Leydig-Cell-Tumor of the Ovary that Responded to GnRH-Analogue Administration – Case Report and Review of the Literature

Abstract

Progressive hirsutism can be a symptom of an androgen-producing tumor, especially in postmenopausal women. We report a case of a 58-year-old woman who complained of progressive hirsutism, nervousness, irritability, anxiousness and an increased libido. Examination showed an unusual redness of her head, décolleté, palms and soles of her feet. Basal laboratory tests revealed a profound elevation of testosterone levels (7.5 μg/l) and normal levels of androstendione, dehydroepiandrosterone-sulfate, 17α-hydroxy-progesterone and thyroid-stimulating hormone. Also remarkable was that her red blood count, hemoglobin and hematocrit values were elevated while erythropoietin was within normal limits. Functional laboratory tests ruled out heterozygous C21-hydroxylase deficiency and showed a moderate insulin resistance on the oral glucose tolerance test. Transvaginal ultrasound revealed a slightly hyperdensic area of 6 mm in the left ovary. Magnetic resonance imaging showed a contrast medium-accumulating area of 2 cm in the left ovary. Since the patient was initially reluctant to undergo surgery, a GnRH-analogue (triptoreline) was administered via intramuscular injection once per month for two months and testosterone levels were lowered to less than one third of the initial level (2 μg/l). Surgery was eventually performed with laparoscopic bilateral salpingoophorectomy, hysteroscopy and uterine curettage. The histologic examination revealed a Leydig cell tumor in the hilus and stroma of the left ovary. Postoperatively testosterone levels dropped dramatically and instantly into the normal range. Within months, the red blood count and hematocrit levels were within normal limits. The patient's face became more feminine, the redness of her face and hirsutism regressed. Her anxiousness and nervosity resolved and the insulin sensitivity improved. In this paper, polyglobulia, the metabolic and psychological changes due to hyperandrogenism are discussed, as well as the phenomenon that the tumor responded to a GnRH-analogue. Such a response implies that the tumor is either under gonadotropin control or that GnRH analogues have direct effects via receptors on tumorous Leydig cells.

