Book Notes: From Fatigued to Fantastic

Chapter 4: Hormones

In this section:

« RETURN TO BOOK NOTES OVERVIEW

Below are 2 excellent articles by Dr. Kent Holtorf of LA on bioidentical hormones and a second on hypothalamic and adrenal dysfunction in CFS/FMS:

His website is: http://www.hormoneandlongevitycenter.com/

The Safety and Effectiveness of Bioidentical Hormones: Natural (Bio-identical) vs. Synthetic HRT

Kent Holtorf, M.D.

Dr. Holtorf is the Medical Director of the Holtorf Medical Group, Inc, Center for Hormone Imbalance and Fatiguing Conditions in Los Angeles, specializing in CFS, FM, hypothyroidism, chronic illness and the treatment of complex endocrine dysfunction. He is board certified and is a Board Examiner for the American Academy of Anti-Aging Medicine.

Kent Holtorf, M.D.
Medical Director
Holtorf Medical Group, Inc
http://www.holtorfmed.com/
23456 Hawthorne Blvd, Suite 160
Torrance, CA 90505
(310) 375-2705 Fax: (310) 375-2701

Below is a review of the medical literature demonstrating how natural hormones are superior to their synthetic counterparts. The conclusion is clear that bio-identical hormones are a safe alternative to Premarin and medroxyprogesterone acetate (MPA), marketed as Provera. The natural bio-identical hormones are very different from their synthetic versions, often having completely opposite physical and cellular effects. Thus, it is critical that women be given the information that these natural hormones do not have the negative side effects of the synthetic hormones and in no way pertain to the conclusions reached by the Women’s Health Initiative (WHI) study. Natural hormones are a safe and more conservative approach to hormone replacement therapy that does not carry the risks associated with Premarin and Provera.

I have found that patients feel great on the natural hormones, but when they are on synthetic hormones, they often do not fully respond or have considerable side-effects. Medical studies confirm that women report improved satisfaction when they are changed from MPA [synthetic progesterone] to natural progesterone and have an improved quality of life (2,50). The medical studies also show that HRT with bio-identical hormones are safer (1-79) and far superior to Premarin and Provera with better outcomes and fewer risks and side effects (1-79).

The WHI study demonstrated that when MPA was added to Premarin, there was a substantial increase in the risk of heart attack and stroke. This was an expected outcome with MPA, as it has clearly been shown to not only negate any cardioprotective effects of estrogen, but also to actually promote cardiovascular disease and increase the risk of heart attack and stroke (12,13,14,15,16,17,34,35,36,49,50,51,53,54,65,70,71,72,73). Natural estrogen and progesterone, on the other hand, have an opposite effect. They maintain and augment the cardioprotective effects of estrogen and decrease the risk of heart attack and stroke (49,50,61,67,70,71,72,76,77).

A number of other medical studies have shown that coronary artery spasm, which increases the risk of heart attack and stroke, can be reduced with estrogen and progesterone (13,14,15,68,69), but the addition of MPA to estrogen has the opposite effect and results in vasoconstriction (13,14,15,69), increasing the risk of heart attack and stroke in postmenopausal women. In a study where 18 monkeys had their ovaries removed to simulate menopause, they were then put on estradiol plus either Provera or natural progesterone. After 4 weeks, the researchers injected a substance that causes the coronary arteries to constrict, cutting off the flow of blood to the heart muscle. The researchers reported that the animals receiving Provera would have died within minutes had they not received protective drug treatment. Those on the natural progesterone required no such treatment. The researchers summarized, “We conclude that medroxyprogesterone (Provera) in contrast to progesterone increases the risk of coronary vasospasm (13).” This coronary spasm induced by MPA acetate, but not progesterone, results in an increased risk of heart attack and stroke with MPA use but not with natural progesterone use.

Researchers compared the effects of [natural] estrogen and progesterone with estrogen and medroxyprogesterone on exercise induced myocardial ischemia (lowered blood flow) in postmenopausal women with coronary artery disease. This was a blinded randomized crossover study. Women were placed on natural estradiol for four weeks. They were then randomized to receive either natural progesterone or Provera along with the estradiol. After 10 days on the combined treatment the patients then underwent a treadmill test. The patients then crossed over to the opposite treatment and repeated the treadmill test. It was found that exercise time to myocardial ischemia was increased with natural progesterone (decreased risk of heart attack) vs. Provera. They state, “These results imply that the choice of progestin in women at higher cardiovascular risk requires careful consideration.” Provera is expected to increase the risk of heart attack and stroke while progesterone is not (14).” This coronary dilatation, produced by natural progesterone, but not MPA, increases blood flow to the heart and decreases the risk of heart attack and stroke.

In a series of studies, Adams (51, 61), studied the cardioprotective effects of estrogen and progesterone verses estrogen and MPA. The estrogen and progesterone combination resulted in a 50% reduction in athrosclerotic plaque in the coronary arteries (61). This effect was independent of changes in lipid concentrations. However, when MPA was combined with estrogen, almost all of the cardioprotective effect (athrosclerotic plaque reduction) was reversed and negated (51). MPA was also shown to increase insulin and glucose levels, further increasing the risk of heart disease, heart attack and stroke (51). A number of additional studies have also shown that progesterone by itself (76,77) or in combination with estrogen (51,61,15) will inhibit athrosclerotic plaque formation. Synthetic progestins, on the other hand, have a completely opposite effect. They promote athrosclerotic plaque formation and inhibit any plaque inhibiting action of estrogen (51,15,53,54). This anti-athrogenic (inhibits plaque formation) effect of progesterone is directly opposite to the effects of synthetic progestins, which is pro-athrogenic (promotes plaque formation). In addition, MPA is unique in that it is shown to increase the amount of collagen in vascular plaques, which promotes thrombus (clot) formation (54,15). This increases the risk of heart attack, stroke and blood clots. Again, there are significant differences in natural progesterone and synthetic progestins, with the former reducing the risk of heart disease, heart attacks, and strokes, while the latter increases the risk of heart disease, heart attack, and stroke.

A review paper by Clarkson, published in the Journal of Reproductive Medicine and entitled Progestogens [term for all progesterone like compounds including progesterone and progestins] and Cardiovascular Disease-A Critical Review, the negative effects of MPA in comparison to progesterone were discussed. The authors summarize, “Of particular interest is the attenuating effect medroxyprogesterone acetate (MPA) has on the cardiovascular benefits of postmenopausal estrogen treatment. MPA reduces the dilatory effect of estrogens on coronary arteries, increases the progression of coronary artery arteriosclerosis, accelerates low-density lipoprotein uptake in plaque, increases the thrombogenic potential of atherosclerotic plaques and promotes insulin resistance and its consequent hyperglycemia. These effects may be largely limited to MPA and not shared with other progestogens.” They boldly display in the middle of the page a summary stating, “The data strongly suggests caution in the use of MPA…” and list as their summary of findings that “These studies, taken together, provide a basis for concern, not about all progestogens, but specifically about MPA.”(15). Again, after a review of the literature, it is of no surprise, rather it was expected that the MPA arm of the WHI study would show an increased risk of coronary and cerebral vascular events.

Estrogen and progesterone are superior to estrogen and Provera in the effects on HDL cholesterol. In the large PEPI trial (11), 875 postmenopausal women were randomized to receive placebo, Premarin, Premarin and Provera, or Premarin and natural Progesterone. This study demonstrates the superior effect of natural progesterone over Provera. HDL (good cholesterol was increased by 9% when estrogen and natural progesterone were used versus just a 3-4% increase with estrogen and Provera. The investigators were surprised by the superiority of natural progesterone over synthetic Provera (34) with Dr. Healy, a PEPI trial investigator, stating, “I think the biggest surprise certainly was the HDL effect of micronized progesterone. And I quite agree with Dr. Barrett-Connor that any ongoing trial now, whether they be the National Heart, Lung Blood Institute study on estrogen in women who have known coronary disease or the Women’s Health Initiative, should relook at the regimens being offered.” Elizabeth Connor, Cardiologist and PEPI investigator, stated, “If I were treating a women primarily because she was worried about heart disease or because she has dyslipidemia and low HDL cholesterol, I would probably see if she wanted to take micronized [natural] progesterone. I was quite impressed with the better effect (12).”

Many experts were surprised when the PEPI trial demonstrated that MPA, but not progesterone, significantly attenuated [blocked] the positive effects of estrogen on lipids. The opposing effects of MPA and progesterone on this cardiovascular risk factor have previously, however, been clearly shown, with MPA and other synthetic progestins negating the positive effects of estrogen on lipids (63,64,65,70,72) while progesterone either maintains or augments estrogen’s positive effects on lipids (66,67,70,71,72). Thus, based on their effects on lipids, progesterone would be expected to decrease the risk of heart disease and stroke, while synthetic progestins such as Provera would be expected to increase the risk of heart attack and stroke.

Based on the results from the PEPI Trial and other studies (11,74), the President of the American Heart Association stated that, just based on this difference in the effects on HDL, a women who changes her medication from MPA to natural progesterone would significantly lower her risk for heart disease (35). The differing effects of progestins[synthetic progesterones] and progesterone on lipids is another risk factor that results in an increased risk for heart disease, heart attack and stroke when the synthetic is used but not natural progesterone.

MPA and synthetic progestins are also shown to significantly increase, even double (52,73,49,75) the amount of insulin resistance (Type II diabetes) when compared to estrogen alone or estrogen and progesterone (52,62,73,49). Thus, synthetic progestins are expected to promote vascular disease and increase the risk of heart attack and stroke while natural progesterone does not possess this detrimental effect.

Progesterone was compared to Provera for its ability to decrease the formation of a protein that initiates athrogenic plaques (coronary artery disease), vascular cell adhesion molecule-1. It was shown that progesterone clearly inhibited this protein, but medroxyprogetreone acetate (MPA) (Provera) did not. The authors write, “Because the expression of VCAM-1 is one of the earliest events that occur in the atherogenic process, this adhesion molecule might be the target of progesterone on vascular walls. The contrasting effects of progesterone and MPA seem clinically important, inasmuch as MPA is a widely used progestin in the regimen of hormone replacement therapy (32).” This is another process in which MPA promotes heart disease and the risk of heart attack and stroke, while progesterone reduces heart disease and the risk of heart attack and stroke.

