Upload
truongtuyen
View
216
Download
0
Embed Size (px)
Citation preview
S.I.B.O.: Paradigm Shift from
Bacterial Infection to Gender Specific Hormonal Dysregulation
Abstract:
In the past 20 years, a gastro-intestinal complex has emerged that has been tentatively linked to
Small Intestinal Bacterial Overgrowth (SIBO). The symptoms of constipation, bloating, and
distress even to the level of cachexia have been presumed to be from bacterial overgrowth of
methane producing Achaea bacteria including Methanobacteriales oralis and
Methanobacteriales smithii. However, the SIBO symptom complex that was initially reported to
be responsive to rifaximin and neomycin antibiotic therapy has subsequently become more and
resistant leaving both patients and treating physicians in a quandary.
The author was asked to consult on 18 patients whom had disruptive gastrointestinal symptoms,
positive SIBO breath test and repeated failure to respond to courses of antibiotic therapy -
primarily rifaximin. The initial evaluation showed that almost all male and female patients were
found to have endocrine, autoimmune and bioavailable free testosterone abnormalities. The
abnormalities of bioavailable free testosterone were measured as the Free Androgen Index (FAI)
and consisted of low serum total testosterone (TT) and increased Sex Hormone Binding Globulin
(SHBG). Hormonal supplementation with anabolic steroids was initiated by protocol. Both men
and women received weekly nandrolone injections and stanozolol. Men in addition receive
testosterone in the injections. The therapeutic goal was to increase the Free Androgen Index to
the ideal range by gender described by Anderson in 1972. The autoimmune serum laboratory
and Heidelberg testing were found unexpectedly to have a very frequent occurrence of rare
gastrointestinal autoimmune disease (pernicious anemia), hyperchlorhydria and autoimmune
gastritis. The serum endocrine laboratory testing found a high incidence of endocrine
dysfunction including hypothyroidism, Hashimoto’s thyroiditis, menopause, male
hypogonadism, adrenal fatigue and low levels of vitamin D3. Concurrent with diagnoses found
in the laboratory assessment, the endocrine, autoimmune and vitamin deficiencies were treated
and corrected.
Twelve of the 15 patients followed for one-year had greater than 75% improvement of symptoms
with anabolic therapy for a minimum of 4 months. The therapeutic goal of raising the total
testosterone divided by the sex hormone binding globulin (SHBG) ratio, the Free Androgen
Index was confirmed within 4 months of anabolic treatments. Diet restriction and supplements
were continued by the naturopathic physician who continued to treated the hyperchlorhydria,
digestion, constipation and SIBO complaints. At the end of 12-months, not one of the 12 patients
remained on rifaximin or any other antibiotic, anti-fungal or anti-helminth agent. Five of the 12
had discontinued the anabolic protocol and remained symptom-free.
Androgen therapy corrected anemia, added weight to those with low BMIs, improved their sense
of well-being, improved muscle mass, strength and libido. For the most part, side effects were
limited to hirsutism which was usually minimized with spirolactone therapy.
Of the original 18, 3 patients were excluded either having not yet completed four months of
anabolic therapy or being lost to follow up. Of the remaining 15, three did not reach the Quality
of Life threshold set by the investigators of 75 percent reported improvement. One discontinued
therapy after one month due to side effects, one had anatomical defects of the pyloric sphincter,
and one was too cachexic to respond adequately. The former did find greater than 50%
improvement at times within the treatment course.
As the relief of symptoms is the focus of treatment, it seems prudent for physicians to begin to
include the evaluation and correction of autoimmune and hormonal disruption as an integral part
of the initial evaluation and subsequent treatment of these antibiotic resistant SIBO patients.
With the increasing failures of multiple and expensive antibiotic treatments for SIBO, this study
demonstrated a paradigm shift that seems warranted: from singularly focusing on treatment of a
breath test to a comprehensive treatment program that includes correction of serum measurement
of autoimmune and hormonal disruption.
Background Information:
The work of Pimentel1 in identifying Archaea bacteria as a cause of inflammatory bowel
syndrome-constipation(IBS-C) in SIBO parallels the work of Barry Marshall, M.D. who linked
the presence of H. pylori to peptic ulcers. However, bacterial resistance for H. pylori has
developed at a rapid pace that it is leaving more than 30% of H. pylori patients worldwide
resistant to standard antibiotic therapy.2,3 Similar concerns of antibiotic resistance have been
voiced to explain the failure of rifaximin and neomycin for SIBO infections as a variety of other
antibiotics, including ciprofloxin, ampicillin, metronidazole, gentamycin, chlortetracycline, and
trimethoprim/ sulfamerazine and polymyxin have been added to SIBO treatment with only fair
results.4-5 Pimentel4 states even the indications for antibiotic use are only “fair.” Other physicians
doubt the treatment and the established breathe tests altogether. Thompson6 stated that there are
no long-term studies of rifaximin that extend over 10 weeks. Chan7 stated that “Rifaximin does
not improve patients' reporting of gastrointestinal symptoms and hydrogen breath tests do not
reliably identify who will respond to antibiotic therapy.”
As Bures8 stated in the World Journal of Gastroenterology, “Therapy for SIBO must be complex,
addressing all causes, symptoms and complications, and fully individualized. It should include
treatment of the underlying disease, nutritional support and cyclical gastro-intestinal selective
antibiotics. Prognosis is usually serious, determined mostly by the underlying disease that led to
SIBO.”
As antibiotic treatments for both H. pylori and SIBO are increasingly becoming ineffective, other
factors must be addressed that affect the host microbiota ecosystem if effective treatments will be
offered to SIBO patients. Since endocrine dysfunctional and autoimmune states are frequently
seen with SIBO patients, the author raised the question, “could the endocrine and autoimmune
dysfunction be a contributing cause of SIBO?”
