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From the Townsend Letter
February/March 2008


Quantum Medicine Update
Disrupted Steroidogenesis and Sex Hormone Binding Globulin in Fibromyalgia and Obesity
by Paul Yanick, PhD

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Hormone replacement therapy (HRT) with progesterone, DHEA, pregnenolone, or other hormones has been advocated as the ultimate way to correct the hormone-related deficiencies of fibromyalgia and to offset premature aging. Fibromyalgia involves endocrine-immune imbalances that perturb immunological reciprocity and the entire neuroendocrine orchestra. The hormone milieu can have a positive or negative effect on digestion, cardiovascular, immune, kidney, and cognitive functions. Fibromyalgia often coexists with gut dysbiosis and irritable bowel syndrome, maldigestion, chronic fatigue syndrome, hypothyroidism, and immune disorders. As a multisystem and multifaceted illness, shouldn't we be addressing fibromyalgia as a whole body disorder that involves a disruption of steroid hormone production (steroidogenesis), protein binding, metabolism, and liver detoxification?

Exciting new evidence on the emerging role of sex hormone binding globulin (SHBG), produced in the liver and critical for steroid uptake into cells, may provide the missing link needed for the successful treatment of fibromyalgia and other diseases. The evidence has shown that SHBG possesses a hitherto unrecognized range of functions and works more efficiently and faster than free steroids. The SHBG model of hormone functions is in sharp contrast to endocrine models that suggest "free" steroids are passively diffused across the cell membrane without a carrier protein and regulate hormone balance via pituitary-hypothalamic axes.1 "As much as 99% of testosterone in men and estradiol in woman is bound by SHBG," says Jack D. Caldwell, PhD, of the Department of Biomedical Sciences at University of Illinois College of Medicine. The dogma that steroid hormones are only bound by intracellular receptors ignores the fact that SHBGs are found in many tissues and only one percent is in the free steroid format, as currently employed in HRT.1 Indeed, studies show that liver conjugated and protein-bound steroids have effects on cells where free steroids do not.1-5

Dr. Caldwell, who spent decades studying steroid hormones, believes that free hormones in the serum do not predict hormone deficiencies and that our calculations regarding the metabolism of endocrine hormones "may have been backwards for a long time." He states, "If our conclusions about steroids have been amiss, then it is time to generate some new hypotheses about how steroids act in the body and the relative importance of various steroids." SHBG-formatted steroids are markers of energy storage, immune reciprocity, cancer and cardiovascular risk, repair, and regeneration, and are linked strongly to the current epidemic of obesity.1-8

SHBGs function as neuroactive peptides that work antagonistically to each other to maintain the balance between excitation and inhibition in the central nervous system and regulate the balance between pro-inflammatory and anti-inflammatory mediators. Neuroactive steroids act as fine-tuning mechanisms, turning receptors on or off to meet the needs of the organism while having a strong influence on learning and emotions.9-11 Uncompensated stress activates pro-inflammatory cytokines that are quickly counteracted by SHBGs, which allow the body to revert to the status quo quickly after the stressful incident and prevent metabolic damage. Patients with fibromyalgia carry on such pro-inflammatory responses to an abnormal extent. It seems as if their endocrine-immune balance point has been shifted to a pro-inflammatory mode. But just as there are two ways to stop a speeding car—by easing off the gas or hitting the brakes—the initiator and arrestor functions of SHBGs function as "on" and "off" switches to normalize inflammation in the body. However, these amazing hormones lose their tight control of physiological responses via the primary stress hormone, corticosteroid. Corticosteroid is controlled via corticotrophin-releasing factor that in turn inhibits the release of excessive corticoid hormones from the adrenal cortex, helping the immune system to divert its attention away from producing pro-inflammatory cytokines. Another negative physiological effect from stress relates to the fact that bile-cholesterol imbalances may keep levels of pregnenolone sulphate too low and thus slow down steroidogenesis and the resultant output of steroid hormones.9

SHBGs maintain homeostasis via bi-directional cross talk routines that execute the function of the immune system as a finely tuned concert. When analyzed by means of mass spectrometry, SHBGs are found in immunocytochemistry and in the hypothalamus and posterior pituitary gland.1 It is well-known that receptors for hormones have been found on cells of the immune system and those receptors for immune-generated cytokines have been found on the endocrine glands and brain. The balance between SHBG hormones influences the extent of immunological responsiveness, so when SHBGs are out of balance, we risk accelerating carcinogenesis and prolonged inflammation in the organism.

