Can Thyroid Function be Monitored in Hypothyroid Dogs Treated with Steroids?

Some of my hypothyroid dogs also intermittently receive corticosteroids at anti-inflammatory doses to treat flare-ups of allergic dermatitis. Does the corticosteroid therapy affect thyroid hormone concentrations and interfere with testing—either for the initial diagnosis or for therapeutic monitoring purposes?

Are thyroxine supplementation dosage adjustments needed during corticosteroid therapy?

My Response:

Glucocorticoids are known to affect serum thyroid hormone concentrations in dogs (1-4). Dogs receiving anti-inflammatory or immunosuppressive doses of prednisone or prednisolone can have altered thyroid function test results, especially if they have been receiving the corticosteroids for more than 2 weeks. In general, I would prefer to see dogs off of all forms of corticosteroids for at least 4-to 6-weeks before trying to evaluate thyroid function.

In dogs receiving thyroid hormone supplementation that subsequently begin to receive corticosteroid therapy, we generally do not perform laboratory tests to evaluate thyroid function until the corticosteroids have been removed. However, one paper in 2011 by O'Neill et al did study the effect of short-term anti-inflammatory doses of prednisone in dogs with naturally occurring hypothyroidism (5).

In that report, 8 dogs with spontaneous hypothyroidism already being treated with levothyroxine (L-T4) were given prednisone (1 mg/kg orally) daily for 7 days and then on alternate days for 14 days (5). Serum total thyroxine (T4), free T4, and thyroid-stimulating hormone (TSH) concentrations were measured on days 7, 21, and 28 and compared with baseline data. Results showed that total T4 concentrations were significantly decreased after 7 days of an anti-inflammatory dose of prednisone, but T4 values were not significantly altered from baseline on days 21 or 28 while on every other day dosing. Free T4 and TSH concentrations were not significantly altered from baseline at any point during the study.

My Bottom Line

Based on the results of the O'Neill study (5) administration of prednisone at a dosage of 1 mg/kg given orally once daily for 7 days decreased total T4 concentrations, while free T4 concentrations were unchanged. This suggests that free T4 concentrations may be less affected by daily prednisone administration. Anti-inflammatory doses of prednisone, when administered every other day, did not interfere with thyroid hormone monitoring.

These results also agree with two previous studies, which showed that anti-inflammatory prednisone did not affect serum total T4 concentrations in thyroid-supplemented, thyroidectomized dogs (3,6).

So, at least with short-term administration of a single daily anti-inflammatory dose of prednisone, thyroid function may be evaluated by looking at free T4 or TSH concentrations. However, these results cannot be generalized to dogs taking prednisone for longer periods or at higher immunosuppressive doses (2-4 mg/kg/day).

References

1. Woltz HH, Thompson FN, Kemppainen RJ, et al. Effect of prednisone on thyroid gland morphology and plasma thyroxine and triiodothyronine concentrations in the dog. Am J Vet Res 1983;44:2000-2003. 
2. Torres SM, McKeever PJ, Johnston SD. Effect of oral administration of prednisolone on thyroid function in dogs. Am J Vet Res 1991;52:416-421. 
3. Moore GE, Ferguson DC, Hoenig M. Effects of oral administration of anti-inflammatory doses of prednisone on thyroid hormone response to thyrotropin-releasing hormone and thyrotropin in clinically normal dogs. Am J Vet Res 1993;54:130-135. 
4. Daminet S, Paradis M, Refsal KR, et al. Short-term influence of prednisone and phenobarbital on thyroid function in euthyroid dogs. Can Vet J 1999;40:411-415. 
5. O'Neill SH, Frank LA, Reynolds LM. Effect of an anti-inflammatory dose of prednisone on thyroid hormone monitoring in hypothyroid dogs. Vet Dermatol 2011;22:202-205.
6. Kaptein EM, Moore GE, Ferguson DC et al. Effects of prednisone on thyroxine and 3,5,3’-triiodothyronine metabolism in normal dogs. Endocrinology 1992;130:1669–1679.

Methimazole Treatment of Canine Hyperthyroidism

My patient is a 13-year old spayed female Golden retriever that presented with history of progressive polydispia, polyuria, panting, and weight loss despite a good appetite. On my physical examination, I palpated a freely-movable right cervical mass (2-3 inch in diameter) in the area of the thyroid gland. I aspirated the mass, and the results of thyroid cytology were consistent with carcinoma of thyroid origin.

Chest radiographs were clear, with no metastasis detected. Routine blood testing (CBC and serum chemistry panel) was normal except for a slightly high serum alkaline phosphatase (281 U/L; reference interval, 20-120 IU/L).

Results of a serum thyroid panel showed a high total T4 concentration (6.5 µg/dl; normal, 1-4 µg/dl), a high free T4 by dialysis (75 pmol/L; normal, 10-50 pmol/L), and suppressed cTSH value (less than 0.03 ng/ml).

I advised a thyroid biopsy and thyroidectomy, but owner is reluctant to do because of the expense and dog’s older age. If this dog is hyperthyroid, what is the treatment of choice? Do I have any medical options to control the signs? Can I use methimazole to lower the high serum T4 and free T4 values?

My Response:

I agree that this dog likely has a hyperfunctioning thyroid tumor, based on the clinical features, high T4 and free T4, suppressed TSH concentration, and results of the thyroid cytology (1-4). As in cats (5), high serum alkaline phosphatase activity is also seen in some dogs with hyperthyroidism, so that finding too goes along with the diagnosis.

Most dogs with hyperfunctioning thyroid tumors have thyroid carcinoma. In general, these thyroid carcinomas are quite malignant in dogs and pulmonary metastasis in not uncommon (1-4).

Methimazole can be used to control the hyperthyroidism but this will not stop tumor growth, local invasion, or metastasis. Radioiodine, surgery followed by chemotherapy, or local external radiation are all options (1-4). In this dog, radioiodine might be ideal because the tumor would likely concentrate the injected radioiodine very nicely; it may result in cure, even if we have undetected metastasis (6).

If methimazole is used, I'd start with 5 mg twice daily, in a dog of this size. You should adjust the dose as needed, monitoring serum T4 concentrations as you would in a hyperthyroid cat. Again, without definitive treatment, this dog’s thyroid tumor will likely metastasize and eventually lead to the dog's death.

References:

1. Rijnberk A. Hyperthyroidism in the dog and its treatment with radioactive iodide. Tijdschr Diergeneeskd 1966;91:789-794.
2. Rijnberk A, der Kinderen PJ. Toxic thyroid carcinoma in the dog. Acta Endocrinological 1969;Supplement 138:177.
3. Peterson ME, Kintzer PP, Hurley JR, et al. Radioactive iodine treatment of a functional thyroid carcinoma producing hyperthyroidism in a dog. J Vet Intern Med 1989;3:20-25. 
4. Peterson ME. Hyperthyroidism and thyroid tumors in dogs In: Melian C, Perez Alenza MD, Peterson ME, et al., eds. Manual de Endocrinología en Pequeños Animales (Manual of Small Animal Endocrinology). Barcelona, Spain: Multimedica, 2008;113-125.
5. Berent AC, Drobatz KJ, Ziemer L, et al. Liver function incats with hyperthyroidism before and after 131I therapy. J Vet Intern Med 2007;21:1217-1223. 
6. Turrel JM, McEntee MC, Burke BP, et al. Sodium iodide I 131 treatment of dogs with nonresectable thyroid tumors: 39cases (1990-2003). J Am Vet Med Assoc 2006;229:542-548. 

Hypothyroidism Associated with Acromegaly and Insulin-resistant Diabetes Mellitus in a Samoyed

PAPER REVIEW

Hypothyroidism Associated with Acromegaly and Insulin-resistant Diabetes Mellitus in a Samoyed

by T. Johnstone, E. Terzo, and C. Mooney

Australian Veterinary Journal 2014; 92:437-442.

Background

Although both hypothyroidism and diabetes mellitus are common disorders of dogs, it is relatively uncommon for a dog to develop both diseases concurrently. Insulin-resistant diabetes has been reported in a few dogs with underlying hypothyroidism (1-3), but the mechanisms underlying the insulin resistance is not clear. However, hypothyroidism may lead to alteration of other hormones that influence glucose metabolism, and previous studies of hypothyroid dogs have documented excessive production of growth hormone (GH), a known insulin antagonist (4,5). In one study, Beagles with radioiodine-induced hypothyroidism were reported to have a progressive elevation in serum GH concentrations (a known insulin antagonist), but none of those dogs developed overt diabetes (6).

The purpose of this case report by Johnstone et al. (7) is to describe a dog diagnosed with naturally occurring hypothyroidism that also had concurrent signs of acromegaly and diabetes. In this dog, the insulin resistance and associated diabetic state was reversed with appropriate L-thyroxine supplementation.

Case Report
A 4-year-old male entire Samoyed presented with an 8-month history of pedal hyperkeratosis and shifting lameness, which had been unresponsive to zinc supplementation, antibiotics, and glucocorticoid therapy. The dog also exhibited exercise intolerance of 12-months duration. Recently, polydipsia and polyuria were also noted.

