Cushing’s Management by Nutrition

PPID Cushing’s 05  Retrospective Study of 23 Cases

Cushing’s Management by Nutrition
Joesph C. Ramaeker,BS,DVM; William J. Hennen, PHD;
Mac T. Barksdale, DVM.

Equine Cushings Syndrome is emerging to become a more common geriatric condition.  A Nutritional approach appears to be an effective therapy to
prolong and extend the useful life of horses.  Authors address: Dr Mac Barksdale, 10151 University Bvld Bx 118, Orlando, Florida  32817  mac.barksdale@yahoo.com

1- Introduction: The Geriatric population of horses is increasing. Many horses have transitioned from utility or work roles to that of pets or companion animals. Many have finished training the children, providing status in urban living and are retired as a part of the family.  Regardless of the cause, the age of the horse population has presented a variety of geriatric challenges. Included among those is the emergence in the last decade of Equine Cushing’s Syndrome[1].

The Etiology of Equine Cushing’s Syndrome is Pituitary Adenoma, or Hyperplasia of the Pars Intermedia of the Pituitary Gland. The mechanism is a loss of dopaminergic innervation from the Hypothalmus that limits cell production  of dopamine, resulting in hyperplasia. The resulting increased plasma ACTH elicits from the Adrenals an elevated Cortisol blood level. A Horse with a Pituitary Adenoma may produce as much as ten times the ACTH as the norm. This hyperadrenocorticism produces various complex physiologic abnormalities.  The interactions of the Endocrine System may produce interruptions of body temperature control; seasonal shedding of the hair coat; appetite vagaries; Glycosuria; Polydipsia/polyuria and insulin resistance.

Initial clinical symptoms may be polydipsia with a three or four fold increase in water consumption; potbelly appearance; increased appetite with no weight gain; and a heavy hair coat that fails to shed in the spring.  Many times the insidious onset of symptoms are observed by the owner but presumed to be the result of aging. Of the 23 horses in this study all were over 18 years of age with the exception of one 5 year old Thoroughbred Stallion.  Most were over 20 years of age.  As reported at the AAEP in December of 2002, a majority of geriatric horses develop Pituitary Adenoma.  Ten of thirteen consecutive presentations at the Teaching Hospital of the Auburn University that were age 20 and over were found to have Equine Cushing’s[2]. Laminitis may be an early presenting sign. Laminitis in the hind hooves has a high probability of being precipitated by Equine Cushing’s[12].  Laminitis is a frequent complicating factor in advanced cases and increases the probability of a requisite poor prognosis.

Pergolide as a dopaminergic agonist and Cyproheptidine as a serotonin antagonist have been used to reduce the hypercortisolism. Specific Equine studies were few on the effectiveness of Pergolide and Cyproheptidine in the literature[3].

Via the aforementioned mechanism, Equine Cushing�s Syndrome is a condition characterized by excess production of the hormone Cortisol as a result of  hyperplasia of the pituitary gland of the brain which produces high levels of the hormone ACTH.  In other species, Cushing’s Disease is an elevation of Cortisol, whether due to hyperplasia of the Pituitary or not.  Also in other species, pituitary tumors may produce other hormones, such as Prolactin.  Further investigation should reveal whether this is the case in the Equine species.

CORTISOL: A hormone produced by the adrenal gland which is released naturally during times of stress. Cortisol is ordinarily elicited by various stimuli. Such stimuli may be physiologic, as directed by the production of ACTH. Cortisol is also produced by the adrenals in neurologic interaction with the environment as in a fright or anxiety. Such excitement can also be a result of loading, transporting, racing and etc. It appears likely that performance horses would be more susceptible to hypercorticoidism. Pathologic stress, such as indigestion, infection or injury also result in an increased Cortisol level. If the Cortisol elevation is sustained for a long period of time, reduction of immune capability can result. The decrease in immune response is probably a result of the effect of Cortisol on the T-Cell function. Wound healing time is increased in hypercorticoidism, possibly from protein catabolism. In keeping with the interactions of various hormonal components other disturbances and imbalances may occur.  Variations in levels of T4 Thyroid hormone were noted in the blood studies on the cases of Equine Cushing’s Syndrome reported herein.

