European Journal of Endocrinology (2009) 161 S65–S74 ISSN 0804-4643

Safety aspects of GH replacement Johan Svensson and Bengt-A˚ ke Bengtsson Department of Endocrinology, Research Centre for Endocrinology and Metabolism, Sahlgrenska University Hospital, Gro¨na Stra˚ket 8, SE-413 45 Go¨teborg, Sweden (Correspondence should be addressed to J Svensson; Email: [email protected])

Abstract In adults, GH replacement therapy will often be maintained for decades. Owing to the long duration of GH replacement in many adults, it is essential to establish the long-term safety aspects of the treatment. In this review, studies that have investigated the safety profile of long-term GH replacement will be reviewed with an emphasis on studies based on data from the Pfizer International Metabolic Database (KIMS). These studies show that long-term GH replacement in adults is safe and that long-term GH replacement may even improve cardiovascular mortality and morbidity in GH-deficient adults.

European Journal of Endocrinology 161 S65–S74

Introduction by GH replacement with reduced total body fat and increased lean body mass (10). However, all short-term In the late 1950s, the profound importance of GH to studies have not displayed a return of sensitivity increase linear bone growth was demonstrated in towards baseline values (11), and in a meta-analysis, GH-deficient (GHD) children (1). Not until the late mainly including the studies of relatively short duration, 1980s, when recombinant human GH was introduced, circulating glucose and insulin values were found to be were the effects of GH in adult life studied in detail. significantly increased after GH replacement (12). During the last 20 years, several studies have shown that During prolonged GH replacement, some studies long-term GH replacement therapy in adults improves report still impaired (13–15) glucose tolerance, whereas quality of life, bone mass and cardiovascular risk factors other studies report unchanged (16, 17) glucose (2–6). Safety studies have also been performed; however, tolerance as compared with baseline. The results of single centres most often have access only to relatively one study, using the hyperinsulinaemic, euglycaemic small number of hypopituitary patients. Therefore, clamp technique, suggest that the decreased baseline studies based on data from the Pfizer International insulin sensitivity persists for at least up to 2 years of GH Metabolic Database (KIMS) have been of great import- treatment (18). However, in a study by Hwu et al., ance to determine the safety profile of long-term GH replacement. Available safety studies will be reviewed 1 year of GH treatment normalized insulin sensitivity as with the emphasis on type 2 mellitus (DM), measured by a modified insulin suppression test (19).In mortality, cardiovascular morbidity, reoccurrence of a study by Jørgensen et al., insulin sensitivity (M-value) pituitary tumour and risk of malignancies. was similar in GHD patients to that in controls after 5 years of GH replacement (20). In a study by Svensson et al., insulin sensitivity was unchanged during 7-year Insulin sensitivity GH replacement, and there was even a tendency that the GH replacement provided protection from the age- Several studies show that untreated GHD in adults is related decline in insulin sensitivity that was observed associated with (7, 8). The effect of GH in the matched control subjects (21). replacement therapy on insulin sensitivity appears to be In two studies with treatment durations of 7 and 10 biphasic. After an initial deterioration during the first years respectively, GH replacement did not affect glucose months of therapy, insulin sensitivity then improves and homeostasis (22, 23); whereas in another study, returns towards baseline values as seen in several studies circulating HbA1c and fasting glucose were increased (9, 10). This improvement and return towards baseline as compared with baseline after 10 years (24).Ina values is probably due to the improved body composition 5-year and a 10-year GH treatment trial, there was a discrepancy in fasting blood levels of glucose and This paper forms part of a special issue on KIMSw and HbA1c, as fasting glucose levels were increased and ACROSTUDYe. Pfizer Inc. has supported the publication of this fasting HbA1c levels were reduced (5, 25). The meaning special issue. of an increase in fasting blood glucose combined with

