Adrenal Disease
Introduction:
Adrenocortical disease (ACD) or adrenal gland disease is one of the most common and devastating conditions diagnosed in domestic ferrets in the United States.1 This disease typically affects neutered, middle-aged to senior male and female ferrets. It is estimated that 70% of domestic ferrets will develop ACD over their lifetime. Adrenocortical disease is an endocrine disorder that releases an oversupply of steroid hormones. The endocrine system is made up of a number of glands that produce and release complex hormones or proteins which act as messengers to control a variety of functions in the body. This is why a ferret with adrenocortical disease may exhibit a mixture of symptoms.
Adrenal Glands:
The adrenal glands are endocrine glands that are located above each kidney in the abdomen as illustrated in the diagram to the left below. Each adrenal gland is composed of an outer region known as the adrenal cortex which produces hormones such as cortisol and releases sex hormones (i.e. estrogen and testosterone plus others) and the inner region known as the adrenal medulla which produces hormones such as adrenaline.2 See the cross section illustration below and to the right to view the regions of the adrenal gland.
Factors around ACD:
Three main factors believed to contribute to the prevalence of adrenocortical disease in ferrets include: 1) neutering at an early age; 2) long light cycles longer durations of light exposure (possibly or something similar to that statement); and 3) genetic predisposition.1
Neutering of ferrets at an early age removes the source of the sex hormones (estrogen for females and testosterone for males). Removal of these reproductive organs stops the body’s natural inhibition of the pituitary gland’s hormone production causing an imbalance leading to overproduction of the sex hormones.
Long light cycles refers to the exposure of ferrets to light for periods of time longer than 8 hours. This over exposure to light stimulates production of gonadotropin-releasing hormone (GnRH) from the Hypothalamus (area of the brain that links the nervous system to the endocrine system) and luteinizing hormone (LH) from the pituitary gland (pea-sized gland located at the base of the brain).
Genetic predisposition describes the likelihood of ACD developing based on the ferret’s genetic makeup. It is a result of genes inherited from a parent and, thus, a result of ferret breeding practices. Most, if not all, ferrets are from Marshall Farms a commercial breeder.
Actions of the Adrenal Glands:
The adrenal glands along with the hypothalamus, pituitary and reproductive organs (or gonads) all participate in a negative feedback loop that regulates production and release of sex hormones.4 Here is how the negative feedback mechanism works: the hypothalamus will release the neuropeptide or hormone GnRH which causes the release of LH which stimulates the production of estrogen and progesterone from the female ovary. In male ferrets, the release of LH stimulates the production and secretion of testosterone from the testes. A second hormone released by the pituitary gland is the Follicle Stimulating Hormone (FSH). In females, FSH stimulates follicle development and maturation of precursor germ cells in the ovary. In males, FSH stimulates the maturation of germ cells within the testes. The pituitary contains receptors for both LH and FSH and when stimulated, will produce and release sex hormones. Both the gonads and adrenal glands will produce and release sex hormones due to the LH and FSH surge from the pituitary gland. When estrogen and /or testosterone reach a certain level in the blood, the hypothalamus is signaled to stop releasing GnRH. As a result, the pituitary is not stimulated to release FSH and LH. Without stimulation from the pituitary gland, the gonads and adrenal glands stop producing and releasing sex hormones. When the estrogen and/ or testosterone fall below a certain level in the blood, the hypothalamus is signaled to release GnRH and the hormonal cascade resumes. The hypothalamus releases GnRH in a pulsatile manner. The negative feedback loop is illustrated below in Diagram A.
Diagram A: Negative feedback loop in a healthy intact ferret.
When the ferret has been neutered, the reproductive organs or gonads have been removed. The absence of the normal secretion of hormones (ie estrogen and testosterone) result in a lack of the negative feedback mechanism with the hypothalamus as illustrated in Diagram B below. The lack of feedback on the hypothalamus causes a continuous secretion of GnRH leading to constant stimulation of the pituitary gland and the adrenal glands resulting in an overproduction of sex hormones. As a sequela (brief definition of term) to the increased secretion of the sex hormones from the adrenal glands, adrenal gland hyperplasia or gross enlargement of the gland occurs which results in adrenocortical disease in the ferret.4
Symptoms:
Ferrets with adrenocortical disease may be clinically asymptomatic (showing no symptoms) or may develop changes in appearance and behavior associated with the increase of circulating sex hormones. Hair loss is the most common symptom exhibited. It is estimated that 80% of male and female ferrets with ACD have this symptom.4 Pruritus or itchiness may be present with or without hair loss. Initially, the tail and rear legs appear to be the first parts of the body affected. The hair loss may be minimal, seasonal based, or fluctuate; however, eventually complete baldness occurs.
