Trilostane is a synthetic steroid analogue that works by blocking a key enzyme involved in producing cortisol and other steroid hormones. It is best known as the go-to medical treatment for Cushing’s syndrome in dogs, where the body chronically overproduces cortisol, but it has a broader story than most pet owners realize. First synthesized in the 1970s as a tool to suppress adrenal steroid output, trilostane has since found roles in feline and equine medicine, was tested in human oncology, and even treats a mysterious hair-loss condition in certain dog breeds.
How Trilostane Works
The drug targets an enzyme called 3β-hydroxysteroid dehydrogenase (3β-HSD), which sits at an early crossroads in steroid hormone production. By competitively and reversibly binding to this enzyme, trilostane dials down the manufacture of cortisol, aldosterone, and other corticosteroids without permanently destroying the cells that make them.1PMC (PubMed Central). Trilostane: Beyond Cushing’s Syndrome That “reversible” part matters: once the drug clears the body, the enzyme can resume normal function. This is a significant practical advantage over older treatments that work by chemically destroying adrenal tissue.
Once trilostane enters the body, it is converted into a metabolite called ketotrilostane. Interestingly, rat studies have shown that this conversion runs in both directions. The body turns trilostane into ketotrilostane and then back again, effectively recycling the active drug and extending its useful life in circulation.2PubMed. The pharmacokinetics of trilostane and ketotrilostane in an interconverting system in the rat Both trilostane and ketotrilostane appear to have enzyme-blocking activity, which means the drug’s clinical effect reflects the combined work of the parent compound and its metabolite.
Cushing’s Disease in Dogs
The condition trilostane is most commonly prescribed for is canine hyperadrenocorticism, better known as Cushing’s disease. Dogs with Cushing’s overproduce cortisol, usually because of a tiny tumor on the pituitary gland (pituitary-dependent disease, which accounts for the large majority of cases) or, less often, because of a tumor on one of the adrenal glands. The excess cortisol causes a constellation of symptoms that owners typically notice: heavy drinking and urination, a bloated belly, thinning skin, hair loss, and muscle weakness.
Trilostane has become the standard medical treatment for both forms. In one study of 30 dogs with pituitary-dependent Cushing’s, 29 were successfully controlled on trilostane, with the researchers describing the drug as safe, effective, and free of side effects at the doses used.3PubMed. Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism Broader reviews echo this, noting that trilostane effectively manages both pituitary-dependent and adrenal-dependent disease in many dogs.4PubMed Central. Update on the use of trilostane in dogs That said, trilostane controls cortisol levels but does not cure the underlying tumor. It is a lifelong therapy for most patients.
One nuance worth knowing: even when cortisol is well controlled, some complications of Cushing’s, such as high blood pressure and protein loss through the kidneys, may not fully resolve and can require separate treatment.5PubMed Central. Update on the use of trilostane in dogs Owners who see their dog’s drinking normalize and their belly shrink may assume everything is fixed, but the vet will often want to keep monitoring blood pressure and urine protein levels.
Beyond Cortisol and Standard Cushing’s
Because trilostane blocks steroid production broadly, not just cortisol, it can help in cases where an adrenal tumor pumps out other hormones. A recent case report described a dog with a recurrent adrenal tumor that was producing a mix of estradiol, testosterone, and progesterone in addition to cortisol. Trilostane therapy reduced concentrations of all these hormones and reversed the dog’s clinical signs, including excessive drinking, low energy, and the characteristic pot-bellied look.6PubMed Central. Case Report: Trilostane therapy in a dog with recurrent adrenocortical carcinoma producing an array of steroid hormones This is palliative rather than curative, but it expands the drug’s utility for animals where surgery or chemotherapy is not an option.
Once a Day or Twice a Day
A question that comes up frequently in veterinary practice is whether trilostane should be given once or twice daily. The drug’s effect on cortisol wears off before 24 hours in many dogs, which theoretically makes twice-daily dosing more logical. A study comparing the two approaches found that twice-daily dosing brought cortisol levels under control faster and in a higher proportion of dogs. However, the practical clinical differences were described as small; both groups showed improved clinical scores over time, and neither experienced serious side effects.7PubMed. A comparison of once and twice daily administration of trilostane to dogs with hyperadrenocorticism
In practice, many vets start with once-daily dosing and switch to twice daily if the dog’s symptoms break through toward the end of the day, such as renewed heavy drinking in the evening. The choice often depends on the individual dog’s response and the owner’s ability to give medication on a reliable schedule.
Monitoring Treatment
Getting the dose right requires ongoing blood tests, and this is one area where the science has evolved. Traditionally, vets relied on a test called the ACTH stimulation test, which measures how much cortisol the adrenal glands can produce when poked with a synthetic hormone. This test remains widely used but has drawbacks: it requires an injection, takes about an hour of waiting, and the synthetic ACTH used can be expensive and sometimes hard to obtain.
