ENDOCRINE SOCIETY
OXFORD
Hyperandrogenism-induced Athletic Excellence in a Young Patient with Adrenocortical Carcinoma: 10 Years of Remission
Takashi Kono,1,2 Satomi Kono,1 Yasuhiro Nakamura,3 Yoichi Fujii,4 Hironobu Sasano, 1,5 and Tomoaki Tanaka 1,2 iD
1Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
2Research Institute of Disaster Medicine, Chiba University, Chiba 260-8670, Japan
3Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Miyagi 983-8536, Japan
4Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan 5Department of Pathology, Tohoku University School of Medicine, Sendai, Miyagi 980-8575, Japan
Correspondence: Tomoaki Tanaka, MD, PHD, Department of Molecular Diagnosis, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Email: tomoaki@restaff.chiba-u.jp.
Abstract
A 17-year-old female softball player presented with progressive virilization and markedly enhanced athletic performance. Laboratory evaluation revealed elevated serum testosterone with autonomous adrenal secretion. Imaging analysis demonstrated an 8-cm right adrenal mass. Adrenalectomy was performed, and histopathological examination confirmed stage Il adrenocortical carcinoma (ACC) with a Ki-67 labeling index of 14%. Postoperatively, she received adjuvant mitotane therapy. At 34 months, a solitary hepatic metastasis was successfully treated with radiofrequency ablation and combination chemotherapy. She has remained disease-free for more than 8 years following initial surgery. This case demonstrates the clinical impact of pathological hyperandrogenism on athletic performance and highlights the potential for long- term remission in young patients with aggressive ACC managed through multimodal therapy.
Key Words: adrenocortical carcinoma, hyperandrogenism, athletics, androgen, virilization
Introduction
Adrenocortical carcinoma (ACC) is a rare endocrine malig- nancy with an incidence of 1 to 2 cases per million [1]. Hormonal excess is the predominant presenting feature, with approximately 20% exhibiting isolated androgen excess and 22% combined cortisol-androgen secretion [2]. Androgen ex- cess in females typically manifests as virilization-hirsutism, voice deepening, and menstrual irregularities.
Excess androgens enhance skeletal-muscle development and athletic performance through multiple mechanisms: in- creased protein synthesis, preferential type II muscle fiber de- velopment, and improved neuromuscular adaptation [3], resulting in measurable performance gains [4]. While andro- genic effects have been well studied therapeutically, patho- logical hyperandrogenism from endocrine malignancies remains poorly understood in sports medicine, particularly during adolescence [5].
This report describes ACC-induced hyperandrogenism in a 17-year-old athlete, quantifying exceptional performance gains through standardized assessments and highlighting the anabolic impact of pathological androgens.
Case Presentation
A 17-year-old female varsity softball player presented with a 2-year history of progressive hirsutism, amenorrhea, and
voice deepening. Following a national training program, her performance metrics (grip strength, sprint time) exceeded age- matched norms by >2 SD. Her performance gains exceeded her teammates, without exogenous steroid use.
Menarche occurred at age 12 with regular cycles until age 15, when oligomenorrhea developed alongside worsening hir- sutism. Physical examination findings are shown in Fig. 1A.
Physical fitness assessments (T-scores: mean 50, SD 10) re- vealed improvements from ages 13 to 17, particularly grip strength (T 56.8 → 109.3), nearly doubling Japanese female norms [6]. Similar gains occurred in cardiorespiratory endurance [7], power output, and muscular strength (Table 1, Fig. 1B).
Physical examination revealed height 165.7 cm, weight 62.4 kg, body mass index 22.7 kg/m2, and blood pressure 130/70 mmHg. Virilization signs included hirsutism (Ferriman- Gallwey score 14; normal <8), acne, clitoromegaly (1 cm), and increased muscle mass without cushingoid features.
