Menopause and Hormone Therapy

The word "menopause" is translated literally as "a pause in the menses." A more technical definition of menopause states that it is a decline in the production of estrogen to the point that periods no longer occur. This failure of ovarian estrogen production can happen naturally, or it can occur when the ovaries are surgically removed. The average age of the natural decline in ovarian estrogen production to this point is age 51. Some ladies reach the menopause by their late 40's and some will go to the mid to late 50's before reaching menopausal status. Once a lady becomes menopausal, she will be menopausal the rest of her life.

The term "perimenopausal" refers to a time, usually in the late 40's, when a lady may experience hot flashes, trouble sleeping, vaginal dryness, emotional lability, or other menopausal symptoms, but yet she still has periods. The lady's cycle will often, but not always, become irregular with missed periods, bleeding between periods, or heavy flow. Physicians formerly thought that the perimenopause was a reflection of a progressive decline in ovarian estrogen production. Longitudinal studies have now demonstrated that there is often a decline in estrogen levels, followed by a compensatory elevation. This fluctuation may result in a net increase in estrogen, not a decrease as we previously thought. This explains why fibroids (non-cancerous uterine tumors that are estrogen dependent) often will suddenly enlarge when a lady is in her mid to late 40's.

The ovaries may be thrown out of balance during the perimenopause. Progesterone production (which is normally increases in the second half of the cycle to balance the proliferative effects of estrogen), may become abnormally low. The estrogen becomes "unopposed," resulting in an irregular bleeding pattern due to an abnormal thickening or overgrowth of the uterine lining. This may be simply an annoyance, or the estrogen can cause an abnormal proliferation of the uterine lining that could result in cancer of the uterus if left unchecked. This thickening of the lining is a common problem, but one that is usually easy to remedy. The simple addition of progesterone in the later half of the cycle, or cycling on the birth control pill will usually reverse the overgrowth. Any lady who is having abnormal bleeding should call her health care provider. Failure to address this problem (which can be easily resolved if managed early) can result in serious changes that might require major surgery or possibly cancer treatment if left unchecked.

When periods completely cease, a lady is said to have entered the menopause. If her ovaries have been surgically removed, she immediately becomes menopausal. If she has had a hysterectomy, but one or both of the ovaries remain, she will usually enter the menopause at the usual age. If she is among the one third of women who enter the menopause with few or no symptoms, it may be hard to be sure when the menopause has arrived. If there is a question in that regard, there is a blood test or a new urine test that can determine if estrogen production has ceased.

Approximately one third of women enter the menopause with minimal or no symptoms, another one third have significant symptoms, and one third have absolutely terrible symptomatology. Symptoms of the menopause are multiple and include:

• hot flashes
• night sweats
• trouble sleeping
• vaginal dryness
• muscle or joint aches
• fatigue
• feeling extremely emotional
• depression
• anxiety
• lowered self esteem
• decreased sex drive
• shrinkage of vaginal tissues
• painful intercourse, or shrinkage and dryness may make intercourse impossible
• thinning of the hair
• increased wrinkling and thinning of the skin
• premature aging

There are additional but less common symptoms as well. Most women will usually have at least some of the above mentioned symptoms. The symptoms vary in degree, and they can sometimes be extremely severe, seriously effecting quality of life. At least two thirds of women have major symptomatology. Fortunately, these symptoms tend to decline with time, and often are not a problem after several years. Unfortunately, some ladies suffer serious symptoms for many years, even decades, and the impact on them and their families and associates can be severe.

The term "getting through the menopause" simply refers to reaching a point where the symptoms of the menopause have faded to a level where they are no longer a problem. This term is a bit of a misnomer because even after the symptoms have subsided, a lady is still in the menopause and will be for life.

In addition to dealing with the troublesome symptamatology, ladies face other challenges associated with the onset of the menopause. These challenges involve major medical concerns and include an increase risk in the incidence of:

• heart disease
• osteoporosis (thinning of the bones) and an increased fracture risk
• diabetes
• colon cancer
• Alzheimer's disease
• cognitive decline

For thousands of years, women simply had to "deal with it." Menstrual symptoms and associated medical declines were considered an inevitable. Then, in 1942, Premarin, the first estrogen replacement product, was introduced. It did not come into major use until the 70's when a book was published that lauded estrogen replacement as the "Fountain of Youth." Estrogen replacement then became very popular, to the point that it was considered "standard of care" to offer estrogen replacement to any woman entering the menopause. But along with popularity, problems were noted. Troublesome bleeding was often encountered, along with breast tenderness and headaches. Then an ominous concern surfaced. Use of estrogen was found to be associated with a significant increase in the risk of cancer of the lining of the uterus. Fortunately, subsequent research found that if progesterone were given along with the estrogen, the increased risk disappeared. Other estrogens came on the market, lower doses were formulated to diminish troublesome side effects, and estrogen replacement again found a significant role in the treatment of menopausal symptoms.

