Rob Lofstedt. RE: Pfizer Australia Animal Health Webmaster Date sent: Fri, 28 Oct :26:27

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1 Rob Lofstedt To: Subject: RE: Pfizer Australia Animal Health Webmaster Date sent: Fri, 28 Oct :26:27 I have an interesting case for which some ideas would be appreciated. The horse is a 6 year old thoroughbred mare. She was examined in Australia in August 2004 as a potential broodmare after just finishing her racing career. At that time, the BSE report indicated no abnormalities with her reproductive tract but that her ovaries were small and inactive (typical of a winter anestrous appearance). She was sold and came to NZ in December She was examined by the stud vet on several occasions during December but did not have any ovarian activity and did not come into estrus. (The breeding season finishes here at the end of December). At that time her failure to cycle was put down to immaturity or stress associated with the change from a racing stable to a broodmare. In January and February 2005 she was examined several times by the referring vet and still her ovaries were small and inactive. Two weeks ago I was asked to examine the mare. Her ovaries are small (both about 3cm in diameter) her cervix seemed small and generally her entire reproductive tract seems infantile. No other abnormalities were detected. My initial thoughts were that this mare was probably an intersex (XO) but her karyotype has come back normal. The referring vet has treated her with regumate and domperidone for variable lengths of time and there has been no response in terms of follicular development. She has not been under lights this season. One of the questions that has arisen with this case is the potential long-term effects of the anti-gnrh vaccine "Equity" which is available in Australia. The current owner is suspicious that this mare was given the vaccine when she was racing. Does anyone have any experience with the effects of such vaccines on future reproductive performance? To me this mare appears to be exactly what you would expect to see with the absence of GnRH. Any comments appreciated. Dave David Hanlon BSc BVMS(Hons) MVSc MACVSc Diplomate ACT (Registered Specialist - Equine Reproduction) Matamata Veterinary Services Ltd & EquiBreed Ltd 26 Tainui St.Matamata New Zealand Ph Fax Mobile Printed for Rob Lofstedt, 28 Oct 2005, 13:26 Page 1 of 6

2 < Dave, An interesting case indeed. My first thought was XO but you've ruled that out. I have no experience with this product (Equity) but the following reference my be helpful. Unfortunately, I don't have the proceedings to give you their findings but maybe some others on the list have it and can do so. Imboden I., Janett F., Burger D., Hässig M., Thun R.: Influence of immunization against GnRH on cycling activity and estrous behavior in the mare. Proc. 15th International Congress on Animal Reproduction, Porto Seguro, Brazil. (Abstract, Poster) 152, It would also be interesting to know what procedures were performed as part of the original "BSE". It appears that only a cursory examination may have been performed. What should be the minimum procedures? The AAEP has established a Task Force to review their guidelines for breeding terminology and the procedures recommended to consider a mare or filly "suitable for breeding". Any input from the ACT members on this subject would be appreciated. Several of the task force members, including myself, are also ACT Diplomates, so response to the list would help disseminate your opinions to the task force. Alternatively, you could respond directly to me. Steven P. Brinsko DVM, MS, PhD, Dipl ACT Associate Professor of Theriogenology Dept. of Large Animal Clinical Sciences College of Veterinary Medicine and Biomedical Sciences Texas A&M University College Station, Texas Phone: (979) FAX: (979) sbrinsko@cvm.tamu.edu FYI, Correction, the current terminology in the AAEP guidelines is "suitable for mating" not "suitable for breeding" as stated in my previous post. SPB Dear Dave and Steven Here are the specifics from the work of Imboden et al.: - 9 mares were vaccinated with GnRH-vaccine (Improvac) twice, 4 wks apart. Also, 9 mares served as controls (saline injection) - Repro exams performed for 54 weeks Findings: - All treated mares ceased cyclic activity within 6 wks - Estradiol levels and number of small (10-20mm) follicles were similar between groups - Sizes of largest follicle were smaller for treated mares - Mean ovarian diameter was smaller for treated mares - P4 was lower for treated mares between 4-30 wks - 3 vaccinated mares resumed normal cyclic activity Printed for Rob Lofstedt, 28 Oct 2005, 13:26 Page 2 of 6

3 (at 25, 47 and 53 weeks) - Remaining 6 treated mares were still suppressed at 54 wks after vaccination. It would be interesting to contact the authors (iimboden@vetclinics.unizh.ch) to see how long it took for the remaining 6 mares to resume ovarian activity. I think that in Dave's case, the use of the GnRH-vaccine could have been the cause for the infantile repro tract, especially if vaccination was repeated (booster shots) over the years. The questions is: if this is the case, will this mare resume ovarian activity sometime in the near future? In my opinion, this mare will resume ovarian activity after sometime (1 yr? 2,3?) of the last vaccination. To assure that these findings are due to the use of GnRH-vaccine, you could check for anti-gnrh antibodies in her blood. You could also treat these mares with lower doses of GnRH analogues and see if ovarian activity is restored. Alternatively, you could try efsh or EPE. If the "problem" is the lack of GnRH because of the vaccine, these treatments should restore ovarian activity during the time of treatment. Just some thoughts... Marco. Marco Coutinho da Silva <macoutinho@yahoo.com Dear Dave, I have 3 comments. The first is that Dr. Andrew Van Kessel (andrew.vankessel@usask.ca) at the University of Saskatchewan may be able to run an anti - GnRH antibody test on the serum from this mare. This will definitively show whether she has persistent vaccine related antibodies to GnRH. From my Austrailian colleagues it is my understanding that there are a proportion of Equity (anti-gnrh) vaccinates that do not cycle back the first year, and it is likely that the mare's titer relates to her reproductive activity. If this mare is a vaccinate it would not be expected that the reproductive tract would be infantile, rather the tract should feel and measure as anestrus, because the tract developed prior to vaccination. A persistent 3 cm ovary on a TB mare I would consider below the normal range for an anestrus mare. My last comment is that other genetic anomalies such as translocations, or partial delections may cause this problem, and an analysis of the sex chromosome banding pattern is helpful to determine the cause. You may want to try another genetics lab, or ask for an analysis of 300 cells, plus banding. Yours, Dr. Claire Card Western College of Vet Med Dave I believe that the insert or some disclaimer from the company (Equity) states that the company will not guarantee when the mare will cycle again after its use and that there are no ill effects on future reproductive performance. I can't remember where I read it but it was enough to scare me off from suggesting its use in performance mares in USA that may be used as broodmares in the future. the company should provide you with information from their studies. Printed for Rob Lofstedt, 28 Oct 2005, 13:26 Page 3 of 6

