Self-reported symptoms in patients with acromegaly: a 6-month follow-up in a single neurosurgical center

Abstract

Acromegaly is characterized by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), accompanied by a compromise in the perception of wellness. The Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) is relevant to assessing signs and symptoms but is mainly used to evaluate the efficacy of a pharmacological intervention. To explore the perioperative variation in symptom severity, the divergence between subgroups stratified according to clinical outcomes or treatment modalities, and the interaction between symptom scores and clinical indices, we prospectively recruited 106 patients with acromegaly from 2016 to 2018. Oral glucose tolerance and GH tests were performed, and PASQ was administered before treatment and 6 months postoperatively. Patients were divided into active (n = 49) and remission (n = 57) groups according to postoperative GH and IGF-1 levels. PASQ scores and GH and IGF-1 levels decreased significantly postoperatively in both groups. A significantly higher preoperative headache score and greater extent of decrease in arthralgia were seen in the active and remission groups, respectively. No significant variation in PASQ scores was found between patients receiving surgery alone and those receiving preoperative somatostatin analogs. Preoperative fasting GH (GH0) levels were positively correlated with preoperative excessive perspiration. Further regression analyses validated the variation in GH0 as a noteworthy determinant of the extent of change in soft-tissue swelling, excessive perspiration, fatigue, and total PASQ scores. Patient-reported symptoms were substantially alleviated after surgery, independent of endocrine remission or use of preoperative somatostatin. A GH level decrease was a notable coefficient for PASQ scores.

ACROMEGALY is a chronic disease characterized by the hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1), most often due to GH-secreting pituitary adenomas [1]. Patients with acromegaly are characterized by facial and acral dysmorphia and sometimes may present with nonspecific symptoms, including headache, fatigue, excessive perspiration, acroparesthesia, and arthralgia. Increased morbidity and mortality and undermined quality of life have been observed in patients compared with the general population [2, 3]. Currently, surgery is the primary treatment for most patients [4]. Subjective symptoms may be relieved with tumor removal [5].

Since its proposal by the World Health Organization, improving health-related quality of life has been a major component of patient-related health outcomes [6]. Regarding GH-producing pituitary adenoma, the measurement of signs and symptoms might be of particular significance since it directly affects patients’ perception of their wellness [7, 8]. Since its development in 2000, the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) has been a commonly accepted tool for assessing the extent of personal signs and symptoms in patients with acromegaly [9]. To date, existing studies applying PASQ have mainly focused on the efficacy of pharmacological therapy [9] and differential effectiveness among different regimens [10], whereas only a few studies have focused on the comparison of symptoms between various treatment modalities [11] or clinical endpoints [12]. Likewise, few studies have explored the interplay between dynamic biochemical changes and the severity of subjective symptoms. In addition, studies from Western countries made up the majority of the existing research in this field, with minor studies involving Chinese patients. The unbalanced ratio of races enrolled in existing studies might continue to be a barrier to precision medicine for different ethnicities.

Thus, we conducted a prospective single-center survey among 106 consecutive patients with acromegaly to explore the severity of subjective symptoms using the PASQ and identify the key parameters that influence the symptoms before and after surgery in Chinese patients.

Materials and Methods

Patients and design

We prospectively collected data from patients diagnosed with acromegaly who were hospitalized in the neurosurgical department of Huashan Hospital, Fudan University, between 2016 and 2018. The inclusion criteria were: (1) confirmed diagnosis of acromegaly based on the Endocrine Society Clinical Practice Guideline [13]; (2) new diagnosis with no history of surgery or radiotherapy; (3) patients who underwent trans-sphenoid surgery; and (4) patients with available follow-up data six months after the operation. After initial evaluation, patients who were unlikely to be cured by surgery owing to cavernous sinus invasion by the tumor, and those with severe pharyngeal swelling, sleep apnea or high-output heart failure, were recommended to receive three months of somatostatin analogue (SSA) therapy before surgery [4, 14, 15]. Patients with contaminant diseases, such as rheumatism and hyperthyroidism, which may cause arthralgia, perspiration, fatigue, or soft tissue swelling, were excluded from the study. Patients who received postoperative adjuvant treatment before six-month follow-up were also excluded from this study. Endocrinological evaluation and PASQ were performed before and six months after surgery. It denotes attention that patients in SSA + surgery group underwent preoperative endocrinology and PASQ evaluation prior to SSA administration.

In the endocrinological assessment, blood samples were collected for baseline blood glucose and GH levels and endocrine tests after overnight fasting. An oral glucose tolerance test (OGTT) was performed. After 75 g of glucose was orally administered, blood glucose and GH levels were sampled at 30, 60, 120 and 180 min. The prefix “△” symbolizes the dynamic change in certain indices, equal to the preoperative indicator minus their postoperative counterpart, and the ratio of a specific parameter is equal to the dynamic change divided by the preoperative value. Due to delayed remission of IGF-1 according to previous reports [16, 17], we defined biochemical remission as preoperative fasting GH (GH0) or nadir GH after OGTT <0.4 μg/L along with IGF-1 index (IGF-1/upper limit of age-matched normal range) ≤1.2 [18].

Patients’ demographics (gender and age), comorbidities (hypertension and diabetes, diagnosed according to respective guidelines [19, 20]), treatment modalities (surgery or somatostatin therapy plus surgery), clinical endpoints (remission or active) and biochemical parameters were collected. This study was approved by the local ethics committee of Huashan Hospital (KY2010-260), Fudan University, and all participants provided informed consent.

