Adrenal disease in the ferret (hyperadrenocorticism)

Adrenal disease is an alteration in an adrenal gland with the production of excessive amounts of the steroid sex hormones. The adrenal gland may develop nodular hyperplasia (56%), adenoma (16%) and adenocarcinoma (26%) or other much rarer tumours. A single gland may be affected (more commonly the left) or both (a rarer occurrence). Adrenal disease is particularly common in ferrets that come from intensive, foreign breeding facilities; a study carried out in 2003 in the USA showed that 70% of ferrets were affected.

Adrenal disease in the ferret is characterized by excessive production of sex hormones (oestradiol, 17-hydroxyprogesterone, androstenedione and dehydroepiandrosterone sulphate) in the zona reticularis of the cortex of the adrenal gland. Only 10% of ferrets with adrenal disease also have hypercortisolaemia. This disease is not, therefore, the same as Cushing’s syndrome, in which there is an increase in the secretion of glucocorticoids in the zona fasciculata. It is the overproduction of steroid sex hormones that causes the signs of adrenal disease in the ferret; this disease can, therefore, be considered a paraneoplastic syndrome.

AETIOLOGY

For years there has been speculation on the precise causes leading to the development of adrenal disease. Recent studies have established a definite relationship between sterilisation (both in males and females) and the appearance of adrenal disease. The earlier the sterilisation, the earlier the development of the disease. Adrenal disease may occur in intact ferrets, but it is much rarer in such animals than in sterilised ones.

It should be recalled that the ferret reaches sexual maturity at 6-9 months of age, in the spring following its birth, under the influence of the photoperiod. It is a seasonal reproducer; the female ferret can have two pregnancies a year. The jill has induced ovulation: ovulation does not occur unless the animal copulates, an act which induces a peak of luteinising hormone (LH). The end of the reproductive season is induced by hormonal feedback from the gonads (therefore, in the absence of the gonads, the signal interrupting hormonal activity is lacking).

It was recently demonstrated that, among various receptors, adrenal gland tissue has receptors for LH, which enable the gland to produce steroid hormones, replacing gonadal production of these hormones if the gonads are absent. In fact, sterilised ferrets are able to produce sex hormones in a seasonally dependent manner but in this case the negative feedback to interrupt hormone production which occurs in sexually intact ferrets is not present. The mechanism is not completely clear, but it is certain that high levels of gonadotropin-releasing hormone (GnRH) and LH cause super-regulation of the production of sex hormones by the adrenal glands, which, over time, react by becoming hyperplastic and then neoplastic. Likewise, it is not clear why GnRH analogues depress the adrenal production of sex steroids, but the clinical efficacy of these products is well-known.

There are ongoing studies on whether there is a genetic component in the development of adrenal disease, because, in humans, the contemporaneous appearance of more than one endocrine tumour, a syndrome named multiple endocrine neoplasia, almost always has a genetic origin. In fact, ferrets with adrenal adenomas and adenocarcinomas have tumour markers that are not present in cases of simple hyperplasia. Furthermore, ferrets with adrenal disease very often also develop insulinomas.

Other hypotheses involve inbreeding (mating between consanguineous individuals for several generations) and the restricted genetic pool in intensive breeding facilities, commercial diets, the artificial photoperiod to which animals kept in a house are exposed to (associated with an increase in gonadotropins) and the maintenance of animals in groups (whereas ferrets are solitary animals in nature), but at present these are only speculations. What is certain is that in the United Kingdom ferrets bred as hunting animals, kept individually, fed with fresh meat and not sterilised have a much lower incidence of adrenal disease.

CLINICAL FEATURES

The incidence of adrenal disease is the same in males and females, even though owners recognize the condition more easily in females because of the development of evident vulvar hyperplasia. In ferrets from intensive breeding facilities, in which animals are sterilised at an early age (4-5 weeks), the disease typically develops at around 3.5-4.5 years; however, the age at onset ranges from 1 to 11 years and, therefore, in practice this disease cannot ever be excluded on the basis of the age of the animal.

