Subjective and Objective Effects of Androgen Ablation Therapy on Voice € u € tfi Kumral, *G€ € nc¸temur, *€Imran Aydog du, *Ziya Salturk, *Ozan C¸akır, *Tolgar Lu uven Yıldırım, †Alper Ot and *Yavuz Uyar, *yIstanbul, Turkey Summary: Objectives. The aim of present study was to evaluate possible side effects of androgen deprivation therapy (ADT) on voice quality by means of objective and subjective measures. Study Design. Cross-sectional. Methods. Thirty-five male patients who had been diagnosed with prostate cancer and who had been using bicalutamide and goserelin acetate combination for at least 12 months were included in the study. Thirty healthy nonsmoker males of similar age and without any laryngeal pathology constituted the control group. Acoustic and aerodynamic voice analyses and voice handicap index-10 were applied to both groups. Maximum phonation time, fundamental frequency, jitter, shimmer, and noise-to-harmonic ratio were determined during acoustic and aerodynamic voice analyses. Results. Maximum phonation times were 18.86 ± 5.24 and 24.20 ± 3.59 in ADT and control groups, respectively. It was significantly higher in the control group. Fundamental frequencies were 143.73 ± 18.47 and 135.00 ± 13.18 in ADT and control groups, respectively. Jitter values were 2.72 ± 0.62 and 1.99 ± 0.27 in ADT and control groups, respectively. Shimmer values were 11.50 ± 1.81 and 10.48 ± 1.36 in ADT and control groups, respectively. Fundamental frequency, jitter, and shimmer values were significantly higher in the ADT group. Noise-to-harmonic ratio values did not differ between groups. Voice handicap index-10 result was significantly higher in the ADT group. Conclusions. ADT has adverse effects on the human voice. Prospective studies with long-term follow-up of a larger cohort are required for more detailed analysis. Key Words: Androgen deprivation therapy–Acoustic voice analysis–Prostate cancer–Adverse effect–Voice handicap index. INTRODUCTION Voice is one of the main tools in human communication and professional life.1 Development of the human voice does not differ between males and females until puberty. The onset of puberty, under the influence of sex hormones, causes differentiation of the human larynx and voice. In males, sex hormones result in more elongated and thicker vocal cords, increased sagittal diameter of the larynx, and a lower angle of thyroid cartilage in comparison with females. This development causes a lower fundamental frequency (F0) in males.2,3 Aging has also effects on the human voice, resulting in atrophy of the extralaryngeal muscles, dehydration of the mucosa, decreased elasticity of ligaments, calcification of cartilage, and loose vocal cords.2 These changes are also related to hormonal changes and physical status.4 Prostate cancer is the most common cancer in the male population and the second most common cause of death from cancer in Western countries.5,6 The treatment of localized prostate cancer commonly involves a radical retropubic prostatectomy with pelvic lymph node dissection with or without radiotherapy in the form of external beam radiation or brachytherapy. However, surgical resection is not suitable for most patients with advanced
Accepted for publication September 8, 2014. This study has not been published partially or totally. From the *Okmeydanı Training and Research Hospital ENT Clinic, Istanbul, Turkey; and the yOkmeydanı Training and Research Hospital Urology Clinic, Istanbul, Turkey. Address correspondence and reprint requests to Ziya Salturk, Okmeydanı Training and Research Hospital ENT Clinic, Darulaceze cad, S¸is¸li, Istanbul, Turkey. E-mail: [email protected] Journal of Voice, Vol. 29, No. 4, pp. 490-493 0892-1997/$36.00 Ó 2015 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2014.09.010
prostate cancer; these patients are commonly treated with androgen ablation hormonal therapy or androgen deprivation therapy (ADT).7,8 Bicalutamide is an oral nonsteroidal antiandrogen drug that competitively antagonizes the actions of androgens of both testicular and adrenal origin at the receptor level, thereby inhibiting the growth of prostate tumors.9 Although it does not inhibit gonadotropin and testosterone production, it results in side effects related to androgen deficiency, including gynecomastia and decreased libido.9,10 Goserelin acetate is a depot luteinizing hormone-releasing hormone superagonist that suppresses release of gonadotropins from the pituitary gland by downregulation.11 This study aimed to evaluate possible side effects of ADT on