Proteins that bind sex hormones are in an indirect pathway for regulating sex steroid action as modulation of SHBG secretion (by the liver) of potent "regenerator-type" hormones that do not affect any components of the hypothalamic-pituitary-gonadal (HPG) axis, the hypothalamic-pituitary-thyroid axis (HPT), or the hypothalamic-pituitary-adrenal (HPA) axis. Since prolonged and chronic stress produces chronically elevated cortisol or corticosterone and causes an exhaustion of one or more of these endocrine axes in fibromyalgia patients, it becomes obvious why the fast hormonal actions of SHBGs are necessary for positive patient outcomes. In addition, we have to keep in mind that the adrenal glands might be failing to produce enough mineralocorticoids (which act on the kidney), opioid peptides, catecholamines, and enkephalins (actions not related to the HPA axis), which antagonize the effects of T4 conversion into T3 and intensify the symptoms of fibromyalgia even more via the HPT.1

Variations in the levels of liver-produced SHBG alter the biological activity of testosterone into dihyrotestosterone (DHT) and estradiol. These two opposing hormones behave in a battery-like or yin-yang fashion to regulate the negative effects of stress in the body. Like initiators and arrestors, or an "on" and "off" switch, they are in tight control of the physiological responses of stress. Leading steroid endocrinologists feel the view that progesterone is a control hormone "is essentially flawed…as estradiol is derived from testosterone via conversion by aromatase and DHT is derived from testosterone via 5a-reductase."1-5 Estradiol and testosterone are bound to SHBG and have exactly the opposite effects at the SHBG receptor. SHBG binds DHT, so DHT or testosterone act as antagonists to SHBG receptors. The yin-yang effects are clear, as estradiol stimulates and testosterone antagonizes the effects mediated by SHBG receptors. In this scenario, both hormones are derived from testosterone. Hence, in both men and woman, testosterone is the hormone that regulates SHBG production, and this fact cannot be ignored in alternative medicine.1-5 The role of testosterone in woman is becoming increasing more recognized and established. Could liver deficits in bile production or hepatic circulation, needed for cholesterol-driven steroidogenesis and SHBG production, be the reason that sex hormones get deficient and that hormone-induced cancers are on the rise? My research in thousands of clinical cases suggests that inefficient liver function and detoxification of xenoestrogens can plausibly account for the widespread hormonal deficiencies in fibromyalgia patients and patients with obesity and other inflammation-driven disorders.

Disrupted Steroidogenesis and Sex Hormone Binding Globulin from HRT and Xenoestrogens
The fundamental role of steroidogenesis is to enable a dynamic, coordinated response that prevents wild swings in hormones that might have detrimental metabolic and pro-inflammatory effects, as in the case of fibromyalgia. Since these reactions are intricately interlinked, HRT or environmental xenoestrogens can disrupt endocrine axes and hormonal cross talk with other systems of the body. The action of xenoestrogens can cause inhibition or induction of aromatase and 5a-reductase enzymes. That is why from a clinical perspective, we have no choice but to detoxify patients of xenoestrogens and make sure these toxicants are excreted out of the body via ample bile production through the body's secretion-excretion channel in the duodenum. The "see-saw" principle or yin-yang polarity that I call quantic harmony is critical for endocrine-immune cross talk routines that maintain homeostasis and counter prolonged inflammation. Changing our view of hormonal regulation to include the important role of SHBGs will undoubtedly improve clinical success rates with fibromyalgia and a wide spectrum of other stress-related illnesses.1-5,29

The co-existence of visceral obesity, increased blood lipids, hypertension, hormone deficits, and impaired glucose tolerance, known as the metabolic syndrome, is a determinant of morbidity and premature mortality.13-23 And studies have shown that fibromyalgia patients have steroid hormone imbalances that elevate immune-generated pro-inflammatory cytokines.24-28 Since testosterone is the control hormone behind SHBG production and since SHBGs might balance the aberrant hormonal responses in fibromyalgia and obesity, shouldn't we be focusing on understanding why and how SHBGs become deficient in the first place? Shouldn't we be trying to restore immune-endocrine reciprocity (cross talk) in an effort to restore the delicate balance between excitation and inhibition mediated by SHBGs?

