A n n a l s o f C l i n i c a l a n d L aboratory S c ie n c e , C o p y r ig h t © 1 9 7 4 , I n s t i t u t e fo r C l i n i c a l S c ie n c e

Vol.

4,

No.

2

Laboratory Aids in the Diagnosis o f Pituitary Tum ors HOWARD D. KOLODNY, M.D.* AND LAWRENCE SHERMAN, M.D. Department of Medicine, Queens Hospital Center, Affiliation of the Long Island Jewish-Hillside Medical Center, Jamaica, NY 11432

ABSTRACT It is the aim of this review to acquaint the reader with the techniques often used in evaluating pituitary function and to show how they help in the diag­ nosis of pituitary tumors and the discernment of their systemic effects.

In tro d u c tio n

cumstances, the physician has three major laboratory criteria for determining ade­ quacy of hormonal function:

The pituitary gland is affected by a vari­ ety of tumors which usually manifest them­ selves by compression of the optic chiasm or alteration of endocrine function. The clinician may not be able to make a spe­ cific histological diagnosis, but he can as­ sess the extent of pituitary malfunction quite accurately and initiate appropriate therapy. Pituitary hormone secretion is a dynamic event, varying throughout the day and night in response to many endogenous and exogenous stimuli. These changes are ex­ quisitely controlled by central nervous sys­ tem mechanisms whose final common path­ way is in the hypothalamus. In fact, most procedures used in testing anterior pitui­ tary function affect the central nervous sys­ tem primarily and the pituitary secon­ darily through its vascular connections with the hypophysiotropic areas of the hypothalamus. Depending on clinical cir­

1. Basal secretion.—Hormone secretion may vary diurnally such as adrenocortical hormone (A C T H ) or monthly such as luteinizing hormone ( L H ) or follicle stim­ ulating hormone (F S H ) and may vary with food ingestion, with sleep or with a wide variety of physiologic and non-physiologic stimuli. A single basal serum level of a pituitary hormone is therefore often inadequate for diagnostic purposes. 2. Effect of provocative stimuli on secre­ tion.—Hormone secretion in excess of the basal rate is required in many situations. This ability to respond adequately to pro­ vocative stimuli is characteristic of a healthy pituitary secretory system. 3. Effect of inhibitory stimuli on se­ cretion.—Pituitary hormone secretion is normally inhibited, and serum hormone concentration reduced, in response to phys­ iologic stimuli which affect each of the * Send reprint requests to Howard D. Kolodny, hypothalamic-pituitary trophic hormone M.D., Director of Medicine, Queens Hospital Center, 82-68 164th Street, Jamaica, NY 11432. systems. The stimulus may be a metabolic 67

K O LO DNY AND SH E R M A N

68

event, a rising serum level of target organ hormone or changes in the level of a me­ tabolite. The exogenous alteration of a spe­ cific stimulus in a direction normally asso­ ciated with hypersecretion of the target hormone (e.g., administration of a gluco­ corticoid or of thyroid hormone) results in decreased secretion of the appropriate trophic hormone (A C TH or thyrotropin [T S H ]) in healthy subjects. Patients with pituitary tumors may pre­ sent with various groups of symptoms that include bitemporal visual field defects, amenorrhea in women and impotence in men, hypersecretory syndromes (including acromegaly, galactorrhea, and Cushing’s syndrome), trophic hormone deficiencies (hypopituitarism), or any combination of these. To use laboratory aids properly for diagnosing these tumors and assessing their hormonal effects, physicians must be ac­ quainted with the normal dynamic changes in pituitary hormone secretion. E v a lu a tio n o f G ro w th H orm on e S e cre tio n B

a sa l

G row th H

orm one

S e c r e t io n

The dual hypothalamic control of human growth hormone (H G H ) secretion by the anterior pituitary and the great number of endogenous and environmental factors that normally influence H GH secretion make it difficult to define what is “normal” for b a­ sal secretion and serum concentration. A highly simplified outline of the neural con­ trol mechanisms, including the speculated sites at which brain catecholamines may affect growth hormone secretion in man, is shown in figure 1. Basal serum levels of H GH are slightly higher in women than in men, the upper limit of normal being approximately 10 and 6 millimicrograms (nanograms, ng) per ml, respectively. There are two difficulties with assigning normality to a given basal serum concentration. First, many normal people have undetectably low basal HGH levels,

as do most patients with growth hormone deficiency. Second, exercise, stress, pro­ longed fasting and recent sleep-induction all stimulate HGH secretion and elevate serum H GH levels. To avoid misinterpre­ tation, it is necessary to measure HGH responses to provocative and inhibitory stimuli. G row th H

orm one

S t im u l a t io n

Insulin-induced hypoglycemia. Insulininduced hypoglycemia is the most con­ sistent stimulus to HGH release. Two fast­ ing control blood samples are drawn at 15 minute intervals with the patient resting comfortably, and then 0.1 unit per kg of crystalline insulin is administered intrave­ nously. Blood samples are then collected every 15 minutes for 90 minutes. Blood glucose and HGH levels are determined on each specimen. A 50 percent fall in blood glucose is required for meaningful results. A positive (normal) H GH response con­ sists of a rise of 5 ng per ml or more in serum H GH above baseline. For the patient’s safety a saline infusion is kept running throughout the study, and the test is terminated by an intravenous bolus of 50 percent glucose. Since patients with hypopituitarism are quite sensitive to insulin, some workers have recommended a smaller insulin dose (0.05 U per kg) for suspected cases of pituitary failure; only if the fall in blood sugar is inadequate (i.e., the concentration remains greater than 50 percent of basal level) is the higher dose then attempted on another occasion. Arginine infusion test. The protocol for arginine infusion test is similar to the in­ sulin test except that 0.5 gms per kg of arginine is infused over 30 to 45 minutes. The rise in serum HGH, as in the inducedhypoglycemia study, should be at least 5 ng per ml over the basal serum level. Other provocative tests. L-Dopa, gluca­ gon, vasopressin, stress and pyrogen have all been proposed and tested in the evalua­

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69

tion of H GH secretion. None has any particular advantage over the two tests mentioned, and most have proven less re­ liable. A positive H GH response to a single provocative stimulus suggests an intact se­ cretory mechanism. Because failure to re­ spond to an individual stimulus can occur in normal subjects, negative responses to several stimuli (insulin hypoglycemia, Ldopa, arginine infusion) best confirm the diagnosis of HGH deficiency. G row th H

orm one

I n h ib it io n

Suppression of H GH secretion in normal subjects is easily accomplished by adminis­ tration of 100 gm of glucose orally. Serum H GH levels decline within a half-hour, re­ main low for up to three hours and then rise above basal levels from four to five hours after the glucose load. This HGH rebound after the initial suppression is ap­ parently related to the normal fall in blood sugar concentration at the third and fourth hours after orally administered glucose. Baseline HGH levels are obtained in over­ night-fasted, rested patients under non­ stressed conditions. This avoids the potent stimulus to H GH secretion of stress. Blood samples are taken half-hourly for three hours, then hourly to the sixth hour if both phases of the diphasic response are to be measured. Normal subjects should have serum H GH reduced to less than 5 ng per ml by the induced hyperglycemia before the normal rebound occurs. Because acro­ megalic patients fail to suppress their se­ rum H GH concentrations to this level, oral glucose loading is an essential test when this diagnosis is clinically uncertain. A cro m egaly The clinical abnormalities that character­ ize acromegaly are produced by chronic hypersecretion of H GH and by pituitary enlargement. These abnormalities can be classified as local, metabolic, visceral and acral. Local effects produce headache and

