Pituitary Gland Cushing's Disease

Pituitary Gland Cushing's Disease

Pituitary gland hyperadrenocorticism (PDH)

Question: Dr. Richards, I have a 5 year old Boston terrier (Simmi) who was diagnosed today with probable Cushing's disease based on a low dose dex supp test.

Values were as follows:

ref range

pre dex 10.7 (1.0-6.0)

post 4 hr dex 0.4 (<1.5)

post 8 hr dex 2.6 (<1.5)

Her alk phos is 490 but the specimen was hemolyzed so it may actually be higher. My vet has consulted an internist who recommended an ACTH stim test to confirm the diagnosis and then possibly a high dose dex supp test to differentiate between pituitary vs adrenal.

#1) In light of the above results, do you feel these additional tests are necessary? (The pattern looks pituitary to me) Her only symptoms are polyuria/polydipsia which I have noted over the last year. The symptoms are not severe, she usually does not have to urinate in the middle of the night and she has never been incontinent (she has a doggy door). No one else (including my husband) had noted her symptoms.

#2)Is there any advantage to starting treatment early or would you wait until she became more symptomatic?

#3)I noted on the website that you diagnosed a dog at age 6 who lived to be 14, you thought possibly because it had been caught early. How did you treat that dog?

#4) Since she is only 5 and her symptoms are still mild at this point, does she have a better prognosis than the standard 2-3 years I have seen quoted or her prognosis still poor?

#5) What is your first line treatment these days, mitotane or Anipryl? I know in general treatment relieves symptoms but does not change the prognosis. However, I also read something about Anipryl possibly prolonging survival.

#6) Is there any truth to this and what has been your experience with Anipryl? I have seen success rates varying from 40-80%. Is there any more recent data on success rates?(I know it is only for pituitary based disease.

If Anipryl makes dogs "feel" better and improves symptoms but doesn't alter cortisol levels it can't alter the damaging effects of excess cortisol, CAN IT? (ie risk of developing diabetes, CV, renal, and hepatic disease.) I realize not much is known regarding mechanism of action, but I had to ask. Simmi is a very smart girl and NOT fond of trips to the vet. The thought of putting her through all the frequent bloodwork needed during mitotane therapy is giving me pause. That is why I am asking all the Anipryl questions. I want her to have the best quality of life possible and I'm not sure that I can put her through all the trips to the vet that would be required. Please let me know if there is any recent literature I can access regarding therapy or if there is anyone specializing in Cushing's who might have further information. I love Simmi with all my heart and soul and I want her to be happy. Thank you so much for your time, it means a lot to Simmi and I. Sincerely, Soni

Answer: Soni- It is probably easiest to respond to your questions in order, as much as possible.

1) I would be content that I was dealing with pituitary dependent hyperadrenocorticism (PDH) with the lab results you sent. The escape at 8 hours but suppression at 4 hours is highly suggestive of this, especially since there is suppression to less than 50% of the baseline value even with the inadequate overall suppression. Some vets are more cautious about this by nature and I can't really fault trying additional testing to confirm the diagnosis. The low dose dexamethasone suppression test is less specific than and ACTH response test so confirming the diagnosis from that makes some sense. I really don't see a lot of need for the high dose dexamethasone suppression test, though. You already have the data it would give you with the results from the LDDS test.

2) It is really hard to answer this question. To the best of my knowledge there are no real studies, in dogs, suggesting that early treatment is actually helpful in extending lifespan. There is a small percentage of dogs who have hypertrophy or Type A tumors of the pars intermedia that might actually be arrested by the use of selegiline. There is some argument about how many dogs have this form of PDH but it is somewhere between 11% and 30% using the lowest and highest estimates I have seen. It is conceivable that this group could have significant improvement with selegiline, although there isn't any long term proof of this that I know of. At this point the benefit is theoretical. It seems to make sense that early treatment would help to eliminate some of the secondary complications, like persistent urinary infections, hypertension, insulin resistance and skin infections that might lead to disability or death. On the other hand, when studies have been done to compare dogs treated with mitotane there doesn't seem to be a statistically significant increase in life span with treatment. I am not sure why this is. It may be that the complications of treatment equal those of not treating or it may just be the general age of the population that has Cushing's disease, in that other disorders may cause death before Cushing's disease does. So at this time, my impression is that it doesn't actually matter when treatment starts except to the patients who have uncomfortable clinical disease that will respond to treatment. They obviously benefit because they feel better, even if they aren't going to live longer as the result of treatment. The only problem is that this opinion is based more on a lack of knowledge than on valid data.

3). Penny, the dog that we treated from 6 years of age to 14 years of age was treated with Lysodren. She had pretty severe polyuria/polydipsia when first diagnosed, or we might have held off on treatment. Her owners were actually considering euthanasia because she couldn't stay in the house for more than an hour or two without urinating.

