TREATMENT OF PITUITARY CUSHINGS
We will begin this section by noting that pituitary-dependent Cushing's syndrome does not always require treatment. The ultimate goal of therapy is to improve the patient's life quality and to fortify the patient's bond with his or her owner so if the Cushing's patient is not having problems with his or her symptoms, treatment may not be indicated. In deciding whether or not to treat Cushing's syndrome, consider symptoms that this particular individual patient is dealing with. For example, if the patient is drinking excessively but is not urinating in the house, this may not be a problem. If the patient has recurrent bladder or skin infections, high blood pressure, urinary protein loss, or is so hungry as to be raiding the kitchen regularly then he or she needs treatment.
There are two medications commonly used in the management of pituitary dependent Cushing’s disease: Lysodren® (also called Mitotane or o,p’-DDD), Trilostane (brand name Vetoryl®). These medications are associated with different side effects potential and expense and any of them can be expected to produce good results in a confirmed case of pituitary-dependent Cushing's syndrome. Two other medications: Ketoconazole and Selegilinere also sometimes used but with less reliable results but they may be applicable in special circumstances. We will review all four choices.
Lysodren® (generically known as mitotane and chemically known as o,p’-DDD) has been the only treatment for pituitary dependent Cushing’s disease until relatively recently. It is convenient to use and relatively inexpensive, though it does have the potential for very serious side effects. One of the disadvantages of Lysodren® therapy is the need for regular monitoring blood tests. Too much Lysodren® is toxic and not enough is not going to control the Cushing's symptoms.
HOW THIS MEDICATION WORKS
Cut surface of adrenal gland
Lysodren® should be considered to be a drug of chemotherapy. It actually erodes the layers of the adrenal gland that produce corticosteroid hormones. The pituitary tumor continues to secrete excess stimulation but the adrenal gland is no longer capable of excess hormone production in response. Instead, if everything has gone according to plan, the adrenal cortex will have been eroded away so as to yield normal (rather than excessive) cortisol production. Over several months all the symptoms of Cushing's syndrome resolve and the patient feels active and happy.
Problems result when too much of the adrenal cortex is eroded. Short-term Lysodren® reactions are common (something like 30% of dogs will have one at some point), necessitating the use of a prednisone antidote pill that the veterinarian supplies. In event of such short term reactions, Lysodren® is discontinued until the adrenal gland can re-grow to the desired thickness and therapy is resumed, possibly at a lower dose. Sometimes excess adrenal erosion is permanent and the dog must be treated for cortisone deficiency. This is more serious and the potential for this kind of reaction has been the driving force behind the search for better medications for the treatment of pituitary dependent Cushing’s disease (though it is worth noting that in Europe it is common to purposely create a cortisol deficiency -see the section below on Addison's disease.)
HOW THIS MEDICATION IS USED
There are two phases to the treatment of Cushing’s disease with Lysodren®: an induction phase to gain control of the disease and a lower dose maintenance phase which ideally lasts for the animal’s entire life.
During induction, the pet owner receives a prescription for Lysodren® (usually obtained through a local human pharmacy) plus a bottle of prednisone tablets to be used as an antidote should any Lysodren® reactions erupt. Be sure you understand which pill is which. Lysodren® is given twice a day with meals during this period so that the plump, excessively stimulated adrenal gland can be rapidly shaved down to the desired size. It is very important that Lysodren® be given with food or it will not be absorbed into your dog’s body. A test called an ACTH stimulation test (the same test which may have been used to diagnose Cushing’s disease originally) is used to confirm that the induction endpoint has been reached.
An approach gaining popularity involves reducing the dog's food intake by 30% the day before induction begins to ensure the dog is very hungry for induction. The food is restricted in this way throughout the induction period. The endpoint of induction is determined by a subtle reduction in the patient's appetite (looking up half way through eating the bowl of food, not running to the bowl as quickly as usual, not finishing the meal etc.) Should any of these signs be observed, this would indicate that the endpoint of induction has been reached and it is time for the ACTH stimulation test. Induction proceeds until endpoint has been reached but if 8-9 days have passed and a clear endpoint has not been observed, the dog should have the ACTH stimulation test at that time anyway
Note: Lysodren® therapy should never be used in a dog that does not have a good appetite.
