Voice Characteristics in Patients with Acromegaly during Treatment

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Voice Characteristics in Patients with Acromegaly during Treatment *,#

Thalijn L.C. Wolters, *,†,#Sean H.P.P. Roerink, *Linda C.A. Drenthen, *,‡Margaretha A.E.M. Wagenmakers, Guido B. van den Broek, ¶Kim I.M. Rutten, §Jasmijn M. Herruer, *Adrianus R.M.M. Hermus, and * Romana T. Netea-Maier, *x{Nijmegen, yArnhem, and zRotterdam, The Netherlands §

Summary: Background. Active acromegaly is characterized by Growth Hormone and Insulin-like Growth Factor (IGF)-1 excess. Voice complaints are common in active acromegaly and are suggested to be caused by effects of Growth Hormone or IGF-1 on vocal cords and the surrounding soft tissues. Prospective studies on the course of voice characteristics in acromegaly patients are scarce and results are conflicting. This study investigates objective changes in voice parameters, self-reported perception of voice and laryngostroboscopic features during the first 2.5 years of acromegaly treatment. Material and Method. In this prospective study, acoustic voice analysis (and videolaryngostroboscopic examination were performed in 27 consecutive treatment-naive acromegaly patients at diagnosis (T0), after 1 year (T1) and after 2.5 years (T2) of treatment. The voice handicap index (VHI-30) questionnaire was taken. Results. During acromegaly treatment, VHI scores decreased, and mucosal edema & hypertrophy diminished. No significant changes in objective voice parameters were detected. The within-subject change in serum IGF-1 levels (97.3 (40.6−208) to 22.4 (10.2−34.1) nmol/L (P < 0.001)) during follow-up correlated positively with the changes in VHI questionnaire scores (R 0.32−0.45; P = 0.002−0.03). Conclusions. At diagnosis and during acromegaly treatment, mean VHI scores were in the normal range, although they decreased during follow-up. Mucosal edema and hypertrophy largely resolved during treatment. No significant changes in objective voice parameters were observed. Voice characteristics are in the normal range in patients with acromegaly, but may change during treatment. However, voice complaints are important to discuss, since they may influence quality of life. Key Words: Acromegaly−Voice−Insulin-like Growth Factor 1−Somatostatin analogue−Voice handicap index.

INTRODUCTION‘ Acromegaly is a rare disorder that results from excessive Growth Hormone (GH) secretion,1,2 mostly caused by a GHsecreting pituitary adenoma.1 GH excess leads to overproduction of Insulin-like Growth Factor-1 (IGF-1).1,2 Prolonged exposure to excessive levels of IGF-1 in patients with acromegaly causes craniofacial abnormalities and respiratory tract tissue proliferation, which can lead to voice changes.3−5 In patients with acromegaly, a lower voice pitch and a hoarser voice quality due to thickening and relaxation of the vocal cords have been described,5,6 next to laryngeal mucosa laxity,7 laryngeal cartilage hypertrophy and joint Accepted for publication January 9, 2020. Declarations of Interest: None. Funding: This is an investigator-initiated study sponsored through an unrestricted research grant from IPSEN Pharmaceuticals. IPSEN Pharmaceuticals had no involvement in the study design, the collection, analysis and interpretation of data, the writing of the report nor in the decision to submit the article for publication. From the *Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands; yDepartment of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands; zDepartment of Internal Medicine, Center for Lysosomal and Metabolic Diseases, Erasmus MC Medical University Center Rotterdam, Rotterdam, The Netherlands; xDepartment of Otolaryngology/Head and Neck Surgery, Radboud University Medical Center, Nijmegen, The Netherlands; and the {Department of Rehabilitation, Section of Speech and Language Therapy, Radboud University Medical Center, Nijmegen, The Netherlands. # T.L.C.W. and S.H.P.P.R. equally contributed to this manuscript. Address correspondence and reprint requests to Thalijn Wolters, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands. E-mail: [email protected] Journal of Voice, Vol. &&, No. &&, pp. &&−&& 0892-1997 © 2020 The Voice Foundation. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jvoice.2020.01.006

chondrocalcification,6,8 compression of the laryngeal nerves, and expansion of the maxillary sinuses.5,8 Normalization of GH levels by treatment may (partially) reverse soft tissue changes to upper airway structures, since soft tissue volume may reduce.5 Importantly, voice pathology has been reported to negatively impact the quality of life (QoL) of patients with acromegaly.3−5 Despite these reported anatomical changes, objective data about changes in voice characteristics in acromegaly are scarce. The fundamental frequency (fo; the average number of vocal cord vibration cycles per second) is perceived as the pitch of the voice.9 In addition, the maximal frequency (Fmax), the minimal frequency (Fmin) and the Pitch range (PR; the lowest to the highest pitch of the voice) are characteristics that can be used to describe the range of a voice. The most frequently reported voice parameter change in patients with active acromegaly is the lowering of the fo, which was more pronounced in women than in men.3,4,10,11 With regard to noise-related parameters, the Harmonics to noise ratio (HNR; the ratio between total energy and energy of noise in dB12) and the Noise to harmonics ratio (NHR; the global inverse of the HNR) reflect noise in a voice signal.13 In addition, jitter is the perturbation of frequency in %, and shimmer is the micro-perturbation of amplitude in %. In male acromegaly patients, increased noise-related parameters and shimmer were common features.3 The increase of noise-related parameters is suggested to be caused by loose adduction and irregular vibration of the

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Journal of Voice, Vol. &&, No. &&, 2020

vocal cords, due to changes to the larynx and vocal cord mass and elasticity. However, no relation between voice changes and IGF-1 levels have been reported.3 In the only prospective study on the effect of pituitary adenomectomy on voice characteristics (with a follow-up of only 11 days), vocal cord edema had largely resolved and fo increased after normalization of GH levels. No correlation of GH levels or fo was found.4 Due to the scarcity of longitudinal data, it is unclear whether and to what extent upper airway anatomy and voice characteristics change after long-term normalization of GH/IGF-1 levels in patients with acromegaly. Perception of voice has not been studied in acromegaly patients. The Voice Handicap Index (VHI) is a widelyapplied, valid and reliable questionnaire to assess patient’s perception of voice constraints,14,15 and consists of 30 items, divided into three subscales of 10 items each: Functional (F), Emotional (E) and Physical (P). The score for each item ranges from 0 to 4 (0 = never to 4 = always), resulting in a maximum total score of 120. The higher the score, the more severe the voice-related limitations. The aim of this study is to comprehensively investigate the changes in voice characteristics in consecutive treatment-naive acromegaly patients during the first 2.5 years of acromegaly treatment. This knowledge can be used to understand the dynamics of upper airway anatomy and voice characteristics following treatment in patients with acromegaly, to prevent premature or unnecessary treatment of residual abnormalities and can contribute to better patient counseling regarding voice changes and follow-up. MATERIAL AND METHODS Subjects All untreated adult patients with acromegaly who visited the outpatient department of the Radboud University Medical Center Nijmegen (The Netherlands) between July 2012 and June 2016 were assessed for eligibility to participate in this study. The diagnosis of acromegaly was biochemically confirmed by an increased serum IGF-1 level (>2 SD above the sex- and age-adjusted mean) and insufficient suppression of serum GH levels during an oral glucose tolerance test (oGTT; GH ≥0.4 mg/L).1 Magnetic resonance imaging (MRI) of the pituitary gland was performed in each patient to identify a pituitary adenoma. Patients with pre-existent voice disorders or nonacromegaly-related vocal cord pathology were not eligible. Thirty-two patients were eligible for participation; four patients refused because of time constraints (N = 2) or fear of the study procedures (N = 2), one patient assigned female at birth underwent gender affirming treatment prior this study and was excluded since the gender affirming treatment likely had influenced his voice. The remaining 27 patients (10 males) were included. Men were younger (44.6 § 12.7) than women (56.2 § 12.2 years; P = 0.03), and had a higher body weight (107.2 § 16.8 in men vs 81.4 § 18.4 kg in women; P = 0.001), but a similar BMI (30.5 § 3.4 in men vs 29 § 5.7 kg/m2 in women; P = 0.38). In men, alcohol

