Thyroid function and dysfunction in horses--part 1 and 2 (Proceedings)

Thyroid function in adult horses

Thyroid hormones are important for growth, maturation of organ systems, and regulation of metabolism. The thyroid gland manufactures and secretes both thyroxine (T4) and tri-iodothyronine (T3), although the main source of T3 in the body is from conversion of T4 to T3 in peripheral tissues.  T3 is more active metabolically than T4.  Thyroid hormones circulate both bound to proteins and “free” (ie unbound), with the free fractions being the active fractions. 

Thyroid hormone secretion from the thyroid gland is regulated by thyrotropin or thyroid stimulating hormone (TSH) from the anterior pituitary, which in turn is regulated by thyrotropin releasing hormone (TRH) from the median eminence of the hypothalamus.

Thyroid dysfunction in adult horses

Both hypothyroidism and hyperthyroidism have been described in the horse, but true thyroid gland dysfunction is probably much rarer in horses than in some other species, including humans, dogs and cats.  A large number of adult horses that are administered thyroid hormones probably have normal thyroid gland function.  Abnormalities of thyroid function that have been described in the horse include thyroid gland neoplasia, hyperthyroidism, and hypothyroidism.  In addition, certain drugs and a variety of physiologic and/or pathologic conditions can alter serum thyroid hormone concentrations.

Thyroid gland neoplasia

Thyroid gland neoplasia is not uncommon in horses, particularly in older horses.  Histologically, adenomas, carcinomas, adenocarcinomas, and C-cell tumors have been described.  Most thyroid gland tumors in the horse are relatively benign, in that they do not tend to metastasize and circulating thyroid hormone concentrations usually remain in the normal range.  Many thyroid tumors are found as incidental findings at necropsy examination. 

However, some tumors enlarge to the point that they interfere with pharyngeal and/or laryngeal function.  These tumors can be removed surgically and the horse managed with thyroid hormone replacement therapy.  There are also scattered case reports in the literature of horses that were found to be hypothyroid or hyperthyroid due to a thyroid tumor.

Hyperthyroidism

Hyperthyroidism is extremely rare in horses.  There have only been a few cases of hyperthyroidism in adult horses properly documented in the literature, and these have been in association with thyroid hormone producing tumors.  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.  Diagnosis is confirmed by measurement of increased circulating concentrations of free fractions of thyroid hormones.

Hypothyroidism

Hypothyroidism is poorly understood in the horse.  While hyperthyroidism is rare, the prevalence of true hypothyroidism in adult horses is unknown and its existence is somewhat controversial.  Autoimmune thyroiditis, while somewhat common in humans and dogs, has only been described in one report from eastern Europe in the horse, in which histologic lesions compatible with Hashimoto thyroiditis-like disease were found in roughly 20% of 622 horses at a slaughterhouse. 

Although thyroid hormone supplementation is commonly advocated for horses suffering from problems such as laminitis, obesity, recurrent myositis, anhidrosis and poor fertility, proper documentation of hypothyroidism in such cases is often non-existent.  Anecdotal reports of beneficial effects of thyroid hormone supplementation in these horses are also largely unsubstantiated. 

s a result, individual horses may receive thyroid hormone medication over an extended period of time when they do not really need it.  Besides the obvious waste of money, potential health risks associated with unnecessary thyroid hormone supplementation have only minimally been explored in horses.  In humans, thyrotoxicosis or over-supplementation with levothyroxine can result in decreased bone density, increased risk of atrial fibrillation, and perhaps increased risk of myocardial infarction or precipitation of congestive heart failure.

Clinical signs of hypothyroidism in adult horses are not well defined. Overweight horses that are easy keepers, with cresty necks, abnormal fat pads, and a predisposition to recurrent laminitis were traditionally described as hypothyroid. However, thyroid function tests in these horses are usually normal.  Instead of hypothyroidism, these horses most like suffer from equine metabolic syndrome or pituitary pars intermedia dysfunction.  Clinical signs in horses properly documented to be hypothyroid in published case reports include lethargy or work intolerance and alterations in haircoat. 

