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Laryngeal Manifestations of Endocrine Disorders

Abdul-Latif Hamdan, Robert Thayer Sataloff, and Mary J. Hawkshaw

Sex Hormones

The larynx is a hormonal target. It is markedly influenced by the hormonal profile that shapes our vocal identity. Sex hormones in particular play a major role in the development of the vocal characteristics that identify a speaker as a man or woman. The effect is thought to be mediated via hormonal receptors in the various laryngeal structures. Estrogen, progesterone, as well as androgenic receptors in the vocal folds have been described by some authors and refuted by others.^1–5 In 1987 Veĕerina-Volić et al demonstrated the presence of androgen cytoplasmic and nuclear receptors in normal and cancerous tissues of the larynx in 16 subjects. The authors highlighted the etiologic role of androgen and the possible benefits of hormonal therapy.⁴ In 2000, Newman et al reported the presence of hormonal receptors in both cytoplasm and nuclei within the vocal folds of 42 subjects.¹ The study was performed using immune-histochemical staining on fresh cadavers. The authors demonstrated an association between gender and androgen receptor staining in glandular cytoplasm. These results were later corroborated by Voelter et al in their study using monoclonal antibodies on 104 patients with different laryngeal pathologies. Their results confirmed the presence of sex hormones receptors in the vocal folds with predominance of androgen receptors followed by estrogen receptors. Their investigation did not demonstrate any evidence of progesterone receptors.² A report by Schneider et al in 2007 failed to show evidence of estrogen alpha, progesterone, and androgen receptors in the muscles, glands, lamina propria, and mucosa of the vocal folds in 15 autopsied patients. Their findings contradicted those of previous reports that found the presence of sex hormone expression in the larynx.⁵ Nacci et al corroborated the report of Schneider and suggested the possible role of growth factors in the development of laryngeal tissues.⁶

Despite these contradictory reports, the phonatory conversion that occurs in parallel with the change in the hormonal climate at puberty is irrefutable. The sex hormones induce growth and differentiation of the laryngeal structures in both genders.^7,8 In females, estrogen and progesterone induce feminization of the voice, whereas in males androgen induces vocal masculinization. As a result of this hormonal influence, the vocal pitch drops by one-third-octave in females and by one octave in males. The “breaking” of voice is generally thought to be caused by the increase in muscle mass that negatively correlates with vocal pitch. As the vocal folds develop more bulk, their rate of vibration becomes slower resulting in a decrease in the fundamental frequency. During puberty, the development and prominence of the thyroid cartilage with widening of the cricothyroid membrane occurs also. This results in the descent of the larynx which is more pronounced in males compared to females. This accentuated drop of the laryngeal structures results in further lengthening of the vocal tract with subsequent decrease in all formants.

The following sections on the female voice and male voice illustrate the vital role of sex hormones in voice maturation, during and after puberty. For the female voice, we discuss voice and menstruation, the premenstrual vocal syndrome, and the postmenopausal vocal syndrome. This will be followed by a section on hormonal therapy and role of adipose tissue, pregnancy and voice, oral contraceptives, and a section on androgen excess and voice. Last there is a section on the male voice.

I. The Menstrual Cycle and Voice

The prevalence of phonatory symptoms in relation to the menstrual cycle has been established. The fluctuation of various sex hormones, mainly estrogen and progesterone, leads to a constellation of systemic changes that can affect the voice either directly or indirectly. The discussion below is focused on the premenstrual syndrome and postmenopausal vocal syndrome. Additional literature review on the impact of sex hormones fluctuation during the menstrual cycle is covered in the section on oral contraceptives and voice.

Pre-Menstrual Vocal Syndrome

It is well established that through the activity of the follicular stimulating hormone and the luteinizing hormone controlled by the hypothalamo-hypophysical axis, the menstrual cycle is regulated. During the follicular phase, estrogen induces endometrial mucosal thickening of the endometrial mucosa and progesterone results in thickening of the endocervical mucus.⁹ Androgen on the other hand causes thickening of the cervical mucosa with reduction in its malleability. With this hormonal climate and cyclic changes in estrogen, progesterone, and androgen, an entity called “premenstrual syndrome” was described in 1953 by Dalton and Green in reference to a constellation of symptoms that recur cyclically in parallel with these hormonal fluctuations.¹⁰ The symptoms include depression, decreased concentration, bloating, nausea, water retention, palpitations, and other systemic manifestations. To confirm the diagnosis of “premenstrual syndrome,” these symptoms must be more problematic or pronounced in the “paramenstrum” period and must resolve between the end of menstrual period and ovulation.^11–16 It is important to note that although this syndrome is based on patient’s complaints primarily, there is some scientific evidence that supports the symptoms reported. The symptoms of the “premenstrual syndrome” can be induced by the administration of ovarian hormones and suppressed following the cessation of ovulation and menstruation.¹⁷ Several theories have been suggested in attempt to explain this syndrome of unknown etiology. These include the increase and decrease in estrogen and progesterone levels, deficiencies in vitamin B6, disturbances in glucose metabolism, and other biomechanical abnormalities.^18,19

