Raise the topic of cortisol hormone replacement for SARDS dogs and veterinary specialists typically respond in two ways. First, they fail to appreciate the difference between prednisone’s role as an anti-inflammatory versus its role as a low-dose hormone replacement. Second, they’ll counter with, “There are no controlled, peer-reviewed studies supporting successful treatment outcomes.”
My reply?
THEN. DO. A. STUDY.
I am not a veterinarian. I don’t write prescriptions or order lab work. I can only follow these cases and write-up the results. And every time someone repeats “there are no controlled studies” it simply underscores the fact that a potential treatment remains uninvestigated.
Years ago, when my first SARDS papers were accepted for publication, a veterinary ophthalmologist called to tell me that I was “making a lot of people angry.” I was dumbfounded. I was trying to help! That conversation made me wonder if I would ever again have a paper published.
You see, peer-review is not all it’s cracked up to be. It’s routinely influenced by egos and income.1-7 As the editor of the Journal of the Royal Medical Society wrote, “People have a great many fantasies about peer review, and one of the most powerful is that it is a highly objective, reliable, and consistent process.” 8
And Casey Luskin, a PhD scientist explains how “…peer-review is increasingly used as a rhetorical weapon, enlisted for the purpose of silencing dissenting, minority scientific viewpoints.” 9
What I can do is post factual information on this site: lab results, followed by the medications doses, followed by lab results. Most people can understand this type of straightforward information without someone else reviewing it for them.
A Controlled Study
The job of running a controlled study belongs to the veterinary specialists (ophthalmologists, endocrinologists, or internists). Perhaps a budding resident will take it on, or someone with a separate degree in biology, or chemistry, or other hard science. Why? Because the concept of LOW-dose prednisone as a daily hormone replacement can be extremely difficult for experienced clinical practitioners to acknowledge. It challenges what they’ve previously done and what they’ve been previously taught.
Veterinary schools teach of only two adrenal pathologies: Cushing’s disease (a tumor) and Addison’s disease (an autoimmune condition). There is no discussion of the many adrenal enzyme deficiencies we’ve recognized in humans such as 21-hydroxylase deficiency, 17-hydroxylase deficiency, or 11-beta hydroxylase deficiency (the latter of which we’re probably seeing in these dogs). These conditions impair cortisol production and result in elevated adrenal sex steroids. This is something we’ve known for a long, long time.
Congenital Adrenal Hyperplasia — The Lancet Seminar Series
“Congenital adrenal hyperplasia is a group of autosomal recessive disorders encompassing enzyme deficiencies in the adrenal steroidogenesis pathway that lead to impaired cortisol biosynthesis. Depending on the type and severity of steroid block, patients can have various alterations in glucocorticoid, mineralocorticoid, and sex steroid production that require hormone replacement therapy.” 10
Gene Mutations in People with Congenital Adrenal Hyperplasia (CAH)
• 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene
• 11-beta-hydroxylase deficiency is caused by mutations in the CYP11B1 gene
• 17-hydroxylase deficiency is caused by mutations in the CYP17A1 gene
• 3-beta-hydroxysteroid dehydrogenase deficiency is caused by mutations in the HSD3B2 gene
• Cytochrome P450 oxidoreductase deficiency is caused by mutations in the POR gene
• Congenital lipoid adrenal hyperplasia is caused by mutations in the STAR gene 11
We have recognized that prednisone functions as a hormone replacement in addition to, but distinctly different from, its role as an anti-inflammatory. But bring up the idea of prednisone-as-a-hormone-replacement to veterinary specialists and they will unfailingly write a prescription for a high-dose, two-week, anti-inflammatory course. They do not distinguish between the two.
For example, in 2013 a survey was published by the American Veterinary Medical Association. That survey asked SARD dog owners if they had tried any treatment including prednisone. The survey concluded that no improvement was detected with any treatment including prednisone.12
I contacted the lead author of this survey to clarify the findings. It was her recollection that the questionnaire did not distinguish between high-dose, short-term prednisone (an anti-inflammatory) and low-dose, long-term prednisone (a hormone replacement). Rather, it was a yes-or-no question.
I sincerely appreciate the author’s candor and assistance, but still, the survey’s conclusion must be questioned. The survey did not identify whether any of the dogs received a low, long-term hormone replacement dose of prednisone. Therefore, it cannot be concluded that all prednisone is ineffective.
In 2021 this scenario was repeated. The ACVO published a survey of dog owners who were asked if they had tried any treatment including “steroids by mouth (Medrol, prednisone, or prednisilone).”13. And once again, the survey question did not distinguish between anti-inflammatory doses and low, hormone replacement doses. Therefore, it cannot be concluded that all prednisone is ineffective.
I’m unclear if veterinary specialists are truly naïve about these concepts. One participant from my 2021 survey stated, “The ophthalmologist said he never heard of it.” Another stated, “The ophthalmologist didn’t know why it would work.” If veterinary colleges don’t teach these concepts and if the information is not discussed at annual meetings, perhaps the younger generation of specialists really is unaware of what I’ve described these past 15 years. I don’t know.
If you’ve missed my hypothesis all these years, allow me to recap.
• Low cortisol production is known to elevate adrenal sex steroids
• SARDS dogs suffer elevated adrenal sex steroids including estrogen
• Estrogen—a known excitotoxin— may increase calcium influx in photoreceptor cells
• Excessive calcium is known to damage mitochondria
• Damage to mitochondria is known to initiate apoptosis
• Apoptosis—a self-destruct message—is reported as one method of cell death in SARDS
Therefore, the goal of therapy is threefold.
