The role of pharmacologic manipulation in adrenal cortical scintigraphy

The Role of Pharmacologic Manipulation in Adrenal Cortical Scintigraphy M. D. Gross, T. W. Valk, D. P. Swanson, J. H. Thrall, R. J. Grekin, and W. H. Beierwaltes

Adrenal scintigraphy is a unique nuclear medicine procedure that provides noninvasive, functional information concerning t h e status of t h e adrenal cortex. The uptake of iodocholesterol, in addition t o localizing adrenal cortical abnormalities, can be manipulated to focus on adrenal cortical dysfunction in either t h e aldosterone, cortisol, or androgenproducing portions of t h e adrenal cortex. ]'he

uptake of iodocholesterol correlates significantly w i t h the abnormal secretion of cortisol in Cushing's syndrome, aldosterone in a model of adrenal zona glomerulosa function, and adrenal androgen secretion in hyperandrogenism. For these reasons, adrenal scintigraphy is an important diagnostic modality in the evaluation of adrenal cortical function.

cortex is a complex endocrine T HEorganadrenal which serves to maintain biochemi-

cal uptake of iodocholesterol can be altered by the same pharmacologic strategies as utilized in the investigation of adrenal steroid secretion. 1 3 In addition, the pharmacologic alteration of adrenal gland iodocholesterol uptake results in similar alterations in the adrenal secretion of steroid hormones. 4-6 For these reasons, adrenal cortical scintigraphy represents a useful adjunct in the investigation and localization of adrenal cortical dysfunction. An understanding of the complex interrelationships that control adrenal gland cholesterol metabolism and steroid hormone secretion is important in the performance and interpretation of adrenal scintigrams. Many drugs routinely used in the daily management of patients have profound effects on adrenal hormone secretion and, in turn, on patterns of adrenal iodocholesterol uptake.

cal homeostasis through the regulation of metabolism and salt and water balance. In the past few decades, adrenal cortical hormones and metabolites have been found to exert profound effects on multiple organ systems. The diagnosis of adrenal cortical disease thus requires a combination of recognizable signs and symptoms in conjunction with abnormal adrenal steroid secretion. The approach to the diagnosis of adrenal cortical disease would be simple if these syndromes were easily recognizable, but this is not always the case. Many diseases masquerade as adrenal disorders. Symptoms and signs may be poorly defined with subtle changes in hormone secretion in the early stages of disease. Under these circumstances, early diagnosis and confirmation of adrenal cortical disease based on basal or single plasma hormone determinations may be difficult or misleading. As a result, considerable effort has been expended in the pharmacologic manipulation of adrenal hormone secretion to accentuate pathologic function and to better delineate adrenal secretory abnormalities. Several studies indicate that the adrenal corti-

From the Divisions of Nuclear Medicine and Endocrinology and Metabolism, University of Michigan and the Veterans Administration Medical Centers, Ann Arbor, Mich. Supported in part by Grants CA-09015-02, Cancer Research Training in Nuclear Medicine from the National Cancer Institute, DHEW, Grant 5-ROl-AM21477-03 from the NIAMDD, and by the Nuclear Medicine Research Fund. Reprint requests should be addressed to M. D. Gross, M.D., Nuclear Medicine Service, Veterans Administration Medical Center, 2215 Fuller Road, Ann Arbor, Mich. 48104. 9 1981 by Grune & Stratton, Inc. 0001-2998/81/1102-0006505.00/0 128

THE FUNCTIONAL ZONES OF THE ADRENAL CORTEX

The adrenal cortex is anatomically and functionally divided into three histologic zones (Fig. 1).7 Within each zone a principal adrenal steroid hormone is synthesized and secreted. Adrenal cortical dysfunction can be attributed to abnormalities of biosynthesis and/or hormone secretion. A specific hormone abnormality can be verified with biochemical testing; however, the ability to localize abnormal function by scintigraphic analysis is unique in the evaluation of adrenal cortical disease. Aldosterone is the principal mineralocorticoid hormone produced within the adrenal gland. 8 It is synthesized in the outermost portion of the adrenal cortex, the zona glomerulosa (Fig. 1). Aldosterone is secreted in response to a decrement in either total body sodium or plasma Seminars in Nuclear Medicine, Vol. XI, No. 2 (April), 1981

ADRENAL CORTICAL SCINTIGRAPHY

129

results in the enzymatic conversion of angiotensinogen (renin substrate) to angiotensin I. Angiotensin I, a decapeptide, is then converted to angiotensin II, an octapeptide, within the lung parenchyma and plasmaJ ~ Angiotensin II, a potent vasoconstrictor, stimulates the zona glomerulosa to secrete aldosteroneJ 2 Figure 2 depicts the interrelationships that control the renin-angiotensin-aldosterone system. Both salt loading and depletion have been shown to exert profound effects on serum aldosterone levels via the renin-angiotensin system. It also has been shown that medications or maneuvers which alter sodium balance affect the renin-angiotensin systemJ ~ Low salt intake or diuretics, particularly of the loop type (furosemide), stimulate renin and aldosterone secretionJ 4 Alternatively, maneuvers that result in increased serum sodium levels suppress plasma renin activity and decrease aldosterone secretion. Propranolol, a fl-receptor antagonist, or indomethacin, a prostaglandin synthetase inhibitor, suppress plasma renin and serum aldosterone levels) 5"16Agents such as spironolactone or op'DDD also cause decreased aldosterone biosynthesis when administered in therapeutic doses. ~7,18

Fig. 1. The histologic anatomy of the adrenal cortex. (From Williams RH: Textbook of Endocrinology, 7 by permission of W.B. Saunders, Philadelphia.)

volume. Potassium may also play a role in its secretion. Its major effect is on the distal nephron where sodium is exchanged for potassium to maintain salt and water balance. 9 The principle mechanisms for the control of aldosterone secretion begin within the kidney in a specialized structure, the juxtaglomerular apparatus (JGA). The JGA derives its name from its close approximation to the renal glomerulus and acts as a "sensor" of renal perfusion, glomerular filtration, and intravascular sodium concentrationJ ~ In response to decreased renal perfusion or plasma volume, renin, a polypeptide hormone, is secreted from the JGA. The secretion of renin

The second principal division of the adrenal cortex, the zona fasiculata (Fig. 1), produces principally cortisol, a glucocorticoid hormone. 8 The effects of cortisol are widespread and generally affect metabolism by a permissive action on numerous enzyme systems. The control of cortisol secretion is via complex negative feedback loops among the hypothalamus, anterior pituitary gland, and the adrenal cortex. Corticotropin-releasing factor (CRF) is secreted by the hypothalamus either i~ response to a decrement of circulating cortisol or to other stimuli, such as stress. 19 CRF then stimulates the secretion of adrenocorticotropic hormone ( A C T H ) and causes an increase in cortisol biosynthesis and secretionJ 9'2~Both the uptake of cortisol precursors, such as cholesterol, and the activity of intraadrenal enzymes important in the biosynthesis of glucocorticoids are affected by ACTH. 2~ Figure 3 illustrates the mechanisms of control of cortisol secretion. The negative feedback of cortisol upon cells that produce CRF and A C T H serves as the basis of one of the oldest pharmacologic tests of adrenal cortical function. The administration of

130

GROSS ET AL.

ACTR (PERMISSIVE)

tK,~'Na

~

Z, GLOMERULOSA ~

/

ALDOSTERONE

ANGIOTENSIN II

ANGIOTENSlNI

(KIDNEY) JGA

.,.,.% _, /

ANGIOTENSlNOGEN

I

I

,

\

1

~ -- ~K

J

~ 9 PLASMAVOLUME

/

I Fig. 2.

