Thyroid Gland

Babetta Breuhaus

Thyroid Gland Physiology

Thyroid gland physiology and control of thyroid hormone secretion in horses is similar to other species. Thyroid hormones are important for growth, maturation of organ systems, and regulation of metabolism.

Thyroid hormone secretion is regulated by the hypothalamus and pituitary. Thyrotropin releasing hormone (TRH), made in the paraventricular nucleus and released from the median eminence of the hypothalamus, stimulates release of thyroid stimulating hormone (TSH) from the anterior pituitary, which circulates to the thyroid gland to stimulate release of thyroid hormones. Plasma thyroid hormones exert negative feedback on the hypothalamus and pituitary to limit further release of TRH and TSH. Neurotransmitters that play a role in thyroid hormone regulation include α-adrenergic agonists (stimulatory) and somatostatin and dopamine (inhibitory). Glucocorticoids and the cytokines TNF and IL-1β also inhibit TSH secretion.

As most recently reviewed,¹ alterations in thyroid hormone status that have been described in horses include thyroid gland neoplasia, hyperthyroidism, and hypothyroidism. Certain drugs, diets, and physiologic or pathophysiologic states can also influence circulating thyroid hormone concentrations.

Thyroid Gland Neoplasia

Thyroid gland neoplasias are not uncommon, and it is not unusual to find them as incidental findings during necropsy of older horses.^2,3 Thyroid adenomas are most common, but other reported thyroid neoplasias include carcinomas, adeno­carcinomas, and C-cell tumors. Although there are also scattered case reports of hypothyroid or hyperthyroid horses due to a thyroid tumor, most thyroid gland tumors are benign and nonfunctional. The glands enlarge physically, but there is no metastasis and circulating thyroid hormone concentrations remain within normal limits. As such, treatment of most thyroid gland neoplasias is unnecessary, until or unless the glands become big enough to start to interfere with swallowing or breathing. Once a thyroid gland tumor becomes enlarged enough for the owner to notice it, a reasonable approach is to measure circulating thyroid hormones (both total and free concentrations of T₄ and T₃). Provided that circulating thyroid hormone concentrations are normal, and provided that the horse is comfortable and the tumor is not big enough to interfere with alimentary or respiratory function, surgical removal is not recommended. The size of the gland should be monitored. If the gland starts to enlarge rapidly or if circulating thyroid hormone concentrations increase, then expedient surgical excision is recommended. After thyroidectomy, the horse will need to be treated with thyroid hormone supplementation to maintain circulating concentrations of thyroid hormones within the normal range.

Hyperthyroidism in Adult Horses

Hyperthyroidism is extremely rare in horses. There are three documented case reports in the literature, and all of these have been associated with thyroid gland neoplasias.^4-6 Circulating thyroid hormone concentrations are also sometimes temporarily increased in horses exposed to excess iodine, such as in a topical blister. Clinical signs of hyperthyroidism in horses include weight loss, tachycardia, tachypnea, hyperactive behavior, ravenous appetite, and cachexia.

Hypothyroidism in Adult Horses

Hypothyroidism in the horse has been poorly understood in the past, but most now agree that primary hypothyroidism is rare. Although autoimmune thyroid disease is somewhat common in people and dogs, it has only been described in one report of histologic changes found at necropsy in a group of horses in Eastern Europe.⁷ The prevalence of true hypothyroid­ism in adult horses is unknown but is almost certainly over­estimated. Hypothyroidism has been thought to contribute to a variety of problems in the horse, including obesity, laminitis, anhidrosis, recurrent rhabdomyolysis, and poor fertility. However, documentation of hypothyroidism in such cases for the most part does not exist. Anecdotal reports of beneficial effects of thyroid hormone supplementation in these horses are also largely unsubstantiated. Despite this, many horses with these conditions receive thyroid hormone medication over extended periods of time, and many—if not all—of them do not need it. Besides the obvious waste of money, potential health risks associated with unnecessary thyroid hormone supplementation have only been minimally explored in horses.⁸ In humans, thyrotoxicosis or oversupplementation with levothyroxine can result in decreased bone density, increased risk of atrial fibrillation, and possible increased risk of myocardial infarction or precipitation of congestive heart failure.⁹

Clinical signs of hypothyroidism in adult horses appear to be subtle.

