INTRODUCTION

Hirsutism is defined as excessive terminal hair growth in a male-pattern distribution among women, primarily affecting androgen-sensitive pilosebaceous units in areas such as the face, chest, abdomen, and thighs [1]. It affects 5–15% of premenopausal women worldwide, with significant psychosocial impact and variable etiologies [2]. Approximately 80–90% of cases are attributable to hyperandrogenemia, driven by conditions such as polycystic ovary syndrome (PCOS), congenital adrenal hyperplasia, or androgen-secreting tumors, which promote the conversion of vellus to terminal hair through elevated circulating androgens [3,4]. The remaining 10–20% are classified as idiopathic hirsutism, characterized by normal serum androgen levels despite clinically evident hair growth, suggesting peripheral mechanisms of androgen action or sensitivity [5].

Ovarian androgen-secreting tumors, including Leydig cell tumors, Sertoli-Leydig cell tumors, and steroid cell tumors, are rare (<0.1% of all ovarian neoplasms) but well-recognized causes of virilization and hirsutism due to direct testosterone or androstenedione secretion [6,7]. In contrast, epithelial ovarian carcinomas, particularly ovarian clear cell carcinoma (OCCC), are not typically associated with endocrine manifestations. OCCC accounts for 1–12% of epithelial ovarian cancers in Western populations and up to 25% in Asian cohorts, often linked to endometriosis and ARID1A/PIK3CA mutations [8,9]. It is characterized by chemoresistance, aggressive behavior, and presentation at an earlier stage compared to high-grade serous carcinoma, with a mean diagnostic age of 56 years (range: 50–55 years) [10,11].

Despite its non-steroidogenic histology, rare paraneoplastic syndromes have been reported in OCCC, including hypercalcemia and thrombotic events; however, hirsutism has not been previously documented [12]. The absence of reported androgen hypersecretion in OCCC raises questions about alternative pathomechanisms in cases of concurrent hirsutism, such as enhanced peripheral 5α-reductase activity, androgen receptor polymorphisms, or tumor-induced cytokine-mediated effects on hair follicle sensitivity [13,14]. This case report presents the first documented instance of clinical hirsutism in a patient with OCCC and normal serum testosterone, aiming to explore potential underlying mechanisms and contribute to the understanding of normoandrogenic hirsutism in the context of ovarian malignancy.

CASE DESCRIPTION

A 51-year-old multiparous woman presented to the gynecology-oncology clinic with a one-year history of progressive abdominal distension, markedly worsening over the preceding three months and significantly impairing ambulation and daily activities. She described intermittent, activity-related lower abdominal pain, episodic dyspnea secondary to diaphragmatic compression, postprandial nausea with occasional bilious vomiting, profound anorexia, and an unintentional 5-kg weight loss over three months. Additionally, she reported non-malodorous, non-pruritic whitish vaginal discharge. Concurrently, she developed new-onset hirsutism involving the chin, mandibular rami, axillae, pubic escutcheon, and lower legs (Figure 1).

Figure 1. Clinical photograph demonstrating moderate hirsutism with terminal hair growth on the chin, upper lip, and mandibular regions (Ferriman–Gallwey score component: 4/4 for chin).

Her past medical history was notable for poorly controlled type 2 diabetes mellitus of 10 years’ duration, managed with oral hypoglycemic agents, and regular menstrual cycles. Obstetric history included four uncomplicated term vaginal deliveries. She had undergone three therapeutic paracenteses in the prior month for symptomatic ascites. Physical examination revealed a chronically ill-appearing, underweight female (BMI 17.8 kg/m²) with marked abdominal distension. Hirsutism assessment using the modified Ferriman–Gallwey scoring system yielded a total score of 13, indicating moderate-to-severe androgen-dependent hair growth. A firm, irregular, mobile pelvic-abdominal mass was palpable, extending two fingerbreadths above the umbilicus with elastic consistency and tenderness on deep palpation. Bimanual vaginal examination confirmed an irregular, fixed, tender mass occupying the right adnexa and cul-de-sac.

Laboratory investigations are summarized in Table 1. Notable findings included hypoalbuminemia (3.22 g/dL), mild renal impairment (creatinine 1.64 mg/dL), and markedly elevated CA-125 (1,480 U/mL). Serum total testosterone was within normal limits (7.5 ng/dL; reference range: 6–82 ng/dL for adult females). The patient underwent exploratory laparotomy, total abdominal hysterectomy, bilateral salpingo-oophorectomy, infracolic omentectomy, and comprehensive surgical staging. Intraoperative findings included a 10 × 10 cm encapsulated right ovarian tumor with surface excrescences, dense adhesions to the posterior uterus and rectosigmoid, hemorrhagic ascites (2,800 mL), and multiple nodular implants on the liver capsule, omentum, and parietal peritoneum. Frozen section analysis indicated carcinoma. Final histopathology confirmed stage IIIC ovarian clear cell carcinoma with endometrioid differentiation and extensive lymphovascular invasion.

