Diagnosis and management of diabetes mellitus in five cats with somatotrophic abnormalities

The clinical findings and management of five cats with abnormalities consistent with acromegaly were examined retrospectively. Growth hormone (GH) concentrations were elevated in four cats. In one, a minimal elevation of GH was accompanied by a marked elevation in insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-1 concentrations supported the diagnosis in three of four cats measured, but was not elevated initially in one cat, despite a markedly elevated GH concentration. These findings suggest that elevated IGF-1 concentrations are a reliable indicator of acromegaly, but that values within the reference range do not exclude such a diagnosis. Clinical signs of acromegaly were similar to those previously reported, although upper respiratory stridor occurred in one cat, and insulin-resistant diabetes mellitus was not a consistent feature. Despite the lack of a widely available definitive treatment for acromegaly, good control of the clinical signs of diabetes mellitus can be achieved for long periods despite high doses of insulin often being required.     

CT and MRI evaluation of skull bones and soft tissues in six cats with presumed acromegaly versus 12 unaffected cats

Feline acromegaly is predominantly caused by an adenoma of the pituitary gland, resulting in excessive growth hormone and insulin-like growth factor (IGF-1) secretion. In advanced cases, cats will display prominent facial features and upper airway congestion secondary to bony and soft tissue proliferation. The purpose of this study was to describe CT and MRI characteristics of soft tissues and skull bones in six cats with presumed acromegaly and to compare findings with those observed in 12 unaffected cats. In the five acromegalic cats with CT or MRI evidence of a pituitary tumor, frontal bone thickness was greater than age-matched controls with and without a history of upper airway disease. These five cats also had evidence of soft tissue accumulation in the nasal cavity, sinuses, and pharynx. One cat with insulin-resistant diabetes mellitus, elevated IGF-1, and a normal pituitary size did not have evidence of frontal bone thickening or upper airway congestion.     

Investigation of serum IGF-I levels amongst diabetic and non-diabetic cats

Since insulin-like growth factor-I (IGF-I) was first discovered as a mediator of glucose homeostasis, it has been extensively investigated in diabetes research in humans, rodents and primates. To date, however, relatively little work has been carried out on this hormone in the cat, despite the pathophysiological similarities between human and feline diabetes mellitus, as well as the relatively common nature of the disease in cats. This study reports on the IGF-I concentrations of 42 insulin treated diabetic cats and 25 normal cats. Diabetic subjects were grouped according to length of insulin treatment as either short, medium or long term. Analysis of variance (ANOVA) and Fischer's pair-wise comparisons revealed that mean IGF-I levels in short-term diabetic cats were significantly lower than those in normal cats whilst mean levels in long-term diabetics were significantly higher. The direction and extent of these alterations may have implications for our understanding of the pathophysiology of feline diabetes mellitus and for the use of this hormone in the diagnosis of acromegaly in diabetic cats.     

Resolution of diabetes mellitus but not acromegaly in a cat with a pituitary macroadenoma treated with hypofractionated radiation

The use of insulin-like growth factor 1 assays in the diagnosis and subsequent monitoring after radiotherapy of an acromegalic cat with a secretory pituitary adenoma and secondary insulin-resistant diabetes mellitus is described. Diabetes resolved, and exogenous insulin was no longer required for the maintenance of normoglycaemia 10 months after completion of a course of hypofractionated radiotherapy. However, insulin-like growth factor 1 remained elevated, and the cat's size and appetite continued to increase. It is suggested that radiotherapy may decrease growth hormone concentration to a level such that diabetogenic effects are no longer evident but not to a level required to decrease insulin-like growth factor 1 secretion.     

