Recent Developments in Equine Pars Intermedia Dysfunc9on (PPID)

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1 Recent Developments in Equine Pars Intermedia Dysfunc9on (PPID) Dr. Jenifer R Gold, DVM, DACVIM- LA Assistant Professor Colorado State University Fort Collins, CO

2 Pituitary Gland Anatomy

3 Physiology Review Melanotropes of the pars intermedia Cor9cotropes of the pars distalis Both produce POMC Undergoes specific posoransla9onal processing to get ACTH, MSH, β- endorphin cor9cotropin- like intermediate lobe pep9de (CLIP), lipotropins, and several other pep9des. Prohormone convertases 1 and 2 (PC1 and PC2) cleave POMC into smaller pep9des PC1 expressed in both cor9ocotropes and melanotropes PC2 which cleaves ACTH into α- MSH and CLIP is only expressed in melanotropes

4 Physiology Review Nearly all plasma ACTH in the healthy horse is produced in the pars distalis Prohormone convertase ac9vity is inhibited by dopamine In mice lacking the dopamine receptor PC 1 increases 4-5 fold and PC 2 increases 2-3 fold The rela9ve difference in magnitude of increase in expression that the 2 enyzmes display when dopamine is absent may explain why horses with PPID produce pars intermedia- derived ACTH; PC2 cannot keep pace with the rela9vely more abundant PC1

5 Review Following cleavage by the convertases POMC pep9des are further processed by N- acetyla9on and carboxy terminal proteolysis Which yields pep9des with altered bioac9vity

6 Review

7 Melanocor9ns Exert biologic effects via interac9on with a family of 5 G- protein coupled melanocor9n receptors α- MSH is a primary product of POMC cleavage in the pars intermedia Has role in metabolism and obesity Potent an9- inflammatory hormone Powerful an9pyre9c 25,000 9mes more potent than acetaminophen in reducing fever Decreases cytokines and other factors contribu9ng to inflamma9on

8 Melanocor9ns LiOle is known about the func9on of CLIP β- endorphin is a potent endogenous opiod agonist that func9ons in analgesia and reduc9on of pain associated inflamma9on

9 Equine Pars Intermedia Inhibited by dopamine S9mulated by thyrotropin releasing hormone (TRH) May be other factors involved that have yet to be revealed Robust seasonal rhythm with increased output as day length shortens. Thus ACTH and α- MSH are greatest in autumn (August- October) Helps animals prepare for metabolic and nutri9onal pressures of winter

10 Seasonal changes Due to increases in pars intermedia ac9vity False posi9ve diagnos9c test results are common when tes9ng is performed in the fall. PPID may also follow a seasonal paoern Lamini9s occurs most frequently in the autumn

11 Seasonal Change

12 Epidemiology Common endocrinopathy of ages horses and ponies Recent inves9ga9ons have suggested a disease prevalence of 15-30% in aged horses Hair coat abnormali9es present in 14-30% of ages horses Using endogenous ACTH or α- MSH concentra9ons as a diagnos9c test 20% of aged horses showed posi9ve test result for one test or the other 80% of horses with posi9ve result have historical or concurrent clinical signs

13 Epidemiology Most important risk factor for PPID is age Most clinical signs appear between years Occurrence in males and females similar Conflic9ng results for breed predilec9on Geographic loca9on has not been studied

14 Pathophysiology Hyperplasia of the pars intermedia Single adenoma Mul9ple small adenomas Previously characterized as a benign neoplasia Studies now show it s a neurodegenera9ve disease Loss of dopaminergic inhibitory input to melanotropes of the pars intermedia

15 Pathophysiology Slowly progressive disease Precise cause of PPID is unknown Evidence suggests oxida9ve stress Histologic examina9on shows 16- fold increase in levels of oxida9ve stress marker 3- nitrotyrosine compared to healthy adult horses Lipofuscin pigment is also abundant in horses with PPID

