Pituitary Tumor

Definition

Pituitary tumor: an abnormal growth in the pituitary gland, the part of the brain that regulates the body’s balance of hormones.

Clinical Signs

May see any combination of the following:

Mechanical disturbances

Ataxia (lack of coordinated movement in limbs) with normal muscle strength.
Gradual weakness hind limbs, wide-based stance, knuckling, stumbling.
Stiffness or inability to flex forelimbs that may gradually progress to the hind limbs as the tumor continues to grow.
Unequal pupil size in one eye compared to the other. This may appear as blown/dilated pupil due to pressure or bleeding behind the eye.
Blindness as a result of optic nerve compression.
Circling, head tilt, seizures, hydrocephalus.
Head pressing/Head bumping. This sign may be present when there is increased intracranial pressure (rat may bump head up when petted, or extend head pressing against a fixed surface).
*Note: this sign should not be confused with normal attention-getting behavior. It is more often seen late in the disease process, and by itself should not be the basis for diagnosis of pituitary tumor!
Difficulty holding food when eating.
A behavioral change (e.g., becomes aggressive).
Clinical signs and death may seem sudden to the owner even though manifestation is often gradual.

Hormonal disturbances

Lactation (ejection of milk) in aged non-pregnant female
Decreased fertility
Thinning skin
Weight loss
Excessive thirst (need to refill water bottles more than usual)
Excessive excretion of very dilute urine
Hypodypsia, an abnormally decreased amount of fluid intake, by the rat, due to possible hypothalamic space-occupying lesions. *Note: in the presence of hypodypsia, the excretion of urine will be diminished.
Dehydration

Although, apparently not common, incidental findings of a pituitary tumor in male rats have been observed where no clinical signs presented.

Finally unilateral proptosis (one eye protruding more than the other) although sometimes present in humans with a pituitary tumor is not a sign commonly associated in rats, and if present may suggest a coexisting disease process such as: a retrobulbar abscess or a retrobulbar tumor.

*Note: for information on recognizing various signs of pain or discomfort refer to: Signs of Pain In Rats.

Etiology

The pituitary gland, also known as the hypophysis or formerly known as the master gland, is a small endocrine gland that stimulates and controls hormone production of other endocrine glands. These glands, in turn, regulate a variety of body processes such as metabolic activity, reproduction and growth. Endocrine glands expel their secretions directly into the blood, as opposed to exocrine glands such as sweat glands.

In rats the pituitary gland is divided into the adenohypophysis (anterior lobe or pars distalis), the intermediate lobe (pars intermedia), and the neurohypophysis (posterior lobe or pars nervosa). It is situated in a bony cavity at the base of, and below the brain, and is connected to the hypothalamus by the pituitary stalk, also referred to as the hypophyseal stalk. The hypothalamus is that region of the brain that, in large part, controls or modulates the activity of the pituitary gland.

Studies show that the pituitary gland growth in female rats and male rats differs at around 6-7 weeks of age, at which time the pituitary gland in the female becomes heavier and increases in size. The difference increases even more as the female ages.
In addition, normal hyperplastic (overgrowth of normal cells) changes that occur to the pituitary gland in aged rats often show no evidence of compression of surrounding tissue, unlike that which can occur with adenomas or carcinomas.

Adenomas are tumors of glandular tissue. Pituitary tumors, often benign adenomas, are slow-growing tumors. Many of these tumors arise in the anterior lobe of the pituitary gland.

Pituitary adenomas can vary in size and are often differentiated as microadenomas (small nodules) or macroadenomas (sometimes ranging greater than 10mm in diameter). Both microadenomas and macroadenomas can be further differentiated as space-occupying non-hormone secreting adenomas, or hormone-secreting adenomas.