Marked interdental spacing

On physical examination, obesity, poor coat condition, widened spaces between the teeth, and mild respiratory stridor were noted (see Figure).

Initial laboratory test results confirmed marked hyperglycemia, consistent with diabetes mellitus. Serum concentrations of total thyroxine (T4), free T4 by equilibrium dialysis, and free triiodothyronine (T3) were below the reference limits, and canine thyroid-stimulating hormone (cTSH) levels was above the reference limits, diagnostic for primary hypothyroidism.

Before treatment for diabetes and hypothyroidism was initiated, further tests were performed to investigate a potential link between these two conditions. An upper airway examination revealed mild soft tissue hypertrophy but normal laryngeal function. The pretreatment serum insulin concentration was above the reference limits, suggesting endogenous insulin resistance. A baseline serum IGF-1 concentration was within reference limits. However, basal serum GH concentrations were markedly elevated, and a further paradoxical increase in GH concentration was noted after administration of thyrotropin-releasing hormone (TRH). CT imaging of the pituitary suggested slight enlargement of the gland but no pituitary tumor was evident.

Overall, the high serum GH concentrations, together with the clinical features (e.g., widened interdental spaces, and mild respiratory stridor), was considered diagnostic for acromegaly.

Treatment was initiated using both insulin (Caninsulin, 20 IU every 12 h) and thyroid supplementation (levothyroxine, L-T4, 0.02 mg/kg every 24 h). Over the next few weeks, the exogenous insulin requirements started to decrease, and all exogenous insulin was discontinued 155 days later. The dog remained euglycemic 2 years after diagnosis, with continued daily supplementation of L-T4 alone.

My Bottom Line:

In this dog, diabetes mellitus was thought to be a secondary consequence of insulin resistance, as demonstrated by the high pretreatment serum insulin concentration. Insulin-resistant diabetes mellitus has been previously described in a few dogs with naturally occurring hypothyroidism (1-3), but the pathogenesis for the concurrent development of the two diseases is not totally understood.

It has been reported, however, that primary hypothyroidism can lead to with functional and morphological changes of the pituitary gland (4-6). Most notably, transdifferentiation of pituitary TSH-producing cells to cells producing both TSH and GH has been documented (6), which can result in increased GH production and secretion in these dogs. The high basal GH concentration and the paradoxical increase of GH after stimulation with TRH in this dog (7) confirmed that hypothyroidism-induced acromegaly and secondary diabetes was likely.

Although the true prevalence of hypothyroidism-induced acromegaly in dogs is not known, our clinical experience suggests that hypothyroidism is rarely associated with acromegaly. However, it is likely that acromegaly goes under-diagnosed in some hypothyroid dogs since many of the clinical signs of both disorders are similar. Furthermore, pituitary transdifferentiation of TSH to GH hypersecretion would be expected to take a long time to develop, and therefore, hypothyroidism-induced acromegaly may only become significant when hypothyroidism remains undiagnosed or untreated for several months to years (6).

In this dog, the fact that the diabetic state resolved during treatment with L-T4 suggests that the pituitary GH overproduction resolved as euthyroidism was achieved. Unfortunately, repeat TRH stimulation testing or serum GH measurements were not repeated after resolution of the diabetic state, so we can not say for certain that the acromegalic state truly resolved. Further studies certainly are needed to investigate hypothyroidism-induced GH production, but this interesting case certainly does add some insight to what may be going on in these dogs.

References:

1. Blois SL, Dickie E, Kruth SA, et al. Multiple endocrine diseases in dogs: 35 cases (1996-2009). J Am Vet Med Assoc 2011;238:1616-1621. 
2. Ford SL, Nelson RW, Feldman EC, et al. Insulin resistance in three dogs with hypothyroidism and diabetes mellitus. J Am Vet Med Assoc 1993;202:1478-1480. 
3. Hess RS, Saunders HM, Van Winkle TJ, et al. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998). J Am Vet Med Assoc 2000;217:1166-1173. 
4. Lee WM, Diaz-Espineira M, Mol JA, et al. Primary hypothyroidism in dogs is associated with elevated GH release. J Endocrinol 2001;168:59-66. 
5. Diaz-Espineira MM, Galac S, Mol JA, et al. Thyrotropin-releasing hormone-induced growth hormone secretion in dogs with primary hypothyroidism. Domest Anim Endocrinol 2008;34:176-181. 
6. Diaz-Espineira MM, Mol JA, van den Ingh TS, et al. Functional and morphological changes in the adenohypophysis of dogs with induced primary hypothyroidism: loss of TSH hypersecretion, hypersomatotropism, hypoprolactinemia, and pituitary enlargement with transdifferentiation. Domest Anim Endocrinol 2008;35:98-111. 
7. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 

Top Endocrine Publications of 2014: The Canine Thyroid Gland

Large goiter due to thyroid carcinoma

In my third compilation of the canine and feline endocrine publications of 2014, I’m moving on to disorders of the canine thyroid gland. Listed below are 21 research papers written in 2014 that deal with a variety of thyroid gland topics and issues of clinical importance.

A number of these publications deal with clinical, pathologic, diagnostic, or therapeutic aspects of thyroid carcinoma (1-6,10,13,14,17,18).  Of these, two papers (1,14) deal specifically with ectopic thyroid tumors arising in the sublingual location, which may indicate that such ectopic tumors are not as uncommon as once thought.

Other publications include a case report of a hypothyroid dog suffering from insulin-resistant diabetes mellitus and acromegaly (8); interestingly, after treatment with L-thyroxine, the insulin resistance and diabetes resolved.

Other papers report on various studies on hypothyroidism in dogs including the effect of age of lipid metabolism (9) to the association between gall bladder mucoceles and hyperlipidemia (12);  and from exercise-induced hypercoagulability, von Willebrand factor, and thyroid hormone concentrations in sled dogs (11) to evaluation of serum thyroid hormones in dogs with systemic inflammation or sepsis (16).

Finally, other papers include a case report of a hypothyroid dog with polyneuropathy that resolved following thyroid supplementation (20), to a study of the pharmacokinetics of total T4 after repeated oral administration of L-T4 solution in hypothyroid dogs (21). 

References:

1. Broome MR, Peterson ME, Walker JR. Clinical features and treatment outcomes of 41 dogs with sublingual ectopic thyroid neoplasia. J Vet Intern Med 2014;28:1560-1568. 
2. Campos M, Ducatelle R, Kooistra HS, et al. Immunohistochemical expression of potential therapeutic targets in canine thyroid carcinoma. J Vet Intern Med 2014;28:564-570. 
3. Campos M, Ducatelle R, Rutteman G, et al. Clinical, pathologic, and immunohistochemical prognostic factors in dogs with thyroid carcinoma. J Vet Intern Med 2014;28:1805-1813. 
4. Campos M, Kool MM, Daminet S, et al. Upregulation of the PI3K/Akt pathway in the tumorigenesis of canine thyroid carcinoma. J Vet Intern Med 2014;28:1814-1823. 
5. Ciaputa R, Nowak M, Kandefer-Gola M, et al. Morphological and immunohistological characteristics of follicular-compact thyroid carcinoma in dog. Folia Histochem Cytobiol 2014;52:157-161. 
6. Deitz K, Gilmour L, Wilke V, et al. Computed tomographic appearance of canine thyroid tumours. J Small Anim Pract 2014;55:323-329. 
7. Higgs P, Costa M, Freke A, et al. Measurement of thyroxine and cortisol in canine and feline blood samples using two immunoassay analysers. J Small Anim Pract 2014;55:153–159. 
8. Johnstone T, Terzo E, Mooney CT. Hypothyroidism associated with acromegaly and insulin-resistant diabetes mellitus in a Samoyed. Aust Vet J 2014;92:437-442. 
9. Kawasumi K, Kashiwado N, Okada Y, et al. Age effects on plasma cholesterol and triglyceride profiles and metabolite concentrations in dogs. BMC Vet Res 2014;10:57. 
10. Kobayashi R, Yamada N, Kitamori T, et al. Follicular thyroid carcinoma characterized by abundant stromal components with chondroid and osseous metaplasia in a dog. J Vet Med Sci 2014;76:1161-1164. 
11. Krogh AK, Legind P, Kjelgaard-Hansen M, et al. Exercise induced hypercoagulability, increased von Willebrand factor and decreased thyroid hormone concentrations in sled dogs. Acta Vet Scand 2014;56:11. 
12. Kutsunai M, Kanemoto H, Fukushima K, et al. The association between gall bladder mucoceles and hyperlipidaemia in dogs: A retrospective case control study. Vet J 2014;199:76-79. 
13. Metivier KS, Deitz K, Xu WW, et al. Gene expression profiling demonstrates differential expression of osteopontin in follicular thyroid carcinomas compared to normal thyroid tissue in dogs. Vet Comp Oncol 2014;12:181-197. 
14. Milovancev M, Wilson DM, Monnet E, et al. Partial resection of the hyoid apparatus during surgical treatment of ectopic thyroid carcinomas in dogs: 5 cases (2011-2013). J Am Vet Med Assoc 2014;244:1319-1324. 
15. Muller TR, Assis MM, Doiche DP, et al. Do thyroid ultrasonographic features change according to age in euthyroid dogs? Anat Histol Embryol 2014;43:468-473. 
16. Pashmakova MB, Bishop MA, Steiner JM, et al. Evaluation of serum thyroid hormones in dogs with systemic inflammatory response syndrome or sepsis. J Vet Emerg Crit Care (San Antonio) 2014;24:264-271. 
17. Pessina P, Castillo V, Sartore I, et al. Semiquantitative immunohistochemical marker staining and localization in canine thyroid carcinoma and normal thyroid gland. Vet Comp Oncol 2014. 
18. Pineyro P, Vieson MD, Ramos-Vara JA, et al. Histopathological and immunohistochemical findings of primary and metastatic medullary thyroid carcinoma in a young dog. J Vet Sci 2014;15:449-453. 
19. Rasmussen SH, Andersen HH, Kjelgaard-Hansen M. Combined assessment of serum free and total T4 in a general clinical setting seemingly has limited potential in improving diagnostic accuracy of thyroid dysfunction in dogs and cats. Vet Clin Pathol 2014;43:1-3. 
20. Utsugi S, Saito M, Shelton GD. Resolution of polyneuropathy in a hypothyroid dog following thyroid supplementation. J Am Anim Hosp Assoc 2014;50:345-349. 
21. van Dijl IC, Le Traon G, van de Meulengraaf BD, et al. Pharmacokinetics of total thyroxine after repeated oral administration of levothyroxine solution and its clinical efficacy in hypothyroid dogs. J Vet Intern Med 2014;28:1229-1234. 