Table 1. Key Laboratory Parameters

Note: Values reflect pre-operative assessment; CA-125 markedly elevated consistent with malignancy; testosterone normal excluding hyperandrogenemia; mild anemia, hypoalbuminemia, and renal impairment secondary to advanced disease.

Transabdominal ultrasonography revealed a complex 10.96 × 10.77 cm right ovarian mass with mixed solid-cystic components, thick septations, and internal vascularity, accompanied by massive ascites and echogenic peritoneal deposits suggestive of carcinomatosis. Non-contrast computed tomography (CT) of the abdomen and pelvis corroborated a 9.5 × 8.3 × 5.5 cm heterogeneous solid-cystic mass arising from the right ovary, with adhesions to the uterine fundus and sigmoid colon, gross ascites, omental caking, and suspicious osteolytic lesions in the T12 vertebra, right ilium, and bilateral femoral heads (Figure 2).

Figure 2. Axial non-contrast CT image showing a large heterogeneous solid-cystic right ovarian mass (white arrow) with adjacent ascites and omental nodularity (arrowhead).

DISCUSSION

Hirsutism, characterized by excessive terminal hair growth in androgen-dependent areas such as the face, chest, and lower abdomen, represents a clinical hallmark of hyperandrogenism in the majority of affected women [10]. Approximately 80–90% of cases are driven by elevated circulating androgens, predominantly testosterone and its potent metabolite dihydrotestosterone (DHT), which prolong the anagen phase of the hair cycle, enlarge the dermal papilla, and promote vellus-to-terminal hair transformation [3,11]. In contrast, idiopathic hirsutism—diagnosed in 10–20% of patients—occurs despite normal serum androgen levels and ovulatory function, implicating peripheral mechanisms of androgen action rather than systemic overproduction [14]. A comprehensive literature review revealed no prior association between hirsutism and ovarian clear cell carcinoma (OCCC), a subtype comprising 1–12% of epithelial ovarian cancers, known for its aggressive biology, platinum resistance, and frequent linkage to endometriosis and ARID1A/PIK3CA mutations [6,7]. With a median diagnostic age of 50.2–55.7 years, OCCC rarely exhibits endocrine activity, making the concurrent hirsutism in this case unprecedented [9].

Instead, the clinical presentation aligns with idiopathic or normoandrogenic hirsutism, wherein heightened end-organ sensitivity amplifies androgenic effects without elevating circulating levels [15]. Central to this phenotype is enhanced cutaneous 5α-reductase type 1 activity within pilosebaceous units, catalyzing the irreversible conversion of testosterone to DHT—a fivefold more potent androgen receptor agonist [16]. Additional contributors include androgen receptor (AR) gene polymorphisms on the X chromosome, where shorter CAG trinucleotide repeats correlate with heightened transcriptional activity and exaggerated phenotypic responses to normal androgen concentrations [17]. Impaired peripheral aromatization, reflected in reduced estradiol-to-testosterone ratios, may further shift the hormonal milieu toward relative hyperandrogenism [18]. Emerging evidence positions the skin as an autonomous steroidogenic organ, expressing the full enzymatic cascade—from StAR protein and P450scc to P450c17—enabling de novo synthesis of DHT from cholesterol or DHEAS independently of gonadal or adrenal input [19,20]. Supporting this, increased mRNA expression of steroid sulfatase and 17β-hydroxysteroid dehydrogenase type 5 has been documented in hirsute skin, facilitating local androgen activation from circulating precursors like dehydroepiandrosterone sulfate (DHEAS) [21]. The normal serum testosterone (7.5 ng/dL) observed herein excludes tumor-derived hyperandrogenemia, a mechanism well-established in ovarian steroid-cell neoplasms such as Leydig or Sertoli-Leydig cell tumors, which secrete testosterone or androstenedione directly [22].

Although OCCC lacks steroidogenic histology, tumor-derived cytokines or paracrine factors could theoretically upregulate these pathways in distant pilosebaceous units, though this remains speculative pending molecular validation. This case thus represents the first documentation of clinically significant hirsutism in OCCC with normoandrogenic profile, challenging conventional etiological frameworks and underscoring the need for integrated genomic, metabolomic, and dermatopathological studies to elucidate non-classical mechanisms of androgen-independent hair growth in malignancy [23].

CONCLUSION

This is the first reported case of hirsutism in ovarian clear cell carcinoma with normal testosterone, indicating idiopathic normoandrogenic hirsutism. Peripheral mechanisms—enhanced 5α-reductase activity and androgen receptor hypersensitivity—likely drive virilization, urging molecular studies to clarify malignancy-related non-hyperandrogenic pathways.

