Does My Mare Need RegumateTM?

By Jos Mottershead

The Simple Answer:

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

The Detailed Answer:

Regumate1 contains the drug altrenogest, a synthetic progestagen, and is labeled for use in mares to suppress estrus ("heat") display. Other altrenogest products are also marketed, however "Regumate" tends to be used as the catch-all name as a result of being the first product commercially available for use in horses. In recent years, some people have presented progestin supplementation as having an almost legendary ability to support pregnancies in mares that appear otherwise 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, altrenogest 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 altrenogest 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 altrenogest.

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 altrenogest 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 a reliable 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 as often as 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 been shown in one study that low serum progesterone concentrations were associated with only 1 of 17 cases of spontaneous early embryonic/fetal death in a large herd (179 mares) that were monitored closely.6 Conversely, another piece of research did note a decrease in progesterone levels prior to early embryonic loss in 6 out of 11 mares - of whom 5 still had levels in excess of 4 ng/ml!7

Another issue to be considered is who recommended that your mare be put on altrenogest? 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 the client. If they provide 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 sometime after about day 90 of pregnancy! Ovariectomized mares that have been used as embryo transfer recipients successfully carry their pregnancies through to term after cessation of altrenogest 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 altrenogest may assist in keeping the cervix more tightly closed in those mares). It has been shown8 that altrenogest 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 altrenogest 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 altrenogest 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 days9.

There are arguments - primarily financial - that can be made for altrenogest 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 altrenogest, even though no need has been proven, can still be less than either the requisite diagnostic work (although at the time of writing, stall-side assay kits are available, costing in the region of US$75 for a pack of 6 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 altrenogest, 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 altrenogest 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 altrenogest 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 altrenogest 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 altrenogest only after they have been checked in foal at 14-16 days! It may be that once again, these are mares that need the altrenogest less than the owners.

To continue our "if" further, if we put the mare onto altrenogest, 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 altrenogest 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 altrenogest 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.

Is It a Benign Panacea?

Again, to offer a short answer "probably not". During the early development of the product, research demonstrated an increase in the clitoris size (enlargement) in female offspring of mares treated throughout pregnancy as well as causing an alteration in gonadotrophin secretion in fillies before puberty. That same research however showed no effect on functional reproductive performance in fillies on the first cycle pregnancy rates.10

More recent research has looked at the effect exogenous progestins play on the immune function of the mare herself. The results demonstrated that both "P4 [progesterone] and ALT [altrenogest] appear to alter the immune system of the non-pregnant mare both systemically in addition to locally within the endometrium". 11 Research is ongoing on the effects in a pregnant mare, but certainly in other species it is recognised that progestins have an immunosuppressive effect on the pregnant female. It is perhaps worthy of thought that the US has a very high usage of supplemental progestin therapy in pregnant mares, but also one of the highest (if not the highest) rate of placentitis in pregnant mares. Are we predisposing those mares to a greater likelihood of placentitis as a result of immune function suppression?

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. This was a significant enough concern that the FDA issued a warning on July 3, 2018 indicating that "Adverse effects were reported in 137 people, including 115 women and 22 men. Eighteen of the women affected were teenage girls. Some reports have described adverse effects in girls as young as 14 years of age."12 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, at one time available in Canada, is not available for use in the US, although it can be obtained through some compounding pharmacies. 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. That progestins suppress uterine immune response is something indicated on the package insert of Regumate. A final point to ponder is that it has been shown that use of altrenogest in the pregnant mare may actually suppress endogenous secretion of progestins, thereby creating a dependency for supplementation in the mare.13,14 This is quite likely related to the fact that progestin therapy appears to suppress eCG secretion which in turn will suppress production of secondary CLs.15 Could we in fact be creating altrenogest addicts by the use of the drug in the mare? It does appear that it may be so!