The premenstrual syndrome has several components to it that include psychological, auditory, metabolic, neurologic, respiratory, as well as phonatory symptoms. The phonatory symptoms associated with premenstruation have been investigated by several authors. In 1978 Silverman and Zimmer evaluated the degree of premenstrual hoarseness in a group of 20 women with no vocal training. The vocal samples recorded at ovulation and few days before menses consisted of sustained vowels /a/, /i/, and /u/ for three seconds. The results suggested rare prevalence of hoarseness at premenstruation in vocally non-trained subjects.²⁰ On the other hand, 15 years later a survey conducted by Clarissa Behr Davis and Michael Lee Davis evaluating vocal changes associated with premenstrual syndrome revealed that singers on average had three vocal symptoms. The study was conducted on 104 female singers and included 67 general symptoms among which 20 were related to voice. Difficulties in singing the high notes was the most frequent symptom reported by the singers.²¹ The aforementioned two studies confirm the differential effect of the menstrual cycle on subjects who are vocally trained versus those who are not.

These reports substantiate the well-known relationship between voice and the reproductive system that was initially described in the 4th century bc and further reported by many authors.^{8, 22–26} It has often been referred to as laryngopathia premenstrualis, in reference to the phonatory symptoms experienced mostly by singers, and which often entailed a grace period that exempted these singers from performing.^27,28 It has been established that the effects of sex hormones are not limited to the genitourinary tract alone, but involve the vocal apparatus as well. The vocal symptoms that were once attributed to psychological factors are now explained on the basis of factual changes in the vocal folds, namely, rheological, vascular, and secretory.²⁵ Estrogen has been shown to have a proliferative and hypertrophic effect on vocal fold mucosa with a marked increase in glandular secretions above and below the true vocal folds. In addition it reduces the extent of desquamation and increases capillary permeability. At its peak on the 21st day of the menstrual cycle, estrogen enhances polymerization of mucopolysaccharides within the vocal fold. Following that peak, there is a decrease in the concentration of these polymers that further break down into smaller molecules. This change in the submucosal ground substance of the vocal folds, together with the increase in tissue permeability of the small vessels, increases the bulk of the vocal folds resulting in deepening of the voice.^{8, 26} On the other hand progesterone has an antiproliferative effect and enhances desquamation with reduction in the amount of secretions. As a result there is dryness of the vocal folds with increased viscosity and acidity of the secretions. Progesterone also induces congestion by reducing capillary permeability with subsequent entrapment of extracellular fluids. Similarly androgens cause dehydration with a decrease in glandular secretions. These findings have been supported by the report of Jean Abitbol et al on the cytological similarities between vocal folds smears and smears taken from the cervix.⁸

As a result of these changes in the vocal fold mucosa prior to menstruation, namely, edema, dilated microvarices, and thickened secretions, patients experience a compilation of vocal symptoms today referred to as premenstrual vocal syndrome. These include vocal fatigue, loss of power, and decrease in vocal range more so for the high notes. These symptoms may also occur during ovulation and may more present in professional voice user as previously reported by the survey of Davis and Davis.²¹ A study by Abitbol conducted on 97 professional voice users suffering from premenstrual vocal symptoms revealed mucosal, vascular, as well as muscular inflammatory signs in the majority of the participants. Vascular signs such as dilatation of microvarices, edema, and/or submucosal hematoma were present in 71 patients. Muscular changes such as hypotonicity and diminished power of contraction were observed in 59 patients.⁷ It is important to note that the phonatory symptoms experienced by women in their premenstrual period may also be accentuated by the presence of laryngopharyngeal reflux, gastric dismotility, and abdominal bloating experienced by these patients.

Postmenopausal Vocal Syndrome

At menopause, following the decreased resistance of the remaining oocytes to the follicular stimulating hormone and luteinizing hormone, and subsequent to the cessation of ovulation, there is depletion of the major source of estrogen and progesterone. The drop in estrogen and progesterone levels at menopause results in a plethora of symptoms related to many systems in the body including the phonatory system. The prevalence of vocal symptoms has been reported as high as 77% depending on the methodology and outcome measures used. Symptoms reported most commonly were dryness of the oropharyngeal mucosa, frequent throat clearing, vocal fatigue, and decrease in vocal pitch. These symptoms are often coupled with acoustic changes, including a decrease in the fundamental frequency, loss of high frequencies, and an increase in the perturbation parameters.⁷