A Cushing's dog that does not have a good appetite has an additional problem
which must be diagnosed before pursuing therapy for Cushing's syndrome.
You should call your veterinarian if any of the following signs observed:
- Diarrhea or vomiting
- Appetite loss (this may be as subtle as less enthusiasm towards eating when the food is served, not running for the bowl etc.)
- Decrease in water consumption (it may be helpful for you to measure water consumption during the induction period)
- Lethargy or listlessness
These signs indicate not only that endpoint has been reached but that a Lysodren® or Addisonian reaction is probably occuring (see below) and your dog may need to receive the antidote. When endpoint is reached, the dog should have an ACTH stimulation test within 24 hours if possible.
It is a good idea to maintain daily telephone contact with your vet after the third day or so of induction as it is at this point that a dog becomes at risk for reaching an early induction endpoint.
If none of the above signs are noted, then the ACTH Stimulation test proceeds as scheduled on the 8th or 9th day of induction. If this test indicates that sufficient adrenal erosion has taken place, then the Lysodren® dose is given once or twice a week instead of twice a day and the dog has successfully entered maintenance. If the test indicates that more adrenal erosion is needed, induction may be continued or the maintenance dose may simply need to be higher than originally planned. Most dogs are ready for maintenance within the first week of induction but others require more time, especially if they are taking concurrent drugs that alter the metabolism of Lysodren®. (Phenobarbital would be the obvious such medication.)
After achieving maintenance, another ACTH stimulation test is recommended after about a month and then twice a year or so thereafter. Approximately 50% of dogs will experience a relapse at some point and require a second round of induction or a change in maintenance dose.
- Full reversal of clinical signs associated with Cushing’s disease can be expected after 4 to 6 months of Lysodren® therapy. Usually the first, sign to show improvement is the excess water consumption. The last sign to show change will be hair re-growth.
- If appetite loss, vomiting, diarrhea or listlessness occur at any time during maintenance, a Lysodren® reaction should be suspected. The veterinarian should be notified; it may be time for one of the prednisone antidote pills. A Lysodren® reaction generally reverses within 30 minutes on an antidote pill.
Trilostane is an inhibitor of an enzyme called 3-beta-hydroxysteroid dehydrogenase. This enzyme is involved in the production of several steroids including cortisol. Inhibiting this enzyme inhibits the production of cortisol. While trilostane is substantially newer to the market than Lysodren®, the traditional treatment, several studies have determined this medication to be as effective as Lysodren® in treating Cushing's syndrome. Further, trilostane is approved for the treatment of pituitary dependent Cushing's disease (and Lysodren® is not) and there is belief that trilostane has less potential for side effects. For these reasons, trilostane has emerged as the most common treatment for pituitary dependent Cushing's disease.
Trilostane is given once or twice a day with food (as opposed to Lysodren® which is given twice a week). Common side effects are mild lethargy and appetite reduction especially when medication is started and the body adapts to its hormonal changes. Addisonian reactions (see below) have been reported where the adrenal cortex actually dies off. Most trilostane reactions are minor and can be reversed with discontinuation of the trilostane; however, permanent Addisonian reactions, where cortisol suppression is too strong (see below), are possible just as with Lysodren® with an important difference. With Lysodren® reactions depend on the amount being given (higher dose = more chance of reaction) but with trilostane reactions are random and unpredictable ("idiosyncratic").
Both Lysodren® and trilostane have their doses adjusted based on results of periodic blood tests (ACTH stimulation tests) typically done at 14 days, 30 days, 90 days and then every 4-6 months depending on results. One might ask why one might consider trilostane given that its monitoring is similar to that of Lysodren® while its dosing schedule is less convenient. Initially it was believed that because trilostane uses an enzyme inhibitor with reversible effects, trilostane would not have the potential to cause a life-threatening Addisonian reaction. This is no longer felt to be true but at least there is an alternative effective medication for pets that do not tolerate Lysodren® or who have had difficulty achieving regulation with Lysodren®.
Advantages of Trilostane over Lysodren®
- Trilostane acts as an enzyme inhibitor and the inhibition it causes is fully reversible. It is unclear why Addisonian reaction is still possible with this medication. In theory it should be safer.
