Development of Acromegaly in Patients with Prolactinomas

European Journal of Endocrinology (2003) 149 17–22 ISSN 0804-4643

CLINICAL STUDY Development of acromegaly in patients with prolactinomas Marianne Andersen, Casper Hagen, Jan Frystyk1, Henrik Daa Schroeder2 and Claus Hagen Department of Endocrinology, Odense University Hospital, 5000 Odense C, Denmark, 1Medical Research Laboratory, Institute of Experimental and Clinical Research, University Hospital of Aarhus, DK-8000 Aarhus, Denmark and 2 Department of Pathology, Odense University Hospital, Denmark (Correspondence should be addressed to Marianne Andersen; Email: [email protected])

Abstract Objectives: Patients with prolactinomas and patients with acromegaly often have heterogenous adenomas. In this study we have focused on patients with prolactinomas who developed acromegaly and acromegalic patients with hyperprolactinaemia. Our hypothesis is that some patients with hyperprolactinaemia may develop clinical acromegaly. Methods: We have included patients examined at department M, Odense University Hospital between 1996 and 2001. Seventy-eight patients with prolactinomas, 65 females and 13 males, with a median age (range) of 30 years (14–74) and 47 years (20–66), respectively, were included in the study. Results: In females and males the median prolactin (PRL) levels were 90 mg/l (27–4700; normal values (NV) #23) and 1075 mg/l (24–6500; NV #14), respectively. The PRL levels were significantly higher in males compared with females (P , 0.002). Fifty-nine patients with acromegaly, 24 females and 35 males, with a median age (range) of 45 years (24–70) and 53 years (19–70), respectively, were included. Seven of the 24 females had hyperprolactinaemia, with PRL levels of 90 mg/l (27– 494). Thirteen of the 35 males had hyperprolactinaemia with PRL levels of 47 mg/l (17–251). Three females with prolactinomas developed acromegaly clinically and biochemically. These patients had a normal low GH level and/or a normal IGF-I level at first diagnosis. Conclusions: Our findings suggest that there is a common group of patients with a pituitary adenoma who secrete PRL and GH unsynchronously. Some of these patients have clinical acromegaly at diagnosis and some patients diagnosed as prolactinomas will develop acromegaly. We suggest an annual IGF-I measurement as a screening test.

European Journal of Endocrinology 149 17–22

Introduction agonists suppressed GH secretion more efﬁciently in acromegalic patients with hyperprolactinaemia It is well known that hyperprolactinaemia is found in compared with those with normoprolactinaemia (8). about 30–40% of acromegalic patients (1). In some Determination of serum insulin-like growth factor acromegalic patients or patients with elevated prolactin (IGF)-I levels may prove to be useful as a screening (PRL) levels without acromegaly, the increased PRL tool for adenomatous GH secretion in patients with levels may be a result of anatomical or functional hypo- prolactinomas (9). Circulating IGF-I has a half-life of thalamic–pituitary disconnection, but the existence of several hours and originates in the liver, although it mixed growth hormone (GH)/PRL adenomas has been is produced in other tissues as well (10). GH is the demonstrated (2). In human fetal (3) and adult (4) major determinant of circulating IGF-I levels and it is pituitaries it has been reported that GH and PRL can through IGF-I that most, though not all, GH-mediated be stored and secreted by the same normal pituitary actions occur (9). cells. These mammosomatotroph cells account for The consensus on the diagnosis of acromegaly was 25–50% of all cells in human pituitaries (4). It has published recently (11). However, the development of been suggested that mammosomatotroph cells acromegaly clinically and biochemically is probably a comprise a signiﬁcant portion of the cell population in continuum from normal biochemistry to the full clini- pituitary adenomas from acromegalic patients (3–6). cal picture (12). We wanted to test the hypothesis We have previously reported that octreotide treatment that hypersecretion of PRL and GH may develop and for 4 weeks normalised PRL levels in patients with acro- appear unsynchronously and therefore some patients megaly and hyperprolactinaemia (7). In accordance with hyperprolactinaemia may develop acromegaly. In with these results treatment with dopamine-D2 this study we have studied patients with prolactinomas

