Extralabel use of cabergoline in the treatment of a pituitary adenoma in a rat

Jörg Mayer Department of Clinical Sciences, Foster Hospital for Small Animals, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.

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Amy Sato Department of Clinical Sciences, Foster Hospital for Small Animals, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.

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Matti Kiupel Department of Pathobiology and College of Veterinary Medicine, Diagnostic Investigation and Diagnostic Center for Population and Animal Health, Michigan State University, Lansing, MI 48910.

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Julie DeCubellis Department of Clinical Sciences, Foster Hospital for Small Animals, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.

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Thomas Donnelly Department of Clinical Sciences, Foster Hospital for Small Animals, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536.

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Abstract

Case Description—A 0.65-kg (1.43-lb) 24-month-old sexually intact male albino pet rat was examined because of a 3-week history of hypodipsia, apparent blindness, and sudden change in behavior.

Clinical Findings—The rat was able to move around its cage but appeared unaware of its surroundings, was visually unresponsive, and seemed unusually aggressive. The rat's hind limbs appeared mildly paretic, and it had sporadic difficulty placing its hind limbs on a flat surface. Given the rat's age, history, and physical examination findings, the primary differential diagnosis was a pituitary tumor. Magnetic resonance imaging (MRI) of the rat's brain was performed and revealed a large pituitary mass, which was indicative of a tumor.

Treatment and Outcome—Cabergoline (0.6 mg/kg [0.27 mg/lb], PO, q 72 h) was administered. On follow-up MRI 2 months later, the pituitary mass had substantially decreased in size. For 6 months following the second MRI study, the rat continued to receive the same dosage of cabergoline and had no clinical signs of disease or unusual behavior. However, at 8.5 months after the start of the treatment, the rat was in poor condition and had clinical signs similar to those initially. A third MRI study was performed and revealed substantial regrowth of the mass. The rat was euthanized and a necropsy was performed; a histopathologic diagnosis of pituitary adenoma was made.

Clinical Relevance—Pituitary adenomas have long been recognized as a common finding in geriatric rats (> 18 months old). Affected rats may respond favorably to oral administration of cabergoline.

Abstract

Case Description—A 0.65-kg (1.43-lb) 24-month-old sexually intact male albino pet rat was examined because of a 3-week history of hypodipsia, apparent blindness, and sudden change in behavior.

Clinical Findings—The rat was able to move around its cage but appeared unaware of its surroundings, was visually unresponsive, and seemed unusually aggressive. The rat's hind limbs appeared mildly paretic, and it had sporadic difficulty placing its hind limbs on a flat surface. Given the rat's age, history, and physical examination findings, the primary differential diagnosis was a pituitary tumor. Magnetic resonance imaging (MRI) of the rat's brain was performed and revealed a large pituitary mass, which was indicative of a tumor.

Treatment and Outcome—Cabergoline (0.6 mg/kg [0.27 mg/lb], PO, q 72 h) was administered. On follow-up MRI 2 months later, the pituitary mass had substantially decreased in size. For 6 months following the second MRI study, the rat continued to receive the same dosage of cabergoline and had no clinical signs of disease or unusual behavior. However, at 8.5 months after the start of the treatment, the rat was in poor condition and had clinical signs similar to those initially. A third MRI study was performed and revealed substantial regrowth of the mass. The rat was euthanized and a necropsy was performed; a histopathologic diagnosis of pituitary adenoma was made.

Clinical Relevance—Pituitary adenomas have long been recognized as a common finding in geriatric rats (> 18 months old). Affected rats may respond favorably to oral administration of cabergoline.

A 0.65-kg (1.43-lb; body condition score, 7/9) 24-month-old sexually intact male albino pet rat was admitted to the veterinary teaching hospital of the Tufts Cummings School of Veterinary because of a 3-week history of hypodipsia, apparent blindness, and sudden change in behavior. The rat was kept alone in a 2-tier pet rat cage and fed a commercial pet rodent diet of approximately 40 g daily, with minor additions of fresh fruit, vegetables, and yogurt drops as an occasional treat. Although the rat was still eating, the owner reported neither seeing the rat drink for several days nor noticing any change in the level of water in the water bottle. When the owner tried to pick up the rat, it suddenly became aggressive and tried to bite.