Doctor Lignieres, from, the Necker Hospital Department of Endocrinology and Reproductive Medicine in Paris, France, reviewed the scientific literature that compared natural oral micronized progesterone and commonly used progestins and published his findings in a 1999 Journal, Clinical Therapeutics. He writes, “…most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone…(49).”

A review of progesterone verses synthetic progestins was done by Fitzpatrick from the department of Internal Medicine at the Mayo Clinic. In this review, entitled Micronized Progesterone: Clinical Indications and Comparison with Current Treatments and was published in Fertility and Sterility, the author summarizes the study’s findings, “A large body of evidence, including the Postmenopausal Estrogen/Progestin Interventions study, suggests that the use of combination estrogen and oral micronized progesterone is optimal for long term hormone replacement therapy…However, use of progesterone-like hormones (progestins) is associated with a number of potential adverse reactions, including bleeding, amenorrhea, and, at higher doses, somnolence. There is also evidence that synthetic progestins have a teratogenic[birth defect] effect when administered during the first 4 months of pregnancy. Treatment with combined estrogen and progestin medication impairs glucose tolerance in some patients (62). The synthetic progestins also may attenuate the beneficial lipid and cardioprotective effects of concomitantly administered estrogen (63,64). Because of the potential adverse reactions, careful medical oversight is required if the synthetic progestins are to be used during the first trimester of pregnancy or by patients with diabetes, hyperlipidemia, or hypertension. For indications in which oral delivery of synthetic progestins currently are used, the theoretic benefits of oral delivery of the natural form of the hormone are obvious. In addition to the decreased potential for adverse effects, there are clear advantages in convenience, cost, compliance, and quality of life (50).”

Premarin, being an oral estrogen, will increase clotting factors and inflammatory proteins, increasing the risk of thromboembolism, stroke and heart attack (16,18). This does not occur with transdermal estrogens (18). In fact, it can be considered malpractice to give oral contraceptives or oral HRT to smokers because of the increased risk of stroke, but non-smokers are at increased risk, as well. When oral Premarin is taken with Provera the risk of thromboembolism, stroke and heart attack increase in a synergistic manner. Ninety percent of my patients are on transdermal natural estrogens for this reason (18).

The Nurses Health Study followed 58,000 postmenopausal women for 16 years (725,000 person-years). The study found that, compared with women who never used hormones, use of unopposed postmenopausal estrogen from ages 50 to 60 years increased the risk of breast cancer to age 70 by 23%. The addition of a progestin to the estrogen replacement resulted in a tripling of the risk of breast cancer to a 67% increase in the risk of breast cancer (78)(9).

A large study compared the risk of breast cancer in 1897 women on combined estrogen and progestin versus 1637 controls that had never used any HRT. It was found that the use of progestin increased the risk of breast cancer by 38%. The authors conclude, “This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone (10).” Again, natural progesterone is documented to reduce the risk of breast cancer.

Premarin is made from pregnant horses’ urine, hence its name Pre (pregnant)-mar (horse)- in (urine). It consists of a combination of conjugated equine (horse) estrogens that are more potent and more carcinogenic than other natural estrogens such as estradiol and especially estriol. 4-hydroxyequilenin, a component of Premarin, is especially potent, 100 times the potency of natural estrogen, and carcinogenic.(20,21,22,80). One author summarizes, “These results suggest that 4-hydroxyequilenin has the potential to be a potent carcinogen through the formation of variety of DNA lesions in vivo (22).” Natural estrogens have no such carcinogenic metabolites.

The natural estrogen, estriol, is shown to cause much less breast cell proliferation and is felt to be a much safer form of estrogen than even estradiol and especially Premarin (23,24,39,25,26,27). Estriol is shown to decrease the incidence and inhibit breast cancer in rats (24,39, 26), while the levels of estriol in a women are inversely correlated with the risk of breast cancer, with low levels being associated with cancer while high levels are protective (25,26,56,57,59,60). An analysis of 6 epidemiologic studies of estrogen levels in women found that there are higher estriol levels in populations with lower risks for breast cancer (26).

Dr. Follingstad published an article in the Journal of the American Medical association, titled, Estriol, the forgotten estrogen? He reviewed a study in which estriol was given to postmenopausal women with breast cancer. Thirty-seven percent of the patients demonstrated remission or arrest of the disease. He concluded that estriol should be given to all women who need estrogen replacement therapy but are at risk for breast cancer. A case can be made that all women are at risk and estriol should be part of all HRT regimens. He writes, “Enough presumptive and scientific evidence has been accumulated that we may say that orally administered estriol is safer than estrone or estradiol…let us have the estrogen that causes the least risk (27).”

In a large study that looked at the effect of estrogens on breast cancer in rats, it was shown that estriol was protective. The authors felt that “The superior protective action of estriol may be partly related to its greater solubility in plasma and decreased binding to plasma-albumin, compared to oestrone [estrone] or 17B-oestradiol [estradiol] (58)” Premarin on the contrary increases the risk of breast cancer (20,21,22,80).

There has been considerable research in estrogen metabolism and its relation to breast cancer. Estradiol can be metabolized to either a potent carcinogenic compound, 16-hydroxyestrone, or to a noncarcinogenic compound, 2-hydroxyestrone. Women who metabolize estradiol to 16-hydroxyestrone have a significantly increased risk for breast cancer, and it is being realized that these metabolites likely play a major role in the incidence of breast cancer (40-48). In a study by Kabat et al, entitled Urinary Estrogen Metabolites and Breast Cancer: A Case Controlled Study, it was found that postmenopausal women with the highest levels of 16-hydroxyestrone compared to 2-hydroxyestrone were shown to have a risk factor for breast cancer that was 32 times that of controls. I routinely check these levels in women and determine the ratios because they have a profound effect on breast cancer risk. Interestingly, women with family histories of breast cancer will usually have elevated 16-hydroxyestrone. If an increased level of the carcinogenic estrone is present, measures are taken to reverse this metabolization pattern and then the levels are re-checked. Estriol, however, does not convert to the carcinogenic 2-hydroxyestrone, making it a much a safer form of estrogen.

Estriol also improves multiple sclerosis while other estrogens make it worse; another indication of its profoundly different effects. (28,29)

A number of studies demonstrate that synthetic progestins, such as Provera, increase breast cell proliferation (4,5,7,9,33,79,19,81), making it pro-carcinogenic and increases the risk of breast cancer (6,78,9,10,55,19). This cell proliferation with Provera has been shown to be particularly bad (7). This increased cell proliferation, as expected, translates into an increased risk of breast cancer with medroxyprogesterone use. Natural progesterone, as opposed to medroxyprogsterone, has a strong anti-proliferate effect on breast tissue (1,8,81). This is the opposite effect of Provera and results in a strong anti-breast cancer effect of natural progesterone (30,31,1,8), again opposite of Provera.

A double blind placebo controlled study looked at the effects of estrogen and progesterone on women prior to breast surgery. Patients were given a placebo, estrogen, or estrogen and progesterone for 10-13 days prior to breast surgery. Estradiol increased cell proliferation rates by 230%, but progesterone decreased cell proliferation rates by 400%. The progesterone, when given with estradiol, inhibited and prevented any breast proliferation (cancer preventive). (1) Progestins do not have this beneficial effect.

In a double blind randomized study, Foidart et al also showed that progesterone eliminated estrogen produced breast cell proliferation (8), demonstrating the strong anti-proliferative and anti-cancer effect of natural progesterone. This effect is opposite of that of synthetic progestins, which increase proliferation and increase the risk of breast cancer (4,5,7,9,33,78,79,19).

A prospective epidemiological study conducted at Johns Hopkins demonstrated the profound anti-breast cancer action and protective role of natural progesterone against breast cancer. In that study, 1083 women who had been evaluated and treated for infertility were followed for 13 to 33 years. The results showed that the risk of breast cancer was 5.4 times in subjects who had a low progesterone level when compared to those with a normal level. This was particularly striking because the result was so significant despite the fact that the high progesterone group actually had significantly more risk factors for breast cancer than the low progesterone group, indicating that the progesterone level is a far more important parameter. Additionally, women in the low progesterone group experienced 10 times more deaths from neoplasm (cancer) when compared to those with normal progesterone (30).

In another study, the protective effect of progesterone or Tamoxifen, a potent estrogen antagonist, was investigated in estrogen-induced breast cancer in rats. Results of the study indicated that the induction rate, multiplicity, and size of estrogen induced mammary tumors were reduced by simultaneous administration of either Tamoxifen or progesterone. (31) Natural progesterone is also shown to reduce the number of estrogen receptors in breast tissue (anti-cancer effect).(3)

These studies indicate that, with respect to the risk of breast cancer, heart disease, heart attacks and stroke, natural hormones offer a safe and more conservative approach to HRT. A large amount of scientific evidence overwhelmingly demonstrates that natural hormones are safer than the study drugs of the WHI, Premarin and Provera. Unfortunately, the overwhelming majority of women do not know that there are safe alternatives to their current HRT or to the one they stopped after the results of the WHI were released. As you can see, it is clear that the negative outcome of the WHI study with the use of MPA is certainly of no surprise, given its clear history of having a negative impact on almost every risk factor for heart disease. Natural progesterone has just an opposite effect of MPA on almost every cardiac risk factor, with MPA increasing the risk of heart attack and stroke, while progesterone decreases the risk. If progesterone was used in the trial, the results would assuredly have been different and their results in no way pertain to natural hormones, which are a safe choice with significantly less risk.

The same is true of the increased incidence of breast cancer demonstrated in the study with the use of Premarin and MPA. This in no way pertains to the use of the natural hormones, estriol and progesterone, which both decrease the risk of breast cancer. The public, and also doctors, need to be told that there is a safer alternative to Premarin and Provera and that HRT [Hormone Replacement Therapy] should not be abandoned based on the results of a known toxic drug combination. It is the utmost importance for women to understand that they have alternatives to Premarin and Provera that are scientifically shown to be safer and healthier.

Selected References

1. Chang HJ, Lee TTY et al. Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil Steril. 1995;63:785-791.

2. Fitzpatrick La et al. Comparison of regimens containing oral micronized progesterone of medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Womens Health Gen Based Med 2000 Mayu;9(4):381-7

3. Gompel et al. Antiestrogen action of progesterone in breast tissue. Breast cancer Res Treat 1986;8(3):179-88.

4.Van der Burg et al. Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factor-defined conditions. J Steroid Biochem Mol Biol 1992 Jun;42(5):457-65.

