Cortisol Abnormality as a Cause of Elevated
Estrogen and Immune Destabilization
Alfred J. Plechner, D.V.M.
To be published in Medical Hypotheses, 2003
Ihave long regarded adrenal dysfunction as a wellspring
of excess estrogen which may contribute to hormonal
imbalances, immune destabilization, and
increased vulnerability to disease. As a practicing clinician,
I have consistently found elevated total estrogen
as part of an endocrine-immune derangement present
in many common diseases of dogs and cats. Ninety
percent of these cases involve spayed females and
neutered or intact males, so the elevated estrogen cannot
be attributed to ovarian activity. Sick and intact
females, tested outside their estrus period, frequently
have an elevated estrogen level as well.
The pattern of derangement identified in thousands
of cases over three decades involves insufficient cortisol,
high estrogen, and abnormally low IgA, IgG, and IgM
levels. This pattern undermines homeostasis and sets the
stage for malabsorption and digestive disorders, allergies,
lung and urinary tract problems, sluggish liver function,
strange or aggressive behavior, epilepsy, obesity, deadly
viral and bacterial infections, periodontitis, vaccine complications,
autoimmunity, and cancer. Moreover, the
same set of imbalances is often present as an underlying
enabling mechanism in multiple illnesses.
The adrenal cortex produces a variety of vital
hormones. Among them is cortisol, the primary
glucocorticoid made in the middle cortex layer (zona
fasciculata). Endogenous cortisol controls inflammation,
1 a function that inspired the development of cortisone
drugs, pharmaceutical versions of cortisol. A profound
loss of cortisol can lead to a critical state of
deranged metabolism and an inability to deal with stress
and infections. Cortisol exerts a discriminating regulatory
effect on molecular mediators. These mediators
trigger activity related to both immunity and inflammation.
A normal level of cortisol seems to be required
for healthy responses.2 Cortisol deficiency may result
in an unresponsive immune system, whereas too
much cortisollike too much cortisone medication
suppresses immune responses.
Adrenocorticotropic hormone (ACTH) from the pituitary
stimulates cortisol production. ACTH is
controlled in turn by the hypothalamic corticotropicreleasing
factor (CRF) in a classical feedback loop.
When cortisol blood concentrations rise to a certain
level, CRF secretion slows, inhibiting ACTH and subsequent
cortisol secretion.
The androgens dehydroepiandrosterone (DHEA)
and dehydroepiandrosterone sulfate (DHEAS) are the
most abundant circulating hormones in the body. These
substances, known as prohormones because they metabolize
into other hormones, are primarily made in the
zona reticularis of the adrenal cortex. Through enzymatic
actions, they convert to androstenedione, androstenediol,
testosterone, and further to the estrogen compounds
estrone and estradiol.3 Androstenedione is the
most important precursor of estrone, the most abundant
circulating estrogen in postmenopausal women.
Androstenediol has inherent estrogenic activity. 4
The exact biological function of adrenal androgens
and the mechanisms underlying their control is still
the object of debate. However, it is well known that
both may have androgenic and estrogenic effects.5
Veterinary researchers have found numerous genetic
defects resulting from contemporary linebreeding and
inbreeding practices.6 Since the 1970s I have reported a
cortisol defect in cats and dogs.7 I believe this stems
largely from questionable breeding practices.
Other potential causes for cortisol deficiency include
prolonged stress and toxicity, which may be a significant
acquired cause of adrenal cortical dysfunction. Harvey
states that the adrenal gland is the most vulnerable
organ in the endocrine system for toxins, and within the
adrenal gland the majority of effects have been
observed in the cortex. Such disturbances can
fundamentally affect the whole body physiology and
biochemistry.8
When the zona fasciculata cannot make enough cortisol,
or for some reason the cortisol is excessively bound
E N D O C R I N E - IMMUNE ME C H A N I S M S A N D HU M A N HE A LT H I M P L I CAT I O N S
(inactive) and thus not recognized by the hypothalamuspituitary
system, the pituitary continues to release
ACTH in order to stimulate more cortisol. The zona
reticularis also responds to ACTH. This part of the adrenal
gland, as noted above, produces androgens that can
convert to the estrogen compound estrone, or to testosterone,
which may then convert in part to the more
potent estrogen compound estradiol.
Some researchers say that an interface or transition
zone of tissue between the zona fasciculata and reticularis
of the adrenal cortex is capable of directly producing sex
hormones, including estrogen compounds.9, 10 Excess
estrogen promotes CRF release from the hypothalamus
and ACTH from the pituitary, and contributes to
hormonal imbalances and deleterious effects in the body.
Researchers working in the field of rheumatoid arthritis
and autoimmune rheumatic diseases believe that hormone
balance is a crucial factor in the regulation of
immune and inflammatory responses. Generally, estrogen
in physiologic concentrations enhances humoral
immune responses and depresses cellular-mediated
responses. At higher and pharmacological concentrations
the hormone has a number of inhibitory actions.
Elevated estrogen, for instance, is associated with atrophy
of the thymus gland. Androgens, by contrast, tend to
suppress both humoral and cellular types of mechanisms.
11 An examination of the endocrinology literature
reveals, however, that mechanisms through which sex
hormones regulate immune and inflammatory responses
are poorly understood.12
POSSIBLE ROLES OF ADRENAL ESTROGEN
I have developed an endocrine-immune blood test
that measures cortisol, total estrogen, T3 and T4, and
IgA, IgG, and IgM antibody levels. The measurement for
estrogen includes all estrogen compounds in the body,
that is estradiol, estrone, and estriol.
The test shows a consistent link between clinical
signs of various illnesses and total estrogen outside of a
normal range. Intact female animals are not tested
during their estrus period. In out-of-estrus females, intact
males, and neutered pets, normal levels are as follows:
Males: 20-25 pg/ml
Females: 30-35 pg/ml
Elevated estrogen appears to contribute to a number
of negative effects:
Cortisol impairment. Studies have shown that estrogen
inhibits cortisol synthesis by specific interference
with enzyme activity,13 thereby exacerbating a cortisol
deficiency and initiating hormonal imbalances.