On physical examination, the rat was mildly overweight. The rat was able to move freely around its travel cage; however, the rat's behavior was unusual and it appeared unaware of its surroundings, would suddenly freeze in motion, and seemed likely to attack if handled. For neurologic examination, the rat was placed on a nonslip surface examination table; the rat appeared mildly paretic in the hind limbs and, on proprioceptive testing, had occasional difficulties placing its hind limbs on the flat surface of the table. On visual testing, the rat did not respond to a menace reflex test in either the left or right eye, did not squint when a bright light was placed in front of both eyes (ie, negative dazzle response), and did not venture near the edge of an upturned cage upon which it was placed (ie, negative sloping obstacle test result). These clinical findings were in agreement with the owner's impression that the rat was blind. Slit-lamp biomicroscopy and indirect ophthalmoscopy were not performed to avoid further stress.

On the basis of the neurologic and visual deficits, the behavioral changes, and the rat's age, the primary differential diagnosis was a brain tumor, as trauma was not mentioned in the history. The most common brain tumor to consider in a 2-year-old rat is a pituitary tumor. To investigate the problem further, MRI of the brain was scheduled. The rat was anesthetized with sevoflurane via a face mask with 8% sevoflurane used for induction and 3% sevoflurane used for maintenance. Magnetic resonance imaging was performed by use of a 1.5-T scanner.a Sagittal and transverse T1-weighted spin-echo and T2-weighted turbo spin-echo images of the brain were obtained. Postcontrast T1-weighted transverse, sagittal, and dorsal plane images were obtained following administration of gadopentetate dimeglumineb at 0.1 mmol/kg (0.045 mmol/lb) via a catheter placed IV into the lateral tail vein. A large 11.4 × 8.6 × 8.3-mm (814-mm3) inhomogeneous and poorly enhancing mass was present in the region of the pituitary gland (Figure 1). The mass was slightly more than half the length of the brain. A hypointense rim was noted on both the T1-weighted and T2-weighted images, compatible with the presence of hemosiderin from previous hemorrhage. The mass caused peripheral displacement of the surrounding brain tissue such that the ventrocaudal margin of the cerebellum was near the foramen magnum.

Figure 1—
Figure 1—

MidsagittalT2-weighted MRI scans of the pituitary gland of a rat with a macroadenoma (asterisk). Images were obtained at the time of diagnosis (A) and 2 months (B) and 8.5 months (C) after initiation of treatment with cabergoline. The mass is inhomogeneous with a hypointense rim suggestive of hemosiderin deposition. The ventrocaudal margin of the cerebellum is located near the foramen magnum on the initial study (arrowhead).

Citation: Journal of the American Veterinary Medical Association 239, 5; 10.2460/javma.239.5.656

Treatment with cabergolinec (0.6 mg/kg [0.27 mg/lb], PO, q 72 h) was begun. As there is no commercially available cabergoline preparation for oral administration in rats, the drug was obtained from a compounding pharmacyc for extralabel use; cabergoline was compounded as a suspension for oral administration at a concentration of 2 mg/mL. The rat was discharged from the hospital the day after MRI. The owner reported that, 3 days after the first cabergoline treatment, the rat appeared able to see a hand approaching its cage and that the rat was less aggressive.

Eight weeks later, the rat was returned for a follow-up examination including another MRI study. The owner reported substantial improvement in the rat's condition, including a return to its previous friendly behavior and an increase in physical activity. On clinical examination, the rat appeared inquisitive. The rat had a normal gait and on proprioceptive testing consistently placed its hind limbs on the flat surface of the table. Visual testing revealed a positive menace reflex, positive dazzle response, and the ability to walk along an edge without falling down (ie, positive sloping obstacle test response).

