ORIGINAL
ARTICLE
Functional Voice Testing Detects Early Changes in
Vocal Pitch in Women During Testosterone
Administration
Grace Huang, Karol M. Pencina, Jeffry A. Coady, Yusnie M. Beleva,
Shalender Bhasin, and Shehzad Basaria
Section of Men’s Health: Aging and Metabolism (G.H., K.M.P., Y.M.B., S.Bh., S.Ba.), Brigham and
Women’s Hospital, Harvard Medical School, Brookline, Massachusetts 02115; and Department of
Speech, Language, and Hearing Sciences (J.A.C.), University of Colorado, Boulder, Colorado 80309
Objective: To determine dose-dependent effects of T administration on voice changes in women
with low T levels.
Methods: Seventy-one women who have undergone a hysterectomy with or without oophorectomy with total T ⬍ 31 ng/dL and/or free T ⬍ 3.5 pg/mL received a standardized transdermal
estradiol regimen during the 12-week run-in period and were then randomized to receive weekly
im injections of placebo or 3, 6.25, 12.5, or 25 mg T enanthate for 24 weeks. Total and free T levels
were measured by liquid chromatography-tandem mass spectrometry and equilibrium dialysis,
respectively. Voice handicap was measured by self-report using a validated voice handicap index
questionnaire at baseline and 24 weeks after intervention. Functional voice testing was performed
using the Kay Elemetrics-Computer Speech Lab to determine voice frequency, volume, and
harmonics.
Results: Forty-six women with evaluable voice data at baseline and after intervention were included in the analysis. The five groups were similar at baseline. Mean on-treatment nadir total T
concentrations were 13, 83, 106, 122, and 250 ng/dL in the placebo, 3-, 6.25-, 12.5-, and 25-mg
groups, respectively. Analyses of acoustic voice parameters revealed significant lowering of average pitch in the 12.5- and 25-mg dose groups compared to placebo (P ⬍ .05); these changes in pitch
were significantly related to increases in T concentrations. No significant dose- or concentrationdependent changes in self-reported voice handicap index scores were observed.
Conclusion: Testosterone administration in women with low T levels over 24 weeks was associated
with dose- and concentration-dependent decreases in average pitch in the higher dose groups.
These changes were seen despite the lack of self-reported changes in voice. (J Clin Endocrinol
Metab 100: 2254 –2260, 2015)
T
here has been an increasing interest in the use of T
therapy to improve sexual function, body composition, and bone mass in postmenopausal women. Potential
safety concerns of androgen supplementation include hirsutism, acne, clitoromegaly, and changes in voice. We recently demonstrated that 24 weeks of T administration
over a wide range of doses to women with low T levels who
have undergone a hysterectomy improved several domains of sexual function, body composition, and muscle
performance with few androgenic adverse effects (1). In
particular, none of the participants reported any intervention-related changes in voice. However, there are relatively few quantitative data on the magnitude of functional voice changes as determined by sophisticated
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2015 by the Endocrine Society
Received March 14, 2015. Accepted April 13, 2015.
First Published Online April 15, 2015
Abbreviations: BMI, body mass index; CV, coefficient of variation; VHI, voice handicap
index.
2254
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J Clin Endocrinol Metab, June 2015, 100(6):2254 –2260
doi: 10.1210/jc.2015-1669
doi: 10.1210/jc.2015-1669
acoustic testing in androgen-deficient women exposed to
exogenous T.
The vocal cord is an important target of gonadal hormones and expresses both androgen and estrogen receptors (2). Androgens are known to exert a profound effect
on the development, structure, and function of the human
larynx by causing hypertrophy of thyroarytenoid muscles,
which results in lowering of the voice pitch (3). Increased
levels of androgens during puberty in boys results in an
increased mass and thickening of the vocal folds, which is
responsible for the characteristic lower frequency of the
male voice (4). Indeed, boys who undergo orchiectomy
before achieving puberty do not achieve these changes in
the vocal folds and retain the female voice (5). Women
with congenital adrenal hyperplasia and polycystic ovary
syndrome, both associated with higher serum androgen
levels, have been reported to have lower voice frequency
than healthy controls (6, 7). Preliminary studies in women
treated with androgens have reported voice changes such
as pitch fluctuations and hoarseness (8 –10).
In female-to-male transsexuals, supraphysiological im
T injections result in the desired voice change to an acceptable male voice within 6 months of therapy (11).