DECLARATIONS

None

CONSENT FOR PUBLICATION

The Authors agree to be published in the Journal of Society Medicine.

FUNDING

None

COMPETING INTERESTS

The authors declare no conflicts of interest in this case report.

AUTHORS’ CONTRIBUTIONS

All authors made substantial contributions to the case report. DFN was responsible for patient management, data collection, and initial drafting of the manuscript. All authors reviewed and approved the final version of the manuscript, ensuring its accuracy and integrity, and are accountable for all aspects of the work.

ACKNOWLEDGMENTS

None

REFERENCE

1. Pasquali R, Gambineri A. New perspectives on the definition and management of polycystic ovary syndrome. J Endocrinol Invest. 2018;41(10):1123-1135.

2. Unluhizarci K, Kaltsas G, Kelestimur F. Non polycystic ovary syndrome-related endocrine disorders associated with hirsutism. Eur J Clin Invest. 2012;42(1):86-94.

3. Azziz R, Carmina E, Sawaya ME. Idiopathic hirsutism. Endocr Rev. 2000;21(4):347-362.

4. Vera L, Bogatti P, Crescini C, et al. Increasing hirsutism due to a granulosa-cell tumor in a woman with polycystic ovary syndrome: case report and review of the literature. Gynecol Endocrinol. 2013;29(4):273-277.

5. Swain J, Sharma S, Prakash V, Agrawal NK, Singh SK. Steroid cell tumor: a rare cause of hirsutism in a female. Endocrinol Diabetes Metab Case Rep. 2013;2013:130030.

6. Angelina Y, Tjokroprawiro B. Advanced stage clear cell ovarian carcinoma mimicking uterine sarcoma without gross residual tumor during primary surgery: a case report. Clin Med Insights Case Rep. 2023;16:11795476231166623.

7. Rodrigues S, Braga M, Felix A, Cunha T. Clear cell carcinoma of the ovary: clues for radiologists to perform a correct diagnosis. Curr Probl Diagn Radiol. 2024;53(2):271-278.

8. del Carmen MG, Birrer M, Schorge JO. Clear cell carcinoma of the ovary: a review of the literature. Gynecol Oncol. 2012;126(3):481-490.

9. Prat J. Ovarian carcinomas: at least five different diseases with distinct histological features and molecular genetics. Hum Pathol. 2018;82:1-10.

10. Armata I, Prakash A. An update on the assessment and management of hirsutism. Obstet Gynaecol Reprod Med. 2024;34(4):91-98.

11. Unluhizarci K, Hacioglu A, Taheri S, Karaca Z, Kelestimur F. Idiopathic hirsutism: is it really idiopathic or is it a misnomer? World J Clin Cases. 2023;11(2):292-298.

12. Rosenfield RL. Plasma free androgen patterns in hirsute women and their diagnostic implications. Am J Med. 1979;66(3):417-421.

13. Ceruti JM, Leirós GJ, Balañá ME. Androgens and androgen receptor action in skin and hair follicles. Mol Cell Endocrinol. 2018;465:122-133. doi:10.1016/j.mce.2017.09.009

14. De Kroon RWPM, den Heijer M, Heijboer AC. Is idiopathic hirsutism idiopathic? Clin Chim Acta. 2022;531:17-24.

15. Legro RS, Shahbahrami B, Lobo RA, Kovacs BW. Size polymorphisms of the androgen receptor among female Hispanics and correlation with androgenic characteristics. Obstet Gynecol. 1994;83(5 Pt 1):701-706.

16. Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med. 2005;353(24):2578-2588.

17. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res. 1994;22(15):3181-3186.

18. Unlühizarci K, Karababa Y, Bayram F, Kelestimur F. The investigation of insulin resistance in patients with idiopathic hirsutism. J Clin Endocrinol Metab. 2004;89(6):2741-2744.

19. Inoue T, Miki Y, Kakuo S, et al. Expression of steroidogenic enzymes in human sebaceous glands. J Endocrinol. 2014;222(3):301-312.

20. Chen W, Thiboutot D, Zouboulis CC. Cutaneous androgen metabolism: basic research and clinical perspectives. J Invest Dermatol. 2002;119(5):992-1007.

21. Fritsch M, Orfanos CE, Zouboulis CC. Sebocytes are the key regulators of androgen homeostasis in human skin. J Invest Dermatol. 2001;116(5):793-800.

22. Alves P, Sá I, Brito M, Carnide C, Moutinho O. An early diagnosis of an ovarian steroid cell tumor not otherwise specified in a woman. Case Rep Obstet Gynecol. 2019;2019:2537480.

23. Markopoulos MC, Rizos D, Valsamakis G, et al. Management of endocrine disease: hyperandrogenism after menopause. Eur J Endocrinol. 2015;172(2):R79-R91.