2- Method: Equine Cushing’s Syndrome cases reported here were presented in several Veterinary Practices in California, Oregon, Arizona and Pennsylvania. Clinically most cases had a provisional diagnosis of Equine Cushing’s as a result of a history of loss of vigor; long non shedding haircoat; fat deposits in the supraorbital fossa; a cresty neck; sometimes accompanied by a loss of muscle mass.  Many cases had a history of repetitive Laminitis.  Reduced immune status evidenced by an increased susceptibility to illness was sometimes mentioned in the history.

The cases were determined to be Cushing’s positive by the criteria of the Cortisol Rhythm, Hyperinsulinism, or variations in T4.[3] In a few cases, all three parameters were used. Cortisol Rhythm is the diurnal variation in  circulating Cortisol. The Rhythm being established as difference between the morning fasting Cortisol level and the evening Cortisol level divided by the greater reading expressed as a percentage of excursion. The number of cases tabulated was twenty-three.    Each case was selected by presenting signs and symptoms indicating a Provisional Diagnosis of Equine Cushing’s Syndrome.  A rhythm of 40-50% was selected as a norm.  30-40% rhythm was classified as borderline tending toward Equine Cushing’s Syndrome.  Below 30% rhythm were classified as positive for Equine Cushing’s.

Although the number of cases tabulated to this point is relatively small,[50 more case reports await tabulation to be added]. The present conclusion of the Veterinarians rporting, is that the Cortisol Rhythm quantification correlates most closely with clinical observations. [BET Labs has done over 10,000 Rhythm Tests] Consideration must be given in interpretation of the Cortisol Rhythm as the levels may be different depending upon the subject.  The circumstance of stall or pasture rest or active performance and/or training may make a difference in Cortisol levels that should be taken into account. Observation of the diurnal variation helps discriminate in those cases.  Of course most of the subjects in this group were not being used at the time of diagnosis.  Many of them returned to active service as saddle horses.  Note case 004 Hannable, 25 year old Gelding, that is now ridden 5 miles three times weekly after two years of inactivity on Pergolide.

Each case was administered per os 1500 mgm of Transfer Factor Plus daily in 4Life Research’s Equine Performance and Show product. Some of the cases treated in early 2001 received 1500 mgm Transfer Factor sans the Plus adjuvant contained in the 4Life Research Equine Performance and Show product. Ponies and horses of less than 300 Kilogram body weight received 700 mgm of Transfer Factor daily in the 4Life Research product.  The length of time of daily administration of Transfer Factor was intended to be 90 days.  However as these cases were in a private practice situation and under the care of their owners, it appears that the daily administration of Transfer Factor may not have been continuous.  Note case 003 and case 008.

3- Results: The average morning Cortisol level was 48.86 ng compared with 20-90ng taken as a normal range. The median morning reading was 39.15 ng.  The average evening Cortisol level was 41.75ng with the median found to be 23.7ng.  Rhythm excursion was found from 1% to 51%.

All 23 Cases were clinically improved.  In many cases the first indication of improvement was a change of attitude and behavior usually described as bright and more alert.   We have records now of at least 75 more cases to be collated and added to this study.

The Shortest period of response was 78 days as quantified by the Cortisol Rhythm. Most of the cases were observed to be clinically improved in two to three weeks. However one case, 004, treated for two years with Pergolide, was sufficiently clinically improved in one week to reverse a Euthanasia decision. Other workers have noted that there is ordinarily clinical improvement noted prior to improvement in the blood value parameters[12].

4- Summary: Twenty-three cases were surveyed.  Most exhibited nominal blood counts and blood chemistry with the exception of the T4, Insulin and Cortisol parameters. All cases were found to be clinically improved after administration of Transfer Factor[r].  Those cases complicated by Thyroid aberrations were the slowest to respond.  One case required two years to reach the point where Thyroid medication was withdrawn.  Some of the cases being maintained on Pergolide were tapered off medication.  However some of the cases had their Pergolide regimen suddenly terminated and replaced by the Transfer Factor.

