L Martel-Duguech and ESE audit on AGHD in clinical 184:2 321–332 Clinical Study others practice ESE audit on management of adult growth hormone deficiency in clinical practice Luciana Martel-Duguech 1, Jens Otto L Jorgensen2,3, Márta Korbonits4,5, Gudmundur Johannsson6,7 and Susan M Webb 1 on behalf of the ESE AGHD Study Group* for a Pan-European audit 1 IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, Universitat Autónoma de Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unit 747), ISCIII, Barcelona, Catalunya, Spain, 2Clinical Lead, Pituitary and Neuroendocrinology, European Society of Endocrinology, Starling House, Bristol, UK, 3Department of Clinical Medicine – The Department of Endocrinology and Diabetes, Arhus, Denmark, 4Adult Chair of the Endo-ERN Research & Science Workpackage and member of Endo-ERN Pituitary Thematic Group, 5Endocrinology, William Correspondence Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of should be addressed London, Charterhouse Square, London, UK, 6Member of Endo-ERN Growth and Genetic Obesity Syndrome Thematic to S M Webb Group, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg, Sweden 7 Email * (Details of the ESE AGHD Study group are prented in the Acknowledgements section) swebb@santpau.cat or webbsusan4@gmail.com Abstract European Journal of Endocrinology Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. Aims: (1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; (2) To evaluate educational status of healthcare professionals about AGHD. Design: Online survey in endocrine centres throughout Europe. Patients and methods: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017–2018. Results: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital midline malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine: 45%; insulin-tolerance: 42%, glucagon: 6%; GHRH alone and clonidine tests: 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. Conclusion: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimise the care of adults with GHD. European Journal of Endocrinology (2021) 184, 321–332 https://eje.bioscientifica.com This work is licensed under a Creative Commons © 2021 The authors https://doi.org/10.1530/EJE-20-1180 Attribution 4.0 International License. Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 322 others practice Introduction and/or treated between 01/01/2017 and 31/12/2018 were included. Additionally, ten questions reflected the practice Adult growth hormone deficiency (AGHD) affects between and perspectives of each centre as reported by the senior 200 and 300 patients/million population, approximately endocrinologist in charge, namely sections on national 100 000 patients across Europe (1). The condition is statistics on AGHD, country treatment reimbursement characterised by a reduction in bone mineral density, lean policies and distribution of the drug, available education body mass, exercise capacity, and overall health-related and training resources and the level of satisfaction related quality of life as well as an increase of body fat and an to AGHD in each local setting. Questions were developed adverse cardiovascular risk profile (2, 3). The concept of on the basis of published guidelines (17). AGHD was established more than 30 years ago, and the Individual patient data were captured in a dedicated accumulated evidence is nowadays overwhelming that Access database (Form A). An aggregated data summary most patients benefit from a daily injection of GH and are form was generated (Form B), which was the basis of the willing to continue treatment (4, 5, 6, 7, 8, 9, 10, 11, 12, information submitted to the ESE in an online e-survey 13, 14). Nevertheless, a small percentage of patients do (Form C and Supplementary Table), which also captured not perceive any benefit and prefer not to be GH replaced the questions on local practices and current site-specific (15, 16). perspectives. Current guidelines recommend that patients with Since the survey did not include personal medical pituitary disease should be tested and treated for AGHD questions but a summary of patient data and clinical (17, 18, 19, 20). Still, it is not universally recognised as practise per centre, ethics approval was not required in all a distinct entity and reimbursement for GH replacement European Journal of Endocrinology countries, however, when necessary, participants obtained therapy is not available in some countries. The European local approval by