Disadvantages of Trilostane Compared to Lysodren®
- Because initial references to trilostane suggested it was safer than Lysodren®, it is possible for a pet owner to have a false sense of security and ignore important signs of drug reaction.
- Some dogs do better with once daily administration and for other dogs, the medication simply does not last long enough to allow for once daily dosing. Monitoring tests will help determine what regimen is best for a given patient. Timing of the monitoring blood tests relative to the administration of the medication is much stricter with trilostane than with Lysodren®.
- Lysodren® costs substantially less since it is given less frequently.
- Trilostane is given once or twice daily while Lysodren® is given only once or twice a week.
WHAT IS ADDISON’S DISEASE / ADDISONIAN REACTION?
Addison’s disease, also called hypoadrenocorticism, is the opposite of Cushing’s disease; Addison's disease results from a deficiency of cortisone. If Lysodren® erodes away too much of the adrenal gland or if there is an idiosyncratic trilostane response, an Addisonian reaction occurs which can be temporary or permanent. The symptoms mentioned above (vomiting, diarrhea, listlessness, appetite loss) may be seen and if untreated, the patient can go into shock and die. If one suspects an Addisonian reaction is occuring, a dose of prednisone (which has hopefully been provided to keep on hand in case of emergency) should reverse the reaction within 30 minutes (a couple of hours at most). If no response to prednisone is seen, the dog has some other illness. If the dog is back to normal after the prednisone dose, then the veterinarian should be contacted for further instructions. The prednisone will likely have to be continued for a couple of weeks.
Addison’s disease can be permanent after a drug reaction. If this occurs, hormone supplementation becomes needed indefinitely to prevent life threatening shock as the body becomes unable to adapt to any sort of stress on its own. Medications to treat Addison's disease can be very expensive, especially for larger dogs, and it is generally felt that the creation of Addison’s disease is undesirable. That said, in Europe it is common to treat Cushing's disease by purposely creating an Addisonian state as it is much simpler to treat Addison's disease than it is to treat Cushing's disease. The technique for purposely creating Addison's disease is called "medical adrenalectomy." It involves very high doses of Lysodren® and is done in a very controlled manner. It is not a common procedure in the U.S.
See more information on Addison's disease, which can also occur in animals (and people) as a natural occurance with no help from Lysodren®.
At the present time, meaningful treatment with medication involves a choice between trilostane and Lysodren® but in the years before trilostane was available in the U.S., alternatives for dogs intolerant of Lysodren® were in great demand. Ketoconazole, an anti fungal medication, was found to have steroid suppressing side effects which could be exploited in the treatment of Cushing's syndrome. Unlike the other drugs, ketoconazole did not pose a risk for Addisonian reaction. Unfortunately, sustained responses were hard to come by and since more effective alternatives have emerged, ketoconazole is now relegated to its original function: the treatment of fungal disease. For more information on ketoconazole, click here.
Selegiline (also called L-Deprenyl or Anipryl®) acts by increasing dopamine and consequently reducing ACTH production. The problem is that this type of ACTH regulation does not work well when a pituitary tumor is involved as tumors tend not to respond to regulation like normal tissues do. Selegiline breaks down into amphetamines (strong stimulants) which may therapeutic in other ways to Cushing's patients. Side effects are minimal though there is some expense compared to the other medications used for the treatment of Cushing's syndrome. For more information about selegiline, click here.
A NOTE ON SURGERY
Since pituitary-dependent Cushing's syndrome is caused by a pituitary tumor, the question arises about removing the tumor surgically. This treatment has received more attention recently but the location of the pituitary (at the base of the brain) makes surgery problematic. Surgery is not at this time a common treatment in the U.S. and very special facilities are required for this type of surgery. Unless you live in a unique community where there is a surgeon with extensive experience in this as yet esoteric procedure, we recommend sticking with the medical therapies.
Choosing a therapy for pituitary Cushing's syndrome should take into account efficacy, cost, monitoring schedule, dosing schedule, and side effects potential. In the future, surgical options are likely to come forward as they have in the treatment of human Cushing's syndrome. Please direct further concerns and questions to your regular veterinarian as you pick an option.
