Tuesday, December 1, 2015

Thyroid Hormone Supplementation: Performance enabling or enhancing?

Supplementation with thyroxine (thyroid hormone) is commonplace among racehorse trainers, and recently this practice has been accompanied by a swirl of confusion.  Like so many other typical racetrack practices, the supplementation with thyroxine has been demonized in some corners, from being used to “cover up” cobalt abuse to being responsible for sudden deaths on the track.  Like so many other typical racetrack practices, thyroxine supplementation is defended by its proponents as making the horses “feel better and do better,” with no real explanation of how it might work. 

So, let’s start this discussion by reviewing what thyroxine actually does.  Thyroxine is normally produced in the thyroid gland, a paired gland on either side of the neck, just behind the head.  Thyroxine affects every cell in an animal’s body, affecting everything from normal growth to normal muscle development in response to exercise.  You can consider that thyroxine is the hormone that permits everything else in the body to function properly.  The basic metabolic rate, including heart rate and temperature are determined by thyroxine.  In fact, veterinarians recommend that horses which suffer from metabolic syndrome, a disease not dissimilar to type 2 diabetes in humans, be supplemented with thyroxine to increase their metabolism for the purpose of weight loss, which requires a dose 3 – 6 times the typical amount supplemented to the average racehorse.  Remarkably, these horses don’t seem to have a higher than average risk of sudden death and unquestionably have had no out of the ordinary exposure to cobalt, despite this large dose of thyroxine.  Most have minimal, transient signs or no signs at all of thyrotoxicosis (dangerously high levels of thyroxine in the blood).
                                                                                                             
What are the signs of thyrotoxicosis in horses?  There are no published reports…actually there are only a few published reports about thyroid hormone in horses at all.  This leaves us with a large hole in the scientific literature to assess whether our horses need extra thyroxine at all.  Thyrotoxicosis in other species is associated with increased heart rates, increased body temperatures, weight loss and diarrhea.  In fact, most veterinarians will tell you that nervousness and diarrhea accompany excessive thyroxine use, and can be seen occasionally in the first few days after starting the very high dose used in metabolic disease (Type 2 Diabetes-like) horses with high doses of thyroxine.  In humans, extremely high levels of thyroxine, such as those seen with thyroid gland tumors, are associated with cardiac arrhythmias and death, which is clearly the far-reaching source of the supposition made by racing officials when they posited a correlation between extra thyroxine and racetrack deaths.  Based on the fact that many racehorses are supplemented with thyroxine, and the spikes of sudden death were only observed in one jurisdiction, suggestions that there is a relationship between thyroxine supplementation and sudden death is irresponsible at best.

So, the next question is, why do so many trainers supplement racehorses with thyroxine, and is it a legitimate practice?  In actuality, while the scientific literature is sparse on the subject in horses, the only studies that exist clearly demonstrate that racehorses tend to be low in thyroxine1,2.  These old studies are likely the original source of the idea.  Luckily, there is a lot of good scientific evidence in other species.  Like the Thoroughbred racehorses in those two early studies, humans undergoing intense exercise can experience a low thyroxine3, which significantly impairs the individual’s ability to perform4.  Additionally, there is a lot of good scientific evidence in people5 and some limited data in horses6 that low thyroxine is associated with rhabdomyolysis (tying up).

Are there other causes besides intensive exercise that can cause low thyroxine in a race horse?  The test for thyroxine in horses measures both active (free) and inactive (protein bound) forms of thyroxine, and many exogenously administered substances, including estrogens and antibiotics can displace thyroxine from its protein binding sites, causing a falsely low thyroxine reading, without actually affecting the thyroid function in the horse.  Other exogenously administered substances can actually drop both the active and inactive forms of thyroxine in the blood.  For example, 5 days in a row of bute causes a profound drop in both forms of thyroxine7, which lasts 2 days for the active form and 10 days for the inactive form. 