their ethics committee. Society of Endocrinology (ESE) therefore aimed to investigate the current practice of AGHD management to benchmark it against existent guidelines (17, 18, Statistical analysis 19, 20). The goal was to collect aggregated patient data Descriptive statistics and Student’s t-test, Chi-squared from regional centres representing several thousand or ANOVA tests were used to analyse the data, where individuals, with either treated or untreated AGHD. appropriate. A level of P <0.05 was considered significant. Analyses were performed using SPSS21.0 (SPSS Inc., Chicago, IL). Patients and methods An ESE Steering Group prepared an online survey to Results collect information on diagnosis and treatment practices country by country (https://www.ese-hormones.org/ In January 2020, 28 Form C-s (online survey) were aghd) and to compare everyday practice with guideline collected from 28 centres in 17 countries. The largest recommendations. contributing countries were Italy (five centres) and Spain Invitations to participate were distributed at ECE2018, (four centres). The general characteristics of participating through the Rare Endocrine Disease European Reference centres and patients are summarised in Fig. 1. Network (Endo-ERN) and the ESE Council of Affiliated Based on the published prevalence of AGHD in Societies (ECAS). Suitable centres were those from Europe, different countries (1), the estimated and captured AGHD who currently treated at least 10 AGHD patients per year patients per country are shown in Table 1; Denmark (32%) or who could not treat AGHD due to local conditions and and Slovenia (20%) were the countries with the highest restrictions. We identified 70 centres which were invited participation. to participate repeatedly, via e-mail. Finally, 28 centres In order to evaluate the global experience of each from 17 European countries were included. centre in the management of pituitary patients, the The survey consisted of 44 questions (Supplementary total number of pituitary patients, as well as surgical Table, see section on supplementary materials given at the and radiotherapy treatments per year were collected, end of this article) and included sections on demographics, independently of their GHD status (Fig. 2). Nine centres diagnostic criteria, patient selection, GH dosing and declared to follow more than 500 pituitary patients follow up, safety and treatment goals. Patients diagnosed per year (Barcelona, Genoa, Ljubljana, Lyon Marseille, https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 323 others practice European Journal of Endocrinology Figure 1 Number and general characteristics of countries, centres and patients involved in the study. aCountries: Bulgaria, Croatia, Denmark, France, Greece, Hungary, Italy, Lithuania, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, United Kingdom. *GH treatment ongoing at survey initiation (January 1, 2017). **Prior GH therapy received, but interrupted at survey initiation (January 1, 2017). CO-AGHD, childhood-onset adult growth hormone deficiency; AO-AGHD, adult-onset adult growth hormone deficiency. Table 1 Estimated and captured prevalence of patients with adult growth hormone deficiency (AGHD) per country from reference (1). Population (million Estimated AGHD AGHD patients Percentage of captured AGHD patients Countries inhabitants) patients captured based on estimated number of patients (%) Bulgaria 7 1225 87 7 Croatia 4 700 25 4 Denmark 5 875 281 32 France 66 11 550 206 1 Greece 10 1750 28 2 Hungary 10 1750 45 3 Italy 60 10 500 622 6 Lithuania 3 525 10 2 Portugal 10 1750 65 4 Romania 19 3325 83 2 Serbia 7 1225 30 2 Slovakia 5 875 67 8 Slovenia 2 350 70 20 Spain 46 8050 192 3 Sweden 10 1750 254 14 Switzerland 9 1575 18 1 UK 66 11 550 91 1 https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 324 others practice European Journal of Endocrinology Figure 2 Number of pituitary patients and identified AGHD patients followed and pituitary surgeries and pituitary radiotherapies performed on average per year in each centre. (A) Centres that follow ≥500 pituitary patients; (B) centres that follow <500 to >100 pituitary patients; (C) centres that follow ≤100 patients. AGHD, adult growth hormone deficiency. https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 325 others practice Messina, Sheffield, Stockholm and Turin), another 65 years, less than 5%. Distribution of age at GH treatment 10, between 100 and 500 patients (Aarhus, Athens, initiation was similar (<18 years-old: 22%; 18–25 years-old: Basel, Bratislava, Bucharest, Milan, Sophia, Tenerife, 13%; 26–45 years old: 31%; 46–65 years old: 30%; >65 years Thessaloniki, Zagreb) and the remaining, 100 patients or old: 4%), indicating that, in general, there was no delay in less per year (between 20 and 100). treatment initiation after the diagnosis of GHD. The aetiology of AGHD and the degree of As far as the tests used to diagnose AGHD, 1103 hypopituitarism are shown in Table 2. The most common patients (52%) underwent a stimulation test, mainly a cause of AGHD was a non-functioning pituitary adenoma GHRH+arginine test (45%) or an insulin tolerance test (26% of all cases reported), followed by craniopharyngioma (ITT) (42%); in 6% a glucagon test was performed and and genetic or congenital midline malformations (13% other tests in another 7% including GHRH alone and each). Only 4% had isolated GHD; 22% had diabetes clonidine. Fourteen per cent (n = 305) of patients did insipidus and most patients had additional pituitary not undergo any GH stimulation test but were diagnosed hormone deficiencies. on the basis of 3 or more other pituitary deficiencies Twenty-eight per cent (n = 594) corresponded to plus a low serum IGF-I (reported in 54% of the centres patients with childhood-onset AGHD (CO-AGHD); to be enough to diagnose AGHD). In the remaining 34% among those with adult-onset AGHD (AO-AGHD), age (n = 731) of patients, information on stimulation tests was of diagnosis was from 18 to 25 years in 10%; between 26 unavailable. Figure 3 depicts the diagnostic test preference and 45 years in 29%; 46–65 years in 28%; and older than in specific clinical situations when a test was either clinically contraindicated or was of limited diagnostic European Journal of Endocrinology Table 2 Aetiology of adult growth hormone deficiency (AGHD) accuracy. and the degree of hypopituitarism in the patient cohort. When all other endocrine axes are normal, 34% of centres do not perform a stimulation test even if an No of patients (n = 2139) % underlying pituitary disease exists, since it is not an Aetiology of AGHD Non-functioning 555 26 indication for substitution therapy in many countries. pituitary adenoma The diagnostic cut-off for the ITT test used to diagnose Craniopharyngioma 285 13 GH deficiency was <3 µg/L, except for three centres which Genetic/congenital 282 13 used the cut-off <5 µg/L (Bratislava, Madrid and Sheffield). midline malformations Other pituitary mass 172 8 The diagnostic cut-off for the GHRH+arginine test was <9 lesions (including cysts, µg/L in Italy in patients with a BMI <30 kg/m2 and <4 inflammatory) μg/L in patients with a BMI ≥30 kg/m2 and <6 µg/L in Prolactinoma 134 6 Cranial irradiation due 117 6 Denmark, irrespective of BMI, while in other countries to another malignant (Romania, Sweden, Switzerland and United Kingdom) a disease peak of <11, <8 or <4 was considered diagnostic of AGHD Cushing’s syndrome 94 4 when BMI is <25, 25–30, or >30 kg/m2, respectively. Two- Vascular causes 82 4 (Sheehan’s syndrome, thirds of the centres (18/28) required IGF-I to be low to apoplexy, etc.) initiate GH therapy, while this was not necessary for the Idiopathic isolated GHD 81 4 remaining 10 centres. Traumatic brain injury 57 3 Treated acromegaly 50 2 When considering GH substitution therapy, patient Other 143 7 compliance and symptoms (i.e. impaired quality of life Not known 82 4 and severe fatigability) were important determinants Other pituitary deficiencies* for initiating treatment (Table 3); age under 65 years No other pituitary 162 8 deficiency and central obesity, however, were only considered by TSH deficiency 1754 82 11% of participating centres. Administrative issues (i.e. LH/FSH deficiency 1622 76 lack of reimbursement and restrictions to provide the ACTH deficiency 1491 70 drug in hospital pharmacies) were the main reason why ADH deficiency 467 22 PRL deficiency 150 7 GH therapy was not initiated in countries like Romania (100% of untreated patients), Portugal and Greece (90%), *Centres were allowed to choose more than one deficiency per patient. Lithuania (70%) and Bulgaria (60%). After diagnosis of ACTH, adrenocorticotrophin hormone; ADH, antidiuretic hormone; FSH, follicle-stimulating hormone; GHD, growth hormone deficiency; LH, AGHD and no coexistent contraindications, treatment luteinising hormone; PRL, prolactin; TSH, thyroid stimulation hormone. was begun in