Thyroid hormone impairment. Estrogen causes an
increase in serum thyroxine-binding globulin, which
may slow the entry of thyroxine into cells and
thereby reduce thyroid hormone action in tissue.14
Elevated estrogen may also directly inhibit thyroid
glandular release.15 Cortisol appears to be involved in
the normal transference of T4 to T3, and the entry of
T3 into cells.16 By interfering with cortisol synthesis,
estrogen may indirectly impair thyroid function.
These combined effects may slow the overall metabolism
and interfere with many basic physiologic
functions.
Inflammation. My patients blood tests consistently
show an association between inflammatory conditions
and the pattern of low cortisol, high estrogen,
and low antibody levels. Studies have shown that cortisol
inhibits the production and accumulation of
excess histamine in tissue17 and the synthesis of
prostaglandins, mediators of the inflammatory
response.18
Cancer. In humans, estrogens are involved in the
development of breast and endometrial cancer.19 All
the dogs and cats I test and treat for cancer have
impaired cortisol and high estrogen, along with
deregulated immune cells.
Autoimmunity. The same abnormal hormonal pattern
is found in pets with autoimmune conditions.
Immune cells are suppressed and appear to be
stripped of normal regulation and the ability to distinguish
between host tissue and foreign matter.
Lahita has reported that recent data indicates
increased estrogen levels might initiate autoimmune
diseases in many women and men.20
Aggressive behavior. Many unpredictable and
aggressive animals have the endocrine-immune
disturbance. In humans, Finkelstein provides
evidence suggesting that estrogen may play a
significant role in the production of aggressive
behavior in both sexes.21
TREATMENT
I initiate corrective therapy when testing indicates
the presence of imbalances. The protocol involves the
use of various cortisone medications, either standard
pharmaceutical compounds or a natural bio-identical
preparation made from an ultra extract of soy. All
18
C O R T I S O L A B N O R M A L I T Y, E L E VAT E D E S T R O G E N, A N D IMMUNE D E S TA B I L I Z AT I O N
plant materialthe part of soy which increases body
estrogen levelshas been removed. The compound is
administered at low, physiologic dosages sufficient to
compensate for deficient cortisol and re-regulate the
immune system. These therapeutic dosages are significantly
lower than standard pharmacologic levels used
for short-term treatment and are usually needed for the
duration of the patients life.
This innovative use of a standard medication consistently
restores lost immune competence. Most canine
conditions require additional T4 thyroid medication.
For some species-specific reason, most affected felines
require only steroid replacement. This treatment
approach has proven to be effective, safe, and free from
side effects in thousands of cases.
After two weeks of therapy, patients are retested.
There is usually a clear normalization of the key
endocrine-immune markers along with parallel clinical
improvements, indicating that a significant healing
process is underway. In general, animals recover and
maintain good health as long as the program is maintained.
A supportive hypoallergenic diet eliminates the
risk of food reactions which can nullify the therapy.
This clinical experience demonstrates the potent regulatory
influences of cortisol and estrogen in immune
function. It shows, perhaps for the first time, how an
adrenal combination of abnormal cortisol and high
estrogen interact to substantially deregulate and weaken
immunity and contribute to multiple diseases.
For decades, William Jefferies, M.D., clinical professor
emeritus at the University of Virginia School of
Medicine, has used low-dosage steroid replacement for
human patients with adrenocortical deficiency and
reported improvement for allergies, autoimmune disorders,
and chronic fatigue.22 The medical community
has largely ignored his clinical research because of an
ingrained fear of using cortisone long-term under any
circumstances. A similar fear exists in veterinary medicine.
At conventional pharmacologic dosages, cortisone
does indeed create side effects. In the past practitioners
often shuddered at any suggestion of long-term cortisone,
and, as the old saying goes, threw the baby out
with the bathwater.
Recently, resistance to long-term physiologic doses
of cortisone appears to be eroding. Medical researchers
have reported successful applications of low-dosage cortisone
in rheumatoid arthritis,23 polymyalgia rheumatica
a systemic inflammatory disorder of the aged24
and sepsis.25 However, none of these studies link specific
conditions to an overall mechanism wherein an
abnormality of cortisol triggers excess estrogen, HPA
destabilization, interference with thyroid, and deregulation
of the immune system. I believe that this pattern of
hormone-immune imbalance is a widespread but largely
unrecognized mechanism among pets, and may contribute
to various human illnesses.
TESTING THE HYPOTHESIS IN HUMANS
The presence of such imbalances in humans could
most readily be tested among symptomatic men and
postmenopausal (non-ERT) women. First, a baseline
blood test would be taken to measure cortisol, total
estrogen, T3/T4, and IgA, IgG, and IgM antibody levels,
along with a 24-hour urine test for active hormones
and other relevant markers. The urine test permits the
clinician to compare results against the blood test. This
is an important evaluation because some blood values
(such as cortisol and thyroid) may appear normal in a
blood test but in fact involve excessively bound, inactive
hormone fractions. Blood tests alone may not indicate
whether or not the hormone is working. The urine test
helps answer this question and contributes to a more
accurate assessment and effective treatment.
Jefferies clinical experience with human patients
suggests that low-dosage cortisol replacement therapy
could be applied to symptomatic patients who are tested
and found to have the endocrine-immune imbalances
described in this article. If their health status improves
and retesting shows a reduction in total estrogen, one
could conclude that a hypocortisol syndrome with wide
systemic impact has been clinically corrected. Such a
result would argue for further investigation of this
testing and therapy method for various illnesses.
Even though post-menopausal women are deficient
in estradiol, their estriol and estrone are often very high
not only from the possible interface layer but because
the tissue enzyme aromatase converts DHEA and
DHEAS and other androgens into total estrogen.
