Microsoft word - dr wright hyperexcretion.rtf

By Jonathan V. Wright, M.D.
Tahoma Clinic Foundation
801 S.W. 16th St., Renton, WA 98055
As many readers know, I’ve been prescribing bio-identical sex steroids, including “triple estrogen”, progesterone, testosterone, and DHEA, since the early 1980s. Usually, bio- identical hormone replacement (with follow-up visits and laboratory testing as appropriate) proceeds without problems. For symptomatic women, “hot flashes”, mood swings, insomnia, depression and other symptoms of declining hormones are relieved, and life can return to relatively normal. However, every practitioner who’s prescribed bio-identical hormones for women has experienced occasional “treatment failures.” In this small percentage of women, despite carefully escalating doses of triple estrogen1 and accompanying hormones, the “hot flashes” and other symptoms of menopause aren’t relieved, or are relieved only In most cases (although certainly not always) these “treatment failures” occur in women who’ve previously taken Premarin or other non-bio-identical “hormone” replacement. In frustration, most of these women will return to taking Premarin or other more risky “hormones”, since “at least they take care of my symptoms”. Over the years, it’s become obvious that almost all “treatment failures” following bio- identical hormone replacement have a unique “biochemical signature”. When given an “average effective treatment dose” of bio-identical estrogens, “treatment failures” I’ve always followed up bio-identical hormone replacement with laboratory testing to determine if the dose of each hormone is within physiologic parameters. I’ve used the 24- hour urine for sex steroids (Meridian Valley Laboratories, to help monitor hormone safety. In addition to the usual measurements of progesterone, DHEA, and testosterone, I always want to know the individual and combined levels of estrone, estradiol, and estriol3 (E1, E2, E3), as well as levels of androsterone and etiocholanolone, for all women taking bio-identical hormone replacement. ESTROGEN HYPEREXCRETION
When tested in this way, nearly all women who don’t respond to bio-identical esrogen replacement are found to be “hyperexcreting” their estrogens. The combined urinary levels of E1+E2+E3 resulting from an “average effective treatment dose” are from 50% to 1800% higher. As a result of estrogen hyperexcretion, apperently very little if any estrogen remains available to the brain and the rest of the body to quench menopausal symptoms. As one woman put it: “It feels like my body is just getting rid of every bit of estrogen supplement I’m putting into it”. AN INITIAL EAV-AIDED SOLUTION
With the help of EAV technology4 applied by Tahoma Clinic staffers Elizabeth Swinton and Hetty Hall, we determined a few years ago that the “problem” might involve the liver and “fat metabolism” (steroids are of course a type of fat). Aided by EAV, we put together a program that (for most women) slowly improves the liver’s handling of bio- identical estrogens. Women for whom even “high” doses of triple estrogen (5 to 7½ milligrams daily or more) had been totally ineffective found that these same doses slowly became more and more effective as they followed the Swinton-Hall program. The program involved the use of (varying doses and types) of liver-supportive botanicals, vitamin C, B-complex, gamma-linoleic acid (GLA), vitamin E, bile salts, and pancreatic enzymes. After several months (usually four to ten) on this program, the previously- ineffective triple estrogen would become effective, usually fully effective, in relieving menopausal symptoms. Periodic laboratory evaluation with the 24-hour urinary sex steroid panel showed combined levels of E1+E2+E3 declining towards normal as symptom relief improved. For those women determined enough to tolerate several months of menopausal symptoms in order to avoid Premarin or other non-bio-identical “hormone” replacement, the program was usually successful. The biggest problem with this approach was the length of time involved. More women than not decided that dedication to bio-identical hormones was outweighed by the grief caused by persistent menopausal symptoms, and returned to Premarin (or other non-bio- identical “hormones”) simply to eliminate these symptoms. METABOLIZING ESTROGENS:
