Introduction

Acromegaly is a chronic disease that affects multiple systems in the body. It is caused by an overproduction of growth hormone (GH) and insulin-like growth factor I (IGF-I) [1]. The main reason is primarily due to the excessive release of growth hormone (GH) from a somatotroph adenoma in the pituitary gland [2]. Given the hypertrophic impact of GH and insulin-like growth factor 1 (IGF-1) overload on soft tissue and bone, it is reasonable to speculate that it could influence internal anatomical and functional structures. The clinical signs include a variety of symptoms, including enlargement of the extremities, joint disease, protrusion of the lower jaw, prominence of the forehead, diabetes mellitus, obstructive sleep apnea, hypertension, and heart failure [3]. Because of the fundamental features of the disease, its effect on different systems is inevitable, and the clinical symptoms resulting from these impacts have become the focus of research.

Based on the available data, it is likely that chronic hyperproduction of GH and IGF-1 may have an impact on the temporal bone’s physical structures and hearing organs. There are findings in the literature that suggest patients with acromegaly experience both sensorineural and conductive hearing loss. The degree of hearing loss was not observed to be correlated with the length of the disease, GH, or IGF-1 levels in these studies [4,5,6]. A metabolic condition involving the middle ear and cochlea is likely to affect the balance organs in the bony labyrinth. Although there are a few studies on balance and poster control in acromegaly in the literature, no study has included standard vestibular tests used in neurootological practice. This disorder can have an impact on the central or peripheral auditory-vestibular system. Acromegaly patients may have alterations in posture and balance due to changes in body composition, joint problems, and disturbances in muscular and visual functions [7].

The impact of acromegaly on the inner ear needs to be better understood, making it essential to initiate research in this area. Existing studies on hearing loss in acromegaly patients have produced conflicting results. This study aims to investigate whether there are any alterations in the hearing and the vestibular system among patients with acromegaly. To the best of our knowledge, this study is the first to examine the combination of conventional audiogram, video head impulse test, videonystagmography, and subjective dizziness assessment in patients with acromegaly.

Materials and methods

Participants and study design

This prospective cross-sectional cohort study was conducted in a tertiary referral center between March 2020 and March 2023. Permission for this study was obtained from Ondokuz Mayıs University Clinical Research Ethics Committee (OMUKAEK 2020000001-1), and informed consent was obtained from the patients. The study excluded individuals with known vestibule disease or complaints of vertigo/dizziness, neurological disease, vestibulosuppressant medication (benzodiazepines, antidepressants, vestibular sedatives, and anxiolytics), or who were unable to cooperate with the test. Acromegaly was diagnosed with characteristic clinical findings, such as an unequivocally elevated serum IGF-1 concentration for age and sex and a GH concentration greater than one ng/mL, within two hours after ingestion of a 75 g oral glucose tolerance test.

The patient group was referred from the Endocrinology clinic and included patients who had been followed for acromegaly for at least a year. The control group consisted of healthy volunteers who were university staff and their acquaintances. Participants in the control group met the following criteria: no history of neurological illnesses, middle ear pathology, or vestibular disorders. Furthermore, those with asymmetry in hearing thresholds between ears greater than 10 dB in any frequency have been excluded to ensure a comparable outcome. Participants were excluded if they had a history of noise exposure, ototoxic drug use, head trauma, or any other known cause of sensorineural hearing loss. These criteria were set up to reduce the potential of confounding factors affecting both hearing thresholds and vestibular function, allowing for a more accurate comparison of acromegaly patients and the control group.