Other Alterations of Thyroid Function been suggested that fescue consumption could lead to secondary hypothyroidism. Fescue ingestion was proposed as the cause of lower serum TSH concentrations in mares and foals consum­ing endophyte-infected fescue on a farm in central Kentucky, compared with mares and foals on a nearby farm grazing pastures that were mainly free of endophyte-infected fescue.⁵¹ However, the author found no differences in baseline concentra­tions of thyroid hormones or TSH or in their responses to administration of TRH, in adult, nonpregnant horses fed endophyte-infected fescue seed for 2 months.⁵² It appears that dopamine acts more as an acute modulator of TSH secretion, rather than as the primary control.

Syndromes Purportedly Associated With Hypothyroidism

Obesity

As mentioned earlier, horses that gain weight easily and have a tendency to deposit fat in the crest of the neck, over the rump and tailhead, or in the sheath have long been regarded as hypothyroid. It is now known that these horses most likely have insulin dysregulation and EMS and have normal thyroid function. Anecdotally, thyroid hormone administration to these horses usually has not resulted in substantial weight loss, especially if feed consumption is not restricted and the amount of thyroid hormone supplementation is titrated to maintain serum thyroid hormone concentrations in the normal range. However, administration of levothyroxine at a dose of approximately 0.1 mg/kg/day (48 mg) long term was associated with weight loss and increased insulin sensitivity in six healthy, euthyroid mares, despite the fact that they had access to pasture and a round bale of hay during the day and were given hay at night when they were stalled.^8,53 Although serum total T₄ concentrations increased four to five times their presupplementation concentrations, no adverse health effects were observed. Thus, when used to help obese horses lose weight, the amount of thyroid hormone given needs to be enough to make the horse mildly hyperthyroid. It is preferable for feed intake to be controlled at 1.5% to 2% of the desired body weight per day, consisting of grass hay or other feed that is low in soluble carbohydrates. It is important to understand that when thyroid hormones are administered in this manner, they are being used as a pharmacologic tool and should only be given for a short period of time; lifelong administration is not indicated.

Laminitis

A role for decreased thyroid function in the pathogenesis of laminitis was proposed but is poorly documented and remains a controversial topic. While decreased serum thyroid hormones have been associated with some horses that experience acute laminitis, it is extremely unlikely that hypothyroidism alone causes laminitis. In 13 studies in which hypothyroidism was induced by either surgical removal of the thyroid glands or administration of propylthiouracil, laminitis did not occur.^13-25 Thus, any alterations in serum thyroid hormone concentrations in horses experiencing laminitis are likely caused by factors associated with the episode of laminitis, rather than the underly­ing cause of laminitis. Such factors could include drugs used to treat laminitis (e.g., phenylbutazone), development of nonthyroidal illness syndrome, or a direct effect of factors such as endotoxin or one of the inflammatory cytokines that contribute to the onset of Iaminitis in some cases. In the author's experience, TRH stimulation tests performed in horses that have suffered an episode of laminitis or that have had bouts of recurrent laminitis show normal thyroid hormone responses when these tests are performed once the horse is stabilized and has been off all medications for 4 weeks.

Despite evidence of normal thyroid function in horses with laminitis, some veterinary clinicians still believe that treatment of horses with iodinated casein during an acute episode of laminitis results in improvement. These horses often are treated without prior measurement of thyroid hormones. Some are treated even when measurement shows serum thyroid hormone concentrations to be within the normal range. These horses are then often kept on thyroid hormone supplementation indefinitely. To date, no controlled studies have been performed to determine whether or not administration of thyroid hormones during acute episodes of laminitis is beneficial. However, since the action of α-adrenergic agonists on vasculature is usually vasodilatory, it is possible that thyroid hormone administration increases circulation to the foot by its ability to potentiate α-adrenergic receptor numbers and sensitivity.^54-56 Or it is also possible that thyroid hormone supplementation alters carbo­hydrate and fat metabolism in a way that increases insulin sensitivity.⁵⁷ Thus, any potential beneficial effect of thyroid hormone administration in horses suffering from laminitis may be pharmacologic rather than physiologic.

