Leuprolide acetate is a long acting gonadotropin-releasing hormone (GnRH) agonist. Administration initially results in an increase in follicle stimulating hormone (FSH) and luteinizing hormone (LH) causing transiently elevated testosterone.5 In mammals testosterone suppression usually follows; it usually approaches zero.
Lupron has been used to suppress testosterone and testicular function in Atlantic bottlenose dolphins (Tursiops truncatus),2,3 to prevent breeding and control aggressive behavior in California sea otters (Enhydra lutris),1,5,6,7 to control undesirable male associated behaviors in California Sea Lions (Zalophus californianus)3,5 and for aggression and birth control in lion-tailed macaques (Macaca silenus).10 It has been shown to lower testosterone levels in black-faced, gray kangaroos (Macropus giganteus), African wild dogs (Lycaon pictus) and spectacled bears (Tremarctus ornatos).4 Lupron has been used to prevent egg-laying problems in cockatiels, where it presumably works as in mammals by down-regulating pituitary GnRH receptors.9 It has been found to be effective in controlling musth in an Asian elephant bull (Elephas maximus).8 It has been used in human males in the treatment of prostatic neoplasia in lieu of orchiectomy and in human females for treatment of endometriosis.11
It seems logical that leuprolide acetate would be similarly effective in other species. However, this was found not to be the case with two, young (2-3 year old) unrelated male African crested porcupines (Hystrix africaeaustralis) (Stremme--not yet published). It was being used to try to treat their inter-male aggression. The expected behavioral response did not occur and blood work did not show the typical drop in testosterone levels either. Never-the-less lupron has been used successfully for inter-male aggression with the gray (Halichoerus grypus) and harbor seals (Phoca vitulina) at the same facility (Stremme--not published).
Two pelagic stingrays (Pteroplatytrygon violacea)--male and female--were acquired in February 2006. Within a month or two the male had become very persistent biting and mating with the female. Both were developing wounds from mating activities and the male was becoming more and more aggressive. They were separated into different systems. The female had pups in June and was released again into the same exhibit with the male about two weeks later. He was again relentless in mating behavior and wouldn't leave her alone. After a day of observing this, the male was moved into a separate system.
The decision was made to try lupron to control the behavior and to monitor blood testosterone levels. A literature search produced 22 different doses of lupron used in various species (no elasmobranchs, however). Based on this search the dose range was 75-200µg (0.075-.2mg)/kg. The male was estimated to be 12-15 lbs (5.46-6.81 kg). A reasonable dose for this animal was estimated to be 0.41 to 1.36 mg. It was decided to use 0.945mg, since this is 1/4 of a 3.78mg vial of the leuprolide acetate.
The male pelagic ray was sedated with 90-100ppm MS-222 each time in order to draw blood. The first (and only) lupron dose was given IM on 7-11-06. At that time we found a resting testosterone level of 4.19ng/ml. The second blood draw was on 7-18. At that time the male was released into the same exhibit with the female. The animals were carefully observed over the next few days and no mating behavior was observed. We anticipated the second testosterone level to have dropped, but it was 7.06ng/ml. The third testosterone value on 7-25 was 8.62ng/ml. No mating behavior was observed, however they did have occasional wounds--thought to be from other stingray species in the exhibit. A fourth sample on 8-1-06 finally showed a decrease in testosterone level; it was 5.42ng/ml. It continued to drop; the value on 8-18 was 3.75ng/ml and on 9-13 was 2.81ng/ml. By the beginning of October mating behavior was again noted, although it wasn't as aggressive as it had been in July. The testosterone level on 10-4-06 was >16ng/ml; this was unexpected. Mating behavior was seen almost every day, but it wasn't as aggressive and the female didn't have the wounds the male had caused in July. By 10-18 the aquarists felt the mating behavior was becoming slightly more aggressive and the testosterone level on that date was again >16ng/ml. After discussion, we decided to wait on giving another lupron injection until the aquarists were sure he was as aggressive as he had been initially. In mid-November he was bitten severely by one of the other stingrays. Unfortunately, despite treatment, the wounds lead to septicemia and death, so further follow up was not possible.
One injection of leuprolide acetate did appear to completely reduce mating aggression in the male pelagic stingray. Also, the blood testosterone level did peak as in mammals, but over a longer period of time. Interestingly, the blood testosterone level did not appear to predict the changes in behavior and vice versa.
The authors would like to thank the aquarists at the Adventure Aquarium for their professional observations and support in capturing and handling the animals involved in this project.
1. Basinger JA, H Walters, PP Calle, DA Thoney, C McClave, M Hall. 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. 1997 Proceedings of the International Marine Animal Trainers Association:24.
2. Briggs MB, W Van Bonn, RM Linnehan, D Messinger, C Messinger, 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). IAAAM Proceedings on CD-ROM:119-120.
3. Briggs MB, D Messinger, C Messinger, RM Linnehan, W Van Bonn, S Ridgway, G Miller. Effects of Leuprolide Acetate in Depot Suspension on Testosterone Levels, Testicular Size and Semen Production in Male Atlantic Bottlenose Dolphins (Tursiops truncatus). 1996 Proceedings of the American Association of Zoo Veterinarians: 330-332.
4. Brigg MB. Effects of a GNRH Agonist on Serum Sex Hormone Level of Male and Female Western Black-faced, Gray Kangaroos, Male African Wild Dogs and Spectacled Bears. 1994 Proceedings of the Association of Reptilian and Amphibian Veterinarians:136-139.
5. Calle PP, MD Stetter, BL Raphael, RA Cook, McClave, J Basinger, H Walters, K Walsh. Use of Depot Leuprolide Acetate to Control Undesirable Male Associated Behaviors in the California Sea Lion (Zalophus californianus) and California Sea Otter (Enhydra lutris). IAAAM Proceedings on CD-ROM:7-9.
6. Calle PP, BL Raphael, RA Cook, C McClave, JA Basinger, H Walters. Use of Depot Leuprolide, Cyproterone, and Deslorelin to Control Aggression in an All Male California Sea Otter (Enhydra lutris nereis) Colony. IAAAM Proceedings on CD-ROM:49-52.
7. Calle PP, C McClave, JA Basinger, H Walters, BL Raphael, RA Cook. Use of Depot Leuprolide, Cyproterone, and Deslorelin to Control Aggression in an All Male California Sea Otter (Enhydra lutris nereis) Colony. 1998 Proceedings AAZV and AAWV Joint Conference:375-77
8. de Oliveira CA, West GD, Houck R, Leblanc M. Control of musth in an Asian elephant bull (Elephas maximus) using leuprolide acetate. J Zoo Wildl. Med. 2004 Mar; 35(1):70-6.
9. Millam JR. Reproductive management of captive parrots. Vet Clin. North Am. Exot. Anim. Pract. 1999 Jan; 2 (1): 93-110.
10. Norton TM, LM Penfold, B Lessnau, W Jochle, SL Staaden, A Jolliffe, JE Bauman, J Spratt. Long-acting Deslorelin Implants to Control Aggression in Male Lion-tailed Macaques (Macaca silenus). 2000 Proceedings AAZV and IAAAM Joint Conference:201-206 (IAAAM CD-ROM Version) and 174-176 (AAZV CD-ROM Version).
11. Plosker GL, Brogden RN. Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders. Drugs. 1994 Dec; 48(6): 930-67.