One has to wonder if fibromyalgia risks are higher in woman because of HRT. As multi-cellular organism ecosystems, SHGBs regulate nearly every facet of our physiology. SHBGs will no doubt revolutionize the field of endocrinology and neurobiology, shedding much-needed light on how to improve health by considering why free steroids are not protein-bound in the liver. The downside of these new discoveries has to do with the fact that there's really no reliable way to assess SHBGs and testosterone clinically. While immunoassays are available to assess SHBG-binding sites, their predictive value appears to be unreliable.29-33

Since HRT with progesterone can disrupt testosterone receptors and thus halt SHBG production, extreme caution must be exercised with the use of oral or topical progesterone in woman and DHEA and testosterone precursors in men.34 The history of breast cancer constitutes a contraindication for HRT because it may activate dormant cancer cells.35-41 A Swedish study published in
Lancet found that breast cancer survivors who took HRT had more than three times as many breast cancer recurrences as survivors who did not take HRT.39,70 JoAnne Zujewski, MD, a medical oncologist who specializes in breast cancer at the National Institutes of Health Clinical Center in Bethesda, Maryland stated "…these results are consistent with those of other studies, including the Women's Health Initiative study. As a practical matter, given what we already know about the serious risks and extremely limited benefits of HRT, these findings can be considered definitive." A team of experts on the Women's Health Initiative Randomized Controlled Trial concluded "overall health risks exceeded benefits."38 Progesterone used as topical sterol diosgenins (wild yam) or synthetic progestins is a palliative that can disrupt SHBG production and powerful SHBG hormonal control mechanisms. In the May 2006 issue of What Doctors Don't Tell You, Dr. Ellen Grant did an excellent review article on the inherent heath dangers of topical progesterone creams stating, "Progesterone is a primitive steroid that is highly immunosuppressive and potentially carcinogenic. The evidence kicks away the main platform on which Lee built his case—that natural progesterone is somehow safer than synthetic progesterone." Dr. Grant cited many prestigious studies to provide evidence that HRT with progesterone may increase the risk of coronary artery disease, stroke, thrombosis, and breast cancer (Journal of Clinical Pharmacology. 2005; 45) and encourage breast cancers to spread rapidly and metastasize and induces leaky blood vessels (Journal of Clinical Endocrinology and Metabolism. 2005:90).40-42

When one considers the potential benefits of HRT against the risks, and the fact that deficits in steroidogenesis are compounded by a plethora of other conditions, it may be too simplistic and dangerous to use steroid forms of HRT in clinical practice. Using HRT as a temporary fix to control symptoms might appear to be beneficial, but in the long run, tinkering with one component of steroidogenesis might suppress steroidogenesis itself and the globulin-binding of other SHBG hormones. Plugging one hormone, synthetic or natural, into the intricately interlinked hormonal pathways will likely create a domino effect with every hormone down the cascade of steroidogenesis. Thus, when faced with fibromyalgia and other disorders involving the neuroendocrine and immune system, we may need to redefine clinical goals to augment SHGBs and cellular functions. No one knows what really happens when one is using HRT to the process of steroidogenesis at the "intracrine" level, where the body manufactures and activates hormones at the multiple cellular and intracellular levels to maintain balance in the organism. Most importantly, even though natural hormones appear safer than synthetics, there are no controlled trials to prove the long-term safety of natural hormones.

What about HRT with testosterone or androstenedione? Again, no long-term studies have weighed the potential benefits against the possible risks, including infertility and prostate problems. Since prostate cancer is an endocrine-sensitive tumor, it can develop under abnormal androgenic stimulation. HRT with androstenedione disrupts liver metabolism and steroidogenesis43,44 and may elevate estrogen too high, causing male gynecomastia45 and breast and pancreatic cancer46,47 and increasing risk of cardiovascular disease by lowering HDL cholesterol and increasing inflammation.44,48 In males, elevated serum levels of androstenedione have been linked to prostate cancer,49 pancreatic cancer,50 and causes of kidney and liver damage, acne, premature baldness, gynecomastia, an enlarged prostate, reduced sperm production, and heightened aggression. In females, studies show it disrupts menstrual cycles, deepens voice, causes hirsutism (increased facial hair growth), acne, masculinization, kidney damage, and liver damage.51 Whenever HRT with testosterone is used, experts believe it disrupts the HPG, HPT, and HPA endocrine axes, suppressing the body's natural production of testosterone and SHBGs while potentially leading to testicular atrophy, stunted bone growth, acne, and an excess of DHT which, in turn, can cause increased facial and body hair, an enlarged prostate, male-pattern baldness, and decreased HDL cholesterol.52-54

Clinical Attempts to Restore Immune-Endocrine Reciprocity and SHGB-Mediated Functions
Synthetic (man-made) chemicals released into the environment, especially xenoestrogens, have adverse effects on human health and cause disease, including cancer. Xenoestrogens have intrinsic hormonal activity and are "endocrine disruptors." It is clear that environmental and lifestyle factors are key determinants of human disease —accounting for perhaps 75% of most cancers.55 New understanding and emerging results are reshaping our thinking regarding how xenoestrogens can disrupt the binding of SHBGs and globulins such as corticosteroid-binding globulin expressed in the brain and androgen-binding protein in the heart.

