HORMONES AND THE BREAST

When women consider whether to use or to stop using hormones, the following concepts and truths should be carefully evaluated:

  • Estrogens are sex hormones which are meant to develop and prepare the breast for breast feeding and milk production. They will enlarge the gland and cause cell proliferation (make more cells), causing engorgement, heaviness and tenderness. This is a normal and expected reaction.
  • The Creator of the female body planned the reproduction period in women only to be for a certain time in her lifespan, from about 14 to 44 yrs of age. Outside these reproductive years she will be infertile and stop menstruating and not ovulate. Her breasts will also reduce in size, become softer and cell proliferation will decrease and cease. Considering the results of trials and the risk factors for developing breast cancer, it becomes very clear that The Great Physiologist  did not intend the breasts (and uterus) to be exposed to stimulation (cell proliferation) for longer times. (it clearly increases the risks)
  • If we extend this exposure time, we could expect problems.
  • She and her doctor should also understand that the loss of fertility and ceasing of her menstruation at menopause, is brought about by decreasing estrogens production by the ovaries, and is not due to a disease (malfunction, disintegration or deficiency) .We do not talk about loss of ovarian function due to surgical removal of the ovaries. That is a disease caused by us doctors and should be corrected.

I found many women to understand “low estrogens levels” on her blood test, as being abnormal for her after 50 and that this abnormality should be corrected. Strangely , many doctors interpret normal estradiol levels after the menopause (being lower than at age 30) as “abnormal” in spite of the fact that it falls in the normal range for the laboratory.

  • The menopause is thus not a disease or a mistake made by God in all women, that should be corrected by man ( we thought we could and tried, since synthetic hormones were developed in the late sixties—with serious consequences to many women who died of uterus cancer, thromboses, stroke and coronary thromboses and now also of breast cancer)
  • I do not know of any non-disease entity on earth that is treated by a potentially harmful chemical every day for years on end, except THE MENOPAUSE. Remember that hormones are the most potent group of chemicals in the body. It can transform a boyish girl of 9yrs into beautiful women of 20yr and totally change many organs. Sadly it is dished out by many doctors like candy. The inventor of DES, the first synthetic estrogens, warned already in the sixties against the use of estrogens in non-disease entities.
  • All women (and doctors alike) should be very careful of the side-effects of all drugs. The patient often learns only about the desired effects of drugs and seldom is the possible harmful side effects spelled out to her. The list of side-effects in the brochure inside your pill package, is not placed there to cover the drug manufacturer, but because it was found to happen during their trials and thus forced upon them by the FDA.
  • Shocking is the fact that 77% of the last >1000 drugs tested by the FDA have no clinical benefit (see their bulletin under NEWSFLASH).
  • Women should also realise that hormones is no cure for hot flushes. It only keeps it away while using the drug and that the flushing will come back worse whenever she stops using it .Also that the protective effect on bone density loss during the menopause wanes faster when she stops using it than in women that never used it. Since HRT has to be stopped at some stage because of increased cancer risk, it has been shown that whether a woman had been on HRT during her menopausal years makes no difference to her bone density in later life when danger of osteoporosis is greatest. (See ref.7 in HRT. IS IT SAFE?
  • I often hear: BUT WHAT ABOUT QUALITY OF LIFE?

Quality of life endpoints cannot and has never been tested. It is an individual experience of life values and depend on the individual’s perceptions. Does it mean that all women of all millennia before 1970(before hormones) did not have quality of life without hormones??

TO HELP WOMEN TO FURTHER THEIR KNOWLEDGE REGARDING HRT, LETS LOOK AT A FEW OTHER OPINIONS AND TRIALS CONCERNING RISK AND BENEFIT.

 

  1. THE VIEW OF A WORLD RENOWNED EPIDEMIOLOGIST AND HARVARD CANCER PREVENTION CENTRE.
  2. OPINIONS OF A SA PROFESSOR
  3. THE FINDINGS OF THE LARGEST TRIAL ON HRT SO FAR.
  4. THE NEGATIVE EFFECTS OF HRT ON EARLY DETECTION OF BREAST CANCER.