consumption (yes/no) was more prevalent (10/10 vs. 6/17 in women; P = 0.001), whereas the number of smokers was similar. These differences persisted during follow-up. The average BMI and body weight did not change in our group significantly during follow-up (Table 1). Nineteen patients (70.4%) were diagnosed with a macroadenoma (>1cm), seven patients with a microadenoma (≤1 cm) and one patient (No. 11; Table 2) with a bronchial GHRH-producing intermediate-grade neuroendocrine tumor (NET). One patient (No. 26) discontinued the study shortly after T0 because she moved to another city and continued her treatment in another hospital. One patient (No. 2) did not undergo measurements at T1 because of time constraints. One female (No. 24) refused the last measurement (T2) because of work-related obligations. One female participant (No. 5) did not fill out questionnaires because of a language barrier, but underwent all other measurements during the study. Twenty-six patients completed the measurements at least twice, whereas 24 patients completed measurements at all three timepoints. Procedure The study structure is displayed in Figure 1. Patients visited our hospital at diagnosis (T0), after 1 year (T1), and after 2.5 years (T2). At each visit, patients underwent a videolaryngostroboscopy (VLS) and acoustic voice analysis (AVA), and they completed the Dutch translation of the Voice Handicap Index-30.16 At T0, weight and height were measured, and GH and IGF-1 levels were measured in the nonfasted state in venous blood. At T1 and T2, weight, and IGF-1 levels were measured in the nonfasted state. After diagnosis, standard care was pretreatment with a long-acting somatostatin receptor analogue (SSA), followed by endoscopic endonasal transsphenoidal adenomectomy (EETA) after about 6 months, or primary medical therapy in patients who were not suitable for surgery. If biochemical control was not obtained by SSA monotherapy, the GHreceptor antagonist Pegvisomant (PEGV) or a dopamine agonist (DA) was added. In case of residual or recurrent disease after surgery, medical therapy was restarted postoperatively. When possible, patients underwent a second surgical procedure. In case of persistent IGF-1 levels above the reference range despite maximal tolerable medical therapy, patients underwent radiotherapy. Surgical control was defined as postoperative IGF-1 levels within the sex- and age-adjusted reference range, combined with a random GH level <1 mg/L or a sufficient suppression of serum GH levels (GH <0.4 mg/L) during an oGTT, performed approximately four months after surgery,1,17,18 without use of medication. Biochemical control was defined as IGF-1 levels within the sex- and age-adjusted reference range17 with use of medication (SSA, DA and/or PEGV). Adrenal insufficiency (AI) was defined as a morning serum cortisol <100 nmol/L without use of glucocorticoids for 24 h, or a maximal cortisol response <550 nmol/L during an insulin tolerance test (ITT).19 Subclinical AI was defined as

Baseline Subject Characteristics (T0)

Females (N = 17)

P Value Males vs Females

51.9 § 13.5 91 § 21.6 29.5 § 5 2 (7.4) 16 (59.3) 8 (2−28) 21.9 (2.9−383) 7.3 (0.97−127.7) 97.3 (40.6−208) 7.1 (3.5−23.2)

44.6 § 12.7 107.2 § 16.8 30.5 § 3.4 1 (10) 10 (100) 6.5 (3−20) 26.9 (7.3−84.0) 9 (2.4−28) 118.1 (66.7−208) 11.8 (6.8−23.2)

56.2 § 12.2 81.4 § 18.4 29 § 5.7 1 (5.9) 6 (35.3) 10 (2−28) 20.7 (2.9−383) 6.9 (1−127.7) 84.5 (40.6−146) 6.2 (3.5−16.7)

0.03 0.001 0.38 1.0 0.001 0.18 0.75 0.75 0.007 <0.001

19 (70.4) 7 (25.9) 1 (3.7) 1 (3.7) 1 (3.7) 7 (25.9)

6 (60) 3 (30) 1 (10) 0 (0) 1 (10) 7 (70)

13 (76.5) 4 (23.5) 0 (0) 1 (5.9) 0 (0) 0 (0)

0.48

148.5 (87.3−210.9) 107.7 § 21.3 473.9 § 117.2 392.9 § 106 110 (62.5−196) 85 (62.5−110) 27 (9−34) 26 (15−34) 2.86 § 0.8 3.11 § 0.51 1.33 (0.97−3.96) 1.37 (1.17−1.69) 9.34 § 1.91 7.94 § 1.42 0.25 § 0.06 0.30 § 0.05

Reference Values Males Reference Values Females 128 (85−196)[25] 168 § 24.9 225 (155−334)[25] 683.4 § 142.5[26] 521.6 § 97.4 891.1 § 157.1[26] 86.5 § 15.6[26] 124 (82.5−196) 160.4 § 48.4[26] 35.7 § 4.9[26] 27 (9−32) 30.2 § 4.1[26] 0.4 § 0.1827 2.71 § 0.92 0.33 § 0.1727 2.3 § 1.3[27] 1.43 (0.97−3.96) 2.7 § 2.3[27] 24 § 4.4[27] 10.16 § 1.7 25 § 4.5[27] 0.04 § 0.01[52] 0.23 § 0.06 0.04 § 0.0152

1.0 0.37 <0.001 <0.001 0.006 <0.001 0.89 0.16 0.12 0.002 0.006

11 (0−50) 3.5 (0−14) 0 (0−19) 4.5 (0−20) 10 (37) 7 (4−10)

10.5 (0−50) 6.5 (0−14) 0.5 (0−19) 3.5 (0−20) 3 (30) 7 (4−10)

10 (0−38) 3 (0−10) 0 (0−12) 4 (0−16) 7 (41.2) 7 (5−9)

0.79 0.42 0.57 0.7 0.69 0.68

1 (0−2) 0 (0−2) 0 (0−1) 0 (0−1) 0 (0−2)

0.5 (0−1) 0 (0−1) 0 (0−1) 0 (0) 0 (0−1)

1 (0−2) 0 (0−2) 0 (0−1) 0 (0−1) 0 (0−2)

0.28 0.49 0.66 0.24 0.1 (Continued)

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Males (N = 10)

The Course of Voice Characteristics in Acromegaly

Age (years) Weight (kg) BMI (kg/m2) Current smoker (yes, %) Alcohol consumption (yes, %) Duration of symptoms (years) GH (mE/l) GH (mg/L) IGF-1 (nmol/L) IGF-1 SDS Etiology (N, %) Macroadenoma Microadenoma GHRH producing NET Hypothyroidism (N, %) Hypocortisolism (N, %) Hypogonadism (N, %) Acoustic voice analysis fo (Hz)† Fmax (Hz)* Fmin (Hz)* PR (ST)* Jitter (%)† Shimmer (%)† HNR (dB)† NHR† Voice Handicap Index (VHI) VHI − total VHI−functional VHI−emotional VHI−physical Voice complaints (yes, %) Voice mark GRBAS scale† Grade Roughness Breathiness Asthenicity Strain

Total Group (N = 27)

Thalijn L.C. Wolters, et al

TABLE 1. Patient and Voice Characteristics at Baseline, in the Total Group, in Males and in Females

3

ARTICLE IN PRESS 4 * These measures were obtained during registration of a phonetogram. † These measures are taken from habitual voice samples.Reference values are represented as mean with range or SD, and were obtained from previous studies using Praat in healthy volunteers, except for 26 53 Fmax, Fmin and PR (Tiger Electronics (Seattle, WA) Dr. Speech software (Voice Assessment, Version 3.0)). , Values are displayed as mean with SD or as median with minimum and maximum, depending on the normality of the distribution. Categorical variables are displayed as numbers (percentage). Abbreviations: BMI, body mass index in kg/m2; fo, mean fundamental frequency in Hertz (Hz); Fmax, maximal frequency in Hz; Fmin, minimal frequency in Hz; GH, growth hormone; GHRH, GH releasing hormone; HNR, harmonics to noise ratio in decibel (dB); IGF-1, Insulin-like Growth Factor 1; NET, neuroendocrine tumor; NHR, noise to harmonics ratio; PR, pitch range in semitones (ST); SDS, standard deviation score; VHI, Voice Handicap Index. Above mentioned reference values are based on reports in literature.25−27,52 Reference values are represented as mean with range or SD, and were obtained from previous studies using Praat in healthy volunteers, except for Fmax, Fmin and PR (Tiger Electronics (Seattle, WA) Dr. Speech software (Voice Assessment, Version 3.0)) 26,53