Along with many other substances, estrogens are metabolized and “detoxified” by cytochrome p450 (and other) cytochrome enzymes. It seemed logical to hypothesize that “non-responders” to bio-identical esrogen replacement have “upregulated” cytochrome enzymes that could be very gradually “downregulated” with the Swinton-Hall program. The challenge was to find a more rapid method. A literature review disclosed clinically- overlooked publications with a direct bearing on this hypothesis. A “central” part of an apparent solution to “estrogen hyperexcretion” was published in 1977. Maines and Kappas5 pointed out that cytochromes are heme proteins, and that the rate-limiting enzyme in heme protein formation is gamma-amino levulenic acid synthetase (ALA synthetase, “ALA-S” in this report). They also noted that the first enzyme in the degradation of heme proteins is heme oxidase (“HO” in this report). As they reported, trace metals regulate the formation (and therefore overall activity) of cytochrome enzymes by simultaneous repression of ALA-S and de novo induction of Inferring from the laboratory data taken from bio-identical estrogen non-responders, and from the Maines and Kappas paper, it seemed at least possible that apparent cytochrome p450 “upregulation” (inferred from estrogen hyperexcretion) might involve the opposite of the trace metal effect described by Maines and Kappas. The hyperexcretion of the estrogens (with consequent unavailability to the somatic tissues) might be due to overactivity of ALA-S and/or underactivity of HO, with consequent excess (or excess function) of the cytochromes p450. Therefore, it might be possible to reverse this situation with the use of trace elements. COBALT, CYTOCHROME P-450, AND GLUTATHIONE
According to Maines and Kappas, of all the trace metals, cobalt has the greatest effect in the induction of HO synthesis, thus promoting cytochrome p450 degradation and, by implication, slowing the hyperexcretion (secondary to presumed “hypermetabolization”) of bio-identical estrogens, and presumably other metabolites. Others found that cobalt (chloride) simultaneously has another very beneficial effect: Inducing the formation of considerably more reduced glutathione (GSH). Reprinting “Treatment of animals with cobaltous chloride caused decreases in hepatic, pulmonary, and renal cytochrome p-450 and alterations in levels of other components of microsomal mixed-function oxidases, which can alter the rate of bio-transformation of certain drug substrates. The treatment also caused a striking, dose-dependent elevation in tissue levels of reduced glutathione (GSH), within 2 to 8 hours. The effect of cobalt on GSH occurred in all tested animal species and strains. Actinomycin-D prevented the cobalt stimulated rise in GSH. Salts of several other divalent metals also produced sharply elevated levels of hepatic GSH, occurring concomitantly with decreased microsomal content of These results suggest that pretreatment of animal with cobaltous chloride, or other
divalent metal salts, could alter the disposition of certain toxic, alkylating drug
metabolites not only by decreasing the rate of formation of the reactive metabolites, but
also by increasing theamount of GSH available for the formation of their less reactive,
less toxic, GSH conjugates6. [Emphasis added for obvious reasons.]
Cobalt also has a “bi-phasic” effect on ALA-S, and therefore on heme synthesis, including the cytochrome p-450 series. It appears to initially inhibit ALA-S, following which an enhanced rate of ALA-S synthesis occurs7. From this very brief review, it appears reasonable to infer that cobalt administration might be of use in slowing the hyperexcretion of estrogens. Of course, this inference requires the assumption that the effect of cobalt’s HO induction and “first phase” ALA-S suppression is greater than cobalt’s “second phase” ALA-S induction effect. PORPHYRINS
P450 AND P488
A small amount of clinical information accumulated so far indicates that in humans, cobalt normalizes estrogen hyper-excretion while relieving menopausal symptoms. Following is preliminary data from a few such cases observed at Tahoma Clinic. A “typical normal response” case is outlined first for comparison purposes. “TYPICAL NORMAL RESPONSE”
