Merriam-Webster's Medical Dictionary defines menopause as the period of natural cessation of menstruation occurring usually between the ages of 45 and 50. About 75 percent of women have menopausal symptoms for at least a year or two, sometimes much longer. These include hot flashes, sleepless nights, strange skin sensations, mood swings, and palpitations. For some women these symptoms are insignificant while for others, they are so bothersome that they make their lives miserable. Also, four out of every ten women develop symptomatic osteoporosis. One of the most important effects of a diminished estrogen supply after menopause is the loss of bone mass, which results in broken hips, fractured wrists, and compressed spines. Until menopause, a plentiful supply of endogenous estrogen helps maintain bone strength. Then, when that supply diminishes and is not replaced, there is a rapid depletion of bone mass, no matter how much calcium is consumed or how much exercise you get. Osteoporosis is not significantly reversible. Therefore, the inevitable excessive bone loss must be prevented before it begins.

One result of menopause is recurrent urinary infections. The tissues lining the urethra, the passageway from the bladder to the outside of the body, gradually shrink and dry, making them susceptible to bacteria and other organisms. Many practical measures can help to prevent the infections, but only estrogen will restore the tissues to a more youthful and infection-resistant state.

Hormone replacement therapy (HRT) can help alleviate some symptoms. Women who take HRT tend to look younger than their years. The skin, because it also has estrogen receptors, remains smoother, oilier, and more flexible when it has a steady supply of this hormone. Estrogen won't reverse the affect of normal aging of the skin, but it can influence the processes that are under its specific control. Estrogen also helps to maintain the firmness and strength of the body's muscle tissue and it keeps hair stronger. Studies have found that it improves memory, delays Alzheimer's disease, reduces the risk of cataracts, and most importantly reduces the risk of heart disease in postmenopausal women.(1)

If the use of estrogen replacement therapy is so beneficial, why are not more women on the program? For one thing, not every woman requires it. Second, many women prefer using as few drugs as possible and are willing to take their chances that no problems will come their way because of their decision to abstain from HRT. Some are not willing to resume menstruation, particularly when they view the cessation of monthly bleeding as one of the benefits of menopause. And there are others, even those who desperately need it, afraid to take estrogen because they are concerned about its side effects and fear that it may not be safe.

Some studies done on HRT have found that these women's fears are substantiated by facts. Although estrogen is not a carcinogen and does not cause uterine cancer, use of it over a long period of time can overstimulate the lining of the uterus and cause an excessive thickening called endometrial hyperplasia. Hyperplasia is not cancer, but can accelerate the growth of a cancer that is already present in the uterus. Also, because estrogen influences breast tissue it stimulates already existing malignant tissue that have estrogen receptors.

Breast cancer is the most common female cancer and one that is associated with substantial mortality. Statistics indicates that the risk of developing breast cancer up to the age of 75 years range between 6% to 7%. For other cancers the absolute risks vary between 1 and 2%, ovarian cancer being the most frequent gynecological cancer, followed by endometrial and cervical cancers. With respect to breast cancer, premature oophorectomy or early menopause is associated with a lower risk of breast cancer whereas early menarche or late menopause seems to increase the risk. Similar risk factors are ascribed to endometrial cancer reflecting the effect of excessive estrogen secretion. For ovarian cancer, factors reflecting the number of lifetime ovulations seem the most important. So, the underlying theory would be that both estrogen and progesterone affect the likelihood of transformation of normal epithelial cells to cancer cells through an effect on cell division rates. It is well known that estrogen increases proliferation in the endometrium whereas progesterone has an anti-mitotic effect. Data on hormonal effects on breast cells seem to suggest that estrogen enhances cell divisions while progesterone might further increase this activity. Direct effects of sex-steroids on the epithelium of the ovary and cervix are uncertain. It is not known how HRT in postmenopausal women will affect the development of cancer in these organs.

