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Co r t i s o l Ab n o r m a l i t y a s a Ca u s e o f E l eva t e d E s t ro g e n a n d I m m u n e De s t a b i l i z a t i o n To be published in Medical Hypotheses, 2003 Ihave long regarded adrenal dysfunction as a well- Adrenocorticotropic hormone (ACTH) from the pitu- spring of excess estrogen which may contribute to hor- itary stimulates cortisol production. ACTH is monal imbalances, immune destabilization, and controlled in turn by the hypothalamic corticotropic- increased vulnerability to disease. As a practicing clini- releasing factor (CRF) in a classical feedback loop.
cian, I have consistently found elevated total estrogen When cortisol blood concentrations rise to a certain as part of an endocrine-immune derangement present level, CRF secretion slows, inhibiting ACTH and sub- in many common diseases of dogs and cats. Ninety percent of these cases involve spayed females and The androgens dehydroepiandrosterone (DHEA) neutered or intact males, so the elevated estrogen can- and dehydroepiandrosterone sulfate (DHEAS) are the not be attributed to ovarian activity. Sick and intact most abundant circulating hormones in the body. These females, tested outside their estrus period, frequently substances, known as prohormones because they metab- have an elevated estrogen level as well. olize into other hormones, are primarily made in the The pattern of derangement identified in thousands zona reticularis of the adrenal cortex. Through enzymat- of cases over three decades involves insufficient cortisol, ic actions, they convert to androstenedione, androstene- high estrogen, and abnormally low IgA, IgG, and IgM diol, testosterone, and further to the estrogen com- levels. This pattern undermines homeostasis and sets the pounds estrone and estradiol.3 Androstenedione is the stage for malabsorption and digestive disorders, allergies, most important precursor of estrone, the most abundant lung and urinary tract problems, sluggish liver function, circulating estrogen in postmenopausal women.
strange or aggressive behavior, epilepsy, obesity, deadly Androstenediol has inherent estrogenic activity. 4 viral and bacterial infections, periodontitis, vaccine com- The exact biological function of adrenal androgens plications, autoimmunity, and cancer. Moreover, the and the mechanisms underlying their control is still same set of imbalances is often present as an underlying the object of debate. However, it is well known that enabling mechanism in multiple illnesses.
both may have androgenic and estrogenic effects.5 The adrenal cortex produces a variety of vital Veterinary researchers have found numerous genetic hormones. Among them is cortisol, the primary defects resulting from contemporary linebreeding andglucocorticoid made in the middle cortex layer (zona inbreeding practices.6 Since the 1970s I have reported a fasciculata). Endogenous cortisol controls inflamma- cortisol defect in cats and dogs.7 I believe this stems tion,1 a function that inspired the development of cor- largely from questionable breeding practices. tisone drugs, pharmaceutical versions of cortisol. A pro- Other potential causes for cortisol deficiency include found loss of cortisol can lead to a critical state of prolonged stress and toxicity, which may be a significant deranged metabolism and an inability to deal with stress acquired cause of adrenal cortical dysfunction. Harvey and infections. Cortisol exerts a discriminating regula- states that the adrenal gland is the most vulnerable tory effect on molecular mediators. These mediators organ in the endocrine system for toxins, and within the trigger activity related to both immunity and inflam- adrenal gland “the majority of effects” have been mation. A normal level of cortisol seems to be required observed in the cortex. Such disturbances can for healthy responses.2 Cortisol deficiency may result “fundamentally affect the whole body physiology and in an unresponsive immune system, whereas too much cortisol—like too much cortisone medication— When the zona fasciculata cannot make enough cor- tisol, or for some reason the cortisol is excessively bound E N D O C R I N E - I M M U N E M E C H A N I S M S A N D H U M A N H E A LT H I M P L I C AT I O N S (inactive) and thus not recognized by the hypothalamus- with enzyme activity,13 thereby exacerbating a corti- pituitary system, the pituitary continues to release sol deficiency and initiating hormonal imbalances.
