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Sellar reconstitution and serum levels of growth hormone in acromegaly before and after pituitary implant
Clin. RadioL (1971) 22, 502-506
SELLAR RECONSTITUTION AND SERUM LEVELS OF GROWTH HORMONE IN ACROMEGALY BEFORE AND AFTER PITUITARY IMPLANT* M. S. F. McLACHLAN, A. D. WRIGHT, F. H. DOYLE and T. RUSSELL FRASER
Departments of Diagnostic Radiology and Medicine, Hammersrnith Hospital and Royal Postgraduate Medical School, London, W.12 Radiographs of the pituitary fossa of 35 acromegalic patients have been studied for evidence of sellar reconstitution after treatment by pituitary implant. Partial reconstitution of the sella was demonstrated in 20 % of patients. The mean lateral area of fossae which showed reconstitution was similar to that of fossae which were unchanged. Patients in whom sellar reconstitution occurred had significantly higher serum levels of growth hormone before treatment, and significantly greater reductions in growth hormone as a result of implant. It is postulated that these patients had more active, cellular pituitary tumours which responded more completely to irradiation than those patients whose sellae showed no change after implantation.
INTRODUCTION RADIOTHERAPY or surgical treatment of pituitary tumours may lead to partial reconstitution of the pituitary fossa (Holm, 1943; Hurxthal et al., 1949; Unger and Roswit, 1959; Radberg, 1963; Jefferson and Lewtas, 1964; Perria et aI., 1966). Radberg (1963). presumed that sellar reconstitution depended on the completeness of removal of tumour. We have examined a group of acromegalic patients for radiographic evidence of sellar reconstitution after pituitary implant. Serum growth hormone levels before and after implant have been related to bony reconstitution of the sella.
METHODS Thirty-five patients aged 27 to 73 years (mean 54 years) were studied. Twenty were male, 15 female. All had obvious clinical features of acromegaly and were treated by pituitary implant. Rods of 198 Au or 90 Y were implanted to deliver an estimated dose of 20,000 rads to the periphery of the gland. Mean duration of follow-up after implant was 3 years (range 1-8~- years). Patients who had been followed for less than one year or who had received previous radiotherapy to the pituitary were excluded. Sellae were examined serially for evidence of change. Lateral radiographs of the skull, and in
most patients, additional coned lateral radiographs of the sella were obtained immediately before implant and at intervals of approximately one year thereafter. Sellar reconstitution was judged by the criteria of increased thickness and density of bony contour and, in some instances, reduction in sellar size (Radberg, 1963; Jefferson and Lewtas, 1964). Because apparent changes in a sella can be produced by differences in radiographic positioning and centering and in exposure factors, strict standards for determining sellar reconstitution were applied. 'Changes' apparent on only one post-implant lateral radiograph were not accepted. Evidence of reconstitution was obtained on at least two postimplant lateral films. Further confirmation from radiographs in P.A. and Towne's projections was obtained in some patients. In 25 out of the total of 35 patients, an estimate of tumour size before implant was obtained from the maximum sellar area measured from lateral tomograms of the sella (Wright et al., 1969). In these 25 patients, all of whom were treated by 90 Y implant, serum levels of growth hormone were measured by radioimmunoassay (Hartog et al., 1964). Mean levels of growth hormone were determined during glucose tolerance tests before implant and approximately one to two years (average 19 months) after implant.
* Based on material presented at the Annual Meeting of RESULTS the Facultyof Radiologistsin London, 19th and 20th June, Seven of the 35 patients (20 %) showed some bony 1970. 502
SELLAR RECONSTITUTION
A N D S E R U M LEVELS OF G R O W T H
HORMONE
503
FIG. 1 FIG. l--Lateral radiograph of the pituitary fossa of a 59 year-old female patient (A) before and (B) after pituitary implant of rods of 90Y. FIG. I(A) shows thinning of the dorsum and posterior part of the floor. In FrG. I(B) the sella is smaller and shows increased thickness and density of its outline, most marked posteriorly. Serum growth hormone level fell from 117-27 ng/ml.
