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Home , Hypopituitarism, Pituitary disease

European Journal of (2009) 161 S75–S83 ISSN 0804-4643

From isolated GH deficiency to multiple pituitary deficiency: an evolving continuum – a KIMS analysis M Klose, B Jonsson1, R Abs2, V Popovic3, M Koltowska-Ha¨ggstro¨m4, B Saller5, U Feldt-Rasmussen and I Kourides6 Department of Medical Endocrinology, Copenhagen University Hospital, PE2131, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, 1Department of Women’s and Children’s Health, Uppsala University, SE-75185 Uppsala, Sweden, 2Department of Endocrinology, University of Antwerp, Antwerp, Belgium, 3Neuroendocrine Unit, Institute of Endocrinology, University Clinical Center Belgrade, Belgrade, Serbia, 4KIMS Medical Outcomes, Pfizer Endocrine Care, Sollentuna, Sweden, 5Pfizer Endocrine Care Europe, Tadworth, UK and 6Global Endocrine Care, Pfizer Inc., New York, New York 10017, USA (Correspondence should be addressed to M Klose; Email: [email protected])

Abstract Objective: To describe baseline clinical presentation, treatment effects and evolution of isolated GH deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) in adult-onset (AO) GHD. Design: Observational prospective study. Methods: Baseline characteristics were recorded in 4110 patients with organic AO-GHD, who were GH naı¨ve prior to entry into the Pfizer International Metabolic Database (KIMS; 283 (7%) IGHD, 3827 MPHD). The effect of GH replacement after 2 years was assessed in those with available follow-up data (133 IGHD, 2207 MPHD), and development of new deficiencies in those with available data on concomitant medication (165 IGHD, 3006 MPHD). Results: IGHD and MPHD patients had similar baseline clinical presentation, and both groups responded similarly to 2 years of GH therapy, with favourable changes in lipid profile and improved quality of life. New deficiencies were observed in 35% of IGHD patients, which was similar to MPHD patients with one additional deficit other than GH. New deficiencies most often presented within the first year but were observed up to 6 years after GH commencement. Conversion of IGHD into MPHD was not predicted by aetiology, baseline characteristics, surgery or radiotherapy, whereas in MPHD additional deficits were predicted by age (P!0.001) and duration (P!0.01). Conclusion: Both AO-IGHD and -MPHD patients have similar baseline clinical presentation and respond equally well to 2 years of GH replacement. in adults seems to be a dynamic condition where new deficiencies can appear years after the initial diagnosis, and careful endocrine follow-up of all hypopituitary patients, including those with IGHD, is warranted.

European Journal of Endocrinology 161 S75–S83

Introduction of similarities and dissimilarities in IGHD versus MPHD. By virtue of its size, the Pfizer International Metabolic Isolated GH deficiency (IGHD) is defined as a condition Database (KIMS) permits such subgroup analysis. in which GHD is not associated with other pituitary In a previous KIMS publication 5 years ago, Abs et al. hormone deficits, as opposed to multiple pituitary (2) described a similar clinical presentation at baseline hormone deficiency (MPHD). Theoretically, IGHD pro- and comparable effects after 1 year of GH replacement vides the ideal model to characterise the influence of in adult-onset (AO) IGHD and MPHD patients. As the GHD per se, without the confounding influence from number of KIMS patients is still growing, and reached other pituitary hormone deficiencies or their treatment. 12 547 by August 2007, the first aim of the present It thus gives the opportunity to address questions about study was to allow a more extensive analysis within a possible differences in clinical presentation and in res- stringently defined cohort of patients with AO-GHD of ponsiveness to GH replacement therapy. The prevalence organic cause, naı¨ve to GH prior to entry in KIMS, and of IGHD is reported to be between 7 and 9% (1, 2), and with a longer follow-up. large cohorts are therefore required for the assessment It is well documented that patients may develop progressive hypopituitarism several years after receiving radiotherapy (3). Non-irradiated IGHD patients are not This paper forms part of a special issue on KIMSw and routinely/regularly evaluated for other pituitary defici- ACROSTUDYe. Pfizer Inc. has supported the publication of this encies in all centres, as the clinical situation is special issue. considered stabilised once the diagnosis of IGHD has