Diagnostic Assessment
Endocrine evaluation revealed androgen elevation (Table 2): testosterone 65.2 ng/ml (226 nmol/L) [reference 0.11-0.47 ng/ml (0.38-1.63 nmol/L)], dehydroepiandrosterone sulfate (DHEA-S) 1970µg/dL (53.8 umol/L) [reference 51-321 µg/dL (1.39-8.76 umol/L)], and androstenedione 55 ng/ml (192 nmol/L) [reference 0.11-0.39 ng/ml (0.38-1.36 nmol/L)]. High-dose
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| Parameter | Age 13 | Age 16 | Age 17 | |||
|---|---|---|---|---|---|---|
| Raw | T-score | Raw | T-score | Raw | T-score | |
| Muscle function | 56.8 | 46 kg | 109.3 | |||
| Grip strength | 27 kg | 88.0 | 57 kg | |||
| Power output | ||||||
| Standing long jump | 175 cm | 52.3 | 200 cm | 62.3 | 225 cm | 71.7 |
| Softball throw | 18 m | 49.7 | 25 m | 73.2 | 25 m | 73.2 |
| Speed | ||||||
| 50 m sprint | 8.5 second | 53.7 | 7.29 second | 67.2 | 6.88 second | 71.1 |
| Endurance | ||||||
| 20 m shuttle run | 73 counts | 56.7 | 101 counts | 73.9 | 116 counts | 79.7 |
| Sit-ups | 27 counts | 56.9 | 28 counts | 57.8 | 35 counts | 67.0 |
| Trunk mobility | ||||||
| Sitting trunk flexion | 43 cm | 49.1 | 42 cm | 45.5 | 54 cm | 56.0 |
| Side steps | 47 counts | 52.2 | 50 counts | 50.6 | 55 counts | 52.4 |
T-score = 50 + 10 x [(raw value - population mean)/population SD]. T-scores are standardized to a population mean of 50 and SD of 10 for age- and sex-matched Japanese adolescents. Normative values were derived from the National Physical Fitness Survey (2008-2012; n = 12 405 females) conducted by the Japan Sports Agency. Adrenocortical carcinoma diagnosed at age 17.
dexamethasone suppression testing demonstrated inadequate cortisol suppression (9.4 µg/dL (259 nmol/L) after 8 mg [nor- mal <1.8 µg/dL (<50 nmol/L)] with a paradoxical increase in testosterone, confirming autonomous hormone production.
Computed tomography (CT) revealed an 8-cm heterogeneous right adrenal mass with contrast enhancement (Fig. 2A), with- out metastases. Endocrine and imaging findings established the diagnosis of androgen-producing ACC with subclinical Cushing syndrome.
Treatment
The patient underwent laparoscopic adrenalectomy at age 17. R0-resection was achieved, with an intact capsule and nega- tive margins, and discharge was on postoperative day 3.
Pathology revealed a 13.5x 8.5 × 8.3 cm tumor weighing 119 g with high-grade nuclear atypia, >5 mitoses per 50 high- power fields and Ki-67 14%. Six of 9 Weiss criteria-high nuclear grade, elevated mitotic rate, atypical mitoses, eosinophilic cytoplasm, diffuse architecture, and capsular
| Parameter | Value (SI units) | Reference range (SI units) |
|---|---|---|
| ACTH-08:00 | 7.7 pg/mL (1.7 pmol/L) | 7.2-63.3 pg/mL (1.6-13.9 pmol/L) |
| ACTH-20:00 | <5.0 pg/mL (<1.1 pmol/L) | <10 pg/mL (<2.2 pmol/L) |
| Cortisol-08:00 | 7.0 µg/dL (193 nmol/L) | 6.2-19.4 µg/dL (171-535 nmol/L) |
| Cortisol-24:00 | 4.0 µg/dL (110 nmol/L) | <10 µg/dL (<276 nmol/L) |
| DHEA-S | 1970 µg/dL (53.8 µmol/L) | 51-321 µg/dL (1.39-8.76 µmol/L) |
| E2 | 72 pg/mL (264 pmol/L) | 30-400 pg/mL (110-1468 pmol/L) |
| Testosterone | 65.2 ng/ml (226 nmol/L) | 0.11-0.47 ng/ml (0.38-1.63 nmol/L) |
| Androstenedione | 55 ng/ml (192 nmol/L) | 0.11-0.39 ng/ml (0.38-1.36 nmol/L) |
| TSH | 0.903 µIU/mL (0.903 mIU/L) | 0.4-4.5 uIU/mL (0.4-4.5 mIU/L) |
| FT3 | 2.59 pg/mL (3.98 pmol/L) | 2.3-4.2 pg/mL (3.5-6.5 pmol/L) |
