Progressive Voice Deepening or Hoarseness in Women: A Clinical Review

A Systematic Approach to an Underrecognized Sign of Virilization

Dr Neeraj Manikath , claude.ai

Abstract

Progressive voice deepening in women represents a subtle yet clinically significant manifestation of hyperandrogenism that is frequently overlooked or misattributed to benign conditions. This review provides a comprehensive framework for internists to recognize, investigate, and manage this insidious symptom, emphasizing the critical distinction between common endocrinopathies and life-threatening virilizing tumors. We discuss the pathophysiology of androgen-induced laryngeal changes, provide a systematic diagnostic approach, and highlight key clinical pearls that can prevent diagnostic delays.

Keywords: Voice deepening, virilization, hyperandrogenism, androgen-secreting tumors, PCOS, hoarseness

Introduction

The human voice is an exquisitely sensitive biomarker of hormonal status. While acute hoarseness prompts immediate evaluation for infectious or structural causes, progressive voice deepening over months to years often elicits diagnostic complacency. Primary care physicians and even subspecialists may attribute this symptom to aging, smoking, gastroesophageal reflux disease (GERD), or "chronic laryngitis" without considering the underlying endocrine etiology.

Clinical Pearl #1: Any woman reporting progressive voice change deserves a focused virilization assessment before reflexive referral to ENT or empiric proton pump inhibitor therapy.

Voice deepening occurs when androgens induce irreversible hypertrophy of the laryngeal muscles and thickening of the vocal cords—changes that persist even after androgen excess is corrected. This irreversibility makes early recognition paramount. The tempo of progression, associated virilizing features, and age of onset provide critical diagnostic clues that distinguish benign hyperandrogenism from potentially malignant causes.

Pathophysiology: Why Androgens Deepen the Voice

The larynx is an androgen-sensitive organ expressing high concentrations of androgen receptors, particularly in the thyroarytenoid muscles and vocal fold epithelium. During male puberty, testosterone drives laryngeal growth, increasing vocal fold length by approximately 60% and mass by 150%, resulting in fundamental frequency reduction from ~280 Hz to ~130 Hz.

In women exposed to supraphysiologic androgens, similar—though less dramatic—changes occur:

Vocal fold thickening: Increased bulk of the thyroarytenoid muscle and lamina propria
Laryngeal cartilage growth: Subtle enlargement of thyroid cartilage
Mucosal changes: Edema and increased vascularity initially, followed by fibrosis
Altered biomechanics: Reduced vocal fold oscillation frequency

These structural changes lower fundamental frequency (perceived pitch) by 20-60 Hz and alter vocal quality, producing breathiness, roughness, or "huskiness." Importantly, once collagen remodeling occurs, voice changes become permanent despite normalization of androgen levels—a phenomenon termed "androgenic voice syndrome."

Hack #1: Ask patients to compare their voice to old voicemail messages, videos, or audio recordings. Subjective perception often underestimates objective change. Family members may notice before the patient does.

The "Virilizing Tumor" Red Flag: When to Panic

The most critical clinical distinction is differentiating slow, chronic hyperandrogenism from acute virilizing tumors. Androgen-secreting neoplasms—though rare—require immediate identification because they may be malignant and are often surgically curable.

Cardinal Features of Virilizing Tumors

Rapid onset is the hallmark: symptom progression over weeks to months (not years) should trigger urgent evaluation. The classic triad includes:

Voice deepening (often the presenting complaint)
Clitoromegaly (clitoral length >10 mm or width >5 mm)
Severe hirsutism with male-pattern distribution

Additional concerning features include:

Temporal balding or frontal hair recession
Increased muscle mass and upper body strength
Severe acne unresponsive to conventional therapy
Breast atrophy
Oligomenorrhea or amenorrhea (though this may be absent in postmenopausal women)

Pearl #2: The presence of clitoromegaly has 90% positive predictive value for an androgen-secreting tumor when combined with voice change. Always perform this examination—many internists neglect pelvic assessment in virilized women.