1 0.68 0.8 1 0.94 0.007 0.63 1 N = 14 6 (42.9) 6 (42.9) 5 (35.7) 4 (28.6) 2 (1−6) 2 (1−6) 1 (1−5) 1 (1−2) N = 24 10 (41.7) 9 (37.5) 7 (29.2) 6 (25) 2 (1−6) 1 (1−6) 1 (1−5) 1 (1−2) Videolaryngostroboscopy Abnormal mucosa (N, %) Mucosal edema (N, %) Mucosal hypertrophy (N, %) Nasal mucosal hypertrophy (N, %) Supraglottic activity Glottic closure Vibration Symmetry

N = 10 4 (40) 3 (30) 2 (20) 2 (20) 2 (1−5) 1 (1−2) 1 (1−3) 1 (1−2)

P Value Males vs Females Total Group (N = 27) Baseline Subject Characteristics (T0)

TABLE 1. (Continued )

Males (N = 10)

Females (N = 17)

Journal of Voice, Vol. &&, No. &&, 2020

normal morning cortisol levels with an insufficient response (cortisol <550 nmol/L) during an ITT. Women were defined as postmenopausal when gonadotrophin levels were in the postmenopausal range and/or when they were older than 55 years. In men and premenopausal women, hypogonadism was defined as total testosterone or estrogen levels below the reference range. Hypothyroidism was defined as free thyroxin (fT4) plasma levels <8 pmol/L (institutional reference range 8−22 pmol/L). Hypopituitarism was defined as the presence of one or more of the aforementioned pituitary hormonal deficiencies. This study was conducted in accordance with the Declaration of Helsinki and approved by our local ethical committee (CMO regio Arnhem-Nijmegen; 2012-131). All subjects signed informed consent prior to participation.

Hormone assays Serum IGF-1 levels were determined using a chemiluminescent immunometric assay (Liaison, DiaSorin, Saluggia, Italy). GH levels were determined using a sandwich-type immunometric assay (Roche Diagnostics, Basel, Switzerland).

Videolaryngostroboscopy A VLS examination using digital video endoscopy was performed at each visit by a phoniatric physician (an experienced ENT-specialist (GvdB), or an ENT-resident (JH) who was supervised by GvdB) to exclude nonacromegalyrelated vocal cord pathology and to detect edema and hypertrophy of the arytenoid, inter-arytenoid region, false vocal folds and aryepiglottic folds. Because of the high quality of these recordings, it was possible for the aforementioned two physicians to analyze the aspect of the vocal cords adequately after the examination. Videoendoscopy was performed using a Pentax Laryngeal Stroboscope model 9400 and a Pentax Radiance Ultra HD screen (Pentax Medical, Hoya Corporation, Tokyo, Japan), a Kay-Pentax 9200C server, and a Pentax Defina EPK 3000 processor. Recordings were saved and reviewed in Clinical assistant (RVC, Baarn, The Netherlands, Build 2017.2.3.7829, created 19-9-2018). Patients were asked to phonate a short /e/ repeatedly in order to evaluate vocal cord mobility. Thereafter, they were asked to perform a low and high prolonged /i/ task. Grading with regard to mucosal edema and hypertrophy was based on the whole VLS assessment. Mucosal edema was scored according to the Reinke’s edema (grade 1−4) grading system as described by Tan et al.20 In the statistical analysis, this score was converted to present (grade 1−4) or absent (0), since all patients with edema scored grade 1. Mucosal hypertrophy was also rated as present or absent. In addition, supraglottic activity (no=1; ventricular phonation=7); glottic closure (S€ odersten glottic closure score; Figure 2 (1-6, A-D)21), vibration (1 normal − 7 severely reduced) and symmetry (1 symmetrical 7 severely asymmetrical) were scored. These parameters were scored using a stroboscopic lamp.

ARTICLE IN PRESS Thalijn L.C. Wolters, et al

5

The Course of Voice Characteristics in Acromegaly

TABLE 2. Course of Treatment and IGF-1 Levels in Individual Subjects Treatment & IGF-1 in Individual Subjects No

Sex

1 2 3 4 5 6 7 8 9

M F M F M F F F F

10 11 12 13

F M F F

14 15

F F

16

M

17

F

18

M

19 20

F F

21

M

22

M

23 24 25 26 27

M F M F F

T0

T1

T2

Treatment

IGF-1

Exam

VHI

IGF-1

Exam

VHI

IGF-1

Exam

VHI

MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: cured MS (0−6) + S: RD MS (14−30): BC (16−30) MS (0−8) + S: cured S (2): cured Primary MS (0−30): BC (6−30) MS (0−6) + S: RD MS (13−30): BC (15−30) MS (0−6) + S: cured MS (0−6) + S: RD MS (12−24) + MP (15−22) + reS (24): cured MS (0−6) + S: RD MS (11−30): BC (12−30) MS (0−6) S: RD MS (8−30) + MP (11−30) + SRT (20−21): BC (29−30) S (1.5): RD MS (2.5−30): BC (14−30) MS (0−11) + S: cured MS (0−6) + S: RD MS (8−30): BC (10-30) MS +MD (0−6) + S: RD MS +MD (14−30): BC (24−30) MS (0−6) + MP (4−6) + S: RD MS (9−30) + MP (10−30) + GRS (12): BC (15−30) MS (0−6) + S: cured MS (0−6) + S: cured MS (0−5) + S: cured Lost to follow-up Primary MS (0−30) + MP (9−30): BC (22−30)

208 118.7 111 54.4 66.7 108 77.2 97.3 79.8

V,A,Q A,Q V,A,Q A,Q V,A V,A,Q V,A,Q V,A,Q A,Q

27 2 0 15 O 8 0 1 18

O 24.7 O 16.8 8.5 23.6 20.4 23.5 36.5

V,A,Q O V,A,Q A,Q V,A,Q V,A,Q V,A,Q V,A,Q V,A,Q

1 O 0 25 3 8 1 2 21

13 19.4 29.8 17.5 34.1 18.2 22.4 25.5 28.3

V,A,Q A,Q V,A,Q A,Q V,A,Q V,A,Q V,A,Q V,A,Q V,A,Q

3 0 2 3 6 4 1 0 9

80.1 122.1 40.6 83.7

V,A V,A,Q V,A,Q V,A,Q

O 13 13 10

19.3 34.2 24.7 48.3

V,A V,A,Q V,A,Q V,A,Q

O 5 0 7

10.2 30.4 28 17.8

V,A V,A,Q V,A,Q V,A,Q

O 2 8 11

63.8 118.7

V,A,Q V,A,Q

7 10

11 54.4

V,A,Q V,A,Q

11 9

11.7 25.8

V,A,Q V,A,Q

23 1

109.5

V,A,Q

0

27.4

V,A,Q

0

20.3

V,A,Q

1

38

83.2

A,Q

29

25.9

A,Q

5

A,Q

9

146

A,Q

132.5

V,A,Q

8

40.7

V,A,Q

4

28

53.5 85.2

V,A,Q V,A,Q

0 30

17.2 20.2

V,A,Q V,A,Q

0 18

15.6 21.1

V,A,Q V,A,Q

0 23

95.7

V,A

O

34.9

V,A,Q

2

34

V,A,Q

5

114.2

V,A,Q

42

45.9

V,A,Q,

24

27

V,A,Q

8

130.4 105.8 145.4 84.5 84.6

V,A,Q V,A,Q V,A,Q V,A,Q V,A,Q

0 14 15 21 12

40.3 31.6 20.6

V,A,Q V,A,Q V,A,Q

V,A,Q O V,A,Q

0 O 16

V,A,Q

20

36.1

6 21.9 17 28.7 13 33 Lost to follow-up V,A,Q 16 19.3

Abbreviations: BC, biochemical control with use of medication; Exam, examinations that were performed at that visit; F, female; GRS, gammaknife radiosurgery; IGF-1 insulin-like growth factor 1; M, male; M, medical treatment; MD, medical treatment with a dopamine agonist; MP, medical treatment with pegvisomant (PEGV); MS, medical treatment with a somatostatin analogue (SSA); MS + MD, medical treatment SSA combined with a dopamine agonist; MS + MP, medical treatment SSA combined with PEGV; O, data not available; Re-s, second surgical procedure; S, surgery; SRT, stereotactic radiotherapy. Surgical outcomes: Cured: normal IGF-1 and oGTT after removal of the pituitary tumor by EETA or partial lobectomy (in case of a GHRH-producing NET). RD: residual or recurrent disease. In patients with medical pretreatment, surgery and cessation of medical treatment took place simultaneously. The moment or timespan of treatment in months is displayed between parentheses. Study-related measurements: V, videolaryngostroboscopy; A, acoustic voice analysis; Q, VHI-questionnaire.