Gruber states that estrogen synthesis increases in
non-ovarian tissues as a function of age and body
weight even though little is known about the factors
that regulate estrogen production in the postmenopausal
population.26 Longcope and colleagues
observed a marked increase in the ratio of estrogens to
androgens in acute illness among postmenopausal
women. Conditions included heart attack, unstable
angina, respiratory illnesses, and congestive heart
failure.27 One physician with whom I have been
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communicating commented that his sickest postmenopausal
(non-ERT) patients have the highest total
estrogen levels and the lowest immunoglobulins.28
Estradiol alone, and not total estrogen, is currently
the standard measurement in patients, yet in postmenopausal
women, estrone is the major estrogen.29
Estriol, generally considered to be a weaker compound
than estradiol and estrone, is present in significantly
greater concentration in premenopausal
women,30 and may have significant though currently
unidentified biological activity. I believe that total
estrogen, including estrone and estriol, is a more
meaningful indicator of estrogen activity than estradiol
alone.
The presence of xenoestrogens and phytoestrogens,
chemicals which mimic estrogen and which can
potentially trigger androgen-estrogen imbalance, complicate
the process of assessing serum estrogen status.
Such compounds appear in the environment and in
food. Ubiquitous estrogenic compounds, including
industrial chemicals, pesticides, and surfactants, affect
wildlife and laboratory animals immune systems.
Further studies are needed to determine the immune
response in humans. These compounds may affect
humans in similar ways.31 Hence, the need to measure
total estrogen.
Mesiano, demonstrated in 1999 that dietary phytoestrogen
compounds found in soy decrease cortisol production
and, as a result, increase androgens. Such consumption,
he suggests, may indirectly increase total
estrogen by raising DHEA and DHEAS levels. In his
opinion it is possible that some of the estrogenic actions
of dietary phytoestrogens may be mediated via their
stimulation of adrenal androgen synthesis.32
One way to determine the influence of dietary phytoestrogens,
at least in men and postmenopausal
women, would be to eliminate soy from the diet of
patients who test high in total estrogen, then retest the
patient again after several weeks. A clear drop in estrogen
level could indicate a dietary effect. An unchanged
or insignificantly changed level would indicate a source
for estrogen unrelated to diet.
Xenoestrogens include birth control pills and chemicalized
estrogen drugs. Can these contribute to a disturbance
of cortisol and thyroid, and contribute to the disease
process? It seems plausible that exogenous estrogen,
or even androgen supplements (such as DHEA, which
can convert to estrogen in the body) could indeed contribute
to imbalances and disease.
My male patients test results make a strong argument
for hypocortisolism as a primary cause of elevated
estrogen. In symptomatic males with endocrineimmune
imbalances, high estrogen occurs almost exclusively
as a consequence of a cortisol abnormality. The
rare exception is the animal whose endocrine-immune
status normalizes spontaneously without any treatment
after moving to another area. I assume in such cases that
a significant toxic or xenoestrogenic compound, perhaps
ingested or inhaled, was present in one area and not in
the other.
IMPLICATIONS FOR HUMANS
Elevated estrogen participates in a broad syndrome of
hormonal-immune imbalances contributing to multiple
diseases in animals. Is estrogen similarly involved in
human conditions?
Is an unsuspected excess of estrogen involved in
AIDS? Veterinarians regard diseased cats infected with
feline immunodeficiency virus (FIV), a retrovirus
similar to HIV, as untreatable. Yet I have a 70 percent
recovery rate among symptomatic FIV patients. These
animals have a typical pattern of low cortisol, high
estrogen, and disturbed immune function. Low-dosage
steroid therapy corrects the underlying imbalances and
restores natural immunity. Cats remain disease-free as
long as they are kept on the therapy. The results raise a
number of questions.
Does the virus cause the disease or do the imbalances
weaken the immune system and give the virus free rein?
Do the imbalances also accelerate the disease process by
deregulating the immune system so that immune cells
attack both viruses and host tissue? Is it not possible that
in humans cortisol-estrogen-immune status may dictate
whether a person develops AIDS symptoms after being
exposed to the HIV virus? My clinical experience with
animals suggests that HIV-positive humans be tested for
endocrine-immune imbalances. If present, appropriate
hormone replacement might offer a significant prevention
and therapy strategy.
All of my cancer patients have the same general
pattern of endocrine-immune disturbance. Based on
this experience I would suggest that human cancer
patients be tested for similar imbalances. If they exist,
appropriate hormone replacement therapy might
offer an effective treatment strategy for humans just
as it does for animals, even in advanced cases.
According to Gunin estrogen generates proinflammatory
responses as well as proliferative
20
C O R T I S O L A B N O R M A L I T Y, E L E VAT E D E S T R O G E N, A N D IMMUNE D E S TA B I L I Z AT I O N
changes associated with a pre-cancerous process in
the uterus. Treatment with cortisone (dexamethasone)
in ovariectomized rats given estradiol reverses
these abnormalities.33
I routinely find the combination of abnormal cortisol
and elevated estrogen in animals with histories of
infertility and miscarriage, suggesting that reproductive
failures may be caused by inflamed and immune-deregulated
reproductive tract tissue. Such failures are routinely
corrected by proper hormone therapy, enabling
animals to conceive and produce healthy offspring.
Over decades of clinical experience, William Jefferies,
an emeritus clinical professor at the University of
Virginia, has reported that patients with cortisol insufficiency
and histories of ovarian dysfunction, infertility,
and failed pregnancies achieve significantly improved
conception and birth rates on low-dosage cortisone
therapy.34
Common variable immunodeficiency (CVID)
appears to be a grossly underdiagnosed enabling mechanism
for a multiplicity of disorders in humans just as it
is in animals, giving rise to chronic infections, autoimmune
conditions, an increased risk of cancer, and poor
response to immunization. In both humans and animals,
CVID is characterized by low IgA, IgG, and IgM
levels and abnormal T cell counts. In humans, the precise
trigger for such immune dysfunction is unknown.