Anhidrosis

Anhidrosis is a condition of adult horses characterized by a decreased ability or inability to sweat in response to appropriate stimuli. The cause is unknown. Hypothyroidism has long been associated with anhidrosis, perhaps because treatment with iodinated casein was reported to help increase sweat production in anhidrotic horses in the 1950s.⁵8 However, the author found that baseline concentrations of thyroid hormones and TSH were normal in horses with anhidrosis.⁵⁹ Thyroid hormone responses to TRH were also normal, but TSH responses to TRH were significantly greater in anhidrotic horses than they were in horses with normal sweat production. The clinical significance of this greater TSH response to TRH in anhidrotic horses is unknown. Because equine sweat glands are stimulated to secrete by activation of α₂-adrenergic receptors and thyroid hormones modulate adrenergic receptor function, perhaps making horses mildly hyperthyroid restores α-adrenergic receptor numbers or sensitivity or potentiates sweat responses to whatever neural stimulation remains.

Rhabdomyolysis

A link between hypothyroidism and rhabdomyolysis was sug­gested by a report of muscle stiffness, poor performance, and rhabdomyolysis in 4 Thoroughbred and 2 Standardbred racehorses that had low baseline T₄ concentrations.⁶⁰ The horses improved after administration of iodinated casein. However, T₄ response to TSH was normal in these horses. A subsequent study showed normal resting concentrations of T₄ but decreased T₄ response to TRH in five horses that had suffered previous episodes of rhabdomyolysis.⁶¹ In a study of 18 Quarter Horses with polysaccharide storage myopathy and 18 Thoroughbreds with recurrent exertional rhabdomyolysis, circulating concentrations of T₄ and T₃ were within normal range. Stimulation tests were not performed.⁶² Thus, a role for hypothyroidism in the pathophysiology of equine rhabdo­myolysis is unclear. Because it is now known that the clinical syndrome of rhabdomyolysis is caused by more than one underlying pathophysiologic etiology, it is possible that hypothyroidism might contribute to some, but not all, cases of equine rhabdomyolysis. If hypothyroidism is suspected, thyroid function should be assessed, ideally by measuring both resting concentrations of free thyroid hormones, as well as by response to TRH or TSH. If resting concentrations of free thyroid hormones are found to be low, nonthyroidal illness syndrome due to other factors should be ruled out before thyroid hormone supplementation is prescribed.

Infertility in Mares

Thyroid hormone administration to broodmares to theoretically improve fertility has been a fairly common practice. This occurs despite a lack of evidence that the mares were actually hypo­thyroid in the first place or that thyroid hormone supplementa­tion improves equine fertility. This practice presumably is an extrapolation from human medicine, where hypothyroidism in women adversely affects fertility. However, two of three fillies that had undergone thyroidectomy became pregnant without thyroid hormone supplementation, and two additional studies including hundreds of horses failed to show an associa­tion between thyroid hormone status and conception rates in mares.^63,64 The first study⁶³ was performed in 329 clinically normal broodmares.⁶³ Resting serum T₄ concentrations were below the reference interval in 12% of the mares, within the reference interval in 86%, and increased in 6% of the mares. There was no association between serum T₄ concentration and whether or not the mare was pregnant 15 to 16 days after ovulation. There also was no association between whether or not the mare was receiving thyroid hormone supplementation (60 were, 269 were not) and pregnancy status. In the second study,⁶⁴ resting serum concentrations of total T₄ and T₃, as well as their responses to TRH, were measured in 79 Thor­oughbred and Standardbred broodmares. Resting and stimulated thyroid hormone concentrations were not different between mares that did and did not become pregnant.