The vocal complaints and acoustic changes experienced by menopausal women are based on the known effect of sex hormones on the vocal folds. With the decrease in estrogen and progesterone at menopause, there is evidence of atrophic changes, both at the mucosal and muscular levels. There is evidence of “sub atrophic mucosa with basophils and reduction in glandular cells in the mucosa of the ventricular band” on vocal fold cytology as reported by Jean Abitbol et al.⁷ Similar findings were reported by Caruso et al in their cytology study of 36 menopausal women. There was evidence of atrophy-dystrophy in vocal fold smears similar to what was observed in vaginal smears.²⁹ As a result of the reduction of glandular cells in in the subglottic and supraglottic mucosa, and the decrease in glandular activity, the concentration of laryngeal mucus increases. This is coupled with mucosal edema secondary to the decrease in the permeability of blood vessels.³⁰ In his study of 100 menopausal women, Abitbol et al reported that 17% had the clinical presentation of postmenopausal vocal syndrome, namely, a decrease in vocal intensity and range, vocal fatigue, and loss of timber described as “flat and colorless.” These symptoms were coupled with endoscopic findings of muscular atrophy, mucosal atrophy, and thinning of the vocal folds.⁷ Similarly, in a survey used by Schneider et al, 49 menopausal women out of 107 reported vocal changes that were associated with subjective discomfort in 70% of the cases. In view of this high prevalence of vocal complaints the authors suggested “—additional systematic registration of voice impairment in future menopause rating scales.”³⁰ Boulet and Oddnes also reported that more than half of all women in their fifth decade experience vocal changes related to menopause. The most common problem in female singers was attaining the high register. The authors alluded to the vulnerability of the female voice around the time of menopause.³¹ Raj et al in their acoustic analysis of 20 menopausal women reported a lower fundamental frequency, a decrease in vocal intensity, and an increase in the perturbation parameters compared to 35 women in their reproductive years. These acoustic changes were attributed theoretically to the variations in vocal fold thickness secondary to the drop in of estrogen and increase in testosterone.³² On the other hand, Laureano et al failed to show any statistically significant difference in jitter and shimmer between menopausal women, those during menarche, and those on hormonal replacement therapy (HRT). Their study evaluated 15 women with regular menstrual cycles, 15 menopausal not on HRT, and 15 menopausal on HRT. The acoustic analysis was performed while subjects were asked to sustain the vowel /i/.³³ The controversies in the aforementioned reports can be attributed to two main factors as reported by Friedman: One is the aging effect. The age difference between menopause and menarche is an imperative confounding factor to consider in the analysis of results. The aging process results in an accumulation of phonotrauma that may skew the true effect of hormonal changes. The second important factor is the limitation in the outcome measures used. Laryngeal videostroboscopy has its limitations in detecting very subtle changes in the lamina propria and acoustic analysis has little value in severely dysphonic subjects.³⁴

II. Hormonal Therapy and Role of Adipose Tissue

The benefits of hormonal replacement therapy in menopausal women has been reported extensively. The intake of estrogen/progesterone has proven to reverse the phonatory changes described by menopausal women. Most of the investigations involved professional voice users, with strong emphasis on the role of estrogen therapy in mitigating the acoustic changes, namely, the drop in fundamental frequency and elevated perturbation parameters. The studies of D’haeseleer et al clearly indicate that menopausal women on hormonal therapy have higher fundamental frequency and habitual pitch compared to those not on therapy, namely, 187.7 Hz versus 178.9 Hz, respectively. These findings were further corroborated by the same authors in another cross-sectional study looking at the effect of menopause on voice and nasal resonance.^35,36 Another investigation of 53 menopausal women, of whom 19 were on hormonal therapy and 34 not on therapy, revealed that those on hormonal therapy had significantly higher habitual pitch compared to those not on hormonal therapy (p-value 0.022). This acoustic finding did not change when body mass index (BMI) was taken into consideration. On the other hand, it is important to note that the study failed to show any significant difference in the prevalence of phonatory symptoms among the two groups.³⁷

Along those lines it is empirical to highlight the important role of adipose tissue as a source of estrogen that is shadowed in the premenopause period because of the cyclic high peaks of estrogen during menstruation. The report by Abitbol J et al “Sex Hormones and the Female Voice” classified women into two types, the “Modigliani type” with little fat and “Rubenesque” with more fat and rounded figure.⁷ Given that the ovaries remain a source of androgens, androstenedione, and testosterone after menopause, the biosynthesis of estrones from androgens derivatives in lipocytes thru cytochrome P450 becomes a crucial substitute for the loss of estrogen and progesterone. To that end, the Rubenesque type of women encumbered with the large adipose tissue reserve, tend to mitigate the loss of estrogen.

Few studies have demonstrated the positive correlation between Body Mass Index and the speaking fundamental frequency in menopausal women.^35,36,38 In the study by D’Haeseller et al, on 26 women, menopausal women with high Body Mass Index tended to have higher fundamental frequency than those with low Body Mass Index.³⁵ This association was not present in those on hormonal therapy or those with low body mass index. In a recent report, Hamdan et al compared the prevalence of phonatory symptoms in 34 menopausal and 35 premenopausal women taking into consideration the impact of Body Mass Index as a confounding variable. Outcome measures included phonatory and laryngopharyngeal symptoms in addition to acoustic analysis and Voice Handicap Index-10. The results indicated no statistically significant difference in any of the phonatory symptoms or acoustic parameters between high Body Mass Index in menopausal women and in premenopausal women. The results substantiated the important role of adipose tissue and the conventional vocal symptoms attributed to menopause.³⁹