voice quality by means of objective and subjective measures. MATERIALS AND METHODS Institutional Review Board approval was obtained from the Okmeydanı Training and Research Hospital Ethical Committee. Thirty-five male patients who had been diagnosed with prostate cancer and who had been using bicalutamide for at least 12 months were included in the study (ADT group). Patients with upper respiratory tract infection, history of laryngeal surgery or pathology, pulmonary problems, history of head and neck radiotherapy, smoking, reflux, or obstructive sleep apnea were excluded. None of the patients had obesity problem; all of them had body mass index below 30. All of the patients had been using a dosage of 50 mg/day bicalutamide orally and 10.8 mg per 3 months of goserelin acetate intramuscularly. Thirty healthy nonsmoker males of similar age and without any laryngeal pathology constituted the control group. All subjects in both groups underwent complete
Ziya Salturk, et al
491
Effects of Androgen Ablation on Voice
head and neck examinations, as well as acoustic and aerodynamic analyses. Voices were recorded using a dynamic microphone kept at a distance of 15 cm from the lips. Following a deep inspiration, the subject tried to say the vowel ‘‘ah’’ for as long as he could and repeated it three times, and the longest recording time was accepted as the maximum phonation time (MPT). Additionally, subjects were asked to read a phonetically balanced passage from a famous Turkish story titled ‘‘Diyet’’ for 40 seconds in a relaxed voice. The Praat software (version 4.4.13, Boersma and Weenink, University of Amsterdam, Amsterdam, The Netherlands) was used for acoustic analysis. The fundamental frequency (F0), jitter, shimmer, and noise-toharmonics ratio (NHR) were determined during acoustic voice analysis. Subjective evaluation was performed using the Voice Handicap Index-10 (VHI-10). The Turkish version of VHI-10 was validated by Kılıc¸ et al12 VHI-10 comprises 10 questions and is scored between 0 (never) and 4 (always). It has emotional, functional, and physical subscales with four, three, and three questions, respectively. Statistical analysis of the data was conducted using SPSS version 17.0 (SPSS, IBM, NY). Data were analyzed using descriptive statistical methods (mean and standard deviation). Parametric independent sample t test was used for the comparison of independent groups. Results were evaluated using the 95% confidence intervals, and the level of significance was set at P < 0.05. RESULTS The mean age of the ADT group was 57.57 ± 3.01 years, and the mean period of bicalutamide use was 16.57 ± 3.07; range (13– 24) months. The mean age of the control group was 57.95 ± 2.81 years. Age did not differ significantly between the two groups. Results of acoustic and aerodynamic analyses are shown in Table 1. MPT was significantly higher in the control group. F0, jitter, and shimmer values were significantly higher in the ADT group. NHR values did not differ between groups. Subjects in the ADT group had significantly higher VHI-10 scores, which indicated that they were more dissatisfied with their voices. DISCUSSION Voice is a secondary sexual characteristic that completes its maturation at the end of puberty. It completes its development at age 16 to 17 years in males. Sex hormones are the main determinants of laryngeal maturation.2 Newman et al13 performed a study with fresh cadavers and reported that there are hormone receptors in the cytoplasm and nucleus of vocal cords with differences in distribution depending on age and sex. Animal studies also proved that androgens cause hypertrophy and hyperplasia of the laryngeal muscles.14 Two studies performed on juvenile Xenopus laevis revealed that androgens induce myogenesis and chondrogenesis. In addition, these effects are more dominant than innervations.15,16 Efforts have been made to assess voice changes depending on testosterone.17–23 Dabbs et al18 performed instant testosterone level measurements and found that higher testosterone levels
TABLE 1. Comparison of Vocal Parameters
Test MPT F0 Jitter Shimmer NHR VHI-10
ADT Group (n ¼ 35)
Control Group (n ¼ 30)
Mean ± SD
Mean ± SD
P
18.86 ± 5.24 143.73 ± 18.47 2.72 ± 0.62 11.50 ± 1.81 0.14 ± 0.94 5.86 ± 2.89
24.20 ± 3.59 135.00 ± 13.18 1.99 ± 0.27 10.48 ± 1.36 0.15 ± 0.02 4.00 ± 1.31
0.000 0.030 0.000 0.012 0.099 0.002
Notes: Independent samples t test *P < 0.05. Abbreviations: ADT, androgen deprivation therapy; F0, fundamental frequency; NHR, noise-to-harmonic ratio; VHI-10, voice handicap index 10.