5. Mol JA; van Garderen E; Rutteman GR; Rijnberk A. New insights in the molecular mechanism of progestin-induced proliferation of mammary epithelium: induction of the local biosynthesis of growth hormone (GH) in the mammary glands of dogs, cats and humans. J Steroid Biochem Mol Biol 1996 Jan;57(1-2):67-71.

6. Hulka BS, Links between hormone replacement therapy and neoplasia. Fertil Steril 1994 Dec;62(6 Suppl 2):168S-175S.

7. Hofseth LJ; Raafat AM; Osuch JR; Pathak DR; Slomski CA; Haslam SZ Hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab 1999 Dec;84(12):4559-65.

8. Foidart JM; Colin C; Denoo X; Desreux J; Beliard A; Fournier S; de Lignieres B. Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil Steril 1998 May;69(5):963-9

9. Colditz GA; Rosner B Cumulative risk of breast cancer to age 70 years according to risk factor status: data from the Nurses' Health Study. Am J Epidemiol 2000 Nov 15;152(10):950-64

10. Ross RK; Paganini-Hill A; Wan PC; Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000 Feb 16;92(4):328-32.

12. Estrogen Replacement therapy and Heart Disease: A Discussion of the PEPI Trial. Women’s Health Information Center.

13. Miyagawa K; Rosch J; Stanczyk F; Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nat Med 1997 Mar;3(3):324-7.

14. Rosano GM; Webb CM; Chierchia S; Morgani GL; Gabraele M; Sarrel PM; de Ziegler D; Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 2000 Dec;36(7):2154-9.

15. Clarkson TB. Progestogens and cardiovascular disease. A critical review. J Reprod Med 1999 Feb;44(2 Suppl):180-4

16. Feeman WE. Thrombotic stroke in an otherwise healthy middle-aged female related to the use of continuous-combined conjugated equine estrogens and medroxyprogesterone acetate. J Gend Specif Med 2000 Nov-Dec;3(8):62-4; discussion 64-5.

17. Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000 Oct-Nov;65(10-11):651-8.

18. Scarabin PY; Alhenc-Gelas M; Plu-Bureau G; Taisne P; Agher R; Aiach M. Effects of oral and transdermal estrogen/progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial Arterioscler Thromb Vasc Biol 1997 Nov;17(11):3071-8

19. Colditz Ga. Hormones and breast cancer: evidence and implications for consideration of risks and benefits of hormone replacement therapy. J Womens Health 1999 Apr;8(3):354-7.

20. Zhang F; Chen Y; Pisha E; Shen L; Xiong Y; van Breemen RB; Bolton JL. The major metabolite of equilin, 4-hydroxyequilin, autoxidizes to an o-quinone which isomerizes to the potent cytotoxin 4-hydroxyequilenin-o-quinone. Chem Res Toxicol 1999 Feb;12(2):204-13.

21. Pisha E; Lui X; Constantinou AI; Bolton JL Evidence that a metabolite of equine estrogens, 4-hydroxyequilenin, induces cellular transformation in vitro. Chem Res Toxicol 2001 Jan;14(1):82-90

22. Zhang F; Swanson SM; van Breemen RB; Liu X; Yang Y; Gu C; Bolton JL. Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, and stable adducts, and oxidized bases. Chem Res Toxicol 2001 Dec;14(12):1654-9

23. Tzingounis VA; Aksu MF; Greenblatt RB Estriol in the management of the menopause JAMA 1978 Apr 21;239(16):1638-41.

24. Lemon HM; Kumar PF; Peterson C; Rodriguez-Sierra JF; Abbo KM Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen. Cancer 1989 May 1;63(9):1685-92.

25. Lemon HM; Wotiz HH; Parsons L; Mozden PJ Reduced estriol excretion in patients with breast cancer prior to endocrine therapy. JAMA 1966 Jun 27;196(13):1128-36.

26. Lemon, H.M. Pathophysiologic considerations tin the treatment of menopausal patients with oestrogens; the role of oestriol in the prevention of mammary carcinoma. Acta Endocrinol Suppl 1980 233:17-27. DNH

27. Follingstad AH Estriol, The Forgotten Estrogen. JAMA Jan 2 1978, 239(1) p29-30

28. Kim S; Liva SM; Dalal MA; Verity MA; Voskuhl RR Estriol ameliorates autoimmune demyelinating disease: implications for multiple sclerosis. Neurology 1999 Apr 12;52(6):1230-8.

29. Bansil S; Lee HJ; Jindal S; Holtz CR; Cook SD. Correlation between sex hormones and magnetic resonance imaging lesions in multiple sclerosis. Acta Neurol Scand 1999 Feb;99(2):91-4

30. Cowan LD; Gordis L; Tonascia JA; Jones GS. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol 1981 Aug;114(2):209-17

31. Inoh A; Kamiya K; Fujii Y; Yokoro K Protective effects of progesterone and tamoxifen in estrogen-induced mammary carcinogenesis in ovariectomized W/Fu rats. Jpn J Cancer Res 1985 Aug;76(8):699-704

32. Otsuki M; Saito H; Xu X; Sumitani S; Kouhara H; Kishimoto T; Kasayama S. Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 2001 Feb;21(2):243-8.

33. Braunsberg HA; Coldham NG; Wong W. Hormonal therapies for breast cancer: can progestogens stimulate growth?. Cancer Lett 1986 Feb;30(2):213-8

34. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1995 Jan 18;273(3):199-208

35. News conference at the American Heart association Annual Meeting, Nov 17, 1994.

36. Hargrove JT, et al. menopausal hormone replacement therapy with continuous daily oral mircronized progesterone. Obstet Gyn 1989;73:606-12.

37. Hargrove, Osteen KG. An alternative method of hormone replacement therapy using the natural sex steroids. Infertile Repro Med Clinics north Am. 1995;6:563-674.DNH

38. Hargrove JT, Eisenberg E. Menopause. Med. Clinics North Am 1995;79:1337-1356.

39. Lemon Hm. Antimammary carcinogenic activity of 17-alpha-ethnyl estriol. Cancer 1987;60:2873-81.

40. Schneider J, Huh MM, Bradlow HL, Fishman J. (1984), Antiestrogen action of 2-hydroxyestrone on MCF-7 human breast cancer cells. J Biol Chem 259:4840-4845.

41. Vandewalle B, Lefebvre J. (1989), Opposite effects of estrogen and catechol estrogen on hormone-sensitive breast cancer cell growth and differentiation. Mol Cell Endocrinol 61:239-246.

42. Bradlow HL, Telang NT, Sepkovic DW, Osborne MP. (1996), 2-hydroxyestrone: the ‘good’ estrogen. J Endocrinol 150:Suppl: S259-S265.

43. Fishman J, Martucci C. (1980), Biological properties of 16alpha-hydroxyestrone: Implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab 51:611-615. DNH

44. Schneider J, Kinne D, Fracchia A, Pierce V, Anderson KE, Bradlow HL, Fishman J. (1982), Abnormal oxidative metabolism of estradiol in women with breast cancer. Proc Natl Acad Sci ,USA 79:3047-3051.DNH

45. Osborne MP, Bradlow HL, Wong GYC, Telang NT. (1993), Upregulation of estradiol C16 alpha-hydroxylation in human breast tissue: a potential biomarker of breast cancer risk. J Natl Cancer Inst 85:1917-1920.

46. Bradlow HL, Hershcopf RJ, Martucci CP,Fishman J. (1985), Estradiol 16-hydroxylation in the mouse correlates with mammary tumor incidence and presence of murine mammary tumor virus: A possible model for the hormonal etiology of breast cancer in humans. Proc Natl Acad Sci ,USA 82:6295-6299.

47. Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL. (1992), Induction by estrogen metabolite 16 alpha-hydroxyetrone of genotoxic damage and aberrant cell proliferation in mouse mammary epithelial cells in culture. J Natl Cancer Inst 82:634-638.

48. Kabat GC, Chang CJ, Sparano JA, Sepkovic DW, Hu XP, Khalil A, Rosenblatt R, Bradlow HL. (1997), Urinary estrogen metabolites and breast cancer: a case-control study. Cancer Epidemiol Biomark Prev 6: 505-509.

49. de Lignieres B. Oral micronized progesterone. Clin Ther 1999. jan;21(1):41-60.

50. Fitzpatrick LA, Good A. Micronized progesterone: clinical indications and comparison with current treatment. Fertil Steril 1999 Sept;72(3):389-97.

51. Adams MR; Register TC; Golden DL; Wagner JD; Williams JK Medroxyprogesterone acetate antagonizes inhibitory effects of conjugated equine estrogens on coronary artery atherosclerosis Arterioscler Thromb Vasc Biol 1997 Jan;17(1):217-21 (ISSN: 1079-5642

52. Wagner JD; Martino MA; Jayo MJ; Anthony MS; Clarkson TB; Cefalu WT. The effects of hormone replacement therapy on carbohydrate metabolism and cardiovascular risk factors in surgically postmenopausal cynomolgus monkeys. Metabolism 1996 Oct;45(10):1254-62

53. Levine RL; Chen SJ; Durand J; Chen YF; Oparil S. Medroxyprogesterone attenuates estrogen-mediated inhibition of neointima formation after balloon injury of the rat carotid artery. Circulation 1996 Nov 1;94(9):2221-7.

54. Register TC; Adams MR; Golden DL; Clarkson TB. Conjugated equine estrogens alone, but not in combination with medroxyprogesterone acetate, inhibit aortic connective tissue remodeling after plasma lipid lowering in female monkeys. Athrioscler Thromb Vasc Biol 1998 Jul;18(7):1164-71.

55. Pike MC, Ross RK. Progestins and menopause: epidemiological studies of risks of endometrial and breast cancers. Steroids 2000;65:659-64.

56. MacMahon B; Cole P; Brown JB; Aoki K; Lin TM; Morgan RW; Woo N. Oestrogen profiles of Asian and North American women. Lancet 1971 Oct 23;2(7730):900-2.

