Scintigraphic Localization of Ovarian Dysfunction

James M. Mountz, Milton D. Gross, Brahm Shapiro, Ariel L. Barkan, MargaretC.Woodbury,DavidE.Schteingart,andJonathanW.T.Ayers University ofMichigan Medical Center, Department oflnternalMedicine, Divisions of Nuclear Medicine and Endocrinology and Metabolism and the Department ofObstetrics and Gynecology, Ann Arbor, Michigan

Toassessthepotentialroleofscintigraphyintheevaluationofdinicallyandbiochemically suspect ovarian hyperandrogenism (HA), dexamethasone suppression 131I-6@-iodomethyl-i9- norcholesterol (NP-59) scans were performed to characterize ovarian function in nine patients. Pelvic ultrasound and/or computed tomography (CT) Identified anatomic abnormalities in the adnexalregioninsixwomeninwhomtherewasdiscerniblepelvicaccumulation(s)of NP-59. Intheremalningthreepatientstestosteronelevelswerenormaloronlyslightlyelevatedand the NP-59 scan did not demonstrate abnormal adrenal or pelvic uptake. CT and/or ultrasound studies failed to demonstrate an abnOrmalityin the peMs suggesting excessive peripheral conversion or abnormal end organ sensitivity of androgen precursors as potential etiologies of their HA. In three women with androgen secreting lipoid tumors of the ovary, unilateral, pelvic NP-59activitywasnoted;thesetumorsweresubsequentlyresected.Twowomenwith bilateralpelvicNP-59uptakewerelatershownto havehyperthecosiswith markedly asymmetric and enlarged ovaries. In one woman the extent of asymmetric NP-59 uptake was antidpatedby the asymmetryof ovarianveinandrogenlevelsat selectivevenous catheterization.Inanotherwomanwithmarkedlyasymmetricpolycysticovarydisease, intensefocaluptakeof NP-59localizedto the sideof the anatomicallyabnormal,enlarged ovary.Thus,ourpreliminarystudyreviewsourexperiencetodateandsuggeststhatNP-59 scintigraphy may be used to localize both tumorous and nontumorous ovarian dysfunction in statesof HAandvinlization.

J Nucl Med 29:1644—1650,1988

irsutism is often a manifestation of androgen or ovarian, the result of excessive peripheralandrogen excess and may be a result of a variety of pathologic precursorconversion, or abnormalend organsensitivity processes as well as familial or ethnic traits (1). The (4). diagnosis is usually reached after the integration of data Studies of anatomic localization to identify the obtained by physical examination, and hormone meas source(s) ofandrogen excess have repeatedly confirmed urements in serum and urine (androgen proffle). Effec this multiplicity of etiologies of androgen production tive treatment depends upon identifying the source(s) that confound attempts at localization with ultrasound of androgen hypersecretion (HA) (2—3).Despite com or high resolution computed tomography (CT), and plete hormonal evaluation, including suppression and make selective venous hormone sampling necessary (5, stimulation studies of plasma and urinary androgens, 6). Functional scintigraphic imaging has been prey their precursors and secretogogues, there are cases in ously shown to identify the adrenal contribution to which distinguishingpotential site(s)ofexcessive andro circulating androgens in women with HA where tu gen secretion is problematic. In these cases it is difficult morous and nontumorous adrenal dysfunction has to ascertainwhether the etiology of HA is adrenaland! been depicted by iodine-13l-6fl-iodomethyl-norcholes terol (NP-59) (7—9).Numerous anecdotal reportshave suggestedthe ability of NP-59 scintigraphyto visualize tumorous ovariandysfunction in HA and this approach ReceivedOct. 6, 1987;revision accepted Mar. 28, 1988. For reprints contact: James M. Mountz, MD, PhD, Div. of was used in the present study to review our experience Nuclear Medicine, University of Michigan MediCalCenter, 1500 in the scintigraphicevaluation ofwomen with suspected East Medical Center Dr., Ann Arbor, MI 48109-0028. ovarian androgen excess (5).