reconstitution of the sella (Figs. 1 and 2). This was evident at times varying from 16 months to 4 years (mean 2 years) after implant. Six were male, one female. The mean age (52 years) was similar to that for the whole group (54 years). The mean period of follow-up (3½ years) did not differ significantly from that for the whole group (3 years). No patient showed progression of sellar destruction. Five of the 25 patients studied in more detail showed some sellar reconstitution. The percentage reduction in serum growth hormone levels as a result of implant was noticeably greater in the 5 who showed sellar reconstitution (Fig. 3). Mean measurements of growth hormone levels in the two groups are expressed on a log scale in Fig. 4. Mean initial level of growth hormone was significantly higher (p < 0.02) and mean fall in growth hormone level significantly greater (p<0.02) in the 5 patients with sellar reconstitution. The means of maximum lateral sellar area were not different in the two groups (Fig. 5). DISCUSSION In the 7 patients whose sellae showed some bony reconstitution, the thickness and density of the dorsum and floor increased. These features were noted also by Radberg (1963) and Jefferson and Lewtas (1964). We saw no example of 'crumpling' and shortening of the dorsum described by Jefferson
and Lewtas (1964). Like Radberg (1963) and Jefferson and Lewtas (1964), we found no evidence of progression of sellar destruction in any patient after treatment. Unlike Holm (1943), we never detected intrasellar calcification after treatment. In none of the patients in our series was the fossa restored to normal. Only 2 0 ~ of the fossae in the present series showed evidence of reconstitution. This percentage is lower than that quoted by other authors (Holm, 1943; Hurxthal et al., 1949; Radberg, 1963; Jefferson and Lewtas, 1964; Perria et al., 1966). In these previously published series, treatment and/or type of tumour varied. In the present series, all patients were acromegalic and treatment was carefully planned to give a 20,000 rad peripheral dose to the pituitary fossa. In the 25 patients studied in greater detail, the same isotope was used. We accepted evidence of sellar reconstitution onJy if it was apparent on at least two lateral radiographs obtained either at the same time post-implant, or on consecutive follow-up studies. We may have underestimated the frequency of sellar change. We made no attempt to compare sellar dimensions before and after implant, as we regard measurements from plain films as insufficiently accurate in the presence of sellar erosion. Though tomography provides a better estimate of sellar size and is invaluable in the initial analysis, we have not assessed serial tomograms in this
504
CLINICAL
RADIOLOGY
FIG. 2 Lateral radiograph of the pituitary fossa of a 55 year-old male patient (A) before and (B) after pituitary implant of rods of 90Y. In Fla. 2(A) slight thinning of the dorsum is demonstrated. Fro. 2(B) shows increased thickness and density of the floor and dorsum, the features of reconstitution seen most commonly in this series. Serum growth hormone level fell from 192-3 ng/ml.
400
Growth Hormone
SELLAR RECONSTITUTION
NO SELLAR RECONSTITUTION
250
I~l)
200
150
100
50
Before implant
After implant
Before implant
After implant
FIG. 3
Serum levels of growth hormone before and after pituitary implant. Mean percentage reduction was 4 times greater in the patients whose sellae showed evidence of bony reconstitution.
SELLAR RECONSTITUTION
AND
S E R U M L E V E L S OF G R O W T H
HORMONE
sellar reconstitution l---I no sellar reconstitution ~o
[]
sellar rec0nstituti0n
[]
no sellar reconstitution
d~
3"0
E
3.0
o~
o r-
s. caJ
2'0 (::: .m
,,,
t~l
1.0
1.0
.=_
A
0
ca,
B
p< 0"02
~ 'l p (
0-02
FIG. 4 Growth hormone levels expressed as logarithms to the base 10. Shaded columns represent patients showing sellar reconstitution. Before implant (A), mean serum level of growth hormone was significantly higher in patients whose sellae subsequently showed evidence of reconstitution. After implant (B), mean fall in growth hormone was significantly greater in this group.