ACTH in order to stimulate more cortisol. The zona ■ Thyroid hormone impairment. Estrogen causes an
reticularis also responds to ACTH. This part of the adre- increase in serum thyroxine-binding globulin, which nal gland, as noted above, produces androgens that can may slow the entry of thyroxine into cells and convert to the estrogen compound estrone, or to testos- thereby reduce thyroid hormone action in tissue.14 terone, which may then convert in part to the more Elevated estrogen may also directly inhibit thyroid glandular release.15 Cortisol appears to be involved in Some researchers say that an interface or transition the normal transference of T4 to T3, and the entry of zone of tissue between the zona fasciculata and reticularis T3 into cells.16 By interfering with cortisol synthesis, of the adrenal cortex is capable of directly producing sex estrogen may indirectly impair thyroid function.
hormones, including estrogen compounds.9, 10 Excess These combined effects may slow the overall metab- estrogen promotes CRF release from the hypothalamus olism and interfere with many basic physiologic and ACTH from the pituitary, and contributes to hormonal imbalances and deleterious effects in the body. ■ Inflammation. My patients’ blood tests consistently
Researchers working in the field of rheumatoid arthri- show an association between inflammatory condi- tis and autoimmune rheumatic diseases believe that hor- tions and the pattern of low cortisol, high estrogen, mone balance is a crucial factor in the regulation of and low antibody levels. Studies have shown that cor- immune and inflammatory responses. Generally, estro- tisol inhibits the production and accumulation of gen in physiologic concentrations enhances humoral excess histamine in tissue17 and the synthesis of immune responses and depresses cellular-mediated prostaglandins, mediators of the inflammatory responses. At higher and pharmacological concentrations the hormone has a number of inhibitory actions.
■ Cancer. In humans, estrogens are involved in the
Elevated estrogen, for instance, is associated with atrophy development of breast and endometrial cancer.19 All of the thymus gland. Androgens, by contrast, tend to the dogs and cats I test and treat for cancer have suppress both humoral and cellular types of mecha- impaired cortisol and high estrogen, along with nisms.11 An examination of the endocrinology literature reveals, however, that mechanisms through which sex ■ Autoimmunity. The same abnormal hormonal pat-
hormones regulate immune and inflammatory responses tern is found in pets with autoimmune conditions.
Immune cells are suppressed and appear to bestripped of normal regulation and the ability to dis- POSSIBLE ROLES OF ADRENAL ESTROGEN
tinguish between host tissue and foreign matter.
I have developed an endocrine-immune blood test Lahita has reported that recent data indicates that measures cortisol, total estrogen, T3 and T4, and “increased estrogen levels might initiate autoimmune IgA, IgG, and IgM antibody levels. The measurement for estrogen includes all estrogen compounds in the body, ■ Aggressive behavior. Many unpredictable and
that is estradiol, estrone, and estriol. aggressive animals have the endocrine-immune The test shows a consistent link between clinical disturbance. In humans, Finkelstein provides signs of various illnesses and total estrogen outside of a evidence suggesting “that estrogen may play a normal range. Intact female animals are not tested significant role in the production of aggressive 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 TREATMENT
Elevated estrogen appears to contribute to a number I initiate corrective therapy when testing indicates the presence of imbalances. The protocol involves theuse of various cortisone medications, either standard ■ Cortisol impairment. Studies have shown that estro-
pharmaceutical compounds or a natural bio-identical gen inhibits cortisol synthesis by specific interference preparation made from an ultra extract of soy. All 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 I M M U N E D E S TA B I L I Z AT I O N plant material—the part of soy which increases body ic conditions to an overall mechanism wherein an estrogen levels—has been removed. The compound is abnormality of cortisol triggers excess estrogen, HPA administered at low, physiologic dosages sufficient to destabilization, interference with thyroid, and deregula- compensate for deficient cortisol and re-regulate the tion of the immune system. I believe that this pattern of immune system. These therapeutic dosages are signifi- hormone-immune imbalance is a widespread but largely cantly lower than standard pharmacologic levels used unrecognized mechanism among pets, and may con- for short-term treatment and are usually needed for the This innovative use of a standard medication consis- TESTING THE HYPOTHESIS IN HUMANS
tently restores lost immune competence. Most canine The presence of such imbalances in humans could conditions require additional T4 thyroid medication.
most readily be tested among symptomatic men and For some species-specific reason, most affected felines postmenopausal (non-ERT) women. First, a baseline require only steroid replacement. This treatment blood test would be taken to measure cortisol, total approach has proven to be effective, safe, and free from estrogen, T3/T4, and IgA, IgG, and IgM antibody lev- els, along with a 24-hour urine test for active hormones After two weeks of therapy, patients are retested.
