While acromegaly is a rare endocrine chronic disease that causes a significant burden on patients, requiring life-long medical surveillance and sometimes multiple therapeutic strategies to achieve disease control, it is expected that besides the increased morbidity and mortality, there is also a significant quality of life impact. In our study, we evaluated the general status of QoL in acromegalic patients and the impact of biochemical status, reported symptoms, and associated comorbidities on the patient’s perceived QoL. The mean AcroQoL total score in our included sample was 60.3, which was similar to the mean score found in a large systematic review by Geraedts et al., where the mean score in cross-sectional studies from a total of 1597 patients was 62.7 .
The most affected QoL domains were associated with appearance and physical characteristics (mean scores: 56.8 and 56.05), indicating patients also scoring lowest on the appearance scale as compared with other studies from UK  and Taiwan . This indicates that the facial disfigurement and bony changes that occur with long-lasting uncontrolled acromegaly represent primary determinants of decreased QoL. Regarding symptoms, fatigue and joint pain were reported as the most severe symptoms experienced by our patients through the PASQ scores (3.48 and 3.41), while headache represented the lowest severity scores (2.37), likely due to the fact that the majority of included patients were surgically treated with detectable tumor remnants present in 64% of the patients, but with dimensions stable and under 10 mm in most patients of our included sample. In comparison with the results from Caron PJ et al., where the total PASQ score was higher than in our patients, the symptoms severity distribution was similar, with fatigue being the most severe symptom (4.5) and headache the least severe (2.8) .
The main target of acromegaly treatment is reaching biochemical cure, defined by normalized IGF-1 values and a random GH < 1 ng/dl, as there is clear evidence that biochemically uncontrolled acromegaly is associated with increased morbidity and mortality. Despite recent advances in treatment,which lead to a noticeable improvement of disease control, patients with persistent active disease still reflect a 1.7–2 times higher mortality than the normal population, indicating the main causes of death being cardiovascular disease and malignancy [14, 15]. The biochemical control rate in our country is still rather unsatisfying, the largest published studies estimating a 28.6% control rate . The control rate in our sample was slightly higher (45.17%), but behind the overall rate reported in the European registries, where published literature revealed a range between 56 and 76% [16,17,18].
While IGF-1 levels at diagnosis are considered a strong and independent negative predictor on mortality and overall morbidity in acromegalic patients [2, 15], the correlations with QoL are less established. In our study there was no significant correlation between IGF-1 levels and QoL or symptom severity, similar to observations made in a review by Geraedts VJ et al., where most included cross-sectional studies did not find a significant association between IGF-1 or GH levels and QoL scores implying that QoL and biochemical control are different entities, although the relationship remains unclear . We found that biochemically controlled patients had higher AcroQoL scores which could have clinical significance indicating a better overall QoL compared to patients with active disease. This difference was observed on all scales, with the most notable difference being noticed on the appearance scale, yet none of the differences reached statistical significance.
Patients with active disease also scored higher on symptoms severity than controlled ones, indicating that active disease is associated with a more florid clinical picture of acromegalic patients, but the difference was significant only on soft tissue swelling. These findings could be explained by the fact that most features of acromegaly that affect QoL are secondary to chronic consequences due to the length of exposure to high IGF-1 levels rather than the simple current status of the GH-IGF-1 axis. Symptoms such as soft tissue swelling might be more clearly related to the current uncontrolled biochemical status than other symptoms or QoL aspects, the differences between disease control groups found in our study could be explained by the extracellular volume expansion and oedemas occurring in states of IGF-1 excess. Supporting this hypothesis, Sievers C et al. discovered in their interventional study that symptoms such as soft tissue swelling were more likely to improve after achieving biochemical control with Pegvisomant treatment compared to other symptoms such as headache, fatigue, and joint paint, where no improvement was observed, and concluded that these might be less specific to acromegaly disease control .
Several studies using the AcroQoL found that female gender was negatively associated with patient reported QoL,[9, 11], also being observed in the largest QoL study from our country . On the other hand, Tseng FY et al. from the Taiwan acromegaly register indicated no significant differences between genders on QoL . In our sample, women reported worse QoL than men on all AcroQoL scales but the differences did not reach statistical significance.
