Feline Acromegaly: A Review of the Syndrome

Clinical and Routine Laboratory Findings

Clinical findings typically include insulin-resistant diabetes mellitus, organomegaly (e.g., liver, spleen, kidneys), hypertrophic cardiomyopathy (HCM), inferior prognathia, prominent or broad facial features, spondylosis deformans, and peripheral neuropathy.^1–4 The respiratory stridor that occurs in humans and dogs has only been reported in one cat.¹

Since many acromegalic cats have cardiac changes consistent with HCM, Kittleson et al. measured GH concentrations in 31 cats that had no clinical signs of acromegaly but had been previously diagnosed with HCM.²⁵ They found that serum GH concentration was significantly greater in the HCM-affected population than in a paired normal population of cats. However, when compared to acromegalic cats with a functional pituitary tumor, the GH increase in HCM cats was meager.²⁵ Gross and histopathological postmortem examination of pituitary glands from eight cats with HCM found no pituitary abnormalities.²⁵ Serum IGF-1 measurements were not reported in this study. It is important to realize that increased GH concentrations can occur with diseases other than acromegaly, and further understanding of GH physiology in health and disease is required.

Serum biochemical abnormalities in acromegalic cats include hyperglycemia, hypercholesterolemia, mild increases in serum alanine aminotransaminase (ALT) and serum alkaline phosphatase (ALP) activities, hypochloridemia, hypercalcemia, hyperphosphatemia, hyperproteinemia, and elevated serum urea nitrogen.^1–4,11 Many of these changes may be explained by unregulated diabetes mellitus and possibly underlying subclinical dehydration. Mild to moderate hyperphosphatemia without overt evidence of renal dysfunction (i.e., azotemia) has been a feature of acromegaly in almost one third of the reported cases.^1–5,11 Growth hormone-induced renal phosphate reabsorption and not renal failure may explain this finding. Total hyperproteinemia was recognized by Peterson et al. in approximately 60% (9/14) of affected cases.⁴ Urinalysis findings have included glucosuria without ketonuria.^4,11 The most commonly reported hematological change in feline acromegalics is erythrocytosis, which has been attributed to GH or IGF-1 effects on the bone marrow.^1,11,26

Definitive diagnosis of acromegaly can be difficult because of an unavailability of relevant laboratory tests and the large financial investment often required of the client to reach a diagnosis. It is a great challenge to establish a timely diagnosis of this chronic, insidious disease. Physical changes of acromegaly may be subtle, and obvious conformational enlargement may not be the most recognizable feature in some cats or may not be present at all. The most significant clinical finding that should prompt a clinician to consider acromegaly in a cat is the presence of insulin-resistant diabetes mellitus.¹

Brain Imaging

Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain may help confirm acromegaly if imaging demonstrates a mass lesion in the area of the pituitary gland^2,4,11 [Figures 1A, 1B, 1C]. Utilizing contrast-enhanced CT, Elliott et al. evaluated the pituitary glands of 16 insulin-resistant cats, 12 of which were considered likely to have acromegaly based on biochemical testing and/or ruling out of other etiologies of insulin resistance.¹⁵ The other four cats were diagnosed with pituitary-dependent hyperadrenocorticism. All 16 cats had exhibited a pituitary mass extending dorsally to the rim of the sella turcica.¹⁵ Additionally, other reports exist of six feline acromegalics with normal adrenal function having pituitary masses visualized on brain CT or MRI.^2,3,16,22 Peterson et al. reported CT-confirmed pituitary masses in five of six cats.⁴ While most of the cases reported by Peterson et al. were screened for hyperadrenocorticism, it was unclear whether hyperadrenocorticism was ruled out in the six cats that underwent brain CT scanning.⁴ Based on the current knowledge of feline acromegaly, finding a pituitary mass lends support to the diagnosis of this disease; however, hyperadrenocorticism, which can also be associated with pituitary masses and cause insulin resistance, must be ruled out via adrenal function testing.