5- References and notes:

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11- AndrewsFM, Eiler H, 01iver JW,et al. Diagnosis of pituitary adenoma by using a combined dexamethasone suppression and TRH stimulation test. Proc Annu Conv Am Assoc Equi Pract 1997;43:154-155.
12- Direct communication from Schott HC II, and Donaldson Mark, AAEP 2004.
13- Johnson PJ, Ganjam VK. Laminitis, “hypothyroidism” and obesity: A peripheral Cushingoid syndrome in horses? In Proceedings. 17th Annu Forum Am Coll Vet Int Med 1999; 192-194.
14- Wilson MG, Nicholson WE, Holscher MA, et al. Proopioli- aH pomelanocortin peptides in normal pituitary, pituitary tumor gla and plasma or normal and Cushing’s horses. Endocrinology 1982; 110:941-955.
15- Orth DN, Holscher MA, Wilson MG, et al. Equine Cushing’s peptide and cortical levels basally and in response to diagpeptide and cortical levels basally and in response to diagnostic tests. Endocrinology 1982,110:1430-1441.
16- Couetil L, Paradis MR, Knoll J. Plasma adrenocorticotropin concentration in healthy horses and in horses with clinical signs of hyperadrenocorticism. J Vet Intern Med 1996;10: 1-6.
17- Schott HC II, Coursen CL, Eberhart SW, et al. The Michigan Cushing’s project, in Proceedings. 47th Annu Am Assoc Equine Pract 2001;22-24.
18- Comparison of Vitex agnus castus Extract and Pergolide in Treatment of Equine Cushing’s Syndrome Jill Beech, VMD; Mark T. Donaldson, VMD; and Sue Lindborg, BS, CAHT.  AAEP PROCEEDINGS / Vol. 48 / 2002 p175-177.
19- Kirkpatrick CH, HamadaL, Morton LC. Murine Transfer Factors dose-response relationships and routes of administration Cell Immunol 1995, 164(2), 203-6.
20-  Pizza G, Dc Vinci C, Fornatols V. Palarcil A, Baricordi 0, Vias D. In vitro studies during long-term oral administration of specific Transfer Factor. Biotherapy 1996.9(1-3), 175-85. [ 14.]
21- Jones JF,Schumacher MJ, Jeter WS, et al, Oral bovine Transfer Factor (OTF) use in the hyper-IgE syndrome. lmmunology of Transfer Factor. Academic Press; New York. 1983, pp 261-70.
22- Wu S. Thong X. Chung Kuo L Observation of the effect of PSTF oral liquor on the positive tuberculin test reaction.  t-tsueh I(o Hsueh Yuan Hiuch Pao 1992, 34(4), 314-6.
23-     Sibi 0, Pekarekj, Ceds K. Secar J. The adjuvant therapy of the nasopharyngeal tumor with Transfer Factor. Research and Application of Transfer Factor and DLE. Bao-lai H, Ru-zhang W. Zhzo-kn,Z (cdi). Xucyusn Press: Bejing,~ China. 1989, pp 403.10.
24- Ktystukova 0. Cech K, Pekarek J, DLE in immunosuppressed patients. Its: Recent advances in Transfer Factor and Dialyzsable Leucocyte Extracts (cdi) Fujiszwa T, Stakawa S, Iikura Y, Komatsu F. Yamagudsi Y. Marutcn Co Lrd: Tokyo. Japan. 1992, pp 315.22.
25-     Pizza G. Dc Vinci C. Cuuocrca D. et al A preliminary report on the use of Transfer Factor for treating stage D3 hormone-unresponsive metastatic prostate cancer.  Biotherapy 1996, 9(l-3),12332.
26-     Pilotti V. Mascrorilil M, Pizza G, et al. Transfer Factor as an adjuvant to non-small cell lung cancer (NSCLC) therapy. Biotherapy 1996, 9(1.3 ),1 17-21.
27-     Whyte RI, Schon MA. Sloan H et al. Adjuvant treatment using Transfer Factor For bronchogenic carcinoma long term follow-up.  Ann Thoracic Surg 1992, 53(3), 391-6.
28-  FulisawaT, Yantaguchi Y. Postoperative immunostimulation after complete resection improves survival of patients with stage I non-small cell lung Carcinoma. Cancer 1996, 71(9),1892-8.