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Downloaded from Bioscientifica.com at 10/01/2021 10:26:23AM via free access 18 M Andersen and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 149 and we have included patients with acromegaly for staining was performed as combined Invision and comparison of age, sex and PRL levels. two layer alkaline phosphatase detection techniques (DAKO). Materials and methods Acromegaly Prolactinoma Fifty-nine patients with acromegaly, 24 females and During the last 5 years we have routinely screened for 35 males, with a median age (min-max) of 46 years GH hypersecretion in most patients with prolactinomas (24–70) and 53 years (19–70) respectively were using determinations of serum IGF-I levels. We have included. The mean age for all patients was 47 years. included all patients examined at department M, All patients had active acromegaly in accordance Odense University Hospital between 1996 and 2001. with the consensus report (11). At diagnosis, 12 out Seventy-eight patients with prolactinomas, 65 females of 24 females and 20 out of 35 males had macroadeno- and 13 males, with a median age (min-max) of 30 mas. An adenoma could not be visualised by MR scans years (14–74) and 47 years (20–66), respectively in three patients (two males and one female). MR scans were included in the study. No patient had clinical were carried out in 26 patients and CT scans were used symptoms of GH-, adrenocorticotrophin (ACTH)- or in 33 patients. IGF-I levels were measured in 48 out of thyrotrophin (TSH)-hypersecretion - all patients had 59 patients at first diagnosis. normal TSH levels. No patient had symptoms or biochemical evidence of other causes of hyperprolactinae- Biochemical analysis mia. No patient was taking any medication known to stimulate PRL. In 51/78 patients we had serum IGF-I Prolactin was determined using an immunofluoro- measurements at diagnosis. In a further seven patients metric assay (Delfia, Wallac Oy, Turko, Finland). The we had GH measurements. Magnetic resonance (MR) intra-assay coefficients of variation for PRL were 2.4% scans were carried out in 52 patients and computed at 7 mg/l and 2.5% at 20 mg/l. The maximal range tomography (CT) scans were used in 26 patients. At values for females and males are 23 mg/l and 14 mg/l, diagnosis 19 out of 65 females had macroadenomas respectively. (.10 mm), and 37 patients had microadenomas. An Serum IGF-I was measured after extraction with adenoma could not be visualized in nine patients (six HCl/ethanol (30 ml serum in 750 ml). After centrifu- MR scans and three CT scans). Ten out of 13 males gation the supernatant was further diluted 1:40 in had macroadenomas, three patients had microadeno- assay buffer. IGF-I was then determined using an mas. In patients that developed elevated IGF-I levels, immunoflurometric sandwich assay with two mono- an oral glucose tolerance test (OGTT) was performed. clonal antibodies following the Delfia principle and In one patient (number 7) a random GH level was using an AutoDelfia reader (Wallac Oy). The sensitivity 0.29 mU/l and no OGTT was performed. Eight out of limit was 2.5 ng/l. Intra- and interassay coefficients of 65 females were treated with oestradiol and 45 patients variation were lower than 1.9% and 8.6% respectively. were treated with a dopamine-D2 agonist. Pituitary The 97.5 percentiles, þ2 S.D., and (the 95% confidence surgery was performed in three patients (Table 1), intervals (CI) for the percentiles) for IGF-I according to one of these patients had surgery before the develop- age were: ,29 years 382 mg/l (418 mg/l); 30–39 years ment of acromegaly (patient no. 2). 257 mg/l (273 mg/l); 40–49 years 239 mg/l (256 mg/l); Paraffin sections, 4 mm thick, were stained with the 50–59 years 202 mg/l (220 mg/l); and $60 years Invision technique for visualisation of human (h) GH 201 mg/l (219 mg/l). and PRL (primary antibodies: polyclonal anti-hGH GH levels were determined by an immunofluoro- (DAKO, Copenhagen, Denmark) and monoclonal anti- metric assay (Delfia, Wallac Oy). The level of detection PRL (NCL-Pro, Novocastra, Newcastle, UK)). Double for the Delfia assay was 0.03 mU/l. The intra-assay

Table 1 Parameters for the three patients who developed acromegaly.

At ﬁrst diagnosis At last visit

Age Follow up PRL IGF-I GH PRL IGF-I GH Micro or Immunohisto- Patient no. Sex (years) (months)a (mg/l) (mg/l) (mU/l) (mg/l) (mg/l) (mU/l) macro chemistry

1 F 35 60 400 271 0.6 45* 803 32 G Macro GH 2 F 49 29 790 162 5 328* 819 4.8 G Macro PRL§ 3 F 39 40 196 270 ND 44* 383 18 G Micro PRL, GH aTime until second diagnosis; *dopamine-D2-agonist therapy; G, nadir GH levels during an OGTT; ND, not done; § the operation was after the ﬁrst diagnosis. No surgery the 2nd time. Signiﬁcantly elevated IGF-I values are written in bold.