and other relevant markers. The urine test permits the There is usually a clear normalization of the key clinician to compare results against the blood test. This endocrine-immune markers along with parallel clinical is an important evaluation because some blood values improvements, indicating that a significant healing (such as cortisol and thyroid) may appear normal in a process is underway. In general, animals recover and blood test but in fact involve excessively bound, inactive maintain good health as long as the program is main- hormone fractions. Blood tests alone may not indicate tained. A supportive hypoallergenic diet eliminates the whether or not the hormone is working. The urine test risk of food reactions which can nullify the therapy. helps answer this question and contributes to a more This clinical experience demonstrates the potent reg- accurate assessment and effective treatment. ulatory influences of cortisol and estrogen in immune Jefferies’ clinical experience with human patients function. It shows, perhaps for the first time, how an suggests that low-dosage cortisol replacement therapy adrenal combination of abnormal cortisol and high could be applied to symptomatic patients who are tested estrogen interact to substantially deregulate and weaken and found to have the endocrine-immune imbalances immunity and contribute to multiple diseases. described in this article. If their health status improves For decades, William Jefferies, M.D., clinical pro- and retesting shows a reduction in total estrogen, one fessor emeritus at the University of Virginia School of could conclude that a hypocortisol syndrome with wide Medicine, has used low-dosage steroid replacement for systemic impact has been clinically corrected. Such a human patients with “adrenocortical deficiency” and result would argue for further investigation of this reported improvement for allergies, autoimmune disor- testing and therapy method for various illnesses. ders, and chronic fatigue.22 The medical community Even though post-menopausal women are deficient has largely ignored his clinical research because of an in estradiol, their estriol and estrone are often very high ingrained fear of using cortisone long-term under any not only from the possible interface layer but because circumstances. A similar fear exists in veterinary medi- the tissue enzyme aromatase converts DHEA and cine. At conventional pharmacologic dosages, cortisone DHEAS and other androgens into total estrogen. does indeed create side effects. In the past practitioners Gruber states that estrogen synthesis increases in often shuddered at any suggestion of long-term corti- non-ovarian tissues as a function of age and body sone, and, as the old saying goes, “threw the baby out weight even though little is known about the factors that regulate estrogen production in the post- Recently, resistance to long-term physiologic doses menopausal population.26 Longcope and colleagues of cortisone appears to be eroding. Medical researchers observed a “marked increase in the ratio of estrogens to have reported successful applications of low-dosage cor- androgens in acute illness” among postmenopausal tisone in rheumatoid arthritis,23 polymyalgia rheumati- women. Conditions included heart attack, unstable ca—a systemic inflammatory disorder of the aged24 — angina, respiratory illnesses, and congestive heart and sepsis.25 However, none of these studies link specif- failure.27 One physician with whom I have been E N D O C R I N E - I M M U N E M E C H A N I S M S A N D H U M A N H E A LT H I M P L I C AT I O N S communicating commented that his sickest post- My male patients’ test results make a strong argu- menopausal (non-ERT) patients have the highest total ment for hypocortisolism as a primary cause of elevated estrogen levels and the lowest immunoglobulins.28 estrogen. In symptomatic males with endocrine- Estradiol alone, and not total estrogen, is current- immune imbalances, high estrogen occurs almost exclu- ly the standard measurement in patients, yet in post- sively as a consequence of a cortisol abnormality. The menopausal women, estrone is the major estrogen.29 rare exception is the animal whose endocrine-immune Estriol, generally considered to be a weaker com- status normalizes spontaneously without any treatment pound than estradiol and estrone, is present in signif- after moving to another area. I assume in such cases that icantly greater concentration in premenopausal a significant toxic or xenoestrogenic compound, perhaps women,30 and may have significant though currently ingested or inhaled, was present in one area and not in unidentified biological activity. I believe that total estrogen, including estrone and estriol, is a moremeaningful indicator of estrogen activity than estradi- IMPLICATIONS FOR HUMANS
Elevated estrogen participates in a broad syndrome of The presence of xenoestrogens and phytoestrogens, hormonal-immune imbalances contributing to multiple chemicals which mimic estrogen and which can diseases in animals. Is estrogen similarly involved in potentially trigger androgen-estrogen imbalance, com- plicate the process of assessing serum estrogen status.