F i g u r e 1. Mechanisms controlling secretion o f growth hormone by the anterior pituitary in man. Possible sites and modes of action of brain cate­ cholamines (norepinephrine and dopamine) are numbered. G IF, growth hormone release-inhibit­ ing factor (som atostatin); GRF, growth hormone releasing factor.

bitemporal field defects. Metabolic conse­ quences include deterioration of glucose tolerance and hypertension. Visceral ab­ normalities include enlargement of the major organs of the body, deepening of the voice, thickening of the tongue and om­ inous cardiomegaly that is associated with increased frequency of congestive heart failure and cardiac deaths. Finally, acral changes include the enlargement of hands and feet, the coarsening of facial features and the prognathism, malocclusion and in­ creased spacing of the teeth that may allow physicians to make the right diagnosis in­ stantly. Though the diagnosis is sometimes ap­ parent at a glance, there are good reasons for proper laboratory testing to make a definitive diagnosis. First, there are many questionable cases of patients with rugged features combined with one or more sug­ gestive findings. Second, the disease is treatable by removing the HGH-secreting pituitary adenoma, particularly with the newer methods of trans-sphenoidal hypo-

70

K O LO DNY AND SH E R M A N

>Acromegalic Patients N=7 F i g u r e 2 . Paradoxical decrease in serum growth hormone concentration after L-dopa administra­ tion in seven acromegalic subjects compared with normal increase in 1 2 control subjects ( left pan el). The responses in both groups cannot be accounted for by changes in blood sugar ( center panel) or in serum free fatty acids (right panel) after L-dopa administra­ tion.

physectomy—and many of the chronic dis­ figuring and disabling features are rever­ sible. Finally, the once-prevalent notion of “burned-out” acromegaly (inactive disease after long-standing activity) has been proven false by persistently elevated serum HGH levels in such patients: in these in­ stances the patient, not the disease, has burned-out. The characteristic abnormality of pa­ tients with acromegaly or pituitary gigan­ tism (the juvenile variant of chronic hypersomatotropism found in patients whose epiphyses are still open) is a persistently elevated basal serum H GH concentration which is not decreased to less than 5 ng per ml by an oral glucose load. The test is performed using a standard 100 gm oral glucose challenge, and blood samples are collected for H GH concentration before glucose administration, and at half-hour intervals for two to three hours. Most interesting has been the unexpected variation (physiologic or paradoxical) in blood H GH concentrations brought on by provocative and inhibitory stimuli, dem­ onstrating that H GH secretion in acromeg­ aly is often nonautonomous and under de­ ranged hypothalamic control.12’21 It is

known that brain catecholamines play an important role in hypothalamic mecha­ nisms controlling H GH secretion by the anterior pituitary and that L-dopa (a pre­ cursor of dopamine) normally stimulates such secretion and raises the serum HGH concentration.21 It has been found that acromegalic subjects characteristically have no increase, or more commonly a paradox­ ical decrease, in serum H GH after oral L-dopa (figure 2 ).22 These results (1 ) re­ emphasize the frequently non-autonomous nature of H GH hypersecretion in acromeg­ aly, (2 ) reinforce the concept of deranged hypothalamic control in acromegaly and (3 ) suggest that in this disease acutely raised levels of brain catecholamines may inhibit secretion of G R F (the reverse of the normal state) or stimulate secretion of somatostatin, or both, causing blood levels of H GH to be suppressed. G row th H

orm one

D

e f ic ie n c y

Laboratory evaluation of possible hypo­ pituitarism must include evaluation of HGH secretion. The patterns of trophic hormone deficiency suggest that H GH se­ cretion is the function most frequently impaired as anterior pituitary deficiency

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71

■unfolds.19 Clinically, disordered sexual function (particularly amenorrhea) is most commonly encountered. Physiologically, in­ adequate H GH secretion is nearly univer­ sal. In adults, H GH deficiency may be clinically silent; growth has already ceased, and the episodes of spontaneous hypo­ glycemia associated with H GH deficiency in children are extremely rare. Neverthe­ less, inadequate response of serum HGH to provocative stimuli in the right, clinical circumstances provides an early and sen­ sitive indicator of developing hypopitui­ tarism. E v a lu a tio n o f P ro la c tin S e cretio n B

a sa l

P r o l a c t in S e c r e t io n

Since the number of prolactin cells in the anterior pituitary varies in different physiological states, it is not remarkable that basal secretion and serum concentra­ tions of this hormone similarly vary. The mean and normal range for different groups is not yet established, but there is agree­ ment that basal serum levels of prolactin are higher in women than in men, increase geometrically during pregnancy and vary only slightly during the menstrual cycle.8’13 Using heterologous radioimmunoassays Buckman et al3 found that normal men had a mean basal prolactin level of 34 ng per ml ± 25.5 S.D., and normal women a level of 45 ng per ml ± 31.5 S.D. They also noted that most patients with functional galactorrhea had serum prolactins that fell within two standard deviations of the mean for normal females, though their mean serum concentration (73.5 ng per m l) was significantly higher than normal. In addi­ tion, patients with prolactin-secreting pitu­ itary tumors had serum prolactins that oc­ casionally overlapped the higher levels of the functional galactorrhea group, despite a mean concentration more than 100 times greater than this group. Friesen et al,8 using a homologous radioimmunoassay, re­ ported a mean basal serum prolactin level

F i g u r e 3 . Mechanisms controlling secretion of prolactin by the anterior pituitary. Whether a separate prolactin releasing factor is elaborated by the hypothalamus, in addition to the bifunctional thyroid releasing hormone (T R H ), remains un­ known. The presence of prolactin inhibiting factor (P IF ) is required to prevent unrestrained secre­ tion of prolactin. When the hypothalamic-pituitary vascular connections are severed, as in high stalk section, hyperprolactinemia results. This powerful inherent secretory ability of prolactin-secreting cells contrasts with that of most other hormonesecreting cells of the anterior pituitary.

in men of 7 ng per ml, with a range up to 28, with a corresponding mean of 10 and range up to 20 in women during the follicular phase, and mean of 11 and range up to 42 in women during the luteal phase of the menstrual cycle. The mean level of 30 ng per ml in the first trimester of preg­ nancy doubled in the second trimester, re­ doubled in the third and nearly redoubled again at term.8-9 P r o l a c t in S t im u l a t io n

Thyroid-releasing hormone (T R H ). This hypothalamic hormone appears to release prolactin by direct action on the anterior pituitary (figure 3). A simple tripeptide, (pyro)Glu-H is-Pro(N H 2), TRH has been synthesized and the synthetic form used to