| FT4 | 0.99 ng/dL (12.7 pmol/L) | 0.8-1.8 ng/dL (10.3-23.2 pmol/L) |
| LH | 0.05 mIU/mL (0.05 IU/L) | 0.5-7.63 mIU/mL (0.5-7.63 IU/L) |
| FSH | 0.06 mIU/mL (0.06 IU/L) | 1.5-3.34 mIU/mL (1.5-3.34 IU/L) |
| Urine cortisol (24 hours) | 86.6 µg/day | 10-100 µg/day |
| (239 nmol/day) | (27.6-276 nmol/day) |
| Parameter | Baseline (SI units) | After 2 mg (SI units) | After 8 mg (SI units) | Reference range (SI units) |
|---|---|---|---|---|
| ACTH | 7.7 pg/mL (1.7 pmol/L) | <1.0 pg/mL (<0.22 pmol/L) | <1.0 pg/mL (<0.22 pmol/L) | 7.2-63.3 pg/mL (1.6-13.9 pmol/L) |
| Cortisol | 7.0 µg/dL (193 nmol/L) | 8.6 µg/dL (237 nmol/L) | 9.4 µg/dL (259 nmol/L) | < 1.8 µg/dL (< 50 nmol/L) |
| Androstenedione | 55 ng/ml (192 nmol/L) | ND | 87 ng/ml (304 nmol/L) | 0.11-0.39 ng/ml (0.38-1.36 nmol/L) |
| DHEA-S | 1970 µg/dL (53.8 µmol/L) | ND | 2640 µg/dL (71.9 µmol/L) | 51-321 µg/dL (1.39-8.76 µmol/L) |
| Testosterone | 65.2 ng/ml (226 nmol/L) | 94.7 ng/ml (328 nmol/L) | 92.9 ng/ml (322 nmol/L) | 0.11-0.47 ng/ml (0.38-1.63 nmol/L) |
Dexamethasone suppression test results
Abbreviations: DHEA-S, dehydroepiandrosterone sulfate; E2, estradiol; ND, not detected; FT3, free T3; FT4, free T4.
invasion-established high-grade ACC (Fig. 2C and 2D). The final stage was T2N0M0 (stage II).
Postoperatively, mitotane was escalated from 1.5 to 4.5 g/ day over 3 weeks, maintaining plasma 14 to 20 mg/L by regu- lar monitoring [8]. Hydrocortisone 40 mg daily prevented ad- renal insufficiency, and this regimen accords with current guidelines for high-risk ACC [9-12].
Outcome and Follow-up
Following confirmation of high-grade ACC (stage II; Ki-67 14%), we performed molecular and immunohistochemical studies to elucidate the extreme androgen excess.
Comprehensive immunohistochemistry of the resected tu- mor demonstrated intense staining for CYP17A1 and cyto- chrome b5, indicating 17,20-lyase activity that preferentially channels precursors toward androgen synthesis. HSD3B2
was likewise strongly positive, whereas CYP21A2 showed only a weak to moderate signal, explaining relatively pre- served cortisol production despite massive androgen output. StAR and CYP11B1 were moderately expressed; SULT2A1 was minimal, confirming selective androgen hypersecretion (Fig. 2E-2K).
Whole-exome sequencing identified somatic BCOR-P1384R and HDAC9-R947P mutations, reported in <3% of ACCs and predicted pathogenic by in silico analysis [13, 14]. TP53 and CTNNB1, the most common drivers in adult ACC, were wild-type. Genome-wide copy-number profiling revealed the gains and losses typical of ACC (Fig. 3) [15-17], fitting a rare BCOR/HDAC9-mutant subset of the recog- nized spectrum.
Postoperative follow-up consisted of quarterly endocrine testing and alternating CT/magnetic resonance imaging every 6 months. At 34 months, a 4-mm segment VIII liver nodule
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emerged and enlarged to 12 mm over 4 months (Fig. 4A and 4B). In view of the small size, subcapsular location, and high Ki-67 index of the primary tumor, percutaneous radiofre- quency ablation (RFA) was selected instead of hepatic resec- tion [18]. Mitotane, previously tapered to maintenance, was re-escalated (1.0 → 1.5 g/day) and combined with 3 cycles of etoposide, doxorubicin, and cisplatin. Hydrocortisone and flu- drocortisone were titrated.
