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Wayne Anderson, ND: It is my privilege to be here with Robert Gitlin, DO, an experienced Lyme-disease practitioner, trained in Osteopathic Manipulative Medicine, with expertise in the endocrine system and hormones. We would like to offer our perspectives on how guiding hormone therapy in the Lyme patient differs from treating other patients, given that intracellular infections have their own unique effects on the endocrine system.
I think that currently one of the problems in medicine is an excessive focus specifically on Lyme disease. What sometimes gets missed is the fact that this is a constellation of toxic influences that all have the same mechanism of action. Our patients may be struggling with infectious processes caused by borrelia or co-infections like babesia, bartonella, ehrlichia, or mycoplasma, as well as toxins such as mold species, petro-based chemicals, and heavy metals. All of those infections and toxins affect the regulatory systems of our body: the brain and nervous system, and the immune and endocrine systems.
Unresponsive to Hormone Therapy
Potential Infection. Wayne: Most Townsend readers are familiar with all the essentials of hormone management. However, Lyme confuses hormonal responses in our patients, causing disorganization and dysregulation. As a result, lab testing and patient outcomes are different than those a provider would expect to see in both men and women with Lyme. When a Lyme infection is present, classic symptoms of hormonal transition can be exaggerated and hormone replacement may not improve symptoms or may improve them only temporarily.
If you are guiding bio-identical hormone replacement therapy (BHRT) and the patient is not responding, they may have an intracellular infection or neurotoxic build-up. I have come to realize that in some cases, the therapy is not working because this is not primarily a hormone patient, this is a Lyme patient. These patients may have a borrelia infection, masquerading as a hormone-related problem.
Toxins. Rob: In my patient population, hormone disruption can be due to environmental estrogen disrupters (EEDs). When I see a man who has low testosterone or a non-menopausal woman with low hormone levels or premature ovarian failure, often it is not Lyme but neurotoxins functioning as estrogen disrupters: for example, xenoestrogens, petrochemicals, or heavy metals. When I evaluate patients with these exposures, I find that many of them also have underlying Lyme. Although 90% of my case load is women, it is possible that males are equally sick in ways that we do not always associate with Lyme, like prostate cancer and cardiovascular disease – but we are not diagnosing their co-morbidities as well.
Adrenal Exhaustion. Rob: Clinically, I found that in a certain percentage of female patients, no matter what I did with hormone replacement or modification, there were failures. (Clinically, this is less often true of men, but it is still the case.) That led me to discover that in the vast majority of these cases, there was a problem with compromised adrenal function. If these issues are not adequately addressed, adrenal depletion will always prevent the patient from fully correcting other hormone issues involving thyroid, DHEA, estrogen, progesterone, and/or testosterone.
Difficult Hormonal Transitions
Wayne: When there is the overlay of intracellular infection and hormone depletion, these individuals really suffer. This is especially true of midlife women with Lyme, who may experience menopause as the worst thing that ever happened to them. Estrogen, progesterone, testosterone, DHEA, and thyroid are all steroidal hormones that have a major effect on how we experience inflammation. Cortisol also neutralizes inflammation and stimulates immune function. Decreases in these hormone levels are the opening that borrelia uses to gain a foothold.
We also see this with perimenopause. We've come to realize that perimenopause is not a gradual reduction of estrogen, but rather a phase in which estrogen levels are rapidly fluctuating, excessively elevated and then plummeting in a roller coaster pattern. Frequently high achievers who contract Lyme and are burning the candle at both ends hit perimenopause and crash. These vulnerabilities create incredible hormonal instability and a fertile environment for borrelia infection.
Rob:Women get half of their testosterone from conversion of DHEA and androstenedione in fat and skin tissues and the other 50% in equal parts from the ovaries and the adrenals. So there is major dependence upon the adrenal axis and greater vulnerability due to increased stress and decreased hormones. In men 90% of their testosterone comes from the testes and the other 10% from DHEA conversion (among others), which could explain why our menopausal Lyme patients are often sicker.
