Wednesday, April 22, 2015

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.

  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. 

Friday, April 17, 2015

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


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

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

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.

  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. 

Wednesday, April 15, 2015

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). 

  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. 

Monday, February 23, 2015

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).

  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. 

Friday, January 30, 2015

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).

  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. 

Friday, January 23, 2015

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).

  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.

Sunday, December 28, 2014

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.

  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. 

Sunday, December 21, 2014

Blood Glucose Curves and the Fractious Diabetic Cat

My problem patient is a 12-year old, DSH, female spayed cat with a 2-year history of insulin-dependent diabetes mellitus. She has been treated with glargine insulin at a variable dose, but typically between 1-3 units, BID. This cat will not eat canned food so we are feeding higher protein, lower carb dry foods (Hill's MD and Purina DM).

Six months ago, the cat was diagnosed with immune-mediated hemolytic anemia (IMHA) and was treated successfully with prednisolone and cyclosporine (Atopica). This led to development of insulin resistance and loss of diabetic control, but the cat did relatively well after raising the insulin dose to 6 units while on prednisolone. After a long and slow taper, the cat is now off all glucocorticoids for the last month, and the insulin dose is back down to 2 U, twice daily. The cat remains on Atopica, probably for life.

We have periodically done in-house blood glucose curves to adjust her insulin dose, but she becomes extremely fractious when hospitalized, and we can't really handle her (she bites, scratches, cries, and screams louder than any other cat I've ever had!). The owner does not care to check blood glucose at home, and given the cat's nature, I doubt if they could even do it. Since weaning her off the prednisolone, we have seen a couple of hypoglycemic readings on spot blood glucose checks so we are now worried that the current insulin dose may be too high.

Therefore a week ago, we performed a serial glucose curve on 2 units glargine, BID. The results were as follows:
  • 6 am = Insulin given
  • 8 am = 317 mg/dl
  • 10 am = 376 mg/dl
  • 12 noon = 352 mg/dl
  • 2 pm = 299 mg/dl
  • 4 pm = 229 mg/dl
We were a bit surprised by the high glucose concentrations during the day on this curve, but we increased glargine from 2 to 3 units BID based on the severe and persistent hyperglycemia. However, when I checked a spot afternoon blood glucose value yesterday, it was low-normal at 69 mg/dl. I rechecked another blood glucose reading 30 minutes later, and it was even lower at 57 mg/dl. Right or wrong, I put her back down to 2 units glargine BID and pm spot check in 1 week.

My main question is this: could this cat's in-hospital curve be leading us astray because she is so fractious? I am aware that spot checks aren't ideal. However, this cat is relatively easy to handle during a quick exam and single spot check, but she become so angry when hospitalized throughout the day.

What would you do? How do I adjust the insulin dosage in this cat? We've been trying to get the cat into remission but it's not looking good!

My Response:

Well, first the bad news: I can almost guarantee that this cat's diabetes will not go into remission, given the fact that she has been diabetic for 2 years. A number of studies have reported that diabetic remission, when it does occur, will generally happen within the first 6 months of diagnosis (1,2). In addition, the fact that she has concurrent disease and has been treated with glucocorticoids certainly hasn't increased her chances for remission.

The good news is that once we decide that diabetic remission is no longer our goal, then we can be more lax with our glucose regulation. Our goal for diabetic cats should then be 3-fold:
  1. Control clinical signs of diabetes (e.g., weight loss, polyuria, polydispsia)
  2. Prevent diabetic ketoacidosis
  3. Avoid hypoglycemia
To do this, it's not really necessary to do the tight glucose regulation and frequent blood glucose monitoring that we would ideally do if we are trying to increase the odds for diabetic remission (3-5).

In fractious diabetic cats, I would never recommend doing serial blood glucoses to determine the best insulin dose. The release of catecholamines during this excitable state can absolutely increase the glucose readings during the curve (commonly referred to as stress hyperglycemia) (6). Overall, this means that all of the serial blood glucose curves you have done in this cat are most likely next to meaningless and that such testing should be stopped.

Spot glucose checks can't hurt, but as you say, they can be hard to interpret and may be misleading. If the blood glucose reading is low, you might want to decrease the insulin dose, but if the blood glucose is in the ideal range or high, you could still be overdosing the insulin.

