CHAPTER 160 Pituitary Pars Intermedia Dysfunction
Equine pituitary pars intermedia dysfunction (PPID) is the most common endocrinopathy of horses and ponies. Clinical signs are caused by increased blood concentrations of the hormones secreted by an adenoma or hypertrophied cells in the pars intermedia of the pituitary gland. Once believed to be a rare condition, PPID is now known to affect a substantial percentage of the aged horse population. Moreover, as the number of horses over 15 years increases and diagnostic techniques improve, the number of equids in which PPID is diagnosed can be expected to increase.
Horses with PPID were originally described as having diabetes mellitus because of the hyperglycemia and glucosuria that are features of advanced disease. When it was recognized that the condition was caused by a pituitary tumor and the associated increase in cortisol concentrations, the syndrome was termed equine Cushing’s disease. There are several differences between the disease in horses and what is typically seen in dogs and people with Cushing’s disease, however. Tumors in horses are found in the pars intermedia of the pituitary gland, not the pars anterior or adrenal gland. The responsible pituitary cell type is the melanotroph, not the corticotroph. Although there is increased secretion of adrenocorticotropic hormone (ACTH), it is accompanied by increased concentrations of other hormones normally elaborated by the pars intermedia, such as α-melanocyte-stimulating hormone and β-endorphin. Finally, hypertrophy of the pars intermedia occurs to some extent in virtually all aged horses, and abnormal secretion by the hypertrophied cells may occur before development of a true adenoma. For all these reasons, terming the problem a dysfunction of the pars intermedia is a more accurate description of the pathologic process, and PPID is the most appropriate name for the condition.
The pituitary gland can be divided into the adenohypophysis and neurohypophysis. The larger adenohypophysis can be further divided into the pars tuberalis, pars anterior, and pars intermedia. Corticotrophs in the pars anterior and melanotrophs in the pars intermedia both secrete proopiomelanocortin (POMC). Corticotrophs secrete POMC in response to hypothalamus-derived corticotrophin-releasing-hormone. This POMC is primarily metabolized into ACTH. The ACTH acts on the adrenal glands to stimulate secretion of glucocorticoids. This, in turn, provides negative feedback to the hypothalamus and corticotrophs directly to downregulate ACTH secretion. Pars intermedia melanotrophs also produce POMC, but most of the melanotroph-derived ACTH is further processed into α-melanocyte-stimulating hormone, β-endorphin, and corticotropin-like intermediate peptide. Melanotrophs do not respond directly to negative feedback via the hypothalamus-pituitary-adrenal axis. Rather, they possess dopamine D2 receptors and are subject to tonic inhibition of dopaminergic neurons that originate in the hypothalamus.
One hypothesis for the pathogenesis of PPID is that it is primarily a dopaminergic neurodegenerative disease. Lending credence to this theory is the fact that dopamine-containing neurons appear to be particularly sensitive to oxidative stress, and markers of oxidative stress are increased in the hypothalamus of horses with PPID, compared with controls. Rats that have undergone experimental denervation of the pars intermedia respond with hypertrophy of pars intermedia melanotrophs, much like horses with PPID. It has been hypothesized that in horses destined to develop PPID, dopaminergic tone on the pars intermedia cells decreases over time as the dopaminergic neurons in the hypothalamus die. Without the inhibitory influence of dopamine, the melanotrophs hypertrophy and eventually undergo neoplastic change to become adenomas. Although ACTH is not a primary product of pars intermedia-derived POMC, enough is produced in instances of hypertrophy and adenoma to cause increased cortisol secretion and subsequently the clinical signs associated with PPID. Cortisol is an insulin antagonist, and horses with PPID are often insulin resistant. Insulin resistance, in turn, is associated with dyslipidemia and laminitis.
Pituitary pars intermedia dysfunction is a disease of horses that are in their late teens or older, and its prevalence increases with advanced age. Although PPID has been reported in horses as young as 7 years old, it is rare in individuals younger than 13 and is typically diagnosed in animals 18 years and older. Studies of aged horses without signs of PPID reveal a high percentage to have some degree of pituitary hypertrophy, suggesting that clinical PPID is an exacerbation of what may be normal changes associated with advanced age. PPID has been described in all breeds of horses, but it is most common in ponies and Morgans. Whether this is associated with the longer life span in those breeds or is a true overrepresentation is not known.
Hirsutism is the classic and most consistent clinical sign associated with PPID. With the exception of the spontaneous hirsutism seen in the Bashkir Curly breed, there is no other condition in which horses develop a long, curly haircoat. For this reason, hirsutism can be considered a positive diagnostic test result for PPID. Before generalized hirsutism is evident, horses often develop elongated guard hairs and increased hair length on the extremities, ventral midline, and under the chin. Before year-round hirsutism develops, there is often a history of shedding later in the spring than other horses and incomplete shedding.
Weight loss and poor muscle tone develop secondary to increased cortisol concentrations. The pendulous abdomen that can develop secondary to poor muscle tone may be confused with weight gain. Condition scoring usually reveals poor cover over the bony prominences and ribs. Abnormal distribution of subcutaneous fat may also be observed. Adipose tissue may be concentrated along the topline, resulting in an abnormally full or cresty neck and increased fat deposition over the tailhead.
Bilateral nonpainful swelling over the eyes in the periorbital fossa can also develop. Periorbital swelling in the absence of ocular disease is extremely suggestive of PPID, as few other conditions produce this clinical sign.
Polyuria and polydipsia develop in instances of hyperglycemia and glucosuria. Polyuria may also occur in horses with PPID that have normal blood glucose concentrations. The reason for this is poorly understood, but it may result from compression of the pars nervosa. Infertility associated with PPID has been reported, although mares can conceive and carry foals to term with the condition.