| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Research Centre for Endocrinology and Metabolism (J.S., B.-Å.B., T.R., G.J.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; and consulting statistician (A.O.), SE-44292 Romelanda, Sweden
Address all correspondence and requests for reprints to: Johan Svensson, M.D., Research Centre for Endocrinology and Metabolism, Gröna Stråket 8, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: Johan.Svensson{at}medic.gu.se.
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In the 1411 hypopituitary patients without GH replacement, overall mortality (P < 0.001), and the rates of myocardial infarctions (P < 0.01), cerebrovascular events (P < 0.001), and malignancies (P < 0.001) were increased compared with the normal population. Colorectal cancer was the most common malignancy in this cohort (P < 0.001 vs. the background population). In the 289 hypopituitary patients on GH replacement, overall mortality and the rate of malignancies were similar to the normal population. In the hypopituitary adults on GH therapy, the rate of myocardial infarctions was lower than that in the background population (P < 0.05), and there was a tendency toward an increased rate of cerebrovascular events.
In conclusion, overall mortality and the rate of myocardial infarctions were increased in hypopituitary patients without GH replacement. An increased rate of malignancies was observed in the hypopituitary adults without GH therapy, with a predominance of colorectal cancer. GH replacement appeared to provide protection from myocardial infarctions. The rate of cerebrovascular events tended to be increased also in hypopituitary adults on GH therapy.
|
Introduction |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
Several important cardiovascular risk factors have been observed in adults with untreated GH deficiency such as abdominal obesity and dyslipoproteinemia, which benefit from GH replacement therapy (6, 7). Moreover, premature atherosclerosis has been found with increased carotid intima media thickness, also suggested to be reduced by GH replacement (8, 9, 10). The extent to which GH replacement therapy in adults can reduce vascular morbidity and mortality is not known. A report from a large postmarketing surveillance program found that adults on GH replacement therapy had similar overall mortality as the background population (11). The safety of GH treatment is, however, still under debate as patients included in such studies may be highly selected. In intensive care unit patients, administration of high doses of GH increased overall mortality (12).
Previous studies have presented conflicting results regarding the incidence of malignancies in patients with pituitary disease. A decreased rate of malignancies in hypopituitary men without GH replacement has been observed in some studies (1, 3), whereas an increased rate of malignancies was observed in hypopituitary women who did not receive GH therapy (3). In retrospective studies by Popovic et al. (13) and Nilsson et al. (14), the rate of, and the mortality from, neoplasia were increased in patients with pituitary tumors. Studies suggest that high GH/IGF-I levels may be associated with increased incidence of colorectal cancer in acromegalic patients (15, 16, 17), as well as in young adults who previously had received long-term GH treatment in childhood (18).
In the present study, a retrospective comparison was made between 1411 hypopituitary adults identified from the National Board of Health and Welfare in Sweden and the normal population in terms of fatal and nonfatal morbidity from cardiovascular disease and malignancies. The rates of vascular disease and malignancy were then determined prospectively in 289 hypopituitary patients being treated with GH at a single center (1443 patient years; mean duration of treatment, 5 yr). Patients with a history of previous acromegaly or Cushing’s disease were excluded from both studies.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
A total of 1411 adult patients (747 men and 664 women) was included in a retrospective study. The mean age at inclusion was 56.9 (SD 18.6) years, the minimum age for inclusion was 18 yr. The patients were selected on the basis of inpatient care in the years 1987–1992 with a primary or secondary medical diagnosis of hypopituitary disease recorded by the National Board of Health and Welfare in Sweden (a governmental institution in Sweden that supervises the health care system) (19, 20). Patients with a diagnosis of previous acromegaly or Cushing’s disease were excluded from the analysis. Only medical diagnoses for inpatient stays are available using the data supplied by the National Board of Health and Welfare in Sweden. Baseline descriptive data such as number of anterior pituitary hormonal deficiencies, estrogen treatment in women, previous surgery or radiotherapy, duration of hypopituitarism, multiple endocrine neoplasia, and other similar baseline data are not given. Therefore, in the retrospective study, the included 1411 patients are presented as hypopituitary patients without giving any further baseline characteristics.