1644 Mountz,Gross,Shapiroetal TheJournalofNuclearMedicine METhODS potassiumiodine solution for 24 hr prior to and for 10days after scintigraphy. Bowel preparation with a mild laxative Nine women with clinically suspect ovarian HA were stud (bisacodyl,10 mg BID) was also given orally 48 hr prior to ied with NP-59 scintigraphy.Each patient was imaged after and throughout the imaging intervals. If doubt remained as history,physicalexamination, and biochemical studiesinclud to NP-59 uptake being in ovary or bowel, imaging was re ing measurementsof urinary 17-ketosteroids,serum testoster peated following additional laxative and enema administra one, and dehydroepiandrosteronesulfate(DHEAS) levels and, tion (10). A gammacameraequippedwith a high-energy, in most cases, the response of testosterone and DHEAS to parallelhole collimator interfaced to a digital minicomputer dexamethasone suppression (8). When performed, CT (GE was used to obtain 50,000 to 100,000 count images of the Models 8800 and 9800) scans ofthe abdomen and pelvis were abdominal and pelvic regions. Serum testosterone, andro obtained to include the region of the adrenal glands and stenedione,and DHEASwere measuredby radioimmuno ovaries. Studies were performed after administration of oral assay (11,12). Urine 17-ketosteroids were measured by fluo and intravenouscontrastusingcontiguous 1-cmslicesthrough rometricmethods (13). the areas of interest. Abdominal and pelvic ultrasound was performed with a variety of commercially available realtime sectorscannersusinga 3.5-or 5-mHztransducer.Thesescans RESULTh were usually limited to the lower pelvis with attention to the adnexal regions. The response of androgen suppression after dexa The NP-59 study was approved by the Human Studies methasone administration was obtained in Cases 3, 4, Committee of the University of Michigan. The nature of the 5, and 7 through 9, (Table 1). The results showed failure study was explained in detail to each patient and written of suppression of peripheralandrogen levels in Patient consent was obtained. NP-59 scintigraphy was performed during a 3—7day interval after injection of 1 mCi of the 3 having a lipoid cell tumor, but Patient 4 with poly radiotracer.Dexamethasone, 4 mg daily in divided doses (1.0 cystic ovarian disease (PCO), Patient 5 with hyperthe mg q 6 hr), was administered orally for 7 days before NP-59 cosis, and Patients 7—9all demonstrated suppression injection and throughout the 7-day postinjection interval (9). of peripheral androgen levels after dexamethasone All patients were given stable iodide, Lugol's or saturated administration. In all cases, however, the ability to

TABLE I SummaryofClinical,Hormonal,ImagingFindings,andDiagnosis PatientNP-59no.Age/ Basal Diagnosis1sex Physical hormones values CT or U/S DEXsuppressed 78/F Hirsutism,viriliza- Testosterone= 18.7 CTandU/S-3 Leftpelvicup- 3 cm leftovarianIi tion tumorAndrostenedioneDHEAS= 4160 cm leftovarian take poidcell mass10.42 = 34/F Hirsutism,amen- Testosterone= 5.4 CT-4cmleft LeftpeMcup- 4 cmleftovarianIi orrhea tumorAndrostenedioneDHEAS= 577 ovarianmass take poidcell 9.13 = 36/F Hirsutism,ovariantionvinliza- Testosterone= 15.4 CT- 12 cm right Rightpelvicup- 12 cm right DHEAStumor1 = 2292 ovarianmass take lipoidcell 41.54 7-Ketosteroid= 29/F Hirsutism TestosteroneovarianDHEAS= 1.4 CT and U/S- 5 Leftpelvicup- Polycystic = 6170 cmdiseasemassleftovarian take 5ovarynormalcm in sizeL ovary5 sizeA 30/F Markedvinlization TestosteroneHyperthecosisDHEAS= 1.9 U/S.12 cm right Bilateralovarian enlarged1= 1510 ovarianmass uptakeR > L Bilaterally ovarIes6 7-Ketosteroids= 15.0 69/F Hirsutism TestosteroneHyperthecosisDHEAS= 4.0 CT - bilateral Bilateralovarian enlarged1= 240 ovarIan uptakeL > A Bilaterally ovaries7 7-Ketosteroids= 6.2 massesL > A 55/F Hirsutism,conversionotherno Testosterone= 0.99 NormalpelvicCT Normal PenPheral 5664vinlizationsignsof DHEAS= 14.28 17-Ketosteroids= 20/F Hirsutism,conversionacneobesity, Testosterone= 0.50 NormalpelvicCT Normal Peripheral DHEASend17-Ketosteroids= 975 andincreased sensitivity9 = 11.8 organ 41/F Hirsutism,obesity TestosteroneconversionDHEAS= 0.1 NormalpelvicCT Normal Peripheral endI = 7355 and U/S and Increased sensitivityNormal 7-Ketosteroids= 26.2 organ ng/ml)levelsrangefor hormone Serumtestosterone(.24—.66ng/ml) Serumandrostenedione(.3—.8 (Women) SerumDHEAsulfate(820—3380ng/ml) Urinary17-ketosteroids(4—14mg/totalvolume)