Questionary

PASQ is a disease-specific questionnaire for detailed severity assessment that consists of 5 key symptoms (soft-tissue swelling, arthralgia, headache, excessive perspiration, fatigue) on a 9-point scale (0, no symptoms; 8, severe incapacitating symptoms). The total PASQ score was the sum of the separate symptom scores, yielding a maximum of 40 points. Generally, higher PASQ scores indicate more unbearable symptoms and thus continue to threaten overall wellness in patients with acromegaly substantially.

Assays

GH levels were analyzed using a two-site chemiluminescence immunoassay (AutoDELFIA^® hGH, PerkinElmer Life and Analytical Sciences, Wallac Oy) with an intra- and inter-assay variance of 5.3–6.5% and 5.7–6.2%, respectively, and a sensitivity of 0.01 μg/L. IGF-1 levels were analyzed using Immulite 2000 solid phase, enzyme-labeled chemiluminescence immunoassay analysis (Siemens Medical Diagnostics Ltd., United Kingdom), with an intra- and inter-assay variance of 2.3–3.5% and 7.0–7.1%, respectively, and a sensitivity of 20 μg/L [21]. Normal age-appropriate ranges of IGF-1 for adults are:19–20 years, 127–483 μg/L; 21–35 years, 115–358 μg/L; 36–50 years, 94–284 μg/L; >50 years, 55–238 μg/L [22].

Statistics analysis

Continuous data were described as mean ± standard deviation (interquartile range for non-normalized data), and count data were described as counts and proportions. The paired t-test or Wilcoxon signed-rank test was used to compare the difference between parameters before and after the operation with normal or non-normal distribution. The correlations between the clinical indices and symptom scores were assessed using Spearman’s rank correlation. Linear regression was used to identify the independent determinants of symptom severity. The significance threshold was set at p = 0.05. All statistical analyses were performed using SPSS for Windows version 23.0 (SPSS, Inc.).

Results

Clinical characteristics of enrolled patients

A total of 106 patients were enrolled in this study and underwent symptom assessment and endocrinology evaluation before surgery and at 6-month follow-up. There were 54 females and 52 males, with a male-to-female ratio of 0.96:1. Twenty (18.9%) patients were diagnosed with hypertension, and 20 (18.9%) had diabetes mellitus.

Seventy-six (71.7%) patients received somatostatin therapy (Octreotide) three months before surgery, of which 27 achieved surgical remission. Thirty (28.3%) patients underwent surgery alone, and 22 achieved surgical remission postoperatively. There was no significant difference in baseline tumor size between surgery and SSA + surgery group (5,243 ± 4,501 vs. 6,010 ± 5,720 mm³, p = 0.81). There were more patients with Knosp grade ≥3 in SSA + surgery group than surgery group (68.4% vs. 33.3%, p = 0.002). And the preoperative occurrence rates of adrenal deficiency, hypothyroidism and hypogonadism were 10.4%, 8.5% and 39.6% respectively. At the six months follow-up, 49 (46.2%) patients (24 males and 25 females) achieved surgical remission, whereas 57 (53.8%) (28 males and 29 females) still had active disease. And the postoperative occurrence rates of adrenal deficiency, hypothyroidism, hypogonadism and GH deficiency were 15.1%, 16.0%, 42.5% and 10.4%.

Surgical outcomes of self-reported symptoms

A total of 101 (95.3%) patients reported soft tissue swelling at baseline, and 89 (88.1%) reported relief after treatment. Fifty-two (49.1%) patients experienced headaches before the operation, of which 45 (86.5%) reported relief at the 6-month follow-up. Four patients reported worsened headaches after surgery, and all failed to achieve endocrine remission. Forty-four (41.4%), 64 (60.4%), and 65 (61.3%) patients had arthralgia, excessive perspiration, and fatigue at baseline, respectively, while 35 (79.5%), 48 (75%), and 45 (69.2%) reported relief after treatment, respectively.

At the 6-month follow-up, 81 (76.4%), 40 (37.7%), 30 (28.3%), 45 (43.4%), and 58 (54.7%) patients had symptoms of soft tissue swelling, headache, arthralgia, excessive perspiration, and fatigue, respectively.

Changes in parameters between remission/active disease groups after surgery

Based on the endocrine status at the 6-month follow-up, patients were divided into remission and active groups (Table 1). The parameters were compared between the 2 groups. At baseline, nadir GH, IGF-1, IGF-1 index, fasting blood glucose (BG0), 2 hour blood glucose (2h BG) and PASQ scores were similar between the 2 groups (all p > 0.05), whereas patients in the active group had higher GH0 and headache scores (p < 0.05). Dramatic changes were observed in biochemical indexes (GH0, nadir GH, IGF-1, IGF-1 index, BG0 and 2h BG) as well as PASQ scores after surgical treatment in both the remission (all p < 0.05) and active (all p < 0.05) groups. At 6 months follow-up, although patients in active group had higher GH0 (7.58 ± 10.77 vs. 1.12 ± 1.76, p < 0.05), nadir GH (4.48 ± 6.32 vs. 0.17 ± 0.13, p < 0.05), IGF-1 (547.88 ± 251.13 vs. 270.31 ± 78.90, p < 0.05) and IGF-1 index (1.78 ± 0.81 vs. 0.92 ± 0.24, p < 0.05) than those in remission group, there was no significant difference in PASQ scores between the 2 groups (p < 0.05).