Horses with experimentally-induced hypothyroidism (either through surgical removal of the thyroid glands or by administration of anti-thyroid drugs) demonstrate vague clinical signs.  Surgical removal of the thyroid glands of adult horses results in decreased basal heart rate, cardiac output, respiratory rate and rectal temperature, and increased serum concentrations of triglycerides, cholesterol and very low density lipoproteins.  However, these changes are mild and do not result in resting values that are clearly outside the normal range for the horse.

Diagnosis of hypothyroidism is based on demonstration of subnormal concentrations of circulating free fractions of serum thyroid hormones, demonstration of increased serum TSH concentration, and/or altered serum thyroid hormone response to TSH or TRH (see section on testing below).

Management of horses that have been properly diagnosed as being hypothyroid, or horses that have undergone thyroidectomy is fairly straightforward.  Thyroxine is most commonly used for supplementation and is available in several forms.  Iodinated casein contains approximately 1% T4 and is given at 5-15g/horse/day orally. 

The recommended starting dose of levothyroxine is 20 µg/kg horse/day orally.  Serum thyroid hormone concentrations should be monitored and dosages of thyroid hormone supplementation adjusted to maintain serum thyroid hormones in the normal range.  If a TSH assay becomes commercially available, dosages should be adjusted to normalize TSH.

Physiologic, pathophysiologic and pharmacologic alterations of thyroid function

Certain drugs and various physiologic or pathologic states can alter thyroid hormone synthesis, metabolism or binding, resulting in altered serum concentrations of thyroid hormone.  In the horse, these include phenylbutazone or dexamethasone administration, fasting, and strenuous exercise.  Diets high in energy, protein, zinc and copper have also resulted in alterations in circulating concentrations of thyroid hormones in horses. 

Assessment of thyroid function in adult horses

Because certain drugs and pathophysiologic states can lower serum concentrations of thyroid hormones in otherwise euthyroid horses, it is important that thyroid function tests not be performed while horses are ill, are receiving certain 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 prior to 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.  TRH or TSH stimulation tests are considered to be superior to measurement of baseline thyroid hormone concentrations for evaluation of thyroid function.  However, these tests are not routinely performed because of the impracticality of having to take multiple blood samples over time and because TRH and TSH are not readily available commercially or are prohibitively expensive.

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 does measurement of total amounts of thyroid hormones alone.  Measurement of serum TSH concentrations in single samples also will likely aid diagnosis of thyroid status, once a TSH assay for the horse becomes commercially available.

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

 "Normal" values for serum concentrations of thyroid hormones vary somewhat by laboratory due to differences in assay procedures, units of measurement, and populations of horses used to establish the laboratory's normal values. Therefore, when choosing a diagnostic laboratory, it is important to verify that the laboratory has validated its assays and established reference ranges in a population of normal horses.

Non-thyroidal illness syndrome in the horse

Non-thyroidal illness syndrome has been described in humans, dogs and cats suffering from systemic illnesses.  In humans, milder forms of illness result in decreases in serum concentrations of T3, with T4 remaining within the normal range or only slightly decreased.  As non-thyroidal illness becomes more severe, total T4 decreases and eventually free T4 also begins to decrease.  The magnitude of thyroid hormone suppression has been correlated to severity of disease and to mortality. 

Mechanisms by which thyroid hormones decrease during illness include decreased peripheral conversion of T4 to T3 by 5'-deiodinase, altered binding to serum carrier proteins, and hypothalamic-pituitary dysregulation or suppression.  Traditional thought has been that administration of thyroid hormones to patients with non-thyroidal illness syndrome is not beneficial, and might even be detrimental.  However, these beliefs have recently been challenged, and the issue remains controversial.

It is thought that non-thyroidal illness syndrome is meant to act as a protective mechanism, with decreased serum concentrations of thyroid hormones resulting in decreased metabolic rate and conservation of lean body mass during times of illness, stress, and decreased food intake.  Traditional thought has been that administration of thyroid hormones to patients with non-thyroidal illness syndrome is not beneficial, and might even be detrimental.  However, these beliefs have recently been challenged, and the issue remains controversial. 

Preliminary data from blood samples collected from horses admitted to the North Carolina State University's Veterinary Teaching Hospital suffering from a variety of illnesses indicate that, not only are serum concentrations of thyroid hormones decreased, but the magnitude of these decreases are profound in many cases, especially in horses that ultimately died or were euthanized.  The contribution of various drugs administered to treat these diseases remains to be determined.

