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. 

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. 

Top Endocrine Publications of 2013: Feline Diabetes Mellitus

In my ninth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline endocrine pancreas. I covered the canine diabetic publications in a blog post last spring. Click this link to review my list of 2013 research papers that pertain to diabetes in dogs.

Listed below are 29 papers published in 2013 that deal with a variety of diabetic topics of clinical importance for diabetic cats.

These topics range from a study of survival time and prognostic factors in cats with newly diagnosed diabetes (2) to studies involving pathogenesis or risk factors for development of diabetes (6,15,20,21,24); from the relationship between diabetes and kidney disease and pancreatits (1,3) to a review of what we know about diabetic remission (10); and, from reviews of insulin treatment of diabetic cats (4,16,26) to the use of oral hypoglycemia agent or incretin hormonal therapy in cats (22,25).

Other studies range from investigations of diet management of obese and diabetic cats (5,7,17,29) to studies of insulin antibodies in cats (28); from reviews of secondary diabetes, including acromegaly and hyperadrenocorticism (18,19) to ketoacidosis (16,23); and finally, from the use of routine home glucose monitoring (9) to continuous glucose monitoring in cats (11,27).

References:

1. Bloom CA, Rand JS. Diabetes and the kidney in human and veterinary medicine. Vet Clin North Am Small Anim Pract 2013;43:351-365. 
2. Callegari C, Mercuriali E, Hafner M, et al. Survival time and prognostic factors in cats with newly diagnosed diabetes mellitus: 114 cases (2000-2009). J Am Vet Med Assoc 2013;243:91-95. 
3. Caney SM. Pancreatitis and diabetes in cats. Vet Clin North Am Small Anim Pract 2013;43:303-317. 
4. Caney SM. Management of cats on Lente insulin: tips and traps. Vet Clin North Am Small Anim Pract 2013;43:267-282. 
5. Coradini M, Rand JS, Morton JM, et al. Fat mass, and not diet, has a large effect on postprandial leptin but not on adiponectin concentrations in cats. Domest Anim Endocrinol 2013;45:79-88. 
6. Dirtu AC, Niessen SJ, Jorens PG, et al. Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus: A clue for endocrine disruption in humans? Environ Int 2013;57-58:60-67. 
7. Farrow HA, Rand JS, Morton JM, et al. Effect of dietary carbohydrate, fat, and protein on postprandial glycemia and energy intake in cats. J Vet Intern Med 2013;27:1121-1135. 
8. Fleischhacker SN, Bauersachs S, Wehner A, et al. Differential expression of circulating microRNAs in diabetic and healthy lean cats. Vet J 2013;197:688-693. 
9. Ford SL, Lynch H. Practical use of home blood glucose monitoring in feline diabetics. Vet Clin North Am Small Anim Pract 2013;43:283-301. 
10. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clin North Am Small Anim Pract 2013;43:245-249. 
11. Hafner M, Lutz TA, Reusch CE, et al. Evaluation of sensor sites for continuous glucose monitoring in cats with diabetes mellitus. J Feline Med Surg 2013;5:117-123. 
12. Hoenig M, Pach N, Thomaseth K, et al. Cats differ from other species in their cytokine and antioxidant enzyme response when developing obesity. Obesity (Silver Spring) 2013;21:E407-414. 
13. Hoenig M, Traas AM, Schaeffer DJ. Evaluation of routine hematology profile results and fructosamine, thyroxine, insulin, and proinsulin concentrations in lean, overweight, obese, and diabetic cats. J Am Vet Med Assoc 2013;243:1302-1309. 
14. Leal RO, Gil S, Brito MT, et al. The use of oral recombinant feline interferon omega in two cats with type II diabetes mellitus and concurrent feline chronic gingivostomatitis syndrome. Ir Vet J 2013;66:19. 
15. Link KR, Allio I, Rand JS, et al. The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis). Gen Comp Endocrinol 2013;188:269-281. 
16. Marshall RD, Rand JS, Gunew MN, et al. Intramuscular glargine with or without concurrent subcutaneous administration for treatment of feline diabetic ketoacidosis. J Vet Emerg Crit Care (San Antonio) 2013;23:286-290.
17. Mimura K, Mori A, Lee P, et al. Impact of commercially available diabetic prescription diets on short-term postprandial serum glucose, insulin, triglyceride and free fatty acid concentrations of obese cats. J Vet Med Sci 2013;75:929-937. 
18. Niessen SJ. Update on feline acromegaly. In Practice 2013;35:2-6. 
19. Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:319-350. 
20. O'Leary CA, Duffy DL, Gething MA, et al. Investigation of diabetes mellitus in Burmese cats as an inherited trait: a preliminary study. N Z Vet J 2013;61:354-358. 
21. Osto M, Zini E, Reusch CE, et al. Diabetes from humans to cats. Gen Comp Endocrinol 2013;182:48-53. 
22. Palm CA, Feldman EC. Oral hypoglycemics in cats with diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:407-415. 
23. Rand JS. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in cats. Vet Clin North Am Small Anim Pract 2013;43:367-379. 
24. Rand JS. Pathogenesis of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:221-231. 
25. Reusch CE, Padrutt I. New incretin hormonal therapies in humans relevant to diabetic cats. Vet Clin North Am Small Anim Pract 2013;43:417-433. 
26. Roomp K, Rand JS. Management of diabetic cats with long-acting insulin. Vet Clin North Am Small Anim Pract 2013;43:251-266. 
27. Surman S, Fleeman L. Continuous glucose monitoring in small animals. Vet Clin North Am Small Anim Pract 2013;43:381-406. 
28. Takashima S, Nishii N, Hachisu T, et al. Natural anti-insulin autoantibodies in cats: enzyme-linked immunosorbent assay for the determination of plasma anti-insulin IgG and its concentrations in domestic cats. Res Vet Sci 2013;95:886-890. 
29. Zoran DL, Rand JS. The role of diet in the prevention and management of feline diabetes. Vet Clin North Am Small Anim Pract 2013;43:233-243. 