High Levels of Inflammation
Wayne: In Phases 1 and 2, neurotoxic infections and neurotoxins do not damage cells as regular bacteria do, but they trigger chronic inflammation. That inflammatory process impairs the function of cells, resulting in their symptomatic presentation. However, when hormone levels are adequate, they are protective against such inflammation. The men who show up in my practice with a Lyme infection tend to those experiencing drops in testosterone, driven down by an aggressive borrelia infection. Others are men in andropause whose testosterone is already dropping, reducing the protective anti-inflammatory effects of their hormones.
Rob: In terms of inflammation, men have an advantage over women given that testosterone appears clinically to have much more of an anti-inflammatory effect than estrogen and progesterone. Women tend to experience more inflammation clinically and those with Lyme are likely to be more symptomatic, and at a much earlier stage. Proactively balancing testosterone levels in these female patients seems to have a highly anti-inflammatory effect. DHEA and estrogen also have anti-inflammatory effects.
Moreover, in the research bio-identical transdermal estrogen has been shown to reduce hs-CRP and MMP9 as well. DHEA, the most abundant steroidal hormone in the body, has been shown to lower TNF-alpha and IL-6 levels in the Prasterone (GL701) studies with lupus using a pharmaceutical form of DHEA. DHEA also stimulates the immune system and enhances immune activation by increasing levels of NK cells and IL-2. Its synergistic effects with other therapies are exemplified by four-fold increases in HAI titers upon co-administration. Pregnenolone, known subjectively for reducing pain and spasms, also has anti-inflammatory effects, and in the past was used as a treatment for rheumatoid arthritis and other inflammatory conditions.
Complex Chronic Illness
Wayne: I encourage practitioners to suspect an underlying infection when you have provided a therapy that should have a predictable response in the average patient, and you get a radically different response, one that is enigmatic or paradoxical. That type of response should be a trigger for the practitioner to suspect an underlying infection. My premise is not that everyone has these infections. However, integrative and functional medicine practitioners – as practitioners sought out by patients who have not responded to conventional therapies – see a disproportionately greater number of these patients. It is those who do not respond to hormone therapy that are most likely to have this complex presentation. For patients who have underlying infections, none of our tried-and-true therapies are going to be the solution. They will mitigate the symptoms, but in the long run, they are not going to resolve the symptoms. The symptoms will gradually creep back in, as the infection adapts to the new baseline.
Rob: These intracellular infections have the ability to hijack our immune system, just as cancer does. For instance, the organism can form blebs that bind free, circulating borrelia antibodies and have potent mitogenic activity that increases immune activation. Borrelia also has cloaking mechanisms in which the pathogen surrounds itself with the body's lymphocytic proteins, thus decreasing immune recognition. Moreover, these pathogens can congregate in biofilms that serve to protect the organisms from effective attack by the host immune system.
Testing and Diagnosis
Physical Exam. Rob: Wayne and I both share a love of the challenge of investigation, the process of clinical evaluation that comes with each new patient. In terms of our approach, as an osteopath I practice a little differently. I place a strong emphasis on the physical exam. I palpate the area around their gallbladder, liver, and spleen. I perform a neurological exam and check to see whether they have cerebellar ataxia and past-pointing, as well as heel to toe walking instability. Celiac patients also present approximately 40% of the time with cerebellar ataxia, a babesia physical exam finding (there are some crossover symptoms between celiac and babesia).
Testing and Challenge Trials. Wayne: The credibility of the Lyme diagnosis has been questioned for the last 30 years due to the inability to culture these bacteria. Laboratory evaluation has not yet caught up with the rapid worldwide proliferation of these microbes. The public health agencies that screen the blood supply are scrambling to nail down screening tests after patients who received blood transfusions developed babesia infections. We currently have antibody tests for two of over one hundred species of babesia. We have used the Advanced Laboratory Services culture for Lyme and are hopeful that it will successfully move forward in the clinical trials that are currently on going. At this point, IGeneX IgG and IgM Western blots are the most reliable testing we have available, reported to be correct 70% to 97% of the time. [A substantive article on testing for Lyme by Dr. Anderson appeared in Townsend Letter in June 2012.]