72

KOLODNY AND SH E RM A N

test for both thyrotropin (T S H ) and pro­ lactin responsiveness. Doses of 100, 200 and 800 micrograms have been given by bolus intravenous injection in 10 cc saline to pa­ tients who have fasted overnight and had blood samples taken in the basal state. D ef­ inite increases in serum prolactin have been noted with all three dosages. A striking and consistent elevation has been noted five minutes after intravenous TRH , with peak values (two to 15 times higher than basal) at 15 to 20 minutes, and a slow decline to the baseline at three hours.11 For clinical purposes, blood can be collected at 15 and 30 minutes after injection, and then at half-hour intervals until the third hour. Though the dose-response function is not yet clear, and no serious side effects have been reported in TRH doses up to two mg intravenously (mild nausea without vomit­ ing, a mild urge to urinate and a flush over the body may be transiently n oted),6 200 micrograms of TRH appears to be an ade­ quate stimulus for prolactin secretion when this test is indicated.11’13 Chlorpromazine stimulation. Phenothiazine derivatives, including chlorpromazine, interfere with availability of brain cate­ cholamines by blocking attachment of these amines to their receptor sites. Pre­ sumably chlorpromazine acts in the hypo­ thalamus to block the effect of prolactininhibiting factor (P IF ), which is under catecholamine control (figure 3 ). This leads to an increase in prolactin secretion by the anterior pituitary, and a rise in serum prolactin concentration. A single intramuscular injection of 25 to 50 m g of chlorpromazine is given to patients who have fasted overnight and had blood sam­ ples taken in the basal state. Further sam­ ples are collected at half-hour intervals for three to six hours. A doubling of the fasting prolactin concentration is normally found in the first 30 to 60 minutes, with peak values found at two to three hours. This peak is as high as 20 times the basal value

when the higher dose is used. Elevations in serum prolactin may continue for six hours or more.7’23 P r o l a c t in In h ib it io n

Water-loading test. Prolactin may play a role in regulating serum osmolality by facilitating water retention (figure 3). Water loading is normally followed by a fall in serum prolactin concentration, which may then contribute to the diuresis. After overnight abstinence from food and water, subjects are given an oral load of 20 cc water per kg of body weight over a halfhour period; blood samples are obtained before the water ingestion and at half-hour intervals afterward for three hours. The normal response is a decrease of at least 50 percent from the baseline serum pro­ lactin concentration at any of the times after the water load. The nadir of serum prolactin is usually reached at one to two hours.3 A similar marked decrease, but one more promptly noted, occurs when a hypotonic load (0.45 percent saline, 20 mg per kg) is infused intravenously over a one hour period. With intravenous infusions, serum prolactin reaches its lowest point within 30 minutes of the start of the infusion. The maximum decrease in serum prolactin (to nonmeasurable levels) correlates with a drop in serum osmolality to less than 274 mOsm per K g induced by the hypotonic load.4 L-dopa administration. Oral ingestion of L-dopa is followed by a decrease in serum prolactin concentration. This effect is prob­ ably related to the ability of L-dopa to cross the blood-brain barrier and be decarboxylated to dopamine. This catechol­ amine (and possible norepinephrine) may act at two sites to inhibit prolactin secre­ tion: on the anterior pituitary to suppress prolactin secretion, and on the hypothal­ amus to stimulate secretion of prolactininhibiting factor (P IF ).15 After an over­

L A BO R A TO R Y AIDS IN DIAG N O SIS O F P IT U IT A R Y TU M O R S

night fast, blood samples are obtained before an oral dose of 500 m g of L-dopa, and at half-hour intervals afterward for three to four hours. In normal subjects serum prolactin declines to less than 4 ng per ml by two to three hours.7 P itu ita r y T u m o r s a n d P ro la c tin The Forbes-Albright Syndrome is char­ acterized by a pituitary tumor associated with nonpuerperal galactorrhea (i.e., in­ appropriate lactation) and amenorrhea ow­ ing to gonadotropin failure. The tumor is almost always a chromophobe adenoma. The immediate cause of the inappropriate lactation appears to be hyperprolactinemia. How this universally present hyperprolatinemia is produced is still unknown. It has been suggested that the adenoma in­ terferes with normal hypothalamic-pituitary mechanisms controlling prolactin se­ cretion (figure 3 ), blocking the restraining effect of prolactin-inhibiting factor (P IF ) and allowing unrestrained prolactin secre­ tion. It has alternatively been suggested that cells of the tumor itself secrete pro­ lactin inappropriately, producing the hy­ perprolactinemia. Prolactin production by tumor homogenates and by incubated tu­ mors gives credence to this latter theory.17 The Forbes-Albright syndrome must be differentiated from other pathologic causes of increased serum prolactin (table I). Among these are two other euphonious syndromes—the Chiari-Frommel syndrome, in which there is pathologically prolonged post-partum lactation (sometimes for dec­ ades), and the Ahumada-Del Castillo syn­ drome, in which the inappropriate lactation is unassociated with pregnancy and par­ turition. The Forbes-Albright syndrome must also be differentiated from an im­ portant, but commonly overlooked pharma­ cological cause of galactorrhea—prolonged secondary amenorrhea provoked by discon­ tinuance of oral contraceptives ( “oversup­ pression syndrome” ).20

73

It is important to distinguish patients with tumor-induced galactorrhea from p a­ tients with these various types of functional galactorrheas for several reasons. A most important one is the clinical fact that long term follow-up of patients with these “functional” states has sometimes finally revealed the presence o f , a pituitary ad­ enoma. Thus, a prolactin-secreting chromo­ phobe adenoma may evolve from, or be the hidden cause of, a clinical picture originally consistent with Chiari-Frommel syndrome, Ahumada-Del Castillo syndrome or second­ ary anemorrhea caused by cessation of oral contraceptives. The laboratory aids most useful in dis­ tinguishing these various galactorrheic states are X-rays of the skull with special views of the sella turcica, basal serum pro­ lactin levels, and the water-load test for prolactin suppression. Prolactin-secreting chromophobe adenomas can be small, and it may be months or years before they become manifest on skull X-rays. However, basal serum prolactin concentrations in pa­ tients with these tumors are usually re­ corded in the microgram per ml level, contrasted with the millimicrogram (nano­ gram) per ml level found in normal sub­ jects and patients with functional galactor­ rhea. In rare cases, serum prolactin levels as “low” as 200 to 300 ng per ml have been found in patients with these tumors, and prolactin levels as high as this have been found in patients with functional galactor­ rhea. In such problem cases depression of the serum prolactin level by oral water loading is useful. In normal subjects and subjects with functional galactorrhea, the water load usually decreases serum pro­ lactin to undetectable levels; in all cases so far reported serum prolactin is reduced by at least 50 percent. In patients with prolactin-secreting pituitary tumors serum prolactin is minimally depressed (less than 50 percent reduction) by the water load.3 L-Dopa suppression has also been at-

KOLODNY AND SH E R M A N

74

TABLE I C

a uses

o f

H

u m a n

H

y pe r pr o la ct in e m ia

I. Physiologic A. Pregnancy (Serum concentration doubles each trimester and peaks ju st before delivery) B. Post-partum 1. Non-nursing mothers, up to 4 weeks 2. Nursing mothers, same ; suckling induces marked but transient increases during next 3 months C. Breast (or breast and nipple) stimulation in non-post-partum women; nipple stimu­ lation in men D. Fetal life E. Early infancy (first week, with decline to adult levels at 3 to 6 months) F . Stress : anesthesia, surgery, exercise, acute anxiety G. Sexual intercourse in women (10 to 30 minutes after completion, perhaps earlier) H. Hypoglycemia II. Pathologic A. Hypothalamic disorders 1. Chiari-Frommel syndrome: pathologi­ cally prolonged post-partum lactation 2. Ahumada-Del Castillo syndrome: idio­ pathic galactorrhea 3. Hypothalamic tumors : craniopharyn­ gioma, ectopic pinealoma, metastatic tumors 4. Nontumorous hypothalamic infiltration (a) Disseminated sarcoidosis (b) Histiocytosis X 5. Post-resection of craniopharyngioma (in children with normal or accelerated growth rates despite decreased growth hormone) B . Prolactin-secreting pituitary tumors 1. Forbes-Albright, syndrome: pituitary tu­ mor with galachtorrhea and (usually) amenorrhea

tempted, but in all groups serum prolactin has decreased by more than 50 percent from the basal level after oral L-dopa. This failure of L-dopa to discriminate between pituitary tumor and functional galactorrhea actually reflects its success as a prolactinsuppressive agent, and it has been used as therapy to decrease serum prolactin and ameliorate symptoms in patients with nonpuerperal galactorrhea due to pituitary tumor and functional pituitary disorders.15