III. Pregnancy and Voice

The dramatic increase in hormonal levels in women during pregnancy imposes major physiologic adaptations. Many systems are affected among which is the phonatory apparatus. Changes in posture, level of hydration, as well as impaired breathing secondary to reduced lung capacity, all impact voice and result in phonatory changes that are often experienced by professional voice users. In a study by Cassiraga et al on 44 third-trimester women, the authors reported a higher prevalence of breathiness and shortness of breath in pregnant women compared to controls.⁴⁰ They reported an increase in the intensity of speech and a decrease in the maximum phonation time. The decrease in the maximum phonation time was based on the reported overall changes in the respiratory system during pregnancy. There are alterations in pulmonary function, namely, a decrease in the “functional residual capacity, expiratory reserve volume, residual volume, and total lung volume.”⁴¹ In another study conducted on 25 pregnant women, the authors reported an increase in the maximum phonation time right after delivery. There was also an increase in the fundamental frequency and a decrease in the voice turbulence index.⁴² The increase in the fundamental frequency was attributed to the drastic decrease in the body water content that follows delivery. It is important to note that toward the end of pregnancy the increase in water content is estimated to be 6.5 to 8.5 L.⁴³

The surge in sex hormones with its potential effect on voice is also observed in patients undergoing in vitro fertilization (IVF). The severity and frequency of vocal symptoms during three visits along the course of in vitro fertilization were investigated in a group of 31 women. The most common symptom reported throughout the visits was throat clearing. Other symptoms such as vocal fatigue and globus sensation occurred in 9.68% of the women. There was no significant change in either the severity or the frequency of these phonatory symptoms between the visits, probably due to the short time window in between and to the wide intersubject variation in the level of estradiol during induction. Noteworthy was that the severity and frequency of throat clearing correlated with the level of estradiol levels in this study population.⁴⁴ These symptoms were attributed to the proliferative lubrication effect of the high estradiol level in the second and third visit (424,16 pg/mL and 1433.48 pg/mL, respectively). Two years later, a prospective study looking at acoustic measures in relation to estradiol level in a group of 10 women undergoing IVF was reported. The results indicated a decrease in F0 and F0 range with the increase in the estradiol level. This was expected given the associated edematous changes observed and with the documented increase in estrogen level. With edema of the vocal folds there is an increase in mass and subsequently a drop in the mean fundamental frequency.⁴⁵

IV. Oral Contraceptives

The impact of sex hormones on the voice is well known. The interaction is thought to be complex and involves direct effects on laryngeal structures through hormonal receptors.¹ During the menstrual cycle, the interplay between sex hormones and voice becomes more accentuated. The fluctuation in estrogen and progesterone levels carries a significant physiologic effect on the vocal folds similar to that seen on the cervix.⁷ During the first phase of the menstrual cycle, estrogen level surges gradually inducing a hypertrophic effect on the vocal folds with an increase in the amount of mucus secretion. After its peak at day 14, it starts declining until day 21 when it peaks again before declining further toward the end of the cycle. The level of progesterone on the other hand starts rising after ovulation and reaches its peak on day 21 causing a decrease in glandular cell secretions, and an increase in mucous viscosity and acidity, with subsequent dehydration of the vocal folds.^46,47 Oral contraceptive pills (OCP) abort the aforementioned fluctuation in sex hormones that occurs during the menstrual cycle. The steady intake of progesterone and estrogen suppresses the luteinizing hormone secretion and follicular stimulating hormone during the luteal and follicular phases. The effect is thought to be compounded resulting in inhibition of ovulation.^48,49

Despite the well-known interplay between sex hormones and phonation, the impact of OCP on voice is still not very clear. Following the introduction of the first generation of OCP that contained nortestosterone derivative, androgenic side effects in particular voice virilization, became an issue of major concern particularly in professional voice users.⁴⁸ Ismail in 1966 reported 87 cases of vocal virilization that were attributed to hypertrophy of the vocal folds’ muscles.⁵⁰ This adverse effect was further substantiated by other investigations reported in 1969. Significant acoustic changes, namely, lowering of the fundamental frequency and increased vocal intensity, have been reported following the usage of oral contraceptives that contained a mixture of chlormadinone acetate and mestranol.^51,52 These reports have led to the development of pills with lesser amount of hormones. The second generation of pills introduced in the 1970s, made of a combination of progesterone derivative (levonorgestrel) and an estrogen derivative (ethinylestradiol), became very popular in view of is scarce side effects. The third generation made of “progestins, gestodene and desogestrel”⁵³ and the fourth generation containing Drospirenone as its progestine component, were also launched in the 1980s but were not as widely used as the second generation.⁵³

Today these modern generations of OCP have led to 30% of women using OCP in their reproductive years.⁵⁴ Despite this high figure, there is still no clear consensus on the impact of OCP on voice.

Where Does the Literature Stand on Usage of Oral Contraceptives Today?

