Chapter 9 Aetiology: Anhidrosis is thought to result from the down-regulation or desensitization of sweat gland β2-adrenergic receptors, but the exact cause of this problem remains unknown. Horses from cooler climates are not predisposed to anhidrosis, but the problem is often first recognized when affected horses are moved into regions with hotter climates. Pathogenesis: Horses sweat to cool the body through evaporation and this process accounts for up to 65% of heat loss in exercising horses. Sweating is stimulated by neural responses and circulating catecholamines that increase in concentration during exercise. Cooling mechanisms are controlled by thermoregulatory centres within the hypothalamus that initiate sweating in response to rising body temperature. Autonomic adrenergic neurons stimulate equine sweat glands and β2 adrenergic receptors respond to agonists such as epinephrine that circulate within the blood. Denervation is an unlikely cause of anhidrosis because this disease is generally reversible and sweat can be produced by denervated horse skin. It is also unlikely that anhidrosis is caused by loss of central nervous system control because exogenous β2 adrenergic agonists, including epinephrine, salbutamol and terbutaline, do not stimulate sweating. It is therefore likely that anhidrosis results from down-regulation of β2 adrenergic receptors or interference with receptor function or signalling. With time, glandular cells undergo degeneration and ducts become blocked with cellular debris. • Exercise intolerance is often the first sign observed by the horse owner and, in milder cases, this may be the only clinical sign observed. Some horses can sweat during exercise, but the response is suboptimal. • An inappropriately elevated respiratory rate may be detected. Tachypnoea is to be expected during exercise, but respiratory rates >100 breaths/min may be detected in affected horses and tachypnoea can persist for longer than expected after exercise. • Decreased or absent sweat production is the best known characteristic of this disease, but this can be difficult to appreciate in milder cases. Sweating is sometimes judged to be inadequate for the ambient temperature and level of exercise. Horses may sweat in certain regions of the body, but fail to show the appropriate degree of sweating overall. Exercising horses should sweat across the neck, beneath the mane, within the axillary region, between the hindlegs, and around the perineum. Sweat should also be present beneath the saddle. • Dry flaky skin and alopecia can develop with chronic anhidrosis, but this clinical sign is rare. • Anhidrosis is a differential diagnosis for exercise intolerance. • Subjective assessment of sweating and measurement of the respiratory rate during and after exercise. • Elevation of the rectal temperature for greater than 30 minutes after exercise has been completed may be suggestive of anhidrosis. • Intradermal terbutaline response test – terbutaline sulphate is a selective β2 agonist that stimulates sweating. Terbutaline sulphate (1 mg/mL) is injected intradermally (0.10 mL volume) at regularly spaced intervals along the neck at dilutions (with saline) of 1 : 1000 (10−3); 1 : 10 000 (10−4); 1 : 100 000 (10−5), 1 : 1 000 000 (10−6), and 1 : 10 000 000 (10−7), along with a negative control injection of physiological saline. When evaluated 30 minutes later, most horses sweat at all sites. Horses with partial anhidrosis fail to sweat at the lowest concentration and severe anhidrosis is associated with the absence of sweating at any site or only the highest concentration. It is advisable to test a healthy horse at the same time to ensure efficacy of the drug. • Alternatively, an epinephrine response test can be performed. Epinephrine solutions of 1 : 1000, 1 : 10 000, 1 : 100 000, and 1 : 1 000 000 are injected intradermally along the neck and sweating should occur at all four injection sites within minutes in a normal horse. Anhidrotic horses sweat only at the highest concentration site and this may take longer to develop. The test should be performed in the region of the neck covered by the mane because epinephrine injections can occasionally cause hairs to turn white. • Clinicopathology – haematological and biochemical values (including electrolytes) generally remain unaffected. • Serum total triiodothyronine (tT3) and total thyroxine (tT4) concentrations are sometimes measured in affected horses because of the anecdotal association between anhidrosis and hypothyroidism. However, detection of lower serum thyroid hormone concentrations is not diagnostic for primary hypothyroidism in the horse and an assay for thyroid-stimulating hormone (TSH) is not commercially available. Abnormal tT3 and tT4 responses to exogenous thyrotropin-releasing hormone (TRH) must be documented to support a diagnosis of hypothyroidism in the horse. • Skin biopsy – histopathological abnormalities include cellular degeneration as a result of thermal stress and occlusion of ducts with debris. These findings provide supportive evidence of anhidrosis, but are not diagnostic for the condition. • Exercise