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Role of Estrogen in Thyroid Disease

Estrogen plays a key role in my theory of thyroid disease.  However, I don't see estrogen as a cause of thyroid disease.  I see estrogen as an accelerator of the nutritional imbalances that underlie thyroid disease.  Let me explain.  

First, however, let me add that estrogen is not one hormone, but three:  estradiol, estrone, and estriol.  Most studies on estrogen use estradiol, which has the most biological function.  I use the term estrogen so you'll know what I'm talking about, but the term estradiol is more accurate.

One of the most fascinating studies that I've run across was performed studying cadmium toxicity in rats.  I believe that cadmium is principle player in the etiology of thyroid disease, but again, not the real cause.

While being female is the largest risk factor for developing thyroid disease, the second largest risk factor that has been identified, especially for hyperthyroidism, is smoking tobacco.

While many chemicals present in tobacco smoke have been identified which affect thyroid function, I believe that the most important ingredient of tobacco smoke which affects the thyroid is the heavy metal cadmium.  

Cadmium is one of the most potent and long-lasting toxic metals known.  Cadmium has been shown to kill animals at a concentration lower than any other commonly occurring toxic metal.  Cadmium has been demonstrated to damage thyroid cells and this damage can be viewed in in vitro studies of thyroid cells in a culture.

Now to get back to our experimental studies of cadmium toxicity in rats.  In this study, both female and male rats were castrated, thereby eliminating the bulk of production of the sex hormones, estrogen and testosterone.  In this way estrogen and testosterone administered and the observed effects can be attributed to the administered hormones.

Both the castrated male and castrated female rats were given cadmium labeled with radioactive cadmium.  Half of the cadmium administered rats were injected with estrogen and half with testosterone.  The course of the cadmium in the body was then able to be followed because it was radioactively labeled.

The amazing result was that estrogen caused the cadmium to be incorporated into and retained by the body, while testosterone caused the cadmium to be excreted from the body.  This is extremely significant and to me represents the key to understanding why 90% of the people with thyroid disease are female.

I've been thinking for a long time about this result.  For a while I thought that females and males had different mechanisms for dealing with toxic metals.  In males, testosterone protected the body by causing the rapid excretion of toxic metals into the blood stream and out of the body via urine and the bile system.   In females, however, this strategy could have disastrous results because the female might be pregnant.  If the toxic metals were put into circulation to be excreted, they would travel in the blood to the fetus and cause the fetus to be possibly damaged.

Now, however, I've come up with a different hypothesis, one that I like much better.  What estrogen might be doing is causing the female body to absorb and store trace elements.  This could be very valuable because the female needs to have a good store of these scarce trace elements in order to pass along a good amount to the offspring.  A baby probably needs a good store of essential trace elements to protect it for years from running out.  Also, because females lose significant amounts of blood each month during menstruation, and thereby lose essential trace elements like iron and copper, having a hormone like estrogen which increases the accumulation of trace elements would be very advantageous.

How could estrogen act as an accelerator of mineral accumulation in the body?  Perhaps estrogen triggers the production of proteins which bind and store minerals in the body.  There is a protein called metallothionein which performs this function in the body.  Perhaps estrogen stimulates the body to manufacture more of this or a similar protein.

When I first started studying the effects of the hormones, estrogen and its antagonist, progesterone, on thyroid function it appeared that estrogen caused the body to slow thyroid function like copper does and progesterone caused the body to increase thyroid function, like zinc.

However, this theory was challenged more than once by women who reported that taking supplemental estrogen caused their hyperthyroidism to worsen.  I tried to ignore these observations because they didn't fit into this theory.  Now however, these observations make sense.

If estrogen is an accelerator of mineral uptake into the body, it can have opposite effects.  Zinc accelerates thyroidal function and copper slows it down.  When copper gets deficient, the thyroid produces excessive hormone and hyperthyroidism results.  The balance of zinc and copper is important in maintaining normal thyroid function and the proper ratio seems to be about 5:1 for females and 10:1 or higher for males.