Voice assessment and analysis Acoustic voice analysis was performed by a single speechlanguage pathologist (SPL), who performed both the examination and the rating. The SPL did not have information about the disease status of the participants (ie, controlled or

uncontrolled). All voice recordings took place in a carpeted room with an ambient noise level <45 dB. Patients were instructed to call the days of the week (in Dutch) for three or more times in sequence at habitual pitch and loudness during at least 60 seconds. We chose this particular task

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FIGURE 1. Overview of the timeline and measurement of the study. IGF-1, Insulin-like Growth Factor 1; preT: pretreatment; VHI, Voice Handicap Index; VLS, videolaryngostroboscopy.

FIGURE 2. S€odersten glottic closure score. 1: Complete closure all along the vocal folds; 2: Indication of incomplete closure of the cartilaginous part; 3: Triangular incomplete closure reaching anterior to the vocal processes; 4: Triangular incomplete closure of the posterior third of the folds; 5: Incomplete closure of the posterior two-thirds of the folds; 6: Incomplete closure all along the folds; A: Spindle-shaped incomplete closure, closure at the vocal processes; B: Spindle-shaped incomplete closure at the posterior third of the membranous folds, closure at the vocal processes; C: Spindle-shaped incomplete closure at the anterior third of the folds, closure at the vocal processes; D: Spindle-shaped incomplete closure at the posterior and the anterior thirds of the folds, closure at the vocal processes and at the middle of the membranous portion (“hourglass”).21 based on the opinion that using the same simple task for all voice analyses has the advantage of a high patient-topatient and session-to-session comparability. In addition, the task of repeating the days of the week is not limited by reading ability and style.22 The distance between the microphone and the patients mouth was 30 cm. Recordings were made with an Edirol by Roland R-09HR recorder (Roland Corporation, Japan). The speech-language pathologist chose the sequence which corresponded best with the pitch and loudness of the patients spontaneous speech, which was observed during the history that was taken prior to the assessment, and with the fo that was obtained from the phonetogram. Praat software23 was used to analyze recordings of the participants reciting the days of the week. The following voice characteristics were determined: the mean fundamental frequency of the voice (fo) in Hertz (Hz),9 jitter (calculated as the average absolute difference between consecutive periods, divided by the average period), and shimmer (calculated as the average absolute difference between the amplitudes of consecutive periods, divided by the average amplitude). In addition, the HNR in dB was calculated as the ratio between total energy and energy of noise,12 and the NHR was calculated as the ratio between the energy of noise and total energy of the voice signal (both measured in dB).13 As general threshold for pathological values is >1.04% for jitter and >3.81% for shimmer.23 An HNR of >20 and an NHR of >0.19 are reported to distinguish between a normal and a pathological voice.13,23

To assess the physiological range of the voice, a phonetogram was constructed using a dB-meter and playing tones on a keyboard. Patients were instructed to reproduce these tones using a sustained vowel /a/ as soft and as loud possible from the lowest to the highest frequencies. Pitch range (PR) in semitones (ST), Fmax in Hz and Fmin in Hz were obtained from this phonetogram.24 The values that were obtained in our cohort of patients were compared with reference values that were obtained in vocally healthy people using Praat software.25−28 Based on the habitual voice which was recorded while participants were citing the days of the week, the GRBAS scale of the Japan Society of Logopedics and Phoniatrics was scored, which is an auditory-perceptual evaluation method which scores the overall grade of hoarseness (G), roughness (R; a harsh and irregular, rasping or rattling sounding voice), breathiness (B; a whispery voice), asthenia (A; a small, weak voice with a low volume and low energy), and strain (S; a tense, hyperfunctional voice or throat-constricted voice), where 0 is normal, 1 is a slight degree, 2 is a moderate degree, and 3 is a severe degree).29

Voice handicap index In this study, the Dutch translation of the Voice Handicap Index-30 (VHI) was used to measure self-assessed voice perception.14,16,30 In general, a cut-off value of 19 points for the VHI Total score has been reported to distinguish

ARTICLE IN PRESS Thalijn L.C. Wolters, et al

The Course of Voice Characteristics in Acromegaly

subjects with benign larynx pathology (eg, benign vocal cord mass, vocal cord paresis, functional dysphonia) and those without larynx pathology.31 Regarding change of VHI scores over time, a difference of ≥14 points between two measurements represents a clinically significant change for the VHI Total score. For the subscales Functional, Emotional and Physical, changes of ≥ 6, 7 respectively 8 points are clinically significant.16 In addition, patients were asked whether they have voice complaints in general (yes/no). Last, they were asked to value their voice by giving a mark using a Likert scale from 0 (worst possible voice) to 10 (excellent voice).

Statistical analysis Data were analyzed with SPSS 25.0. Data were presented as number with percentages for categorical variables and as mean with SD or as median with range for continuous variables, depending on the normality of the distribution, which was tested by the Shapiro-Wilk test. Given the intrinsic difference in voice characteristics between men and women, sex-based subgroup analyses were performed. Between-group differences for continuous variables were tested with an independent sample t-test for normally distributed and a Mann-Whitney U test for non-normally distributed data; the Fisher’s exact test was used for categorical variables. Spearman rank correlation was used to determine associations at baseline. Prospective data were analyzed with a multilevel linear model or with the Friedman’s two-way analysis, depending on the normality of the distribution. In non-normal distributed data, a logarithmic transformation was performed and residuals were tested again for normality. If log-transformation did not result in normally distributed residuals, nonparametric tests were used. The Hodges-Lehman test was used to determine median differences between measurements in nonparametric tests. For categorical values, generalized linear mixed models were used. To calculate correlation coefficients on repeated observations within subjects, the method of Bland and Altman was used.32 All tests were two-tailed. P values of <0.05 were considered statistically significant. RESULTS Disease control and acromegaly treatment IGF-1 levels at diagnosis were higher in men compared to women, both with regard to absolute (median 118.1 (66.7−208) vs 84.5 (40.6−146) nmol/L; P = 0.007) and ageand sex-corrected values (IGF-1 SDS 11.8 (6.8−23.2) vs 6.2 (3.5-16.7); P < 0.001) (Table 2). Twenty-two patients (84.6%) completed pretreatment with a SSA, for a mean duration of six months (range 5−11), followed by EETA (Table 2). Because of insufficiently controlled IGF-1 levels with SSA monotherapy, PEGV was added in one (No. 22) and a dopamine agonist in another patient (No. 21) to the pretreatment. One patient (No. 18) refused SSA pretreatment and underwent EETA 6 weeks