Cobalt chloride also interferes with normal thyroid function.  While a critical and necessary mineral in trace amounts, cobalt has been used in higher than normal quantities for a variety of reasons in horses.  At levels exceeding daily requirements, especially many orders of magnitude above required amounts, cobalt activates and upregulates over 300 genes, of which a number might influence performance.  At modest amounts cobalt has been administered to racehorses to counteract low red blood cell counts, although there is no evidence that it works for this purpose, and has been used as a preventative for rhabdomyolysis8.  Very high persistent levels of cobalt in the blood interfere with the iodine uptake by the thyroid gland resulting in hypothyroidism, which is clearly the source of the rumored association between the two.  However, in addition to dropping the thyroxine level, injudicious use of cobalt causes heart and liver damage9.  Simple thyroxine supplementation does not counteract these adverse effects.  Additionally, the implementation of regulations limiting cobalt levels renders the exogenous administration of cobalt obsolete.

The veterinary community has not invested a lot of research on thyroxine in racehorses, but clearly the scientific data that do exist support limited use of this therapeutic substance in racehorses.  At the dosages typically used in racehorses, toxicity is unlikely, but the best method to determine if your horse needs supplementation is to have a baseline thyroxine test, and only supplement if your horse actually has a low thyroxine.  The best method to determine a reproducible level of thyroxine is to have the blood test drawn in the morning before training, when the horse has not received other medications within 10 days.

Conclusions?  The use of thyroxine supplementation is clearly an appropriate therapeutic treatment for horses, but it is critical to test for a low blood thyroid before starting on therapy, rather than indiscriminately treating all horses.  Has overuse of thyroxine been responsible for sudden deaths among racehorses?  Highly unlikely.  Is it good to investigate all possible variables when there is an unexpected number of deaths or other incidents involving animals?  Absolutely.  Is it irresponsible to suggest a cause without solid scientific evidence?  Yes.  Both regulators and horsemen are under pressure to have an answer whenever injuries or deaths occur, but kneejerk responses without science to back it up doesn’t get us any closer to solving the problems in our industry.  At the same time, it is critically important that we understand every therapy we institute in our athletes and apply each of them appropriately.

1.       1.      Bayly W, Andrea R, Smith B, Stensislie J, Bergsma G. Thyroid hormone concentrations in racing Thoroughbreds. Pferdeheilkunde; 12, 1996, pg 534-538.2.     Blackmore DJ, Greenwood RES, Johnson C. Observations on thyroid hormones in the blood of Thoroughbreds. Res Vet Sci; 25, 1978, pg 294-297.
3.     Pakarinen A, Häkkinen K, Alen M.  Serum thyroid hormones, thyrotropin and thyroxine binding globulin in elite athletes during very intense strength training of one week.  J Sports Med Phys Fitness. 1991 Jun;31(2):142-6.
4.     Werneck FZ1, Coelho EF, de Lima JR, Laterza MC, Barral MM, Teixeira PD, Vaisman M. Pulmonary Oxygen Uptake Kinetics During Exercise in Subclinical Hypothyroidism.  Thyroid. 2014 Mar 21. [Epub ahead of print]
5.     Lochmüller H, Reimers CD, Fischer P, Heuss D, Müller-Höcker J, Pongratz DE.  Exercise-induced myalgia in hypothyroidism.  Clin Investig. 1993 Dec;71(12):999-1001.
6.     Harris P, Marlin D, Gray J.  Equine thyroid function tests: a preliminary investigation.  Br Vet J. 1992 Jan-Feb;148(1), pg 71-80.
7.     Ramirez S, Wolfsheimer KJ, Moore RM, Mora F, Bueno AC, Mirza T. Duration of Effects of Phenylbutazone on Serum Total Thyroxine and Free Thyroxine Concentrations in Horses. J Vet Int Med 1997 11: 371–374.
8.     Fenger CK, Sacapolus, P.  2015.  What is Cobalt?  Horseman’s Journal Winter 2015.
9.     Ebert B, Jelkmann W. Intolerability of cobalt salt as erythropoietic agent. Drug Test Anal 2014 Mar;6(3):185-9.


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