Women's Health Update. . .
Use of Hormone Replacement Therapy
Risks and Benefits: A Preliminary Response
to Recent Research
by Tori Hudson, ND

     Two clinical trials have been published recently in The Journal of the American Medical Association regarding postmenopausal women's use of oral conjugated equine estrogens (CEE)= "Premarin” and oral medroxyprogesterone acetate (MPA)= Provera. The significant findings and the confusion it may have created, require some explanation. This hormone replacement therapy (HRT) regimen is often prescribed for women to relieve acute menopause-related symptoms, such as hot flashes and vaginal atrophy, and to reduce the long-term risk for other conditions, such as osteoporosis and, possibly, heart disease. Both trials address the significant issue of whether a woman who has not had a hysterectomy should consider HRT to prevent chronic disease.

     The first trial, HERS II,^1,2 investigated the effect of this HRT regimen on prevention of coronary heart disease (CHD) in older US women (average age 71) with pre-existing CHD. There were no significant decreases in rates of primary CHD events or strokes or clots among women assigned to the HRT group in women who already had CHD prior to taking the HRT regimen. These results were similar to the HERS I study. In addition, women who already have CHD and go on HRT may experience an increase in the number of strokes and clots within the first year. The conclusion reached was that "postmenopausal hormone replacement therapy (HRT) should not be used to reduce the risk of CHD events in women who already have CHD.”

     The second trial was the Women's Health Initiative (WHI),³ which investigated the effect of this same HRT regimen on prevention of CHD in healthy, younger US women (aged 50 to 79 years) who do not have CHD. After a mean of 5.2 years of follow-up, the trial was stopped earlier than planned for the women using HRT because overall health risks (in particular, the rate of breast cancer) exceeded benefits. The conclusion reached was that this HRT regimen "should not be initiated or continued for primary prevention of CHD.”

     Both studies used an estrogen-progestogen HRT regimen of conjugated equine estrogens (CEE, at 0.625 mg/day, also known as Premarin) and medroxyprogesterone acetate (MPA, at 2.5 mg/day, also known as Provera). It is standard practice to add a progestogen (in this case, MPA) to estrogen therapy for any woman with an intact uterus to guard against any increased risk for uterine cancer associated with estrogen alone. Following hysterectomy, it is standard practice for women to use estrogen alone. WHI is still ongoing for women without a uterus who are taking estrogen alone, as no significant adverse effect has been observed to require trial termination.

     "These two studies raise some serious concerns for postmenopausal women,” said Wulf H. Utian, MD, PhD, Executive Director of The North American Menopause Society (NAMS). "Never has it been more important for a woman to discuss her specific situation with her healthcare provider. For women with an intact uterus, there are other options more appropriate than HRT for reducing CHD risk.” _ Nutrition, exercise, numerous natural nutritional and herbal supplements have a significant body of research to support their effects in reducing the risk of CHD.

     The WHI noted that women using HRT exhibited a 26% increase (which translates to 38 cases among HRT users vs 30 cases among placebo users per 10,000 person-years) in invasive breast cancer. However, no significant difference was observed for in situ breast cancers. Although previous studies have suggested an association between HRT and breast cancer risk, this is the first randomized, controlled trial to confirm that combined CEE plus MPA does increase the risk of incident breast cancer and to quantify the degree of risk. Previous research has raised a concern about a slight increase in the risk of breast cancer for use longer than 5 years. The WHI study was stopped at 5 years due to these concerns. It may be that women need to consider using this regimen for less than 5 years to relieve troublesome menopause symptoms, without increasing their risk of breast cancer.

     An important limitation of the WHI is the use of only one HRT regimen. The dose and the kind of estrogens and progestogens are very different than other regimens. Thus, the results do not necessarily apply to lower CEE and MPA doses, other oral estrogens such as natural estriol, estradiol, estrone, and other progestogens such as natural progesterone, or to transdermal estrogens and progesterone. Also, since the trial was stopped prematurely, it is not known whether a longer trial would have found more significant beneficial effects, particularly in fracture prevention and colon cancer prevention.

     In the WHI, overall rates for CHD events were low for women using this HRT regimen. Those using HRT experienced a 29% increase in CHD events compared with placebo (which translates to 37 cases among HRT users vs 30 among placebo users per 10,000 person-years). Most of the excess was in nonfatal myocardial infarction. Stroke rates were 41% higher (29 vs 21 per 10,000 person-years). Rates of venous thromboembolism were twice as high as placebo (34 vs 16 per 10,000 person-years).