reduction − mildly or moderately affected horses should not be worked strenuously for 30 days. This provides time for spontaneous resolution. • Environmental management − mildly affected horses are managed by housing them in air conditioned stalls, whereas severely affected horses are sometimes sold to owners that live in colder climates. Housing horses in a cooler environment prevents ongoing thermal damage, which allows regeneration of sweat glands over time. After rehabilitation, horses can be exercised during the cooler times of the day. • Oral electrolytes – hypokalaemia may play a role in anhidrosis, so oral supplementation with potassium chloride is recommended. • A feed supplement containing L-tyrosine, choline bitartrate, niacin, pyrodoxine HCl, and D-calcium pantothenate (One AC, Magic Powder Co., Phoenix, Arizona, USA) is commonly used in the United States. Tyrosine is a precursor for dopamine and therefore catecholamines and may be involved in the resensitization of sequestered β2 receptors. Very little scientific evidence is available to support the use of this product and it cannot be determined if positive results are partially a result of the manufacturer’s recommendation to avoid intense exercise for 3 weeks after initiating treatment. • Levothyroxine sodium – this treatment remains popular despite a lack of scientific evidence because it is thought that hypothyroidism and anhidrosis are associated in horses. This is the most common endocrinopathy affecting older horses and ponies. Pituitary pars intermedia dysfunction (PPID) should be considered as a potential medical problem in any horse over 10 years of age. The pathognomonic clinical sign of PPID is an abnormally long hair coat, which is referred to as hirsutism (Figure 9.1). There is no sex predilection, and all breeds of horses, ponies and donkeys are affected, but the risk of PPID increases with age. Figure 9.1 A horse with advanced hirsutism attributed to pituitary pars intermedia dysfunction (PPID). Aetiology: Advanced PPID is caused by the presence of a small tumuor(s) within the pars intermedia of the pituitary gland. This tumour is active and produces hormones and other peptides with hormone-like activity. In humans, we refer to the anterior and posterior pituitary gland, but these terms are not relevant when discussing the equine pituitary gland because of anatomical differences between species. The anterior pituitary gland of the horse is better described as the pars distalis and the posterior pituitary should be referred to as the pars nervosa. The pars intermedia can be found between these structures. The pars distalis secretes six hormones: adrenocorticotropin hormone (ACTH; also called corticotropin), thyroid-stimulating hormone (TSH; also called thyrotropin), growth hormone (also called somatotropin), follicle-stimulating hormone, luteinizing hormone, and prolactin. In the healthy animal, melanotropes of the pars intermedia primarily secrete alpha melanocyte-stimulating hormone (α-MSH). Oxytocin and anti-diuretic hormone (ADH; also called vasopressin) are secreted by the pars nervosa. Clinical signs and proposed pathogenesis: In the healthy state, the hypothalamic-pituitary-adrenal axis begins with the production of corticotropin-releasing hormone (CRH) from the hypothalamus, which stimulates corticotropes within the pars distalis of the pituitary gland to produce the prohormone pro-opiomelanocortin (POMC). This large peptide is cleaved by prohormone convertase I to generate ACTH, which enters the circulation and stimulates cortisol release from the adrenal cortex. Circulating cortisol exerts negative feedback effects on both the hypothalamus and pars distalis. Hormone production within the pars intermedia also begins with POMC synthesis, but two enzymes are active within this region of the pituitary gland – prohormone convertase I that cleaves ACTH from POMC and prohormone convertase II that converts ACTH into α-MSH. Only α-MSH is normally secreted from the pars intermedia. • Laminitis – horses with PPID are more susceptible to insidious-onset laminitis. Hyperadrenocorticism promotes vasoconstriction and protein depletion within the dermis and epidermis, which may lower the threshold for agents that initiate laminitis. Horses or ponies with PPID are predisposed to laminitis triggered by grazing on pasture. This predisposition may be a result of concurrent insulin resistance (IR) and hyperinsulinemia. It is therefore important to diagnose and manage IR when treating a horse or pony with PPID. • Hirsutism – this clinical sign is considered to be pathognomonic for PPID in older horses, and has been used as the gold standard for diagnosing the disease. Early evidence of hirsutism includes retention of the winter hair coat for longer than expected or detection of longer hairs on the palmar or plantar aspects of the lower leg. Hairs are arrested in telogen and may become lighter in colour over time. Hirsutism is attributed to alterations in MSH secretion or increased production of androgens by the adrenal cortex. • Body composition changes – skeletal muscle