Ovarian Leydig Cell Tumor in a Peri-Menopausal Woman With Severe Hyperandrogenism and Virilization

By Nardo, L G; Ray, D W; Laing, I; Williams, C; Et al


The authors report a case of Leydig cell tumor in a 46-year-old woman who first presented with severe clinical hyperandrogenism and associated complex medical history. Investigations revealed markedly raised serum concentrations of testosterone (28.3 nmol/l) and free androgen index (54.4), whereas sex hormone binding globulin, random cortisol, androstenedione, 17-hydroxyprogesterone and dehydroepiandrosterone sulphate concentrations were all within the normal range. Transabdominal ultrasound and computed tomography scan of the pelvis and abdomen showed a slightly bulky right ovary, but no other abnormalities. An ovarian source of androgens was suspected and surgery was arranged. Following a three-year history of defaulting appointments due to agoraphobia, she underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and intraoperative selective ovarian venous sampling. Histopathological examination revealed a 2 cm Leydig cell tumor within the right ovary. Successful intraoperative ovarian venous sampling demonstrated significantly elevated testosterone levels (> 260 nmol/ l) from the right ovarian vein. Hyperandrogenaemia normalized post- operatively. The patient showed significant regression of clinical signs and symptoms, including the anxiety disorder. Clinical presentation, biochemistry and imaging modalities should allow to detect androgen-secreting ovarian tumors, while selective venous sampling should be reserved for patients whom uncertainty remains. The present case confirms that androgen-secreting ovarian tumors represent a diagnostic and therapeutic challenge. They have to be considered in the differential diagnosis of severe hyperandrogenism even in peri-menopausal women. Although selective venous sampling is of diagnostic value, however, its impact on future management should be considered on individual basis.

Keywords: Hyperandrogenism, ovarian Leydig cell tumor, peri- menopause, selective venous sampling, virilization


Though polycystic ovary syndrome (PCOS) and nonmalignant androgen excess disorders are common causes of hyperandrogenism, other aetiologies such as ovarian or adrenal tumors have to be excluded. Leydig cell tumors and hilus cell tumors are distinctive functioning ovarian tumors that produce testosterone leading to hyperandrogenism and virilization in women [1]. These rare benign tumors are found more frequently in postmenopausal women. Nevertheless, a case of ovarian mucinous cystadenoma with functioning stroma and signs of virilization during pregnancy has been recently reported [2]. The diagnosis can be very difficult because the size of such tumors is often too small to be detected by imaging techniques [3]. The diagnostic role and impact on management of ovarian and adrenal venous sampling in women presenting with symptoms and signs of hyperandrogenism has recently been debated [4]. Bilateral ovarian stromal hyperthecosis is being increasingly recognized as a cause of significant hyperandrogenaemia in perimenopausal women. This is frequently accompanied by marked insulin resistance with other florid features of the metabolic syndrome which include hypertension, obesity, low HDL cholesterol and high triglycerides [5,6]. Such patients are at greatly increased risk for cardiovascular events particularly when coronary heart disease is established. As such they represent an at-risk group for surgical and anaesthetic procedures, and as surgical management of this condition is optional, minimally invasive diagnostic procedures assume increased importance.

We report a rare case of ovarian Leydig cell tumor in a peri- menopausal woman with severe hyperandrogenism and virilization.

Case report

A 46-year-old woman of Caucasian origin was referred to the joint gynae-endocrine clinic with worsening history of hyperandrogenism and virilization. She presented with severe facial and body hirsutism, receding hairline, male-pattern baldness and 7-year history of amenorrhoea. She was gravida 2 para 2 having had 2 spontaneous vaginal deliveries. She had an intra-uterine device in situ as contraception. Her medical history was complicated by ischaemic heart disease, myocardial infarction, hypertension, hypercholesterolaemia, osteoarthritis, asthma and anxiety disorder with prominent agoraphobia. She admitted to be a non-smoker and consumed no alcohol.