Fescue ingestion

Tall fescue (Festuca arundinaceae) is a cool-season perennial grass that is grown commonly in the Southeast because it is relatively easy to establish, has a long growing season, and has good disease and drought resistance that allow it to survive hot, humid summers.  A variety of reproductive problems have been described in mares consuming fescue, and these have been shown to be caused by alkaloids produced by an endophytic fungus (Neotyphodium coenophialum) that lives symbiotically on the fescue plant and acts as a dopamine agonist. 

Since TSH release from the pituitary is inhibited by dopamine, it has 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 to mares and foals on a nearby farm grazing pastures that were mainly free of endophyte-infected fescue.  However, the author found no differences in baseline concentrations of thyroid hormones or TSH, or in their responses to administration of TRH, in adult, non-pregnant horses fed endophyte-infected fescue seed for 2 months. 

It appears that dopamine acts more as an acute modulator of TSH secretion, rather than as the primary control.  In humans, while acute dopamine blockade results in increased TSH secretion and increased circulating thyroid hormones, chronic administration does not cause long-term alterations in thyroid hormone status.  It has been proposed that compensatory mechanisms maintain TSH secretion and euthyroidism.  A similar situation likely exists in the horse. 

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 1950's.  However, the author found that baseline concentrations of thyroid hormones and TSH were normal in horses with anhidrosis.  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.  It may be that increased TSH release compensates for decreased ability of the glands to secrete thyroid hormones.  In humans with subclinical hypothyroidism, serum TSH concentrations are increased, while serum thyroid hormone concentrations remain within the normal range.  It seems unlikely, however, that subclinical hypothyroidism caused anhidrosis in the horses in this study, since many of them had been anhidrotic for years.  One would have expected subclinical hypothyroidism to have progressed to clinical hypothyroidism in those horses over that period of time.

Since serum thyroid hormone concentrations remain within normal limits in anhidrotic horses, the usefulness of exogenous thyroid hormone administration is doubtful.  It is possible that, if thyroid hormone supplementation does indeed facilitate sweating in anhidrotic or hypohydrotic horses, the effect may be pharmacologic rather than physiologic.  Equine sweat glands are stimulated to secrete by activation of b2-adrenergic receptors, and, although not demonstrated so far, it has been proposed that anhidrosis results from desensitization or downregulation of these receptors. 

Thyroid hormones modulate adrenergic receptor function, such that tissues from hypothyroid individuals are less responsive to ?-adrenergic agonists.  Both desensitization and downregulation of b-adrenergic receptors have been shown in hypothyroid animals.  Thus, perhaps making horses mildly hyperthyroid iatrogenically restores b-adrenergic receptor numbers or sensitivity, or potentiates sweat responses to whatever neural stimulation remains.

Laminitis

Laminitis is a significant clinical problem in horses, resulting in pain and decreased quality of life, decreased usefulness or athletic ability, and even loss of life itself.  The pathophysiology of laminitis is incompletely understood, and its cause is probably multifactorial. However, endocrine dysfunction almost certainly plays a role in many cases of laminitis. 

The classical description of a hypothyroid horse used to be one that is overweight with a cresty neck, that may have reduced exercise tolerance, and that has a predisposition to suffer from mild but recurrent bouts of laminitis.  Horses fitting this description were traditionally supplemented with thyroid hormone medication, and some clinicians continue to do so at this time, with or without prior evaluation of thyroid hormone status.  However, clinical signs in these horses are more likely associated with equine metabolic syndrome or pituitary pars intermedia dysfunction. 

Horses with equine metabolic syndrome or pituitary pars intermedia dysfunction tend to be insulin resistant, have abnormal fat deposits in the neck, over the rump, and in the sheath, and may experience recurrent episodes of laminitis.  Thyroid hormone concentrations and responses to TRH stimulation have been shown to be normal in both of these groups of horses. 

A role for decreased thyroid function in the pathogenesis of laminitis 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 unlikely that decreased thyroid function alone causes laminitis.  In three studies in which hypothyroidism was induced either by surgical removal of the thyroid glands or by administration of propylthiouracil, laminitis did not occur.  Thus, any alterations in serum thyroid hormone concentrations in horses experiencing laminitis may be caused by factors associated with the episode of laminitis, rather than the cause of the laminitis itself.  

