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Department of Endocrinology (H.F., G.J.), Sahlgrenska Academy at Gothenburg’s University, SE-413 45 Gothenburg, Sweden; St. Bartholomew’s Hospital (J.P.M.), Queen Mary University of London, London EC1A 7BE, United Kingdom; KIGS/KIMS/ACROSTUDY Medical Outcomes (M.K.-H., A.M.), Endocrine Care, Pfizer, SE-191 90 Sollentuna, Sweden; and Department of Pharmacy (M.K.-H.), Uppsala University, Uppsala, Sweden
Address all correspondence and requests for reprints to: Helena Filipsson, Department of Endocrinology, Gröna Stråket 8, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. E-mail: helena.filipsson{at}telia.com.
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Abstract |
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Objective: The aim of the study was to examine the influence of GC substitution on clinical characteristics in hypopituitary patients before and after GH replacement therapy.
Method: A total of 2424 hypopituitary patients within the KIMS (Pfizer International Metabolic Database) were grouped according to ACTH status. Comparisons were performed between subjects on hydrocortisone (HC) (n = 1186), cortisone acetate (CA) (n = 487), and prednisolone/dexamethasone (n = 52), and ACTH-sufficient patients (AS) (n = 717) before and after 1 yr of GH treatment in terms of body mass index, waist and hip circumference, blood pressure, glucose, glycosylated hemoglobin (HbA1c), serum lipids, IGF-I, and comorbidity. Hydrocortisone equivalent (HCeq) doses were calculated, and measurements were adjusted for sex and age.
Results: At baseline, the HC group had increased total cholesterol, triglycerides, waist circumference, and HbA1c, and the prednisolone/dexamethasone group had increased waist/hip ratio as compared with AS. After HCeq dose adjustment, the HC group retained higher HbA1c than the CA group. GC-treated patients showed a dose-related increase in serum IGF-I, body mass index, triglycerides, low-density lipoprotein cholesterol and total cholesterol levels. Subjects with HCeq doses less than 20 mg/d (n = 328) at baseline did not differ from AS in metabolic endpoints. The 1-yr metabolic response to GH was similar in all GC groups and dose categories. All new cases of diabetes (n = 12), stroke (n = 8), and myocardial infarction (n = 3) during GH treatment occurred in GC-treated subjects.
Conclusion: HCeq doses of at least 20 mg/d in adults with hypopituitarism are associated with an unfavorable metabolic profile. CA replacement may have metabolic advantages compared with other GCs.
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Introduction |
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Interconversion of active cortisol and inactive cortisone occurs in a predominately reductive manner by action of 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1). 11ß HSD1 is most abundantly expressed in adipose tissue, the liver, the gonads, and the central nervous system (5) and may determine local tissue exposure to GCs. 11ß HSD1 activity is inhibited by GH and IGF-I in acromegaly (6) and is increased in GHD (7, 8), predicting augmented tissue exposure to GCs in GHD. This could explain some of the metabolic features and increased cardiovascular mortality associated with severe GHD (9).
Recently, a reduction in GC dose has been advocated because physiological cortisol production has been shown to be lower than previously thought (10). Hydrocortisone (HC) is most commonly used for replacement therapy. However, some European centers use the biologically inactive GC, cortisone acetate (CA), which requires conversion to cortisol by 11ß HSD1 in the liver. Therefore, there may be differences in cortisol exposure in CA- and HC-treated patients (11). Also, synthetic longer-acting GCs have been used for replacement therapy in selected patients. We have studied the impact of different GC regimens and doses on metabolic outcome, before and after the initiation of GH substitution in the KIMS (Pfizer International Metabolic Database) population of hypopituitary adult patients with GHD.
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Subjects and Methods |
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By 30 January 2004, the KIMS database (12) included 8836 GH-deficient patients from 28 countries. This study was carried out in European patients enrolled in the database, with the following exclusion criteria: inaccurate data (n = 1224), non-European patients (n = 1391), less than 1 yr of follow-up (n = 1063), non-naive patients (n = 1974), ACTH/GH-producing adenomas (n = 225), delayed GH treatment (n = 117), patients commencing GC replacement after baseline (n = 79), or GH peak greater than 3.0 µg/liter in response to a stimulation test (n = 339). Therefore, 2424 patients with severe GHD were available for study.