Acromegaly (infrequent) Nelson’s syndrome: hyperpigmentation often with pituitary tumor after bilateral adrenalectomy for Cushing’s syndrome 4. “ Nonfunctioning” chromophobe ade­ noma (3 0 percent of cases) Surgical transection of pituitary stalk Primary hypothyroidism, with pituitary prolactin secretion apparently stimulated by increased secretion of thyrotropinreleasing hormone (TRH ) of hypothalamus Chronic renal failure (2 0 percent of cases) Ectopic prolactin production by tumors 1 . Bronchogenic carcinoma 2 . Hypernephroma Irritative lesions of the chest wall 1. Herpes zoster 2 . Chest surgery 3 . Traum a to the intercostal nerves 2. 3.

C.

D. E. F. G.

III. Pharmacologic A. Psychotropic drugs 1. Phenothiazines: chlorpromazine, fluphenazine, promazine, perphenazine 2 . Tricyclic antidepressants: amitryptyline, nortriptyline, imipramine, desipramine 3 . Reserpine 4. Sulpiride (an antiemetic and tran­ quilizer) 5. Butyrophenones: haloperiodol (Note: psychotropic drugs without effect on serum prolactin include lithium car­ bonate and chlordiazepoxide) B. Anti-hypertensive drugs 1 . Reserpine 2 . Alpha-methyldopa C. After discontinuance of oral contraceptives 1). Estrogen therapy E . Injection of thyrotropin-releasing hormone (TRH )

C h ro m o p h o b e A d en o m a Until very recently the inclusion of a major discussion of chromophobe adeno­ mas as part of a section on prolactin would have been unthinkable; today, the authors of such a discussion deserve at worst a rebuke for slight exaggeration. All still agree that chromophobe adenomas may slowly destroy the function of the anterior lobe, and may also cause headache and visual field defects by their propensity to

LA BO R A TO R Y AIDS IN DIAGNOSIS O F P IT U IT A R Y TU M O R S

enlarge the sella turcica and grow out of it. Classically, these most common of all pitu­ itary tumors were considered hormonally inactive. Now, however, it is clear from electron microscopic studies of the anterior pituitary in various species including man, that the term chromophobe, “connoting an inactive cell, is a misnomer. . . . Secretory granules have been present in every chro­ mophobe adenoma that we have studied with the electron microscope although they may be few in number and lack the elec­ tron density of granules in normal cells.”14 Indeed, when appropriate stains are used the chromophilic nature of the cells of such adenomas becomes so apparent that the very existence of nonsecretory, agranular “chromophobe” cells in the human pituitary is now doubted.16 Moreover, it seems that prolactin-secreting “chromophobe” adeno­ mas are the commonest hormone-secreting tumors of the pituitary.8’9 Because most of these prolactin-secreting tumors do not produce galactorrhea despite chronically elevated serum prolactin levels, they were classified as “nonfunctional” chromophobe adenomas until sensitive and specific assays for prolactin became avail­ able. Now it is recognized that about 30 percent of chromophobe adrenomas secrete prolactin, with more than two-thirds of these remaining hormonally silent (i.e., not producing the Forbes-Albright syndrome with galactorrhea and amenorrhea).9 Why this hormonal silence in some patients? The answer is not known, except that other hormones (estrogens and glucocorticoids) are needed in the right environmental “mix” for lactation to occur. Despite the absence of galactorrhea, serum prolactin levels are very high in patients with these prolactin-secreting chromophobe adenomas ( higher than 200 ng per m l). Lesser eleva­ tions of prolactin may be due to infiltrative or other diseases involving the hypothal­ amus (table I), or to extension to the hypo­ thalamus of any type of pituitary tumor

75

(or craniopharyngioma). The water-load test may be helpful in the uncommon pa­ tient with serum prolactin levels of 200 to 300 ng per ml. On the other hand, when clinical findings are nonspecific (e.g., per­ sistent headache), there is no evidence of extrasellar disease, and there is no certain increase in the size of the sella turcica; markedly elevated serum prolactin levels indicate the presence of chromophobe ad­ enoma of the anterior pituitary. Secretory or not, chromophobe adenomas can produce hypopituitarism. This ability to destroy the hormone-producing capacity of the anterior pituitary is shared by many other diseases that may thus mimic chro­ mophobe adenoma. These include intrasellar cysts, granulomas, and aneurysms, postpartum pituitary necrosis, and necrosis due to diabetes mellitus, shock, increased intracranial pressure and head trauma—to recount some of the more celebrated causes. The hypopituitarism induced by chromo­ phobe adenoma may be partial or com­ plete. Rabkin and Frantz,19 estimating the frequency of hormone loss in 25 patients with hypopituitarism, found abnormally low growth hormone responses in all pa­ tients, abnormally low urinary gonadotro­ pins in 88 percent, and abnormally low A CTH and TSH in 56 percent and 52 per­ cent respectively. The clinically evident extent of the hypopituitarism is usually far less than the deficiency revealed by testing hormonal function. It is therefore necessary to assess each function, taking particular care to use provocative tests to best elicit the individual hormonal deficiency. E v a lu a tio n o f A C TH S e cretio n B

a sa l

A CTH

S e c r e t io n

A radioimmunoassay for ACTH has been developed, but is not yet readily available. Moreover, the hormone is measured in micromicrogram (picogram, p g ) per ml quantities, and reproducibility of results

KOLODNY AND SHERM AN

76

NOtMAL RESPONSE 10 METYRAPOME TESTING

rv

RESPONSE TO METYRAPONE IN PITUITARY TUMOR WITH ACTH DEFICIENCY(SECONDARY ADRENAL INSUFFICIENCY

RESPONSE TO METYRAPONE IN BILATERAL ADRENAL HYPERPLASIA (WITH OR WITHOUT PITUITARY TUMOR ■CONTROL CtNltR

' res coBiiconwm

P lism a Cortisol Concentration :

m n t m fnjb*ck

Decreased Plasma Cortisol Concentration

No C ortisol Or II- Oeoxy - Cortisol In Absence Of ACTH_____________

Cortisol Concentration Wo CNS Effect]

II {HYDROXYLASE CORTISOL

11-DEOXYCOtTISOl

CORTISOL

Decreased Plasma Cortisol Concentration Increased Plasma, II- Deoxy Cortisol Concentration

IIB-HYDROXYLASE CORTISOL

iMClnctnis« F i g u r e 4. Mechanisms controlling secretion of adenocorticotropic hormone (A C T H ) by the anterior pituitary, and responses to metyrapone testing in different clinical situations. CRF, corticotropin releasing factor.