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Downloaded from Bioscientifica.com at 10/01/2021 10:26:23AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 149 Development of acromegaly 19 coefficients of variation for GH were 7% at 0.5 mU/l and normalised during treatment (Fig. 3). None of the 3% at 18 mU/l. three patients who developed acromegaly and/or elevated IGF-I levels received octreotide before the diagnosis of acromegaly was established clinically and biochemi- Statistical analyses cally. In two tumours only one of the antigens was Data are presented for each individual and as present in the available material, and in the third the median (range) or mean^S.E.M.; P values less hGH and prolactin were found in separate cell popu- than 5% were considered statistically significant. The lations (Table 1). Wilcoxon signed rank test was used for testing paired The females with prolactinomas were significantly differences, and the Mann–Whitney U test was used younger than the males (P , 0.006). for comparing differences between two groups. IGF-I An additional five patients had significantly elevated levels above the 95% CI for the 97.5 percentile were IGF-I levels (Table 2). Two of these patients had a GH considered significantly increased. The ‘last visit’ was nadir .1 mU/l during an OGTT (patients 4 and 6) with- the visit where an increased IGF-I was recorded for out dopamine-D2 agonist therapy (Table 2). These five the first time. patients had no symptoms or signs of acromegaly.

Results Acromegaly Prolactinoma The mean (min-max) IGF-I level at diagnosis in 48 patients was 730 mg/l (268–1753) (Fig. 2). Seven The median (range) PRL levels in all patients were out of 24 females had hyperprolactinaemia with a 100 mg/l (24–6500). In females and males the median (min-max) of 90 mg/l (27–494) (Fig. 1). Four median PRL levels were 90 mg/l (27–4700) and out of seven patients had macroadenomas. Thirteen 1075 mg/l (24–6500), respectively. The PRL levels out of 35 males had hyperprolactinaemia with a were significantly higher in males compared with median (min-max) of 47 mg/l (17–251). Ten out of females (P , 0.002). Three females developed acrome- 13 adenomas were macroadenomas. Neither PRL galy clinically and biochemically (Table 1, Fig. 1). All levels nor age differed when comparing males and patients had normal levels of GH and/or IGF-I at the females with acromegaly and hyperprolactinaemia. time when hyperprolactinaemia was first diagnosed (Fig. 2). The three acromegalic patients developed elev- Prolactin levels, age and sex ated serum IGF-I levels and abnormal OGTT within 29 to 60 months of dopamine-D2 agonist therapy. The PRL levels were significantly higher in males with average amount of dopamine-D2 agonist (parlodel) prolactinomas compared with males with acromegaly administered in patients 1, 2 and 3 was 5, 20 and and hyperprolactinaemia (P , 0.002). There was no 2.5 mg per day. Only in patient 1 were PRL levels significant difference between females.

Figure 1 (Left panel) Individual prolactin levels at ﬁrst diagnosis in prolactinoma patients who developed acromegaly (V), in males (X) and in males whose PRL levels were .1400 mg/l (O), in females (A) and in females whose PRL levels were .1400 mg/l (K). (Right panel) Prolactin levels in patients with acromegaly with hyperprolactinaemia. Males (X), females (A). Medians are indicated by horizontal bars.

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Patients with acromegaly and hyperprolactinaemia were significantly older than patients with prolactinomas (47 (20–66) vs 32 (14–74) years) (P , 0.005). Females with acromegaly and hyperprolactinaemia were significantly older than females with prolactinomas (47 (31–66) vs 32 (14–74) years) (P , 0.03) but there was no significant difference between the ages of males with acromegaly and hyperprolactinaemia and those with prolactinomas (45 (19–67) vs 47 (20–66) years) (P . 0.05).