R.F. is a 48 year old woman whose last menstrual period was four months prior to her first visit with me at Tahoma Clinic. She has been experiencing increasing “hot flashes”, night sweats, irritability, insomnia, and mood swings. Although she had an FSH determination done elsewhere, confirming menopause, she had read about various options, and had come in for bio-identical hormone replacement therapy. After history and physical examination, initial quantities of bio-identical hormone replacement were prescribed on a 28 day cycle, including “triple estrogen” 2.5 milligrams on “days 1-25”, progesterone 25 milligrams on “days 12-25”, and DHEA 15 milligrams every day. [“Triple estrogen” is a combination of estrone (10%), 17-b estradiol (10%), and estriol (80%).] She was advised to have follow-up 24-hour urinary steroid determination done in 60 days or after her symptoms subsided, whichever came first. She was advised (as usual) that the urine specimen should be collected during a day when she was using all three replacement hormones. Approximately 10 weeks later, she reported that nearly all the above noted symptoms were gone with the exception of occasional insomnia. Her urinary estrogens were: Micrograms Per 24 Hours
Total Estrogens
· Postmenopausal normal range, total estrogens = 0-60 micrograms/24 hours · Progesterone and DHEA were also within the expected range. In my experience with hundreds of women relieved of menopausal symptoms with 2.5 milligrams Triple Estrogen daily (along with progesterone, DHEA, and in many cases testosterone), the usual range of total estrogens has been from 90-180 micrograms/24 ESTROGEN HYPEREXCRETION:
The data in this first case were collected by my colleague at Tahoma Clinic, Davis RW is a 49 year old white woman with a prior history of chronic fatigue syndrome. In December 1997, she saw Dr. Lamson concerning menopausal symptoms, including moderately severe hot flashes, insomnia, and anxiety. She collected a 24 hour urine specimen, upon which a comprehensive steroid determination was performed, and reported in January 1998. Estrogens were reported as: Micrograms Per 24 Hours
Total Estrogens
She was started on Triple Estrogen [E1:E2:E3/10:10:80], 1.25 milligrams daily with no ensuing symptom relief. Triple Estrogen was then increased to 2.5 milligrams daily. While still using the 2.5 milligram daily dosage of triple estrogen, she collected another 24-hour urine specimen, upon which the same steroid determinations were performed. Micrograms Per 24 Hours
Total Estrogens
Along with her continuing Triple Estrogen, RW then started cobalt supplementation with “Meira” cobalt “beads” (20 micrograms ionic cobalt per bead, DSD International, Phoenix; see below). She used 20-25 beads daily, a total of 400-500 micrograms daily. Two weeks later, she reported her hot flashes and other menopausal symptoms ceased for the first time. However, she also reported that if she skipped a daily dose of cobalt, her hot flashes promptly returned, only to disappear with resumption of the cobalt. Slightly over a month after starting the cobalt, she reported that on another “skipped dose” occasion, she not only had return of hot flashes, but “spotting”. The spotting continued at a low level for two weeks, even though the hot flashes ceased as before with As she has continued cobalt (along with the Triple Estrogen at 2.5 milligrams daily, taken on a 25/28 day cyclic basis) she had no further hot flashes. She gradually became able to omit the occasional cobalt dosage without recurrence of hot flashes. After 10 weeks of supplemental cobalt along with the continuing triple estrogen, her 24- hour steroid analysis yielded the following estrogen values: Micrograms Per 24 Hours
Total Estrogens
As noted above, this estrogen total is within the anticipated range for postmenopausal women supplemented with 2.5 milligrams of Triple Estrogen daily. The data in this and the next case were collected by my former Tahoma Clinic colleague Joni Olehausen, N.D., (now in Minnesota), and her patients J.S. and J.K. J.S. is a 63 year old woman. She had been on bio-identical hormone replacement therapy for approximately three years. She was still having night sweats and difficulty sleeping, as well as difficulty with memory and concentration. Twenty-four hour urinary estrogens Micrograms Per 24 Hours
Total Estrogens
Following this, she was continued on triple estrogen 2.5 milligrams. Approximately six months later, she was advised to start 20-25 Meira cobalt beads daily. Eleven weeks later, Micrograms Per 24 Hours
Total Estrogens
JK is a 52 year old woman with symptoms of hypothyroidism and menopause, the latter including night sweats, vaginal dryness, anxiety, irritability, mood swings. Her last menstrual period was four months previously She was already taking “Bi-estrogen” (Estriol 1 milligram, estradiol 250 micrograms) twice daily, along with Provera 2.5 milligrams8, daily. Her sex hormones were evaluated with the 24-hour urine for sex steroids with the result below: Micrograms Per 24 Hours
