Does My Mare Need RegumateTM?

By Jos Mottershead

Well, the simple answer is that if you don't know, she probably doesn't need it!

Regumate1 contains the drug Altrenogest, a synthetic progestagen, and is labeled for use in mares to suppress estrus (heat) display. In recent years, some have presented it as having an almost legendary ability to support pregnancies in mares that otherwise appear unable to retain the pregnancy through to birth. Is this truly an ability, or just a legend?

Research performed by McKinnon et. al. indicated that of five progestagens that were tested, Regumate alone had the ability to prevent abortion in pregnancies that were threatened by an experimentally induced lowering of the endogenous progesterone levels. In one experiment2, mares that were pregnant at 14 days post ovulation received one of 5 progestagens, of which Regumate was one. Two days later, the mares were given a luteolytic dose of prostaglandin, which resulted in a drop in blood-progesterone levels in all mares by 2 days after that. It should be noted that the synthetic progestagen altrenogest (Regumate) does not assay as progesterone, so one would not expect to see the continuance of elevated progesterone levels in these mares. All mares in the experiment lost their pregnancies in the next 2-8 days with the exception of those mares that were receiving Regumate.

In a second experiment3, pregnant mares that were in excess of 40 days post original ovulation were ovariectomized after receiving supplementation with exogenous progestagens. Again, only those mares that received Regumate maintained their pregnancies.

There is little doubt therefore, that in mares that do not have endogenous sources for progesterone during the first 3-4 months of pregnancy, the use of Regumate can maintain a pregnancy. The irrational reaching for the Regumate bottle that is commonly seen in the horse breeding public however may well be an overreaction to this proven ability4.

Once again, we have to ask "does my mare need Regumate", and if there is not a clear indication of continued low progesterone levels (generally 4 ng/ml is considered sufficient to maintain pregnancy, although 2 ng/ml is considered sufficient by some researchers5), then the answer is probably "no". The single testing of a progesterone level however is insufficient as an indicator of an ongoing low (or high) level, as progesterone levels - as with other hormonal levels in the body - can and do fluctuate on a day-to-day basis, and even within a single day. To establish that a mare does indeed have "low progesterone" it is necessary to test her 3 or 4 times a day for 3 or 4 days in a row with a continued indication of insufficient levels. Added to that, we must ask another very important question: Is the mare losing the pregnancy because the progesterone levels are low, or are the progesterone levels low because the mare is losing the pregnancy? It has in fact been shown that low serum progesterone concentrations in one study6 were associated with only 1 of 17 cases of spontaneous early embryonic/fetal death in a large herd (179 mares) that were monitored closely!

Another issue to be considered is who recommended that your mare be put on Regumate? Was this a recommendation of your veterinarian familiar with your animals, or a friend or other non-trained person trying to be helpful? If the former, it is likely that the recommendation was made after reviewing your mare's individual situation, and is therefore valid. It should be noted though that most theriogenologists would voice a concern about use of supplemental progestagens if there were not a distinct indication for such supplementation4. Much use of Regumate to allegedly support pregnancy in "low progesterone mares" is carried out at the recommendation of a layperson. A veterinarian who is then approached for a prescription or the drug is placed in an awkward position. If they respond as they should to the request, with the advice that more investigation is needed, they are regarded as attempting to usurp more money from you. If they provide you with the drug or a prescription, they will be considered heroes in the event the mare foals successfully in the spring - even though they may have just caused you to spend money for a drug that was not needed!

There are instances of progesterone levels in the pregnant mare falling to as low as 1 ng/ml (although not for an indefinite period) with the pregnancy being retained5. Likewise, there are many instances of people observing that they resent the cost and inconvenience of daily dosing with Regumate, and therefore use Medroxyprogesterone acetate (Depo-provera) on a weekly or monthly basis - even though McKinnon et. al. have proven that the drug does not maintain pregnancy in mares whose endogenous progesterone secretion has been suppressed! Others observe that they needed to "keep their mare on Regumate throughout pregnancy" as they "checked the mares progesterone levels frequently and found that the levels were 'low'" - this despite the fact that progesterone levels naturally drop to a base-line level by about day 210 of pregnancy! Ovariectomized mares that have been used as embryo transfer recipients successfully carry their pregnancies through to term after cessation of Regumate treatment around day 120-150 of pregnancy, thereby conclusively proving that progesterone secretion by the ovaries plays no part in pregnancy maintenance after that point. One has to wonder therefore about the apparent need of some mare owners to supplement throughout pregnancy. In fairness, there are individual situations that may warrant such supplementation, most commonly associated with an incompetent cervix or impending abortion as a result of placentitis (the Regumate may assist in keeping the cervix more tightly closed in those mares). It has been shown7 that Regumate treatment in late pregnancy (>300 days) fails to elevate total progestagen levels and is probably not of assistance to the 5-alpha pregnane group as a whole that take over the work of progesterone somewhere around 150 days of pregnancy. This group of progestins originates from the feto-placental unit, and not from the mare. The same research suggested that treatment of mares with Regumate in late pregnancy did result in an increase in one type of endogenous progestagen, 5-alpha DHP, but the significance of this, or the possibility of an association with myometrial quiescence, is unclear and requires further research. Similarly, whether the same effect occurred with Regumate treatment earlier in pregnancy was not evaluated. It should be noted that 5-alpha DHP levels while increased after 260 days of pregnancy, are at their highest in late-term pregnancy after 300 days8.