Feline acromegaly

Acromegaly, or hypersomatotropism, results from chronic, excessive secretion of growth hormone in the adult animal. The anabolic effects of growth hormone are exerted through the intermediary hormone, insulin-like growth factor 1, which is produced in the liver under the influence of growth hormone. Feline acromegaly is caused by a pituitary adenoma that secretes excessive amounts of growth hormone. Characteristic effects of excessive growth hormone secretion include the development of diabetes mellitus and growth of the acral segments of the body (jaw, extremities, skull, etc.). Acromegaly occurs in older, predominately male cats and is often associated with diabetes mellitus. Other clinical signs include stridor, enlargement of the jaw and extremities, lean weight gain, and organomegaly (heart, liver, kidney, etc.). Diagnosis is made by documentation of increased levels of growth hormone or insulin-like growth factor (or both) and demonstration of a pituitary mass via magnetic resonance imaging or computed tomography. The most effective treatment to date has been radiation therapy. Prognosis is fair to good with proper treatment.     

Feline acromegaly: a review of the syndrome

Acromegaly is characterized by chronic excessive growth hormone (GH) secretion by the pituitary gland. Feline acromegaly is most commonly caused by a functional pituitary tumor. Definitive diagnosis can be difficult because of the gradual disease onset, subtle clinical signs, unavailability of relevant laboratory tests, and client financial investment. The most significant clinical finding of acromegaly is the presence of insulin-resistant diabetes mellitus. Diagnosis is currently based upon brain imaging and measurement of serum GH and/or insulin-like growth factor-1 concentrations. Definitive treatment in cats is not well described, but radiation therapy appears promising.     

Growth hormone excess and the effect of octreotide in cats with diabetes mellitus

In this prospective study 16 cats with diabetes mellitus were examined for concurrent acromegaly by measuring plasma growth hormone (GH) and insulin-like growth factor-I concentrations, and magnetic resonance imaging (MRI) of the pituitary fossa. Additionally, the effects of octreotide administration on the plasma concentrations of glucose, GH, α-melanocyte-stimulating hormone (α-MSH), adrenocorticotrophic hormone (ACTH), and cortisol were measured.Five cats were diagnosed with hypersomatotropism. The pituitary was enlarged in these 5 cats and in 2 other cats. Six cats that required a maximum lente insulin dosage ≥1.5 IU/kg body weight per injection had pituitary enlargement and 5 of these cats had acromegaly. Plasma concentrations of GH, ACTH, and cortisol decreased significantly after single intravenous administration of the somatostatin analogue octreotide in the acromegalic cats. The effect on GH concentrations was more pronounced in some of the acromegalic cats than in others. In the non-acromegalic cats only ACTH concentrations decreased significantly. In both groups plasma glucose concentrations increased slightly but significantly, whereas α-MSH concentrations were not significantly affected.In conclusion, the incidence of hypersomatotropism with concomitant pituitary enlargement appears to be high among diabetic cats with severe insulin resistance. Some of these cats responded to octreotide administration with a pronounced decrease in the plasma GH concentration, which suggests that octreotide administration could be used as a pre-entry test for treatment with somatostatin analogues.     

GH-producing mammary tumors in two dogs with acromegaly

Two intact female dogs were admitted for growing mammary tumors. They had symptoms 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-I), and insulin were elevated in the two cases. From these findings, both dogs were diagnosed with acromegaly. In case 1, the GH, IGF-I, and insulin levels subsided after removal of the focal benign mammary tumors and ovariohysterectomy. In case 2, those levels subsided after removal of only focal mammary carcinoma. In both cases, immunohistochemical investigations for GH were positive in the mammary tumor cells but not in the normal mammary glands. We concluded that GH-producing mammary tumors caused the present acromegaly.     

