Hormone Replacement and Menopause: What are the Issues?


Symptoms related to menopause, including insomnia, nervousness, melancholia, vertigo, weakness, fatigue, hot flashes, vaginal dryness, and urinary incontinence, denote a decline in a woman's quality of life. Further, the symptoms a woman may experience vary according to age.

Data Presented from The 22nd Annual Meeting of The American Society for Bone and Mineral Research
Re-printed with permission of C 2000 Millennium Medical Communications, Inc.

This report was reviewed for medical and scientific accuracy by Michael Divon, MD, Director of OB/GYN, Lenox Hill Hospital, New York.

Symptoms related to menopause, including insomnia, nervousness, melancholia, vertigo, weakness, fatigue, hot flashes, vaginal dryness, and urinary incontinence, denote a decline in a woman's quality of life. Further, the symptoms a woman may experience vary according to age:

30s-Early symptoms can include menstrual irregularity or heavy vaginal bleeding. A modest, natural loss of bone also begins.

40s-As estrogen levels begin to decline, women may experience hot flashes, night sweats, and menstrual irregularity. Women who have surgical menopause may experience more severe symptoms, as well as vaginal dryness and bone loss, due to a rapid decline in estrogen.

50s-After menopause, as much as 20 percent of total lifetime bone loss occurs within five to seven years. There is an increased incidence of hot flashes, night sweats, and vaginal dryness. As well, incidence of cardiovascular disease (CVD) begins to increase.

60s-Incidence of osteoporosis, CVD, colon cancer, vaginal dryness, and related sexual problems all increase.

70s-The incidence of CVD more than doubles. As well, the incidence of Alzheimer's disease begins to increase, which affects more women than men.

80s-Incidence of Alzheimer's disease rises sharply, doubling every 4.5 years. Eye conditions, such as cataracts, also become increasingly common.

Estrogen Replacement Therapy (ERT)-estrogen alone-and Hormone Replacement Therapy (HRT)-estrogen plus progesterone-have been found to reduce or reverse most menopausal symptoms. However, the long-term use of ERT and HRT appears to be associated with increased risk for breast cancer. Furthermore, the protection these therapies might provide against the onset of cardiovascular disease, remain controversial. Several studies presented at the 22nd Annual American Society of Bone and Mineral Research examined the clinical evidence.

The Risk of Breast Cancer

More than 50 clinical studies involving over 350,000 women have evaluated the relationship between HRT and increased risk of breast cancer. Analysis of the data from these studies showed there was no increased risk of breast cancer within the first five years of HRT therapy. However, the risk increased by 38 percent for women who were on HRT for more than five years. In addition, for every thousand women who begin estrogen use at age 50 and continue using it for five years, there will be two additional cases of breast cancer. That number increases, for every 1,000 women, to six additional cases of breast cancer for ten years of HRT therapy. Further studies have shown that there is an increased risk for breast cancer relative to the number of years HRT is taken. Essentially, that increased risk is equivalent to the risk for women who have delayed menopause. In other words, the later menopause occurs, the greater the risk of breast cancer, and this risk, although small, is no different than the increased risk associated with long-term HRT use.

Is ERT Safer than HRT?

One of the questions resulting from these studies is whether or not women taking HRT are at greater risk for breast cancer than women taking estrogen alone. A recent Swedish study, which included many women who had invasive breast cancer, found the excess risk to be quite high-2.5 percent annually. The excess risk in this group continued for

at least ten years after the last time they used HRT. In the largest study done to-date, only ten percent of women took HRT. In this study, there were over 2,000 new cases of breast cancer. The relative risk with ERT was 1.2 percent, while the risk with HRT was 1.4 percent. Those risks increased by 0.03 percent per year for ERT alone, while increasing by 0.12 percent per year for HRT. This may be due, in part, to the fact that progesterone has been found to increase breast density, which is a risk factor for breast cancer.

Elizabeth Barrett-Connor, MD, Professor and Chief of the Division of Epidemiology, University of California, San Diego, explained that there have been nine studies comparing women who got breast cancer while taking estrogen and women who got breast cancer who were not taking estrogen. All nine studies showed that the women who developed breast cancer while taking estrogen had a better survival rate than those who developed breast cancer while not taking estrogen. "This could mean one of two things, either that estrogen causes a slower-growing tumor with a better prognosis, or that women taking estrogen have [an] earlier diagnosis. It seems that both are possible," said Dr. Barrett-Connor.

"The data are beginning to suggest that HRT may be more of a risk factor for breast cancer than ERT alone. Clearly, mores studies are needed to determine if this is in fact the case," Dr. Barrett-Connor commented.

Although ERT and HRT may increase the risk of breast cancer, "studies done to-date indicate that those risks are relatively small and that the cancer seems to have a very good prognosis, as long as women maintain active surveillance with mammograms and self-examination," said Dr. Barrett-Connor.

What About Heart Disease?

Although it was initially thought that estrogen had a beneficial effect on reducing the risk of heart disease in postmenopausal women, recent studies have shown this may not be the case. There seems to be no firm data one way or the other. Some studies have shown a higher risk with estrogen alone, while others have not. Much depends on a woman's individual history and state of health prior to using ERT or HRT. For example, it is a well-known fact that women who are overweight, smoke, or have more than the occasional drink are already at increased risk of cardiovascular disease.