In cats like this, I'd recommend that you adjust the insulin dose based on the presence or absence of clinical signs, including body weight and water intake (7).  If the owners can measure water intake at home, that can be a very sensitive way to help determine if more insulin is needed. If there are no clinical signs of diabetes and the weight is stable, the cat is probably adequately controlled. Monitoring an occasional serum fructosamine level can also help (8,9), as well as home measurement of urine glucose, if the owner can do it (7,19,11). A weekly check for urinary ketones can also be used to monitor for pending ketoacidosis, and become extremely important if anorexia, vomiting, or any other signs of illness develop.

Bottom Line:
In fractious cats, I would not recommend in-hospital blood glucose curves for monitoring. Stress hyperglycemia will give you results that are meaningless, and one could easily be misled into giving higher doses of insulin than are actually needed. This is especially true in cats with long-term diabetes that are unlikely to ever develop remission.

In cats like this case, I use a combination of clinical signs and blood/urine values, looking at the overall trend in results rather than the specific or individual values. For example, I don't use serum fructosamine concentration as the sole means of judging control, but I still think it is helpful as one piece of the puzzle. If it is high, that suggests that the insulin dosage may have to be increased; if the fructosamine value is low to low-normal, this may indicate overdosage and hypoglycemia.

Believe me, both your hospital staff and the fractious diabetic cat will all be better off with this approach!

  1. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clinics North America 2013: 43: 245-249
  2. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321.
  3. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
  4. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
  5. Nack R, DeClue AE. In cats with newly diagnosed diabetes mellitus, use of a near-euglycemic management paradigm improves remission rate over a traditional paradigm. Vet Q 2014; 34:132-136.
  6. Rand JS, Kinnaird E, Baglioni A, et al. Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine. J Vet Intern Med 2002;16:123-132. 
  7. Miller E. Long-term monitoring of the diabetic dog and cat. Clinical signs, serial blood glucose determinations, urine glucose, and glycated blood proteins. Vet Clin North Am Small Anim Pract 1995;25:571-584. 
  8. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med 1996;10:360-364. 
  9. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64-68. 
  10. Bennett N. Monitoring techniques for diabetes mellitus in the dog and the cat. Clin Tech Small Anim Pract 2002;17:65-69. 
  11. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 

Sunday, December 14, 2014

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).

  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. 

Saturday, November 15, 2014

Managing Diabetic Dogs with Exocrine Pancreatic Insufficiency

My problem patient is a 9-year old, female spayed Yorkie with concurrent exocrine pancreatic insufficiency (EPI) and diabetes mellitus. The stools, which had been very large and odoriferous, are smaller and not as smelly now that we have started the pancreatic enzyme replacement therapy.  However, the stools are still not completely normal. The dog remains very thin, but she has gained a pound over the past month.

The diabetic control has been more problematic. Six weeks ago, the dog was on 3 units of Novolin N every 12 hours and had serial blood glucose values running in the range of 400-600 mg/dl throughout the day.  After starting on the enzyme powder, the insulin dosage has fallen to only 0.5 unit twice daily. The current glucose curves start with a morning reading of 400 mg/dl, but the blood glucose then drops down during the day to values in the 100's or, at times, to as low as 45 mg/dl. The owner is trying to be as consistent as possible in feeding (the dog has a very good appetite) and giving the insulin. The dog has shown signs of clinical hypoglycemia, despite the low blood glucose values.  

What do you suggest? Is there a better insulin for this dog?  Would a special diet help?

My Response:

The vast majority of dogs with EPI have a concurrent B12 (cobalamin) deficiency; therefore, cobalamin should be part of this dog's treatment regimen (1). If this Yorkie weighs less than 7 kg, I would suggest administering 250 µg SC every 7 days for 8 weeks, then 250 µg every 14 days for 2 months, then 250 µg once monthly for a couple more months. The treatment may need to be repeated based on serum cobalamin levels.

In addition, some dogs with EPI have dysbiosis (the new term for bacterial overgrowth/gut microbial imbalance), so metronidazole or tylosin power given for a couple weeks plus a probiotic may be helpful. Lastly, if the stools don't get better with the above treatments then the dog may have inflammatory bowl disease (IBD) in addition to the EPI (2). This breed appears predisposed to developing IBD or lymphangietasia (2). As far as what to feed this dog, I'd recommend a diet low in fat because of the concurrent diabetes and GI issues (1).