q 2009 European Society of Endocrinology DOI: 10.1530/EJE-09-0287 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 10/01/2021 12:33:10AM via free access S66 J Svensson and B-A˚ Bengtsson EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 a reduction in blood HbA1c is not straight-forward, GH-treated hypopituitary patients with normal BMI is but it could be hypothesized that it indicates an not increased as compared with that in the background approximately unchanged insulin sensitivity as com- population (27). Furthermore, it was concluded that a pared with baseline. high BMI is a risk factor for the development of DM in In conclusion, GHD adults not receiving GH replace- GHD adults (27). ment have impaired insulin sensitivity that is further In a Swedish retrospective multi-centre study by deteriorated during the first months of treatment. Holmer et al. (28), 750 adult hypopituitary patients During prolonged GH replacement, insulin sensitivity with confirmed GHD and 2314 matched population- returns towards baseline values, but it is still debatable based controls were included (28). Most of the GHD whether insulin sensitivity is still decreased, unchanged patients received GH replacement with a mean duration or even improved compared with baseline after long- of 6 years. The prevalence of DM was not statistically term treatment. However, the results of most studies different from that in the controls in GHD men (28).In suggest an approximately unchanged insulin sensitivity GHD women, the prevalence of DM was increased, as compared with baseline after GH replacement for partly attributed to higher BMI and lower physical several years. activity (28). In conclusion, there are at present only a few studies that have determined the incidence or prevalence of DM Type 2 diabetes mellitus during GH replacement in adults. The scarce data available give at present no evidence that GH replace- In children, data from the Pfizer International Growth ment increases the risk of DM in GHD patients with Database (KIGS) reported that GH treatment in normal BMI. The risk of developing DM type 2 in adult children might induce a very modest increase in the GHD patients with high BMI and low physical activity incidence of type 2 DM (26). The effect of GH on glucose needs to be determined in further studies. It is metabolism is, however, considerably different in adults recommended that GH replacement is initiated with a compared with that seen in children. Although there low dose in GHD adults with high BMI, and also in other are few data, there is no evidence that GH replacement groups of GHD patients predisposed to type 2 DM, such increases the risk of DM in GHD adults. An analysis was as GHD patients with a positive family history or who performed in 5120 (2706 men) patients included in are older. Furthermore, in GHD patients predisposed to KIMS (27). Each patient had at least one return visit type 2 DM, the dose of GH should be slowly increased corresponding to a total of 11 049 years of GH based on the clinical response, and careful monitoring of replacement. Twenty-six men and 17 women developed glucose homeostasis is needed. de novo DM during the follow-up (16 of these during the first year of GH replacement; Table 1). Mean age and body mass index (BMI) of the patients that developed The heart DM were 44.0 years and 34.0 kg/m2 in women and 2 49.2 years and 32.8 kg/m in men. The standard Short-term placebo-controlled studies have demon- incidence ratio was calculated using a Swedish cohort of strated that GH replacement in adults improves diastolic 138 000 of the general population above 18 years of (29) and systolic (30–33) functions. The long-term age followed prospectively for 3 years as reference (27) effects of GH replacement on the heart have been (Table 1). No significant sex difference was found. The investigated in a few open studies. During 38 months of conclusion was that the incidence of type 2 DM in GH replacement therapy, cardiac structure was normalized, whereas heart rate and cardiac index Table 1 The development of diabetes mellitus during GH increased to supernormal levels (34). In 38 young men replacement therapy in 5120 (2706 men) patients included in KIMS. Each patient had at least one return visit corresponding to a with childhood-onset GHD followed openly for 55 (range total of 11 049 years of GH replacement. In this analysis, the study 39–69) months, GH replacement increased stroke population was divided in five body mass index (BMI) groups. The volume and maximal exercise capacity without any standard incidence ratio (SIR) was calculated with a Swedish cohort long-term increase in left ventricular mass (35). In seven of 138 000 of the general population above 18 years of age followed prospectively for 3 years as reference. adults with adult-onset GHD, 42 months of GH replacement increased left ventricular mass and Observed decreased the atrial emptying index, which reflects cases of diastolic function, as compared with healthy matched diabetes 2 controls (36). This last study might suggest, although a BMI (kg/m ) mellitus SIR 95% Confidence higher dose of GH was given than that used today, that Below 20 0 0.0 0.0–6.4 increased age might increase the susceptibility to 20–25 3 0.5 0.1–1.5 develop inappropriate increment in left ventricular 25–30 10 0.9 0.4–1.7 mass during long-term GH replacement. Therefore, 30–35 18 3.8 2.2–6.0 Above 35 12 5.9 3.1–10.4 in conclusion, low dose, individualized GH replacement therapy improves cardiac function, which may partly