These findings are in contrast to those observed among
postmenopausal women treated with a physiological dose
of transdermal T for the same period where no adverse
effects on voice were reported (12). Despite a lack of subjective voice changes reported by participants, it is plausible that subclinical changes in functional voice parameters, which can only be determined by sophisticated
acoustic testing, may occur. Hence, it remains unclear
whether the virilizing effects of T replacement are limited
to pharmacological doses and whether androgen replacement at physiological doses can be safely administered in
postmenopausal women without alterations in voice. To
date, randomized controlled trials evaluating the dosedependent effects of exogenous T on objective and subjective voice parameters in women with low T levels have
not been conducted. Accordingly, we investigated the
dose-response relationships of T administration on both
subjective and objective voice parameters in women with
low serum T concentrations who have undergone a
hysterectomy.
Subjects and Methods
Study design
The Testosterone Dose Response in Surgically Menopausal
Women (TDSM) trial was a two-center, parallel group, placebocontrolled, double-blind randomized trial designed to determine
the dose-response effects of T on a range of androgen-dependent
outcomes. The eligibility criteria and design of the TDSM trial
press.endocrine.org/journal/jcem
2255
have been previously reported (1) and are described here briefly.
The trial consisted of a 12-week run-in period of transdermal
estradiol administration, a 24-week treatment period, and a 16week recovery period. The study was approved by the institutional review boards of Boston University Medical Center and
the Charles Drew University of Medicine and Science (Los Angeles, California). All participants provided written informed
consent.
Participants
The participants were healthy women, 41– 62 years of age,
who had undergone hysterectomy with or without partial or
total oophorectomy. The participants had serum total T concentrations ⬍ 31 ng/dL or free T concentrations ⬍ 3.5 pg/mL
(less than the median for healthy young women) (13). We included women who had hysterectomy alone or partial oophorectomy if their FSH levels were ⱖ 30 U/L or if they were already
receiving estrogen therapy. Inclusion required a documented
normal Papanicolaou test and mammogram within the last 12
months. We excluded women with major psychiatric illness, recent hospitalization, active cancers, poorly controlled diabetes
mellitus (Hemoglobin A1c ⬎ 8.5%), uncontrolled hypertension,
severe obesity (body mass index [BMI] ⬎ 40 kg/m2), illicit drug
use, alcohol dependence, and abnormal liver function. Women
with a history of breast, ovarian, endometrial, or cervical cancer;
hyperandrogenic disorders; cardiac disease; or thromboembolic
disorders; and those taking glucocorticoids, androgens, spironolactone, and GnRH agonists were also excluded.
Randomization and study interventions
All eligible women were administered a regimen of transdermal estradiol patch applied twice a week and designed to achieve
nominal delivery of 50-␮g estradiol daily (Alora; Watson Pharmaceuticals) for a 12-week run-in phase. After the run-in, the
subjects were randomized in a double-blinded fashion to one of
five groups to receive weekly im injections of placebo, 3, 6.25,
12.5, or 25 mg T enanthate (ENDO Pharmaceuticals) for 24
weeks.
Hormone assays
Serum total T levels were measured by liquid chromatography-tandem mass spectrometry with sensitivity of 2 ng/dL, as
described elsewhere (14). The cross-reactivity of dehydroepiandrosterone, dehydroepiandrosterone sulfate, dihydrotestosterone, androstenedione, and estradiol in the T assay was negligible at 10 times the circulating concentrations of these
hormones. The interassay coefficient of variation (CV) was
15.8% at 12.0 ng/dL, 10.6% at 23.5 ng/dL, 7.9% at 48.6 ng/dL,
7.7% at 241 ng/dL, 4.4% at 532 ng/dL, and 3.3% at 1016 ng/dL,
respectively. As part of the Centers for Disease Control’s (CDC)
Testosterone Assay Harmonization Initiative, quality control
samples provided by the CDC were run every 3 months; the bias
in quality control samples in the 3.47-to-34.7 nmol/L (100-to1000 ng/dL) range was ⬍ 6.2%. Free T was measured using
equilibrium dialysis with an interassay CV of 12.3% (13, 15).
SHBG levels were measured using an immunofluorometric assay
with a sensitivity of 0.5 nmol/L (16). The interassay CVs were
8.3, 7.9, and 10.9%, and intra-assay CVs were 7.3, 7.1, and
8.7%, respectively, in the low, medium, and high pools.