Volume 29 •Number 10 •October1988 1645 suppress peripheral androgens provided no anatomic localization information concerning the source(s) of excessive androgens. NP-59 scintigraphy successfully imaged the sites of ovarian dysfunction in the six cases with proven ovarian disease (Table 1). The biochemical data of Cases 1 through 3 and the pelvic NP-59 scan of Case 3 have been presented in separate previous reports; (Refs. 5 and 14, respectively). Three patterns of NP-59 images were observed in the nine patients studied. In all cases, bowel activity was excluded as accounting for tracer accumulation by repeat imaging on Days 3 through 7, and demonstration of persistent and focal activity in the abnormal adnexal region(s). Pattern 1: unilateral pelvic uptake. Four patients demonstrated this pattern; three were diagnosed as hay ing unilateral,virilizing, lipoid cell tumors aftersurgical resection of the neoplasm and pathologic tissue exami nation. In all three patients with lipoid tumors of the ovary, each had marked elevation in serum testosterone (range 5.4—18.7ng/ml) with ovarian masses depicted on CT and/or ultrasound and all demonstrated unilat eral uptake ofNP-59 on the side ofthe pelvis harboring the ovarian tumor. Figure lÀshows the abnormal CF scan ofthe lipoid cell tumor in Patient 2 (Table 1)with the corresponding abnormal NP-59 scan shown in Fig ure lB. The fourth patient had PCO, (Patient 4, Table 1). Figure 2A shows the abnormal CT scan and Figure 2B shows the NP-59 scan in this case demonstrating marked asymmetric tracer uptake localized to the left pelvis. In this case the unilateralleft ovarian uptake was expected since the right ovary had a normal CT ap pearance. Pattern 2: bilateralpelvic uptake. Two patients dem BR onstrated this pattern, both diagnosed at laparotomy with hyperthecosis(luteal cell hyperplasia).In these two FIGURE 1 patients (5 and 6, see Table 1) with luteal cell hyperpla A: CT scan,transversesectionthroughthe levelof the pelvisshowinga left ovarianmass(arrow)representing sia the CT scans were abnormal and the serum testos thelipoidcelltumorinPatient2 (Table1).B:Anteriorpelvic terone concentration was in the range regardedas di scan at 5 days post NP-59 injection. Abnormal activity in agnostic for virilizing tumors. The asymmetric (right> theregionoftheleftpelvis(arrow)representingincreased left) pattern of uptake correlated with the results of traceruptakein the lipoidcelltumor.At laparotomya 4.0 selective catheterization of the ovarian veins in Case 5, cm in diameter left ovarian lipoid cell tumor was found. Blackcirclesmarkthe iliaccrest. where a markeddifference in ovarian effluent testoster one (right ovarian vein = 48.9 ng/ml, left ovarian vein = 9.8 ng/ml, peripheral vein = 1.9 ng/ml) was meas. Pattern 3: no definite pelvic uptake. In three of the ured. In each case there was bilateral enlargement of cases (Patients 7—9,Table 1) without anatomic abnor both ovaries depicted on CT and/or ultrasound. This malities of the adrenal or ovaries by CF or ultrasound diffuse asymmetric pelvic uptake is exemplified by the examination and minimal clinical evidence of hirsut anteriorpelvic NP-59 scan ofPatient 5, shown in Figure ism, the testosterone levels were in the normal rangeor 3. This patient received repeated laxatives and enemas, only slightly elevated (Table 1). There was accumula and in all scintigraphsof the anterior pelvis the diffuse tion of NP-59 in the adrenals, which appeared late: 5 abnormal activity pattern was seen, indicating bilateral days or more after dexamethasone suppression (DS), ovarian uptake, (R > L). This diffuse asymmetric pat which is normal and no discernible NP-59 uptake in tern may be compared to Figure 4, in which no abnor the pelvic region (Fig. 4), a normal finding on DS mal ovarian uptake was found. scintigraphy (7).