RFA achieved complete local control, and subsequent im- aging has shown no recurrence for more than 8 years. Mitotane was discontinued after 2 consecutive years of nega- tive scans while low-dose hydrocortisone (20 mg) was contin- ued. Serum testosterone, DHEA-S, and androstenedione remain within reference limits (Fig. 5A).
Serial cross-sectional imaging at the L3 vertebral level quantified the reversal of androgen-driven hypertrophy [19]. Preoperative skeletal-muscle area and skeletal-muscle index (SMI) were 150.2 cm2 and 55.8 cm2/m2, respectively- well above female norms. Skeletal-muscle area/SMI fell to 120.1 cm2 and 44.2 cm2/m2 at 6 months, 95.2/35.0 cm2/m2 at 20 months, and 62.5/23.0 cm2/m2 at 45 months, represent- ing an overall 59% decline. The final SMI lies below consensus
sarcopenia thresholds for both sexes, corroborating the patient’s subjective loss of explosive strength during daily activity. (Fig. 5B and 5C).
The patient’s menstrual cycles resumed 14 months after mi- totane withdrawal and stabilized at 30- to 45-day intervals, indicating partial recovery of hypothalamic-pituitary-ovarian function. Formal postoperative athletic testing was not per- formed, but the patient noted greater fatigue in sprinting and throwing activities than during endurance exercise, con- sistent with the preferential androgen effect on fast-twitch type II fibers. Her body composition normalized with re- duced shoulder and upper-arm definition and increased ilio- femoral adiposity.
Co-expression of CYP17A1 and cytochrome b5 is crucial: cytochrome b5 enhances the 17,20-lyase reaction, diverting pregnenolone and progesterone toward androgen synthesis. This cooperative mechanism, documented in fewer than 10% of ACCs, explains the tumor’s testosterone output. Weak CYP21A2 further restrains cortisol biogenesis, preventing ad- renal insufficiency while permitting androgen precursors to ac- cumulate. Minimal SULT2A1 hampers sulfation and clearance of DHEA. This biochemical milieu yielded a serum DHEA-S of
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1970 µg/dL, among the highest in adolescent ACC, underscor- ing the diagnostic value of enzyme-level mapping.
This case illustrates that aggressive multimodal treatment- R0 adrenalectomy, sustained mitotane exposure, and definitive
therapy for oligometastatic relapse-can deliver durable remis- sion in high-risk adolescent ACC. Integration of immunohisto- chemical, genomic, and functional readouts clarified tumor biology; guided surveillance intensity; and provided objective
documentation of the reversible anabolic impact of pathologic- al hyperandrogenism. Ongoing management focuses on life- long endocrine follow-up; bone-mineral monitoring; and counseling regarding fertility, pregnancy, and adrenal-crisis prevention. At the latest review-9 years after the initial operation-the patient remains recurrence-free, normotensive, and engaged in full-time study.
Discussion
We report ACC-driven hyperandrogenism in a 17-year-old softball player achieving remission through surgery, mitotane, RFA, and chemotherapy. Key findings include (1) marked fiber-type-specific athletic performance gains from pathological androgens, (2) rare BCOR/HDAC9 mutations expanding the molecular spectrum of ACC, and (3) aggressive treatment and long-term management yielding >8-year disease-free survival.
Supraphysiologic testosterone produced gains most evident in power tasks relying on fast-twitch (type II) fibers: grip strength almost doubled, and standing long-jump rose 46%. Endurance capacity, dependent on type I fibers, increased 26%. This differential mirrors laboratory work showing that androgens preferentially expand type II myofibers and in- crease motor-unit firing [20, 21], while oxidative capacity ris- es modestly. While a causal relationship is likely, underlying genetic or training-related factors may have contributed to the observed gains. In competitive sports, performance gains exceeding 2 SDs above population norms may trigger anti-doping investigations. Therefore, clinicians and regula- tory authorities should consider underlying endocrine disor- ders, including rare tumors like ACC, to prevent diagnostic errors and avoid unjust sanctions [22].