57. Lemon HM. Genetic predisposition to carcinoma of the breast: multiple human genotypes for estrogen 16 alpha hydroxylase activity in Caucasians. J Surg Oncol 1972;4(3):255-73

58. Lemon Hm. Oestriol and prevention of breast cancer. Lancet 1973;march 10:546-7.

59. Bulbrook RD; Swain MC; Wang DY; Hayward JL; Kumaoka S; Takatani O; Abe O; Utsunomiya J. Breast cancer in Britain and Japan: plasma oestradiol-17beta, oestrone and progesterone,and their urinary metabolites in normal British and Japanese women. Eur J Cancer 1976 Sep;12(9):725-35.

60.Speroff L. The breast as an endocrine target organ. Contemp Obst Gyn 1977 9:69-72. DNH

61. Adams MR et al. Inhibition of coronary artery athrosclerosis by 17-beta estradiol in ovariectomized monkeys: Lack of an effect of added progesterone. Arteriosclerosis 1990;10:1051-7.

62. Spellacy WN. A review of carbohydrate metabolism and the oral contraceptives. Am J Obstet Gynecol 1969 Jun 1;104(3):448-60.

63. Tikkanen MJ; Kuusi T; Nikkila EA; Sipinen S. Post-menopausal hormone replacement therapy: effects of progestogens on serum lipids and lipoproteins. A review. Maturitas 1986 Mar;8(1):7-17.

64. Newham HH. Oestrogens and atherosclerotic vascular disease: lipid factors. Baillieres Clin Endo Metab 1993;7:61-93.

65. Lobo RA. The role of progestins in hormone replacement therapy. Am J Obstet Gynecol 1992 Jun;166(6 Pt 2):1997-2004

66. Bolaji II; Grimes H; Mortimer G; Tallon DF; Fottrell PF; O'Dwyer EM. Low-dose progesterone therapy in oestrogenised postmenopausal women: effects on plasma lipids, lipoproteins and liver function parameters. Eur J Obstet Gynecol Reprod Biol 1993 Jan;48(1):61-8.

67. Moorjani S; Dupont A; Labrie F; De Lignieres B; Cusan L; Dupont P; Mailloux J; Lupien PJ. Changes in plasma lipoprotein and apolipoprotein composition in relation to oral versus percutaneous administration of estrogen alone or in cyclic association with utrogestan in menopausal women. J Clin Endocrinol Metab 1991 Aug;73(2):373-9.

68. Minshall RD; Miyagawa K; Chadwick CC; Novy MJ; Hermsmeyer K. In vitro modulation of primate coronary vascular muscle cell reactivity by ovarian steroid hormones. FASEB J 1998 Oct;12(13):1419-29

69. Minshall RD; Stanczyk FZ; Miyagawa K; Uchida B; Axthelm M; Novy M; Hermsmeyer K. Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab 1998 Feb;83(2):649-59.

70. Fahraeus L; Larsson-Cohn U; Wallentin L. L-norgestrel and progesterone have different influences on plasma lipoproteins. Eur J Clin Invest 1983 Dec;13(6):447-53.

71. Jensen J; Riis BJ; Strom V; Nilas L; Christiansen C. Long-term effects of percutaneous estrogens and oral progesterone on serum lipoproteins in postmenopausal women. Am J Obstet Gynecol 1987 Jan;156(1):66-71.

72. Ottosson UB; Johansson BG; von Schoultz B. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: a comparison between progestogens and natural progesterone. Am J Obstet Gynecol 1985 Mar 15;151(6):746-50.

73. Elkind-Hirsch KE; Sherman LD; Malinak R. Hormone replacement therapy alters insulin sensitivity in young women with premature ovarian failure. J Clin Endocrinol Metab 1993 Feb;76(2):472-5.

74. Bush TL; Barrett-Connor E; Cowan LD; Criqui MH; Wallace RB; Suchindran CM; Tyroler HA; Rifkind BM. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987 Jun;75(6):1102-9.

75. Godsland IF; Gangar K; Walton C; Cust MP; Whitehead MI; Wynn V; Stevenson JC. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral or transdermal hormone replacement therapy. Metabolism 1993 Jul;42(7):846-53.

76. Morey AK; Pedram A; Razandi M; Prins BA; Hu RM; Biesiada E; Levin ER. Estrogen and progesterone inhibit vascular smooth muscle proliferation. Endocrinology 1997 Aug;138(8):3330-9.

77. Lee WS; Harder JA; Yoshizumi M; Lee ME; Haber E. Progesterone inhibits arterial smooth muscle cell proliferation. Nat Med 1997 Sep;3(9):1005-8.

78.Colditz GA; Hankinson SE; Hunter DJ; Willett WC; Manson JE; Stampfer MJ; Hennekens C; Rosner B; Speizer FE. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995 Jun 15;332(24):1589-93.

79. von Schoultz B; Soderqvist G; Cline M; von Schoultz E; Skoog L Hormonal regulation of the normal breast Maturitas 1996 May;23 Suppl:S23-5.

80. Chen Y; Liu X; Pisha E; Constantinou AI; Hua Y; Shen L; van Breemen RB; Elguindi EC; Blond SY; Zhang F; Bolton JL. A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines. Chem Res Toxicol 2000 May;13(5):342-50

81. Desreux J; Kebers F; Noel A; Francart D; Van Cauwenberge H; Heinen V; Thomas JL; Bernard AM; Paris J; Delansorne R; Foidart JM. Progesterone receptor activation. an alternative to SERMs in breast cancer. Eur J Cancer 2000 Sep;36 Suppl 4:S90-1

Treatment of Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Points addressed:

• A review of the literature regarding evidence of significant hypothalamic-pituitary-adrenal axis (HPA) dysfunction in CFS and FM.

• Indications and efficacy of treatment with physiological doses of cortisol

• Expected risks and benefits of such treatment

Abstract:

There is clear evidence that adrenal axis dysfunction is present in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM) 1-21,23-28 and that treatment with low physiologic doses of cortisol have been shown to be safe, appropriate and effective.8,9,10,23,30 It should be considered the standard of care to treat patients with CFS and FM who have baseline cortisol levels under 12 ug/ml.8,9,10,31,32,33

Evidence for significant HPA axis dysfunction with resultant adrenocortical dysfunction:

A study published in the Annals New York Academy of Sciences entitled Evidence for and Pathophysiologic Implications of Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome discussed the evidence for HPA axis insufficiency in CFS and FM. They conclude, “Our group has established the impaired activation of the hypothalamic-pituitary-adrenal axis is an essential neuroendocrine feature of this condition.” 27

Cleare et al published a study in the American Journal of Psychiatry that obtained 24-hour urine collections from 121 consecutive patients with CFS. They found low 24 hour cortisol levels in all of the CFS patients. The authors conclude, “Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness…From whatever cause, low circulating cortisol is associated with fatigue; furthermore, raising cortisol levels can reduce fatigue in chronic fatigue syndrome. Thus, this study provides further evidence that adrenocortical dysfunction in chronic fatigue syndrome, whatever the etiology and whether primary or secondary, may be one piece of the multifactorial jigsaw underlying the production of symptoms in chronic fatigue syndrome.” 7 The authors agree that treating this adrenocortical dysfunction with cortisol replacement is a fundamentally necessary part of the appropriate multi-system treatment of this condition.

Another study published in the Journal of Endocrinological Investigation performed a combination of stimulation tests on FM patients. They found over 95% of these patients had HPA axis dysfunction.3 They state, “The etiology and pathophysiology of this disease is not fully understood but the current data suggests that the PFS [Primary Fibromyalgia Syndrome] is not a primary disease of muscle. In contrast, an increasing amount of evidence suggests that the central stress axis, the HPA axis, seems to play an important role in the development of PFS…This study clearly shows that the HPA axis is underactivated in PFS...” 3

Trophy et al. administered interleukin-6 (IL-6), which is a potent stimulator of the HPA axis, and measured plasma ACTH and cortisol levels. They found a delayed ACTH response in these patients, a state that is consistent with a defect in the hypothalamic CRH neuronal function, as an etiology of symptoms in these patients.2

Cortisol levels normally increase with pain, but it has been shown that patients with CFS and FM either cannot appropriately increase cortisol production with pain or the inability to increase cortisol causes the increased pain. A study published in the November 2005 Journal Arthritis and Rheumatism demonstrated this strong relationship between cortisol levels and pain in individuals with CFS and FM and that low cortisol levels alone explained 38% of the variation in pain upon waking. The authors conclude, “The results of this study indicate that pain symp­toms in women with FM are associated with cortisol concentrations during the early part of the day…These data support the hypothesis that HPA axis function is associated with symptoms in FM and accounts for the substantial percentage of pain symptom variance during the early part of the day.” 28

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study as well as by others is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

Dynamic testing:

Dynamic testing is certainly useful in straight forward primary and secondary adrenal insufficiency, but in patients with CFS, there is a complex interaction of hypothalamic and pituitary dysfunction. This results in a complex response that is initially elevated and then blunted, resulting in what is thought to be conflicting results, depending on which stimulation test was used, how an abnormal is defined and whether or not ACTH/cortisol ratios were used. 1,3,8,9,19,34-39 Consequently, the standard criteria does not apply to these patients significantly reducing the usefulness of dynamic testing with CFS and FM.1,9,19,27,34-39

It has been shown that a single ACTH stimulation test misses the majority of FM/CFS patients that have adrenocortical deficiency, but when a combination of stimulation tests are used, such as metyrapone test, or more sophisticated analysis is used, close to 100% of these individuals have documented adrenocortical dysfunction.1,3,8,9,19,27,34-39

Numerous studies demonstrate that this lack of sensitivity likely explains the seemingly contradictory findings between studies using stimulation tests.1,3,8,9,19,27,34-40 For instance, Scott et al in Clinical Endocrinology did 1ug ACTH stimulation tests on subjects with CFS and found a significant decrease in the delta cortisol value of patients with CFS vs. normals, but found that the reliance on this test and the arbitrary cutoffs that apply significantly impacts the sensitivity of stimulation tests in the patient population. They conclude, “In conclusion, the amount of cortisol released following stimulation with 1ug ACTH, is lower in CFS patients than in healthy volunteers…We propose, as has been suggested from previous studies, that the abnormality of HPA regulation is more likely to be central in origin. The demonstration of low basal ACTH in our CFS cohort [as in this case] would have supported this view…There is considerable debate surrounding the optimal dose of ACTH to use, with concern that the 250 mcg dose is “superphysiologic’ and may produce cortisol responses in patients suspected of having pituitary adrenal insufficiency that are falsely reassuring...Disparities between our healthy volunteer data and those of other groups using the 1 microgram ACTH test suggest that the test may not be as reliable as previously indicated…replacement therapy may more appropriately involve not only glucocorticoid, but mineralcorticoid supplements also.” 19

