Aging mares play a key role in advancing equine breeding programs, but pituitary pars intermedia dysfunction (PPID), formerly known as equine Cushing’s disease, might interfere with their reproductive performance. Testing broodmares 15 years old and older for this disease and treating when needed might help minimize the negative consequences of PPID on mare fertility, said Sophia Panelli Marchio, DVM, a PhD candidate at Texas A&M University’s College of Veterinary Medicine, in College Station. Marchio spoke about the effects of PPID on mare fertility during her presentation at the 2024 American Association of Equine Practitioners Convention, held Dec. 7-11, in Orlando, Florida

What is PPID in Horses?

Pituitary pars intermedia dysfunction is a neurodegenerative disease that progresses with age, with worsening clinical signs in older horses. Following stimuli such as stressful events, thyrotropin-releasing hormone, or TRH, stimulates melanotropes—cells that produce melanocyte-stimulating hormone—in the pars intermedia of the pituitary gland to express a gene called pro-opiomelanocortin (POMC). The body then breaks POMC into smaller hormones, including adrenocorticotropin hormone (ACTH). In turn, the horse’s body releases ACTH into circulation where it stimulates the adrenal gland to release a variety of compounds and hormones. 

Dopamine produced by dopaminergic neurons in the hypothalamus inhibits the production of ACTH and other POMC-derived hormones. Thus, horses with neurodegeneration of the dopaminergic neurons lose control over the production of ACTH and other hormones. Often, they overproduce these hormones and, as a result, hyperplastic growth—an abnormal increase in cell number—of the pars intermedia.

Recognizing and Diagnosing PPID in Horses

Classic signs of PPID include polydipsia and polyuria (excessive drinking and urinating), hyperhidrosis (extreme sweating), secondary infections, lethargy, neurologic problems, abnormal fat distribution, hirsutism (a long, shaggy coat due to abnormal shedding), hyperinsulinemia-associated laminitis (HAL), muscle wasting, and a pendulous abdomen.

Veterinarians most commonly diagnose PPID by measuring basal (resting) ACTH levels.

“If evaluating basal ACTH, veterinarians must appreciate that the reference values will change based on season,” said Marchio. “ACTH values can also differ if the animal has been through a stressful situation.”

Effects of PPID on Mare Fertility

In addition to the clinical signs mentioned above, broodmares with PPID might experience an absence of seasonal anestrus, abnormal cycles, anovulatory follicles, subfertility, recurrent endometritis, and abnormal lactation.

“Dopamine plays an important role in controlling reproductive hormones,” said Marchio. “It regulates reproductive seasonality and inhibits cyclicity during the anovulatory season.”

The POMC-derived hormones, including ACTH, increase in mares with PPID. To determine the effect of high ACTH on reproduction, researchers on one study (Hedberg et al., 2007) treated healthy mares with ACTH. “They found a higher concentration of steroid hormones that inhibit gonadotropin-releasing hormone (GnRH) release and an increase in cortisol,” said Marchio. “In turn, high cortisol can repress GnRH as well as luteinizing hormone (LH) release. Further, high follicular fluid cortisol levels can disrupt oocyte quality.” Researchers on another study of healthy mares treated with the synthetic glucocorticoid dexamethasone also reported a reduced LH concentration (Asa et al. 1982).

“Only one study clearly correlates ACTH with impaired reproductive performance (Tsuchiya et al., 2021),” said Marchio. “As ACTH increased, cortisol increased, and mares had lower reproductive success determined by live foaling rates.”

Marchio also said researchers believe the enlargement of the pars intermedia can compress the pars distalis and interfere with the production and release of follicle-stimulating hormone (FSH) and LH, impairing the mare’s cyclicity. They also hypothesize that recurrent endometritis might develop due to the immunosuppressing effects of high cortisol levels.

Treating Broodmares That Have PPID

Administering a dopamine agonist such as pergolide (an FDA-approved dopamine receptor agonist labeled for treating clinical signs of PPID) or cabergoline (another dopamine receptor agonist) and good management practices improve the well-being and reproductive performance of aged broodmares with PPID, said Marchio.

“Be certain to suspend pergolide treatment at least 30 days before foaling and implement the treatment 30 days after foaling as it can interfere with lactation,” she added.

Take-Home Message

Formerly known as equine Cushing’s disease, PPID in horses might have negative effects on mare fertility. “We only have hypotheses on how PPID affects reductive performance,” said Marchio. “The exact mechanisms are still unknown and must be studied in depth utilizing horses with PPID.”