Genetic testing. The LabCorp test DRB-HLA is an evaluation of 10 allele strands on the 6th chromosome associated with genetic vulnerability to neurotoxins. When the DRB-1 is 01 and the DQ is 05, this represents what Ritchie Shoemaker terms hypothalamic dysregulation. Clinically, what it often suggests is the need to be more aggressive in supporting hormones. Patients with this pattern tend to have more hormonal dysregulation, which probably reflects lack of communication from the hypothalamus to downstream hormones. Rob also has patients checked for MTHFR genetic mutations, which can be performed by any local lab. This is one of many bases we cover in seeking to detoxify our patients. It is also helpful to check and correlate B vitamins and homocysteine levels.
Generally speaking, patients with these genetic vulnerabilities are the sickest of our Lyme patients. For these people, it is particularly important to stop metal and chemical exposure and to chelate them with great care, because they are those most likely to be disrupted by chelation and metal detox. [For more information, see Ritchie Shoemaker's Mold Warriors and the website www.survivingmold.com.]
Challenge testing. Frequently we are left with only the patient's symptomatic presentation and response to therapeutic interventions for cues on the presence of intracellular organisms, which include pathogens like the rickettsial species, the smallest life forms on earth identified to date.
Challenge test protocol may be performed with a Byron White Formula, but it could even be done using an antibiotic. I learned about babesia from giving Mepron with Zithromax. The symptoms that got better in response to a trial of Mepron were often symptoms associated with babesia and the antibiotic served as a provoking agent in the absence of definitive testing. [Dr. Anderson's approach to challenge testing using the Byron White Formulas was published in an article in June 2012.]
Neurotoxic Build-up. Rob: Research on a representative population for exposure to approximately 200 known toxins such as petrochemicals, xenoestrogens, and fungicides found that 100% of the toxins were present in 100% of the people tested. These are all endocrine disrupters. We do not have to test for these things. By definition, all of us have disruption in our endocrine system, so diagnosis means looking deeper at what else is causing disruption. It is an interesting coincidence that for the average person, all hormones decrease by 14% per decade after the age of 30.
High Mercury, Low Magnesium, and Low Testosterone
Rob: Optimizing treatment involves normalizing levels of mercury, magnesium, and testosterone. I use the following guidelines:
If mercury levels are high, that must be addressed to achieve effective treatment. There is a documented synergistic relationship between borrelia and mercury. To test for mercury, I usually do a six-hour urinary DMSA pre- and post-provocation challenge test. To treat for high levels, I will generally use a gentle oral chelation protocol at the appropriate time in the treatment sequence. IV chelation is appropriate as well, and I typically send people to another clinic for that. [For further information on challenge testing for mercury, see the article by Joseph Hickey, MD in the November 2013 issue of Townsend Letter.]
Magnesium is rapidly depleted by Lyme, so we need to constantly replace magnesium when treating Lyme. Otherwise the Jarisch-Herxheimer reactions can be more severe. This is a vital aspect of the treatment protocol, since magnesium is an important co-factor in many of the hormonal production pathways, and in normal physiological functioning on a cellular level. To test for magnesium, it is best measured by using a serum RBC Mg+ level. However, I do not typically test for magnesium. In many cases, patients' history will reveal leg cramping at night, insomnia, or signs of occasional to frequent blepharospasms (eyelid spasms/twitches); these symptoms are surprisingly common. For treatment, I simply have patients titrate magnesium to bowel tolerance, with one to five capsules at bedtime, using an approach similar to the titration of vitamin C. The ideal amount indicates how much the body can absorb. Magnesium glycinate or malate are preferable.
A low-testosterone state provides an opening for opportunistic infections such as borrelia and the co-infections. Testosterone levels are best measured using the serum free and total levels at local labs. Some practitioners use spot blood, 24-hour urine levels, or salivary testing. I use measurements in serum, as that is the local standard of care.
Clinical Design (Design is Everything)
Rob: When someone has acute Lyme of long-standing duration, there is a temptation to go right into Lyme treatment mode using antibiotics. However, the patients we are primarily discussing here are not the typical acute presenters; they are those who are chronically ill, have seen several practitioners, received short blasts of inadequate treatment, and are often very depleted.
I find clinical design to be everything in these cases. There is no rush to treat, since often the patient has been sick for years. We need to take the time to set the stage for a reasoned approach.