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Testosterone and Voice in Women
J Clin Endocrinol Metab, June 2015, 100(6):2254 –2260
Voice analysis
Results
Functional voice assessments
Flow of participants through the study
Of the 850 women who underwent telephone screening, 218 met eligibility criteria, 85 entered the estrogen
run-in period, 71 were randomized, 59 completed the
study, and 46 who had baseline and postintervention voice
outcome data constituted the analytic sample (placebo,
n ⫽ 10; 3 mg, n ⫽ 8; 6.25 mg, n ⫽ 9; 12.5 mg, n ⫽ 11; or
25 mg, n ⫽ 8.
Functional voice analyses were performed by a single clinical
phonetician who was blinded to treatment assignment. Digital
audio recordings of the subjects’ voices were made in a soundproof room with a head-mounted electret microphone placed at
a distance of 15 cm from the mouth. The first test was a sustained
“Ah.” After practicing a couple of times in their regular voice,
subjects were then instructed to sustain an “Ah” for at least 4 – 6
seconds on a single breath. In the second test, subjects were instructed to read aloud the whole sentence of the following passage within an 8-second window (“When the sunlight strikes
raindrops in the air, they act as a prism and form a rainbow”).
The audio recordings were saved as sound files for acoustic analysis. Using the Kay Elemetrics-Computer Speech Lab program,
the voice recordings were analyzed for average fundamental frequency (hertz), mean volume (decibels), mean percentage vocal
jitter and shimmer, and harmonics-to-noise ratio (decibels). Fundamental frequency (or pitch) measures the number of vibrations
produced by the vocal fold per second. Jitter and shimmer measures cycle-to-cycle variability in pitch and amplitude, respectively. Harmonics-to-noise ratio compares the relative amplitude
of harmonics compared to relative amplitude of additional noise
coming from the vocal folds.
Voice handicap index
Self-assessment of voice handicap was measured using a validated voice handicap index (VHI-10) questionnaire before and
after 24 weeks of intervention (17). This questionnaire consists
of 30 items asking individuals to describe their voice and the
effects of their voice on their daily activities. Three subscales
assess the functional, physical, and emotional aspects of voice
impairment. Points from the questions are combined to assign a
total score and combined by subscale.
Statistical analysis
Analyses were performed on all subjects who had data on VHI
scores at baseline and 24 weeks. Outcome questionnaires were
imputed at the level of domains (subscores) such that partially
complete records were retained and used. Analyses were also
performed on a subset of women who underwent objective functional voice testing at baseline and again at either 12 or 24 weeks.
Functional voice analyses included all participants with baseline
and at least one postrandomization measurement of acoustic
data. Tabular and graphical displays were used to compare baseline characteristics of groups. Mean change in outcomes was
compared across treatment doses using analysis of covariance
models for VHI data and linear mixed models for functional
voice data incorporating adjustment for baseline outcome measurements. Linear regression models, adjusted for baseline values, were used to test the association between change in each
voice outcome measure with changes in total and free T levels. All
tests were performed at ␣ ⫽ 0.05 level of significance. No adjustments for multiple comparisons were made because of the
exploratory nature of these analyses. Statistical analyses were
conducted using SAS 9.3 software (SAS Institute, Inc).
Baseline characteristics
Baseline characteristics across the five treatment
groups are displayed in Table 1. Mean age was 53 years,
and average BMI was 29.8 kg/m2. Participants across the
dose groups were similar in terms of age, BMI, smoking
status, T concentrations, baseline voice handicap scores,
and baseline acoustic voice parameters; 74% of the
women had undergone bilateral oophorectomy.
Hormone levels
Baseline mean total and free T concentrations were
16.0 ng/dL and 1.0 pg/mL, respectively, well below the
range for healthy, menstruating women. Serum nadir total
and free T levels, measured during week 24, one week after
the previous injection, increased from baseline in a dosedependent fashion. Mean on-treatment nadir total T concentrations were 13, 83, 106, 122, and 250 ng/dL, and free
T concentrations were 2.4, 14, 15, 22, and 48 pg/mL at the
0, 3-, 6.25-, 12.5-, and 25-mg doses, respectively.