After inclusion of the 1411 hypopituitary patients, the number of these patients who had received inpatient care up to the end of year 1994 (if not dead before) with a primary or secondary diagnosis of a stroke, myocardial infarction, or malignancy (recorded by the National Board of Health and Welfare in Sweden) was determined. A total of 5593 patient years were studied. Fatal as well as nonfatal events were included. Subsequently, the number of these hypopituitary patients who had received inpatient care with a primary or secondary diagnosis of stroke, myocardial infarction, or malignancy was compared with that in the normal population during the same time period. A maximum of one inpatient stay for stroke, myocardial infarction, and malignancy, respectively, for each patient was permitted in the calculation to exclude the possibility of there having been several hospitalizations for the same event.
Before the end of 1994, the use of GH replacement therapy in GH-deficient adults was limited to research in Sweden. It can therefore be assumed that a large majority of the hypopituitary patients included in this retrospective analysis did not have GH replacement therapy. The number of patients with childhood or adult-onset hypopituitary disease and the number of patients who had received GH replacement therapy during childhood could not be determined from the National Board of Health and Welfare. As stated above, the mean age of the 1411 hypo-pituitary patients at inclusion in 1987–1992 was 56.9 (SD 18.6) yr. GH replacement therapy in children was introduced in the early 1960s in Sweden. Most of the included patients were therefore older than 18 yr of age when GH replacement therapy in children became available in Sweden. A small portion may, however, have received GH therapy during childhood.
In addition to medical diagnoses for inpatient stays, data were also available from the National Board of Health and Welfare in Sweden relating to fatal myocardial infarctions occurring outside a hospital. Fatal coronary events occurring outside a hospital are obviously the most serious ones with very rapid time courses; death most frequently occurs during transport to hospital (21). Data regarding myocardial infarctions are therefore presented as myocardial infarctions (including fatal events occurring outside a hospital) or myocardial infarctions (excluding fatal events occurring outside a hospital). Data relating to fatal cerebrovascular events occurring outside a hospital were not available, but fatal cerebrovascular events generally have a slower time course than fatal myocardial infarctions (21).
Mortality data for the 1411 hypopituitary patients as well as the background population were available from the Swedish Cause of Death Registry (for instance, see Ref. 22). The reporting rate is 99.6% (22). The Swedish Cause of Death Registry contains information of all deaths in Sweden and underlying as well as contributing causes of death (22). Overall mortality in malignant diseases as well as mortality in colorectal cancer could also be calculated in the 1411 hypopituitary patients without GH replacement therapy and in the background population using the Swedish Cause of Death Registry.
The morbidity in malignant diseases (fatal as well as nonfatal) was, in the 1411 hypopituitary patients without GH replacement therapy, as stated above, determined based on inpatient stays with a primary or secondary diagnosis of a malignancy recorded by the National Board of Health and Welfare in Sweden. A maximum of one inpatient stay for malignancy for each patient was permitted in the calculation to exclude the possibility of there having been several hospitalizations for the same event. For the background population, the number of expected malignancies was calculated based on data from the Swedish Cancer Registry (for instance, see Ref. 23). According to the law in Sweden, all physicians must report all malignancies to the Swedish Cancer Registry. Ninety-eight percent of all diagnosed tumors are reported to the Swedish Cancer Registry (23). Also, malignancies that are treated without any inpatient stays, for instance some skin cancers, are also included in the Swedish Cancer Registry. Therefore, in the hypopituitary patients, the number of malignancies was based on inpatient stays with a primary or secondary diagnosis of a malignancy, whereas in the normal population, the expected number of malignancies was calculated based on both outpatient and inpatient medical care reported to the Swedish Cancer Registry.
Prospective study
The prospective study is an ongoing, prospective, open-label treatment trial of the replacement of recombinant human GH in adult patients with GH deficiency. The database was started on October 8, 1990 and was closed for analysis on August 15, 2000. Two hundred eighty-nine adults with pituitary deficiency (186 men and 103 women) and with a mean age of 47.6 (SD 14.8; range, 17–75) yr were included. At analysis, the mean duration of GH replacement therapy was 59.9 (SEM 1.9; range, 2–118.5) months; a total of 1443 patient years. Patients with previous acromegaly or Cushing’s disease were excluded from the analysis. Sixty-four of the patients had previously received GH treatment during childhood. The diagnosis of GH deficiency was based on known pituitary disease combined with a GH stimulation test in 268 of the patients. In 21 patients with multiple anterior pituitary hormonal deficiencies, the diagnosis was based on measurements of the GH secretory pattern or serum IGF-I concentration. The pituitary deficiency was mainly caused by pituitary tumors or their treatment (Table 1
). One hundred one patients (35%) had been treated with transfrontal surgery, and 97 (34%) had previously had transsphenoidal surgery. Ninety-two (32%) of the patients had previously received radiotherapy. Most patients had multiple anterior pituitary deficiencies (Table 1). When required, patients received replacement therapy with glucocorticoids, thyroid hormone, gonadal steroids, and desmopressin throughout the study period. At entry in the study, 70% (62 of 89) of the hypogonadal women received estrogen replacement therapy. All the hypogonadal men received testosterone replacement therapy.
