ASSESSMENT OF PITUITARY FUNCTION IN PATIENTS WITH SERUM PROLACTIN LEVELS GREATER THAN 100 NG/ML*t

FERTILITY AND STERILITY Cpyright 1979 The American Fertility Sciety Vl. 32, N.2, August 1979 Printed in U.s.A. ASSESSMENT OF PITUITARY FUNCTION IN PATIENTS WITH SERUM PROLACTIN LEVELS GREATER THAN 100 NG/ML*t RICHARD E. BLACKWELL, PH.D., M.D.:j: LARRY R. BOOTS, PH.D. ROBERT L. GOLDENBERG, M.D. J. BENJAMIN YOUNGER, M.D. Department f Obstetrics and Gyneclgy, University f Alabama Schl f Medicine, Birgham, Alabama 35294 Twelve wmen with galactrrhea-amenrrhea and prlactin levels greater than 100 were evaluated with dynamic pituitary challenge testing. Frty-tw per cent f the patients had psitive findings n ply tmgraphy and subsequent surgical cnfirmatin f a pituitary tumr. Patients with tumrs had a delayed elevatin f grwth hrmne (GH) and crtisl fllwing inductin f insulin hypglycemia. Patients had increased thyrid-stimulating hrmne levels after injectin f thyrtrpin-releasing factr, but shwed blunting f prlactin secretin. Patients with tumrs had decreased basal levels f GH and shwed a blunted respnse t luteinizing hrmne-releasing hrmne (LRF) stimulatin. These patients had nrmal elevatins f fllicle-stimulating hrmne after LRF challenge. Patients with tumrs shwed a delay in elevatin f GH levels fllwing l-dpa treatment. They als failed t shw prlactin suppressin fllwing this treatment. There are cnsistently predictive changes that ccur in pitutiary functins in the presence f a pituitary tumr. Hwever, abslute prlactin levels and sellar ply tmgraphy are mre reliable in diagnsing the presence f a pituitary tumr in the patient with galactrrhea-amenrrhea. Fertil Steril 32:177, 1979 Patients with galactrrhea-amenrrhea and assciated hyperprlactinemia have been evaluated by several investigatrs. The principal methds f evaluatin have been measurement f abslute prlactin levels, hypcyclidal ply tmgraphy, and dynamic pituitary functin studies including single and sequential tests with insulin hypglycemia, i-dpa suppressin, and challenge with luteinizing hrmne-releasing factr (LRF) and/r Received February 5, 1979; accepted April 10, 1979. *Supprted by the General Clinical Research Center, Natinal Institutes f Health Grant RR-032, and the University f Alabama in Birgham. tpresented at the Thirty-Fifth Annual Meeting f The American Fertility Sciety, April 3 t 7, 1979, San Francisc, Calif. :j:reprint requests: Richard E. Blackwell, Ph.D., M.D., Department f Obstetrics and Gyneclgy, University f Alabama, University Statin, Birgham, Ala. 35294. 177 thyrtrpin-releasing factr (TRF). These studies have cnfirmed the predictive pwer f tmgraphy and abslute prlactin levels greater than 0 in identifying patients with a very high prbability f having a pituitary tumr. Pituitary challenge testing has been less effective in predicting the presence f a tumr. Hwever, it has been reprted that pituitary tumrs Cause blunting f prlactin release after TRF stimulatin, augmentatin and suppressin f the release fluteinizing hrmne (LH) and fllicle-stimulating hrmne (FSH) after LRF stimulatin, and failure'f l-dpa t inhibit prlactin release.1-4 This paper presents data frm patients with galactrrhea-amenrrhea and prlactin levels greater than 100 wh have been evaluated with dynamic pituitary challenge testing."the respnses f patients with tumr are cmpared with thse f patients with idipathic galactrrhea-