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Downloaded from Bioscientifica.com at 10/01/2021 12:33:10AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 GH safety S67 explain the increased exercise capacity observed in some than in older studies, in which the hypopituitary studies after GH replacement (30, 37–40) including a patients did not receive GH replacement. First, treat- recent meta-analysis of placebo-controlled, randomized ment with radiotherapy of pituitary tumours may GH treatment trials (41). However, if a too high dose of contribute to the increased mortality observed in GH is given, there is a risk of inappropriate increment in hypopituitary patients not receiving GH replacement left ventricular mass in elderly GHD adults during long- (43, 47), and possible lower use of irradiation in more term treatment. recent studies may be one reason for the trend towards lower mortality observed in these studies. Furthermore, more frequent use of lipid-lowering drugs and anti- hypertensive medication may at least to some extent Mortality explain the more beneficial results observed in more A retrospective study by Rose´n et al. showed doubled recent studies (28). Large prospective, randomized and overall mortality in hypopituitary adults with routine controlled studies would provide definite conclusions on hormonal replacement therapy, but without GH these issues, but practically this is not feasible and replacement therapy, as compared with the normal unlikely to be undertaken. population (42). Four additional retrospective studies Although the above given data clearly show that (43–46), and one prospective study (47), have overall mortality is increased in hypopituitary patients confirmed that total mortality is increased in hypopi- not receiving GH replacement and that GH replacement tuitary adults without GH replacement therapy. Most of appears to reduce overall mortality in these patients, the studies showed that the increased overall mortality it should be noted that transgenic mice with low activity in hypopituitary adults without GH replacement of the GH/insulin-like growth factor-1 (IGF1) axis have therapy was mainly due to an almost doubled increased life expectancy. Mice with low GH secretion cardiovascular mortality (42–44, 47). due to mutations of Prop-1 (Ames dwarf mice) (50) or A study by Bengtsson et al. included 1903 hypopitui- Pit-1 (51) have impaired development tary patients enrolled in KIMS that had received GH for resulting in low circulating GH levels and a life span altogether 2334 patient years (48). Expected mortality extension of around 50% as compared with control was obtained from sex- and age-specific death rates in mice. Furthermore, mice with global inactivation of the each country. The calculated standardized mortality GHRH receptor (51) or the GH receptor (52) have long rate (SMR) was similar to that in the normal population lives. Although mice completely lacking the IGF1 and, furthermore, the mortality rate was significantly receptor have low viability and do not usually survive lower than that previously observed by Rose´n et al., in the postnatal period (53), mice with heterozygous hypopituitary patients without GH replacement therapy inactivation (w50% reduction) of the IGF1 receptor in (42, 48). In a study by Svensson et al., increased overall total body or the central nervous system including the mortality was observed in a cohort of 1411 hypopitui- hypothalamus survive the postnatal period and then tary patients without GH replacement, whereas in have long lives (54, 55). An elongation of life span was another cohort (nZ289) of hypopituitary patients also observed in mice with reduced local bioavailability receiving GH replacement therapy, overall mortality of IGF1 (56) and in mice strains with defect IGF1- was similar to that in the background population (45). signalling downstream of the IGF1 receptor (57, 58). Therefore, it appears that GH replacement may even The reason for the discrepancy between the trans- reduce the increased mortality observed