7

after baseline. Two women (No. 12 and 27) did not undergo EETA due to old age and the presence of an inoperable giant adenoma. They were primarily treated with a SSA (No. 12) and a SSA combined with PEGV (No. 27). The patient with the bronchial NET (No. 11) underwent a partial lobectomy without pretreatment eight weeks after diagnosis. At T1, 15 of the 24 surgically treated patients (62.5%) were in surgical remission and 9 patients had residual or recurrent disease. Three of these patients repeatedly had normal IGF-1 levels combined with a mildly disturbed oGTT (GH nadir 0.7−0.8 mg/L). Since their IGF-1 values fell in the reference range, they were considered surgically controlled patients in the analysis. Of the patients who underwent AVA at T1 (N = 25), 14 patients (56%) were surgically controlled and 3 (12%) in biochemical remission; eight (32%) patients had uncontrolled acromegaly despite treatment. Six patients were treated with SSA monotherapy, one patient with a SSA combined with a dopamine agonist, and four patients with a SSA combined with PEGV. Between T1 and T2, one female (No. 15) underwent a second surgical procedure and was in surgical remission afterwards. In addition, one male (No. 22) underwent gammaknife radiosurgery and one female (No. 17) underwent stereotactic radiotherapy while they were treated with a SSA and PEGV between T1 and T2 (Table 2). At T2, all 25 patients who underwent the study procedures were in surgical (N = 15; 60%) or biochemical remission (N = 10; 40%). Six patients were treated with SSA monotherapy, one with a SSA combined to a dopamine agonist and three patients with a SSA combined with PEGV. Serum IGF1 levels decreased between T0 and T2 from 97.3 (40.6−208) to 22.4 (10.2−34.1) nmol/L (P < 0.001) as did the IGF-1 SDS (from 7.1 (3.5−23.2) to 0.6 (1.2; 2.3); P < 0.001). At T2, men had higher serum IGF-1 levels compared to women (28.9 (13−34.1) vs 19.4 (10.2−08.5); P = 0.02), but the IGF-1 SDS were not significantly different (1.1 (1.1; 2.3) vs 0.5 (1.2; 1.9); P = 0.22).

Hormonal deficiencies At T0, one patient (No. 27) had primary hypothyroidism and was adequately substituted with levothyroxine for at least 3 months. One woman (No. 6) developed a Hashimoto thyroiditis-related hypothyroidism (anti-TPO levels >1000 U/mL) during SSA treatment, and had been adequately substituted with levothyroxine for 3 months at T1. At diagnosis until the end of the study, one subject (No. 22) had normal unstimulated cortisol levels but failed to reach the maximal cortisol response (ie, serum cortisol level >550 nmol/L) during an ITT both before and after EETA. Therefore, he only used substitution during physical or mental stress. One woman (No. 15) developed subclinical adrenal insufficiency after a second surgical approach between T1 and T2. At T0, seven men had hypogonadism, of which one had unsubstituted primary hypogonadism as a result of a bilateral

ARTICLE IN PRESS 8 orchidopexy in childhood, and six had unsubstituted secondary hypogonadism. Thirteen women were postmenopausal. At T2, three men had already recovered from secondary hypogonadism after surgery. The other four hypogonadal men were substituted with a stable dose of testosterone for at least 3 months. One premenopausal woman (No. 17) developed secondary amenorrhea combined with estrogen values below the reference range after postoperative radiation therapy between T1 and T2 and was prescribed oral hormonal replacement therapy. Videolaryngostroboscopy Twenty-three of the 25 patients underwent VLS at the three time points; two women (No. 2 and 17) refused because of fear of the procedure. At each time point, one VLS could not be performed because of technical issues (this involved different patients at the three different time points). At baseline, apart from mucosal edema and hypertrophy, no other pathology that was not acromegaly-related was found (Table 1, 3 and 4). Mucosal edema decreased significantly over time: it was found in nine patients (37.5%) at T0, in two out of those nine patients (8.7%) at T1, and in one patient (4.5%) at T2 (P = 0.006). This last patient (No. 10) had edema at T0, but not at T1. There was no difference in prevalence between men and women. In addition, laryngeal and nasal mucosal hypertrophy were present at T0 in seven (29.2%) and six patients (25%) respectively, and were not present at T1 and T2 (change over time P < 0.001 and P = 0.001, respectively). Figure 3 depicts the VLS findings of a patient (No. 13) who had mucosal edema at T0, which had resolved at T1. Voice assessment and analysis Habitual voice As expected, fo was lower in men than in women at baseline (107.7 § 21.3 vs. 168 § 24.9 Hz; P < 0.001; Table 1). HNR was higher in women (10.16 § 1.7 vs. 7.04 § 1.42; P = 0.002) and NHR was higher in men (0.3 § 0.05 vs. 0.23 § 0.06; P = 0.006; Tables 3 and 4; Figure 4). Compared to sex-specific reference values obtained in subjects with a healthy voice,25 fo was situated in the lower end of the range in patients with acromegaly at diagnosis, especially in women (Table 1). However, the values of noise parameters (eg, jitter, HNR and NHR) of acromegaly patients exceeded the reference values (Table 1).26,28 Phonetogram Fmax and Fmin were higher in women (392.9 § 106 vs 521.6 § 97.4 Hz; P = 0.006 and 85 (62.5−110) vs 124 (82.5−196) Hz; P < 0.001; Table 1)). Fmax and Fmin were lower than mean values that were observed in vocally healthy subjects.25,27 During follow-up fo, Fmin and Fmax did not significantly change for both sexes (Table 4). The sex-dependent difference was also relatively stable during follow-up, except for

Journal of Voice, Vol. &&, No. &&, 2020

Fmax. No other significant changes were observed in the sexbased subgroups. Voice handicap index In the total group, mean VHI Total scores did not reach the pathological limit of 19 points (Tables 1, 3 and 4; Figure 5). However, scores of certain participants were well above this pathological limit, as depicted in Table 2. For the whole cohort, VHI Functional (3.5 (0−14) to 1.5 (0−9); P = 0.003) and Physical scores (4.5 (0-−20) to 2 (0−16); P = 0.014) decreased during follow-up, with the largest changes taking place during the first year of treatment (Figure 5; Table 3). VHI Total scores also decreased (11 (0−50) to 4.5 (0−23); Table 3), but this difference was not statistically significant. VHI scores did not differ significantly between both genders at each time point, except for the Physical subscale (P = 0.026) at T1. However, during follow-up, VHI Functional scores significantly decreased in men (P = 0.012), but not in women (Table 4). Correlation analysis Changes in IGF-1 values within subjects correlated with changes in VHI Total (R 0.45; P = 0.002), Functional (R 0.32; P = 0.03), Emotional (R 0.38; P = 0.009) and Physical scores (R 0.45; P = 0.002). No significant correlations with objective voice characteristics were observed. DISCUSSION Our main finding is that mucosal edema and hypertrophy diminished, and self-assessed voice handicap scores decreased during the first 2.5 years of acromegaly treatment, although no large abnormalities were observed on a group level. These changes take predominantly place in the first year of treatment and are more pronounced in males compared to females. The first innovative and distinctive aspect of our study is that our population consists of a homogeneous group of consecutive treatment-naive patients, who underwent a standardized treatment protocol and were studied at three predetermined time points during 2.5 years of follow-up. Inclusion of treatment-naive patient excludes treatmentrelated effects on voice characteristics at baseline. No prospective study of this size and extent that analyses these end points has been conducted before. The only prospective study that was found, performed AVA at prior to and 10 days after pituitary adenomectomy in eight acromegaly patients (4 males, 4 females).4 Secondly, our approach is more extensive than those used in previous studies, since it also included the patients’ perception of their voice complaints using the VHI, which has never been applied to acromegaly patients. Furthermore, our study contained enough patients to be able to form subgroups based on gender, which enabled us to analyze gender differences in voice characteristics in patients with acromegaly.