some but not all centres (Fig. 4). As far as the https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 326 others practice Figure 3 Number of centres that chose to perform different stimulation tests in specific situations. Centres were allowed to choose more than one test per each situation. ITT, Insulin tolerance test; GHRH, growth hormone-releasing hormone. European Journal of Endocrinology starting dose of GH, 0.3 mg/day was most often prescribed (0.2 mg/day). In Portugal, the initial dose was prescribed as first choice in those aged 26–45 years, and 0.2 mg/day according to the patient’s body weight. in those aged 46 to above 65 years, irrespective of gender. Most recommended administering GH injections in However, in patients aged 25 years or younger, higher the evening (60%) and considered a switch from oral to doses were prescribed in women (0.75 mg/day if <18 years transdermal or transvaginal oestrogens (10%), increased and 0.5 mg/day if aged between 18 and 25) than in men monitoring for patients >65 years old (4%), checking of free T4 when taking thyroxin replacement therapy (57%) and considering an increase in hydrocortisone Table 3 Features considered when initiating growth replacement dose (26%). hormone (GH) substitution therapy. Data is presented as n (%). In 284 patients, GH substitution had been interrupted Centres Patients at the time of the survey. The causes of GH treatment (n = 28) (n = 2139) interruption are shown in Table 4. Adverse events were Requirements for GH responsible in 57% of the cases, while lack of compliance, treatment initiation* administrative reasons and lack of perceived improvement Patient compliance 21 (75) Impaired quality of life 12 (43) while on therapy, and death (4%) were also reported. Severe fatigability 9 (32) As far as the transitioning from childhood to adult Age <65 years 3 (11) care, the age was >18 years in 19 centres and between 14 Central obesity 3 (11) and 18 years in another 8 centres (this information was Others** 2 (7) Factors that stopped initiation missing in the remaining centre). Most of the CO-AGHD of GH therapy*** patients were referred by the paediatrician or another Administrative issues 220 (10) practitioner to adult care (68%), although 17% were Compliance considerations 119 (6) Persistent and stable pituitary 96 (4) seen after direct patient inquiry. In the remaining (15%), tumour rests this information was unavailable. In 224/594 CO-AGHD Age >65 years 52 (2) patients, GH substitution was interrupted during Concomitant diabetes mellitus 20 (1) transitioning to adult care for more than 24 months Other 141 (7) None 1270 (59) (n = 157). The reasons for GH treatment interruption during transition to adult care are shown in Table 5. *Centres were allowed to choose more than one requirement; **No While lack of reimbursement and patients own decision current or prior history of malignancy (Athens) and decreased bone mineral density (Madrid); ***Centres were allowed to choose more than to stop GH treatment was the most frequent reason one factor per patient. for treatment interruption, discharge by the paediatric https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 327 others practice European Journal of Endocrinology Figure 4 Number of patients diagnosed with adult growth hormone deficiency (AGHD), who were either treated or not with growth hormone in each centre. CO-AGHD, childhood-onset AGHD; AO-AGHD, adult-onset AGHD. consultant or poor patient compliance and difficulty in and partner satisfaction in less than 11%. A specific referral to an adult clinic were also reported. quality of life (QoL) questionnaire was administered for As far as follow-up after starting GH therapy, half treatment monitoring in 45% of AGHD patients. The the centres measured IGF-I 2–3 months after initiating most commonly used were The QoL Assessment of GH treatment and every 12 months once a stable dose was Deficiency Adults questionnaire (QoL-AGHDA) and the reached. Considering the targeted IGF-I concentration Questions on Life Satisfaction Hypopituitarism Module to be reached during treatment, 40% aimed at a value (QLS-H) (21, 22). In 2%, a generic questionnaire was used within the normal range, 26% within the mid-normal (SF-36). range, 14% aimed at a high-normal range, and 3% aimed When asked whether a pituitary MRI was performed at a low-normal range. Other variables used for GH dose at initial evaluation, in 84% of the patients the answer titration, were