Top Endocrine Publications of 2014: The Canine and Feline Pituitary Gland

For my next review of the endocrine publications of 2014 that concern companion animals, I'm going to turn to the theme of diagnosis and treatment of pituitary problems in dogs and cats. Listed below are 18 clinical and research papers written in 2014 that deal with a variety of pituitary gland issues of clinical importance in dogs and cats.

These range from case studies of cats with primary hypodipsia and inappropriate antidiuretic hormone secretion (1,2) to an investigation of the clinical utility of formulas of estimated serum osmolality (3); from a study of acromegaly in a series German shepherd dogs (4) to a number of excellent studies of the clinical features, diagnosis, or treatment of feline acromegaly (8,9,13,15); and from investigation of the stress response in dogs (5,14) to a study of the intraoperative changes of circulating vasopressin during elective ovariohysterectomy in dogs (6).

Other publications include a study investigating the problems associated with commercial assays for determination of feline ACTH (7) to a review of the use of GnRH agonists in dogs and cats (10); from a report of a transsphenoidal surgical technique for removal of pituitary adenomas in dogs with pituitary-dependent Cushing's disease (11) to a review of the role of prolactin in canine mammary tumor development (12); and finally, from a report of the clinical findings, diagnostic test results, and treatment outcome of 30 cats with spontaneous Cushing's disease (16) to an investigation of the mutations associated with pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs (18).

References:

1. Bach J, Claus K. Primary hypodipsia in a cat with severe hypernatremia. J Feline Med Surg 2014;16:240-242. 
2. Demonaco SM, Koch MW, Southard TL. Syndrome of inappropriate antidiuretic hormone secretion in a cat with a putative Rathke's cleft cyst. J Feline Med Surg 2014;16:1010-1015. 
3. Dugger DT, Epstein SE, Hopper K, et al. A comparison of the clinical utility of several published formulae for estimated osmolality of canine serum. J Vet Emerg Crit Care (San Antonio) 2014;24:188-193. 
4. Fracassi F, Zagnoli L, Rosenberg D, et al. Spontaneous acromegaly: a retrospective case control study in German shepherd dogs. Vet J 2014;202:69-75. 
5. Hekman JP, Karas AZ, Sharp CR. Psychogenic stress in hospitalized dogs: cross species comparisons, implications for health care, and the challenges of evaluation. Animals (Basel) 2014;4:331-347. 
6. Hoglund OV, Hagman R, Olsson K, et al. Intraoperative changes in blood pressure, heart rate, plasma vasopressin, and urinary noradrenalin during elective ovariohysterectomy in dogs: repeatability at removal of the 1st and 2nd ovary. Vet Surg 2014;43:852-859. 
7. Kemppainen RJ. Amino acid differences in cat adrenocorticotropin account for the inability of a human-based immunoradiometric assay to detect the molecule in cat plasma. J Vet Diagn Invest 2014;26:431-433.
8. Lamb CR, Ciasca TC, Mantis P, et al. Computed tomographic signs of acromegaly in 68 diabetic cats with hypersomatotropism. J Feline Med Surg 2014;16:99-108. 
9. Lourenco BN, Randall E, Seiler G, et al. Abdominal ultrasonographic findings in acromegalic cats. J Feline Med Surg 2014.  
10. Lucas X. Clinical use of deslorelin (GnRH agonist) in companion animals: a review. Reprod Domest Anim 2014;49 Suppl 4:64-71. 
11. Mamelak AN, Owen TJ, Bruyette D. Transsphenoidal surgery using a high definition video telescope for pituitary adenomas in dogs with pituitary dependent hypercortisolism: methods and results. Vet Surg 2014;43:369-379. 
12. Michel E, Rohrer Bley C, Kowalewski MP, et al. Prolactin--to be reconsidered in canine mammary tumourigenesis? Vet Comp Oncol 2014;12:93-105. 
13. Myers JA, Lunn KF, Bright JM. Echocardiographic findings in 11 cats with acromegaly. J Vet Intern Med 2014;28:1235-1238. 
14. Nagasawa M, Shibata Y, Yonezawa A, et al. The behavioral and endocrinological development of stress response in dogs. Dev Psychobiol 2014;56:726-733. 
15. Rosca M, Forcada Y, Solcan G, et al. Screening diabetic cats for hypersomatotropism: performance of an enzyme-linked immunosorbent assay for insulin-like growth factor 1. J Feline Med Surg 2014;16:82-88. 
16. Valentin SY, Cortright CC, Nelson RW, et al. Clinical findings, diagnostic test results, and treatment outcome in cats with spontaneous hyperadrenocorticism: 30 cases. J Vet Intern Med 2014;28:481-487. 
17. van Rijn SJ, Riemers FM, van den Heuvel D, et al. Expression stability of reference genes for quantitative RT-PCR of healthy and diseased pituitary tissue samples varies between humans, mice, and dogs. Mol Neurobiol 2014;49:893-899. 
18. Voorbij AM, Leegwater PA, Kooistra HS. Pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs is associated with a mutation in LHX3. J Vet Intern Med 2014;28:1770-1774. 

Clinical use of Gonadotropin-Releasing Hormone (GnRH) Agonists in Companion Animals: An Overview

In dogs, cats, ferrets, and pet birds, reproductive physiology is under the control of the hypothalamic­pituitary­-gonadal (HPG) axis. Many hormones are responsible for estrus and reproduction, the most significant being luteinizing hormone (LH), follicle stimulating hormone (FSH), and gonadotropin-releasing hormone (GnRH). Short-lived GnRH is released in a pulsatile fashion from the hypothalamus and acts on the pars distalis of the pituitary gland to stimulate the synthesis and release of the gonadotropins, FSH and LH (Figure 1). Secretion of these gonadotropins into the circulation lead to changes gonadal hormone production and reproductive function.

Figure 1: Regulation of gonadal secretion via the hypothalamic-pituitary-gonadal axis.

Chemical modification of the native short-acting GnRH molecule has led to development of long-acting, potent GnRH agonists, which have been used as a medical means of management for a number of reproductive issues and diseases of companion animals (1-3). GnRH agonists may either stimulate estrus or effectively sterilize the patient, depending on the duration of action and the dosage applied. These agents work by initially stimulating gonadotrophin secretion, followed shortly thereafter with desensitization of the GnRH receptor to the GnRH agonist (Figure 2). This results in a temporary but long-term, fully-reversible down-regulation of gonadotrophin secretion, leading to suppression of reproduction function in both male and female animals (4).

Figure 2: GnRH agonists initially stimulate pituitary LH and FSH secretion, followed by desensitization and down-relation of gonadotrophin secretion.

In recent years, effective low-dose, slow-release implants containing potent GnRH agonists have been released for use in veterinary medicine, especially in Europe and Australia. In companion animals, the deslorelin implant (Suprelorin, Virbac) is the most commonly GnRH agonist used in small animals (5). Deslorelin implants work by lowering pituitary gonadotrophin section. This is not a permanent change but depending on the deslorelin dose, can last up to many months. The implant does not have to be removed, but subsequent doses are needed to sustain the effect.

Unfortunately, GnRH agonist availability is limited in the United States. Although there are GnRH agonists available that are approved for the treatment of human diseases, such as prostate cancer, they are costly and not financially feasible for a pet owner to consider. To date, deslorelin acetate (Suprelorin, Virbac Animal Health, Fort Worth, TX, USA) is the only GnRH agonist that is currently available in the United States but only for the treatment of adrenal disease in ferrets (6). However, it is not legal to use Suporelin in non-ferret species in the United States and extra-label use is explicitly prohibited.