cause lower pitch. It was reported that the vocal characteristics of a professional singer were converted to baritone from tenor with use of testosterone for hypogonadotropic hypogonadism.17 F0 values of male patients with isolated hypogonadotropic hypogonadism declined significantly at the end of testosterone replacement therapy.19 Evans et al20 claimed that F0 values were inversely proportional to the daily changes in testosterone level. Table 2 illustrates the studies17–20 which evaluated F0 changes related to testosterone. On the other hand, Gugatschka et al21 did not find differences in voice parameters, including F0 and mean voice range, of osteoporotic patients with low and normal testosterone levels, but they found differences in F0 between patients with low and normal estradiol levels. Androgens cause a decrease in F0 and increase of voice instability.22,23 Gerrtisma et al22 explained that this situation results from histologic changes and problems in adaptation to these changes. Hormone replacement therapies applied for female-to-male sex conversion cause decreases in voice pitch range and F0.24,25 Nakamura et al26 investigated testosterone replacement therapy in persons who changed sex from female to male and showed that higher testosterone dosage was more effective in producing male characteristics, including voice, at 1 month, but at 6 months, the three groups exhibited identical results. This study showed that the acute phase of hormonal changes causes a more unstable situation. ADT can be applied to patients by maximal androgen blockade and peripheral androgen blockade. The antiandrogen bicalutamide is the leading agent used in both regimens. Because this agent inhibits androgen receptors competitively, all side effects that depend on androgen blockade might be observed in patients. These include hot flashes, osteoporosis, anemia, loss of libido, erectile dysfunction, metabolic syndrome, and so forth. As a secondary sex characteristic, the voice might be affected by ADT because of lower testosterone level.9,10 Goserelin acetate is added to therapy to maximize the efficacy of bicalutamide; because it has effects similar to those of orchiectomy, it could also increase the incidence of side effects.11,27 MPT reflects prolonged vocalization and continuous speech; it is related to the resistance and force generated at the glottal
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Journal of Voice, Vol. 29, No. 4, 2015
TABLE 2. Fundamental Frequency Changes Related to Testosterone Author King et al17 Dabbs et al18 Akc¸am et al19 Evans et al20
Patient Number 1 61 male, 88 female 30 40
Testosterone (ng/dL)
Fundamental Frequency (Hz)
Testosterone (ng/dL)
Fundamental Frequency (Hz)
79 9.63 (male)*
277.9 99
Replaced 1.78 (female)*
120.6 181
Idiopathic hypogonadotropic hypogonadism 118.11
229 99.78
Replaced 97.32
173 108.8
Abbreviations: Hz, hertz; ng/dL, nanogram per deciliter. * Salivary testosterone.
region.28 Acoustic and aerodynamic analyses revealed shorter MPT in the ADT group. F0 is the main parameter of the listener’s perception of a speaker’s pitch. It is the lowest frequency and is determined primarily by the elasticity, tension, and mass of the vocal folds.3 We found higher F0 in the ADT group. Jitter and shimmer percentages represent the vibrational action of the glottis and the short-term (period-to-period) irregularity of pitch and irregularity of the peak-to-peak amplitude of voice, respectively.29 The present study detected higher jitter and shimmer in the ADT group. An increase in the NHR ratio indicates an increase in the irregular versus regular components of voice.30 Results of NHR did not differ between the two groups. The VHI-10 results of this study revealed that the ADT group was less satisfied with their voices in comparison with the control group. Hamdan et al31 performed a study similar to ours. They used a gonadotropin-releasing hormone agonist for ADT and found a significantly higher habitual pitch and perturbation parameters. On the other hand, they could not find any difference in F0. The difference between our findings and theirs may result from both the use of different drug regimens and the older population in their study. They included patients who had used gonadotropin-releasing hormone analogs with and without an antiandrogen, whereas we used combination therapy. In addition, their range of durations of drug use was 5 months to 4 years, whereas all of our patients had completed 1 year.