The renin-angiotensin-aldosterone

axis.

exogenous steroids provides a rapid method to test the integrity of the hypothalamic-pituitaryadrenal axis. 22 Suppression of cortisol secretion is achieved normally by the administration of glucocorticoid analogs, such as dexamethasone. Dexamethasone feedback upon the hypothalamus and pituitary results in a fall of both plasma A C T H and cortisol levels. As a result of its structure and metabolism, dexamethasone does not interfere with the radioimmunoassay of plasma cortisol or indices of urinary glucocorticoid excretion, and is an ideal agent for the study of adrenal function. Inhibition of adrenal enzymes responsible for glucocorticoid biosynthesis will result in decreased cortisol secretion with augmentation of A C T H secretion. 23 An inhibitor of 1 1-fl-hydroxylase, metapyrone, decreases cortisol biosynthesis and the tonic negative feedback of cortisol upon the pituitary and hypothalamus. A C T H secretion increases as a result, and intermediates of cortisol biosynthesis prior to the 1 1-fl-hydrox-

~1~( ~ HYPOTHALAMUS

ylase block accumulate. 23 These metabolites can be measured either in the urine as urinary 17hydroxycorticosteroids or in the plasma as 1 1deoxycortisol. An increase in these metabolites serves as a test of the functional integrity of the adrenocortical-hypothalamic-pituitary axis. 22 Other adrenolytic agents, aminoglutethimide and op'DDD, suppress synthesis and secretion of adrenal steroid hormones and are used in the treatment of hypercortisolism. 22 Androstenedione and dihydroepiandrosterone are the two major androgenic steroid hormones produced and secreted by the third and innermost segment of the adrenal cortex, the zona reticularis. 8 These hormones are involved along with the gonadal steroids in the maintenance of primary and secondary sex characteristics. Both of these hormones appear to be under the control of ACTH, but studies indicate the existence of a separate tropic hormone, possibly the pituitary gonadotrophin luteinizing hormone (LH), as a controlling factor in adrenal androgen secretion, z4 Figure 3 depicts the control of androgen biosynthesis and secretion from the adrenal cortex.

CORTICOTROPHIN

RELEASINGFACTOR

ADRENAL CORTICAL CHOLESTEROL UPTAKE

(CRF)

(~)1~

PITUITARY

ADRENOCORTICOTROPHIC HORMONE (ACTH)

~| ADRENAL CORTEX

~(~)=1

LOL-CHOLESTEROL

PREGNENOLONE

Z. GLOMERULOSA

Z. FASCICULATA

Z. RETICULARIS

1

1

1

ALOOSTERONE

CORTISOL

ANDROGENS

I J Fig. 3.

The hypothalamic-pituitary-adrenal axis.

The adrenal gland derives cholesterol for steroid hormone biosynthesis from circulating cholesterol and de novo from biosynthesis using acetatefl 5 The bulk of circulating cholesterol arises from dietary s o u r c e s . 26 As cholesterol is insoluble, it is carried in the plasma by lowdensity lipoproteins (LDL). 25-27 Adrenal gland cholesterol uptake is under the control of the low-density lipoprotein receptor, a specialized region on the surface of the adrenal cortical cell.Z7 29 Studies indicate that the numbers and affinity of the LDL-receptor are controlled by the levels of intracellular and extracellular cholesterol. 29 An increase of circulating and/or

ADRENAL CORTICAL SCINTIGRAPHY

LOL

\

131

-CHOLESTEROL

ACTH

\/

\.

LDL.RECEPTOR

It

ACTH RECEPTOR

-,'

PGF

PGE

PROSTAGLANDIN~

+f----

/

,.

C,OLESTEROL

~

.....

_

"~ ... . . . .

,-

.

:"CHOLESrE,OL.

~

t

o..,'"~" "''''-., ,. ."

SCC-MITOCHONORIA

"~ "

9 " * . . . . . . . . . 9" ""

Fig. 4,

PREGNENOLONE

Mechanisms and control of adrenal cholesterol uptake, storage, and metabolism.

intraadrenal cholesterol results in decreased LDL-receptor affinityfls'29 A decrease of either circulating LDL-cholesterol or intraadrenal cholesterol results in an increase in the number of LDL-receptorsfl8'29 These mechanisms serve to maintain a constant supply of cholesterol for adrenal steroid hormone biosynthesis. 29 31 A C T H and prostaglandins are also implicated as factors modulating adrenal cortical uptake of LDL-cholesterol. 32'33 Drugs that alter A C T H or prostaglandin levels result in alterations of cholesterol uptake and, in turn, steroid hormone biosynthesis and secretion. 32'33 Figure 4 illustrates the mechanisms and modulating factors of adrenal gland LDL-cholesterol uptake. IODOCHOLESTEROL AS A PROBE OF ADRENAL CHOLESTEROL METABOLISM

The agent =3q-6fl-iodomethyl- 19-norcholesterol (NP-59) has been shown to be a marker of adrenocortical cholesterol uptake. It appears to be bound to plasma LDL and is under the control of ACTH, as increased plasma A C T H levels result in increased adrenal iodocholesterol uptake. 34-36 NP-59 adrenal uptake also is affected by mechanisms that alter LDL-receptor activity. Decreased or increased circulating cholesterol levels result in stimulation or suppression of adrenal gland uptake of iodocholesterol, respectively. 36 Although esterification and storage of iodinated cholesterol does occur, less than 4% of NP-59 is converted to measurable adrenal steroid hormone metabolites. 37-38

This intraadrenal sequestration of NP-59 once was felt to be a drawback to its use, but the persistance of the agent within the adrenal cortex provides images that are of diagnostic utility. The use of semi-operator-independent computer algorithms to estimate adrenal cortical uptake of NP-59 allows a simple spatial and functional assessment of the adrenal cortex. 39 ADRENAL CORTICAL SCINTIGRAPHY

Previous publications have detailed the method of adrenal cortical scintigraphy. 4'4~ The performance of adrenal cortical imaging is rigorous and requires particular attention to the time intervals at which images are collected, as the appropriate scan interpretation in many Table 1. A. Adrenal cortical scintigraphy 1. 1 mCi 1311_6/~_lodomethyl_ 19-norcholesterol (NP-59) 2. Lugol's solution 2 - 3 drops twice d a i l y - - 4 8 hr prior to

radiotracer injection and for 7 - 1 0 days thereafter 3. Posterior imaging at 5 - 6 days post NP-59 injection (parallel-hole high energy collimator, 2 0 rain or 50K counts) 4. Lateral adrenal image distinguishes anterior structures (gall bladder from adrenal activity) for depth attenuation correction and calculation of iodocholesterol uptake B. Dexamethasone suppression adrenal scintigraphy 1. 4 mg dexamethasone (1 mg every 6 hr) for 7 days prior to and throughout the imaging interval 2. Image at 3, (4), and 5 days after N P - 5 9 3. Posterior, left lateral, and oblique projections are often

necessary to distinguish adrenal activity from other abdominal structures

132

GROSS

instances is dependent not only on the pattern of imaging, but also on the intervals during which scintiscans are collected. Table 1 outlines the present protocol for adrenal scintigraphic imaging. THE EFFECT OF SERUM CHOLESTEROL LEVELS ON ADRENAL IODOCHOLESTEROL UPTAKE

The possibility that serum cholesterol affects adrenal cholesterol uptake has been suggested recently by Gordon et al. in a case of Cushing's disease complicated by severe hypercholesterolemia where discernible adrenal gland uptake of iodocholesterol was not observed. 42 Therapy with cholesterol-lowering agents resulted in bilateral imaging and uptake consistant with the diagnosis of Cushing's disease. Subsequently, in a study of adrenal scintigraphic imaging and NP-59 uptake in Cushing's syndrome, a negative correlation has been observed between iodocholesterol uptake and serum cholesterol levels ranging from 145 to 390 mg/dl (Fig. 5 ) , 43 NO correlation was observed between NP-59 uptake and other indices of lipid metabolism. A plausible explana2.0

ET AL.

tion for this observation is a pool effect of cholesterol upon NP-59 adrenal gland uptake; however, recent animal studies by Counsel et al. indicate that the uptake of iodocholesterol is also under the control of the LDL-receptor.37 Perturbations of serum cholesterol levels with agents known to inhibit LDL-cholesterol synthesis (4-aminopyrazolopyrimidine) have resulted in enhanced adrenal gland iodocholesterol uptakefl7 Such studies suggest that the LDL-receptor is important in the control of adrenal iodocholesterol uptake. Speculations concerning the contribution of LDL-receptor activity to iodocholesterol adrenal gland uptake in the human, however, await confirmation. Representative adrenal scintiscans in patients with varying cholesterol levels are shown in Figs. 6 and 7. As cholesterol is an important factor in the control of iodocholesterol adrenal gland uptake, excessively low iodocholesterol uptake in a patient with Cushing's syndrome should prompt an investigation of the cholesterol status of the patient. Cholesterol levels in excess of 400 mg/dl are associated with markedly decreased or absent visualization under conditions in which bilateral adrenal uptake would be anticipated.43

1,8

o

1.6 ACTH-DEPENDENT (n=8) l ACTH iNDEPENDENT (n = 4} ECTOPIC ACTH (n = 2)

ZI

1.4 O. u~

1.2

~ ~1

1.0

y = 0.0025x + 1.2 r = 0.78 p 0.01 n=8

0

O:~ 0.8

9

zl

0.6

ee

0.2

I

100

I

200

{

300

L

400

CHOLESTEROL (mg/dl)

The relationship of NP-59 adrenal gland uptake (right and l e f t ) t o serum cholesterol levels in Cushing's syndrome, Fig. 5.