The main clinical sign, which constitutes the reason for the clinical examination (particularly for owners who are accustomed to looking for information on Internet!) is alopecia, present in 90% of cases. The alopecia is bilateral and symmetrical and often starts from the tail (Fig. 1), progressively extending anteriorly to involve the back, abdomen and trunk (Figs. 2 and 3). The head and paws are involved last and at this point the ferret is completely hairless. In other cases the alopecia starts from the trunk and spares the tail (Fig. 4).

The trend in the alopecia is characteristic. At first the owner notices the hairless tail during the hot season (which can also be a physiological phenomenon not related to adrenal disease), but the hair regrows spontaneously during the cold season. The following year the phenomenon recurs, but with more extensive alopecia, and so on in the next year, but then the hair no longer grows back and the alopecia extends progressively. Furthermore, affected by the sex hormones, the skin once again starts emanating the typical, strong, musky odour of sexually intact male ferrets.

Itching and inflammation of the skin are common (30-40% of cases) and can be accompanied by excoriations due to scratching (Fig. 5) (which must be differentiated from flea infestations). In some ferrets this cutaneous pruritus is the only symptom. Evident comedones on the tail and abdomen (Fig. 1) are typical of adrenal disease (some ferrets normally have a discrete number of  comedones on the tail).

The females usually develop vulvar hyperplasia (Fig. 6), which must be differentiated (in sprites, i.e. spayed females) from the result of residual ovarian tissue. However, if this sign was not present in the previous year(s), it is a clear indicator of adrenal disease. Despite the increased levels of oestrogen, adrenal disease is not usually associated with bone marrow hypoplasia and anaemia, in contrast to what occurs in the hyperoestrogenism due to prolonged ovarian activity in sexually intact jills or sprites with residual ovarian tissue. Other signs that may be present in female ferrets are hyperplasia of the mammary glands and a vulvar discharge.

Sexual behaviour may reappear in sterilised males with adrenal disease which may show an increase of aggressiveness typical of the sexually intact ferret. Prostatic hyperplasia may also develop, with dysuria - strangury and possible partial or total obstruction (this last being an emergency which, if not treated immediately, leads rapidly to the animal’s death). In advanced cases, there is generalised muscle atrophy (made obvious by the alopecia), a pendulous abdomen and lethargy.

The adrenal neoplasm may be accompanied by an increase in the volume of the uterus or uterine stump (stump pathology) and a purulent vaginal discharge. Given the different pathogenic mechanisms, animals with adrenal disease almost never present with the classical signs of Cushing’s syndrome seen in the dog (polyuria, polydipsia and polyphagia).

DIAGNOSIS

The diagnosis is suspected on the basis of the signs, which are very suggestive. Sometimes the enlarged adrenal gland can be palpated, particularly that on the left, but only in cases in which it has reached an exceptional size, which does not usually occur.

Results of blood-chemistry tests are non-specific; on rare occasions these tests show anaemia, lymphocytopenia and eosinopenia, but are usually normal. The basal level of cortisol and the ACTH stimulation test are usually normal; these investigations should not be requested since they are not useful for diagnostic purposes. Forty percent of ferrets with adrenal disease have high serum levels of oestradiol, but this finding is also present in females in oestrus and in those with residual ovarian tissue. Tests that are useful for the diagnosis are assays of 17-OH-progesterone, dehydroepiandrosterone sulphate (DHEAS) and androstenedione, which are not currently carried out in Italian laboratories.

The safest and most practical way to confirm the diagnosis is an ultrasound examination (Fig. 7) which, if carried out by an expert, can locate and measure the dimensions of the glands precisely (Tab. 1), evaluating changes in the size and structure which are so small that they can be missed by the naked eye during laparotomy. In rare cases the adrenal glands may appear normal by ultrasound examination even when adrenal disease is present.