|
The initial target dose of GH in the first 80 patients was 11.9 µg/kg·d (0.25 IU/kg·wk). The dose was gradually lowered and individualized when the weight-based dose regimen was abandoned (24). In the remaining 209 patients, the GH dose was individualized from the start (24). The dose of GH was individualized with the aim of normalizing IGF-I SD score and body composition (24). Dose titration, safety monitoring, and determinations of serum IGF-I concentrations were performed on visits every 3 months during the first year and every 6 months thereafter. Mortality, arthrosclerotic vascular disease, and malignancy were evaluated. Overall mortality, cardiovascular and cerebrovascular morbidity, and the rate of malignancies were compared with those in the normal population (based on data relating to the normal population in Sweden obtained from the National Board of Health and Welfare in Sweden in a similar way as in the retrospective study).
Ethical considerations
Informed consent was obtained from all the patients in the prospective part of the study. The present study was approved by the Ethics Committee at the University of Göteborg and the Swedish Medical Products Agency (Uppsala, Sweden).
Biochemical assays
Serum IGF-I concentration was determined by a hydrochloric acid-ethanol extraction RIA using authentic IGF-I for labeling (Nichols Institute Diagnostics, San Juan Capistrano, CA). Interassay and intraassay coefficients of variation were less than 7%. The individual serum IGF-I values were compared with age- and sex-adjusted values obtained from a reference population (25). The individual IGF-I SD scores could then be calculated (26).
Statistical methods
For serum IGF-I concentration and IGF-I SD score, all the descriptive statistical results are presented as the mean (SEM). The statistical analyses for IGF-I values are based on a one-way ANOVA with time as the independent variable, followed by Student-Newman-Keuls post hoc test.
The expected number of deaths provided that the death hazard function coincided with that of the general population was calculated taking the current age, gender, and current calendar time into account. In a similar way, the expected number was calculated for other events. Confidence intervals were calculated using Poisson distributions.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
In the 1411 hypopituitary patients identified from the National Board of Health and Welfare in Sweden, overall mortality and the incidence of and mortality in malignant diseases were increased in both sexes as compared with the normal population (Table 2). The mean age of the patients in whom a malignancy was diagnosed was 64.7 (SD 14.8; range, 20–92) yr. The most common malignancy was cancer of the colon and rectum (Table 2). The mean age of the patients with colorectal cancer was 70.0 (SD 14.1; range, 32–92) yr. Both the incidence of and mortality in colorectal cancer were increased in the hypopituitary adults without GH therapy as compared with the background population (Table 2). The malignancies (apart from cancer of the colon and rectum) in the 1411 hypopituitary patients were as follows: malignant head/neck tumor (n = 18), malignant brain tumor (n = 16), malignant tumor in other endocrine organs (n = 15), lymphoma (n = 12), malignant breast tumor (n = 7), malignant primary liver tumor (n = 7), malignant gynecologic tumor (n = 5), myeloid leukemia (n = 5), malignant prostate tumor (n = 4), malignant tumor in the urinary bladder (n = 4), malignant tumor in the kidney (n = 4), malignant tumor in the thymus (n = 2), malignant esophageal tumor (n = 1), malignant bile bladder tumor (n = 1), and malignant meningeal tumor (n = 1).
|
). However, if fatal myocardial infarctions occurring outside a hospital were excluded, the rate of myocardial infarctions was similar in both hypopituitary men and women to that observed in the normal population (Table 3). The rate of cerebrovascular events was increased in both sexes as compared with the normal population (Table 3).
|
Serum IGF-I concentrations and IGF-I SD scores in the 289 GH-deficient adults are given in Table 4. In patients in whom a malignant disease was diagnosed during the study period (n = 7), mean IGF-I SD score before the diagnosis of the malignant disease was statistically similar to that in the total study population: –0.56 (0.46) at baseline, 2.60 (0.98) at 1 yr, 1.66 (0.63) at 3 yr, and 1.41 (0.58) at 5 yr. At the actual time point of the diagnosis of the malignant disease, IGF-I SD was 1.61 (0.44) in these patients. Serum IGF-binding protein-3 (IGFBP-3) concentration was not measured in the present study.
|
). The causes of death were radiation-induced encephalitis (n = 1; after 1.3 yr of GH replacement), malignant brainstem tumor (n = 1; 2.9 yr), cerebral hemorrhage (n = 1; 3.1 yr), renal carcinoma (n = 1; 3.3 yr), pulmonary edema due to suspected myocardial infarction (n = 1; 8.3 yr), cerebral infarction (n = 1; 8.6 yr), and unknown cause of death (n = 2; 1.0 and 3.9 yr, respectively).
|
).