16 Clinical Signs Mechanism of clinical signs is unclear Interrela9onship of clinical signs is not well understood Example: Horse with PPID and abnormal fat deposits Do they also have insulin resistance, hyperglycemia, polyuria/polydipsia and lamini9s Could be that PPID is a collec9on of syndromes

17 Clinical Signs Development of abnormal hair coat Includes: Hirsui9sm Delayed shedding Incomplete shedding Lightening of coat color Horses with hirsui9sm or incomplete shedding 5 x more likely to have posi9ve PPID test than aged horses with normal coats Mechanism of ac9on unknown

18 Muscle Atrophy Sarcopenia or muscle was9ng Most prominent in the epaxial and gluteal muscles Also characteris9c of aging in horses and people in the absence of the disease Muscle changes reveal atrophy of type 2 fibers Sarcoplasmic lipid accumula9on

19 Muscle Atrophy Increased myofiber size varia9on Subsarcolemmal accumlua9on of swollen mitochondria These type of findings are noted in other animals with high levels of glucocor9coids Other hormone derangements IR and chronic inflamma9on can cause sarcopenia as well. Further studies are needed to clarify the mechanism underlying muscle was9ng

20 Lamini9s Endocrine disease is the most common cause of lamini9s Both PPID and EMS are associated with an increase risk Hyperinsulinemia has been implicated

21 Lamini9s Studies suggest 9ssue specific varia9on in 11βhydroxysteroid dehydrogenase ac9vity occurs in the neck adipose 9ssue of horses with lamini9s and EMS Tissue ac9vity of 11βhydroxysteroid dehydrogenase has not been evaluated in horses with PPID at this 9me. Further studies of all are warranted

22 PU/PD About 30% of horses have PU/PD Several proposed mechanism of ac9on Loss of ADH because of compression of the pars nervosa Increased thirst due to ac9ons of hypercor9solemia

23 PU/PD Osmo9c diuresis because of hyperglycemia and glucosuria However some horses have marked hyperglycemia without increase in water intake Thus osmo9c diuresis less likely in at least some cases of PPID

24 Hyerhydrosis Excessive swea9ng is reported in some horses with PPID Some may sweat excessively due to long hair coat Others truly have hyperhydrosis Exact causes is unclear

25 Abnormal Fat Distribu9on Abnormal fat deposi9on is present in % of horses with PPID Fat pads in horses with PPID typically located above the eyes in the supra orbital fossa Along the crest of the neck Over the tail head In the sheath and mammary region Unclear if the fat deposi9on occurs as a result of PPID Or abnormal fat accumula9on is a

26 Insulin Resistance 60% of horses with PPID have insulin resistance Defined as increased fas9ng insulin levels Adiposity and insulin resistance cause chronic inflamma9on and mitochondrial impairment resul9ng in oxida9ve stress May have a role in development of PPID Longitudinal popula9on studies are needed to determine how frequently horses with obesity and its related condi9ons progress to develop

27 Opportunis9c Infec9on and Immunosuppression Opportunis9c or secondary infec9ons occur in 35 % of horses with PPID Common infec9ons include Dermatophilis Sinus Infec9on Pneumonia Abscesses

28 Infec9ons and Immune Suppression More likely to have occult infec9ons likely due to lack of inflammatory response to pathogens Necropsy results of horses with PPID have pathologic evidence of chronic pneumonia without history of clinical disease Horses with PPID also have been shown to have a higher fecal strongyle egg counts Sugges9ng more suscep9ble to endoparasi9sm

29 Infec9ons and Immune Suppression It used to be thought higher serum cor9sol concentra9on is responsible for immunosuppression in PPID Most likely oversimplified Blood concentra9ons of several immunosuppressive hormones are increased in horses with PPID Including α- MSH, β- endorphin, and ACTH The hormones func9on in concert to alter immune response and create a pathogen

30 Infec9ons and Immunosuppression Aging with no disease is associated with changes in immune func9on Characterized by loss in the ability to respond appropriately to challenges Baseline inflammatory state PPID horses have a leukocyte proinflammatory cytokine profile typical of adult horses not aged horses