If the diet has a zinc/copper ratio which is too high, which is pretty much characteristic of some diets, estrogen can have an accelerative effect of causing this zn/cu imbalance in the body to get too high and causing hyperthyroidism.  If the zinc/copper ratio is too low, then estrogen can have the opposite effect, of causing the body to incorporate too much copper and not enough zinc and thereby slowing the thyroid too much.  This may be the most prevalent situation since there are more people with hypothyroidism than hyperthyroidism.

The important thing about estrogen is that it probably does not affect the thyroid itself, but only has thyroidal effects because it influences mineral uptake.  Taking estrogen will not cause the correction of thyroid disease but can facilitate correction if the proper minerals in the proper ratios are taken.

Thinking of estrogen as an accelerator of body accumulation of minerals, both essential and toxic, can also shed light on the controversial results seen from consuming foods with estrogen-like substances like tofu.  Many reports indicate that tofu promotes hypothyroidism while others report that it promotes hyperthyroidism.  If tofu is eaten with a  diet high in cadmium, such as from eating large amounts of green leafy vegetables or from smoking, then the estrogen-like substances could accelerate the body's uptake of cadmium, leading to hyperthyroidism or TED.  However, if tofu is consumed along with a diet high in beans and nuts (high in copper), the copper intake could be accelerated and hypothyroidism could result.  Tofu is also high in phytates which bind zinc, increasing the possibility of hypothyroidism.

Also, estrogen probably increases the retention of all minerals.  Another observation is that females suffer from the effects of mercury toxicity from silver amalgam dental fillings at a much higher rate than males.  This is probably another effect of estrogen acting as an accelerator of mercury uptake into the body.

Mercury is one of the metals that cause hypothyroidism since it is a direct antagonist to selenium.  Selenium deficiency is known to cause hypothyroidism and goiter and selenium is the trace element that is essential to form the deiodinase enzymes which convert T4 (the hormone our thyroid gland makes) into T3 (the hormone our cells use).

Since many people have mercury dental fillings, those people with high estrogen (women in child-bearing years or supplementing with estrogen) will more likely suffer from hypothyroidism as a result of mercury toxicity from dental fillings.



This first study shows that estrogen can be diminished by cadmium, but progesterone is not.
Cadmium interferes with steroid biosynthesis in rat granulosa and luteal cells in vitro.
Paksy K; Varga B; LŽazŽar P
National Institute of Occupational Health, Budapest, Hungary.
Biometals, 5(4):245-50 1992 Winter

Recently, cadmium has been described to disturb ovarian function in rats. In this paper the direct influence of cadmium on steroid production of ovarian cells in vitro has been studied. Granulosa and luteal cells were obtained from proestrous and pregnant rats, and incubated with 0, 5, 10, 20 or 40 micrograms ml-1 CdCl2 in the presence or absence of 0.1-1000 ng ml-1 follicle stimulating hormone (FSH) or luteinizing hormone (LH) for 24 or 48 h. Production of progesterone (P) and 17 beta-estradiol (E2) by granulosa and that of P by luteal cells were measured by radioimmunoassay. In FSH-stimulated granulosa cell cultures, 5 and 40 micrograms ml-1 CdCl2 suppressed P accumulation to 65 and 10%, respectively; accumulation of E2 (at 5 micrograms ml-1 CdCl2) decreased to 44%. P production of LH-supported luteal cells dropped to 86 and 66%, respectively, when 5 and 40 micrograms ml-1 CdCl2 was added to the medium. No alteration in basal P accumulation occurred in granulosa and luteal cell cultures following incubations with 20 and 40 micrograms ml-1 CdCl2, whereas basal E2 production of granulosa cells was markedly diminished. It is concluded that CdCl2 suppressing steroid synthesis in vitro exerts a direct influence on granulosa and luteal cell function.

