J. Endocrinol. Invest. 11: 57, 1988

COMMENT

Criteria for the cure of acromegaly: comparison between basal growth hormone and somatomedin C plasma concentrations in active and· non-active acromegalic patients

D. Giannella-Neto*l, B.L. Wajchenberg*, B.B. Mendonc;a*, S.F. Almeida*, M. Macchione*, and E.M. Spencer** *Hospital das Clinicas, University of Sao Paulo School of Medicine, 10000 Sao Paulo, Brazil, and **Laboratory of Growth & Development, Children's Hospital, San Francisco, CA 94118, USA

ABSTRACT. Fasting plasma growth hormone (GH) and somatomedin C (SmC) levels were compared as criteria for the cure of acromegaly in 7 untreated and 16 treated acromegalic patients studied 1 to 16 yr after pituitary surgery and/or radiotherapy. The patients without active disease presented a signifi­cant correlation between GH and SmC. Only when basal GH was lower than 2.5 ng/ml were SmC values within the normal range. The subjects with active acromegaly (both treated and untreated) presenting GH higher than 5 ng/ml did not show any correlation between GH and SmC levels.

INTRODUCTION The cure of acromegaly is very difficult to define, requir­Ing clinical and biochemical criteria such as: remission of clinical symptoms and glucose intolerance; plasma GH concentrations lower than 5 ng/ml; normal re­sponses to suppression and stimulation tests as ma­nifested by disappearance of paradoxical responses to TRH and dopaminergic drugs; and reappearance of the sleep-related rise of GH secretion (1). However, none of the above criteria seems to be definitive by itself. Plasma concentrations of somatomedin C (SmC) determined by radioimmunoassay has been shown to be a useful, convenient and reliable index to monitor therapy, mainly in those patients without elevated basal GH levels or with a normal suppressibility to oral glu­cose load, when a random serum GH level could not reflect the total 24-hour GH secretion (1-3). There is no agreement in the literature about the real plasma GH level that should be considered below which the cure of acromegaly can be claimed (4-7). Considering that SmC concentration reflects more ac­curately the activity of the disease, and multiple sam­pling of plasma for the 24 h secretion of GH is a very cumbersome procedure, we evaluated in this study the clinical value of basal GH plasma concentration as

1 Recipient of a Doctoral Fellowship from CNPq No.1 01748-82

Key-words: Growth hormone, somatomedin-C, acromegaly diagnosis, acromeg aly treatment, radioimmunoassay

Correspondence: Dr. Daniel Giannella-Neto. Diabetes &Adrenal Unit. Hospital das Clin,cas. PO Box 8091. Sllo Paulo. Brazil

Received October 3. 1986; accepted July 23. 1987

57

cure criteria in acromegaly as compared to SmG. For this purpose, G Hand SmC concentrations were de­termined in the plasma of 7 untreated and 16 previously treated acromegalic patients, using very sensitive and precise assays

MATERIALS AND METHODS

All patients studied were acromegalics classified into 3 groups depicted as follows (Table 1 ) Group A consisted of 7 clinical and biochemically ac­tive acromegalic untreated patients (4 men and 3 women, aged 17-47 yr) with persistently fasting basal GH concentrations above 5 ng/ml. Group B consisted of 1 man and 9 women aged 17 -73 yr, studied 1 to 16 yr after transsphenoidal micro­surgery and/ or radiotherapy, who had significant im­provement of the classical symptoms of active acromegaly (90ft tissue enlargement, sweating, pares­thesias, arthralgias and arterial hypertension), signifi­cant amelioration of glucose intolerance, reduction of insulin levels, and fasting plasma G H concentrations repeatedly below 5 ng/ml. Group C included 3 men and 3 women, aged 23-49 yr, clinically active acromegalic patients, previously treat­ed, presenting persistently fasting basal GH concentra­tions above 5 ng/ml. At the time of the study, the hypothyroid patients were on hormonal replacement. Poor nutritional status was ruled out by clinical criteria. Plasma PRL and GH concentrations were determined in all samples drawn after at least 1 h bed rest by double antibody RIA using the reagents commercially pro­vided by T ravenol-Genentech Diagnostics (Cambridge,

D. Gianne//a-Neio, BL Wajchenberg, BB Mendonr;a, et a/.

Table 1 - PRL, GH, SmC plasma concentrations and yr after therapy in 7 untreated clinically active acromegalic (Group A), 10 clmically inactive and 6 clmically active acromegalic patients previously treated (Groups Band C, respectively).

