Lupron vs. Lysodren

I'll try to explain how and why Lupron works and how Lysodren works. However it takes a lot of adrenal physiology, endocrinology, and pharmacology, so that is where I'll start.

The adrenal gland is divided into 2 big sections: the cortex and the medulla. The adrenal cortex is the section where the majority of the problems arise from (hyperplasia, adenomas, and carcinomas). Tumors from the medulla are called pheochromocytomas and are rare in ferrets. The adrenal cortex is subdivided into 3 zones. The outer zone is the zona glomerulosa, and it secretes mineralocorticoid hormones (mainly aldosterone). The middle zone is the zona fasciculata (it comprises about 70% of the cortex), and it secretes the glucocorticoid hormones (mainly cortisol). The inner zone is the zona reticularis, and it secretes the sex steroids (estrogens, progestins, testosterone) and the androgens (DHEA,and Andro.). In people and dogs, adrenal hyperplasia and tumors overproduce cortisol (ie zona fasciculata) and are called Cushing’s disease or Cushing’s syndrome. In ferrets it is quite different. Ferret adrenal hyperplasia and tumors overproduce the sex steroids and the androgens (ie zona reticularis). In ferrets it is called hyperadrenocorticism, not Cushings.

In dogs and people, the normal hypothalamic-pituitary-adrenal axis is straight forward. The hypothalamus secretes CRH which stimulates the pituitary to secrete ACTH which stimulates the adrenal glands to secrete cortisol. The cortisol has negative feedback to the hypothalamus and to the pituitary to stop the stimulation to the adrenal glands. In canine Cushings disease there is an adenoma or hyperplasia of the ACTH secreting cells in the pituitary gland. This over secretes ACTH which stimulates the adrenals and results in adrenal hyperplasia ( ie zona fasciculata)and cortisol being over secreted. This is called pituitary dependent hyperadrenocorticism and occurs in about 90% of the canine cases. Actual adrenal tumors (Cushing’s syndrome) are about 10% of the canine cases. Again these cases over secrete cortisol.

In ferrets it is actually a modified hypothalamic-pituitary- gonadal axis (where the adrenal glands are acting like gonads due to early spay/neutering and the long day photoperiods) that is involved. The hypothalamus secretes GnRH which stimulates the pituitary to secrete LH and FSH which stimulates the adrenal glands (zona reticularis) to secrete the sex steroids (estrogens, progestins, testosterone) and the androgens (DHEA and Andro). In ferrets there is no pituitary tumor. It is the long day photoperiod and early spay/neuter that stimulates the hypothalamus to over secrete GnRH which stimulates the pituitary which stimulates the adrenal glands. This over stimulation leads to hyperplasia or tumors of the adrenal glands (zona reticularis) and the over production of the sex steroids and the androgens.

LUPRON DEPOT is a synthetic analog of GnRH. It acts as a potent inhibitor of GnRH secretion. This results in decreased levels of LH and FSH. This results in decreased levels of the sex steroids and the androgens. These decreases occur within 2-4 weeks and have been demonstrated to last for more than 5 years with continuous use in people. Many animal studies were done by TAP Pharmaceuticals in rats, mice, dogs, monkeys, and rabbits. In humans it is used to treat endometriosis, uterine fibroids, mammary tumors, and prostatic tumors. In ferrets Lupron works by the same mode of action. It stops GnRH secretion by the hypothalamus, which stops LH and FSH secretion by the pituitary, which stops the stimulation to the adrenal glands, which stops the production of the sex steroids and adrogens by the adrenal glands (zona reticularis). The improvement in clinical signs is usually rapid and impressive. Typically the vulva will return to normal size in 1-2 weeks, and hair stops falling out in 2-3 weeks, and hair regrowth starts in 1-2 months. Completely normal haircoats take 2-5 months. The ferret I saw on Friday (2/4/00) was just 4 weeks since her first dose. The vulva was normal in size and new hair was already growing at the rump and base of the tail area. See MODERN FERRET (May/ June 1999) for an article by Dr Charles Weiss plus before and after photos. Lupron depot is safe. I have only seen 1 minor side effect (on only 1 ferret). It was purple striae on the caudal, ventral abdomen that resolved in a few days. Lupron does not lower cortisol levels or glucose levels. Unfortunately it does not work as well in cases of carcinomas, but it works well in hyperplasia and adenomas.

To answer your questions about biopsy studies, and ultrasound studies: The only controlled study on Lupron in ferrets is on going through the University of Tennessee. Preliminary results verify a reduction in the sex steroids and androgen levels. To do a biopsy study would require surgery. This is a drug for ferrets that are not good surgical cases or where owners object to surgery. Thus no biopsy studies have been done. Ultrasound is not an accurate enough test for adrenal gland disease. In a study at the Animal Medical Center in New York City (Dr Karen Rosenthal, etc.) only 50% of the diseased glands were diagnosed by ultrasound. In addition you would need a control group that was left untreated to compare adrenal gland size differences with. Thus the only studies are based on clinical signs and the most accurate test: hormone levels. Again the results have been good.

LYSODREN is a chemical derived from the insecticide DDT. It has been used in dogs for the past 25 years. It works by destroying the cortisol producing cells (zona fasciculata) and some of the cells in the zona reticularis. It works well in canine adrenal hyperplasia because cortisol is being over secreted. Side effects of lysodren in dogs include GI irritation (vomiting and anorexia), CNS signs (ataxia, weakness, and seizures), hypoglycemia, and a moderate increase in a liver enzyme (alk phos). In dogs adrenal tumors are relatively resistant to Lysodren. In a histopath (biopsy) study in dogs, the zona fasciculata was destroyed in the hyperplasia group, but the tumor group contained a clear description of the tumor histology. Clinical response also shows that adrenal tumors are relatively resistant to lysodren.

Lysodren in ferrets has 2 problems. It does not work well, and it produces low blood glucose (hypoglycemia). Dr Karen Rosenthal writes, "in my experience, mitotane (lysodren) does not reliably produce resolution of the clinical signs in ferrets.." "The primary danger associated with mitotane (lysodren) administration in ferrets is the possible development of severe hypoglycemia after several days of therapy in animals with concurrent insulinoma." Dr Susan Brown does not recommend giving Lysodren if they also have an insulinoma. Dr Charles Weiss even goes farther by saying "..mitotane is not recommended for ferrets with hyperadrenocorticism." In my opinion Lupron works better, is safer (no change in glucose level), and has little or no side effects. Dr Cathy Johnson- Delaney presented info on her clinical use of Lupron at the exotic pet medicine seminar at Texas A&M (Dec 97). I talked to her then and since then, and to Dr Weiss about Lupron. We all agree it works well and is safe.

I hope you see how these 2 drugs work quite differently. Lupron stops the stimulation to the adrenal glands which stops the production of the sex steroids and the androgens. [Remember it is the sex steroids and the androgens that cause the problems in ferrets].

Lysodren destroys the cortisol producing cells in the adrenal glands and some of the cells in the zona reticularis. The lower cortisol level lowers the blood glucose level which is a serious problem in ferrets, especially if they have an insulinoma! It does not stop the stimulation to the adrenal glands, and it does not work well on adrenal tumors. Please note there have been no biopsy study, ultrasound study, or hormone study with lysodren in ferrets that I know of.