SELLAR
N O SELLAR
RECONSTITUTK)N
RECONSTITUTION
400, MAXFMUM LATERAL SIELLARA R | A ' Imm 2 ) 350,
!
300,
250,
FIG. 5 Maximum lateral sellar area before implant. The means in each group are almost identical.
505
506
CLINICAL RADIOLOGY
study because of the difficulty of repeating cuts reduction in growth hormone levels alter implant at identical levels. We did not apply the extensive was more than 4 times greater in this group. tomographic examinations in several projections This suggests that these patients had more active, apparently employed serially by Radberg (1963). cellular tumours which were more sensitive to the Our method of follow-up is similar to that used effects of irradiation. On our evidence, acromegalic by Jefferson and Lewtas (1964). Most of the patients with high serum levels of growth hormone quoted series consisted largely or exclusively of relative to maximum lateral area of the sella are patients treated by operative hypophysectomy. more likely to show a better response to pituitary Radberg (1963) reported reduction in sellar implant in terms of reduction of growth hormone size with thickening and sclerosis of its bony secretion and reeonstitution of the sella. contours after hypophysectomy in patients without Aeknowledgements.--We are grateful to Miss Nicola pituitary disease. Some of the changes reported after operative hypophysectomy may be due in Watson and Miss Susan Russell for their help. The radioimmunoassay of growth hormone was supported by a part to bony reaction to surgical trauma. grant from the Medical Research Council. Our results suggest that reconstitution o f the sella does not depend on the age of the patient. REFERENCES The long time-lag after implant before sellar changes were manifest is worthy of comment. HARTOG, M., GAAFAR, M. A., MEISSER,B. & FRASER, R. (1964). lmmunoassay of Serum Growth Hormone in The earliest change detected by us was 16 months Acromegalic Patients. British Medical Journal 2, after treatment. In one patient, partial sellar 1229-1232. reconstitution occurred 4 years after implant, HOLM,O. F. (1943). Uber Heilungsph~inomene in der Sella Turcica nach Behandlung yon intrasellfiren Tumoren. although intermediate follow-up films had shown Acta Radiologica, 24, 495-510. no change. Maximum sellar area measured on lateral HURXTHAL,L. M., HARE,H. F., HORRAX,G. & POPPEN,J. L. (1949). The Treatment ofAeromegaly. JournalofClinical tomograms was not different in the two groups. Endocrinology, 9, 126-148. Initial tumour size is therefore unlikely to be a JEFFERSON,A. & LEWTAS,N. (1964). Radiological Signs in the Long-term Management of Treated Chromophobe factor influencing subsequent reconstitution of the Pituitary Adenoraata. Acta Neurochirurgica, 2, 694-715. sella. In untreated acromegaly, maximum lateral PERRiA, C., GIOVANELLbM. & DE DONS*TO, E. (1966). area of the sella is moderately correlated Le modifieazioni della sella turcica negli adenomi impofi(r = 0-47; p < 0.001) with serum levels of growth sari dopo terapia chirurgiea e/o radiante. Atti-Accademia Medica Lombarda, 21, 568-580. hormone (Wright et al., 1969). In the present series, however, mean serum level of growth RADBERG,C. (1963). Appearance of Sella Tureica following Trans-sphenoidal Hypophysectomy. Aeta Radiologica hormone before implant was over twice as high in Diagnosis, 1, 140-151. patients showing reconstitution of the sella. UNGER, S. M. & ROSWIT, B. (5959). Restoration of the Thus, although mean size of the pituitary tumour Sella Turcica after Treatment of Pituitary Adenomas. American Journal of Roentgenology, 81, 967-971. before implant appeared to be the same in both groups, mean serum level of growth hormone WRIGHT, A. D., MCLACI4LAN,M. S. F., DOYLE,F. H. & FRASER, T. R. (1969). Serum Growth Hormone Levels was much higher in those who subsequently showed and Size of Pituitary Tumour in Untreated Acromegaly. sellar reconstitution. Furthermore, the percentage British Medical Journal 4, 582-584.