Audiological evaluation

Every participant underwent ear examinations to rule out any abnormalities that could impair hearing, such as a perforated tympanic membrane or known middle ear pathologies. An otolaryngologist (E.T) conducted the otoscopic examination, while an expert audiologist (A.K) did the audiometry. Individuals with normal tympanic membranes based on otoscopic testing were included in the study. Before doing the audiogram and vestibular tests, a history and clinical examination, including otoscopy and ocular movements, were performed. Standard immittance audiometry (GSI TympStar Pro, Midlefart, Denmark) revealed that all subjects had normal middle ear function. Pure-tone audiometry (Interacoustics A/S, Denmark) was performed in a double-walled box with frequencies ranging from 250 Hz to 8000 Hz. Radioear B7 and headphones from RadioEar (Midlefart, Denmark) were used. All audiometry testing equipment was calibrated in line with ISO 389-5 and EN ISO 8253-1:2010 standards.

The Pure Tone Average (PTA) was determined by summing the hearing thresholds measured at 500, 1000, and 2000 Hz, and then dividing the total by 3. Monosyllabic words were employed to measure speech discrimination (SD). Speech reception threshold (SRT) was determined using spondaic words (two-syllable syllables with equal stress on each syllable). The SRT was estimated as the decibel hearing threshold below which the patient could not distinguish two-syllable words. During the speech discrimination test, words consisting of a single syllable are given to the individual by placing 25–40 dB above the SRT limit. The correct words are summed and multiplied by 4%. The result is the speech discrimination score of the individuals. The SRT is decibel hearing level (dB HL), and SD is percentage (%).

Vestibular assessment

Videonystagmography (VNG)

VNG was utilized to assess nystagmus, one of the most essential characteristics used to evaluate vestibular functions. The experiments were conducted using Visual Eyes™ (Interacoustics, Middlefart, Denmark). Participants were instructed to sit upright while wearing VNG test goggles, with a 1 m screen in front of them. Calibration was done initially.

The vestibulo-ocular reflex (VOR) was measured by analyzing and recording eye movements spontaneously or responding to visual-vestibular stimuli. The VNG battery included the gaze test, pursuit test, saccade test, optokinetic test, positioning test, spontaneous nystagmus test, head shake test, and Dix-Hallpike and supine roll tests based on positional testing. Computerized eye tracking was used to watch and record the patient’s eye movements at rest and while exposed to various visual and vestibular stimuli.

Video head impulse test

The v-HIT test was conducted using the Eye SeeCam VHIT gadget manufactured by Interacoustics in Assens, Denmark. Binocular eye video recorder goggles with a high-speed recording capability of 150–250 Hz were utilized. During the examination, the individual being examined was instructed to focus on a small stationary target 1.2 m away. The patient’s eyes were focused on the target as his/her head was rapidly moved at a maximum speed of 150°/s, at an angle of 10–20 degrees in the horizontal direction. The patient received an unanticipated head push, provided at an unexpected time and in an unexpected direction [8]. The examiner positioned himself posterior to the seated subject and rotated his cranium. The examiner carefully rotated the head by securely grasping the mandible with all three fingers below and a thumb and forefinger slightly above the jawline. A sole investigator (A.K) conducted all of the tests during the experiment. Initially, the process of calibrating is carried out. The instrument was calibrated by instructing the patient to shift their focus among five dots displayed on the wall in front of them, with each dot positioned 8.5° apart. The dots were created using a laser affixed to a pair of goggles and a diffraction grating. The fixation pattern exhibited a random distribution, and the participant received instructions to refrain from allocating more than one second of attention to each dot. In the event of any errors, the examiner has the option to retake the calibration process. In total, ten head thrusts were performed in various directions. The equipment automatically determined the patient’s VOR gain. The criterion for identifying a pathologic v-HIT response was a vestibulo-ocular reflex (VOR) gain of less than 0.8 or the presence of corrective saccades with a peak velocity over 100◦/s [9]. Figure 1 demonstrates a normal and pathologic VHIT test result.