Page last updated: 9/16/2020
Medications to control excessive production of cortisol at the adrenal gland include ketoconazole, mitotane (Lysodren) and metyrapone (Metopirone). Mifepristone (Korlym, Mifeprex) is approved for people with Cushing syndrome who have type 2 diabetes or glucose intolerance.Which drug would be effective for the treatment of pituitary Cushing's syndrome? ›
Cabergoline, a drug used mostly to treat prolactin-secreting pituitary tumors, can normalize ACTH and cortisol production in approximately 30 percent of patients. Similarly, pasireotide can normalize ACTH and cortisol in 20 to 25 percent of patients with Cushing's disease.What is the first line treatment for Cushing's syndrome? ›
Essential Points. The Endocrine Society recommends that the first-line treatment for endogenous Cushing's syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol.Is it worth treating Cushings disease in dogs? ›
In general, a dog with untreated Cushing's can actually live as long as a treated dog, but will likely have more side effects (over time) from the disease if not treated.Can you treat Cushing's without surgery? ›
Management and Treatment
If a tumor is causing Cushing's syndrome, it might need to be killed with radiation or removed surgically. Another option is for your healthcare provider to prescribe a medication such as ketoconazole that will slow down the production of cortisol.
Slow down with the salt
Excess cortisol from Cushing's syndrome can increase blood pressure, leading to hypertension. Avoid processed foods packed with sodium, which contributes to high blood pressure. Focus on fruits, vegetables, and reduced-sodium soups, dressing, and spreads.
- Melatonin. ...
- Calcium and vitamin D. ...
- Potassium. ...
- Other natural interventions that may help people with adrenal disorders include vitamin A, curcumin, licorice, DHEA, pantothenic acid, and coenzyme Q10.
- Bromocriptine and cabergoline for pituitary adenomas called prolactinomas, which produce too much of the hormone prolactin. ...
- Somatostatin analogs (for example, Lanreotide®, Octreotide®) for pituitary adenomas that produce excess growth hormone.
Cushing's syndrome can be caused by overuse of cortisol medication, as seen in the treatment of chronic asthma or rheumatoid arthritis (iatrogenic Cushing's syndrome), excess production of cortisol from a tumor in the adrenal gland or elsewhere in the body (ectopic Cushing's syndrome) or a tumor of the pituitary gland ...What is the best cortisol reducer? ›
- Ashwagandha. ...
- Omega-3 Fatty Acids. ...
- Prebiotics and Probiotics. ...
- Cordyceps Sinensis. ...
- Phosphatidylserine. ...
The most common is a noncancerous tumor of the adrenal cortex, called an adrenal adenoma, but only a small fraction of adenomas produce too much cortisol. Cancerous tumors of the adrenal cortex are rare, but they can cause Cushing syndrome as well.What are three symptoms of Cushing's syndrome? ›
- Weight gain, especially in the upper body.
- Rounded face and extra fat on the upper back and above the collarbones.
- High blood sugar (diabetes)
- High blood pressure (hypertension)
- Thin bones (osteoporosis)
- Muscle loss and weakness.
- Thin, fragile skin that bruises easily.
The most important factors in considering euthanasia are uncontrollable urination and excessive drinking. Dogs with neurological signs from a pituitary tumor have a poor prognosis. Medical therapy for adrenal-dependent Cushing's has a fair to good prognosis with a survival rate of about 15 months.What happens if a dog is not treated for Cushing's? ›
Pets with Cushing's disease face an increased risk of developing a host of serious conditions including kidney damage, high blood pressure, blood clots, and diabetes if the condition is left untreated.What is end stage Cushings in dogs? ›
As the disease progresses, dogs lose muscle and become weak. Owners might notice a thinning of the skin, lesions on the skin, and hair loss on the flanks, neck, and perineum. Obesity and lack of energy are also symptoms.How long can you live with Cushing syndrome? ›
Cushing's disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said. “This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.”Can you reverse Cushing's? ›
Untreated Cushing syndrome can be life-threatening. Fortunately, most people with the syndrome are treated and cured.Can stress cause Cushing's? ›
Although cortisol is related to stress, there is no evidence that Cushing's syndrome is directly or indirectly caused by stress. Cushing's syndrome is considered rare, but that may be because it is under-reported.How do you reverse Cushing's disease naturally? ›
Discontinuing use of medications that increase cortisol (such as steroids) or taking a lower dose. For those with Cushing's syndrome, lowering cortisol can be at least helped by switching to a whole foods, anti-inflammatory foods diet, reducing stress levels, and changing the level of exercise and physical activity.How do you feel with Cushing's? ›
People with Cushing's syndrome may see their face get round ("moon face"), they gain weight in unusual ways, bruise easily or feel weak, tired and sad. Women and men may also notice fertility and other problems. CS is most often found in adults between the ages of 20 and 50.