4) It is my personal opinion that dogs that are diagnosed at a younger age live longer than the average PDH patient because all affected patients tend to live almost their normal expected life span at the time of diagnosis. I really think that the reason that the "two year average" figure came about is that most dogs are 9 to 12 years old at the time of diagnosis. But that really is my opinion. I can't actually find any studies that have been done to show what the real averages are for patients diagnosed early or diagnosed when young and without these I have to accept that I'm just guessing.

5) If we believe that the hyperadrenocorticism is pituitary in nature and there isn't secondary diabetes at the time of diagnosis, we start with selegiline. Our success rate seems to be running about the reported average (20 to 40% good to very good response based on clinical symptoms). We only try selegiline for one to two months (one if no response at all) and so we think it doesn't really set us back much to try it first.

6) Selegiline does lower cortisol levels in most patients. In 15% of dogs it will lower these levels to normal values within a year of treatment. In about 20% of dogs there is no effect at all on cortisol levels. In the remaining dogs, there are lower levels than when treatment is started but not low enough to make the LDDS test "negative" and not enough to prevent ACTH stimulation results from suggesting HAC is still present. There isn't the big risk of causing hypoadrenocorticism that comes with mitotate usage and there isn't a good way to adjust dosage of selegiline based on test results, so the testing just doesn't make a lot of sense clinically. I think that this point isn't very clear on our website because I tend to think that if the levels don't fall to normal it isn't really fair to say that they are controlled. However, there is a change, at least according to Dr. Bruyette's research, so there is some control.

The argument of proponents of selegiline is that treatment with selegiline lowers the cortisol levels enough to make the clinical signs disappear and that this should be beneficial for secondary side effects, as well. They argue further that mitotane creates mild hypoadrenocorticism (when well regulated) and that the potential effects of that are just as bad as mild hyperadrenocorticism. This may be true but I don't know how anyone would quantify that with the current level of available data. The whole issue of whether to use selegline or not has generated a lot of strong opinions among endocrinologists who treat and research hyperadrenocorticism on a regular basis. There are well respected endocrinologists who believe that selegiline should not be used at all based on the inability to verify its effects through "normalizing" cortisol levels. These are countered by the endocrinologists who really feel that the choice is between dealing with mild hyperadrenocorticism and mild hypoadrenocorticism and who currently feel that the mild hyperadrenocorticism is safer for the patient and easier on the client. A small group of endocrinologists seems to think that the best approach is to try selegiline, hoping it will have an excellent effect (good movement towards normal cortisol levels, normal LDDS values and good clinical response), but knowing that it probably won't. Then moving to mitotane after the trial period if there isn't a good effect. I tend to fall somewhere between the second and third groups. I am content with good clinical response and usually base my decision to continue selegiline or not on clinical impression alone but I would be happier if the test results supported my conclusions because I tend to want something objective to verify success. I know from experience that I am susceptible to the placebo effect, just like most other people.

Mike Richards, DVM 9/12/2002

Pituitary gland hyperadrenocorticism

Question: Dear Dr. Richards: My dog Muffin, a Bichon, was diagnosed with Cushing's Disease in August 2000. I found her in the garden one night and she acted slightly disoriented and the next day I noticed about 20% of her hearing had gone. She also broke into a cabinet for food and her water consumption was way out of line. This all happened within a week. Her tests results from the liver enzymes test and the low dose dex test are as follows: ALKP ALT AST 8/24 978 291 70 11/29 751 247 43 Low Dose Dex Test Base line Cortisol 4 hours 8 hours 8/24 4.6 less than 1 1.6 11/29 5.0 1.4 3.5 She was put on 5 mg of anipryl and was doing very well, but over Thanksgiving she tried to break into the cabinets again; however, water consumption did not increase. Her vet gave her another full physical and thyroid test plus a second low dose dex. and that is the reason for the second set of figures. She is now on 10 mg. of anipryl. She eats Hill's W/D food. She was overweight by 9 lbs. a few years ago, and had to have two cruciates done so I have taken all that weight off her. This spring she had a mast cell tumor in the back of her thigh which was removed and given a Grade 2 but it showed the cells were well differentiated. But now something else has happened and I don't know what to make of it. This past week she fell three times. Her vet checked her out, had her walking up and down, checked her spine, ears for inner ear infection, and also could find no loss of muscle tone. She hasn't fallen since. My question to you is could she be starting with that hind end weakness associated with Cushing's disease? Can it start early in the diagnosis? Muffin is 12 and a 1/2 and other than some trembling in the beginning, and the food/water and all of that is under control, she shows no outward signs of this disease. She flies out to the car in the morning and jumps in very much like the younger dog. She also has a thyroid condition which is under control and has been checked out recently again. Her vet also thinks she might have had a minor stroke that night I found her in the garden slightly disoriented and hence the hearing loss so abruptly. She is very perky and in extremely good health. Her vet wants to redo the low dose dex test in the beginning of January. The other question, I have is considering the numbers up above does it look like we should be heading to Lysodren. What are the numbers that would tell you when it is time to go to Lysodren? By the way, she was tested for Cushing's disease two or three years ago because of her pot belly appearance, but my vet said the numbers did not support his thinking at the time and when she lost the weight, the pot belly went too. Thanking you in advance for your reply. Cathy