With the increased importance of voice as a means of communication and the rising usage of OCP, a better understanding of the effect of these pills on voice has become paramount. To that end, numerous investigations on vocal changes associated with OCP usage have emerged. Most of these investigations are based on auditory perceptual evaluation, subjective ratings, laryngeal videostroboscopic examination, as well as objective measures such as acoustic, electrolaryngographic, and aerodynamic analysis. Below is a brief review of the literature on the impact of OCP on voice, stratified according to different outcome measures.

Perceptual, Acoustic and Phono-articulatory Changes

In 1995, Wendler et al et reported a thorough perceptual and acoustic analysis of sustained vowels /a/, /e/, /i/, and /u/, while comparing two types of OCPs, one containing “2 mg cyproterone acetate and 0.035 mg ethinylestradiol “(Diane-35) and another containing “0.15 mg levonorgestrel and 0.03 mg ethinylestradiol “(Microgynon).⁵⁵ The study was conducted on 91 patients throughout a one-year period during which patients had stroboscopic examination in addition to subjective assessment and phoniatric investigation. Subjective information included complaints such as vocal fatigue and throat symptoms, whereas perceptual assessment comprised vocal characteristics such as onset of voice, mean speaking frequency, as well as the overall sound quality. The mean speaking fundamental frequency, voice range profile, and dynamic range were also measured. The results of this study indicated the lack of any vocal/throat symptoms, or audio-acoustic changes as side effects to the usage of OCP. These findings were commensurate with normal laryngeal stroboscopic examination. More so, there were no significant differences in any of the measured parameters between the two preparations used. The authors concluded that OCPs used in this investigation were rather safe compared to the first generation introduced in the 1960s.⁵⁵ This conclusion was corroborated by other investigators who furthermore alluded to the beneficial effect of these medications. In a study in 2002 by Amir et al, the authors reported a favorable effect of OCP on voice in terms of stability. The analysis of two sustained vowels /i/ and /a/ recorded during six intervals of the menstrual cycle in 10 patients (five on OCP and five not on OCP) revealed lower perturbation parameters for intensity and frequency in subjects on pills versus those not on pills (five on pills and five not on pills). The authors attributed vocal stabilization to the reduced fluctuation in the hormonal profile naturally witnessed during a menstrual cycle.⁵⁶ More so, there was no significant difference in the fundamental frequency between the two groups unlike the results of previous studies on the first generation of OCP. However, there were changes in F0 toward the middle of the menstrual cycle in the pill group that were not present in the group not on pills, and to which the authors had no clear explanation. It is worth noting that the recordings were made over the course of 40 days and all 10 participants were non-professional voice users with no formal singing training. In conclusion the authors advocated the safety and beneficial effect of the new generation of OCP. Similarly in 2003, the same authors evaluated the effect of low dose monophasic OCP on voice in six women compared to six controls. All participants were non-professional voice users and the recordings were made during six intervals of one to two menstrual cycles. The same findings were reported, namely, lower values for variations in frequency and amplitude in subjects on pills versus those not on pills (0.86% vs 1.27% for jitter and 0.24 db vs 0.37 db for shimmer). The authors alluded to the stabilizing effect of the monophasic low dose OCP on these acoustic parameters,⁵⁷ although the study was limited because of the small number of subjects.

In 2004, Amir and Kishon-Rabin expanded their acoustic analysis to include additional perturbation parameters such as “relative average perturbation, pitch period perturbation quotient and amplitude average perturbation quotient.”⁵⁸ The authors reported lower values for all acoustic variables except F0 in a group of seven women using low-dose monophasic OCP in comparison to controls. The recordings and analysis were conducted on sustained vowels /a/ and /i/ over the course of 36 to 45 days.⁵⁸ These results were in alignment with the results of previous reports substantiating the favorable effect of OCP on voice. Based on the study by Higgins and Saxman, the fluctuation in sex hormones around the time of ovulation may result in an increase in cycle-to-cycle variations in pitch and intensity. This increase is secondary to alterations in the speed of neural transmission and or to changes in the laryngeal mechanoreceptor sensitivity.⁵⁹ With the intake of OCP this hormonal fluctuation is obviously attenuated with subsequent reduction in the aforementioned perturbation parameters. During the same year, Gorham-Rowan corroborated the aforementioned stabilizing effect of OCP on voice by reporting “—greater stability during phonation” in subjects on OCP. The authors have investigated 28 women, 18 on OCP and 10 not on any OCP. The acoustic recordings were made prior to menses and included two phonatory tasks, a sustained vowel /a/ and reading of the “Rainbow Passage.” There was a significant effect of OCP on shimmer and amplitude perturbation quotient APQ, with higher values being reported in the non OCP group. These findings were again attributed to the steadiness of the hormonal profile induced by the intake of oral contraceptives. On the other hand, the authors disagreed with Amir et al with respect to the effect of OCP on the fundamental frequency. During sustained vowel analysis, the group on OCP had higher fundamental frequency values F0 compared to the non OCP group (230.51 Hz vs 205.11 Hz). Similarly, during connected speech the speaking fundamental frequency in the OCP was also higher (213.62 Hz vs 199.14 Hz). The difference in the results between the two studies could be attributed to the difference in time of voice recording, which were primarily done prior to menses in the study by Gorham-Rowan. However, it is worth noting that there was no significant difference in the standard deviation of the speaking fundamental frequency between those on pills and those not on pills, which probably means that the stabilizing effect of OCP is more pronounced or effective in sustained vowel production rather than in connected speech.⁶⁰