The author hypothesized that should the findings of endocrine and autoimmune dysregulation be
apparent in the data collected, then correction of these endocrine and autoimmune disease states
might also improve the signs and symptoms of the SIBO infection in susceptible individuals--
thereby offering a new direction for treatment and understanding the contributing causes to this
disorder.
Method:
The referring physician identified 18 SIBO patients whom had failed treatment with not only
recurrent trials of various antibiotic regimens including rifaximin/ neomycin, but also
naturopathic and vitamin/mineral supplementation. They reported having their Quality of Life
interrupted by their gastrointestinal disease symptoms. Eight of the 18 had to discontinue their
fulltime employment due to SIBO. Five were retired or unemployed. Supplements used during
the 12-month review were listed. (Table I). Three of the 18 patients were eliminated from this
review because the anabolic therapy had not been in place for 4 months, their records were
incomplete or they were lost to follow up.
Fifteen patients were included. Each was interviewed separately by the second author who also
independently reviewed their charts, laboratory tests and conducted a personal telephone
interview. The SIBO LABORATORY CHECK LIST includes pertinent gastrointestinal and
autoimmune testing. (Table II). Rare gastrointestinal disorders of hyperchlorhydria, anatomical
disruption of the pyloric sphincter, pernicious anemia and chronic autoimmune atrophic gastritis
(CAAG) were identified by utilizing the Heidelberg test, autoimmune and serum assays pertinent
to the gastrointestinal tract. As hyperchlorhydria, hypochlorhydria, pernicious anemia and
chronic autoimmune atrophic gastritis were discovered, naturopathic and medical therapies were
begun. This occurred often weeks after stabilization of hormones had occurred with the anabolic
therapy protocol. Esophageal-Diagnostic Gastroscopy (EDG) was ordered in select individuals.
Concurrently, the HORMONAL LABORATORY CHECK LIST included those laboratory tests
pertinent to the endocrine system: serum assays of pituitary, thyroid, adrenal, pancreatic, gonadal
function and Vitamin D3 25-OH were evaluated. (Table III). SHBG and calculated Free
Androgen Index (FAI) was added as it addresses bioavailability of gonadal hormones. Normal
FAI ranges by gender was taken from Burke and Anderson9. IGF-1 range was taken from RM
Bennett.10 Therapeutic range was considered normal if it exceeded the mid-range. The range and
mid-point of these serum assay values by gender and age from Quest Diagnostic Reference
Laboratories appear next. (Table III). The full set of laboratory tests, medications and treatment
course are listed in the SPREAD SHEET including 1) occurrence of autoimmune diseases, 2)
ocurrences of medical diseases, 3) laboratory tests, and 4) medical treatments. The information
was recorded from the initial assessment and as recorded at the 12-month follow up. (Table IV).
In these resistant SIBO patients, the summary of their concurrent medical diagnoses, doses and
forms of medications prescribed, benefits and side-effects are listed at 12-months. (Table V). If
the patient had discontinued the anabolic protocol, the laboratory tests of testosterone, SHBG
and FAI were listed when the patient was on therapy. Hormone therapy included ICD 10
Diagnosis, doses and frequency of prescription medications, intramuscular injections of
testosterone (men), nandrolone (men and women), stanozolol (men and women) and
methylcobalamin were noted (Table V.) Estradiol replacement by cream or patch was
selectively prescribed to women with menopausal or vaginal complaints (Table V). The table
listing previously prescribed antibiotic medications that potentially disrupted the microflora of
the GI tract in SIBO resistant patients are noted. (Table VI)
Results:
Naturopathic and over-the-counter medications remained in use in 9 patients of the 15 patients in
the 12-month study. Twelve of the 15 previous antibiotic- SIBO failures reported greater than
75% improvement during the follow up year with this multiple discipline approach to treatments.
The unexpected high frequent occurrence of auto-immune and hormonal disease treatment in this
population of 15 patients appears summarized herein. (Table VI.)
Based on prior experience, the women patients were titrated from 10mg to 20mg of nandrolone
intramuscular injection weekly. Forty mg was the maximum tolerated. Stanozolol was given as
10mg to 20mg in a weekly injection or 25mg weekly or bimonthly depending on the serum
assays of total testosterone and SHBG. Rarely was 25mg of stanozolol prescribed twice per
week. The medications were adjusted to maximize the biomarker, FAI and the patient’s response
to treatment. In only one patient was the medication temporarily discontinued probably due to
her underlying medical problem of biliary cholangitis.
Men were titrated from 40mg to a maximum of 80mg nandrolone in the weekly intramuscular
injections. The stanozolol injection was given as 10mg to 20mg in a weekly injection or an oral
capsule of 25mg weekly, twice weekly to rarely bimonthly depending on the serum assays of
both total testosterone and SHBG the components of the key biomarker, FAI.
The goal of endocrine therapy was to reduce the thyroid antibodies, TSH, FSH and LH while
increasing the DHEA-s, morning cortisol, baseline Vitamin D3 and IGF-1. The goal of anabolic
therapy was to raise the total testosterone, lower the SHBG, and raise the FAI. All patients were
followed closely for changes in blood pressure, weight, heart palpitations, fluid retention, breast
tenderness, any side-effects and hirsutism.
Failures of Therapy:
One 74-year old cachexic male made some significant albeit temporary improvement after
suffering from SIBO related diseases for more than 20 years and reported a 50 to 70 percent
improvement in quality of life. The combination therapies with human growth hormone (hGH)
increased his weight by 15 pounds, reduced his gastrointestinal symptoms but, he remained
cachexic. As he continued to self-doctor his medications, he lost weight off the nandrolone/
testosterone/ stanozolol protocol and his overall course of therapy was not considered fully
successful by the author’s standards.