The aim of this blog is to review the applications and treatments of the deslorelin (GnRH agonist) currently used in companion animal medicine.

Deslorelin Use in Intact Male Dogs
In male dogs treated with deslorelin, this GnRH agonist leads to decreased gonadotropins secretion and resultant lowered plasma testosterone concentrations, decreased testicular volume, and azoospermia (1-3,7-9). However, the response to this GnRH agonist can be very variable from one dog to another, and the duration of inhibition of testosterone secretion depends both on the concentration of the deslorelin implant and the size of the dog.

Many studies have confirmed that use of GnRH agonists for reversible chemical sterilization in male dogs is both safe and well-tolerated (7-9). Furthermore, repeated implantation can be used to maintain circulating testosterone at low concentrations. If the deslorelin implants are stopped, the treated dogs will regain normal serum testosterone levels within a few weeks, with full recovery of seminal quality once the GnRH implant has lost its efficacy (10,11).

In addition to contraception, GnRH agonists have also been used to reduce the size of the prostate gland, an effect that may be useful in dogs with benign prostatic hyperplasia (12-14).

Deslorelin in Intact Male Cats
As in dogs, GnRH agonists are gaining increased importance in feline reproductive medicine (2,3,15). In intact male cats, deslorelin implants induce chemical sterilization, as in dogs. In these cats, testosterone concentrations decline rapidly to undetectable values by 3 weeks after implantation and remain low for weeks in the majority of the tomcats treated. As the circulating testosterone falls, the testicular volume decreases and penile spines disappear.

However, high individual variability has been reported, with the duration of efficacy varying between 6 and 24 months (15-17). Similar to dogs, it is possible to use repeated implantation of deslorelin to sustain the drug’s effect.

Deslorelin in Intact Bitches
Although deslorelin implants are only approved for male dogs in Europe (and again, not at all in the USA), studies have been performed in the bitch to investigate its use either as a contraceptive or a method of estrus induction (1-3,18-20).

The first step in the mechanism of action of all GnRH agonists is the stimulation in FSH and LH secretion (so-called "flare-up effect") (4). This followed within a few days by a profound hypogonadal effect (i.e., decrease in FSH and LH levels), which is achieved through receptor down-regulation by internalization of receptors. Generally this induced and reversible hypogonadism is the therapeutic goal, as noted above for the male dogs and cats (1-3).

The initial stimulating effect on gonadotrophin secretion is more pronounced in females than in males (18,19). Thus, estrus induction will be observed in the majority of bitches implanted in anestrus. If pregnancy is achieved, most recommend removal of the deslorelin implant either at the beginning of proestrus, at the time of the LH surge, or at the time of ovulation (2,3,18,19). However, some have reported that some bitches carried their pregnancies to term without the implant being removed, suggesting that down-regulation of gonadotrophin secretion may not be strong enough to induce luteal failure in all bitches.

For use as a contraceptive method, the main problem with using deslorelin implants in female dogs is estrus induction, as discussed above (20). For this reason, deslorelin implants cannot be considered a viable alternative to other, current used contraception in bitches.

Deslorelin in Intact Queens
In contrast to female dogs, the main indication for the use of deslorelin in the female queen is estrus inhibition. Studies have confirmed that this GnRH agonist can be used to effectively suppress ovarian activity (15,20-22), but the duration of inhibition was highly variable among the individual queens depending on the dosage administered. However, deslorelin generally suppresses ovarian activity for many months.

Deslorelin in Spayed Bitches with Urinary Incontinence
Ovariectomy results in elevated circulating concentrations of pituitary LH because of the lack of gonadal negative-feedback on the pituitary gland. LH receptors are present throughout the canine urinary tract (23-25), and it has been postulated that elevated gonadotropins may contribute to the development of urethral sphincter mechanism incompetence (26,27).

Treatment of bitches with long-acting GnRH agonists, such as delorelin, downregulates LH secretion for prolonged time periods and temporarily restores continence to incontinent bitches for varying durations, ranging from 50-738 days (26,27). Similar to alpha-adrenergic agonists (e.g., phenylpropanolamine; PPA), GnRH agonists are not completely effective for the treatment of this urinary incontinence. However, unlike PPA, no adverse effects to GnRH agonists have been reported.

Deslorelin in Ferrets with Adrenal Disease
As in dogs and cats, deslorelin is also a promising and suitable method for contraception in ferrets (28-31). However, GnRH agonists are useful in medical management of ferrets suffering from adrenal disease (hyperadrenocorticism) a common disease in castrated males and females (32-34). In one study of ferrets with adrenal disease, the clinical signs (e.g., vulvar swelling, pruritus, sexual behavior, and aggression) were reduced or markedly suppressed within 14 days of implantation of the deslorelin (34). The time for signs to recur in these ferrets ranged from 8.5–20.5 months (34).

References:

1. Trigg TE, Doyle AG, Walsh JD, et al. A review of advances in the use of the GnRH agonist deslorelin in control of reproduction. Theriogenology 2006;66:1507-1512. 
2. Fontaine E, Fontbonne A. Clinical use of GnRH agonists in canine and feline species. Reprod Domest Anim 2011;46:344-353. 
3. Lucas X. Clinical use of deslorelin (GnRH agonist) in companion animals: a review. Reprod Domest Anim 2014;49 Suppl 4:64-71. 
4. Ortmann O, Weiss JM, Diedrich K. Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action. Reprod Biomed Online 2002;5 Suppl 1:1-7. 
5. Suprelorin (deslorelin acetate). Summary report from the European Medicines Agency. 
6. Suprelorin F. Package insert. Fort Worth, Texas: Virbac Animal Health 
7. Junaidi A, Williamson PE, Martin GB, et al. Pituitary and testicular endocrine responses to exogenous gonadotrophin-releasing hormone (GnRH) and luteinising hormone in male dogs treated with GnRH agonist implants. Reprod Fertil Dev 2007;19:891-898. 
8. Junaidi A, Williamson PE, Martin GB, et al. Dose-response studies for pituitary and testicular function in male dogs treated with the GnRH superagonist, deslorelin. Reprod Domest Anim 2009;44:725-734. 
9. Romagnoli S, Siminica A, Sontas BH, et al. Semen quality and onset of sterility following administration of a 4.7-mg deslorelin implant in adult male dogs. Reprod Domest Anim 2012;47 Suppl 6:389-392. 
10. Trigg TE, Wright PJ, Armour AF, et al. Use of a GnRH analogue implant to produce reversible long-term suppression of reproductive function in male and female domestic dogs. J Reprod Fertil Suppl 2001;57:255-261. 
11. Gentil M, Hoffmann B, Spang A, et al. Restart of steroidogenesis in dogs during recrudescence of testicular function following downregulation with a GnRH-agonist implant. Cell Tissue Res 2012;350:513-523. 
12. Vickery BH, McRae GI, Bonasch H. Effect of chronic administration of a highly potent LHRH agonist on prostate size and secretory function in geriatric dogs. Prostate 1982;3:123-130. 
13. Nizanski W, Levy X, Ochota M, et al. Pharmacological treatment for common prostatic conditions in dogs - benign prostatic hyperplasia and prostatitis: an update. Reprod Domest Anim 2014;49 Suppl 2:8-15. 
14. Polisca A, Orlandi R, Troisi A, et al. Clinical efficacy of the GnRH agonist (deslorelin) in dogs affected by benign prostatic hyperplasia and evaluation of prostatic blood flow by Doppler ultrasound. Reprod Domest Anim 2013;48:673-680. 
15. Goericke-Pesch S, Wehrend A, Georgiev P. Suppression of fertility in adult cats. Reprod Domest Anim 2014;49 Suppl 2:33-40. 
16. Goericke-Pesch S, Georgiev P, Antonov A, et al. Clinical efficacy of a GnRH-agonist implant containing 4.7 mg deslorelin, Suprelorin, regarding suppression of reproductive function in tomcats. Theriogenology 2011;75:803-810. 
17. Goericke-Pesch S, Georgiev P, Fasulkov I, et al. Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat. Theriogenology 2013;80:65-69. 
18. Volkmann DH, Kutzler MA, Wheeler R, et al. The use of deslorelin implants for the synchronization of estrous in diestrous bitches. Theriogenology 2006;66:1497-1501. 
19. Fontaine E, Mir F, Vannier F, et al. Induction of fertile oestrus in the bitch using Deslorelin, a GnRH agonist. Theriogenology 2011;76:1561-1566. 
20. Maenhoudt C, Santos NR, Fontaine E, et al. Results of GnRH agonist implants in oestrous induction and oestrous suppression in bitches and queens. Reprod Domest Anim 2012;47 Suppl 6:393-397. 
21. Goericke-Pesch S. Reproduction control in cats: new developments in non-surgical methods. J Feline Med Surg 2010;12:539-546. 
22. Goericke-Pesch S, Georgiev P, Atanasov A, et al. Treatment of queens in estrus and after estrus with a GnRH-agonist implant containing 4.7 mg deslorelin; hormonal response, duration of efficacy, and reversibility. Theriogenology 2013;79:640-646. 
23. Coit VA, Dowell FJ, Evans NP. Neutering affects mRNA expression levels for the LH- and GnRH-receptors in the canine urinary bladder. Theriogenology 2009;71:239–47.
24. Ponglowhapan S, Church DB, Khalid M. Differences in the expression of luteinizing hormone and follicle-stimulating hormone receptors in the lower urinary tract between intact and gonadectomised male and female dogs. Domest Anim Endocrinol 2008;34:339-351. 
25. Reichler IM, Welle M, Sattler U, et al. Comparative quantitative assessment of GnRH- and LH-receptor mRNA expression in the urinary tract of sexually intact and spayed female dogs. Theriogenology 2007;67:1134–42.
26. Reichler IM, Hubler M, Jöchle W, et al. The effect of GnRH analogs on urinary incontinence after ablation of the ovaries in dogs. Theriogenology 2003;60:1207–16.
27. Reichler IM, Jöchle W, Piché CA, , et al. Effect of a long-acting GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles and clinical signs of urinary incontinence due to sphincter mechanism incompetence in bitches. Theriogenology 2006;66:1227–36.
28. Schoemaker NJ, van Deijk R, Muijlaert B, et al. Use of a gonadotropin releasing hormone agonist implant as an alternative for surgical castration in male ferrets (Mustela putorius furo). Theriogenology 2008;70:161-167. 
29. Prohaczik A, Kulcsar M, Trigg T, et al. Comparison of four treatments to suppress ovarian activity in ferrets (Mustela putorius furo). Vet Rec 2010;166:74-78. 
30. Goericke-Pesch S, Wehrend A. The use of a slow release GnRH-agonist implant in female ferrets in season for oestrus suppression. Schweiz Arch Tierheilkd 2012;154:487-491. 
31. van Zeeland YR, Pabon M, Roest J, et al. Use of a GnRH agonist implant as alternative for surgical neutering in pet ferrets. Vet Rec 2014;175:66. 
32. Rosenthal KL, Peterson ME, Quesenberry KE, et al. Hyperadrenocorticism associated with adrenocortical tumor or nodular hyperplasia of the adrenal gland in ferrets: 50 cases (1987-1991). J Am Vet Med Assoc 1993;203:271-275. 
33. Schoemaker NJ, Teerds KJ, Mol JA, et al. The role of luteinizing hormone in the pathogenesis of hyperadrenocorticism in neutered ferrets. Mol Cell Endocrinol 2002;197:117-125. 
34. Wagner RA, Piche CA, Jochle W, et al. Clinical and endocrine responses to treatment with deslorelin acetate implants in ferrets with adrenocortical disease. Am J Vet Res 2005;66:910-914. 