Two myocardial infarctions occurred after 5.7 and 8.3 yr of GH replacement therapy, respectively. This rate of myocardial infarctions (including out-of-hospital deaths from myocardial infarctions) was lower than that in the normal population (Table 5). However, if fatal myocardial infarctions occurring outside a hospital were excluded, the rate of myocardial infarctions in the 289 patients was similar to that in the normal population.
The rate of cerebrovascular events was statistically similar to that in the normal population (Table 5). The cerebrovascular events consisted of six cerebral infarctions (diagnosed after 0.6, 0.7, 2.3, 2.4, 7.6, and 8.6 yr, respectively) and one hemorrhage after 3.1 yr of GH replacement therapy. Four of the six patients with cerebral infarctions had previously received radiotherapy.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
The study cohort in the retrospective study is not comparable with the study cohort in the prospective study. The study cohort in the retrospective study was older [mean age, 56.9 (SD 18.6) yr] and larger (n = 1411) than that in the prospective study [mean age, 47.6 (SD 14.8) yr; n = 289]. Although comparisons with the background population were corrected for age, sex, and calendar time, differences in the outcome of the patients in the retrospective and the prospective study could be an effect of factors other than GH replacement therapy.
The retrospective study of 1411 hypopituitary adults without GH replacement revealed an increase in cardiovascular and cerebrovascular morbidity. These data on both fatal and nonfatal morbidity are in line with and confirm previous observations of an increase in the relative risk of total and vascular mortality in hypopituitary patients (1, 2, 5). The 3.8-times increase in the relative risk for total mortality in the 1411 hypopituitary patients in this study is larger than that observed in previous publications (1, 2, 3, 4, 5). If the prevalence of hypopituitarism was similar to that estimated in Spain in 1992 (27), the total number of hypopituitary adults in Sweden would be 2500. We cannot therefore exclude the possibility that some selection bias may have occurred, because the age of our patients was higher than that reported in previous mortality studies and our patients might have a more severe hypothalamic-pituitary disease. On the other hand, some patients may not have been included in previous reports that mainly included patients from referral centers.
In the 289 hypopituitary adults who received GH replacement, 30% percent of the women were not receiving estrogen treatment at baseline. This is a similar percentage than that reported in a prospective trial of survival in hypopituitary patients in whom untreated gonadotropin deficiency was associated with increased mortality (5). In the 1411 hypo-pituitary patients who did not receive GH replacement, data regarding estrogen replacement were not available. In the general population, however, recent studies have shown an increased risk of breast cancer during estrogen replacement therapy in postmenopausal women (28), and estrogen replacement did not improve cardiovascular disease outcomes (29, 30). Therefore, the outcome of estrogen replacement in hypopituitary patients is not yet clear.
Overall mortality in the 289 hypopituitary adults on GH replacement therapy was similar to that in the normal population. The upper limit of the 95% confidence interval for the relative risk was 1.66 in the total study population. As a result, this study does not have the statistical power to exclude a small increase in overall mortality in hypopituitary adults on GH replacement as compared with the normal population. However, as discussed above, the relative risk of overall mortality was 3.8 in the 1411 hypopituitary adults without GH replacement therapy. Although the study cohort in the retrospective study is not fully comparable with the study cohort in the prospective study, the present results could suggest that GH replacement therapy reduces mortality in hypopituitary adults.
The rate of myocardial infarctions was increased in hypo-pituitary women without GH replacement therapy if fatal out-of-hospital myocardial infarctions were included. Furthermore, the rate of myocardial infarctions (including fatal events occurring outside a hospital) in the hypopituitary patients on GH replacement therapy was even lower than that in the normal population. If fatal myocardial infarctions occurring outside a hospital were excluded, however, no difference was found between hypopituitary adults with or without GH therapy and the background population. The present results therefore suggest that GH may play an important role in providing protection from serious myocardial infarctions with a rapid time course. Furthermore, in the hypopituitary women, no death and only one malignancy (malignant tumor in the urinary bladder) were observed, and only one woman suffered from a cerebrovascular event. The present results could therefore suggest that GH replacement is accompanied by less adverse events in women than in men. One possible explanation for this could be that men were overtreated during the first years of GH replacement, as their mean IGF-I SD score was above +2 SD during yr 1–5 of treatment.