Results showed exercise does significantly (p<0.001) and substantially elevate cortisol to near Cushing's Syndrome levels. However, the cortisol response to exercise in athletes is highly transient and abates rapidly.What vitamin helps reduce cortisol? ›
But if recommended, the most important mineral we use in our clinical practice is magnesium, which helps to regulate cortisol levels. Vitamin B12, folic acid, and Vitamin C can also help support the metabolism of cortisol.What deficiency causes Cushing's? ›
Vitamin D Deficiency in Cushing's Disease: Before and After Its Supplementation.What foods heal the pituitary gland? ›
Diet for healthy Pituitary gland
Important nutrients for good pituitary function are a variety of minerals- especially manganese, magnesium, and vitamin E. Foods rich in minerals are wheat, leafy greens, nuts and some legumes. Other important nutrients are iron and iodine.
Yoga asanas, breathing, relaxation and meditation all help to keep the pituitary gland healthy. Some flowing asanas such as Salute to the Sun stimulate the circulatory system which brings fresh nutrients to the pituitary tissue.What foods keep pituitary glands healthy? ›
A healthy diet is one which consists of an appropriate balance of protein (meat, poultry, fish, eggs and pulses), carbohydrates (whole meal bread, cereals and potatoes) and fat (oils, diary products, nuts and fish) as well as other essential ingredients such as vitamins and some minerals – found in fruit and vegetables ...Which patient has the greatest risk of developing Cushings syndrome? ›
Women, ages 20 to 50, are at the highest risk of developing Cushing disease. Other risk factors include having diabetes, high blood pressure (hypertension), kidney stones, being obese, and living with pituitary or adrenal tumors.How quickly does Cushing's progress? ›
Because Cushing's progresses slowly and gradually, in most cases, it can go unrecognised for quite some time, sometimes resulting in depression. Looking back, many patients realise that there were clues to the condition two or more years before they were referred to an endocrinologist.What is the most common psychiatric manifestation of Cushing syndrome? ›
Depression is the most prevalent psychiatric disturbance in Cushing's syndrome. A major depressive syndrome is seen in 50%–70% of the cases .What reduces cortisol quickly? ›
Deep breathing stimulates the parasympathetic nervous system, which is responsible for relaxation and lower cortisol levels. Meditation, yoga, tai chi, and qigong are great ways to practice deep breathing.
Research suggests these herbs and natural supplements might lower stress, anxiety and/or cortisol levels: Ashwagandha. Rhodiola. Lemon balm.What reduces cortisol overnight? ›
Getting enough sleep
Getting adequate sleep and having a regular sleep-wake schedule may help reduce cortisol levels.
