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Nonfatal Stroke, Cardiac Disease, and Diabetes Mellitus in Hypopituitary Patients on Hormone Replacement Including Growth Hormone

Department of Internal Medicine (H.H.), Centralsjukhuset, SE-291 85, Kristianstad, Sweden; Endocrine Unit (H.H., E.-M.E.), Departments of Medicine and Neurology (B.N.), Lund University Hospital, SE-221 85 Lund, Sweden; Research Centre for Endocrinology and Metabolism (J.S., G.J., T.R., B.-A.B.), Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden; Division of Occupational and Environmental Medicine and Psychiatric Epidemiology (L.R., L.H.), Lund University, SE-221 00 Lund, Sweden; Department of Endocrinology, Metabolism and Diabetes (M.T., C.H., M.D.), Karolinska University Hospital Solna, SE-141 86 Stockholm, Sweden; Department of Endocrinology (M.B.), University Hospital, SE-205 02 Malmö, Sweden; Department of Medicine (E.H.), University Hospital, SE-901 87 Umeå, Sweden; Department of Medical Sciences (B.E.E.), Internal Medicine, Uppsala University Hospital, SE-751 85 Uppsala, Sweden; and Internal Medicine (B.E.), Department of Medicine and Care, University Hospital, SE-581 83 Linköping, Sweden

Address all correspondence and requests for reprints to: Eva-Marie Erfurth, Department of Endocrinology, Lund University Hospital, SE-221 85 Lund, Sweden. E-mail: Eva-Marie.Erfurth{at}med.lu.se.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: The impact of long-term GH replacement on cerebrovascular and cardiovascular diseases and diabetes mellitus in hypopituitary patients is unknown.

Objective: The incidence of nonfatal stroke and cardiac events, and prevalence of type 2 diabetes mellitus (T2D) and cardioprotective medication were compared between cohorts of GH-deficient (GHD) patients and population controls.

Design and Participants: The incidence of nonfatal stroke and cardiac events was estimated retrospectively from questionnaires in 750 GHD patients and 2314 matched population controls. A prevalence of T2D and cardioprotective medication was recorded at the distribution of questionnaires. Time since first pituitary deficiency to start of GH therapy was 4 and 2 yr, and time on GH therapy was 6 yr for GHD women and men, respectively.

Results: Lifelong incidence of nonfatal stroke was tripled in GHD women and doubled in GHD men, but a decline was seen in both genders during periods after first pituitary hormone deficiency and GHD, during which most patients had GH therapy. The lifelong incidence of nonfatal cardiac events declined in GHD men during first pituitary hormone deficiency and GHD periods. GHD women had a higher prevalence of T2D and lipid-lowering medication, whereas GHD men had a higher prevalence of antihypertensive medication.

Conclusions: The declined risks of nonfatal stroke in both genders and of nonfatal cardiac events in GHD men during periods on GH replacement may be caused by prescription of cardioprotective drugs and 6-yr GH replacement. GHD women had an increased prevalence of T2D, partly attributed to higher body mass index and lower physical activity.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
EPIDEMIOLOGICAL STUDIES HAVE revealed increased cerebrovascular and cardiovascular mortality in patients with hypopituitarism on conventional hormone treatment, but without GH therapy (1, 2, 3). The greatest increase was seen in cerebrovascular disease (2, 3), with a more pronounced risk in women, but without gender difference in cardiac mortality (2). Furthermore, an increased incidence of nonfatal cerebrovascular and cardiovascular events (4) was recorded among GH-deficient (GHD) patients, along with higher prescription of cardioprotective medication in GHD women (5). Untreated GHD has been assumed to be responsible for early atherogenesis in hypopituitarism because cardiovascular risk factors have been improved on GH therapy (6).

Hypertension is an important risk factor for myocardial infarction (MI) and stroke (7, 8). In unsubstituted GHD an increased prevalence of treated hypertension has been recorded (9). It is noteworthy that GH treatment has decreased diastolic blood pressure (10), but the risk ratio for nonfatal cerebrovascular events tends to increase in GHD patients, even after 5-yr GH therapy (4).