Voice outcomes
Sustained “Ah” test
A significant decrease in average pitch was observed in
the 12.5- and 25-mg dose groups when compared to placebo (⌬-21 and ⌬-40 Hz, respectively; P ⬍ .05). These
changes in pitch were related significantly to increases in
serum free T concentrations (Figure 1A). Changes in the
harmonics-to-noise ratio were not related to changes in T
concentrations. There was a small increase in shimmer in
the 12.5-mg dose group, but overall, the changes in shimmer were not significantly related to T concentrations. No
dose or concentration-dependent changes were seen in average volume or percentage jitter (Supplemental Tables 1
and 3).
Sentence test
There was a significant decrease in average pitch at the
highest dose when compared to placebo (⌬-21 Hz; P ⬍
.05) (Figure 1A). A trend toward reduction in pitch was
observed with increasing T concentrations; however, in
contrast to the sustained “Ah” test, it was not statistically
doi: 10.1210/jc.2015-1669
Table 1.
press.endocrine.org/journal/jcem
2257
Baseline Demographic and Voice Characteristics by Treatment Group of the Analytic Sample (n ⫽ 46)
Dose of Testostrone
Enanthate, mg/wk
(n ⴝ 46)
Demographics
Age, y
BMI, kg/m2
Current smoker, n
Hysterectomy alone, n (%)
Partial oophorectomy, n (%)
Bilateral oophorectomy, n (%)
Baseline hormone levels
Total T, ng/dL
Screening
Post-estrogen run-in
Free T, pg/mL
Screening
Post-estrogen run-in
SHBG, nmol/L
VHI, n ⴝ 41
Functional score
Physical score
Emotional score
Overall VHI score
Acoustic Values, n ⴝ 36
Sustained “Ah” test
Average pitch, Hz
Pitch range, Hz
Average volume, dB
Volume range, dB
Jitter, %
Shimmer, dB
Harmonics/noise
Sentence test
Average pitch, Hz
Pitch range, Hz
Average volume, dB
Volume range, dB
Placebo
(n ⴝ 10)
3
(n ⴝ 8)
6.25
(n ⴝ 9)
12.5
(n ⴝ 11)
25
(n ⴝ 8)
54 (6)
32 (5)
1
3 (30)
1 (10)
6 (60)
53 (6)
32 (7)
1
2 (25)
1 (13)
5 (63)
52 (6)
30 (5)
2
1 (11)
0 (0)
8 (89)
52 (5)
29 (5)
1
1 (9)
0 (0)
10 (91)
54 (4)
26 (6)
1
3 (38)
0 (0)
5 (63)
11 (9)
15 (9)
17 (14)
16 (5)
20 (18)
14 (14)
16 (17)
11 (6)
16 (11)
17 (10)
1 (1)
3 (2)
64 (24)
1 (0)
3 (1)
64 (29)
1 (1)
2 (3)
53 (18)
1 (1)
2 (1)
63 (38)
1 (1)
2 (1)
82 (14)
nⴝ9
nⴝ7
nⴝ8
nⴝ9
nⴝ8
4 (3)
9 (8)
7 (7)
21 (14)
5 (6)
4 (6)
4 (7)
13 (17)
11 (15)
10 (14)
10 (16)
30 (44)
7 (5)
9 (7)
4 (5)
21 (14)
5 (5)
4 (4)
2 (4)
11 (10)
nⴝ9
nⴝ6
nⴝ6
nⴝ9
nⴝ6
182 (28)
47 (36)
71 (6)
11 (7)
0.5 (0.2)
0.3 (0.2)
19 (2)
187 (26)
50 (42)
73 (7)
12 (5)
0.5 (0.3)
0.4 (0.1)
19 (2)
189 (49)
43 (27)
74 (7)
9 (2)
0.4 (0.2)
0.4 (0.3)
22 (4)
173 (63)
45 (22)
69 (4)
19 (11)
0.8 (0.9)
0.5 (0.2)
17 (7)
184 (38)
38 (33)
72 (4)
8 (2)
0.4 (0.1)
0.4 (0.2)
17 (8)
164 (34)
147 (61)
66 (6)
35 (7)
174 (15)
137 (33)
70 (6)
31 (4)
160 (30)
129 (47)
68 (4)
28 (4)
166 (23)
145 (38)
67 (5)
31 (7)
163 (32)
149 (52)
68 (6)
31 (5)
Data represent mean (SD) or n (%). Overall VHI and domain baseline scores are out of a maximum possible score of 120 and 40, respectively. Jitter
is cycle-cycle variability in pitch; normal range for jitter is 0.2–1.0%. Shimmer is cycle-cycle variability in amplitude; normal values are ⬍ 0.5 dB.