4. 5. 6. 7.
8.
9. 10.
11.
12.
13. 14.
15.
CONCLUSIONS ADT has effects on the human voice. Our study revealed that F0, jitter, shimmer, and MPT were affected in subjects receiving ADT. In addition, satisfaction of the patients with their voice was affected negatively. Because of the limited number of patients in this study, prospective studies with long-term followup of a larger cohort are required for more detailed analysis.
16. 17. 18. 19.
20.
REFERENCES 1. Titze IR, Lemke J, Montequin D. Populations in the U.S. workforce who rely on voice as a primary tool of trade: a preliminary report. J Voice. 1997;11:254–259. 2. Aronson AE, Bless DM. Normal voice development. In: Aronson AE, Bless DM, eds. Clinical Voice Disorders. 4th ed. New York, NY: Thieme; 2009:10–24. 3. Raphael LJ, Borden GJ, Harris KS. The raw materials — phonation. In: Raphael LJ, Borden GJ, Harris KS, eds. Speech Science Primer: Physi-
21.
22.
ology, Acoustics, and Perception of Speech. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2007:85–103. Sataloff RT, Rosen DC, Hawkshaw M, Spiegel JR. The aging adult voice. J Voice. 1997;11:156–160. Chan JM, Stampfer MJ, Giovannucci EL. What causes prostate cancer? A brief summary of the epidemiology. Semin Cancer Biol. 1998;8:263–273. Ekman P. Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol. 1999;35:362–369. Olsson M, Ekstr€om L, Schulze J, Kjellman A, Akre O, Rane A, Gustafsson O. Radical prostatectomy: influence on serum and urinary androgen levels. Prostate. 2010;70:200–205. Abedinpour P, Baron VT, Welsh J, Borgstr€om P. Regression of prostate tumors upon combination of hormone ablation therapy and celecoxib in vivo. Prostate. 2011;71:813–823. Fradet Y. Bicalutamide (Casodex) in the treatment of prostate cancer. Expert Rev Anticancer Ther. 2004;4:37–48. Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A. Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiol Drug Saf. 2006;15:253–259. Goldspiel BR, Kohler DR. Goserelin acetate implant: a depot luteinizing hormone-releasing hormone analog for advanced prostate cancer. DICP. 1991;25:796–804. Kilic MA, Okur E, Yildirim I, et al. Reliability and validity of the Turkish version of the voice handicap index. Kulak Burun Bogaz Ihtis Derg. 2008; 18:139–147. Newman SR, Butler J, Hammond EH, Gray SD. Preliminary report on hormone receptors in the human vocal fold. J Voice. 2000;14:72–81. Talaat M, Talaat AM, Kelada I, Angelo A, Elwany S, Thabet H. Histologic and histochemical study of effects of anabolic steroids on the female larynx. Ann Otol Rhinol Laryngol. 1987;96:468–471. Sassoon D, Segil N, Kelley D. Androgen-induced myogenesis and chondrogenesis in the larynx of Xenopus laevis. Dev Biol. 1986;113:135–140. Tobias ML, Marin ML, Kelley DB. The roles of sex, innervation, and androgen in laryngeal muscle of Xenopus laevis. J Neurosci. 1993;13:324–333. King A, Ashby J, Nelson C. Effects of testosterone replacement on a male professional singer. J Voice. 2001;15:553–557. Dabbs JM Jr, Mallinger A. High testosterone levels predict low voice pitch among men. Pers Individ Dif. 1999;27:801–804. Akcam T, Bolu E, Merati AL, Durmus C, Gerek M, Ozkaptan Y. Voice changes after androgen therapy for hypogonadotropic hypogonadism. Laryngoscope. 2004;114:1587–1591. Evans S, Neave N, Wakelin D, Hamilton C. The relationship between testosterone and vocal frequencies in human males. Physiol Behav. 2008; 93:783–788. Gugatschka M, Kiesler K, Obermayer-Pietsch B, Schoekler B, Schmid C, Groselj-Strele A, Friedrich G. Sex hormones and the elderly male voice. J Voice. 2010;24:369–373. Gerritsma EJ, Brocaar MP, Hakkesteegt MM, Birkenh€ager JC. Virilization of the voice in post menopausal women due to the anabolic steroid nandrolone decanoate (Decadurabolin). The effects of medication for one year. Clin Otolaryngol Allied Sci. 1994;19:79–84.