body weight: 62% (1319/2139), HbA1c: was positive; in 10% this information was unavailable 60% (1284/2139), blood pressure: 58% (1245/2139), BMI: and in 6% the answer was negative; whether a CT scan 58% (1240/2139), total cholesterol: 56% (1203/2139), was performed in these latter patients was not collected. high-density lipoprotein (HDL): 52% (1223/2139), Additionally, most centres performed new MRIs 6–12 low-density lipoprotein (LDL): 47% (1006/2139), bone months after initiating GH treatment (85%) in patients mineral density: 41% (876/2139), waist circumference: with residual tumour, and after 12 months in patients 34% (728/2139), and body fat: 13% (270/2139). Overall without residual tumour. wellbeing and energy level was regularly asked for in In Romania, the indication of GH treatment for AGHD 61% of patients, while the number of sick day leave is not reimbursed. In Lithuania and Portugal, full public https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 328 others practice Table 4 Causes of growth hormone treatment interruption dissatisfaction was high in relation to AGHD awareness in adult growth hormone deficiency patients.* by non-endocrine healthcare professionals; additionally, there was room for improvement in the curriculum of Number of patients (n = 284) % postgraduate training related to AGHD. Adverse events 162 57 New cancer 36 12 When the centres with a higher percentage of patients Tumour recurrence 25 9 under GH treatment were compared to those with a lower Fluid retention/oedema 16 6 percentage, a correlation was observed with a higher Arthromyalgia 13 8 level of satisfaction in overall quality of AGHD treatment Hyperglycaemia 9 5 Headache 0 0 in the formers (P = 0.005). Not surprisingly, where full Other 63 22 public treatment reimbursement was available, more GH Lack of compliance 61 22 treatments were prescribed (P = 0.020). Also, the level Administrative reasons 54 19 of satisfaction with the overall quality of AGHD patient Lack of positive effect 51 18 perceived by the patient treatment in each setting correlated with full public Death 12 4 reimbursement of GH therapy (P = 0.018). Not specified 106 37 *Centres were able to choose more than one cause for treatment interruption per patient. Discussion reimbursement was approved only recently (2018–2019), We report data from a survey on current practice of AGHD European Journal of Endocrinology whereas, in Slovakia, reimbursement is partial. In Greece, management across Europe and benchmarked these real- despite approval, hospital pharmacies are reluctant to life data with pertinent guidelines (17, 18, 19, 20). supply GH, while in Bulgaria full public reimbursement Underlying diagnoses of hypothalamic–pituitary is only approved in CO-AGHD. In Hungary, only those disease was congruent with the guidelines. Only 81/2139 endocrinologists who work at accredited GH centres are (4%) patients with idiopathic isolated adult-onset GHD able to prescribe GH substitution. were reported, an entity not recognised as occurring de As far as the dispensation of the drug, it was most novo in adults (17). frequently dispensed in regional or reference hospital As far as diagnostic tests, stimulation tests not pharmacies (18/28), while in the others it was dispensed considered valid in adults, such as GHRH alone or in the local pharmacy. In two countries (United Kingdom clonidine, were used in certain centres (17). Regarding the and Sweden) patients had the option of receiving their ITT diagnostic threshold for AGHD, most centres followed GH at home, via a registered online delivery service. the European consensus of <3 µg/L (17), although The level of satisfaction regarding available education Bratislava, Madrid and Sheffield accepted the Endocrine and training resources and AGHD management in each Society consensus of <5 µg/L (20). In contrast with the local setting is shown in Fig. 5. While the greatest level of guidelines, BMI-dependent cut-off values were not always satisfaction was in the extent and quality of nurse training, considered for the GHRH+arginine test (17). A low baseline IGF-I level was required to start GH therapy in two-thirds Table 5 Causes of growth hormone treatment interruption of the centres, despite that the guidelines state that a in childhood-onset adult growth hormone deficiency during normal IGF-I does not rule out GHD at any age. transition to adult care.