Background: Hyperandrogenism is a rare symptom of juvenile ovarian granulosa cell- tumors (JGCTO). This study aimed to determine whether hyperandrogenism was related to overexpression of SOX9, decreased expression of FOXL2 or absent aromatase expression in tumor with particular scheme of expression of P450scc and P450c17α. Methods: Through a nationwide study including the French Society of Pediatric Oncology, 6/30 patients with JGCTO presented with clinical hyperandrogenism and high plasma testosterone. Tumor specimens underwent immunofluorescence (SOX9, FOXL2) and immunochemistry (aromatase, P450scc, P450c17α). Results were compared with patients without hyperandrogenism. Results: SOX9 was expressed in the granulosa cell nucleus in 2/6 cases but also in 9/24 tumors without hyperandrogenism (p = n.s.). FOXL2 was absent or decreased in 3/6 cases of JGCTO with hyperandrogenism with no statistical difference from the group without this symptom. In 6/6 patients, the intratumoral expression of aromatase was absent (n = 5) or dramatically reduced (n = 1). In contrast, 15/24 patients without virilization exhibited conserved aromatase expression in their tumor (p < 0.05). A variable number of tumoral cells expressed P450scc while some interstitial cells were focally immunopositive for P450c17α. Conclusion: Unusual virilization in girls with JGCTO is not explained by a dysregulation in SOX9 or FOXL2 expression, but is related to a localized defect of aromatase expression in granulosa cells and to the ability of interstitial cells to produce testosterone.

1.
Merras-Salmio L, Vettenranta K, Mottonen M, Heikinheimo M: Ovarian granulosa cell tumors in childhood. Pediatr Hematol Oncol 2002;19:145–156.
2.
Vassal G, Flamant F, Caillaud JM, Demeocq F, Nihoul-Fekete C, Lemerle J: Juvenile granulosa cell tumor of the ovary in children: a clinical study of 15 cases. J Clin Oncol 1988;6:990–995.
3.
Zaloudek C, Norris HJ: Granulosa tumors of the ovary in children: a clinical and pathologic study of 32 cases. Am J Surg Pathol 1982;6:503–512.
4.
Kalfa N, Patte C, Orbach D, Lecointre C, Pienkowski C, Philippe F, Thibault E, Plantaz D, Brauner R, Rubie H, Guedj AM, Ecochard A, Paris F, Jeandel C, Baldet P, Sultan C: A nationwide study of granulosa cell tumors in pre- and postpubertal girls: missed diagnosis of endocrine manifestations worsens prognosis. J Pediatr Endocrinol Metab 2005;18:25–31.
5.
Kalfa N, Ecochard A, Patte C, Duvillard P, Audran F, Pienkowski C, Thibaud E, Brauner R, Lecointre C, Plantaz D, Guedj AM, Paris F, Baldet P, Lumbroso S, Sultan C: Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor? J Clin Endocrinol Metab 2006;91:1842–1847.
6.
Kalfa N, Philibert P, Patte C, Ecochard A, Duvillard P, Baldet P, Jaubert F, Fellous M, Sultan C: Extinction of foxl2 expression in aggressive ovarian granulosa cell tumors in children. Fertil Steril 2007;87:896–901.
7.
Nakashima N, Young RH, Scully RE: Androgenic granulosa cell tumors of the ovary: a clinicopathologic analysis of 17 cases and review of the literature. Arch Pathol Lab Med 1984;108:786–791.
8.
Martinez L, Salmeron M, Carvia RE, Campello TR, Molina R, Herruzo AJ, Nogales FF: Androgen producing luteinized granulosa cell tumor. Acta Obstet Gynecol Scand 1997;76:285–286.
9.
Kalfa N, Fellous M, Boizet-Bonhoure B, Patte C, Duvillard P, Pienkowski C, Jaubert F, Ecochard A, Sultan C: Aberrant expression of ovary determining gene foxl2 in the testis and juvenile granulosa cell tumor in children. J Urol 2008;180:1810–1813.
10.
Benedet JL, Bender H, Jones H, 3rd, Ngan HY, Pecorelli S: FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers: FIGO committee on gynecologic oncology. Int J Gynaecol Obstet 2000;70:209–262.
11.
Cocquet J, Pailhoux E, Jaubert F, Servel N, Xia X, Pannetier M, De Baere E, Messiaen L, Cotinot C, Fellous M, Veitia RA: Evolution and expression of foxl2. J Med Genet 2002;39:916–921.
12.
de Santa Barbara P, Moniot B, Poulat F, Berta P: Expression and subcellular localization of SF-1, SOX9, WT1, and AMH proteins during early human testicular development. Dev Dyn 2000;217:293–298.