Fig. 6. Posterior adrenal scintiscan of a patient with ACTH-dependent Cushing's syndrome, a normal serum cholesterol of 1 2 5 m g / d l , and adrenal gland percent uptake of 0.79 (right and l e f t ) .

ADRENAL CORTICAL SCINTIGRAPHY

133

Posterior adrenal scintiscan of a Fig. 7. patient w i t h A C T H - d e p s n d e n t Cushing's syndrome and an elevated serum cholesterol of 3 9 0 mg/dl and adrenal gland percent uptake of 0.21.

THE RELATIONSHIP OF IODOCHOLESTEROL ADRENAL GLAND UPTAKE TO INDICES OF ADRENAL CORTICAL FUNCTION IN CUSHING'S SYNDROME

The adrenal gland uptake of NP-59 has provided a useful measure of adrenal function in patients with Cushing's syndrome. The patterns of adrenal visualization in Cushing's syndrome are well established, nl'n+.n5 Numerous studies indicate that the patterns of NP-59 uptake allow diagnostic separation of bilateral adrenal hyperplasia from cortical adenoma in over 95% of cases. 41'n5 Recent investigations also have shown that the level of adrenal gland uptake of iodocholesterol can be used in addition to conventional biochemical tests in the evaluation of Cushing's syndrome. 46 With the use of a semi-operator-independent computer algorithm for estimating iodocholesterol uptake, the adrenal gland accumulation of NP-59 is significantly higher in Cushing's disease as compared to normal (Fig. 8). 46 The highest adrenal gland uptakes are observed (Fig. 8) in the most severe forms of the disease, the ectopic A C T H syndrome, bilateral nodular hyperplasia, and adrenal adenoma. Although the number of patients with these rare conditions studied to date is small, the adrenal gland uptake of NP-59 may be used to separate pituitary from

nonpituitary etiologies of Cushing's syndrome. The distinction of pituitary from nonpituitary disease is important since the successful treatment of these patients is dependent on the localization of the source(s) of glucocorticoid or A C T H excess. The pattern of NP-59 activity and the adrenal gland uptake can be used to assist in the differentiation of these conditions, n~ As an indicator of adrenal cortical function in 1.5

i

I.U

o. -i

1.0

o. Z ..I

< I-O II:=, w (.1

0.5

§ (*p<.05)

I ACTH DEPENDENT Fig. 8.

syndrome.

I ACTH INDEPENDENT AND ECTOPIC

I NORMAL

The adrenal gland uptake of N P - 5 9 in Cushing's

134

GROSS ET AL.

jo

12,000 --

y = 76B74x +1150

1~,000 10,000

9,000 ~rJ ~r

8,000

O

7,000

,~

6,000

~:

5,000

p 0.0001

~NOENT (~ I Z~ ACTHINDEPENDENT (n=4) I I O ECTOPICACTH (n = 2)

j

L

Io J

~

4,000 3,000 2,000 1,000

99 0.2

9 0.4

A 0.6

0.8

I

1.0

L

1.2

NP-59 UPTAKE (% dose R & L)

Cushing's syndrome, a significant correlation has been observed between adrenal iodocholesterol uptake and urinary cortisol excretion in patients with ACTH-dependent Cushing's syndrome (Fig. 9). 46 The adrenal gland uptake of NP-59 in patients with ACTH-independent disease does not correlate with urinary free cortisol excretion, probably as a result of increased noncortisol metabolite production. Additionally, in two patients, the effect of dexamethasone and op'DDD administration on adrenal gland NP-59

Fig. 1 0 . Posterior adrenal scintiscan of a patient with A C T H - d e p e n d e n t bilateral adrenal hyperplasia while on d e x a m e t h a s o n e suppression (8 mg d a i l y ) ( a d r e n a l percent uptake - 0.32).

]

1.4

I

1.6

I 1.8

2.0

Fig. 9. The relationship of urinary cortisol excretion to N P - 5 9 adrenal gland uptake in Cushing's syndrome.

uptake and cortisol excretion has been illustrated. Suppression of ACTH or inhibition of cortisol biosynthesis resulted in decreased NP-59 uptake and urinary free cortisol excretion. The adrenal scintiscans of these patients are shown in Figs. 10 and 11. The relationship of adrenal NP-59 uptake to urinary free cortisol excretion is a reflection of the integrative nature of these studies. Tests of function that are not integrative, i.e., plasma cortisol, plasma ACTH, and cortisol excretion

ADRENAL CORTICAL SCINTIGRAPHY

135

Fig. 11. Posterior adrenal scintiscan of a patient with Cushing's syndrome while on op'DDD therapy ( a d r e n a l p e r c e n t uptake = 0.18).

rates do not correlate with adrenal iodocholesterol uptakeJ 6 As a result of dexamethasone suppression of NP-59 uptake, adrenal scintigraphy is not combined with pharmacologic manipulations of cholesterol or A C T H levels in the evaluation of Cushing's syndrome. It is important, however, that the intrascintigraphic conditions are defined so that proper scan interpretation can be made. DEXAMETHASONE SUPPRESSION

lodocholesterol Scintigraphy and Adrenal Cortical Function In an attempt to improve the diagnostic accuracy of adrenal scintigraphy, dexamethasone suppression (DS) was incorporated into adrenal cortical imaging. 47 The rationale for DS of pituitary A C T H and zona fasiculata activity was to accentuate abnormal adrenal cortical function, particularly in cases of aldosteronism 5 and adrenal hyperandrogenism. 47 The addition of DS to adrenal scintigraphy has resulted in the anticipated increase of sensitivity and accuracy, but

at a cost of considerable difficulty in the performance and interpretation of these studies. 48 With more widespread acceptance of adrenal suppression scintigraphy, discrepancies have arisen as to the sensitivity and accuracy of the study.49 51 One of the major considerations in DS-adrenal scintigraphy is the visualization of the normal adrenal cortex. It has been shown previously that the normal adrenal cortex will visualize during constant DS, thus increasing the number of false positive studies. 4'5~ To investigate this phenomenon, two groups of normal volunteers were given dexamethasone, 8 mg for 2 days (8mg-DS) prior to NP-59 administration and 4 m g a day for 7 days (4mg-DS) prior to NP-59 administration, and both regimens were continued throughout the imaging intervals. 4 The total amount of dexamethasone received by each group and the indices of adrenal cortical function on DS were comparable (Table 2). However, the parameters of imaging were quite different in the two groups studied. In Fig. 12, the 8mg-DS regimen resulted in discernible

Table 2. Indices of Adrenal Cortical Function on Dexamethasone 8 mg/day Suppression interval (days) Mean plasma cortisol ( 1 0 - 2 0 #g/dl) Mean urinary 17-hydroxycorticosteroids ( 5 - 1 0 rag/day) Mean urinary 17-ketosteroids ( 4 - 1 4 rag/day)

3.7 0.47 1.35 7.70

+_ 0.45 • 0.29 -+ 0.29 • 1.48

Suppression p

4 mg/day

<0.05 NS NS NS

5.9 -+ 0.41 0.43 • 0.06 1.24 • 0.20 6 . 7 3 +_ 0 . 3 7

136

GROSS ET AL.