hyperandrogenemia - androgen-producing tumor - leydig-cell tumor - GnRH-analoga

References

• 1 Bertram KA, Bratloff B, Hodges GF. et al . Treatment of malignant Leydig cell tumor.  Cancer. 1991;  68 2324-2329
• 2 Bohlmann MK, Rabe T, Sinn HP. et al . Intraoperative venous blood sampling to localize a small androgen-producing ovarian tumor.  Gynecol Endocrinol. 2005;  21 ((3)) 138-141
• 3 Böhm J, Röder-Weber M, Höfler H. et al . Bilateral stromal Leydig cell tumour of the ovary.  Pathol Res Pract. 1991;  187 348-352
• 4 Corbould A. Effects of androgens on insulin action in women: is androgen excess a component of female metabolic syndrome?.  Diabetes Metab Res Rev. 2008;  24 ((7)) 520-532
• 5 De Rosa LU. Hypertensive retinopathy caused by a rare ovarian tumor: case report and photo assay.  J Am Optom Assoc. 1991;  62 ((2)) 132-136
• 6 Drife JO, O’Malley BP, Rosenthal FD. Long-term suppression of a testosterone-producing ovarian tumour by oestrogen/progestogen therapy.  Clin Endocrinol. 1987;  27 121-124
• 7 Duun S. Bilateral virilizing hilus (Leydig) cell tumors of the ovary.  Acta Obstet Gyn Scan. 1994;  73 76-77
• 8 Echt CR, Hadd HE. Androgen excretion patterns in a patient with a metastatic hilus cell tumor of the ovary.  Am J Obstet Gynecol. 1968;  100 ((8)) 1055-1061
• 9 Emons G, Ortmann O, Pahwa GS. et al . In-vivo und In-vitro-Effekte von GnRH-Analoga auf einen ovariellen Leydigzelltumor.  Geburtsh Frauenheilk. 1992;  52 487-493
• 10 Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women.  J Clin Endocr Metab. 1961;  21 1440-1447
• 11 Girsh T, Lamb MP, Rollason TP. et al . An endometrioid tumour of the ovary presenting with hyperandrogenism, secondary polycythaemia and hypertension.  BJOG. 2001;  108 ((3)) 330-332
• 12 Gutierrez S, Bermudez M, Zylbersztein C. et al . LH receptor in testosterone-producing ovarian tumor. In vivo and in vitro hCG-stimulated testosterone production.  Eur J Gynaecol Oncol. 1983;  4 ((3)) 182-191
• 13 Horny HP, Braumann W, Weiss E. et al . Virilizing stromal Leydig cell tumor (Leydig cell-containing thecoma) of the ovary in pregnancy. A case report with extensive immunohistochemical investigation of the tumor cells.  Gen Diagn Pathol. 1995;  141 ((1)) 57-60
• 14 Ichinohasama R, Teshima S, Kishi K. et al . Leydig cell tumor of the ovary associated with endometrial carcinoma and containing 17 beta-hydroxysteroid dehydrogenase.  Int J Gynecol Pathol. 1989;  8 ((1)) 64-71
• 15 Kennedy L, Traub AJ, Atkinson AB. et al . Short term administration of gonadotropin-releasing hormone analog to a patient with a testosterone-secreting ovarian tumor.  J Clin Endocr Metab. 1987;  64 1320-1322
• 16 Kienitz T, Quinkler M. Testosterone and blood pressure regulation.  Kidney Blood Press Res. 2008;  31 ((2)) 71-79
• 17 Kim SW, Hwang JH, Cheon JM. et al . Direct and indirect effects of androgens on survival of hematopoietic progenitor cells in vitro.  J Korean Med Sci. 2005;  20 ((3)) 409-416
• 18 Kirschner MA. Adrenal and gonadal venous catheterization studies in hirsute women.. In: Mahesh VB, Greenblatt RB, (eds). Hirsutism and virilism. 1st edn. Boston; John Wright, PSG Inc; 1983: 309-332
• 19 Lamberts SW, Timmers JM, Oosterom R. et al . Testosterone secretion by cultured arrhenoblastoma cells: suppression by a luteinizing hormone-releasing hormone agonist.  J Clin Endocr Metab. 1982;  54 ((2)) 450-454
• 20 Littleton-Kearney M, Hurn PD. Testosterone as a modulator of vascular behaviour.  Biol Res Nurs. 2004;  5 ((4)) 276-285
• 21 Livingstone C, Collison M. Sex steroids and insulin resistance.  Clin Science. 2002;  102 151-166
• 22 Lobo RA. Ovarian hyperandrogenism and androgen-producing tumors.  Endocrin Metab Clin. 1991;  20 ((4)) 773-805
• 23 Loffredo V, Netter A, Musset R. et al . Virilizing Leydig cell tumor of the ovary, discovered and treated during pregnancy.  Gynecol Obstet (Paris). 1967;  66 ((1)) 23-34
• 24 Luton JP, Clercc J, Paoli V. et al . Bilateral Leydig cell tumor of the ovary in a woman with congenital adrenal hyperplasia. The first reported case.  Presse Med. 1991;  20 109-112