As expected, we found that overall symptoms severity, measured by the PASQ total score, was correlated with lower QoL. A clinically relevant finding was that bodily pain, both headache as well as neuropathic pain, was found to be a determinant of impaired QoL for acromegalic patients , which was observed in our study as a worsening headache association with a lower QoL score on the physical dimension of the AcroQoL, while the other areas of QoL were not significantly affected. Although fatigue is a relatively non-specific symptom that could be caused by a large spectrum of associated diseases, the symptom severity scores on PASQ were negatively correlated with all QoL dimensions, both physical and psychological. Acromegalic patients are known to suffer from higher rates of affective disorders such as depression, where fatigue might be a consequence of these psychocognitive impairments, leading to a lower perceived QoL which might be less related to the acromegalic disease control per se. Therefore, additional emphasis on patient counseling and psychiatric treatment for these conditions is necessary .
When it comes to adenoma type, similar to the findings by Scânteie CL et al. , patients with microadenomas scored higher than those with macroadenomas on the AcroQoL, which is expected as these patients usually have an indolent evolution and a better response to therapy, yet the difference was statistically insignificant in our lot, probably due to the low number of included patients with microadenoma. Radiotherapy is usually applied for acromegalic patients non-respondent to all other treatment modalities which have an aggressive disease evolution. Moreover, some detrimental side effects, such as neuro-cognitive dysfunction or late hypopituitarism, are not infrequent in acromegalic patients undergoing radiotherapy. It was therefore expected that a history of radiotherapy might be related to impaired QoL, which was confirmed in older studies [21, 22]. On the other hand, more recent findings including some from our country reported no significant associations between radiotherapy history and QoL [12, 19]. Our study found no differences in terms of QoL or symptoms between the previously irradiated group compared to the patients that didn’t undergo radiotherapy.
Acromegalic patients frequently suffer from cardiovascular complications, such as arterial hypertension, cardiomyopathy, and associated consequences. Besides being some of the major causes of excess mortality, these associated comorbidities may also lead to impairment in patients’ QoL. In the study by Scânteie CL et al. , it was found that cardiovascular complications played a negative role on acromegalic patients’ QoL. In our study we found that cardiovascular complications negatively impacted patients’ QoL and there was also a higher reported symptoms severity in this group of patients which didn’t reach statistical significance but might be due to the more aggressive and prolonged disease evolution of these patients.
Metabolic complications, such as diabetes mellitus, are frequently associated in acromegalic patients. Webb et al. found that diabetic acromegalic patients presented worse QoL than their non-diabetic peers , while Scânteie CL et al. found that both diabetes and cardiovascular complications impacted the QoL of acromegalic patients . Diabetic patients in our sample had a worse QoL only on the appearance dimension, while the severity of symptoms was significantly higher in diabetic patients, with the most notable difference found for excessive sweating, a symptom which can also overlap with the clinical picture of uncontrolled diabetes with autonomic neuropathy.
As acromegaly is frequently diagnosed in advanced macroadenoma stages, where multiple aggressive treatment strategies are required to achieve disease control, a commonly occurring complication in these patients is hypopituitarism. In our study, we found pituitary insufficiency in 35.4% of the patients, lower than the prevalence found in another study from Romania (63.2%) . Data about pituitary insufficiency and impaired QoL is conflicting, with some studies indicating a negative determinant on overall QoL . More recent studies found no evidence that patients with hypopituitarism suffer from worse QoL, probably due to the fact that most patients are adequately controlled with hormone replacement for the insufficient lines . In our study pituitary insufficiency was not associated with worse AcroQoL scores or higher symptoms severity.
Although acromegaly is a rare disorder, a main limitation of this study is the limited sample size (n = 31). Moreover, a significant limitation can be attributed to the cross-sectional design, which made it impossible to assess QoL and symptoms variability over time. Another important limitation is due to the highly variable timeframe after which patients achieved biochemical control of the GH-IGF-1 axis. Lastly, we would also mention the lack of a matched control group of non-acromegalic patients as a limitation, especially for the assessment of associated comorbidities impact on QoL and symptoms.
In conclusion, we found that both QoL and symptoms severity play an important role in the overall outcome of acromegalic patients, and instruments such as the AcroQoL and the PASQ questionnaire might be useful tools to implement in both clinical studies as well as in daily practice to improve the therapeutic management of acromegaly. There is a clear relationship between symptom severity and impaired QoL, while the relationships between biochemical control, gender, previous radiotherapy, hypopituitarism, and QoL are less evident. Cardiovascular complications appeared to be associated with lower QoL, but it remains to be elucidated how specific this is to the acromegalic population and whether biochemical control can lead to improvements.