These patients were divided into four groups according to their GC replacement regimen (Table 1
): 48.2% received HC treatment (HC group), 20.1% CA (CA group), and 2.1% prednisolone (n = 46) or dexamethasone (n = 6) (PD group). Thirty percent of the patients were considered ACTH sufficient (AS group).
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). Ethics
In KIMS, each center obtains approval from their local ethics committee, and the patients give informed consent, either verbally or in writing, depending on the local legal requirements. The study was performed in accordance with the Declaration of Helsinki.
Study design
Patients were studied at baseline and after 1 yr of GH replacement. The design of the KIMS survey is as previously described (12). At baseline, medical history, quality of life, age of onset of pituitary disorder and GHD diagnosis, duration of GH therapy, and number of additional pituitary hormonal deficiencies were documented. Anthropometric measurements and blood pressure (BP) were recorded, and blood samples were collected for measurement of IGF-I, lipids, blood or plasma glucose, and glycosylated hemoglobin (HbA1c).
All participants received sc recombinant human somatropin (Genotropin, Pfizer, Stockholm, Sweden). At the inception of KIMS, GH was administered according to dose schedules based on body weight or body surface area, but subsequently, in the late 1990s, a more individualized schedule was instituted in most centers (13, 14) aiming to normalize IGF-I.
Information on adverse events (AEs) (defined as any untoward medical occurrence) was obtained from spontaneous reports by the patients, active inquiry according to an AE check list, observations of the investigator during physical examination, or the results of laboratory tests.
Methods
Anthropometric measures. Height was measured with an accuracy of 0.5 cm and weight (in kilograms) to one decimal place. BMI was calculated from the formula: weight/height squared (kilograms per square meter). Waist circumference (WC) was measured in the supine position midway between the iliac crest and the lowest level of the thorax and hip as the maximal circumference.
Biochemical assays. Blood lipids and IGF-I were measured centrally in a single laboratory. Serum total cholesterol (TC) (15), triglycerides (16), and high-density lipoprotein cholesterol (HDL-C) (17) were measured as previously described, and low-density lipoprotein cholesterol (LDL-C) was calculated by the Friedewald formula (18).
Serum IGF-I measurements were performed between 1994 and October 1997 by Kabi Pharmacia (Stockholm, Sweden) (19) and thereafter until November 2002 by Sahlgrenska University Hospital (Gothenburg, Sweden), using a RIA (Nichols Institute Diagnostic, San Juan Capistrano, CA). In subsequent years, a chemiluminescence immunoassay was used (Nichols Advantages system) (20). IGF-I data are presented as SD score (SDS). The reference range, ±2 SDS, was calculated from an age- and sex-corrected algorithm in which IGF-I was expressed in micrograms per liter.
Fasting plasma glucose (F-glucose) and HbA1c were analyzed locally by each participating center.
Hydrocortisone equivalent (HCeq) dose. To be able to estimate the impact of GC dose and compare GC groups, a HCeq dose was calculated for all patients not receiving HC. Thus, the equivalent dose of 20 mg HC was 25 mg CA, 5 mg prednisolone (PN) and 0.65 mg dexamethasone (DX) according to previous antiinflammatory comparisons (21, 22, 23, 24).
The mean dose of CA was 30.5 mg/d, PN 6.7 mg/d, and DX 0.3 mg/d. According to the above calculations, the mean HCeq doses were 24.1, 24.4, 26.8, and 9.6 mg/d for HC, CA, PN, and DX, respectively.
GC patients were divided into three groups, with low (<20 mg/d, n = 328), medium (20–29 mg/d, n = 677), and high (
30 mg/d, n = 664) HCeq doses.
Three patients had unusually high HCeq doses (>100–180 mg/d) and were therefore censored in the analyses.