Fig. 1
figure 1

vHIT findings of one patient in the control group (normal gain) and one patient in the MS group (abnormal gain)

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Subjective vestibular assesment

The Dizziness Handicap Inventory (DHI) is a standard survey for assessing dizziness handicaps. Jacobson and Newman created the DHI to assess disability grade [10]. The DHI was first established in English and has been translated and validated in Turkish by Canbal et al. [11]. The DHI scale assesses the impact of vestibular symptoms on a person’s quality of life. It is divided into three subcategories: physical (7 questions), emotional (9 questions), and functional (9 questions), totaling 25 questions. Each question is rated as 0 = never, 2 = sometimes, or 4 = always, and the total score ranges from 0 to 100. A higher score indicates an increased impairment because of vestibular discomfort.

Statistical analysis

The statistical data was processed using the R Studio program. The Shapiro-Wilk and Andersen Darling tests assessed the data’s distribution pattern. Nonparametric tests were utilized for variables that did not follow a normal distribution.

Results are demonstrated as mean ± SD or median (interquartile range: IQR). The Mann-Whitney U test compared variables that were not normally distributed, whereas the independent samples t-test compared normally distributed data. Categorical variables were analyzed using Chi-square tests (Pearson’s Chi-square with or without Yates correction or Fisher’s exact test). p values < 0.05 were accepted as statistically significant.

Sample size calculation

G*Power (v3.1.7) program was used to calculate the sample size. An effect size of 1.001 was calculated based on the VHIT-LARP gains variable in the study by Tan et al. [12]. Power analysis revealed that a sample of 66 participants with two groups of equal size (n1 = 33 and n2 = 33) has a power (1- β) of 0.979.

Results

The study included 33 patients with acromegaly (male/female: 10/23; mean age: 49.2) and 33 healthy controls (male/female: 13/20; mean age: 51.2). The distribution of age (independent samples t-test, p = 0.482) and sex groups (Pearson’s chi-square test, p = 0.605) matched across groups (Table 1).

Table 1 Demographic findings of study and control groups
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Hearing thresholds at all frequencies (250, 500, 1000, 2000, 4000, and 6000 Hz) were significantly higher in acromegaly patients compared to the control group. Figure 2 represents the frequency-dependent hearing thresholds in patients’ and controls’ right and left ears.

Fig. 2
figure 2

Comparison of hearing levels between groups in right (a) and left (b) ears

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Median PTA in the right ear was 10 (11.7) in the patient group and 5 (5.4) in the control group (p < 0.001). PTA in the left ear was 10 (13.3) in the patient group and 6.6 (8.3) in the control group (p < 0.001). In the patient group, the median (IQR) SD in both the left and right ears was 92% (4), while in the control group, the median (IQR) SD was 96% (4) in both ears (p < 0.01.

The VNG gaze horizontal, gaze vertical, saccade, spontaneous nystagmus, optokinetic, smooth pursuit, and positional tests were used to compare the control and patient groups. Although pathologic nystagmus was rarely observed in a few patients in the patient group, there was no statistically significant difference between both groups (Fisher’s Exact test, p values > 0.05). Table 2 presents the VNG results for each nystagmus parameter.

Table 2 Comparison of pathological findings in Videonystagmography between groups
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When VOR gains were examined between the groups, the patient group exhibited lower VOR gains than the control group in the right anterior, right posterior, left anterior, and left posterior channels (p < 0.001, p = 0.002, p = 0.003, and p = 0.004, respectively). There was no statistically significant difference between the patient and control groups in horizontal channel VOR gains (p values > 0.05) (Table 3). When comparing the groups, it was found that a small number of participants in the patient group had aberrant saccades in some channels. As the groups were examined for abnormal (overt/overt) saccades, abnormal saccades were detected in a few participants in some channels in the patient group. In contrast, no abnormal saccades were observed in any participant in the control group. There was no significant difference between the two groups in terms of the presence of abnormal saccades (Fisher’s Exact test, p values > 0.05) (Table 3).

Table 3 v-HIT findings of patient and control groups
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The total DHI score was 8.7 ± 3.9 in the patient group and 4.7 ± 2.6 in the control group (independent samples t-test; p < 0.001). Subjective vestibular symptoms were statistically higher in the patient group (Fig. 3).

