Pituitary pars intermedia dysfunction (Proceedings)

The pituitary gland plays an important role in many bodily functions.  It is divided into three parts, the anterior, intermediate and posterior lobes.  The posterior lobe secretes oxytocin (important in parturition and milk letdown) and vasopressin (important in maintaining body water balance) into the circulation. 

A large variety of hormones are produced in the anterior pituitary, including thyroid stimulating hormone (TSH), growth hormone, prolactin, luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropic hormone (ACTH), b-lipotropin, b-endorphin, and melanocyte stimulating hormone (MSH).  The intermediate lobe synthesizes a large precursor protein, pro-opiomelanocortin (POMC), that is broken down into ACTH, MSH, b-lipoprotein, b-endorphin, and corticotrophin-like intermediate lobe peptide (CLIP).

Pituitary pars intermedia dysfunction (PPID) is diagnosed fairly commonly, and has been estimated to affect 15-30% of older horses and ponies.  It appears to be caused by degeneration of dopaminergic neurons, originating in the hypothalamus, that normally inhibit production and/or secretion of POMC from the intermediate lobe.  The cause of the neurodegeneration is unknown, but recent evidence suggests that oxidative stress plays a role.  Oxidative stress probably tends to accumulate as horses age, until some critical threshold is reached that results in slowly progressive neurodegeneration. 

In addition, some horses may be genetically more sensitive to oxidative stress and/or neurodegeneration through overexpression of α-synuclein, a nerve terminal protein that is found in the Lewey bodies and neurites of people with Parkinson's disease, a dopaminergic neurodegenerative disease of people.  The function of α-synuclein is currently unknown. 

However, synuclein decreases tyrosine hydroxylase activity and dopamine synthesis and release, and people with multiple copies of the α-synuclein gene are at increased risk to develop Parkinson's disease.  Thus, it has been proposed that horses that overexpress α-synuclein, either due to genetic predisposition or in response to environmental stimuli, are more susceptible to oxidative stress, are more likely to develop neurodegeneration of dopaminergic neurons, and are more likely to develop PPID.

One of the earliest clinical signs of PPID is the presence of a long, shaggy haircoat or a delay in shedding of a winter coat.  The coat may also have a greasy feel, due to hyperhydrosis (increased sweat production).  Dermatophilus infection is common, probably secondary to the moist environment and decreased immune function.  

Muscle atrophy of the epaxial and gluteal muscles is common, and often interpreted by owners as weight loss.  PPID probably contributes to infertility in older mares.  Increased water intake and urine output occur in approximately 30% of horses with PPID as the disease progresses. Occasionally non-pregnant mares will lactate.  One of the biggest problems experienced by horses with PPID is that they are prone to recurrent bouts of laminitis. 

This is further complicated by a predisposition to develop sole abscesses.  In addition to sole abscesses, horses with PPID have trouble fighting other infectious diseases, such as pneumonia, tooth root abscesses, and sinusitis.  Wounds tend to be slow to heal.  In very advanced cases, circling, blindness and seizure activity have been described.  These clinical signs are likely caused by expansion of the pituitary gland and exertion of pressure on the optic chiasm and hypothalamus.

The traditional view of PPID is that clinical signs are caused by overproduction of ACTH, leading to excessive circulating corticosteroids.  However, baseline plasma concentrations of cortisol are usually within normal range in horses with PPID.  Clinical signs may be caused by an apparent loss of the normal diurnal rhythm for cortisol. However, it is also likely that at least some of the clinical signs of PPID are caused by other metabolites and peptides that are being produced in excess (eg MSH).

A large number of tests have been proposed for diagnosis of PPID, but most of them are neither sensitive nor specific.  Earlier evidence for good sensitivity and specificity for some tests has more recently been discounted as more horses with more subtle signs are being tested earlier in the course of disease.  Additional problems that have more recently been encountered include seasonal influences on results, as well as variation in results within the same individual when tests are repeated.  Thus, while diagnosis of PPID is fairly straightforward in horse exhibiting classical clinical signs, diagnosis in horses with vague clinical signs, just starting to develop PPID, is problematic.

In horses with classic clinical signs, CBC and serum chemistry panel often show a mature neutrophilia, lymphopenia and mild hyperglycemia (similar to a stress response).  Hyperglycemia above the renal threshhold (180-240g/dl - diabetes mellitus) occurs occasionally, but is the exception rather than the rule.  Measurement of serum cortisol is not a useful test for diagnosis of PPID, because it is usually within the normal range.

It has been proposed by some that PPID can be diagnosed by finding less than a 30% decrease in serum cortisol measured in the late afternoon relative to measurement in the early morning.  However, loss of a diurnal pattern of cortisol secretion is not specific to PPID, occurring both with other systemic diseases as well as with normal aging.  Measurement of elevated serum insulin concentration relative to serum glucose concentration is neither specific nor diagnostic for this disease, but is useful in predicting susceptibility to laminitis.

The test traditionally used to diagnose PPID is the dexamethasone suppression test, in which a positive diagnosis of PPID is made by demonstrating a lack of cortisol suppression in response to dexamethasone administration.  Although the risk appears to be low, there is some fear that administration of dexamethasone to a horse with PPID and laminitis might exacerbate the laminitis.  For this reason, additional tests have been developed over the years to try to avoid administration of dexamethasone. 