On physical examination, her weight was 65 kg and height was 161cm (BMI 25kg/m^sup 2^), and blood pressure was 128/90 mmHg while on medications. Initial biochemistry included baseline hormone profile, amenorrhoea work-up including prolactin, thyroid function test, testosterone, androstenedione, free androgen index (FAI), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), 17-hydroxyprogesterone and random cortisol, full blood count and liver function tests. Testosterone and free androgen index were markedly raised at 28.3nmol/l and 54.4, respectively. Table I shows endocrine parameters at the time of initial referral. Liver function test showed raised cholesterol (8.6mmol/l) and triglyceride (5.1mmol/l), and normal HDL (0.87 mmol/1). Transabdominal ultrasound scan of the pelvis and abdomen showed normal findings, although the right ovary was reported as being slightly larger compared with the left ovary (4cc and 3cc, respectively). These findings were confirmed by computed tomography (CT) scan. An ovarian source of clinical and biochemical hyperandrogenism was suspected. The patient was therefore advised to undergo surgery in the form of total abdominal hysterectomy and bilateral salpingo-oophorectomy. Due to her rather complicated medical history, she was referred for pre- operative anaesthetic and cardiology assessment. Despite continuous attempts in recalling, the patient ended up missing three-year appointments as a consequence of her prominent agoraphobia, for which she was largely house-bound.

Subsequent to a long period of counselling and anti-depressant treatment, she presented again with far worse signs and symptoms of hyperandrogenism. Biochemistry showed elevated serum testosterone levels and FAI. At the time, paired fasting insulin was raised at 13.3 mU/1, while glucose was within normal range (5.4 mmol/1). Urine free cortisol levels were also normal (53 nmol/24-h), with a volume of 1250ml. In accordance with previous imaging investigation, transabdominal ultrasound scan of the pelvis and abdomen demonstrated only an enlarged right ovary at 5 cc volume, but no cystic lesions were seen. The patient was advised to have surgery, and the need for such treatment was highlighted. Pre-operative investigations were arranged and she was operated on four weeks after her last outpatient appointment.

At laparotomy, the right ovary was slightly enlarged showing a pale-brown solid nodule measuring approximately 2 cm in diameter (Figure 1). There were no ascites or peritoneal lesions. No other abnormalities were found. Each ovarian vein was cannulated and blood sampling performed prior to total abdominal hysterectomy and bilateral salpingooophorectomy. Surgery was uneventful and she made a satisfactory post-operative recovery. Biochemistry of right ovarian vein sampling showed markedly increased testosterone levels ( > 260 nmol/1) compared with the contralateral (38.4nmol/1). Histopathology confirmed a 2cm Leydig cell tumor of the right ovary (4.0 1.8 1.5cm), localized in the stroma (Figure 2). Microscopic examination as follows: the cytoplasm was predominantly eosinophilic; rodshaped Reinke crystals were identified; the stroma was fibrotic and hyalinized and blood vessels showed fibrinoid change. The left ovary (3.0 1.8 1.3cm) showed a mild degree of stromal hyperplasia, but no evidence of hyperthecosis. The pre- operative elevated androgen levels normalized following surgery (Table II). Post-operatively, the clinical signs of hyperandrogenism improved significantly. The case was discussed at the multidisciplinary tumor meeting, but no further action was taken. At 6-month follow-up, the patient remains fit and well, with significantly improved signs of virilization and completely resolved anxiety.

Table I. Endocrine parameters at the time of first referral.

Figure 1. Right ovary contains the pale-brown nodule representing the area of tumor.

Figure 2. Leydig cell tumor containing Reinke crystals (arrow) (HJE).

Table II. Androgen measurements pre- and post-surgery.