As far as the insulin type, it looks like the duration of NPH activity is too short for this dog. Use of an insulin with a longer duration of action, such as Vetsulin or glargine, may be a better choice for this case. Based on the fact that the insulin dose is so small and the dog is so very sensitive to the insulin, I'd go with glargine, starting with 1 U,  twice daily. This insulin is much less potent than either NPH or Vetsulin in dogs, making hypoglycemia less unlikely (3).

  1. Wieberg, M. Exocrine pancreatic insufficiency in dogs. In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013;558-560.
  2. Simmerson SM, Armstrong PJ, Wünschmann A, J., et al. Clinical features, intestinal histopathology, and outcome in protein-losing enteropathy in Yorkshire Terrier dogs. J Vet Intern Med. 2014;28:331-7. 
  3. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. doi: 10.1136/vr.100070.

Sunday, November 2, 2014

Hyperthyroidism in Guinea Pigs: An Emerging Disease


Hyperthyroidism in Four Guinea Pigs: Clinical Manifestations, Diagnosis, and Treatment
by F. Künzel, B. Hierlmeier, M. Christian, and M. Reifinger


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.

  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. 

Saturday, October 11, 2014

Unmasking Kidney Disease In Hyperthyroid Cats after Treatment

I have two hyperthyroid cats that both had "completely normal" kidney function until we started treating with methimazole. On treatment, the serum T4 concentrations in both cats have come down nicely to 1.2 and 2.0 µg/dl, respectively (reference interval, 1.0-4.0 µg/dl), so these values are within the low-normal range, which is what I aim for after treatment.

In the first cat, the serum creatinine has increased from 1.2 mg/dl up to 2.0 mg/dl, whereas the serum creatinine value in the second cat rose from 1.5 mg/dl up to 2.5 mg/dl. Based on the IRIS staging system, both cats could be classified as having stage 2 chronic kidney disease (CKD).

How do I manage such hyperthyroid cats that develop "new" CKD after treatment? Should I lower the methimazole or stop it all together in order to help improve the kidney function?

My Response:

Hyperthyroidism and CKD are both very common problems of the older cat and may occur concurrently in the same patient (1,2). Because hyperthyroidism increases the glomerular filtration rate (GFR) and renal blood flow (RBF), the kidney disease may be masked and only revealed once the cat is rendered euthyroid (3-5). As you know, that's what happened in these two feline patients.

However, it is very important to understand that treatment of hyperthyroidism doesn't cause new kidney problems; the CKD was already present in your cats before the methimazole treatment, but the serum creatinine values were normal, in part due to the high GFR associated with hyperthyroidism. Now that you have the hyperthyroidism under control, the lowering of circulating thyroid hormone concentrations has also resulted in a drop in GFR, unmasking the underlying CKD that was already there.

Management of hyperthyroid cats that develop kidney disease after treatment
So what do we do with hyperthyroid cats like your two patients here— cats that develop mild CKD after treatment of hyperthyroidism with methimazole?

It was once thought that if azotemia developed following medical treatment, then it would be best to stop the methimazole and leave the hyperthyroidism untreated (or at least under-treat it) to maximize renal function. This recommendation has now been widely abandoned, with the realization that hyperthyroidism could actually be causing renal injury in these cats through the process of glomerular hyperfiltration (1,2,6). This increase in glomerular pressure has been associated with proteinuria and evidence of tubular damage, which could result in progressive renal injury. In other words, hyperthyroidism has the potential to exacerbate these processes and worsen, rather than help, renal function.

On the other hand, it's also important not to over control hyperthyroidism. In other words, we don't want the post-treatment T4 concentrations to go too low because iatrogenic hypothyroidism will make the azotemia worse (7). Even mild degrees of hypothyroidism can worsen the azotemia in susceptible cats. This means that the serum T4 value does not have to be below reference range — even a serum T4 in the lower third of the reference range may be too low, especially if the serum TSH is high, diagnostic for mild hypothyroidism (8).

Because of this association between development of iatrogenic hypothyroidism and worsening of azotemia, my "goal" in treating cats with hyperthyroidism is to reduce the total T4 concentration into the middle of the reference range (e.g., 2.0-3.0 µg/dl with your lab). So in your first cat, you may want to lower the methimazole dose and allow the serum T4 to come up into the mid-normal range. This may help increase GFR and improve kidney function in that cat. One recent study found that restoration of euthyroidism in cats with iatrogenic hypothyroidism resulted in a significant reduction in serum creatinine concentration, with azotemia resolving in half of the cats (9).

