Wednesday, February 20, 2013

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

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.

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  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. 

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