A high prevalence of impaired glucose tolerance (11, 12) and type 2 diabetes mellitus (T2D) has been shown in GHD patients (13). GH treatment may further increase insulin and glucose levels (14), and even lead to diabetes mellitus (DM) in GHD children (15), which is most likely explained by the insulin antagonistic effect of GH (15). In GHD adults, 6-month low-dose GH replacement showed impairment of insulin sensitivity (16), but it has also been suggested that GH therapy decreases insulin resistance because of reduction in fat mass (17, 18). However, an actual prevalence of DM among GH-treated GHD patients is unknown.

Information regarding the impact of long-term GH therapy (i.e. >2 yr) on the incidence of nonfatal cerebrovascular and cardiovascular diseases in sufficiently large populations of hypopituitary patients is currently lacking. Therefore, the aim of the present study was 2-fold: 1) to make a retrospective comparison of the incidence of nonfatal stroke and cardiac events between a large cohort of patients with confirmed GHD on GH replacement and a control cohort from the general population; and 2) to compare the prevalence of DM and cardioprotective medication between the cohorts at the time of questionnaire distribution with adjustment for possible confounders and effect modifiers.

	Patients and Methods

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Patient study base

Prevalent cases of adult-onset (AO) GHD were recruited from the Department of Endocrinology at all Swedish University Hospitals and one county hospital, with the inclusion criterion of severe GHD determined by dynamic testing (peak GH < 3 µg/liter). Tests included the: insulin tolerance test (n = 409); arginine and arginine-insulin tests (n = 203 and n = 2, respectively); GHRH and GHRH-arginine tests (n = 32 and n = 29, respectively); and others (n = 66), such as glucagon, clonidine, L-dopa, apomorphine, and a 24-h GH profile (n = 103). At least one of the other aforementioned tests had been used among 64 patients with a 24-h GH profile, and among remaining patients (n = 39), only five had less than two other pituitary deficiencies (19), and their 24-h GH profile showed a maximum GH 1.7 µg/liter. Of the patients, 87% had a today recommended test (20), and the test was repeated in 13%. Among those with a less accurate test, only 14% had less than two other pituitary deficiencies. GHD diagnoses were made between 1967 and 2001. Local representatives of the study group submitted information for each patient concerning cause of pituitary deficiency and other patient characteristics.

A total of 750 patients (82%) responded to a questionnaire sent in April 2003. After completion of information (n = 26), they then constituted the study base. Of the study base, 53% (n = 399) were men, and 47% (n = 351) were women. Median age at the end of study was 59 (5th-95th percentile, 31–78) in men and 58 (31–76) in women. The major cause of pituitary deficiency was pituitary adenoma (Fig. 1), hyperfunctional in 31% of the cases. Of adenomas, 4% in men and 15% in women were ACTH secreting, and 92% of men and 84% of women were cured upon GHD diagnosis. Four percent of adenomas in men and 8% in women were GH secreting. Of the patients with pituitary adenomas, 82% underwent surgery, 49% had received conventional cranial radiotherapy (CRT), and 7% stereotactic irradiation. The frequency of CRT-treated adenomas in males and females with and without stroke (lifelong incidence) was similar (54 vs. 50% and 57 vs. 51%, respectively), and no patients with CRT due to reasons other than pituitary adenoma suffered strokes. Figure 2 presents the frequencies of different pituitary substitutions when GHD was confirmed and replacements at the end of study period. Only 7% of men and 9% of women had isolated GHD, and the remaining patients had multiple pituitary deficiencies. At the end of the study, women underwent sex steroid replacement therapy to the same extent, regardless of whether they were 50 or younger than 50 yr old (50 vs. 53%, respectively). Female patients with or without a history of stroke also underwent sex steroid replacement to the same extent (50 vs. 52%, respectively). Combination therapies (estrogens and gestagens) were mainly administered orally (62%) or through transdermal application (6%), followed by estradiol administered as oral (21%) or transdermal (11%) therapy.

View larger version (14K): [in this window] [in a new window]   FIG. 1. Causes of pituitary deficiencies in 399 AO GHD men and 351 AO GHD women. 1 Examples include Sheehan’s syndrome, empty sella syndrome, meningioma, pituitary cyst, and hypophysitis. 2 For reasons other than pituitary adenoma or craniopharyngioma.