ARTICLE IN PRESS Thalijn L.C. Wolters, et al

9

The Course of Voice Characteristics in Acromegaly

TABLE 3. Patient and Voice Characteristics During Followup, in the Total Group of Patients Subject Characteristics Total Group Weight (kg) BMI (kg/m2) Current smoker (yes, %) Alcohol consumption (yes, %) Duration of symptoms (years) GH (mg/L) IGF-1 (nmol/L) IGF-1 SDS Disease status (N, %) Untreated Biochemical control Surgical control Active despite treatment Hypothyroidism (N, %) Hypocortisolism (N, %) Hypogonadism (N, %) Acoustic voice analysis fo (Hz) Fmax (Hz) Fmin (Hz) PR (ST) Jitter (%) Shimmer (%) HNR (dB) NHR Voice Handicap Index (VHI) VHI − total VHI − functional VHI − emotional VHI − physical Voice complaints (yes, %) Voice mark GRBAS scale Grade Roughness Breathiness Asthenicity Strain Videolaryngostroboscopy Abnormal mucosa (N, %) Mucosal edema (N, %) Mucosal hypertrophy (N, %) Nasal mucosal hypertrophy (N, %) Supraglottic activity Glottic closure Vibration Symmetry

T0 (N = 27)

T1 (N = 25)

T2 (N = 25)

P Value T0−1

P Value T0−2

91 § 21.6 29.5 § 5 2 (7.4) 16 (59.3) 8 (2−28) 7.3 (0.97−127.7) 97.3 (40.6−208) 7.1 (3.5−23.2)

94.6 § 24.6 30.6 § 5 1 (4) 14 (56) NA NA 27.4 (8.5−83.2) 1.5 (2; 9.1)

91.1 § 21.9 29.4 § 6.1 2 (8) 14 (56) NA NA 22.4 (10.2−34.1) 0.6 (1.2;2.3)

0.14 0.09 0.58 0.69 NA NA <0.001 <0.001

0.1 0.09 0.79 0.92 NA NA <0.001 <0.001

27 (100) 0 (0) 0 (0) 0 (0) 1 (3.7) 1 (3.7) 7 (25.9) N = 27 148.5 (87.3−210.9) 473.9 § 117.2 110 (62.5−196) 27 (9−34) 2.86 § 0.8 1.33 (0.97−3.96) 9.34 § 1.91 0.25 § 0.06 N = 24 11 (0−50) 3.5 (0−14) 0 (0−19) 4.5 (0−20) 10 (37) 7 (4−10) N = 25 1 (0−2) 0 (0−2) 0 (0−1) 0 (0−1) 0 (0−2) N = 24 10 (41.7) 9 (37.5) 7 (29.2) 6 (25) 2 (1−6) 1 (1−6) 1 (1−5) 1 (1−2)

0 (0) 3 (12) 14 (56) 8 (32) 2 (8) 1 (4) 5 (20) N = 25 141.6 (82.5−203.4) 460.5 § 130.9 110 (49−175) 28 (9−36) 2.86 § 0.61 1.32 (1.09−1.53) 9.29 § 1.65 0.25 § 0.06 N = 24 6.5 (0−29) 3 (0−9) 0 (0−10) 3.5 (0−18) 4 (16) 7.5 (6−9) N = 25 0 (0−1) 0 (0−1) 0 (0−1) 0 (0) 0 (0−1) N = 23 3 (13) 2 (8.7) 0 (0) 0 (0) 2 (1−4) 1 (1−6) 1 (1−4) 1 (1−3)

0 (0) 10 (40) 15 (60) 0 (0) 2 (8) 2 (8) 5 (20) N = 25 143.8 (96.5−249.7) 514.2 § 148.5 98 (62.5−196) 27 (11−40) 2.84 § 0.68 1.30 (0.92−1.56) 9.8 § 2.11 0.24 § 0.06 N = 24 4.5 (0−23) 1.5 (0−9) 0 (0−8) 2 (0−16) 4 (16) 7 (5−10) N = 25 0 (0−1) 0 (0−1) 0 (0−1) 0 (0) 0 (0−1) N = 22 4 (18.2) 1 (4.5) 0 (0) 0 (0) 2 (1−5) 1.5 (1−7) 1 (1−3) 1 (1−2)

0.001

<0.001

0.54 0.98 0.56

0.76 0.75 0.81

0.93 0.69 0.64 0.46 0.89 0.38 0.91 0.46

0.42 0.11 0.66 0.007 0.98 0.3 0.74 0.49

0.87 0.044 0.83 0.04 0.1 0.3

0.92 0.003 0.72 0.014 0.12 0.53

0.08 0.43 0.68 0.09 0.13

0.04 0.52 0.89 0.1 0.03

0.036 0.031 0.005 0.12 0.56 0.43 0.8 0.56

0.056 0.006 <0.001 0.001 0.6 0.34 0.95 0.83

Values are displayed as mean with SD or as median with minimum and maximum, depending on the normality of the distribution. Categorical variables are displayed as numbers (percentage). Abbreviations: BMI, body mass index in kg/m2; fo, mean fundamental frequency in Hertz (Hz); Fmax, maximal frequency in Hz; Fmin, minimal frequency in Hz; GH, Growth Hormone; GHRH, GH Releasing Hormone; HNR, Harmonics to Noise Ratio in decibel (dB); IGF-1, Insulin-like Growth Factor 1; NET, neuroendocrine tumor; NHR, Noise to Harmonics Ratio; PR, pitch range in semitones (ST); SDS, Standard Deviation Score; VHI, Voice Handicap Index.

10

TABLE 4. Patient and Voice Characteristics During follow-up, in Males and in Females Subject Characteristics Followup (T1-T2) Male-Female

106.9 § 16.8 30.4 § 4.3 0 (0) 10 (100)

86.5 § 24.1 30.7 § 7.9 1 (6.7) 4 (26.7)

34.6 (8.5−45.9) 1.9 (2; 3.5)

23.6 (11−83.2) 1.3 (1; 9.10)

0 (0) 1 (10) 6 (60) 3 (30)

0 (0) 2 (13.3) 8 (53.3) 5 (33.3)

0 (0) 1 (10) 5 (50)

2 (12.5) 0 (0) 0 (0)

103.9 § 12.5 159.6 § 19.5 28 (12−36) 27 (9−31) 399.6 § 130.8 501.13 § 118.12 77.5 (49−110) 110 (82.5−175) 2.9 § 0.4 2.83 § 0.72 1.32 (1.19−1.42) 1.29 (1.09−1.53) 8.29 § 0.84 9.89 § 1.74 0.28 § 0.04 0.23 § 0.07

P Value MaleFemale T1

P Value MaleFemale T2

T2 Male (N = 10)

T2 Female (N = 15)

0.04 0.9 1.0 0.001

100.8 § 14.3 28.7 § 2.2 1 (10) 10 (100)

84.6 § 24.1 30 § 7.7 1 (6.7) 4 (26.7)

0.05 0.60 1 0.001

0.51 0.78

28.9 (13−34.1) 1.1 (1.1; 2.3)

19.4 (10.2−28.5) 0.5 (1.2; 1.9)

0.02 0.22

0 (0) 4 (40) 6 (60) 0 (0)

0 (0) 6 (40) 9 (60) 0 (0)

0 (0) 1 (10) 4 (40)

1

0.51 0.39 0.004 <0.001 0.43 0.06 <0.001 0.75 0.82 0.006 0.07

Males T0 - T1

Males T0 - T2

0.88 0.88 1 1

0.12 0.12 0.43 1

<0.001 <0.001 <0.001 <0.001

Females Females T0 - T1 T0 - T2 0.05 0.05 1 0.52

0.28 0.28 1 0.79

<0.001 <0.001

<0.001 <0.001

1

0.023

0.001

0.013

<0.001

2 (13.3) 1 (6.7) 1 (6.7)

0.5 1 0.12

1 1 0.37

1 1 0.38

0.52 1 1

0.73 0.31 0.31

110.2 § 9 28 (21−40) 463.7 § 130.8 82.5 (62.5−110) 2.9 § 0.41 1.36 (1.21−1.56) 8.58 § 1.18 0.27 § 0.05

167 § 30.7 27 (11−38) 547.8 § 164.2 110 (62.5−196) 2.81 § 0.82 1.2 (0.92−1.52) 10.61 § 2.23 0.22 § 0.06

<0.001 0.34 0.14 0.003 0.73 0.03 0.007 0.04

0.39 0.33 0.78 0.74 0.51 0.26 0.49 0.4

0.5 0.35 0.33 0.69 0.66 0.48 0.49 0.81

0.36 0.82 0.8 0.53 0.5 0.89 0.57 0.69

0.26 0.013 0.97 0.76 0.77 0.076 0.24 0.59

3.5 (0−24) 3 (0−9) 0 (0−10) 0.5 (0−5) 1 (10) 8 (7−8)