178 BLACKWELL ET AL. August 1979 amenrrhea, and the predictive value f these studies in differentiating the tw syndrmes is discussed. MATERIALS AND METHODS Twelve patients, ages 18 t 40 with 1 t 6 years f galactrrhea and 1 t 14 years f secndary amenrrhea f unknwn etilgy, were admitted t the clinical research unit at the University f Alabama in Birgham. N patient was admitted fr study unless prlactin levels f greater than 100 had been btained n tw ccasins. Admitting data included a histry and physical exaatin; baseline endcrine studies cnsisting f T 3, T 4, FSH, LH, mrning and evening crtisl, and thyrid-stimulating hrmne (TSH); admissin prfile; chest x-ray; and electrcardigram. Fllwing admissin, the patient underwent visual field exaatin, sella turcica x-rays, and ply tmgraphy. Metapyrne testing was perfrmed using a dse f mg/kg. Subsequently, insulin hypglycemia was induced by intravenus push n the mrning f admissin, using 0.1 unit/kg, and bld samples were btained at -,, 15, 0, + 15,, 45,, and utes. The samples were assayed fr grwth hrmne, crtisl, and bld sugar levels. The next day, the patients underwent l-dpa suppressin testing using a 500-mg ral dse, with bld samples being btained at -,, 0, +,,,, 150, and 180 utes. The bld was assayed fr grwth hrmne and prlactin cntent. The fllwing day, all patients were given 100 flg f LRF (furnished by Dr. Rger Guille and Jhn Rivier f the Salk Institute) via intravenus push. Bld samples were btained at -, -, -, 0, + 15,, 45,,, and utes. The bld was assayed fr LH and FSH levels. That afternn, the patients were given TRF (furnished by Dr. Rger Guille and Jhn Rivier), 500 flg by intravenus push; bld samples were btained at -,40,, 15, +5, 10, 15, 20,, and utes fr assay f prlactin and TSH cntent. All radiimmunassays were carried ut using mdificatins f Sern kits. If the patients had x-ray findings highly suggestive f pituitary tumr, they were subjected t pituitary arterigraphy in preparatin fr neursurgical explratin. All data in this study were analyzed using Student's t-test. RESULTS Patients had a mean age f26.7 years; 75% were Caucasian and 58% were nulliparus. They had had galactrrhea fr an average f 2.4 years and secndary amenrrhea fr an average f 4.2 years. Fifty per cent f patients had taken birth cntrl pills at sme time. Frty-tw per cent had psitive sellar tmgrams and all f these patients had surgical cnfirmatin f their tumrs. The patients had a mean prlactin level f 276 with a range f 106 t 10 n admissin t the study (Table 1). All patients had nrmal levels f T 3, T 4, FSH, and LH, and nrmal admissin prfile data. N patient had visual field disturbances. All patients respnded t metapyrne challenge and had cyclic variatins in their mrning and evening crtisl levels. Analysis f the data fllwing insulin hypglycemia shwed that bth ppulatins had significantly increased crtisl levels. There was n significant difference between the ppulatins TABLE 1. Summary f Clinical Data fr Twelve Patients with Galactrrhea-Amenrrhea Histry Initial Patient Age Race Parity Duratin f galactrrhea Duratin f secndary amenrrhea f ral cntraceptive Psitive plytmgrams Tumr prlactin level use yr yr 1 28 W 0000 1 1 + + + 150 2 23 W 0000 4 2 + + + 339 3 24 B 0000 6 6 + + 10 4 26 B 0000 <1 6 + + + 339 5 27 W 0000 4 10 + + + 152 6 35 W 0010 1 1 108 7 18 W 0000 0 1 + 208 8 29 W 0000 <1 14 + 106 9 24 W 1001 3 3 150 10 40 W 2002 1.5 2 + 136 11 20 B 0000 2 2 189 12 26 W 2002 4 2 133 W POOOO Mean 26.7 75% 58% 2.4 4.2 50% 42% 42% 276