The following study shows that estradiol is low in Wilson's disease patients. My theory for this is that there is a metabolic problem with copper metabolism either from a genetic error or a deficiency of a nutrient needed for copper metabolism.  This results in copper not being able to fulfill all of its functions.  Since copper seems necessary to form the enzymes which convert progesterone to estradiol, there is a resulting deficiency of estradiol.
Endocrine studies of the ovulatory disturbances in Wilson's disease (hepatolenticular degeneration).
Kaushansky A; Frydman M; Kaufman H; Homburg R
Fertil Steril, 47(2):270-3 1987 Feb

Women with Wilson's disease may have severe oligomenorrhea or amenorrhea whose cause is unknown. The endocrine profile of four such cases was investigated by measuring basal values and the response to dynamic tests of hypothalamic, pituitary, thyroid, and adrenal function, which all proved normal. Ovarian function was disturbed, as witnessed by low estradiol, high total testosterone (T) levels with normal free T, and mildly elevated androstenedione. An interference of ovarian follicular aromatase activity possibly due to copper intoxication could explain these findings as the cause of the ovulatory disturbances of Wilson's disease.

Estrogen is degraded by estrogen sulfotransferase (EST) (a selenium enzyme) which is regulated by the levels of progesterone.

Regulation of estrogen sulfotransferase in human endometrial adenocarcinoma cells by progesterone.
Falany JL; Falany CN
Department of Pharmacology and Toxicology, University of Alabama, Birmingham, Alabama 35294, USA.
Endocrinology, 137(4):1395-401 1996 Apr

During the secretory phase of the human menstrual cycle, the endometrium is minimally responsive to the estrogens secreted from the ovaries. Conjugation of beta-estradiol (E2) with sulfate is thought to be an important mechanism in the regulation of the levels of active E2 in endometrial tissue. Estrogen sulfation is reportedly increased during the secretory phase in response to the high levels of progesterone secreted by the ovaries. Estrogen sulfotransferase (hEST), a distinct form of human cytosolic sulfotransferase (ST) with an affinity for E2 and estrone at low nanomolar concentrations, has recently been cloned and expressed in mammalian cells and in bacteria (J Steroid Biochem Mol Biol 52:529, 1995). At least two other forms of human cytosolic ST, dehydroepiandrosterone ST (hDHEA-ST) and the phenol-sulfating form of phenol-ST (hP-PST), also conjugate estrogens but at micromolar concentrations. This report describes the specific induction of hEST in human Ishikawa endometrial adenocarcinoma cells by progesterone as a model for the increases in estrogen sulfation observed in women during the secretory phase of the menstrual cycle. Treatment of Ishikawa cells with 10 microns progesterone for 48 h resulted in a 7-fold increase in the sulfation of 20 nM E2. The sulfation of selective substrates for human dehydroepiandrosterone sulfotransferase (hDHEA-ST) and the two forms of phenol sulfotransferase (hP-PST, hM-PST) were not affected by treatment with progesterone. The levels of immunoreactive hEST and hEST mRNA in the Ishikawa cells were both increased by progesterone, whereas the levels of immunoreactive hDHEA-ST, hP-PST, and hM-PST were not altered. hEST activity was not induced by treatment of Ishikawa cells with varying concentrations of E2, testosterone, or cortisol. The induction of hEST by progesterone was inhibited by RU-486, indicating that progesterone is acting via the progesterone receptor. These results indicate that progesterone is capable of specifically inducing hEST and estrogen sulfation in human Ishikawa adenocarcinoma cells and suggest a mechanism for increasing estrogen sulfation in the endometrium during the secretory phase of the menstrual cycle.

The following article describes the prevalence of estrogen mimics.  Of particular interest is the statement that the estrogen mimic "bisphenol-A was found to contaminate the contents of canned foods." This may explain why cat hyperthyroidism occurs at a much higher rate among cats fed canned food and may be a direct suggestion that persons with thyroid disease should avoid eating any food from cans.  The estrogen mimics may have very powerful effects on increasing the uptake of cadmium.  Also note that "Bisphenol-A is also used in dental sealants and composites."

1 : J Steroid Biochem Mol Biol 1998 Apr;65(1-6):143-50

An updated review of environmental estrogen and androgen mimics and antagonists.

Sonnenschein C, Soto AM

Tufts University School of Medicine, Department of Anatomy and Cellular Biology, Boston, MA 02111, USA.

