Available disease-specific questionnaires like the Acromegaly Quality of Life questionnaire have confirmed that quality of life (QoL) is impaired in acromegaly, especially in active disease. Successful therapy improves QoL, but it may not normalize completely even after endocrine cure; furthermore, there is not always a correlation between growth hormone (GH) and insulin-like growth factor 1 and subjective health perception of QoL. Appearance is the dimension most affected and has the highest impact on the patient's QoL. Worse QoL is associated with the presence of musculoskeletal pain, headache (if only medical therapy, not surgery, has been provided), having required treatment with radiotherapy, being older, of female gender, with a longer disease duration, coexisting diabetes mellitus, a higher BMI or becoming GH deficient after treatment for acromegaly.

As therapeutic options improve for pituitary adenomas in general and acromegaly in particular, we like to think we are capable of ‘curing' patients with these diseases. This would imply attaining a normal daily living and quality of life (QoL) outcome and no consequences of having suffered from the disease. The availability of instruments to evaluate the patient's subjective perception of QoL outcome of these diseases, however, evidences the existence of residual morbidity, despite endocrine control of hormonal dysfunction, including physical and psychological problems, which can be evidenced with questionnaires that evaluate health-related QoL [1].

QoL assessment is an important outcome measured in clinical practice, as it gives the clinician information on the patient's point of view regarding issues often not addressed by health professionals but which are of importance for the patient's everyday life. It is a concept that refers to how an individual feels, functions and responds in daily life. Apart from reflecting the overall effects of a disease and treatment, it is influenced by the patient's goals, expectations, standards, concerns and cultural context, as well as life events. QoL is nowadays an endpoint in the evaluation of patients with acromegaly and is measured with questionnaires designed to be used in the general population or in any kind of disease [generic questionnaires, i.e., the Nottingham Health Profile (NHP) [2], the Psychological General Well Being Scale (PGWBS) [3], the EuroQol which includes the EQ-5 Dimensions and EQ-Visual Analog Scale [4,5,6] and the Short Form 36 (SF-36) [7]] or aimed at the specific dimensions affected in this condition [disease-generated or specific questionnaires, i.e., the Acromegaly Quality of Life (AcroQoL) questionnaire]. This instrument, available in over 30 languages, is more likely to identify the impairments due to the underlying disease, as well as the benefits of treatment [1]. As for biochemical or any other parameters, they all require a validated translation, following standard methodology, when used in different cultural/language settings; this allows a comparison of the results in multicountry studies. Similar results are reported in all languages, namely lower scores in active disease than in remission, and appearance being the most affected dimension, while the least impact is in the personal relations area [8].

Acromegaly, a chronic disease which implies physical and psychological limitations (including joint pain, headache, low energy and libido) and morphological changes (change in body image, excessive sweating, change in the patients voice) that are often not completely reversible, may go undiagnosed for years despite the presence of signs and symptoms. The impact of the disease and its treatment on the patients' QoL is high. This was evidenced with generic questionnaires like the SF-36, when patients with acromegaly had a lower perceived QoL than the general population in physical function dimensions but not in mental function [9]. The use of the AcroQoL questionnaire in randomized clinical trials and clinical practice has contributed to the understanding of the specific impairments in acromegaly [8]. It includes 22 questions that evaluate physical and psychological dimensions, the latter subdivided into appearance and personal relations domains.

In clinical practice in the UK, patients with acromegaly exhibited severe impairment of QoL [10], which was observed with generic questionnaires (PGWBS, EQ-5D), a symptom and signs score and AcroQoL. In this study, AcroQoL scores were correlated with growth hormone (GH) and insulin-like growth factor 1 (IGF-1), but this is not always the case. Acromegalic patients scored worse on the PGWBS than the general population and patients treated for a nonfunctioning pituitary adenoma (NFPA), mainly in the domains of general health and vitality, and similarly bad or worse than adults with GH deficiency.

QoL was severely impaired years after remission in acromegalic patients from the Netherlands; generic questionnaires (SF-36, NHP), for which normative data from the Dutch general population are available, evidenced lower scores in cured acromegaly than in controls. Disease duration, age, treatment with radiotherapy and presence of joint problems were negatively correlated with the AcroQoL scores [11,12], while endocrine control was not associated with normalization of QoL. The appearance dimension (which was the most impaired) was weakly correlated with circulating GH levels (p < 0.05), being better with lower GH levels.