Although the studies referenced earlier suggest there is no association between thyroid status and fertility or infertility in the mare, hypothyroidism might contribute to infertility in a small subset of mares as in women. However, given that true hypothyroidism appears to be rare in the horse, this would have to be a small number of mares, certainly not the number of mares that are currently being routinely supplemented with thyroid hormone. Is there any basis then to the clinical impres­sion held by some that thyroid hormone supplementation helps some mares get pregnant? Perhaps if there is, it is more related to obesity, insulin resistance, and equine metabolic syndrome than to hypothyroidism. Women with insulin resistance and metabolic syndrome are subfertile, and there is evidence that thyroid hormone administration to normal weight mares increases insulin sensitivity.^53,57 Thus, it is possible that some insulin-resistant, overweight mares are subfertile, and thyroid hormone supplementation is beneficial in those cases, not because they were hypothyroid in the first place but because it improves their insulin sensitivity. At the time of this writing, no studies have been performed to examine this hypothesis.

Assessment of Thyroid Function in Adult Horses performed while horses are ill, are receiving other drugs, or are on thyroid hormone supplementation. The author recommends that thyroid hormone testing be performed in horses that have not received any medications for at least 2, and preferably 4, weeks before testing. If a horse has been receiving thyroid hormone supplementation without prior documentation of hypothyroidism, the author recommends weaning the horse off supplementation and then testing thyroid function once the horse has not received any supplementation for at least 4 weeks.

Tests that are currently available for assessment of thyroid function in the horse include measurement of total and free fractions of T₄ and T₃ and response of these hormones to administration of either TRH or TSH.^27-29,,^66-69 Although results of TRH or TSH stimulation tests are thought to provide a better indication of thyroid status than single point-in-time measurements of thyroid hormone concentrations, they can be more difficult to perform in a field setting.

To perform a stimulation test, a control blood sample is obtained, TRH (1 mg to the average 450- to 500-kg horse) or TSH (5 IU) is given intravenously, and subsequent blood samples are obtained. Most references say that T₃ should double at 2 hours, and T₄ should double at 4 hours. The author routinely performs TRH stimulation tests and prefers to measure both T₃ and T₄ before and 1, 2, and 4 hours post TRH administration in order to make sure the peaks are not missed. In 36 normal horses that participated in various studies conducted by the author, the mean increase in total T₄ was 2.2 times baseline at 4 hours. However, the range was 1.3 to 3.8 times baseline. Increases in free T₄ and free T₄ by dialysis (mean and range) were 1.7 (1.1 to 2.1) times and 1.8 (1.1 to 2.8) times at 4 hours, respectively. Increases in total and free T₃ (mean and range) were 3 (1.1 to 10.3) times and 4.2 (1 to 53) times at 2 hours, respectively. These seemingly lower thyroid hormone responses to TRH injection are in agreement with findings in a recent report of levothyroxine administration to normal horses.⁷⁰ Closer examination of data from the author's horses revealed that, in general, the few individuals with small increases in T₄ or T₃ either started with higher resting values or had peaks that occurred later (T₄) or earlier (T₃) than 4 or 2 hours. Individuals with lower T₄ responses in general were not the same individuals with lower T₃ responses. Thus, one must be careful when interpreting results of a TRH stimulation test. Failure of T₃ to double by 2 hours or T₄ to double by 4 hours after TRH injection does not necessarily mean that the horse is hypothyroid. Animals with high responses tended to be animals with very low resting thyroid hormone concentrations.

If single point-in-time measurement of thyroid hormones is the only option available for evaluation of thyroid status, measurement of free fractions of thyroid hormones (alone or in conjunction with measurement of total amounts of hormone) provides more useful information than measurement of total amounts of thyroid hormones alone. Measurement of serum TSH concentrations in single samples also likely will aid diagnosis of thyroid status, though a well-validated methodology for this test in horses is not commercially available.