Sex Age PRL GH SmC Yr after (yr) (ng/ml) (ng/ml) (ng/ml) OP/RT

Group A

1 M 44 7.7 60.3 875.0 2 F 47 48.0 25.0 618.0 3 M 38 10.0 29.0 1018.0 4 F 37 10.6 105.5 939.0 5 M 35 5.0 13.1 1276.0 6 F 17 62.6 60.6 1370.0 7 M 45 7.0 272.5 1489.0

Mean 37.6 21.6 80.9 1083.6

SE 3.8 8.9 30.6 116.4

Group B

1 F 46 12.0 1.0 132.61 -/16 2 F 43 44.4 1.5 128.21 5/5 3 F 27 7.0 3.7 758.0 3/-4 M 34 5.0 1.9 196.71 3/-5 F 49 3.0 2.9 415.5 7/5 6 F 55 12.0 3.0 548.1 1/1 7 F 73 142.0 3.8 685.1 -/1 8 F 17 42.0 3.9 740.0 5/5 9 F 60 9.0 0.4 198.01 10/-

10 F 38 10.7 2.6 300.01 1/-

Mean 44.2 28.7 2.5 410.2

SE 5.2 13.4 0.4 80.0

Group C

1 M 23 176.0 25.0 366.9 1/-2 M 40 2.7 90.2 1894.0 3/-3 F 44 53.0 39.4 1746.0 3/3 4 F 34 104.0 153.7 1060.8 1/-5 F 49 5.0 28.0 501.0 6/62

6 M 49 31.3 535.7 1915.0 2/-

Mean 39.8 62.0 145.3 1246.3

SE 4.1 27.4 80.6 287.5

1 SmC plasma values within adult normal limit (71.8 - 340.7 ng/ml); 2Subsequent to two pituitary surgeries.

MA., USA) and Radioassay Systems Laboratories (Carson, CA., USA), respectively. Normal values ranged 50-25.0 ng/ml for plasma PRL and 0.5-5.0 ng/ml for plasma GH. The SmC RIA was based on an equilibrium protocol with several modifications in the method originally de­scribed by Lanes et al. (8). Plasma samples were ex­tracted with acid-ethanol to separate the binding pro­tein by a modification of the method of Oaughaday et al. (9). The recovery of SmC after extraction was about 96%. Purified .SmC was used for standards and for iodination using solid-phase lactoperoxidase beads according to the BioRad protocol (Richmond, USA). The SmC antiserum [prepared by Reber and Liske (10)] was used in a final concentration of 1 :22,000. The incubation was carried out at 4 C for 18 h and the free 1251-SM C was separated from bound by double anti-

58

body plus 6% polyethylene glycol precipitation. Sensi­tivity and 50% displacement in the assay were about 0.2 ng and 1.0 ng, respectively. The inter- and intraas­say variations were 12% and 15%, respectively. The 95% confidence intervals for 14 prepubertal normal children were 79.9-152,8 ng/ ml, for 16 intrapubertals 88.1-478.8 and for 29 normal adults 71.8-340.7 (unpub­lished data). The SmC mean plasma concentrations in groups A, B and C were statistically compared employing the un­paired Student's t test Exponential regression analysis was used to correlate the results obtained from GH and SmC.

RESULTS The mean ± SE PRL plasma concentration$ were 21.6 ± 8.9, 28.7 ± 13.4, and 62.0 ± 27.4 ng/ml in groups A,

770

660

:: 550 E ~ 440 c

SmC·91.1 r • 0.92 n. 10

0.53 GH II

P < 0.001

~ 3301-----'-----......,(" • u

~ 220 • I 10

o~~-~-~-~--L-~~~~~

o 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 GH (no I ml )

Fig. 1 - CorrelatIOn between basal plasma GH and SmC levels m 10 clinically mactive acromegalic patients previously treat­

ed (Group B).