based on such miniscule concentrations is still difficult. At 8 AM, following an over­ night fast of at least eight hours, the basal plasma ACTH level is 10 to 70 pg per ml. More useful clinically are plasma cortisol levels. Biosynthesis of cortisol in the zona fasciculata of the adrenal cortex is directly dependent on circulating ACTH. It is well established that ACTH and cortisol are secreted cyclically throughout each 24 hour period, with their maximum concentrations occurring at about 8 AM, and their lowest levels between 8 PM and midnight. This normal diurnal variation in plasma cortisol concentration is tested by obtaining blood from resting subjects at 8 AM and again at 8 PM. The normal plasma cortisol level is 5 to 30 micrograms per 100 ml at 8 AM, with a decline of at least 50 percent to less than 10 microgram per 100 ml 12 hours later. In Cushing’s syndrome, this diurnal variation is absent. There is no significant decrease from the morning cortisol level even though the morning concentration, considered by itself, is normal or high-

normal. This loss of diurnal variation of plasma cortisol is the sine qua non for the diagnosis of Cushing’s syndrome. A CTH

S t im u l a t io n

Many stimuli can provoke ACTH secre­ tion. This review will be limited to the two most important provocative agents, mety­ rapone and pyrogen. Metyrapone test ( figure 4). Metyrapone (Metopirone) is an inhibitor of the adrenal cortical enzyme, 11-beta-hydroxylase. In figure 4 A and B are depicted the usual sequence of events following normal corti­ sol secretion and after metyrapone has ef­ fected a substantial block in cortisol syn­ thesis. In essence, metyrapone produces a marked rise in serum ACTH consequent to the fall in serum cortisol and the excess production of the metabolic intermediary, 11-deoxycortisol (compound S ), which is not a glucocorticoid and, therefore, is with­ out suppressive effect on the hypothalamic hormone that stimulates ACTH release, corticotropin releasing factor ( C R F ). How­

LA BO R A TO R Y AIDS IN DIAGNOSIS O F P IT U IT A R Y TU M O R S

ever, ll-deoxycortisol, like cortisol, has a 17,21-dihydroxyacetone side chain, and therefore reacts with phenylhydrazine to form the Porter-Silber chromagen in the standard test for 17-hydroxycorticosteroids. Thus, there is normally an increase in uri­ nary 17-hydroxycorticosteroids (17-OHCS) after metyrapone administration, secondary to the increased secretion of ACTH and ll-deoxycortisol. To perform a metyrapone challenge correctly, three consecutive sepa­ rate 24 hour urine specimens must be ac­ curately collected. The first specimen is a baseline study. The second is collected on the day of metyrapone administration (750 m g orally every four hours for 24 hours). The third urine specimen is collected the day after drug administration, since some patients demonstrate the maximum re­ sponse at this time. In normal subjects a doubling or tripling of urinary 17-OHCS is usual. There is no response when there is complete A CTH deficiency. An atten­ uated response suggests a partial defect in ACTH secretion. Either of these responses may be found in patients with pituitary tumors ( figure 4C, D ). It must be emphasized that the adrenal cortex must be capable of responding to endogenous ACTH in order for the physi­ cian to assess the metyrapone test. Patients with primary adrenal failure cannot re­ spond to metyrapone because their adre­ nals are incapable of producing steroids even under maximum stimulation by cir­ culating ACTH. Pyrogen test. This test demonstrates the ability of the hypothalamic-pituitary sys­ tem to respond to a singular form of stressfever. The pyrogen test has been reported to be less sensitive than the metyrapone test and more distressing to the patient.2 The test is easily performed. A basal blood sample is drawn at 8 AM, 0.30 /xgm of bacterial pyrogen injected intravenously and another blood specimen obtained 4 hours later. A rise in body temperature

77

must be documented. Plasma 17-OHCS are determined on each specimen. At least a doubling of serum cortisol levels occurs in normal subjects. A CTH

I n h ib it io n

Dexamethasone test. A decrease in 24hour excretion of 17-OHCS reflects sup­ pression of A CTH secretion when certain testing maneuvers are used; normal urinary excretion is 3 to 10 m g per 24 hours for men, 2 to 8 m g per 24 hours for women. A fall in serum A CTH and urine 17-OHCS excretion occurs after the administration of small doses of exogenous glucocorticoids in normal subjects. This observation forms the basis of the dexamethasone test (figure 5 ), which assists the clinician in differentiating the normal but “Cushingoid” patient from patients with benign adrenal hyperplasia or adrenal tumor (benign or malignant) associated with hypercorticism. Dexamethasone is an extremely potent synthetic glucocorticoid which is not de­ tected by the usual clinical assays of uri­ nary 17-OHCS. The test is carried out at two dose levels, two mg per day (0.5 mg every six hours), which suppresses the 24 hour urinary 17-OHCS excretion below five m g per 24 hours in normal subjects (figure 4A ), but is usually without effect in pa­ tients with benign adrenal hyperplasia or adrenal tumor (figure 5 B ); and eight m g per day (two mg every six hours), which reduces the excretion of 17-OHCS by 50 percent or more in patients with benign adrenal hyperplasia ( figure 5 C ). The eight m g dose level is without effect in patients with adrenal tumors or hypercorticism sec­ ondary to ectopic ACTH production by carcinomas. The dexamethasone suppression test is easily performed on in-patients and care­ fully instructed out-patients. A baseline 24hour urine is collected, dexamethasone is administered in four equal six hourly doses for 48 hours at the two mg and then at

KOLODNY AND SHERM AN

78

/ NEURAL STIM U LI

NEURAL STIM U LI *

CONTROL CENTER FOR HYPOTHALAMUS

HYPOTHALAMUS

Normal Response To Dexamethasone, 2 mg/d

Bilateral Adrenal Hyperplasia: Dexamethasone, 8 mg/d

F i g u r e 5. The dexamethasone test of ACTH inhibition in normal subjects and patients with bilateral adrenal hyperplasia.

eight mg per day dose levels. A 24-hour urine is collected on the second day of drug administration at each dosage level. Uri­ nary 17-OHCS are determined on each specimen. A single midnight-dose (1 or 1.5 m g) dexamethasone test utilizing morning se­ rum cortisol determinations has been re­ ported. However, it has proven less reliable than the urinary studies, and we cannot recommend its use at this time. C u sh in g ’s Syndrom e

Chronic hypersecretion of adrenal gluco­ corticoids causes Cushing’s syndrome. The clinical expression is highly variable. When advanced, characteristic abnormalities in­ clude hypertension, moon facies, redistri­ bution of body fat, easy bruisability, di­ abetes mellitus, and osteoporosis. The syndrome is most commonly caused by bilateral adrenal hyperplasia (80 to 85 per­ cent), but can be produced by an adrenal adenoma or carcinoma. Bilateral adrenal hyperplasia is associated with significant elevations of serum ACTH and is of hypothalamic-pituitary origin ( “Cushing’s dis­ ease” ). A pituitary tumor may or may not

be present at the time of diagnosis. Adrenal adenomas and carcinomas are primary ad­ renal disorders associated with suppression of hypothalamic-pituitary ACTH release. This suppression is a normal hypothalamicpituitary response to the elevated levels of circulating cortisol resulting from tumor production. The basic differences in the pathophysi­ ology of the three types of Cushing’s syn­ drome make it reasonable to expect that the adrenal cortex in bilateral hyperplasia is responsive to maneuvers that alter ACTH levels, while adrenal tumors (benign or malignant) are less responsive. Although tests designed to distinguish hyperplasia from tumor have been of great assistance to the clinician, there are times when the results are not consistent with the proven pathological diagnosis. The clinician must not ignore his suspicions of hypercorticism and eliminate this diagnosis because of a single normal study. Multiple studies and repeated observations of the patient’s clin­ ical appearance and course may be re­ quired to make the diagnosis. In table II are shown the usual responses to be expected in Cushing’s syndrome to

