Equine Endocrinology

Preface

This first edition of Equine Endocrinology is designed for veterinary students and equine practitioners; it aims at providing a comprehensive yet user-friendly tool to approach and manage common endocrine disorders. Equine endocrinology is a very fast moving field and clinical signs of endocrine and metabolic disorders have become dominant presenting complaints in practice.

Equine Endocrinology is divided into an introductory chapter providing the key steps of the clinical approach of equine endocrinology and eight chapters covering the disorders of the main hormonal axes responsible for equine diseases, including female and male reproductive endocrinology. Each chapter is organised in a classic disease-oriented format, briefly presenting the main physiological elements of the key hormonal players and then detailing the epidemiology, clinical signs, diagnostic steps, management and prognosis of each endocrine condition reported in horses. This edition contains more than 50 colour figures and tables to illustrate the physiological mechanisms, clinical findings, diagnostic tests or treatment plans and to allow a better visualisation and understanding of equine metabolic diseases.

The motivation for this first edition of Equine Endocrinology stemmed from the inquisitiveness of our students, the dedication of our colleagues in the field and the resilience of horse owners; we hope this book will provide a source of information to improve the management of horses around the world.

We also want to thank Alexandra Lainsbury, Ali Thompson and Jill Northcott at CABI who have guided us along this journey.

François-René Bertin

Acknowledgements

To

Constantin, Annie, Alain, Olivier, Karl and Otto for their love and support.

Thank you to Janice Kritchevsky and Nick Frank for showing me the way and to my students and patients for making it all worthwhile.

Thank you to

Nick Bamford, Chris Elliot, Nick Frank, Jen Gold, Janice Kritchevsky, Sascha Nott, Chiara Palmieri, Allison Stewart and Alex Young for sharing pictures.

Dr François-René Bertin

1Clinical Approach to Equine Endocrinology

Equine endocrinopathies present with a variety of clinical signs. While some clinical signs, like hypertrichosis, are quite obvious and almost pathognomonic, others, like decreased fertility or weight loss, are subtle and might require a more thorough evaluation (Frank et al., 2010b; McFarlane et al., 2011). In addition, several endocrinopathies can be present in the same animal at the same time, and only early recognition and proper management of both conditions will allow a successful outcome (McGowan et al., 2013b). Therefore, a comprehensive and systematic examination is recommended when evaluating patients.

History

A detailed history is a key step to approach cases in which an endocrinopathy is suspected.

Signalment

Close attention to signalment should be paid as there are age-related endocrinopathies, such as pituitary pars intermedia dysfunction (PPID), and some breeds known to be predisposed to some endocrine disorders, such as insulin dysregulation (ID) in ponies or Morgans (McGowan et al., 2013a; Bamford et al., 2014). Gender can also be an important element to consider as endocrine disorders such as equine metabolic syndrome (EMS) have been shown to decrease conception rates (Sessions-Bresnahan and Carnevale, 2014). Thus, a close examination of a mare’s reproductive performance can indicate subclinical endocrinopathies.

Complaint

The primary complaint is often a clear suggestion of an endocrine disorder; however, some owners might overlook minor changes, such as delayed coat shedding or increased water consumption, and only seek veterinary advice when the endocrinopathy impairs the function of the horse and causes more severe signs such as lameness (Horn et al., 2019). Although the awareness of endocrine disorders has increased in the last two decades, early signs of endocrinopathies can be mistaken for normal age-related changes and might not therefore trigger veterinary attention (Miller et al., 2016).

Season

As many hormones have a circannual rhythm, clinical signs can vary with seasons (Frank et al., 2010a; Funk et al., 2011; Borer-Weir et al., 2013). Therefore, collecting history on the previous 12 months and comparing with recent years can be critical when assessing some cases. For example, horses with early signs of PPID can only show delayed coat shedding; comparing the time of shedding over consecutive years might give an indication of early endocrinopathies. Similar considerations are valid for horses with EMS with seasonal episodes of laminitis (Coleman et al., 2018).