31 Infec9on and Immunesuppression The cytokine response to endotoxin s9mula9on is greater in PBMC s from horses with PPID than adult horses Neutrophil func9on is also impaired Chemotaxis and oxida9ve burst are decreased when compared to age- matched controls

32 Infec9on and Immunosuppression Equine neutrophilic oxida9ve burst ac9vity was found to be strongly correlated to α- MSH/insulin ra9o Not correlated to serum cor9sol concentra9ons in the same sample

33 Behavioral Abnormali9es Horses are oien described as becoming lethargic or docile with PPID Lethargy may result due to metabolic abnormali9es such as insulin resistance concurrent disease high plasma β- endorphin concentra9ons

34 Reproduc9ve Infer9lity PPID should be on the differen9al diagnosis list of aged mares that fail to conceive or have abnormal estrous cycles Decreased dopaminergic regula9on of hormonal output and chronic uterine infec9ons may contribute to infer9lity in mares with PPID

35 Reproduc9ve Infer9lity Pergolide may restore reproduc9ve func9on and normal cycling Administra9on of pergolide to pregnant mares appears to be safe Discon9nuing pergolide a month before foaling is recommended to avoid agalac9a

36 Neurologic Disease Ataxia, blindness, seizures, and narcolepsy occurs in 6% to 50% of PPID cases In a herd of 37 aged horses neurologic dysfunc9on was noted in horses with PPID (27% ) than in normal aged horses.

37 Clinical Pathology Rou9ne hematology and biochemistry panels are recommended in any aged horse In horses with PPID rou9ne blood analysis is not diagnos9c May provide informa9on regarding general health and PPID associated secondary infec9ons Most common laboratory profile is hyperglycemia Very nonspecific but PPID should be

38 Clinical Pathology Increased liver enzymes may include increased liver enzymes May indicate steroid induced hepatopathy Histopathology shows swollen vacuolated hepatocytes Seen in 73% of horses with PPID and 71% of horses with hepatocellular swelling also had adrenocor9cal hyperplasia

39 Diagnos9c Tests for PPID Dexamethasone suppression has long been considered the gold standard That has come into ques9on over the past several years At present there are no unbiased studies comparing the overnight dexamethasone suppression test directly with other diagnos9c tests using clinical signs and postmortem exam as the gold standard

40 Dexamethasone Suppression Test Some pa9ents with confirmed PPID have abnormal ACTH concentra9ons before abnormal dexamethasone suppression results Other 9mes its converse Data is insufficient to say which diagnos9c method is the best at different stages of the disease Remember, PPID is a clinical syndrome of different causes all culmina9ng in dysfunc9on of pars intermedia

41 Endogenous α- MSH Concentra9ons Measurement of plasma ACTH or α- MSH has been useful in diagnosis of PPID In healthy horses α- MSH is produced primarily by the pars intermedia α- MSH is strongly influenced by season and seasonal reference ranges are needed to maximize the test Has beoer accuracy than ACTH but no commercial test available at this 9me

42 Plasma ACTH Concentra9ons ACTH is produced by both the pars intermedia and the pars distalis In PPID, ACTH is released by the pars intermedia Measurement of plasma ACTH concentra9on for diagnosis of the disease can be confounded by many factors

43 Plasma ACTH Concentra9ons ACTH concentra9on can increase in response to stress, compe99on and exercise The effect of disease, debilita9on, inflamma9on, or trauma has not been inves9gated Likely other diseases or events may confound interpreta9on of plasma ACTH concentra9ons for diagnosis of PPID

44 TRH S9mula9on Test Appears to be the best test for the grey area cases TRH tes9ng cor9sol is now largely discredited However the use of ACTH levels is valid Inject horses with 1 mg TRH IV PPID horses have a big surge in ACTH concentra9ons 10 minutes aier injec9on of TRH Horses tested 10 minutes post TRH uses 100 pg/ml cutoff