Endocrine Testing

Current requirements for definitive diagnosis of acromegaly include documentation of elevated serum GH and/or IGF-1 concentrations.^6,11 Growth hormone measurements are not currently commercially available in the United States, but they are available at Utrecht University in the Netherlands. Growth hormone secretion is normally pulsatile.^25,27 Even during acromegaly, GH secretion is episodic; however, the duration, amplitude, and frequency of secretory events are increased.^1,7 Owing to an extremely short half-life, GH is rapidly cleared from the circulation, and basal GH levels are usually undetectable.⁷ Single, random, serum GH measurements have been unreliable in the diagnosis of acromegaly in humans.^1,7,28

In contrast, of the reported feline cases having single serum GH measurements performed, all have had documented increases in serum GH, which suggests that this test may be useful in the diagnosis of acromegaly in the cat.^{1,3–5,18,22} In a report of 14 acromegalic cats, serum basal GH levels measured by a heterologous canine radioimmunoassay (RIA) method were found to be increased when compared with paired normal samples.⁴ Ten subjects from that study underwent necropsy, which confirmed the presence of a pituitary acidophil adenoma.⁴ Increased GH concentration measured by RIA has been reported in three other feline acromegalics with a necropsy-confirmed pituitary acidophil adenoma.^1,18,22 Finally, two additional reports documented increased GH levels in eight acromegalic cats that had a pituitary mass confirmed with contrast-enhanced CT scanning.^3,15 These findings suggest that GH measurements, when available, are an important component of the diagnostic strategy for acromegaly in cats.

The diagnostic utility of GH measurements may be improved by concurrent measurement of serum IGF-1, which serves as an indicator of serum GH levels over a 24-hour period.^1,7 The veterinary literature has documented increased serum IGF-1 concentrations in five cats with naturally occurring, necropsy-confirmed acromegaly.^1,2,16,17 Additionally, above-normal serum IGF-1 concentrations were documented in six diabetic cats suspected of having naturally occurring acromegaly based on consistent clinical signs, CT-confirmed pituitary masses, elimination of other differential diagnoses, and/or increased serum GH concentration.^1,15 Elliott et al. confirmed pituitary macroadenomas at necropsy in two insulin-resistant diabetic cats suspected of acromegaly, but it was unclear whether IGF-1, GH, or both were measured in these cats.¹⁵ Norman and Mooney found a normal serum IGF-1 concentration at initial presentation in one cat diagnosed with acromegaly, but an increased serum IGF-1 concentration was eventually documented in this animal.¹

Lewitt et al. recently published data suggesting that circulating serum IGF-1 concentrations may be increased in diabetic cats that do not exhibit clinical signs consistent with acromegaly.²¹ From this work, it was concluded that use of IGF-1 concentrations to screen for GH excess might be unreliable in diabetic cats. However, this report only examined eight diabetic cats and compared the results to only eight normal cats.²¹ Acromegaly was not definitively ruled out in these eight diabetic cats. Three of the eight diabetic cats had brain CT scans that failed to demonstrate a pituitary tumor, but GH was not measured in any animal.²¹ Drawing conclusions about the ability of IGF-1 to screen for GH excess when GH concentrations have not been measured is difficult. The report by Lewitt et al. does address, however, the need for further investigation of the use of different biochemical markers in the diagnostic pursuit of acromegaly.²¹

Current research has also focused on the use of other biochemical markers in the diagnosis of acromegaly.⁷ Insulin-like growth factor binding-protein-3 (IGFBP-3) is a heterodimeric, apparently GH-dependent, glycoprotein that binds IGF-1 and IGF-2 in circulation.^7,29 Initial assessment of this marker showed it is a fairly sensitive indicator of GH excess even in acromegalic humans who demonstrate GH suppression (i.e., <2 ng/mL after glucose administration).^7,21,29 Initial evaluation by Lewitt et al. indicated that the biochemical behavior of IGFBP-3 may be different in diabetic cats when compared to normal cats, so its utility in the diagnosis of feline acromegaly has yet to be determined.²¹ Further investigation of various biochemical markers in normal and abnormal GH physiology in small animals is needed.

