Sex-Hormone Production in Adrenal Tumors in Cats
World Small Animal Veterinary Association World Congress Proceedings, 2014
Claudia Reusch, DECVIM-CA
Clinic for Small Animal Internal Medicine, Zürich, Switzerland

The adrenal gland consists of two functionally distinct endocrine glands of different embryological origin. The medulla, which is of neuroectodermal origin, comprises approximately ¼ of the adrenal mass and secretes norepinephrine and epinephrine. The surrounding cortex arises from mesoderm and is composed of 3 zones: an outer zona glomerulosa, a zona fasciculate, and an inner zona reticularis. The zona fasciculate and reticularis appear to function as a single unit. The zona glomerulosa produces mineralocorticoids (mainly aldosterone) and as it lacks 17α-hydroxylase activity it cannot produce cortisol or androgens. The zona fasciculate is the thickest layer and produces glucocorticoids (cortisol and corticosterone) and androgens. The zona reticularis produces androgens such as dehydroepiandrosterone (DHEA), its sulfate analog DHEA sulfate, and androstenedione as well as glucocorticoids. Those adrenal androgens are converted by peripheral tissues into testosterone and estradiol, whereas conversion within the adrenal cortex is minimal. The physiological role of the adrenal androgens seems to be relatively small. In the absence of gonads, androgen production of the adrenal cortex does not meet physiological requirements. Cortisol and adrenal androgen synthesis is mainly regulated by ACTH, although other factors may also have some effect. Interestingly, cats (and dogs) with pituitary-dependent hypercortisolism do not develop dermal or behavioral symptoms of androgen excess. Their clinical signs are primarily the result of the glucocorticoid excess. The situation is similar in cats with hypercortisolism due to an adrenocortical tumor (e.g., the clinical signs are determined by the major product of the tumor, which is usually cortisol). However, occasionally, adrenocortical tumors may produce other hormones than cortisol. This phenomenon is best characterized in neutered ferrets, in which uni- or bilateral adrenocortical tumors produce sex hormones, mainly androstenedione, 17α-hydroxyprogesterone, DHEA, and estradiol rather than cortisol. In cats, sex hormone-producing adrenal tumors seem to be rare. Most tumors reported so far were carcinomas, which is similar to human medicine. The majority of tumors were unilateral; however, bilateral tumors have also been described. The exact mechanism for the overproduction of sex hormones is unclear at the moment; aberrant biosynthetic pathways within the adrenal cortex have been suggested to be a potential cause. The tumors may secrete predominantly one sex hormone, and the clinical picture is dominated by the effect of the particular hormone. However, production of a hormone mixture may also occur.

The following "categories" of sex-hormone-producing adrenal tumors have been described:

 Excessive progesterone production
The main clinical signs in three cats were polyuria/polydipsia, unkempt hair coat, alopecia (usually truncal), thin skin with increased fragility, abdominal distension. Clinical pathology revealed hyperglycemia consistent with diabetes mellitus. ACTH stimulation test and low-dose dexamethasone test revealed normal or low cortisol concentration. During further workup, uni- or bilateral adrenal masses as well as increased plasma progesterone concentrations were found. In some of the cats, other precursors or hormones of the steroid biosynthesis pathway were increased additionally.

 Excessive progesterone and aldosterone production
Concurrent hyperprogesteronism and hyperaldosteronism has been described in 2 cats. Clinical manifestations were a combination of progesterone excess (see above) and of aldosterone excess; the latter was represented by weakness, hypokalemia, mild azotemia, and metabolic alkalosis. Cortisol concentration post-ACTH stimulation was low. Diagnosis was based on the findings of high plasma/serum progesterone and high plasma aldosterone concentrations in concert with the ultrasonographic finding of an adrenal mass.

 Excessive secretion of estradiol and/or androstenedione and testosterone
One female spayed and one male castrated cat developed male-type behavior, including spraying urine that had a strong "tom-cat" smell, aggressive behavior; the castrated male cat revealed spines on the penis and spayed female cat had hyperplasia of the vulva. Abdominal ultrasonography revealed adrenal masses in both cats. Cortisol concentration post-ACTH stimulation was low. Various precursors of the steroid biosynthesis pathway were increased, the clinical signs were attributed to increased concentrations of androstenedione and testosterone. In one cat, adrenalectomy was performed, which resulted in complete resolution of the clinical signs. The other cat showed moderate improvement of clinical signs during treatment with trilostane. One spayed female cat demonstrated cyclic intermittent estrous behaviour and aggression which was attributed to an adrenal tumor secreting increased amounts of estradiol, androstenedione, progesterone, and 17α-hydroxyprogesterone. Clinical signs resolved immediately after adrenalectomy.

In summary, sex-hormone-producing adrenal tumors are rare events and may pose a diagnostic challenge. Clinical signs of hyperprogesteronism are identical to those of hypercortisolism and a progesterone-producing adrenal tumor should be considered if cortisol concentrations after the administration of ACTH and dexamethasone are low. An estradiol- or androstenedione/testosterone-producing adrenal tumor may be present in neutered male and female cats with newly developed physical and behavioral sexual changes. Of note, those tumors are usually malignant.


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Speaker Information
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Claudia Reusch, DECVIM-CA
Clinic for Small Animal Internal Medicine
Zürich, Switzerland

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