Such factors could include drugs used to treat laminitis (eg phenylbutazone), development of non-thyroidal illness syndrome, or a direct effect of factors such as endotoxin or one of the inflammatory cytokines that contribute to the onset of laminitis in some cases.  In the author's experience, 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 to TRH 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 b-adrenergic agonists on vasculature is usually vasodilatory, it is possible that thyroid hormone administration increases circulation to the foot by its ability to potentiate b-adrenergic receptor numbers and sensitivity.  Or it is also possible that thyroid hormone supplementation alters carbohydrate and fat metabolism in a way that increases insulin sensitivity. 

Thus, as suggested for anhidrosis, any beneficial effect of thyroid hormone administration in horses suffering from laminitis may be pharmacologic rather than physiologic.  Recent evidence suggests that thyroid hormone supplementation at supraphysiologic doses can facilitate weight loss in these horses, as long as food consumption is controlled at the same time. No adverse effects were reported in these studies, other than some horses developed behavioral changes, attributed to becoming hyperthyroid. Insulin sensitivity improved with weight loss and was thought to decrease the likelihood of recurrent bouts of laminitis.

Pituitary pars intermedia dysfunction

Pituitary pars intermedia dysfunction tends to occur in older horses and is caused by hypertrophy or hyperplasia of the intermediate lobe of the pituitary.  The pars intermedia of the pituitary gland consists mainly of melanocytes that produce proopiomelanocortin (POMC), a precursor peptide that is split into α-melanophore stimulating hormone (α-MSH), b-endorphin, and ACTH. 

The traditional view of pituitary pars intermedia dysfunction is that clinical signs are caused by overproduction of ACTH, leading to excessive circulating corticosteroids.  However, baseline plasma concentrations of cortisol are usually within normal range in horses with pituitary pars intermedia dysfunction.  Clinical signs may be caused by an apparent loss of the normal diurnal rhythm for cortisol.

Cortisol inhibits release of TSH from the anterior lobe of the pituitary, as well as inhibiting thyroid hormone release from the thyroid gland.  This is thought to be one of the mechanisms for decreased circulating serum thyroid hormone concentrations in response to stress or in non-thyroidal illness syndrome.  Increased serum cortisol or loss of cortisol diurnal rhythm has been proposed to cause decreased TSH concentrations in horses with pituitary pars intermedia dysfunction. 

However, horses with pituitary pars intermedia dysfunction have been shown to have normal resting serum thyroid hormone concentrations and normal thyroid hormone responses to TRH administration.  The author has preliminary data that show that resting TSH concentrations and TSH response to TRH is also normal in horses with pituitary pars intermedia dysfunction.

Thyroid function in the perinatal period

Thyroid hormones are important for growth, maturation of organ systems, and regulation of metabolism.  Free T3 binds to intracellular thyroid hormone receptors, stimulating the production of proteins.  In a general sense, thyroid hormones increase mitochondrial number and size, increase activity of Na,K-ATPase, increase protein synthesis and catabolism, increase heat production, and stimulate basal metabolic rate. 

Of particular importance to the fetus and neonate, they increase growth and maturation of a number of organ systems, resulting in increased mental activity and neural development, lung maturation, increased gastrointestinal function (eg. increased appetite and intake, increased GI secretion and motility), increased cardiovascular function (eg. increased heart rate, cardiac output, blood volume, and pulse pressure), and growth and maturation of the skeletal system.

The fetal thyroid gland develops from endodermic cells from the posterior face of the pharynx, and begins synthesizing T4 around 10-12 weeks gestation in humans.  However, early fetal thyroid hormone synthesis is very low and maternal thyroid hormones are important for fetal development in the first trimester.  After that, fetal thyroid status is relatively independent of maternal influence in normal pregnancies because of the placenta. 

The placenta is, however, permeable to iodide, and excess maternal iodide ingestion can cross the placenta and inhibit the fetal thyroid gland, producing congenital hypothyroidism.  Iodide excess is more of a problem to the fetus than the mother because the mother can autoregulate iodide transport into follicular cells, whereas the fetus cannot autoregulate iodide transport until it is near term.  Iodide deficiency also causes congenital hypothyroidism.