Fig. 12. Posterior adrenal scintiscans in a normal volunteer while on dexamethasone suppression, 8 mg for 2 days prior to NP-59 injection and continued throughout the imaging intervals, Bilateral adrenal uptake of NP-59 is observed at 3 days after NP-59 injection.

adrenal cortical imaging in the normal at 3 days after NP-59 injection. Using 4mg-DS, normal adrenal cortical visualization could be delayed for 5 days after NP-59 injection (Fig. 13). There was no difference in imaging when the dose of NP-59 was varied from 500 tsCi to 2 mCi while on either dosage regimen. The concept of the normal adrenal cortical suppression interval is critical to the interpretation of the DS-adrenal scintiscan. The knowledge that the normal adrenal cortex will visualize at a particular time interval after NP-59 administration and that this interval is dependent on the duration of prior DS greatly affects the scan interpretation. Table 3 outlines the present DS interpretation scheme for a 4mg-DS regimen. Although the documentation of the normal suppression interval clarifies the interpretation of DS scintiscans, the mechanism of the breakthrough of adrenal gland iodocholesterol uptake

in normals and the relationship of adrenal gland function to NP-59 uptake on DS have not been addressed previously. To investigate the phenomenon of adrenal gland breakthrough during DS imaging, an animal model of DS adrenal scintigraphy has been developed. 5 In this model, dexamethasone suppression was given (4 mg for 7 days prior to NP-59 injection and throughout the imaging intervals) to dogs in a manner analogous to the DS-regimen used in human studies. Manipulation of salt balance, either by salt loading (150 meq sodium diet plus 9 fluorohydrocortisone) or salt depletion (10 meq sodium diet and furosemide) was incorporated with DS to assess the sensitivity of iodocholesterol adrenal uptake as a marker for the activity of the reninangiotensin-aldosterone axis. DS resulted in a marked suppression of both plasma cortisol (<0.2 ug/dl) and urinary ]7hydroxycorticosteroids (<1.0 mg/dl). Adrenal cortical uptake fell to approximately 50% of

ADRENAL CORTICAL SCINTIGRAPHY

137

Fig. 13. Posterior adrenal scintiscans in a normal volunteer while on dexamethasone suppression, 4 mg x 7 days prior to NP-59 injection and continued throughout the imaging interval. Bilateral uptake of NP-B9 is seen on day 5 after NP-B9 injection.

basal while on DS (Fig. 14). Salt depletion and loading resulted in an expected increase and a decrease of serum aldosterone levels, respectively (Fig. 15). The adrenal cortical uptake of NP-59 was increased over that of DS in saltdepleted animals (DS-low salt) and decreased over that of DS in salt-loaded animals (DS-high salt) (Fig. 14). Adrenal scintigrams obtained at the time of biochemical investigations (day 3 or day 5 after NP-59 injection) exhibited a time course of uptake similar to that of patients and Table 3. Interpretation of Dexamethasone Suppression Adrenal Scintigrams Time Interval After Injection Bilateral imaging

< 5 Days

Unilateral or lateralizing imaging

< 5 Days

Bilateral late or nonvisualization

> 5 Days

Interpretation Bilateral hyperfunction (suspect hyperptasia) Unilateral hyperfunction (suspect adenoma) Nondiagnostic

normals. In the control group, bilateral uptake was observed at both 3 and 5 days after tracer injection (Fig. 16A). On DS, bilateral uptake was observed at the fifth day post-NP-59 injection (Fig. 16B). The DS-low salt group exhibited bilateral uptake at the 3 and 5 day intervals after NP-59 injection (Fig. 16C), while DS-high salt animals exhibited bilateral nonvisualization at both time intervals. These data indicate that the uptake of iodocholesterol can be modified by DS and that uptake of NP-59 by the aldosterone-secreting portion of the adrenal cortex is responsive to manipulation of salt balance. From these studies, the adrenal cortical uptake of iodocholesterol can be schematically represented (Fig. 17). Approximately 50% of adrenal iodocholesterol uptake is ACTH-dependent, whereas 10% of iodocholesteroi uptake is dependent on the renin-angiotensin system (angiotensin-lI-dependent). Stimulation of renin and aldosterone results in an approximate 14% increase in iodocholesterol adrenal uptake (angiotensin-II-stim-

138

GROSS ET AL.

-.x-* * .xCONTROL

52

O '10 O') V UJ e,

,< ,J

Z uJ

!]

48 ~12"' u.l

~'=~~~ ~....~.~-~

DEX (Low Hal oEx

~ 0

10

~

6

-

q a -

~ 4w

r ,<

~

~

. ~

~

2

-

DEX (HIGHNa) DAY

i 3

DS

"4

5

3

5

DS LOW SALT

3

5 DS HIGH SALT

Fig. 15. The effect of dexamethasone suppression (DS), DS + l o w salt diet (DS-Iow salt), and DS + high salt diet ([}S-high salt) on serum aldosterone levels in a model of DS-adrenal scintigraphy.

I

I

72

120

HOURS

Fig. 14. The adrenal gland uptake of NP-59 in a canine model of dexamethasone suppression (DS). On continued DS, adrenal uptake falls to approximately 50% of control. Salt depletion and DS (DS-Iow) results in an increased uptake over that of DS, and salt loading and DS (DS-high) results in adrenal gland uptake that is less than DS.

ulated). About 40% of the total adrenal cortical uptake of NP-59 is nonsuppressable (nonACTH, non-angiotensin-II-dependent). It also is evident that a 4% kg-dose/g uptake is necessary for adrenal gland imaging in the dog. Thus, in a

model of DS-adrenal scintigraphy, normal adrenal gland visualization occurs on the fifth day after NP-59 administration while on constant 4mg-DS. The adrenal gland suppression interval (the time from NP-59 administration to imaging) can be influenced by prior DS and dietary salt and drug manipulation. These are critical maneuvers in the evaluation of DS adrenal scintiscans and can be used to study patients with aldosterone-secreting (zona glomerulosa) adrenal cortical abnormalities. 5'47'48'51

ADRENAL CORTICAL SCINTIGRAPHY

8--

6-.~,

_

_1 ~ o 4~ < ~ ,z,: ..,. ~ Q~ <

CONTROL (100%)

ACTH DEPENDENT (50%)

DS

LOW SALT ~

DS (50%) DS _ HIGH SALT (40 %)

2--

139

:................. - - 1 :~:~:i:i:i:~:i:i:i / !:!?!:~:i:i:i:i: ~ l ::::::::::::::::::

ANGIOTENSIN II DEPENDENT (10%)

t RESIDUAL (40%)

Fig. 17. Schematic representation of NP-59 adrenal cortical uptake. Dexamethasone suppression results in 50% decrease of uptake from control levels ( A C T H - d e p e n dent). A f u r t h e r 10% reduction of NP-59 uptake is observed on DS and high salt (angiotensin-II-dependent). A 14% increase in adrenal uptake is observed in the salt-depleted state (DS-low salt) as compared t o DS (angiotensin-|lstimulated), A residual uptake of 40% is unaffected by suppression maneuvers ( n o n - A C T H , non-angiotensin-II dependent).

Scintigraphic Evaluation of Hypertensive States The scintigraphic evaluation of patients with primary aldosteronism (PA) is dependent on the demonstration of elevated serum and/or urinary aldosterone levels) 2 Plasma renin activity is a critical component affecting aldosterone secretion and must be measured on a known salt intake and posture to assess its relation to the concomitant level of urinary or serum aldosterone. In PA, as a result of excessive aldosterone

Fig. 18. Posterior adrenal scintiscans in a patient with a right-sided aldosteronoma pretreated with d e x a m e t h a s o n e , 4 mg • 7 days prior t o and throughout the day 3 (left) and the day 5 (right) imaging intervals. Note the appearance of left-sided adrenal activity at the day 5 interval after NP-59 injection.

secretion from bilateral adrenal hyperplasia or solitary adrenal adenoma, plasma renin activity is suppressed and/or does not respond to provocative stimuli. 53 Generally, patients with adrenal adenomas producing aldosterone manifest moderate to severe hypertension, hypokalemia, and aldosterone levels that are higher than in patients with bilateral adrenal hyperplasia) 4'55 Serum aldosterone levels respond to postural changes in a majority of patients with idiopathic aldosteronism. 56 These considerations are critical for the successful management of PA, as adrenal adenomas are generally best managed by adrenalectomy, whereas bilateral hyperplasia is not surgically curable and requires long-term medical therapy, s~ Previous studies indicated that adrenal scintigraphy was accurate in distinguishing adenomas from hyperplasia in approximately 75% of cases of PA. 57 The addition of DS to adrenal scintigraphy has been shown to increase both the sensitivity and accuracy of the procedure to 90%. 48'5~ Reports of lower sensitivity and accuracy are indicative of discrepancies in the amount and duration of dexamethasone utilized and adrenal imaging at intervals not consistant with the present knowledge of the breakthrough of adrenal gland visualization in normals observed on constant Late imaging provides scans that invariably show some degree of bilateral iodocholesterol uptake (Fig. 18). Particularly with shortened DS regimens, imaging of the normal adrenal occurs early and obscures diagnostic information necessary to distinguish adrenal hyperplasia from adenoma. Using the proposed 4mg-DS scheme, three patterns of imaging are found in patients with PA (Table 3). Adenomas show early unilateral

DS.49'50

140

GROSS ET AL.