LA BO R A TO R Y AIDS IN DIAGNOSIS O F P IT U IT A R Y TU M O R S

79

TABLE II R

es u lt s o f

o f

A

B

a s a l

S

e r u m

d r e n o co r t ica l

A C T H F

L

e v e ls

u n ctio n

in

a n d

D

V

a rio u s

if f e r e n t

Bilateral Adrenal Hyperplasia

C

St

im u la t o r y

a u s es

o f

C

a n d

u sh in g’s

In

h ibito ry

Sy

T

ests

n d r o m e

Adrenal Adenoma

Adrenal Carcinoma

Low

Low

Serum ACTH

High with loss of diurnal variation

Dexamethasone Suppression (2 mg per d)

Usually no suppression

No suppression

No suppression

Dexamethasone Suppression (8 mg per d)

More than 50% fall in urinary 17-hydroxy cortico­ steroids

No suppression

No suppression

Brisk response (increased plasma cortisol and 17 -hydroxycortico­ steroids)

May or may not respond

No response

Brisk response (increased 17-hydroxycorticosteroids)

Usually no response

No response

ACTH Stimulation

Metyrapone Test

the provocative and inhibitory stimuli al­ ready discussed. Some changes in the hypo­ thalamic-pituitary-adrenocortical relation­ ships are found in figures 4D and 5B and C. It should also be noted that patients with adrenal carcinoma may be virilized

as well as Cushingoid. Marked elevations in 24 hour urinary 17-ketosteroids (over 30 m g) are very suggestive of malignant ad­ renal disease. The normal circadian rhythm of serum ACTH and cortisol is absent in all forms of Cushing’s syndrome.

80

KOLODNY AND SH E R M A N

P o sta d re n a le c to m y S y n d ro m e (N elso n ’ s Sy n d ro m e) In 1958 Nelson and coworkers described a woman who developed marked cutaneous and buccal pigmentation and a chromo­ phobe adenoma several years after total adrenalectomy for Cushing’s syndrome due to bilateral adrenal hyperplasia.18 The au­ thors noted that “it was not possible to be sure whether the pituitary tumor antedated the adrenalectomy,”18 an uncertainty that persists to this day in such cases. Hyper­ pigmentation following adrenalectomy for Cushing’s syndrome, often (but not al­ ways) associated with development of pituitary tumor, is now called the “post­ adrenalectomy syndrome,” or Nelson’s syn­ drome. The syndrome has been found only in patients who have had Cushing’s syn­ drome, not in those who have had adre­ nalectomies for other reasons. Corticoid replacement therapy in the postadrenalec­ tomy period has no effect on the develop­ ment of the clinical picture. The pituitary tumors, when they occur, are usually chromophobe adenomas that tend to invade surrounding neural or vas­ cular structures, and sometimes metastasize to extracranial areas. Despite uncertainty concerning time of onset of these tumors, present evidence favors the idea that their development is somehow provoked by ad ­ renalectomy, and is not a part of the nat­ ural history of Cushing’s syndrome.5 The important histologic, secretory, and clinical differences between pituitary tumors that cause Cushing’s syndrome and those aris­ ing in the postadrenalectomy state are summarized in table III. The intense hyperpigmentation of Nel­ son’s syndrome appears to be caused by increased secretion of the anterior pituitary hormone, /3-melanocyte stimulating hor­ mone (/J-M SH). The plasma concentration of /J-MSH in normal subjects is 10 to 100 pg per ml, and in patients who have had adrenalectomy for Cushing’s syndrome

without further complications the mean value is 300 to 400 pg per ml. In patients with Nelson’s syndrome the mean value is 4,300 pg per ml, more than 40 times the highest normal concentration.1 Although ACTH, which is also hypersecreted in Nel­ son’s syndrome, has intrinsic melanotropic activity, it is not a major contributor to the hyperpigmentation. The reason is appar­ ent: the plasma concentrations of ACTH and /J-MSH are approximately equal, but the melanotropic activity of /?-M SH is 25 times greater than that of ACTH .1 It is interesting that there is one form of Cush­ ing’s syndrome in which hyperpigmenta­ tion has been occasionally observed as a part of the natural history of the disease. This is the “ectopic ACTH syndrome”— hypercorticism caused by nonpituitary tu­ mors that secrete ACTH. In these cases, there is also proven hypersecretion of ¡3MSH, accounting for the unusual presence of hyperpigmentation in Cushing’s syn­ drome. The hyperpigmentation of primary adrenal insufficiency is also produced by hypersecretion of /?-MSH. This common hormonal cause explains the similar type and distribution of pigmentation noted in Nelson’s syndrome, the ectopic ACTH syn­ drome, and Addison’s disease. A C T H D eficien cy D u e to P itu ita r y Tum or ACTH deficiency results in secondary adrenocortical failure. Chronic weight loss, anorexia, weakness, irritability, and occa­ sionally hypoglycemia may dominate the clinical picture. Although the adrenal cor­ tex is atrophied for lack of normal ACTH stimulation, it is still responsive to exog­ enous ACTH. This characteristic is the key to proper testing for secondary adrenocor­ tical failure. ACTH must be administered at rates of 40 to 80 units each day for three to five days to stimulate the atrophied ad­ renal cortex and enhance steroid output. A steady rise in the 24 hour excretion of

LA BO R A TO R Y AIDS IN DIAGNOSIS O F P IT U IT A R Y TU M O R S

81

TABLE III D

iff e r e n ce s

F

o u n d

in

B

e t w ee n t h e

P

P

itu ita ry

T

u m o rs

o s t a d ren a lect o m y

St

T

h a t

a t e

A

C

a u s e

C

sso ciated

u s h in g ’s

W

ith

N

Sy

n d r o m e

e ls o n

’s

Sy

a n d

T

ho se

n d r o m e

Pituitary Tumor Causing Cushing's Syndrome

Pituitary Tumor Associated with Nelson's Syndrome

Histologic Characteristics

Basophil, eosinophil, chromophobe or mixed tumors

Usually chromophobe adenomas

Secretory Characteristics

Increased g-MSH secretion; plasma levels 100 to 600 pg per ml

Markedly increased 0-MSH secretion; plasma levels 900 to 10,000 pg per ml

Increased ACTH secretion; plasma levels up to 200 pg per ml

Markedly increased ACTH secretion; plasma levels up to 12,000 pg per ml

Slow-growing tumors

More rapidlygrowing tumors; locally invasive, sometimes metastasizing extracranially