Any practitioner can start Lyme treatment, but once you start, you are soon in "the middle game." That is a place where you need to keep your bearings, or it is easy to get lost. This translates to frequent visits in which we are constantly tracking our patient's multitude of clinical symptoms, along with a thorough physical exam, and correlating those symptoms with the patterns currently triggered by the pathogen that is predominating at the time.
Infectious Agents. Wayne: In sequencing treatment, I go after the most pathogenic process, the pathogen that is most threatening to the immune system. Almost always, reproductive species (infectious agents) will have a more pathogenic effects than inert substances (metal and chemical), because by definition life forms proliferate and grow at logarithmic rates. Borrelia, bartonella, et al. are reproducing cyclically, whereas metals and chemicals are like sludge in our bodies. Each individual patient needs to be assessed for their unique situation. There are cases in which it is important to go after the metals first, when the accumulation of these toxins is so excessive that it compromises the patient's immune system and their ability to fight the Lyme effectively.
Heavy Metals. Rob: I start evaluating for heavy metals with a DMSA challenge and track the results and the patient's response during testing. Do they feel light headed, woozy, or develop a headache? And what are the actual numbers? Then we stop the upstream exposure, depending upon the biological terrain of the individual patient, which could mean having dental amalgams systematically removed while you are treating their Lyme. An additional option is to use an oral chelator such as Metalloclear™ from Metagenics, typically three tabs twice a day for at least two months, to slowly reduce the level of metal toxicity while not needing to replace minerals. Another useful remedy recommended by Richard Horowitz, MD, is low doses of chlorella, which effectively bind metals. Nutritionally you can also use a quarter cup of cilantro daily. You would be surprised how much of a herx patients can develop from this detox. Detoxification baths are also very helpful and well tolerated. Many of these approaches can take up to a year, but have the benefit of being slow and methodical, and minimizing herx reactions. [For more information on Dr. Horowitz' perspective, see Why Can't I Get Well: Solving the Mystery of Lyme and Chronic Disease, from St. Martin's Press, 2013.]
I tend to take a moderate approach to the issue of metals. I do not consider IV chelation an initial step in someone who has Lyme or co-infections, viruses, metals, and hormone dysregulation. If I am going to chelate Lyme patients, my goal is to initially reduce their Lyme load a little. In our experience, if chelation is performed too early in the sequencing of Lyme treatment, patients may experience increased disorganization neurologically or health-wise. Their symptoms tend to get worse, rather than better, an indication that treatment needs to be approached in a different order. In short, we stay away from metals until the end of treatment unless a compelling reason presents: for example, someone with a cadmium level of 6000.
Wayne: Churning up those neurotoxic metals has an additive effect and can cause a disproportionally negative response. All neurotoxins are additive, increasing inflammation, so if the patient has lead or mercury deposits stored in their fat tissue and you chelate that out, it can be like pouring gasoline on a fire, causing a flare of symptoms.
Tracking Clinical Responses to Lyme Treatment
Wayne: Let's talk about the pros and cons of replacing hormones. In functional medicine we thrive on replacing hormones. Here I'd like to look at reasons for delaying hormone replacement. First, you and I are in total agreement that each individual patient requires a different approach. That is absolutely the most important underlying principle. Second, as providers we need not be wedded to any one rigid philosophical approach to treatment. Third, as we have discussed, there is a difference in treating values outside the reference range as opposed to those inside the range or optimal. There is wisdom in reading the symptoms that reflect immune system activity in the moment. Fundamentally, in the absence of comprehensive and reliable testing, these symptoms are the most important evidence we have of elusive intracellular infections, and they guide treatment. So here is my controversial view: I do not always do hormone replacement first.
Treating new patients. If I'm seeing a new patient I don't want to interfere with my patient's symptomatic presentation by making hormonal changes. I want to be guided by the wisdom of the immune system and my understanding of how this patient is wired. I want to understand the underlining reason(s) for this patient's chronic illness. If I change the picture too soon, that could interfere with my ability to read this patient's symptoms and could delay my efforts to determine the type of infection for which the patient needs to be treated.
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