Diet

Diet is a paramount element in the assessment of a patient suspected of an endocrine disorder. The clinician should focus on the type of feed offered to the horse (pasture vs hay vs concentrate), the quality of the feed (calcium/phosphorous imbalance can lead to secondary hyperparathyroidism; excessive non-structural carbohydrates, NSC, can lead to ID) and the quantity actually ingested by the horse (Toribio, 2011; Frank and Tadros, 2014). In critical cases such as severely hyperinsulinaemic patients, regular diet analysis is essential to minimize post-prandial hyperinsulinaemic peaks and limit lamellar damage. It is also important to remember that horses and ponies have different eating behaviours and time on pasture might not adequately represent the amount of food ingested: large amounts of grass can be ingested in a short period of time, mainly when the time is restricted. Water intake should also be recorded as increased water intake might suggest a disorder of the hypothalamo−pituitary−adrenal axis (Schott, 2011). Although difficult to properly measure with automatic waterers, a water intake above 3 ml/kg/h in an adult horse warrants further investigation.

Concurrent diseases

By nature, endocrine disorders can affect multiple body systems as hormones regulate metabolism, immunity and homeostasis. For example, by modulating immunity, hypothalamo−pituitary−adrenal axis dysregulation can result in recurrent infections or non-healing wounds (Hofberger et al., 2015; McFarlane et al., 2015; Horn et al., 2019). In addition, some endocrinopathies can be the consequence of systemic diseases. For instance, in foals with sepsis, the hypothalamo−pituitary−adrenal axis can be depressed and in adult horses with systemic inflammatory response syndrome, the endocrine pancreas function can be impaired (Hart et al., 2009b; Bertin et al., 2018). Accordingly, a comprehensive evaluation of the horse is required.

Concurrent treatments

Hormones have systemic effects and their action can be modified by drug administration. For example, phenylbutazone has been identified as the cause of endocrine dysregulation in horses: by either altering the protein binding of thyroxine (T4) or by directly decreasing thyroid-stimulating hormone (TSH) secretion, phenylbutazone administration can result in decreased total and free T4 (Ramirez et al., 1997). In addition, phenylbutazone has been shown to extend the preovulatory period of mares by the inhibition of prostaglandin (Lima et al., 2015). As some drugs, such as non-steroidal anti-inflammatory drugs or sedatives, are routinely administered by owners or veterinarians, the clinician should be careful when examining a horse or interpreting a laboratory result (Kritchevsky et al., 2020).

Physical Examination

A thorough physical examination is an essential step of the diagnostic approach for all diseases. For complaints that are likely to have an endocrine cause, particular attention should be paid to level of alertness and activity, body weight and body condition, haircoat, musculoskeletal system and reproductive system.

Alertness and activity

The hypothalamus is the link between the nervous and the endocrine systems. As part of the limbic system, the hypothalamus integrates environmental and intrinsic stimuli and controls alertness, behaviour and emotions through the secretion of releasing hormones (Clarke, 2015). Therefore, changes in activity level can suggest an endocrine disorder at the level of the hypothalamus. For example, in horses with PPID, decreased alertness is reported and can be reversed with proper treatment (Donaldson et al., 2002).

Body weight and body condition

Morphometric measurements and their changes over time are key elements in the evaluation of patients with endocrine disorders. Whether the horse is overweight or underweight, a careful evaluation of fat distribution and muscle mass is warranted. For example, EMS is associated with increased adiposity, whereas PPID is associated with muscle loss (Aleman et al., 2006; Pleasant et al., 2013). Although body weight is a relevant piece of information, it is a poor indicator of muscle/fat ratio and obtaining an accurate body weight can be challenging in equine practice. A 9-point body condition score, initially developed on morphometric measurements from 12 Quarter Horse mares, is now commonly used in practice for all breeds and has been shown to be a useful tool to predict laminitis in horses with EMS (Henneke et al., 1983; Coleman et al., 2018). The score is based on the adiposity in specific areas such as neck, withers, shoulders, ribs, back and tailhead as well as on the density of the fat deposits (Table 1.1 and Figs 1.1–1.9).

In addition to a full body condition score, a cresty neck score has been developed and is mainly relevant in cases of EMS, as the neck is a common site of fat deposition in horses (Table 1.2 and Figs 1.10–1.15) (Carter et al., 2009; Martin-Gimenez et al., 2016).