The Biochemical Signature

Testosterone levels provide the most discriminatory laboratory finding:

Total testosterone >200 ng/dL strongly suggests tumor
Total testosterone >150 ng/dL warrants imaging even without other features
Rapid doubling of testosterone levels on serial measurements (weeks apart)

DHEAS elevation >700 μg/dL points toward adrenal rather than ovarian source, though significant overlap exists. Some virilizing tumors produce predominantly testosterone with normal DHEAS.

Oyster (Hidden Trap) #1: Don't be falsely reassured by "borderline elevated" testosterone (e.g., 80-100 ng/dL in a reproductive-age woman with upper normal limit ~70 ng/dL). Serial measurements showing upward trajectory are more concerning than absolute values. Context matters: a postmenopausal woman with testosterone of 80 ng/dL has marked hyperandrogenism.

Common Culprits

Ovarian sources (60% of virilizing tumors):

Sertoli-Leydig cell tumors (most common, typically reproductive age)
Granulosa-theca cell tumors
Hilar cell tumors
Lipoid cell tumors
Krukenberg tumors (metastatic, usually GI primary)

Adrenal sources (40%):

Adrenocortical carcinoma (often large >6 cm, associated with Cushing syndrome)
Androgen-secreting adenomas

Reference: Derksen J, Nagesser SK, Meinders AE, et al. Identification of virilizing adrenal tumors in hirsute women. N Engl J Med. 1994;331(15):968-973.

Differentiating from PCOS: Not All Hyperandrogenism Is Equal

Polycystic ovary syndrome (PCOS) affects 6-12% of reproductive-age women and is the most common cause of chronic hyperandrogenism. However, voice deepening is distinctly unusual in PCOS—its presence should prompt reevaluation of the diagnosis.

Why PCOS Rarely Causes Significant Voice Change

PCOS typically produces total testosterone levels of 50-90 ng/dL—elevated above normal female range (15-70 ng/dL) but insufficient for laryngeal virilization in most cases. The chronic, stable nature of PCOS-related androgen excess allows physiologic compensation and rarely crosses the threshold for irreversible voice changes.

When PCOS patients DO develop voice deepening:

Often related to exogenous androgen exposure (bodybuilding supplements, testosterone therapy)
May indicate underlying non-classic congenital adrenal hyperplasia (CAH) misdiagnosed as PCOS
Coexistent ovarian hyperthecosis (a more severe form producing higher testosterone)

Pearl #3: If a patient carries a PCOS diagnosis and reports progressive voice deepening, question the diagnosis. Obtain complete hormonal reevaluation and imaging. Many virilizing tumors are initially misdiagnosed as PCOS.

Clinical Comparison Table

Feature	PCOS	Virilizing Tumor
Onset	Gradual (years)	Rapid (weeks-months)
Voice change	Rare/mild	Common/severe
Testosterone	<100 ng/dL	Usually >150 ng/dL
Clitoromegaly	Absent	Often present
Imaging	Polycystic ovaries	Discrete mass

Reference: Alpañés M, Álvarez-Blasco F, Fernández-Durán E, et al. Combined oral contraceptives plus spironolactone compared with cyproterone acetate for polycystic ovary syndrome. Obstet Gynecol. 2017;129(6):1052-1060.

Key Laboratory Evaluation: The Androgen Panel

Initial Screening (All patients with progressive voice deepening)

1. Total Testosterone (early morning, 8 AM)

Most specific marker for virilizing tumors
Must be drawn in follicular phase (days 3-10) in menstruating women
Avoid testing during oral contraceptive use (suppresses levels)

Interpretation:

<100 ng/dL: Unlikely tumor, consider functional causes
100-150 ng/dL: Gray zone, requires close monitoring and imaging
150 ng/dL: Tumor highly likely, urgent imaging indicated
200 ng/dL: Tumor until proven otherwise

2. DHEAS (Dehydroepiandrosterone Sulfate)

Adrenal-specific marker (99% adrenal origin)
Not significantly affected by menstrual cycle
Long half-life makes single measurement reliable

Interpretation:

<700 μg/dL with elevated testosterone: Ovarian source likely
700 μg/dL: Adrenal source probable
800 μg/dL: Adrenal imaging mandatory

3. 17-Hydroxyprogesterone (17-OHP, 8 AM)

Screens for non-classic CAH (21-hydroxylase deficiency)
Can mimic or coexist with PCOS
Must be drawn in follicular phase

Interpretation:

<200 ng/dL: CAH unlikely
200-1000 ng/dL: Perform ACTH stimulation test
1000 ng/dL: Non-classic CAH confirmed

Hack #2: If initial screening suggests CAH, perform cosyntropin (ACTH) stimulation test. Inject 250 μg cosyntropin IV, measure 17-OHP at baseline and 60 minutes. Stimulated 17-OHP >1500 ng/dL confirms diagnosis. This can be coordinated same-day with endocrinology.