Fig. 3
figure 3

Comparison of Dizziness Handicap Inventory (DHI) total scores of the patient and control groups. Boxes indicate the first and third quartiles, and median ob-servations are denoted by a line in each box. Mean values are demon- strated by a black squate in the boxes. Whisker caps indicate the minimum and maximum values

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Discussion

This study demonstrates, for the first time, that individuals with acromegaly experience a decline in hearing capacity and peripheral vestibular dysfunction. Our study revealed that acromegaly patients exhibit elevated hearing thresholds across all frequencies compared to healthy controls, indicating the existence of hearing loss in acromegaly patients. Consistently, PTA was higher in acromegaly patients, while speech discrimination scores were lower in comparison to controls. Both groups interpret Audiological speech discrimination values as ‘good.’ If the patients are followed up for a more extended period, it can be researched whether a more prominent decrease in discrimination can be detected in the following periods. Similarly, despite a difference in PTA between the two groups, the hearing abilities of individuals in both groups can be assessed as ‘normal’ in a clinical setting.

Although there are some screening protocols for complications of acromegaly, hearing and balance screening still needs to be routine in most clinics; acromegaly can cause excessive growth hormone output, harming structures such as the inner ear, middle ear, and Eustachian tube. Excess growth hormone causes abnormal growth of bones and soft tissues, which can affect the function of the Eustachian tube, causing fluid collection in the middle ear and conductive hearing loss. Additionally, damaging the inner ear components can result in sensorineural hearing loss [13]. Tabur et al. found abnormal tympanometry results in 17% of the individuals in their study. This finding could result from aberrant soft tissue buildup in the eustachian tube and middle ear. We did not include patients who could not produce standard tympanogram curves in this study. This issue limits the number of patients we can include in our study. Tabur et al. also discovered decreased pure tone average levels in acromegaly patients versus healthy controls. Another interesting finding is that hearing status is unrelated to remission. The effects are irreversible if the auditory system is exposed to excessive GH/IGF-1 [14]. These effects are also a worthwhile investigation of the balance system. The vestibular system controls neural pathways in both central and peripheral vestibular pathways. Functional or biochemical disturbances in neuronal networks can cause various vestibular syndromes (persistent postural perceptual dizziness, psychogenic vertigo, benign positional vertigo, vestibular migraine, etc.) [15].

Videonystagmography (VNG) is an objective method for measuring the function of the eye muscles and vestibular system by tracking eye movements with a camera and infrared light [16]. The Video Head Impulse Test (vHIT) assesses the vestibular system’s function during rapid head movements. It is specifically designed to evaluate the semicircular canals’ function and measure the vestibular system’s high-frequency components [9].

According to our findings, although nystagmus in VNG was detected in a few participants in the patient group, no statistically significant difference was observed. On the other hand, corrective saccades were observed in a minor number of patients in the VHIT test. Even though a statistically significant finding is not always clinically significant, vertigo of central origin was detected in a few patients in the acromegaly group. This situation can be regarded as the peripheral vestibular system is primarily affected in patients with acromegaly. The primary finding was a decreased VOR gain in the posterior-anterior channel pairs in the VHIT test. Despite this decreased VOR gain, no positional nystagmus was observed in the positional tests (Dix Hallpike and supine roll). It may be interpreted that acromegaly causes dysfunction in the semicircular canals even if it does not produce clinical manifestations. The fact that the most commonly affected semicircular canal in benign positional vertigo was affected in our patient group may be interpreted that this canal is also the most commonly affected canal by metabolic events.