The rat was anesthetized again as during the first MRI study. The second MRI study was performed similarly to the first but also included a transverse T2*-weighted gradient echo sequence. In this study, the pituitary tumor had substantially decreased in size (Figure 1). The tumor measured 8.4 × 6.7 × 5.9 mm (332 mm3), corresponding to 41% of the original volume, and the cerebellum was no longer near the foramen magnum. The mass had a large hemorrhagic component as indicated by the signal void seen on the gradient echo sequence (not shown).

For 6 months following the second MRI study, the rat continued to receive the same dosage of cabergoline and had no signs of clinical abnormalities or unusual behavior on regular recheck examinations. At 6.5 months (about 8.5 months after the start of the cabergoline treatment), the rat was admitted for a recheck examination and reevaluation of the pituitary mass. However, this time the rat was in poor condition and had clinical signs that were similar to those at the time of initial admission. The rat was paralyzed in the hind limbs but appeared able to see as evidenced by a positive menace reflex and positive dazzle response. The coat was rough, and the rat had lost about one-quarter of its body weight (from 650 to 500 g [1.4 to 1.1 lb]). Signs of respiratory distress were present. A third MRI study was performed, and substantial regrowth of the mass was evident. The mass measured 9.1 × 8.0 × 7.3 mm (531 mm3), which was an increase in volume of 63% from the second MRI study (Figure 1). Because of advanced age (32.5 months old) and the poor condition of the rat, the rat was euthanized and a necropsy was performed.

Necropsy findings confirmed the clinical diagnosis of a pituitary tumor; there were no other noteworthy lesions. Sections of fixed tumor tissue were stained with H&E, and by use of light microscopy, it was determined the tumor was composed of cells arranged predominantly in cords, with a few focal solid areas. A histopathologic diagnosis of pituitary adenoma was made. Sections of the pituitary adenoma were submitted to the Tufts Medical Center in Boston for prolactin immunohistochemical staining. Additional sections of the tumor were submitted to the Diagnostic Center for Population and Animal Health at Michigan State University for follicle-stimulating hormone, adreno-corticotropin, thyroid-stimulating hormone, melanocyte-stimulating hormone, and growth hormone immunohistochemical staining.

On immunohistochemical evaluation, the adenoma stained strongly positive for prolactin. Throughout the adenoma-anterior pituitary lobe, there were moderate numbers of cells that had positive staining results for adrenocorticotropin and growth hormone; these cells focally rimmed nodular aggregates of prolactin-positive neoplastic cells. Growth hormone-positive neoplastic cells (that were also prolactin-positive) were interspersed throughout the prolactin neoplastic cell population. All neoplastic cells had negative staining results for follicle-stimulating hormone, thyroid-stimulating hormone, and melanocyte-stimulating hormone. On the basis of immunohistochemical staining results, the pituitary adenoma was classified as a bimorphous prolactin-growth hormone producing pituitary adenoma.

Discussion

Pituitary adenomas are a common clinical and necropsy finding in geriatric rats.1–8 The percentage of affected rats varies depending on factors such as age and sex; these types of factors should be considered when comparing the results among studies. However, in Sprague-Dawley and Fisher strains of rats that were > 24 months old, prevalences of pituitary adenomas were reported as 85% and 83%, respectively.7,9

In geriatric rats, prolactin secretion is increased and manifested by high blood prolactin concentrations in both sexes. This change is due to a reduction of hypothalamic dopamine activity. Prolactin secretion by lactotrophs is unique, compared with secretion of other pituitary hormones, as there are no specific prolactin hypophysiotropic hormones or releasing factors. Rather, prolactin secretion is inhibited by dopamine. Although other factors of hypothalamic origin such as thyrotropin-releasing hormone or several neuropeptides can modulate prolactin secretion, none appear to be a major determinant of prolactin secretion.10–12 The escape from hypothalamic inhibitory control leads to lactotroph hyperplasia of the pituitary gland and a high rate of prolactin-producing pituitary adenomas in geriatric rats.9,13

