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
Dr. Caldwell, who spent decades studying steroid hormones, believes that
free hormones in the serum do not predict hormone deficiencies and that our
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
SHBGs function as neuroactive peptides that work antagonistically to each
other to maintain the balance between excitation and inhibition in the central
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
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
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
Disrupted Steroidogenesis and Sex Hormone Binding Globulin from HRT
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
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
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
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
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
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
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
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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