Prevalence of pituitary tumors among diabetic cats with insulin resistance

OBJECTIVE: To determine prevalence of pituitary tumors, detectable by means of computed tomography or magnetic resonance imaging, in cats with insulin resistance suspected to have acromegaly or hyperadrenocorticism versus cats with well-controlled diabetes mellitus. DESIGN: Case series. ANIMALS: 16 cats with insulin resistance that were also suspected to have acromegaly (n = 12) or pituitary-dependent hyperadrenocorticism (4) and 8 cats with well-controlled diabetes mellitus. PROCEDURE: Computed tomography was performed on all 16 cats with insulin resistance and 2 cats in which diabetes mellitus was well-controlled. The remaining 6 cats in which diabetes mellitus was well-controlled underwent magnetic resonance imaging. Images were obtained before and immediately after i.v. administration of contrast medium. RESULTS: Computed tomography revealed a mass in the region of the pituitary gland in all 16 cats with insulin resistance. Maximum width of the masses ranged from 4.4 to 12.7 mm; maximum height ranged from 3.1 to 12.6 mm. Results of computed tomography performed on 2 cats with well-controlled diabetes and magnetic resonance imaging performed on the remaining 6 cats were considered normal. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that cats with insulin resistance suspected to have acromegaly or pituitary-dependent hyperadrenocorticism are likely to have a pituitary mass detectable by means of computed tomography or magnetic resonance imaging.     

Diabetes mellitus caused by pancreatitis in a bull

This paper describes a 6-year-old Simmental bull with diabetes mellitus. The animal was referred to our clinic because of severe weight loss and chronic indigestion. Clinical examination revealed markedly disturbed general condition, impaired forestomach function and polyuria. There was aciduria, glucosuria and ketonuria. The most important biochemical findings were severe hyperglycemia, markedly increased activities of hepatic enzymes and severe metabolic acidosis. Plasma concentrations of insulin, insulin-like growth factor-I, thyroxine and 3,5,3'-triiodothyronine were lower than normal, whereas those of glucagon were higher than normal. Based on these findings, a diagnosis (secondary) diabetes mellitus was made. The bull was slaughtered and histological examination revealed mixed cell pancreatitis with severe degeneration of islet cells. Immunohistochemical examination of the pancreas showed that very few insulin-, glucagon-, somatostatin- and pancreatic polypeptide, insulin-like growth factor-I and adrenomedullin-producing islet cells were present.     

Serum insulin-like growth factor-I concentration in cats with diabetes mellitus and acromegaly

BACKGROUND: Serum insulin-like growth factor-I (IGF-I) has been used in place of serum growth hormone quantification for identifying acromegaly in diabetic cats. The utility of IGF-I as a screening test for acromegaly has not been critically evaluated. This retrospective study was performed to evaluate the usefulness of serum IGF-I concentration for identifying acromegaly. HYPOTHESIS: Serum IGF-I is a useful screening test for acromegaly in diabetic cats. ANIMALS: A review was made of the medical records of 74 diabetic cats that had serum IGF-I quantified. The diabetes was classified as well controlled (15 cats), poorly controlled because of problems with the insulin treatment regimen, concurrent disease, or both (40), or poorly controlled with clinical findings consistent with acromegaly (19). METHODS: A review of medical records was made. RESULTS: Serum IGF-I concentration was significantly (P < .0001) increased in acromegalic diabetic cats, compared with well-controlled and poorly controlled diabetic cats. Sensitivity and specificity for serum IGF-I concentration were 84% (95%/ confidence interval [CI] = 60.4-96.6%) and 92% (95% CI = 81.3-97.2%), respectively. There was no significant correlation between serum IGF-I concentration and duration of insulin treatment (r = 0.23, P = .089), insulin dosage (r = 0.14, P = .30), age (r = 0.16, P = .12), and pituitary volume (r = 0.40, P = .11), but a modest correlation was found between serum IGF-I concentration and body weight (r = 0.48, P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Results support the use of serum IGF-I concentration as a screening test for acromegaly in diabetic cats that have clinical findings supportive of the disease.     