The rate of cerebrovascular events was increased in both hypopituitary men and women without GH replacement therapy. In the 289 hypopituitary adults undergoing GH replacement therapy, there was a tendency toward a higher rate of cerebrovascular disease than predicted. A power analysis revealed that a 3.8-times-larger study cohort was needed in the prospective study to achieve 80% power. Radiation-induced angiopathy has been suggested as a risk factor for stroke (31, 32), and two previous studies (2, 5) have found that radiotherapy is a predictor of stroke in hypopituitary patients. A possible interpretation of our data is that GH replacement therapy does not provide protection from strokes that are caused by radiation angiopathy. This is perhaps supported by the fact that four of the six patients treated with GH who suffered cerebral infarctions had previously received radiotherapy. This suggests that the increase in morbidity and mortality that we and others have observed in hypopituitary patients is multifactorial, including untreated hypogonadism, previous radiotherapy, and underlying disease as important contributory factors together with untreated GH deficiency.
In the 1411 hypopituitary adults without GH replacement, the incidence as well as the mortality in malignancies was increased as compared with the normal population. The mean age of the patients in whom a malignancy was diagnosed was 64.7 (SD 14.8; range, 20–92) yr. As discussed above, the patients included in the retrospective study were older than in previous mortality studies (1, 2, 3, 4, 5). The relatively high age of the patients with malignant disease in the present retrospective study may possibly explain why we, in contrast to most previous studies, found an increased incidence of malignant disease in hypopituitary patients without GH therapy. One cause of the increased incidence of malignancies in hypopituitary patients without GH therapy could be that surgery and radiotherapy on pituitary tumors had caused secondary brain tumors (33). Furthermore, 15 malignant tumors in other endocrine organs were found in the 1411 hypopituitary adults, which is probably explained by multiple endocrine neoplasia in these patients. It is therefore plausible that the increased rate of malignancies in the hypopituitary patients can be partly explained by factors other than their hypopituitarism.
Studies of acromegalic patients suggest that high GH/IGF-I levels are associated with an increased risk of colorectal cancer (15, 16, 17). In mice with deficiency of liver-derived IGF-I, the onset and development of colon cancer and mammary tumors are delayed (34, 35). In vitro data suggest that functional IGF-I receptors on the tumor cells may be needed for tumor formation and progression (36, 37). An association between serum IGF-I levels and prostate, breast, and colon cancer risk in the general population has been demonstrated in prospective trials (38, 39, 40, 41, 42). There appears to be an inverse association between risk of prostate, breast, and colon cancer and serum IGFBP-3 concentration (37, 38, 39, 40, 41, 42). In the present study, in patients in whom a malignant disease was diagnosed during the study period, serum IGF-I concentration was similar to other patients. Serum IGFBP-3 concentration was not measured in the present study.
The number of the 1411 hypopituitary patients who had childhood- or adult-onset disease as well as the number of patients who had received GH treatment during childhood could not be obtained in the retrospective study. However, GH replacement therapy in children was introduced in the early 1960s in Sweden. Only three of the patients with colorectal cancer could therefore have received GH treatment (born 1947 and later). All other patients with colorectal cancer were too old to have received GH treatment in childhood (born 1937 and earlier). Even if the three patients who could possibly have received GH treatment in childhood were excluded, the increase in colorectal cancer was still highly significant (P < 0.001 vs. the background population). We can therefore exclude the possibility that the increase in colorectal cancer in the hypo-pituitary patients without GH treatment in adult life was due to GH treatment in childhood. In contrast, our data suggest that not only increases in GH/IGF-I levels play a causal role in the development of colorectal cancer in patients with pituitary disease. Two retrospective studies (13, 14) have found increased rate and mortality from neoplasia in patients with pituitary tumors, suggesting an association that may be inherent or due to increased surveillance of this patient population.
In the prospective study, the rate of malignancies was similar to that in the normal population. Two patients had colorectal cancer in the 289 hypopituitary patients who received GH replacement therapy (P = 0.46 vs. normal population). The risk ratio for malignant disease in hypopituitary adults undergoing GH replacement therapy must, however, be determined in studies with longer follow-up time than that in the present study.