1646 Mountz,Gross,Shapiroetal TheJournalof NuclearMedicine @ L . : @: •

to determine the site of HA (18) and even the combi nation of hormonal tests and anatomic imaging may fail to discern an abnormally functioning gland(s), and at times can be frankly misleading (19). Since precise differentiation of ovarian from other sources of andro gen hypersecretionis requiredfor the optimal manage ment of these patients, direct hormone levels obtained by selective catherization of the venous effluent from the ovary and adrenalglands may be the most accurate kN@ method to discern the correct etiology of HA in many cases (20). Although this approach is successful in RA L localizing the source(s) ofHA, it is technically demand ing, and invasive. Successful sampling from both adre nal and both ovarian veins can be achieved in not more than 75—80%ofattempted cases (6). High resolution CF and abdominal ultrasound are useful, but successful localization by each is dependent upon changes in organ anatomy and contour, (usually enlargement of the ovaries in the cases discussed here) sufficient to identify tumorous involvement. This ap g; proachdepicts abnormal anatomy, but because there is

.@ much variabilityin size and configuration ofthe normal @- . adrenal and nonfunctional adrenal mass (21,22) as well as the normal and abnormal ovary (23,24) enlargement does not necessarily correlate with the degree or pres ence of a functional abnormality.

@‘,@.@.. . Scintigraphic localization ofovarian dysfunction has been suggestedin previous case reportsand small series @ @... ..@ S S •••

@ @. :

@: @ FIGURE2 @:@‘@-•. A: CT scantransversesectionthroughthe levelof the pelvis showinga left ovarian mass (arrow) in Patient 4 :@ (Table 1)with polycystic ovarian disease. B: Anterior pelvic scan at 6 days post NP-59 injection. There is an area of

increased tracer uptake localized to the region of the left 5— ovary (arrow) representingincreaseduptake in the left @ polycysticovary.At laparotomyan enlarged5 cm in di • . 5' @ ametercysticleftovarywasfound.Blackcirclesmarkthe @.S,. • @ iliaccrest. ,

@ DISCUSSION @T ‘@:. L R

Androgen-secreting ovarian neoplasms are rare, and .. . often present difficult diagnostic problems. The results of hormonal stimulation and suppression tests are fre quently unable to discern the origin(s) of abnormal FiGURE 3 hormonal secretion in women with HA (15,16) since Anterior peMc scan at 6 days post NP-59 injection. There many ovarian and adrenal neoplasms respond similarly is bilateralovarianuptakenght(arrow)greaterthanleft (open arrow), in Patient 5 representing bilateral ovarian to both gonadotropin and adrenocorticotropin stimu hyperthecosis. At laparotomy an enlarged 12 cm in diem lation and suppression maneuvers (1 7). There is lack eternghtovaryand4 cmindiameterleftovarywasfound. of specificity of the traditional endocrine function tests Blackcirclesmarktheiliaccrest.

Volume29 •Number10 •October1988 1647 preparation and, if necessary, delayed imaging in the evaluation of pelvic NP-59 uptake cannot be overem J phasized (10). Moreover, in milder forms of PCO the dysfunctional state of the ovaries may not be sufficient @ - S • @..; S