Fetal concentrations of T3 and cortisol are low.  In many species, fetal serum thyroid hormones increase just before birth and probably play a role in the rapid growth and organ system development that occur in late gestation.  In sheep and pigs, there is a gradual rise in fetal cortisol and T3 in late gestation, with a rapid increase several days before birth.  Prepartum surges of cortisol and T3 have also been demonstrated in foals, although the increases appear to begin later in gestation and continue after birth.  

The rise in thyroid hormones seems to be linked to the cortisol surge, but the precise mechanism by which this occurs is unknown. It is unlikely that cortisol directly stimulates the thyroid gland.  Alterations of thyroid hormone metabolism have been proposed as a mechanism, since peripheral conversion of T4 to T3 in fetal liver and kidney is enhanced by pre-treatment with cortisol and exogenous infusion of cortisol in the fetal lamb decreases the metabolic clearance rate of T3.  Fetal TSH measurements have not been performed.

Normal neonatal foals have serum concentrations of thyroid hormones that are approximately ten times adult concentrations.  Thyroid hormones remain very high during the first week of life, and then slowly decline, reaching normal adult concentrations by approximately one month of age.  Thus, when assessing thyroid function in equine neonates, it is important to compare values obtained for circulating concentrations of thyroid hormones to age-matched controls. 

These high concentrations of thyroid hormones are thought to be important in maintaining thermogenesis, regulation of cell differentiation, and maturation of many body systems, especially the respiratory, nervous and musculoskeletal systems.  Thyroid hormones increase thermogenesis by increasing metabolic rate and, of particular relevance to the neonate, increasing heat production from brown fat.  Thyroid hormones also stimulate lung development and surfactant production, and these effects are potentiated by concurrent administration of glucocorticoids.  Skeletal growth and maturation are stimulated synergistically by thyroid hormones and growth hormone.

Congenital hypothyroidism - goiter

Abnormalities of thyroid function can originate from any part of the hypothalamic-pituitary-thyroid axis. In term foals, primary hypothyroidism can result from dietary deficiencies or excesses of iodine intake by the mare, or by ingestion by the mare of goitrogenic plants.  Sulfurated organic compounds, thiocyanates, and isothyocynates cause goiter in humans. 

Selenium deficiency and mustard have been suggested as potential dietary goitrogens in the horse.  Kelp, a seaweed product, is very high in iodine and administration to pregnant mares has resulted in birth of hypothyroid foals.  Hypothyroidism in equine neonates results in incoordination, poor sucking and righting reflexes, hypothermia, and developmental abnormalities of the musculoskeletal system, including incomplete ossification of the cuboidal bones.  These foals are often born with visible enlargement of the thyroid gland, or goiter.

Neonatal goiter can be prevented by ensuring proper iodine concentrations in diets fed to pregnant mares.  Thyroid hormone supplementation may be helpful in treatment of hypothyroid foals in terms of body temperature regulation, suck reflex, mental alertness, etc.  Since T4 must be converted to T3 for biological activity, there is a greater lag period between administration and metabolic effect for T4 compared to T3. 

Therefore, a combination of T3 and T4 supplementation would theoretically be more beneficial to a neonate, but appropriate dosage is unclear.  The current dosage recommendation for levothyroxine (T4) for foals is 20-50 μg/kg/day PO.  The suggested dosage for T3 is 1 μg/kg/day PO.  It is important to monitor serum thyroid hormone concentrations to ensure that supplementation increases thyroid hormones to normal concentrations for the age of the foal, without overdosing.

Congenital hypothyroidism - western syndrome

A syndrome of hypothyroidism associated with thyroid gland hyperplasia and various skeletal abnormalities has been described in foals born in Western Canada and the United States.  The etiology of this second syndrome is not known at this time, but factors such as nitrate, low iodine, low selenium or goitrogenic plant ingestion by the mare have been suggested. 

Clinical signs include congenital 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.  At birth, serum concentrations of thyroid hormones may be normal in these foals.  It is thought that the musculoskeletal problems are caused by hypothyroidism during key developmental stages in utero.