in hypopitui- genic mice and the hypopituitary humans with tary patients without GH replacement therapy. increased life span in GH/IGF1-deficient mice versus In an evaluation based on KIMS data, 4486 GHD decreased life span in hypopituitary patients with patients receiving GH replacement were followed from untreated GHD is unclear. One reason could be that their 1 year visit, representing 17 573 patient years of the increased mortality in hypopituitary adults is not follow-up (49). Rates in KIMS were compared with age– due to the severe GHD, but that previous treatment with gender–country-stratified external rates using the SMR surgery or radiation therapy, or inadequate treatment of (49). In terms of overall mortality, there were 136 the deficiency of other pituitary hormones, is of most observed cases and 130 expected corresponding to a importance. There may also be species differences as SMR of 1.05 (95% confidence interval, CI: 0.88–1.24) mice have very low cardiovascular mortality, whereas (49). Forty-three deaths in cardiovascular diseases were this is the major cause of death in hypopituitary patients reported (SMR 0.98; 95% CI: 0.7–1.3) (49). Taken into with severe GH deficiency. Finally, it is unclear whether account that total mortality is increased in hypopitui- life in a cage is representative of how mice survive in tary patients not receiving GH replacement, the results real life, and the possibility can not be excluded that give further support for the notion that GH replacement transgenic mice with low activity of the GH/IGF1 axis may reduce overall and cardiovascular mortality. There would not be very successful in real life. However, further are, however, possibilities other than the GH replace- research is needed to clarify why the consequences of ment to explain why there is a trend towards lower GHD are so different in transgenic mice versus mortality in more recent studies using GH replacement hypopituitary humans in terms of overall mortality.

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Cardiovascular morbidity controls (28). Most of the GHD patients received GH replacement with a mean duration of 6 years. The It is well known that GHD adults without GH results of this study suggested that the GH replacement replacement have premature atherosclerosis (59), combined with increased prescription of cardioprotec- and that GH replacement can improve measures of tive drugs resulted in a reduced risk for non-fatal atherosclerosis such as carotid intima-media thickness stroke, particularly noted in women, and in a decline in (60, 61). However, little is known of cardiovascular non-fatal cardiac events in GHD men (28). Thus, the morbidity in GHD adults with or without GH results of this study give further support for a beneficial replacement. In a study based on data recorded by effect of modern treatment of hypopituitary adults the Board of Health and Welfare in Sweden, cerebro- including increased use of GH replacement and vascular and cardiovascular morbidities were cardioprotective drugs. Further studies are needed to determined in 1411 hypopituitary patients not receiv- investigate how much of this improvement is due to the ing GH replacement (45). In these patients without GH GH replacement and how much is due to the increased replacement, cerebrovascular morbidity was increased prescription of lipid-lowering and antihypertensive compared with that in the background population. medications. The increase in the total number of myocardial infarctions (fatal and non-fatal) was less marked than the increase in cerebrovascular events (45). The risk ratio for myocardial infarction in the hypopituitary Hypothalamic–pituitary tumours patients without GH replacement was 1.40, 95% CI: It is, during long-term GH replacement, important to 1.10–1.75. This increased risk of myocardial infarction consider the risk of regrowth or recurrence of the was mainly due to an increased risk of very severe hypothalamic–pituitary tumour responsible for most of myocardial infarctions with rapid time courses. Also, the hypopituitarism seen in patients with adult-onset in a later study from Denmark by Stochholm et al., an GHD. In a study of GHD adults, no increase in pituitary increased morbidity in circulatory diseases was tumour recurrence rate was found during an average of observed in GHD adults (62). 