Additional Useful Studies

Free testosterone: More sensitive than total testosterone for mild hyperandrogenism but less useful for tumor detection (usually order total testosterone first)

Androstenedione: Elevations suggest ovarian source but adds limited information beyond testosterone and DHEAS

Sex hormone-binding globulin (SHBG): Suppressed in hyperandrogenism; useful to calculate free androgen index but not for tumor detection

LH/FSH ratio: Elevated in PCOS (>2:1) but normal in tumors; helpful for differential diagnosis

24-hour urinary free cortisol or overnight dexamethasone suppression: If clinical features suggest concurrent Cushing syndrome (adrenal carcinomas often coproduce cortisol)

Pearl #4: Timing matters. Testosterone and 17-OHP fluctuate during menstrual cycle. Always draw in early follicular phase (days 3-10) or random if anovulatory. Document timing on requisition. DHEAS is stable throughout cycle.

Oyster #2: Oral contraceptives suppress ovarian and adrenal androgen production and increase SHBG (reducing free testosterone). If a woman on OCPs has virilization, this represents autonomous production—tumor is even more likely. Do not postpone evaluation by discontinuing contraception first.

Reference: Carmina E, Rosato F, Jannì A, et al. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab. 2006;91(1):2-6.

The Imaging Imperative: Finding the Source

Once biochemical hyperandrogenism is confirmed, anatomic localization is mandatory.

Imaging Algorithm

Step 1: Transvaginal/Pelvic Ultrasound

First-line for ovarian evaluation
Excellent for masses >2 cm
Limited sensitivity for small tumors (<1.5 cm)
Cannot reliably distinguish benign from malignant

When ultrasound is sufficient:

Obvious unilateral ovarian mass (>3 cm) with elevated testosterone
Proceed directly to gynecologic oncology evaluation

Step 2: MRI Pelvis with Contrast

Superior soft tissue resolution
Better characterizes adnexal masses
Can detect small (<1 cm) Sertoli-Leydig tumors missed on ultrasound

Indications for MRI:

Testosterone >150 ng/dL with negative/equivocal ultrasound
Concern for concurrent pelvic pathology requiring detailed mapping

Step 3: CT or MRI Abdomen/Adrenals

Indicated when DHEAS >700 μg/dL
CT adrenal protocol (thin cuts, pre/post-contrast) preferred for adrenal masses
MRI with chemical shift imaging can distinguish adenomas from carcinomas

Indications:

DHEAS elevation suggesting adrenal source
Negative pelvic imaging with persistent testosterone elevation
Clinical features concerning for adrenal carcinoma (Cushing's features, large size)

Hack #3: If both ovaries and adrenals appear normal despite marked testosterone elevation (>200 ng/dL), consider selective venous catheterization (ovarian and adrenal vein sampling). This invasive procedure, performed by interventional radiology, can lateralize occult tumors. Coordinate through experienced endocrinology.

Pearl #5: Small virilizing tumors (<1 cm) are notoriously difficult to detect. Don't abandon suspicion if first imaging is negative. Serial imaging every 3-6 months may be necessary. Some centers use PET-CT with specialized tracers (18F-FDG or 11C-metomidate) for occult tumors.

Oyster #3: Incidental adrenal adenomas are present in 4% of abdominal CTs. Not every adrenal nodule in a virilized woman is the culprit. Confirm functionality with adrenal vein sampling if diagnosis unclear. Conversely, don't assume a 1 cm ovarian "functional cyst" explains testosterone of 180 ng/dL—functional cysts don't produce these levels.

Reference: Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601-610.

