test to 98.2% at 100% specifi c-ity for diagnosis of Cushing’s disease [21]. IV—intravenous. (Adapted from Trainer and Besser [5].)

88 Atlas of Clinical Neurology

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