For the last 40 y, substantial evidence has surfaced on the hormone-like effects of environmental chemicals such as pesticides and industrial chemicals in wildlife and humans. The endocrine and reproductive effects of these chemicals are believed to be due to their ability to: (1) mimic the effect of endogenous hormones, (2) antagonize the effect of endogenous hormones, (3) disrupt the synthesis and metabolism of endogenous hormones, and (4) disrupt the synthesis and metabolism of hormone receptors. The discovery of hormone-like activity of these chemicals occurred long after they were released into the environment. Aviation crop dusters handling DDT were found to have reduced sperm counts, and workers at a plant producing the insecticide kepone were reported to have lost their libido, became impotent and had low sperm counts. Subsequently, experiments conducted in lab animals demonstrated unambiguously the estrogenic activity of these pesticides. Man-made compounds used in the manufacture of plastics were accidentally found to be estrogenic because they fouled experiments conducted in laboratories studying natural estrogens. For example, polystyrene tubes released nonylphenol, and polycarbonate flasks released bisphenol-A. Alkylphenols are used in the synthesis of detergents (alkylphenol polyethoxylates) and as antioxidants. These detergents are not estrogenic; however, upon degradation during sewage treatment they may release estrogenic alkylphenols. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant. When administered to lab animals it is metabolized to free nonylphenol. Bisphenol-A was found to contaminate the contents of canned foods; these tin cans are lined with lacquers such as polycarbonate. Bisphenol-A is also used in dental sealants and composites. We found that this estrogen leaches from the treated teeth into saliva; up to 950 microg of bisphenol-A were retrieved from saliva collected during the first hour after polymerization. Other xenoestrogens recently identified among chemicals used in large volumes are the plastizicers benzylbutylphthalate, dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive p-phenylphenol and the disinfectant o-phenylphenol. These compounds act cumulatively. In fact, feminized male fish were found near sewage outlets in several rivers in the U.K.; a mixture of chemicals including alkyl phenols resulting from degradation of detergents during sewage treatment seemed to be the causal agent. Estrogen mimics are just a class of endocrine disruptors. Recent studies identified antiandrogenic activity in environmental chemicals such as vinclozolin, a fungicide, and DDE, and insecticide. Moreover, a single chemical may produce neurotoxic, estrogenic and antiandrogenic effects. It has been hypothesized that endocrine disruptors may play a role in the decrease in the quantity and quality of human semen during the last 50 y, as well as in the increased incidence of testicular cancer and cryptorchidism in males and breast cancer incidence in both females and males in the industrialized word. To explore this hypothesis it is necessary to identify putative causal agents by the systematic screening of environmental chemicals and chemicals present in human foods to assess their ability to disrupt the endocrine system. In addition, it will be necessary to develop methods to measure cumulative exposure to (a) estrogen mimics, (b) antiandrogens, and (c) other disruptors.

The following information may support the idea that estrogen is an accelerator of cadmium uptake into the body since cadmium is probably the heavy metal that induces lung cancer.  The fact that lung cancer typically strikes women in their 60s may stem from the post-menopausal decline of estrogen which decreases the uptake of zinc (or possibly copper) which may protect the lungs from cadmium-induced damage.  Because of the very long half-life of cadmium, it stays in the body much longer than zinc or copper.

High estrogen linked to lung cancer
From Science News, Vol. 157, April 22, 2000.

Women seem more susceptible than men to the carcinogenic effects of tobacco smoke, research has indicated. New findings suggest that estrogen may also play a role.

When estrogen is present, some cells produce a protein on their surfaces called an estrogen receptor. The hormone can then bind to these cells and spur cell proliferation. Pharmacologist Jill M. Siegfried of the University of Pittsburgh found evidence of estrogen receptors in a five kinds of tumors from patients with non-small-cell lung cancer, the most common variety of lung cancer. Healthy lung cells rarely show estrogen receptors.

Initial tests showed that the tumors made the RNA that directs production of the estrogen receptor known as alpha. A second experiment revealed a profusion of estrogen receptor alpha on the surface of tumor cells, she says.

In another experiment, which compared lung tumors from two men and two women, Siegfried found that the surfaces of cancerous cells from the women had roughly twice as many estrogen receptor alpha molecules as those from the men had.

Women have more estrogen circulating in their systems before menopause than after it. Yet, on average, lung cancers strike women in their early 60s. It may take years for the carcinogenic effect of estrogen to result in diagnosable cancer, she says.