View larger version (17K): [in this window] [in a new window]   FIG. 2. Substitution therapies at confirmed GHD (A), and pituitary hormone deficiencies and substitution therapies at end of study (B) in 399 AO GHD men and 351 AO GHD women. ADH, Antidiuretic hormone.

Population controls

Statistics Sweden selected four controls each from the Swedish population register, and successfully matched these for age, gender, county of residence, and country of birth. They were otherwise randomly selected. A total of 2314 (77% of those alive and living in Sweden) subjects responded to the questionnaire in November 2003. The participation rate was 79% in women (n = 1104) and 76% in men (n = 1210). Median age was 60 yr (5th-95th percentile 31–78) for men and 58 (30–75) for women. Statistics Sweden completed questionnaire information through interview in 6% of the respondents.

Statistics Sweden provided information on age, country of birth, marital status, income, and urban/rural residence for the responding and nonresponding population controls. Despite the fact that participating men were somewhat younger and the participants of both genders were more often married compared with nonparticipants, no other socioeconomic characteristics differed (data not shown). Women underwent sex steroid replacement more frequently at 50 than younger than 50 yr of age (26 vs. 7%, respectively), but there was no difference in sex steroid use between population controls with or without a history of stroke (21% in both groups). Combination therapies were administered mainly through oral (53%) or transdermal application (5%), followed by estradiol administered as oral (31%) or transdermal therapy (10%).

Questionnaire and outcome measures

The same questionnaire was used for both patient and control cohorts. The questions addressed background information, including current alcohol consumption, smoking history, country of birth, educational level and residency, body weight, and height. Physical activity during work/leisure time was classified on a four-grade scale (21). A composite measure of physical activity was then constructed from these variables, and dichotomized into "low" and "high."

Information pertaining to present DM, antidiabetic therapy (diet, oral, or insulin medication), and use of antihypertensive, lipid-lowering, or antithrombotic drugs was requested. Participants were asked whether they had had a stroke (ischemic or hemorrhagic) or cardiac event defined as MI, percutaneous transluminal coronary angioplasty (PTCA), or bypass surgery, and during what calendar year. Two outcome measures were used for incidence calculations: 1) nonfatal stroke, and 2) nonfatal cardiac event.

Distributions of matching criterion, potential confounders, and effect modifiers

Table 1 shows successful age matching along with distribution of potential confounders and effect modifiers.

Three follow-up periods were defined for the incidence studies. Start of follow-up for the three periods was defined respectively as: 1) from birth (lifelong period), 2) from calendar year of first confirmed pituitary hormone deficiency (FHD) period, and 3) from calendar year of confirmed GHD period. All periods were followed until the calendar year of first stroke or December 31, 2002, whichever occurred first (Fig. 3). The corresponding end of follow-up was defined for cardiac event. The same follow-up periods were applied for the matched population control cohort.

View larger version (12K): [in this window] [in a new window]   FIG. 3. Timetable illustrating the length (yr) of the follow-up periods for stroke (lifelong, FHD, and GHD) for median man and median woman. The figures within brackets are the 5th and 95th percentiles for the whole groups. Corresponding analyses were performed for cardiac events. Dec, December.

Information on GH dose at the end of study was available in 96% of patients. GH doses were 0.4 mg/d in women (range 0.15–0.9) and 0.3 mg/d in men (range 0.13–0.6) at the time of collection of questionnaires. At the end of study, median serum IGF-I levels were available among 86% of the patients groups. Expressed as SD values, the IGF-I level in AO GHD women was 0.0 (–2.0–2.3) and in men 0.5 (–2.5–3.4).

Time since FHD to start of GH treatment was 4 and 2 yr for GHD women and men (0–27 and 0–21, respectively). Time since confirmed GHD to start of GH therapy was 1 yr for both GHD women and men (0–4) (Fig 3).