In conclusion, overall mortality and the rate of all observed malignancies were increased in hypopituitary adults before GH replacement therapy in adult life became available. Colorectal cancer was the most frequently found malignancy in these patients. GH replacement appeared to provide protection from fatal myocardial infarctions with rapid time courses. An increased rate of cerebrovascular events was also present in hypopituitary adults who received long-term GH replacement therapy, demonstrating that factors other than GH in the overall treatment have an important effect on the outcome in this patient group.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Results of this work were presented in part at the 85th Annual Meeting of The Endocrine Society, Philadelphia, Pennsylvania, June 2003.
Abbreviation: IGFBP-3, IGF-binding protein-3.
Received September 12, 2003.
Accepted April 5, 2004.
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  K. Stochholm, T. Laursen, A. Green, P. Laurberg, M. Andersen, L. O. Kristensen, U. Feldt-Rasmussen, J. S. Christiansen, M. Frydenberg, and C. H. Gravholt Morbidity and GH deficiency: a nationwide study. Eur. J. Endocrinol., April 1, 2008; 158(4): 447 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. R Walker Glucocorticoids and Cardiovascular Disease Eur. J. Endocrinol., November 1, 2007; 157(5): 545 - 559. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Holmer, J. Svensson, L. Rylander, G. Johannsson, T. Rosen, B.-A. Bengtsson, M. Thoren, C. Hoybye, M. Degerblad, M. Bramnert, et al. Nonfatal Stroke, Cardiac Disease, and Diabetes Mellitus in Hypopituitary Patients on Hormone Replacement Including Growth Hormone J. Clin. Endocrinol. Metab., September 1, 2007; 92(9): 3560 - 3567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Stochholm, C. H. Gravholt, T. Laursen, P. Laurberg, M. Andersen, L. O. Kristensen, U. Feldt-Rasmussen, J. S. Christiansen, M. Frydenberg, and A. Green Mortality and GH deficiency: a nationwide study Eur. J. Endocrinol., July 1, 2007; 157(1): 9 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gotherstrom, B.-A. Bengtsson, I. Bosaeus, G. Johannsson, and J. Svensson A 10-Year, Prospective Study of the Metabolic Effects of Growth Hormone Replacement in Adults J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1442 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rizzo, R. Trepp, K. Berneis, and E. R Christ Atherogenic lipoprotein phenotype and low-density lipoprotein size and subclasses in patients with growth hormone deficiency before and after short-term replacement therapy Eur. J. Endocrinol., March 1, 2007; 156(3): 361 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bergthorsdottir, M. Leonsson-Zachrisson, A. Oden, and G. Johannsson Premature Mortality in Patients with Addison's Disease: A Population-Based Study J. Clin. Endocrinol. Metab., December 1, 2006; 91(12): 4849 - 4853. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Abs, U. Feldt-Rasmussen, A. F Mattsson, J. P Monson, B.-A. Bengtsson, M. I Goth, P. Wilton, and M. Koltowska-Haggstrom Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis. Eur. J. Endocrinol., July 1, 2006; 155(1): 79 - 90. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Svensson, G. Johannsson, A. Iranmanesh, K. Albertsson-Wikland, J. D Veldhuis, and B.-A. Bengtsson GH secretory pattern in young adults who discontinued GH treatment for GH deficiency and decreased longitudinal growth in childhood. Eur. J. Endocrinol., July 1, 2006; 155(1): 91 - 99. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bollerslev, T. Ueland, A. P Jorgensen, K. J Fougner, R. Wergeland, T. Schreiner, and P. Burman Positive effects of a physiological dose of GH on markers of atherogenesis: a placebo-controlled study in patients with adult-onset GH deficiency. Eur. J. Endocrinol., April 1, 2006; 154(4): 537 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Dalle and V. Claude Growth Hormone for "Antiaging" JAMA, February 22, 2006; 295(8): 889 - 889. [Full Text] [PDF]
|
|
|
|
|
|
J. Bollerslev, J. Hallen, K. J Fougner, A. P. Jorgensen, C. Kristo, H. Fagertun, O. Gudmundsen, P. Burman, and T. Schreiner Low-dose GH improves exercise capacity in adults with GH deficiency: effects of a 22-month placebo-controlled, crossover trial Eur. J. Endocrinol., September 1, 2005; 153(3): 379 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gola, S. Bonadonna, M. Doga, and A. Giustina Growth Hormone and Cardiovascular Risk Factors J. Clin. Endocrinol. Metab., March 1, 2005; 90(3): 1864 - 1870. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