Researchers have not linked CVID or other so-called
immunodeficiency mechanisms to hormones. I suggest
that exploring this connection, and looking specifically
at cortisol activity, may generate major clues for diagnosis
and treatment.
My clinical success and the growing clinical applications
of low-dosage cortisone therapy for humans
strongly argue for sustained research into the nature,
magnitude, and impact of cortisol defects, including an
associated estrogen-immune problem, in the etiology of
disease. While it is now recognized that the hypothalamic-
pituitary-adrenal axis, as part of the neuroendocrine
system, has central importance to immune
homeostasis,35 we still dont understand the countless
details and interactions.
Estrogen measurements are generally assumed to
be expressions of ovarian function. This seems an
invalid assumption, since a deficit of active cortisol
from genetics, stress, toxicity, or phytoestrogenscan
initiate a significant estrogen buildupestrogen
dominanceindependent of the ovaries. Estrogen
dominance not only causes inflammation of many of
the arteries, but it also binds active cortisol and active
thyroid, and deregulates the immune system. It can
also contribute to such ailments as cancer, autoimmunity,
and hypersensitivity diseases. It will contribute
to loss of homeostasis, deregulated immune
function, and increased risk of disease among females
with or without ovaries as well as neutered or intact
males. In other words, none are exempt.
In humans, routine testing for a cortisol deficit and
consequential hormonal-immune abnormalities, followed
by an appropriate low-dosage, remedial steroid
therapy program, may provide breakthrough strategies
in the perpetual battle against disease.
21
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22
1. Munck A., Naray-Fejes-Toth. A. Glucocorticoid action. In:
Endocrinology, Third edition, (Ed: DeGroot L). Philadelphia: W. B.
Saunders Co, 1995: 1642-1654.
2. Ibid.
3. Parker, L. N. Adrenal androgens. In: Endocrinology, Third edition, (Ed:
DeGroot L). Philadelphia: W. B. Saunders Co, 1995: 1836-47.
4. Adams, J. B. Control of secretion and the function of C19-delta 5-
steroids of the human adrenal gland. Molecular and Cellular Endocrinology,
1985; 41: 1-17.
5. Alesci S., Koch C. A., Bornstein S. R., Pacak K. Adrenal androgens regulation
and adrenopause. Endocrine Regulations, 2001; 35: 95-100.
6. Lemonick M. D. A Terrible Beauty: An obsessive focus on show-ring
looks is crippling, sometimes fatally, Americas purebred dogs. Time,
December 12, 1994; 65.
7. Plechner A. J., Shannon M. Canine immune complex diseases. Modern
Veterinary Practice, 1976: 917.
8. Harvey P.W. The Adrenal in Toxicology: Target Organ and Modulator of
Toxicity, Bristol, PA: Taylor & Francis, 1996: 7.
9. Symington T. Functional Pathology of the Human Adrenal Gland,
Edinburgh: E & S. Livingstone, 1969: 63-68.
10. Roberts E. The importance of being dehydroepiandosterone sulfate (in
the blood of primates): A longer and healthier life? Biochemical
Pharmacology, 1999; 57: 329-346.
11. Cutolo M., Seriolo B., Villaggio B., Pizzorni C., Craviotto C., Sulli A.
Androgens and estrogens modulate the immune and inflammatory
responses in rheumatoid arthritis. Annals of the New York Academy of
Sciences, June 2002; 966: 131-142.
12. Cid, M., Schnaper H. W., Kleinman H. Estrogens and the vascular
endothelium. Annals of the New York Academy of Sciences, June 2002; 966:
143-157.
13. Gell J.S., Oh J., Rainey W.E., Carr B.R. Effect of estradiol on DHEAS
production in the human adrenocortical cell line, H295R. Journal of the
Society for the Gynecologic Investigation, 1998; 5:144-148.
14. Arafah B.M. Increased need for thyroxine in women with hypothyroidism
during estrogen therapy. New England Journal of Medicine, 2001;
344 (23): 1743-1749.
15. Gross H.A., Appleman M.D., Nicoloff J.T. Effect of biologically active
steroids on thyroid function in man. The Journal of Clinical Endocrinology
and Metabolism, 1971; 33: 242-248.
16. Jefferies W.McK. Safe Uses of Cortisol, Springfield: Charles C. Thomas
Publisher, 1996: 160, 181.
17. Ibid, 106.
18. Orth D.N., Kovacs W.J. The adrenal cortex. In: Williams Textbook of
Endocrinology, Ninth edition, (Eds: Wilson J.D., Foster D.W., Kronenberg
H.M., Larsen P.R). Philadelphia: W. B. Saunders Co, 1998: 545.
19. Gruber C. J., Tschugguel W., Schneeberger C., Huber J.C. Production
and actions of estrogens. New England Journal of Medicine, 2002; 346 (5):
340-352.
20. Lahita R.G. The connective tissue diseases and the overall influence of
gender. International Journal of Fertility and Menopausal Studies (now
International Journal of Fertility and Womens Medicine), 1996; 41 (2):
156-165.
21. Finkelstein J., Susman E.J., Chinchilli V.M., et al. Estrogen or testosterone
increases self-reported aggressive behaviors in hypogonadal adolescents.
The Journal of Clinical Endocrinology and Metabolism, 1997; 82 (8):
2433-2438.
22. Jefferies, op. cit., 91-113, 163-166.
23. Hickling P, Jacoby R.K, Kirwan J.R. Joint destruction after glucocorticoids
are withdrawn in early rheumatoid arthritis. British Journal of
Rheumatology, 1998; 37: 930-936.
24. Cutolo M., Sulli A., Pizzorni C., et al. Cortisol, dehydroepiandrosterone
sulfate, and androstenedione levels in patients with polymyalgia
rheumatica during twelve months of glucocorticoid therapy. Annals of the
New York Academy of Sciences, June 2002; 966: 91-96.