10 (0−29) 3 (0−7) 2 (0−9) 5 (0−8) 3 (20) 7 (6−9)

0.14 0.89 0.15 0.026 0.63 0.47

4 (0−16) 2 (0−6) 0 (0−3) 1 (0−8) 1 (10) 7 (6−10)

4.5 (0−23) 0.5 (0−9) 0 (0−8) 2.5 (0−16) 3 (20) 7 (5−9)

0.8 0.47 0.84 0.24 0.63 0.68

0.54 0.012 0.11 0.2 0.28 0.31

0.55 0.012 0.27 0.39 0.4 0.42

0.5 0.48 0.31 0.34 0.25 0.41

0.39 0.49 0.44 0.36 0.31 0.85

0 (0−1) 0 (0−1) 0 (0−0) 0 (0−0) 0 (0−1)

0 (0−1) 0 (0−1) 0 (0−1) 0 (0−1) 0 (0−1)

0.39 1 0.25 1 1

0 (0−1) 0 (0−1) 0 (0−1) 0 (0−0) 0 (0−1)

0 (0−1) 0 (0−1) 0 (0−1) 0 (0−0) 0 (0−0)

1 1 0.54 1 0.4

0.20 1 0.08 1 1

0.42 1 0.17 1 1

0.17 0.23 0.62 0.09 0.07

0.047 0.36 0.55 0.1 0.10 (Continued)

ARTICLE IN PRESS

T1 Female (N = 15)

Journal of Voice, Vol. &&, No. &&, 2020

Weight (kg) BMI (kg/m2) Current smoker (yes, %) Alcohol consumption (yes, %) IGF-1 (nmol/L) IGF-1 SDS Disease status (N, %) Untreated Biochemical control Surgical control Active despite treatment Hypothyroidism (N, %) Hypocortisolism (N, %) Hypogonadism (N, %) Acoustic voice analysis fo (Hz) PR (ST) Fmax (Hz) Fmin (Hz) Jitter (%) Shimmer (%) HNR (dB) NHR Voice Handicap Index (VHI) VHI − total VHI - functional VHI − emotional VHI - physical Voice complaints (yes, %) Voice mark GRBAS scale Grade Roughness Breathiness Asthenicity Strain

T1 Male (N = 10)

ARTICLE IN PRESS Values are displayed as mean with SD or as median with minimum and maximum, depending on the normality of the distribution. Categorical variables are displayed as numbers (percentage). Abbreviations:BMI, body mass index in kg/m2; fo, mean fundamental frequency in Hertz (Hz); Fmax, maximal frequency in Hz; Fmin, minimal frequency in Hz; GH, Growth Hormone; GHRH, GH Releasing Hormone; HNR, Harmonics to Noise Ratio in decibel (dB); IGF-1, Insulin-like Growth Factor 1; NET, neuroendocrine tumor; NHR, Noise to Harmonics Ratio; PR, pitch range in semitones (ST); SDS, Standard Deviation Score; VHI, Voice Handicap Index.

0.52 0.4 0.86 0.79 0.68 0.2 0.96 0.88 0.93 0.18 0.84 0.7 0.71 0.49 0.65 0.48 0.57 0.47 0.54 0.57 1 (1−4) 2 (1−7) 1 (1−3) 1 (1−2) 2 (1−5) 1 (1−7) 1 (1−3) 1 (1−2) 2 (1−4) 1 (1−6) 1 (1−4) 1 (1−3) 2 (1−3) 1 (1−2) 1 (1−3) 1 (1−2)

0.84 1 0.28 0.14

0.009 0.045 0.11 0.1 1 0 (0) 0 (0) 0 (0) 0 (0)

1

0.029 0.002 0.052 0.018 0.11 0.11 0.33 0.1 0.3 1 1 (7.7) 0 (0) 0 (0) 0 (0) 1 (7.1) 0 (0) 1 (11.1) 0 (0)

1 1

0.06 0.05 0.62 0.41 0.69 N = 13 2 (15.4) N=9 2 (22.2) N = 14 1 (7.1) N=9 2 (22.2)

Videolaryngostroboscopy Abnormal mucosa (N, %) Mucosal edema (N, %) Mucosal hypertrophy (N, %) Nasal mucosal hypertrophy (N, %) Supraglottic activity Glottic closure Vibration Symmetry

T1 Female (N = 15)

0.54

The Course of Voice Characteristics in Acromegaly

T1 Male (N = 10) Subject Characteristics Followup (T1-T2) Male-Female

TABLE 4. (Continued )

P Value MaleFemale T1

T2 Male (N = 10)

T2 Female (N = 15)

P Value MaleFemale T2

Males T0 - T1

Males T0 - T2

Females Females T0 - T1 T0 - T2

Thalijn L.C. Wolters, et al

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Mucosal edema and hypertrophy were present in 37.5% and 29.2%, respectively (Table 1), of patients at diagnosis, and were largely resolved after treatment. Since the vibration of vocal cords is influenced by their mass, elasticity and length,4 the presence of edema may have influenced patients voice characteristics, although we did not find significant abnormalities during VLS or AVA, nor did mean VHI Total scores reach the pathological limit in our cohort. At diagnosis, fo, Fmin and Fmax were in the lower range of reference values obtained from people without voice problems,4,11,25,27 which is in line with earlier reports.3,4 Presence of acromegaly may have an impact on the range of the voice via changes in vocal cord volume and elasticity,3,4 since in an earlier study it has been observed that fo increased 10 days after surgery, compared to preoperative values.4 For this reason, it has been suggested that the increase in fo soon after surgery could be caused by quick recovery of mucosal edema, leading to changes in vocal cord mass and elasticity. However, a 10-day interval is most likely too short to reliably detect structural changes to upper airway structures that will also reflect long-term post-therapeutic effects. In addition, the conduction of a representative measurement is hampered by the effects of anesthesia and intubation (eg, soft tissue and vocal cord edema) on upper airway structure and function in the first weeks after surgery33 and by unstable levels of GH and IGF-1 during this period.34 Therefore, it is not clear whether the increase in fo in the study of Williams et al4 was influenced by decreasing GH and IGF-1 levels or by other surgery-related events. In our study, fo, Fmin and Fmax (and PR) did not change significantly during and after treatment. This difference with the previous study is possibly caused by methodological differences, since we studied a larger, less heterogeneous group of patients and we measured fo after 1 year of treatment (6 months after surgery) instead of 10 days after surgery. However, we did not observe a difference in jitter or shimmer between active and controlled acromegaly, in concordance with a previous study that reported increased jitter in both controlled and active acromegaly patients compared to healthy controls.11 As expected from these results and in concordance with earlier reports,3,11 there was no correlation between changes in voice parameters and serum IGF-1 levels. Besides functional consequences, voice pathology also impacts on QoL.3-5 In contrast to the lack of evident changes in objective voice parameters and the nonpathological mean VHI Total score that was observed, perception of voice did change significantly during acromegaly treatment (Table 3). The median VHI Total score in our group of patients at baseline was 11 (range 0−50; mean 14.1 § 14.1), which declined to a median score of 4.5 (range 0−23; mean 6.7 § 7.2) during treatment. In healthy controls, VHI Total mean scores of 4 to 6.86 (SD 5.6 to 9.9) have been reported.35 This indicates that most untreated acromegaly patients do not experience a voice handicap, although certain participants reported a VHI Total score well above the

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FIGURE 3. VLS findings in a patient (No. 13) which mucosal edema at T0 (left frame), which has resolved at T1 (right frame).