Statistical methods. The statistical analyses for the metabolic outcomes were performed by covariance analyses for unbalanced designs (SAS version 8.2, PROC GLM; SAS Institute Inc., Cary, NC). Treatment group comparisons and dose-response (linear compartment trend) tests were adjusted, in general, for age and sex. Additionally, analyses of BMI were adjusted for country. Because the country distribution differed between treatment groups and categories, the variable "country" was categorized as United Kingdom, Sweden, Belgium + Netherlands, Germany + Spain, and other countries, respectively, based on groups of countries with patients with similar BMI. WC and waist-hip ratio (W/H) were additionally adjusted for BMI (BMI = 28 kg/m2) and country. In tables, means of treatment group or dose category are presented at age 45 yr, with equal gender distribution. Heterogeneity tests and trend tests were based on the F-test. Confidence intervals (CIs) for treatment group differences were based on large sample theory. Adjustment for multiple comparisons was performed according to the Bonferroni method.
The analyses of occurrence of AEs were performed with Fischer’s exact test. The AS group was used as the internal reference. Due to the sparse incidence of some outcomes, the GC groups were treated as one single group and compared with the AS group. Prevalences at baseline were compared with 
2 tests. CIs were Wald based. Statistical significance was set to P < 0.05.
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Results |
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Comparison between types of GC
Anthropometry.
At inclusion, the GC groups had greater WC than AS, although BMI did not differ between the groups. W/H was increased in the PD group, compared with the other groups, a difference that remained after adjustment for HCeq dose (Table 2).
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Metabolic risk factors.
At baseline, HC-treated patients had increased serum levels of TC and triglycerides compared with AS. This difference disappeared after adjustment for HCeq dose (Table 2). HDL-C, LDL-C, systolic and diastolic BP did not differ among the study groups.
F-glucose was lower at baseline in the GC groups compared with AS. In contrast, HbA1c was higher in HC compared with CA and AS, even after adjustment for HCeq dose. CA demonstrated a lower HbA1c as compared with AS (Table 2).
After 1 yr of GH replacement, serum triglycerides and HDL-C concentrations were unchanged, but a decrease in LDL-C (mean change, –0.31 mmol/liter) and TC (–0.36 mmol/liter) was observed. BP did not change during GH treatment. F-glucose and HbA1c increased similarly in all groups, +0.26 mmol/liter and 0.12%, respectively.
Serum IGF-I.
At baseline, all GC-treated groups had reduced serum IGF-I SDS, as compared with AS. The HC group had increased serum IGF-I SDS as compared with both the CA and PD groups after adjustment for HCeq dose (Fig. 1A).
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). Impact of HCeq dose levels
Serum IGF-I, anthropometry, and metabolic risk factors.
Before the GH treatment, patients with a HCeq dose less than 20 mg/d had lower serum IGF-I levels than those with doses of at least 30 mg/d. Using a linear trend analysis, IGF-I SDS increased significantly by HCeq dose category (Fig. 1B).
No difference was seen in BMI, W/H, and BP between groups at baseline, but WC was larger in medium- and high-dose groups compared with AS group (Fig. 2A).
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), and triglycerides levels were increased in HCeq groups using doses of at least 20 mg/d (Fig. 2C) compared with AS. Moreover, TC and LDL-C were increased in the high-dose as compared with the low-dose group (Fig. 2, B and D), whereas serum levels of HDL-C did not differ. Using a trend test, a GC dose response was found in TC, triglycerides, LDL-C, and BMI (Fig. 2, B–E). No difference between sexes could be established in any variable (data not shown). After 1 yr of GH replacement, the effect on anthropometric and metabolic risk factors was similar for the HCeq dose groups and AS. A GC dose response was seen in W/H (trend P = 0.006) and BMI (trend P = 0.03), the lowest HCeq group being most responsive. In contrast, the trend analysis showed a higher serum IGF-I SDS level in the highest HCeq group (Fig. 1B). The results were similar in men and women for all parameters after 1 yr of GH (data not shown). Association with metabolic diseases at baseline and after 1 yr of GH
The frequency of hypertension, diabetes mellitus (DM), cerebrovascular disease, and coronary heart disease was similar among the ACTH-insufficient and -sufficient groups at entry into KIMS. After 1 yr of GH treatment, all new cases of DM (P < 0.05), stroke, and myocardial infarction had occurred in the GC-treated groups (Table 3). The frequency of metabolic events was not related to dose or type of GC, although new cases of DM had a higher BMI. If all reports of hyperglycemia and glucose intolerance were included in the DM reports, the statistical difference between the GC and AS groups disappeared.