When to Refer to ENT: Ruling Out Structural Causes

Not every case of voice change in women stems from hyperandrogenism. Structural laryngeal pathology must be excluded, particularly when:

Indications for Otolaryngology Referral

Urgent referral (within 2 weeks):

Hoarseness >3 weeks with negative androgen workup
Concomitant dysphagia, odynophagia, or hemoptysis (red flags for malignancy)
Progressive dyspnea or stridor
History of neck surgery/radiation
Known or suspected thyroid mass

Routine referral (coordinate with endocrine workup):

Vocal quality changes inconsistent with androgen exposure (e.g., breathy voice without deepening)
Professional voice users (singers, teachers) with any voice change
Associated symptoms: chronic cough, throat clearing, globus sensation (may indicate reflux laryngitis)
Heavy smoking history (>20 pack-years)

What ENT Evaluation Provides

Videolaryngoscopy: Direct visualization of vocal cords identifies:

Vocal fold polyps, nodules, or cysts
Laryngeal papillomatosis
Vocal fold paralysis (recurrent laryngeal nerve injury)
Reinke's edema (smoking-related)
Laryngeal carcinoma

Stroboscopy: Dynamic assessment of vocal fold vibration detects subtle mucosal wave abnormalities missed on static examination

Acoustic analysis: Objective measurement of fundamental frequency, jitter, and shimmer

Pearl #6: Even if androgen excess is confirmed, ENT evaluation helps document baseline laryngeal anatomy and severity. If voice changes are irreversible post-treatment, documentation supports disability claims and guides voice therapy.

Dual Pathology Scenario: A woman with GERD-related laryngitis AND underlying hyperandrogenism. ENT treats the reflux component while endocrinology addresses hormonal cause. Voice improvement may be partial, requiring multidisciplinary management.

Hack #4: Request acoustic voice analysis at baseline and after androgen normalization. Objective data (fundamental frequency in Hz) documents irreversibility better than subjective assessment and may inform medicolegal or disability evaluations.

Reference: Abitbol J, Abitbol P, Abitbol B. Sex hormones and the female voice. J Voice. 1999;13(3):424-446.

Other Causes of Voice Deepening: The Differential Diagnosis

While hyperandrogenism dominates the differential, alternative etiologies warrant consideration:

Hypothyroidism: Myxedematous infiltration of vocal folds produces low-pitched, breathy voice. Check TSH.

Exogenous androgens: Anabolic steroids (bodybuilding), testosterone therapy, DHEA supplements. Detailed medication/supplement history is essential.

Acromegaly: Growth hormone excess thickens soft tissues including larynx. Look for acral enlargement, frontal bossing, macroglossia.

Amyloidosis: Rare laryngeal infiltration. Consider if systemic amyloid suspected.

Smoking: Chronic irritation causes Reinke's edema. Voice is husky but doesn't continue deepening progressively.

Chronic laryngitis: GERD, chronic cough, voice overuse. Symptoms fluctuate rather than relentlessly progress.

Presbyphonia: Age-related vocal fold atrophy. Onset after age 60, stable once established.

Neurologic disorders: Parkinson's disease (hypophonia, monotone), myasthenia gravis (fatigable voice)

Oyster #4: Transgender men receiving testosterone therapy develop predictable voice deepening within 6-12 months. If a patient's gender identity is not immediately apparent or disclosed, approach history-taking sensitively. Ask about prescribed and non-prescribed hormone use without assumptions.

Management Principles and Prognosis

Tumor Management

Surgical resection is definitive treatment for androgen-secreting tumors:

Ovarian tumors: Unilateral salpingo-oophorectomy (fertility-sparing if benign)
Adrenal tumors: Laparoscopic or open adrenalectomy depending on size/suspicion for malignancy

Prognosis:

Sertoli-Leydig tumors: >95% 5-year survival if stage I, completely resected
Adrenal adenomas: Curative resection
Adrenal carcinoma: Poor prognosis (30-40% 5-year survival even with complete resection and adjuvant mitotane)

Pearl #7: Voice changes do NOT reverse after tumor removal. Counsel patients preoperatively. Some improvement in vocal quality may occur as mucosal edema resolves, but pitch remains low. Voice therapy with speech-language pathology can optimize residual function.