SELLAR RECONSTITUTION AND SERUM LEVELS OF GROWTH HORMONE IN ACROMEGALY BEFORE AND AFTER PITUITARY IMPLANT* M. S. F. McLACHLAN, A. D. WRIGHT, F. H. DOYLE and T. RUSSELL FRASER
Departments of Diagnostic Radiology and Medicine, Hammersrnith Hospital and Royal Postgraduate Medical School, London, W.12 Radiographs of the pituitary fossa of 35 acromegalic patients have been studied for evidence of sellar reconstitution after treatment by pituitary implant. Partial reconstitution of the sella was demonstrated in 20 % of patients. The mean lateral area of fossae which showed reconstitution was similar to that of fossae which were unchanged. Patients in whom sellar reconstitution occurred had significantly higher serum levels of growth hormone before treatment, and significantly greater reductions in growth hormone as a result of implant. It is postulated that these patients had more active, cellular pituitary tumours which responded more completely to irradiation than those patients whose sellae showed no change after implantation.
INTRODUCTION RADIOTHERAPY or surgical treatment of pituitary tumours may lead to partial reconstitution of the pituitary fossa (Holm, 1943; Hurxthal et al., 1949; Unger and Roswit, 1959; Radberg, 1963; Jefferson and Lewtas, 1964; Perria et aI., 1966). Radberg (1963). presumed that sellar reconstitution depended on the completeness of removal of tumour. We have examined a group of acromegalic patients for radiographic evidence of sellar reconstitution after pituitary implant. Serum growth hormone levels before and after implant have been related to bony reconstitution of the sella.
METHODS Thirty-five patients aged 27 to 73 years (mean 54 years) were studied. Twenty were male, 15 female. All had obvious clinical features of acromegaly and were treated by pituitary implant. Rods of 198 Au or 90 Y were implanted to deliver an estimated dose of 20,000 rads to the periphery of the gland. Mean duration of follow-up after implant was 3 years (range 1-8~- years). Patients who had been followed for less than one year or who had received previous radiotherapy to the pituitary were excluded. Sellae were examined serially for evidence of change. Lateral radiographs of the skull, and in
most patients, additional coned lateral radiographs of the sella were obtained immediately before implant and at intervals of approximately one year thereafter. Sellar reconstitution was judged by the criteria of increased thickness and density of bony contour and, in some instances, reduction in sellar size (Radberg, 1963; Jefferson and Lewtas, 1964). Because apparent changes in a sella can be produced by differences in radiographic positioning and centering and in exposure factors, strict standards for determining sellar reconstitution were applied. 'Changes' apparent on only one post-implant lateral radiograph were not accepted. Evidence of reconstitution was obtained on at least two postimplant lateral films. Further confirmation from radiographs in P.A. and Towne's projections was obtained in some patients. In 25 out of the total of 35 patients, an estimate of tumour size before implant was obtained from the maximum sellar area measured from lateral tomograms of the sella (Wright et al., 1969). In these 25 patients, all of whom were treated by 90 Y implant, serum levels of growth hormone were measured by radioimmunoassay (Hartog et al., 1964). Mean levels of growth hormone were determined during glucose tolerance tests before implant and approximately one to two years (average 19 months) after implant.
* Based on material presented at the Annual Meeting of RESULTS the Facultyof Radiologistsin London, 19th and 20th June, Seven of the 35 patients (20 %) showed some bony 1970. 502
SELLAR RECONSTITUTION
A N D S E R U M LEVELS OF G R O W T H
HORMONE
503
FIG. 1 FIG. l--Lateral radiograph of the pituitary fossa of a 59 year-old female patient (A) before and (B) after pituitary implant of rods of 90Y. FIG. I(A) shows thinning of the dorsum and posterior part of the floor. In FrG. I(B) the sella is smaller and shows increased thickness and density of its outline, most marked posteriorly. Serum growth hormone level fell from 117-27 ng/ml.