Answer: Cathy- Low dose dexamethasone testing can sometimes give information on whether pituitary disease is due to adrenal gland tumors or pituitary gland tumors or disorders. When the four hour blood levels drop below 1.4 or have levels 50% or more below the baseline (first sample) it is very likely that pituitary dependent hyperadrenocorticism is present. So it would appear to be likely, based on the test results, that Muffin has pituitary dependent hyperadrenocorticism. Pituitary gland hyperadrenocorticism can lead to apparent weakness due to hypertension (high blood pressure), due to actual muscular weakness in the rear limbs, due to neurologic damage from a pituitary tumor and heart muscle weakness. So it is definitely possible that hyperadrenocorticism is causing the problems with the weakness but it is not a certainty. The hearing loss may or may not be related to the Cushing's disease, as well. I would tend to think it would be less likely than muscular weakness as a clinical sign of Cushing's disease, though. There is no effective way to test for the success of treatment with selegiline (Anipryl Rx), which is one of the reasons that some vets are against using it. On the other hand, careful observation of clinical signs really does suggest that it works really well for about 20% of dogs and works acceptably well for at least another 20%. It does not change the results of low dose dexamethasone suppression or ACTH response testing, though. Clinical signs are the only way to judge the effect of selegiline. If you feel that the drinking and urinating is under control, if signs such as muscular weakness are improving, then it is worth continuing with the selegiline. However, if you feel, or your vet feels, that treatment is not working, or is not working well enough, then you do need to consider the use of mitotane ( Lysodren Rx) because it is more consistently effective. It also has more side effects but when selegiline doesn't work, it is clearly the best choice. For many vets, the difference in effectiveness is sufficient reason to consider Lysodren as the first choice medication in all cases of pituitary dependent Cushing's disease. I still like selegiline and I am content with reduction in clinical signs, so I don't mind (too much) the lack of ability to test for effectiveness of treatment. However, I understand why many vets would rather be able to show effectiveness through lab work. I hope this helps. If this reply causes questions, please feel free to ask them. Mike Richards, DVM 12/23/2000

Cushing's from tumor and Lysodren (Rx) treatment in Wolf

Question: I am trying to find out whether my wolf Shoona has an adrenal or pineal tumor - the local vet says it doesn't matter but I think it does. I am wondering if chewing the plastic conductors on the electric fence when she was younger had stressed her. None of the other wolves ate plastic but she would rip them off the fence and chew them to bits. I took so many away from her but there was something in the plastic which she loved to eat. After three weeks of lysodren her coat looks better and she is better, she does not drink so much but still has the rapacious appetite which does help as I give a large serving of one or more servings of either spinach, broccoli, cabbage, carrots cottage cheese or yoghurt each night along with her vitamins C, E, Glucosamine, Fishoil, , liquid B's and I have added pancreatic enzymes. She does look a lot healthier than she did when diagnosed but I know it could just be because of the lysodren which I am sure has side-effects after a while. Her tongue is clear so her digestion does not seem to be upset. Her lovely howl has changed to short gasping sounds and she does still pant. How does one know whether the three times a week lysodren is the correct dosage for her. I really hate these pat formulae which go by weight. I guess I should have the ACTH test again in a couple of weeks. Thank you for any further advice and new information you may have on Cushings. Sincerely, Paulle

Answer: Paulle- I do think that there is a significant difference in hyperadrenocorticism caused by adrenal tumors, in that the adrenal gland can be removed, which can potentially cure the Cushing's disease. The tumor has to be confined to one adrenal gland for this to work out well but that happens often enough to make it worth looking for, if adrenalectomy is not ruled out by other health problems. Most cases of hyperadrenocorticism are pituitary in origin, though. Removing adrenal glands is a relatively high risk surgery and many vets will not do this surgery but it is possible to refer a patient to a board certified surgeon familiar with the procedure. It is necessary to monitor the effect of Lysodren (Rx). The signs of problems from reactions or death of too much adrenal tissue include a drop in appetite, lethargy, vomiting, weakness, diarrhea and death. The first sign is usually a major decrease in appetite. Dropping water consumption is a good hint that Lysodren is working and so it is a good idea to carefully monitor water consumption. Usually, ACTH response testing is done every 5 to 10 days until the resting and post-ACTH cortisol levels are both in the 1 to 5 ug/dl range and then a switch to a maintenance dosage of Lysodren is made. When this stage is reached it is still a good idea to do periodic ACTH response testing and to continue to monitor water consumption. If there is an increase in water consumption it is likely that the dose of Lysodren has to be adjusted again. Good luck with this. You may still see a return of her voice and a decrease in panting as time goes on. Mike Richards, DVM 7/10/2000 Last edited 01/30/05