q 2009 European Society of Endocrinology DOI: 10.1530/EJE-09-0328 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 10/01/2021 07:14:51PM via free access S76 M Klose and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 been made. Therefore, the second aim of the present Associated disorders, recorded as medical history, study was to assess the evolution of IGHD, in terms of were obtained with specific reference to: peripheral prevalence of patients who converted from IGHD to vascular disease (claudication), cerebrovascular disease MPHD after initiation of GH replacement therapy. (stroke), (angina, myocardial ), arthrosis, epilepsy, mellitus, hyper- tension and bone fractures. Subjects and methods Patients Diagnostic procedures The diagnosis of severe GHD was usually based on a single stimulation test (60.3% in The recruitment of patients to the KIMS database IGHD and 62.9% in MPHD), whereas two or more tests follows good clinical practice guidelines with a quality were performed in the remaining patients. The number control system, as described previously (4). of tests performed did not differ between IGHD and The total number of subjects in KIMS as of August MPHD. The ITT was performed in 64% of MPHD and 2007 was 12 547, of which 4110 were eligible for in 59% of IGHD patients; the glucagon test in 18% baseline analysis, meeting the following inclusion of both MPHD and IGHD patients; and the arginine test criteria: i) GH naı¨ve prior to entry in KIMS; ii) an in 13% of MPHD and in 21% of IGHD patients, whereas organic cause of hypopituitarism, and iii) severe AO-GHD the arginineCGHRH test was performed in 4% of ! as defined by a peak GH 3 mg/l in response to the MPHD and in 3% of IGHD patients. tolerance test (ITT) or the glucagon test, a peak GH !0.4 mg/l in response to the arginine test, or below Clinical and metabolic assessment Baseline data at body mass index (BMI) related cut-offs in response to the entry into KIMS included age, gender, insulin-like growth arginineCGHRH test, defined as a peak GH !11.5 mg/l with BMI !25 kg/m2, a peak GH !8 mg/l with factor 1 (IGF1) SDS, BMI, waist circumference (WC), BMI 25–30 kg/m2 or a peak GH !4.2 mg/l with BMI waist-to-hip ratio (WHR), lean body mass (LBM) and fat O30 kg/m2. Of the 4110 patients, 3827 had MPHD mass (FM) as assessed by bioelectric impedance analysis, and 283 (7%) had IGHD. Two years GH replacement fasting blood glucose (FBG), HbA1c and lipid profile. The data were available in 2340 patients, 2207 with MPHD percentage of patients exceeding internationally defined and 133 with IGHD (6%). target values of increased cardiovascular risk were O 2 Further analysis was performed to assess the evaluated and defined as follows: BMI 30 kg/m ; O O O development of other pituitary hormone deficits in WHR 1.0 (men) and 0.9 (women); WC 102 cm O both IGHD and MPHD patients, as evidenced by the (men) and 88 cm (women); total O initiation of , , sex steroids 5.2 mmol/l; high-density lipoprotein (HDL)-cholesterol or during follow-up. For this purpose, !1.04 mmol/l (men) and HDL-cholesterol !1.3 mmol/l data on concomitant medication were drawn from (women); low density lipoprotein (LDL)-cholesterol patients classified as either IGHD (nZ165) or MPHD O3.38 mmol/l and triglycerides O1.65 mmol/l (6). (nZ3006) at baseline, in order to identify those in Lipids and IGF1 were measured centrally in a single whom new substitution therapy was added during laboratory. Serum total cholesterol, triglycerides and follow-up. Patients with IGHD at baseline developing HDL-cholesterol were measured as previously described MPHD within 2 years of follow-up were classified as (2) and LDL-cholesterol was calculated by the Friede- MPHD in the analysis of GH treatment effect. wald formula (7). Serum IGF1 measurements were performed between 1994 and October 1997 at Kabi Methods Pharmacia, Stockholm, Sweden and thereafter at Sahlgrenska University Hospital, Gothenburg, Sweden, Background information Data were collected con- until November 2002 using a RIA with acid/ethanol cerning: age at entry to KIMS; estimated duration of precipitation of IGF-binding proteins (Nichols Institute pituitary disorder and time since GHD diagnosis; Diagnostic, San Juan Capistrano, CA, USA), until duration of GH therapy and number of additional September 2006 using a chemiluminescence immu- pituitary hormonal deficiencies (based on recorded noassay (Nichols Advantage System, San Clemente, CA, deficiencies or recorded use of medications for pituitary USA) and since then using Immulite 2500, DPC deficiencies other than GHD); history of radiotherapy Siemens. IGF1 values were adjusted for age and gender and time from irradiation. and expressed as SDS. The aetiologic diagnoses responsible for GHD were merged into nine groups with related pathologies: Quality of life assessment Quality of life (QoL) was non-functioning pituitary adenomas (NFPA), secreting assessed using the QoL-assessment for GHD in adults pituitary adenomas, other sellar tumours, craniophar- (QoL-AGHDA) form, which is a disease-orientated yngioma, other extra-sellar tumours, malignancy questionnaire, measuring the impact of GHD in one outside the cranium, (TBI) and overall dimension (8). Each of the 25 items represents a other (the remaining diagnoses (5)). problem and is scored dichotomously, acknowledging or