B, and C, respectively. No significant differences were observed between the 3 groups. The mean ± SE GH plasma concentrations were 80.9 ± 30.6, 2.5 ± OA, and 145.3 ± 80.6 ng/ml in groups A, B, and C, respectively, being significantly lower in group B than in groups A and C (p < 0.05). However, no significant differences were observed in the mean levels between groups A and C (p> 0.05). The mean ± SE SmC plasma was significantly lower in group B (41 0.5 ±80.0 ng/ml) than in groups A (1 083.6 ±.116A, P < 0.001) and C (1246.3 ± 287.5, P > 0.05) with no significant differences between the last two. All patients from group A and patients no 3, 5, 6, 7 and 8 from group B presented SmC concentrations higher than the upper adult normal limit (340.7 ng/ml). A significant exponential correlation was observed be­tween GH and SmC plasma concentrations (r = 0.92; p < 0.001) only in group B (Fig. 1 ), but not in groups A (r = 0.53; p> 0.05) and C (r= 0.52; p> 0.05). This relation was expressed by the equation: SmC = 91.1 e053GH where, e = 2.718 From the regression line in Figure 1 we have obtained for the upper normal limit of SmC concentration (340.7 ng/ml) a plasma GH level correspondent to 2.5 ng/ml.

DISCUSSION The effectiveness of the surgical and actinic treat­ments in acromegaly is still difficult to evaluate. Al­though some authors have used many approaches to monitor the therapy, clinical and specific biochemical criteria are not definitive and cannot be analyzed alone. Some authors (4-6) have considered the GH plasma concentrations below 5 ng/ml as a satisfactory criter­ion, but the actual limits of the normal GH plasma concentration that is associated to clinical inactivity of acromegaly is difficult to define. The assessment of the integrated 24-h GH secretion, the GH response to TRH or after glucose load were suggested as criteria to

59

Somatomedin-C in acromegalics

evaluate the course of the disease more precis.ely than basal GH levels, but they do not seem to fare better (1 ). Although Wass et al. (2) stated that serum SmC con­centrations correlate better with clinical status than does serum GH, Stonesifer et al. (11) observed poor correlations between symptomatic response to surgi­cal therapy and SmC and also between the latter and GH. Five patients with elevated SmC levels in group B (2 of them had been studied 1 yr after'treatment) indicated that these patients are not cured in spite of their seem­ingly low GH level and apparent lack of clinical activity. Since SmC is what causes the actual pathology in acromegaly (12), this must be normal before cure can be claimed. Since their GH levels were higher than 2.9 ng/ml, it suggested that basal GH plasma levels must be lower than 2.9 ng/ml to consider cure of the dis­ease. Actually, the regression curve in Figure 1 indicat­ed that GH levels below 2.5 ng/ml correspond to a normal SmC. The one "low" value in group C could be considered high normal and correspond to the lowest GH value in that group. As Stonesifer et al. (11 ) and Clemmons et al. (12), we have not observed any significant correlation between SmC levels and fasting GH in plasma of active acromegalic patients (groups A and C). The described influence of PRL as cause of SmC generation (13) could be ruled out in our series as in ali groups there were patients with variable levels of PRL independent of their correspondent GH and SmC values. GH-dependency of SmC is shown by the highly signifi­cant difference between the mean concentrations of SmC in group B and groups A and C. This dependence could also be demonstrated by the significant correla­tion between GH and SmC plasma concentration found in group B. The lack of correlation observed in groups A and C could be explained by the more evident fluctuations of the elevated GH levels. Also, the fre­quent discrepancy observed between high levels of GH and SmC in active acromelagy suggests that sim­ilar levels of GH may have different biological activity at least as far as their capability of stimulating SmC pro­duction IS concerned. Divergence between the immu­noreactivity and the biological potency of GH has been firstly reported by Lewis et al. (14). Our data confirm the observation of Oppizzi et al. (15) Indicating the dependency of plasma SmC levels on plasma GH levels in acromegaly. Thus, with some pre­cautions, GH could be considered a helpful index of therapeutical effectiveness when its values are below 2.5 ngiml.