Another study that clearly demonstrates this confusion and that standard stimulation tests are not a reasonable method of evaluation of adrenal-cortical dysfunction is published in the Journal of Clinical Endocrinology and Metabolism entitled Evidence for Impaired Activation of the Hypothalamic Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome. The study found that compared to normal individuals, CFS patients were shown to have significantly reduced basal glucocorticoid levels (average 89 vs 148 nmol/l) and a low 24 hour urinary free cortisol excretion (122.7 nmol/L vs 203 nmol/L). The level of cortisol binding globulin CBG was also significantly higher in CFS patients making the free cortisol index lower in the patients (2.9 vs 8.9). There was a significant attenuated net integrated ACTH response to CRH but there was an initial increased initial sensitivity to ACTH with a reduced maximal response.1

Although this cortisol response to ACTH is clearly abnormal for all of the patients with CFS, the dose response curve varies. There is an initial exaggerated response followed by an abnormally blunted response, which is not the case for patients with primary or secondary adrenocortical insufficiency without a dysfunctional hypothalamus. Consequently, standard dynamic testing is not medically useful in these patients and it is improper to use the defined normal cutoffs of response as is done with other conditions. This has been demonstrated in other studies as well.1,3,8,9,19,27,34-39

Kirnap et al in a study published in Clinical Endocrinology compared standard and low dose ACTH stimulation tests on patients with primary fibromyalgia syndrome (PFS). They found a significantly reduced peak cortisol response in the PFS verses controls. They also found that if the standard cutoff of 550 nmol/l was used with the standard ACTH stimulation, many of the patients would have misdiagnoses as normal.4

There are a number of theories that have been postulated to explain such a response. The author of this study postulates that this is due to a lack of CRH (corticotrophin releasing hormone) with a secondary hyperresponsivness from inadequate levels of ACTH. They alternatively state that this HPA axis defect could be secondary to a chronic viral infection.

Treatment:

Further supporting the use of low dose cortisol in these patients is the fact that such treatment has been shown to improve the HPA axis response in these patients. This is counterintuitive to what physicians are taught and have found with higher pharmacological doses of glucocorticoids. In a study published in the 2001 Journal of Clinical Endocrinology & Metabolism entitled Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy, the authors utilized ACTH and cortisol responses to CRH, insulin stress test, D-fenfluramine and 24 hour urinary free cortisol in 37 patients with CFS and treated these patients with low dose cortisol. They found that the treatment resulted in significant improvement and not only was there no adrenal suppression, but rather there was an improvement in the HPA axis as documented with CRH testing. They concluded, “In this group, there was a significant increase in the cortisol re­sponse to human CRH, which reversed the previously ob­served blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone (same as cortisol) treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.” 8

In a randomized, double-blind, placebo controlled, crossover, intent to treat trial published in The Lancet, patients with chronic fatigue syndrome were treated with low dose hydrocortisone (5-10 mg/day) or placebo. The study found significant improvements in those treated with low dose hydrocortisone vs. placebo and 28% improved to normal levels. The authors concluded, “This study shows that low-dose hydrocortisone results in significant reduction in self-rated fatigue and disability in patients with chronic fatigue syndrome…The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone.” 9 This demonstrates the effectiveness and appropriateness of this treatment.

Another randomized control trial published in JAMA also found significant improvement in fatigue scores with hydrocortisone replacement, but they used excessive dosing of 25-35 mg of cortisol. It is recommended that dosing be limited to 10-20 mg/day, as these doses have been shown to not be associated with any untoward effects and carries little to no risk of adrenal suppression.10,23,30,31 This considerable safety and negligible risk is also confirmed in endocrinology texts.54

Bashetti has published a number of studies on cortisol and CFS. He writes in the Journal of Endocrinology and Metabolism, “Hydrocortisone, the glucocorticoid that is routinely prescribed to correct the chronic cortisol deficiency of patients with Addison’s disease, has recently been confirmed to be significantly effective also in the treatment of chronic fatigue syndrome (CFS). This comes as no surprise if we consider that CFS and Addison’s disease share 26 features.” 41

A randomized, double blind placebo-controlled, intent to treat study by Teitelbaum published in the Journal of Chronic Fatigue Syndrome documented the effectiveness of an integrative treatment approach to CFS and FM that includes low dose cortisol (7.5-20 mg/day). The authors conclude,” Significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS.” 31

A subsequent editorial in the peer reviewed, Journal of the American Academy of Pain Management reviewed this study and agreed that an integrative approach that includes low dose cortisol is the standard of care for these conditions. The author states, “The study by Dr. Teitelbaum et al. and years of clinical experience makes this approach an excellent and powerfully effective part of the standard of practice for treatment of people who suffer from FMS and MPS [myofacial pain syndrome]— both of which are common and devastating syndrome.” 48 The consensus opinion among those who are experts in the treatment of CSF and FM is that a treatment approach that includes low-dose cortisol is the standard of care.

A subsequent commentary by Teitelbaum published in JAMA states, “Our previously published pilot study and the work of Jefferies suggests that using low-dose hydrocortisone in CFS as dosages of 7.5 mg to 20 mg/day is safe and effective. These low dosages have not caused adrenal suppression…We recently completed a randomized, double-blind study that tested the effectiveness of treating patients with fibromyalgia and CFS for hypothalamic dysfunction in an integrated manner. This included treating suspected hormonal deficiencies (including low hydrocortisone) and the sleep disorder simultaneously. Using this protocol in 72 patients resulted in a significant improvement in active vs. placebo group.” 42 Cortisol replacement appears to be an essential part of a comprehensive treatment approach that can be used successfully in the treatment of CFS and FM.31,42

A study published in JAMA found that nearly half of the patients treated with mineralcorticoid reported complete or nearly complete resolution of CFS symptoms.43

The safety of low dose glucocorticoids was addressed in a 48 page review article published in last month’s Annals of Rheumatic Diseases entitled Low-dose glucocorticoid therapy in rheumatoid arthritis- A review on safety: published evidence and prospective trial data. This extensive review assessed the incidence and severity of adverse effects of long-term low-dose glucocorticoid therapy in rheumatoid arthritis. This review considered low dose as any dose below or equivalent to 40 mg hydrocortisone (this patient received a fraction of this dose 10mg/day). They concluded, “Adverse-effects of glucocorticoids are abundantly referred to in literature. However, in the available literature on low-dose glucocorticoid therapy very little of the commonly held beliefs about their incidence, prevalence and impact of GC [glucocorticoid] proved to be supported by clear scientific evidence. Additional data from the randomized controlled clinical trials reviewed showed that the incidence, severity and impact of adverse effects of low dose glucocorticoid therapy in rheumatoid arthritis trials are modest, and often not statistically different to those of placebo.” 10

Low dose cortisol has been shown to improve immunity, as opposed to the well known immunosuppressive effect of pharmacological doses of glucocorticoids, 23,30,45,46 and has been shown to improve recovery from chronic infections such as EBV.47,22,29

In summary, it is becoming clear that the majority of patients with CFS and FM suffer from clinically significant adrenocortical dysfunction and that physiologic replacement of cortisol is an appropriate intervention in these patients. Cortisol doses of 15-20 mg/day have been shown to be safe, with little associated risk including adrenal suppression, and have the potential for significant clinical benefit. The current evidence supports the use of physiologic doses of cortisol in the treatment of CFS and FM, and a therapeutic trial of cortisol should be considered in these patients, especially those with basal cortisol levels less than 12 ug/dl.

References

1. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP, et al. Evidence For Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients With Chronic Fatigue Syndrome. J Clin Endocrinol Metab 1991;73:1224-1234.

2. Torpy DJ et al. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6 in fibromyalgia. Arthritis and Rheumatism. 2000; 43: 872-880.

3. Calis M, Gokce C. Investigation of the hypothalamo-pituitary-adreanl axis (HPA) by 1ug ACTH test and metyrapone test in patients with primary fibromyalgia syndrome. J Endocrinol Invest 2004 27:42-46

4. Kirnap M, Colak REser C, Ozsoy OTutus A, Kelestimur F. A comparison between low-dose (1 microg), standard-dose (250 microg) ACTH stimulation tests and insulin tolerance test in the evaluation of hypothalamo-pituitary-adrenal axis in primary fibromyalgia syndrome. Clin Endocrinol (Oxf). 2001 Oct;55(4):455-9

5. Griep EN, Boersma JW, de Kloet ER. Altered Reactivity of the Hypothalamic-Pituitary-Adrenal Axis in the Primary Fibromyalgia Syndrome. J Rheumatol 1993;20:469-74

6. Jens Gaab, PhD, Dominik Hüster, MSc, Renate Peisen, MSc, Veronika Engert, BSc, Vera Sheitz, BSc, Tanja Schad, BSc, Thomas H. Schürmeyer, PhD, MD and Ulrike Ehlert, PhD. Hypothalamic-Pituitary-Adrenal Axis Reactivity in Chronic Fatigue Syndrome and Shealth Under Psychological, Physiological, and Pharmacological Stimulation. Psychosomatic Medicine 64:951-962 (2002)

7. Cleare AJ, Blair D, Chambers S, Wessely S, Urinary Free Cortisol in Chronic Fatigue Syndrome Am J Psychiatry 158:641-643, April 2001

8. Cleare A et al. Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy. The Journal of Clinical Endocrinology & Metabolism 2001. 86(8):3545–3554.