Top Endocrine Publications of 2014: Canine and Feline Reproductive Endocrinology

As I've done for the last 5 years, I’ve now finished compiling a fairly extensive list of references concerning canine and feline endocrinology that were written last year (in 2014). I’ll be sharing these with you over the next few months, as well as reviewing a few of the best papers from my lists of clinical endocrine publications.

In my last post, I provided my last list for the 2013 papers on canine and feline endocrine reproduction, so I've decided to start this year off with papers that deal with the same theme of endocrine disorders of the canine and feline gonads, prostate, and mammary gland.

Listed below are 23 papers published in 2014 that deal with a variety of topics of importance for reproductive endocrinology in dogs and cats. These range from the identification and study of kisspeptin (a protein ligand that activate GnRH neurons) in dogs (1) to the use of relaxin measurements to diagnose pregnancy status (2); as well as from a study of the effects of GnRH agonist and antagonists during the postnatal period in cats (3) to the effects of GnRH immunization for treatment of urinary incontinence in spayed bitches (4).

Other publication included studies dealing with suppression of fertility in dogs and cats (4-6,12,13,14,21) to endocrinologic investigations of pyometra (9), ovarian cysts (10), mammary neoplasia (16,19), and benign prostatic hyperplasia and prostatitis (17); and finally, from a study of oxytocin and social bonding in dogs (20) to a review of the influence of sex hormones on seizures in dogs and man (22).

References:

1. Albers-Wolthers KH, de Gier J, Kooistra HS, et al. Identification of a novel kisspeptin with high gonadotrophin stimulatory activity in the dog. Neuroendocrinology 2014;99:178-189.
2. Bergfelt DR, Peter AT, Beg MA. Relaxin: a hormonal aid to diagnose pregnancy status in wild mammalian species. Theriogenology 2014;82:1187-1198.
3. Carranza A, Faya M, Merlo ML, et al. Effect of GnRH analogs in postnatal domestic cats. Theriogenology 2014;82:138-143.
4. Donovan CE, Gordon JM, Kutzler MA. Gonadotropin-releasing hormone immunization for the treatment of urethral sphincter mechanism incompetence in ovariectomized bitches. Theriogenology 2014;81:196-202.
5. Fagundes AK, Oliveira EC, Tenorio BM, et al. Injection of a chemical castration agent, zinc gluconate, into the testes of cats results in the impairment of spermatogenesis: a potentially irreversible contraceptive approach for this species? Theriogenology 2014;81:230-236.
6. Favre RN, Bonaura MC, Praderio R, et al. Effect of melatonin implants on spermatogenesis in the domestic cat (Felis silvestris catus). Theriogenology 2014;82:851-856.
7. Goericke-Pesch S, Wehrend A, Georgiev P. Suppression of fertility in adult cats. Reprod Domest Anim 2014;49 Suppl 2:33-40.
8. Hoglund OV, Hagman R, Olsson K, et al. Intraoperative changes in blood pressure, heart rate, plasma vasopressin, and urinary noradrenalin during elective ovariohysterectomy in dogs: repeatability at removal of the 1st and 2nd ovary. Veterinary Surgery 2014;43:852-859.
9. Jitpean S, Holst BS, Hoglund OV, et al. Serum insulin-like growth factor-I, iron, C-reactive protein, and serum amyloid A for prediction of outcome in dogs with pyometra. Theriogenology 2014;82:43-48.
10. Knauf Y, Bostedt H, Failing K, et al. Gross pathology and endocrinology of ovarian cysts in bitches. Reprod Domest Anim 2014;49:463-468.
11. Kobayashi M, Hori T, Kawakami E. Efficacy of low-dose human chorionic gonadotropin therapy in dogs with spermatogenic dysfunction: a preliminary study. Reprod Domest Anim 2014;49:E44-47.
12. Lucas X. Clinical use of deslorelin (GnRH agonist) in companion animals: a review. Reprod Domest Anim 2014;49 Suppl 4:64-71.
13. Maenhoudt C, Santos NR, Fontbonne A. Suppression of fertility in adult dogs. Reprod Domest Anim 2014;49 Suppl 2:58-63.
14. Marino G, Rizzo S, Quartuccio M, et al. Deslorelin implants in pre-pubertal female dogs: short- and long-term effects on the genital tract. Reprod Domest Anim 2014;49:297-301.
15. Meloni T, Comin A, Rota A, et al. IGF-I and NEFA concentrations in fetal fluids of term pregnancy dogs. Theriogenology 2014;81:1307-1311.
16. Michel E, Rohrer Bley C, Kowalewski MP, et al. Prolactin--to be reconsidered in canine mammary tumourigenesis? Vet Comp Oncol 2014;12:93-105.
17. Nizanski W, Levy X, Ochota M, et al. Pharmacological treatment for common prostatic conditions in dogs - benign prostatic hyperplasia and prostatitis: an update. Reprod Domest Anim 2014;49 Suppl 2:8-15.
18. Parker K, Snead E. Atypical presentation of ovarian remnant syndrome in a dog. J Am Anim Hosp Assoc 2014;50:e1-5.
19. Queiroga FL, Perez-Alenza MD, Gonzalez Gil A, et al. Clinical and prognostic implications of serum and tissue prolactin levels in canine mammary tumours. Vet Rec 2014;175:403.
20. Romero T, Nagasawa M, Mogi K, et al. Oxytocin promotes social bonding in dogs. Proc Natl Acad Sci U S A 2014;111:9085-9090.
21. Schafer-Somi S, Kaya D, Gultiken N, et al. Suppression of fertility in pre-pubertal dogs and cats. Reprod Domest Anim 2014;49 Suppl 2:21-27.
22. Van Meervenne SA, Volk HA, Matiasek K, et al. The influence of sex hormones on seizures in dogs and humans. Vet J 2014;201:15-20.
23. Volta A, Manfredi S, Vignoli M, et al. Use of contrast-enhanced ultrasonography in chronic pathologic canine testes. Reprod Domest Anim 2014;49:202-209.

Top Endocrine Publications of 2013: Canine and Feline Reproductive Endocrinology

In my tenth compilation of the canine and feline endocrine publications, I’m moving on to endocrine disorders of the canine and feline gonads and mammary gland. Listed below are 20 papers published in 2013 that deal with a variety of topics of importance for reproductive endocrinology in dogs and cats.

Of all of these publications, one of the most common and clinically useful topics involves the use of gonadotropin-releasing hormone (GnRH) agonists for management of a variety of disorders. These include the use of GnRH agonist for treatment of queens in estrus and after estrus (3), for reproductive control in queens (4) and tom cats (5), and in dogs affected by benign prostatic hyperplasia (12).