A common sign amongst female ferrets with ACD is vulvar swelling. Female ferrets only release eggs when they mate (induced ovulation) and an enlarged vulva in an intact female is a sign of heat without mating or excessive estrogen secretion over a long period of time. Aplastic anemia, a life threatening low red blood cell count, can be seen in intact females due to the excessive estrogen. Aplastic anemia is rarely seen since most female ferrets are spayed before purchase in the United States. Therefore, an enlarged vulva in a spayed female ferret as demonstrated in the picture below is primarily a sign of adrenocortical disease.
Difficulty urinating may be a complaint with neutered male ferrets and is a result of enlarged prostatic tissue or formation of urinary stones. Occasionally, the prostate can be so large it physically blocks the male’s ability to urinate. A male unable to urinate is an emergency situation because it may lead to bladder rupture or kidney failure. A distended or full bladder is palpable during physical exam and confirmed with a radiograph.
Both sexes of ferrets may exhibit increased sexual behaviors such as mounting or aggression due to the production of excessive sex hormones. The symptom of aggression tends to be seen more in ferrets with a malignant form of adrenal cancer known as adrenal adenocarcinoma.
Less frequently observed symptoms associated with ACD include a decrease in energy or lethargy and loss of muscle mass or muscle atrophy. Abdominal atrophy may be noticed as a pot-bellied appearance. It is important to note that lethargy and muscle atrophy may be associated with other diseases found in ferrets.
Diagnosis:
Adrenocortical disease in ferrets is most commonly diagnosed through signalment, i.e physical examination and clinical signs.4 Specialized laboratory blood work to check circulating sex hormones may be submitted if ACD is suspected and not physically evident or if response to therapy needs to be evaluated. Additional diagnostics such as ultrasound, surgery, and biopsy findings may be required to confirm the diagnosis of ACD since other medical conditions such as insulinoma, diabetes, inflammatory bowel and other types of cancers may cause similar symptoms.5
Because of the tiny size of the adrenal glands, ultrasound and exploratory surgery will provide the best visualization of the glands as well as surrounding organs. Biopsies can be performed at the time of exploratory surgery to rule out or diagnosis other diseases.
Treatment:
Adrenocortical disease can be surgically treated or medically managed.6 Surgical treatment is limited to the left adrenal gland as the right gland is more difficult to approach due to its location in the abdomen. Surgery is the most invasive and probably most expensive way to treat ACD in ferrets. Although one gland may be initially affected, the other gland will become diseased eventually. Medical management involves the use of injections of synthetic GnRH analogue that suppresses the reproductive endocrine system; and thus, preventing the production and release of pituitary and sex hormones. Clinical signs may respond as early as 10 days. The two medical therapies available are Leuprolide® (Lupron) Implant and SUPRELORIN® F (deslorelin acetate) 4.7mg Implant. Expectation of therapy, side effects and injection protocol should be discussed with the veterinarian when considering medical management. Melatonin has been used in cases of ACD with benefit to alter the ill-effects of long light cycle.
Two reliable sources for additional information regarding adrenocortical disease in ferrets is www.veterinarypartner.vin.com and the American Ferret Association at www.ferret.org.
1. Simone-Freilicher E. Adrenal gland disease in ferrets. Vet Clin North Am Exot Anim Pract.2008;11(1):125–137.
2. Sargis RA. An Overview of the Adrenal Glands. EndocrineWeb
3. Gandolfi RC, Weiss CA. Adrenal disease (hyperadrenocorticism). http://www.ferret.org/pdfs/health/Adrenal_Disease_Comprehensive_with_Medical_Therapy.pdf. Accessed January 15, 2016.
4. Rosenthal KL. Adrenal gland disease in ferrets. Veterinary clinics of North America: small animal practice. 1997 Mar 31;27(2):401-18.
5. Fox JG, Marini RP. Diseases of the endocrine system. Biology and Diseases of the Ferret. 2nd ed. Baltimore: Williams’ Wilkins. 1998:291-305.
6. Rosenthal, KL, Wyre NR. Endocrine Diseases. In: Quesenberry, KE and Carpenter, JW eds. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. 3rd ed. St. Louis: Saunders Elsevier; 2012: 86-91.