No dermal hyper­ pigmentation

Intense dermal hyperpigmentation

Clinical Characteristics

17-OHCS from an initially low baseline level after administration of ACTH by in­ travenous drip for six hours each day, or after intramuscular injection of A CTH gel twice daily, indicates normally responsive adrenal glands. However, the patient with secondary adrenal failure responds abnor­ mally to metyrapone stimulation because there is no A CTH response to the presum­ ably lower levels of serum cortisol induced by metyrapone-inhibition of adrenal corti­ sol synthesis. Aldosterone function in secondary adre­ nal failure is adequate, for A CTH plays

only a small role in control of its secretion. Therefore, hyponatremia and hyperkalemia, which are produced by aldosterone defi­ ciency, are much more likely to be found in primary adrenal failure (Addison’s dis­ ease) than in secondary adrenal failure caused by ACTH deficiency. In primary adrenal insufficiency, exogenous A CTH is without effect since little or no responsive adrenal tissue exists. The history, physical findings (field defects, pigmentation), se­ rum electrolytes, skull films for changes in sella turcica size or evidence of erosion of clinoid processes all enable the physician

KOLODNY AND SHERM AN

82

Primary Thyroidal Failure

F i g u r e 6 . Mechanisms controlling secretion of thyroid-stimulating hormone (T S H ) by the anterior pituitary, and their alteration in pituitary failure and primary thyroidal failure. TRH, thyroid releasing hormone.

to pursue the most logical course in differ­ entiating primary from secondary adrenal failure. O th e r H o r m o n a l D eficien cies D u e to P itu itary T u m o rs

TSH

D

e f ic ie n c y

Having made the diagnosis of hypothy­ roidism on the basis of clinical findings, low serum thyroxine concentration, and low 24 hour thyroidal radioactive iodine (R A I) uptake, the clinician must differen­ tiate primary thyroidal failure (primary hypothyroidism) from pituitary failure (secondary hypothyroidism) or hypothal­ amic failure (tertiary hypothyroidism). This is especially important in the rela­ tively few patients whose hypothyroid symptoms are clinically apparent but who have unprepossessing evidence of under­ lying hypopituitarism. The unknowing ini­ tiation of thyroid replacement therapy in these patients without simultaneous gluco­ corticoid replacement can precipitate acute adrenal failure leading to shock and death.

Until recently, there was only one way to distinguish primary hypothyroidism from the other, and rarer, forms. That method, which is still useful, consisted of giving 10 units of TSH intramuscularly daily for three days after performing a baseline 24 hour RAI uptake, and repeating the 24 hour RAI uptake on the fourth day. A sig­ nificant rise in uptake indicates a thyroid gland responsive to the stimulatory effects of TSH, thus eliminating primary thyroidal failure and placing the defect somewhere in the hypothalamic-pituitary area con­ trolling thyroidal function. Failure to re­ spond to the TSH injections indicates the presence of primary thyroidal failure. A simpler approach is now possible be­ cause of the availability of an immunoassay method for measuring serum TSH concen­ tration (figure 6). In primary hypothyroid­ ism, serum TSH levels are considerably higher than the normal upper limit for basal concentration (6 to 8 microunits per m l). This constitutes a normal response by hypothalamic TRH and pituitary TSH to the absent hormonal components (thyrox­

LABORATORY AIDS IN DIAGNOSIS O F PITU ITA RY TUMORS

83

F i g u r e 7. Mechanisms controlling secretion of follicle stimulating hormone (F S H ) and luteinizing hormone ( L H ) by the anterior pituitary and their alteration in pituitary failure and primary gonadal failure. FSH RF, follicle stimulating hormone releasing factor; LH R F, luteinizing hormone releasing factor.

ine and triiodothyronine) of the negative feedback loop (figure 6C ). In pituitary or hypothalamic disease producing hypothy­ roidism, serum TSH is low despite the in­ adequate negative feedback. The situation pertaining to hypothyroidism induced by pituitary failure is depicted in figure 6B. Synthesis of the hypothalamic tripeptide, TRH, now allows differentiation of hypo­ thalamic and pituitary hypothyroidism. In a hypothyroid patient who has low serum TSH levels, the intravenous administration of 500 micrograms of synthetic TRH may or may not stimulate the secretion of pitu­ itary TSH and increase the serum TSH level. If serum TSH increases, pituitary secretion is intact and the defect is in the hypothalamus. If serum TSH does not in­ crease, pituitary failure is the cause of the hypothyroidism. Hypothyroidism in association with pitu­ itary tumor is well-documented; hyperthy­ roidism caused by a TSH-secreting pitu­ itary tumor is extremely rare. In only three cases of the tens of thousands of cases of

thyrotoxicosis has there been any evidence of a pituitary tumor secreting excessive amounts of TSH and thereby producing hyperthyroidism. A single well-documented case of a TSH-producing chromophobe adenoma causing hyperthyroidism is on record.10 G

o n a d o t r o p in

D

e f ic ie n c y

Deficiency of the gonadotropins, luteiniz­ ing hormone (L H ) and follicle stimulating hormone (F S H ), is common in patients with pituitary tumors. Symptoms due to altered gonadal function are among the most common complaints in these patients. Post-pubertal women experience secondary amenorrhea, and men lose libido and be­ come functionally impotent. Both sexes ex­ perience an insidious loss of secondary sexual characteristics. The most frequently used gonadotropin assay is the 24 hour total gonadotropin (both LH and F SH ) urinary excretion. This bioassay lacks the sensitivity of the radioimmunoassay method, which can be

KOLODNY AND SHERM AN

84

.» ABNORMALLY DECREASED M?0 REABSOfiPTION; INAPPROPRIATELY DILUTE URINE

Dehydrated Normal

Diabetes Insipidus

F i g u r e 8 . Mechanisms controlling secretion of antidiuretic hormone (A D H ) by the neuro­ hypophysis in hydrated and dehydrated normal subjects, and their alteration in diabetes insipidus.

used for measuring blood levels of each gonadotropin. The distinction between pri­ mary gonadal failure and pituitary failure causing gondal hormone deficiency can be made by utilizing the pathophysiological changes shown in figure 7. Patients who have signs and symptoms of hypogonadism with significantly reduced estrogen or tes­ tosterone production, and low total urinary gonadotropins ( or low serum levels of FSH and L H ), have hypogonadotropic hypo­ gonadism (figure 7B ). Pituitary tumor is one of many pituitary or hypothalamic dis­ eases that can interfere with gonadotropin production and cause this form of hypo­ gonadism. A

n t id iu r e t ic

(D

ia b e t e s

H

orm one

D

e f ic ie n c y

I n s ip id u s )

Diabetes insipidus, which results from a lack of the antidiuretic hormone, arginine vasopressin, is characterized clinically by persistent polyuria and polydipsia. Vaso­ pressin is normally synthesized in the supraoptic and paraventricular nuclei of

the hypothalamus and reaches its storage site, the neurohypophysis, by axonal flow (figure 8). In primary diabetes insipidus there is a marked reduction in the number of neurons in these hypothalamic nuclei. In the less common secondary form, tumors of the pituitary itself (usually chromo­ phobe adenomas) or craniopharyngiomas interfere with transmission of the hormone down the pituitary stalk or interfere with its orderly storage and secretion by the neuro­ hypophysis. The physiological changes to be expected in normal subjects and those with diabetes insipidus are shown in figure 8. It is a good general rule that patients with secondary forms of diabetes insipidus also show the clinical features of the under­ lying disease. Thus patients with pituitary tumors causing vasopressin deficiency can be expected to show the usual local and endocrine manifestations of their disease, in addition to polyuria and polydypsia. Two points must be remembered. First, other endocrinopathies can cause polyuria and polydipsia; these include diabetes mel-

LA BO R A TO R Y AIDS IN DIAGNOSIS O F P IT U IT A R Y T U M O R S

litus and conditions causing hypokalemia or hypercalcemia (these electrolye dis­ orders can produce pathological inhibition of water reabsorption by the distal renal tubules). Second, some patients with pitu­ itary tumors have panhypopituitarism and diabetes insipidus; in these patients, poly­ uria and polydypsia may become evident only after the patient has received gluco­ corticoid and thyroid replacement. Radioimmunoassays for antidiuretic hor­ mone are not readily available, and still cannot reliably detect the hormone at its normal plasma concentration of about 2.5 micrograms per ml. Therefore a diagnosis of diabetes insipidus is best established by demonstrating an elevated serum osmolal­ ity in the presence of an inappropriately dilute urine. A normal but dehydrated sub­ ject can concentrate his urine to more than 1,200 mOsm per kg (figure 8B ). In con­ trast, the patient with diabetes insipidus may have urine osmolalities less than 300 mOsm per kg despite dehydration and a high serum osmolality (figure 8C ). The more complete the vasopressin deficiency, the less able is the patient to raise his urine osmolality as required by a dehydration test.