@ - .@!S;bS:; . S to accumulate adequate NP-59 for discernible visuali zation. Taylor et al. (5) reported an inability to visualize @ S @‘•.-- @ S •@ S : • S @:••: proven bilateral ovarian hyperthecosis in two patients on NP-59 scanning. This may be because of inadequate bowel preparation,since in the two cases reportedhere, vigorous bowel preparation was performed and pelvic . c@ uptake was seen in each case (10). A critical level of anatomic abnormality characterized by CF and/or @ Rt :: ‘-. ultrasound in PCO and hyperthecosis and abnormal hormone secretion by the ovary in these and other tumorous ovarian conditions would be necessary for successful localization by scintigraphy. Rare reports of ovarian tumors accumulating sufficient NP-59 for im aging have appeared in the literature, but to date these have been case reports of incidental observations (14, 30). In the present series we have characterizedand eval uated NP-59 imaging in nine women clinically sus pected of having an ovarian source of HA. Although FIGURE4 the numbers ofpatients studied is small, and a statistical Anterior pelvic NP-59 scan at 6 days post NP-59 injection. evaluation ofefficacy cannot be made, in this particular Normalscan findings in Patient8 after vigorous bowel group, four etiologies of HA that span much of the cleansing showing no discernible tracer uptake in the pelvic spectrum ofHA were evaluated. One cause ofHA found region (brackets). Black cIrcles mark the iliac crest. in three women in this series who demonstrated unilat eral uptake ofNP-59 was the result oflipoid cell ovarian tumors. All of these women had marked elevation of (5,14,25). The rationale for the imaging of gonadal serum testosterone levels. All subsequently underwent tissues is an extension of that of adrenal accumulation surgical exploration and resection ofthe tumor after an of NP-59. Gonadal steroid-producing tissues, like the anatomically abnormal ovary was found. One woman adrenal, express the lipoprotein receptors necessary for in our series had endocrine studies characteristic of the internalization of cholesterol contained within cir PCO (31-33), and asymmetric NP-59 uptake was lo culating lipoproteins(26,27). It is throughthis receptor calized to the left pelvis. An enlarged left ovary was dependent pathway that the bulk of cholesterol (and confirmed on the CF scan and at subsequent laparot NP-59) for steroidogenesis is made readily available to omy. Two patientswith luteal cell hyperthecosisshowed these tissues (26,27). We have demonstrated in adrenal a pattern of NP-59 uptake characterized by diffuse but tissues that once incorporated within the cholesterol asymmetric pelvic uptake and in one of these women ester storage pool, NP-59 is not further metabolized to selective ovarian vein hormone sampling corroborated steroid hormones and thus, it remains as a marker of the NP-59 findings. Thus, NP-59 correctly identified substrateaccumulation (28). the ovary as the primarycontributing source of andro To date the major thrust of imaging using NP-59 in gens in this woman. This may be of importance, since HA has been performed primarily for the nomnvasive unilateral oophorectomy has been recommended in evaluation of adrenal involvement in this syndrome asymmetric hyperthecosis to remove the predominant (9). The accumulation of NP-59 into both tumorous source ofandrogens; such therapyhas been followed by and hyperplasticadrenalglands has correlatedwith 17- restoration of menses and amelioration of hirsutism ketosteroid excretion, a measure of hormonal dysfunc while maintaining fertility (34,35). tion (29). As these previous studies were designed to In each case the NP-59 scan, either by the presence evaluate adrenal function, adequate and persistent of unilateral (in ovarian tumors and PCO), or bilateral bowel preparationwas not incorporated into their pro (in hyperthecosis)uptake depicted ovarian dysfunction. tocols, which may serve to explain the absence of dis Moreover, in the two cases of hyperthecosis NP-59 not cernible ovarian accumulation of NP-59 seen in pa only confirmed the anatomic abnormality, but also tients with PCO both on and off prior dexamethasone correctly identified the asymmetric nature of the ovar suppression (7,29). The importance of adequate bowel ian disease (Table 1). The final group was comprised of