3.6 years of GH replacement as compared with controls In the study by Svensson et al., there was also a not receiving GH treatment (65). In a prospective study prospective study of 289 hypopituitary patients that of 100 adult-onset GHD patients with pituitary and received GH replacement (mean duration of GH peripituitary tumours receiving GH replacement treatment 60 months, range 2–118 months) (45).In therapy, only one case of slight intrasellar tissue the 289 patients receiving GH replacement, the risk ratio enlargement was noted after 1–4 years of follow-up for cerebrovascular events tended to be higher than that (66). The majority of these patients had received in the background population. Radiation-induced external radiotherapy (66). In a prospective study of angiopathy has been suggested as a risk factor for stroke 60 childhood brain tumour survivors receiving adult (63, 64), and radiotherapy is a predictor of stroke in GH replacement therapy over a mean period of 6.7 hypopituitary patients (43, 47). A possible interpre- years, only one incurable ependymoma and one tation of the tendency to an increased risk ratio for residual meningioma progressed in size (67). Secondary cerebrovascular events also during GH replacement neoplasias were detected both before and after commen- therapy is therefore that GH replacement does not cing GH replacement (67). Finally, in 130 patients with provide protection from strokes that are caused by non-functioning pituitary adenoma treated with radiation angiopathy. Furthermore, the relative risk for surgery alone, treatment with GH for a mean period of myocardial infarctions was even lower in the 289 6.8 years was not associated with increased recurrence hypopituitary patients on GH replacement therapy of the pituitary tumour (68). Therefore, these relatively than that in the background population (45). Taken small studies do not suggest that GH replacement into account that the relative risk of myocardial increases the recurrence or regrowth of hypothalamic– infarctions was increased in hypopituitary patients pituitary tumours. without GH replacement, the reduced rate of myocardial Data from KIMS, including 1034 hypopituitary infarctions in hypopituitary adults receiving GH replace- adults treated with GH for a total of 818 patient years, ment suggests that GH replacement in adults is a safe reported four patients with recurrent pituitary ade- procedure and that GH replacement mayeven reduce the noma, one with recurrent gonadotrophinoma and one risk of myocardial infarctions in hypopituitary patients. with pituitary dysgerminoma (3). These results were In a Swedish retrospective multi-centre study by compared with data from 43 clinical trials involving a Holmer et al. (28), the incidence of non-fatal stroke total of 1145 hypopituitary adults with a similar (ischemic or hemorrhagic) and non-fatal cardiac events geographic distribution. This selection included eight (defined as myocardial infarction, percutaneous trans- cases of central nervous system or pituitary tumours, luminal coronary angioplasty or bypass surgery) was four during administration of placebo and four during investigated in 750 adult hypopituitary patients with administration of GH. In a later case–control study, the confirmed GHD and 2314 matched population-based treatment group comprised patients from the German

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KIMS database, and the control group comprised Risk of malignant disease patients who had never been exposed to GH therapy (69). Out of the 55 matched pairs, there were 16 In retrospective trials, patients with and GH tumour progressions in the GH treatment group and 12 excess have increased the frequency of malignant in the control group (69). Statistical analysis revealed no diseases (78, 79). The most frequently found is significant increase in either recurrence (PZ0.317) or mammary cancer and colorectal cancer, and the overall progression (PZ0.617) within the follow-up period observed/expected ratio for cancer in these studies is of 5 years (69). Therefore, in conclusion, available data between 1.27 and 2.5. In prospective trials, the rate of do not suggest that GH replacement increases tumour patients with tubular adenomas and hyperplastic colon recurrence or regrowth in adults, although further and polyps is increased with some studies also showing more larger studies are still needed. than expected numbers of colon cancer (78, 79).Ina Studies that have assessed the risk of tumour retrospective survey from the UK including 1362 patients recurrence in patients with craniopharyngioma as the with acromegaly, a lower overall cancer incidence rate cause of hypopituitarism have mainly involved child- in the patients than in the general population was found hood populations, although there are some data also in (80). The colon cancer mortality rate was, however, adults. In 23 cases of childhood craniopharyngioma higher than expected with a SMR of 2.47 (CI: 