Vl. 32, N.2 ASSESSMENT OF PITUITARY FUNCTION IN HYPERPROLACTINEMIA 179 prir t r after insulin treatment, althugh crtisl reached a level f significance at 45 utes in nntumr patients and at utes in tumr patients. Bth grups had significantly increased grwth hrmne levels in respnse t insulin hypglycemia, but there was n significant difference between tumr and nntumr patients. Grwth hrmne in patients withut demnstrable tumr reached a significant level in utes, whereas thse with tumr reached significance at 45 utes (Table 2). When all patients were given TRF, they had significantly increased TSH levels within 5 utes. Patients with pituitary tumrs had a slight, but significant, increase in the baseline level f TSH as cmpared with nntumr patients. Analysis f prlactin levels fllwing TRF adistratin shwed n significant difference in respnses in either tumr r nntumr grups (Table 3). There was a high significant difference between bth the pre- and pst-test levels in tumr and nntumr grups. TABLE 2. Insulin Challenge Test When patients were given LRF, each grup shwed a highly significant increase in LH levels within 15 utes. There was a significant difference in baseline levels between tumr and nntumr grups (nntumr patients, 13.6 miu/ml ± 2.1 [SEl; tumr patients, 5.6 miu/ml ± 0.5 [SED. Als, there was a significant difference between tumr and nntumr patients which prbably reflects the difference in baseline values. Likewise, FSH levels reached a significant level by 15 utes in bth grups. Hwever, the baseline and pst-lrf levels are nt significantly different in tumr and nntumr grups (Table 4). When patients were treated with l-dpa, thse patients with n demnstrable tumr shwed a significant decrease in prlactin levels by 180 utes. Hwever, patients with tumrs did nt significantly decrease their prlactin levels. There was a significant difference between nntumr and tumr grups prir t and after treatment which prbably reflects the baseline differences. Patients had increased grwth hrmne levels fl- - - -15 15 45 - - -15 15 45 Crtisl pgldl 11.0 9.5 9.4 9.8 9.7 10.4 16.8 20.5 19.5 20.9 Baseline VS. treatment Baseline NT VS. treatment Baseline T VS. treatment GH nglml 0.79 0.89 0.80 0.84 0.69 2.48 11.24 18.20 13.49 9.53 Treatments NT VS. T Baseline NT vs. treatment Baseline T vs. treatment BE Crtisl BE pgldl 1.5 10.9 1.7 1.3 10.6 2.0 1.2 8.8 1.6 1.5 9.2 1.3 1.3 9.6 1.6 1.4 11.0 2.4 1.7 14.0 2.6 1.7 15.8 3.6 3.0 19.6 2.7 1.8 20.5 3.0 (NT) P < 0.01 (T) a NT (at 45 ) T P < 0.02 (at ) BE GH BE nglml 0.14 0.94 0.20 0.10 1.38 0.52 0.14 1.82 0.93 0.13 2.20 1.21 0.15 1.57 0.71 0.86 2.70 1.25 2.97 5.78 1.78 2.80 10.44 3.72 3.68 11.00 4.91 4.31 8.04 5.57 P < 0.05 NT (at ) T P < 0.01 (at )