Haircoat

Aspect, quality, length and shedding pattern of hair-coat should be assessed when evaluating patients with endocrine conditions, in which the aspect and the quality of the hair can be altered. For example, in foals with congenital hypothyroidism, the hair can appear silky; in geriatric patients with PPID, the abnormal ratio of hair in anagen and telogen phases results in hypertrichosis and delayed or absent shedding (Fig. 1.16) (Breuhaus, 2011; Innera et al., 2013). Close examination of the haircoat will also allow the identification of an abnormal sweating pattern with both hyperhidrosis and anhidrosis reported in horses with PPID (Rohrbach et al., 2012; Spelta and Axon, 2012). Finally, close examination of the integument can allow the identification of non-healing wounds or chronic ulcers.

Table 1.1. Description of individual body condition scoring system. From Henneke et al., 1983.

Fig. 1.1. Body condition score of 1/9 in a 12-year-old mixed breed horse (Author’s own photograph).

Musculoskeletal system

Examination of the musculoskeletal system is an important part of the assessment of the endocrine patient. Lameness is a common presenting complaint for horses with EMS, PPID, hypothyroidism or hyperparathyroidism (Ronen et al., 1992; Frank et al., 2010b; Breuhaus, 2011; Horn et al., 2019). Lameness can have multiple origins such as: laminitis in cases with ID; suspensory ligament degeneration in cases of PPID; poor carpus or tarsus development in premature or dysmature foals with hypothyroidism; or general bone pain in cases of hyperparathyroidism (Ramirez et al., 1997; Asplin et al., 2010; Hofberger et al., 2015; Coleman and Whitfield-Cargile, 2017). In addition, decreased muscle mass and myositis observed in horses with PPID can result in lameness exacerbation (Aleman et al., 2006). In all these cases, a thorough lameness examination and a more detailed evaluation with radiographs, ultrasounds or advanced imaging techniques is indicated.

Fig. 1.2. Body condition score of 2/9 in a 9-year-old Thoroughbred mare (Author’s own photograph).

Fig. 1.3. Body condition score of 3/9 in a 15-year-old Australian Stockhorse mare (Author’s own photograph).

Fig. 1.4. Body condition score of 4/9 in a 4-year-old Thoroughbred mare (Author’s own photograph).

Fig. 1.5. Body condition score of 5/9 in a 13-year-old Thoroughbred gelding (Author’s own photograph).

Fig. 1.6. Body condition score of 6/9 in a 16-year-old Australian Stockhorse mare (Author’s own photograph).

Fig. 1.7. Body condition score of 7/9 in a 12-year-old Welsh pony (courtesy of Dr Allison J. Stewart).

Reproductive system

The reproductive system and the endocrine system are highly interdependent: an endocrine disorder can present as failure to conceive or subfertility before showing overt signs of endocrinopathy (Frank et al., 2010b). Diseases such as ovarian tumours, cryptorchidism or testicular neoplasia are obvious disorders originating from the reproductive system and are diagnosed by endocrine testing (anti-Müllerian hormone, AMH; human chorionic gonadotropin, hCG; androgens) (Brinsko, 1998; Claes et al., 2013; Murase et al., 2020). However, other endocrine disorders, initially independent of the reproductive system, can alter the equine reproductive function; reproductive disorders, initially independent of the endocrine system, can disturb the hormonal balance (Drew et al., 1975; Boosinger et al., 1995; Buff et al., 2006; Fazio et al., 2016a, b). For example, pregnancy can significantly alter insulin regulation, lipid metabolism and thyroid hormone concentrations and function (Watson et al., 1993; Huszenicza et al., 2000; Gutierrez et al., 2002; Hoffman et al., 2003; Meredith and Dobrinski, 2004; George et al., 2011; Fazio et al., 2016a, b). Thus, careful documentation of a mare’s oestrous cycle and a stallion’s fertility are recommended when assessing a case suspected of endocrine disorders.

Fig. 1.8. Body condition score of 8/9 in a 14-year-old Quarter Horse gelding (courtesy of Dr Janice E. Kritchevsky).

Fig. 1.9. Body condition score of 9/9 in a Quarter Horse gelding (courtesy of Dr Nicholas Frank).

Table 1.2. Cresty neck scoring system. From Carter et al., 2009.