5.

h r i s t y , N. P.: Cushing’s syndrome: the nat­ ural disease. The Human Adrenal Cortex. Christy, N. P., ed. New York, Harper & Row, pp. 359-394, 1971. 6 . F l e i s c h e r , N. a n d G u i l l e m i n , R.: Clinical applications of hypothalamic releasing factors. Advances in Internal Medicine, Vol. 18. Stollerman, G . H., ed. Chicago, Year Book Medi­ cal Publishers, pp. 303-323, 1972. 7. F r i e s e n , H . , G u y d a , H . , H w a n g , P., T y s o n , I. E., a n d B a r b e a u , A.: Functional evaluation of prolactin secretion: a guide to therapy. I. Clin. Invest. 51:706-709, 1972.

8

.

9.

10.

11.

12.

Acknowledgment The able secretarial assistance of Harriet Gold­ berg and Mabel Abano is gratefully appreciated.

13.

R eferen ces 1.

K., N i c h o l s o n , W. E., L i d d l e , G. W., D. N., a n d I s l a n d , D. P.: Normal and abnormal regulation of /3-MSH in man. J. Clin. Invest. 4 8 :1580-1585, 1969. 2. B r i n c k -J o h n s e n , T., S o l e m , J. H., B r i n c k J o h n s e n , K., a n d I n g v a l d e n , P.: The 17hydroxycorticosteroid response to corticotrophin, metopiron and bacterial pyrogen. Acta Med. Scan. 173:129-140, 1963. 3. B u c k m a n , M. T., K a m i n s k y , N., C o n w a y , M., a n d P e a k e , G. T .: Utility of L-dopa and water loading in evaluation of hyperprolac­ tinemia. I. Clin. Endocr. Metab. 36:911-919, 1973. 4. B u c k m a n , M. T. a n d P e a k e , G. T.: Osmolar control of prolactin secretion in man. Science 181:755-757, 1973. A

b e

O

b t h

85

,

,

14.

15.

16.

C

ries en , H . an d H w a n g , P.: Human pro­ lactin. Annual Review of Medicine, Vol. 24. Creger, W. P., Coggins, C. H . , and Hancock, E . N., eds. Palo Alto, Annual Reviews, Inc., pp. 251-270, 1973. F r i e s e n , H . , H w a n g , P., G u y d a , H . , T o l i s , G . , T y s o n , }., a n d M y e r s , R .: A radioimmu­ noassay for human prolactin. Prolactin and Carcinogenesis. Proceedings of the Fourth Tenovus Workshop. Boyns, A. R. and Griffiths, K., eds. Cardiff, Wales, Alpha Omega Alpha Publishing, pp. 64-80, 1972. H a m i l t o n , C. R., Jr., A d a m s , L . C., a n d Ma l o o f , F .: Hyperthyroidism due to a thyrotropic-producing pituitary chromophobe aden­ oma. New Engl. J. Med. 2 8 3 :1077-1080, 1970. Ja c o b s , L . S ., S n y d e r , P. J., W i l b e r , J. F., U t i g e r , R. D . , a n d D a u g h a d a y , W . H .: In­ creased serum prolactin after administration of synthetic thyrotropin releasing hormone (T R H ) in man. J. Clin. Endocr. Metab. 33: 996-998, 1971. K o l o d n y , H. D . , Sh e r m a n , L ., S i n g h , A., K im , S ., a n d B en jam in , F .: Acromegaly treated with chlorpromazine: a case study. New Engl. J. Med. 284:819-822, 1971. L ’H e r m it e , M., D e l v o y e , P., N o k i n , J ., V e k e m a n s , M., a n d R o b y n , C.: Human pro­ lactin secretion, as studied by radioimmuno­ assay: some aspects of its regulation. Prolactin and Carcinogenesis. Proceedings of the Fourth Tenovus Workshop. Boyns, A. R . and Griffths, K . , eds. Cardiff, Wales, Alpha Omega Alpha Publishing, pp. 81-97, 1972. M a c k a y , B., I b a n e z , M . L ., A y a l a , A . G . , a n d T o b l e m a n , W. T.: Pathology of pituitary tumors. Endocrine and Non-endocrine Hor­ mone-producing Tumors. Chicago, Year Book Medical Publishers, pp. 103—114, 1973. M a l a r k e y , W. B., J a c o b s , L. S., a n d D a u g h ­ a d a y , W. H .: Levodopa suppression of pro­ lactin in nonpuerperal galactorrhea. New Engl. J . Med. 285:1160-1163, 1971. M c C o r m i c k , W. F. a n d H a l m i , N. S.: Ab­ sence of chromophobe adenomas from a large series of pituitary tumors. Arch. Path. 92:231— 238, 1971.

F

KOLODNY AND SH E R M A N

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17.

M o z a f f a r i a n , G., P e n s k y , J., a n d O. H .: Prolactin-secreting pituitary tumors in women. J . Clin. Endocr. Metab. 35: 505-512, 1972. 18. N e l s o n , D . H., M e a k i m , J. W., D e a l y , J. B., N

a sr

,

H.,

P

ea rs o n

M

atso n

,

, D . D ., E

m ers o n

, K . , J r .,

a n d

T

h o r n

,

G. W .: ACTH-producing tumor of the pitu­ itary gland. New Engl. J. Med. 259:161-164, 1958. 19. R a b k i n , M. T. a n d F r a n t z , A. G.: Hypopitu­ itarism: A study of growth hormone and other functions. Ann. Int. Med. 64:1197—1207, 1966. 20. S c h w a r t z , T. B.: What you always wanted to know about prolactin but were afraid to ask. 1973 Year Book of Endocrinology. Schwartz,

T. B., ed. Chicago, Year Book Medical Pub­ lishers, pp. 7—24, 1973. 21. S h e r m a n , L. a n d K o l o d n y , H. D . : The hypo­ thalamus, brain catecholamines, and drug therapy for gigantism and acromegaly. Lancet 1:682-685, 1971. 22. S h e r m a n , L., K o l o d n y , H. D . , S i n g h , A., D e u t s c h , S ., a n d B e n j a m i n , F . : Suppressive effect of a single dose of L-dopa on serum growth hormone in acromegaly. Clin. Research 2 0 : 8 6 , 1972. 23. T u r k i n g t o n , R. W .: Phenothiazine stimula­ tion test for prolactin reserve: the syndrome of isolated prolactin deficiency. J . Clin. Endocr. Metab. 34:247-249, 1972.