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Downloaded from Bioscientifica.com at 10/01/2021 07:14:51PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 From IGHD to MPHD S77 denying the problem. The sum of recognised problems (number of ‘yes’ answers) constitutes a score, ranging from 0 (no problems) to 25 (all problems recognised), thus a high QoL-AGHDA score denotes poor QoL.

Assessment of GH treatment effect All participants received recombinant human GH (Genotropin, Pfizer, Stra¨ngna¨s, Sweden). The initial GH dosing according to body size was, in the late 1990s, replaced with a more individualised schedule aiming to normalise IGF1 SDS in the upper part of the age-based reference interval. Treatment effect was evaluated as a change in the baseline parameters after 2 years of GH replacement, Figure 1 Aetiologic distribution in 4110 patients with adult-onset GH and as a difference in the percentage of patients deficiency, divided into those with multiple pituitary hormone exceeding the predefined target values. deficiencies (MPHD; dark grey) and those with isolated GH deficiency (IGHD; light grey). A significant difference was observed in the prevalence distribution of all aetiologies except that for Ethics In KIMS, each centre obtains approval from its secreting pituitary adenomas (PA) and ‘other’, P!0.001. local ethics committee, and the patients gave informed consent, verbally or in writing, depending on the local extrasellar tumours, patients treated for extracranial legal requirements. The study was performed in malignancy and in patients with TBI, whereas MPHD accordance with the Declaration of Helsinki (9). was more frequently observed in patients treated for (P!0.01). Statistical methods The frequency of associated disorders is given in Fig. 2. IGHD and MPHD patients presented similar Outcome variables studied were IGF1 SDS, FM, LBM, profiles of associated disorders (ns). Fractures were lipids, blood pressure, BMI, WC, WHR and QoL-AGHDA the most frequently reported condition in both groups, score. Data are presented as meanGS.D. Differences being more frequent in men than in women, although between and within groups were studied using only reaching significance in the MPHD (24 vs parametric statistics (t-tests). In cases where variances 19%; P!0.001) but not in the IGHD (22 vs 18%; were likely to be unequal (Levene’s test) Satterthwaite’s PZ0.4) group. correction of degrees of freedom was applied (10). Non- There was a higher proportion of women in the parametrical analyses were also performed and IGHD group than in the MPHD group (55 vs 49%; compared, and produced similar conclusions. Four P!0.05). Patients with IGHD were younger at entry in field tables were analysed with Fisher’s exact tests. KIMS (46.5G13.20 vs 48.6G12.79 years, P!0.01), Sex- and age-adjusted differences between groups were and had a shorter history of both GHD (1.3G2.61 vs calculated using linear regression methods. When 2.0G3.65 years, P!0.001) and pituitary disease analysing differences between groups on treatment (5.3G6.29 vs 7.4G7.60 years, P!0.001) compared effects (changes), respective outcome values at baseline with the MPHD group. were used as predictors. The standard statistical After adjustment for age and gender, the IGHD group package (SPSS version 15.0) for Windows, V15.0 had lower LBM (P!0.01) and higher IGF1 SDS (SPSS Inc., Chicago, IL, USA) was utilised. Statistical (P!0.001) as compared with the MPHD group, but significance was considered if P!0.05. did not otherwise differ. Step-wise forward logistic regression using new A history of irradiation was recorded in 36% of pituitary hormone deficiency (noZ0/yesZ1) as depen- patients with IGHD and in 37% of patients with MPHD dent variable and baseline characteristics, surgery, (ns), whereas surgery was less frequently reported in radiotherapy and aetiology as independent variables IGHD (69%) versus MPHD (86%), P!0.001. was used to identify predictors of developing new additional pituitary hormone deficits. Influence of 2 years of GH replacement therapy Results Two years of GH treatment caused an increase in mean IGF1 SDS from K1.3 to 0.6 in the IGHD group and from Baseline characteristics K1.8 to 0.6 in the MPHD group. In the IGHD group, The most common causes of both IGHD and MPHD were GH replacement resulted in a significant improvement non-functioning and secreting pituitary adenomas, in terms of a significant decrease in total and which were less frequent in the IGHD group (58%) LDL-cholesterol, a significant increase in LBM, an than in the MPHD group (65%) (P!0.05; Fig. 1). IGHD improvement in QoL and an increase in HbA1c, while was more common in patients with other sellar or no other significant changes were observed (Table 1).