Fig. 1.10. Cresty neck score of 0/5 in a 20-year-old Thoroughbred gelding (Author’s own photograph).

Fig. 1.11. Cresty neck score of 1/5 in an 8-year-old mixed breed pony (courtesy of Dr Allison J. Stewart).

Other relevant body systems

Respiratory system

The respiratory system is not affected by endocrine disorders per se; however, in some cases, the immune system is compromised in endocrine conditions such as PPID or relative adrenal insufficiency (RAI), and respiratory infections can develop (Hart and Barton, 2011; McFarlane, 2011). Attention to the respiratory rate should also be paid as it has been shown to be a common sign of PPID, mainly in tropical and subtropical climates (Horn et al., 2019).

Fig. 1.12. Cresty neck score of 2/5 in a 9-year-old Thoroughbred mare (courtesy of Dr Allison J. Stewart).

Fig. 1.13. Cresty neck score of 3/5 in a 7-year-old mixed breed pony (courtesy of Dr Allison J. Stewart).

Fig. 1.14. Cresty neck score of 4/5 in an 11-year-old Welsh pony (courtesy of Dr Allison J. Stewart).

Fig. 1.15. Cresty neck score of 5/5 in an 18-year-old mixed breed pony mare (courtesy of Dr Nicholas J. Bamford).

Fig. 1.16. Areas of hypertrichosis associated with pituitary pars intermedia dysfunction (PPID) in a 22-year-old Stockhorse mare (Author’s own photograph).

Alimentary system

Examination of the gastrointestinal system rarely yields abnormal findings in horses with endocrine conditions; however, horses with PPID are more likely to have higher faecal egg counts than age-matched controls and horses with primary hyperparathyroidism can present with clinical signs of colic (Hudson et al., 1999; McFarlane et al., 2010).

Neurological system

Beyond the altered alertness mentioned above, some endocrine disorders can present with neurological signs such as seizures (McFarlane, 2011).

Ocular system

Chronic corneal ulcers are a common alerting sign of PPID as horses suffering from this disorder have a reduced corneal sensitivity and are prone to developing calcific band keratinopathy (Miller et al., 2013; Berryhill et al., 2017).

Haematology and Serum Chemistry

Haematology

A complete blood count can yield subtle changes compatible with an endocrine disorder; however, changes are usually mild and poorly specific (Rohrbach et al., 2012). Nevertheless, the test should be submitted to rule out infectious diseases or malignant haemopathies (Marr et al., 1989; Horn et al., 2019).

Serum chemistry

Specific parameters of a generic chemistry profile can be very valuable when assessing a patient with suspected endocrinopathy. For example, hyperglycaemia can be suggestive of diabetes mellitus, hypercalcaemia can indicate hyperparathyroidism and increased triglyceride concentration is a marker of hyperlipaemia (Peauroi et al., 1998; Durham et al., 2009; McKenzie, 2011). That being said, these changes are usually poorly specific and only considered significant when large or sustained variations are observed. When equivocal results are obtained, additional or more refined testing is warranted. A serum chemistry report should also be submitted to exclude a disease originating from a specific organ, as acute liver or renal diseases can result in similar serum chemistry profiles.

Urinalysis

Endocrine disorders can alter urinary production, urinary specific gravity or urinary composition.

Urine volume and concentration

A urinary production above 30 ml/kg/day in an adult horse is considered abnormal and, if associated with hypo- or isosthenuria, can be suggestive of nephrogenic or neurogenic diabetes insipidus (Schott et al., 1993; Morgan et al., 2012). Other endocrine disorders, such as PPID, have also been shown to alter urinary production and specific gravity (Ireland and McGowan, 2018).

Water deprivation tests have been developed to determine the ability of a horse to concentrate urine and increase urinary specific gravity (Schott, 2011). The standard water deprivation test consists of keeping a horse in a stall overnight with no access to water. A urine specific gravity of less than 1.025 after water deprivation would indicate failure to concentrate urine and suggest a diabetes insipidus (Genetzky et al., 1987). In some cases, when a medullary washout is suspected, longer water deprivation can be required to assess the ability to concentrate urine. The standard test can be extended to up to 2 days or a modified water deprivation test can be used. This modified test is undertaken over 4 days during which the horse has a limited access to water (2 ml/kg/h) (Genetzky et al., 1987; Schott, 2011). Failure to concentrate urine after 4 days of restricted water access would be consistent with a diagnosis of a diabetes insipidus. As there is a risk of significant dehydration, these tests should be stopped if the horse loses more than 5% of body weight. Therefore, water deprivation tests can only be undertaken if a scale is available and after ruling out any primary renal disorder.