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To address the question as to whether GH sensitivity was affected by GC dose or type, we calculated 
IGF-I SDS/0.1 mg/GH dose. There were no differences’ concerning types or doses of GC in IGF-I SDS response either for the whole group or if men and women were analyzed separately (data not shown). However, men demonstrated a greater IGF-I SDS/0.1 mg GH dose than women: 0.82 (95% CI, 0.76–0.87) and 0.64 (95% CI, 0.58–0.71), respectively (P < 0.0001).
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Discussion |
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Historically, 30 mg of oral HC daily was the dose of choice for patients with adrenal insufficiency (25). However, daily cortisol production rates are substantially lower than reported previously (10). More recent studies have demonstrated a safe reduction toward a mean daily dose of 20 mg (26, 27) for most patients.
Hypopituitary patients on GC replacement showed reduced insulin sensitivity on the mornings HC was given compared with mornings without HC in one study (28), but this was not confirmed in a further study (29). Another study found no difference in fasting glucose or HbA1c after a reduction of HC from 30 to 15 mg over a 3-month period (30). We were unable to document a major impact on glucose metabolism in relation to either GC dose or type of GC replacement. The current data therefore suggest that the influence of short- and long-term GC replacement therapy on glucose metabolism is not strong.
We found a clear GC dose response relation with BMI, serum triglyceride, TC, and LDL-C levels. Of interest was the observation that patients receiving a HCeq dose of less than 20 mg per day had a similar metabolic profile to those with an intact HPA axis. This is therefore the first study to demonstrate that a mean GC replacement dose of at least 20 mg HCeq augments the metabolic perturbations associated with hypopituitarism and untreated GHD. The association between GC and obesity, abdominal fat distribution, and glucose intolerance is a well-recognized concept, and it is therefore of some surprise that the relationship between these factors and dose of GC was not stronger in this large cohort of subjects. This indicates that other endocrine insufficiencies may have strong modulating effects and may attenuate some of the differences between the GC-deficient and GC-sufficient patients. It is also possible that increased tissue exposure to GC, as a result of increased 11ß HSD1 activity, which occurs in both ACTH deficient and replete GHD subjects, may exert a major influence over and above that resulting from exogenous GC dose.
Apart from the specific GC treatment, the ACTH-insufficient and AS groups differ in two aspects that may confound our comparisons. Firstly, patients with ACTH insufficiency have lower serum androgen levels, including DHEA sulfate (DHEAS), than AS (31, 32). After GH replacement, DHEAS increases in patients with AS but not in ACTH-insufficient subjects (32). High DHEAS concentrations have been suggested to be protective for cardiovascular disease (33) and exert a favorable influence on insulin sensitivity (34, 35), but data are conflicting (33, 36, 37). Because only seven of 2424 patients were on DHEA, the contribution of androgen replacement in the female patient population is therefore regarded to be small in our study. Secondly, more extensive pituitary damage is found in the GC group compared with AS patients. This could explain some of the metabolic differences and in particular the different levels of IGF-I.
We also examined the possibility that choice of GC may be important for metabolic outcome. HC-treated and PD-treated patients had increased HbA1c and W/H, respectively, suggesting that they may be less favorable choices of GC replacement than CA. Group size and country of origin could, however, be confounding factors, although the latter was statistically corrected for. There have been studies suggesting important differences between CA and HC. In untreated GHD patients, HC, but not CA, seems to give a supraphysiological cortisol tissue exposure, which is attenuated by GH replacement. However, patients treated with CA are more vulnerable to the inhibitory effect of GH on 11ß HSD1 with a reduction of serum cortisol levels (11). Estimates of bioequivalent GC doses have been based on the antiinflammatory effect of GCs and not their metabolic effect. There are some indirect data suggesting that HC may have a higher potency than CA using the traditional estimate (11). However, in the absence of an alternative method for normalizing GC potencies, we have retained the published one. Also, DX and PN are more potent GCs with longer plasma half-life and duration of action and therefore have a practical advantage of being administered only once daily. Their high potency may, however, lead to overexposure to GC and thus contribute to the less favorable metabolic profile as indicated in this study.