1648 Mountz, Gross, Shapiro et al TheJournalofNuclearMedicine three women with mild signs of hirsutism who were organs. EndoRev 1984; 5:221—281. suspected by physical and hormonal examination to 5. Taylor L, AyersJWT, Gross MD, Peterson EP, Menon KMJ. Diagnostic considerations in virilization: io have lesser degrees of ovarian dysfunction. The NP-59 domethylnorcholesterol scanning in the localization scan and pelvic CF were normal suggesting either pe of androgen secreting tumors. Fertil Steril 1986; npheral conversion ofandrogen precursors or increased 46:1005—1010. end organ sensitivity as possible explanations for the 6. KirschnerMA, Jacobs JB. Combined ovarian and mild hirsutism in these women. Confirmation from adrenal vein catheterization to determine the site(s) of androgen overproduction in hirsute women. J Clin selective ovarian and adrenal vein catheterization was Endocrinol1971;33:199—209. not performed as this procedure is usually reservedfor 7. Gross MD, Freitas JE, Swanson DP, Woodbury MC, patients with greaterdegrees of hormonal abnormality Schteingart DE, Beierwaltes WH. Dexamethasone and virilization. Furthermore,follow-up for a period of suppression adrenal scintigraphy in hyperandrogen 4 to 7 yr has not lead to modification of the clinical ism: concise communication. J Nuci Med 1981; 22:12—17. diagnoses in these cases. 8. Gross MD, Valk TW, Swanson DP, Thrall JH, Grekin The scintigraphic approach provides functional in RJ, Beierwaltes WH. The role of pharmacologic ma formation that is not available by other noninvasive nipulation in adrenal conical scintigraphy. Semin radiographic techniques. It has been previously sug NuclMed 1981;11:128—148. gested that, with the exception of the patient with a 9. GrossMD, ShapiroB, FreitaSJE, et al. The relation ship of 1-131 6@-iodomethyl-l9-norcholesterol (NP diagnosis of congenital adrenal hyperplasia, virilized 59) adrenal cortical uptake to indices of androgen women may benefit from NP-59 scintigraphy (7). This secretion in women with hyperandrogenism. Clin Nucl procedure however, due to its relatively unfavorable Med 1984;9:264—270. dosimetry (“.-6-8rad/mCi ovary exposure, 1 rad/mCi, 10. ShapiroB, Nakajo M, Gross MD, FreitasJ, Copp J, total body) (36), should not be used as a screening Beierwaltes WH. Value of bowel preparation in adre nocortical scintigraphy with NP-59. JNuclMed 1983; modality but be reserved for women with clinical and 24:732—734. biochemical findings compatible with definite ovarian 11. Buster JE, Abraham GE. Radioimmunoassay of and/or adrenal dysfunction. If all these findings (in plasma DHEA-sulfate. Anal Let: 1972; 5:203—215. cluding scintigraphy)remain nondiagnostic then selec 12. Niswender GD, Nett TM, Meyer DL, et al. Factors tive adrenaland/or ovarian venous catheterizationand influencing the specificity ofantibodies to steroid hor mones. In:CameronEH, HillierSO, GriffithsK, eds. sampling could be performed in an attempt to locate Proceedings of the Fifth Tenovos Workshop. Cardiff the source(s) of HA. Our data suggest that the NP-59 Cardiff, Wales: Alpha Omega Publishers, 1974: 61. scan may be used to advantage in some cases to supple 13. Silber RH, PorterCC. The determinationof 17,21- ment the anatomic information of CF and/or ultra dihydroxy-20-ketosteroids in urine and plasma. J Biol sound in the evaluation of ovarian androgen secretion Chem 1954; 210:923—932. 14. BarkanAL, CassorlaF, LoriauxDL, Kelch RP, Mar and dysfunction in the virilized woman. shall JC. Steroid and gonadotropin secretion in a patient with a 30 year history of virilization due to lipoid-cell ovarian tumor. Obstet Gynecol 1984; ACKNOWLEDGMENTS 64:287—295. 15. Steinberger E, Smith KD, Rodriguez-Rigau U. Tes TheauthorsthankMs.MicheleCurroandMrs.AnrnseL. tosterone, dehydroepiandrosterone, and dehydroepi Johnson for their expert secretarial assistance. They also ac androsterone sulfate in hyperandrogenic women. I knowledgetheassistanceofDr. T. Mangnerand H. Anderson CilnEndocrinolMetab 1984;59:471—477. Davis for the synthesis of NP-59, and the Phoenix Memorial 16. AyersJWT. Differentialresposeto adrenocorticotro Laboratories for the use oftheir radiochemical facilities. This pin hormonestimulationin polycysticovariandisease workwassupportedbyGrants—NCL(CA-090l5),NIAMDD with high and lowdehydroepiandrosterone sulfate 1ev ( R0l-AM-21477RAD),GCRC(HEW3MO1-RR-0042- els.FertilSteril1982;37:645—649. 17. Sirinathsinghji DJS, Mills IH. Effect of human pitui 21CLR),NIH(ROl-CA-43300-Ol)andtheNuclearMedicine tary luteinizing hormone administration on plasma ResearchFund. levelsof dehydroepiandrosterone, androstenediol and their sulphates and testosterone in women with see ondary amenorrhoea. 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1650 Mountz,Gross,Shapiroetal The Journal of Nudear Medicine