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was significantly reduced after 2 years of GH therapy where 15% of IGHD and 22% of MPHD patients exceeded the BMI target (P!0.001). Similarly, 41 vs 17% of IGHD, and 42 vs 25% of MPHD patients exceeded the WC target before and after GH treatment; 33 vs 21% of IGHD, and 35 vs 21% of MPHD patients exceeded the cholesterol target, before and after GH treatment; 18 vs 11% of IGHD, and 19 vs 14% of MPHD patients exceeded the HDL-cholesterol target, before and after GH treatment; 28 vs 19% of IGHD, and 28 vs 16% of MPHD patients exceeded the LDL-cholesterol target, before and after GH treatment; and 30 vs 18% of IGHD, and 31 vs 21% of MPHD patients exceeded the TG target, before and after GH treatment (P!0.001). The proportion of patients reaching normalisation Figure 2 Reported medical history in 4110 patients with adult-onset after 2 years of GH treatment was not significantly GH deficiency, divided into those with multiple pituitary hormone different comparing the IGHD and the MPHD groups, deficiencies (MPHD; dark grey) and those with isolated GH deficiency (IGHD; light grey). No significant difference was with the exception of WC as a larger percentage of IGHD observed in the medical history in MPHD versus IGHD. patients reached normalisation (P!0.05).

In the MPHD group, the treatment resulted in a decreased WC, WHR, body fat, total and LDL-cholesterol, Evolution of pituitary hormone deficits: IGHD increased LBM, HDL-cholesterol and decreased QoL- versus MPHD AGHDA score, but also caused a slight but significant Out of 283 patients classified as IGHD at baseline, 165 increase in FBG and HbA1c. patients had available data on concomitant medication. The gender and age adjusted influence of 2 years GH New deficiencies, as evidenced by commencement of replacement did not differ significantly between the new substitution therapy, were recorded during follow- IGHD and the MPHD group. up in 58 (35%) of these patients (Table 2). New deficiencies were recorded in 24 (41%) of the patients Patients exceeding target values within the first year after start of treatment, but conversion was recorded up to 6 years after GH start More than 35% of both IGHD and MPHD patients had a (mean 2.1G0.93 years from baseline). Secondary BMI exceeding the target value of 30 kg/m2 at baseline, was the most often recorded new and were thus obese prior to treatment. This percentage deficiency (nZ41; 25%) followed by secondary

Table 1 Longitudinal characteristics of patients with isolated GH deficiency (IGHD) and multiple pituitary hormone deficiencies (MPHD), assessed at baseline and after 2 years of GH replacement therapy.

IGHD MPHD

Baseline 2 years Change Baseline 2 years Change n MeanGS.D. MeanGS.D. DeltaGS.D. P! n MeanGS.D. MeanGS.D. DeltaGS.D. P!