The relationship between HRT and breast cancer risk has been studied extensively. While data on hormonal effects on breast cells are contradictory and controversial, several studies report an increased relative risk estimates in association with many years of hormone intake. One reported a 30% increase relative risk after more than 15 years of use.(2) There are two forms of estrogen given (estradiol compounds in Scandinavia and United Kingdom and conjugated estrogens in United States) but studies are inconclusive as to which of the two has lower relative risks of breast cancer. Furthermore, HRT regimens with estradiol compounds or conjugated estrogens have similar biological effects. Results of tumor characteristics from a few American studies indicate that HRT is mainly associated with early stage and small breast cancers. Hormone replacement therapy's effects on risk of breast cancer may be modified by patient characteristics. Findings in some studies indicate that a family history of breast cancer, especially in first degree relatives, may further increase the risk after HRT. There is no firm evidence of an interaction of HRT with other breast cancer risk factors such as age at first full-time pregnancy, smoking and alcohol consumption or previous use of oral contraceptives.

During the late 1970s and 1980s numerous epidemiological studies demonstrated a clear risk relationship between HRT and an increased risk of endometrial cancer. These studies were mainly done on women in the USA and reflected the treatment practice at that time. The treatment practice was administration of conjugated estrogens in high dosages and without added progestins. Aggregated data from these studies were fairly consistent. The strongest determinant of risk was found to be the duration of estrogen intake, the risk being significantly elevated after 2-4 years of treatment and thereafter rising continuously to about a 10-fold increase after 10 years duration. The risk level seemed to return in most, but not all, studies to baseline some years after the discontinuation of the treatment. The dose may also affect the risk level. Also, the selection of patients and their characteristics appear to be important since the presence of other risk factors for endometrial cancer such as obesity and late menopause may potentiate the risk.

Estrogen can also cause hypertension. In about one out of every twenty women, estrogen replacement taken orally causes the release of two enzymes, renin from the kidneys and angiotensin from the liver, which precipitate a transient and reversible rise in blood pressure. Other risks of oral estrogen are gallbladder disease and liver impairment. Oral estrogen can raise the risk of developing symptomatic gallstones because it tends to thicken and concentrate the bile produced by the liver. The liver is responsible for metabolizing the estrogen that passes through it. When the liver is damaged, it may not do this job properly and so the levels of the hormone can become toxic.(1)

HRT also has an effect on heart disease in postmenopausal women. There have been many studies done on this issue and the results have shown that the use of estrogen or estrogen with progestin can reduce the risk of cardiovascular disease. One such study published in the Journal of American Medical Association (JAMA), concluded that there is a 50% reduction in heart disease risk in postmenopausal women taking estrogen. The participants of the Postmenopausal Estrogen/Progestin Interventions (PEPI) were women aged 45 to 64 years, with or without a uterus. Preliminary telephone screening was used to exclude clearly ineligible women as a result of age, serious illness, or unwillingness to be in a clinical trial. The women were required to be naturally or surgically menopausal. If naturally menopausal, it had to be at least 1 year, but not greater than 10 years past their last menstrual period. If surgically menopausal, it had to be at least 2 months after hysterectomy and with a follicle stimulating hormone level greater than or equal to 40 IU/L. Normal baseline results of mammography and endometrial biopsy also were required.

