The efficacy of L-deprenyl for treating PDH remains controversial. Because L-deprenyl is neither adrenocorticolytic nor an
inhibitor of steroidogenesis, ACTH stimulation testing cannot be used to monitor efficacy. Owners' impressions of improvement
have been used to measure treatment efficacy in several studies. Because a metabolite of L-deprenyl is a potent sympathomimetic
and CNS stimulant, perceived improvements in the behavior of geriatric dogs with PDH may not be directly attributable to control
of PDH.38,39 Improvements in clinical signs of PDH in up to 77% of dogs treated with L-deprenyl have been reported in studies sponsored
by the manufacturer.36,40 In these same studies, low-dose dexamethasone suppression test results normalized at one or more time points in only 17%
of patients. These studies have been criticized for relying largely on subjective data collected from many independent observers.4
An independent investigation of L-deprenyl found that 20% of dogs with PDH exhibited a good response.38 This proportion is similar to the proportion of dogs with PDH resulting from a tumor of the pars intermedia rather than
the more common pars distalis tumors (Figure 2). There is little evidence that dopamine plays a major role in suppressing ACTH secretion from the pars distalis, which may
explain L-deprenyl's low efficacy in treating all dogs with PDH. Although dogs with pars intermedia tumors causing PDH may
have a good response to L-deprenyl, no clinically applicable test exists to identify this subset of dogs.7 Because of its low efficacy, L-deprenyl is generally not recommended for treating PDH.4,5,7,24 In rare, select cases in which more effective treatments are contraindicated or when clinical signs are relatively mild,
L-deprenyl therapy may be warranted.
2. Control of ACTH secretion from the pars intermedia portion of the pituitary gland differs from that of the pars distalis
portion. Corticotrophs in the pars distalis are responsible for most ACTH secretion in health and for about 80% of all pituitary
adenomas resulting in PDH. They are stimulated by both positive (corticotropin-releasing hormone) and negative (cortisol,
ACTH) feedback. In the pars intermedia, serotoninergic and dopaminergic nerve fibers stimulate and suppress ACTH secretion,
respectively. Theoretically, decreased serotonin concentrations (as induced by cyproheptadine) or increased dopamine concentrations
(as induced by L-deprenyl or bromocriptine) should suppress ACTH secretion by the pars intermedia. Tumors of the pars intermedia
are responsible for about 20% of dogs with PDH.
Administration and monitoring
L-Deprenyl is administered at a dosage of 1 mg/kg/day given orally, preferably in the morning. If no response is observed
after two months of therapy, the dose can be doubled for an additional month. If a good response is seen, normalization of
low-dose dexamethasone suppression test results and urinary cortisol:creatinine ratios should occur. If remission is not attained
within three months, alternative treatments should be investigated.6
Because of the cost of medication and monitoring and the risk of serious drug side effects, treating dogs with PDH can be
challenging. Therapy should only be instituted when clinical signs (i.e. Cushing's syndrome) are present. Generally, treatment of PDH is undertaken to improve the quality of life for the pet and
the owner (e.g. improving polyuria, resolving dermatopathy) rather than to increase the length of the pet's life. We do not advocate medical
therapy of PDH based on endocrinologic test results alone. Usually, therapy should be undertaken when clinical signs of Cushing's
syndrome adversely affect quality of life. Treatment should also be instituted in circumstances in which PDH is exacerbating
or causing other serious illnesses (e.g. diabetes mellitus, hypertension, thromboembolic disease, protein-losing nephropathy).
While many treatment options exist, mitotane remains the most effective, readily available therapy for PDH in the United States.
The protocol for selective adrenocorticolysis with mitotane remains our typical choice for therapy. Trilostane is gaining
acceptance as an alternative to mitotane, but it is not readily available. The cost of trilostane is generally higher than
that of mitotane. In our hospital, trilostane is nearly twice the cost for an average-sized dog with PDH. Ketoconazole therapy
can ameliorate signs of PDH, but the therapy may have greater utility in the short-term treatment of dogs with adrenal-dependent
disease, pending adrenalectomy, than for long-term management of PDH. If diagnostic tests become available to allow differentiation
of PDH due to pars intermedia tumors from the more common pars distalis tumors, L-deprenyl may be the safest treatment for
this subset of patients. Regardless of the treatment chosen, frequent monitoring is critical to allow adjustment of therapy
while minimizing adverse effects.
Amy E. DeClue, DVM
Leah A. Cohn, DVM, PhD, DACVIM
Marie E. Kerl, DVM, DACVIM, DACVECC
Department of Veterinary Medicine and Surgery
College of Veterinary Medicine
University of Missouri
Columbia, MO 65211
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