Use of proligestone in the management of three German shepherd dogs with pituitary dwarfism

Three German shepherd dogs were diagnosed with pituitary dwarfism and subsequently treated with proligestone. Treatment resulted in development of an adult hair coat, increased bodyweight and elevated insulin-like growth factor-1 concentration. Two dogs received thyroid supplementation during proligestone therapy. Adverse effects (cystic endometrial hyperplasia and acromegaly) were reported in two cases. No side effects were reported in the remaining case. This is the first report of the use of proligestone in the management of pituitary dwarfism.     

Growth Hormone-producing Pituitary Adenoma, Elevated Serum Somatomedin C Concentration and Diabetes Mellitus in a Cat

A pituitary acidophil adenoma in a domestic shorthaired cat with diabetes mellitus and elevated serum somatomedin C level is described. Growth hormone production by the neoplasm was confirmed by an appropriate reaction using an immunoperoxidase technic.     

MAGNETIC RESONANCE IMAGING FINDINGS IN 15 ACROMEGALIC CATS

Feline acromegaly is characterized by chronic excessive growth hormone secretion, most commonly caused by a functional pituitary adenoma. In this study, acromegaly was diagnosed in 15 cats on the basis of compatible clinical signs, laboratory, and magnetic resonance imaging (MRI) findings. MRI findings were reviewed retrospectively. Enlargement of the pituitary gland with suprasellar extension was present in all cats. No characteristic signal patterns were identified on T1‐weighted and T2‐weighted sequences. Contrast enhancement was nonuniform in all cats, as was suspected involvement of the adjacent hypothalamus. A mass effect on the cavernous sinus and third ventricle was present in 13 cats. Mild peritumoral edema was present in four cats, and moderate edema in one cat. Transtentorial herniation was present in one cat. Histopathology confirmed the presence of a pituitary adenoma in two cases. MRI is a useful modality to establish the diagnosis of acromegaly.     

Transsphenoidal hypophysectomy for treatment of pituitary-dependent hyperadrenocorticism in 7 cats

OBJECTIVE: Evaluation of microsurgical transsphenoidal hypophysectomy for the treatment of pituitary-dependent hyperadrenocorticism (PDH) in cats. STUDY DESIGN: Prospective clinical study. ANIMALS OR SAMPLE POPULATION: Seven cats with PDH. METHODS: Urinary cortisol/creatinine ratios, pituitary-adrenocortical function tests, and computed tomography (CT) were performed on 7 cats that presented with a provisional diagnosis of hyperadrenocorticism. All cats underwent microsurgical transsphenoidal hypophysectomy with histologic examination of the excised specimen. Follow-up consisted of clinical evaluation, repeat adrenocortical function testing, and CT. RESULTS: Four cats had concurrent diabetes mellitus. In all cats, the urinary cortisol/creatinine (C/C) ratios were elevated. The dexamethasone screening test showed that 2 cats did not meet the criterion for hyperadrenocorticism. The response of the cats' plasma concentrations of cortisol and adrenocorticotrophic hormone to a high dose of dexamethasone varied from very sensitive to completely dexamethasone resistant. Basal plasma alpha-melanocyte-stimulating hormone concentrations were elevated in 2 cats with a pars intermedia adenoma and in 3 cats with an adenoma that originated from the anterior lobe. Preoperative CT enabled accurate assessment of pituitary size (5 nonenlarged pituitaries with a height <4 mm and 2 enlarged pituitaries with a height >5 mm) and localization relative to intraoperative anatomic landmarks. Two cats died within 4 weeks after surgery of a nonrelated disease. In the remaining 5 cats, the hyperadrenocorticism went into both clinical and biochemical remission. Hyperadrenocorticism recurred in 1 cat after 19 months, but no other therapy was given and the cat died at home 28 months after surgery. CT evaluation of this cat had identified pituitary remnants 6 weeks after surgery. The main postoperative complications were oronasal fistula (1 cat), complete dehiscence of the soft palate (1 cat), and transient reduction of tear production (1 cat). One cat died at 6 months (undefined anemia), and another cat at 8 months (recurrent nose and middle ear infection secondary to soft palate dehiscence) after surgery. In the surviving 2 cats, the remission periods at the time of writing were 46 and 15 months. In the 2 cats with sufficient follow-up time, the concurrent diabetes mellitus disappeared, ie, insulin treatment could be discontinued at 4 weeks and 5 months after hypophysectomy. In all 7 cats, the histologic diagnosis was pituitary adenoma. CONCLUSIONS: Microsurgical transsphenoidal hypophysectomy is an effective method of treatment for feline PDH in specialized veterinary institutions having access to advanced pituitary imaging techniques. Concurrent diabetes mellitus is usually reversible after hypophysectomy. Thorough presurgical screening for coexisting diseases is imperative. CLINICAL RELEVANCE: PDH in cats can be effectively treated by hypophysectomy. The neurosurgeon performing hypophysectomy must master a learning curve and must be familiar with the most frequent complications of the operation to treat them immediately and effectively. Urinary C/C ratios are sensitive indicators for the assessment of remission and recurrence of hyperadrenocorticism.     

