Adrenocortical disease (ACD, adrenal gland disease, hyperadrenocorticism) is a common malady affecting middle-aged to older
ferrets with no sex predilection. ACD can affect ferrets under a year old. First reported in ferrets in 1987, the prevalence
of ACD is reported to range from 0.55% to 25%. Ferret adrenal disease is different from human, canine, and feline hyperadrenocorticism
because in ferrets adrenal sex hormones are overproduced instead of cortisol. Estradiol, 17-hydroxyprogesterone, or one or
more of the plasma androgens may be increased as a result of adrenocortical hyperplasia, adenoma, or adenocarcinoma. The adrenal
cortex of the ferret is divided into three layers: zona glomerulosa (outermost), which produces aldosterone; the middle (zona
fasciculata) which produces cortisol; and the inner (zona reticularis) which produces androgens. Hyperadrenocorticism can
therefore be divided into three syndromes: hyperaldosteronism (the most common form in cats, but also reported in a ferret);
hypercortisolism (true "Cushing's disease", the most common form in dogs and man); and hyperandrogenism (the most common form
in ferrets). Excess androgen levels are produced by ferrets with ACD by cells under the influence of luteinizing hormone (LH).
Androgens can be further metabolized to estrogens by the action of aromatase enzymes by cells under the influence of follicle
stimulating hormone. ACD in ferrets may therefore result in excesses of androgens or estrogens, and the clinical signs will
vary according to which sex steroid(s) are present. The current theory is that neutering and long-photoperiod interact such
that the ferret hypothalamus stays under continuous stimulation, and produces unregulated amounts of gonadotropin releasing
hormone (GNRH). This, in turn, stimulates the pituitary to produce continuously high levels of LH and FSH. By the continuous
stimulation of LH and FSH, adrenal androgen producing cells are thought to become hyperplastic, and through continued stimulation
to progress from hyperplastic, to adenoma, and eventually adenocarcinoma.
Adrenal disease is most commonly characterized by hair loss in both sexes and by vulvar enlargement in females. Pruritus,
sexual or aggressive behavior, and a noticeable increase in musky odor may occur. Affected males may present with stranguria
or urinary obstruction secondary to prostatic hyperplasia, prostatic cysts, prostatic abscesses, or prostatitis. Additional
clinical signs may include estrogen-induced bone marrow toxicity, mammary gland hyperplasia, cystitis, paraurethral /paraprostatic
cysts, muscle atrophy, and lethargy. Clinical signs may vary depending on which sex hormones are elevated, and clinical
signs do not always correlate with the size of the affected gland or the degree of adrenal pathology. In some cases, clinical
signs caused by the space-occupying or catabolic effects of the neoplastic process may be seen. It has been reported that
approximately 85% of ferrets with hyperadrenocorticism have enlargement of one adrenal gland, and that the other 15% have
the disease bilaterally. The most important differential diagnosis for a ferret with signs of ACD is a non-ovariectomized
female or a female with an active ovarian remnant. In intact female ferrets, or those with ovarian remnants, treatment with
1000 U of human chorionic gonadotropin, repeated 2 weeks apart will reduce the vulva size. Ultrasonography may help to differentiate
these conditions, or exploratory surgery may be required. Severe alopecia and pruritus in a ferret has been seen due to food
The underlying cause of the pathologic changes in the adrenal glands of ferrets with ACD is unknown. There is growing evidence
that neutering plays a role. Most ferrets with adrenocortical disease have been neutered before six weeks of age, and the
disease rarely occurs in sexually intact ferrets. In the prepubescent gonadectomized ferret, lack of negative gonadal hormonal
feedback on hypothalamic gonadotropin-releasing hormone (GnRH) leads to a persistently elevated luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). High LH may induce hyperplastic and/or neoplastic adrenocortical enlargement via functional
LH receptors. LH binds with these receptors, causing the adrenal gland to overproduce sex hormones. It is thought that the
ferret adrenal gland can do this because nests of undifferentiated gonadal cells have been carried with the adrenal glands
during embryological development.
There is a debate as to whether neutering has to take place at an early age for ACD to occur. In the US, ferrets are neutered
at an early age (4-5weeks), whereas ferrets in the Netherlands are typically neutered after physical maturity. Ferrets in
both countries tend to develop adrenal disease about 3.5 years after neutering. In Great Britain and Australia, on the other
hand, ferrets typically remain intact, and adrenal disease is rarely reported. This suggests that neutering promotes ACD in
ferrets, and that the age at neutering does not.
Husbandry conditions (including diet and photoperiod) of ferrets in the US, where adrenal disease is common, differs from
that in Europe and Australia, and this also may play a role in the prevalence of ferret adrenal disease. For example, in Great
Britain where ACD is uncommon, ferrets are usually kept outdoors, and are thus exposed to natural photoperiod. In the US,
where ACD is very common, ferrets are usually kept indoors and are exposed to a relatively uniform, long photoperiod. This
difference suggests that photoperiod may also play role in the development of ACD.
A genetic predisposition in US ferrets is suspected as the ferret population in the US is more inbred than that in Great Britain.
About 80% of all ferrets in the US come from one breeding farm, and this has been blamed for the high occurrence of ACD in
the US. However, in the Netherlands, where breeding stock are widely distributed, the prevalence ACD is similar to that in
the US. One could therefore conclude that inbreeding or a particular breeding facility cannot be blamed. Genetics could still
play a role in ACD, however, because it has been shown that the protein marker GATA-4 is expressed in cases of ferret adrenocortical
adenomas and carcinomas, but is not present in cases of adrenal hyperplasia. One or more tumor suppressor gene aberrances
may exist in the US ferret population. In fact, it has been proposed that the progression of adrenal gland tumors is not under
pituitary control, but rather under the control of an abnormal tumor suppressor gene, because the pituitary of affected ferrets
has a low density of gonadotropin-positive cells.