25. Klaitman V., Almog Y. Corticosteroids in sepsis: A new concept for an
old drug. The Israel Medical Association Journal, 2003; 5 (1): 51-54.
26. Gruber, op. cit., 340-352.
27. Spratt D. I., Longcope C., Cox P.M., Bigos S.T., Wilbur-Welling C.
Differential changes in serum concentrations of androgens and estrogens
(in relation with cortisol) in postmenopausal women with acute illness.
The Journal of Clinical Endocrinology and Metabolism, 1993; 76 (6):
1542-1547.
28. Personal communication with David Brownstein, M.D.,
West Bloomfield, Michigan.
29. Gruber, op cit., 340-352.
30. Wright J.V., Schliesman B., Robinson L. Comparative measurements
of serum estriol, estradiol, and estrone in non-pregnant, premenopausal
women: A preliminary investigation. Alternative Medicine Review, 1999;
4 (4): 266-270.
31. Ahmed S.A. The immune system as a potential target for environmental
estrogens: a new emerging field. Toxicology, 2000; 7 (150): 191-206.
32. Mesiano S., Katz S. L., Lee J. Y., Jaffe R. B. Phytoestrogens alter
adrenocortical function: genistein and daidzein suppress glucocorticoid and
stimulate androgen production by cultured adrenal cortical cells. The
Journal of Clinical Endocrinology and Metabolism, 1999; 84 (7): 2443-2448.
33. Gunin A.G., Sharov A.A. Proliferation, mitosis orientation, and morphogenetic
changes in the uterus of mice following chronic treatment with
both estrogen and glucocorticoid hormones. The Journal of Endocrinology,
2001; 169: 23-31.
34. Jefferies, op. cit., 67-90.
35. Cutolo M., Bulsma W. J., Lahita R.G., Masi A.T., Straub R. H.,
Bradlow H.L. Altered neuroendocrine immune (NEI) networks in
rheumatology. Annals of the New York Academy of Sciences, June 2002; 966:
xvii.
REFERENCES
Estrogen and Immune Destabilization
Alfred J. Plechner, D.V.M.
To be published in Medical Hypotheses, 2003
Ihave long regarded adrenal dysfunction as a wellspring
of excess estrogen which may contribute to hormonal
imbalances, immune destabilization, and
increased vulnerability to disease. As a practicing clinician,
I have consistently found elevated total estrogen
as part of an endocrine-immune derangement present
in many common diseases of dogs and cats. Ninety
percent of these cases involve spayed females and
neutered or intact males, so the elevated estrogen cannot
be attributed to ovarian activity. Sick and intact
females, tested outside their estrus period, frequently
have an elevated estrogen level as well.
The pattern of derangement identified in thousands
of cases over three decades involves insufficient cortisol,
high estrogen, and abnormally low IgA, IgG, and IgM
levels. This pattern undermines homeostasis and sets the
stage for malabsorption and digestive disorders, allergies,
lung and urinary tract problems, sluggish liver function,
strange or aggressive behavior, epilepsy, obesity, deadly
viral and bacterial infections, periodontitis, vaccine complications,
autoimmunity, and cancer. Moreover, the
same set of imbalances is often present as an underlying
enabling mechanism in multiple illnesses.
The adrenal cortex produces a variety of vital
hormones. Among them is cortisol, the primary
glucocorticoid made in the middle cortex layer (zona
fasciculata). Endogenous cortisol controls inflammation,
1 a function that inspired the development of cortisone
drugs, pharmaceutical versions of cortisol. A profound
loss of cortisol can lead to a critical state of
deranged metabolism and an inability to deal with stress
and infections. Cortisol exerts a discriminating regulatory
effect on molecular mediators. These mediators
trigger activity related to both immunity and inflammation.
A normal level of cortisol seems to be required
for healthy responses.2 Cortisol deficiency may result
in an unresponsive immune system, whereas too
much cortisollike too much cortisone medication
suppresses immune responses.
Adrenocorticotropic hormone (ACTH) from the pituitary
stimulates cortisol production. ACTH is
controlled in turn by the hypothalamic corticotropicreleasing
factor (CRF) in a classical feedback loop.
When cortisol blood concentrations rise to a certain
level, CRF secretion slows, inhibiting ACTH and subsequent
cortisol secretion.
The androgens dehydroepiandrosterone (DHEA)
and dehydroepiandrosterone sulfate (DHEAS) are the
most abundant circulating hormones in the body. These
substances, known as prohormones because they metabolize
into other hormones, are primarily made in the
zona reticularis of the adrenal cortex. Through enzymatic
actions, they convert to androstenedione, androstenediol,
testosterone, and further to the estrogen compounds
estrone and estradiol.3 Androstenedione is the
most important precursor of estrone, the most abundant
circulating estrogen in postmenopausal women.
Androstenediol has inherent estrogenic activity. 4
The exact biological function of adrenal androgens
and the mechanisms underlying their control is still
the object of debate. However, it is well known that
both may have androgenic and estrogenic effects.5
Veterinary researchers have found numerous genetic
defects resulting from contemporary linebreeding and
inbreeding practices.6 Since the 1970s I have reported a
cortisol defect in cats and dogs.7 I believe this stems
largely from questionable breeding practices.
Other potential causes for cortisol deficiency include
prolonged stress and toxicity, which may be a significant
acquired cause of adrenal cortical dysfunction. Harvey
states that the adrenal gland is the most vulnerable
organ in the endocrine system for toxins, and within the
adrenal gland the majority of effects have been
observed in the cortex. Such disturbances can
fundamentally affect the whole body physiology and
biochemistry.8
When the zona fasciculata cannot make enough cortisol,
or for some reason the cortisol is excessively bound
E N D O C R I N E - IMMUNE ME C H A N I S M S A N D HU M A N HE A LT H I M P L I CAT I O N S
(inactive) and thus not recognized by the hypothalamuspituitary
system, the pituitary continues to release
ACTH in order to stimulate more cortisol. The zona
reticularis also responds to ACTH. This part of the adrenal
gland, as noted above, produces androgens that can
convert to the estrogen compound estrone, or to testosterone,
which may then convert in part to the more
potent estrogen compound estradiol.