Discussion Figure 2 Individual IGF-I levels at first diagnosis in prolactinoma (n ¼ 50) (V) and in acromegalic patients (n ¼ 48) (A). The 95% We found that three out of 78 patients with CI for the 97.5 percentiles for the IGF-I levels are indicated with prolactinomas developed acromegaly. We suspect that horizontal lines for each age group. more patients could have developed acromegaly as 45 patients were treated with a dopamine-D2 agonist at the last visit and it has been found that GH levels, especially in patients with acromegaly and hyperprolactinaemia, are sensitive to dopamine-D2 agonists (8). Our findings emphasise the need for careful endocrine evaluation of prolactinoma patients including those with microprolactinomas (patient 3). The interval from onset of symptoms to diagnosis of acromegaly may range from 1 year to several decades (13). The interval in patients with hyperprolactinaemia with no initial acromegalic symptoms to the possible development of acromegaly in a subgroup of patients needs to be established in a large prospective study. The five patients who had only elevated IGF-I levels (Table 2) need to be followed annually to clarify the clinical importance of elevated IGF-I levels. Patients with acromegaly commonly show incomplete suppression, no suppression, or a paradoxical rise in GH during an OGTT. In two small series (n ¼ 13 and n ¼ 30 respectively) (14, 15), initial IGF-I concentrations in acrome- galics diagnosed by OGTT were shown not to overlap with those in control subjects. Thus an elevated IGF-I level in a patient with the appropriate clinical picture is diagnostic of acromegaly (16). This leads to the possi- bility of using a single IGF-I measurement for diagnosis (9). The routine use of serum IGF-I as a marker of GH activity in acromegaly is potentially very attractive for several reasons (9): (a) it involves a single serum sample; (b) IGF-I has a long half-life and therefore a stable serum concentration unlike GH; (c) it may be the ideal physiological marker of GH activity, as GH exerts most of its actions via IGF-I production; and (d) many treated acromegalic patients with GH ,5mU/l continue to exhibit elevated IGF-I levels. During a 24-h profile the trough levels of serum GH were posi- tively associated with raised IGF-I levels in acromegalic subjects even when mean 24-h serum GH was ,5 mU/l (17). IGF-I levels are affected to some degree Figure 3 The individual PRL (V) and IGF-I (B) levels for patients 1, 2 and 3 (see Table 1). The instituted therapies, Parlodel by the type and route of other hormone replacement (bromocriptine), Octreotide, Operation (Op) and Irradiation (Irr) therapy (e.g. with oestrogen) (9). In our study, however, are indicatated on the figure. the IGF-I changes could not be explained by oestradiol

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Table 2 Parameters for the ﬁve patients who had signiﬁcantly elevated IGF-I levels.

At ﬁrst diagnosis At last visit

Patient Age Follow up PRL IGF-I GH PRL IGF-I GH Micro or no. Sex (years) (months)a (mg/l) (mg/l) (mU/l) (mg/l) (mg/l) (mU/l) macro