13.
Couzinet B, Meduri G, Lecce MG, Young J, Brailly S, Loosfelt H, Milgrom E, Schaison G: The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab 2001;86:5060–5066.
14.
Boukari K, Ciampi ML, Guiochon-Mantel A, Young J, Lombes M, Meduri G: Human fetal testis: source of estrogen and target of estrogen action. Hum Reprod 2007;22:1885–1892.
15.
Osawa Y, Higashiyama T, Fronckowiak M, Yoshida N, Yarborough C: Aromatase. J Steroid Biochem 1987;27:781–789.
16.
Kominami S, Ogawa N, Morimune R, De-Ying H, Takemori S: The role of cytochrome B5 in adrenal microsomal steroidogenesis. J Steroid Biochem Mol Biol 1992;42:57–64.
17.
Hanukoglu I, Suh BS, Himmelhoch S, Amsterdam A: Induction and mitochondrial localization of cytochrome P450scc system enzymes in normal and transformed ovarian granulosa cells. J Cell Biol 1990;111:1373–1381.
18.
Castro CY, Malpica A, Hearne RH, Silva EG: Androgenic adult granulosa cell tumor in a 13-year-old prepubertal patient: a case report and review of the literature. Int J Gynecol Pathol 2000;19:266–271.
19.
Patel SS, Carrick KS, Carr BR: Virilization persists in a woman with an androgen-secreting granulosa cell tumor. Fertil Steril 2009;91:933.e13–933.e15.
20.
Nomelini RS, Micheletti AM, Adad SJ, Murta EF: Androgenic juvenile granulosa cell tumor of the ovary with cystic presentation: a case report. Eur J Gynaecol Oncol 2007;28:236–238.
21.
Larizza D, Calcaterra V, Sampaolo P, Lanati G, Brambilla P, Mondello T, Cesari S: Unusual presentation of juvenile granulosa cell tumor of the ovary. J Endocrinol Invest 2006;29:653–656.
22.
Kabaca C, Karateke A, Gurbuz A, Cesur S: Androgenic adult granulosa cell tumor in a teenager: a case report and review of the literature. Int J Gynecol Cancer 2006;16(suppl 1):368–374.
23.
Sekido R, Bar I, Narvaez V, Penny G, Lovell-Badge R: SOX9 is up-regulated by the transient expression of SRY specifically in Sertoli cell precursors. Dev Biol 2004;274:271–279.
24.
Vidal VP, Chaboissier MC, de Rooij DG, Schedl A: SOX9 induces testis development in XX transgenic mice. Nat Genet 2001;28:216–217.
25.
Gasca S, Canizares J, De Santa Barbara P, Mejean C, Poulat F, Berta P, Boizet-Bonhoure B: A nuclear export signal within the high mobility group domain regulates the nucleocytoplasmic translocation of SOX9 during sexual determination. Proc Natl Acad Sci USA 2002;99:11199–11204.
26.
Chaboissier MC, Kobayashi A, Vidal VI, Lutzkendorf S, van de Kant HJ, Wegner M, de Rooij DG, Behringer RR, Schedl A: Functional analysis of SOX8 and SOX9 during sex determination in the mouse. Development 2004;131:1891–1901.
27.
Qin Y, Bishop CE: SOX9 is sufficient for functional testis development producing fertile male mice in the absence of SRY. Hum Mol Genet 2005;14:1221–1229.
28.
Prueitt RL, Zinn AR: A fork in the road to fertility. Nat Genet 2001;27:132–134.
29.
Cocquet J, De Baere E, Gareil M, Pannetier M, Xia X, Fellous M, Veitia RA: Structure, evolution and expression of the Foxl2 transcription unit. Cytogenet Genome Res 2003;101:206–211.
30.
Erickson GF, Magoffin DA, Dyer CA, Hofeditz C: The ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev 1985;6:371–399.
31.
Tsonis CG, Carson RS, Findlay JK: Relationships between aromatase activity, follicular fluid oestradiol-17 beta and testosterone concentrations, and diameter and atresia of individual ovine follicles. J Reprod Fertil 1984;72:153–163.
32.
Simpson ER: Aromatization of androgens in women: current concepts and findings. Fertil Steril 2002;77(suppl 4):S6–S10.
33.
Labrie F, Belanger A, Cusan L, Candas B: Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology. J Clin Endocrinol Metab 1997;82:2403–2409.
34.
Labrie F, Belanger A, Luu-The V, Labrie C, Simard J, Cusan L, Gomez JL, Candas B: DHEA and the intracrine formation of androgens and estrogens in peripheral target tissues: its role during aging. Steroids 1998;63:322–328.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.