9. Cleare AJ et al. Low-dose hydrocortisone in chronic fatigue syndrome: a randomized crossover trial. Lancet 1999 Feb 6;353(9151):455

10. Gaab J, Huster D, Peisen R, Engert V, Schad T, Schurmeyer TH, Ehlert U. Low-dose dexamethasone suppression test in chronic fatigue syndrome and health. Psychosom Med. 2002 Mar-Apr;64(2):311-8

11. Altemus M, Dale JK, Michelson D, Demitrack MA, Gold PW, Straus SE. Abnormalities in response to vasopressin infusion in chronic fatigue syndrome. Psychoneuroendocrinology 2001 Feb 1;26(2):175-188

12. Scott LV, Svec F, Dinan T. A preliminary study of dehydroepiandrosterone response to low-dose ACTH in chronic fatigue syndrome and in healthy subjects. Psychiatry Res 2000 Dec 4;97(1):21-28

13. Scott LV, Teh J, Reznek R, Martin A, Sohaib A, Dinan TG. Small adrenal glands in chronic fatigue syndrome: a preliminary computer tomography study. Psychoneuroendocrinology 1999 Oct;24(7):759-68

14. Heim C, Ehlert U, Hellhammer DH. The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology. 2000 Jan;25(1)

15. Scott LV, Medbak S, Dinan TG. Desmopressin augments pituitary-adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry 1999 Jun 1;45(11):1447-54

16. De Becker P, De Meirleir K, Joos E, Campine I, Van Steenberge E, Smitz J, Velkeniers B Dehydroepiandrosterone (DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome. Horm Metab Res 1999 Jan;31(1):18-21

17. Z Crofford L. The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome. J Rheumatol 1998;57 Suppl 2:67-71

18. Kuratsune H, Yamaguti K, Sawada M, Kodate S, Machii T, Kanakura Y, Kitani T. Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome. Int J Mol Med 1998 Jan;1(1):143-6

19. Scott LV, Medbak S, Dinan TG The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol (Oxf) 1998 Jun;48(6):733-7

20. Scott LV, Medbak S, Dinan TG. Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatr Scand 1998 Jun;97(6):450-457

21. Strickland P, Morriss R, Wearden A, Deakin B A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls. J Affect Disord 1998 Jan;47(1-3):191-194

22. Bender CE. The value of corticosteroids in the treatment of infectious mononucleosis. JAMA 199;529, 1967

23. Jefferies W. Mild adrenocortical deficiency, chronic allergies, autoimmune disorders and the chronic fatigue syndrome: a continuation of the cortisone story, Med Hypotheses, 1994, Issue: 3, Volume: 42, Page: 183-9, ISSN: 0306-9877

24. Cleare AJ; Bearn J; Allain T; McGregor A; Wessely S; Murray RM; O'Keane V. Contrasting neuroendocrine responses in depression and chronic fatigue syndrome, J Affect Disord, 1995 Aug 18, Issue: 4 Volume: 34 Page: 283-9

25. Moutschen M; Triffaux JM; Demonty J; Legros JJ; Lefèbvre PJ; . Pathogenic tracks in fatigue syndromes Acta Clin Belg, 1994, Issue: 6 Volume: 49 Pagination: 274-89 ISSN: 0001-5512

26. Carruthers et al. Myalgic Encepalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome.Vol 11(1) 2003

27. Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci 1998 May 1;840:684-697

28. Samuel A. McLean,1 David A. Williams,1 Richard E. Harris,1 Willem J. Kop,2 Kimberly H. Groner,1 Kirsten Ambrose,1 Angela K. Lyden,1 Richard H. Gracely,1Leslie J. Crofford,3 Michael E. Geisser,1 Ananda Sen,1 Pinaki Biswas,1 and Daniel J. Clauw1. Momentary Relationship Between Cortisol Secretion and Symptoms in Patients With Fibromyalgia. Arthritis & Rheumatisim Vol. 52, No. 11, November 2005, pp 3660–3669

29. Manji RJ et al. Depression of cell-mediated immunity durng acute infectious mononucleosis. N Engl J Med 291:1149, 1974

30. Jefferies W. Cortisol and Immunity. Medical Hypotheses 1991;34:198-208

31. Teitelbaum J, Bird B, Greenfield R, Weiss A, Muenz L, Gould L. Effective Treatment of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study. Journal of Chronic Fatigue Syndrome Volume 8, Issue 2 – 2001

32. Takeshita S et al. Intravenous immunoglobulin preparations promote apoptosis in lipopolysaccharide-stimulated neutrophils via an oxygen-dependent pathway in vitro. APMIS 2005:113:269-77.

33. Wolff FH, Nhuch C, Cadore LP, Glitx CL, Lhullier F, Furlanetto TW. Low-dose adrenocorticotropin test in patients with the Acquired Immunodeficiency Syndrome. Braz. J. Infect. Dis. Apr. 2001, vol.5, no.2

34. Tordjman K., Jaffe A., Grazas N. et al. The role of the low dose (1 mg) adrenocorticotropin test in the evaluation of patients with pituitary diseases. J Clin Endocrinol Metab 1995; 80:1301 5.

35. Dickstein G., Schechner C., Nicholson W.E., et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of the day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773-8

36. Crowley S., Hindmarsh P.C., Honour J.W., Brook C.G.D. Reproducibility of the cortisol response to stimulation with a low dose of ACTH (1-24): the effect of basal cortisol levels and comparison of low dose with high dose secretory dynamics. J Endocrinol 1993;136:167-72

37. Baraia-Etxaburu Artetxe J., Astigarraga Aguirre B., Elorza Olabegova R., et al. [Primary adrenal failure and AIDS: report of 11 cases and review of the literature]. Rev Clin Esp 1998;198:74-9.

38. Zarkovic M., Ciric J., Stojanovic M., et al. Optimizing the diagnostic criteria for standard (250-mg) and low dose (1-mg) adrenocorticotropin tests in the assessment of adrenal function. J Clin Endocrinol Metab 1999;84:3170-3.

39. Abdu TA, Elhadd T.A., Neary R., Clayton R.N. Comparison of the low dose short synacthen test (1 mg), the conventional dose short synacthen test (250 mg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 1999;84:838-43.

40. Courtney CH et al. Authors’ Response: HPOA Axis Testing after Pituitary Surgery. Journal of clinical Endocrinology and Metabolism 2005;90:6744

41. Riccardo Baschetti, M.D. Investigations of Hydrocortisone and Fludrocortisone in the Treatment of Chronic Fatigue Syndrome The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2263-2264

42. Teitelbaum et al. To the Editor re: McKenzie et al. Low-Dose Hydrocortisone for Chronic Fatigue Syndrome. 281 No. 20, May 26, JAMA,1999 Vol. 281 No. 20, May 26, 1999. JAMA May 26, 1999 (281)20:1888

43. Bou-Holaigah et al. the relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995;274:961-7

44. Bashetti R. hydrocortisone and chronic Fatigue Syndrome. Lancet 1999;353:1618

45. Grayson J et al. Immunoglobulin production induced in vitro by glucocorticoid hormones:T-cell dependent stimulation of immunoglobulin production without B cell proliferation in cultures of human peripheral blood lympocytes. J clin Invest 68:1539,1981

46. Jeroen TJ et al. Altered Glucocorticoid Regulation of the Immune Response in the Chronic Fatigue Syndrome. Annals of the New York Academy of Sciences 917:868-875 (2000)

47. Chappel MR. Infectious mononucleosis. Southwest Med 43:253,1962

48. Blatman H, Effective Treatment of Fibromyalgia and Mypfacial Pain Syndrome: A Clinician’s Perspective. Journal of the American Academy of Pain Management. April 2002.

Pregnancy and CFS/FMS – Q & A

Women often worry about getting pregnant with CFS/FMS. I have done this chapter in a question and answer format to answer some of the most common concerns. This is followed by general advice for a healthy pregnancy and how to deal with infertility if you are having trouble conceiving.

Thank you very much for agreeing to answer these questions for my Fibromyalgia Aware Magazine article on Pregnancy and Fibromyalgia. Parents (old, new or expectant) as well as parent hopefuls, have fears and concerns regarding the impact of FM/CFIDS on their pregnancy. I did receive today the ten tips – thank you for that.

If possible, could you please return your answers in one week? Your answers can go right under each question. You can return by attachment to me at: ShanerMD@aol.com . If you have any questions, feel free to email me.

On behalf of people with fibromyalgia, I thank you most sincerely – Catharine Shaner, MD.

Pregnancy in FMS Q & A

What is your specialty? How long have you been practicing? Do you care for many patients with fibromyalgia?

A- I am a board-certified in internal medicine and have been practicing for 25 years. For the last 15 years or so my specialty has been CFS, fibromyalgia, and pain management. I have treated over 2000 CFS/fibromyalgia patients.

Please spell your name, including degree:

A- Jacob E. Teitelbaum M.D.

Where is your practice located? Are you associated with any organization (i.e., spokesperson for _________, practices at _______ hospital)?

A- Annapolis, MD. I am a medical director of the Annapolis Research Center for Effective CFS/Fibromyalgia Therapies. I am a medical adviser for numerous groups. I have a policy of not accepting money from any group or any company whose products I recommend. I am an emeritus member of the Anne Arundel Medical Center

A. PRE-CONCEPTION:

Q) Do you agree with the following advice for women with FM or CFIDS prior to conceiving (& do you give any other advice)?

* Get in the best shape possible physically

* Wait to conceive until you are not in a flare

* Reduce stress

A) In terms of exercise, it is important to realize that people should not push to the point of crashing. Instead, they should slowly increase walking as is tolerated without causing next day flares. It is a good idea for fibromyalgia patients to reduce stress in general.

Most importantly, I think that the fibromyalgia should be treated with an integrated metabolic regimen for about a year before pregnancy, so that people have largely recovered before they get pregnant. Our randomized double-blind placebo controlled study showed that treatment can be very helpful (P. < .0001 versus placebo).

Q) Would you agree that fertility problems with FM are no different than the general population?

A) Although infertility is not a significant problem, I do find it to be more frequent in fibromyalgia than in the general population. On the other hand, when the nutritional deficiencies (especially iron) and subclinical hypothyroidism are treated, the infertility problems often resolve (as is also seen in the Non- fibromyalgia general population)

Q) Do you see problems with irregular cycles, hormone imbalances, ovarian cysts, vaginosis, endometriosis, or other GYN problems in women with FM/CFIDS?

A) Yes, especially hormonal imbalances, irregular periods, and endometriosis. There is also an increased frequency of polycystic ovary syndrome associated with elevated DHEA -- S and testosterone as well as glucose intolerance. This can result in infertility, which responds well to treatment. In addition, elevated prolactin is common in associated with the hypothalamic dysfunction (and rarely pituitary adenoma). This can also result in infertility, and also responds excellently to therapy.