Some researchers say that an interface or transition
zone of tissue between the zona fasciculata and reticularis
of the adrenal cortex is capable of directly producing sex
hormones, including estrogen compounds.9, 10 Excess
estrogen promotes CRF release from the hypothalamus
and ACTH from the pituitary, and contributes to
hormonal imbalances and deleterious effects in the body.
Researchers working in the field of rheumatoid arthritis
and autoimmune rheumatic diseases believe that hormone
balance is a crucial factor in the regulation of
immune and inflammatory responses. Generally, estrogen
in physiologic concentrations enhances humoral
immune responses and depresses cellular-mediated
responses. At higher and pharmacological concentrations
the hormone has a number of inhibitory actions.
Elevated estrogen, for instance, is associated with atrophy
of the thymus gland. Androgens, by contrast, tend to
suppress both humoral and cellular types of mechanisms.
11 An examination of the endocrinology literature
reveals, however, that mechanisms through which sex
hormones regulate immune and inflammatory responses
are poorly understood.12
POSSIBLE ROLES OF ADRENAL ESTROGEN
I have developed an endocrine-immune blood test
that measures cortisol, total estrogen, T3 and T4, and
IgA, IgG, and IgM antibody levels. The measurement for
estrogen includes all estrogen compounds in the body,
that is estradiol, estrone, and estriol.
The test shows a consistent link between clinical
signs of various illnesses and total estrogen outside of a
normal range. Intact female animals are not tested
during their estrus period. In out-of-estrus females, intact
males, and neutered pets, normal levels are as follows:
Males: 20-25 pg/ml
Females: 30-35 pg/ml
Elevated estrogen appears to contribute to a number
of negative effects:
Cortisol impairment. Studies have shown that estrogen
inhibits cortisol synthesis by specific interference
with enzyme activity,13 thereby exacerbating a cortisol
deficiency and initiating hormonal imbalances.
Thyroid hormone impairment. Estrogen causes an
increase in serum thyroxine-binding globulin, which
may slow the entry of thyroxine into cells and
thereby reduce thyroid hormone action in tissue.14
Elevated estrogen may also directly inhibit thyroid
glandular release.15 Cortisol appears to be involved in
the normal transference of T4 to T3, and the entry of
T3 into cells.16 By interfering with cortisol synthesis,
estrogen may indirectly impair thyroid function.
These combined effects may slow the overall metabolism
and interfere with many basic physiologic
functions.
Inflammation. My patients blood tests consistently
show an association between inflammatory conditions
and the pattern of low cortisol, high estrogen,
and low antibody levels. Studies have shown that cortisol
inhibits the production and accumulation of
excess histamine in tissue17 and the synthesis of
prostaglandins, mediators of the inflammatory
response.18
Cancer. In humans, estrogens are involved in the
development of breast and endometrial cancer.19 All
the dogs and cats I test and treat for cancer have
impaired cortisol and high estrogen, along with
deregulated immune cells.
Autoimmunity. The same abnormal hormonal pattern
is found in pets with autoimmune conditions.
Immune cells are suppressed and appear to be
stripped of normal regulation and the ability to distinguish
between host tissue and foreign matter.
Lahita has reported that recent data indicates
increased estrogen levels might initiate autoimmune
diseases in many women and men.20
Aggressive behavior. Many unpredictable and
aggressive animals have the endocrine-immune
disturbance. In humans, Finkelstein provides
evidence suggesting that estrogen may play a
significant role in the production of aggressive
behavior in both sexes.21
TREATMENT
I initiate corrective therapy when testing indicates
the presence of imbalances. The protocol involves the
use of various cortisone medications, either standard
pharmaceutical compounds or a natural bio-identical
preparation made from an ultra extract of soy. All
18
C O R T I S O L A B N O R M A L I T Y, E L E VAT E D E S T R O G E N, A N D IMMUNE D E S TA B I L I Z AT I O N
plant materialthe part of soy which increases body
estrogen levelshas been removed. The compound is
administered at low, physiologic dosages sufficient to
compensate for deficient cortisol and re-regulate the
immune system. These therapeutic dosages are significantly
lower than standard pharmacologic levels used
for short-term treatment and are usually needed for the
duration of the patients life.
This innovative use of a standard medication consistently
restores lost immune competence. Most canine
conditions require additional T4 thyroid medication.
For some species-specific reason, most affected felines
require only steroid replacement. This treatment
approach has proven to be effective, safe, and free from
side effects in thousands of cases.
After two weeks of therapy, patients are retested.
There is usually a clear normalization of the key
endocrine-immune markers along with parallel clinical
improvements, indicating that a significant healing
process is underway. In general, animals recover and
maintain good health as long as the program is maintained.
A supportive hypoallergenic diet eliminates the
risk of food reactions which can nullify the therapy.
This clinical experience demonstrates the potent regulatory
influences of cortisol and estrogen in immune
function. It shows, perhaps for the first time, how an
adrenal combination of abnormal cortisol and high
estrogen interact to substantially deregulate and weaken
immunity and contribute to multiple diseases.
For decades, William Jefferies, M.D., clinical professor
emeritus at the University of Virginia School of
Medicine, has used low-dosage steroid replacement for
human patients with adrenocortical deficiency and
reported improvement for allergies, autoimmune disorders,
and chronic fatigue.22 The medical community
has largely ignored his clinical research because of an
ingrained fear of using cortisone long-term under any
circumstances. A similar fear exists in veterinary medicine.
At conventional pharmacologic dosages, cortisone
does indeed create side effects. In the past practitioners
often shuddered at any suggestion of long-term cortisone,
and, as the old saying goes, threw the baby out
with the bathwater.