Table 1 Peri-operative comparison of clinical parameters and PASQ scores in patients stratified by clinical endpoints

	Remission group (n = 49)			Active group (n = 57)
	Preoperatively	Postoperatively	p	Preoperatively	Postoperatively	p
Clinical parameters
GH0 (ng/mL)	22.82 ± 21.58	1.12 ± 1.76	<0.001	32.80 ± 28.04a	7.58 ± 10.77b	<0.001
nadir GH (ng/mL)	19.93 ± 19.62	0.17 ± 0.13	<0.001	28.60 ± 25.50	4.48 ± 6.32b	<0.001
IGF-1 (μg/L)	771.14 ± 231.81	270.31 ± 78.90	<0.001	801.88 ± 216.99	547.88 ± 251.13b	<0.001
IGF-1 index	2.67 ± 0.81	0.92 ± 0.24	<0.001	2.70 ± 0.85	1.78 ± 0.81b	<0.001
BG0 (mmol/L)	5.63 ± 0.86	5.12 ± 0.81	<0.001	6.07 ± 1.54	5.10 ± 0.93	<0.001
2h BG (mmol/L)	10.32 ± 4.94	7.32 ± 3.14	<0.001	11.56 ± 4.92	7.48 ± 3.13	<0.001
PASQ scores
headache	0.00 (0.00–2.50) (1.41 ± 2.00)	0.00 (0.00–1.00) (0.69 ± 1.21)	0.011	2.00 (0.00–5.00)a (2.61 ± 2.87)	0.00 (0.00–2.00) (1.14 ± 1.82)	<0.001
arthralgia	0.00 (0.00–3.00) (1.82 ± 2.51)	0.00 (0.00–1.00) (0.61 ± 1.08)	<0.001	0.00 (0.00–3.00) (1.39 ± 2.02)	0.00 (0.00–1.00) (0.89 ± 1.71)	0.010
soft tissue swelling	4.00 (4.00–7.50) (4.92 ± 2.43)	2.00 (0.00–3.00) (1.84 ± 1.74)	<0.001	5.00 (4.00–7.00) (5.28 ± 1.95)	2.00 (1.00–4.00) (2.42 ± 1.83)	<0.001
excessive perspiration	2.00 (0.00–5.00) (2.39 ± 2.71)	0.00 (0.00–2.00) (1.29 ± 1.85)	0.002	2.00 (0.00–5.00) (2.88 ± 2.69)	0.00 (0.00–2.50) (1.49 ± 2.37)	<0.001
fatigue	2.00 (0.00–5.00) (2.38 ± 2.58)	1.00 (0.00–2.00) (1.39 ± 1.84)	0.003	2.00 (0.00–5.00) (2.74 ± 2.70)	1.00 (0.00–3.00) (1.60 ± 1.94)	<0.001
total score	11.00 (5.50–19.50) (12.91 ± 8.83)	5.00 (2.00–9.00) (5.82 ± 5.21)	<0.001	12.00 (9.00–21.00) (14.89 ± 8.33)	5.00 (2.00–12.50) (7.54 ± 7.40)	<0.001

^ap < 0.05 compared with preoperative level in remission group; ^bp < 0.05 compared with postoperative level in remission group. PASQ: Patient-assessed Acromegaly Symptom Questionnaire; GH0: fasting growth hormone; nadir GH: nadir level of growth hormone in oral glucose tolerance test; IGF-1: insulin-like growth factor 1; IGF-1 index: IGF-1/upper limit of age matched normal range; BG0: fasting blood glucose; 2h BG: 2-hour blood glucose.

We then analyzed the changes in these parameters before and after treatment (Table 2). The extent of decrease in IGF-1 (p < 0.001), IGF-1 index (p < 0.001), and arthralgia score (p = 0.044) was notably higher in the remission group than in the active group. Meanwhile, there were no significant differences in the changes in other clinical indices and PASQ scores.

Table 2 Comparison of temporal change in clinical parameters and PASQ scores between patients with different clinical endpoints

	Remission group (n = 49)	Active group (n = 57)	p value
Clinical parameters
△ GH0 (ng/mL)	21.70 ± 21.87	25.22 ± 28.92	0.487
△ nadir GH (ng/mL)	19.77 ± 19.64	24.12 ± 25.16	0.329
△ IGF-1 (μg/L)	500.84 ± 213.88	254.00 ± 291.80	<0.001
△ IGF-1 index	1.74 ± 0.79	0.92 ± 1.05	<0.001
△ BG0 (mmol/L)	0.51 ± 0.83	0.97 ± 1.54	0.055
△ 2h BG (mmol/L)	3.53 ± 4.30	3.76 ± 3.47	0.861
PASQ scores
△ headache	0.71 ± 1.87	1.47 ± 2.15	0.057
△ arthralgia	1.20 ± 2.11	0.49 ± 1.32	0.044
△ soft tissue swelling	3.08 ± 2.18	2.86 ± 2.09	0.594
△ excessive perspiration	1.10 ± 2.27	1.39 ± 2.22	0.517
△ fatigue	0.99 ± 2.23	1.14 ± 2.24	0.730
△ total score	7.09 ± 8.02	7.35 ± 7.12	0.861

The prefix “△” symbolizes the dynamic change in certain indices, equal to pre-operative indicator minus their post-operative counterpart. PASQ: Patient-assessed Acromegaly Symptom Questionnaire; GH0: fasting growth hormone; nadir GH: nadir level of growth hormone in oral glucose tolerance test; IGF-1: insulin-like growth factor 1; IGF-1 index: IGF-1/upper limit of age matched normal range; BG0: fasting blood glucose; 2h BG: 2-hour blood glucose.

Comparison of self-reported symptoms between different treatment modalities

To explore whether preoperative somatostatin may reduce postoperative PASQ scores, we divided patients into 2 subgroups: surgery and SSA + surgery groups after stratification into remission and active branches to reduce the interference of GH.