Response of QoL to Treatment in Acromegaly

Successful surgery or response to medical treatment improves the patient's perceived overall health, despite not always normalizing biochemical parameters like GH and IGF-1. QoL also improves but rarely normalizes completely and is not always correlated with biochemical markers.

Pharmacological treatment, which lowers GH and IGF-1, improves both comorbidities of acromegaly and QoL [1,8]. However, the chronic need for monthly injections of somatostatin analogs to control the disease may negatively impact on AcroQoL scores [13]. In this French study of treated acromegaly in clinical practice, no difference in AcroQoL scores were observed when globally comparing controlled and uncontrolled disease. However, when adjusted to age and disease duration since diagnosis, controlled patients improved their psychological subscale appearance, which was not observed in uncontrolled patients. In patients with uncontrolled, active disease, the appearance subscale was better if the patients had undergone surgery (65 ± 18%) than if they had only received medical treatment (54 ± 14%, p = 0.009), and this was correlated with circulating IGF-1 concentrations. This study shows that despite not always attaining endocrine cure, neurosurgery was associated with greater improvement in QoL when compared to medical therapy alone.

Neggers et al. [14] have shown how including QoL assessment evidenced clinical improvement perceived by the patients, despite not showing any change in circulating IGF-1. Despite a normal baseline IGF-1, when adding pegvisomant (but not placebo) to somatostatin analogs, acromegalic patients improved their AcroQoL and Patient-Assessed Acromegaly Symptom Questionnaire scores. The physical dimensions of the AcroQoL score were correlated with weight loss, suggesting that despite being within reference IGF-1 concentrations, some body tissues of these patients were ‘still acromegalic' and benefitted from the addition of GH receptor blockers. In this study, therefore, the evaluation of perceived QoL and clinical improvement with these questionnaires was more sensitive than circulating IGF-1 to assess subjective disease activity in acromegaly.

Radiotherapy is usually required for more aggressive cases of acromegaly that remain active after surgery and medical therapy [15] and was found to be the main indicator of progressive impairment in QoL in a subtle but progressive way during 4 years of follow-up in patients cured from acromegaly using different generics and the disease-specific AcroQoL questionnaire [16]. It negatively influenced energy, pain and social isolation (NHP), physical fatigue and reduction in activity and motivation [measured with the Multidimension Fatigue Inventory (MFI-20)], depression and total anxiety and depression scores [measured with the Hospital Anxiety and Depression Scale (HADS)] and physical performance (AcroQoL). During follow-up, the scores in 5 of 26 QoL subscales significantly worsened (namely physical and social functioning of the SF-36, physical fatigue of the MFI-20 and psychological well-being and personal relations of the AcroQoL questionnaire).

Effect of Musculoskeletal Symptoms on QoL

The impact of musculoskeletal problems on QoL was investigated in a cross-sectional study from the UK in patients with long-standing acromegaly [17] and in cured acromegalic patients from the Netherlands [12]. Using the SF-36, the Arthritis Impact Measurement Scales 2 and the AcroQoL questionnaires, acromegalic patients in the British study scored worse on the SF-36 than the normal population for physical and social functioning, role physical, energy/vitality, pain and general health but better than patients with NFPA for physical and social functioning, pain and general health. Most patients reported current pain at evaluation; when comparing those with and without pain, AcroQoL scores (global, physical and psychological) were significantly worse in those referring pain, but this difference was not so clear with the other questionnaire. The authors recommend that patients with acromegaly are asked about these problems so that advice on analgesia, physiotherapy, occupational therapy, foot wear and weight loss may be offered. In the Dutch study, joint complaints contributed significantly to a reduction in perceived QoL in ‘cured' acromegalic patients [12].