During illness in humans, measurement of serum free T₄ by direct methods often underestimates values, when compared with measurements of free T₄ after dialysis or ultrafiltration.^71-75 This also appears to be the case in dogs⁷⁶ and horses.⁴³ Thus, serum concentrations of free T₄ measured by equilibrium dialysis are more likely to reflect true thyroid status in ill horses, compared with other methods of free T₄ measurement. Measurement of fT₄D instead of fT₄ may help prevent equine clinicians from misdiagnosing ill horses as being hypothyroid.

A T₃ suppression test has been described^5,6 and may be useful to confirm hyperthyroidism. A blood sample is obtained before intramuscular administration of 2.5 mg 3,5,3'-triiodothyro-L- thyronine (T₃) diluted in 5 mL sterile saline, given twice daily for 7 doses (4 days). Additional blood samples are drawn 5 minutes before each dose of T₃ and then twice daily on days 5 and 7 and in the morning of day 10. In normal horses, T₄ and T₃ measurements will be within reference range in the control blood sample. Administration of exogenous T₃ should result in a 10- to 20-fold increase in T₃ concentration, while T₄ gradually decreases, remaining suppressed for at least 5 days after the last dose of T₃. In hyperthyroid horses, control blood samples will have increased concentrations of T₄ and T₃. The increase in serum T₃ after T₃ administration is not as pronounced as in normal horses, but T₃ does remain increased throughout the administration period. T₄ does not suppress.

Ultrasound imaging is most helpful when thyroid glands are enlarged. Ultrasound imaging can differentiate enlargement due to solid tissue versus cystic fluid. It is also useful as an aid in getting a representative biopsy sample if thyroid neoplasia is suspected. Nuclear scintigraphy is useful to demonstrate gland activity, which may or may not be equal in the right and left lobes.

Treatment of Hypothyroidism in Adult Horses

Management of horses that have been properly diagnosed as being hypothyroid or horses that have undergone thyroidectomy theoretically should be fairly straightforward. Serum thyroid hormone concentrations should be monitored, and dosages of thyroid hormone supplementation adjusted to maintain serum thyroid hormones in the normal range. This is not necessarily as simple as it sounds. T₄ is the most common form of thyroid hormone supplementation, and while T₄ administration increases serum concentrations of T₄, serum concentrations of T₃ may not change or may actually decrease if T₃ is not also given or if the horse is not truly hypothyroid. In addition, T₄ dosage recommendations have been made on the basis of thyroid hormone concentrations obtained after thyroid administration to normal horses with intact thyroid glands⁷⁷ (Chen 1984). Thyroid hormone pharmacokinetics may be different in truly hypothyroid horses; pharmacokinetic studies in horses made hypothyroid by thyroidectomy or by administration of antithyroid drugs would be useful. Until such studies are performed, the following recommenda­tions can be made. T₄ is available in several forms. Iodinated casein contains approximately 1% T₄ and is given at 5 to 15 g/horse/day PO¹³ (Lowe 1974). The recommended start­ing dose of levothyroxine was 20 ug/kg horse/day PO,^77,78 but a more recent study suggested that doses as high as 50 to 100 ug/kg/day are well tolerated and may be necessary.⁷⁰ If a sensitive TSH assay becomes commercially available, dosages should be adjusted to normalize TSH.

Thyroid Function in Normal Neonatal Foals of glucocorticoids.⁸³ Skeletal growth and maturation are stimulated synergistically by thyroid hormones and growth hormone.⁸⁴ The mechanism(s) by which thyroid hormones are increased in the peripartum period is (are) unknown. One might expect the increase to be centrally driven. However, in a study by the author,⁴⁸ serum TSH concentrations were not increased in equine neonates, compared with adults, nor did they change over the first month of life, while serum thyroid hormone concentrations were declining.