Hyperthyroidism in Guinea Pigs: An Emerging Disease

PAPER REVIEW

Hyperthyroidism in Four Guinea Pigs: Clinical Manifestations, Diagnosis, and Treatment

by F. Künzel, B. Hierlmeier, M. Christian, and M. Reifinger

Journal of Small Animal Practice 2013; 54:667-671.

Background

Only limited information regarding hyperthyroidism in guinea pigs has been reported, much of which has been published as a general review article (1-3). Therefore, veterinarians may not be aware of this disease, resulting in under-diagnosis of this condition.

The purpose of this case series by Künzel et al. (4) is to describe the results of diagnosis, treatment, and outcome of guinea pigs with hyperthyroidism. The goal was to provide additional information about this disease to help clinicians dealing with guinea pigs that may be suspected of having this disease.

Case Series of 4 Guinea Pigs Suffering from Hyperthyroidism

Signalment: Hyperthyroidism was diagnosed in four guinea pigs (3 females and 1 male), ranging in age from 3 to 6 years. These 4 cases represented 1.3% of guinea pigs examined at the University clinic during the same 2.5-year period.

Clinical features: Clinical signs reported in all guinea pigs included weight loss despite the maintenance of a normal appetite.   Polyuria was noted in 2 of the 4 cases.

Physical examination findings: Physical examination revealed evidence for weight loss and a palpable mass in the ventral cervical region in all guinea pigs. Additional findings in individual guinea pigs included unkempt hair coat, tachycardia and tachypnea.

Serum chemistry results and thyroid hormone determinations: All 4 of the guinea pigs showed elevated serum alanine aminotransferase (ALT) activity. The diagnosis of hyperthyroidism was confirmed by demonstration of increased serum total thyroxine (T4) concentrations in all guinea pigs, as measured by chemiluminescent technique (5).

Treatment: Surgical thyroidectomy was attempted in 1 case but the guinea pig died during anesthetic induction. Histopathology confirmed thyroid adenoma.

The other 3 guinea pigs were treated with methimazole, using starting doses of 1-1.4 mg/kg/day. Based on clinical signs and results of follow-up serum T4 values, the final methimazole doses ranged from 2-3 mg/kg every 24 hours in 2 cases and 2.5 mg/kg every 8 hours in the third guinea pig. In this latter case, radioactive iodine treatment was eventually performed.