Research suggests a simpler approach may work well. Measuring the dog’s cortisol level before the daily trilostane dose and again about three hours after the dose provides results that correlate better with how well the dog is actually doing, as judged by owners’ assessments of their pet’s symptoms.8PubMed Central. Pre-trilostane and three-hour post-trilostane cortisol to monitor trilostane therapy in dogs A separate review of the evidence found moderate support for using a basal cortisol measurement taken four to six hours after the dose as a good screening tool, particularly for ruling out oversuppression of the adrenal glands.9Veterinary Evidence. Trilostane monitoring in canine hyperadrenocorticism: can basal cortisol measurement replace the ACTH stimulation test? The takeaway for owners is that your vet’s monitoring protocol may vary, and simpler blood draws are becoming more accepted alongside or in place of the traditional stimulation test.
Side Effects and the Adrenal Necrosis Question
Most dogs tolerate trilostane well, but the side effects that do occur tend to fall into two categories. Mild reactions include loss of appetite, sluggishness, vomiting, and diarrhea. These are relatively common at the start of treatment or after dose increases and often resolve with a temporary dose reduction.10PubMed Central. Update on the use of trilostane in dogs
More serious, though less common, are signs of adrenal crisis: dangerously low cortisol, electrolyte imbalances (high potassium, low sodium), and in severe cases, collapse from low blood volume. These reflect oversuppression of the adrenal glands and are one reason regular monitoring is non-negotiable.
The most unsettling complication is adrenal necrosis, where the adrenal gland tissue actually dies. Because trilostane is supposed to be a reversible inhibitor, this was unexpected when it was first reported. Histopathology in one early case revealed cortical necrosis with inflammation and scarring.11PubMed. Adrenal necrosis in a dog receiving trilostane for the treatment of hyperadrenocorticism The mechanism is not entirely clear, but it may relate to chronic overstimulation of the adrenal glands. When trilostane lowers cortisol, the pituitary gland responds by sending more stimulatory signals (ACTH) to the adrenals, and ultrasound studies confirm that the adrenal glands often enlarge during trilostane therapy.12PubMed. Changes in ultrasonographic appearance of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane Over time, this chronic drive combined with the enzyme blockade may push some glands past their limits. Adrenal necrosis can be life-threatening, but prompt treatment with fluid support and steroid replacement can be lifesaving if the problem is caught quickly.
Trilostane Versus Mitotane
Before trilostane became widely available for veterinary use, the standard drug for canine Cushing’s was mitotane (also known by its brand name Lysodren). Mitotane works very differently from trilostane: rather than reversibly blocking an enzyme, it selectively destroys the outer layers of the adrenal cortex. This makes it effective but also inherently more aggressive, with a narrower safety margin and more frequent serious side effects.
Whether trilostane actually improves survival compared with mitotane has been debated. A systematic review and meta-analysis found trilostane may provide a long-term benefit, with an 11% higher survival rate at 36 months compared to mitotane.13PubMed Central. Effectiveness of Medical Treatment on Survivability in Canine Cushing’s Syndrome: A Systematic Review and Meta-Analysis However, individual head-to-head studies have generally found no significant survival difference. One study of pituitary-dependent cases reported median survival times of 662 days for trilostane and 708 days for mitotane, with no significant effect of drug choice after accounting for age and body weight.14Journal of Veterinary Internal Medicine. A Comparison of the Survival Times of Dogs Treated with Mitotane or Trilostane for Pituitary-Dependent Hyperadrenocorticism A study focused specifically on adrenal-dependent cases found essentially the same thing: median survival of about 14 to 16 months with either drug, with the authors noting that trilostane’s less frequent and milder adverse effects make it a reasonable first choice when surgery is not possible.15PubMed Central. Long-term survival of dogs with adrenal-dependent hyperadrenocorticism: a comparison between mitotane and twice daily trilostane treatment
So the honest picture is that survival tends to be similar with either drug, but trilostane’s safety profile is friendlier. Most veterinary internists now reach for trilostane first, reserving mitotane for cases that do not respond adequately or where specific clinical circumstances favor it.
Trilostane in Cats
Cushing’s disease is rare in cats compared with dogs, but it does occur and tends to be harder to manage. Diabetes is a common complication, present in the majority of affected cats, which adds a layer of treatment complexity. Trilostane is considered the most effective medical option available for feline Cushing’s, though the evidence base is smaller simply because so few cats develop the condition.