On my next blog post, I will review the mechanism of action for the GnRH agonists, along with their many potential uses and dosage forms.

References:

1. Adams GP, Ratto MH. Ovulation-inducing factor in seminal plasma: a review. Anim Reprod Sci 2013;136:148-156. 
2. Faya M, Carranza A, Miotti R, et al. Fecal estradiol-17beta and testosterone in prepubertal domestic cats. Theriogenology 2013;80:584-586. 
3. Goericke-Pesch S, Georgiev P, Atanasov A, et al. Treatment of queens in estrus and after estrus with a GnRH-agonist implant containing 4.7 mg deslorelin; hormonal response, duration of efficacy, and reversibility. Theriogenology 2013;79:640-646. 
4. Goericke-Pesch S, Georgiev P, Atanasov A, et al. Treatment with Suprelorin in a pregnant cat. J Feline Med Surg 2013;15:357-360. 
5. Goericke-Pesch S, Georgiev P, Fasulkov I, et al. Basal testosterone concentrations after the application of a slow-release GnRH agonist implant are associated with a loss of response to buserelin, a short-term GnRH agonist, in the tom cat. Theriogenology 2013;80:65-69. 
6. Greenberg M, Lawler D, Zawistowski S, et al. Low-dose megestrol acetate revisited: a viable adjunct to surgical sterilization in free roaming cats? Vet J 2013;196:304-308. 
7. Leroy C, Conchou F, Layssol-Lamour C, et al. Normal canine prostate gland: repeatability, reproducibility, observer-dependent variability of ultrasonographic measurements of the prostate in healthy intact beagles. Anat Histol Embryol 2013;42:355-361. 
8. Luu VV, Hanatate K, Tanihara F, et al. The effect of relaxin supplementation of in vitro maturation medium on the development of cat oocytes obtained from ovaries stored at 4 degrees C. Reprod Biol 2013;13:122-126. 
9. Marino G, Zanghi A. Activins and inhibins: expression and role in normal and pathological canine reproductive organs: a review. Anat Histol Embryol 2013;42:1-8. 
10. Mattoso CR, Takahira RK, Beier SL, et al. Evaluation of von Willebrand factor during pregnancy, lactation and oestrous cycle in bitches affected and unaffected by von Willebrand disease. Reprod Domest Anim 2013;48:416-422. 
11. Nishida CR, Everett S, Ortiz de Montellano PR. Specificity determinants of CYP1B1 estradiol hydroxylation. Mol Pharmacol 2013;84:451-458. 
12. Polisca A, Orlandi R, Troisi A, et al. Clinical efficacy of the GnRH agonist (deslorelin) in dogs affected by benign prostatic hyperplasia and evaluation of prostatic blood flow by Doppler ultrasound. Reprod Domest Anim 2013;48:673-680. 
13. Poppl AG, Mottin TS, Gonzalez FH. Diabetes mellitus remission after resolution of inflammatory and progesterone-related conditions in bitches. Res Vet Sci 2013;94:471-473. 
14. Rota A, Tursi M, Zabarino S, et al. Monophasic teratoma of the ovarian remnant in a bitch. Reprod Domest Anim 2013;48:e26-e28. 
15. Serafim MK, Silva GM, Duarte AB, et al. High insulin concentrations promote the in vitro growth and viability of canine preantral follicles. Reprod Fertil Dev 2013;25:927-934. 
16. Sozmen M, Kabak YB, Gulbahar MY, et al. Immunohistochemical characterization of peroxisome proliferator-activated receptors in canine normal testis and testicular tumours. J Comp Pathol 2013;149:10-18. 
17. Spankowsky S, Heuwieser W, Arlt SP. Does oral administration of the amino acid tyrosine affect oestradiol-17beta concentration and sexual behaviour in the bitch? Vet Rec 2013;172:212. 
18. Trisolini C, Albrizio M, Roscino MT, et al. Leptin and queen ovary: new insights about ovulation. Res Vet Sci 2013;94:707-710. 
19. Tvarijonaviciute A, Carrillo-Sanchez JD, Ceron JJ. Effect of estradiol and progesterone on metabolic biomarkers in healthy bitches. Reprod Domest Anim 2013;48:520-524. 
20. Wongbandue G, Jewgenow K, Chatdarong K. Effects of thyroxin (T4) and activin A on in vitro growth of preantral follicles in domestic cats. Theriogenology 2013;79:824-832. 

Confirming the Diagnosis of Addison's Disease in Dogs on Corticosteroids

Is it possible to confirm diagnosis of Addison's disease with an ACTH stimulation test after treatment has been initiated? My patient is a 6-year-old, male West Highland White Terrier seen on an emergency basis for severe lethargy, vomiting, diarrhea, and anorexia that all began shortly after he was at the groomers. There was no history of dietary indiscretion in this dog.

A serum chemistry profile revealed hypoglycemia (glucose, 61 mg/dl), hyperphosphatemia (phosphorus, 9.1 mg/dl), hyponatremia (130 mEq/L), and hyperkalemia (6.1 mg/dl). The dog was also moderately azotemic, with a serum urea nitrogen of 52 mg/dl and serum creatinine of 2.2 mg/dl.

The dog was treated at the emergency clinic overnight with IV dexamethasone and IV fluids (normal saline). The following morning, he was given an injection of IM Percorten-V (25 mg) and started on oral prednisone (2.5 mg once daily).

He has now been home a week and has shown a marked response to replacement therapy. The dog is scheduled to recheck with me in a few days to recheck his serum chemistry panel and electrolytes. Although this case certainly seems to fit a diagnosis of primary hypoadrenocorticism (Addison's disease), I'd be happier if we could confirm the diagnosis with an ACTH stimulation test.

Is that possible, now that the dog has been treated with dexamethasone, prednisone, and Percorten-V?

My Response:

Yes, you certainly can (and should) do an ACTH stimulation test to confirm the preliminary diagnosis of Addison's disease, even after treatment has been instituted.

Confirming the diagnosis by documenting low serum cortisol secretion before and after ACTH stimulation is always a very good idea, since many other diseases can mimic the clinical features seen with this disease. In addition, even having the classical electrolyte changes associated with Addison's disease (hyponatremia, hypocholemia, and hyperkalemia) are not totally diagnostic, inasmuch as other diseases (e.g., whipworms, renal failure, pancreatitis) can also produce the same electrolyte abnormalities in some dogs.

Diagnostic workup for dogs with suspected Addison's disease on treatment with glucocorticoids and mineralocorticoids
On your recheck in a week, this is what I'd recommend. First of all, if the dog is doing well, have the owners stop the prednisone for at least 24 hours before the recheck exam and ACTH stimulation test is scheduled (48 hours is even better). The Percorten-V has minimal to no glucocorticoid activity so that drug isn't going to interfere with the results of the ACTH stimulation test.

If the dog is normal or is suffering from nonadrenal illness (but does not have Addison's disease), the glucocorticoid treatment (both the IV dexamethasone and oral prednisone) might result in adrenocortical suppression, but not nearly to the degree that we see in dogs with Addison's disease.

• Dogs with primary Addison's disease generally have very low basal and post-ACTH cortisol concentrations (both cortisol values less than 1.0 μg/dl in almost all dogs and always less than 2.0 μg/dl). 
• In dogs treated with glucocorticoids that develop suppression of the hypothalamic-pituitary-adrenal axis, the basal cortisol value may be low and the cortisol response to ACTH stimulation may be abnormal and "blunted."
• However, the serum cortisol values in dogs that do not have Addison's disease will rise to above 2-3 μg/dl after ACTH stimulation in these dogs, and many dogs will show a completely normal cortisol response. In these dogs, a search for other causes of hyperkalemia should be undertaken.

References:

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014; pp 233-237.
4. Klein SC, Peterson ME. Canine hypoadrenocorticism: part II. Can Vet J 2010;51:179-184.

Top Endocrine Publications of 2013: The Canine Adrenal Gland

I've decide to take a break from my review of the endocrine abstracts presented at the 2014 ACVIM forum and turn back to my review of the canine and feline endocrine publications of 2012. So in the next 2 posts, I'll cover the disorders of the canine and feline adrenal gland.

Listed below are 55 research papers written in 2013 that deal with a variety of adrenal gland issues of clinical importance in dogs.

These range from the investigations of trilostane protocols used in the treatment of dogs with Cushing's disease (1,7,12,23) to the pathogenesis, clinical features, or outcome of dogs with adrenal tumors (2,4,31-34); from adrenal imaging in normal dogs and dogs with Cushing's syndrome (3,16,24,46) to investigations involving diagnosis or treatment of hypoadrenocorticism (5,18,36,37,50); and from studies dealing with diagnostic testing for hyperadrenocorticism (6,8-11,14,42) to research studies investigating the effect of "stress" on adrenal function in dogs (15,45,49,51).

Other research studies involved diagnostic testing for pheochromocytoma in dogs (21,22) to reports of extra-adrenal paraganglioma or chemodectomas in dogs (25,27); and from studies of the renin-angiotensin-aldosterone (38,39) to studies of the complications of Cushing's syndrome, including hypercoagulability (43,44,47,48) and sudden acquired retinal degeneration syndrome (52).