Response to treatment: All 3 of the treated guinea pigs showed progressive weight gain as serum T4 concentrations fell to within the reference interval. However, all died of unknown causes 18-28 months following initial treatment.

My Bottom Line:

Hyperthyroidism in guinea pigs represents a relatively new addition to the list of differential diagnoses for weight loss in guinea pigs (2-4). In many ways, the description and management of hyperthyroidism in these 4 guinea pigs mimics the situation we had with feline hyperthyroidism in the early 1980’s, as we were just starting to routinely recognize this common disease in cats (6,7).

The signalment (middle-aged to senior), clinical signs (weight loss despite a good appetite) and physical exam findings (palpable thyroid nodule) displayed by these guinea pigs are all remarkably similar to those of the typical hyperthyroid cat. The finding of a high total T4 concentration was diagnostic in all of these 4 guinea pigs, as it is in over 90% of hyperthyroid cats.

Treatment with methimazole was successful in management of 3 of the 4 guinea pigs. However, on a body weight basis, much higher daily doses were needed for the guinea pigs, at least compared to the typical hyperthyroid cat.  Use of radioiodine therapy also appears to be a safe and promising treatment for guinea pigs suffering from hyperthyroidism (2,5). However, more work needs to be done before this becomes an accepted therapeutic approach for hyperthyroidism in the guinea pig.

References:

1. Mayer J, Hunt K, Eshar D, et al. Thyroid scintigraphy in a guinea pig with suspected hyperthyroidism. Exotic DVM 2009;11:25-29.
2. Mayer J, Wagner R, Taeymans O. Advanced diagnostic approaches and current management of thyroid pathologies in Guinea pigs. Vet Clin North Am Exot Anim Pract 2010;13:509-523. 
3. Brandao J, Vergneau-Grosset C, Mayer J. Hyperthyroidism and hyperparathyroidism in guinea pigs (Cavia porcellus). Vet Clin North Am Exot Anim Pract 2013;16:407-420. 
4. Kunzel F, Hierlmeier B, Christian M, et al. Hyperthyroidism in four guinea pigs: clinical manifestations, diagnosis, and treatment. J Small Anim Pract 2013; 54:667-671. 
5. Muller K, Muller E, Klein R, et al. Serum thyroxine concentrations in clinically healthy pet guinea pigs (Cavia porcellus). Vet Clin Pathol 2009;38:507-510. 
6. Peterson ME, Johnson JG, Andrews LK. Spontaneous hyperthyroidism in the cat. Spontaneous hyperthyroidism in the cat. Proceedings of the American College of Veterinary Internal Medicine 1979: 108.
7. Peterson ME, Kintzer PP, Cavanagh PG, et al. Feline hyperthyroidism: pretreatment clinical and laboratory evaluation of 131 cases. J Am Vet Med Assoc 1983;183:103-110. 

Top Endocrine Publications of 2013: The Feline Thyroid Gland

In my eighth compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline thyroid gland.

Listed below are 26 papers published in 2013 that deal with a variety of thyroid gland topics of issues of clinical importance in cats.

These range from from studies of the duration of serum T4 suppression in cats treated with methimazole (1) to the results of a long-term follow-up study of cats treated with transdermal methimazole (2); and from case reports of methimazole or carbimazole-induced toxicity in cats (3,6,19) to the results of an online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications (5).

Other studies report the variability in iodine concentrations found in commercial cats foods in the USA (7) to investigation of the radioactivity in the excreta of hyperthyroid cats treated with radioiodine (8); from a comparison of computed tomography and scintigraphy for thyroid imaging in hyperthyroid cats (9) to a review of the clinical usefulness of an assay for measurement of circulating B-type natriuretic peptide (BNP) concentration in hyperthyroid cats (11); and from an overview of the diagnostic tests useful for confirming feline hyperthyroidism (4,12,13,15,17) and hypothyroidism (14) to a study of the effects of an iodine-restricted diet for management of cats with hyperthyroidism (22); from investigations of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats (24) to studies of the renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without hypertension (25).