One premenopausal woman showed pyloric dysfunction on the Heidelberg test and a normal
EGD except with antral gastritis. She failed to improve on any and all therapies and was deemed
a failure.
One cachexic woman discontinued the therapy after one month. She failed to gain weight or find
relief of her symptoms as she was resistant to all naturopathic and prescription medications. She
was in the group eliminated from the study.
One adult female patient showed moderate improvement on anabolic therapy, but then developed
tan stools and upper abdominal pain. She was treated as a case of primary biliary cholangitis
with clinical pernicious anemia with 5000mcg of methyl-cobalamin daily with dramatic clinical
improvement. She had periods of very good control on a combination of hormonal, naturopathic
and methylcobalamin medications, hormonal stability was difficult to establish. Improvement
was noted at greater than 50 and as high as 75 percent. Her improvement and course on
hormonal therapy is ongoing. She and her husband consider her a great success so she is, for the
purpose of this study, not included with the three failures listed above.
Discussion:
Are Antibiotic Therapies Bound to Fail?
Based on molecular subtyping and antimicrobial susceptibilities of diarrheal patients in China11,
it is expected that more of the gastrointestinal microbiome will become resistant quickly as
antibiotic resistance spreads. Antibiotic resistance to Campylobacter coli was noted in nalidrixic
acid (100%), ciprofloxacin (100%), levofloxin (99%), tetracycline (94%), metronidazole (93%),
erythromycin (61%), streptomycin (72%), gentamicin (59%), ampicillin (50%), and
chloramphenicol (29%). Multidrug resistance was detected in 108 of 109 Campylobacter coli
isolates.
Eamonn Quigley, M.D., outgoing president of the American College of Gastroenterology and
Professor of Medicine and Human Physiology at the National University of Ireland in Cork
stated “we’re seeing more resistance to some of the more conventional therapies in term of H.
pylori eradiation.” “This is of concern for both “patient acceptance of treatment regimens” and
the cost and some of the drugs are quite new.”12
Expect antibiotic resistance in the treatment of SIBO to increase likewise. Already, it is being
seen in neomycin therapy. Although unlikely for rifaximin, prospective data are needed.”11
The Existence of Autoimmunity
There are a number of autoimmune diseases that have been found to have a higher incidence of
SIBO than in control populations. There are three groupings of autoimmune diseases that are
diagnosed by serum assay and associated with SIBO. They are:
1) Autoimmune disease in the gastrointestinal tract: pernicious anemia with anti-parietal
cell antibodies and with anti-intrinsic factor antibodies. Chronic Autoimmune Atrophic
Gastritis (CAAG) may have some of the same antibodies in addition to elevated gastrin
serum levels.
2) Organ specific autoimmune diseases such as Hashimoto’s thyroiditis with anti-parietal
and anti-intrinsic factor antibodies, that may coexist with any other autoimmune diseases
and have other tissue specific auto-antibodies, and
3) Systematic autoimmune diseases such as rheumatoid arthritis and lupus that may be
associated with other either or both autoimmune diseases previously listed (with or
without anti-parietal and anti-intrinsic factor antibodies). They may have general
inflammatory markers such as sedimentation rate, C-reactive protein and general
autoimmune test such as Anti-nuclear antibodies (ANA), anti-streptolysin O (ASO) ,
antibodies to angiotensin-converting enzyme (ACE), and Rheumatoid Factor (RF).
The serum assays and clinical data from these 18 chart reviewed patients are representative
of all three.
Firstly, autoimmune diseases of the gastrointestinal tract are well recognized. Pernicious anemia
is an autoimmune disease that destroys the parietal cells. Deficiency of intrinsic factor, presence
of intrinsic factor blocking and binding antibodies, and anti-parietal cell antibodies can be found
in both pernicious anemia and chronic autoimmune atrophic gastritis (CAAG). Clinically,
intrinsic factor is essential for vitamin B12 absorption and severe deficiency leads to
megaloblastic anemia and the potential for neurological consequences. CAAG patients have
abnormal gastrin and chromogranin A (CgA). Treatment of both conditions is by intramuscular
injections of cobalamin (B12) and iron to treat respectively B12 and iron deficiency anemia.
There are inconsistencies of serum diagnostic testing and treatment. The bioidentical forms of
B12 treatment available as methyl-, hydroxy- and adenosyl- cobalamin are preferred over
cyanocobalamin14. Recommended dosages of B12 in clinical treatment vary widely from oral to
intramuscular as shown in the literature.
There is proven coexistence of chronic autoimmune atrophic gastritis (CAAG) and
hyperparathyroidism (PHPT). Since CAAG is four times more frequent in autoimmune
hyperparathyroidism (PHPT) than in the general population, and the occurrence of PHPT is
three-fold greater in CAAG than in the general population, the author and others suggests “a
potential role for autoimmunity.”15
While the autoimmune disease of the gastrointestinal tract consistently show anti-parietal
antibodies and anti-intrinsic factors, these antibodies are present in endocrine and autoimmune
diseases outside of the gastrointestinal tract. Such diseases include primary hyperparathyroidism
(PHPT)12, Type I diabetes14-17, latent autoimmune diabetes18, autoimmune thyroid disease19-20,
vitiligo21-22, celiac7,20, recurrent aphthous stomatitis23, pangastritis24, lupus25 and multiple
sclerosis26.
Secondly, these endocrine and autoimmune states, such as diabetes, have comorbidity with other
autoimmune disease states. Type I diabetes characterized by the autoimmune loss of insulin-
producing pancreatic β cells exhibit an increased risk of other autoimmune disorders such as
autoimmune thyroid disease(AT), Addison’s disease, autoimmune gastritis, coeliac disease and
vitiligo.27-28 Vitiligo patients and their relatives have increased frequency of anti-thyroid
microsomal, anti-parietal cell and anti-adrenal autoantibodies. This highlights the strong genetic
contribution.29
These autoimmune organ diseases respond to individual therapy: insulin replacement for
diabetes, thyroid replacement for autoimmune thyroid disease and anti-inflammatory
medications for lupus. Treatment of one of the individual diseases does not improve the other
autoimmune medical conditions.