180 BLACKWELL ET AL. August 1979 TABLE 3. TRF Challenge Test Prllictin SE Prlactin nglml nglml - 135 22 1310-45 136 22 1285-132 22 1233-15 137 20 8 0 138 20 1218 5 142 21 1336 10 148 25 1316 15 158 25 1529 20 1 29 1283 168 31 1268 165 1299 Baseline VS. treatment a Baseline NT VB. T TSH SE TSH pljlml pljlml - 3.1 0.59 4.9-45 3.3 0.59 4.9-3.0 0.50 5.5-15 3.3 0.71 5.9 0 2.8 0. 5.7 5 10.2 2.42 15.8 10 18.2 2.46 22.7 15 24.7 4.51 27.4 20 28.7 5.22.0 26.9 5.10 27.5 19.9 4.23 24.2 Baseline VS. treatment Tumr (T) (at 5 ) SE 711 688 658 640 654 731 714 791 682 668 706 SE 1.28 1.08 1.38 1.50 1.44 2.31 3.56 5.77 6.02 4.93 5.64 lwing I-dpa treatment, with nntumr grups reaching significance at utes and tumr grups reaching significance at utes. There was n significant difference between the baseline and pst-treatment grups when cmparing tumr and nntumr (Table 5). DISCUSSION Mst investigatrs agree that abslute prlactin levels are useful in identifying patients with pituitary tumrs. Over the past few years, the level f prlactin that was thught t be diagnstic f pituitary tumrs has been reduced t 0. This is suggested by the data f Frantz, 5 invlving the study f 235 patients with nnpuerperal galactrrhea. Frty-seven patients with tumrs had prlactin levels ranging frm 4.5 t 10,000 (mean f 658 ). All f these patients with prlactin levels greater than 0 had pituitary tumrs. Wiebe et ap studied 11 patients with galactrrhea-amenrrhea and fund pituitary tumrs in each case. Prlactin levels ranged frm t 970 with a mean f281. Our data are similar in that all f ur patients with prlactin. levels greater than 0 had pituitary tumrs. The mean prlactin level was 276 with a range f 106 t 10. Frty-tw per cent f these patients had pituitary tumrs. These data agree with thse f Rakff and Yen, 6 wh evaluated 100 patients with galactrrhea and fund tumrs in 33% f the cases. Their mean prlactin level was apprximately 180 with a range f 10 t 1000. Frty-nine per cent f their patients had prlactin levels greater than 100. Fifty-ne per cent ftheir patients had prlactin levels fless than 100 ng/nl. Keye et a1. 4 have reprted tumrs in 9 f 42 patients with prlactin levels less than r equal t 100 ng/mlthese data wuld suggest that prlactin levels greater than 0 are diagnstic f pituitary tumrs, prlactin levels greater than r equal t 100 give a 50% chance f tumr detectin, and prlac- TABLE 4. LRFChallenge Test LH SE LH SE miu/ml miulml -. 13.2 3.9 6.5 1.2-10.5 2.9 5.3 0.8-14.6 4.4 5.4 1.4 0 16;4 5.8 5.6 0.9 +15 102.7 27.4 61.6 21.2. 142.2 42.7 68.2 19.6 45 123.9 35.3.2 17.3 98;9 28.0 53.5 15.3 80.0 23.6 38.9 11.4 66.2 18.2.4 8.9 Baseline VS. treatment (at 15 ) P < 0.01 P < 0.01 FSH SE FSH SE miulml miulml - 10.0 1.0 8;4 1.3-9.0 0.8 8.0 1.4-9.4 1.0 7.3 0.5 0 9.2 1.2 9.1 1.8 +15 17.1 2.7 16.9 4.6 20.8 3.0 21.3 5.9 45 23.4 3.3 21.6 5.4 21.6 3.6 25.0 4.7 21.4 2.8 20.6 4.9 19.4 2.6 19.9 4.6 Baseline VS. treatment (at 15 ) a Treatment NTvs. T

Vl. 32, N.2 ASSESSMENT OF PITUITARY FUNCTION IN HYPERPROLACTINEMIA 181 TABLE 5. l-dpa Challenge Test - - 150 180 - - 150 180 Prlactin 139 125 126 127 102 91 79 63 70 Baseline VS. treatment GH 0.80 0.71 0.76 0.76 3.69 6.41 3.76 1.78 0.93 Tumr (T) SE Prlactin SE 27 1276 703 24 1283 708 22 7 6 23 1188 639 25 1022 540 28 1051 3 16 898 520 8 938 857 8 910 8 a NT P < 0.02 (at 180 ) T P < 0.01 Tumr (T) SE GH SE 0.13 0.78 0.19 0.12 0.96 0.14 0.10 0.86 0.19 0.19 1.16 0.16 1. 