References:

1. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Duration of T4 suppression in hyperthyroid cats treated once and twice daily with transdermal methimazole. J Vet Intern Med 2013;27:377-381. 
2. Boretti FS, Sieber-Ruckstuhl NS, Schafer S, et al. Transdermal application of methimazole in hyperthyroid cats: a long-term follow-up study. J Feline Med Surg 2013;16:453-459. 
3. Bowlt K, Cattin I, Stewart J. Carbimazole-associated hypersensitivity vasculitis in a cat. J Small Anim Pract 2013; doi: 10.1111/jsap.12154. 
4. Bruyette D. Feline hyperthyroidism: Diagnosis and therapeutic modalities. Today's Veterinary Practice 2013;3:25-30.
5. Caney SM. An online survey to determine owner experiences and opinions on the management of their hyperthyroid cats using oral anti-thyroid medications. J Feline Med Surg 2013;15:494-502. 
6. Castro Lopez J, Lloret A, Ravera I, et al. Pyogranulomatous mural folliculitis in a cat treated with methimazole. J Feline Med Surg 2013;16:527-531. 
7. Edinboro CH, Pearce EN, Pino S, et al. Iodine concentration in commercial cat foods from three regions of the USA, 2008-2009. J Feline Med Surg 2013;15:717-724. 
8. Lamb V, Gray J, Parkin T, et al. Measurement of the radioactivity in the excreta of cats treated with iodine-131 for hyperthyroidism. Vet Rec 2013;172:45. 
9. Lautenschlaeger IE, Hartmann A, Sicken J, et al. Comparison between computed tomography and Tc-Pertechnetate scintigraphy characteristics of the thyroid gland in cats with hyperthyroidism. Vet Radiol Ultrasound 2013;54:666-673. 
10. North DL. Uptake of 131-I in households of thyroid cancer patients. Health Phys 2013;104:434-436. 
11. Oyama MA, Boswood A, Connolly DJ, et al. Clinical usefulness of an assay for measurement of circulating N-terminal pro-B-type natriuretic peptide concentration in dogs and cats with heart disease. J Am Vet Med Assoc 2013;243:71-82. 
12. Paepe D, Verjans G, Duchateau L, et al. Routine health screening: findings in apparently healthy middle-aged and old cats. J Feline Med Surg 2013;15:8-19. 
13. Peterson ME. More than just T4: Diagnostic testing for hyperthyroidism in cats. J Feline Med Surg 2013;15:765-777. 
14. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compend Contin Educ Vet 2013;35:E4. 
15. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hyperthyroidism. Compend Contin Educ Vet 2013;35:E3. 
16. Ramoo S, Bradbury L, Anderson G, et al. Sedation of hyperthyroid cats with subcutaneous administration of a combination of alfaxalone and butorphanol. Aust Vet J 2013;91:131-136. 
17. 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 (Letter). Vet Clin Pathol 2014;43:1-3. 
18. Sabatino BR, Rohrbach BW, Armstrong PJ, et al. Amino acid, iodine, selenium, and coat color status among hyperthyroid, Siamese, and age-matched control cats. J Vet Intern Med 2013;27:1049-1055. 
19. Snead E, Kerr M, Macdonald V. Cutaneous lymphoid hyperplasia mimicking cutaneous lymphoma in a hyperthyroid cat. Can Vet J 2013;54:974-978. 
20. Sparkes A. Health screening of cats: some timely justification. J Feline Med Surg 2013;15:5. 
21. Taylor BE, Leibman NF, Luong R, et al. Detection of carcinoma micrometastases in bone marrow of dogs and cats using conventional and cell block cytology. Vet Clin Pathol 2013;42:85-91.
22. van der Kooij M, Becvarova I, Meyer HP, et al. Effects of an iodine-restricted food on client-owned cats with hyperthyroidism. J Feline Med Surg 2013;14:491-498. 
23. Whitehouse-Tedd KM, Cave NJ, Ugarte CE, et al. Isoflavone metabolism in domestic cats (Felis catus): Comparison of plasma metabolites detected after ingestion of two different dietary forms of genistein and daidzein. J Anim Sci 2013;91:1295-1306. 
24. Williams TL, Elliott J, Berry J, et al. Investigation of the pathophysiological mechanism for altered calcium homeostasis in hyperthyroid cats. J Small Anim Pract 2013;54:367-373. 
25. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 
26. 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. 