* Administrative reasons contributed to treatment interruption during transition, since AGHD is not an Number of patients (n = 224) % approved indication for GH therapy reimbursement in Lack of reimbursement 75 33 Patient electing to stop the 68 30 Romania; in Lithuania and Portugal, reimbursement treatment for AGHD was only recently approved. In Slovakia Discharge by the paediatric 29 13 reimbursement is only partial, and in Greece hospital consultant pharmacies are reluctant to supply treatment for budget Poor patient compliance 15 7 Difficulty in referral to an 5 2 reasons despite approval of the indication. In Bulgaria, adult clinic full public reimbursement is only approved for adults if Not known/not answered 146 64 they are diagnosed as CO-AGHD. Finally, in Hungary, *Centres were able to choose more than one cause for treatment only endocrinologists who work at accredited GH centres interruption per patient. are allowed to prescribe reimbursed GH substitution for https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 329 others practice European Journal of Endocrinology Figure 5 Level of satisfaction across centres (n = 28). AGHD, adult growth hormone deficiency. adults. Other reported reasons for stopping GH treatment differences in dosing were reported. In Portugal, GH dose at transition included patient preference, lost to follow-up was prescribed based on body weight, although this is and poor patient compliance. not recommended in the guidelines (17). Most centres Not all centres reported data on non-treated AGHD recommended GH to be administered in the evening, patients, especially in countries where most are offered mimicking the greater nocturnal secretion, but this was not therapy after diagnosis. In fact, the guidelines state that the case in over 40% of patients. Dose was initially adjusted AGHD should be confirmed if treatment is a possibility. after 2–3 months based on IGF-I concentration and clinical Thus, eligible patients in whom GH therapy was not response, and on an annual basis thereafter; additionally, initiated were not reported in many centres. Additionally, most centres considered adjusting the dose of other some patients with organic isolated AGHD could be pituitary replacement therapies. However, it was surprising underdiagnosed and therefore not reported, since up to a that only 10% considered switching oral oestrogens to a third of centres do not perform stimulation tests when the transdermal or transvaginal route, given the inhibitory rest of the endocrine axes are normal; this is in line with the effect of oral oestrogens on hepatic synthesis of IGF-I (17). regulation in many countries, where GH treatment is not Treatment interruption due to adverse events, lack of indicated in these cases. Even though the decision to treat compliance or perceived benefit, as well as administrative AGHD requires a detailed evaluation of potential risks and reasons were as expected. Twelve deaths were reported benefits by knowledgeable healthcare providers, evidence is (0.56% of the 2139 patients), but it is not known whether now convincing of the benefits of GH replacement therapy, any was related to GH therapy. especially if symptomatic and in young adults with persistent As far as safety during GH treatment, both at baseline GHD after attaining final height, since it enables full somatic and follow-up, pituitary MRIs were performed for safety development, accrual of maximal bone and muscle mass, as suggested in the guidelines; however, in long-term and improvement persists during chronic treatment (17). follow-up, interval between subsequent imaging depended Only in patients <25 years did women receive higher on the underlying diagnosis and treatment received, that doses than men, as stated in the guidelines. After 26 is, after radiotherapy, the interval between imaging was years, starting doses declined with age, but no gender prolonged in some centres. https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 330 others practice For efficacy, the guidelines state that IGF-I should be Societies to raise awareness around AGHD, not just in the maintained within the age- and gender-related normal medical community but primarily also to health policy range, also if IGF-I was normal (17, 20) and this was evidenced officials and funding bodies. Including this topic in the ESE in 83% of the patients in whom information was available. pan-European curriculum for Endocrinology, Metabolism Other efficacy variables reported in approximately