45 TRH S9mula9on Tes9ng

46 Domperidone Response Test Measures ACTH release in response to administra9on of domperidone Healthy horses have minimal ACTH produc9on from pars intermedia because cor9cotropes are not regulated by dopamine Only persons with PPID should produce ACTH when relieved of dopaminergic inhibi9on Not enough data to prove ideal

47 Serum Insulin Concentra9on Fas9ng serum insulin concentra9on is increased in 60% of horses with PPID Condi9ons other than PPID also increase fas9ng insulin levels (EMS) Many false posi9ve and nega9ve tests provides limited value to this test for the diagnosis or screening of PPID

48 Other tests Urinary cor9sol/crea9nine ra9o ACTH s9mula9on test Neither valid for use in PPID horses

49 Imaging Use of advanced diagnos9c imaging may not ever prove prac9cal for diagnosis of PPID because of expense and the need for general anesthesia Contrast enhanced MRI has capability to image the pituitary in enough detail so the par intermedia can be differen9ated from the other lobes So can learn about dynamic changes of the pituitary with season with disease and

50 Treatment Health management Dental care Nutri9on Parasite control All incredibly important Clipping body hair Fecal egg counts Good nutri9onal support

51 Treatment Drug of choice is pergolide mesylate Ergot derived dopamine 2 receptor agonist Down regulates POMC pep9de produc9on Prascend is FDA approved beoer to use than compounded drugs

52 Treatment Most clinicians start with 1 mg dose per horse Titrate to effect with 0.5 to 1 mg units Clinical and diagnos9c test improvement is typically not apparent for several months Recheck examina9ons with recommenda9ons for dose adjustments every 6 to 12 months are appropriate Adverse effects are uncommon at this dose

53 Treatment Anorexia usually can be resolved by abruptly decreasing the dose adjustment Then slowly increasing the dose over 9me un9l the desired dose is achieved Some horses do beoer with with the total dose split and administered BID Lifelong treatment with pergolide is recommended

54 Treatment Doses of pergolide tend to increase over 9me May be possible with season fluctua9ons in hormone levels of pars intermedia to treat mild cases for only 6 months of the year (June- December) HOWEVER this approach has not been cri9cally assessed

55 Treatment Cyproheptadine has been used as a second line drug in combina9on with pergolide Mixed ac9on drug with serotonin antagonist, an9histamine, and an9muscarinic effects Typically when maximal doses of pergolide alone are insufficient to achieve resolu9on of clinical signs Typically maximum dose is 5 mg

56 Treatment Trilostane is a compe99ve inhibitor of 3βhydroxsteroid dehydrogenase The enzyme responsible for produc9on of cor9sol to cholesterol Reported to improve clinical signs of PPID BUT not the dexamethasone suppression test Trilostane may be beneficial to horses with PPID with adrenal gland hyperplasia and hypercor9solemia However it would have no effect on the

57 Nutraceu9cals Only one product tested Chasteberry (Vitrex agnus castus) Failed to resolve clinical signs or improve diagnos9c test results Some animals worsened CONTRAINDICATED

58 TAKE HOME MESSAGE Much has been learned about PPID over the past decade Far more remains to be accomplished S9ll need accurate tes9ng methods and season specific changes Need to understand the complex hormonal derangements in PPID to formulate more individualized therapy plans

59 Take Home Message Hyperglycemia should make one take note of the clinical signs of the disease TRH is the best test for early disease No true gold standard test Pergolide s9ll treatment of choice

Cushing s Disease. Avondale Veterinary Group. Avondale House Strathaven Rural Centre Strathaven Lanarkshire ML10 6SY.

Cushing s Disease. Avondale Veterinary Group. Avondale House Strathaven Rural Centre Strathaven Lanarkshire ML10 6SY. Avondale Veterinary Group Avondale House Strathaven Rural Centre Strathaven Lanarkshire ML10 6SY Tel: 01357 520251 Cushing s Disease Equine Cushing s Disease (ECD), also known as Pars Pituitary Intermedia