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23. Baker J. A report on alterations to the speaking and singing voices of four women following hormonal therapy with virilizing agents. J Voice. 1999; 13:496–507. 24. Van Borsel J, De Cuypere G, Rubens R, Destaerke B. Voice problems in female-to-male transsexuals. Int J Lang Commun Disord. 2000;35: 427–442. 25. Damrose EJ. Quantifying the impact of androgen therapy on the female larynx. Auris Nasus Larynx. 2009;36:110–112. 26. Nakamura A, Watanabe M, Sugimoto M, et al. Dose-response analysis of testosterone replacement therapy in patients with female to male gender identity disorder. Endocr J. 2013;60:275–281. 27. Boccardo F, Pace M, Rubagotti A, et al. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic
28.
29. 30.
31.
prostate cancer. The Italian Prostatic Cancer Project (PONCAP) Study Group. Eur J Cancer. 1993;29A:1088–1093. Topaloglu I, Koc¸ak I, Salt€urk Z. Multidimensional evaluation of vocal function after supracricoid laryngectomy with cricohyoidopexy. Ann Otol Rhinol Laryngol. 2012;121:407–412. Horii Y. Jitter and shimmer differences among sustained vowel phonations. J Speech Hear Res. 1982;25:12–14. G€oksel AO, Topaloglu I. Voice quality assessment via acoustic and spectrographic analysis in patients who had endolaryngeal microsurgery. Kulak Burun Bogaz Ihtis Derg. 2009;19:253–258. Hamdan AL, Jabbour J, Saadeh R, Kazan I, Nassar J, Bulbul M. Vocal changes in patients with prostate cancer following androgen ablation. J Voice. 2012;26:812.e11–812.e15.
Accepted for publication September 8, 2014. This study has not been published partially or totally. From the *Okmeydanı Training and Research Hospital ENT Clinic, Istanbul, Turkey; and the yOkmeydanı Training and Research Hospital Urology Clinic, Istanbul, Turkey. Address correspondence and reprint requests to Ziya Salturk, Okmeydanı Training and Research Hospital ENT Clinic, Darulaceze cad, S¸is¸li, Istanbul, Turkey. E-mail: [email protected] Journal of Voice, Vol. 29, No. 4, pp. 490-493 0892-1997/$36.00 Ó 2015 The Voice Foundation http://dx.doi.org/10.1016/j.jvoice.2014.09.010
prostate cancer; these patients are commonly treated with androgen ablation hormonal therapy or androgen deprivation therapy (ADT).7,8 Bicalutamide is an oral nonsteroidal antiandrogen drug that competitively antagonizes the actions of androgens of both testicular and adrenal origin at the receptor level, thereby inhibiting the growth of prostate tumors.9 Although it does not inhibit gonadotropin and testosterone production, it results in side effects related to androgen deficiency, including gynecomastia and decreased libido.9,10 Goserelin acetate is a depot luteinizing hormone-releasing hormone superagonist that suppresses release of gonadotropins from the pituitary gland by downregulation.11 This study aimed to evaluate possible side effects of ADT on voice quality by means of objective and subjective measures. MATERIALS AND METHODS Institutional Review Board approval was obtained from the Okmeydanı Training and Research Hospital Ethical Committee. Thirty-five male patients who had been diagnosed with prostate cancer and who had been using bicalutamide for at least 12 months were included in the study (ADT group). Patients with upper respiratory tract infection, history of laryngeal surgery or pathology, pulmonary problems, history of head and neck radiotherapy, smoking, reflux, or obstructive sleep apnea were excluded. None of the patients had obesity problem; all of them had body mass index below 30. All of the patients had been using a dosage of 50 mg/day bicalutamide orally and 10.8 mg per 3 months of goserelin acetate intramuscularly. Thirty healthy nonsmoker males of similar age and without any laryngeal pathology constituted the control group. All subjects in both groups underwent complete