Consequently, 49 patients in the remission (surgery, 22; SSA + surgery, 27) and 57 patients in the active (surgery, 8; SSA + surgery, 49) branches were included in the analysis. In both branches, the demographic features, including age and gender ratio, were comparable between the surgery and SSA + surgery groups. In addition, no remarkable difference was detected regarding the extent of changes in clinical indices (GH0, nadir GH, IGF-1, IGF-1 index, BG0, 2h BG) and PASQ scores in either remission (Table 3) or the active (Supplementary Table 1) branch.

Table 3 Comparison of clinical parameters and PASQ scores between patients received different treatment modalities in remission branch

	Surgery group (n = 22)	SSA + Surgery group (n = 27)	p value
Clinical parameters
age	43.09 ± 13.19	43.96 ± 11.18	0.803
male: female	10:12	14:13	0.656
△ GH0 (ng/mL)	22.54 ± 19.02	21.02 ± 24.29	0.812
△ nadir GH (ng/mL)	21.74 ± 17.81	18.16 ± 21.21	0.531
△ IGF-1 (μg/L)	524.05 ± 238.48	481.93 ± 194.13	0.499
△ IGF-1 index	1.62 ± 0.85	1.84 ± 0.73	0.324
△ BG0 (mmol/L)	0.59 ± 0.87	0.45 ± 0.81	0.565
△ 2h BG (mmol/L)	5.40 ± 0.71	3.34 ± 4.48	0.532
PASQ scores
△ headache	0.82 ± 1.71	0.63 ± 2.02	0.730
△ arthralgia	1.41 ± 1.94	1.04 ± 2.26	0.545
△ soft tissue swelling	2.55 ± 2.13	3.52 ± 2.15	0.121
△ excessive perspiration	1.36 ± 2.32	0.89 ± 2.24	0.472
△ fatigue	0.77 ± 2.20	1.17 ± 2.28	0.545
△ total score	6.91 ± 8.38	7.24 ± 7.87	0.887

The prefix “△” symbolizes the dynamic change in certain indices, equal to pre-operative indicator minus their post-operative counterpart. PASQ: Patient-assessed Acromegaly Symptom Questionnaire; GH0: fasting growth hormone; nadir GH: nadir level of growth hormone in oral glucose tolerance test; IGF-1: insulin-like growth factor 1; IGF-1 index: IGF-1/upper limit of age matched normal range; BG0: fasting blood glucose; 2h BG: 2-hour blood glucose.

Correlation analysis and regression analysis

Correlation analysis was performed to identify the potential contributing factors associated with patient symptoms (Fig. 1). Among the preoperative clinical indices and baseline PASQ parameters, baseline excessive perspiration (r = 0.286, p = 0.003) was positively correlated with baseline GH0.

Fig. 1

Correlation heat map between parameters of PASQ and biochemical indices of the patients

Baseline excessive perspiration was positively correlated with baseline GH0. The depth of color directly shows the degree of correlation between biochemical indices and parameters of PASQ. At the same time, correlation significance test was carried out, with + and * symbolizing p < 0.05 and p < 0.01 respectively. PASQ: Patient-assessed Acromegaly Symptom Questionnaire; GH0: fasting growth hormone.

Subsequently, a multivariate linear regression analysis was performed further to delineate the influence of clinical indices on symptom severity. After stepwise filtration, △ GH0 was established as a significant determinant in linear models for △ soft-tissue swelling (B = 0.023, p = 0.003), △ excessive perspiration (B = 0.029, p < 0.001), △ fatigue (B = 0.017, p = 0.044), and △ total score (B = 0.085, p = 0.002), indicating the fundamental role of GH attenuation in PASQ scores. And ratio of △ BG0 was confirmed as the determinant of the ratio of △ total score (B = 0.778, p = 0.002). Besides, IGF-1 index (B = 0.570, p = 0.017) was found to be an influential factor in △ soft-tissue swelling. The separate partial linear regression plots in Fig. 2 present the linearities between the aforementioned parameters of PASQ and their corresponding notable determinants, and the detailed criteria of the multivariate linear regression analysis are shown in the Table 4.

Fig. 2

Multivariate linear regression models to unfold significant determinants of individual and total score of PASQ

(A) △ GH0 was confirmed as determinant of △ soft-tissue swelling, △ excessive perspiration, △ fatigue and △ total score. (B) Ratio of △ BG0 was validated as significant coefficient for ratio of △ total score. (C) IGF-1 index were detected as influential coefficients of △ soft-tissue swelling score. B: coefficient. The prefix “△” symbolizes the dynamic change in certain indices, equal to pre-operative indicator minus their post-operative counterpart. PASQ: Patient-assessed Acromegaly Symptom Questionnaire; GH0: fasting growth hormone; IGF-1: insulin-like growth factor 1; IGF-1 index: IGF-1/upper limit of age matched normal range; BG0: fasting blood glucose. Ratio of △ BG0 = △ BG0/BG0.