Fig. 19. Posterior adrenal scintiscan in a patient with idiopathic aldostaronism pretreated with dexamethasone, 4 mg • 7 days prior to and throughout the imaging intervals. On day 3 after NP-59 injection, slight left and definite right-sided adrenal activity are seen. The day 5 postinjection study shows bilateral, but asymmetric, adrenal activity.

(<5 days) and late lateralizing (>5 days) images. Idiopathic aldosteronism is characterized by early bilateral visualization (<5 days). In some cases of bilateral hyperplasia, there is marked asymmetry of uptake. However, when the suppression interval is considered, the appropriate diagnosis can be made in spite of the marked lateralization of adrenal NP-59 activity. Later images, particularly those collected at times when the normal adrenal cortex would be expected to visualize (>5 days postinjection), provide little diagnostic information in the evaluation of these patients. Figure 19 is an example of asymmetric adrenal hyperplasia that illustrates the importance of early adrenal images.

Fig. 20.

Posterior adrenal scintiscan on day 6 after

NP-59 injection in a patient with a loft-sided adrenal adenoma. Pretraatment with daxamethasona (4 m g • 7

days) was given prior to and throughout the imaging intervals. Bilateral and asymmetric adrenal activity was observed.

Figure 20 demonstrates the breakthrough of adrenal iodocholesterol uptake in a patient with an adenoma when imaging was performed later than 5 days after NP-59 administration. A comparison of these images reveals that there is little difference between them, although the diagnoses and therapeutic implications in these cases are different. In addition to the difficulties encountered with the visualization of the normal adrenal cortex, DS results in longer retention of NP-59 activity within the liver, gall bladder, and bowel. Occasionally increased background activity makes the interpretation of DS-adrenal scintiscan difficult. Oblique, anterior, and lateral views have proven useful to separate liver and bowel from adrenal activity (Figs. 21 A and B, 22 A and B). Low renin essential hypertension (LREH) is another entity that has been studied with DSadrenal scintigraphy.58 Plasma renin activity in this syndrome is low and results in confusion of LREH with PA. Aldosterone secretion usually is normal and serves to separate patients with LREH and PA. Whether LREH is the result of mineralocorticoid excess or as yet other undefined factors has not been established, but approximately 50% of patients studied have abnormal early (<5 days) imaging. The abnorm a l scintigraphic images observed in LREH support the contention that there is an adrenal component to the hypertension in a significant proportion of patients. An example of a DSadrenal scintiscan in a patient with LREH is shown in Fig. 23. The effect of salt balance on renin and adrenal iodocholesterol uptake is an important consideration in the imaging of patients with PA. Diuretics administered during adrenal scintigraphic procedures stimulate renin activity and mimic

ADRENAL CORTICAL SCINTIGRAPHY

141

Fig. 21. Posterior adrenal dexamethasone suppression scintiscan (4mg-DS) in a patient w i t h aldosteronism. Intense bowel and liver activity are observed. (A) An area of increased uptake in the left abdomen is seen but obscured by bowel. (B) The left posterior oblique projection defines the area as outside bowel and corresponding to that of the left adrenal adenoma.

the bilateral patterns of NP-59 uptake seen in cases of idiopathic aldosteronism. This poses difficulties in the interpretation of DS-adrenal scintiscans, since the normal adrenal cortex will visualize at times that adrenal hyperplasia would be expected to be imaged (Fig. 24). An example of early bilateral visualization in a case of a right-sided adrenal adenoma imaged while on diuretic therapy for hypertension is shown in Fig. 25. In addition to diuretics, oral contraceptives have been shown to elevate PRA and will result in DS-adrenal scans with patterns of early bilateral visualization (vida infra). Hyperaldosteronism can occur in conditions other than PA. Renal hypoperfusion results in a marked elevation of PRA and DS-adrenal scin-

Fig. 22. Posterior (A) and left lateral (B) adrenal dexamethasone suppression scintiscans (4mg-DS) in a patient w i t h a right-sided aldosteronoma. (A) High liver and questionable gall bladder uptake obscures right adrenal activity. (B) The left lateral scintiscan demonstrates the activity to be posterior to liver (large arrow) and confirms it as the right adrenal. The linear activity in the scan is a l~Ba marker placed along the lumbar spine (small arrow),

tiscans with early (<5 days postinjection) bilateral adrenal visualization. Figure 26 illustrates bilateral early imaging in a case of an elevated PRA due to severe renovascular hypertension. A knowledge of both serum and urinary aldosterone concentrations and renin activity are important not only in the biochemical investigation but also in the scintigraphic evaluation of patients with suspected adrenal hypertension. DEXAMETHASONE SUPPRESSION SCINTIGRAPHY IN HYPERANDROGENISM

Recent studies indicate that DS-adrenal scintigraphy can be useful in the evaluation of the adrenal contribution of androgens in women with hyperandrogenism. 3'6"59 This is a common

142

Fig. 23, Posterior adrenal dexamathasone suppression (4mg-DS) adrenal scintiscan in a patient w i t h low renin hypertension, There is bilateral adrenal visualization at 3 days after NP-59 injection.

endocrine disorder and can be the result of androgen excess from the ovary, the adrenals, or from the peripheral conversion of precursor steroids to androgens. 24 Although the ovary generally is considered to be the primary site of androgen hypersecretion, there is a significant degree of combined ovarian-adrenal androgen excess in patients with hyperandrogenism. 6~ Dexamethasone suppression adrenal scintigraphy can be utilized to identify those patients with an adrenal contribution to their hyperandrogenism. 6 The biochemical investigation of such patients is complicated because traditional suppression/ stimulation tests do not accurately separate adrenal from ovarian dysftlnction. 6~ Additionally, measurement of basal plasma andro-

GROSS ET AL.

Fig. 25. Bilateral adrenal visualization on day 3 after tracer injection in a patient w i t h a right aldosteronoma on daxamethasone suppression (4mg-DS) and diuretic therapy for blood pressure control.

gens and gonadotropin concentrations may not accurately reflect the metabolic derangement due to pulsatile gonadotrophin and circadian ovarian and adrenal hormone secretion. 64 Urinary studies of androgens are useful as screening tests, but cannot separate ovarian and adrenal steroids, making their interpretation difficult.67 Three patterns of images are seen in women with hyperandrogenism using the established 4mg-DS regimen. Such investigations have provided insight into the adrenal contribution of androgens in these patients. 3'6 The first pattern seen is bilateral visualization 5 days after NP-59 administration. This pattern was observed in 17 of 37 (46%) patients studied to date and is considered normal based on recent studies of

Fig. 24. Posterior analog and computer-enhanced dexamethasone suppression (4mg-DS) adrenal scintiscan in a patient on diuretic therapy for hypertension. There is bilateral adrenal activity observed at 3 days after NP-59 injection.

ADRENAL CORTICAL SCINTIGRAPHY

143

,25

! .20 o "o LM v <( FQ. O3 O= Z

.15

Bilateral adrenal gland imaging (day 3 postFig. 26. NP-59 i n j e c t i o n , 4 m g - D S ) in a patient with severe renovascular hypertension and marked elevation of plasma renin levels.