Medical Management of Functional Hyperandrogenism

PCOS/Non-tumor causes:

Combined oral contraceptives (suppress ovarian androgen production)
Spironolactone 50-200 mg daily (androgen receptor antagonist)
Finasteride 5 mg daily (5α-reductase inhibitor, off-label)
Weight loss if overweight (reduces insulin resistance driving hyperandrogenism)

Non-classic CAH:

Low-dose glucocorticoids (prednisone 2.5-5 mg nightly or dexamethasone 0.25-0.5 mg nightly)
Suppress ACTH-driven adrenal androgen production

Voice-specific interventions:

Voice therapy: Techniques to optimize vocal efficiency and quality within altered anatomy
Laryngeal framework surgery (rare): Medialization or shortening procedures for severe cases; limited evidence

Hack #5: Prioritize prevention. In women with hyperandrogenism, initiate anti-androgen therapy BEFORE voice changes occur. Once established, changes are irreversible. Treat biochemical hyperandrogenism even if hirsutism is the only complaint—voice is the canary in the coal mine.

Reference: Elbers JM, Giltay EJ, Teerlink T, et al. Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol (Oxf). 2003;58(5):562-571.

Conclusion: Key Take-Home Points

Progressive voice deepening in women is a sentinel sign of significant hyperandrogenism that demands systematic evaluation. The tempo of progression, associated virilizing features, and biochemical severity differentiate benign functional causes from potentially life-threatening tumors.

The Internist's Action Plan:

History: Document timeline (weeks vs. months vs. years), associated symptoms (clitoromegaly, balding, severe acne), medication/supplement use
Examination: Inspect for hirsutism, acne, clitoromegaly, temporal balding, increased muscle mass
Laboratory: Total testosterone, DHEAS, 17-OHP (8 AM, follicular phase if cycling)
Imaging: Pelvic ultrasound if testosterone >100 ng/dL; MRI pelvis and/or CT adrenals based on pattern
Referral: Endocrinology for all cases; ENT if symptoms >3 weeks with negative workup or red flag features; gynecologic oncology if ovarian mass identified

Remember: Voice change is irreversible—early detection and treatment of underlying hyperandrogenism prevents progression but cannot restore original pitch. The goal is to identify rapidly progressive cases where tumor resection is curative and to prevent further virilization in functional causes.

Final Pearl: Trust the patient. If a woman tells you her voice has changed, believe her. Objective acoustic analysis confirms what she hears. Investigate persistently—occult tumors require serial imaging and multidisciplinary expertise.

References

Derksen J, Nagesser SK, Meinders AE, et al. Identification of virilizing adrenal tumors in hirsute women. N Engl J Med. 1994;331(15):968-973.
Young WF Jr. Clinical practice. The incidentally discovered adrenal mass. N Engl J Med. 2007;356(6):601-610.
Carmina E, Rosato F, Jannì A, et al. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab. 2006;91(1):2-6.
Abitbol J, Abitbol P, Abitbol B. Sex hormones and the female voice. J Voice. 1999;13(3):424-446.
Alpañés M, Álvarez-Blasco F, Fernández-Durán E, et al. Combined oral contraceptives plus spironolactone compared with cyproterone acetate for polycystic ovary syndrome. Obstet Gynecol. 2017;129(6):1052-1060.
Elbers JM, Giltay EJ, Teerlink T, et al. Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol (Oxf). 2003;58(5):562-571.
Wild RA, Carmina E, Diamanti-Kandarakis E, et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J Clin Endocrinol Metab. 2010;95(5):2038-2049.
Kaltsas GA, Isidori AM, Kola BP, et al. The value of the low-dose dexamethasone suppression test in the differential diagnosis of hyperandrogenism in women. J Clin Endocrinol Metab. 2003;88(6):2634-2643.

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This review provides a framework for recognizing and evaluating progressive voice deepening in women, emphasizing the critical distinction between common and catastrophic causes. The irreversible nature of androgen-induced voice changes makes early detection essential—internists serve as the frontline in identifying this subtle but significant manifestation of virilization.

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