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 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. 

Canine Acromegaly and GH-Secreting Mammary Gland Tumors

GH-Producing Mammary Tumors in Two Dogs with Acromegaly

Atsuko Murai, Naohito Nishii, Takehito Morita, and Masashi Yuki

The Journal of Veterinary Medical Science 2012;74:771-774.

Acromegaly is the clinical syndrome caused by growth hormone (GH) excess, and is characterized by overgrowth of the soft tissue, bone, and viscera (1). In humans and cats, acromegaly is commonly caused by pituitary adenomas producing GH (1-4), whereas the pathogenesis of the GH excess in dogs is completely different.

In female dogs, acromegaly is most often caused by endogenous or exogenous progestagens that induce GH overproduction (4-6). Old, intact, female dogs may spontaneously develop acromegaly because of the high progesterone concentrations characteristic of diestrus. Attempts to suppress estrus by administration of a long-acting progestagen (e,g,, medroxyprogesterone acetate) may also lead to acromegaly in dogs. This progestin-induced GH excess originates from foci of hyperplastic ductular epithelium in the mammary glands (7-9). Mammary GH is biochemically identical to GH produced and secreted by the pituitary gland (7).

Canine acromegaly is usually associated with GH oversecretion by hyperplastic mammary glands (7-10), but GH can also be produced by mammary tumors in dogs (11). However, to date, there has been no report of dogs that suffered from acromegaly associated with GH-producing mammary tumors.

In this report by Murai et al (12), the authors describe the clinical course of two well-documented dogs with acromegaly caused by GH-producing mammary tumors.

Case studies —Two intact female dogs (10 -year-old Miniature Dachsund and 13-year-old Papillon) were examined because of growing mammary tumors. Based upon history and clinical examination findings, both dogs had clinical features of acromegaly including weight gain, enlargement of the head, excessive skin folds, and inspiratory stridor. Serum concentrations of growth hormone (GH), insulin-like growth factor-I (IGF-1), and insulin were elevated in both dogs (Table 1). From these findings, both dogs were diagnosed with acromegaly.

Table 1

In the Miniature Dachsund, the GH, IGF-1, and insulin levels normalized within a few days after removal of focal benign mammary tumors and ovariohysterectomy (Table 1).

In the Papillon, metastasis of the mammary tumor was suspected from thoracic radiographs. Despite this finding, one of the mammary tumors was so large that the owner opted for the mammary tumor excision to improve the quality of life. Therefore, the mammary tumors were removed focally with regional lymph node. Histological examination of the large tumor revealed mammary complex carcinoma and metastasis to the regional lymph node. The serum concentrations of GH, IGF-1, and insulin fell dramatically within a few days of surgery, despite the fact that metastasis was present (Table 1)

In both dogs, immunohistochemical staining for GH was positive in the mammary tumor cells but not in the normal mammary glands.

Conclusions and Clinical Relevance— In dogs, high GH secretion and clinical features of acromegaly may be caused by mammary tumors that hypersecrete GH.

My Bottom Line:

Overall, the two dogs reported in this study by Murai et al (12) clearly demonstrate that the acromegalic features and higher serum concentrations of GH and IGF-1 were caused by excessive GH production from the mammary tumors. In both dogs, removing the mammary gland tumor lead to remission of the acromegalic state, as well as a marked decrease in serum GH and IGF-1 values. To the best of my knowledge, this is the first report providing concrete evidence of a causal relationship between GH-producing mammary tumors and naturally occurring canine acromegaly.

Canine acromegaly typically occurs in middle-aged to elderly female dogs in the luteal phase or after administration of exogenous progestins (4-6). Endogenous progesterone or exogenous progestins stimulate GH production in hyperplastic mammary glands in dogs (7-10), This GH can act via the autocrine system to promote the growth of mammary glands or elevate systemic IGF-1 secretion (1). Excessive GH also induces glucose intolerance, which can lead to hyperinsulinemia and/or hyperglycemia (1,6).

A previous report demonstrated that complete removal of normal mammary glands can reduce GH and IGF-I levels in dogs (2). In the two dogs of this report, normal mammary tissue was left intact, and removal of only the mammary tumors decreased the serum concentrations of both GH and IGF-1. In addition, the positive immunostaining for GH were found only in the mammary tumor cells but not in the normal mammary glands, suggesting that GH produced by mammary tumors caused the acromegaly. This is supported by a previous report that most mammary tumors produce GH in dogs (12).

In contrast to the dogs of this report, a previous study has shown that canine malignant mammary tumors contain high GH levels without causing acromegalic symptoms (13).The differences that determine whether mammary tumors do or do not develop high serum GH concentrations or clinical features of acromegaly is not clear.

In any case, now that we know that canine acromegaly can develop as a result of GH-secreting mammary gland tumors, we should be looking for this syndrome in dogs that present with mammary gland tumors. To that end, determination of serum concentrations of insulin, IGF-1, and GH (if available) should be monitored in dogs with mammary gland tumors, especially in those in which complete resection is not possible.

References:

1. Niessen S, Peterson ME, Church DB. Acromegaly In: Mooney CT,Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;35-42.
2. Peterson ME, Taylor RS, Greco DS, et al. Acromegaly in 14 cats. J Vet Intern Med 1990;4:192-201.
3. Fischetti AJ, Gisselman K, Peterson ME. CT and MRI evaluation of skull bones and soft tissues in six cats with presumed acromegaly versus 12 unaffected cats. Vet Radiol Ultrasound 2012;53:535-539. 
4. Concannon P, Altszuler N, Hampshire J, et al. Growth hormone, prolactin, and cortisol in dogs developing mammary nodules and an acromegaly-like appearance during treatment with medroxyprogesterone acetate. Endocrinology 1980;106:1173-1177. 
5. Eigenmann JE, Venker-van Haagen AJ. Progestagen-induced and spontaneous canine acromegaly due to reversible growth hormone overproduction: Clinical picture and pathogenesis. J Am Anim Hosp Assoc 1981;17:813-822 
6. Eigenmann JE, Eigenmann RY, Rijnberk A, et al. Progesterone-controlled growth hormone overproduction and naturally occurring canine diabetes and acromegaly. Acta Endocrinol (Copenh) 1983;104:167-176. 
7. Selman PJ, Mol JA, Rutteman GR, et al. Progestin-induced growth hormone excess in the dog originates in the mammary gland. Endocrinology 1994;134:287-292. 
8. Mol JA, van Garderen E, Selman PJ, et al. Growth hormone mRNA in mammary gland tumors of dogs and cats. J Clin Invest 1995;95:2028-2034. 
9. Mol JA, Lantinga-van Leeuwen I, van Garderen E, et al. Progestin-induced mammary growth hormone (GH) production. Adv Exp Med Biol 2000;480:71-76. 
10. Rijnberk A, Mol JA. Progestin-induced hypersecretion of growth hormone: an introductory review. J Reprod Fertil Suppl 1997;51:335-338. 
11. van Garderen E, de Wit M, Voorhout WF, et al. Expression of growth hormone in canine mammary tissue and mammary tumors. Evidence for a potential autocrine/paracrine stimulatory loop. Am J Pathol 1997;150:1037-1047. 
12. Murai A, Nishii N, Morita T, et al. GH-producing mammary tumors in two dogs with acromegaly. J Vet Med Sci 2012;74:771-774. 
13. Queiroga FL, Perez-Alenza MD, Silvan G, et al. Crosstalk between GH/IGF-I axis and steroid hormones (progesterone, 17-beta-estradiol) in canine mammary tumours. J Steroid Biochem Mol Biol 2008;110:76-82.