• Reduce elevated sex steroid levels by providing cortisol hormone replacement
• Mitigate calcium influx
• Protect the mitochondria from damage until sex steroid levels normalize
Strategies for the Future
If the veterinary community chooses to run a controlled study, here are some suggestions I hope they consider.
Researchers should not confuse the SARDS protocol with any other protocol or other glucocorticoid therapy. What I’ve described for the past 15 years is not an anti-inflammatory or immune-suppressive therapy. It is not Dr. Plechner’s high-dose therapy. It is not Dr. Grozdanic’s immunoglobulin therapy. What I describe is low-dose hormone replacement that holistic veterinarians use and akin to the treatment of elevated adrenal sex steroids in humans. We replace the body’s daily needs for cortisol and no more.
As I reported in 2008 and again in 2012, low-dose cortisol replacement reduces elevated sex steroid levels in 95% of SARDS dogs. To see the lab results, the meds, and the repeat lab results of these dogs, click here and here.
The SARDS protocol should to be followed verbatim. It is available here. In addition to low-dose cortisol replacement, the protocol includes strategies to reduce suspected calcium influx as well as previously reported apoptosis.14 Researchers should not omit some pieces and/or include others not described.
Study participants should consist of dogs with recent-onset SARDS. Blood tests and treatment should ideally commence within four weeks of significant vision loss. Dogs that have been blind for many months will not regain vision but routinely demonstrate improved endocrine assays and clinical presentation.
Researchers should use one of the adrenal assays specified in the SARDS protocol. Others are inadequate. Researchers should understand the concept of “cross reactivity” between cortisol and cortisol precursors as well as the difference between estradiol and total estrogen assays. These are important concepts. Read more here.
Researchers should design the study for a sufficient period. If vision is to return, it is a delayed reaction requiring 3-4 months. Therefore, the study must be designed for a period to last at least six months and preferably a year.
A year of therapy is often necessary before sex steroid levels approach the normal range. This is a gentle, low-dose therapy that requires sufficient time. And as with humans, hormone replacement is necessary for life. This is not anti-inflammatory treatment. It is a life-long replacement therapy.
Researchers should routinely monitor these dogs, both in the clinical setting and via regular adrenal sex steroid assays: once at onset, then again after a month of therapy, and every three months thereafter for the length of the study period.
This adrenal condition is subject to the seasonal activity of the HPA axis which may affect patient outcome. If the restoration of vision, rather than research, is the goal of therapy, seasonal adjustments in therapy appear to be beneficial. These are described in the SARDS protocol and also here and here. This adrenal condition requires management rather than a “See ya next year!” approach. Poorly-controlled cases can result in the loss of vision for a second time.
I’ve described these issues for many years. I’m happy to help the specialists but I can’t do this for them.
Caroline
References
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2) Tomkins A, Zhang M, Heavlin WD. Reviewer bias in single- versus double-blind peer review. Proceedings of the National Academy of Sciences of the United States of America, 2017; 114: 48.
3) Manchikanti L, Kaye AD, Boswell MV, Hirsch JA. Medical journal peer review: process and bias. Pain Physician 2015; 18: E1-E14.
4) Young, SN. Bias in the research literature and conflict of interest: an issue for publishers, editors, reviewers and authors, and it is not just about the money. Journal of Psychiatry and Neuroscience 2009; 34: 412–417.
5) Slocum JM. Bias, Power, Influence, and Competence: The Implications of Human Nature on the New NIH Conflicts of Interest Regulations. Journal of Research Administration 2012; 43: 135-148.
6) Hedin RJ, Umberham BA, Detweiler BN, Kollmorgen L, Vassar M. Publication Bias and Nonreporting Found in Majority of Systematic Reviews and Meta-analyses in Anesthesiology Journals. Anesthesia & Analgesia 2016; 123: 1018-1025.
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8) Smith, R. Peer review: a flawed process at the heart of science and journals. Journal of the Royal Medical Society 2006; 99(4): 178–182.
9) Luskin C. Intelligent design is peer-reviewed but is peer-review a requirement of good science? The Discovery institute. https://www.discovery.org/a/18301/author ; February 15, 2012.
10) El-Maouche D, Arkt W, Merke DP. Congenital Adrenal Hyperplasia: The Lancet Seminar Series. The Lancet 2017; 390: 2194-2210.
11) Genetic and Rare Diseases Information Center. Congenital Adrenal Hyperplasia. https://www.rarediseases.info.nih.gov ; December 26, 2014.
12) Stuckey JA, Pearce JW, Giuliano EA, Cohn LA, Bentley E, Rankin AJ, Gilmour MA, Lim CC, Allbaugh RA, Moore, CP, Madsen RW. Long-term outcome of sudden acquired retinal degeneration syndrome in dogs. Journal of the American Veterinary Medical Association 2013; 243: 1425-31.
13) Washington DR, Li Z, Fox LC, Mowat FM. Canine sudden acquired retinal degeneration syndrome: Owner perceptions on the time to vision loss, treatment outcomes, and prognosis for life. Veterinary Ophthalmology 2021; 24: 156-168.
14) Miller PE, Galbreath EJ, Kehren JC, Steinberg H, Dubielzig RR. Photoreceptor cell death by apoptosis in dogs with sudden acquired retinal degeneration syndrome. American Journal of Veterinary Research 1998; 59(2); 149-52.