On light microscopic examination, most prolactin-producing pituitary adenomas of rats contain large spaces filled with RBCs. Large tumors have areas of focal necrosis and macrophage infiltrates. On the basis of staining affinities, pituitary adenomas have been classified as chromophobic, acidophilic, basophilic, or mixed. Hormone content as demonstrated by immunohistochemical staining and ultrastructural features of adenoma cells allows for classification that reflects cellular composition and endocrine activity. For the rat of this report, the classification system used was based on results obtained from Sprague-Dawley rats in which immunocytochemical and ultrastructural correlations were performed.4,9,14 Almost all known adenohypophysial hormones have been immunocytochemically identified. Prolactin-producing pituitary adenomas are the most common, followed by gonadotroph cell adenomas and immunonegative adenomas; mixed prolactin and growth hormone–producing adenomas also have been described4,9,14

Two types of prolactin-producing pituitary adenomas are recognized in rats.4,9,14 The more common prolactin-producing pituitary adenoma is described as a sparsely granulated adenoma. They are chromophobic, slightly acidophilic, and most often hemorrhagic. In contrast, the densely granulated acidophilic prolactin-producing pituitary adenoma is rare. Although the pituitary adenoma of the rat of this report stained strongly positive for prolactin, some cells had positive immunohistochemical stain results for both prolactin and growth hormone. Therefore, a prolactin-producing pituitary adenoma was discounted as the final diagnosis for the rat of this report.

Chromophobic or acidophilic, mixed prolactin and growth hormone–producing adenomas have a solid pattern with extravascular pools of RBCs, especially in large tumors. Mitotic figures are common. Two types of mixed prolactin and growth hormone–producing adenomas are described.4,9,14 Monomorphous pituitary adenomas are composed of cells immunoreactive for both prolactin and growth hormone. In contrast, bimorphous pituitary adenomas have predominantly immunoreactive cells only for prolactin, but some cells contain both growth hormone and prolactin. Ultrastructurally, 2 types of cells are recognized, which was true for the rat of this report. There are sparsely granulated prolactin cells, as seen in prolactin-producing pituitary adenomas, as well as densely granulated cells, which correspond to the cells immunoreactive for both growth hormone and prolactin.

Vannevel6 described the clinical signs and physical examination findings of 5 pet rats with pituitary adenoma confirmed at necropsy. Typically, affected rats have signs of central vestibular disease, characterized by a wide-based stance, head tilt, proprioceptive deficits, ataxia with normal muscle strength, knuckling, and stumbling.6 The rat of the present report had proprioceptive and visual deficits that were reversed with shrinkage of the pituitary tumor. The blindness seen initially in the rat of this report is typical of optic nerve compression. Although retinal degeneration, corneal dystrophy, and cataracts are common morphological changes in the aging rat eye, they are more typically associated with impaired vision.15

The hypodipsia observed initially in the rat of this report was typical of hypodipsic hypernatremia syndrome, an uncommon disorder of water and sodium homeostasis reported clinically for humans,16 dogs,17 a cat,18 and a horse19 with hypothalamic space-occupying lesions. Since the early 1970s, experimentally induced lesions in the dorsomedial hypothalamic nucleus of rats have been known to cause hypodipsia.20 Adipsia or hypodipsia and subsequent hypernatremia result from dysfunction of specialized hypothalamic neurons (osmostats) located along the anterior wall of the third ventricle. These cells respond to small changes in plasma osmolality by affecting the release of antidiuretic hormone from the neurohypophysis and stimulating the sensation of thirst.21 As practitioners see more geriatric rats, it will be interesting to observe whether hypodipsia is reported for rats with space-occupying brain lesions or hypothalamic defects.