Immunohistochemistry confirmed a steroidogenic profile di- verting precursors toward testosterone: intense CYP17A1 + cytochrome b5, weak-moderate CYP21A2, strong HSD3B2, and minimal SULT2A1.
To better understand the molecular drivers of the tumor’s aggressive and hyperandrogenic phenotype, we performed whole-exome sequencing, which uncovered 2 rare somatic mutations-BCOR P1384R and HDAC9 R947P-in the ab- sence of TP53 or CTNNB1 alterations. Each variant occurs in <3% of catalogued ACCs and is predicted pathogenic, ex- panding the spectrum of epigenetic regulators implicated in pediatric ACC. While the prognostic significance of these BCOR/HDAC9 variants remains uncertain, their identifica- tion highlights the molecular heterogeneity of ACC beyond common TP53/CTNNB1 alterations.
Although laparoscopic resection of tumors >6 cm remains controversial, we achieved R0 margins despite the 8-cm size, as imaging showed a well-encapsulated lesion without vascular invasion, our center had extensive laparoscopic experience, and the patient preferred a minimally invasive approach. Current guidelines for ACC management emphasize the importance of complete surgical resection and adjuvant therapy in high-risk cases [23]. Mitotane was titrated to 14 to 20 mg/L, and quarter- ly laboratory review plus semi-annual CT/magnetic resonance imaging provided surveillance. At 34 months, a segment VIII liver nodule emerged (4 mm) and grew to 12 mm within 4 months. Given its subcapsular location, percutaneous RFA was chosen [18]; mitotane was re-escalated and 3 cycles of eto- poside, doxorubicin, and cisplatin added. This strategy achieved complete remission exceeding 8 years, far surpassing
the ~35% 5-year survival typical of stage II ACC. Long-term follow-up has focused on managing adrenal insufficiency, mon- itoring anthracycline cardiotoxicity risk, and addressing skeletal-muscle loss following androgen normalization.
Serial L3 CT images showed an SMI decline from 55.8 to 23.0 cm2/m2 (-59%) over 45 months-below the 29 cm2/m2 threshold for young women-mirroring loss of explosive power. Menstruation resumed 14 months after mitotane cessa- tion, and body composition shifted toward a typical female pat- tern, highlighting the reversible-but quality-of-life-relevant- impact of pathological androgen excess. Given the substantial quality-of-life impact of androgen withdrawal and treatment sequelae, survivorship planning for young women with ACC must also include fertility preservation, psychosocial support, and adrenal-crisis preparedness.
Durable remission also demands structured toxicity monitoring. Mitotane can impair cognition and raise lipids, while cumulative anthracycline doses threaten cardiomy- opathy. Our protocol includes annual echocardiography, lipid profiling, neurocognitive testing, dual-energy X-ray absorptiometry scans, and emergency hydrocortisone edu- cation cards.
Study limitations include uncertain prognostic significance of BCOR/HDAC9 variants and single-case design. Multicenter registries are needed to validate these findings and refine ACC risk stratification in athletes.
Learning Points
· Pathological hyperandrogenism from ACC can dramatic- ally enhance athletic performance, with reversible effects following treatment.
· Aggressive multimodal therapy (surgery, mitotane, RFA for oligometastatic disease) achieved long-term remission in this high-risk ACC (Ki-67 14%), suggesting potential benefit of comprehensive treatment in young patients.
· Exceptional athletic gains with virilization in young ath- letes warrant endocrine evaluation to exclude underlying pathologies.
· Young women with ACC require comprehensive care ad- dressing both oncological outcomes and quality-of-life is- sues, including fertility and adrenal insufficiency.
· Clinicians and sports authorities must remain vigilant for pathological hyperandrogenism, which can mimic doping and lead to misclassification in athletic contexts.
Acknowledgments
We thank Professor Seishi Ogawa at the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University for genomic analysis.
Contributors
T.K. and T.T. diagnosed and managed the patient; T.T. led endocrine evaluation/planning; T.K., S.K., and Y.F. per- formed molecular/genetic analyses; Y.N. and H.S. interpreted pathology; T.K. and T.T. drafted the manuscript.
Funding
None.
Disclosures
The authors have nothing to disclose.
Informed Patient Consent for Publication
Signed informed consent was obtained from the patient.
Data Availability Statement
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
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