IGF1 SDS 86 K1.3G1.2 0.6G1.1 1.9G1.35 0.001 1127 K1.8G1.5 0.6G1.4 2.3G1.6 0.001 BMI (kg/m2) 98 28.5G6.0 28.7G6.5 0.2G2.0 NS 1743 28.9G5.3 29.1G5.5 0.2G2.1 0.01 Waist-to-hip ratio 91 0.9G0.1 0.9G0.1 K0.01G0.07 NS 1393 0.9G0.1 0.9G0.1 K0.01G0.06 0.001 Waist (cm) 91 93.7G13.7 93.3G14.2 K0.4G6.8 NS 1401 97.9G13.6 96.5G13.1 K1.4G6.5 0.001 Body fat (BIA, kg) 37 30.8G16.3 29.4G15.6 K1.4G6.0 NS 464 28.4G11.9 27.2G11.9 K1.2G6.6 0.001 Lean body mass 37 49.5G11.9 51.2G11.7 1.8G5.0 0.05 464 57.0G13.2 58.1G13.1 1.1G5.3 0.001 (BIA, kg) Cholesterol (mmol/l) 65 5.9G1.2 5.4G1.0 K0.5G1.0 0.001 916 5.9G1.2 5.5G1.1 K0.4G1.1 0.001 LDL-cholesterol 62 3.8G1.1 3.4G0.8 K0.5G1.0 0.001 844 3.7G1.1 3.3G1.0 K0.4G0.9 0.001 (mmol/l) HDL-cholesterol 65 1.2G0.3 1.2G0.3 K0.01G0.03 NS 916 1.2G0.4 1.3G0.4 0.03G0.29 0.001 (mmol/l) Triglycerides 65 1.9G1.3 1.8G0.9 K0.1G0.9 NS 916 2.2G1.5 2.1G1.2 K0.1G1.3 0.01 (mmol/l) HbA1c (%) 99 5.1G0.9 5.3G0.9 0.2G0.6 0.001 1349 5.2G0.9 5.4G1.7 0.2G1.6 0.001 B-glucose (mmol/l) 53 4.8G0.6 4.9G0.7 0.1G0.7 NS 1111 4.7G1.1 5.0G2.4 0.3G2.4 0.001 QoL-AGHDA-score 70 13.6G6.9 8.1G7.0 K5.5G6.6 0.001 1082 11.5G7.0 6.8G6.3 K4.7G6.1 0.001

Treatment effect was evaluated as the change in the evaluated parameters. Data are given as meansGS.D. and within group changes (2 years baseline) with associated P values. The patients evaluated were identical at baseline and at 2-year evaluation.

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Table 2 Number (%) of new pituitary deficits in relation to number of additional pituitary deficits at baseline, in multiple pituitary hormone deficiencies (MPHD) and isolated GH deficiency (IGHD) patients.

New

Baseline 0123Total

MPHD 0 n (%) 3 (33) 2 (22) 2 (22) 2 (22) 9 (100) 1 n (%) 386 (69) 129 (23) 38 (7) 6 (1) 559 (100) 2 n (%) 602 (79) 151 (20) 8 (1) 0 (0) 761 (100) 3 n (%) 1563 (97) 43 (3) 0 (0) 0 (0) 1606 (100) Total n (%) 2625 (87) 325 (11) 48 (2) 8 (0.3) 3006 (100) IGHD 0 n (%) 107 (65) 37 (22) 18 (11) 3 (2) 165 (100)