mass decreases as PPID develops and is often accompanied by regional adiposity. Type 2A (oxidative-glycolytic) and 2B (glycolytic) muscle fibres undergo atrophy. Regional adiposity is characterized by expansion of adipose tissues in specific regions, including the neck (commonly referred to as a ‘cresty neck’), either side of the tail head, and prepuce. Cortisol-induced protein catabolism results in a thinner body condition, loss of epaxial muscle mass, and rounding of the abdomen. • Polyuria/polydipsia – owners report excessive water consumption and urination. Polyuria can be attributed to ACTH- or cortisol-mediated antagonism of ADH at the collecting tubule, glucosuria, or reduction in ADH secretion by the pars nervosa (diabetes insipidus) caused by compression or invasion of the pars nervosa by neoplastic tissue. • Chronic infections and delayed wound healing – common examples include tooth root infections, sinusitis, and sole abscesses. Wounds and lacerations may take longer to heal. These problems are attributed to immunosuppression secondary to hyperadrenocorticism, but tissues may also be weakened by protein depletion. • Lethargy – this has been attributed to increased beta endorphin release from the pars intermedia. Horses with advanced PPID also appear to be more tolerant of pain. • Hyperhidrosis – this may simply result from hirsutism, but some horses that are clipped continue to sweat excessively, so a disturbance in hypothalamic body temperature regulation is suspected. • Other clinical signs include central nervous system deficits such as seizures, which should only be attributed to compression by a pituitary adenoma in advanced cases, and persistent lactation. The latter problem may result from increased prolactin production. 1. Detection of hirsutism in an older horse is sufficient for diagnosis, particularly when accompanied by other clinical signs. 2. Complete blood count (CBC) – hyperadrenocorticism is associated with mature neutrophilia, lymphopenia, and monocytosis. This is the stress response recognized in many patients when they first present for evaluation, but in the case of PPID, these alterations persist after stress has subsided. 3. Resting hormone measurements – commercial laboratories currently measure plasma ACTH levels and may soon offer α-MSH measurements. Care should be taken to collect blood samples under the conditions recommended by the laboratory. Blood should be collected in the morning after the horse has remained calm overnight. Sampling horses under stressful or painful conditions (i.e. during acute laminitis) is likely to lead to spurious results. Blood should be collected in a plastic tube containing ethylenediamine tetraacetic acid (EDTA) and immediately cooled in ice. Samples should be refrigerated until centrifuged, and centrifugation should be performed as soon as possible after blood collection. Harvested plasma should be shipped overnight with ice packs or frozen. Pituitary pars intermedia dysfunction is confirmed when the resting plasma ACTH concentrations exceed 35 pg/mL (7.7 pmol/L). It is important to use a seasonally adjusted reference range in August, September, and October because ACTH concentrations increase during these months of the year. If the laboratory provides a seasonally adjusted reference range, testing in the late summer and autumn is encouraged to diagnose early disease and assess treated horses during this period of natural stimulation. 4. Resting glucose and insulin concentrations – horses with PPID can be normoglycaemic or hyperglycaemic (fasting glucose >110 mg/dL or >6.1 mmol/L), and glucosuria may be present if blood glucose levels exceed 180 mg/dL (10.0 mmol/L). Serum insulin concentrations are elevated if compensated IR is present. Insulin resistance is detected in some patients with PPID and this is likely to be determined by whether the animal was insulin resistant prior to developing PPID. Cortisol inhibits the action of insulin at the tissue level and CLIP stimulates release of insulin from the pancreas. Pituitary pars intermedia dysfunction may therefore exacerbate hyperinsulinaemia and IR. 5. Diurnal cortisol rhythm test – blood cortisol concentrations vary markedly within minutes, so single cortisol measurements do not aid in the diagnosis of PPID. However, plasma or serum cortisol concentrations generally decrease throughout the day, so morning and evening concentrations can be compared. A healthy horse usually has an evening blood cortisol concentration that is >30% lower than the morning value. Unfortunately, healthy horses often have false-positive results because blood cortisol concentrations are fluctuating throughout the day and false-positive test results occur more frequently in older horses, so this test not recommended. 