Further research indicated that estrogen not only alleviated menopausal symptoms far better than any other medication available, but it also had significant protective effects such as substantial reduction in the risks of osteoporosis, heart disease, colon cancer and premature aging. Estrogen was noted to help with the cognitive decline so commonly noted after the menopause, and it was also found to be helpful in the management of depression, anxiety, and the decreased self esteem frequently noted in menopausal women. Physicians often prescribed estrogen not only for the treatment of symptoms, but for the protective effects noted above. Again, estrogen was experiencing a marked rise in popularity. But all was not roses.

Serious deleterious effects of estrogen began to surface or at least be suspected. Studies demonstrated that estrogen increased the risk of blood clots in the deep veins (deep vein thrombosis). The risk was low, going from 1 in 10,000 to 2 or 3 in 10,000. Also noted was an increased risk in gall stones and an increase in migraine headaches (though some patients noted a decrease in migraines on estrogen). Of major concern was a suspected increase in the risk of stroke (with some studies suggesting an increased risk and others suggesting no increase or even a decreased risk). The greatest concern revolved around a possible increased risk of breast cancer. This was a terrifying concern, one very worrisome to patients and their physicians. Unfortunately, the data was not clear. Over 50 studies had been done to look into this possible relationship, and some showed a small but worrisome increased risk, others showed no increase risk, and still others actually showed a decreased risk. Confusion reigned.

While there was confusion about the risk of breast cancer, there was little confusion about the effects of estrogen on the risk of heart attack. Multiple studies had shown a major reduction in the risk of heart attacks. These very large retrospective studies showed a nearly 50% reduction in the incidence of heart attacks in women on estrogen replacement.

Heart disease is the leading cause of death in women. About 44% of women will die of heart disease, while breast cancer is the cause of death in approximately 4% of women. Most doctors felt that estrogen increased the risk of breast cancer, but that this was more than balanced by the protection of the heart. They felt that a minimal increase in the 4% killer of women was more than compensated for by the nearly 50% reduction of the 44% killer. Risks and benefits were discussed with patients and many saw that protections outweighed risks and accepted hormone therapy. But still the concern about breast cancer remained a nagging uncertainty.

Enter the Women's Health Initiative, better known as the WHI. The WHI is an extremely ambitious and complex study started in the late 90's. It is a multimillion dollar project funded by your tax dollars and mine. Many areas of women's health were to be investigated, with a major portion of the study directed at assessing the risks and benefits of hormone therapy. This portion of the study was divided into two parts. One looked at estrogen and progestin therapy for women with their uterus intact (the progestin was needed to protect from an increased incidence of uterine cancer that would have been a problem if estrogen alone were used). The second arm looked into the risks and benefits of estrogen only therapy (ET) in women with a history of hysterectomy. This research was highly advertised as a beautifully designed study, and on the surface it appeared to be exactly that. It was a prospective, randomized, double blinded study, with tens of thousands of participants and a study duration of eight years. It was felt that this research would finally give statistically significant, highly relevant data that would allow women and their physicians to balance risks and benefits. The study looked at the incidence of breast cancer, uterine cancer, ovarian cancer, colon cancer, heart attacks, stroke, deep vein thrombosis, and senile dementia (which is similar to Alzheimer's disease). Sadly, the study did not look at a very important aspect, the effect on quality of life.

The results of this study was being eagerly anticipated by the medical community, when much to everyone's shock, the estrogen/progestin arm of the study was abruptly stopped after just 5 years because the investigators had noted an increased risk in the areas of breast cancer, heart disease, stroke, and deep vein thrombosis with pulmonary embolism (a clot to the lung). These are all terrible, sometimes fatal problems, and the news was terrifying to many women on hormone therapy and of grave concern to their doctors. The relative risks were reported by the media, and the numbers were frightening. What disturbed women the most was the report of a 26% increased risk of breast cancer. What concerned physicians even more was the finding that hormone therapy did not protect the heart, but in fact raised the risk of a heart attack by 28%. The risk of stroke was up by a similar degree, and the risk of deep vein thrombosis was up by 100%. Needless to say, women dropped their hormone replacement by the thousands and doctors found ourselves suddenly backtracking. Many recommended that their patients come off of hormone therapy if at all possible. The screeching halt of the estrogen/progestin arm of the study sounded like a disaster and was treated as exactly that by many.