Women who had severe menopausal symptoms were excluded, as were women who had used estrogens or progestins within 3 months. Women treated with thyroid hormone who had not been taking a stable dose for at least 3 months and who did not have a normal thyroid stimulating hormone level were also excluded. Other exclusion criteria were serious illness such as myocardial infarction within 6 months, congestive heart failure, stroke, transient ischemic attack or contraindications to estrogen, including prior breast or endometrial cancer. The screening process resulted in a total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy. The women were categorized into 5 groups according to similar lifestyle and menopause-related characteristics. Overall, their average age was 56.1 years, 89% were white, 5% Hispanic, 4% African American, 2% Asian, and 0.5% Native American. More than half had one to three children and had previously used noncontraceptive estrogen. 49% had never smoked and 50% drank more than 12 alcoholic beverages per year but less than 30 drinks per month, and almost two thirds reported at least moderate physical activity. Approximately 32% had a hysterectomy at an average age of 41.8 years. The five groups were assigned random treatments in 28-day cycles. The treatments were: (1) placebo; (2) CEE, 0.625 mg/d; (3) CEE, 0.625 mg/d, plus MPA, 10 mg/d for the first 12 days; (4) CEE, 0.625 mg/d, plus MPA, 2.5 mg/d; or (5) CEE, 0.625 mg/d, plus MP, 200 mg/d for the first 12 days. How will these treatments affect the levels of high density lipoprotein (HDL) and low density lipoprotein (LDL)? LDLs are the major cholesterol supplier to peripheral tissues. Then, LDLs return to the liver to be removed from the circulation by LDL receptors located on the surface of liver cells. The HDLs are involved in a 'reverse cholesterol transport' from the peripheral tissues to the liver. Nascent HDL particles form during lipoprotein lipase mediated degradation of very low density lipoprotein (VLDL) particles. This occurs when VLDL surface phospholipid-cholesterol layer becomes excessive and partly separates from the rest of the particle. These surface components form structures which serve as acceptors for free cholesterol derived from peripheral cells. The free cholesterol becomes esterified by the enzyme lecithin cholesterol acyl transferase. The cholesterol esters form a hydrophobic core of small sized spherical particles. It is advantageous to have higher levels of HDL than LDL, since HDL transports cholesterol from peripheral cells to the liver to be metabolized.

Each active treatment had significantly greater increment in mean high density lipoprotein cholesterol (HLD-C) levels than placebo. The average increase in HDL-C levels were similar in women assigned to conjugated equine estrogen (CEE) alone (5.6 mg/dL) or CEE with micronized progesterone (MP) (4.1 mg/dL). These women had significantly greater HDL-C elevations than women assigned to CEE with cyclic or continuous medroxyprogestrone acetate (MPA) (1.6 and 1.2 mg/dL, respectively). For all hormone regimens, HDL-C levels increased during the first 6 to 12 months and gradually decreased thereafter, although not to the baseline level. Hysterectomized women taking unopposed estrogen had HDL-C levels that were greater at the end of the study than levels in women without a hysterectomy who were assigned to unopposed estrogen. This was consistent with the observation that many women with a uterus developed endometrial hyperplasia and were unable to continue unopposed estrogen. Changes in all active treatment regimens were similar while at the same time significantly different from placebo. This was evident in women with or without a hysterectomy.

Triglyceride levels increased comparably in all active treatment arms from a mean of 98.3 mg/dL to 111 mg/dL and differed significantly from placebo. Compared with placebo treated women, cholesterol levels were significantly lower only in women treated with CEE plus MPA regimens which probably reflects the lesser increase in HDL-C. Also, in pairwise comparisons, women assigned to placebo had greater increases in fibrinogen than women assigned to active treatment. In other words, the placebo group had more blood clot incidences. Also, patterns were similar among women with and without a uterus.(3)

Estrogen has many modes of action in which it reduces cardiovascular disease. The low dose, natural estrogens given as replacement therapy in postmenopausal women lower LDL-C and fibrinogen, and raise HDL-C. Estrogen has a direct anti-atherosclerotic effect in arteries. It augments vasodilating and antiplatelet aggregation factors, specifically, nitric oxide and prostacyclins, which are endothelium dependent mechanisms. There are direct inotropic actions on the heart, improvement in peripheral glucose metabolism and a subsequent decrease in circulatory insulin levels. It also has a favorable impact on the clotting mechanism, at least partially mediated by endothelial nitric oxide and prostacyclin synthesis.(4)

Finally, now that all the facts have been presented on both sides, does the benefit outweigh the risk of HRT? The answer to this questions a decision that each woman must make herself with the help of her doctor. Every woman is different, and therefore no one choice is right for all. It is a tough decision to make, but with current facts and information women can decide wisely on their option.

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