Q) Should women stop all meds? (please list any acceptable ones to take, if known) particularly:

* NSAIDS, acetominophen
* Muscle relaxants
* Anti-depressants
* Guiafenesen
* Neurontin
* Medications for migraines
* Medications for irritable bowel

A) I leave my pregnant patients on the Energy Revitalization System powder as this was also made to be an excellent support for pregnancy. They also need to be on a stabilized, mercury free fish oil (I recommend the Eskimo 3 Brand), calcium 1500 milligrams, and iron if needed (i.e. -- if the ferritin is less than 40). They can also stay on thyroid hormone, and if needed, Ultra low-dose Cortef -- both of which supports pregnancy. If critical, they can stay on Prozac, which has not been associated with increased birth defects. Besides for these, I stop almost all medications and herbals. I would note that in general, acetaminophen (Tylenol) is a poor choice for fibromyalgia patients as it depletes glutathione -- a critical antioxidant that is likely already deficient in CFS/fibromyalgia.

B. PREGNANCY & DELIVERY:

Q) Do you agree with the following concerning treatment of FM flares (pain, fatigue, stiffness) while pregnant (& do you give any other advice)?

* PT
* Stretching
* Massage therapy

A) Pregnant women need to be careful to avoid hot tubs and hot baths (and likely hot packs in the area of the fetus) as the increased body temperature is associated with an increased risk of birth defects. Taking calcium and magnesium at night can help sleep. In addition, a taking 5 – HTP 200-300 mg/night can help both sleep and pain, although it takes six weeks to work. As long as the PT is done gently it can be helpful, as can stretching and massage therapy. Most importantly, by giving appropriate treatment before pregnancy, flares can usually be avoided during pregnancy.

Q) What can a woman do if she experiences a flare of: depression, migraine or irritable bowel while pregnant?

A) Migraine attacks can often be knocked out by giving magnesium 2 g IV over a ten minute period. In addition, avoiding chocolate and sugar, which are common triggers for migraines, is helpful. Taking magnesium orally (and this is already present in the vitamin powder) decreases migraine attacks as well. Taking the fish oil and the nutrients in the vitamin powder and B-complex (plus 5- HTP) decreases the tendency to depression considerably. Our study and clinical experience show that most people will find that their irritable bowel syndrome resolves when the underlying opportunistic bowel infections have been treated (e.g. -- Clostridium, SIBO, fungal infections, and parasites). These do however need to be treated before the patient becomes pregnant. If the patient is constipated, taking magnesium is very helpful. Adjusting the thyroid dose for those who are hypothyroid is also critical, and constipation can be a marker for this. The iron and calcium dose can be adjusted to help with diarrhea.

Q) Anecdotaly, women with FM report improvement of symptoms with pregnancy. The few studies and surveys generally report the opposite. What is your experience? Are there particular trimesters when an improvement or exacerbation is likely to occur? What would be the reason for improvement (immune system turned off, particular hormones, or other reason?)

A) In my experience with treating thousands of patients, once the patient has gotten past the morning sickness, they usually feel much better during pregnancy. Morning sickness can often be avoided by taking adequate vitamin C (500 milligrams a day) and vitamin B6 (100 -- 200 milligrams a day). The improvement that occurs during pregnancy can occur for many reasons (increased CRH, blood volume, estradiol levels which improve immune function, relaxin levels, etc.). Overall, people do great during pregnancy (if given proper nutritional and thyroid hormone support) but may crash after. Even the crash after pregnancy can often be avoided with proper therapy.

Q) Are there any particular complications of pregnancy or delivery related to FM or CFIDS (ectopic pregnancies, miscarriages, symphysis pubis disruption, breech presentation, for example)? Do women with FM lack muscle strength or tone for pushing? Do you advocate warm water birthing to ease the muscle pain of FM?

A) As long as the woman is on adequate magnesium to decrease to risk of eclampsia, they tend to do just fine with their delivery. Warm water birthing would be reasonable for anybody.

Q) Does an epidural help to conserve energy during birth and speed recovery afterwards?

A) I think that an epidural is quite reasonable, but leave this to the preference of the mother as in any other delivery.

Q) Does FM affect length of stay in the hospital for mom or baby?

A) Not in my experience.

C. NEWBORN:

Q) If FM or CFIDS inheritable? Do you find many parents worried about that?

A) Although approximately half of my patients have a family member with CFS/fibromyalgia, the risk of any one individual child getting it is low because we have so many family members. This reassurance is very helpful for the parents. In addition, regardless of the popular misconception, fairly effective treatment has shown to be available for fibromyalgia -- as demonstrated in my placebo-controlled study. (I would note that the journal of the American academy of pain management -- one of the largest multidisciplinary societies of pain specialists in the U.S. -- had an editorial noting that our treatment protocol is "an excellent and highly effective part of the standard of practice for treating fibromyalgia and myofascial pain syndrome.)

Q) Should moms with FM breastfeed? Are there the same restrictions on meds? Is it too tiring to breastfeed?

A) I generally apply the same principles to breast-feeding as being pregnant. If possible, I have the Mother breast-feed for at least six months and avoid the same medications that were avoided during pregnancy. I do not think it is too tiring to breast-feed and breast-feeding also helps with weight loss -- which is emotionally important to the patient as well (while also decreasing the risk of sleep apnea). It is, of course, also very healthy for the baby. It is critical however that the Mother stay on her nutritional regimen while breast-feeding.

Q) Is the severity or incidence of postpartum depression worse in moms with FM?

A) If adequate support is given with fish oils and progesterone, postpartum depression seems to be less common.

WRAP-UP:

Q) Do you have any other advice for women concerning pregnancy and fibromyalgia?

A) Be sure that thyroid hormone levels are adjusted to the level that feels optimal while keeping the free T4 within the normal range. Otherwise, the information in the top 10 tips for pregnancy below applies.

10 Tips for a Healthy Pregnancy

By Dr. Jacob Teitelbaum

As mothers tend to sacrifice during their lives to meet their children’s needs, a mother’s body will give up its own essential nutrients to provide health and growth for her developing baby. Unfortunately, the Standard American Diet (S.A.D.) is often so nutritionally deficient that even this sacrifice does not guarantee adequate nutrition for the unborn baby.

Fortunately, there are a number of tips that if followed during pregnancy, can help both baby and mother stay healthy and vital!

Here is my top 10 list for ensuring a healthy pregnancy. It includes recommendations on nutrition, vitamins, minerals and other common sense tips that can lead to a happier, healthier and more vital pregnancy. Powdered vitamin formulas are available that can markedly decrease the number of supplement tablets needed (e.g.-Energy Revitalization System by Enzymatic Therapy is excellent for both fibromyalgia and pregnancy):

1. Zinc

Inadequate zinc is the most common and problematic deficiency during pregnancy. Zinc is critical for two reasons: proper growth and for developing a healthy immune system for the baby. Studies suggest that inadequate zinc may even cause immune deficiency in the next generation (i.e. your grandchild) as well. Be sure to get at least 15 milligrams per day of zinc in your diet, which can be found in high protein foods such as meat and beans.

2. Folic Acid

Getting enough folic acid is critical both before and during pregnancy to help assure proper growth and to prevent birth defects. It is present in deep green, leafy vegetables. Women should get at least 400 to 800 micrograms per day.

3. Magnesium

Magnesium deficiency is routine in the American diet and can increase the possibility of high blood pressure and seizures during pregnancy, a condition known as eclampsia. To prevent this deficiency, take 200 milligrams of magnesium in the glycinate form daily. Whole grains, green leafy and other vegetables and nuts are good sources of magnesium. Taking the proper amount of magnesium a day also helps to decrease the leg cramps and constipation often experienced during pregnancy. In addition, magnesium is critical for more than 300 other body functions and will generally help you to feel a lot healthier.

4. B Vitamins

These are critical for energy, mental clarity and to prevent depression. B vitamins have also been found to improve pregnancy-related complications such as gestational diabetes. Taking 200 milligrams a day of vitamin B6 can improve the health of those women suffering from this form of diabetes. But please note that only women who develop gestational diabetes during pregnancy should take this high level of B vitamins, and should drop the level of consumption to 100 milligrams per day during the last month. For all other soon-to-be moms, take approximately 25 to 50 milligrams a day of B vitamins and plenty of vitamin B12 for normal nerve function.

5. Fish Oils

The human brain is made predominantly of DHA, an essential fatty acid found in fish oils. Perhaps this is why there is an old wives' tale about fish being brain food. Regardless, DHA deficiency is very common and it is critical that pregnant women get adequate fish oils so that their baby can develop healthy and optimal brain tissue. DHA may also decrease the risk of postpartum depression. Unfortunately, though, the FDA has raised concerns about high mercury levels in the same deep sea fish (salmon and tuna) that have the highest levels of these oils. An excellent alternative for those who'd rather not risk it is to take one half to one tablespoon of Eskimo 3 fish oil. This is a special form of fish oil that actually tastes good (most do not), and has been tested to make sure that it does not have mercury or other problematic compounds.

6. Calcium

Ideally, pregnant women should ingest 1,500 milligrams of calcium per day plus 400-600 units of Vitamin D. It is best to take Calcium at night (it helps with sleep) in the liquid, powdered or chewable form. Many calcium tablets are simply chalk and do not dissolve in the stomach, and therefore are not absorbed properly. Each cup of milk or yogurt contains 400 milligrams of calcium.

7. Iron

Approximately 18 to 36 milligrams of iron per day can be helpful. Interestingly, iron deficiency can sometimes cause infertility. And pregnant women who don't get enough iron are at risk for anemia, fatigue, poor memory and decreased immune function.

8. Water

Be sure to drink plenty of water. When pregnant, blood volume can increase about 30 percent and it is easy to become dehydrated. If your mouth or lips are dry, drink more! Adequate salt is also helpful in preventing dehydration (less so if you have problems with fluid retention).

9. CHECK YOUR THYROID!

Millions of women have undiagnosed hypothyroidism, which accounts for over 6% of miscarriages, and is associated with learning disabilities when the child is born. Treating a low thyroid is both safe and easy during pregnancy. The earlier it is treated the better. As soon as you know you’re pregnant (or trying to get pregnant), check a TSH blood test to check your thyroid. Most doctors do not yet know that the TSH HAS TO BE LESS THAN 3 OR YOU NEED TREATMENT, SO SEE THE RESULT FOR YOURSELF (Many still use the dangerous and outdated criteria of a TSH over 5 being abnormal). If you like, you can get a lab requisition for a TSH to take to your lab at http://www.vitality101.com/ (click on “online program” then on ”Laboratory Requisition Form”). If you were on thyroid before getting pregnant, it is normal to need to increase the dose during pregnancy (the TSH should be kept between .5 and 2.0). If your doctor is not familiar with the new guidelines, let them know they can e-mail me at the web site above and we’ll send a copy to them.