Thyroid Function in Premature Foals

Premature human infants experience transient hypothyroxin- emia, with serum T₄ concentrations correlated to gestational age.^85-88 In a study by the author, serum concentrations of total and free thyroid hormones and TSH, both at rest and in response to TRH, were measured in normal, healthy neonatal foals that were full term (normal foals), in hospitalized premature neonatal foals (premature foals), and in full-term neonatal foals that were ill and hospitalized for conditions similar to premature foals (sick foals) to determine the possible contributions of an immature hypothalamic-pituitary axis and nonthyroidal illness to thyroid dysfunction in premature foals.⁴⁸ Normal foals did not receive any medications. Both sick and premature foals received medications routinely used to treat conditions including (but not limited to) failure of passive transfer, sepsis, and perinatal asphyxia syndrome. Premature foals had significantly lower serum concentrations of total and free fractions of thyroid hormones than normal foals. Baseline serum concentrations of TSH were not different, but TSH responses to TRH were exaggerated in premature foals compared with normal foals. Serum concentrations of total and free T₃ and TSH were similar in sick term foals and sick premature foals, suggesting that both of these groups of foals were experiencing nonthyroidal illness syndrome, primarily a low T₃ state. However, premature sick foals also had significantly lower total and free T4 concentra­tions compared with age-matched full-term sick foals, suggesting that premature foals also experience hypothyroxinemia, similar to infants. More profound alterations in thyroid function in premature foals, compared with sick term foals, may be caused by an immature hypothalamic-pituitary-thyroid axis. It remains to be seen whether early thyroid hormone supplementation in premature foals might improve short-term survivability and preserve long-term athletic function. Traditional thought has been that administration of thyroid hormones to patients with nonthyroidal illness syndrome is not beneficial and might even be detrimental. However, these beliefs have been challenged,^38,39 and the issue remains controversial. While results are variable, treatment of premature human infants with T₄ has resulted in improved IQ and neurologic development at 2 years of age^85,86 and may reduce the incidence of cerebral palsy in extremely preterm infants.⁸⁹ T₃ administration to human neonates with severe respiratory distress syndrome improved survival.⁹⁰ However, in a recent study, levothyroxine administration to premature infants was associated with development of late- onset refractory hypotension.⁹¹ By increasing metabolism, levothyroxine therapy may lead to acute adrenal insufficiency.⁹²

Congenital Hypothyroidism in Foals

Two syndromes of congenital hypothyroidism have been described in foals. Hypothyroid foals with visible goiters have been produced by mares ingesting either too much or too little iodine or by mares ingesting goitrogenic plants.^93-95 These foals are born weak, with poor sucking and righting reflexes, hypo­thermia, and developmental abnormalities of the musculoskeletal system, including tendon contracture or rupture and delayed bone development, particularly of the small cuboidal bones of the carpus and tarsus. Thyroid hormone supplementation to more severely affected foals may improve survivability, but dosage recommendations are scarce. Irvine recommends basing the dose on secretion rate.⁸⁴ For oral administration of T₄, this would equal 10 ? 0.22 ? kg bwt ? 0.08 ? plasma T₄ (μgy'L), or approximately 2.5 mg/day PO for a 1- to 3-day-old 50-kg foal. Because there is a time delay for T₄ to act and T₃ is more active than T₄, T₃ supplementation at one-third the calculated T₄ dose may provide more benefit initially.

A second syndrome of congenital hypothyroidism has been described in foals, primarily in the western parts of the United States and Canada.^96-100 This syndrome is characterized by thyroid gland hyperplasia, increased gestational length, and musculoskeletal abnormalities, including mandibular prognathia, flexural limb deformities of the front legs, ruptured digital extensor tendons, and incomplete ossification of the carpal and tarsal bones. Despite the prolonged gestation, other indicators of prematurity may be present, such as a silky hair coat. At the time of birth, baseline serum concentrations of T₄ and T₃ are usually within the normal neonatal ranges, but the response to TSH administration is decreased.¹⁰¹ The cause is unknown but suspected to be a dietary deficiency or toxicity of the mare during gestation. Likely candidates include nitrate toxicity, iodine and/or selenium deficiency, or goitrogenic plant ingestion by the mare.^99,101 Because thyroid hormone concentrations are normal at the time of birth, thyroid hormone supplementation is usually not administered. Supportive care to try to prevent collapse of the carpal and tarsal bones is recommended.