reconstitution of the sella (Figs. 1 and 2). This was evident at times varying from 16 months to 4 years (mean 2 years) after implant. Six were male, one female. The mean age (52 years) was similar to that for the whole group (54 years). The mean period of follow-up (3½ years) did not differ significantly from that for the whole group (3 years). No patient showed progression of sellar destruction. Five of the 25 patients studied in more detail showed some sellar reconstitution. The percentage reduction in serum growth hormone levels as a result of implant was noticeably greater in the 5 who showed sellar reconstitution (Fig. 3). Mean measurements of growth hormone levels in the two groups are expressed on a log scale in Fig. 4. Mean initial level of growth hormone was significantly higher (p < 0.02) and mean fall in growth hormone level significantly greater (p<0.02) in the 5 patients with sellar reconstitution. The means of maximum lateral sellar area were not different in the two groups (Fig. 5). DISCUSSION In the 7 patients whose sellae showed some bony reconstitution, the thickness and density of the dorsum and floor increased. These features were noted also by Radberg (1963) and Jefferson and Lewtas (1964). We saw no example of 'crumpling' and shortening of the dorsum described by Jefferson
and Lewtas (1964). Like Radberg (1963) and Jefferson and Lewtas (1964), we found no evidence of progression of sellar destruction in any patient after treatment. Unlike Holm (1943), we never detected intrasellar calcification after treatment. In none of the patients in our series was the fossa restored to normal. Only 2 0 ~ of the fossae in the present series showed evidence of reconstitution. This percentage is lower than that quoted by other authors (Holm, 1943; Hurxthal et al., 1949; Radberg, 1963; Jefferson and Lewtas, 1964; Perria et al., 1966). In these previously published series, treatment and/or type of tumour varied. In the present series, all patients were acromegalic and treatment was carefully planned to give a 20,000 rad peripheral dose to the pituitary fossa. In the 25 patients studied in greater detail, the same isotope was used. We accepted evidence of sellar reconstitution onJy if it was apparent on at least two lateral radiographs obtained either at the same time post-implant, or on consecutive follow-up studies. We may have underestimated the frequency of sellar change. We made no attempt to compare sellar dimensions before and after implant, as we regard measurements from plain films as insufficiently accurate in the presence of sellar erosion. Though tomography provides a better estimate of sellar size and is invaluable in the initial analysis, we have not assessed serial tomograms in this
504
CLINICAL
RADIOLOGY
FIG. 2 Lateral radiograph of the pituitary fossa of a 55 year-old male patient (A) before and (B) after pituitary implant of rods of 90Y. In Fla. 2(A) slight thinning of the dorsum is demonstrated. Fro. 2(B) shows increased thickness and density of the floor and dorsum, the features of reconstitution seen most commonly in this series. Serum growth hormone level fell from 192-3 ng/ml.
400
Growth Hormone
SELLAR RECONSTITUTION
NO SELLAR RECONSTITUTION
250
I~l)
200
150
100
50
Before implant
After implant
Before implant
After implant
FIG. 3
Serum levels of growth hormone before and after pituitary implant. Mean percentage reduction was 4 times greater in the patients whose sellae showed evidence of bony reconstitution.
SELLAR RECONSTITUTION
AND
S E R U M L E V E L S OF G R O W T H
HORMONE
sellar reconstitution l---I no sellar reconstitution ~o
[]
sellar rec0nstituti0n
[]
no sellar reconstitution
d~
3"0
E
3.0
o~
o r-
s. caJ
2'0 (::: .m
,,,
t~l
1.0
1.0
.=_
A
0
ca,
B
p< 0"02
~ 'l p (
0-02
FIG. 4 Growth hormone levels expressed as logarithms to the base 10. Shaded columns represent patients showing sellar reconstitution. Before implant (A), mean serum level of growth hormone was significantly higher in patients whose sellae subsequently showed evidence of reconstitution. After implant (B), mean fall in growth hormone was significantly greater in this group.