DS-adrenal scintigraphy in volunteers.6 The second pattern, bilateral early visualization, was seen in 15 of 37 (40%) with uptake of NP-59 seen prior to 5 days after tracer injection. The third pattern of imaging was unilateral or lateralizing imaging before 5 days postinjection and has been observed in 5 of 37 patients. The groups with early imaging patterns have had confirmatory studies consisting of adrenal vein sampling and/or adrenalectomy. In all the patients studied with the bilateral early imaging pattern, elevated adrenal vein androgen concentrations have been found. The imaging pattern observed in this group would then be consistent with excessive bilateral adrenocortical androgen secretion. Adrenal cortical adenomas have been resected in 4 of the 5 patients with lateralizing scan patterns studied to date. The DS of ACTH and cortisol secretion (z. fasiculata) accentuates the abnormal secretion of androgens from the adrenal cortex in these patients. The contribu-

I

I

I

I

R

L

R

L

NORMAL

I "NORMAL"

BILATERAL V$SUALIZATtON

I ADENOMA

UNILATERAL EARL~ VISUALIZATION

Fig. 27. Dexamethasone suppression NP-59 adrenal gland uptake in hyperandrogenism.

tion of uptake from the aldosterone-secreting portion of the adrenal cortex is probably small in this regard, particularly in the basal state. 38The adrenal gland uptake of iodocholesterol in hyperandrogenism is a reflection of the adrenal secretion of androgens either from hyperplasia (bilateral visualization) or adenoma (unilateral visualization). The biochemical indices of hyperandrogenism in a group of patients studied while on a 4mg-DS regimen are shown in Table 4. Dexamethasone, suppression resulted in suppression of urinary 17-ketosteroids and plasma testosterone levels in a group with bilateral patterns of imaging but not in a group with unilateral or lateralizing imaging patterns. 68 The calculated NP-59 uptake in the bilateral and unilateral groups compared to normal is shown in Fig. 27. The adrenal gland uptake of NP-59 correlates with

Table 4. Biochemical Indices of Hyperandrogenism Urinary 17-Ketosteroid (4-14 mg/d)

Plasma Testosterone (0.45 + 0.2 ng/ml) Imaging Pattern Bilateral Unilateral *Mean • SEM. t P < 0 . 0 5 versus basal.

n

Basal

DS

Basal

DS

12

1.7 _+ 0 . 2 2 *

0.9 • 0 . 1 2 "

2 0 . 5 • 1.3

7.0 • 1.2 t

2 . 4 • 1.1

2.0 • 0.99

19.3 • 8 . 0

4

13,1 • 5 . 0

144

GROSS ET AL.

.50

3,6 --

oo~~o uo

,4O

3.2 --

Z ,30

2,8

uJ k-

e Bilateral Imaging {13) I o Unilateral Imaging (4)

E 2.4 .ZO

<

O 2,0 no .10

y = 0.022x + 0.143 r = 0.72 p<.005

-o I

1

I

I

I

3

I

I

5

I

I

7

I

I

9

I

i

11

I

O

e

F-

p<~ ]

13

1.2

a.

15

1.6

URINARY 17 - KETOSTEROIDS (m9/24~

0

O

9

0

.8

Fig. 28. T h e r e l a t i o n s h i p o f NP-59 a d r e n a l gland u p t a k e (R + L) t o u r i n a r y 1 7 - k e t o s t e r o i d e x c r e t i o n in p a t i e n t s w i t h bilateral imaging p a t t e r n s and h y p e r a n d r o g e nism.

e

,4 -

urinary androgen excretion in both groups of patients (Figs. 28 and 29), but does not correlate with plasma testosterone levels (Fig. 30). 68 The significant correlation observed between iodocholesterol uptake and urinary androgens is probably a reflection of the integrative nature of both urinary androgen excretion and the adrenal cortical uptake of iodocholesterol, whereas measurements of plasma and/or adrenal vein androgens are subject to considerable variations due to pulsatile secretion of pituitary gonadotrophins and testosterone, particularly in women with hyperandrogenism.64 Oral contraceptives (OCP) have been found to

a a

I

I

t

l

t

J

.2

.4

.6

.8

1.0

1.2

% ADMINISTERED NP-59 UPTAKE Fig. 30. T h e r e l a t i o n s h i p o f plasma t e s t o s t e r o n e t o N P - 5 9 u p t a k e in h y p e r a n d r o g e n i s m .

alter iodocholesterol uptake and patterns of adrenal visualization. Increases in both cortisol secretion and plasma renin activity are noted in women on O C P . 69'7~ DS results in less cortisol suppression than normal in women on OCP from either changes in cortisol binding to cortisolbinding globulin (CBG) or to decreased metabolic clearance of cortisol 7w2 (Table 5). In addi-

.7 i

A

<

F-

.5

,=, Z

LU

.4

~.3 z

IE

~.2

r = 0.99 p<0,O01 I 1

!

I

I

! 5

I

!

[

|

t

~

I

s

]

t

I

I

I

15 URINARY 17- KETOSTEROIDS (mg/24~ 10

1

I

20

I

I[

1

I 26

3

Fig. 29. The relationship of NP-59 a d r e n a l gland u p t a k e t o u r i n a r y 17k e t o s t e r o i d e x c r e t i o n in p a t i e n t s w i t h h y p e r a n d r o g e n i s m and u n i l a t e r a l imaging p a t t e r n s ,

145

ADRENAL CORTICAL SCINTIGRAPHY

Table 5. Oral Contraceptives (OCP) and Adrenal Scintigraphy*

Patients Control 1 2 OCP 1 2 3

Day of Visualization After NP-59

Urinary 17-Hydroxycorticosteroids (mg/d) (5-10)

Urinary 17-Ketosteroids (mg/d) (4-14)

Cortisol Plasma (#g/dl) (10-20)

5 5

2.8 --

9.2 --

0.91 0.60

3 3 3

1.2 1.2 2.4

3.1 5.4 4.6

1.4 1.4 1.3

*DS regimen--4 mg DS given daily for 7 days before NP-59 injection and throughout the imaging intervals.

tion, elevation of plasma renin activity and blood pressure observed on OCP are common and may indicate a degree of adrenal cortical stimulation and "functional hyperplasia." Early bilateral adrenal visualization is seen in women studied while on OCP (Fig. 31). This is an important consideration in adrenal imaging procedures in women with hyperandrogenism, for OCP therapy is used to treat a number of the symptoms seen in this condition. ADRENAL SCINTIGRAPHY IN HYPOADRENALISM

Blair et al. have shown that exogenous A C T H will augment adrenal gland iodocholesterol uptake. 35 This stimulation of NP-59 uptake can be used in states of hypoadrenalism to delineate the adrenal cortex in patients treated with prolonged adrenal cortical suppression. In a case of prolonged steroid suppression and unilateral

imaging, bilateral uptake of tracer was observed when A C T H was administered (Fig. 32 A and

B). Additionally, the uptake of NP-59 can be used to assess the probability of remission of Cushing's syndrome in patients treated with adrenolytic therapy. Measurements of the biochemical indices of adrenal cortical and pituitary function are unreliable while on op'DDD (lysodren) and the presence of adrenal gland uptake of iodochoiesterol has been reported to predict relapse once drug therapy is discontinued. 73 CLINICAL PERSPECTIVE

Adrenal cortical scintigraphy has been shown to be a sensitive indicator of adrenal cortical function. The uptake of iodocholesterol is affected by numerous medications and maneuvers that alter the known physiologic mecha-

Fig. 32.

Fig. 31. Bilateral adrenal visualization on day 3 postNP-59 injection (4mg-DS) in a patient on oral contraceptive therapy.