In the largest published series, 15 cats treated with trilostane showed improved clinical signs and ACTH stimulation results in the majority of cases. Diabetic cats saw their insulin requirements drop by about a third within the first two months. The median survival time was 617 days, and the drug was well tolerated over the long term.16PubMed. Trilostane therapy for treatment of spontaneous hyperadrenocorticism in cats: 15 cases (2004-2012) Complications in that study were mostly unrelated to the adrenal disease itself and included kidney disease, infections, and pancreatitis. A review of the feline literature echoes these findings, noting that most treated cats show a reduction in clinical signs even if complete resolution is uncommon, and that starting doses have trended lower over time as clinicians gain experience.17PubMed Central. Peculiarities of feline hyperadrenocorticism: Update on diagnosis and treatment
Trilostane for Horses
Horses develop their own version of cortisol-related endocrine disease, called pituitary pars intermedia dysfunction (PPID, formerly equine Cushing’s). Today, the drug pergolide is the standard treatment for PPID, but trilostane was explored as an option before pergolide became dominant. In a study following horses over one to two years, trilostane reduced lethargy in all treated animals, improved excessive drinking and urination across the board, and resolved or improved chronic laminitis in about four out of five cases. No side effects were reported.18PubMed. Efficacy of trilostane for the treatment of equine Cushing’s syndrome Despite these promising results, trilostane never became the first-line treatment in horses. Pergolide targets the root hormonal dysfunction in PPID more directly, while trilostane only reduces cortisol downstream. Trilostane remains a backup option for horses that cannot tolerate or fail to respond to pergolide.
Alopecia X and Hair Regrowth
One of the more surprising uses of trilostane has nothing to do with Cushing’s disease. Alopecia X is a mysterious hair-loss condition that primarily affects Nordic and plush-coated breeds like Pomeranians, Alaskan Malamutes, and miniature poodles. The affected dogs lose fur symmetrically over the trunk while remaining otherwise healthy. The cause is poorly understood, and the condition has gone by several names over the years, none of which fully explains it.
Trilostane has shown remarkable results for these dogs. In one study, treatment led to complete hair regrowth in 85% of Pomeranians and in all of the miniature poodles, typically within four to eight weeks. No adverse effects were observed.19PubMed. Treatment of canine Alopecia X with trilostane A smaller study in Alaskan Malamutes found the same outcome: full hair regrowth in all three dogs within six months, with no side effects.20PubMed. The use of trilostane for the treatment of alopecia X in Alaskan malamutes The mechanism is unclear. Researchers have speculated that the effect may come from reducing adrenal steroid levels, from trilostane’s ability to block estrogen receptors at the hair follicle, or from some combination of both. This is a cosmetic condition rather than a dangerous one, so the decision to treat involves weighing the benefits of regrown fur against the costs and monitoring requirements of ongoing steroid-modifying therapy.
Trilostane in Human Medicine
Trilostane had a brief life in human clinical use before its veterinary career took off. In the 1980s, researchers investigated it as a treatment for advanced breast cancer in postmenopausal women, on the theory that blocking steroid production could starve hormone-sensitive tumors. Combined with supplemental corticosteroids (to replace the cortisol trilostane was suppressing), the drug produced objective tumor responses in roughly a quarter of patients in one trial, with another 13% achieving disease stabilization.21PubMed. Trilostane in the treatment of advanced breast cancer A later trial using a similar regimen in women whose disease had progressed after other hormonal therapies found complete remission in one patient and partial responses in five out of 26.22PubMed. Trilostane with hydrocortisone in treatment of metastatic breast cancer
These results were modest, and trilostane was eventually overtaken by aromatase inhibitors, which more selectively block estrogen production with fewer systemic effects. Trilostane was withdrawn from the UK human market in 1994. Its legacy in human medicine is largely as a stepping stone toward the more targeted hormonal therapies now used in breast cancer and Cushing’s syndrome.
Trilostane was also studied for its effects on progesterone during pregnancy, since blocking 3β-HSD reduces progesterone production along with cortisol. Randomized trials confirmed that trilostane significantly lowered progesterone and estradiol levels in women while maintaining normal cortisol rhythms.23PubMed. Inhibition of progesterone secretion with trilostane for mid-trimester termination of pregnancy: randomized controlled trials The drug’s effects on reproductive hormones vary across species: in rabbits, trilostane triggers premature delivery by dropping progesterone, but in dogs it fails to terminate mid-term pregnancies even after a week of treatment, suggesting that canine pregnancy maintenance relies less heavily on adrenal progesterone.24PubMed Central. Trilostane: Beyond Cushing’s Syndrome
The Compounding Problem
One practical concern that rarely makes it into the conversation between vet and pet owner involves drug quality. The branded trilostane product (Vetoryl) comes in fixed capsule sizes, which do not always match the dose a particular dog needs. This leads many veterinarians to prescribe compounded trilostane, custom-prepared by a compounding pharmacy in a more precise dose. The problem is that compounded formulations are not always accurate. A study evaluating compounded trilostane packets found that only about 41% contained an acceptable amount of the drug.25PubMed Central. Evaluation of compounded trilostane packets for dogs with naturally occurring hyperadrenocorticism
That is a striking failure rate. If a packet contains too little trilostane, the dog’s Cushing’s symptoms go uncontrolled. If it contains too much, the risk of oversuppression and adrenal crisis goes up. For owners whose dogs are on compounded trilostane and seem to swing between under-control and over-control despite consistent dosing, inconsistent drug content is a real possibility worth discussing with the prescribing vet. Using the branded product where the capsule sizes allow can sidestep this issue, though it sometimes means accepting a slightly less precise dose.