Top Endocrine Publications of 2013: The Feline Adrenal Gland

In my next compilation of the canine and feline endocrine publications of 2013, I’m moving on to disorders of the feline adrenal gland.

Listed below are 12 research papers written in 2013 that deal with a variety of adrenal gland topics of issues of clinical importance in cats.

These range from a study of body condition on the bioavailability of prednisone and prednisolone in cats (1) to investigation of adrenal gland ultrasonography in normal and sick cats (2); from a study that designed an oral fludrocortisone suppression test for diagnosis of hyperaldosteronism (Conn's syndrome) in cats (3) to another that designed a corticotropin-releasing hormone (CRH) protocol for evaluation of the hypothalamic-pituitary-adrenal axis (4); and from a study which measured cortisol levels in cats' hair (5) to a case report of ACTH-secreting pituitary carcinoma causing Cushing's disease in a cat (6).

Other studies included a retrospective study of trilostane treatment of cats with Cushing's disease (7) to a review of hyperadrenocorticism and diabetes mellitus in cats (8); from studies of the effects of stress on glucocorticoid metabolites (9) to a case report of a cat with double GH- and ACTH-secreting pituitary adenomas (10); and finally, from a case report of a cat that presented in Addisonian crisis (11) to an investigation of the renin-angiotensin-aldosterone system in hyperthyroid cats with and without hypertension (12).

References:

1. Center SA, Randolph JF, Warner KL, et al. Influence of body condition on plasma prednisolone and prednisone concentrations in clinically healthy cats after single oral dose administration. Res Vet Sci 2013;95:225-230. 
2. Combes A, Pey P, Paepe D, et al. Ultrasonographic appearance of adrenal glands in healthy and sick cats. J Feline Med Surg 2013;15:445-457. 
3. Djajadiningrat-Laanen SC, Galac S, Boeve SAEB, et al. Evaluation of the oral fludrocortisone suppression test for diagnosing primary hyperaldosteronism in cats. J Vet Intern Med 2013;27:1493-1499. 
4. Eiler KC, Bruyette DS, Behrend EN, et al. Comparison of intravenous versus intramuscular administration of corticotropin-releasing hormone in healthy cats. J Vet Intern Med 2013;27:516-521. 
5. Galuppi R, Leveque JF, Beghelli V, et al. Cortisol levels in cats' hair in presence or absence of Microsporum canis infection. Res Vet Sci 2013;95:1076-1080. 
6. Kimitsuki K, Boonsriroj H, Kojima D, et al. A case report of feline pituitary carcinoma with hypercortisolism. J Vet Med Sci 2014;76:133-138. 
7. Mellett Keith AM, Bruyette D, Stanley S. Trilostane therapy for treatment of spontaneous hyperadrenocorticism in cats: 15 cases (2004-2012). J Vet Intern Med 2013;27:1471-1477. 
8. Niessen SJ, Church DB, Forcada Y. Hypersomatotropism, acromegaly, and hyperadrenocorticism and feline diabetes mellitus. Vet Clin North Am Small Anim Pract 2013;43:319-350. 
9. Ramos D, Reche-Junior A, Fragoso PL, et al. Are cats (Felis catus) from multi-cat households more stressed? Evidence from assessment of fecal glucocorticoid metabolite analysis. Physiol Behav 2013;122:72-75. 
10. Sharman M, FitzGerald L, Kiupel M. Concurrent somatotroph and plurihormonal pituitary adenomas in a cat. J Feline Med Surg 2013;15:945-952. 
11. Sicken J, Neiger R. Addisonian crisis and severe acidosis in a cat: a case of feline hypoadrenocorticism. J Feline Med Surg 2013;15:941-944. 
12. Williams TL, Elliott J, Syme HM. Renin-angiotensin-aldosterone system activity in hyperthyroid cats with and without concurrent hypertension. J Vet Intern Med 2013;27:522-529. 

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.