Posterior adrenal scintiscan in a patient on adrenal imaging, (B) bilateral adrenal imaging after ACTH administration.

prolonged adrenal suppression. (A) Unilateral

146

GROSS ET AL. Table 6. Factors That Alter Adrenal Cortical Function and Adrenal Scintigraphic Imaging Scan Effect

Zona fasiculata-reticularis Glucocorticoids: dexamethasone

Mechanism

Appearance

Reference

CRF ACTH

~ Uptake

~' ACTH Adrenal pituitary suppression

1` Uptake ~ Uptake 1' Uptake

23 73 35

/3-receptor blockade

~ Uptake

15

Adrenal suppression i" Plasma renin activity

,L Uptake 1' Uptake

17 52

[ Cortisol secretion rate Plasma renin activity

1" Uptake ~ Uptake

71 52

Serum cholesterol

(?) Cholesterol pool effect

[ Uptake

42

Serum cholesterol

1' LDL-receptor activity

1' Uptake

37

(?) Cholesterol pool effect (?) ~ LDL-receptor activity

~ Uptake

43

Cortisol Androgens

Metabolic inhibitors:

Aminoglutethimide Metyrapone op'DDD Exogenous ACTH Zona glomerulosa Antihypertensives: propranolol Antagonists: spironolactone Diuretics: all Oral contraceptives: all Excessive salt intake General Cholesterol lowering agents

~, Cortisol synthesis 1' Adrenal cholesterol uptake CortisoI-ACTH Direct adrenal stimulation Plasma renin activity Aldosterone Serum sodium Plasma volume 1' Plasma renin activity Aldosterone

Cholestyramine 4-Aminopyrazolopyrimidine (experimental) Hypercholesterolemia

1' Serum cholesterol

nisms of adrenal cortical hormone biosynthesis and secretion. These effects can be utilized to investigate abnormal function by differential suppression and stimulation tests. Dexamethasone suppression is, at present, the best studied pharmocologic manipulation of adrenal gland iodocholesterol uptake. In Cushing's syndrome, patients with known ACTHdependent disease can be shown to have a decrement of uptake while on DS. Suppression of ACTH and cortisol produces increased sensitivity in the scintigraphic investigation of the aldosterone and androgen-producing zones of the adrenal cortex. Manipulation of salt balance results in detectable alterations of iodocholesterol adrenal cortical uptake, serum aldosterone levels, and indices of imaging. Plasma renin activity and cortisol levels are increased by oral contraceptive medications and early bilateral

images, in otherwise normal individuals, can be produced. Table 6 is a summary of known drug effects on adrenal cortical function and iodocholesterol adrenal gland uptake and imaging. From these studies it is obvious that accurate adrenal scintiscanning requires attention to adrenocortical biochemical abnormalities, the prevailing cholesterol levels, and if incorporated into the study, the dose and duration of prior DS. With these considerations in mind, the adrenal scintiscan can provide both localization and functional information concerning the adrenal cortex that is not available by other noninvasive diagnostic modalities.

ACKNOWLEDGMENT

The authors would like to thank Diane Vecellio for secretarial assistance in the preparation of this manuscript.

REFERENCES

1. Conn JW, Morita R, Cohen EL, et al: Primary aldosteronism: Photoscanning of tumors after administration of ~3q-iodocholesterol. Arch Intern Med 129:417 425, 1972 2. Dige-Petersen H, Munkner T, Fogh J, et al: 131I-iodocholesterol of the adrenal cortex. Acta Endocrinol 80:81 94, 1975 3. Freitas J, Beierwaltes WH, Nishiyama R: Adrenal hyperandrogenism: Detection by adrenal scintigraphy. J Endocrine Invest 1:59 64, 1978

4. Gross MD, Freitas JE, Swanson DP, et al: The normal dexamethasone suppression adrenal scintiscan. J Nucl Med 20:1131-1135, 1979 5. Gross ME, Grekin R J, Brown LE, et al: The relationship of adrenal iodocholesteral uptake to adrenal zona glomerulosa function. J Clin Endocrinol Metab (in press) 6. Gross MD, Freitas JE, Swanson DP, et al: Dexamethasone suppression adrenal scintigraphy in hyperandrogenism. J Nucl Med 22:12-17, 1981

ADRENAL CORTICAL SCINTIGRAPHY

7. Liddle GW, Melmon KL: The adrenals, in Williams RH (ed): Textbook of Endocrinology. Philadelphia, Saunders, 1974, p 235 8. Neville AM, O'Hare M J: Aspects of structure, function and pathology, in James VHT (ed): The Adrenal Gland. New York, Raven, 1979, pp 1-15 9. August JT, Nelson DH, Thorn GW: Aldosterone. N Engl J Med 259:917-923, 1958 10. Nelson DH: The importance of aldosterone in clinical medicine. Med Clin North Am 42:1195-1204, 1958 11. Laragh JT, Angers M, Kelley WG, et al: The effect of epinephrine, norepinephrine, angiotensin II and others on the secretory rate of aldosterone in man. JAMA 174:234-240, 1960 12. Skeggs LT, Dorer FE, Kahn JR, et al: The biochemistry of the renin angiotensin system and its role in hypertension. Am J Med 60:737-748, 1976 13. Liddle GW, Bartter FC, Duncan LE Jr, et al: Mechanisms regulating aldosterone production in man. J Clin Invest 34:949-950, 1955 14. Bartter FC, Liddle GW, Duncan LE Jr: The regulation of aldosterone secretion in man: The role of fluid volume. J Clin Invest 35:1306-1315, 1956 15. Atlas SA, Sealey JE, Laragh JH, et al: Plasma renin and prorenin in essential hypertension during sodium depletion, beta-blockade and reduced arterial pressure. Lancet 2:754-759, 1977 16. Tan SY, Shapiro R, Franco R, et al: lndomethacininduced prostaglandin inhibition with hyperkalemia: A reversible cause of hyporeninemic hypoaldosteronism. Ann Intern Med 90:783-785, 1979 17. Chang SC, Suzuki K, Sadie W, et al: Effects of spironolactone, canrenone and canrenote-K on cytochrome P-450 and 11 fl and 18-hydroxylation in bovine and human adrenal cortical mitochondria. Endocrinology 99:1097-1106, 1976 18. Touitou Y, Bogdan A: Influence of op'DDD, op'DDE and solubilization procedures on the in vitro biosynthesis of 18-hydroxycorticosterone and aldosterone in sheep adrenals. lnt J Biochem 9:691-695, 1978 19. Nelson DH: The Adrenal Cortex: Physiological Function and Disease. Philadelphia, WB Saunders, 1980, pp 65-88 20. Shima S, Mitsonaga M, Nakao T: Effects of ACTH on cholesterol dynamics in rat adrenal tissue. Endocrinology 90:808 814, 1972 21. Eipper BA, Mains RE: Structure and biosynthesis of pro-adrenocorticotrophin/endorphin and related peptides. Endocrinol Rev 1:1-27, 1980 22. Nelson DH: The Adrenal Cortex: Physiological Function and Disease. Philadelphia, WB Saunders, 1980, pp 48-64 23. Liddle GW, Island D, Meador CK: Normal and abnormal regulation of corticotrophin secretion in man. Rec Prog Horm Res 18:125-166, 1962 24. Givens JR: Hirsutism and hyperandrogenism. Adv Intern Med 21:221-247, 1976 25. Samuels LT, Uchikawa T: Biosynthesis of adrenal steroids, in AB Eisenstein (ed): The Adrenal Cortex. Boston, Little & Brown, 1967, pp 61-102 26. Jackson RL, Morrisert JD, Gotto AM: Lipoprotein structure and metabolism. Physiol Rev 56:259-316, 1976