     Consistent with previous studies (HERS and PEPI), this HRT regimen showed greater reductions in low-density lipoprotein cholesterol (-12.7%) and increases in high-density lipoprotein cholesterol (7.3%) and triglycerides (6.9%) relative to placebo.

     Despite the negative overall findings, the WHI supports the beneficial effects of HRT on the risks of osteoporotic fracture and colorectal cancer. The WHI study is the first US clinical trial with definitive data showing that HRT can prevent fractures associated with postmenopausal osteoporosis (with hip fracture, HRT users had 10 fractures vs 15 for placebo users per 10,000 person-years). Colorectal cancer rates were also significantly reduced by 37% (10 for HRT users vs 16 for placebo users per 10,000 person-years). Endometrial cancer, lung cancer, and total cancer incidences were not affected. This WHI publication did not consider in its overall benefit-risk analysis a variety of other conditions that may be positively or negatively affected by HRT, including gallbladder disease, diabetes, cognitive function, and quality of life.

     The bottom line after a mean of 2.5 years of follow-up looks like this: 8,506 women on conventional HRT (cHRT) and 8,102 women on placebo.

     CHRT*       Placebo            Difference

Breast Cancer  3.8       3.0       +26%

Heart Disease   3.7       3.0       +23%

Stroke  2.9       2.1       +38%

Clots    2.6       1.3       +100%

Hip fracture      1.0       1.5       -33%

Colon Cancer   1.0       1.6       -37%

* Cases per 1,000 women per year

     Natural compounded estrogens and natural compounded progesterone, as well as natural testosterone and DHEA, such as those used by compounding natural pharmacies and the natural progesterone sold over the counter are distinct and different in several critical ways from conjugated equine estrogens, conjugated plant estrogens, synthetic estrogens and synthetic progestins. Natural hormones are made from either beta sitosterol extracted from the soybean or from diosgenin extracted from Mexican Wild Yam root. Those compounds are then made into the desired hormone and are biochemically identical to the hormone the body produces. By definition, a natural hormone is plant derived and bio-identical. The natural compounded estrogens that are made are either estriol, estrone or estradiol. Estriol is particularly unique because it is approximately one-fourth the potency of estradiol and estrone. Natural compounded estrogens are generally used in lower doses due to the combined effect of the weaker estriol along with the estradiol and/or estrone. These natural estrogens are thought to be metabolized significantly differently by the body, can be used in customized dosing regimens and potencies to fit each individual woman and clinical situation, and can be adjusted stronger or weaker in small units to taper off or onto hormones.

     Conjugated equine estrogens, those that were used in the WHI study, are quite different. In the 1970s it was believed that Premarin only consisted of 10 estrogens. These are: 17 beta estradiol, 17 beta dihydroequilin, 17 beta dihydroequilenin, 17 alpha dihydroequilin, 17 alpha estradiol, estrone, equilin, 17 alpha dihydroequilenin, delta 8-9 dehydroestrone sulfate and equilenin. Since then, advancements in technology have revealed that the original 10 estrogens make up less than 40% of the hormonal content of Premarin. Using modern analytical techniques, today over 200 individual components have been identified, including androgens and progestins._ The composition of Premarin is complex and different estrogens produce various effects in different tissues. Herein may lie an explanation for problems with conjugated equine estrogens vs natural bio-identical estradiol, estrone and estriol. All steroid hormones, including the sex steroids produced by the ovary, represent a subclass of lipids which share a four-ring steroid structure. The native compound from which all the sex steroids are derived is cholestane, the parent of cholesterol. When nutritional states of the individual and cell are normal, the principal precursor of steroid production is cholesterol in the plasma. The cholesterol enters the cells through a lipoprotein receptor system. The activity of the enzymes within the cells of that tissue are the determining factor in order for that tissue to produce a particular class of steroids. The tissues that are responsive to steroids have very specific intracellular receptors with a high affinity for their particular steroid. The primary action of the steroids is the binding of a steroid hormone to a receptor and the interactions of this receptor-hormone complex with the components of the cell. When the steroid binds, the steroid-receptor complex becomes activated and binds with very specific regions within the steroid-responsive region of the genes. Most of the effects of steroids on responsive cells are mediated through the activation of very specific genes.