Thirdly, not only do these endocrine and autoimmune disease states have higher incidence of
comorbidity with other endocrine -autoimmune states (previously called Polyglandular
autoimmune syndrome type II (PSAS Type II))30 but, the diseases are systemic: rheumatoid
arthritis, Sjögren syndrome, and systemic lupus erythematosus for example. Fallahi19 found all
three types of autoimmune disorders could exist in the same population. He suggested that
patients with AT who remain unwell, or who develop new non-specific symptoms (despite
adequate treatment) should be screened for other autoimmune disorders.19 Vrkljan suggested that
the diseases (pernicious anemia, primary hypothyroidism, and Addison’s disease) “share the
same etiological factors but also overlap in pathophysiology and clinical characteristics… favors
older classifications of APS which consolidate all endocrine and other organ specific
autoimmune diseases into one category.”31 Wielosz32 instituted immunosuppressive therapy in
autoimmune polyglandular syndrome which reduced the symptoms of connective tissue disease.
Zampetti18 made an association missing from all previously referenced articles on the
interrelationship of 1) autoimmune disease of the gastrointestinal tract, 2) autoimmune disease of
specific organs and 3) systemic autoimmune disease. He referenced the word gender.
Gender Specific Medicine or Molecular Mimicry?
It has been hypothesized that “functional disorders such as irritable bowel syndrome, chronic
fatigue syndrome and anorexia nervosa are caused by auto-antibodies to neuronal proteins
induced by molecular mimicry with microbial antigens.” For 40 years, some have hypothesized
that pooled immunoglobulin and elimination of the bacteria from the microbial flora that express
the cross-reacting antigens should be possible.33-34
The literature repeatedly demonstrates that treating the autoimmune disease, whether it be
pernicious anemia35 or hypothyroidism36, can clear the SIBO. Clearing the SIBO does not
improve the underlying autoimmune disease nor do antibiotics offer any consistent, long-term
solution.
Why then put the bacteria first? Is it not logical that the underlying autoimmune state changes the
bacterial flora?
The immunology of these previously listed diseases that have a comorbid association with SIBO
has been recognized for 40 years.37 Stockbruegger38 stated that “the bacterial overgrowth in
pernicious anemia may be facilitated by altered immunological conditions” rather than the
molecular mimicry hypothesis that bacteria are causative.
The objective data from Stockbruegger38 and Ngo39 offer an alternative hypothesis to the cause
of autoimmunity that rejects molecular mimicry. They hypothesize that the overlap of bacterial
overgrowth and autoimmune disease is dependent on:
1) altered immune conditions38 and
2) gender,38 genetics and
3) exposure to external factors (i.e., hormones) and the subsequence response to such factors
might influence susceptibility to autoimmune disease.39
The altered immune conditions in these patients has been extensively noted by Ngo at
macrophage, T cells, cytokines, interleukins and natural killer cell levels.39 He notes that the
differences in immunology function can depend on the gender and age of the individual. The
gender of the host dictates the basic normal levels of Gender Specific Hormones.
SIBO, certain autoimmune diseases such as pernicious anemia, autoimmune thyroiditis, and
systemic diseases such as lupus, rheumatoid arthritis and multiple sclerosis share a gender
predilection of female: male of 3:1 or greater. This 3:1 ratio only persists during the reproductive
years; 15 to 50 years of age. This gender deferential is not pronounced in either the pediatric or
elderly population.
Prior Knowledge
Before beginning this retrospective chart review, Lichten40 hypothesized that the failure in these
SIBO patients was due to Wolbachia. Wolbachia bacteria exist within microfilaria (host
nematode). The Wolbachia is necessary for the life cycle of microfilaria because Wolbachia
introjects a second X chromosome. Without the second chromosome, the microfilaria becomes
male and dies; only the XX chromosome female reproduces. The author hypothesized that the
increasing estrogenic milieu caused by the changing exposure to xeno-estrogens in hormonal
contraception, environmental disrupting chemicals (EDCs) and persistent organic
pesticides(POP) was shifting the balance to producing more microfilaria females. The most
effective previous treatment was referenced to be doxycycline and albendazole.
Therefore, in the treatment of these patients, a number were treated with albendazole and
doxycycline per protocol.41 GI distress was noted in greater than 50 percent and only one was
able to continue therapy for the required 3 months. Her improvement on the anabolic protocol
continued independent of starting and stopping the Wolbachia protocol. Reference to the wide
range of prescription medications previously used to disrupt the GI flora in this population
appear in Table VI.
Lichten42 published a report in 1991 on the treatment of 141 premenstrual women with menstrual
migraine. He addressed the presumed hormonal cause of migraine by prescribing danazol, an
anabolic steroid, to lower the estradiol luteal surge, raise the testosterone level and lower the Sex
Hormone Binding Globulin(SHBG). In 67 of 81 patients followed for one year, dramatic relief of
the signs and symptoms of migraine were documented. Migraine is now considered an auto-
immune-mediated disease with 3 times higher anti-phospholipid antibodies, anti-cardiolipid and
anti-β2-glycoprotein I antibodies.43
Lichten44 offered proof of a novel medical protocol to treat extensive stage IV endometriosis that
in this case report prevented hemicolectomy. The patient remains pain-free after 8 years after
initiating and continuing weekly nandrolone and stanozolol injections.45 Endometriosis is now
considered an auto-immune disease46 with the sensitivity of 6 biomarkers (anti-TMOD3b-
autoAb, anti-TMOD3c-autoAb, anti-TMOD3d-autoAb, anti-TPM3a-autoAb, anti-TPM3c-
autoAb, and anti-TPM3d-autoAb) higher at the specificity of ≥80% for diagnosis of rAFS stage I
to II endometriosis as well as ultrasound-negative endometriosis. Endometriosis is also
statistically associated with autoimmune Graves’ Disease.47
Lichten48 and James Sowers in an unpublished IRB in 1999 documented that parenteral
testosterone lowered insulin requirements in brittle diabetic men by 50%. Kapoor49 and
Vonhueler50 subsequently reported that testosterone reduced hemoglobin A1c on average by 2%
in long-term studies lasting up to 52-weeks. Diabetes Type I (insulin requiring) and Type II
(adult onset) are both considered autoimmune diseases.