Statistical analyses

Medians with 5th and 95th percentiles were applied for descriptive statistics. For comparisons between the GHD patients and the population controls (cohort affiliation), incidence rate ratio (IRR) and 95% confidence intervals (CIs) for first stroke or first cardiac event (MI/PTCA/bypass surgery) were calculated with Poisson regression models using EGRET software (Statistics and Epidemiology Research Corp., Seattle, WA). A lower limit of the 95% CI more than 1.00 is interpreted as a significantly increased incidence. Likewise, an upper limit of the 95% CI less than 1.00 is interpreted as a significantly decreased incidence. Separate analyses were performed for men and women to account for possible effect modification. The absolute number of cases, especially among the GHD patients, was generally very low, so models did not include potential confounders.

The prevalence of DM and use of antihypertensive, lipid-lowering, or antithrombotic drugs was compared between the patient and control cohorts, calculating prevalence odds ratios (PORs). Smoking habits (ever/never), body mass index (BMI) (<20, 20–30, and >30 kg/m²), and physical activity (low and high) were considered potential confounders and included in the model, one at a time, together with cohort affiliation, and retained if they changed the crude effect estimate by more than 15%. If adjusted effect estimates differed less than 15% from the crude estimates, we presented only the crude estimates. In a second estimation of the aforementioned incidence and prevalence calculations, acromegaly and Cushing’s disease patients were excluded.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Incidence of nonfatal stroke and nonfatal cardiac event

Analyzed retrospectively, the lifelong incidence of nonfatal stroke was three times as high among the female patients, whereas it was twice as high among the male patients, when compared with controls (Table 2). For the FHD period, IRRs nearly double in numerical terms were observed for nonfatal stroke between both genders but did not reach significance. For the GHD period, a nonsignificant 58% increase of nonfatal stroke was observed for the male patients, whereas not even a numerical risk increase was observed for the female patients. However, the latter analysis was hampered by the low number of cases.

Prevalence of DM and cardioprotective drugs

Even after confounder (BMI, smoking, and physical activity) adjustment, the prevalence for DM among GHD women was twice that of the population controls, whereas no enhanced prevalence was noted among the GHD men (Table 3). GHD women and controls had diet (25 vs. 27%), oral medication (21 vs. 19%), combination of oral medication and insulin (18 vs. 16%), or insulin treatment (36 vs. 38%) for their DM to the same extent, and this was also true for GHD men. When excluding acromegaly and Cushing’s disease patients, the prevalence for DM among female patients was higher than in controls [POR 2.02 (1.17–3.49); P = 0.01], but after confounder adjustment, the POR for DM was no longer statistically significant [POR 1.57 (0.87–2.84); P = 0.13].

There was no difference in the effect modifier "educational level" between patients and controls, but both GHD men and women were likely to live alone, and GHD men abstained from alcohol to a greater extent than controls (Table 1). When living alone was included in the model, the prevalence for DM or cardioprotective drugs did not change (data not shown).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
This is the first comprehensive study on cerebrovascular and cardiovascular morbidity in hypopituitary patients with confirmed AO GHD on long-term GH therapy. Both women and men with GHD had significantly increased risk for nonfatal stroke during the lifelong follow-up, and again women were at higher risk than men. However, among the GHD women, no risk increase for nonfatal stroke was recorded during the FHD (IRR 1.98) or GHD periods (IRR 0.97), during which most patients had GH replacement. However, the latter period was hampered by a minute number of observations. The same pattern was seen among the GHD men, but risk for nonfatal stroke did not seem to level off quite as much during the FHD (IRR 1.70) and GHD periods (IRR 1.58). We excluded patients with acromegaly and Cushing’s disease, well known to have an increased cardiovascular risk (22, 23), but the estimates did not change.

The incidence of nonfatal stroke was high before the FHD and GHD periods in the present study. The cause is not known, but the patients may have been pituitary deficient before the date of diagnosed pituitary tumor (2). It is also relevant that women with longer duration of hypopituitarism symptoms before pituitary tumor diagnosis later suffered fatal strokes (24).

One reason for the reduced risk for nonfatal stroke among the GHD women may be increased prescription of lipid-lowering drugs, possibly explained by the increased prevalence of DM, shown in our GHD women because guidelines recommend lipid-lowering drugs at low levels of total cholesterol (25). Furthermore, women with DM have greater lipoprotein abnormalities than men with the same cardiovascular risk (26). Most likely, lipid-lowering drugs and GH therapy contributed to the reduction in nonfatal strokes in GHD women in the present study.