Is an unsuspected excess of estrogen involved in Such compounds appear in the environment and in AIDS? Veterinarians regard diseased cats infected with food. Ubiquitous estrogenic compounds, including feline immunodeficiency virus (FIV), a retrovirus industrial chemicals, pesticides, and surfactants, affect similar to HIV, as untreatable. Yet I have a 70 percent wildlife and laboratory animals’ immune systems.
recovery rate among symptomatic FIV patients. These Further studies are needed to determine the immune animals have a typical pattern of low cortisol, high response in humans. These compounds may affect estrogen, and disturbed immune function. Low-dosage humans in similar ways.31 Hence, the need to measure steroid therapy corrects the underlying imbalances and restores natural immunity. Cats remain disease-free as Mesiano, demonstrated in 1999 that dietary phytoe- long as they are kept on the therapy. The results raise a strogen compounds found in soy decrease cortisol pro- duction and, as a result, increase androgens. Such con- Does the virus cause the disease or do the imbalances sumption, he suggests, may indirectly increase total weaken the immune system and give the virus free rein? estrogen by raising DHEA and DHEAS levels. In his Do the imbalances also accelerate the disease process by opinion it is “possible that some of the estrogenic actions deregulating the immune system so that immune cells of dietary phytoestrogens may be mediated via their attack both viruses and host tissue? Is it not possible that stimulation of adrenal androgen synthesis.”32 in humans cortisol-estrogen-immune status may dictate One way to determine the influence of dietary phy- whether a person develops AIDS symptoms after being toestrogens, at least in men and postmenopausal exposed to the HIV virus? My clinical experience with women, would be to eliminate soy from the diet of animals suggests that HIV-positive humans be tested for patients who test high in total estrogen, then retest the endocrine-immune imbalances. If present, appropriate patient again after several weeks. A clear drop in estro- hormone replacement might offer a significant preven- gen level could indicate a dietary effect. An unchanged or insignificantly changed level would indicate a source All of my cancer patients have the same general pattern of endocrine-immune disturbance. Based on Xenoestrogens include birth control pills and chemi- this experience I would suggest that human cancer calized estrogen drugs. Can these contribute to a distur- patients be tested for similar imbalances. If they exist, bance of cortisol and thyroid, and contribute to the dis- appropriate hormone replacement therapy might ease process? It seems plausible that exogenous estrogen, offer an effective treatment strategy for humans just or even androgen supplements (such as DHEA, which as it does for animals, even in advanced cases. can convert to estrogen in the body) could indeed con- According to Gunin estrogen generates pro- inflammatory responses as well as proliferative 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 I M M U N E D E S TA B I L I Z AT I O N changes associated with a pre-cancerous process in My clinical success and the growing clinical applica- the uterus. Treatment with cortisone (dexametha- tions of low-dosage cortisone therapy for humans sone) in ovariectomized rats given estradiol reverses strongly argue for sustained research into the nature, magnitude, and impact of cortisol defects, including an I routinely find the combination of abnormal corti- associated estrogen-immune problem, in the etiology of sol and elevated estrogen in animals with histories of disease. While it is now recognized that the hypothala- infertility and miscarriage, suggesting that reproductive mic-pituitary-adrenal axis, as part of the neuroen- failures may be caused by inflamed and immune-dereg- docrine system, has central importance to immune ulated reproductive tract tissue. Such failures are rou- homeostasis,35 we still don’t understand the countless tinely corrected by proper hormone therapy, enabling animals to conceive and produce healthy offspring.
Estrogen measurements are generally assumed to Over decades of clinical experience, William Jefferies, be expressions of ovarian function. This seems an an emeritus clinical professor at the University of invalid assumption, since a deficit of active cortisol— Virginia, has reported that patients with cortisol insuf- from genetics, stress, toxicity, or phytoestrogens—can ficiency and histories of ovarian dysfunction, infertility, initiate a significant estrogen buildup—estrogen and failed pregnancies achieve significantly improved dominance—independent of the ovaries. Estrogen conception and birth rates on low-dosage cortisone 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 appears to be a grossly underdiagnosed enabling mech- also contribute to such ailments as cancer, autoim- anism for a multiplicity of disorders in humans just as it munity, and hypersensitivity diseases. It will con- is in animals, giving rise to chronic infections, autoim- tribute to loss of homeostasis, deregulated immune mune conditions, an increased risk of cancer, and poor function, and increased risk of disease among females response to immunization. In both humans and ani- with or without ovaries as well as neutered or intact mals, CVID is characterized by low IgA, IgG, and IgM levels and abnormal T cell counts. In humans, the pre- In humans, routine testing for a cortisol deficit and cise trigger for such immune dysfunction is unknown.
consequential hormonal-immune abnormalities, fol- Researchers have not linked CVID or other so-called lowed by an appropriate low-dosage, remedial steroid immunodeficiency mechanisms to hormones. I suggest therapy program, may provide breakthrough strategies that exploring this connection, and looking specifically in the perpetual battle against disease. at cortisol activity, may generate major clues for diag-nosis and treatment.
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