Seventy-one patients with records in concomitant medication had panhypopituitarism. (nZ21; 13%) and secondary hypoa- distribution into consideration, the clinical baseline drenalism (nZ20; 12%), whereas ADH deficiency was characteristics were similar in patients with IGHD as not recorded. Development of IGHD into MPHD was compared with patients with MPHD, and both groups not predicted by baseline characteristics, surgery, radio- responded similarly to 2 years of GH replacement therapy or aetiology. Patients with stable IGHD had therapy, with favourable changes in lipid profile, higher mean WHR and WC at baseline compared with improved QoL and a decrease in the observed proportion those who developed MPHD, but did not otherwise differ, of patients with increased cardiovascular risk factors, as and no difference was observed in treatment effect assessed by the frequency of patients exceeding comparing the two groups. internationally defined metabolic targets. New deficiencies were recorded in 381 (13%) of 3006 Given the size of the study, it also allowed for a patients with MPHD. Patients with a low number of separate evaluation on development of additional deficient axes at baseline were more likely to develop pituitary hormone deficits in both patients with initial new deficiencies, illustrated by a 31% risk in patients IGHD and MPHD. Our observation that new pituitary with one additional pituitary deficit, a 21% risk in hormone deficits occurred not only during the first year patients with two additional deficits, and a 3% risk in of GH treatment but during the entire follow-up period patients with three additional deficits (Table 2). New in a substantial proportion of IGHD and MPHD patients deficiencies occurred within the first year in 34% of the suggests that hypopituitarism is a dynamic condition patients, and were recorded up to 11 years from that requires careful endocrine monitoring in IGHD as baseline (Fig. 3). As in IGHD, secondary hypothyroidism well as in MPHD. Z was the most often recorded new deficiency (n 191; Since KIMS is a large observational pharmaco- Z 6.4%), followed by secondary hypoadrenalism (n 121; epidemiologic survey, reflecting routine clinical practice Z 4%), secondary hypogonadism (n 93; 3.1%) and ADH and open for all hypopituitary patients treated with Z deficiency (n 40; 1.3%). In the regression model, Genotropin, a certain level of patient selection bias only age and duration of pituitary disease were cannot be excluded. Currently, all patients being identified as predictors of development of new additional ! ! considered at risk of hypopituitarism are likely to be pituitary hormone deficits (P 0.001 and P 0.005 assessed for GHD, excluding a small group of patients respectively), i.e. the risk of development of new with such poor clinical condition that treatment is deficits decreased with age and with the duration of considered irrational. However, in previous years pituitary disease. patients with severe symptomatology were more likely to be considered for evaluation of the GH axis and, thus to be included in the database. Further bias could be Discussion caused by the approach used in the UK, which is prioritising patients with severely impaired QoL who Few data exist on the comparison of IGHD with MPHD have a documented treatment effect in terms of with respect to clinical presentation and treatment improved QoL for prolonged GH replacement. The effect. The main objective of such analysis is to obtain an extent of selection bias was minimised by the inclusion indirect assessment of the impact of GH by itself upon of a stringently defined cohort including only patients the clinical syndrome and the biochemical disturbances with severe GHD. An additional limitation of multi- accompanying hypopituitarism. By virtue of the centre, observational studies worth mentioning is the growing size of the KIMS database, it was possible to diversity of incorporated laboratory methodologies. assess an even larger, more stringently defined cohort of Although in KIMS this limitation for IGF1 and lipids is patients with GH naı¨ve AO-GHD of organic origin, with partly overcome by central analyses offered to all a prolonged follow-up time compared to the previous investigators, other results, e.g. GH peaks, are measured study (2). Taking differences in age and gender based on different GH assays. Therefore, variations in