If one is trying to avoid administration of dexamethasone, the next best test currently available for diagnosis of PPID is measurement of resting plasma concentration of ACTH.  (In the future, measurement of plasma concentration of MSH may also be found to be a useful test for diagnosis of PPID.)  The advantages of measuring resting plasma ACTH (or MSH) concentration are that it requires collection of only one blood sample and it does not require administration of dexamethasone. 

The primary disadvantage of using plasma ACTH concentration to diagnose PPID is that it appears that plasma ACTH concentration remains normal for some unknown period of time early on in disease.  Thus, false negatives are a problem.  If one uses a cut-off value of 50-55 pg/dl (ie horses are not diagnosed as having PPID unless their plasma ACTH concentrations are greater than 50-55 pg/dl), the likelihood of a false positive is very very low, except possibly in the fall (see below). 

Another disadvantage of ACTH measurement is that ACTH is labile and sticks to glass.  Blood is collected (preferably in the morning) into EDTA in plastic tubes, placed on ice, and processed as soon as possible (ideally within an hour, but certainly within 3 hours) after collection.  Plasma is stored frozen in a plastic container to prevent adherence of the ACTH to glass.  The sample must be shipped to the laboratory frozen.

There is recent evidence that results of dexamethasone suppression tests or measurement of plasma ACTH, when performed on multiple occasions, may vary within an individual horse to the point of giving conflicting results as to whether or not a horse truly has PPID.  Necropsy confirmation of diagnosis has not been performed in many of these horses, so the cause of the variation is unknown at this time.  It may be that horses that are just beginning to develop PPID may have varying test results until the status of their disease is more advanced.  A seasonal variation has also been reported, with concentrations of plasma ACTH and MSH being higher in the fall than in the spring.

Since endogenous ACTH is often within the normal range in horses with PPID early in the course of disease, two additional tests have more recently been described as being more sensitive in these horses.  Both tests rely on the principle that stimulation of ACTH release will be exaggerated in horses with PPID, even if their baseline concentrations are in the normal range. One test uses administration of thyrotropin releasing hormone (TRH) intravenously to stimulate ACTH release, whereas the other uses administration of domperidone orally.

Other tests that have been proposed for diagnosis of PPID include ACTH stimulation test (measuring plasma cortisol response to ACTH), thyrotropin releasing hormone (TRH) stimulation test (measuring plasma cortisol response to TRH), combinations of dexamethasone suppression with ACTH or TRH stimulation, and measurement of urinary corticoid to creatinine ratio.  However, in general these tests do not have very good sensitivity or specificity for PPID, are more cumbersome to perform, and have not gained popularity.

Treatment and prevention

Horses without serious complications can be managed without medications.   Excess hair should be removed as needed by body clipping.  In addition to body temperature control, this helps to prevent sweat buildup and facilitates keeping the coat clean and free of infection.  In colder weather the horse can be blanketed.  Regular dental and hoof care must be provided, an adequate deworming and vaccination schedule must be followed, and attention must be paid to providing a nourishing diet. 

Horses with dental problems that cannot be resolved (eg multiple missing teeth, wave mouth, excessively worn teeth) should be fed a complete pelleted feed that has been softened so that it does not require chewing.  Care should also be taken to control the weight of horses that tend to be obese.

Horses with complications such as laminitis, respiratory or skin infections, sinusitis, dermatitis, etc. should be treated medically, in addition to the management practices described above.  It must be emphasized to owners that medications are not curative.  At best, they can only be expected to improve clinical signs and, in order to remain effective, must be given for the rest of the horse's life. 

This is not economically feasible for all owners.  The two most commonly prescribed medications for treatment of PPID are pergolide and cyproheptadine.Pergolide is a type 2 dopamine agonist, thought to act by inhibiting POMC production by the pituitary pars intermedia.  Doses from 0.002 to 0.011 mg/kg given orally once a day (1-5mg/day to a 500kg horse) have been reported to improve clinical signs, lower plasma ACTH concentration, and improve results of dexamethasone suppression testing.

Improvements can take several months to become apparent.  It is usually recommended to start a horse at a lower dose (eg 0.002mg/kg (1 mg/horse), gradually increasing the dose if needed.  Adverse side effects of pergolide administration at doses up to 0.006 mg/kg/day appear to be uncommon.  Compounded formulations of pergolide in aqueous preparations should be stored refrigerated and in the dark for no more than 30 days.Cyproheptadine is a serotonin antagonist, thought to act by inhibiting secretion of ACTH.  There are reports that cyproheptadine improved clinical signs in horses with PPID, particularly in those with laminitis. 

However, it is not clear how much concurrent management practices contributed to the reported improvements.   Cyproheptadine does not appear to be as effective at lowering plasma ACTH concentration or normalizing results of dexamethasone suppression tests as does pergolide.  The recommended dose for cyproheptadine is 0.3-0.5 mg/kg orally once daily.  Currently cyproheptadine is mainly used in addition to pergolide in horses that have not responded to pergolide at the maximum recommended dose.

Various dietary supplements have been proposed for treatment of PPID, including magnesium, chromium and vanadium.  These minerals are thought to work by decreasing insulin resistance.  There have been few controlled studies on the effectiveness of these supplements, although one study did find that chromium supplementation was not beneficial. The herbal product chasteberry has also been suggested for treatment of PPID, but it was not found to be useful in one reported study.