Since the cause of the Western syndrome of thyroid dysfunction in foals is unknown at this time, preventive measures are also unknown.  Exercise should be restricted in foals born with incompletely ossified cuboidal bones and/or ruptured extensor tendons.  Lightweight splints may be necessary to prevent foals from knuckling or to prevent collapse of the cuboidal bones on the medial sides of the joints.  If used, splints must be applied carefully and monitored closely.  Foals wearing splints may need help getting up to nurse and are at risk for developing rub sores.

Prematurity and thyroid function

Normal equine neonates are precocious. Their eyes are open, they have a complete haircoat, and their neural, muscular, and skeletal systems are well developed. By contrast, premature foals are characterized by small body size, a domed forehead, a short silky haircoat, floppy ears, weak flexor tendons, and decreased or absent ossification of the cuboidal bones of the carpi and tarsi.

Premature foals have trouble maintaining body temperature and blood glucose concentrations, and require a great investment of time (and money) to save their lives, with death most commonly occurring secondary to immature lung development and sepsis.  Foals that survive these first challenges face additional complications from decreased gastrointestinal, neural, and musculoskeletal development.  While causes of problems experienced by premature foals are multifactorial, an immature hypothalamic / pituitary / thyroid axis probably contributes.

Premature human infants experience transient hypothyroxinemia, with serum T4 concentrations correlated to gestational age.  Premature foals also have lower serum thyroid hormone concentrations at birth compared to term foals.  While some of the hypothyroxinemia observed in premature foals is directly related to their prematurity, some of it is also likely caused by non-thyroidal illness syndrome (see below). 

Significant problems of premature foals that could be related to thyroid insufficiency include an inability to maintain body temperature (thermogenesis), decreased surfactant production leading to respiratory distress syndrome and hyaline membrane disease, and musculoskeletal abnormalities (weak tendons, joint laxity and incompletely ossified cuboidal bones) that limit the foal's ability to get up, nurse, and evade predators.  Musculoskeletal weakness and gastrointestinal immaturity also can contribute to the development of failure of passive transfer of maternal antibodies and subsequent development of sepsis. 

Respiratory distress syndrome and sepsis are the two most likely causes of early death in premature neonates, and require intensive veterinary intervention.  If the foal survives these initial challenges, it is still at risk for developing collapse of the immature carpal and tarsal bones when it begins to bear weight.  Early recognition of the problem, splinting of the legs, and exercise restriction may decrease the incidence of angular limb deformities and degenerative joint disease, but the longer it takes the bones to ossify, the less likely the foal will become an athlete.

While results are variable, treatment of premature human infants with T4 has resulted in improved IQ and neurological development at 2 years of age, and T3 administration to human neonates with severe respiratory distress syndrome improved survival.  Further study of T3 supplementation to premature human infants has been advocated. 

Equine neonates have much higher serum thyroid hormone concentrations at birth than other species studied, and it has been proposed that this is responsible for the high degree of neurological and musculoskeletal development that foals exhibit at birth, compared to these species.  Thus, thyroid dysfunction or hypothyroidism in neonatal foals may have a more profound effect on early morbidity and mortality than it does in other species.  Early thyroid hormone supplementation in premature foals might improve short-term survivability and preserve long-term athletic function.

Prematurity, non-thyroidal illness syndrome and thyroid function in foals

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 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. 

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.  Blood samples were collected for measurement of baseline concentrations of thyroid hormones and TSH at predetermined ages, and TRH stimulation tests were performed in foals at less than 3 days of age. 

As expected, normal, term foals had markedly increased circulating concentrations of free and total T4 and T3 at birth.  Interestingly, neonatal serum TSH concentrations were within the normal adult range for horses, and did not vary over the same time period.  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 to normal foals.  Serum concentrations of T3 and TSH were similar in sick term foals and premature foals, but serum concentrations of T4 in sick term foals were intermediate between premature and normal foals. 

These results suggest that sick foals experience non-thyroidal illness syndrome, primarily a low T3 state.  Further alterations in thyroid function in premature foals may be caused by an immature hypothalamic-pituitary-thyroid axis. The effect of drugs commonly used to treat ill foals on serum thyroid hormone concentrations in the premature and sick foals in this study have not been examined. Further alterations in thyroid function in premature foals may be caused by an immature hypothalamic-pituitary-thyroid axis.