half the and Diabetes is also desirable (2, 3, 24, 25, 26). Improvement patients, were BMI and waist circumference, haemoglobin of perceived health with GH therapy, as well as long-term A1c, and surrogate biomarkers of cardiovascular risk outcome and quality of life with optimal substitution including blood pressure and lipids. therapy in hypopituitary patients, are strong arguments to Finally, attentive questioning to assess quality of offer treatment to eligible patients (27). Sharing experience life, energy level, partner satisfaction, sick day leave and with other patients can be very helpful (28). vitality, to monitor treatment response during follow up, Among the limitations of this survey is the variable was often not contemplated, although considered essential participation in different countries, reaching a third of (17). Overall wellbeing and energy level were routinely estimated patients in Denmark, one-fifth in Slovenia, questioned in only 61%, while the number of sick days and 14% in Sweden, but less than 5% of the population- and partner satisfaction were recorded in less than 11%. based estimation of AGHD patients in 12 countries. Some Good patient compliance, and to a lesser extent, large countries, such as Germany, did not participate. impaired QoL and severe fatigue were considered before Considering the gap between the estimated and captured initiating GH therapy (23). In 10%, administrative issues AGHD patients across Europe, this disease is more (mostly lack of reimbursement) prevented GH therapy, prevalent than currently thought in practice and probably European Journal of Endocrinology whereas tumour remnants, patient age >65 years or not so rare. Centres with less experience in the diagnosis diabetes mellitus prevented treatment in <5% of patients. and treatment of AGHD were not included, since it was In the United Kingdom, impaired baseline QoL using considered of greater educational value to collect data the AGHDA questionnaire is a prerequisite to initiate from centres with at least ten treated patients. GH substitution (21), and QoL is supposed to improve. The initial idea of comparing results from European with In other countries, however, QoL questionnaires are not other countries was not feasible since only one Australian used, which is in accordance with the guidelines. centre provided nine cases; however, it is worth mentioning Growth hormone was predominantly provided by that at survey initiation in 2017, GH was not reimbursed in hospital pharmacies, which in some centres was enforced Australia, but has now become part of the pharmaceutical to prevent illicit use of the drug (20) or in order to reduce benefit scheme. A strength, however, is collecting real-life costs. Only in some countries, were central data collection data from clinical centres responsible for the diagnosis and of GH treated patients in place, allowing health authorities management of AGHD. Given that the current guidelines to evaluate its scope and cost. were published in 2007 and 2016 and that since then further Eighteen out of the 28 participating centres were data on efficacy and safety on GH therapy in AGHD have satisfied with the overall quality of AGHD patients’ become available, confirming the benefits of treatment, an management, and especially with the extent and quality of update of the guidelines would seem pertinent. nurse training. Not surprisingly, the degree of satisfaction In summary, this ESE-led audit has identified was higher in centres that treated more patients than in country-specific differences in the diagnosis and those with less experience. management of AGHD patients. Although the guidelines The global cost of orphan drugs for the 7 to 8 thousand are followed to a large extent, several exceptions were rare diseases is around 5% of the global pharmaceutical identified. GH substitution in adults does not appear expenditure in countries such as The Netherlands, France, to be a priority among health administrators, despite Sweden and in Catalonia (’Report on evaluation of results: the fact that the cost of GH treatment in comparison to Treatment of rare disease with individually authorised global health costs is negligible. Despite that nearly 25 drugs in the year 2019’. Barcelona. Catalan Health System. years have passed since the initial 1996 Post Stephens Department of Health. Generalitat of Catalonia; 2020. AGHD consensus (29), equality of health care in Europe Accessed August 