So other than enlarged clitorides in fillies, does altrenogest present any other negative aspect related specifically to the fetus or foal? In mares treated with altrenogest (0.088 mg/kg bwt) during late pregnancy, the second stage of parturition was prolonged and foals had a significantly lower respiratory rate during the first 30 minutes of life. The research concluded that "treatment with altrenogest did not prevent parturition and its effectiveness to prevent abortion or preterm foalings in mares with disturbed pregnancies should be doubted. In addition, altrenogest treatment of mares affected adaptation of the foals to the extrauterine environment."16. Additional research looked at post-foaling effects of altrenogest treatment during late pregnancy and found that a significantly lower neutrophil/lymphocyte ratio on the first day after birth was seen, as well as higher basal plasma cortisol concentrations immediately after birth. The research concluded that "A reduced neutrophil/lymphocyte ratio in these foals may suggest either immunomodulatory effects of altrenogest or dysmaturity of the foals."17

Conclusions:

While there is ample research to demonstrate the ability of altrenogest to maintain pregnancy in mares clinically modified in such a manner as to normally cause pregnancy loss, this does not necessarily demonstrate an ability to prevent pregnancy loss in mares which are potentially undergoing EED or later term loss. Indeed the very fact that mares will foal when still being treated with altrenogest suggests a potential lack of ability to prevent such loss. There are definitely situations where supplementation is warranted and valuable - mares with a degree of cervical incompetency may benefit from treatment, as well as mares exhibiting later pregnancy issues such as placentitis (when supplementation is used in conjunction with other treatments) for example. What is not demonstrated by research is a "cure-all" effect to maintain all pregnancies regardless - which in many cases would have been maintained without the addition of altrenogest supplementation. We can conclude therefore - as have others - that there is a distinct overuse of such supplementation. In reviewing the research which has demonstrated potential negative aspects of such supplementation of pregnant mares, it should lead us to develop a distinct degree of awareness and caution, and only make use of such supplementation where specifically indicated, and with consideration of the various risks presented.


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., 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., 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: Betteridge K.J., Raeside J.I., Waelchli R.O., Christie H.L., Hayes, M.A. (2018) Patterns of conceptus development and of progesterone concentrations in maternal blood preceding spontaneous early pregnancy failure in mares. Reprod. Fertil. Dev. 30, 1066-1076.
8: 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.
9: 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.
10: Naden J, Squires E.L., Nett TM (1990) Effect of maternal treatment with altrenogest on age at puberty, hormone concentrations, pituitary response to exogenous GnRH, oestrous cycle characteristics and fertility of fillies. J. Reprod. Fertil 88 185-195.
11: Fedorka C.E., Ball B.A., Walker O.F., Conley A.J., Corbin C.J., Lu K.G., Hanneman J.M., Troedsson M.H.T., Adams A.A. (2019) Alteration of the Mare's Immune System by the Synthetic Progestin, Altrenogest. Am J Reprod Immunol 82(2).
12: FDA Animal Drug Safety Communication: FDA highlights potential health risks to people exposed to altrenogest products for horses or pigs: https://www.fda.gov/animal-veterinary/cvm-updates/fda-animal-drug-safety-communication-fda-highlights-potential-health-risks-people-exposed
13: Daels P.F., DeMoreas J., Stabenfeldt G.H., Hughes J.P. (1992) The effect of altrenogest on the development of secondary corpora lutea. Proceedings of the 12th ICAR.
14: DeLuca C.A., McCue P.M., Patten M.L., Squires E.L. (2011) Effect of nonsurgical embryo transfer procedure and/or altrenogest therapy on endogenous progesterone concentration in mares. J. Equine Vet. Sci. 31, 57-62.
15: Willmann C., Schuler G., Hoffmann B., Parvizi N., Aurich C. (2011) Effects of age and altrenogest treatment on conceptus development and secretion of LH, progesterone and eCG in early pregnant mares. Theriogenology 75, 421-428.
16: Neuhauser S., Palm F., Ambuehl F., Aurich C. (2008) Effects of altrenogest treatment of mares in late pregnancy on parturition and on neonatal viability of their foals. Exp. Clin. Endocrinol. Diabetes 116, 423-428
17: Neuhauser S., Palm F., Ambuehl F., Mostl E., Schwendenwein I., Aurich, C. (2009) Effect of altrenogest-treatment of mares in late gestation on adrenocortical function, blood count and plasma electrolytes in their foals. Equine Vet. J. 41, 572-577