Pseudo-Cushing syndrome presents with some symptoms and mildly abnormal hormone levels that overlap with those seen in Cushing syndrome. These patients, however, do not have the tumors that are associated with Cushing syndrome.What are some other issues that could be a problem in the future with Cushing's syndrome? ›
These may include hypertension, dyslipidemia, central obesity or persistent diabetes mellitus, among others, leading to an increased cardiovascular risk (13).What's the difference between Cushing's syndrome and Cushing's disease? ›
What is the difference between Cushing disease and Cushing syndrome? Cushing disease occurs when Cushing syndrome is caused by an ACTH-producing pituitary tumor, whereas Cushing syndrome is the set of symptoms that results when there is a surplus of cortisol in the body.What are the stages of Cushings disease? ›
These three Cushing's disease signs are known as the three P's—polydipsia, polyuria, and polyphagia.What is the best test to diagnose Cushing's disease? ›
The best screening test for Cushing's syndrome is a 24-hour urine collection with analysis for urinary free cortisol excretion.What kind of doctor diagnose Cushing's disease? ›
The rarity of Cushing's disease makes it hard to diagnose. In fact, most endocrinologists treat few or no people with Cushing's disease in their entire careers. After ruling out other conditions, you and your primary care physician or endocrinologist may suspect Cushing's disease.Why do dogs with Cushing's pant at night? ›
The basis for increased panting in dog's with Cushing's disease is multifactorial. First, Cushing's disease results in increased fat deposits in the abdominal cavity and around the chest. Second, an increase in liver size impedes the diaphragm from being able to expand with ease.Should you withhold water from a dog with Cushings? ›
You must continually monitor your dog's food and water intake. Both should return to a normal level. Water intake should be less than 1 ounce per pound (66 ml per kilogram) of body weight per day, but do not limit the water if your dog needs to drink more.
Highly digestible protein source - Pooches with Cushing's disease fare better with digestible proteins. They need the amino acid building blocks to help prevent muscle wasting, which is common in dogs with Cushing's. Good sources of digestible proteins include eggs and muscle meats like beef, chicken, and lamb.Should I treat my old dog for Cushings? ›
Usually treatment for Cushing's is not even recommended unless the dog has clinical signs because treatment does not necessarily change their overall life span - it just keeps them from being polyuric (urinating a lot), polydypsic (drinking a lot), losing their hair, etc.Are dogs with Cushing's in pain? ›
Most dogs with Cushing's are not in any pain and their symptoms can be easily managed through medication. Dogs that have developed the condition due to a tumor on the adrenal gland may require the tumor to be surgically removed as these tumors are aggressive.How long can a dogs live with a pituitary tumor? ›
The outlook for dogs with pituitary-dependent Cushing disease is survival for about 2 years, with or without medications. Dogs treated with radiation or surgery may survive 2–5 years. Dogs that undergo surgery for a tumor on one of the adrenal glands may survive about 18 months.How does Cushing's cause death? ›
Vascular disease is the main cause of death in CS patients (2, 4, 8, 12, 14). Indeed, the risk of cardiovascular and cerebrovascular events is greater in patients with active CS as compared with the general population and persists during long-term follow-up, even after remission has been achieved (7, 14).How does a dog with Cushing's feel? ›
The increased appetite is a direct result of elevated levels of cortisol, which stimulate appetite. Lethargy (drowsiness or lack of activity) and a poor hair coat are also common in pets with hyperadrenocorticism. "Many dogs with Cushing's disease develop a bloated or pot-bellied appearance."How can I help my dog with Cushing's disease? ›
Most veterinarians treat both adrenal- and pituitary-dependent Cushing's disease with medication. The only way to "cure" Cushing's disease is to remove the adrenal tumor if the disease is adrenal-dependent and the tumor hasn't spread, says Stohlman.What is life expectancy with Cushings? ›
Cushing's disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said. “This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.”Can the Cushing disease be cured with medicine? ›
Untreated Cushing syndrome can be life-threatening. Fortunately, most people with the syndrome are treated and cured.What is the most common overall cause of Cushing's syndrome? ›
The most common is a noncancerous tumor of the adrenal cortex, called an adrenal adenoma, but only a small fraction of adenomas produce too much cortisol. Cancerous tumors of the adrenal cortex are rare, but they can cause Cushing syndrome as well.
Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality.Does Cushings affect the brain? ›
Brain structural abnormalities related to Cushing's syndrome have been repeatedly found, including smaller hippocampal volumes, enlarged ventricles, and cerebral atrophy3.Can Cushings cause death? ›
The causes of premature death in untreated Cushing's syndrome are vascular disease (myocardial infarction/stroke), uncontrolled diabetes mellitus and complications and infections.Can stress cause Cushing's disease? ›
Although cortisol is related to stress, there is no evidence that Cushing's syndrome is directly or indirectly caused by stress. Cushing's syndrome is considered rare, but that may be because it is under-reported.