Ultrasonography has the advantage of determining which glands are affected (Fig. 8), their dimensions, any extension of the tumour to adjacent structures (aorta, vena cava, liver) and any concomitant disorders. Adenomas and adenocarcinomas frequently increase the width of the gland, but not its length; more rarely both dimensions are increased or nodules are formed which alter the normal profile of the gland. The structural alterations may be represented by increased echogenicity, heterogeneity or mineralisation. In some cases, adenomas or hyperplasia may leave the size and structure unaltered. The focal absence of periglandular fat between the adrenal gland and the vena cava, aorta or liver and displacement or compression of the large vessels may be indicators of malignancy, suggesting that these structures have been invaded by the tumour.

There is no correlation between the dimensions of the gland affected and the clinical signs. Since glands with hyperplasia or adenomas may appear ultrasonographically normal, if compatible clinical signs are present, the effects of trial medical treatment with leuprorelin or deslorelin can be evaluated or an exploratory laparotomy can be performed.

X-rays are not useful for the examination; only very rarely do adrenal gland become enlarged enough to be seen on an X-ray or to displace adjacent structures and they do not mineralise evidently. Magnetic resonance imaging and computed tomography are excellent examinations for diagnosing both adrenal disease and any concomitant disorders, even though they are not always applicable in practice.

Vulvar hyperplasia due to adrenal disease in sprites can be differentiated from the effects of residual ovarian tissue by using drugs that terminate oestrus (HCG or GnRH); if the hyperplasia is due to residual ovarian tissue, the volume of the vulva decreases, whereas if it due to adrenal disease these drugs have no effect.

Following its surgical excision, the adrenal gland should undergo histological analysis. Indicators of malignancy are necrosis, cellular atypia and a mitotic index greater than 1/10 high power fields.

Tab. 1. Sizes (in mm) of normal adrenal glands [from Neuwirth L et al. Adrenal ultrasonography correlated with histopathology in ferrets. Vet Radiol Ultrasound. 1997;38(1):69-74].

The following images show some examples of normal and pathological adrenal glands (post-mortem findings).

TREATMENT

Adrenal disease can be treated medically, surgically or with a combination of both techniques. The choice depends on many factors: the clinical condition of the ferret, its age, the presence of concomitant diseases, the type of tumour (invasion of contiguous organs, the practical feasibility of excising it), the owner’s willingness to accept the surgical and anaesthetic risks and the financial commitment and the veterinarian’s experience, surgical skill and available equipment. The animal’s age is not, per se, a factor limiting surgery, but in a very old ferret with a limited life expectancy, medical therapy can be a valid alternative. One of the advantages of surgery is that various biopsies of internal organs can be performed at the same time, thus enabling concomitant diseases, which are present in a quite a large number of cases, to be diagnosed.

The surgical treatment is unilateral or bilateral adrenalectomy (depending on the glands affected) or tumour debulking if the gland cannot be removed completely. Before performing surgery it is important to evaluate the animal thoroughly to determine whether it is in a satisfactory condition to undergo the operation and whether there are any other disorders present. Besides an abdominal ultrasound examination, the minimum work-up consists of a full blood count, blood-biochemistry screen and a chest X-ray. Not uncommonly ferrets have two or more concomitant, severe pathologies: the adrenal disease may co-exist with an insulinoma, lymphoma, other types of tumour and cardiac disorders.

The improvements following surgery appear after 2 to 6 weeks, while complete resolution of the problem can take up to 5 months.

There are descriptions of the use of cryosurgery (which requires specialised equipment) and ultrasound-guided alcoholisation (for which the equipment is very simple, but adequate documentation of its efficacy is lacking).

Medical therapy can be combined with surgical management or be the only choice, for example in very elderly ferrets, in animals which are not candidates for surgery, or if the owner refuses surgery. It is important that the owner understands that medical therapy affects the clinical manifestations of the tumour (alopecia, sexual behaviour, etc.) but may not influence the progression of the tumour.

Various products can be used in clinical practice.