Although GHD is the first deficiency occurring (27), it was previously seldom detected, probably because GH therapy was not available. Unsubstituted GHD has been advocated as a strong candidate for the increased cardiovascular risk in these patients. However, even if the incidence of nonfatal stroke was no longer increased during the GHD period, we cannot conclude that GH therapy per se protected against stroke because patients with fatal stroke were not included in this study. However, a recent prospective population-based study showed that low-serum IGF-I levels increase the risk for ischemic stroke (28). The type of stroke was not defined in the present study, but a near significant increase in antithrombotic medication in AO GHD men (35%) favors ischemic stroke.

In population-based studies, sex steroid therapy for postmenopausal women was related to increased cardiovascular risk (29, 30). In comparison to population controls, GHD women in the present study used sex steroid replacement more frequently before age 50 yr. However, it is not known whether this early replacement contributed to an increased incidence of lifelong nonfatal stroke. In comparison to population controls, there was no difference in the use of the different estrogen and gestagen compounds, or evidence that GHD women who suffered a nonfatal stroke used sex steroid replacement more often than those who did not.

Subclinical hypothyroidism causes increased cardiovascular risk (31). However, in a previous study, hypopituitary patients had slightly higher circulating free thyroxine levels (5), not shown to increase cardiovascular risk. Furthermore, thyroxine doses and the percentage on replacement were similar in GHD men and women with or without lifelong stroke in the present study.

Glucocorticoid overdose has also been advanced as a potential inducer of cardiovascular risk (32). In the present study, there was no significant difference in glucocorticoid dosage or percentage on replacement between GHD men and women with or without lifelong stroke (data not shown).

An important issue is whether CRT of a pituitary tumor increases the risk for subsequent stroke, which has been suggested (33, 34). No difference in the incidence of nonfatal stroke was recorded in GHD patients with or without CRT in the present study. This concurs with studies revealing no association between the biological equivalent dose of radiotherapy and risk for subsequent stroke (24, 35).

A decreased incidence of nonfatal cardiac events was seen among GHD men, but not in women, during both the FHD and GHD periods. A decline in MI has been reported after 5-yr GH therapy, if both fatal and nonfatal events were included (4). However, when excluding fatal events, no difference remained, suggesting that GH provides protection against serious MI with a rapid time course. This is consistent with findings that low-serum IGF-I may be involved in the pathogenesis of ischemic heart disease (36). Another explanation is the significant increase in antihypertensive drug prescription recorded in GHD men, who were also more likely than controls to have no smoking history. As for all other cardioprotective drugs in the present study, an observational bias is possible not only because patients on GH therapy visit their doctor more often and have investigations on blood pressure, lipid levels, and glycosylated hemoglobin, but also because endocrinologists are now aware of the increased cardiovascular risk among GHD. However, this cannot explain the difference between men and women. On the contrary, because target blood pressure levels in diabetics are narrower (<130/80 mm Hg) (25), a higher prescription of antihypertensive drugs would be expected among GHD women. Medical health care is also very uniform in Sweden, meaning that all patients in the present study received equal attention from endocrinologists.

This is the largest study investigating nonfatal cardiovascular disease in GH-treated GHD patients to date, allowing us sufficient capacity to significantly detect risk estimates observed in previous studies (2, 3), whereas for specific subgroup analyses with fewer cases, this capacity was naturally lower. Because of wide CIs, relatively large effects could not be excluded. To detect a significant risk increase of about three with 80% power (e.g. upper confidence limit for stroke among men for the GHD period), a study size of about half the present is required. Conversely, to detect a significant risk increase of about 1.6 (as in the present study), a study size of about four times the present is required. The present patient cohort was based on a cross-section of survivors, and our results may be hampered by fatal cerebrovascular and cardiovascular events before this study. However, because survival within 28 d after both stroke and MI has improved markedly in Sweden (37), the incidence of nonfatal events has become a major issue.