Coarse Fractionated Radiation Therapy for Pituitary Tumours in Cats: A Retrospective Study of 10 Cases

Introduction:  Pituitary tumours are uncommon in cats. Signs may be due to either an expansile mass or paraneoplastic effects (acromegaly and/or unstable diabetes mellitus). There are a few small case series providing evidence of efficacy for radiotherapy of pituitary tumours in cats. This retrospective study describes the outcome of ten cats with pituitary tumours treated with course‐fractionated radiation.
Methods:  The medical records of cats with MRI‐confirmed pituitary tumours that underwent radiotherapy were reviewed. A standard coarse‐fractioned radiation protocol was used; 37 Gy in 5 once‐weekly fractions using two parallel‐opposed 4MeV X‐ray beams. Survival times were calculated from date of first radiation dose.
Results:  Ten cats with pituitary tumours underwent radiotherapy. 5 cats had CNS signs and 5 had evidence of growth hormone excess (1 cat also showed CNS signs). 2 cats with pre‐existing moderate to severe CNS signs died of unknown causes before completing the radiation course. Of the remaining 4 with CNS signs, 3 had complete resolution of signs and the fourth showed partial improvement. Of the 5 cats with unstable diabetes, 2 no longer required insulin and 3 became stable at a lowered dose. The median survival time was 77.6 weeks. 6 cats died: 2 without completing the radiation course, 2 from unrelated causes (CRF, VAFS) and 2 from relapse and/or progression of CNS signs. 4 cats remain alive (range 34–191 weeks).
Conclusions:  Radiation therapy is confirmed as an effective treatment for pituitary tumours in cats giving extended survival and control of both direct mass effect and paraneoplastic signs.     

Coarse fractionated radiation therapy for pituitary tumours in cats: a retrospective study of 12 cases

This retrospective study describes the clinical progression of 12 cats with pituitary tumours treated with a coarse fractionated radiation protocol delivering a total dose of 37 Gy in five once weekly fractions. A pituitary macrotumour was identified in all 12 cats: 4 with neurological signs only and 8 with insulin‐resistant diabetes mellitus secondary to acromegaly. One of the cats with central neurological signs died before completing the radiotherapy course; the remaining three had partial or complete remissions of their central neurological signs. Of the cats with unstable diabetes mellitus, five no longer required insulin therapy, one required less insulin and two became stable. The overall median survival time was 72.6 weeks; four cats died from related causes, two from unrelated problems and six remain alive. Radiation therapy is confirmed as an effective treatment for feline pituitary tumours, giving prolonged survival and control of both paraneoplastic and mass effect signs.     