Harmonics-to-noise ratio measures relative amplitude of harmonics compared to relative amplitude of noise. Higher values indicate that harmonics
is louder than noise. Lower values indicate that noise is louder relative to the harmonics.
significant (P ⫽ .069) (Supplemental Tables 1 and 3). Average volume increased by 3.58 dB at the highest dose group
relative to placebo, but the changes were not statistically significant or related to T concentrations (P ⬎ .05).
Voice handicap index
Overall, VHI scores did not change significantly at any
dose group compared to placebo and were not related to
increases in T concentrations (Figure 1B). Similarly, there
were no significant dose- or concentration-dependent
changes in functional, physical, or emotional subscores of
the VHI (Supplemental Tables 2 and 3).
Discussion
Exogenous T administration for 6 months in women who
have undergone hysterectomy was associated with dose-
and concentration-dependent changes in average pitch.
These findings were further corroborated by the significant relation between the changes in pitch and the increases in serum free T concentrations. The changes in
pitch were noted during acoustic voice analysis despite the
lack of significant self-reported changes in voice. Moreover, the changes in pitch were observed more consistently
in the sustained vowel phonation (“Ah” test) than during
the sentence test, consistent with the observations that
changes in voice quality are more accurately measured in
the sustained vowel phonation than during articulation of
running speech (18). We conclude that supraphysiological
doses of T in hysterectomized women may induce changes
in voice frequency that are detectable during acoustic
voice analysis even before the participants are able to perceive changes in their voice quality.
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J Clin Endocrinol Metab, June 2015, 100(6):2254 –2260
Average Frequency (Hz)
Δ Sustained Vow el Test
A
Testosterone and Voice in Women
30
P=0.005
200
10
100
-10
0
-30
*
-50
-100
*
-70
0
3
6.25
12.5
25
-200
-2
0
Δ
TE, mg/wk
2
4
6
8
Free Testosterone, ng/dL
P=0.069
Δ Sentence Test
20
20
10
10
0
0
-10
-10
-20
-20
-30
*
-40
0
3
6.25
12.5
25
-30
-40
-2
TE, mg/wk
B
0
Δ
2
4
6
P=0.167
Voice Handicap Index
Δ Voice Handicap Index
8
Free Testosterone, ng/dL
25
20
15
10
5
0
-5
-10
-15
-25
0
3
6.25
12.5
25
TE, mg/wk
-20
-2
0
Δ
2
4
6
8
Free Testosterone, ng/dL
Figure 1. A, Average frequency (hertz). B, VHI. A and B, In the bar graphs on the left, data represent absolute mean changes ⫾ SE from baseline
to end of the study for each treatment group. *, A significant difference between mean on-treatment change in dose group vs placebo at the
0.05 ␣ levels. Scatterplots on the right show linear regression line with 95% confidence intervals as a function of change in free T levels adjusted
to baseline value of outcome. The P values displayed are from significance test of no association. Hz, Hertz; TE, T enanthate.
Previous studies have shown that the human larynx is
a highly sensitive target of androgen action (2). The sex
differences in voice quality have been well recognized, although there are cultural and ethnic variations in these sex
differences. However, across various cultural and ethnic
groups that have been studied, the most consistent difference between men and women is the higher pitch in
women than in men. Historically, the deliberate induction
of male hypogonadism by prepubertal castration in choir
boys was widely practiced to preserve the high-pitched
feminine voice of the castrati that dominated opera in
western Europe in the 18th century (5). Increased levels of
androgens are known to increase mass of the laryngeal
tissues, resulting in lowering of the pitch of the voice in
both sexes (3). Women with congenital adrenal hyperplasia have significantly lower fundamental frequency of the
voice compared to healthy controls (6). Similarly, women
with polycystic ovary syndrome report more vocal complaints (deepening of voice) compared to healthy controls
(19); however, elevated serum androgen levels in women
with polycystic ovary syndrome have not been consistently correlated with subjective and objective voice pa-
rameters (7). Similarly, in female-to-male transsexuals,
long-term administration of supraphysiological doses of T
results in a significant lowering of pitch into the male range
(11). Thus, it is possible that a certain threshold of T dose
and concentration and duration of exposure has to be
achieved before virilizing voice changes are detectable.