It has been shown that of the pituitary adenomas, prolactin-producing tumors called prolactinomas primarily composed of lactotrophs (type of cell that stains well in acidic media) are among the more common pituitary tumors found in geriatric rats, often female rats between 13 and 24 months of age. This may be as a result of the normally increased prolactin secretion in geriatric rats as seen by higher concentration levels of prolactin in the blood. The reason for this change in prolactin levels, in geriatric rats of both sexes, is due to a reduction of hypothalamic dopamine activity.¹

Prolactinomas can be chromophobic (type of cell that does not readily stain in media) which is a sparsely granulated, slightly acidophilic and often hemorrhagic adenoma, or eosinophilic which is more densely granulated and acidophilic. The latter is not commonly seen in rats. Other types of pituitary adenomas rarely seen are gonadotroph cell adenomas, immunonegative adenomas, mixed prolactin and growth hormone–producing adenomas.¹

It has been noted in studies that previously bred females, as well as spayed (more specifically ovariectomy) females tend to show a decreased rate of pituitary tumors sensitive to estrogen (e.g., prolactinomas).

While pituitary tumors do not seem as prevalent in male rats, they can and do occur.

Even though the majority of pituitary tumors are often benign in rats, and do not metastasize to other areas of the body, some can grow large enough to compress nearby brain tissue. This compression of tissue can produce mechanical disturbances (such as listed above in the Clinical Signs section).

Pituitary tumors can also produce signs of hormonal disturbances when they secrete excess hormones or cause an insufficient amount of hormone to be secreted. Examples of this are:

Lactation in an aged non-pregnant female rat with a prolactin-secreting/lactotroph (prolactinoma) tumor.
Cushing’s syndrome seen in tumors producing excess ACTH (adrenocorticotropic hormone), in rats, such as: decreased fertility, thinning skin, and weight loss.
Central Diabetes Insipidus resulting from a deficiency of vasopressin/ADH (antidiuretic hormone) release from the posterior lobe.

*Note: clinical signs can reflect a combination of both mechanical and hormonal disturbances depending on the type of tumor present.

Though the cause of pituitary tumors remains elusive, factors that may play a role in their development in rats include:

Age
Genetic factors
Diet (incidence of pituitary tumors shown to increase where high-calorie ad libitum (free-fed) diets are given)
Breeding history
Infections
Injury

While pituitary carcinomas (cancer) are rare findings in rats, leading to the speculation that death occurs due to compression of the brain before progression of the tumor can occur to other sites, the prognosis for rats suspected of having, or diagnosed as having a benign pituitary adenoma, can be just as grave. Just the location of the tumor and the pituitary gland alone make them inoperable, in rats. However, in recent years, prolactin-inhibiting, dopamine receptor agonists, such as cabergoline or bromocriptine that have the ability to shrink some hormone producing tumors have been offering promising results for the pet rat, when begun early in the disease process. When used in conjunction with corticosteroids (that help reduce tissue swelling) the quality of life may be extended for a few additional months until such time that euthanasia may be required.

It is worth mentioning that, although it is not a common finding in rats, carcinomas of different histological types have been found to metastasize from other areas to the pituitary.

Figures

Pituitary Tumors In Rats

Pituitary tumor case histories

Fig. 1: Neurologic changes related to pituitary tumor in 16-month-old female rat (Maya). Shows videos and photos.
Fig. 2: Neurologic changes related to pituitary tumor in 15-month-old female rat (Ariel). Shows videos and photos.
Fig. 3: Pituitary tumor in 18-month-old male rat (Jecht). *Note: graphic photos.
Fig. 4: Pituitary Tumor in a 25-month-old female rat (Jemma). *Note: graphic photos.

Anatomy, Overview, and Diagram of the rat pituitary gland

Fig. 1: Diagram of Pituitary gland and functions.
Fig. 2: Pituitary gross anatomy (normal and neoplastic). *Warning: necropsy photos are extremely graphic.*
Fig. 3: Pituitary tumor overview. *Warning: necropsy photos extremely graphic.*

Diagnostics

Obtain history from pet owner. Observe for clinical signs that may indicate presence of tumor.