Table 4 Multivariate linear regression analyses identify influential factors for parameters of PASQ

	Beta	SE	95% CI	p value
△ soft tissue swelling
△ GH0	0.023	0.008	0.008–0.038	0.003
IGF-1 index	0.570	0.235	0.103–1.036	0.017
△ excessive perspiration
△ GH0	0.029	0.008	0.013–0.045	<0.001
△ fatigue
△ GH0	0.017	0.008	0.000–0.033	0.044
△ total score
△ GH0	0.085	0.027	0.031–0.139	0.002
Ratio of △ total score
Ratio of △ BG0	0.778	0.241	0.301–1.255	0.002

The prefix “△” symbolizes the dynamic change in certain indices, equal to pre-operative indicator minus their post-operative counterpart. PASQ: Patient-assessed Acromegaly Symptom Questionnaire; SE: standard error; CI: confidence interval; GH0: fasting growth hormone; IGF-1: insulin-like growth factor 1; IGF-1 index: IGF-1/upper limit of age matched normal range; BG0: fasting blood glucose.

Discussion

In the current study, we prospectively evaluated dynamic changes in symptom severity using the PASQ questionnaire during the perioperative period. Most patients with acromegaly had symptoms of soft tissue swelling, fatigue, excessive perspiration, headache, and arthralgia. These symptoms were alleviated to various degrees after the decrease in GH, regardless of endocrine remission. The use of somatostatin therapy before surgery failed to improve the PASQ scores after surgery. GH attenuation was validated as a significant coefficient in linear regression models for the PASQ scores.

Patient-reported symptom assessment is an important outcome measure for patients, probably more responsive to acromegaly treatment than the health-related quality of life (HRQoL) [23]. The PASQ is the most frequently used symptom questionnaire and was first proposed by Trainer et al. in 2000 [9]. Previous research mainly focused on the efficacy of pharmacological intervention and comparison among different pharmacological regimens [9, 10, 24-30], with limited studies considering the change in patients’ symptom assessment after surgery as the primary treatment option. As summarized in Table 5, previous research in this field has focused on the merits of pharmacological interventions and their related regimens, with limited studies involving other treatment modalities. Quite differently, our current study was surgery-oriented and assessed the effects of clinical endpoints or pharmacological adjuvants. Our study found that all the PASQ symptoms were relieved after treatment. There were positive correlations between changes in GH and PASQ scores; however, the persistence of related symptoms after surgery was not apparently associated with biochemical control of the disease. Caron et al. conducted a prospective clinical trial involving 90 patients who had received Lanreotide treatment [12]. No correlation between changes in PASQ scores and changes in GH or IGF-1 levels was detected, suggesting a dissociation between hormonal control and symptom improvement. The discrepancy between our study and Caron et al.’s may have resulted from different treatment modalities. Generally, IGF1 is thought to be responsible for peripheral changes [31]. However, previous studies have demonstrated that relatively low or normalized serum IGF-1 levels do not necessarily result in a change in perceptive symptoms [32-37]. In contrast, subjective symptoms were significantly improved without significantly changing IGF-1 levels [38]. Decreased GH levels have been associated with alleviating clinical symptoms [11]. Therefore, our results are in line with those of earlier studies. The differential sensitivities of various tissues to GH and IGF-1 may explain the underlying mechanisms of these associations. Specifically, GH is known to increase extracellular volume [39], and a high concentration of GH can activate the renin-angiotensin-aldosterone system, thus leading to fluid retention [40, 41]. As a result, parameters such as soft tissue swelling and perspiration are more sensitive to fluctuations in GH levels owing to the GH-induced increase in extracellular volume and fluid retention [25]. Additionally, we inferred that GH might affect PASQ scores nonlinearly, and postoperative moderately higher GH levels against the normal range in the active group had little effect on patients’ related symptoms.

Table 5 Existed researches utilizing PASQ and their corresponding information

Reference	Patients number	Duration	Study design	Results and conclusions
Trainer et al. [9]	112	12 weeks	Prospective clinical trial, different daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo	Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score for total symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant.
Jehle et al. [10]	10	18 months	Prospective clinical trial, pegvisomant was begun at 10 mg daily but then titrated up in dose or down to alternate-day dosing	Signs and symptoms scores improved in eight of 10 patients and, overall, showed a trend for improvement. Of the five patients on qod pegvisomant, these scores continued to improve in two patients and remained stable in the other three.
Schreiber et al. [24]	56	6 months	Prospective observational, all received pegvisomant treatment	Soft tissue swelling, headache, joint pain and the total score were found improved.
Neggers et al. [25]	20	16 weeks	Prospective clinical trial, PEG-V or placebo for two consecutive treatment periods in acromegalic patients with normal age-adjusted IGF-I concentrations during long-acting somatostatin analog (SSA) treatment	A significant decrease in signs and symptoms was observed in the questions soft tissue swelling, excessive sweating when PEG-V was added.
Buchfelder et al. [26]	371	118 weeks	Prospective observational, all received pegvisomant treatment	Joint pain, soft tissue swelling, numbness or tingling of limbs and the general physical condition was significantly improved after 6 months of treatment, while only soft tissue swelling and numbness were significantly improved after 24 months of treatment. Excessive sweating was significantly reduced at the 12 months follow-up visit.
Ghigo et al. [27]	118	52 weeks	Prospective clinical trial, pegvisomant vs. octreotide long-acting release (LAR)	Patients in the pegvisomant and octreotide LAR groups achieved similar improvements in total and individual signs and symptom scores (mean reductions approximately 5).
Trainer et al. [28]	27	40 weeks	Prospective clinical trial, pegvisomant monotherapy (PM) or add pegvisomant to LAR (P-LAR)	Both treatment groups reported improvements from baseline in mean total scores for acromegaly signs and symptoms.
Sievers et al. [29]	131	1 year	Retrospective, all received pegvisomant therapy	Perspiration, soft tissue swelling, and perceived health improved after 1 year of pegvisomant therapy while other symptoms such as headache, fatigue and joint pain remained largely unchanged over time.
Neggers et al. [30]	107	48 weeks	Prospective clinical trial, extended dosing intervals (EDIs) every 4, 6 or 8 weeks	Mean (S.D.) total PASQ symptom scores changed little between baseline (12.9 (7.8)) and weeks 24 (12.8 (8.6)) and 48 (14.0 (8.5)). Individual PASQ symptom scores were also generally stable throughout the study, and different dosing intervals had no clear effect on PASQ symptom scores.
Rubeck et al. [11]	63		Retrospective, cross-sectional, surgery alone (n = 36) or SA (n = 27)	By contrast, the disease-specific health status (PASQ) was significantly reduced in the SA-treated patients. The disease-specific health status of SA-treated patients was significantly poorer as compared with patients treated only with surgery.
Caron et al. [12]	90	1 year	Prospective clinical trial, all received lanreotide autogel treatment	Acromegaly symptoms significantly improved from week 12 to week 48. Changes in PASQ scores were similar in biochemically controlled and uncontrolled groups. There was no correlation between changes in PASQ scores and changes in GH or IGF-1 levels.
Coopmans et al. [38]	54	9 months	Prospective clinical trial, all received combination treatment at baseline and 9 months later they switched to pasireotide LAR either as monotherapy (n = 28) or in combination with pegvisomant (n = 26)	Patients experienced improved QoL during pasireotide LAR, either as monotherapy or in combination with pegvisomant. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in PASQ headache, osteoarthralgia and soft tissue swelling score.
Salvatori et al. [37]	544		An extension study of a non-interventional study (ACROSTUDY), including 434 rollover subjects from ACROSTUDY and 110 treatment naïve/semi-naïve patients	Patients treated with pegvisomant had small improvements in PASQ. While IGF-I normalization increased with pegvisomant treatment, IGF-I control had no effects on PASQ scores.