Total Estrogens
Menopausal symptoms continued. On a return visit, six months later, she was advised to start on Meira cobalt beads, 20-25 beads daily, while continuing her bio-identical estrogens. Ten weeks later, her estrogens were as follows: Micrograms Per 24 Hours
Total Estrogens
Although her total estrogens had not yet diminished to a more expected range, except for continuing sleeping difficulty, her menopausal symptoms were improved. Unfortunately, she has not followed up since Dr. Olehausen left for a clinic directorship in Minnesota. (In both Case 2 and Case 3, although total estrogen excretion declined dramatically following the ingestion of ionic cobalt, the relative proportion of estriol as a fraction of total excreted estrogens also declined dramatically. Many readers familiar with the work of Henry Lemon, M.D., recognize that a larger percentage of estriol is likely advisable as a “target”. This will addressed in a future posting.) The data in this case were colllected by my Tahoma Clinic colleagues Joni Olehausen N.D., David Steele M.D., and their patient S.T. S.T. is a 46 year old woman first seen with problems of depression, mood swings, night sweats, and insomnia. Two years previously she had undergone hysterectomy with bilateral ovariectomy, and at the time of first consultation was using only a non- prescription “progesterone cream”. (She was taking no bio-identical estrogens or estrogenic hormones of any kind. Her 24-hour urinary estrogens were: Micrograms Per 24 Hours
Total Estrogens
On follow-up she was started on 3 milligrams triple estrogen daily, along with progesterone 50 milligrams, DHEA 30 milligrams, and testosterone 5 milligrams. Four months later there had been no symptomatic improvement. Follow-up 24 hour urinary steroid analysis was done; her 24-hour urinary estrogens were: Micrograms Per 24 Hours
Total Estrogens
Notably, her DHEA and progesterone levels were within anticipated physiologic limits, but testosterone was supraphysiologically elevated to 125.5 milligrams/24 hours (pre- supplemented testosterone level 28.5 milligrams/24 hours, unsupplemented women’s Her symptoms continued as before. Without alteration of hormone supplementation, cobalt supplementation was begun. Eight weeks later (just before this report was written), Micrograms Per 24 Hours
Total Estrogens
Progesterone and DHEA remained within the physiologic range; testosterone was still supraphysiologic, but declined to 71.8 micrograms/24 hours. Symptoms were partially improved, but some of that improvement was attributed to an adjustment in thyroid supplementation made by another practitioner. She has been advised to continue all hormone supplementation (and cobalt) unchanged, and to repeat her test in another 2 to 4 months. In contrast to the women reported in “cases 1-3”, this individual had estrogen hyperexcretion “on her own” without any known ingestion of exogenous estrogens. As noted below, one wonders about “environmental estrogen” exposure with consequent “upregulation” of the cytochrome p450 series. IONIC COBALT
The use of low-dose ionic minerals was introduced (as were many innovations in mineral therapeutics) by John A. Myers, M.D., who practiced in Baltimore. He developed barely- visible negatively-charged “ion-transfer” resin beads, which were then coated with positively-charged electrostatically-adherent minerals. Approximately 20 micrograms of each mineral adheres to a single bead, making this delivery system more suitable for trace The ion-transfer beads are placed on the tongue, where the mineral is nearly- instantaneously dissolved in body fluids and subsequently absorbed. Although the ion- transfer beads are not digestible, it’s advisable to scrape them off the tongue after a minute or two. Since the beads coated with cobalt initially have a deep purple color, it’s quite obvious after they’re scraped off that the cobalt is gone. Myers’ ion transfer beads are still sold by DSD International of Phoenix, Arizona, under the “Meira” brand name. In addition to cobalt, silver, chromium, copper, manganese, zinc, calcium, magnesium, sodium, and potassium are available. (I am not in any way In this application, symptomatic women who hyperexcrete estrogen are advised to use 20 to 30 beads (400-600 micrograms) daily until symptoms subside and laboratory tests normalize. At present, it’s anticipated that the cobalt supplement can be discontinued once the cytochrome enzymes have been “downregulated” to an apparent normal level of activity. If symptoms return, laboratory evaluation can easily detect “recurrent hyperexcretion (and apparent “re-current cytochrome p450 up-regulation) and cobalt can COBALT SAFETY