Figure 1: Effects of Xenoestrogens

Figure 1

Over the last two decades, the incidence of fibromyalgia, obesity, and associated metabolic syndrome diseases has risen dramatically. An increased bioaccumulation or body burden of xenoestrogens is believed to represent the root cause of this dramatic rise.56 Xenoestrogens disrupt the normal developmental and homeostatic controls over inflammation, adipogenesis, and energy balance.

The exponential rise in worldwide pollution demands that new strategies be developed to detoxify and cleanse the body of xenoestrogens. More and more evidence is pointing to the undeniable correlation between xenoestrogens and health risks.73-78 In several of my earlier Quantum Medicine Update columns, I explained how xenoestrogens-generated estrogen dominance inhibits the conversion of T4 to T3 and causes hepatic circulation and biliary tract damage by disturbing the normal chemical exchange between the vessel lining and the blood (Figure 1). 61-65 Blood tests rarely are able to find T3 deficits as the T3 uptake test measures the in vitro partition of the T3 between the patient's serum and a specifically resin previously charged with T3. In this test, the unsaturated thyroid binding globulin (TGB) competes with the resin for the radioactive T3. Hence, the procedure is altered by changes in the level of TGB and commonly yields erroneous results that do not parallel what is really happening in the body via the HPT. And T2 the metabolically-active iodothyronine produced by the thyroid is rarely ever tested in cases of fibromyalgia and obesity.59

Hormones are important controllers of the vascular system, and hypothyroidism and low testosterone levels have been linked to high cholesterol levels, hypertension, fatigue, and maldigestion. Figure 2 illustrates the intricately interlinked hormonal pathways and the cross talk (integration) of endocrine axes with SHBGs. The liver is the key area of SHBG binding and where T4 is converted to T3. When SHBGs are allowed to regulate multiple metabolic pathways, patients lose weight efficiently. I believe this is because the HPT axis is working more efficiently, allowing the thyroid to make more T2. When inflammation-generating abdominal fat cells shrink, the pain of fibromyalgia decreases dramatically.5

Figure 2

Figure 2

While the SHBG link to fibromyalgia is explored further, doctors need to focus more on finding ways to restore immune-endocrine reciprocity and SHBG-mediated functions. The precautionary principle asks: What is the core physiological issue underlying fibromyalgia or obesity? In answering this question, we obviously realize that supporting liver physiology and detoxification makes the most sense. It makes no sense to counter the estrogen dominance of stored xenoestrogens with progesterone without first exploring ways to detoxify and excrete these toxicants out of the body. Hence, approaching fibromyalgia with the intent of nourishing and cleansing the body might lead to a higher percentage of clinical success. Treating fibromyalgia in this manner targets and may restore the following:

1. Hepatocyte Polarity: All xenoestrogens have a positive ionic charge and disrupt hepatocyte polarity to the point of causing Deficient Bile Syndrome (DBS), a condition of decreased bile production that allows for the excessive bioaccumulation of xenoestrogens, causing widespread damage to the organism. Researchers have discovered that the battery-like "positive" and "negative" charges of hepatocytes, determine how efficiently toxicants like xenoestrogens are excreted out of the body. Moreover, in the case of steroidogenesis, ample bile is necessary to breakdown cholesterol into steroid hormones.45,57,66

2. Hepatic Circulation: Xenoestrogens and other man-made chemicals damage hepatic circulation, thereby reducing the functional efficiency of liver performance. As I explained in my last four columns, circulatory, respiratory, metabolic, endocrine, neurological, lymphatic-immune, and bio-energetic systems operate efficiently when toxins with a positive ionic charge are cleared out of the circulation. Moreover, when cholesterol is properly used to make steroids, less of it will pile up in the liver's circulatory system and elsewhere in the body.45-66,73-78

3. Synbiotic Nutriture: Since the vast majority of cells in the body—by a factor of ten—are commensal-probiotic cells that manufacture hormone precursors and co-factor nutrients and the proteins needed to maintain steroidogenesis, symbiotic/probiotic protein matrixes derived from "mold-free" raw food ferments and concentrates may provide the nutriture to maintain hormone balance. Commensals thrive on this nourishment and are activated to the point of finding a permanent home in the gut. These powerful and genetically diverse cells perform indispensable functions in nourishing and detoxifying the body. Optimization of commensal cells optimizes detoxification and reestablishes a "strategic alliance" or symbiosis with human cells and various systems of the body. Since commensal cells manufacture nanoscale nutrients with the correct polarity and fabricate powerful anti-inflammatory and immune-regulating carrier proteins that form SHBGs, they can dramatically increase the usability, bioavailability, and versatility of hormones.45,57-66

Despite the lack of scientific evidence, HRT is growing in popularity. Pharmacies filled 2.4 million testosterone prescriptions in 2004 — more than twice the number filled in 2000, according to IMS Health, a company that tracks pharmaceutical sales. At the core of the controversy is whether hormone deficiencies need to be corrected to suppress symptomatology and tame hormone havoc or whether they need to addressed via the core pathways of steroidogenesis and protein-binding in the liver and cell membrane via SHBGs.