1.31–4.22) treated by surgery with or without radiotherapy, which (80). Furthermore, an association between serum IGF1 were assessed up to the age of completed growth (mean levels in the upper quartile and the risk of prostate, breast follow-up 6.3 years), no significant difference was found and colonic cancer has been demonstrated in the in the recurrence rates before and after commencing GH general population in prospective trials (81–84). treatment (70). In children with craniopharyngioma In the retrospective study by Rose´n et al. (42), the who received GH (National Cooperative Growth Study, mortality from malignant diseases was reduced in the 1985–1999), there was a recurrence rate of 6.4%, hypopituitary patients not receiving GH replacement. In a number of other studies of hypopituitary patients which was considered lower than the previously repor- not receiving GH replacement, an unchanged or even ted rate in the general paediatric population (71).In increased risk of malignancies has been found. Bates two studies based on KIGS data, the recurrence rate of et al. observed an increased mortality from malignan- craniopharyngiomas did not appear to be increased cies in hypopituitary women (44), whereas the risk of compared with other reports (72, 73). In the OZGROW death in a malignant disease was unaffected in the database (a database collecting information on children prospective study by Tomlinson et al. (47). In the retros- receiving GH in Australia and New Zealand), the pective study by Popovic et al., the rate of neoplasia in percentage of recurrence/patient year was 3.8% and non-functional and GH-producing pituitary adenoma not different from the recurrence in individuals not was compared with that in the general population (85). treated with GH (74). In a series of 60 children treated They found increased frequency of cancer both in with GH, there was no difference in the number of patients with non-functional pituitary adenoma and in recurrences between patients on GH and those who had acromegalic patients as compared with the expected not received such treatment (75). Abs et al. reported no incidence in the general population (85). In a large recurrence in 127 GH-treated adult patients with retrospective Swedish study including all individuals craniopharyngioma enrolled in KIMS 1994–1996 (3). with pituitary tumours included in the Swedish Cancer In the study by Frajese et al., no recurrence was detected Registry between 1958 and 1991, an excessive mortality in a series of 13 adults with craniopharyngioma treated from all tumours (pituitary excluded) and malignant with GH (66). In a study reporting the results of tumours of the brain was found (86). Finally, in nation- prospective imaging in 28 consecutive patients with wide studies from Sweden and Denmark, an increased craniopharyngioma and adult-onset GHD, an apparent mortality in malignant disease was observed in adults increase in tumour volume was found in one subject not receiving GH replacement (45, 46).Therefore,the 6 years after the commencement of GH (76). In another results of some studies suggest that other forms of cancer study, 32 patients with a mean age of 17.6 years at may be associated with pituitary tumours and/or its diagnosis of craniopharyngioma and with GH replace- treatment independent of GH status. Furthermore, there is ment for a mean period of 6.3 years were compared also evidence that surgery of pituitary tumours followed with 53 patients who had not received GH but by radiotherapy can increase the risk of secondary brain otherwise with a similar tumour and treatment tumours independent of GH status (87, 88). characteristics and follow-up period (77). During the In a study by Swerdlow et al., young adults who period of observation, 4 patients treated with GH and 22 previously had received long-term GH treatment in not receiving GH developed tumour recurrence (77). childhood were studied (89). A small but significant Thus, in conclusion, data published so far are excess of cancer deaths was observed due to colorectal reassuring and there is, to date, no evidence that GH cancer (two cases) and Hodgkin’s disease (two cases) replacement increases the recurrence rate of cranio- (89). However, as discussed above, the risk of neoplasms pharyngiomas in children or adults. in hypopituitary patients may be increased independent

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Table 2 Summary table of safety aspects of GH replacement therapy in adults. Current data are summarized and some clinical recommendations are given. The clinical recommendations are partly based on a Consensus Workshop held by the GH Research Society (93).