10. Things to Avoid

A few cautions for pregnant women: avoid taking more than 8,000 units of vitamin A per day. And don't partake in anything that can raise your body temperature too high (hot tubs, saunas or steam rooms). These have been implicated as possibly increasing the risk for birth defects. Most pregnant women are also, of course, aware that smoking, drugs and alcohol should all be avoided during pregnancy. Exercise, on the other hand, has been shown to be very beneficial and results in babies and moms that are quite healthy.

Best wishes on a healthy baby and mom!

Effective Natural Treatment for Infertility

By Jacob E. Teitelbaum, M.D.

Infertility is becoming an increasingly frequent problem. Many people go to fertility experts and, by discovering an anatomic problem (e.g. blocked fallopian tubes), or problems with ovulation, are able to get help. Unfortunately, many people find their tests are negative or, despite treatment, find they are unable to get pregnant.

Comprehensive Medicine, which includes both prescription/surgical and natural therapies, can often help when regular day-to-day medical approaches cannot. Infertility is one such case. It is important to recognize that 40% to 50% of problems with infertility are secondary to the man having a low sperm count or underactive sperm activity. Because of this, I recommend the man and woman both do the things noted below to increase their fertility. Before one begins with these things, it is important to look at the optimum timing for intercourse.

When Is The Best Time To Get Started?

Research shows that intercourse which occurs even one day after ovulation is unlikely to result in pregnancy. Intercourse the day of ovulation is most effective and often effective during the three to four day period before ovulation. Intercourse more than six days before ovulation is also unlikely to result in pregnancy. One can use an ovulation thermometer to time their ovulation. Also, the more frequently one has intercourse in the three or four days before ovulation, the more likely one is to get pregnant. New research has overturned the old misconception that frequent intercourse within this three to four day period decreases the chance of pregnancy.

What Can The Woman Do?

There are many day to day things which worsen and improve fertility. Having more than four cups of coffee a day (and possibly any coffee) can result in infertility. Some researchers joke that coffee actually acts as a reasonable form of birth control (I would not rely on it though!). Alcohol also increases infertility caused by ovulatory problems. This results because of increases in a hormone called prolactin. In people who have ovulatory infertility, alcohol can increase the problem by 30% if you have even one drink a day and by 60% if you have more thantwo drinks a day. Alcohol can also aggravate infertility caused by endometriosis. Of much greater concern, however, is the problem of birth defects caused by drinking alcohol during the pregnancy. This is called fetal alcohol syndrome and it is important that alcohol be avoided during the pregnancy. I would also note that taking very hot baths during pregnancy, including hot tubbing, can increase birth defects quite a bit as can taking more than 8,000 IU of vitamin A daily (beta carotene is okay). In addition, it is important that any woman of childbearing age take at least 800 mcg (0.8 mg) of folic acid a day to prevent birth defects. If the woman has had a child with neural tube birth defects in the past, I would increase this up to 4,000 mcg a day. For most women, taking a good multivitamin (we recommend From Fatigued To Fantastic Energy Revitalization System - available on our web site and many health food stores) is very helpful.

Other things which can cause infertility include taking more than 1,000 mg of vitamin C a day. If a woman is doing this and trying to get pregnant, she should decrease it to 500 mg a day. Infertility caused by a higher dose should resolve within a few weeks. Drinking caffeinated sodas (even one a day) can decrease conception by 50%. It is also important to avoid toxic metals (lead, mercury, cadmium), and I would not take melatonin (or much of anything else besides a good multivitamin as noted above and magnesium) when pregnant. High doses of melatonin can raise prolactin levels and may result in temporary infertility. A recent study has also found douching temporarily decreases the probability of getting pregnant by 30%. If your doctor has not checked your prolactin level, be sure this is not elevated.

Now that we have looked at some of the avoidable things which can keep you from getting pregnant, lets take a look at things you can do to help you get pregnant. These include:

1. Taking a good multivitamin with folate as noted above. This can increase fertility.

2. Taking extra vitamin B6 (approximately 50 mg a day-also present in the Energy Revitalization System by Enzymatic Therapy) can also help you to get pregnant. This is especially true if one has irregular periods or absent periods or inappropriate production of breast milk outside of one's period.

3. Be sure your iron levels are adequate. A blood test (a ferritin level combined with an iron level and iron binding capacity) will tell you this. Unfortunately, doctors are trained to say the iron is normal if your ferritin level is at least 9 ng/ml. Although a ferritin level of 9 shows you have enough iron to prevent anemia, one can have infertility from ferritin levels less than 40. Because of this, I would look at your ferritin test results yourself and make sure the level is at least 40 ng per ml. In a study of women with hair loss with ferritin levels less than 40, seven women who also had infertility became pregnant within 7 months when put on iron. If for some reason you are unable to get your ferritin level checked, it is not unreasonable to take iron (e.g. Chromagen FA 1 tablet a day) for 7 months. Take it on an empty stomach and with at least 200 mg of Vitamin C. Do not take it with in 6 hours of thyroid hormone therapy, or you will not absorb the thyroid. I also would take iron if the percent saturation of iron (calculated from the iron & percent saturation tests noted above) is under 22%.

4. If one's thyroid is low, and this is frequently the case even with normal blood tests, a very low dose of thyroid hormone will often result in people getting pregnant. If you have a tendency to constipation, cold intolerance, dry skin and thin hair, and/or temperatures which run under 98.2 during the day, there is a good chance your thyroid may be slightly underactive despite normal blood tests. In the absence of underlying heart disease, a trial of a low dose of thyroid hormone (e.g. Armour Thyroid 1/2 grain a day) may help you get pregnant and has a low risk of causing problems. You might have to fight with your doctor a bit to get them to try this for you, but it is worth it. If you have the symptoms I mentioned, remind your doctor that the best endocrinologists stress that it is important to treat the patient and not the blood test. Something he or she might want to remember is that each time we come up with a new thyroid blood test we find a large number of people with an underactive thyroid that the old test missed. There is a very high probability that our current tests are still missing many people with this disease. Do not take iron within six hours of thyroid supplements or the iron will prevent absorption of the thyroid hormone.

5. Research by William Jeffries, M.D., an emeritus professor of endocrinology at Case Western Reserve University, has shown that some women's difficulty getting pregnant can be overcome by taking a low dose of cortisol (Cortef). Although cortisol in high doses for prolonged periods can be very toxic, taking Cortef 5 mg twice a day for 2 to 3 months is unlikely to cause major problems in the absence of high blood pressure or a family history of diabetes. His experience is this can often result in people with infertility getting pregnant as well (although he uses 5 mg 4 times a day). This is especially true with polycystic ovaries (Stein-Leventhal syndrome).

6. Avoid a high protein diet. An animal study conducted at the Colorado Center for Reproductive Medicine has linked high protein diets to impaired pregnancy and less viable offspring. The researchers fed half of their study mice a diet of 25 percent protein (typical daily Atkins' protein consumption) and the other half 14 percent protein (normal protein consumption) for four weeks before mating them. Only one third of the mouse mothers on the high-protein diet were able to become pregnant, compared to 70% in the normal diet group. The researchers then transferred 174 mice embryos from both groups of mice to surrogate mice fed a normal diet. Only 36 percent of the high protein moms' embryos developed into fetuses, compared to 70 percent in the control group. The study results were presented European Society of Human Reproduction and Embryology.

What About The Guys?

Research suggests that sperm counts are dropping throughout the industrialized world. There is a good possibility this is coming from chemicals, especially pesticides, which mimic estrogen effects in the body. In many countries this is becoming an area of major concern. Avoiding chemicals or other toxins is helpful.

I would note there has been over a 50% decrease in sperm counts in the last over 50 years. Interestingly studies show that organic farmers have had increasing sperm counts, as opposed to farmers who use chemicals (who have had a large drop in sperm counts). Using meat from cows that have not been raised and fattened using estrogen (such as meat which is available at Whole Foods Market) is important in any man whose wife is having trouble getting pregnant. Melatonin, verapamil and nifedipine (common heart and blood pressure medicines), or excess alcohol can also cause reversible infertility in males.

There are several things a man can do to markedly improve his sperm count and motility:

1. Although in females high dose vitamin C can cause infertility, increasing vitamin C to at least 500 to 1,000 mg a day in males has a marked effect on increasing sperm count and motility. The vitamin C also protects the sperm from genetic damage which can cause inherited diseases or cancer in the child. Taking 500 mg twice a day, for example, can cure infertility in 20% of infertile males.

2. Astragalus--an herbal remedy, can increase sperm motility by about 50%.

3. Research has shown that high doses of intramuscular vitamin B12 (which are very safe) can increase sperm count in 50% of males with low counts. The dose used in the study was quite high at 1,500 to 6,000 mcg intramuscularly daily. Although the tablets might be helpful, one would only absorb a tiny fraction of the B12 taken by mouth and the treatment needs to be given by injection.

4. Coenzyme Q10 200 mg/day (use only the Vitaline form-many others are poor quality) can be very helpful.

5. L-arginine Aspartate 9 gm a day for low sperm motility or 4 gram a day for low sperm counts can be helpful.

6. Ginkgo Biloba - another herbal remedy taken 120 mg twice a day can help with erectile dysfunction. This takes about 6 to 12 weeks to start working.

7. Acetyl-L-carnitine 1.5-3 gram (1500-3000 mg) a day for 4 months can also increase sperm motility.

8. Selenium 200 mcg a day (not more than this as higher doses can be toxic). Taking the Energy Revitalization System multivitamin is a good idea for the man as well as the woman and will supply the 200 mcg of selenium (and 49 other key nutrients).

9. Vitamin E 400 IU a day (not more) can also increase male fertility.

10. 50 mg of zinc a day for four months is also helpful.

What Are The Risks Of These Treatments?

Although even natural remedies sometimes have side effects, they are usually safe. Too much iron can be toxic and I prefer to check the iron levels (as noted above) before treating with iron. The risk of taking iron for only three to four months (in the absence of a genetic iron excess disease), however, is low. The main side effect of taking high-dose zinc intake for short periods is nausea.

e-mail icon
Facebook icon
Twitter icon
Google icon
LinkedIn icon