Lichten51 in a yet unpublished case report combined testosterone, nandrolone and stanozolol to
reverse a case of Crohn’s disease scheduled for hemicolectomy and ileocecal pouch in an 18-
year old Caucasian male who had experienced a 100-pound weight loss. Testosterone therapy in
Germany and Syria for up to 7 years was effective at dramatically reducing the Crohn’s Disease
Activity Index and C-reactive protein.52
Nassser52 clearly summarized why these observations can be made about testosterone and why
they clinically applied to its first derivative, nandrolone: “Low serum testosterone is associated
with an increase in inflammatory factors, while testosterone administration reduces them. There
is evidence for an immunomodulatory effect of testosterone on differentiation of regulatory T
cells.”52
CONCLUSIONS:
This retrospective chart review analysis is the first to document the utilization of anabolic
steroids in a rifaximin- antibiotic resistant SIBO population. This data supports the findings that
the altered immune serum laboratory findings associated with SIBO and comorbid autoimmune
diseases can be influenced by Gender Specific Hormones. Treatment with anabolic steroids that
are Gender Specific can improve the signs, symptoms and autoimmune markers of autoimmune
diseases including potentially Crohn’s and Inflammatory Bowel Disease (IBD).
Together, this retrospective chart review, prior knowledge and previous publications offers
observational proof that Gender Specific Anabolic Hormones can be an effective and supportive
treatment regimen of SIBO, IBD and autoimmune diseases. The Free Androgen Index (FAI) may
prove to be a key reproducible biomarker for diagnosis, recovery and follow up improvement of
not only resistant cases of SIBO but also select autoimmune disease states.
It is clear that the anabolic therapy protocol applied herein was directed at normalizing Gender
Specific Hormones levels to that of a young adult. The effect of gender on autoimmune function
is well known.53 What about its effect on autoimmune antibodies? Nandrolone and testosterone
both have direct effects on natural killer cells (NK)54, interleukins, thymus serum factor and IL-1
production mediated by macrophages. This may explain why nandrolone was effective in these
autoimmune cases, not dissimilar to the attempt by Wielosz32 to use azathioprine to treat
autoimmune polyglandular syndrome.
There is further loss of support for the hypothesis of molecular mimicry as a subset of these
patients treated with medications that disrupt microbiota of the gastrointestinal tract were
ineffective in improving SIBO complaints. (Table VI).
Gender Specific Hormones of antibiotic resistant SIBO appears to offer an effective treatment
and the FAI offers a biomarker of disease and potential for follow up of recovery.
Conclusions:
Gender Specific Medicine may offer effective treatment for both antibiotic failure in SIBO
patients and for supporting the underlying autoimmune disease. The ability to increase the FAI
bio-marker value strongly correlated with improvement in the patient’s symptoms in this chart
review. The authors feel that there is strong support that the paradigm shift of medical
investigation and treatment of SIBO alone and autoimmune diseases in general needs to be
expanded to include Gender Specific Medicine hormonal evaluations, anabolic therapy and the
potential use of the FAI as these disease states progress and during potential recovery.
References:
1. Mark Pimentel MD. Methanogens in Human Health and Disease, et.al, Am J
Gastroenterol Suppl (2012) 1:28–33; doi:10.1038/ajgsup.2012.6
2. Bruley des Varannes S. [How to treat after Helicobacter pylori eradication failure].
Gastroenterol Clin Biol 2003 Mar;27(3 Pt 2): 478-83
3. Borody T. Center for Digestive Diseases. [http://www.cdd.com.au/index.html]
4. Pimentel M, et.al. How to Test and Treat Small Intestinal Bacterial Overgrowth: an
Evidence-Based Approach. Curr Gastroenterol Rep. 2016 Feb;18(2):8. doi:
10.1007/s11894-015-0482-9. [PMID: 26780631] or
5. Peralta, S, et.al. Small intestinal bacterial overgrowth and irritable bowel syndrome
related symptoms: Experience with Rifaxmin. W J Gastroenterology 2009 June 7;
15(21):2628-31 [PMID: 19496193]
6. Thompson JR. Is irritable bowel an infectious disease? World J Gastroenterol 2016
Jan28; 22(4): 1223-4 [PMID: 26818502]
7. Chang MS, et.al. Double-blind randomized controlled trial of rifaximin for persistent
symptoms in patients with celiac disease. Dig Dis Sci 2011 Oct: 56(1): 2939-46. [PMID:
21647654]