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test was used infrequently. For patients diagnosed with the arginine test an even lower cut-off value (0.4 mg/l) was introduced following the recommendation of Biller et al. (16). Therefore, we believe that by using appropriate, more stringent cut-off values for this less potent agent (arginine) we ensured inclusion of properly diagnosed patients. Although more than one-fifth of patients with IGHD (versus 13% of MPHD) were diagnosed using the arginine test, overall only 8.5% of patients with IGHD were diagnosed by the arginine test used as a single test (24 out of 283) and in 5.5% of patients with MPHD (212 out of 3827), and it is reassuring that the diagnosis in the majority of these patient was based on two or more tests. The aetiologic distribution of the present cohort is comparable with that previously reported (2, 17), with more than half of the IGHD and MPHD cases being caused by NFPA or secreting pituitary adenomas, or their treatment, and MPHD being more prevalent in Figure 3 Number of patients with MPHD at baseline who developed patients with craniopharyngiomas, as compared with central hypothyroidism, hypoadrenalism, hypogonadism or ADH deficiency in relation to years from baseline. IGHD which was more prevalent in extra-sellar tumours, extra-cranial malignancy and TBI, probably reflecting differences of invasiveness and proximity to the GH assays, i.e. some assays that generate higher and hypothalamic pituitary area. some lower values, should be taken into account and it The observed difference in age and gender distri- cannot be ruled out that in clinics where GH assays bution between IGHD and MPHD was also reported in generating lower results are used, patients are more the first KIMS publication on IGHD (2), and was likely to be diagnosed with GHD. On the other hand, we accounted for in the present analysis. Independent of think that such situations mostly refer to ‘borderline age and gender, IGHD patients had higher baseline IGF1 cases’ and believe that by applying very stringent cut-off SDS, and higher peak GH compared with those with values, significant inclusion of such ‘false positive’ cases MPHD, which may be explained by the aetiologic in the studied cohort is prevented. distribution with MPHD being more prevalent in diseases with a higher degree of invasiveness into and The prevalence of IGHD in the present study of closer proximity to the hypothalamic pituitary area, selected patients was 7% at baseline and 6% at 2 years and thus with a higher theoretical impact on overall follow-up, which is in accordance with or even lower pituitary function including GH. than previously reported (1, 2, 11), suggesting that A history of fracture was the most frequently reported misclassification of MPHD patients as IGHD was associated disorder in the present study. Several studies minimal. The exact prevalence of IGHD may in the have reported that patients with hypopituitarism future be influenced by the inclusion of more patients and GHD have an increased incidence of bone fractures with TBI or subarachnoid haemorrhage as these (18, 19), with an estimated 2.6 higher incidence rate in patients often present with GHD in its isolated form hypopituitary men as compared with a control group (12, 13). (19). Osteopenia is a well-established surrogate marker Nowadays, IGHD is recognised as a clinical entity in of fracture risk, and reduced bone mineral density patients with organic hypothalamic pituitary disease (BMD) has been reported in hypopituitary patients (20), (14), as GH is often the first hormone to become a reduction that has been associated with the severity of deficient in the spectrum leading from isolated pituitary GHD, rather than the presence of additional hormone hormone deficiency to panhypopituitarism. Two defects (21). A history of fracture was reported in up to different dynamic tests were previously demanded for 24% of male IGHD and MPHD patients. The equal the diagnosis of IGHD (15), but the most recent occurrence in the two groups might suggest GHD to be recommendations of the GH Research Society require the most important hormonal factor for the increased only a single test, as in MPHD, when using adequate fracture risk in hypopituitarism. However, conflicting stimulation tests with stringent cut-offs. In the present data exist within this field as some studies do not find study, the diagnosis of IGHD was based on a single test decreased BMD in AO-GHD patients (22, 23). in 60% of the patients. The exclusive inclusion of severe Initiation of GH treatment caused a significant rise in GHD was ensured by the use of the stringent cut-offs for mean IGF1 SDS to above mean in both groups, GH peak, i.e. !3 mg/l for ITT and glucagon, and BMI indicating that the IGHD and MPHD patients were related cut-offs for the arginineCGHRH test, though this equally well substituted. The fact that the two groups