Insulin sensitivity Short-term GH replacement impairs insulin sensitivity During long-term GH replacement over several years, insulin sensitivity returns towards baseline values Diabetes mellitus There is at present no evidence that GH replacement affects the risk of developing type 1 or type 2 diabetes mellitus. In obese patients, the risk of type 2 diabetes mellitus during GH replacement needs to be explored in further studies Individuals predisposed to type 2 diabetes mellitus, mainly obese patients but also older patients and patients with a positive family history, require careful monitoring GHD patients diagnosed with type 2 diabetes mellitus can be managed in the same manner as all other patients with the disease, and GH replacement therapy can be continued The heart The results of most studies suggest beneficial cardiac effects of GH replacement with improved systolic and diastolic functions In elderly patients, replacement with overly high doses of GH can induce an inappropriate increment in left ventricular mass Overall mortality and cardiovascular morbidity Overall mortality as well as cardiovascular mortality and morbidity is increased in hypopituitary patients not receiving GH replacement therapy Long-term GH replacement therapy may, at least when combined with increased use of cardioprotective medication, reduce cardiovascular mortality and morbidity in hypopituitary patients not receiving GH replacement Recurrence of hypothalamic–pituitary tumour There is no evidence that hypothalamic or pituitary tumour recurrence is influenced by GH replacement therapy Pituitary imaging should be performed before GH replacement is initiated Risk of malignant disease There is no evidence that GH replacement in adults increases the risk of de novo malignancy or recurrence For survivors of childhood cancer, GH treatment may slightly increase the relative risk of developing a second neoplasia. However, there are no comparable data in adults GH therapy should be stopped in all patients with active malignancy until the underlying condition is controlled of GH status. Specifically, in the study by Svensson et al. KIMS was 14 073 years. One hundred and eighteen in which 1411 hypopituitary patients without GH neoplasms were reported in 115 patients, which did not replacement therapy were studied retrospectively, the indicate that GH replacement in KIMS increased the risk most predominant malignancy in hypopituitary adult to develop a malignant neoplasm (92). In another patients not receiving GH replacement was colorectal evaluation based on KIMS data, 4486 GHD patients cancer, which was increased compared with the normal receiving GH replacement were followed from their population (45). Therefore, with regard to the results of 1 year visit, representing 17 573 patient years of follow- the studies discussed above and specifically the study by up (49). Thirty-nine observed deaths in malignant Svensson et al. (45), the meaning of the results from the neoplasm corresponded to a SMR of 0.82 versus the study by Swerdlow et al. (89) is unclear. background population (95% CI: 0.60–1.12) (49). Of some concern is the report of a small increase in Therefore, in KIMS, there is no evidence of an increase the number of patients who survived childhood cancer in the risk of malignant disease during GH replacement, but subsequently developed secondary neoplasms (90). but since the average follow-up time is still limited, no Survivors of childhood cancer treated with GH had a final conclusion about the long-term risk can be made. 2.15-fold greater risk of developing a secondary In conclusion, for survivors of childhood cancer, there neoplasm, mostly meningiomas, as compared with are some data indicating that GH could induce a slight survivors that had not received GH treatment (90). increase in the relative risk of developing a second neo- The investigators concluded that the increased risk plasia. However, the number of events has been very small associated with GH use appeared to decrease over time in the studies of childhood cancer survivors and there are because a previous report from the same cohort no comparable data in adults. On the contrary, in adults, demonstrated a relative risk of secondary neoplasia of there is no evidence that GH replacement increases the 3.12 (91). The data should, however, be interpreted risk of developing a new or a recurrent malignancy. with caution, given the small number of events. In adults, there is at present no comparable data. In KIMS, the incidence of neoplasms was evaluated in Summary and conclusions 6428 patients (3281 men) enrolled in KIMS (92). All patients had at least one baseline visit and one return A summary of current data of safety aspects of GH visit on GH replacement therapy. Median age was 44.4 replacement in adults and some clinical recommen- years and total duration on GH replacement therapy in dations are presented in Table 2. Available data suggest