4 F 30 18 31 257 1 G 30 304 2 G Micro 5 F 35 204 1320 ND ND 208 324 0.22 G Macro 6 F 26 195 206 ND ND 46 325 1.3 G Macro 7 F 30 8 106 230 0.28 G 7* 324 0.29 G Micro 8 F 18 97 2195 ND ND 11* 450 0.46 G Macro a Time until elevated IGF-I and or GH; *dopamine-D2-agonist therapy; G, nadir GH levels during an OGTT; ND, not done. Significantly elevated IGF-I values are written in bold. therapy - none of the patients that developed increased before. Several years ago Pagesy et al.(24) reported that IGF-I levels were treated with oestradiol. one has to be aware of apparently silent somatotroph The adenomas in patients with primary hyperprolac- adenomas. In that study the patients had weak signs tinaemia may be heterogenous (18). In a large study on of acromegalic features and they all had macroadeno- transsphenoidal surgery on prolactinomas (176 micro- mas. Yamada and coworkers (25) have studied a clini- adenomas and 233 macroadenomas), Feigenbaum et al. cally silent somatotroph adenoma. They suggest that (19) found that 50 patients had a chromophobe the lack of clinical acromegaly in patients with elevated adenoma and 50% of these patients had microadeno- GH and IGF-I levels is due to the short duration of GH mas. Interestingly, the preoperative PRL levels were hypersecretion. similar in those 50 patients and in patients with The role of dopamine in healthy adults and acrome- histologically confirmed prolactinomas. Mixed PRL- galic patients is different. Dopamine is a weak stimu- and GH-secreting adenomas were found in an lator of GH secretion in healthy adults, and L-dopa additional 31 female patients, one of these adenomas has been used for diagnosing GH deficiency (13). In stained only for GH. No clinical features of acromegaly acromegaly dopamine reduces GH levels in up to 25% were noted in this patient. There was, however, no of patients (13). We have found an increase in IGF-I endocrinological data on the patients with mixed levels in patients on dopamine-D2 agonist therapy as adenomas, focusing on GH hypersecretion (19). well as in patients without therapy. Are the increased In agreement with Feigenbaum et al. (19) we found IGF-I levels due to the effect of dopamine-D2 agonist that the females with prolactinomas were significantly therapy on the normal somatotroph cells? No, this is younger than the males. We also found that females unlikely. On the other hand, Torring and coworkers with acromegaly and hyperprolactinaemia were signifi- (26) found no change in IGF-I levels in patients cantly older than females with prolactinomas with hyperprolactinaemia where bromocriptine had (P , 0.03). There was, however, no significant differ- normalised PRL levels. ence between the males. All eight patients who devel- In conclusion, our findings suggest that there may be oped elevated IGF-I levels and even acromegaly (three a common group of patients with a pituitary adenoma patients) were females. These data may suggest that and unsynchronised PRL and GH secretion. Some of in females with a possible heterogenous adenoma, the these patients have clinical acromegaly at diagnosis hyperprolactinaemia may lead to the first diagnosis and some patients will develop clinical or subclinical because of the amenorrhea-galactorrhea syndrome; in acromegaly. However, future studies are necessary to contrast in males acromegaly may lead to the first clarify the risk of developing acromegaly in patients diagnosis. Our mean age for acromegalic patients of with hyperprolactinaemia. We suggest an annual 47 years was in accordance with the mean age of 46 IGF-I measurement as a screening test. We are plan- years reported by Bengtsson and coworkers (20). It is ning a prospective study on GH hypersecretion in necessary to consider the possible changes in pituitary patients with hyperprolactinaemia. adenomatous secretion even during medical therapy. In 1984 Badawy and colleagues (21) published a case study where a patient with a prolactinoma developed References acromegaly during 5 years of bromocriptine therapy and they suggested that comprehensive and periodic 1 Lamberts SW, Liuzzi A, Chiodini PG, Verde S, Klijn JG & evaluation of hypothalamic–pituitary endocrine func- Birkenhager JC. The value of plasma prolactin levels in the tion is indicated in patients with hyperprolactinaemia. prediction of the responsiveness of growth hormone secretion to bromocriptine and TRH in acromegaly. European Journal of Clinical Two other case studies have reported findings in Investigation 1982 12 151–155. accordance with this study (22, 23). The problems 2 Functional Endocrine Pathology, vol. 1. Eds K Kovacs & SL Asa. with underdiagnosing acromegaly have been discussed Oxford: Blackwell Scientific Publications, 1991.