Finally, if you unmask kidney disease after treatment of a hyperthyroid cat, this also means that you should take steps to attempt to slow the progression of CKD, just as you would in a geriatric cat with CKD alone. These steps may include one or more of the following, depending on secondary factors and stage of the CKD (10,11):
  • Antibiotics, if urinary tract infection
  • Antihypertensives, if hypertensive
  • Low-phosphate diet
  • Phosphorus binders
  • Calcitriol or ACE-inhibitors, if necessary
  • Subcutaneous fluids
Survival times of hyperthyroid cats that develop mild CKD after treatment
In most cats that develop newly-diagnosed azotemia after treatment for hyperthyroidism, the CKD is mild (usually IRIS stage 2) and associated with few clinical signs other than mild polyuria and polydipsia. Owners of cats that have developed azotemia still report that treatment of the hyperthyroidism has improved the clinical condition of their cat, as shown by weight gain and resolution of other clinical signs of hyperthyroidism.

The survival time of cats that develop azotemia following treatment of hyperthyroidism does not differ from those that do not develop any azotemia (7). This fact may be surprising to many practicing veterinarians who naturally assume that the development of CKD is associated with a worse prognosis. However, CKD progresses relatively slowly in cats, and only about half of all cats diagnosed with mild CKD will ultimately succumb to the disease (12). Many CKD cats die because of unrelated causes.

Survival times of hyperthyroid cats that are azotemic prior to treatment
The situation is completely different in cats that are already clearly azotemic (serum creatinine >2 mg/dl), even before any treatment for hyperthyroidism has been given. In general the survival of this group of cats with azotemic CKD prior to treatment is poor. In one study, the median survival time for azotemic cats was only 178 days; however, survival times in that study was very variable,  ranged from 0 days up to 1,505 days (4.1 years) (13).

Bottom Line:

Hyperthyroid cats that develop "new" CKD after treatment are common, but the azotemia is generally mild and we should not withhold methimazole treatment in those cats. However, we don't want to induce iatrogenic hypothyroidism, and steps should be taken to address the underlying CKD. Unless prior azotemia was present, the prognosis of most treated cats with mild CKD is good to excellent.

  1. Langston CE, Reine NJ. Hyperthyroidism and the kidney. Clin Tech Small Anim Pract 2006;21:17-21.  
  2. Syme HM. Cardiovascular and renal manifestations of hyperthyroidism. Vet Clin North Am Small Anim Pract 2007;37:723-743.  
  3. Graves TK, Olivier NB, Nachreiner RF, et al. Changes in renal function associated with treatment of hyperthyroidism in cats. Am J Vet Res 1994;55:1745-1749.  
  4. Boag AK, Neiger R, Slater L, et al. Changes in the glomerular filtration rate of 27 cats with hyperthyroidism after treatment with radioactive iodine. Vet Rec 2007;161:711-715.  
  5. van Hoek I, Lefebvre HP, Peremans K, et al. Short- and long-term follow-up of glomerular and tubular renal markers of kidney function in hyperthyroid cats after treatment with radioiodine. Domest Anim Endocrinol 2009;36:45-56.  
  6. Syme H. Are methimazole trials really necessary? In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
  7. Williams TL, Elliott J, Syme HM. Association of iatrogenic hypothyroidism with azotemia and reduced survival time in cats treated for hyperthyroidism. J Vet Intern Med 2010;24:1086-1092.  
  8. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidism. Compendium 2013;35:E4. 
  9. Williams TL, Elliott J, Syme HM. Effect on renal function of restoration of euthyroidism in hyperthyroid cats with iatrogenic hypothyroidism. J Vet Intern Med 2014;28:1251-1255. 
  10. Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012;42:669-692.
  11. Polzin DJ. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract 2011;41:15-30. 
  12. Elliott J, Rawlings JM, Markwell PJ, et al. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J Small Anim Pract 2000;41:235-242.
  13. Williams TL, Peak KJ, Brodbelt D, et al. Survival and the development of azotemia after treatment of hyperthyroid cats. J Vet Intern Med 2010;24:863-869.