Furthermore, subclinical changes in functional voice parameters may precede clinical complaints.
Women treated with supraphysiological doses of androgenic drugs have reported dysfunction in their speaking and singing after starting treatment, with some subjects suffering permanent vocal dysfunction (8, 9). In our
trial, a standardized self-assessment questionnaire with
the widely used VHI showed no significant dose- or concentration-dependent changes in total score or in subscores for emotional, functional, and psychological aspects of voice impairment, even at doses that achieved
supraphysiological T concentrations. Based on our findings, it appears that T doses given over a wide range for 24
weeks had no significant effect on their voice-related quality of life. However, none of our study participants were
professional speakers or singers; it is conceivable that
doi: 10.1210/jc.2015-1669
voice professionals would differ in their self-perceived
voice quality. Although there were no adverse changes in
subjective vocal parameters, this 24-week dose-response
interventional trial showed a significant lowering of vocal
pitch at the two highest T-dose groups (12.5 and 25 mg)
when compared to placebo, and these changes were significantly associated with increases in T concentrations.
The early changes in acoustic parameters before clinical
manifestation have also been reported in patients with
Parkinson’s disease, in whom changes in vocal frequency
can be detected a decade before clinical diagnosis (20),
supporting the notion that early changes detected during
functional acoustic testing can be a useful marker for subsequent clinical voice changes from T administration.
Our study has notable strengths and some limitations.
The trial had many features of a good trial design: concealed randomization, placebo control, blinding and oversight by an independent Data Safety Monitoring Board.
Total and free T levels were measured using liquid chromatography-tandem mass spectrometry and equilibrium
dialysis, respectively, both of which are widely considered
the reference methods with the highest sensitivity and
specificity. Testosterone injections were effective in raising T concentrations in a dose-dependent fashion over a
wide range. The dose-response effects of T administration
on acoustic parameters in postmenopausal women have
not been previously studied in the setting of clinical trials.
However, measurement of voice outcomes was not the
primary outcome of the trial, and the trial was not designed to detect changes in these voice parameters. Our
analysis was therefore limited by small sample size, which
may have reduced our power to detect small effects. Furthermore, because some small studies have reported better
subjective voice quality in postmenopausal women on estrogen replacement (21), it is possible that virilizing effects
of T on some voice parameters may have been attenuated
because of concurrent estrogen therapy.
In conclusion, short-term T administration over a wide
range of doses for 24 weeks in hysterectomized women
was associated with dose- and concentration-dependent
changes in lowering of vocal pitch, even in the absence of
subjective voice changes. Based on the findings of this trial,
referral for functional voice assessment may be useful for
early detection of any potential changes in voice characteristics in women receiving similar doses of T.
Acknowledgments
We thank the staff of the General Clinical Research Unit of Boston University’s Clinical and Translational Science Institute and
the Clinical Research Center of Charles Drew University of Med-
press.endocrine.org/journal/jcem
2259
icine and Science for their help with these studies and the study
participants for their commitment and generosity.
Address all correspondence and requests for reprints to:
Grace Huang, MD, Brigham and Women’s Hospital, Section of
Men’s Health: Aging and Metabolism, BLI-5, 221 Longwood
Avenue, Brookline, MA 02115. E-mail: [email protected].
Data Safety Monitoring Board: Dr Jan Shifren, Massachusetts General Hospital, Boston, Massachusetts (Chair); Dr Raja
Sayegh, Boston Medical Center; and Dr Anita Nelson, HarborUCLA Medical Center.
This study was supported by Grants 5U54HD041748 – 04 (to
Charles Drew University of Medicine and Science) and 2008 TF
D2274G (sub award to Boston University) from the National
Institute of Child Health and Human Development and the Boston Claude D. Pepper Older Americans Independence Center
Grant 5P30AG031679 from the National Institute of Aging.
Watson Pharmaceuticals provided the transdermal estradiol
patch for this trial.
Clinical Trials Registration No. NCT00494208.
Disclosure Summary: S.B. has received grant support from
Abbott Pharmaceuticals for investigator-initiated studies. S.B.
has previously consulted for Eli Lilly, Inc. S.B. has received research grant support from Abbvie Pharmaceuticals and Eli Lilly
and Co. for investigator-initiated research; these research grants
are managed by the Brigham and Women’s Hospital and are
unrelated to this study. No other potential conflict of interest
relevant to this article was reported.
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