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3 Mulcahy SS & Jaffe RB. Detection of a potential progenitor cell in 16 Stoffel-Wagner B, Springer W, Bidlingmaier F & Klingmuller D. the human fetal pituitary that secretes both growth hormone A comparison of different methods for diagnosing acromegaly. and prolactin. Journal of Clinical Endocrinology and Metabolism Clinical Endocrinology 1997 46 531–537. 1988 66 24–32. 17 Peacey SR, Toogood AA, Veldhuis JD, Thorner MO & Shalet SM. 4 Lloyd RV, Anagnostou D, Cano M, Barkan AL & Chandler WF. The relationship between 24-hour growth hormone secretion Analysis of mammosomatotropic cells in normal and neoplastic and insulin-like growth factor I in patients with successfully human pituitary tissues by the reverse hemolytic plaque assay treated acromegaly: impact of surgery or radiotherapy. Journal of and immunocytochemistry. Journal of Clinical Endocrinology and Clinical Endocrinology and Metabolism 2001 86 259–266. Metabolism 1988 66 1103–1110. 18 Asa SL, Kovacs K, Horvath E, Singer W & Smyth HS. Hormone 5 Bassetti M, Spada A, Arosio M, Vallar L, Brina M & Giannattasio G. secretion in vitro by plurihormonal pituitary adenomas of the Morphological studies on mixed growth hormone (GH)- and acidophil cell line. Journal of Clinical Endocrinology and Metabolism prolactin (PRL)-secreting human pituitary adenomas. Coexist- 1992 75 68–75. ence of GH and PRL in the same secretory granule. Journal of 19 Feigenbaum SL, Downey DE, Wilson CB & Jaffe RB. Transsphenoi- Clinical Endocrinology and Metabolism 1986 62 1093–1100. dal pituitary resection for preoperative diagnosis of prolactin- 6 Lloyd RV, Cano M, Chandler WF, Barkan AL, Horvath E & secreting pituitary adenoma in women: long term follow-up. Kovacs K. Human growth hormone and prolactin secreting Journal of Clinical Endocrinology and Metabolism 1996 81 pituitary adenomas analyzed by in situ hybridization. American 1711–1719. Journal of Pathology 1989 134 605–613. 20 Bengtsson BA, Eden S, Ernest I, Oden A & Sjogren B. Epidemiol- 7 Andersen M, Hansen TB, Bollerslev J, Bjerre P, Schrøder HD & ogy and long-term survival in acromegaly. A study of 166 cases Hagen C. Effect of 4 weeks of octreotide treatment on prolactin, diagnosed between 1955 and 1984. Acta Medica Scandinavica thyroid stimulating hormone and thyroid hormones in acromega- 1988 223 327–335. lic patients. A double blind placebo-controlled cross-over study. 21 Badawy SZA, Anderson GH, Shende MC & Marshall L. Develop- Journal of Endocrinological Investigation 1995 18 840–846. ment of acromegaly in a patient with prolactinemia: a case 8 Lamberts SW, Klijn JG, van Vroonhoven CC, Stefanko SZ & study. Fertility and Sterility 1984 42 926–928. Liuzzi A. The role of prolactin in the inhibitory action of 22 Bacsy E, Fazekas I, Slowik F, Pasztor E & Czirjak S. Transformation bromocriptine on growth hormone secretion in acromegaly. of a human mixed GH-PRL adenoma cell population in response Acta Endocrinologica 1983 103 446–450. to long-term bromocriptine treatment. Folia Histochemica 9 Peacey SR & Shalet SM. Insulin-like growth factor I measurement Cytobiologica 1997 35 69–74. in diagnosis and management of acromegaly. Annals of Clinical 23 Page MD, Bridges LR, Barth JH, McNichol AM & Belchetz PE. Biochemistry 2001 38 297–303. Development of acromegaly during treatment of hyperprolacti- 10 Daughaday WH & Rotwein P. Insulin-like growth factors I and naemia with bromocriptine: an unusual acidophil stem cell II. Peptide, messenger ribonucleic acid and gene structures, adenoma. Journal of Clinical Endocrinology and Metabolism 1996 serum, and tissue concentrations. Endocrine Reviews 1989 10 81 4484–4487. 68–91. 24 Pagesy P, Li JY, Kujas M, Peillon F, Delalande O, Visot A et al. 11 Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Apparently silent somatotroph adenomas. Pathology, Research Ho K et al. Criteria for cure of acromegaly: a consensus statement. and Practice 1991 187 950–956. Journal of Clinical Endocrinology and Metabolism 2000 85 25 Yamada S, Sano T, Stefaneanu L, Kovacs K, Aiba T, Sawano S et al. 526–529. Endocrine and morphological study of a clinically silent somato- 12 Yamada S, Aiba T, Sano T, Kovacs K, Shishiba Y, Sawano S et al. troph adenoma of the human pituitary. Journal of Clinical Growth hormone-producing pituitary adenomas: correlations Endocrinology and Metabolism 1993 76 352–356. between clinical characteristics and morphology. Neurosurgery 26 Torring O, Isberg B, Sjoberg HE, Bucht E & Hulting AL. Plasma 1993 33 20–27. calcitonin IGF-I levels and vertebral bone mineral density in 13 Felig P, Baxter JD & Frohman LA. In Endocrinology and Metabolism, hyperprolactinemic women during bromocriptine treatment. edn 3. Eds P Felig, JD Baxter & LA Frohman. New York: Acta Endocrinologica 1993 128 423–427. McGraw-Hill Inc., 1995. 14 de Herder WW, van der Lely AJ, Janssen JA, Uitterlinden P, Hoﬂand LJ & Lamberts SW. IGFBP-3 is a poor parameter for assessment of clinical activity in acromegaly. Clinical Endocrin- ology 1995 43 501–505. 15 Ho KY & Weissberger AJ. Characterization of 24-hour growth hormone secretion in acromegaly: implications for diagnosis Received 4 December 2002 and therapy. Clinical Endocrinology 1994 41 75–83. Accepted 8 April 2003

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