• 25 Marcondes JA, Nery M, Mendonca BB. et al . A virilizing Leydig cell tumor of the ovary associated with stromal hyperplasia under gonadotropin control.  J Endocrinol Invest. 1997;  20 ((11)) 685-689
• 26 Matuszczyk A, Petersenn S, Lahner H. et al . Androgenproduzierender Leydig-Zell-Tumor des Ovars als Ursache von Hirsutismus bei einer postmenopausalen Frau.  Med Klein. 2007;  102 ((3)) 259-262
• 27 Muechler EK. Testosterone-producing ovarian tumor associated with erythrocytosis, hyperuricemia, and recurrent deep vein thrombosis.  Am J Obstet Gynecol. 1977;  129 ((4)) 467-469
• 28 Nagajothi N, Sanmugarajah J. Erythrocytosis associated with gestational hyperandrogenism.  Am J Hematol. 2006;  81 ((12)) 984-985
• 29 Nardo LG, Ray DW, Laing I. et al . Ovarian Leydig cell tumor in a peri-menopausal woman with severe hyperandrogenism and virilization.  Gynecol Endocrinol. 2005;  21 ((4)) 238-241
• 30 Nishiyama S, Hirota Y, Udagawa Y. et al . Efficacy of selective venous catheterization in localizing a small androgen-producing tumor in ovary.  Med Sci Monitor. 2008;  14 ((2)) CS9-12
• 31 Oler A, Singh M, Ural SH. Bilateral ovarian stromal hyperplasia concealing a nonhilar, pure stromal-Leydig cell tumor.  J Reprod Med. 1999;  44 ((6)) 563-566
• 32 Outwater EK, Marchetto B, Wagner BJ. Virilizing tumors of the ovary: Imaging features.  Ultrasound Obst Gyn. 2000;  15 365-371
• 33 Paoletti M, Pridjian G, Okagaki T. et al . A stromal Leydig cell tumor of the ovary occurring in a pregnant 15-year-old girl. Ultrastructural findings.  Cancer. 1987;  60 ((11)) 2806-2810
• 34 Paraskevas M, Scully RE. Hilus cell tumor of the ovary. A clinicopathological analysis of 12 Reinke crystal-positive and 9 crystal-negative cases.  Int J Gynecol Pathol. 1989;  8 299-310
• 35 Reman O, Reznik Y, Casadevall. et al . Polycythemia and steroid overproduction of a gonadotropin-secreting seminoma of the testis.  Cancer. 1991;  68 2224-2229
• 36 Rhoden EL, Morgentaler A. Risks of Testosterone-Replacement Therapy and Recommendations for Monitoring.  New Engl J Med. 2004;  350 ((5)) 482-492
• 37 Rittmaster RS. Hirsutism.  Lancet. 1997;  349 191-195
• 38 Roth LM, Sternberg WH. Ovarian stromal tumors containing Leydig cells: II. Pure Leydig cell tumor, non-hilar type.  Cancer. 1973;  32 952-960
• 39 Sanz OA, Martinez PR, Guarch RT. et al . Bilateral Leydig cell tumor of the ovary: A rare cause of virilization in postmenopausal patient.  Maturitas. 2007;  57 ((2)) 214-216
• 40 Stegner HE, Löning TH. Endokrin aktive Tumoren des Ovars.  Pathologe. 2003;  24 314-322
• 41 Stephen MR, Lindop GBM. A renin secreting ovarian steroid cell tumour associated with secondary polycythaemia.  J Clin Pathol. 1998;  51 75-82
• 42 Sternberg WH, Roth LM. Ovarian stromal tumors containing Leydig cells. I. Stromal Leydig cell tumor and non-neoplastic transformation of ovarian stroma to Leydig cells.  Cancer. 1973;  32 940-951
• 43 Stewart RS, Woodward DE. Malignant ovarian hilus cell tumor. The first reported case.  Arch Pathol. 1962;  73 91-99
• 44 Surrey ES, de Ziegler D, Gambone JG. et al . Preoperative localization of androgen secreting tumours: clinical, endocrinologic and radiologic evaluation of ten patients.  Am J Obstet Gynecol. 1988;  158 1313-1322
• 45 Takeuchi S, Ishihara N, Ohbayashi C. et al . Stromal Leydig Cell Tumor of the Ovary.  Int J Gynecol Pathol. 1999;  18 178-182
• 46 Tanaka YO, Tsunoda H, Kitagawa Y. et al . Functioning ovarian tumors:direct and indirect findings at MR imaging.  Radiographics. 2004;  24 ((Suppl. 1)) 147-166
• 47 Tönnies P, Mlynek-Kersjes ML, Gellén Jr J. et al . Ovarieller Leydig-Zell-Tumor.  Zentralbl Gynaekol. 1997;  119 241-245
• 48 Young RH, Scully RE. Sex Cord-Stromal, Steroid Cell, and other ovarian tumors with endocrine, paraendocrine, and paraneoplastic manifestations.. In: Kurman RJ, (ed) Blaustein's pathology of the female genital tract. 5th edn. New York: Springer; 2002: 905-960
• 49 Zhang J, Young RH, Arseneau J. et al . Ovarian stromal tumors containing lutein or Leydig cells (luteinized thecomas and stromal Leydig cell tumors): a clinicopathological analysis of fifty cases.  Int J Gynecol Pathol. 1982;  1 270-285

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