According to a current major textbook9 concerning minerals: “Cobalt has a low order of toxicity in all species studied, including humans.” A study of children in 28 institutions scattered across the United States found that unsupplemented dietary cobalt ingestion ranged from 300 to 1770 micrograms daily10. However, other investigators have published data concerning daily cobalt intakes ranging from 6 micrograms to 580 micrograms daily11,12,13,14. Well-known trace mineral researcher Henry Schroeder estimated the daily intake of Americans to be at the upper end of this range, at 160 to 580 Even though cytochromes are heme proteins whose synthesis can be diminished by cobalt and other trace minerals (as noted above), cobalt does not decrease hemoglobin synthesis. Cobalt is a well-known hematopoetic whose effect is apparently brought about through increased renal synthesis of erythropoetin. However, the quantities of cobalt required to achieve a hematopoetic effect are large, 20 to 30 milligrams (20,000 to 30,000 micrograms) daily, amounts well beyond any reported daily dietary intake. At this dosage range, toxic manifestations including thyroid hyperplasia, myxedema, and congestive Specifically discussing the role of cobalt in the synthesis of hemoglobin, cytochrome p- 450, and other liver proteins, Tephly and Hibbein wrote: “Cobalt chloride administration to rats stimulates erythropoesis, but inhibits the synthesis of hepatic microsomal p-450….No effect on NADPH-cytochrome c reductase activity was observed….cobalt treatment of rats has no effect on hepatic protein synthesis over the course of these experiments, cobalt administration may be valuable as a tool for studying the role(s) of p-450 in various biological reactions16.” UNANSWERED QUESTIONS
From the above data, it seems reasonable to infer: A small minority of women have “upregulated” estrogen-metabolizing enzymes, Ionic cobalt “downregulates” these enzymes and “normalizes” the “upregulated enzymes”. In doing so, ionic cobalt enables normalization of bio-identical hormone metabolism, with co-incident symptom relief. Many questions remain. These include (but are not limited to): Does “upregulation” of cytochrome p450 (and possibly other) enzymes mean more total enzymes, hyperactivity of a “normal” number of enzymes, or some Is cobalt-mediated “downregulation” simply a matter of lessening total enzyme synthesis, as described by Maines and Kappas, or is there a component of Which substances induce significant cytochrome p450 “upregulation”? At least a partial answer to this last question is probably “Premarin” and other “conjugated equine estrogens”, as a preponderance of cases so far have been former Premarin users. My (non-statistically verified) impression is that more cases occur among longer-term Premarin users. However, estrogen hyperexcretion in response to physiologic dosage of bio-identical estrogen has also been observed in women who’ve not taken any known exogenous estrogens, as in Case 4 above. A second strong possibility carries the general descriptor of “environmental estrogens”. These include (but are likely not limited to) components of plastics, pesticides, solvents, detergents, and dioxins. If the exogenous, non-bio-identical but “natural” estrogens contained in Premarin are associated with “upregulation” of cytochromes, it’s likely that a sufficient quantity (whatever that might be) of one or more “environmental estrogens” OTHER IMPLICATIONS