29-  A. Basten and S.Croft  Transfer Factor: Clinical usage and experimental studies. Immunological Engineering Jirsch DW(ed) MTP Press Ltd. Falcon House; Lancaster, England. 1978. pp 83-120.
30:  Okada T, Yuguchi K, Kiso Y, Morikawa Y, Nambo Y, Oikawa M, Sasaki F. Related Articles, OMIA, Compound via MeSH, Substance via MeSH, Books, LinkOut
A case of a pony with Cushing’s disease.
J Vet Med Sci. 1997 Aug;59(8):707-10.
PMID: 9300369 [PubMed – indexed for MEDLINE]
32:  Reeves HJ, Lees R, McGowan CM. Related Articles, OMIA, Compound via MeSH, Substance via MeSH, Books, LinkOut
Measurement of basal serum insulin concentration in the diagnosis of Cushing’s disease in ponies.
Vet Rec. 2001 Oct 13;149(15):449-52.
PMID: 11688747 [PubMed – indexed for MEDLINE]
33:  Dichek HL, Nieman LK, Oldfield EH, Pass HI, Malley JD, Cutler GB Jr. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut
A comparison of the standard high dose dexamethasone suppression test and the overnight 8-mg dexamethasone suppression test for the differential diagnosis of adrenocorticotropin-dependent Cushing’s syndrome.
J Clin Endocrinol Metab. 1994 Feb;78(2):418-22.
PMID: 8106630 [PubMed – indexed for MEDLINE]
34:  Orth DN, Holscher MA, Wilson MG, Nicholson WE, Plue RE, Mount CD. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut
Equine Cushing’s disease: plasma immunoreactive proopiolipomelanocortin peptide and cortisol levels basally and in response to diagnostic tests.
Endocrinology. 1982 Apr;110(4):1430-41. No abstract available.
PMID: 6277607 [PubMed – indexed for MEDLINE]
35:  Moore JN, Steiss J, Nicholson WE, Orth DN. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut
A case of pituitary adrenocorticotropin-dependent Cushing’s syndrome in the horse.
Endocrinology. 1979 Mar;104(3):576-82.
PMID: 220013 [PubMed – indexed for MEDLINE]
36:  van der Kolk JH, Wensing T, Kalsbeek HC, Breukink HJ. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut
Laboratory diagnosis of equine pituitary pars intermedia adenoma.
Domest Anim Endocrinol. 1995 Jan;12(1):35-9.
PMID: 7621678 [PubMed – indexed for MEDLINE]
37:  Donaldson MT, LaMonte BH, Morresey P, Smith G, Beech J. Related Articles, OMIA, Compound via MeSH, Substance via MeSH, Books, LinkOut
Treatment with pergolide or cyproheptadine of pituitary pars intermedia dysfunction (equine Cushing’s disease).
J Vet Intern Med. 2002 Nov-Dec;16(6):742-6.
PMID: 12465775 [PubMed – indexed for MEDLINE]
38:  Schott HC 2nd. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut
Pituitary pars intermedia dysfunction: equine Cushing’s disease.
Vet Clin North Am Equine Pract. 2002 Aug;18(2):237-70. Review.
PMID: 15635907 [PubMed – indexed for MEDLINE]
39:  McCue PM. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut
Equine Cushing’s disease.
Vet Clin North Am Equine Pract. 2002 Dec;18(3):533-43, viii. Review.
PMID: 12516933 [PubMed – indexed for MEDLINE]
40:  Love S. Related Articles, OMIA, Books, LinkOut
Equine Cushing’s disease.
Br Vet J. 1993 Mar-Apr;149(2):139-53. Review.
PMID: 8485640 [PubMed – indexed for MEDLINE]
41:  Harman J, Ward M. Related Articles, Books, LinkOut
The role of nutritional therapy in the treatment of equine Cushing’s syndrome and laminitis.
Altern Med Rev. 2001 Sep;6 Suppl:S4-16. Review.
PMID: 11591169 [PubMed – indexed for MEDLINE]
42:  Toribio RE. Related Articles, Books, LinkOut
Diagnosing equine pars intermedia dysfunction: are we there yet?
J Vet Intern Med. 2005 Mar-Apr;19(2):145-6. No abstract available.
PMID: 15822556 [PubMed – indexed for MEDLINE]