Recently, resistance to long-term physiologic doses
of cortisone appears to be eroding. Medical researchers
have reported successful applications of low-dosage cortisone
in rheumatoid arthritis,23 polymyalgia rheumatica
a systemic inflammatory disorder of the aged24
and sepsis.25 However, none of these studies link specific
conditions to an overall mechanism wherein an
abnormality of cortisol triggers excess estrogen, HPA
destabilization, interference with thyroid, and deregulation
of the immune system. I believe that this pattern of
hormone-immune imbalance is a widespread but largely
unrecognized mechanism among pets, and may contribute
to various human illnesses.
TESTING THE HYPOTHESIS IN HUMANS
The presence of such imbalances in humans could
most readily be tested among symptomatic men and
postmenopausal (non-ERT) women. First, a baseline
blood test would be taken to measure cortisol, total
estrogen, T3/T4, and IgA, IgG, and IgM antibody levels,
along with a 24-hour urine test for active hormones
and other relevant markers. The urine test permits the
clinician to compare results against the blood test. This
is an important evaluation because some blood values
(such as cortisol and thyroid) may appear normal in a
blood test but in fact involve excessively bound, inactive
hormone fractions. Blood tests alone may not indicate
whether or not the hormone is working. The urine test
helps answer this question and contributes to a more
accurate assessment and effective treatment.
Jefferies clinical experience with human patients
suggests that low-dosage cortisol replacement therapy
could be applied to symptomatic patients who are tested
and found to have the endocrine-immune imbalances
described in this article. If their health status improves
and retesting shows a reduction in total estrogen, one
could conclude that a hypocortisol syndrome with wide
systemic impact has been clinically corrected. Such a
result would argue for further investigation of this
testing and therapy method for various illnesses.
Even though post-menopausal women are deficient
in estradiol, their estriol and estrone are often very high
not only from the possible interface layer but because
the tissue enzyme aromatase converts DHEA and
DHEAS and other androgens into total estrogen.
Gruber states that estrogen synthesis increases in
non-ovarian tissues as a function of age and body
weight even though little is known about the factors
that regulate estrogen production in the postmenopausal
population.26 Longcope and colleagues
observed a marked increase in the ratio of estrogens to
androgens in acute illness among postmenopausal
women. Conditions included heart attack, unstable
angina, respiratory illnesses, and congestive heart
failure.27 One physician with whom I have been
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E N D O C R I N E - IMMUNE ME C H A N I S M S A N D HU M A N HE A LT H I M P L I CAT I O N S
communicating commented that his sickest postmenopausal
(non-ERT) patients have the highest total
estrogen levels and the lowest immunoglobulins.28
Estradiol alone, and not total estrogen, is currently
the standard measurement in patients, yet in postmenopausal
women, estrone is the major estrogen.29
Estriol, generally considered to be a weaker compound
than estradiol and estrone, is present in significantly
greater concentration in premenopausal
women,30 and may have significant though currently
unidentified biological activity. I believe that total
estrogen, including estrone and estriol, is a more
meaningful indicator of estrogen activity than estradiol
alone.
The presence of xenoestrogens and phytoestrogens,
chemicals which mimic estrogen and which can
potentially trigger androgen-estrogen imbalance, complicate
the process of assessing serum estrogen status.
Such compounds appear in the environment and in
food. Ubiquitous estrogenic compounds, including
industrial chemicals, pesticides, and surfactants, affect
wildlife and laboratory animals immune systems.
Further studies are needed to determine the immune
response in humans. These compounds may affect
humans in similar ways.31 Hence, the need to measure
total estrogen.
Mesiano, demonstrated in 1999 that dietary phytoestrogen
compounds found in soy decrease cortisol production
and, as a result, increase androgens. Such consumption,
he suggests, may indirectly increase total
estrogen by raising DHEA and DHEAS levels. In his
opinion it is possible that some of the estrogenic actions
of dietary phytoestrogens may be mediated via their
stimulation of adrenal androgen synthesis.32
One way to determine the influence of dietary phytoestrogens,
at least in men and postmenopausal
women, would be to eliminate soy from the diet of
patients who test high in total estrogen, then retest the
patient again after several weeks. A clear drop in estrogen
level could indicate a dietary effect. An unchanged
or insignificantly changed level would indicate a source
for estrogen unrelated to diet.
Xenoestrogens include birth control pills and chemicalized
estrogen drugs. Can these contribute to a disturbance
of cortisol and thyroid, and contribute to the disease
process? It seems plausible that exogenous estrogen,
or even androgen supplements (such as DHEA, which
can convert to estrogen in the body) could indeed contribute
to imbalances and disease.
My male patients test results make a strong argument
for hypocortisolism as a primary cause of elevated
estrogen. In symptomatic males with endocrineimmune
imbalances, high estrogen occurs almost exclusively
as a consequence of a cortisol abnormality. The
rare exception is the animal whose endocrine-immune
status normalizes spontaneously without any treatment
after moving to another area. I assume in such cases that
a significant toxic or xenoestrogenic compound, perhaps
ingested or inhaled, was present in one area and not in
the other.
IMPLICATIONS FOR HUMANS
Elevated estrogen participates in a broad syndrome of
hormonal-immune imbalances contributing to multiple
diseases in animals. Is estrogen similarly involved in
human conditions?
Is an unsuspected excess of estrogen involved in
AIDS? Veterinarians regard diseased cats infected with
feline immunodeficiency virus (FIV), a retrovirus
similar to HIV, as untreatable. Yet I have a 70 percent
recovery rate among symptomatic FIV patients. These
animals have a typical pattern of low cortisol, high
estrogen, and disturbed immune function. Low-dosage
steroid therapy corrects the underlying imbalances and
restores natural immunity. Cats remain disease-free as
long as they are kept on the therapy. The results raise a
number of questions.
Does the virus cause the disease or do the imbalances
weaken the immune system and give the virus free rein?