Stretching this line of thought a little further, it might reasonably be asked: “Since Premarin is a known carcinogen for a small number of women, but not all, and since it’s very likely that “environmental estrogens” are also carcinogens for a small number of women (and perhaps men), but not all, could estrogen hyperexcretion, either in response to physiologic dose bio-identical estrogen replacement, or with no known cause, be a “Most of the time, increased mitochondrial oxidative activity and cytochrome p450 content are desirable since for most drugs and some carcinogens, “oxidation” and “detoxification” are the same thing. By contrast, for a small group, “oxidation” and “activation” are the true synonyms. “Activation” means these metabolites may in some cases be more dangerous to cells than their parent compounds.” “Depletion of cellular heme proteins including cytochromes p450 and p448 should not always be viewed as augmenting toxicity; in some cases, this depletion is preventing the formation of toxic metabolites.” These comments imply that the answer to this question may be “yes”. If so, dietary-range cobalt supplementation may help prevent estrogen-related cancers in women whose
exposure to Premarin and “environmental estrogens” results in “upregulation” of the cytochrome p450 system with consequent estrogen hyperexcretion. A clue to the strength of this “cobalt may prevent estrogen-related cancer” hypothesis is found in data concerning a parallel situation: carbon tetrachloride hepatotoxicity. Carbon tetrachloride is a known hepatotoxin whose toxicity depends on the “activation” of free radical metabolites17. This activation is mediated by the cytochrome p450 system, and is decreased by cobalt pretreatment18. “The administration of cobaltous chloride to rats produced a selective dose-dependent decrease in the cytochrome p450 component of the microsomal electron transport system. A concomitant of this alteration….was a refractoriness to the carbon tetrachloride- induced elevation in serum glutamic oxaloacetic transaminase (SGOT), serum glutamicpyruvic transaminase (SGPT), serum isocitric dehydrogenase, (ICDH), and the decrease in hepatic microsomal glucose-6-phosphatase activity. Cobaltous chloride pretreatment alos decreased the intensity of micro-somal diene conjugation absorption observed after carbon tetrachlorideadministration.” If cobalt decreases the “activation” of carbon tetrachloride into toxic metabolites through it’s effects on the cytochrome p450 system, it’s possible that it also reduces the “activation” of estrogens into toxic and perhaps carcinogenic metabolites. It’s also possible that the simultaneous GSH-generating effect of cobalt would help neutralize “activated” estrogen metabolites, also reducing the risk of cancer. IN CONCLUSION
Reverses bio-identical estrogen replacement failure May help reduce the risk of estrogen-related and “environmental estrogen”-related 1 In this report, “triple estrogen” is 80% estriol, 10% estradiol, 10% estrone. 2 Indeed I am a consultant for Meridian Valley Labs 3 Remember Henry Lemon? For those who don’t, there will be a posting on the importance of monitoring certain steroid metabolites in the future. Hint: estriol is the “detoxified metabolite” of 16a-hydroxyestrone. 4 EAV, Electroacupuncture According to Voll, sometimes termed MSA (Meridian Stress 5 Maines MD, Kappas A. Metals as regulators of heme metabolism. Science 6 Sasame HA, Boyd MR. Paradoxical effects of cobaltous chloride and salts of other divalent metals on tissue levels of reduced glutathione and microsomal mixed-function oxidase components. J Pharm Exp Ther 1978;205(3):718 7 Maines MD, Janousek V, Tomio JM, Kappas A. Cobalt inhibition of synthesis and induction of gamma-aminolevulinate synthase in liver. Biochemistry 1976;73(5):1499 8, there was no known explanation for the previous physician’s prescription of two bio- identical estrogens along with the non-bio-identical medroxyprogesterone (Provera) 9 Smith RM, Cobalt, page 174, in Mertz, W, ed., Trace Elements in Human and Animal Nutrition, 5th edition, Academic Press, San Diego, 1987 (the most recent edition) 10 Murthy GK, Rhea U, Peeler, JT. Environ Sci Technol 1971;5:436-442 11 Harp MJ, Scoular FI. J Nutr 1952;47:67-72 12 Schroeder HA, Nason AP, Tipton IH. J Chron Dis 1967;20:869-890 13 Tipton IH, Stewart PL, Martin PG. Health Phys 1966;12:1683-1689 14 Yamagata N, Kurioka W, Shimuzu T. J Radiat Res 1963;4:8-15 15 Smith RM, ibid., p. 173 16 Tephly TR, Hibbein P. The effect of cobalt chloride administration on the synthesis of hepatic microsomal cytochrome p-450 Biochem Biophys Res Comm 1971;42(4):589 17 Recknagel RO, Glende R. Carbon tetrachloride hepatotoxicity: an example of lethal cleavage. CRC Critical Reviews in Toxicology 1973;2:263-297 18 Suarez KA, Bhonsle P. The relationship of cobaltous chloride-induced alterations of hepatic microsomal enzymes to altered carbon tetrachloride hepatotoxicity. Toxicology


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