147

27. Brown M, Goldstein J: Receptor-mediated control of cholesterol metabolism. Science 91 : 15(~154, 1976 28. Faust JR, Goldstein JL, Brown MS: Receptormediated uptake of low density lipoproteins and utilization of its cholesterol for steroid synthesis for cultured mouse adrenal cells. J Biol Chem 252:4862-4871, 1977 29. Brown MS, Goldstein JL: Regulation of the activity of the low density lipoprotein receptor in human fibroblasts. Cell 6:307-316, 1975 30. Clinkenbeard KD, Reed WD, Mooney RA, et at: lntracellular localization of 3-hydroxy-3-methylglutaryl coenzyme A enzyme in liver. Separate cytoplasmic and mitochrondrial 3-hydroxy-3-methylglutaryl coenzyme-A generating system for cholesterolgenesis and steroidogenesis. J Biol Chem 250:3108 3116, 1975 31. Balasubramaniam S, Goldstein JL, Faust JR, et al: Lipoprotein-mediated regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol ester metabolism in the adrenal gland of the rat. J Biol Chem 252:1171-1179, 1977 32. Gwynne JT, Mahattee D, Brewer AB, et al: Adrenal cholesterol uptake from plasma lipoproteins: Regulation by corticotrophin. Proc Natl Acad Sci USA 73:4329-4333, 1976 33. Honn KV, Chavin W: Prostaglandin modulation of the mechanism of ACTH action on the human adrenal. Biochem Biophys Res Commun 73:164-170, 1976 34. Fukuchi S, Nakajima K, Miura T, et al: Comparative study of adrenal scanning agents, 6-/3-iodomethyl-19-norcholest-5(10)-er-3B-ol-J~q (NCL-6-13q) and l~q-19-cholesterol (Cl-19-13q). Jpn J Nucl Med 13:775-779, 1976 35. Blair R J, Beierwaltes WH, Lieberman LM, et al: Radiolabelled cholesterol as an adrenal scanning agent. J NuclMed12:176 182, 1971 36. Rizza RA, Wahner HW, Spelsberg TC et al: Visualization of non-functioning adrenal adenomas with iodocholesterol: Possible relationship to subcellular distribution of tracer. J Nucl Med 19:458 463, 1978 37. Counsell RE, Schappa LW, Korn N, et al: Tissue distribution of high density lipoprotein labeled with radioiodinated cholesterol. J Nucl Med 21:852 858, 1980 38. Nordblom GD, Schappa LW, Floyd EE, et al: A comparison of cholesteryl oleate and 19-iodocholesteryl oleate as substrates for adrenal cholesterol esterase. J Steroid Biochem 13:463466, 1980 39. Koral KF, Sarkar SD: An operator-independent method for background subtraction in adrenal uptake measurements. Concise communication. J Nucl Med 18:925-928, 1977 40. Freitas JE, Thrall JH, Swanson DP, et al: Normal adrenal asymmetry: Explanation and interpretation. J Nucl Med 19:149-154, 1971 41. Thrall JH, Freitas JE, Beierwaltes WH: Adrenal scintigraphy. Semin Nucl Med 8:23~ll, 1978 42. Gordon L, Mayfield RK, Levine JH, et al: Failure to visualize adrenal glands in a patient with bilateral adrenal hyperplasia. J Nucl Med 21:49-51, 1980 43. Valk TW, Gross MD, Freitas JE, et al: The relationship of serum lipids to adrenal gland uptake of 131-1-6/3 -iodomethyl-19-norcholesterol in Cushing's syndrome. J Nucl Med 21:1069-1072, 1980 44. Miles JM, Wahner HW, Carpenter PC, Salassa RM,

148

Northcott RC: Adrenal scintiscanning with NP-59: A new radioiodinated cholesterol agent. Mayo Clin Proc 54:321327, 1979 45. Sarkar SD, Cohen EL, Beierwaltes WH, et al: A new and superior adrenal imaging agent ~Jq-6-iodomethyl-19norcholesterol (NP-59) evaluation in humans. J Clin Endocrinol Metab 45:353-362, 1977 46. Gross MD, Valk T, Freitas J, et al: The relationship of adrenal iodonorcholesterol uptake and cortisol secretion in Cushing's Syndrome. J Clin Endocrinol Metab (in press) 47. Corm JW, Cohen EL, Herwig KR: The dexamethasone-modified adrenal scintiscan in hyporeninemic aldosteronism (tumor vs hyperplasia). A comparison with adrenal venography and adrenal venous aldosterone. J Lab Clin Med 88:841-855, 1976 48. Freitas JE, Grekin R J, Thrall JH, et al: Adrenal imaging with iodomethyl-norcholesterol (I-131) in primary aldosteronism. J Nucl Med 20:7-10, 1979 49. Ryo OY, Johnston AS, Kim I, et al: Adrenal scanning and uptake with tJq-6~-iodomethyl-norcholesterol. Radiology 128:157-161, 1978 50. Weinberger MH, Grim CE, Holifield JW, et al: Primary aldosteronism: Diagnosis, localization and treatment. Ann Intern Med 90:386-395, 1979 51. Gross MD, Freitas JE, Thrall JH, et al: Adrenal scintiscanning and aldosteronism. Ann Intern Med 91:651652, 1979 52. Conn JW: Primary aldosteronism, a new clinical syndrome. J Lab Clin Med 45:3 17, 1955 53. Conn JW, Cohen EL, Rovner DL: Suppression of plasma renin activity in primary aldosteronism. Distinguishing primary from secondary aldosteronism in hypertensive disease. JAMA 190:213-221, 1964 54. Atchison J, Brown J J, Feriss JB: Quadric analysis in the preoperative distinction between patients with and without adrenocortieal tumors with aldosterone and low plasma renin. Am Heart J 82:660-671, 1971 55. Ganguly A, Melada GA, Leutscher JA: Cortisol or plasma aldosterone in primary aldosteronism: Distinction of adenoma and hyperplasia. J Clin Endocrinol Metab 37:765775, 1973 56. Corm JW, Beierwaltes WH, Leiberman LM, et al: Primary aldosteronism: Preoperative tumor visualization by scintillation scanning. Endocrinology 89:713-716, 1971 57. Brown J J, Fraser R, Levin AF: Aldosterone: Physiological and pathophysiological variations in man. Clin Endocrinol Metab 1:397 449, 1972 58. Rifai A, Beierwaltes WH, Freitas JE, et al: Adrenal scintigraphy in low renin essential hypertension. Clin Nucl Med 3:282-286, 1978 59. Schteingart DE, Woodbury MC, Tsao HS, et al: Virilizing syndrome associated with an adrenal cortical

GROSS ET AL.

adenoma secreting predominantly tesosterone. Am J Med 67:140-146, 1979 60. Kirschner MA, Zucker IR, Jespersen DL: Idiopathic hirsutism--an ovarian abnormality. N Engl J Med 294:637 640, 1976 61. Northrop G, Archie J, Patel S, et al: Adrenal and ovarian vein androgen levels and laparoscopic findings in hirsute women. Am J Obstet Gynecol 122:192 198, 1975 62. Oake R J, Davies S J, McLachlan MSF, et al: Plasma testosterone in adrenal and ovarian vein blood of hirsute women. Q J Med 53:603 613, 1974 63. Wentz A, White R, Migeon C, et al: Differential ovarian and adrenal vein catheterization. Am J Obstet Gynecol 125:1000~1007, 1976 64. James HT, Rippon AF, Jacobs HS: Plasma androgens in patients with hirsutism, James HT, Erior M, Giosti G (eds): The Endocrine Function of the Human Ovary. New York, Academic, 1976, pp 457-470 65. Lloyd C, Lobotsky J, Segre E, et al: Plasma testosterone and urinary 17-ketosteroids in women with hirsutism and polycystic ovaries. J Clin Endocrinol Metab 26:314-324, 1966 66. Nichols T, Nugent C, Tyler F: Glucocorticoid suppression of urinary testosterone excretion in patients with idiopathic hirsutism J Clin Endocrinol Metab 42:41 51, 1976 67. Veremuelen A, Rubens R: Adrenal virilism, in James VHT (ed): The Adrenal Gland. New York, Raven, 1979, pp 259 282 68. Gross MD, Valk T, Swanson DP, et al: lodomethylnorcholesterol (NP-59) adrenal gland uptake is a measure of dexamethasone suppression 17-ketosteroid excretion in hyperandrogenism. J Nucl Med 21:29, 1980 (abstr) 69. Newton MA, Sealy JE, Ledingham JGC: High blood pressure and oral contraceptives, changes in plasma renin substrate and in aldosterone excretion. Am J Obstet Gynecol 101:1037-1039, 1968 70. Weinberger MH, Collins RD, Dowdy A J, et al: Hypertension induced by oral contraceptives containing estrogen and gestagen. Ann Intern Med 71:891-902, 1969 71. Crane MG, Harris JJ: Plasma renin activity and aldosterone excretion rate in normal subjects. II. Effect of oral contraceptive agents. J Clin Endocrinol Metab 558-563, 1969 72. Durber S, Lawson J, Daly J: The effect of oral contraceptives on plasma cortisol and cortisol binding capacity throughout the menstrual cycle in normal women. Br J Obstet Gynecol 83:814-818, 1976 73. Luton JP, Mahoudeau JA, Bouchard PH, et al: Treatment of Cushing's disease by op'DDD. N Engl J Med 300:459-464, 1978