As you can see from all of these many publications, it was a good year to study the canine adrenal gland!

References:

1. Arenas C, Melian C, Perez-Alenza MD. Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: twice daily versus once daily. J Vet Intern Med 2013;27:1478-1485. 
2. Arenas C, Perez-Alenza D, Melian C. Clinical features, outcome and prognostic factors in dogs diagnosed with non-cortisol-secreting adrenal tumours without adrenalectomy: 20 cases (1994-2009). Vet Rec 2013;173:501. 
3. Bargellini P, Orlandi R, Paloni C, et al. Contrast-enhanced ultrasonographic characteristics of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism. Vet Radiol Ultrasound 2013;54:283-292. 
4. Barrera JS, Bernard F, Ehrhart EJ, et al. Evaluation of risk factors for outcome associated with adrenal gland tumors with or without invasion of the caudal vena cava and treated via adrenalectomy in dogs: 86 cases (1993-2009). J Am Vet Med Assoc 2013;242:1715-1721. 
5. Bates JA, Shott S, Schall WD. Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism. Aust Vet J 2013;91:77-82.
6. Behrend EN, Kooistra HS, Nelson R, et al. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med 2013;27:1292-1304. 
7. Braun C, Boretti FS, Reusch CE, et al. Comparison of two treatment regimens with trilostane in dogs with pituitary-dependent hyperadrenocorticism. Schweiz Arch Tierheilkd 2013;155:551-558. 
8. Bromel C, Nelson RW, Feldman EC, et al. Serum inhibin concentration in dogs with adrenal gland disease and in healthy dogs. J Vet Intern Med 2013;27:76-82. 
9. Bryan HM, Adams AG, Invik RM, et al. Hair as a meaningful measure of baseline cortisol levels over time in dogs. J Am Assoc Lab Anim Sci 2013;52:189-196. 
10. Bugbee AC, Smith JR, Ward CR. Effect of dexamethasone or synthetic ACTH administration on endogenous ACTH concentrations in healthy dogs. Am J Vet Res 2013;74:1415-1420. 
11. Burkhardt WA, Boretti FS, Reusch CE, et al. Evaluation of baseline cortisol, endogenous ACTH, and cortisol/ACTH ratio to monitor trilostane treatment in dogs with pituitary-dependent hypercortisolism. J Vet Intern Med 2013;27:919-923. 
12. Cho KD, Kang JH, Chang D, et al. Efficacy of low- and high-dose trilostane treatment in dogs (< 5 kg) with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2013;27:91-98. 
13. Claude AK, Miller WW, Beyer AM, et al. Quantification and comparison of baseline cortisol levels between aqueous and plasma from healthy anesthetized hound dogs utilizing mass spectrometry. Vet Ophthalmol 2014;17:57-62. 
14. Corradini S, Accorsi PA, Boari A, et al. Evaluation of hair cortisol in the diagnosis of hypercortisolism in dogs. J Vet Intern Med 2013;27:1268-1272. 
15. Dalla Villa P, Barnard S, Di Fede E, et al. Behavioural and physiological responses of shelter dogs to long-term confinement. Vet Ital 2013;49:231-241. 
16. de Chalus T, Combes A, Bedu AS, et al. Ultrasonographic adrenal gland measurements in healthy Yorkshire Terriers and Labrador Retrievers. Anat Histol Embryol 2013;42:57-64. 
17. De Vries F, Leuschner J, Jilma B, et al. Establishment of a low dose canine endotoxemia model to test anti-inflammatory drugs: effects of prednisolone. Int J Immunopathol Pharmacol 2013;26:861-869. 
18. Floettmann JE, Buckett LK, Turnbull AV, et al. ACAT-selective and nonselective DGAT1 inhibition: adrenocortical effects--a cross-species comparison. Toxicol Pathol 2013;41:941-950. 3
19. Frank CB, Valentin SY, Scott-Moncrieff JC, et al. Correlation of inflammation with adrenocortical atrophy in canine adrenalitis. J Comp Pathol 2013;149:268-279. 
20. Frank LA, Watson JB. Treatment of alopecia X with medroxyprogesterone acetate. Veterinary Dermatology 2013;24:624-e154. 
21. Gostelow R, Bridger N, Syme HM. Plasma-free metanephrine and free normetanephrine measurement for the diagnosis of pheochromocytoma in dogs. J Vet Intern Med 2013;27:83-90. 
22. Green BA, Frank EL. Comparison of plasma free metanephrines between healthy dogs and 3 dogs with pheochromocytoma. Vet Clin Pathol 2013;42:499-503. 
23. Griffies JD. Old or new? A comparison of mitotane and trilostane for the management of hyperadrenocorticism. Compend Contin Educ Vet 2013;35:E3. 
24. Haers H, Daminet S, Smets PM, et al. Use of quantitative contrast-enhanced ultrasonography to detect diffuse renal changes in Beagles with iatrogenic hypercortisolism. Am J Vet Res 2013;74:70-77. 
25. Hardcastle MR, Meyer J, McSporran KD. Pathology in practice. Carotid and aortic body carcinomas (chemodectomas) in a dog. J Am Vet Med Assoc 2013;242:175-177. 
26. Huang HP, Lien YH. Treatment of canine generalized demodicosis associated with hyperadrenocorticism with spot-on moxidectin and imidacloprid. Acta Vet Scand 2013;55:40. 
27. Ilha MR, Styer EL. Extra-adrenal retroperitoneal paraganglioma in a dog. J Vet Diagn Invest 2013;25:803-806. 
28. Ishibashi M, Akiyoshi H, Iseri T, et al. Skin conductance reflects drug-induced changes in blood levels of cortisol, adrenaline and noradrenaline in dogs. J Vet Med Sci 2013;75:809-813. 
29. Kemppainen RJ. Inoculation of dogs with a recombinant ACTH vaccine. Am J Vet Res 2013;74:1499-1505. 
30. Kol A, Nelson RW, Gosselin RC, et al. Characterization of thrombelastography over time in dogs with hyperadrenocorticism. Vet J 2013;197:675-681. 
31. Kool MM, Galac S, Kooistra HS, et al. Expression of angiogenesis-related genes in canine cortisol-secreting adrenocortical tumors. Domest Anim Endocrinol 2013. 
32. Kool MM, Galac S, Spandauw CG, et al. Activating mutations of GNAS in canine cortisol-secreting adrenocortical tumors. J Vet Intern Med 2013;27:1486-1492. 
33. Larson RN, Schmiedt CW, Wang A, et al. Adrenal gland function in a dog following unilateral complete adrenalectomy and contralateral partial adrenalectomy. J Am Vet Med Assoc 2013;242:1398-1404. 
34. Lee HC, Jung DI, Moon JH, et al. Clinical characteristics and outcomes of primary adrenal hemangioma in a dog. Res Vet Sci 2013;95:572-575. 
35. Mak G, Allen J. Simultaneous pheochromocytoma and third-degree atrioventricular block in 2 dogs. J Vet Emerg Crit Care (San Antonio) 2013;23:610-614. 
36. Massey J, Boag A, Short AD, et al. MHC class II association study in eight breeds of dog with hypoadrenocorticism. Immunogenetics 2013;65:291-297. 
37. McGonigle KM, Randolph JF, Center SA, et al. Mineralocorticoid before glucocorticoid deficiency in a dog with primary hypoadrenocorticism and hypothyroidism. J Am Anim Hosp Assoc 2013;49:54-57. 
38. Mochel JP, Fink M, Peyrou M, et al. Chronobiology of the renin-angiotensin-aldosterone system in dogs: relation to blood pressure and renal physiology. Chronobiol Int 2013;30:1144-1159. 
39. Mochel JP, Peyrou M, Fink M, et al. Capturing the dynamics of systemic renin-angiotensin-aldosterone system (RAAS) peptides heightens the understanding of the effect of benazepril in dogs. J Vet Pharmacol Ther 2013;36:174-180. 
40. Mongillo P, Prana E, Gabai G, et al. Effect of age and sex on plasma cortisol and dehydroepiandrosterone concentrations in the dog (Canis familiaris). Res Vet Sci 2014;96:33-38.
41. Naan EC, Kirpensteijn J, Dupre GP, et al. Innovative approach to laparoscopic adrenalectomy for treatment of unilateral adrenal gland tumors in dogs. Veterinary Surgery 2013;42:710-715. 
42. Ouschan C, Kuchar A, Mostl E. Measurement of cortisol in dog hair: a noninvasive tool for the diagnosis of hypercortisolism. Vet Derm 2013;24:428-431, e493-424. 
43. Pace SL, Creevy KE, Krimer PM, et al. Assessment of coagulation and potential biochemical markers for hypercoagulability in canine hyperadrenocorticism. J Vet Intern Med 2013;27:1113-1120. 
44. Park FM, Blois SL, Abrams-Ogg AC, et al. Hypercoagulability and ACTH-dependent hyperadrenocorticism in dogs. J Vet Intern Med 2013;27:1136-1142. 
45. Perego R, Proverbio D, Spada E. Increases in heart rate and serum cortisol concentrations in healthy dogs are positively correlated with an indoor waiting-room environment. Vet Clin Pathol 2014;43:67-71. 
46. Pey P, Daminet S, Smets PM, et al. Contrast-enhanced ultrasonographic evaluation of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism. Am J Vet Res 2013;74:417-425. 
47. Romao FG, Campos EF, Mattoso CR, et al. Hemostatic profile and thromboembolic risk in healthy dogs treated with prednisone: a randomized controlled trial. BMC Vet Res 2013;9:268. 
48. Rose L, Dunn ME, Bedard C. Effect of canine hyperadrenocorticism on coagulation parameters. J Vet Intern Med 2013;27:207-211. 
49. Shiverdecker MD, Schiml PA, Hennessy MB. Human interaction moderates plasma cortisol and behavioral responses of dogs to shelter housing. Physiol Behav 2013;109:75-79. 
50. Short AD, Boag A, Catchpole B, et al. A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds. J Hered 2013;104:807-820. 
51. Siniscalchi M, McFarlane JR, Kauter KG, et al. Cortisol levels in hair reflect behavioural reactivity of dogs to acoustic stimuli. Res Vet Sci 2013;94:49-54. 
52. Stuckey JA, Pearce JW, Giuliano EA, et al. Long-term outcome of sudden acquired retinal degeneration syndrome in dogs. J Am Vet Med Assoc 2013;243:1425-1431. 
53. Winnick JJ, Ramnanan CJ, Saraswathi V, et al. Effects of 11-beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis. Am J Physiol Endocrinol Metab 2013;304:E747-756. 
54. Yu J, Fu X, Chang M, et al. The effects of intra-abdominal hypertension on the secretory function of canine adrenal glands. PLoS One 2013;8:e81795. 
55. Zeugswetter FK, Neffe F, Schwendenwein I, et al. Configuration of antibodies for assay of urinary cortisol in dogs influences analytic specificity. Domest Anim Endocrinol 2013;45:98-104.

