Use of Depot Leuprolide and Cyproterone to Control Aggression in an All-Male California Sea Otter (Enhydra lutris nereis) Colony
Male marine mammals in zoos and aquariums are sometimes maintained alone or in same sex groups for behavioral demonstrations, to prevent breeding, control aggressive behavior, or retain the genetic representation of animals for future reproduction. These management schemes may be complicated by undesirable behaviors (aggression, anorexia, and loss of operant training). While castration effectively minimizes these problems, anesthesia and surgery are required and it eliminates future reproduction.
Leuprolide acetate is a long-acting, but reversible, gonadotropin-releasing hormone (GnRH) agonist. Administration initially results in an increase in follicle stimulating hormone (FSH) and luteinizing hormone (LH) causing transiently elevated testosterone. A progressive suppression then occurs reducing circulating testosterone levels to those of a castrate. Leuprolide acetate has been previously demonstrated to suppress testicular function in Atlantic bottlenose dolphins (Tursiops truncatus).2,3 Cyproterone is an orally administered testosterone receptor blocking agent. In addition to blocking androgen receptors, it exerts a negative feedback on the hypothalamic pituitary axis inhibiting LH secretion and consequently suppresses testicular testosterone production.
Four male California sea otters (Enhydra lutris nereis) were exhibited together at the Aquarium for Wildlife Conservation. As they matured, intraspecific aggression developed until eventually they could no longer be maintained as a compatible colony. During this study (July 1996–December 1997) parenteral leuprolide acetate in either a 1-month (phase 1)1,4 or 4-month (phase 2) depot suspension, or oral cyproterone acetate (phase 3), were administered in succession to control aggression.
Four otters were included in phase 1.1,4 One otter died of causes unrelated to the study and the remaining three otters were included in phases 2 and 3. Ages and weights of otters ranged from 3.5–6 years, and 20–34 kg, during the course of the study. Otters were manually confined in an otter restraint device for venipuncture and all injections.5
During phase 1 otters received 3.75 mg (0.11–0.19 mg/kg) of a 1-month depot formulation of leuprolide acetate IM at monthly intervals. Initiation of drug administration in each otter was staggered, so animals received 3–7 injections in a 6-month interval. In phase 2, otters were given 30 mg (0.9–1.1 mg/kg) of a 4-month depot formulation of leuprolide acetate administered either IM or SC twice at intervals of 3.5–4 months. Leuprolide was administered in the dorsal surface of a pelvic limb. In phase 3, otters were given 50 or 75 mg (1.5–2.3 mg/kg) cyproterone acetate PO, SID for 84 days.
Testicular lengths of two otters were measured before the initial treatment and at the end of each phase. Marked testicular atrophy occurred and was maintained in all phases. Pretreatment testicular length (mean ± SD) (53±3.5 mm) was significantly greater (paired t-test; p<0.05) than at the end of each phase (35±2.5 mm, 27.5±2.5 mm, and 26.8±2.6 mm for phases 1, 2, and 3; respectively). Mean testicular length in phase 1 was significantly greater (Tukey Honest Test, p<0.05) than in phases 2 and 3; there was no significant difference in testicular size between phases 2 and 3.
Testosterone levels were determined by radioimmunoassay before treatment and then monthly in phase 1; 3–5 times at 4–6-week intervals in phase 2; and 2–3 times 4–12 weeks after initiation of treatment in phase 3. Testosterone levels of the youngest otter were below the assay detection limit (<0.05 ng/ml) on all sampling dates. Pretreatment values for the two others ranged from 0.31–2.28 ng/ml. Testosterone levels in phase 1 decreased after 1 month of treatment (<0.05–0.19 ng/ml) and after 2 months of treatment all were undetectable. In phase 2, all testosterone levels except one (0.7 ng/ml) were below the assay detection limit. In phase 3, testosterone was below the assay detection limit on all sampling dates.
Despite the effectiveness of leuprolide at inducing testicular atrophy and testosterone suppression, with consequent reduction in intraspecific aggression, treatment was discontinued due to adverse injection site reactions. These consisted of anorexia and depression with moderate to marked injection site lameness, swelling, or sterile abscesses. Preventing or treating these reactions with either diphenhydramine (1.5 mg/kg PO, BID for 7 days) or flunixin meglumine (0.9 mg/kg PO, SID for 5 days) was not successful while carprofen (1.5–2 mg/kg PO, BID for 5–10 days) was a more effective treatment. Some otters were also treated with trimethoprim sulfa (33.6 mg/kg PO, SID for 10 days). No adverse effects were noted in phase 3.
Administration of depot leuprolide acetate or cyproterone acetate was successful in suppressing testosterone and controlling aggression in an all-male sea otter colony. This enabled otters to be maintained in a more compatible social group. Leuprolide was more effective than cyproterone in controlling aggression. Compared to castration, advantages of these medications include no requirement for anesthesia or surgery and reversibility. Disadvantages of leuprolide are the drug cost, injection site reactions, and the necessity for frequent animal handling. Cyproterone acetate is currently not commercially available in the United States but offers the advantage of oral administration with no animal handling required. These treatments have potential application for the control of male-associated undesirable behaviors in sea otters in zoos and aquariums. A trial with a long-lasting GnRH agonist implant (deslorelin) is currently underway.
The authors are grateful to TAP Pharmaceuticals for the generous donation of depot leuprolide acetate, to Karen Drayer and the PKD Trust for financial support, and veterinary technicians and animal keepers for their expert technical assistance.
1. Basinger, J.A., H. Walters, P.P. Calle, D.A. Thoney, C. McClave, and M. Hall. 1997. Efforts to reduce dominant and aggressive behavior in an all male California sea otter (Enhydra lutris nereis) colony by the use of testosterone suppressing drug therapy. In: Proc Int Marine Anim Trainers Assoc. 24.
2. Briggs, M.B., W. Van Bonn, R.M. Linnehan, D. Messinger, C. Messinger, and S. Ridgway. 1995. Effects of leuprolide acetate in depot suspension on testosterone levels, testicular size, and semen production in male Atlantic bottlenose dolphins (Tursiops truncatus). In: Proc Int Assoc Aquat Anim Med. 112–114.
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5. Williams, T.D., D.M. Baylis, S.H. Downey, and R.O. Clark. 1990. A physical restraint device for sea otters. J Zoo and Wild Med. 21(1):105–107.