Balance is a complex phenomenon requiring the proper and cooperative operation of the visual, proprioceptive, and motor systems. Problems affecting the skeletal musculature can impair balance by disrupting the sensory-motor organization. In acromegaly, joint degeneration, abnormal muscular and skeletal growth, muscle weakness, and changes in body composition (body mass increase, body water expansion, and body fat decrease) can all lead to balance instability [7, 17]. Lopes et al. investigated posture and balance in acromegaly patients and discovered poor static balance and deviation of the center of pressure in the anteroposterior and mediolateral directions. They also observed posture distortions in these cases [17]. Haliloglu et al. used posturography to evaluate static and dynamic balance and the effect of exercise on patients with acromegaly. They found a decline in various static and dynamic measures in acromegaly patients, particularly in the posterior direction. After three months of exercise, they observed an essential improvement in dynamic balance, while static balance remained relatively stable [7]. Because the vestibular system was also impacted in our study, we recommend that proper exercise programs be initiated early in acromegaly patients before the vestibular system becomes clinically affected, resulting in vertigo. This will help to prevent balance and gait problems, as well as falls.

The vestibuloocular reflex (VOR) is a reflex that controls the balance and visual systems in the human body. This reflex enables the eyes to stabilize and follow the target in the event of random head movements or a loss of balance in the body.The inner ear’s vestibular system sends balancing information to the VOR, which then controls eye movements. Metabolic conditions can affect the vestibulo-ocular reflex. Diabetes, for example, can have a deleterious impact on the vestibular system. Diabetic neuropathy can cause damage to peripheral nerves in particular, resulting in balance issues and reduced vestibular function [18].

Diabetes or impaired glucose tolerance is a primary clinical concern in acromegaly patients. This predisposition is due to the insulin-antagonist properties of growth hormones. Increased growth hormone inhibits glucose metabolism, resulting in insulin resistance [19]. Diabetes can lead to microvascular problems and neuropathy, affecting vestibular system function. Diabetes can reduce blood flow by damaging microvascular systems in the inner ear. Diabetic neuropathy causes nerve damage, impacting the vestibular nerves and interfering with the semicircular canals’ normal function.Diabetic-induced semicircular canal dysfunction can cause an inability of the eyes to respond to head movements during vHIT with the expected speed or accuracy [20].

The inner ear’s otolith organs (utricle and saccule) are important structures for detecting static and dynamic balances such as gravity and linear acceleration. They are covered with otolith membranes and otoconia (calcium carbonate crystals). Calcium is a crucial component in the structure of otoconia. Calcium imbalances can disrupt the structure or impair the function of these crystals [21].Calcium level disturbances can cause otoconia displacement or dislocation, which can cause vestibular problems, including benign paroxysmal positional vertigo (BPPV) [22]. Calcium is also necessary for neurotransmitter release and synaptic function. Calcium metabolism disturbances can influence the synaptic activity of hair cells in otolith organs, impairing signal transmission across the vestibular nerve to the central nervous system [23]. The vHIT, which measures the vestibular-ocular reflex (VOR), can reveal abnormal VOR gain and compensatory saccades in individuals with vestibular dysfunction caused by metabolic disorders such as hypercalcemia [24]. Acromegaly may cause disturbances in calcium and vitamin D metabolism. In patients with acromegaly, increased levels of GH and IGF-1 may increase bone resorption. This process can lead to calcium release from bones and, thus, hypercalcemia [25].

Furthermore, increased levels of GH and IGF-1 may increase calcium absorption by affecting the production of calcitriol, the active form of vitamin D [25]. Instability in calcium levels can lead to vertigo and balance problems by impairing the functioning of otolith organs [26]. Vitamin D deficiency or imbalance can cause dysfunctions in the vestibular system by disrupting calcium metabolism [23].

Increased GH/IGF-1 levels in acromegaly patients can cause hypogonadism by inhibiting gonadotropin secretion and decreasing sex hormone synthesis [27]. Sex hormones such as estrogen and progesterone act directly on the vestibular system via receptors in the inner ear and central nervous system. These hormones control vestibular function by influencing ion channels and neurotransmitter release. In some women, abnormal amounts of estrogen and progesterone throughout the menstrual cycle might produce vestibular system sensitization [15, 28].