PASQ: Patient-assessed Acromegaly Symptom Questionnaire.

Previous studies have shown that pharmacological therapy can relieve the signs and symptoms to various extents, depending on the specific regimen. Rubeck et al. reported that the PASQ scores of SSA-treated patients were significantly higher than that of those treated only with surgery [11]. Our cohort demonstrated that symptoms alleviation induced by surgery alone or surgery with pharmacological intervention was generally equivalent. This observation may be because the somatostatin validity period is relatively short and had little effect on patients after 6 months.

Patients with acromegaly present with facial and acral dysmorphia. Acral growth is predominantly due to soft tissue swelling, which is attributed to glycosaminoglycan deposition, increased connective tissue collagen production, and edema [42], and constitutes the chief initial symptom when patients seek medical attention [4]. Ezzat et al. prospectively analyzed 500 patients with acromegaly and found that more than 70% had soft tissue swelling [43]. Our study showed that soft tissue swelling is the most common symptom in patients with acromegaly before and after surgery. Of the patients with acromegaly, 95.3% had soft tissue swelling at baseline, and this symptom remained disturbing in more than 60% of patients at the 6-month follow-up. Our previous study showed that extremities, including thumb circumference and hand volume, persistently declined during 6-month postoperative follow-up [44], indicating that the improvement is a continuous and slow procedure. A longer follow-up period may be needed to clarify whether the symptoms are reversible.

Headache is a prominent and disabling symptom reported in >50% of patients with acromegaly [45]. Acromegaly-associated headache is multifactorial and may be related to dural stretch, cavernous sinus invasion, and GH hypersecretion [46]. We inferred a relationship between GH level and headache scores but failed to obtain corresponding results in the correlation analysis. A larger cohort and in-depth research are still needed to identify whether circulating GH levels parallel the clinical presentation of headaches.

The major limitations of this study include: First, the selection criteria might have potentially resulted in the recruitment of patients with the more severe disease into the surgery + SSA group, which might have undermined the additional efficacy of symptomatic alleviation of combined therapy (SSA + surgery) compared to surgery alone. Second, most patients were aware of the endocrinology status while underwent PASQ assessment, only few patients who didn’t perform endocrinologic evaluation at three-month follow-up didn’t know if they achieved endocrine remission, which may affect self-scoring at the six months follow-up. In addition, given the influence of multiple factors, such as the time lag between symptom onset and diagnosis, comorbidities, illness perception, patients’ cognitive function and tolerance for disease and inter-person variation of tissue sensitivity to GH and IGF-1 excess, we propose to use more than one appropriate questionnaire to fully evaluate clinical outcomes in further studies. Additionally, there is a lack of comparison between patients with acromegaly and a normal healthy population. Finally, according to our definition of biochemical remission after surgery, we included several patients with normal GH and elevated IGF-1 levels in the remission group, which may have interfered with the results. Although IGF-1 may revert to the normal range after several months and show a delayed remission change [16, 17, 47], the PASQ scores in patients with discordant GH and IGF-1 levels in the short term after surgery are still unknown.

In conclusion, patients reported symptoms alleviated significantly after surgery, independent of endocrine remission or the use of preoperative somatostatin. There were positive correlations between changes in GH levels and PASQ scores. Further studies are required to clarify the determinants of subjective symptom severity before and after surgery.

Acknowledgments

The authors thank all patients involved in the study, as well as their caregivers and care team. This study was supported by the National Natural Science Foundation of China (Grant No. 81901243) and Clinical Research Plan of Shanghai Hospital Development Center (Grant No. SHDC2020CR2004A) to Professor Yao Zhao.

Disclosure

None of the authors have any potential conflicts of interest associated with this research.