24, 2020, via: https​://ca​nalsa​lut.g​encat​ for rare diseases, an aim of both the European Health .cat/​ca/sa​lut-a​-z/m/​malal​ties_​minor​itari​es/tr​actam​ent). The Directives and EndoERN (the European Reference contribution to this expense of substitution therapy with Network for Rare Endocrine Diseases) is not globally GH is minimal. Based on the results of this survey, this gap is guaranteed for AGHD. To improve the final outcome an opportunity for a joint effort, of the ESE and the National of AGHD patients; education and a greater alert of https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 01/12/2023 08:25:58AM via free access Clinical Study L Martel-Duguech and ESE audit on AGHD in clinical 184:2 331 others practice the advantages of GH substitution therapy in these C Höybye, Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; T Kocjan and K Mlekuš Kozamernik, Department deficient patients would seem desirable, including by of Endocrinology, Diabetes and Metabolic Diseases, University Medical non-endocrine healthcare providers. Centre Ljubljana, Ljubljana, Slovenia and Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; M Kužma and Juraj Payer, 5th Department of Internal Medicine, Comenius University Faculty of Medicine and University Hospital Bratislava, Bratislava, Slovakia; M Medic Stojanoska, Supplementary materials University of Novi Sad, Faculty of Medicine, Clinic for Endocrinology, This is linked to the online version of the paper at https​://do​i.org​/10.1​530/ Diabetes and Metabolic Disease, Clinical Center of Vojvodina, Novi Sad, E​JE-20​-1180​. Serbia; A Novak and T Miličević, Department of Endocrinology, University Hospital Center Split, Split, Croatia; S Pekic and D Milijic, Clinic for Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center Declaration of interest of Serbia & Medical Faculty, University of Belgrade, Belgrade, Serbia; J The authors declare that there is no conflict of interest that could be Perez Luis, Division of Endocrinology and Nutrition, Hospital Universitario perceived as prejudicing the impartiality of this study. de Canarias, Faculty of Health Sciences, University of La Laguna, Santa Cruz de Tenerife, Spain; A Pico, Endocrinology & Nutrition Department, Health and Biomedical Research Institute of Alicante (ISABIAL), Hospital General Universitario de Alicante, University Miguel Hernandez, Centro Funding de Investigación Biomédica en Red de Enfermedades Raras (CIBERER, This work was funded by a Pfizer Independent Grant for Learning & GCV 13), ISCIII, Alicante, Spain; V Preda, Department of Clinical Medicine, Change: (IGLC): ID 9939445. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia; G Raverot and F Borson-Chazot, Fédération d’Endocrinologie, Centre de Référence Maladies Rares Hypophysaires (HYPO), Groupement Hospitalier Est, Hôpital Louis Pradel, Lyon, France; V Rochira and M L Acknowledgements Monzani, Unit of Endocrinology, Department of Biomedical, Metabolic and The authors wish to acknowledge the contribution in data collection and European Journal of Endocrinology Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy thank Haifa Rahabi-Layachi and Aude Bourgeois-André from Assistance and Unit of Endocrinology, Department of Medical Specialties, Azienda Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, Marseille, and Aix-Marseille Université, U1251, Marseille Medical Genetics Modena, Italy; K Sandahl, Endocrinology and Internal Medicine, Aarhus (MMG), France and Marta Franco from Endocrinology Unit, Department University Hospital, Aarhus, Denmark; S Tsagarakis and V Mitravela, of Internal Medicine and Medical Specialties (DIMI), University of Genoa, Department of Endocrinology, Evangelismos General Hospital, Athens, Genoa, Italy. Technical support to design the forms for data collection was Greece; S Zacharieva, Department of Endocrinology, Medical University provided by Lohmann & Birkner (Berlin), and the specific discussions and – Sofia, Sofía, Bulgaria; B Zilatiene and R Verkauskiene, Department of insight of Holger Franz is gratefully acknowledged. Without the contribution Endocrinology and Institute of Endocrinology, Lithuanian University of of Nik Screen in applying to the Independent Learning & Change call, Health Sciences, Kaunas, Lithuania. this survey would not have been possible. The helpful discussions and suggestions of Dirk de Rijdt are very much appreciated. 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