Ziya Salturk, et al
491
Effects of Androgen Ablation on Voice
head and neck examinations, as well as acoustic and aerodynamic analyses. Voices were recorded using a dynamic microphone kept at a distance of 15 cm from the lips. Following a deep inspiration, the subject tried to say the vowel ‘‘ah’’ for as long as he could and repeated it three times, and the longest recording time was accepted as the maximum phonation time (MPT). Additionally, subjects were asked to read a phonetically balanced passage from a famous Turkish story titled ‘‘Diyet’’ for 40 seconds in a relaxed voice. The Praat software (version 4.4.13, Boersma and Weenink, University of Amsterdam, Amsterdam, The Netherlands) was used for acoustic analysis. The fundamental frequency (F0), jitter, shimmer, and noise-toharmonics ratio (NHR) were determined during acoustic voice analysis. Subjective evaluation was performed using the Voice Handicap Index-10 (VHI-10). The Turkish version of VHI-10 was validated by Kılıc¸ et al12 VHI-10 comprises 10 questions and is scored between 0 (never) and 4 (always). It has emotional, functional, and physical subscales with four, three, and three questions, respectively. Statistical analysis of the data was conducted using SPSS version 17.0 (SPSS, IBM, NY). Data were analyzed using descriptive statistical methods (mean and standard deviation). Parametric independent sample t test was used for the comparison of independent groups. Results were evaluated using the 95% confidence intervals, and the level of significance was set at P < 0.05. RESULTS The mean age of the ADT group was 57.57 ± 3.01 years, and the mean period of bicalutamide use was 16.57 ± 3.07; range (13– 24) months. The mean age of the control group was 57.95 ± 2.81 years. Age did not differ significantly between the two groups. Results of acoustic and aerodynamic analyses are shown in Table 1. MPT was significantly higher in the control group. F0, jitter, and shimmer values were significantly higher in the ADT group. NHR values did not differ between groups. Subjects in the ADT group had significantly higher VHI-10 scores, which indicated that they were more dissatisfied with their voices. DISCUSSION Voice is a secondary sexual characteristic that completes its maturation at the end of puberty. It completes its development at age 16 to 17 years in males. Sex hormones are the main determinants of laryngeal maturation.2 Newman et al13 performed a study with fresh cadavers and reported that there are hormone receptors in the cytoplasm and nucleus of vocal cords with differences in distribution depending on age and sex. Animal studies also proved that androgens cause hypertrophy and hyperplasia of the laryngeal muscles.14 Two studies performed on juvenile Xenopus laevis revealed that androgens induce myogenesis and chondrogenesis. In addition, these effects are more dominant than innervations.15,16 Efforts have been made to assess voice changes depending on testosterone.17–23 Dabbs et al18 performed instant testosterone level measurements and found that higher testosterone levels
TABLE 1. Comparison of Vocal Parameters
Test MPT F0 Jitter Shimmer NHR VHI-10
ADT Group (n ¼ 35)
Control Group (n ¼ 30)
Mean ± SD
Mean ± SD
P
18.86 ± 5.24 143.73 ± 18.47 2.72 ± 0.62 11.50 ± 1.81 0.14 ± 0.94 5.86 ± 2.89
24.20 ± 3.59 135.00 ± 13.18 1.99 ± 0.27 10.48 ± 1.36 0.15 ± 0.02 4.00 ± 1.31
0.000 0.030 0.000 0.012 0.099 0.002
Notes: Independent samples t test *P < 0.05. Abbreviations: ADT, androgen deprivation therapy; F0, fundamental frequency; NHR, noise-to-harmonic ratio; VHI-10, voice handicap index 10.
