Nicholas Frank
Pituitary Pars Intermedia Dysfunction
Pituitary pars intermedia dysfunction (PPID), also called equine Cushing’s disease, is the most common endocrine disorder of aged equids. Some horses are presented for veterinary examination because clinical signs of PPID have developed, whereas others are identified when routine health care evaluations are performed. Horses can also present with a variety of secondary conditions that develop as a consequence of immunosuppression, including periodontal disease, white line disease, and sole abscesses.
Clinical Signs of Advanced Disease
Hypertrichosis (previously called hirsutism) and muscle atrophy are the most prominent clinical signs of advanced PPID. Hypertrichosis has been adopted as the more appropriate term to describe horses with advanced PPID because the anagen phase of hair growth is prolonged, and this increases hair length. A horse with advanced PPID has a long curly haircoat that is duller and thicker than normal, is shed later in the year or not at all, and remains through the summer. Loss of muscle mass is often noticeable across the topline as epaxial muscles atrophy, and the large muscle groups of the limbs also decrease in size over time. Sweating can be affected by PPID and varies markedly among horses, with hypohidrosis or hyperhidrosis reported. Polyuria and polydipsia are hard to assess in horses because they are usually housed outdoors in groups, but are components of PPID in some cases.
Clinical Signs of Early Disease
Haircoat Abnormalities
Horses in the earlier stages of PPID have subtler haircoat abnormalities. They experience delayed shedding of the winter haircoat, and the hairs are longer and duller than normal. Owners should be advised to record the time when the horse sheds its winter haircoat and compare it with other horses in the same barn, because this process is governed by day length and therefore varies by latitude. Some horses with early PPID have regional hypertrichosis. These horses shed most of their winter haircoat but retain hairs along the palmar or plantar aspects of the limbs, behind the elbow, or beneath the mandibles.
Metabolism Shift
Owners of horses with PPID sometimes report a shift in energy needs, particularly in horses with a previous diagnosis of equine metabolic syndrome (EMS). Affected horses have often battled obesity in the past and have been described as easy keepers, but they begin losing muscle mass and requiring more calories. Owners may attribute this loss of body condition to aging, but the clinician should judge whether the decrease in muscle mass is appropriate or accelerated in an individual horse. In many cases, loss of muscle mass has developed over a few months rather than a more prolonged period that would be consistent with the gradual process of aging.
Regional Adiposity
Enlarged adipose tissues within the neck region (“cresty neck”) and fat pads cranial to the tailhead are referred to as regional adiposity. These physical characteristics are components of EMS that persist after PPID develops and accompany generalized obesity until the horse loses body condition. Anecdotally, horses with PPID that have regional adiposity are more likely to have insulin dysregulation and develop laminitis.
Poor Performance, Change in Attitude, and Declining General Appearance
These presenting complaints are vague and not specific for PPID, but are part of the initial presentation for many horses with early PPID. Affected horses are described as dull, and owners report changes in personality and a lack of energy.
Lameness
This is a presenting complaint for PPID in early and advanced cases. Pituitary pars intermedia dysfunction has been associated with laminitis and is likely to contribute to this condition through exacerbation of insulin resistance (IR) and hyperinsulinemia.
Reproductive Problems
Pituitary pars intermedia dysfunction should be considered when aged mares develop fertility problems. More research is required to determine the effects of PPID on the reproductive cycle and uterine environment. At present, only anecdotal evidence is available to suggest that reproductive performance improves in mares with PPID that are treated with pergolide. Abnormal (pseudo) lactation can also be a presenting complaint.
Pathophysiology
Under normal physiologic conditions, melanotrophs of the pars intermedia primarily secrete α-melanocyte–stimulating hormone (αMSH), corticotropin-like intermediate peptide (CLIP), and β-endorphin. Minimal quantities of adrenocorticotropic hormone (ACTH) are normally produced by the pars intermedia. Corticotrophs within the pars distalis produce most of the ACTH, which acts on the adrenal glands and stimulates release of cortisol. Hormones produced by both regions of the pituitary gland originate from the prohormone proopiomelanocortin (POMC). In the pars distalis, ACTH is cleaved from POMC by prohormone convertase I and secreted into the blood, whereas two enzymatic steps occur in the pars intermedia, and almost all ACTH is converted into αMSH and CLIP by prohormone convertase II.
When hyperplastic or neoplastic cells develop in the pars intermedia, POMC synthesis increases, and normal enzymatic processes are overwhelmed. α-MSH and CLIP secretion increases first, and then ACTH and other POMC products are released as the condition progresses. Secretion of ACTH from the pars intermedia is significant because this region of the pituitary gland functions outside the hypothalamic-pituitary-adrenal axis and its negative feedback control mechanisms. Excessive secretion of ACTH from the pars intermedia therefore induces hyperadrenocorticism, which manifests as muscle atrophy, hyperglycemia, IR, immunosuppression, and polyuria-polydipsia. However, PPID differs from hyperadrenocorticism in other animals because multiple POMC hormones are secreted in excess, and this leads to unique clinical signs in the horse, including delayed shedding of the winter haircoat and hypertrichosis.
Older horses are more likely to develop PPID because dopaminergic inhibition decreases with age. Dopaminergic neurons extend from the periventricular nuclei within the hypothalamus to the pars intermedia of the pituitary gland and produce dopamine. Dopamine secreted by these neurons binds to D2 receptors on melanotrophs and inhibits their activity. Loss of dopaminergic neurons through oxidative damage is a normal aging process, but degeneration is accelerated in some horses, and these animals are susceptible to PPID. As dopaminergic inhibition decreases, melanotrophs become more active, and hyperplasia develops. Hyperplasia is a permissive environment for neoplasia, and functional pituitary adenomas develop within the pars intermedia over time.
A relationship exists between PPID and EMS. Horses with EMS appear to be predisposed to developing PPID, and anecdotal evidence suggests that they develop the condition at a younger age. Breed predispositions for EMS and PPID are also the same, with ponies and Morgan Horses overrepresented. Increased adiposity, hyperinsulinemia, and IR are all components of EMS and are potential predisposing factors for PPID. Research is presently underway to determine whether obesity increases production of inflammatory cytokines from adipose tissues and induces oxidative stress in horses, which might accelerate the degeneration of dopaminergic neurons. It is also important to examine the effects of PPID on the health of horses with preexisting hyperinsulinemia and IR (now referred to collectively as insulin dysregulation). Insulin sensitivity decreases as hyperadrenocorticism develops, and cortisol inhibits the actions of insulin. Hyperinsulinemia can also be exacerbated as insulin secretion increases to compensate for IR or through the actions of CLIP, which acts as an insulin secretagogue. Insulin dysregulation may have a genetic basis, so individual susceptibility to IR and hyperinsulinemia varies. It is therefore important to assess the insulin status of every horse with PPID, and particularly those with preexisting EMS. Laminitis has been associated with hyperinsulinemia in horses, and PPID must be controlled before it exacerbates underlying insulin dysregulation.