High peripheral androgen levels and virilization may be associated with an androgen-producing tumor of either the ovary or the adrenal. Leydig cell tumors, which account for less than 0.1% of all ovarian tumors, are more often diagnosed in postmenopausal women [7]. These tumors are, whenever suspected, a diagnostic and therapeutic challenge for the clinician. They are small (

Ovarian stromal hyperthecosis is usually associated with a long history of anovulation, amenorrhoea and of slowly, but relentlessly, progressing virilization. However, in peri-menopausal and reproductive age women symptoms of hyperthecosis may be of rapid onset whilst androgen-producing tumors characteristically cause rapidly progressing signs of androgen excess [2,5,6,8]. With all \androgen-producing ovarian tumors, serum testosterone is elevated in conjunction with normal or mildly elevated serum DHEAS levels. The lack of a significant increase in DHEAS distinguishes ovarian from adrenal androgen-producing tumors. In this case, while DHEAS levels were within the normal range, testosterone and FAI measurements were markedly increased, hence suggesting an ovarian origin.

Androgen-secreting ovarian tumors, which are small and often embedded within the ovary, may be missed if no sensitive imaging techniques are used [9,1O]. Transvaginal ultrasonography associated with colour Doppler plays a role in the detection and characterization of ovarian tumors [U]. Our patient did repeatedly deny transvaginal ultrasound, so transabdominal and CT scan were carried out instead. Although not very sensitive, however both these imaging modalities showed a right ovary slightly enlarged compared with the contralateral. Whether the use of transvaginal ultrasonography would allow making a prompt and more certain diagnosis and demonstrating more features cannot be argued.

During the last two decades, several authors have reported the role of selective ovarian and adrenal venous catheterization as investigation for hyperandrogenism [9,10,12,13]. A unilateral androgen gradient allows the localization of the lesion. Nevertheless, successful selective catheterization, even in expert hands, has been achieved in about 27% of cases [4], with the main limitation being anatomical variation in venous size and drainage [14]. In the present case, significantly elevated testosterone levels in the intraoperative sample collected from the right ovarian vein confirmed the site of lesion. In agreement with other authors [14], we sustain that selective venous catheterization should not be performed routinely in women presenting with symptoms and signs of severe hyperandrogenism. On the other hand, it should be reserved for women in whom uncertainty remains, especially after adrenal CT and ovarian transvaginal ultrasonography have failed to demonstrate any pathology [9,10,13]. Clinical presentation in conjunction with the imaging findings lead to a correct diagnosis in the vast majority of women presenting with hyperandrogenism.

The management of hirsutism and virilization should be directed toward its specific causes, aiming to suppress the abnormal androgen secretion. While neoplasms warrant surgical intervention, hyperandrogenism due to stromal hyperthecosis may be medically suppressed with GnRH agonist depending on age and fitness to surgery. Prompt improvement of clinical and biochemical hyperandrogenism following surgery has been reported [15,16]. In our case, clinical symptoms and signs of virilization improved significantly post-operatively. Of relevance, the anxiety disorder presenting as agoraphobia disappeared and the patient ceased pharmacological treatment. Also, the pre-operative markedly increased serum testosterone levels and FAI normalized after surgery.

In conclusion, this case-report confirms that androgen-secreting ovarian tumors have to be considered amongst other disorders causing virilization in peri-menopausal and reproductive age women. Appropriate diagnostic approach encompassing clinical presentation, conventional biochemical and imaging methods (i.e., transvaginal ultrasound) is paramount. Although selective venous catheterization and sampling has good diagnostic value to further investigate an ovarian source or to plan conservative management, however it should be generally reserved for patients whom uncertainty remains. The role of this invasive diagnostic tool to help in selecting the adequate surgical approach remains a matter of much debate.


1. Takeuchi S, Ishihara N, Ohbayashi C, Itoh H, Maruo T. Stromal Leydig cell tumour of the ovary. case report and literature review. Int J Gynecol Pathol 1999;18:178-182.

2. Antoniou N, Varras M, Akrivis CH, Demou A, Bellou A, Stefanaki S. Mucinous cystadenoma of the ovary with functioning stroma and virilization in pregnancy: A case report and review of the literature. CHn Exp Obstet Gynecol 2003;30:248-252.