Melanotroph pituitary adenoma in a cat with diabetes mellitus

A 13-year-old male, castrated, crossbred cat was referred for insulin-resistant diabetes mellitus. The cat had a ravenous appetite and a dull coat. Basal urinary corticoid/creatinine ratios were normal. In the low-dose dexamethasone suppression test there was no suppression of the (nonelevated) plasma cortisol concentration, whereas the (nonelevated) plasma adrenocorticotropic hormone (ACTH) concentration declined to low values. Basal plasma alpha-melanocyte-stimulating hormone (alpha-MSH) concentrations were highly elevated (> 1,500 ng/liter). Computed tomography revealed a pituitary tumor originating from the pars intermedia (PI). After microsurgical transsphenoidal hypophysectomy, the clinical signs resolved and the cat no longer required insulin administration. Microscopic examination of the surgical specimen revealed a pituitary adenoma originating from the PI with infiltration into the neural lobe. The adenoma immunostained intensely positive for alpha-MSH and only weakly for ACTH. It is concluded that the ACTH-independent cortisol production was probably due to the (weak) glucocorticorticotropic effects of the extremely high plasma concentration of alpha-MSH and related peptides.     

Exogenous Insulin Treatment after Hypofractionated Radiotherapy in Cats with Diabetes Mellitus and Acromegaly

Background: The optimal treatment for feline acromegaly has yet to be established. Surgical and medical therapies are minimally effective although radiotherapy might have greater efficacy. The purpose of this study was to review the response and outcome of cats with acromegaly and insulin-resistant diabetes mellitus (DM) to radiotherapy.
Hypotheses: That radiotherapy improves glycemic control in cats with acromegaly and that improved glycemic control is due to remission of clinical acromegaly; demonstrated by a fall in serum insulin-like growth factor-1 (IGF-1) concentrations.
Animals: Fourteen cats with naturally occurring acromegaly.
Methods: Retrospective case review; records of all cats treated for acromegaly with radiotherapy were reviewed from 1997 to 2008. Cats were selected on the basis of compatible clinical signs, laboratory features, and diagnostic imaging findings. Fourteen cats received radiotherapy, delivered in 10 fractions, 3 times a week to a total dose of 3,700 cGy.
Results: Thirteen of 14 cats had improved diabetic control after radiotherapy. These improvements were sustained for up to 60 months. DM progressed in 2 cats and 1 did not respond. Seven cats responded before the final treatment. Ten cats were euthanized, 1 as a consequence of radiotherapy. In 8 cats in which IGF-1 was measured after treatment, changes in its concentration did not reflect the clinical improvement in glycemic control.
Conclusions and Clinical Importance: Radiotherapy represents an effective treatment for cats with insulin-resistant DM resulting from acromegaly. IGF-1 concentration after treatment does not provide a suitable method by which remission from either acromegaly or insulin-resistant DM may be assessed.     

Comparative Aspects of the Endotoxin- and Cytokine-Induced Endocrine Cascade Influencing Neuroendocrine Control of Growth and Reproduction in Farm Animals

Disease in animals is a well-known inhibitor of growth and reproduction. Earlier studies were initiated to determine the effects of endotoxin on pituitary hormone secretion. These studies found that in sheep, growth hormone (GH) concentration was elevated, whereas insulin-like growth factor-I (IGF-I) was inhibited, as was luteinizing hormone (LH). Examination of the site of action of endotoxin in sheep determined that somatotropes expressed the endotoxin receptor (CD14) and that both endotoxin and interleukin-Iβ activated GH secretion directly from the pituitary. In the face of elevated GH, there is a reduction of IGF-I in all species examined. As GH cannot activate IGF-I release during disease, there appears to be a downregulation of GH signalling at the liver, perhaps related to altered nitration of Janus kinase (JAK). In contrast to GH downregulation, LH release is inhibited at the level of the hypothalamus. New insights have been gained in determining the mechanisms by which disease perturbs growth and reproduction, particularly with regard to nitration of critical control pathways, with this perhaps serving as a novel mechanism central to lipopolysaccharide suppression of all signalling pathways. This pathway-based analysis is critical to the developing novel strategies to reverse the detrimental effect of disease on animal production.