Do the imbalances also accelerate the disease process by
deregulating the immune system so that immune cells
attack both viruses and host tissue? Is it not possible that
in humans cortisol-estrogen-immune status may dictate
whether a person develops AIDS symptoms after being
exposed to the HIV virus? My clinical experience with
animals suggests that HIV-positive humans be tested for
endocrine-immune imbalances. If present, appropriate
hormone replacement might offer a significant prevention
and therapy strategy.
All of my cancer patients have the same general
pattern of endocrine-immune disturbance. Based on
this experience I would suggest that human cancer
patients be tested for similar imbalances. If they exist,
appropriate hormone replacement therapy might
offer an effective treatment strategy for humans just
as it does for animals, even in advanced cases.
According to Gunin estrogen generates proinflammatory
responses as well as proliferative
20
C O R T I S O L A B N O R M A L I T Y, E L E VAT E D E S T R O G E N, A N D IMMUNE D E S TA B I L I Z AT I O N
changes associated with a pre-cancerous process in
the uterus. Treatment with cortisone (dexamethasone)
in ovariectomized rats given estradiol reverses
these abnormalities.33
I routinely find the combination of abnormal cortisol
and elevated estrogen in animals with histories of
infertility and miscarriage, suggesting that reproductive
failures may be caused by inflamed and immune-deregulated
reproductive tract tissue. Such failures are routinely
corrected by proper hormone therapy, enabling
animals to conceive and produce healthy offspring.
Over decades of clinical experience, William Jefferies,
an emeritus clinical professor at the University of
Virginia, has reported that patients with cortisol insufficiency
and histories of ovarian dysfunction, infertility,
and failed pregnancies achieve significantly improved
conception and birth rates on low-dosage cortisone
therapy.34
Common variable immunodeficiency (CVID)
appears to be a grossly underdiagnosed enabling mechanism
for a multiplicity of disorders in humans just as it
is in animals, giving rise to chronic infections, autoimmune
conditions, an increased risk of cancer, and poor
response to immunization. In both humans and animals,
CVID is characterized by low IgA, IgG, and IgM
levels and abnormal T cell counts. In humans, the precise
trigger for such immune dysfunction is unknown.
Researchers have not linked CVID or other so-called
immunodeficiency mechanisms to hormones. I suggest
that exploring this connection, and looking specifically
at cortisol activity, may generate major clues for diagnosis
and treatment.
My clinical success and the growing clinical applications
of low-dosage cortisone therapy for humans
strongly argue for sustained research into the nature,
magnitude, and impact of cortisol defects, including an
associated estrogen-immune problem, in the etiology of
disease. While it is now recognized that the hypothalamic-
pituitary-adrenal axis, as part of the neuroendocrine
system, has central importance to immune
homeostasis,35 we still dont understand the countless
details and interactions.
Estrogen measurements are generally assumed to
be expressions of ovarian function. This seems an
invalid assumption, since a deficit of active cortisol
from genetics, stress, toxicity, or phytoestrogenscan
initiate a significant estrogen buildupestrogen
dominanceindependent of the ovaries. Estrogen
dominance not only causes inflammation of many of
the arteries, but it also binds active cortisol and active
thyroid, and deregulates the immune system. It can
also contribute to such ailments as cancer, autoimmunity,
and hypersensitivity diseases. It will contribute
to loss of homeostasis, deregulated immune
function, and increased risk of disease among females
with or without ovaries as well as neutered or intact
males. In other words, none are exempt.
In humans, routine testing for a cortisol deficit and
consequential hormonal-immune abnormalities, followed
by an appropriate low-dosage, remedial steroid
therapy program, may provide breakthrough strategies
in the perpetual battle against disease.
21
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22
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2. Ibid.
3. Parker, L. N. Adrenal androgens. In: Endocrinology, Third edition, (Ed:
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4. Adams, J. B. Control of secretion and the function of C19-delta 5-
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11. Cutolo M., Seriolo B., Villaggio B., Pizzorni C., Craviotto C., Sulli A.
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13. Gell J.S., Oh J., Rainey W.E., Carr B.R. Effect of estradiol on DHEAS
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14. Arafah B.M. Increased need for thyroxine in women with hypothyroidism
during estrogen therapy. New England Journal of Medicine, 2001;
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15. Gross H.A., Appleman M.D., Nicoloff J.T. Effect of biologically active
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17. Ibid, 106.
18. Orth D.N., Kovacs W.J. The adrenal cortex. In: Williams Textbook of
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20. Lahita R.G. The connective tissue diseases and the overall influence of
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21. Finkelstein J., Susman E.J., Chinchilli V.M., et al. Estrogen or testosterone
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22. Jefferies, op. cit., 91-113, 163-166.
23. Hickling P, Jacoby R.K, Kirwan J.R. Joint destruction after glucocorticoids
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Rheumatology, 1998; 37: 930-936.
24. Cutolo M., Sulli A., Pizzorni C., et al. Cortisol, dehydroepiandrosterone
sulfate, and androstenedione levels in patients with polymyalgia
rheumatica during twelve months of glucocorticoid therapy. Annals of the
New York Academy of Sciences, June 2002; 966: 91-96.
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26. Gruber, op. cit., 340-352.
27. Spratt D. I., Longcope C., Cox P.M., Bigos S.T., Wilbur-Welling C.
Differential changes in serum concentrations of androgens and estrogens
(in relation with cortisol) in postmenopausal women with acute illness.
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28. Personal communication with David Brownstein, M.D.,
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29. Gruber, op cit., 340-352.
30. Wright J.V., Schliesman B., Robinson L. Comparative measurements
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31. Ahmed S.A. The immune system as a potential target for environmental
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32. Mesiano S., Katz S. L., Lee J. Y., Jaffe R. B. Phytoestrogens alter
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34. Jefferies, op. cit., 67-90.
35. Cutolo M., Bulsma W. J., Lahita R.G., Masi A.T., Straub R. H.,
Bradlow H.L. Altered neuroendocrine immune (NEI) networks in
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