Top 10 Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Adrenal 3

Below is the next installment of our review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum. As with all of these ACVIM research abstract reviews, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine.

In this post, we will review another of these "top 12" abstracts in our adrenal gland selections.

Midence JN, Drobatz KJ, Hess RS. Low Cortisol Concentrations in Well-Regulated Trilostane-Treated Dogs with Hyperadrenocorticism. J Vet Intern Med 2014;28:1032-1033.

     Currently there are no clear treatment guidelines for dogs with clinically well-regulated hyperadrenocorticism in which cortisol concentration before and after ACTH stimulation test performed 3–6 hours after trilostane (Vetoryl) administration is < 2.0 μg/dL. The goal of this study was to determine if an ACTH stimulation test performed 9–12 hours after trilostane administration may clarify treatment guidelines. 
     Ten client-owned dogs were enrolled into this ongoing prospective study if they had clinically well-regulated hyperadrenocorticism and had serum cortisol concentrations < 2.0 μg/dL before (Pre1) and after (Post1) ACTH stimulation performed 3–6 hours following trilostane administration. Dogs then had a second ACTH stimulation test (Pre2 and Post2) performed 9–12 hours after trilostane administration, on the same day they had the first ACTH stimulation test. 
     Mean (± standard deviation) pre- and post-ACTH stimulation cortisol concentrations were compared using a paired t-test. Mean Pre1 and mean Post1 cortisol concentrations (1.23 ± 0.35 μg/dL and 1.35 ± 0.27 μg/dL, respectively) were significantly lower than mean Pre2 cortisol concentration (2.74 ± 1.18 μg/dL, p = 0.002 each). Mean Post1 cortisol concentration was also significantly lower than mean Post2 cortisol concentration (4.62 ± 2.07 μg/dL, p = 0.006). 
     These results suggest that in dogs with clinically well-regulated, trilostane treated, hyperadrenocorticism, in which Pre1 and Post1 cortisol concentrations are < 2 μg/dL, a second ACTH stimulation test performed 9–12 hours after treatment may result in significantly higher cortisol concentrations that could support continued trilostane treatment.

Comments— First of all, we were somewhat surprised by the first sentence (introduction) of this abstract stating that there are no clear treatment guidelines for dogs with clinically well-regulated hyperadrenocorticism, in which serum cortisol concentrations before and after ACTH stimulation test performed 3–6 hours after trilostane administration are < 2.0 μg/dL. We thought that that the current recommendations about what action steps to take in such a scenario were already fairly clear (1-5).

For example, in a 2010 chapter on hyperadrenocorticism in dogs published in Ettinger and Feldman's Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (2), this issue is addressed rather specifically:

If a dog on SID or BID trilostane is doing clinically well but the serum cortisol values are low (post-ACTH cortisol less than 2 µg/dL), we recommend that one stop the trilostane for 5-7 days and restart treatment at a 25-50% lower dose. Then one should retest after 2 weeks of treatment with the lower dose. If the serum cortisol values remain subnormal on the reduced dosage, the trilostane should be discontinued indefinitely, with repeat ACTH stimulation testing scheduled for 1 month and every 3-6 months thereafter. The trilostane should only be restarted in these dogs if clinical signs of hyperadrenocorticism return and the post-ACTH cortisol becomes high once again.

Even in the Vetoryl product drug insert (1), in which the desired cortisol ranges are wider than what we recommend, it states the following:

If the ACTH stimulation test is < 1.45 µg/dL (< 40 nmol/L) and/or if electrolyte imbalances characteristic of hypoadrenocorticism (hyperkalemia and hyponatremia) are found, Vetoryl capsules should be temporarily discontinued until recurrence of clinical signs consistent with hyperadrenocorticism and test results return to normal (1.45-9.1 µg/dL or 40-250 nmol/L). Vetoryl capsules may then be re-introduced at a lower dose.

So, at least in our opinion, we have pretty clear monitoring guidelines for what to do when post-ACTH cortisol concentrations are low— we should temporary stop the trilostane completely for 5-7 days, then restart treatment at a 25-50% lower dose (if doing well), and finally, repeat the ACTH stimulation test in 2 weeks. Or we can be more cautious and completely stop and withhold the drug until we prove that cortisol concentrations recover (1-5).

The fact that the low serum cortisol values in the dogs of this study were higher when tested later in the day is not surprising, and indeed is exactly what you might expect in a dog with no clinical signs of hypoadrenocorticism. In healthy dogs, trilostane reaches peak concentrations at 1.5-2 hours and concentrations return to baseline levels after 10-18 hours (1-4). The duration of cortisol suppression appears to vary substantially between dogs with hyperadrenocorticism; however, cortisol concentrations generally remain suppressed for less than 13 hours, which explains the higher cortisol values when tested later in the day.

Yes, we all know that some dogs do very well with low cortisol concentrations at peak trilostane action, but I believe that this could be dangerous. Once a dog is on trilostane, we should worry about safety first and efficacy second. We know that the lower serum cortisol values in these dogs, the greater the chance of hypoadrenocorticism and possibly the greater risk for adrenal necrosis (2-4). If a dog is doing well and basal and post-ACTH cortisol values are < 2 µg/dL, this is too close for comfort, at least if one of our safety goals is to prevent the development of iatrogenic hypoadrenocorticism.  In addition, we also know that many dogs treated with trlostane will have a slow decrease in adrenal reserve over time, necessitating a gradual reduction in the daily trilostane dose over time. 

Bottom Line— In dogs that develop low cortisol levels on trilostane, the safest action to take is to lower the daily dose, or, if on once daily treatment (as the dogs of this study), divide the total daily dose into BID administration. We do not know what doses were used in the dogs of this study by Midence et al, but we do know that using lower dosages of trilostane and maintaining cortisol values within a more normal range will help prevent hypocortisolism and hopefully will greatly reduce the change of acute adrenal necrosis (8).  

References:

1. Dechra website. Veteryl product insert.
2. Melián CM, Pérez-Alenza D, Peterson ME. Hyperadrenocorticism in dogs. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition) Philadelphia, Saunders Elsevier, pp 1816-1840, 2010. Seventh ed. Philadelphia: Saunders Elsevier, 2010;1816-1840.
3. Ramsey IK. Trilostane in dogs. Vet Clin North Am Small Anim Pract 2010;40:269-283.
4. Herrtage ME, Ramsey IK. Canine hyperadrenocorticism. In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2012:167-189.
5. Griffies JD. Old or new? A comparison of mitotane and trilostane for the management of hyperadrenocorticism. Compend Contin Educ Vet 2013;35:E3.
6. Feldman EC. Evaluation of twice-daily lower-dose trilostane treatment administered orally in dogs with naturally occurring hyperadrenocorticism. J Am Vet Med Assoc 2011;238:1441-1451.
7. Arenas C, Melian C, Perez-Alenza MD. Evaluation of 2 trilostane protocols for the treatment of canine pituitary-dependent hyperadrenocorticism: twice daily versus once daily. J Vet Intern Med 2013;27:1478-1485.
8. Reusch CE, Sieber-Ruckstuhl N, Wenger M, et al. Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane. Vet Rec 2007;160:219-224.