But time has passed, the frantic reaction to the news has subsided, and cooler heads have had a chance to really look at the study design and the data generated. Also, there has been a reevaluation of some of the WHI data, evaluation of new data from additional studies, and there has been new data from ongoing WHI investigations.

First, it became obvious that there was a lot of knee-jerk reaction generated by the premature cancellation of the estrogen with progestin arm of the study. The way the study was reported had a lot to do with this reaction. It was actually disclosed to the media first, not hitting the medical literature until a short while later. This brief, but significant delay allowed panic to set in as doctors tried to react to the concerns of their patients when all they had to go on was a report on CNN or an article in their local news paper. When the report did surface in the medical literature, it was by its very nature complex and confusing.

A major problem revolved around the fact that the risks reported through the media involved relative risk, not actual risk which is vastly different. Relative risk looks at how the use of a substance increases or decreases the baseline risk of a condition. Actual risk determines the chance of an adverse occurrence happening because of the use of a substance. For example, in the WHI findings, the relative increased risk of a deep vein thrombosis due to estrogen/progestin usage was 100%. But the baseline risk in the placebo group was 1 in a thousand per year. A 100% increase in deep vein thrombosis actually translates into a 2 in 1,000 risk. This further translates into an increase in risk of 1 in 1,000, or a 0.1% actual risk per year. Similarly, the study reported a 26% increased relative risk of breast cancer. What the study found was that there were 8 more breast cancers per 10,000 patients on estrogen/progestin compared to the numbers of breast cancers in 10,000 women not on estrogen/progestin. This means the actual risk is 0.08% per year. There was no increased risk over the first 4 years of the study, and the risk per year is cumulative, so the risk of contracting cancer of the breast because of the use of estrogen/progestin after 14 years of steady use is still less than 1% (0.8% actual risk). Interestingly, the actual risk of heart attack noted in the study and the actual risk of stroke both came out to 0.08% per year also.

Sadly, many women who received their information from the media focused on the "26% relative risk of breast cancer" that was quoted and assumed that if they took estrogen, they had a 26% chance of getting breast, when in reality they could use estrogen and progestin for 14 years with a total cumulative risk of breast cancer due to taking estrogen with progestin of 0.8%. A study that was supposed to shed light actually generated a great deal of confusion instead.

To add further confusion, the estrogen only arm of the study was not stopped, and it continued for seven years. When it was stopped, many of us were surprised to see that their data showed no increased risk of breast cancer after 7 years of usage. In fact, there was a decreased incidence. The estrogen only arm of the study is now out to 9 years, and there is still the decreased risk. The amount of decrease is about the same magnitude as increased risk noted in the first arm of the study. We found it interesting that this reassuring data did not generate a media frenzy. In fact, there was very little mention by the media of a decreased breast cancer risk in women on estrogen only. This is another example of how one sided sensationalistic reporting shapes public opinion.

Further evaluation of the WHI revealed that there were several major flaws in the methodology of the study. The most glaring flaw and the one that makes much of the information generated very confusing and misleading is the fact that women with menopausal symptoms were generally excluded from the study. As a result, the majority of women allowed into the study were more than a decade into the menopause. The average age of a woman entering the study was 63. A significant percentage of them were in their 70's or even their 80's at the onset of the study. This is terribly significant because the vast majority of women considering starting hormone therapy are in their late 40's to early 50's. The risk of heart disease, cancer, stroke, and deep vein thromboses is significantly higher for ladies in their 60's and 70's, and extrapolating risk back to a younger population really does not make sense. The 0.08% actual risks per year quoted for a population with an average age of 63 may well be much higher than the actual risk of someone a decade or more younger. After a great deal of pressure from the medical community, the WHI reevaluated their findings by age. This reassessment by age found that women in their 50's have an incidence of breast cancer just slightly more than half of the risk noted for the study as a whole (0.05% per year instead of 0.08% per year). The risk of heart disease was similarly reduced, as were the risks of stroke and deep vein thrombosis.

Even more profound was the risks noted in the estrogen only arm when broken down by age. For women in their 50's there were major decreases in the risks of breast, colon cancer, and heart disease, the risk of stroke was essentially non-existent, and the risk of venous thromboembolism was minimally increased.