There is no evidence for selection of patients alive at inclusion in the study because the causes of GHD were distributed as expected (38). GHD was confirmed after adequate testing in most patients, and GH doses seemed adequate with higher doses in women than men (39), and with SD IGF-I levels at the mid ranges.

Population controls matched for potential confounders, age, gender, county of residence, and country of birth were used in the present study. The participation rate among controls was uniquely high (77%) and very close to that among the patients (82%). The same questionnaire was sent in the same manner to both patients and control cohorts.

This study is the first to show the prevalence of DM and cardioprotective medication after 6-yr GH therapy. The cause was not overtreatment of GH because the SD IGF-I level was exactly in the mid range. Based on a majority of noninsulin treatments, the GHD women had an increased prevalence of T2D. This increase was seen even after exclusion of acromegaly and Cushing’s disease patients, but when including confounders in the model, POR for T2D was no longer significant, indicating that the increased prevalence of DM was partly attributed to higher BMI and lower physical activity. When including the effect modifier "living alone" in the model, no change was seen in these estimates. Thus, it seems that T2D can only be avoided if BMI and physical activity are carefully observed. Previously, shorter GH treatment periods have shown an increase in blood glucose levels (14), more deleterious in GHD women (14), but provided that fat mass was reduced and lean mass increased during longer GH therapy unchanged insulin sensitivity has been recorded (40). Unfortunately, given the lack of information on the incidence of DM in this study, we cannot state whether there was a decline or an increase in DM after 6-yr GH therapy.

In conclusion, in a cohort of 750 patients with AO GHD, prescription of cardioprotective drugs and 6-yr GH therapy may have resulted in a reduced risk for nonfatal stroke, particularly noted in women, and in a decline in nonfatal cardiac events in GHD men. GHD women had an increased prevalence of T2D, partly attributed to higher BMI and lower physical activity. Continuous surveillance of cardiovascular risk, and especially of DM, is recommended in this patient population.

	Footnotes

 
This work was supported by the Swedish Research Council (Grant K 2002-72X-14257-01), the Swedish Children’s Cancer Foundation, and the Medical Faculty, Lund University, Sweden. Generous grants were provided by Pfizer AB, Eli Lilly Sweden AB, and Ipsen Scandinavia A/S.

This study is retrospectively registered at www.clinicaltrials.gov (March 2007).

Disclosure Statement: E.-M.E. received grant support from Pfizer AB, Eli Lilly Sweden AB, and Ipsen Scandinavia A/S.

First Published Online July 10, 2007

Abbreviations: AO, Adult-onset; BMI, body mass index; CI, confidence interval; CRT, cranial radiotherapy; DM, diabetes mellitus; FHD, first confirmed pituitary hormone deficiency; GHD, GH deficient; IRR, incidence rate ratio; MI, myocardial infarction; POR, prevalence odds ratio; PTCA, percutaneous transluminal coronary angioplasty; T2D, type 2 diabetes mellitus.

Received March 1, 2007.