Figure 3 illustrates how SHBGs are the primary regulators of hormone metabolism that interlink with all endocrine axes. The liver is the key area of SHBG binding and also where T4 is converted to T3. When SHBG-Testosterone and SHBG-Estradiol are balanced, T2 is produced more efficiently by the thyroid, and this accounts for weight loss in stubborn cases of obesity. When abdominal fat cells that generate inflammation shrink, the pain of fibromyalgia subsides.59 While these empirical observations need to be studied further, the principles of providing proper nutriture to provide the raw materials needed for the manufacture of T1 and T2, and other hormones can be fruitful in clinical practice. Indeed, T1 and T2 appear to be the missing link in the current obesity epidemic, as they exert powerful control over adipocytes in the body.59

Steroid hormones control gene-expression to coordinate cell differentiation, growth, organogenesis, metabolism, and repair and regeneration in the organism. Adding steroid hormones—whether synthetic or natural—can irreversibly damage the organism by mimicking, blocking, or otherwise disrupting pathways that have been fine-tuned over millions of years to respond to minuscule changes in hormone levels. Commensal cells contribute monumentally to the intracrine production of hormones. Using synbiotics and commensals to nourish and detoxify the body can provide the raw nutriture necessary to make thyroid hormones and fuel steroidogenesis. As an added bonus, they also cleanse the body of toxicants that cause estrogen dominance, cancer, and all sorts of degenerative disease.68-72

New research on SHBGs is opening the door to the long-dreamed-of cure of many pro-inflammatory disorders by employing the body's innate healing mechanisms and regulatory systems. This new knowledge may help save patients and their children from xenoestrogen-induced cancer and neurodegenerative and cardiovascular diseases. Epidemiologist Devra Davis of the University of Pittsburgh Cancer Institute and her colleagues documented that, because of xenoestrogens from heavy metals, pesticides, plastics, solvents phthalates, and PCBs, the proportion of male babies being born in the US and Japan has been steadily declining since 1970.72

Figure 3

Though this article is primarily an overview of the current evidence on the powerful regulatory effects of SHBGs, it is intended to encourage doctors to look deeper into the aberrant physiology of fibromyalgia, obesity, and other illnesses. In this hugely contentious area, polarized opinions predominate (because it seems that many doctors are comfortable suppressing symptoms of steroid imbalances with natural hormones, vitamins, or botanical extracts).

Finally, there is artistry to healing that needs to take into account the whole of a person and the underlying core issues and inherent complexities of how the body regulates and protects itself from stress-induced or toxicant-induced damage. Laboratory testing is unreliable by itself to understand the powerful regulatory and balancing effects of SHBGs.30-33,71 Therefore, as we examine the failures and dangers of HRT and the limits of our current diagnostic and treatment protocols for fibromyalgia and obesity, may we attempt to treat the cause and not the symptoms in our patients.

The author is supported in part by American Academy of Quantum Medicine, a non-profit foundation dedicated to frontier research in Quantum Medicine. The author is affiliated with QuantaFoods, LLC a firm that develops and researches probiotics and fermentation to develop novel forms of mineral-ligand and protein-bound synbiotic nutrients and is a research consultant for several independent, university-based laboratories. The content of this article was neither influenced nor constrained by these facts.

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73. Yanick P. Cardiovascular and cerebrovascular disorders and estrogen dominance syndrome. Townsend Letter for Doctors. November, 1999.
74. Yanick P. Hormone resistance and the GRS. Townsend Letter for Doctors. January 1999.
75. Yanick P. Auto-immune disease and xenobiotic toxicity. Townsend Letter for Doctors. Aug-Sept 1999.
76. Yanick P. Novel detoxification methods to counteract global pollution. Townsend Letter for Doctors. June, 1999.
77. Yanick P. Female urogenital disorders. Townsend Letter for Doctors. January 2000.
78. Yanick P. Functional disturbances of the liver and lymphatic system. Townsend Letter for Doctors. October 1994.


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