Acromegaly’s expansion of the skull and surrounding tissues can impact the inner ear’s structural integrity. Changes in the inner ear can impair the function of the balance organs and the vestibulo-ocular reflex. However, the nature and intensity of these impacts still need to be determined due to the absence of research on this topic.

Some clinical observations of balance abnormalities in acromegaly patients have led to discussion about possible rationales. According to the studies above, patients with acromegaly are more prone to problems with balance and gait. This has been related to growth hormone-induced bone and joint growth, but little is known about the direct influence of the vestibulo-ocular reflex. Additional research is needed to understand the association between acromegaly and balance problems. Such studies can add to our knowledge of the disease’s origin, symptoms, and treatment and improve clinical practice.

The Dizziness Handicap Inventory (DHI) is a self-report questionnaire to evaluate how dizziness and imbalance affect individuals’ everyday lives. The DHI assesses patients’ physical, emotional, and functional challenges associated with dizziness and imbalance [10]. It shows that even after treatment of acromegaly, patients continue to experience specific symptoms. Such chronic symptoms can include dizziness and balance problems. In the long term, the affected balance system can lead to symptoms such as persistent postural perceptual dizziness [29]. Psychiatric symptoms such as anxiety and depression may also be present in acromegaly patients. This condition is caused by physical signs of the disease, hormonal changes, and declining quality of life [19]. Although anxiety and depression may not directly damage the vestibular system, they can cause symptoms like dizziness and imbalance due to their effects on the central nervous system and physiological stress reactions [30]. Chronic disease anxiety and stress may have also contributed to patients’ subjective feelings of imbalance and dizziness. The strength of this study is that it is the first to perform objective evaluation with VNG and VHIT and subjective evaluation with DHI in patients with acromegaly. However, this study also has some limitations. Firstly, the study population was small; however, since acromegaly is a rare disease, this number of participants could be enrolled. Second, the vestibular evaluation was only performed with VNG and VHIT. The difficulties we encountered during vestibular evaluation in these patients were:

  • the need to spend more time on calibration due to increased head diameter.

  • the need to perform more head thrust for VHIT due to decreased neck movements.

  • the difficulty of patients’ cooperation with the test due to metabolic problems.

Skin thickness did not allow electrodes to adhere efficiently in patients with acromegaly, and the VEMP test could not be performed in all patients. The VEMP test can be included in the battery using other solutions instead of sticking electrodes in future studies. High-frequency audiograms up to 16 kHz can be incorporated into the audiologic evaluation. In this way, how the cochlea is affected by acromegaly can be clarified in more detail. In this study, we did not perform a high-frequency audiogram because our main focus was on the vestibular system, but in a future study, we may also address this topic. This study did not control for factors such as genetic predisposition to hearing loss or family history. This may represent a potential limitation in the assessment of hearing thresholds and it is recommended that these factors be taken into account in future studies. Additionally; in patients with acromegaly, a variety of endocrine disturbances may coexist, which complicates the attribution of vestibular dysfunction solely to acromegaly. Additionally, the involvement of the musculoskeletal system may further impair balance functions in these patients. In this study, subjective dizziness was assessed using the Dizziness Handicap Inventory (DHI). However, it is important to note that the reported dizziness may not be entirely attributable to acromegaly, but could also be influenced by these other comorbidities. This limitation should be considered when interpreting the results, as the observed vestibular dysfunctions could reflect a broader spectrum of underlying endocrine and musculoskeletal conditions rather than acromegaly alone. While this study focuses on vestibular dysfunction in acromegaly, other factors such as comorbid musculoskeletal and endocrine disorders may also contribute to balance impairments. Future studies should assess these conditions and their interactions with vestibular function in more detail.

If hearing screening is performed early in patients with acromegaly, it can be determined whether hearing loss will increase over time. On the other hand, relatively easy-to-use vestibular tests such as VHIT can detect balance problems at an early stage, include patients in appropriate rehabilitation/exercise programs, and prevent falls.