SELLAR
N O SELLAR
RECONSTITUTK)N
RECONSTITUTION
400, MAXFMUM LATERAL SIELLARA R | A ' Imm 2 ) 350,
!
300,
250,
FIG. 5 Maximum lateral sellar area before implant. The means in each group are almost identical.
505
506
CLINICAL RADIOLOGY
study because of the difficulty of repeating cuts reduction in growth hormone levels alter implant at identical levels. We did not apply the extensive was more than 4 times greater in this group. tomographic examinations in several projections This suggests that these patients had more active, apparently employed serially by Radberg (1963). cellular tumours which were more sensitive to the Our method of follow-up is similar to that used effects of irradiation. On our evidence, acromegalic by Jefferson and Lewtas (1964). Most of the patients with high serum levels of growth hormone quoted series consisted largely or exclusively of relative to maximum lateral area of the sella are patients treated by operative hypophysectomy. more likely to show a better response to pituitary Radberg (1963) reported reduction in sellar implant in terms of reduction of growth hormone size with thickening and sclerosis of its bony secretion and reeonstitution of the sella. contours after hypophysectomy in patients without Aeknowledgements.--We are grateful to Miss Nicola pituitary disease. Some of the changes reported after operative hypophysectomy may be due in Watson and Miss Susan Russell for their help. The radioimmunoassay of growth hormone was supported by a part to bony reaction to surgical trauma. grant from the Medical Research Council. Our results suggest that reconstitution o f the sella does not depend on the age of the patient. REFERENCES The long time-lag after implant before sellar changes were manifest is worthy of comment. HARTOG, M., GAAFAR, M. A., MEISSER,B. & FRASER, R. (1964). lmmunoassay of Serum Growth Hormone in The earliest change detected by us was 16 months Acromegalic Patients. British Medical Journal 2, after treatment. In one patient, partial sellar 1229-1232. reconstitution occurred 4 years after implant, HOLM,O. F. (1943). Uber Heilungsph~inomene in der Sella Turcica nach Behandlung yon intrasellfiren Tumoren. although intermediate follow-up films had shown Acta Radiologica, 24, 495-510. no change. Maximum sellar area measured on lateral HURXTHAL,L. M., HARE,H. F., HORRAX,G. & POPPEN,J. L. (1949). The Treatment ofAeromegaly. JournalofClinical tomograms was not different in the two groups. Endocrinology, 9, 126-148. Initial tumour size is therefore unlikely to be a JEFFERSON,A. & LEWTAS,N. (1964). Radiological Signs in the Long-term Management of Treated Chromophobe factor influencing subsequent reconstitution of the Pituitary Adenoraata. Acta Neurochirurgica, 2, 694-715. sella. In untreated acromegaly, maximum lateral PERRiA, C., GIOVANELLbM. & DE DONS*TO, E. (1966). area of the sella is moderately correlated Le modifieazioni della sella turcica negli adenomi impofi(r = 0-47; p < 0.001) with serum levels of growth sari dopo terapia chirurgiea e/o radiante. Atti-Accademia Medica Lombarda, 21, 568-580. hormone (Wright et al., 1969). In the present series, however, mean serum level of growth RADBERG,C. (1963). Appearance of Sella Tureica following Trans-sphenoidal Hypophysectomy. Aeta Radiologica hormone before implant was over twice as high in Diagnosis, 1, 140-151. patients showing reconstitution of the sella. UNGER, S. M. & ROSWIT, B. (5959). Restoration of the Thus, although mean size of the pituitary tumour Sella Turcica after Treatment of Pituitary Adenomas. American Journal of Roentgenology, 81, 967-971. before implant appeared to be the same in both groups, mean serum level of growth hormone WRIGHT, A. D., MCLACI4LAN,M. S. F., DOYLE,F. H. & FRASER, T. R. (1969). Serum Growth Hormone Levels was much higher in those who subsequently showed and Size of Pituitary Tumour in Untreated Acromegaly. sellar reconstitution. Furthermore, the percentage British Medical Journal 4, 582-584.