6. Dynamic testing for PPID – none of the available tests have sensitivity or specificity values of 100%, so it is important to use clinical judgement when interpreting results. • Overnight dexamethasone suppression test (DST) – this test is performed by collecting a pre-injection blood sample, injecting dexamethasone intravenously (or intramuscularly) at a dosage of 40 µg/kg body weight (20 mg for a 500-kg horse), and collecting a second blood sample 19 or 24 hours post-injection. In the healthy horse, dexamethasone acts via negative feedback to suppress CRH and ACTH production, which lowers plasma cortisol concentrations for more than 24 hours. Detection of a plasma cortisol concentration below 10 ng/mL (equivalent to 1.0 µg/dL or 27 nmol/L) after 24 hours is the response expected in a healthy horse, so a value >10 ng/mL is a positive result for PPID. In the affected horse, dexamethasone transiently suppresses ACTH release from the pituitary gland, but the pars intermedia remains unaffected. Continued ACTH secretion by this region of the pituitary gland causes blood cortisol concentrations to rise above 10 ng/mL by 24 hours post-injection. As with ACTH measurements, more false-positive dexamethasone suppression test results occur in the autumn, so horses should be tested in the spring or early summer. It has been suggested that horses with equine metabolic syndrome are more likely to develop laminitis following the DST, so this should be discussed with the client prior to testing. • Thyrotropin-releasing hormone (TRH) stimulation test – this test is recommended when early disease is suspected and other tests yield normal results. In the author’s opinion the TRH stimulation test is the most sensitive diagnostic test for PPID in horses. A pre-injection blood sample is collected, followed by injection of TRH (1.0 mg total) intravenously. After 30 minutes, a second blood sample is collected and both samples are submitted for measurement of ACTH concentrations. Detection of a plasma ACTH concentration > 35 pg/mL at 0 or 30 minutes supports the diagnosis of PPID. Horses with PPID show an increase in plasma ACTH concentration following TRH administration because cells within the abnormal pars intermedia possess more receptors for this hormone and secrete ACTH when stimulated. The major limitation of this test is the cost and availability of medical grade TRH. Horses occasionally yawn or show mild muscle fasciculations after injection of TRH, but these signs are transient. • ACTH stimulation test – this test should be selected if an adrenal tumour is suspected, but results can be difficult to interpret because horses with PPID sometimes develop adrenal hyperplasia. Adrenal tumours should be suspected when clinical signs of advanced hyperadrenocorticism are present in the absence of hirsutism. • Oral domperidone test – domperidone is a D2 dopamine receptor antagonist. Transient blocking of dopamine action causes an exaggerated release of ACTH from the pars intermedia because this region is synthesizing more hormone than normal in the PPID patient. Treatment: There are two important components of PPID management – drug therapy and laminitis prevention. 1. Three drugs are used to treat PPID in horses: • Pergolide mesylate – this is a dopaminergic agonist which compensates for the loss of dopaminergic neurons and may slow the progression of PPID. Dopamine suppresses ACTH production by the pars intermedia, which is why clinical signs of PPID improve with treatment. This drug is widely used and is recognized to be the most effective treatment available for PPID in horses. A starting dosage of 1 mg pergolide total dose (or 0.002 mg/kg body weight) once daily orally is recommended. Some practitioners recommend twice daily administration because of perceived improvement in efficacy. Responses to therapy include increased activity, decreased recurrence of laminitis, improved insulin sensitivity, gain in muscle mass, return to normal shedding pattern, and improvement with respect to polyuria/polydipsia. Plasma ACTH measurements or dexamethasone suppression testing can be repeated to assess the response to therapy. The dose of pergolide can be increased in 0.5 mg/day increments for 30-day periods until clinical signs improve or a maximum dosage of 3 mg/day is attained. • Trilostane – this drug is used in Europe and has recently become available in the United States. Trilostane acts at the adrenal cortex by inhibiting the enzyme 3-β-hydroxysteroid dehydrogenase, which is involved in cortisol production. This drug is available in 30, 60 or 120 mg capsules (Vetoryl®, Arnolds Veterinary Products Ltd, UK) and is given orally in the evening at a dosage of 1.0 mg/kg body weight once daily. • Cyproheptadine – this drug inhibits the action of the excitatory neurotransmitter serotonin and was widely used before pergolide was prescribed. Some horses or ponies respond well to the drug and it is occasionally used in combination with pergolide. 2. Laminitis is a major concern for horses with PPID, so every effort should be made to lower the risk of disease. If the patient suffers from IR as well as PPID, diet and exercise recommendations should be made to improve insulin sensitivity (refer to the section on equine metabolic syndrome).
Endocrinology
9.1 Anhidrosis (dry coat syndrome)
9.2 Pituitary pars intermedia dysfunction (PPID) or equine Cushing’s disease (ECD)
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