cause lower pitch. It was reported that the vocal characteristics of a professional singer were converted to baritone from tenor with use of testosterone for hypogonadotropic hypogonadism.17 F0 values of male patients with isolated hypogonadotropic hypogonadism declined significantly at the end of testosterone replacement therapy.19 Evans et al20 claimed that F0 values were inversely proportional to the daily changes in testosterone level. Table 2 illustrates the studies17–20 which evaluated F0 changes related to testosterone. On the other hand, Gugatschka et al21 did not find differences in voice parameters, including F0 and mean voice range, of osteoporotic patients with low and normal testosterone levels, but they found differences in F0 between patients with low and normal estradiol levels. Androgens cause a decrease in F0 and increase of voice instability.22,23 Gerrtisma et al22 explained that this situation results from histologic changes and problems in adaptation to these changes. Hormone replacement therapies applied for female-to-male sex conversion cause decreases in voice pitch range and F0.24,25 Nakamura et al26 investigated testosterone replacement therapy in persons who changed sex from female to male and showed that higher testosterone dosage was more effective in producing male characteristics, including voice, at 1 month, but at 6 months, the three groups exhibited identical results. This study showed that the acute phase of hormonal changes causes a more unstable situation. ADT can be applied to patients by maximal androgen blockade and peripheral androgen blockade. The antiandrogen bicalutamide is the leading agent used in both regimens. Because this agent inhibits androgen receptors competitively, all side effects that depend on androgen blockade might be observed in patients. These include hot flashes, osteoporosis, anemia, loss of libido, erectile dysfunction, metabolic syndrome, and so forth. As a secondary sex characteristic, the voice might be affected by ADT because of lower testosterone level.9,10 Goserelin acetate is added to therapy to maximize the efficacy of bicalutamide; because it has effects similar to those of orchiectomy, it could also increase the incidence of side effects.11,27 MPT reflects prolonged vocalization and continuous speech; it is related to the resistance and force generated at the glottal
492
Journal of Voice, Vol. 29, No. 4, 2015
TABLE 2. Fundamental Frequency Changes Related to Testosterone Author King et al17 Dabbs et al18 Akc¸am et al19 Evans et al20
Patient Number 1 61 male, 88 female 30 40
Testosterone (ng/dL)
Fundamental Frequency (Hz)
Testosterone (ng/dL)
Fundamental Frequency (Hz)
79 9.63 (male)*
277.9 99
Replaced 1.78 (female)*
120.6 181
Idiopathic hypogonadotropic hypogonadism 118.11
229 99.78
Replaced 97.32
173 108.8
Abbreviations: Hz, hertz; ng/dL, nanogram per deciliter. * Salivary testosterone.
region.28 Acoustic and aerodynamic analyses revealed shorter MPT in the ADT group. F0 is the main parameter of the listener’s perception of a speaker’s pitch. It is the lowest frequency and is determined primarily by the elasticity, tension, and mass of the vocal folds.3 We found higher F0 in the ADT group. Jitter and shimmer percentages represent the vibrational action of the glottis and the short-term (period-to-period) irregularity of pitch and irregularity of the peak-to-peak amplitude of voice, respectively.29 The present study detected higher jitter and shimmer in the ADT group. An increase in the NHR ratio indicates an increase in the irregular versus regular components of voice.30 Results of NHR did not differ between the two groups. The VHI-10 results of this study revealed that the ADT group was less satisfied with their voices in comparison with the control group. Hamdan et al31 performed a study similar to ours. They used a gonadotropin-releasing hormone agonist for ADT and found a significantly higher habitual pitch and perturbation parameters. On the other hand, they could not find any difference in F0. The difference between our findings and theirs may result from both the use of different drug regimens and the older population in their study. They included patients who had used gonadotropin-releasing hormone analogs with and without an antiandrogen, whereas we used combination therapy. In addition, their range of durations of drug use was 5 months to 4 years, whereas all of our patients had completed 1 year.
4. 5. 6. 7.
8.
9. 10.
11.
12.
13. 14.
15.
CONCLUSIONS ADT has effects on the human voice. Our study revealed that F0, jitter, shimmer, and MPT were affected in subjects receiving ADT. In addition, satisfaction of the patients with their voice was affected negatively. Because of the limited number of patients in this study, prospective studies with long-term followup of a larger cohort are required for more detailed analysis.
16. 17. 18. 19.
20.
REFERENCES 1. Titze IR, Lemke J, Montequin D. Populations in the U.S. workforce who rely on voice as a primary tool of trade: a preliminary report. J Voice. 1997;11:254–259. 2. Aronson AE, Bless DM. Normal voice development. In: Aronson AE, Bless DM, eds. Clinical Voice Disorders. 4th ed. New York, NY: Thieme; 2009:10–24. 3. Raphael LJ, Borden GJ, Harris KS. The raw materials — phonation. In: Raphael LJ, Borden GJ, Harris KS, eds. Speech Science Primer: Physi-
21.
22.
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