In 2005, Amir et al compared the effect of different formulations of OCP on voice in 29 women. These were divided into 3 groups, Drospirenones, Desogestrol, and Gestodone. An acoustic evaluation performed twice during the cycle revealed similar results between the three groups except for slight difference between the Drospirenone group and the remaining two groups.⁶¹ One year later they increased the sample size to 30 women using different OCP with different progestin levels in comparison to 10 who were not on pills. The results revealed no significant difference in all acoustic measures between the two groups. More so, a meta-analysis combining the previous studies showed lower perturbation parameters in subjects on OCP compared to controls.⁶² In that same year, Van Lierde et al investigated vocal changes in 24 women using monophasic pills. Assessment of two vocal recordings were made using various subjective and objective measures, one a few days before or after ovulation (day 10–17) and one during the first three days of menses. The results indicated no significant differences between the two assessments in terms of voice quality, dysphonia severity index, maximum phonation time, voice range, and acoustic parameters. To that end the authors concurred the stabilizing effect of OCP on sex hormones during the menstrual cycle. Nevertheless, it is worth noting the limitations of this study, namely, the lack of vocal samplings during the luteal phase and the lack of a control group.⁶³

La et al in 2007 conducted the first randomized placebo controlled trial investigating variations in pitch and amplitude in a group of nine classical singers (one mezzo-soprano and 7 sopranos) taking a combined monophasic OCP (containing drospirenone) and a matched placebo over the course of three menstrual cycles. Using electrolaryngography, the authors analyzed period-to-period variations in frequency peaks (CFx) and period-to-period variations in amplitude peaks (CAx), as quantitative measures of variations in pitch and amplitude. The results indicated less irregularities in these measures when OCP were used. The period-to period amplitude peaks was higher in the menstrual and follicular phases while using placebo.⁶⁴ During the luteal phase, there were no differences in pitch and amplitude variations between women on OCP and placebo, which means that the variations seen in the follicular and menstrual phases are not necessarily secondary to hormonal fluctuations as suggested by Amir et al. Two years later, a similar study by the same authors was conducted on 20 professional voice users, 10 using OCP and 10 controls. Unlike the previous investigation, not all participants were classical singers and other professional voice users such as teachers were included. More so, both reading and singing samples were recorded for analysis (“Rainbow Passage” and “Yesterday” sung by the Beatles). In contrary to the previous investigation, the results of this study showed no effect of OCP on the two aforementioned electrographic parameters, namely, CFx and CAx.⁶⁵ The authors attributed this controversy to the study design, short duration of OCP intake and to the less demanding singing task of the song chosen in comparison to the German Classical song. In 2012, La et al reported different findings in a study investigating vibrato rate and pitch control in nine singers. Using audio-electrolaryngograph recordings during all phases of the menstrual cycle, the authors reported significant differences for pitch control at F5.⁶⁶ The results of this investigation highlight the importance of the phonatory task used in recording and analysis, which plays a crucial role in the interpretation of the results.

Voice onset time (VOT) and the vocal folds vibratory pattern have also been investigated in women receiving OCP. Morris et al examined the effect of OCP on VOT during two phases of two menstrual cycles, with the hypothesis that VOT variations are less evident in women on OCP compared to those not on OCP.⁶⁷ This hypothesis stemmed from the fact that fluctuation in sex hormones do affect VOT as reported by Whiteside et al.⁶⁸ The findings of their investigation on 20 women divided equally into two groups, one on OCP and another not on pills, contradicted those of Whiteside et al. There was no significant difference in the mean VOT between the two phases of the menstrual cycle in either groups. More so, the differences in the means of VOT between those on OCP and those not on pills did not reach any statistical significance either. Nevertheless, it is worth noting that the non OCP group had longer mean VOT for the /b/ phoneme whereas the OCP had longer VOT for the /p/ phoneme.⁶⁷ Two years later in 2011, Morris et al conducted a longitudinal study in order to better evaluate the effect of shifting to OCP use in a women with a natural menstrual cycle. The voice recordings of a 23-year-old women were collected during 2 cycles when she was naturally menstruating and in six cycles when she was on OCP. The recordings consisted of 3 sustained /ae/ vowels at comfortable pitch and loudness. Acoustic measures that correlated with closed quotient duration, glottal width, and vocal fold speed of closure were obtained. Unlike the previous study that showed no effect of OCP on VOT, the results of this investigation indicated changes in H1-H2 differences and in H1-A1 differences, which correlated with closed quotient duration and glottal width, respectively. In the follicular phase, there was a reduction in the H1-H2 difference and H1-A1 difference, whereas in the luteal phase, there was an increase in the difference of H1-H2 and H1-A1. On the other hand there were no changes in the difference H1-A3 before and after intake of OCP. The results also showed an increase in jitter level in both follicular and leuteal phases after intake of OCP but with no difference in shimmer and noise-to-harmonic ratio.⁶⁹