Findings on MRI of the pituitary gland have been reported for rats with experimentally induced prolactinomas.22–25 Although a high-resolution computed tomography scanner might also be effective in detecting large pituitary lesions, its relatively poor contrast resolution may hamper detection of small pituitary adenomas. For MRI, 2-mm-wide, midsagital images of the brain are the most helpful for detecting pituitary gland enlargement in rats.22,24 In 1 study22 of rats with experimentally induced tumors, the first indication of pituitary gland enlargement on MRI (ie, rounding of the cranial aspect of the normally triangular gland) coincided with the development of increased prolactin concentrations in plasma. Similar to the MRI observations for the rat of this report, experimentally induced prolactinomas in rats are heterogeneous in intensity with variable amounts of hemorrhage and nonuniformity in contrast enhancement.24

Hemorrhage or infarction of the pituitary gland (ie, pituitary apoplexy), can be an acute clinical syndrome in patients with a pituitary adenoma, usually a macroadenoma. Although usually spontaneous, pituitary hemorrhage has been associated with bromocriptine and cabergoline use in human patients.26 A hemorrhagic appearance of the pituitary gland is frequently seen in rats with large spontaneous tumors that are < 10 mm in diameter.1,5,7,27 In the report by Vannevel,6 2 of 5 rats with pituitary adenomas had substantial pituitary hemorrhage found on necropsy. In the rat of the present report, evidence of previous hemorrhages in the area of the pituitary gland was observed on the initial MRI scan that preceded administration of cabergoline.

No report of effective treatment for pituitary adenomas in pet rats has been previously published. Pet rats that have clinical signs suggestive of a pituitary tumor are often euthanized because of the poor prognosis. Cabergoline, a dopamine receptor agonist that increases hypothalamic dopamine activity, is not approved in the United States for veterinary use. However, it is available as an FDA-approved human medication.d In Europe, cabergoline is available as a veterinary-approved drug.e In humans, cabergoline is used as a second-line agent in the management of prolactinomas when bromocriptine is ineffective. When compared with administration of bromocriptine to animals, cabergoline has greater dopamine receptor specificity, a longer duration of action, and less of a tendency to cause vomiting.28 Cabergoline appears to be a safe drug, as adverse effects are minimal and absorption following oral administration provides prolonged blood concentrations of drug. Researchers have looked at the effect of cabergoline on prolactin secretion and prolactinoma growth in female rats with pituitary adenomas induced by long-term administration of high doses of estrogens.29,30 The administration of cabergoline resulted in a marked and sustained decrease in prolactin secretion and counteracted the development of the prolactinoma in rats under experimental conditions, as judged by the weight of the pituitary gland at necropsy.29,30

For the rat of this report, cabergoline was administered in preference to bromocriptine for several reasons. The dosing interval of cabergoline at every 72 hours, compared with every 24 hours for bromocriptine, is established and minimally stressful for the animal.29,30 Cabergoline was compounded at a concentration of 2 mg/mL, so the rat received 0.2 mL of cabergoline suspension every 72 hours, a dosing regimen likely to achieve higher client compliance than a more frequently dosed drug. According to the compounding pharmacy,c and in accordance with manufacturer's instructions, a suspension of cabergoline diphosphate is stable at room temperature (approx 25°C). Furthermore, banana-apple flavoring of the suspension was chosen because it was pH neutral. In contrast, a suspension of bromocriptine mesylate must be refrigerated, and consequently, shelf life and stability of bromocriptine mesylate suspension were a concern. To avoid this problem, bromocriptine is typically administered SC to animals in research studies.30 Cabergoline also offers considerable advantages over bromocriptine in terms of drug efficacy.31 In humans, the decrease in prolactin secretion was significantly greater with cabergoline treatment than with bromocriptine treatment (93% decrease vs 87.5% decrease, respectively) and normalization of blood prolactin concentrations was greater with cabergoline than with bromocriptine.32 Approximately 24% and 11% of human patients are resistant to treatment with bromocriptine and cabergoline, respectively.33

Because of the limited remaining treatment options, advanced age, and eventual poor condition of the rat of this report, it was ultimately euthanized. However, this is the first reported case of the use of cabergoline to treat successfully an in vivo–documented pituitary adenoma in a pet rat. Magnetic resonance imaging proved to be the diagnostic imaging modality of choice to detect the pituitary adenoma. Cabergoline administered at a dosage of 0.6 mg/kg PO every 72 hours was safe and temporarily effective in controlling the clinical signs associated with pituitary macroadenomas in rats.