The frequency of cardiovascular morbidity was similar between the GC and AS groups, which may be surprising given the evidence that GC treatment is associated with a dose-related increase in the frequency of cardiovascular disease, with no safe lower dose threshold (38, 39). New cases of DM, stroke, and myocardial infarction were confined to the GC-treated group after commencement of GH replacement. It should, however, be considered that the duration of GH treatment in this report is short; the number of new events was low, and the AS patients were on average 6 yr younger than the GC group.
One year of GH replacement induced a similar metabolic response among the different types of GC despite differences in serum IGF-I generation. Therefore, the differences in anthropometry and metabolic risk factors between types of GC remained. However, it is important to recognize that GH may expose hypoadrenalism in patients on low GC doses because the inhibition by GH of 11ß HSD1 activity reduces cortisol availability. Moreover, the lower serum IGF-I SDS observed in the CA group as compared with AS at 1 yr may confound the results. This cannot be explained by an increased proportion of young females because data were adjusted for age and sex. Furthermore, childhood onset hypopituitarism was less prevalent in the CA group. Because GH doses were similar in AS and CA patients, the explanation for the lower serum IGF-I levels in the CA-treated subjects is unclear.
Serum IGF-I concentrations appear to be influenced by type and dose of GC, a phenomenon that has not been described previously. The lower basal IGF-I found in GC-treated compared with AS patients could merely reflect more extensive hypopituitarism. An increasing dose of GC was associated with increased serum IGF-I both at baseline and after 1 yr of GH treatment. There are some previous data suggesting that GC augments serum IGF-I generation (40) only in the presence of GH (41). A direct hepatic effect of GC on IGF-I secretion after GH administration has been suggested (42), and it is also possible that higher serum insulin concentrations in GC-treated patients may augment the serum IGF-I response during GH replacement.
This study has for the first time been able to delineate the adverse metabolic profile associated with small differences in doses of GC replacement therapy. Our data suggest that an average HC dose of less than 20 mg/d is not associated with a more adverse metabolic profile than that observed in hypopituitary patients with an intact HPA axis. Moreover, our data suggest that patients receiving HC and more long-acting synthetic GCs are more prone to develop an adverse metabolic profile than those using CA. Finally, the serum level of IGF-I in severe GHD is dependent on GC status, whereas the metabolic response to GH replacement is not. Our data support further efforts in optimizing the GC replacement therapy using the lowest effective dose without compromising short-term safety and well-being.
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Footnotes |
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First Published Online August 8, 2006
Abbreviations: AE, Adverse event; AS, ACTH-sufficient (patients); BMI, body mass index; BP, blood pressure; CA, cortisone acetate; CI, confidence interval; DHEA, dehydroepiandrostenedione; DHEAS, DHEA sulfate; DM, diabetes mellitus; DX, dexamethasone; GC, glucocorticoid; GHD, GH deficiency; F-glucose, fasting plasma glucose; HbA1c, glycosylated hemoglobin; HC, hydrocortisone; HCeq, HC equivalent; HDL-C, high-density lipoprotein cholesterol; HPA, hypothalamic-pituitary-adrenal; 11ß HSD1, 11ß hydroxysteroid dehydrogenase type 1; LDL-C, low-density lipoprotein cholesterol; PD, prednisolone/dexamethasone; PN, prednisolone; SDS, SD score; TC, total cholesterol; WC, waist circumference; W/H, waist-hip ratio.
Received March 8, 2006.
Accepted July 27, 2006.
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, P < 0.0001 vs. less than 20 mg/d. The broken line represents a dose response analysis within the GC-treated groups.