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Downloaded from Bioscientifica.com at 10/01/2021 07:14:51PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 161 From IGHD to MPHD S81 were well matched further strengthens the results from therapy does not entirely explain the observed evolution the comparative analysis on treatment effect. Overall, in pituitary function in either IGHD or MPHD patients the current study showed a similar responsiveness to since half of the patients developed new deficiencies 3–6 2 years of GH replacement therapy, although fewer years after commencement of GH therapy. Irradiation significant treatment effects were observed in IGHD, per se could explain the gradual impairment of the possibly explained by lack of power, rather than true pituitary function in some patients. Surprisingly, neither biological difference. irradiation nor duration between radiotherapy and Several studies have shown that adult patients with entry into KIMS was identified as a predictor of new untreated GHD present with a series of cardiovascular deficiencies in either IGHD or MPHD patients, which risk factors including increased blood pressure, may be explained by lack of power, as the number of increased BMI, abnormal body composition and an patients with recorded time from radiation and/or adverse lipid profile (11, 24–27). Introduction of GH surgery was very small. There was an inherent replacement may induce a favourable change in the limitation in the way new deficiencies were evaluated very same parameters (27–29). An adverse cardiovas- because registration of new medication was the only cular risk profile was confirmed in the present cohort, means by which new deficiencies could be assessed where 20–40% of all patients exceeded internationally within the present design. Definite proof by biochemical defined metabolic targets, with no difference between data and local reference ranges would have been the IGHD and MPHD group. This profile improved after preferable. 2 years of GH treatment. In the IGHD group, although Our data suggest that hypopituitarism in adults significant changes were only observed for total and LDL seems to be a dynamic condition where new deficiencies cholesterol, a significant reduction was observed in the can appear years after the initial diagnosis, and the percentage of patients exceeding target values within all implication of this new and clinically very important parameters evaluated, being approximately halved observation is that careful long-term endocrine follow- within the treatment period. Again, the similar up is indicated in both IGHD and MPHD. treatment response observed suggests GH as an important hormonal factor responsible for the observed Declaration of interest changes, though the database was not designed to answer these questions in a very precise manner. M Koltowska-Haggstrom is employed by Pfizer Health AB, Sweden; B Saller is employed by Pfizer Ltd UK; I Kourides is employed by Pfizer It is well documented that GHD has a negative impact Inc., USA; M Klose has received lecture fees from Pfizer and Novartis on QoL in adults (8, 30, 31), and several studies have Health Care; U Feldt-Rasmussen has received research grants and reported an improvement following GH treatment lecture fees from Novo Nordisk and Pfizer; B Jonsson has received (32–35); this has been reported to be paralleled by consulting fees from Pfizer; V Popovic has received lecture fees from Pfizer and is on the advisory board for the KIMS database; R Abs has a reduction in healthcare consumption (34, 35). received lecture fees from Pfizer. KIMSw is supported by Pfizer Inc. The present data showed QoL to be equally impaired This paper forms part of a European Journal of Endocrinology in the IGHD and the MPHD group at baseline; both supplement supported by Pfizer Inc. groups responded favourably to 2 years of GH treatment. This finding corroborates the previous Acknowledgements KIMS study on IGHD (2). More patients with MPHD than IGHD had available The authors are indebted to all KIMS investigators for providing the follow-up data concerning treatment effect and con- data on their patients. comitant medication, which could reflect an under- standing of IGHD as a stable condition with less impact for the patient. The present study demonstrates that References IGHD of organic origin is not a stable condition, but may evolve into MPHD in a significant number of patients. In 1 Stochholm K, Gravholt CH, Laursen T, Laurberg P, Andersen M, the present cohort, the risk of new pituitary hormone Kristensen LO, Feldt-Rasmussen U, Christiansen JS, Frydenberg M deficits in IGHD patients was similar to that in MPHD & Green A. Mortality and GH deficiency: a nationwide study. European Journal of Endocrinology 2007 157 9–18. patients with only one additional deficit. Some of the 2 Abs R, Mattsson AF, Bengtsson BA, Feldt-Rasmussen U, Goth MI, new deficiencies in the first year after starting GH Koltowska-Haggstrom M, Monson JP, Verhelst J & Wilton P. replacement could have been precipitated by initiation Isolated (GH) deficiency in adult patients: of GH treatment. It is well documented that GHD can baseline clinical characteristics and responses to GH replacement in comparison with hypopituitary patients. A sub-analysis of the mask central hypothyroidism or central hypoadrenal- KIMS database. Growth Hormone and IGF Research 2005 15 ism in a significant proportion of hypopituitary patients, 349–359. and that this is exposed upon commencement of GH 3 Maiter D, Abs R, Johannsson G, Scanlon M, Jonsson PJ, Wilton P & treatment. The mechanisms seem to be GH-induced Koltowska-Haggstrom M. Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated enhancement of the peripheral deiodination of T4 to for or : data from the T3, and reduction of cortisone to conversion Pfizer International Metabolic Database. European Journal of (36, 37). However, precipitation by initiation of GH Endocrinology 2006 155 253–260.

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