Presence of Headache and QoL

In a study among patients medically treated with somatostatin analogs for up to 4 years in clinical practice conditions, baseline AcroQoL scores were re-evaluated after octreotide long-acting release (LAR) treatment. AcroQoL scores improved in parallel to biochemical markers, being greater in those patients who normalized both GH and IGF-1 than when GH and IGF-1 improved but did not normalize; in patients with discordant results, there was only a nonsignificant trend in AcroQoL score improvement. The exception, however, were the 3 patients in whom severe headache persisted, since their QoL did not improve, independently of their hormonal values after therapy [18]. In a further recent study, the presence of headache was also correlated with worse QoL but not with depression in acromegaly, while neuropathic pain determined both impaired QoL and depression [19].

Comparison of QoL in Acromegaly and Other Pituitary Diseases

QoL in different pituitary diseases has been compared using Z scores (or standard deviation scores) for the different questionnaires investigated. With this approach, age and gender, two determinants of QoL, are accounted for, so comparisons with other reference populations are possible [16]. The questionnaires evaluated were HADS, MFI-20, NHP and SF-36. Total and subscale QoL scores of the questionnaires were worse in acromegalic patients compared to normal controls, confirming impairment of QoL in this disease during long-term follow-up after treatment. Acromegaly determined more impairment of physical ability and functioning and more bodily pain than in NFPA or prolactinomas. Hypopituitarism further impaired multiple aspects of QoL. It is important to be aware of these persistent adverse effects of pituitary disease on QoL in order to discuss it with the patient and to prevent inappropriate expectations with respect to the long-term results of treatment.

Cognition and Psychopathology and Their Influence on QoL in Acromegaly

Cognitive dysfunction has been identified as a common comorbidity of pituitary tumors. The mechanisms through which this occurs are still unclear but could include neurovascular decline, aging, suffering a chronic disease or hormone imbalance (chronic hormone excess or deficiency, mainly GH or cortisol). Although normal cognitive function has been reported in patients with long-term cured acromegaly [20], others showed deficits in attention, executive functions and memory [21,22,23]. Furthermore, increased psychopathology (mainly anxiety and depression), maladaptive personality traits or less effective coping strategies have been described in patients with controlled acromegaly, which in turn may affect cognition and QoL [24,25,26,27]. Patients describe themselves as more harm-avoiding and neurotic and showed a high social conformity [26,28]. They also show a reduction in novelty-seeking behaviour, especially in terms of a decreased impulsiveness, which was not seen in NFPA. This pattern related to increased anxiety may affect QoL, treatment adherence and patient-doctor contact.

A recent American study [29] evaluated self-perception of cognitive deficits and QoL/health, including questions on the ability to learn, concentration/distractibility, mental agility, memory/recall and verbal recall in patients with active and controlled acromegaly compared to those with NFPA. All 3 groups of patients had a similar prevalence of cognitive dysfunction, reaching 69% in NFPA, 54% in controlled and 57% in active acromegaly. Patients with NFPA expressed greater cognitive dysfunction for mental agility, memory/recall and verbal recall, but for ability to learn and concentration/distractibility, the group with active acromegaly had more problems and greater dysfunction. Other studies have reported attention and memory problems and attenuation of electrophysiological brain activity in naïve acromegaly [30,31].

Patients in long-term remission of acromegaly have been shown to have more negative illness perceptions compared with those with acute pain or vestibular schwannoma [25]. This may be related to the chronic nature of acromegaly, often requiring repeated treatment and periodic follow-up, even in so-called ‘controlled' or ‘cured' cases.

Development of GH deficiency after treatment of acromegaly also affects QoL. In fact, the patients whose QoL was least affected were those who attained a normal GH after treatment (i.e., between 0.3 and 1 μg/l), while if GH was higher (reflecting active disease), or lower (indicating that these patients had become GH deficient), more impairment ensued [32]. Young adult patients who became GH deficient after treatment of acromegaly (with surgery and/or radiotherapy) improved their QoL as assessed by the GH deficiency disease-specific questionnaire Adult GH Deficiency Assessment after substitution therapy with recombinant human GH [33], but this was not confirmed in older patients [34]. Anecdotally, 2 women in their late 30s, treated for acromegaly in their early 20s who became GH deficient, have repeatedly manifested to us that experiencing GH deficiency was much worse than having GH excess; both experienced significant improvements in energy and general well-being after starting recombinant human GH substitution therapy. Studies to further clarify the scope of benefits of substituting recombinant human GH in these patients, especially in the younger ones, would be helpful.