Most decision making involving estrogen or estrogen plus progestin is associated with women entering the menopause during their late 40's or early 50's. Much of the data quoted from the WHI has little to do with women in that age range. I think we need to keep this carefully in mind as very critical decisions are made in the area of menopausal management.

Another compelling area of concern is the effect of estrogen on the brain. The WHI again used an older subgroup of women to study this phenomenon. Their subgroup had an average age of 70 for women entering that part of the study, with a significant number in their 80's. The youngest were 65 years of age. After several years, they noted an increase in the incidence of senile dementia in the women on estrogen or estrogen with progestin compared with placebo. This certainly is of concern. However, there have been several studies now that looked at women who started hormone therapy at their entry into menopause and used it for a few years and then stopped, or who started it early and then continued use long term. These two groups were then compared to women who never used HT. The Columbia Longitudinal Study of Health and Aging looked at these three groups and found that by age 85, those who had never used hormone therapy had a 40% incidence of Alzheimer's disease. Those who used hormone therapy for only a short time at the onset of menopause reduced the 40% incidence of Alzheimer's noted in non-users of estrogen by nearly half, and those that initiated it at the onset of menopause and used it long term had an Alzheimer's incidence of only 5%.

The Alzheimer's data and the cardiac risk data of the WHI point to a very significant concern. That is the fact that with some medications and some activities, there is a window of opportunity for doing good, and when that window closes, a window of opportunity to do harm opens. Women started on estrogen at the onset of menopause seem to have a major protective benefit for the heart and brain. Once that window closes at about 10 years beyond entry into the menopause, beginning the use of the same medication can cause significant harm. We need to keep this clearly in mind when we discuss risks and benefits with our patients and we need to take the time to be sure they understand when certain data is pertinent to them and when it truly is not.

A woman entering the menopause at 51 needs to be aware that if she is a candidate for estrogen only therapy, the WHI data shows that she is at no increased risk of breast cancer for at least 9 years, and that the WHI data and data from the Nurses Health Study and other similar studies indicate that she has no increased risk of coronary heart disease, and in fact may have a 30 to 40% reduction of risk. Also, she has no increased incidence of stroke for at least 7 years and the risk of thromboembolism is only slightly increased.

If the same woman were a candidate for estrogen with progestin therapy, she would be faced with no increase in risk of breast cancer for the first 4 years, then a 0.05% increased risk per year. The risk of stroke would be increased by 0.04% per year and the risk of venous thromboembolism would be minimal at 0.1% per year. The same woman would stand to gain a major decline in the incidence of Alzheimer's if she uses estrogen for even a short time, and a potentially huge reduction if she uses it for an extended time.

In summary, a woman entering the menopause and considering HT must balance risks that are small (or in some cases are not risks at all but possibly benefits) against known benefits such as the reduction or elimination of sometimes severe symptoms, protection of the skin, hair, and vaginal tissues, protection of the bones and reduced fracture risk, reduction in the risk of colon cancer, reduction in the incidence of blindness from macular degeneration, reduction in personality changes, depression, and anxiety, protection of the brain (reduction of cognitive decline and Alzheimer's disease), reduction of diabetes, and overall improvement in quality of life issues ( the later being a subject not evaluated at all by the WHI).

We have also learned from the WHI and other studies that certain women would not be good candidates for starting hormone therapy. This includes women with a history of breast or uterine cancer (in most cases), a history of deep vein thrombosis or clotting disorders, women with a history of coronary artery disease, women who have had a previous stroke or women who are at excessive risk for stroke, or women who are over 60 and contemplating starting hormone therapy. Other women with certain other circumstances might also be poor candidates for the initiation of hormone therapy.

There are many other areas of concern, such as which estrogen would be the best for a certain lady, what is the best route of administration (pill, patch, trans-dermal gel or cream, vaginal ring, vaginal cream, shot, or pellet implant). Also, what is the best choice of a progesterone or progestin for a particular individual? What about herbals or bio-identical hormones? What alternatives are there to hormone therapy and how effective are they? How long should a woman use hormones and how should she stop them? What is the risk of breast cancer for a woman taking estrogen if she has a strong family history of breast cancer? (The short answer to that question is that it is essentially the same as for a woman without a strong family history of breast cancer). These and many more questions deserve a thorough discussion, but we do not have the time or space to do justice to them now. Hopefully, what we have covered has shed some light on a complex situation that seems to be inundated with ever changing data and concerns. Stay tuned. I am sure there will be more to come.

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Dr. Roy Stringfellow is a gynecologist in Colorado Springs, Colorado, and a member of Focus on the Family's Physicians Resource Council.