8. Burke CW, Anderson DC. Sex-hormone-binding globulin in an oestrogen amplifier.
Nature. 1972 Nov 3;240(5375):38-40. [PMID:4120573]
9. Bennett RM, Clark SC, Walczyk J. A randomized, double-blind, placebo-controlled
study of growth hormone in the treatment of fibromyalgia. Am J Med. 1998
Mar;104(3):227-31. [PMID:9552084]
10. Bures J. Small intestinal bacterial overgrowth syndrome World J Gastroenterol 2010:
June 28: 16(24): 2978-2990. [PMID: 20572300]
11. Shah SC, Day LW, et.al. Meta-analysis: antibiotic therapy for small intestinal bacterial
overgrowth. Aliment Pharacol Ther 2013 Oct; 38(8): 925-34. [PMID: 2400410]
12. http://www.medscape.com/viewarticle/711657
13. Cash BD. Emerging role of probiotics and antimicrobials in the management of irritable
bowel syndrome. Curr Med Res Opin 2014 Jul; 30(7):1405-15 [PMID: 24666019]
14. Paul C, Brady DM. Comparative Bioavailability and Utilization of Particular Forms of
B12 Supplements with Potential to Mitigate B12-related Genetic Polymorphisms. Integr
Med (Ecinitas 2017 Feb: 16(1):42-49. [PMID: [28223907]
15. Massironi S, et.al. Chronic autoimmune atrophic gastritis associated with primary
hyperparathyroidism: a transversal prospective study. Eur J Endocrinol 2013 Apr15;
168(5): 755-61. [PMID: 23447517]
16. Pan XF, et.al. Type 1 Diabetic Populations Have an Increased Prevalence of Parietal Cell
Antibody: A System Review and Meta-Analysis. Medicine (Baltimore) 2015 Sept;
94(38): e1440. [PMID: 26402802]
17. Villanacci V, Casella G et.al. Autoimmune gastritis: relationships with anemia and
Helicobacter pylori status. San J Gastroenterol 2017 Jun-Jul: 52(6-7):674-677 [PMID:
28276835]
18. Zampetti S, et.al. GADA titer-related risk for organ-specific autoimmunity in LADA
subjects subdivided according to gender (NRAD study 6). J Clin Endocrinol Metab 2012
Oct; 97(10):3759-65 [PMID:22865904]
19. Fallahi P, et.al. The association of other autoimmune diseases in patients with
autoimmune thyroiditis: Review of the literature and report of a large series of patients.
Autoimmun Rev. 2016 Dec; 15(12): 1125-28. [PMID: 27639841]
20. Centanni M, et.al. Atrophic body gastritis in patients with autoimmune thyroid disease:
an underdiagnosed association. Arch Intern Med 1999 Aug 9-23; 159(15): 1726-30.
[PMID: 10448775]
21. Gil L, et.al Comorbid autoimmune diseases in patients with vitiligo: A Cross sectional
study. Am Acad Dermatol 2016 Feb; 74(2): 295-302 [PMID: Epub 2015’oct 27 [PMID:
26518171]
22. Rusak E, et.al. Anti-parietal cell antibodies – diagnostic significance. Adv Med Sci 2016
Sep: 61(2): 175-79. [PMID: 26918709]
23. Wu YC, et.al. Anti-gastric parietal cell and anti-thyroid autoantibodies in patients with
recurrent aphthous stomatitis. J Formos Med Assoc 2017 Jan; 116(1):4-9 [27793414]
24. Jevremovic D, et.al. atrophic autoimmune pangastritis: distinctive form of antral and
fundi gastritis associated with systemic autoimmune disease. Am J Surg Pathol l2006
Nov; 20(11): 1412-9 [PMID: 17063082]
25. Picceli VF, et.al. Spectrum of autoantibodies for gastrointestinal autoimmune disease in
systemic lupus erythematosus patients. Lupus 2013 Oct; 22(11): 1150-5. [PMID:
24057059]
26. Banati M, et.al. Antibody response against gastrointestinal antigens in demyelinating
diseases of the central nervous system. EurJ Neur 2013 Nov; 20(11): 1492-5. Epub 2013
Jan7. [PMID: 23293933]
27. Angelousi A, Larger E. Anaemia, a common but often unrecognized risk in diabetic
patients: a review. Diabetes Metab 2015 Feb;41(1): 18-27 Epub. [PMID: 25043174]
28. Paruk IM, et.al. High prevalence of anti-thyroid peroxidase and anti-parietal cell
antibodies among patients with type 1 diabetes mellitus attending a tertiary diabetes
centre in South Africa. Postgrad Med J. 2016 Oct 14. Epub a head of print [PMID:
27742863]
29. Mandry RC, et.al. Organ-specific autoantibodies in vitiligo patients and their relatives.
Int J Dermatol 1996 Jan; 25(1): 18-21. [PMID: 8838923]
30. Kahaly GJ, et.al. [Endocrinology and interdisciplinary consultation in internal medicine:
Illustrated using the example of polyglandular autoimmune syndrome]. Internist (Berl)
2017 Apr: 58(4): 308-328. [PMID: 28233015]
31. Vrkljjan AM, et.al. Existence of Addison’s Disease and Pernicious Anemia: Is the New
Classification of Autoimmune Polyglandular Syndrome Appropriate? Acta Clin Croat
2015 Jun; 54(2): 232-5 [PMID: 26415323]
32. Wielosz E, et.al. [Autoimmune polyglandular syndromes-literature review and analysis of
clinical course in chose cases]. Wlad Lek 2016; 69(1): 27-32 [PMID: 27162292]
33. Morris JA, et.al. Microbes, molecular mimicry and molecules of mood and motivation.
Med Hypotheses 2016 Feb; 87:40-3. [PMID:26826639]
34. Benvenga S, Guarneri Molecular mimicry and autoimmune thyroid disease. Rev Endocr
Metab Disord 2016 Dec; 17(4): 485-498. [PMID: 27307072]
35. Chesner IM, Montgomery RD. Small bowel contamination and vitamin B12 deficiency in
the elderly. J Clin Gastroenterol 1986 Aug; 8(4): 447-50. [PMID: 3760523]
36. Lauritano EC, et.al Association between hypothyroidism and small intestinal bacterial
overgrowth. J Clin Endocrinol Metab. 2007 Nov; 92(11): 4180-4 Epub 2007 Aug 14.