There are arguments - primarily financial - that can be made for Regumate use in pregnant mares, despite an unproven need, and we would be remiss were we not to present those too.

The cost associated with the use of Regumate, even though no need has been proven, can still be less than either the requisite diagnostic work (9-12 progesterone assays - although at the time of writing, stall-side assay kits are available from Hamilton Research Inc. and/or Exodus Breeders Corporation costing in the region of US$80-90 for a pack of 12 tests - significantly less than a single bottle of Regumate!), or keeping a mare that is intended to produce a foal open for a year. It is these factors above all others that probably lead to excessive use of Regumate, despite the drug not being labeled for use to support pregnancy in alleged "low progesterone mares".

If - and it is a large "if" - one decides that Regumate does need to be used in a mare to support pregnancy, when should one be commencing treatment? All indications suggest that the time when the pregnancy is most at risk is during the early embryonic stage - from shortly after ovulation until 20-30 days after that ovulation. The recommended protocol for treatment with Regumate is to commence treatment about 3½ days after ovulation has been detected. At this time, the cervix is almost closed, and there will be little or no further clearance of post-breeding fluids (starting the Regumate prior to that may result in delayed uterine clearance and subsequent endometritis in susceptible mares). As we are aware that the largest proportion of the pregnancy loss risk period occurs before day 20 post ovulation, it is surprising that some people start their mares on Regumate only after they have been checked in foal at 14-16 days! It may be that once again, these are mares that need the Regumate less than the owners.

To continue our "if" further, if we put the mare onto Regumate, when do we take her off it? If the mare checks not in foal at 15 days, then one can take her off immediately, and she should return to estrus in 3-5 days (note that if she doesn't she may be pregnant!). If she is confirmed in foal, then the first time that is suggested as suitable for taking the mare off Regumate is 40-45 days. By this stage of pregnancy, the mare will have developed secondary corpora lutea (CL's) and will have increased endogenous progesterone levels. The next occasion that one should consider stopping the treatment would be between 120 and 150 days of pregnancy. By then, the fetoplacental unit is secreting 5-alpha pregnanes, and the endogenous progesterone levels would be decreasing naturally. If one desires, one can keep the mare on a little longer, until perhaps 210 days, at which time progesterone levels are naturally base-lined. The last stage one would consider maintaining the mare on Regumate until is 310 days. By then, the mare is probably starting to prepare for foaling, and a fetus delivered at that stage should be viable.

Just to add a little more food for thought, and to raise both awareness and alarm levels a little higher, the potential impact on the human hormonal cycle in the event of accidental absorbency of the drug through the skin should be considered. To confuse the issue more, many people who are aware of this problem make it a practice to only dose their mares while wearing latex gloves. Unfortunately, latex will allow the passage of Regumate through it, although not as easily as skin. Hence, once the Regumate has been spilled on the gloves and soaked through, it is then more easily absorbed by the skin than being able to pass back through the glove. Essentially this practice creates a "Regumate patch" similar to a birth control or nicotine patch for the wearer! It is somewhat puzzling why the paste version of the product, available in Canada, is not available for use in the US. It significantly reduces the potential for accidental human exposure. Next, the use of any progestin in a mare with a uterus of an unknown pathogenic status, or one that is known to have had pathogenic inflammatory issues in the past may stimulate a uterine infection. Progestins suppress uterine immune response something that is indicated on the package insert of Regumate. A final point to ponder is that it has been suggested that use of Regumate in the pregnant mare may actually suppress endogenous secretion of progestins, thereby creating a dependency for supplementation in the mare. Could we in fact be creating Regumate addicts by the use of the drug in the mare? It appears that it may be so.



References:
1: Regumate is a registered trademark of Intervet, the producing company.
2: McKinnon A.O.; Allen W.R.; Lescun T.B.; Walker J.H.; Vasey J.R.; (1999) The Inability of Many Progestagen Formulations to Maintain Pregnancy in Mares Undergoing Luteolysis; A report for the Rural Industries Research and Development Corporation.
3: McKinnon, A.O., Tarrida del Marmol Figueroa, S., Nobelius, A.M., Hyland, J.H. and Vasey, J.R. (1993) Failure of hydroxyprogesterone caproate to maintain pregnancy in ovariectomised mares. Equine. Vet. J. 25, 158-160.
4: Allen W.R. (2001) Luteal deficiency and embryo mortality in the mare. Reprod. Domest. Anim. 36(3-4): 121-31.
5: Daels P.F. (2004) Hormonal therapy in the pregnant mare. Proc. 10th Annual Meeting of the Italian Association of Equine Veterinarians - SIVE
6: Irvine, C.H.G., Sutton, P., Turner, J.E. and Mennick, P.E. (1990) Changes in plasma progesterone concentrations from days 17 to 42 of gestation in mares maintaining or losing pregnancy. Equine. Vet. J. 22, 104-106.
7: Ousey J.C., Rossdale P.D., Palmer L., Houghton E., Grainger L., Fowden A.L. (2002) Effects of progesterone administration during late gestation. Theriogenology 58, 793-795.
8: Fowden A.L., Ousey J.C., Forhead A.J., Rossdale P.D., Grainger L., Houghton E. (2002) Uteroplacental production of 5-αpregnane-3,20-dione (5αDHP) in pregnant mares. Theriogenology 58, 821-824.


© 2004 Jos Mottershead and Equine-Reproduction.com
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