Cushing’s Management by Nutrition Tabulation of Blood Chemistry:

Morning   Evening   %                     AM       PM
Cortisol  Cortisol Rhythm  AM T4   PM T4  Insulin  Insulin
Normals  20-90ng   20-90ng  40-60%  0.9-2.8 ug/dl  4-40 iu  4-40 iu

001 Lady 28Yr � Mare
001 3/24/01     37.6    38.2  1.60%   12.8    16.6    100     28.4
001 12/19/01    30.2    30.5  0.00%   8.3     11.3    111.4   62.3
001 1/6/03      28.3    22.8   19%    8.1     6.7     83.8    3.4

002 High Voltage 28 yr � Geld
002 1/15/03     75.8    68.2    10%     9.9     14.7    13.7    11

003 Khazan 30Yr Arab G
003 6/26/02     46.2    44.1    4%      19.3    17      26      6.8
003 9/14/02     92.5    45.5    51%     14.4    14.7    29.2    34.9
003 9/16/02     20.2    29.9    32%     14.1    13.3    43.2    82

004 Hannable 25Yr Quarter G
004  1/26/00    31      36.3    15%     5.1     5.4     97.2    79.5
004  7/31/02    51.4    62.1    17%     13.3    13.5    10.6    21.9

005 Marka 20Yr TBx Mare
005 7/4/01      44.7    43.6    2%      7       5.6     128.3   54
005 9/7/01      69.8    34.3    51%     4.9     11      16.8    78.1

006 Tess 20Yr Arab
006 1/17/01                             less than 0.2
006 10/19/01                            0.4
006 6/3/02                              1.5

007 Jazz 18Yr Arab Geld
007 4/17/00     31.6    51.5    39%     3.5     5.9     94      138.3
007 7/3/00      58.8    54.6    7%      25.4    25.4    217.1   273.8
007 6/20/01                             3.4
007 9/8/01      53.7    37.5    30%     22.4    29.6    142.6   160.4
007 1/22/02     39      25.1    36%     23.6    25.9    100     242.9
007 3/5/02                              0.9

008 Tachitts xxYr Arab Geld
008 6/1/99      24.3    18.5    24%     11.6    9.9     127.9   132.7
008 8/10/99     14.2    22.6    37%
008 8/10/99     14.8    22      37%
008 12/1/99     25.8    33.6    23%     5.3     7.4     142.8   110.2
008 10/18/00    39.8    45.6    13%     17      16.1    110.3   65.2
008 11/04/00    29.2    23.2    20%     5.5     10.1    75.4    120.5

009 Rico 25Yr Quarter
009 11/20/00    55.7    62      10%     31.6    31.5    12.1    2.5

010 Sterrschimmer xxYr  ?
010 10/18/00    59.4    42.7    28%     20.5    18.1    67.5    30.3

011 Pajarro 25 Yr Mare
011 1/19/01     51.8    66.9    22%     22.3    19.8    31      43.2
011 2/22/01     62.6    56      10.50%  28.4    42.7    40.3    33.6
011 8/1/01      43      33.4    22%     6.7     8.5     21.8    36.8
011 11/13/02    50.4    34.8    30%     16.6    17.4    36.4    25.6

012 Crickett 22Yr Conamara Mare
012 6/25/01             ACTH pre 6    ACTH 013
012 6/4/02                                        2.9

013 Early 24Yr App Mare
013 4/3/00              ACTH pre 7.6    ACTH post 1.0
013 11/16/01            ACTH pre 4.9    ACTH post 3.0
013 8/10/02             ACTH 187 pg/ml
013 2/22/03             ACTH 175 pg/ml

014 Tess 18Yr TB Mare
014 8/4/99                              2.6
014 11/15/00                            6.1
014 12/29/00    55.8                    27.6                    40.7
014 7/26/01                             1.4

015 Victor 5 Yr TB Stallion
015 10/22/99                            1.7
015 7/26/01                             1.6
015 10/20/00                            2.5

016 Hammel 20Yr TB Geld
016 8/11/00
016 8/29/00
016 10/20/00                            1.1
016 12/6/00                             2

017 Wilbur 17 Yr App Geld
017 8/1/01                              1
017 4/1/02                              1.2

018 Blue 19Yr POA Geld
018 7/31/00     55.8    58.5    5.00%   11.9
018 4/23/01     70.4    29.1    59%     15.2    14.6    44.1    243.5

019 Karajean 22Yr Arab Geld
019 10/5/01                             1.9
019 5/24/02                             1.2
019 6/22/02     66.7    67.4    1%      7.2     9.3     46.1    37.3
019 9/16/02     92.5    45.5    51%     14.4    14.7    29.2    34.9

020 Blancia
020 6/22/02     51.5    53.1    3.00%   19.7    17.7    19.2    26.3

021 Karazen xxYr Arab Geld
021 9/16/02     20.2    29.9    32%     14.1    13.3    43.2    82

022 Princess xx Yr  YYY  HHH
022 10/16/01    72.3    66.5    8.00%   9.2     9.8     50      85.1
022 3/20/03     75.6    53.1    29%     12.9    10.7    16.1    17.2

023 Patrick xxYr  YYY  HHH
023 3/20/03     68      42      38%     20.4    18.3    8.7     9.9

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