[PMID: 17698907]
37. Wright R. Henry Barnes Lecture: Immunological aspects of Gastrointestinal Disease.
Proc R Soc Med 1974 Jun; 67(6Pt 2): 574-80. [PMC 1645587]
38. Stockbrugeer RW, et.al. Pernicious anaemia, intra-gastric bacterial overgrowth, and
possible consequences. Scn J Gastroenterol 1984 May; 19(3): 355-64. [PMID: 6740211]
39. Ngo ST, et.al. Gender differences in autoimmune disease. Frontiers in
Neuroendocrinology 2014 Agu; 35(3): 347-369.
[https://doi.org/10.1016/j.yfrne.2014.04.004]
40. Lichten EM. Wolbachia and SIBO. Are Environmental Toxins causing a shift to a more
Estrogen Milieu? Medical Hypothesis. Submission.
41. De Britto RL1, Vanamail P2, Sankari T3, Vijayalakshmi G1, Das LK1, Pani SP4.
Enhanced efficacy of sequential administration of Albendazole for the clearance of
Wuchereria bancrofti infection: Double blind RCT. Trop Biomed. 2015 Jun;32(2):198-
209.
42. Lichten EM. Efficacy of danazol in the control of hormonal migraine. J Reprod Med
1991 Jun; 36(6): 419-24. [PMID: 1865397]
43. Islam MA, et.al. Comorbid association of antiphospholipid antibodies and migraine: A
systemic review and meta-analysis. Autoimmun Rev 2017 May; 16(5): 512-522. Epub
2017 Mar 7 [PMID: 28279839]
44. Lichten EM. Novel Medical Protocol Offers Alternative to Total Abdominal
Hysterectomy with Bilateral Salpingo-oophorectomy and Hemicolectomy in Stage IV
Endometriosis. Ob Gyn 2014 May; 124-125.
[http://journals.lww.com/greenjournal/Abstract/2014/05001/Novel_Medical_Protocol_Of
fers_Alternative_to_Total.258.aspx]
45. Ibid. http://www.endometriosiscenters.com
46. Gajbhiye R, et.al. Panel of Autoimmune Markers for Noninvasive Diagnosis of Minimal-
Mild Endometriosis. Reprod Sci 2017 Mar; 24(3): 413-20. Epub 2016 Sep 27. [PMID:
27485360]
47. Yuk JS, et.al. Graves’ Disease is Associated with Endometriosis: A 3-Year Population-
Based Cross-Sectional Study. Medicine (Baltimore) 2016 Mar; 9591)): e2975. [PMID:
26962803]
48. Lichten EM, Sowers JP. Unpublished IRB 97-607. Parenteral Testosterone use in Brittle
Diabetics. [http://www.usdoctor.com/research.htm]
49. Kapoor D, et.al. Testosterone replacement improves insulin resistance, glyacemic control,
visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes.
Eur J Endocrinol 2006 Jun; 154(6): 899-906. [PMID:16728551]
50. Huefelder AE, et.al. Fifty-two-week treatment with diet and exercise plus transdermal
testosterone reverse the metabolic syndrome and improves glycemic control in men with
newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009
Nov-Dec; 30(6):726-33. Epub 2009 Jul 3. [PMID:19578132]
51. Lichten EM, Higgins P. Unpublished Case Report. Pre-surgical for hemicolectomy in a
19-year old male with Crohn’s Disease.
52. Nasser M, et.al. Testosterone therapy in men with Crohn’s disease improves the clinical
course of the disease: data from long-term observational registry study Horm Mol Biol
Clin Investig.2015Jun; 2293): 111-7. [PMID: 26020563]
53. Oertelt-Prigione S1. The influence of sex and gender on the immune
response.Autoimmun Rev. 2012 May;11(6-7):A479-85. doi:
10.1016/j.autrev.2011.11.022. Epub 2011 Dec 3. PMID:22155201
54. Bruley-Rosset M, Dardenne M, Schuurs A. Functional and quantitative changes of
immune cells of ageing NZB mice treated with nandrolone decanoate. I. Effect on
survival and autoantibody development. Clin Exp Immunol. 1985 Dec;62(3):630-8.
PMID:3878753 PMCID: PMC1577483
TABLE I. NUTRACEUTICALS and SUPPLEMENTS
Pepto-Bismol™
Alka-Selzer™ Gold (sodium bicarbonate)
Bilex™
Ox bile
Digestive Enzymes
Aygestin™ 23 Colloidal Silver
Aloe Vera
Olive Leaf Extract
Mastic gum
Betaine hydrochloric acid
Allimed™
Neem Plus™
Vitamin B12
Vitamin B6
Vitamin D
Boron/ Boric Acid
Probiotic
Proton Pump Inhibitors
TABLE II. SIBO LABORATORY CHECK LIST
□ SIBO Breath Test (Lactulose Breath Test)
□ IBS serum check of the migrating motor complex
□ CdT
□ Vinculin
□ Pernicious Anemia Serum Antibodies and B12 levels
□ Intrinsic Factor
□ Intrinsic Factor Blocking Antibody
□ Intrinsic Factor Binding Antibody
□ B12 (cobalamin) serum assay
□ Chronic Autoimmune Atrophic Gastritis
□ Gastrin serum assay
□ Gastric Cancer Screen (optional)
□ Pepsinogen II
□ Heidelberg Test of Gastric ‘pH’ at baseline and sodium bicarbonate challenge
□ Esophageal-gastro-duodenoscopy (EDG)
□ Celiac Disease
□ IgA-transglutaminase (IgA-TTG)
□ deaminated gliadin (IgG-DGL)
□ Demographics
□ Height □ Weight □ BMI
□ Birth Year □ Environmental Toxin Exposure
□ Smoker □ Alcohol
□ Medications
□ Proton Pump Inhibitors
□ Thyroxine
TABLE III. HORMONAL LABORATORY CHECK LIST
Disease State Laboratory Test Range Women Men
□ Complete Blood Count
□ Metabolic panel
□ Auto-immunity Profile
□ Sedimentation rate
□ Anti-nuclear antibody
□ C- reactive protein
□ Hypothalamic
□ hypovitaminosis D Vitamin D3 25-OH > 60 > 60
□ hyperparathyroidism Parathyroid Hormone
□ Thyroid
□ hypothyroidism Thyroid Stimulating Hormone < 2.