Goals and Monitoring

Treatment of acromegaly presents the veterinarian with an even greater challenge than that offered by diagnosis, and the veterinary literature regarding treatment is sparse. Several treatment modalities in humans are reported, but the definition of “cure” is controversial.^7,30–34 The most appropriate way to treat this disease in cats has yet to be described. Attention should also be paid to how veterinarians measure response to treatment. Tracking of exogenous insulin requirements and glycemic control have been utilized as indicators of GH normalization in cats.^3,4 Perhaps a broader assessment should be sought and should include owner opinion of an animal’s quality of life, pituitary tumor size, serum IGF-1 concentrations, and serum GH concentrations. Abrams-Ogg et al. have reported increasing serum IGF-1 concentrations as a negative indicator of therapeutic response.¹⁶ Establishing a biochemical marker to facilitate surveillance of treatment success and disease progression is imperative.

Surgical Options

Abrams-Ogg, et al. reported on the application of trans-sphenoidal cryotherapy as treatment for a cat with a biopsy-confirmed GH-producing pituitary acidophil adenoma.¹⁶ The cat was clinically stable for several weeks postoperatively, but then developed severe neurological clinical signs (i.e., seizures, aggression, visual impairment, etc.).¹⁶ Cryoinjury to neural tissues surrounding the pituitary gland and neural damage secondary to hypoglycemia were suspected.¹⁶ The surgical approach most often utilized for affected humans is the trans-sphenoidal hypophysectomy or adenomectomy.^7,32 These procedures have not been evaluated in the cat.³⁵

Radiotherapy

Radiation therapy is used for human acromegalics when surgery is not an option, when there is extensive postoperative residual disease, or when clinical signs of acromegaly return despite surgical and/or medical intervention.³³ Efficacy of radiation therapy in humans is controversial.^34,36,37 A major disadvantage of radiotherapy is that it may take a considerable amount of time (months to years) before it is fully effective.^34,38

Reports on the use of radiation therapy for treatment of acromegaly in animals are rare. Goossens et al. reported on the use of Cobalt⁶⁰ radiotherapy in three diabetic, acromegalic cats diagnosed with pituitary tumors via CT scanning.³ After radiation therapy, all cats experienced a decrease in exogenous insulin requirement. Two cats had complete resolution of diabetes mellitus at 8 and 10 months, respectively.³ Plasma GH levels were measured in all cats at 5, 12, and 24 months, with two cats experiencing euglycemia having significant decreases in circulating GH. The cat that did not have resolution of its diabetes had an increase in circulating GH at 12 months.³ This same cat was diagnosed with renal insufficiency 4 months postradiation therapy, and its diabetes remained unregulated.³

Peterson et al. reported the use of Cobalt⁶⁰ radiotherapy in two diabetic acromegalic cats with pituitary tumors.⁴ A 50% reduction in tumor size was noted in one cat on CT scan 2 months after completion of the radiation protocol, and this cat experienced normalization of serum GH and a remission in insulin resistance.⁴ However, relapse of insulin resistance recurred 6 months postradiation. In the other cat of this report, an increase in serum GH concentration occurred, the tumor appeared larger on follow-up CT scanning, and insulin resistance persisted despite radiation therapy.⁴ Early results with new radiotherapy methods, such as gamma-knife excision, offer promising results in human acromegalics.^38,39 Gamma-knife is a type of stereotactic radiosurgery involving ionizing radiation from a Cobalt⁶⁰ source. The radiation is delivered by convergent collimated beams focused on a stationary point.⁴⁰ The result is a single dose of radiation that is sharply focused, potentially with less damage to surrounding tissues.⁴⁰ Long-term follow-up is still pending for these newer treatments.

