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Induction of Ovarian Granulosa Cell Tumors in SWXJ-9 Mice with Dehydroepiandrosterone¹

The Jackson Laboratory,² Bar Harbor, Maine 04609

Spontaneous ovarian granulosa cell (GC) tumors develop in SWXJ-9 inbred mice at approximately the time of puberty. The effect of dehydroepiandrosterone (DHEA), a steroid secreted by the adrenals and reported to have antitumor actions, was examined in this ovarian tumor model. In contrast with expectations, administration of diet supplemented with 0.4% DHEA or Silastic capsules containing 10 mg DHEA resulted in a significant multifold increase in GC tumor incidence. Similar studies with metabolites of DHEA, i.e., testosterone (TESTO), dihydrotestosterone (DHT), and 17ß-estradiol (E₂), revealed that TESTO was as effective as DHEA in increasing GC tumor incidence. DHT was without effect, and E₂ suppressed GC tumor incidence.

Serum steroid levels and steroid target tissue responses were assessed to determine if a correlation between a change in level or response to specific steroids and GC tumorigenesis existed. In both tumor-free and GC tumor host mice, dietary or capsular treatment with DHEA, TESTO, or DHT resulted in substantial alteration in one or more of serum steroids, DHEA, androstenedione, TESTO, and DHT, in addition to the administered steroid. No consistent correlation was observed between changes in a single steroid or pattern of steroids and GC tumorigenesis. Although significant increases in serum estrogens could be detected in GC tumor hosts treated with DHEA but not TESTO, estrogens did not induce these tumors. Treatment with E₂ increased only serum E₂ levels. In tumor-free mice, DHEA and E₂ treatments were associated with vaginal cytological evidence of estrogen action, whereas the androgens induced a leukocytic pattern. Eighty-eight % of GC tumor host mice, regardless of steroid treatment, showed a vaginal cytology pattern that included cornified cells.

The evidence presented in this report leads us to hypothesize that (a) spontaneous and steroid-induced GC tumorigenesis in these mice have the same mechanism, and (b) subtle increases in DHEA or a closely related metabolite during the peripubertal period may initiate GC tumors in these genetically susceptible mice. The mechanism whereby these steroids initiate GC tumorigenesis remains to be determined.

¹ This research was supported by American Cancer Society Grant CD-265 and National Cancer Institute Grant CA-24145 (W. G. B.) and by NIH National Research Service Award T32-CA-09217 (B. J. T.). Its contents are solely the responsibility of the authors and The Jackson Laboratory.

² The Jackson Laboratory is fully accredited by the American Association for Accreditation of Laboratory Animal Care.

Received 8/25/87. Revised 12/22/87. Accepted 2/15/88.

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