FIGURE 4. Acoustic voice analysis parameters during followup. A: fo in Hertz (Hz) in males and females; B: Maximal Frequency (Fmax) in Hz in males and females; C: Harmonics to Noise Ratio (HNR) in dB in the total group of patients and D: Pitch Range (PR) in semitones (ST) in males and females. Values are displayed as mean. Each line represents a subject. pathological limit indicating a mild to moderate voice handicap.36 In addition, VHI scores decreased during acromegaly treatment, especially in men, and were correlated with changes in serum IGF-1 levels. The absolute change in VHI

scores in men was also larger compared to women. VHI scores did not correlate with objective voice or laryngostroboscopic parameters; it has been described that there is no or a weak correlation between VHI subscale or Total scores

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FIGURE 5. Voice Handicap Index (VHI) scores during followup in the total group of patients. A: VHI total scores; B: VHI Functional scale; C: VHI Emotional scale and D: VHI Physical scale. Values are displayed as mean. Each line represents a subject. and objective voice parameters.37,38 These findings suggest that, although no clear changes in objective speech parameters were observed, patients’ perception of their voice improved during treatment although no significant voice handicap was observed based on the mean VHI Total score in our cohort. This improvement is likely of clinical importance, considering the negative impact of voice complaints on QoL. The discrepancy between the improved VHI-scores and the absence of clear improvements in objective voice parameters may be explained by insensitivity of our acoustic voice analysis for small improvements or compensatory changes that may have influenced voice perception. In addition, treatment of acromegaly is associated with improvement of general well-being and QoL,39 and this may also have rendered improved VHI scores, despite the absence of clear changes in voice parameters. Last, habituation to voice changes may play a role, since it is known that patients adapt to their voice disturbances over time, as was observed in boys with puberphonia.40 Next to GH, other pituitary hormones are also known to influence voice characteristics. In active acromegaly, hypogonadism has a high overall prevalence of 53%,41

even up to 70% in premenopausal women,42 and restores after (biochemical) remission by surgery or SSA treatment in a significant amount of cases.42−44 Elevated testosterone levels are reported to increase the volume of laryngeal muscles and ligaments, which causes frequent cracking and a drop in the higher octaves of the voice. In elderly males, low estrogen levels rather than low androgen levels are reported to increase fo and change highest and lowest frequencies via reduction of vocal fold mass.45 With advancing age, the fo and the vocal range decrease in females and increase in males, and noise parameters increase due to relative androgen excess in women and relative androgen deficit in men.9 In this study, three of the hypogonadal males recovered and the remaining four started substitution therapy. Possibly, the increase in testosterone levels influenced voice parameters during followup. However, both the recovered and the substituted patients had testosterone levels in the lower normal range and voice parameters did not correlate with presence of hypogonadism. In hypothyroidism, hoarseness and a loss of range of voice are described; substitution treatment increases fo.46 In our study, voice parameters were not correlated with presence of hypothyroidism.

ARTICLE IN PRESS 14 Since the prevalence of hormonal deficiencies did not differ between men and women and did not correlate with voice parameters, we did not correct for hormonal deficiencies in our statistical analysis. The fact that we studied a relatively small group of patients may hamper finding differences and makes it difficult to compare subgroups of patients to elucidate factors that influence the prevalence and extent of changes in voice characteristics and voice perception in acromegaly. However, given the rare character of acromegaly and the scarcity of treatment-naive patients, it is extremely hard to obtain larger and more homogeneous groups of patients. In addition, since we did not include healthy controls, it was not possible to compare patients with controls using the same equipment and protocol. However, we compared values obtained in patients to previously reported reference values obtained from the general population. Next, despite our thorough examination of both objective as subjective voice characteristics, we did not observe large abnormalities or changes over time. However, we did observe a decline in the VHI scores and a decrease in the occurrence of mucosal edema and hypertrophy, which suggests that acromegaly-related abnormalities may be present although they are relatively mild or subtle, which may not be easily detected by the used methodology in our study. In addition, since AVA was performed by a single SLP, the lack of interrater corroboration is a limitation in this study. In the year between T0 and T1 most patients underwent SSA treatment followed by EETA. Consequently, it is not possible to differentiate between the distinct effects of those treatments and to identify the time point at which the largest changes take place in more detail. Since SSA are reported to have anti-inflammatory effects (independent of their GH/ IGF-1 lowering effects),47 they theoretically might have a direct effect on the vocal cords via attenuation of the inflammatory reactions that cause and maintains vocal cord edema. Last, we used Praat software for acoustic voice analysis; it is well-known that some absolute measures of voice characteristics, especially noise parameters, differ between Praat software and an acoustical rating system as the MultiDimensional Voice Program, which has been used in various previous studies.3,11,48−50 Despite the fact that the methods are not numerically comparable for jitter and HNR, the correlations between parameters measured with both methods are strong.28,48 In addition, reference values obtained in healthy subjects may not always differentiate normal from pathological voices, as has been reported for fo.51 CONCLUSIONS Upper airway anatomy and voice characteristics and perception may be mildly affected in active acromegaly. Although objective voice characteristics were in the normal range and did not significantly change, mucosal edema and hypertrophy diminished significantly during treatment. In

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addition, mean VHI scores decreased during treatment, although no significant voice handicap seemed present on the whole-group level. The largest changes have been observed after the first year of treatment and the improvement is correlated with the decrease in serum IGF-1 levels. Mild to moderate voice complaints seem to be present in a proportion of untreated acromegaly patients, and are an important issue in patient counseling, since voice-related complaints are associated with a reduced QoL and may be influenced by acromegaly treatment. ACKNOWLEDGMENTS We sincerely thank E.E. Coopman; R.B.T.M. Sterenborg, N. M. Rokx, I.F. Mustafajev, I. Mommers, and A.F.J. de Haan, MSc for their excellent help in the conductance of this study. SUPPLEMENTARY DATA Supplementary data related to this article can be found online at https://doi.org/10.1016/j.jvoice.2020.01.006. REFERENCES 1. Katznelson L, Laws Jr. ER, Melmed S, et al. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:3933–3951. https://doi.org/10.1210/jc.2014-2700. 2. Colao A, Ferone D, Marzullo P, et al. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004;25:102–152. https://doi.org/10.1210/er.2002-0022. 3. Bogazzi F, Nacci A, Campomori A, et al. Analysis of voice in patients with untreated active acromegaly. J Endocrinol Invest. 2010;33: 178–185. https://doi.org/10.1007/BF03346578. 4. Williams RG, Richards SH, Mills RG, et al. Voice changes in acromegaly. Laryngoscope. 1994;104:484–487. https://doi.org/10.1288/ 00005537-199404000-00015. 5. Fatti LM, Scacchi M, Pincelli AI, et al. Prevalence and pathogenesis of sleep apnea and lung disease in acromegaly. Pituitary. 2001;4:259–262. 6. Hassan SZ, Matz GJ, Lawrence AM, et al. Laryngeal stenosis in acromegaly: a possible cause of airway difficulties associated with anesthesia. Anesth Analg. 1976;55:57–60. 7. Motta S, Ferone D, Colao A, et al. Fixity of vocal cords and laryngocele in acromegaly. J Endocrinol Invest. 1997;20:672–674. https://doi. org/10.1007/BF03348030. 8. Edge WG, Whitwam JG. Chondro-calcinosis and difficult intubation in acromegaly. Anaesthesia. 1981;36:677–680. 9. Hari Kumar KV, Garg A, Ajai Chandra NS, et al. Voice and endocrinology. Indian J Endocrinol Metab. 2016;20:590–594. https://doi.org/ 10.4103/2230-8210.190523. 10. Weinberg B, Dexter R, Horii Y. Selected speech and fundamental frequency characteristics of patients with acromegaly. J Speech Hear Disord. 1975;40:253–259. 11. Aydin K, Turkyilmaz D, Ozturk B, et al. Voice characteristics of acromegaly. Eur Arch Otorhinolaryngol. 2013;270:1391–1396. https://doi. org/10.1007/s00405-013-2369-4. 12. Michaelis DG, T., Strube HW. Glottal-to-Noise Excitation Ratio − a New Measure for Describing Pathological Voices. Acustica/Acta Acustica. 1997;83:700–706. 13. Finger LS, Cielo CA, Schwarz K. Acoustic vocal measures in women without voice complaints and with normal larynxes. Braz J Otorhinolaryngol. 2009;75:432–440. https://doi.org/10.1016/S18088694(15)30663-7. 14. Jacobson BH, Johnson A, Grywalski C, et al. The Voice Handicap Index (VHI): development and Validation. Am J Speech Lang Pathol. 1997;6:66–70. https://doi.org/10.1044/1058-0360.0603.66.

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