Radiation may represent one of the most effective means of controlling acromegaly in cats, especially as new technologies become available. Many of the side effects reported in humans typically occur at a point in time far removed from the actual radiation treatment (i.e., years later).³⁸ Because the life span of the cat is significantly shorter than that of humans, it is possible that these side effects would only rarely develop in the cat. On the other hand, timely improvement may not be witnessed in cats because of the delayed effects of radiation therapy.

Medical Options

Medical options are available to control over-secretion of GH, and they are used in humans when surgery or radiation therapy is not possible, is contraindicated, or has failed.⁷ Dopamine agonists, somatostatin analogs, and GH receptor antagonists have all been used.^{2,5,7,11,19,40–45}

Abraham et al. treated an acromegalic cat with L-deprenyl (5 mg per os [PO] q 24 hours for 30 days, then 10 mg q 24 hours), a monoamineoxidase-B inhibitor that prolongs dopamine activity in the pituitary gland.² Facilitation of prolonged dopamine activity could, in theory, result in a clinical response similar to that seen in people being treated with dopamine agonists such as bromocriptine or cabergoline.² However, the cat in that report did not show any clinical improvement while taking L-deprenyl.² Serum IGF-1 levels were not measured, so it was uncertain whether L-deprenyl had any physiological effect. It was reported that the insulin requirements remained high and that the cat developed a severe degenerative arthropathy and became progressively weaker and more lethargic over a 9-month period, after which it was euthanized.² More research is needed to better understand the role, if any, that L-deprenyl has in the treatment of feline acromegaly.

Reubi and Landolt demonstrated the presence of somatostatin receptors in the pituitary adenomas of humans.⁴⁶ Octreotide and lanreotide are the most widely used somatostatin analogs in the treatment of acromegaly in humans.⁴⁰ These drugs inhibit GH secretion and lower levels of circulating IGF-1.⁴⁷ Between 70% and 90% of humans reportedly respond to these drugs and achieve some control of GH secretion.^7,40,41 Additionally, alleviation of soft-tissue clinical signs associated with acromegaly occurred in as many as 90% of treated cases.^7,41,48 Even under the scrutiny of more stringent “cure” definitions (i.e., normalization of IGF-1 levels), somatostatin analogs are successful in people. Some reports indicate that as many as 47% to 60% of treated humans achieve normal IGF-1 levels on these drugs.^7,40

Use of octreotide has been reported in only a small number of cats, but unfortunately, it appeared to have no therapeutic effect.^4,5 Peterson et al. administered octreotide (5 to 10 μg, subcutaneously [SC] q 12 hours) to two cats that had previously undergone radiotherapy and found no decrease in serum GH concentrations.⁴ Similarly, Morrison et al. failed to see a response in serum GH concentrations of an acromegalic cat treated with octreotide (100 μg, SC q 12 hours).⁵

Although initial use of octreotide in feline acromegaly has not been rewarding, further investigation is warranted. There are several theories as to why these cats may not have responded. Perhaps dosing was inappropriate, or perhaps feline tumors do not express the appropriate receptors required for successful drug action. A subset of human patients have tumors that do not express somatostatin receptors, and these patients do not respond to treatment with somatostatin analogs.^2,4,43 It is tempting to think that newer, long-acting somatostatin analogue preparations may offer a more reliable means of delivering these potentially useful drugs to acromegalic cats, but their use has not been investigated to date.

Pegvisomant is a genetically engineered analogue of human GH that binds to peripheral GH receptors, rendering the receptors unresponsive to endogenous GH.^19,40,42,44 This novel treatment leads to a decrease in IGF-1 production in tissues responsive to GH, resulting in alleviation of anabolic clinical signs or those signs caused by increased circulating IGF-1 concentration.^19,40,42 Preliminary reports show that 98% to 100% of humans given daily injections SC experienced a reduction in serum IGF-1 concentration.^44,45 Investigation is necessary to determine the role pegvisomant might have in the treatment of feline acromegaly, as the drug has not been evaluated in cats.