4 michelle leblanc Pat McCue published a study in AAEP several years ago with the results of a study on implants. By the way they did not work Ed Squires Hi Dave We saw and managed a case like the one you describe at Cornell. The mare was also relatively young, had reportedly cycled earlier in life, then became erratic, was successfully kickstarted once with P&E, but then shut down permanently (for at least 18 months). During the end of last summer and the better part of the first half of the 2005 season we sytematically tried to get the mare to build follicles with GnRH, porcine FSH and equine FSH, but all failed to produce anything beyond a 15mm follicle. The mare's karyotype is normal and she looks entirely feminine. Fiona will tell you more about her when she gets to you. Dietrich This is the drug company spiel for Equity. Scott Norman Registered Name Equity Oestrus Control Vaccine for Horses Composition Each ml of vaccine provides GnRF-protein conjugate 200 microgram. Prepared from an analogue of gonadotropin releasing factor (GnRF) linked to a carrier protein, and adjuvanted with iscomatrix to increase the level and duration of immunity. Actions Through its inhibitory effect on GnRF and indirectly on luteinising hormone (LH) and follicle stimulating hormone (FSH), Equity aids in preventing follicular development in the ovaries. The ovaries in vaccinated horses become small and inactive. Cyclic oestrus activity commences to decline or will cease within about two weeks following the second dose of vaccine in most horses. Vaccine induced suppression of oestrus should last for at least three months and in a percentage of horses will continue for six months or longer. If continued anoestrus is desired, additional booster doses will probably be required. Indications Aid in the control of oestrus and oestrus related behaviour in fillies and mares not intended for breeding. Oestrus related behaviour varies between horses, though it is often characterised by squealing, nervousness, squatting and urinating, increased agitation and clitoral 'winking'. Some horses display aspects of oestrus related behaviour when they are not in oestrus, but generally this type of behaviour is increased during the oestrous period of the oestrous cycle. Following vaccination, ovarian activity is suppressed, leading to markedly reduced oestrus related behaviour in most horses. Printed for Rob Lofstedt, 28 Oct 2005, 13:26 Page 4 of 6

5 Contraindications Use in horses intended for breeding, or in pregnant mares. Warnings The effect of this product on fertility in breeding horses is unknown. The extent and duration of effect of booster doses of vaccine have not been studied. Precautions Safety directions. Repeated exposure may cause allergic disorders. Wash hands after use. Care should be taken to avoid accidental self-injection and needle stick injury when administering this product. Accidental self-injection may affect fertility in both men and women. As this vaccine may affect pregnancy, particular care should be taken by women of childbearing age. Caution should be exercised at all times when handling horses. First aid. In the event of accidental self-injection, seek medical advice immediately. Disposal. Dispose of containers and syringes by wrapping in paper and putting in garbage. Discarded needles should immediately be placed in a designated and appropriately labelled sharps container. Withholding Periods Nil. Adverse Reactions Some swelling may develop at the site of vaccination in a small number of horses but resolves quickly, usually within a few days. Dosage and Administration The dose on all occasions is 1 ml injected intramuscularly. The most convenient site for injection is the centre of the side of the neck. Before the vaccine is injected, the proposed site of inoculation on the horses skin may be cleaned by swabbing with cotton wool soaked in a suitable antiseptic solution, such as methylated spirits. For primary immunisation two doses of vaccine should be administered four weeks apart. Effective control of oestrus (associated with the development of anti-gnrf antibodies) develops approximately ten to 14 days after administration of the second dose of vaccine in most horses. Primary immunisation should be completed in advance of when the desired vaccination effect is needed. For continued effect further booster doses will probably be required. Pfizer Australia, Animal Health wrote: Thank you for your Enquiry. For more information on Equity go to our website,the password is- animalhealth and the vet login name is - pfizer. Kind regards Lorna McNeill Veterinary Associate Pfizer Animal Health Printed for Rob Lofstedt, 28 Oct 2005, 13:26 Page 5 of 6

6 Thanks to everyone for their helpful comments. Rather than reply to each person separately the bottom line is: 1. Yes, there is still the possibility that this mare received anabolic steroids, we'll never know. 2. The cytogenetics lab is currently running G banding and R banding. 3. We will probably try and get an anti-gnrh titre done as mentioned by a few people. 4. I don't know how complete (or otherwise) the initial BSE was. 5. By "infantile" I probably mean under-developed. I wonder whether the anti-gnrh vaccine would have a more profound effect on the reproductive tract if it was administered peri-pubertally? It is possible that this mare was first given the vaccine when she was being broken-in as a young filly. 6. The vaccine is produced by Pfizer and the packaging states that "it is not recommended for use in potential breeding animals". 7. We will still try all the usual tricks; lights, domperidone, efsh, receptal, P+E etc. I'll let you all know how this progresses. Cheers Dave Printed for Rob Lofstedt, 28 Oct 2005, 13:26 Page 6 of 6