5.00 4.00 3.76 3.58 2.27 2.49 5.54 2.77 1.00 3.43 1.33 0.17 1.70 0.70 Baseline NT vs. treatment Baseline T vs. treatment NT (at ) T P < 0.01 (at ) tin levels less than r equal t 50 are highly suggestive f pituitary tumr. The rle f hypcycidal ply tmgraphy is established as a standard methd f diagnsis f pitutiary lesins. All patients in ur series with psitive findings had pituitary tumrs demnstrated at surgery (that is, 42%). This figure is in accrd with rates reprted by ther investigatrs. It is apparent that the presence f pituitary tumrs and idipathic hyperprlactinemia results in changes in pituitary functin. We wuld agree with Kletzky et ap that elevatin f grwth hrmne is delayed fllwing insulin hypglycemia. Furthermre, we find a similar delay in crtisl elevatin. Likewise, there is a delay in grwth hrmne elevatin fllwing l-dpa treatment. Wiebe et ai.3 have suggested that patients with pituitary tumr fail t suppress with l-dpa treatment. Our data supprt this bservatin, althugh we find blunting with nntumr patients as well. Patients unifrmly had increased TSH levels fllwing TRF treatment, and this respnse did nt vary between nrmal patients with idipathic galactrrhea and tumr patients. Hwever, mst investigatrs agree that the release f prlactin is blunted. Furthermre, ur data agree with thse f Lachelin et al. l that blunting ccurs in bth patients with tumr and thse with hyperprlactinemia withut x-ray diagnsis f tumr (these patients were called "prbably tumr"). The respnse f varius patient grups t LRF stimulatin has prduced cnflicting data. We did nt find a significant difference in the baseline levels f FSH in tumr versus nntumr grups, nr did we find a significant difference in their respnse t LRF. Kletzky et ap and Lachelin et al. I reprted increased FSH release in tumr grups as cmpared with nrmal patients. This difference may be due t the fact that ur nntumr grup cannt be equated with a nrmal ppulatin. Our patients shwed a significant difference in baseline LH levels, and the respnse f LH t LRF was significantly less than that f the tumr ppulatin. This finding agrees with the data f Lachelin et al.,! wh demnstrated that patients with

182 BLACKWELL ET AL. August 1979 tumrs had a significantly smaller respnse than thse "prbably with tumr" r cntrls. In cnclusin, we prpse that there are cnsistently predictable changes that ccur in pituitary functin in the presence f pituitary tumrs. Hwever, we believe that serial prlactin levels and evaluatin f the abslute levels f prlactin in a patient's bld are mre useful fr the diagnsis f tumr. This, cupled with careful histry taking, physical exaatin, and hypcycidal ply tmgraphy, seems t be a simple and reasnably safe methd f rutinely evaluating patients with galactrrhea and/r amenrrhea. 2. Kletzky 0, Davajan V, Mishell D, Nclff J, Mims R, March C, Nakamura R: A sequential pituitary stimulatin test in nrmal subjects and in patients with amenrrheagalactrrhea with pituitary tumrs. J Clin Endcrinl Metab 45:631, 1977 3. Wiebe RH, Hammnd CB, Handwerger S: Prlactin-secreting pituitary micradenma: detectin "and evaluatin. Fertil Steril 29:282, 1978 4. Keye W, Chang J, Jaffe R: Prlactin secreting pituitary adenmas in wmen with amenrrhea r galactrrhea. Obstet Gynecl Survey 32:727,1977 5. Frantz A: Prlactin. NJM 298:201, 1978 6. Rakff J, Yen SSC: Chrnic anvulatin due t Chypthalamic-pituitary dysfunctin. In Reprductive Endcrinlgy, Edited by SSC Yen, R Jaffe. Philadelphia, WB Saunders C, 1978, p 354 REFERENCES 1. Lachelin G, Salim A, Yen SSC: Functinal delineatin f hyperprlactinemic-amenrrhea. J Clin Endcrinl Metab 44:1163, 1977