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HRT RISKS - IS THERE SOMETHING NEW TO TALK ABOUT?

There is a lot of confusion about the meaning of the study, published in July 2002, known as the Women's Health Initiative (WHI). This study looked at the effects of the most prescribed drug combination hormone replacement therapy (HRT) for menopausal women, Premarin (conjugated equine estrogens) and Provera (medroxyprogesterone acetate).

More recently, an updated analysis of the breast cancer findings of the WHI Trial, titled the WHI Estrogen-Alone Trial, was published. This analysis demonstrated that estrogen-alone hormone therapy may not increase the risk of breast cancer in postmenopausal women. The Estrogen-Alone Trial was a placebo-controlled study that involved 10,739 postmenopausal women ages 50-79 with no uterus. The study participants in the active "Estrogen-alone" group were given 0.625 mg/day of conjugated equine estrogens without progestin (synthetic progesterone).
While this study enlightens many as to whether the concerns are the estrogen or the synthetic progestins, NHLBI Director and WHI Director Elizabeth G. Nabel, MD, states "this new analysis does not alter the overall conclusion from the WHI that hormones, including estrogen-alone and estrogen plus progestin, should not be used for the prevention of chronic disease." However, WHI Project Officer Jacques Rossouw, MD, stated, "This finding underscores the need to individualize treatment for menopause symptoms based on a woman's medical history and her risk profile".
This study confirms that overall, postmenopausal women without a uterus who choose to take estrogen-alone do not have an increased breast cancer risk, at least over the first 7 years of treatment. However, women who are taking estrogen should be aware that they will likely need more repeat mammograms and more breast biopsies. The reason for this is that while participants taking estrogen had 50 percent more abnormal mammograms that required follow-up and underwent 33 percent more breast biopsies (747 compared to 549), there was no increase in breast cancer as an abnormal mammogram does not necessarily signal cancer.

Clearly, more research is needed on the role of progestin. Participants in the Estrogen-Alone and Estrogen Plus Progestin trials began at the same level of risk for breast cancer. According to Dr. Rossouw, the increased risk of breast cancer found in women taking combined hormones may be due to the effects of progestin – when it is combined with estrogen. Other trials have shown similar results. A study of postmenopausal women receiving pellet implants of testosterone in addition to estrogen therapy had substantially lower rates of breast cancer than the group who received testosterone pellets in addition to estrogen and progestin therapy.

There have been contrasting results with PremPro, and the authors of the WHI trial commented that "the results of this study do not necessarily apply to other formulations of oral estrogens and progestins." For example, bio-identical hormone replacement therapy uses molecules that are structurally identical to the endogenous human hormones, as opposed to synthetic (manmade) preparations such as medroxyprogesterone. Additionally, compounded bioidentical hormone replacement therapy commonly uses alternative dosage forms to oral therapy, such as topical formulations or sublingual tablets, which bypass the liver on first-pass metabolism.

While the WHI trial was ended early it did show a reduction in fractures, conferring protection from osteoporosis when replacing hormones. There have been other studies showing positive benefits of hormone replacement therapy in reducing the risk of heart disease, osteoporosis, stroke, cancer and Alzheimer's disease. Generally, these studies showed no increased risk of breast or endometrial cancer.

The Nurses' Health Study (NHS), recently published in May of 2006, by lead investigator Wendy Chen, with Brigham and Women's Hospital, showed that estrogen only raises breast cancer risk if it is used for more than 20 years. The NHS, which focused on data from more than 120,000 registered nurses, showed no increased risk among postmenopausal women on estrogen-alone therapy for less than 10 years. This study also showed an insignificant increase in breast cancer risk among women who used estrogen-along therapy for 10 to 20 years. The NHS data add to a growing body of evidence suggesting that estrogen-alone therapy might not heighten breast-cancer risk if taken for shorter periods of time.

Much attention has also been directed towards an article recently published on July 2006 in the Archives of Internal Medicine. The title of this article is "Combined Estrogen and Testosterone Use and Risk of Breast Cancer in Postmenopausal Women." The authors of this article conclude that combination therapy with estrogen and testosterone in postmenopausal women can increase the risk of invasive breast cancer. However, several factors should be considered when reviewing this article.

This is a prospective epidemiologic study, not a controlled trial. It is an analysis of data that was self-reported by women who participated and was not originally designed to look at testosterone use. The questionnaires that were used did not specifically inquire about testosterone or offer this as a choice, so data collected on testosterone users was based on that which was volunteered by participants only. This is a limitation of the study, because it may result in a significant underestimation of the number of women who used estrogen / testosterone therapy. Therefore, these are women who were not evaluated. Plus, because the use of combination of estrogen and testosterone is a more recent clinical practice, the majority of current users evaluated in this study were past users of other types of hormone therapy, so there is a potential that past use of other therapies confounded these results.

This study considered women who were using a combination of methyltestosterone and esterfied estradiol, which are synthetic hormone preparations and not bioidentical hormone replacement therapy. Greater than 90% of the women reported to be on Estratest, which is an oral synthetic combination of estrogen and testosterone. Oral therapy gets swallowed and then undergoes metabolism by the liver. Hepatic (liver) metabolism results in high estrone levels, often associated with higher risks of cancer. Also, this metabolic process results in an elevation of creatinine reactive protein (CRP) and other pro-inflammatory markers, and cancer is an inflammatory disease.

Other data has shown conflicting evidence. Animal and cell studies suggest that testosterone inhibits proliferative effects of estrogen on breast cells. One study in primates reported that testosterone reduced estrogen-induced proliferation by 40 percent.

New research published May 2006 in The Journal of Clinical Endocrinology&Metabolism by researchers led by Karen K. Miller, MD, showed the first positive effect of testosterone on bone density, body composition and emotional, cognitive and behavioral function in women with low testosterone levels resulting from under-active pituitary glands. Loss of ovarian and/or adrenal function can cause many women to experience hypopituitarism or under-active pituitary glands, and therefore low levels of testosterone, which is responsible for producing estrogen. This lack of testosterone can be blamed for loss of sex drive, loss of muscle tone and decrease of cognitive sharpness.

Getting a yearly mammogram evaluation is always recommended, as well as performing monthly breast self-examinations.