The more recent literature on acoustic changes associated with OCP usage is in partial agreement with the previous reports but still not conclusive. In 2015, Meurer et al conducted a cross-sectional study investigating phonoarticulatory changes in four groups of women, two using low dosage OCP and two not on pills. Using both sustained vowels and connected speech, the authors reported better voice acuity for the sustained vowels in the groups not on pills, but slower speech in both midfollicular and midluteal phases. On the other hand, patients on OCP had higher frequency modulation for the connected speech.⁷⁰ In 2017, the effect of OCP on vocal folds vibration have been investigated by Kunduk et al in a group of 13 women divided in two subgroups, six on OCP and 7 not on pills. Voice recordings of sustained vowel /i/ coupled with high-speed videoendoscopic imaging were collected at three phases of the menstrual cycle; premenstruation, ovulation, and postmenstruation. Using several acoustic measures such as fundamental frequency, harmonic-to-noise ratio, harmonic richness factor, in addition to subjective ratings such as perceptual evaluation, the authors reported no significant effect of OCP on vocal fold vibration. Their results, in particular the lack of significant difference on fundamental frequency deviation and harmonic-to-noise ratio in women on OCP were not in total agreement with the results of Amir et al who have reported lower perturbation parameters, jitter and shimmer, and lower noise-to-harmonic ratio in women using OCP compared to those not on pills.⁶² Based on the author’s interpretation, the discrepancy might be attributed to the high sensitivity of videoendoscopy to frequency perturbation and to possible differences in the background noise characteristics between the two studies.⁷¹ On the other hand, the higher value of the harmonic richness factor and lower mean value of H1-H2, speak for a voice rich in harmonics, which is in keeping with the “better voice quality” as reported by Amir et al.⁶² In the same year, Meurer et al 2017 investigated the impact of monophasic low dose OCP on vocal range in a group of 72 women (48 on pills and 24 controls). Subjects were asked to read a sentence in six variations. The authors reported that the “highest vocal tones for the same sentence uttered using an exclamatory fashion”⁷² were lower in the OCP group compared to those not on pills. Similarly, the lowest vocal tones in the sentence uttered in a joyful intonation were higher in the OCP group. In conclusion the authors demonstrated that OCP have an effect on vocal range in women during their reproductive years.⁷²

Aerodynamic Measures and OCP

The aerodynamic measures in patients on OCP have also been investigated with the purpose of providing more information on the vibratory behavior of the vocal folds during a stable hormonal environment. In 2008 Mary Gorham-Rowan and Linda Fowler measured peak flow, minimum and alternating flows, in addition to the sound pressure level and fundamental frequency in a group of 16 women, eight of whom were receiving OCP. The subjects were asked to repeat the vowel /a/ three times at two phases of the menstrual period, directly after menstruation and around time of ovulation. The authors reported significant difference in some of the airflow measures between those on pills versus controls, with higher peaks and alternating flow rates reported in those on pills. However, after having eliminated the outliers, the results revealed no significant difference in the glottal airflow measurements between the two groups At this point, the authors emphasized that the aforementioned airflow measures may not be very useful in depicting vocal changes in patients using OCP.⁷³ A year later, the same authors reported different findings in another study where subjects were asked to repeat the syllable /pa/ instead of a vowel. The study which was conducted on 16 women (eight on OCP and eight not on OCP) and voice recordings were obtained at two phases in the menstrual cycle. The authors concluded that OCP have no effect on laryngeal airflow,⁷⁴ which is in keeping with the findings of La et al, namely, the lack of significant differences in the vocal vibrational pattern between subjects on OCP pills versus those not on pills.