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Downloaded from Bioscientifica.com at 10/01/2021 12:33:10AM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 GH safety S71 that long-term GH replacement therapy is safe in 8 Hew F, Koschmann M, Christopher M, Rantzau C, Vaag A, Ward G, hypopituitary adult patients in terms of incidence of Beck-Nielsen H & Alford F. Insulin resistance in - type 2 DM, although the risk of type 2 DM during GH deficient adults: defects in glucose utilization and glycogen synthase activity. Journal of Clinical Endocrinology and Metabolism replacement in obese patients needs to be determined in 1996 81 555–564. further studies. There is no evidence that GH replace- 9 O’Neal D, Kalfas A, Dunning P,Christopher M, Sawyer S, Ward G & ment in adults increases the reoccurrence of pituitary Alford F. The effects of 3 months treatment of recombinant human tumours or the risk of malignancies. Long-term GH growth hormone (GH) therapy on insulin and glucose-mediated replacement therapy is safe in terms of overall mortality, glucose disposal and insulin secretion in GH-deficient adults. A minimal model analysis. Journal of Clinical Endocrinology and and at least when combined with increased use of Metabolism 1994 79 975–983. cardioprotective medication, GH replacement may 10 Fowelin J, Attvall S, Lager I & Bengtsson B-A˚ . Effects of treatment reduce the increased cardiovascular mortality and with recombinant human growth hormone on insulin sensitivity morbidity observed in hypopituitary patients not and glucose metabolism in adults with growth hormone receiving GH replacement therapy. Long-term moni- deficiency. Metabolism 1993 42 1443–1447. 11 Bramnert M, Segerlantz M, Laurila E, Daugaard J, Manhem P & toring is, however, mandatory in terms of glucose Groop L. Growth induces insulin resistance by metabolism, cardiovascular measurements and under- activating the glucose-fatty acid cycle. Journal of Clinical lying neoplasia. Endocrinology and Metabolism 2003 88 1455–1463. 12 Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B & Chanson P. Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis Declaration of interest of blinded, randomized, placebo-controlled trials. Journal of Clinical The authors have no potential conflicting relationship with Pfizer. J Endocrinology and Metabolism 2004 89 2192–2199. Svensson has no conflict of interest. B-A˚ Bengtsson was co-founder of 13 Weaver J, Monson J, Noonan K, John W, Edwards A, Evans K & Tercica Inc., a company that produced IGF1 for use in children of short Cunningham J. The effect of low dose recombinant human stature. Tercica Inc. was acquired by Ipsen June 2008. 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90 Ergun-Longmire B, Mertens A, Mitby P, Qin J, Heller G, Shi W, 92 Wilton P, Mattsson A, Abs R, Bengtsson B-A˚ , Feldt-Rasmussen U, Yasui Y, Robison L & Sklar C. Growth hormone treatment and risk Goth M & Monson J. Neoplasms reported during growth hormone of second neoplasms in the childhood cancer survivor. Journal of replacement in KIMS. Oral presentation at the 85th Annual Clinical Endocrinology and Metabolism 2006 91 3494–3498. Meeting of the Endocrine Society, Philadelphia, USA, 2003. 91 Sklar C, Mertens A, Mitby P, Occhiogrosso G, Qin J, Heller G, 93 Johannsson G. Treatment of growth hormone deficiency in adults. Yasui Y & Robison L. Risk of disease recurrence and second Hormone Research 2009 71 116–122. neoplasms in survivors of childhood cancer treated with growth hormone: a report from the Childhood Cancer Survivor Study. Journal of Clinical Endocrinology and Metabolism 2002 87 Received 22 June 2009 3136–3141. Accepted 25 June 2009

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