One of the largest studies done to-date, which included more than 3,000 postmenopausal women who had heart disease at the beginning of the study, found that there was absolutely no difference in the overall frequency of coronary heart disease between women who took a placebo, women who took estrogen alone, or women who took conjugated estrogens/medroxyprogesterone acetate (Prempro®). Surprisingly, however, there was a 50 percent increased risk of cardiovascular events (heart attack or coronary artery disease) in the first year of the study. "Although there may be long-term benefit associated with ERT and HRT for CVD, this study does not provide any evidence of that," Dr. Barrett-Connor said.

Another recently published study, which included 300 women who received either placebo, ERT, or HRT, also showed "absolutely no difference in terms of development of CVD, either at the beginning of the study or three years later," confirmed Dr. Barrett-Connor.

A much larger study, involving approximately 30,000 women, 90 percent of whom did not have heart disease at the beginning of the trial, is currently underway. Results are expected in approximately five years.

Endometrial Cancer

The incidence of endometrial cancer is approximately one case per thousand women per year, and the risk increases with age. The risk factors associated with endometrial cancer include nulliparity, obesity, hypertension, diabetes, and ERT, if used alone. For women who have a uterus, even a low dose of estrogen, administered on a consistent basis over time, is a significant risk for endometrial cancer. Therefore, some form of progesterone is required to oppose the estrogen effect on the endometrium. However, when postmenopausal women who have a uterus are given HRT, they will develop recurrent uterine bleeding. Is that bleeding a risk factor for hyperplasia (the excessive growth of normal cells in tissue) and/or neoplasia (the development of new, abnormal tissue, such as tumors)? Studies have shown that women who have irregular bleeding or spotting while on continuous combined therapy have a very low incidence of hyperplasia. However, women who are on ERT have a very high incidence of hyperplasia. "It is with the estrogen-only therapy that you will see a problem," said Dr. David R. Archer, Clinical Research Center, Eastern Virginia Medical School, Norfolk.

Treatment options for recurrent uterine bleeding include stopping therapy, beginning cyclic therapy for women on continuous therapy, increasing the progestin dose, or decreasing the estrogen dose. Progestin is required for women who have a uterus in order to prevent endometrial neoplasia. "While HRT will reinitiate uterine bleeding in the vast majority of women, a diagnostic study need only be done if prolonged and extensive bleeding is occurring. 'No bleeding' can be achieved with continuous combined HRT," Dr. Archer advised.

Urogenital Problems Associated with Menopause

Urogenital symptoms of menopause are common and profound. Recent studies suggest that 80 percent of women aged 40–60 years suffer problems such as urinary tract infections, and 31 percent experience changes in sexual function directly due to vaginal dryness and dyspareunia (the occurrence of pain in the labia, vagina, or pelvis during or after sexual intercourse). Ten percent of women age 61 and over experience vaginal burning; 41 percent experience dyspareunia, and as many as 73 percent experience urinary incontinence.

However, there is proof that extremely low doses of estradiol improve vaginal symptoms. A recent study showed great improvements were associated with the use of very small doses of estradiol administered by means of a vaginal ring device (Estring®). The study involved 136 women aged 45–80, all of whom were experiencing various urogenital symptoms. After treatment, 95 percent believed their dryness was cured, 94 percent noted their vulvar itching was improved, and 81 percent said their dyspareunia was improved. "It has also been shown that estrogen can reduce the likelihood of urinary tract infections, by treating with very low doses of a weak estrogen cream preparation-estirol (Estrace®)," Dr. James A. Simon, Clinical Professor, George Washington University; Medical Director, Women's Health Research Centre, Laurel, Maryland, commented.

HRT and the Brain-Does it Reduce the Risk of Alzheimer's?

Alzheimer's disease, which affects more women than men, is and will continue to be a major public health problem in populations where aging and long life are common. Although research into the effects of ERT and HRT on the brain is ongoing, early studies have shown that estrogen has a neuroprotective effect. It can improve immediate recall in women with normal cognitive function. Estrogen also helps prevent cell death in the brain, reduces anti-inflammatory effects, increases blood flow, and enhances transport of nutrients to the brain as well as coping responses to psychological stress. Estrogen also has effects that may be directly beneficial in the prevention of Alzheimer's disease. "The data are rather convincing," Dr. Simon commented. He explained that one study has shown that the higher the dose of estrogen, and the longer the duration of estrogen therapy, the lower the risk estimate for developing Alzheimer's disease. Furthermore, a second, prospective clinical study also demonstrated that in aging individuals, treatment with estrogen for as little as one year showed an increase in Alzheimer-free probability. "There may be important preventative implications for Alzheimer's disease associated with estrogen use," he said.


This Report is a product of Millennium Medical Communications, Inc. ("MMC, Inc."), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. This Report is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein as well as the guest editor. The ideas and opinions expressed by the guest editor are those solely of the guest editor and do not necessarily reflect the opinions of Millennium Medical Communications, Inc. or any Sponsor hereto. This Report may contain data on products, product uses, indications, and dosages, which are not approved for use in the USA, Canada and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. This Report is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was paid for by MMC, Inc.

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