□ Total triiodothyronine
□ Free T3 (triiodothyronine)
□ Free Thyroxine (T4)
□ Reverse T3 (triiodothyronine)
□ Thyroid Antibodies
□ Thyroid Peroxidase Antibodies
□ Adrenal
□ Dehydroandosterone-sulfate
□ Cortisol AM
□ Cortisol PM
□ Pancreas
□ Hemoglobin A1c
□ Fasting insulin
TABLE III. HORMONAL LABORATORY CHECK LIST -part 2
□ Ovarian Hormones
□ Total Estradiol
□ Total Testosterone
□ Progesterone
□ Sex Hormone Binding Globulin
□ Free Androgen Index- calculated 0.01.
□ Pituitary
□ hypopituitarism Insulin Like Growth Factor-1 >200 >225
□ menopause Follicle Stimulating Hormone <20
Luteinizing Hormone <20
□ Testes Hormones
□ Total Estradiol
□ Total Testosterone
□ Sex Hormone Binding Globulin
□ Free Androgen Index-calculated > 0.075.
□ hypogonadism Follicle Stimulating Hormone < 3.5
Luteinizing Hormone < 2.0
□ Prolactin
TABLE V.
The Number of Patients with laboratory findings, autoimmune diseases, medical diseases, medical treatments at initial evaluation and at 12-month follow up
TABLE VI.
3 cases of pernicious anemia treated with high dosages of methyl-cobalamin (B12) between
1000mcg and 5000mcg daily. [SB,____, ____, _____, ____, ____, ____, ____}. [____, _____]
3 cases of undiagnosed hypothyroid disease . [SB,____, ____, _____, ], one case of Grave’s
disease [CJ},and 3 cases of previously diagnosed Hashimoto’s thyroiditis [,_____, _____, ____]
was diagnosed by TSH, Free T3, Free T4, Reverse T3, thyroid antibodies, thyroid peroxidase
antibodies. Treatment consisted of combining thyroid therapy with thyroxine (T4) with
triiodothyronine (T3).
In the 15 patients followed for 12-months, all 3 men and 10 of 12 women showed 3 to 10-fold
elevation of the SHBG associated with abnormally low FAI based on the ideal range on
Anderson. The women were treated with nandrolone and stanozolol by weekly intramuscul.ar
injections. When the patients complained of painful injections, they were shifted to oral
stanozolol starting at one capsule weekly
The 3 men with low FAI had evidence of hypogonadism/ low testosterone (male) defined by
elevated serum assays FSH/ LH. Testosterone was added to the previously described nandrolone
and stanozolol for men.
Of the 12 women, 3 cases of menopause (female) were identified as these 3 had elevated serum
assays of FSH/LH and low serum total estradiol. When menopausal symptoms were still present
after initiating nandrolone, they were treated with add back estradiol topical or transdermal
patches.
There were 6 cases of hypopituitarism defined by IGF-1 below ideal range of RM Bennett MD
for fibromyalgia. Five patients were prescribed human growth hormone (hGH) after having good
but incomplete relief with anabolic therapy. Three found the medication beneficial and
continued the therapy. Two men and one woman returned to full employment. The remaining
individual was the 74-year old cachexic male considered a failure of therapy although some
improvements over all were noted. The remaining female individual discontinued the medication
due to cost. An L-arginine stimulation test was ordered for each of the patients continuing
therapy.
One presumed case of primary biliary cholangitis was seen by the author’s request at a major
University Teaching Hospital in Boston. The patient’s right upper quadrant pain dissipated on
5000mcg of methylcolbamin intramuscularly every day and subsequently redued to 5000mg
every other day. The tan stools remained but therapeutic treatment with ox bile, methylcolbamin
and anabolic therapy dramatically improved her quality of life.
Two patients had positive findings of Antinuclear Antibody (ANA) titers of 1:160 that fluctuated
to 1:80 on anabolic treatment. This was considered normal range variation, but, the presence of
positive ANA was noted in the findings of autoimmune disease states in 2 of these 18 patients.
TABLE VI.
PRESCRIPTION AGENTS THAT DISRUPT THE MICROFLORA OF THE GI TRACT
Class Individual agent Number of Pubmed.com references
Number of Patients in study on meds
Number of trials
Aminoglycosides Neomycin 24 Cepaholsporins- 1st Cefalexin 1 Cephalosporins- 2nd Cefprozil 1 Cephalosporins- 3rd Ceftriaxone 5 Glycopeptides Vancomycin 33 Lincosamindes Cleocin 18 Macrolides Biaxin 6 Monobactams Aztreonam 4 Nitrofurans Nitrofurantoin 0 Xazolidinones Linezolid 1 Penicillins Amoxicillin 23 Penicillin Combination
Amoxicillin/ clavulanate
5 Augmentin
Quinolones Ciproflaxacin 28 Sulfonamides Trimethoprim-
Sslfamethoxazole 7 Bactrim
Tetracyclines Doxycycline 9 Drugs against mycobacteria
Rifampicin 110
Steptomycin 8 Others Chloramphenicol 6 Metromidazole 73 Nitazoanide 1 Antifungal Fluconazole 13 Antiparasitic Albendazole 0