     My hypothesis, is that a non bio-identical hormone may act like a constant environmental toxin to the genetic material within the cell because even though it can bind to the receptor hormone complex, it is a foreign substance. In the case of CEE, in that there are over 200 mostly foreign substances to a human, these are now a part of that complex and therefore are activating those genes within the cell. This, I contend is a profound distinction between a non bio-identical hormone and a bio-identical hormone. Besides the effect on the genes themselves, bio-identical hormones and non bio-identical hormones may very well leave a different metabolic footprint on the rest of the body with different metabolic consequences. It is this distinction and potential difference in metabolic consequences, as well as the shorter half-life of natural hormones, that motivates me to use almost exclusively, bio-identical natural estrogens. Natural progesterone has been studied and shown to have less adverse effects on the cardiovascular system than do synthetic progestins such as MPA. Specifically, it lowers HDL significantly less than MPA and it does not cause coronary artery spasm whereas MPA does.

     Natural estradiol may not be without concerns on the cardiovascular system and breast. However, again, it is typically used in a half strength dose (.5 mg total daily, because it is combined with the significantly weaker estriol. Estriol has been shown to have some ability to act as an anti-estrogen in the breast and no significant impact on the cardiovascular system.) Further considerations of a natural hormone approach and a more holistic approach to menopause would be to use the hormones in combination with other strategies that are known to reduce the risk of breast cancer and heart disease. For example, soy and flax seeds and cabbage family foods and supplements can promote the metabolism of estrogens to their anti-carcinogenic breakdown products. Breast cancer and heart disease prevention diets can also be emphasized with nutritional and botanical supplements to be considered such as vitamin E, C, carotenes, soy, Co-enzyme Q10, green tea, garlic, and others.

     Women who are using CEE and MPA should consider other natural estrogen and natural progesterone regimens or non-hormonal menopause management. Women who are using natural estrogens and natural progesterone, should consider a re-evaluation of their hormone regimen to establish the lowest dose to achieve the benefits and to minimize the risks. Women who do not have a uterus and are on any hormone regimen should consider taking just estrogen alone. Neither synthetic MPA nor natural progesterone is needed.

     Additional herbal and nutritional supplements may be considered as well. Studies on black cohosh, red clover, soy, bioflavonoids, kava, and a proprietary formula "Women's Phase II” have all shown proven scientific efficacy in menopausal symptoms. Many women will only require these nonhormonal supplements for their symptom relief and never need any kind of drug therapy. Other women may be able to lower their dose of cHRT or natural hormones while using them in combination with the herbal and nutritional supplements.

     "Women who are using CEE and MPA only to prevent CHD should probably be tapered off therapy,” said Dr. Utian. "Women who are using CEE and MPA or another estrogen-progestogen HRT combination for benefits other than preventing CHD will need a careful re-evaluation of the primary reasons they are using HRT, determining whether the potential benefits exceed the potential risks. No change is recommended at this time for women without a uterus who are using estrogen alone.”

     Overall, it must be remembered that the absolute risks associated with Premarin and Provera in this current WHI study were small although certainly important. As always, especially in naturopathic medicine and a holistic approach, each woman must be evaluated individually and benefits and risks must be determined for her particular situation. Low dose, compounded, plant-derived natural hormones can be used very effectively to manage menopause symptoms and lower fractures. When hormone replacement therapy is needed, low dose natural hormones, along with other breast cancer and heart disease prevention strategies offer women the safest, most gentle, least invasive form of hormone replacement.

References

1.  Grady D, Herrington D, Bittner V, et al, for the HERS Research Group. Heart and estrogen/progestin replacement study follow-up (HERS II): Part 1. Cardiovascular outcomes during 6.8 years of hormone therapy. JAMA 2002;288:49-57.

2.  Hulley S, Furberg C, Barrett-Connor E, et al, for the HERS Research Group. Heart and estrogen/progestin replacement study follow-up (HERS II): Part 2. Non-cardiovascular outcomes during 6.8 years of hormone therapy. JAMA 2002;288:58-66.

3.  Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Healht Initiative randomized controlled trial. JAMA 2002; 288:321-333.

5.  Klein R. The composition of Premarin. Int J Fertil 1998;43(4):223