3. Pugeat M, Mirakian P, Dutrieux-Berger N, Forest MG, Tourniaire J. Androgen secreting ovarian neoplasm. In: Azziz R, Nestler JE, Dewailly D, editors. Androgen excess disorders in women. New York: Lippincott-Raven; 1997. pp 555-568.

4. Kaltsas GA, Mukherjee JJ, Kola B, Isidori AM, Hanson JA, Daciet JE, Reznek R, Monson JP, Grossman AB. Is ovarian and adrenal venous catheterization and sampling helpful in the investigation of hyperandrogenic women? CHn Endocrinol 2003;59:34-43.

5. Barth JH, Jenkins PM, Belchetz P. Ovarian hyperhecosis, diabetes and hirsuties in post-menopausal women. CHn Endocrinol 1997;46:123-128.

6. Ayuk P, Stringfellow H, Donnai P, Beardwell CG, Holt A, Laing I. Hirsutism of recent onset with marked hyperandrogenaemia after the menopause. Ann CHn Biochem 1998;35: 145-148.

7. Monteagudo A, Heller D, Husami N, Levine RU, McCaffrey R, Timor-Tritsch IE. Ovarian steroid cell rumours: Sonographic characteristics. Ultrasound Obstet Gynecol 1997; 10: 282-288.

8. Judd HL, Scully RE, Herbst AL, Yen SS, Ingersol FM, Kliman B. Familial hyperthecosis: comparison of endocrinologie and histologie findings with polycystic ovarian disease. Am J Obstet Gynecol 1973;! 17:976-982.

9. Surrey ES, de Ziegler D, Gambone JC, Judd HL. Preoperative localization of androgen secreting tumours: clinical, endocrinologie and radiologie evaluation often patients. Am J Obstet Gynecol 1988;158:1313-1322.

10. Outwater EK, Marchetto B, Wagner BJ. Virilizing tumors of the ovary: Imaging features. Ultrasound Obstet Gynecol 2000; 15:365- 371.

11. Varras M. Benefits and limitations of ultrasonographic evaluation of uterine adnexal lesions in early detection of ovarian cancer. CHn Exp Obstet Gynecol 2004;31:85-98.

12. Moltz L, Schwartz U, Sorensen R, Pickartz H, Hammerstein J. Ovarian and adrenal vein steroids in patients with nonneoplastic hyperandrogenism: Selective catheterization findings. Fertil Steril 1984;42:69-75.

13. Stephens JW, Katz JR, McDermott N, MacLean AB, Bouloux PM. An unusual steroid-producing ovarian tumour: case report. Hum Reprod 2002;17:1468-1471.

14. Sorensen R, Moltz L, Schwartz U. Technical difficulties of selective blood sampling in the differential diagnosis of female hyperandrogenism. Cardiovasc Intervent Radiol 1986;9:75-82.

15. Amato G, Izzo G, Izzo A. A paradoxical inhibition of androgenic hyperproduction by a Sertoli-Leydig cell tumour ovary. Hum Reprod 1995;10:2967-2969.

16. Surbeck DV, Hoesli I, Torhorst J, Almendral AC, Delias A, Holzgreve W. Virilizing ovarian tumour of low malignant potential associated with antecedent tamoxifen use for breast cancer. Gynecol Oncol 1998;68:293-296.

L. G. NARDO1, D. W. RAY2, I. LAING3, C. WILLIAMS3, R. J. McVEY4, & M. W. SEIF1

1Academic Unit of Obstetrics, Gynaecology and Reproductive Health, St Mary’s Hospital, 2 Department of Endocrinology, 3Department of Clinical Biochemistry, and 4Department of Histopathology, Central Manchester and Manchester Children University Hospital, Manchester, UK

(Received 21 December 2004; revised 26 April 2005; accepted 27 April 2005)

Correspondence: Dr Luciano G. Nardo, Department of Reproductive Medicine, St Mary’s Hospital, Whitworth Park, Manchester M13 OJH, UK. Tel: +44 0161 276 6371/6340. Fax: +44 0161 224 0957. E-mail: [email protected]

Copyright CRC Press Oct 2005