1. Gonadotropin-releasing hormone superagonists

Superagonists are molecules capable of inducing a greater response than that induced by the natural agonist of the target receptor, that is, they have an efficacy of greater than 100%. In the case of GnRH, the superagonists act by blocking the production of LH and FSH induced by persistent pituitary stimulation resulting from the negative feedback (due to the absence of the gonads). Although the precise mechanism is not yet clear, initially there is a peak in the production of gonadotropic hormones, followed rapidly by desensitisation of the receptors for these hormones which leads to the inhibition of the production of LH and FSH.

Besides being a treatment for adrenal disease, these hormones can also be used to improve the general condition of very debilitated subjects prior to surgery and as adjuvant therapy in the case that it is not possible to remove the tumour completely. They are effective drugs that are tolerated extremely well (no side effects have been reported), although they are relatively expensive.

a) Leuprorelin (1-month depot injection). The recommended dosage regimen is 100 mg for ferrets up to 1 kg and 150-200 mg for those over 2 kg, once a month for 3 months, then every 2 months (although some authors suggest continuing with monthly treatment). The treatment must be continued for the animal’s whole life, otherwise the signs reappear. Over time some subjects can become refractory to the action of leuprorelin. After reconstitution, the contents of a vial can be stored frozen for at least 1 year.

b) Deslorelin. Deslorelin implants are marketed for the temporary chemical castration of dogs.These implants consist of a slow-release biocompatible capsule which is injected subcutaneously with a specific syringe, similar to the syringes used for microchips. The implant is inserted under the skin in the region of the neck (Fig. 13). Considering the difficulty in penetrating the skin of the ferret and the relatively large needle required, it is preferable to carry out the injection after induction with isoflurane (the procedure is very quick). The area should be disinfected before the injection; just as following insertion of a microchip, a stitch is not normally necessary. A single capsule is inserted for ferrets of any weight.

The preliminary studies on the use of deslorelin are very encouraging. After the implantation, the vulvar hyperplasia, pruritus and sexual behaviour disappear within 2 weeks; the hair begins to grow again within 4-6 weeks. According to one study, remission, with control of the clinical manifestations, lasts for 8-30 months, with the mean duration being 17.6 ± 5, after insertion of a single capsule. In some subjects the volume of the affected adrenal glands also decreases, returning to normal.

This product has the considerable advantage over leuprorelin of having a much longer duration of action. It is sold in packages of two and five implants, making the financial outlay less than that for leuprorelin, which has the additional disadvantage of having to be divided into individual doses to be frozen.

Deslorelin is also a very interesting product in view of its potential use as an alternative to surgical sterilisation, or in association with this, in healthy subjects, for the prevention of adrenal disease. Studies on this possibility are underway. Its effect of chemical castration lasts about 1-2 years and a new implant is inserted when the ferret becomes fertile again (as indicated by an increase in the volume of the testicles or vulvar hyperplasia).

2. Melatonin

Melatonin is a hormone produced by the pineal gland; high levels of circulating melatonin inhibit the secretion of GnRH and, therefore, the production of LH and FSH. The precise mechanism of action of melatonin in adrenal disease in the ferret is not known, but various studies seem to indicate that it is effective. Melatonin is administered by subcutaneous implantation (as for a microchip). Its effect lasts 3 months. Melatonin is not currently available in Italy, which makes it less practical than deslorelin. It does not have particular advantages from an economic point of view.

3. Androgen receptor blockers

These drugs are used in males in which an excess of androgens causes problems of prostatic hyperplasia. They would have to be administered life-long, but it is advisable to intervene directly on the adrenal disease in order to stop the production of androgens. Flutamide (10 mg/kg per os every 12-24 hours) and bicalutamide (5 mg/kg per os every 24 hours) are quickly effective in reducing the volume of the prostate. Bicalutamide is administered until complete remission of the signs is achieved, and then in alternate weeks.

Drugs that are ineffective and which should NOT, therefore, be used in adrenal disease are:

• Mitotane
• Ketoconazole
• Deprenyl
• Cyproheptadine
• Bromocriptine

Other drugs which should not be used, in this case because they have not yet been evaluated sufficiently, are:

• Trilostane
• Aminoglutethimide
• Metapyrone