Accepted June 28, 2007.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Rosén T, Bengtsson BÅ 1990 Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 336:285–288[CrossRef][Medline]
2. Bülow B, Hagmar L, Mikoczy Z, Nordström CH, Erfurth EM 1997 Increased cerebrovascular mortality in patients with hypopituitarism. Clin Endocrinol (Oxf) 46:75–78[CrossRef][Medline]
3. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM, West Midlands Prospective Hypopituitary Study Group 2001 Association between premature mortality and hypopituitarism. Lancet 357:425–431[CrossRef][Medline]
4. Svensson J, Bengtsson BÅ, Rosén T, Odén A, Johannsson G 2004 Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. J Clin Endocrinol Metab 89:3306–3312[Abstract/Free Full Text]
5. Bülow B, Hagmar L, Eskilsson J, Erfurth EM 2000 Hypopituitary females have a high incidence of cardiovascular morbidity and an increased prevalence of cardiovascular risk factors. J Clin Endocrinol Metab 85:574–584[Abstract/Free Full Text]
6. Carroll PV, Christ ER, Bengtsson BA, Carlsson L, Christiansen JS, Clemmons D, Hintz R, Ho K, Laron Z, Sizonenko P, Sonksen PH, Tanaka T, Thorne M 1998 Growth hormone deficiency in adulthood and the effects of growth hormone replacement: a review. Growth Hormone Research Society Scientific Committee. J Clin Endocrinol Metab 83:382–395[Abstract/Free Full Text]
7. Kannel WB 1989 Risk factors in hypertension. J Cardiovasc Pharmacol 13:4–10
8. MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J 1990 Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 335:765–774[CrossRef][Medline]
9. Rosén T, Edén S, Larson G, Wilhelmsen L, Bengtsson BÅ 1993 Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 129:195–200[Medline]
10. Caidahl K, Edén S, Bengtsson BÅ 1994 Cardiovascular and renal effects of growth hormone. Clin Endocrinol (Oxf) 40:393–400[Medline]
11. Johansson JO, Fowelin J, Landin K, Lager I, Bengtsson BA 1995 Growth hormone-deficient adults are insulin-resistant. Metabolism 44:1126–1129[CrossRef][Medline]
12. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG 1992 Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 340:1188–1192[CrossRef][Medline]
13. Beshyah SA, Henderson A, Niththyananthan R, Sharp P, Richmond W, Johnston DG 1994 Metabolic abnormalities in growth hormone deficient adults. II. Carbohydrate tolerance and lipid metabolism. Endocrinol Metab 1:173–180
14. Maison P, Griffin S, Nicoue-Beglah M, Haddad N, Balkau B, Chanson P, Metaanalysis of Blinded, Randomized, Placebo-Controlled Trials 2004 Impact of growth hormone (GH) treatment on cardiovascular risk factors in GH-deficient adults: a metaanalysis of blinded, randomized, placebo-controlled trials. J Clin Endocrinol Metab 89:2192–2199[Abstract/Free Full Text]
15. Cutfield WS, Wilton P, Bennmarker H, Albertsson-Wikland K, Chatelain P, Ranke MB, Price DA 2000 Incidence of diabetes mellitus and impaired glucose tolerance in children and adolescents receiving growth-hormone treatment. Lancet 355:610–613[CrossRef][Medline]
16. Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L 2003 Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. J Clin Endocrinol Metab 88:1455–1463[Abstract/Free Full Text]
17. Fowelin J, Attvall S, Lager I, Bengtsson BA 1993 Effects of treatment with recombinant human growth hormone on insulin sensitivity and glucose metabolism in adults with growth hormone deficiency. Metabolism 42:1443–1447[CrossRef][Medline]
18. O’Neal DN, Kalfas A, Dunning PL, Christopher MJ, Sawyer SD, Ward GM, Alford FP 1994 The effect of 3 months of recombinant human growth hormone (GH) therapy on insulin and glucose-mediated glucose disposal and insulin secretion in GH-deficient adults: a minimal model analysis. J Clin Endocrinol Metab 79:975–983[Abstract]
19. Toogood AA, Beardwell CG, Shalet SM 1994 The severity of growth hormone deficiency in adults with pituitary disease is related to the degree of hypopituitarism. Clin Endocrinol (Oxf) [Errata (1994) 41:845; (1995) 42:109] 41:511–516
20. 1998 Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society Workshop on Adult Growth Hormone Deficiency. J Clin Endrocrinol Metab 83:379–381
21. Wilhelmsen L, Tibblin G, Aurell M, Bjure J, Ekström-Jodal B, Grimby G 1976 Physical activity, physical fitness and risk of myocardial infarction. Adv Cardiol 18:217–230[Medline]
22. Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G 1999 Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J Clin Endocrinol Metab 84:2664–2672[Abstract/Free Full Text]
23. Lombardi G, Galdiero M, Auriemma RS, Pivonello R, Colao A 2006 Acromegaly and the cardiovascular system. Neuroendocrinology 83:211–217[CrossRef][Medline]
24. Erfurth EM, Bulow B, Svahn-Tapper G, Norrving B, Odh K, Mikoczy Z, Bjork J, Hagmar L 2002 Risk factors for cerebrovascular deaths in patients operated and irradiated for pituitary tumors. J Clin Endocrinol Metab 87:4892–4899[Abstract/Free Full Text]
25. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 2002 American Diabetes Association: clinical practice recommendations 2002. Diabetes Care 25(Suppl 1):S1–S147
26. Knopp RH, Paramsothy P, Retzlaff BM, Fish B, Walden C, Dowdy A, Tsunehara C, Aikawa K, Cheung MC 2006 Sex differences in lipoprotein metabolism and dietary response: basis in hormonal differences and implications for cardiovascular disease. Curr Cardiol Rep 8:452–459[CrossRef][Medline]
27. Littley MD, Shalet SM, Beardwell CG, Ahmed SR, Appelgate G, Sutton ML 1988 Hypopituitarism following external radiotherapy for pituitary tumours in adults. Q J Med 262:145–160
28. Johnsen SP, Hundborg HH, Sorensen HT, Ørskov H, Tjonneland A, Overvad K, Jorgensen JO 2005 Insulin-like growth factor (IGF) I, -II and IGF binding protein-3 and risk of ischemic stroke. J Clin Endocrinol Metab 90:5937–5941[Abstract/Free Full Text]
29. Barrett-Connor E 2003 Clinical review 162: cardiovascular endocrinology 3: an epidemiologist looks at hormones and heart disease in women. J Clin Endocrinol Metab 88:4031–4042[Free Full Text]
30. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R, Curb D, Gass M, Hays J, Heiss G, Hendrix S, Howard BV, Hsia J, Hubbell A, Jackson R, Johnson KC, Judd H, Kotchen JM, Kuller L, LaCroix AZ, Lane D, Langer RD, Lasser N, Lewis CE, Manson J, Margolis K, Ockene J, O’Sullivan MJ, Phillips L, Prentice RL, Ritenbaugh C, Robbins J, Rossouw JE, Sarto G, Stefanick ML, Van Horn L, Wactawski-Wende J, Wallace R, Wassertheil-Smoller S, Women’s Health Initiative Steering Committee 2004 Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712[Abstract/Free Full Text]
31. Owen PJ, Lazarus JH 2003 Subclinical hypothyroidism: the case for treatment. Trends Endocrinol Metab 14:257–261[CrossRef][Medline]
32. Beshyah SA, Johnston DG 1999 Cardiovascular disease and risk factors in adults with hypopituitarism. Clin Endocrinol (Oxf) 50:1–15[CrossRef][Medline]
33. Brada M, Burchell L, Ashley S, Traish D 1999 The incidence of cerebrovascular accidents in patients with pituitary adenoma. Int Radiat Oncol Biol Phys 45:693–698[CrossRef]
34. Hashimoto N, Handa H, Yamashita J, Yamagami T 1986 Long term follow-up of large invasive pituitary adenomas. Surg Neurol 25:49–54[CrossRef][Medline]
35. Erfurth EM, Hagmar L 2005 Cerebrovascular disease in patients with pituitary tumors. Trends Endocrinol Metab 16:334–342[CrossRef][Medline]
36. Juul A, Scheike T, Davidsen M, Gyllenborg J, Jorgensen T 2002 Low serum insulin-like growth factor I is associated with increased risk of ischemic heart disease: a population-based case-control study. Circulation 106:939–944[Abstract/Free Full Text]
37. Wilhelmsen L, Koster M, Harmsen P, Lappas G 2005 Differences between coronary disease and stroke in incidence, case fatality, and risk factors, but few differences in risk factors for fatal and non-fatal events. Eur Heart J 26:1916–1922[Abstract/Free Full Text]
38. Regal M, Páramo C, Sierra JM, García-Mayor RV 2001 Prevalence and incidence of hypopituitarism in an adult Caucasian population in northwestern Spain. Clin Endocrinol (Oxf) 55:735–740[CrossRef][Medline]
39. Janssen YJ, Frölich M, Roelfsema F 1997 A low dose of genotropin in growth hormone-deficient adults. J Clin Endocrinol Metab 82:129–135[Abstract/Free Full Text]
40. Svensson J, Fowelin J, Landin K, Bengtsson B-Å, Johansson J-O 2002 Effects of seven years of growth hormone (GH) replacement therapy on insulin sensitivity in GH deficient adults. J Clin Endocrinol Metab 87:2121–2127[Abstract/Free Full Text]

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