Wheelbarrow test (https://www.ivis.org/). May indicate central nervous system deficit if rat is unable to move forelimbs normally when hind limbs are elevated by base of tail near the rump.

Presence of head pressing/ head bumping.

Blood sampling for hormone levels may determine type of hormone-producing tumor, but may only be pertinent if normal values are known.

If x-ray of skull taken, and enlargement of the sella turcica can be determined, suspect pituitary mass.

MRI, where available and if deemed prudent.

Since in the majority of times pituitary adenomas, in rats, can only be confirmed upon necropsy, assess clinical signs for presence of possible pituitary tumor formation and initiate treatment for palliative care.

Histology of tissue upon necropsy.

Upon necropsy, pituitary adenomas can be found to vary in size. Margins may be well-defined, and hemorrhaging may also be present.

Treatment

Recommended treatment is geared for comfort and the reduction of clinical signs, and may include the following:

Cabergoline or bromocriptine, dopamine receptor agonists, that inhibit prolactin secretion; thereby reducing circulating prolactin in the blood stream and reducing tumor size. Depending on when initiated in the disease process may extend life/quality time from 3-6 months.
Since it has been shown that significant shrinkage of the tumor may take a number of weeks following the initiation of a dopamine receptor agonist; the veterinarian may wish to treat with a corticosteroid (e.g., dexamethasone or prednisone or prednisolone) on a more extended reduction schedule to address brain swelling, until tumor reduction is significant enough to alleviate clinical signs.¹¹^,¹²^,¹³
*Note: a corticosteroid may also be given as a stand-alone agent where end stage palliative comfort for the rat is required or desired.

In the event long-term corticosteroid (e.g., prednisone, prednisolone, or dexamethasone) therapy is instituted, given the commonality of chronic mycoplasma infections in the pet rat population, it is advised to consider including broad-spectrum antibiotics such as Baytril and doxycycline.

For information on the medication listed above for recommended treatment see: Rat Medication Guide.

For information on seizures see: Seizure article in the Rat Guide Health section.

For information on hydrocephalus see: Hydrocephalus article in the Rat Guide Health section.

Euthanasia should be considered if the rat’s clinical signs preclude comfort and quality of life.

Nursing Care

Give medications as prescribed.
Provide a safe environment.
If mobility is impaired, or if seizures develop, provide a one level cage with soft bedding/litter.
Prevent dehydration and weight-loss. Keep food and water within easy reach.
Provide additional food and fluid supplements if appetite is poor. If rat is unable to grasp and hold food, assist. If chewing becomes difficult, offer easy-to-chew foods.
Assist with grooming if rat is not able to do so.

Outcome

Comfort, mobility, and quality of life helped with medications prescribed.
Emotional support for those having to consider euthanasia for their rat.

Prevention

Offering a diet that is nutritiously low in fat, calories, amines and nitrates, is recommended, (example: Harlan 2014 rat block, https://www.envigo.com/teklad).
Because some pituitary tumors, like some mammary tumors, are believed to be estrogen-induced (as a result of increased prolactin secretion), it is believed that spaying female rats can reduce their chance of incidence (Hanson, n.d.). The benefit versus risk of spaying female rats remains controversial. It is important to discuss this option thoroughly with a veterinarian familiar with rats.