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Critical study of the growth hormone respons~ to dynam-

D. Gianne/la -Neto, BL Wajchenberg, B.B. Mendonr:;a, et al.

ic tests and the insul in growth factor assay in acromeg­aly after microsurgery. Cl in. Endocrinol. (Ox!.) 18. 541,1983.

2. Wass JAH., Clemmons D.R., Underwood L.E., Barrow I., Besser G.M., Van Wyk J.J. Changes in circulating somatomedin-C levels in bro­mocriptine treated acromegaly. Clin. Endocrinol. (Oxf.) 17. 369, 1982.

3. Rieu M , Girard F., Bricarie H.C. , Binoux M. The importance of insulin-like growth factor (somato­medin) measurements in the diagnosis and surveillance of acromegaly. J. Clin. Endocrinol. Metab. 55. 147, 1982.

4. Tucker H.S.G., Grubb S.R., Wigand JP., Watlington CO., Blackard W.C., Becker DP The treatment of acromegaly by transsphenoidal surgery. Arch. Intern. Med. 140: 795, 1980.

5. Ludecke D., Kautsky R., Saeger X, Schararder D. Selective removal of hypersecreting pituitary adeno­mas. An analysis of endocr ine function , operative and microscopical findings in 101 cases. Acta NeurochlL (Wien) 35. 27, 1976.

6. Laws JR , Piepgras DG, Randall RV, Abboud G.F. Neurosurgical management of acromegaly: results in 82 patients treated between 1972 and 1977. J. Neurosurg. 50. 454, 1979.

7. Spencer E.M. Anterior Pituitary & Somatomedins: " Somatomedins. In Greenspan F.S ., Forsham PH (Eds)., Basic and Clin­Ical Endocrinology. Lange Med ical Publicat ions, Los Altos, 1983, p. 98.

8. Lanes R., Plotn ick LP, Spencer EM, Daughaday WH, Kowarski AA Dwarfism associated with normal serum growth hor­mone and increased bioassayable, receptorassayable

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and immunoassayable somatomedin. J. Clin. Endocrlnol. Metab. 50. 465, 1980.

9. Daughaday WH, Ward A.P ., Goldberg A.C., Triverd l B, Kapadia M Characterization of somatomedin binding human serum by ultracentrifugation and gel filtrat ion .. J. Clin. Endocrinol. Metab. 55. 916, 1982.

10 Reber K, Liske R. Rad ioimmunoassay for non-suppressible insulin-like acliv ity. Horm. Res. 7. 201, 1976.

11. Stonesifer LD, Jordan R.M., Kohler P.O. Somatomedin C in treated acromegaly: Poor correlation with growth hormone and clinical response. J. Clin. Endocrinol. Metab. 53. 921, 1981.

12. Clemmons DR., Van Wyk JJ, Ridgway EG, Kliman B, Kjellberg RH, Underwood LE Evaluation of acromegaly by radioimmunoassay of so­matomedln C N. Engl. J. Med. 301. 1138, 1979.

13. Clemmons DR, Underwood L.E., Ridgway EC , Kliman B, Van Wyk J.J Hyperprolactinemia is associated with increased im­munoreactive somatomedin C in hypopitu itar ism. J. Clin. Endocrinol. Metab. 52. 731, 1981.

14. Lewis J.J ., Dunn JT, Bonewald L.F., Seavy BK, Vander­laan WP A naturally occurring structural variant of human growth hormone. J. BioI. Chem. 253. 2679, 1978.

15. OppiZZI G, Petroncini M.M., Dallabonzana D, COZZI R , Verde G , Chiodini PG, Liuzzi A. Relationship between somatomedin C and growth hor­mone level s In acromegaly Basal and dynamic evalua­tion. J. Clin. Endocrinol. Metab. 63. 1348, 1986.