References

• 1   Melmed  S (2006) Medical progress: acromegaly. N Engl J Med 355: 2558–2573.
• 2   Sherlock  M,  Ayuk  J,  Tomlinson  JW,  Toogood  AA,  Aragon-Alonso  A, et al. (2010) Mortality in patients with pituitary disease. Endocr Rev 31: 301–342.
• 3   Wolters  TLC,  Roerink  SHPP,  Sterenborg  RBTM,  Wagenmakers  MAEM,  Husson  O, et al. (2020) The effect of treatment on quality of life in patients with acromegaly: a prospective study. Eur J Endocrinol 182: 319–331.
• 4   Colao  A,  Grasso  LFS,  Giustina  A,  Melmed  S,  Chanson  P, et al. (2019) Acromegaly. Nat Rev Dis Primers 5: 20.
• 5   Geraedts  VJ,  Andela  CD,  Stalla  GK,  Pereira  AM,  van Furth  WR, et al. (2017) Predictors of quality of life in acromegaly: no consensus on biochemical parameters. Front Endocrinol (Lausanne) 8: 40.
• 6  (1995) The World Health Organization Quality of Life assessment (WHOQOL): position paper from the World Health Organization. Soc Sci Med 41: 1403–1409.
• 7   Biermasz  NR (2019) The burden of disease for pituitary patients. Best Pract Res Clin Endocrinol Metab 33: 101309.
• 8   Guyatt  GH,  Feeny  DH,  Patrick  DL (1993) Measuring health-related quality of life. Ann Intern Med 118: 622–629.
• 9   Trainer  PJ,  Drake  WM,  Katznelson  L,  Freda  PU,  Herman-Bonert  V, et al. (2000) Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N Engl J Med 342: 1171–1177.
• 10   Jehle  S,  Reyes  CM,  Sundeen  RE,  Freda  PU (2005) Alternate-day administration of pegvisomant maintains normal serum insulin-like growth factor-I levels in patients with acromegaly. J Clin Endocrinol Metab 90: 1588–1593.
• 11   Rubeck  KZ,  Madsen  M,  Andreasen  CM,  Fisker  S,  Frystyk  J, et al. (2010) Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery. Eur J Endocrinol 163: 717–726.
• 12   Caron  PJ,  Bevan  JS,  Petersenn  S,  Houchard  A,  Sert  C, et al. (2016) Effects of lanreotide Autogel primary therapy on symptoms and quality-of-life in acromegaly: data from the PRIMARYS study. Pituitary 19: 149–157.
• 13   Katznelson  L,  Laws  ER Jr,  Melmed  S,  Molitch  ME,  Murad  MH, et al. (2014) Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 99: 3933–3951.
• 14   Shen  M,  Yang  Y,  He  W,  Qiao  N,  He  M, et al. (2020) Efficacy and predictors of short-term first-generation somatostatin analog presurgical treatment in acromegaly: a hospital-based study of 237 cases. Growth Horm IGF Res 55: 101354.
• 15   Shen  M,  Shou  X,  Wang  Y,  Zhang  Z,  Wu  J, et al. (2010) Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study. Endocr J 57: 1035–1044.
• 16   Albarel  F,  Castinetti  F,  Morange  I,  Conte-Devolx  B,  Gaudart  J, et al. (2013) Outcome of multimodal therapy in operated acromegalic patients, a study in 115 patients. Clin Endocrinol (Oxf) 78: 263–270.
• 17   Arafat  AM,  Mohlig  M,  Weickert  MO,  Perschel  FH,  Purschwitz  J, et al. (2008) Growth hormone response during oral glucose tolerance test: the impact of assay method on the estimation of reference values in patients with acromegaly and in healthy controls, and the role of gender, age, and body mass index. J Clin Endocrinol Metab 93: 1254–1262.
• 18   Gonzalez  B,  Vargas  G,  de Los Monteros  ALE,  Mendoza  V,  Mercado  M (2018) Persistence of diabetes and hypertension after multimodal treatment of acromegaly. J Clin Endocrinol Metab 103: 2369–2375.
• 19   American Diabetes  Association (2014) Diagnosis and classification of diabetes mellitus. Diabetes Care 37 Suppl 1: S81–S90.
• 20   Reboussin  DM,  Allen  NB,  Griswold  ME,  Guallar  E,  Hong  Y, et al. (2018) Systematic review for the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 71: 2176–2198.
• 21   Shen  M,  Wang  M,  He  W,  He  M,  Qiao  N, et al. (2018) Impact of long-acting somatostatin analogues on glucose metabolism in acromegaly: a hospital-based study. Int J Endocrinol 2018: 3015854.
• 22   Annamalai  AK,  Webb  A,  Kandasamy  N,  Elkhawad  M,  Moir  S, et al. (2013) A comprehensive study of clinical, biochemical, radiological, vascular, cardiac, and sleep parameters in an unselected cohort of patients with acromegaly undergoing presurgical somatostatin receptor ligand therapy. J Clin Endocrinol Metab 98: 1040–1050.
• 23   Broersen  LHA,  Zamanipoor Najafabadi  AH,  Pereira  AM,  Dekkers  OM,  van Furth  WR, et al. (2021) Improvement in symptoms and health-related quality of life in acromegaly patients: a systematic review and meta-analysis. J Clin Endocrinol Metab 106: 577–587.
• 24   Schreiber  I,  Buchfelder  M,  Droste  M,  Forssmann  K,  Mann  K, et al. (2007) Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study. Eur J Endocrinol 156: 75–82.