Since after therapy, improvement in the AcroQoL score is usually observed, one may ask in the individual patients when an improvement in score can be considered meaningful. This was approached in a large phase 3 clinical trial where the AcroQoL questionnaire was used to assess QoL comparing baseline and month 12 data after monthly pasireotide LAR (n = 176), a novel multireceptor somatostatin analog, or octreotide LAR (n = 182) [35]. Biochemical control was defined as GH <2.5 μg/l and normal IGF-1 at month 12.

The baseline AcroQoL score was 57.2 ± 19.6. For both drug groups, QoL was better in patients who achieved biochemical control at month 12 than in those that did not. Using a distribution-based estimate of the half-standard deviation method as recommended by the Food and Drug Administration Patient-Reported Outcomes guidance for longitudinal studies, a change in AcroQoL total score of ±9.8 (50% of the baseline standard deviation of the AcroQoL score, i.e., 19.6) could therefore be considered meaningful (minimum important difference) [36]. Overall, 38.6% patients from the pasireotide LAR group met the AcroQoL criteria of a clinically meaningful change versus 34.3% patients from the octreotide LAR group. This pattern was consistent for both the AcroQoL physical and psychological subscales. From baseline to month 12, the AcroQoL score improved with both pasireotide LAR (from 58.5 ± 19.7 to 65.3 ± 21.6) and octreotide LAR (from 55.9 ± 19.6 to 61.5 ± 21.1).

Since QoL reflects patient-related parameters, it is complementary to biochemical, radiological and other common objective parameters used by clinicians in everyday clinical practice. Usually, patients are pleased to be asked about problems and concerns that often affect them and may never have been verbalized. For clinicians, the information provided will complete the knowledge on the patients' condition and sometimes bring to attention problems which otherwise pass unaware. Self-administered questionnaires should be ideally completed in a quiet environment by the patient himself/herself, preferably before seeing the doctor or nurse, since answers may vary depending on the information perceived during the clinical visit. Finally, the use of adequate QoL instruments tends to improve patient-health care provider relationships, favouring a sense of high-quality health care.

The availability of a disease-specific questionnaire such as the AcroQoL questionnaire has confirmed that QoL is impaired in acromegaly, especially if the disease is active. Successful therapy is associated with improvement, but disease control often does not normalize QoL scores completely. Patients with acromegaly experience increased anxiety (as those with NFPA) but specifically, also a reduction in impulsiveness, which may impact on the patients' QoL. The physical dimension of the AcroQoL questionnaire was more sensitive than circulating IGF-1 to detect the patients' improvement after adding pegvisomant to somatostatin analog treatment in patients who at baseline were considered ‘controlled', since their IGF-1 was within the normal range; this would indicate that ‘normal' circulating GH and IGF-1 do not always mean ‘control' or ‘cure' since they are not always correlated with the QoL scores or patients' subjective well-being. The dimension with a higher impact on patients' QoL is appearance, suggesting that an earlier diagnosis before irreversible morphological changes have occurred would be beneficial. Apart from disease activity, worse QoL is associated with the presence of musculoskeletal pain, headache (if only medical therapy, not surgery, has been provided), having required treatment with radiotherapy [9,31], being older [11,32], of female gender [1], with a longer disease duration [11], coexisting diabetes mellitus [32], a higher BMI [31] or becoming GH deficient after treatment for acromegaly [32,33]. Having suffered from a pituitary tumor, even if dysfunction is controlled, confers a premature increase in health risks. The challenge for the future is how to improve the outcome of pituitary patients, so that they can be nearer to the concept of attaining a sufficient state of physical and mental well-being and to be considered healthy. For this reason, establishing the relationship between QoL items or dimensions and changes in hormonal status is key to understanding the relationship between biochemical and clinical (QoL) changes. To improve long-term prognosis, as well as offer the patient realistic expectations with respect to the results of treatment, awareness of the lack of complete normalization of cognitive function outcome and impaired QoL should be considered.

For further reading on acromegaly in this issue, see [37,38,39,40,41,42,43,44,45,46].

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