Vocal Resonance and OCP

Resonance is defined as amplification of sound by mechanism of reflection. In phonation, the vocal signal is amplified in the vocal tract, nose, and paranasal sinuses. As such the nose plays an important role in vocal resonance, diseases of which may markedly impact voice quality. During pregnancy, the etiologic role of sex hormones in nasal congestion and hypersecretion has been well investigated in the literature. Several hypothesis have been suggested to explain the compilation of nasal symptoms in the last trimester of pregnancy. These include interstitial edema, reduction in apha-adrenergic supply resulting in venous sinusoidal congestion within the nasal mucosa, and last an upsurge in estrogen level.⁷⁵ The pathogenic role of the latter has been substantiated by the therapeutic usage of topical estrogen in cases of atrophic rhinitis and the presence of estrogen receptor in the nasal mucosa.^76,77 Nevertheless, conflicting studies on the pathogenic role of estrogen in patients with nasal symptoms have been reported. Ellegard and Karlsson investigated the extent of nasal obstruction during a menstrual cycle. The study was conducted on 27 women using nasal peak expiratory flow and subjective grading of nasal stuffiness from 0 to 4. Unexpectedly, the degree of nasal obstruction correlated negatively with the estrogen level. In the menstrual phase during which estrogen level is low, the nasal resistance was high.⁷⁵ These findings were further corroborated by a report by Paulson et al, which included three studies on the relationship between sex hormones and nasal congestion. All three studies failed to demonstrate an association between estrogen, progesterone, and nasal congestion. The outcome measures used in the first two studies included both subjective rating of nasal stuffiness and objective measures such as acoustic rhinometry and nasal expiratory peak-flow. These findings were in keeping with the absence of estrogen and progesterone receptors in biopsies taken from the nasal mucosa in the third study of this same report.⁷⁸ On the other hand, two other reports, one by Haeggstrom et al and another by Philpott et al confirmed the interplay between estrogen surge and nasal congestion. The study by Haeggstrom et al did show that with an increase in estrogen level, at the pre-ovulatory stage of the menstrual cycle, there is hyperactivity of the nasal mucosa to histamine. The investigation was carried out on 10 women whose nasal mucosa was examined at baseline and after being challenged with histamine. The examination was performed three times during the menstrual cycle using acoustic rhinometry and rhinostereometry.⁷⁹ Similarly, the study by Philpott et al did show that nasal congestion occurs with an increase in estrogen level. The study included several diagnostic measures, self reported questionnaire on rhinitis, nasal airflow measures, examination of the nasal cavity, and acoustic rhinometry.⁸⁰

With all the aforementioned data on the speculative association between estrogen level and nasal congestion, it was intuitive to investigate the clinic-pathologic effects of OCP on the nasal mucosa and hence on vocal resonance. Indeed, the first histologic study on nasal mucosal changes in patients on OCP was reported by Toppozada et al in 1984. The authors took a punch biopsy from the inferior turbinates of 15 women who were on OCP, five of whom had nasal symptoms and the others were symptom free. Using histochemical and ultramicroscopic analysis of the human respiratory nasal mucosa, the authors demonstrated the presence of high acid mucoplysaccharide content and increased glandular and phagocytic activity in the symptom-free subjects. In those with nasal symptoms, there was evidence of “squamous metaplasia, intra-epithelial edema, glandular hyperplasia and histiocytic proliferation.”⁸¹ More than 2 decades later, the effect of OCP on resonance and other vocal parameters were investigated by Van Lierde et al in 2006. The study was conducted on 24 professional voice users during two phases of the menstrual cycle, around the time of ovulation and within three days after menses. The comparative analysis indicated no significant difference in nasality, nasalance, or any of the various subjective and objective measures used in this investigation. The authors concluded that OCP do provide a stable hormonal profile that works in favor of professional voice users who desire no phonatory disturbance during performance. However, the results of this study may not be as conclusive to non-professional voice users who lack the adaptive skills of professional voice users.⁶³ A similar study that includes singers, non-singers, and a control group may ascertain or refute the impact of OCP on resonance.

Conclusion

In conclusion, thorough review of the literature reveals no clear consensus on the effect of OCP on voice. The lack of uniformity in the results can be attributed to several factors thoroughly discussed in Chapter 39 “The Effects of Oral Contraceptives and Voice” in the 4th edition of “Professional Voice: The Science and Art of Clinical Care.”⁴⁸ In brief these include: (1) the type of OCP used, taking into consideration the large variety of pills available in the market, (2) the voice sample analyzed, whether sustained vowels or connected speech, (3) lack of standardization of the time or phase of the menstrual cycle during which voice recordings were made, (4) variations in the voice outcome measures, and (5) the disparity in subject selection, whether professional voice users or non-professional voice user. This issue is of paramount importance knowing that singers have more adaptive skills to hormonal variations in comparison to subjects with no history of vocal training.⁴⁸ More evidence-based studies are needed to clearly elucidate the interplay between OCP and voice.

V. Androgen Excess and Voice

Endogenous Excess of Androgen

The pre-pubertal surge of testosterone is responsible for the growth and development of laryngeal structures in both genders. In concert with estrogen and progesterone, testosterone and its derivatives define our sexual identity. Despite the ubiquity of reports on the pre-and pubertal effect of sex hormones on voice, less has been reported on the pathogenic role of androgenic hormones in vocal virilization in the post-pubertal phase. To that end, various hormones have been implicated among which are testosterone, dihydrotestosterone (DHT), or dehydroepiandrosterone (DHEAS), complemented with metabolic hormonal disorders.⁸² When androgen levels are high enough to induce symptoms and signs of virilization, a thorough investigation looking for the source of androgen excess should be undertaken. In parallel, medical treatment of hypernadrogenism should be initiated. This may include androgen receptor blockers such as cyproterone acetate, adrenal androgen production blockers such as glucocorticoid, and ovarian androgen production blockers.⁸³ Early initiation of therapy is crucial in reversing many of the androgenic signs except for voice deepening which invariably is irreversible.

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