ABBREVIATION

MRI

Magnetic resonance imaging

a.

MAGNETOM Symphony, Siemens Medical Solutions USA Inc, Malvern, Pa.

b.

Magnevist, Bayer HealthCare Pharmaceuticals Inc, Wayne, NJ.

c.

Cabergoline suspension (2 mg/mL), Hopkinton Drug Inc, Hopkinton, Mass.

d.

Dostinex, Pfizer, New York, NY.

e.

Galastop, Pharmacia & Upjohn, Milan, Italy.

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  • Figure 1—

    MidsagittalT2-weighted MRI scans of the pituitary gland of a rat with a macroadenoma (asterisk). Images were obtained at the time of diagnosis (A) and 2 months (B) and 8.5 months (C) after initiation of treatment with cabergoline. The mass is inhomogeneous with a hypointense rim suggestive of hemosiderin deposition. The ventrocaudal margin of the cerebellum is located near the foramen magnum on the initial study (arrowhead).

  • 1. Coleman GL, Barthold W, Osbaldiston GW, et al. Pathological changes during aging in barrier-reared Fischer 344 male rats. J Gerontol 1977; 32: 258278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Sass B, Rabstein LS, Madison R, et al. Incidence of spontaneous neoplasms in F344 rats throughout the natural life-span. J Natl Cancer Inst 1975; 54: 14491456.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3. Kroes R, Garbis-Berkvens JM, de Vries T, et al. Histopathological profile of a Wistar rat stock including a survey of the literature. J Gerontol 1981; 36: 259279.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4. McComb DJ, Kovacs K, Beri J, et al. Pituitary gonadotroph adenomas in old Sprague-Dawley rats. J Submicrosc Cytol 1985; 17: 517530.

  • 5. Suzuki H, Mohr U, Kimmerle G. Spontaneous endocrine tumors in Sprague-Dawley rats. J Cancer Res Clin Oncol 1979; 95: 187196.

  • 6. Vannevel JY. Clinical presentation of pituitary adenomas in rats. Vet Clin North Am Exot Anim Pract 2006; 9: 673676.

  • 7. Burek JD. Pathology of geriatric rats: a morphological and experimental study of the age-associated lesions in aging BN/Bi, WAG/Rij, and (WAG × BN)F b1 s rats. West Palm Beach, Fla: CRC Press, 1978.

    • Search Google Scholar
    • Export Citation
  • 8. McComb DJ, Hellmann P, Kovacs K, et al. Spontaneous sparsely-granulated prolactin-producing pituitary adenomas in geriatric rats. A prospective study of the effect of bromocriptine. Neuroendocrinology 1985; 41: 201211.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9. McComb DJ, Kovacs K, Beri J, et al. Pituitary adenomas in old Sprague-Dawley rats: a histologic, ultrastructural, and immunocytochemical study. J Natl Cancer Inst 1984; 73: 11431166.

    • Search Google Scholar
    • Export Citation
  • 10. Sun B, Fujiwara K, Adachi S, et al. Physiological roles of prolactin-releasing peptide. Regul Pept 2005; 126: 2733.

  • 11. Galas L, Raoult E, Tonon MC, et al. TRH acts as a multifunctional hypophysiotropic factor in vertebrates. Gen Comp Endocrinol 2009; 164: 4050.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Samson WK, Taylor MM, Baker JR. Prolactin-releasing peptides. Regul Pept 2003; 114: 15.

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