• 25   Neggers  SJ,  van Aken  MO,  de Herder  WW,  Feelders  RA,  Janssen  JA, et al. (2008) Quality of life in acromegalic patients during long-term somatostatin analog treatment with and without pegvisomant. J Clin Endocrinol Metab 93: 3853–3859.
• 26   Buchfelder  M,  Schlaffer  S,  Droste  M,  Mann  K,  Saller  B, et al. (2009) The German ACROSTUDY: past and present. Eur J Endocrinol 161 Suppl 1: S3–S10.
• 27   Ghigo  E,  Biller  BM,  Colao  A,  Kourides  IA,  Rajicic  N, et al. (2009) Comparison of pegvisomant and long-acting octreotide in patients with acromegaly naive to radiation and medical therapy. J Endocrinol Invest 32: 924–933.
• 28   Trainer  PJ,  Ezzat  S,  D’Souza  GA,  Layton  G,  Strasburger  CJ (2009) A randomized, controlled, multicentre trial comparing pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly. Clin Endocrinol (Oxf) 71: 549–557.
• 29   Sievers  C,  Brubach  K,  Saller  B,  Schneider  HJ,  Buchfelder  M, et al. (2010) Change of symptoms and perceived health in acromegalic patients on pegvisomant therapy: a retrospective cohort study within the German Pegvisomant Observational Study (GPOS). Clin Endocrinol (Oxf) 73: 89–94.
• 30   Neggers  SJ,  Pronin  V,  Balcere  I,  Lee  MK,  Rozhinskaya  L, et al. (2015) Lanreotide Autogel 120 mg at extended dosing intervals in patients with acromegaly biochemically controlled with octreotide LAR: the LEAD study. Eur J Endocrinol 173: 313–323.
• 31   Colao  A,  Ferone  D,  Marzullo  P,  Lombardi  G (2004) Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 25: 102–152.
• 32   Rowles  SV,  Prieto  L,  Badia  X,  Shalet  SM,  Webb  SM, et al. (2005) Quality of life (QOL) in patients with acromegaly is severely impaired: use of a novel measure of QOL: acromegaly quality of life questionnaire. J Clin Endocrinol Metab 90: 3337–3341.
• 33   Bonapart  IE,  van Domburg  R,  ten Have  SM,  de Herder  WW,  Erdman  RA, et al. (2005) The ‘bio-assay’ quality of life might be a better marker of disease activity in acromegalic patients than serum total IGF-I concentrations. Eur J Endocrinol 152: 217–224.
• 34   Biermasz  NR,  Pereira  AM,  Smit  JW,  Romijn  JA,  Roelfsema  F (2005) Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab 90: 2731–2739.
• 35   Hua  SC,  Yan  YH,  Chang  TC (2006) Associations of remission status and lanreotide treatment with quality of life in patients with treated acromegaly. Eur J Endocrinol 155: 831–837.
• 36   Biermasz  NR,  van Thiel  SW,  Pereira  AM,  Hoftijzer  HC,  van Hemert  AM, et al. (2004) Decreased quality of life in patients with acromegaly despite long-term cure of growth hormone excess. J Clin Endocrinol Metab 89: 5369–5376.
• 37   Salvatori  R,  Maffei  P,  Webb  SM,  Brue  T,  Loftus  J, et al. (2022) Patient-reported outcomes in patients with acromegaly treated with pegvisomant in the ACROSTUDY extension: a real-world experience. Pituitary 25: 420-432.
• 38   Coopmans  EC,  El-Sayed  N,  Frystyk  J,  Magnusson  NE,  Jorgensen  JOL, et al. (2020) Soluble Klotho: a possible predictor of quality of life in acromegaly patients. Endocrine 69: 165–174.
• 39   Bengtsson  BA,  Brummer  RJ,  Eden  S,  Bosaeus  I,  Lindstedt  G (1989) Body composition in acromegaly: the effect of treatment. Clin Endocrinol (Oxf) 31: 481–490.
• 40   Hansen  TK,  Moller  J,  Thomsen  K,  Frandsen  E,  Dall  R, et al. (2001) Effects of growth hormone on renal tubular handling of sodium in healthy humans. Am J Physiol Endocrinol Metab 281: E1326–E1332.
• 41   Moller  J,  Nielsen  S,  Hansen  TK (1999) Growth hormone and fluid retention. Horm Res 51 Suppl 3: 116–120.
• 42   Vilar  L,  Vilar  CF,  Lyra  R,  Lyra  R,  Naves  LA (2017) Acromegaly: clinical features at diagnosis. Pituitary 20: 22–32.
• 43   Ezzat  S,  Forster  MJ,  Berchtold  P,  Redelmeier  DA,  Boerlin  V, et al. (1994) Acromegaly. Clinical and biochemical features in 500 patients. Medicine (Baltimore) 73: 233–240.
• 44   Zhang  Z,  Li  Q,  He  W,  Qiu  H,  Ye  H, et al. (2018) The comprehensive impact on human body induced by resolution of growth hormone excess. Eur J Endocrinol 178: 365–375.
• 45   Giustina  A,  Gola  M,  Colao  A,  De Marinis  L,  Losa  M, et al. (2008) The management of the patient with acromegaly and headache: a still open clinical challenge. J Endocrinol Invest 31: 919–924.
• 46   Darendeliler  F,  Karagiannis  G,  Wilton  P (2007) Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database. Horm Res 68 Suppl 5: 41–47.
• 47   Nishioka  H,  Fukuhara  N,  Yamaguchi-Okada  M,  Takeshita  A,  Takeuchi  Y, et al. (2017) Pitfalls in early biochemical evaluation after transsphenoidal surgery in patients with acromegaly. Endocr J 64: 1073–1078.