References

Mayer, J., Sato, A., Kiupel, M., DeCubellis, J., & Donnelly, T. (2011). Extralabel use of cabergoline in the treatment of a pituitary adenoma in a rat. J Am Vet Med Assoc., 239(5), 656-60.
Allen, D., Mitchner, N., Uveges, T., Nephew, K., Khan, S., & Ben-Jonathan, N. (1997). Cell-Specific Induction of c-fos Expression in the Pituitary Gland by Estrogen. Endocrinology, 138 (5): 2128. Retrieved November 11, 2008, from http://endo.endojournals.org/cgi/content/full/138/5/2128.
Cracchiolo, D., Swick, J., McKiernan, L., Sloan, E., Raina, S., Sloan, C., & Wendell, D. (2002). Estrogen-dependent growth of a rat pituitary tumor involves, but does not require, a high level of vascular endothelial growth factor. Exp Biol Med (Maywood), 227(7), 492-9. Retrieved November 11, 2008, from http://www.ebmonline.org/cgi/content/full/227/7/492.
Dungworth, D., Mohr, U., & Capen, C. (1993). Pathobiology of the Aging Rat, Vol. 2. Washington DC: Intl Life Sciences Inst.
Hanson, A. (2003). Tumors and Spaying. Retrieved November 11, 2008, from http://www.ratbehavior.org/TumorSpaying.htm.
Sandusky, G., Van Pelt, C., Todd, G., & Wightman, K. (1988). An immunocytochemical study of pituitary adenomas and focal hyperplasia in old Sprague-Dawley and Fischer 344 rats. Toxicol Pathol, 16(3), 376-80. Retrieved November 12, 2008, from http://www.ncbi.nlm.nih.gov/pubmed/3194659?dopt=Abstract
Suckow, M., Weisbroth, S., & Franklin, C. (2006). The Laboratory Rat, 2nd Edition. Toronto: Academic Press.
Thamburaj, A. (n.d.). Pituitary adenomas. Retrieved November 12, 2008, from http://www.thamburaj.com/pituitary-tumors.htm.
Eguchi, K., Kawamoto, K., Uozumi, T., Ito, A., Arita, K., & Kurisu, K. (1995). In vivo effect of cabergoline, a dopamine agonist, on estrogen-induced rat pituitary tumors. Endocr J., 42(2), 153-61.
Sarne DH 2001 Medical therapy of pituitary adenomas and hyper-secretory states. in Principles and Practice of Endocrinology and Metabolism (3rd Edition) Becker KL (ed) JB Lippincott Company Philadelphia, PA (237-243)
Lohrer, P., Gloddek, J., Hopfner, U., Losa, M., Uhl, E., Pagotto, U., Stalla, G. K., & Renner, U. (2001). Vascular endothelial growth factor production and regulation in rodent and human pituitary tumor cells in vitro. Neuroendocrinology, 74(2), 95–105. https://doi.org/10.1159/000054675
Naess, O., Haug, E., & Gautvik, K. (1980). Effects of glucocorticosteroids on prolactin and growth hormone production and characterization of the intracellular hormone receptors in rat pituitary tumour cells. Acta Endocrinologica, 95(3), 319–327. https://doi.org/10.1530/acta.0.0950319
Heiss, J. D., Papavassiliou, E., Merrill, M. J., Nieman, L., Knightly, J. J., Walbridge, S., Edwards, N. A., & Oldfield, E. H. (1996). Mechanism of dexamethasone suppression of brain tumor-associated vascular permeability in rats. Involvement of the glucocorticoid receptor and vascular permeability factor. Journal of Clinical Investigation, 98(6), 1400–1408. https://doi.org/10.1172/jci118927
Piroli, G., Grillo, C., Ferrini, M., Díaz-Torga, G., Rey, E., Libertun, C., & De Nicola, A. F. (1993). Restoration by bromocriptine of glucocorticoid receptors and glucocorticoid negative feedback on prolactin secretion in estrogen-induced pituitary tumors. Neuroendocrinology, 58(3), 273–279. https://doi.org/10.1159/000126550
Bertorelli, R., Adami, M., Di Santo, E., & Ghezzi, P. (1998). MK 801 and dexamethasone reduce both tumor necrosis factor levels and infarct volume after focal cerebral ischemia in the rat brain. Neuroscience Letters, 246(1), 41–44. https://doi.org/10.1016/s0304-3940(98)00221-3
Trouillas, J., Girod, C., Claustrat, B., Curé, M., & Dubois, M. P. (1982). Spontaneous pituitary tumors in the Wistar/Furth/Ico rat strain. An animal model of human prolactin adenoma. The American journal of pathology, 109(1), 57–70. PMID: 7124908
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