Urine composition

Equine urine is rich in calcium; however, in some endocrine conditions, its composition can change. Although diet has a major effect on urinary fractional excretions (FE), calculation of those ratios can be helpful when diseases such as hyperparathyroidism or RAIs are suspected (Table 1.3) (McKeever et al., 2002; Toribio et al., 2005, 2007). In addition, measurement of urine concentrations of specific neurotransmitters or hormones may be useful in some endocrinopathies. For example, measuring urinary catecholamines is diagnostic for pheochromocytoma (Fouché et al., 2016).

Hormone Analysis

Determination of hormone concentration is the most commonly used diagnostic test in equine endocrinology; however, the interpretation of a single value can be complicated as factors such as diet, geographic location, season, time of the day, treatments or assay can confound basal values. The most commonly measured hormones in equine practice are adrenocorticotropic hormone (ACTH), insulin, cortisol, triiodothyronine (T3), T4 and parathormone, but more unusual hormones such as leptin, glucagon-like peptide 1 (GLP-1) or glucose-dependent insulinotropic polypeptide (GIP) can be measured and, to some extent, they can all have results increased or decreased by factors unrelated to the primary endocrine condition. As a result, the clinician should ideally standardize testing protocols to reduce as much as possible variability between results.

Individual variation

In all endocrine studies, there is a significant possibility of factors such as age, gender, breed, oestrous cycle, adiposity or level of activity of the horse having a potential confounding effect (Bamford et al., 2014; Bamford et al., 2016; de Laat et al., 2016a; Beythien et al., 2017; Rapson et al., 2018). Although individual reference intervals cannot be established for all horses, clinicians should keep in mind that interpretation of laboratory results should also be performed in light of the clinical picture and possibly of previous results obtained under similar conditions in the same individual.

Table 1.3. Urinary fractional excretion (FE) where [X] is the concentration of a given ion in serum or in urine (mmol/l) and [Creatinine] is the concentration of creatinine in serum or urine (µmol/l). From King, 1994.

FEX (%) = ([X]urine / [X]serum} × {[Creatinine]serum / [Creatinine]urine) × 100

Diet

Hormones such as insulin, leptin, GLP-1 or GIP can vary tremendously with changes in type of feed, feeding amounts or feeding schedules. For example, increased carbohydrate intake increases insulin concentrations; acute feed restriction decreases leptin concentrations; and fasting of horses decreases insulin sensitivity (Buff et al., 2006; Bamford et al., 2015; Bertin et al., 2016). Consequently, it is paramount for the clinician to assess the horse with its usual diet to be able to accurately interpret a laboratory result.

Circannual variations

The acknowledgement of seasonal variations in hormone concentrations is critical in the interpretation of laboratory results. ACTH, and its derivates such as α-MSH, are the hormones that have been the most studied with expected increases in autumn, regardless of the geographical location and regardless of the disease status of the horse (Fig. 1.17) (Copas and Durham, 2012; Cordero et al., 2012; Secombe et al., 2017). A similar pattern has also been documented in equine insulin, with higher concentrations in spring and in autumn (Hart et al., 2016; Beythien et al., 2017).

Geographic variations

Latitude, altitude and exposure to rainfall, temperatures and daylight amplitude have a specific effect on hormones such as ACTH or alpha-melanocyte-stimulating hormone (α-MSH). For example, the reference intervals for ACTH at lower latitudes (closer to the equator) are wider than the reference intervals at higher latitudes (further from the equator) (Secombe et al., 2017). In addition, elevation, rainfall andtemperatures will interfere with reference intervals in areas with similarlatitude (McFarlane et al., 2011). Therefore, it is recommended that clinicians work with local laboratories that have developed specific reference intervals, as given ACTH results