 

JOURNAL OF WOMEN’S HEALTH

Volume 8, Number 3, 1999

Mary Ann Liebert, Inc.

Review:

Hormones and Breast Cancer:

Evidence and Implications for Consideration of Risks

and Benefits of Hormone Replacement Therapy

GRAHAM A. COLDITZ, MD., Dr.P.H., F.A.F.P.H.M.

Channing Laboratory, Brigham and Women’s Hospital, Harvard Medical School and The Harvard Centre for Can­cer Prevention, Boston, Massachusetts. Supported by grant CA 40356 from the National Cancer Institute. Based on a paper presented at the American Association for Cancer Research, San Diego, 1997. A longer review in Journal of the National Cancer Institute (1998;90:814) includes more details.

ABSTRACT

The role of estrogen replacement therapy (ERT) in the aetiology of breast cancer continues to be debated. The implications for counselling women about a causal relation between hor­mones and breast cancer with regard to long-term use of postmenopausal hormones remain controversial. The literature on hormones and breast cancer, including articles on cell prolif­eration, endogenous hormone levels, epidemiologic studies, and the risk of breast cancer, is reviewed.  A cause of cancer is defined as a factor that increases the probability that cancer will develop in an individual.  A causal relation between female hormones and breast cancer is based on duration of use, dose-response, biologic plausibility, temporality, strength of as­sociation, and coherence. The magnitude of the increase in risk of breast cancer caused by us­ing hormone replacement therapy (HRT) is comparable to that seen in delayed menopause. The positive relation between endogenous hormone levels and risk of breast cancer supports a biologic mechanism for this relationship. The increase in risk of breast cancer with in­creasing duration of use, which does not vary substantially across studies, offers further ev­idence for a causal relation. The reduction in total mortality with short-term use of hormones, although strongest among women with risk factors for cardiovascular disease, adds complexity to the risk-benefit trade off associated with the use of hormones for longer durations. All ev­idence supports a causal relation between both endogenous estrogens and the use of post­menopausal estrogens and progestins and breast cancer incidence in postmenopausal women. Among postmenopausal women, prior use of oral contraceptives is not related to risk of breast cancer. Strategies for relief of menopausal symptoms and long-term prevention of osteo­porosis and heart disease that do not cause breast cancer are urgently needed.

INTRODUCTION

It has long been known that the incidence of breast cancer rises rapidly through the pre­-menopausal years and slows dramatically at about age 50, which corresponds to the mean age of menopause in Western cultures. Among pre-­menopausal women, the annual rate of increase in risk is approximately 8% per year, and among postmenopausal women the rate of increase in risk is 3% per year. (1,2)  After menopause, hormone levels decline to substantially lower levels than those observed among pre-menopausal women.

In the latter part of the 20th century, we have moved from a period when the use of post­menopausal estrogen was advocated to reduce the risk of breast cancer (3) to the present, when a plethora of epidemiologic studies suggest a pos­itive relation among estrogen levels, markers of estrogen exposure, the use of estrogens after menopause, and an increased risk of breast can­cer. Numerous meta-analyses indicate that a significant positive relation exists between the du­ration of use of postmenopausal hormones and the risk of breast cancer.(4,5) Further, a combined reanalysis of original data from 51 epidemiologic studies, including over 52,000 patients with breast cancer and over 100,000 women without breast cancer, indicates that risk of breast cancer increases significantly for each year a woman uses postmenopausal hormones, and the findings do not vary significantly between studies.(6)   In large part, the remaining uncertainty is to what extent varying hormone formulations affect the magnitude of this relationship rather than if there is a relationship.

Thus, clear benefits of long-term use of post­menopausal hormones counterbalance the ad­verse effects of hormones on the risk of endome­trial and breast cancer. To resolve the risk-benefit equation, the clinical question, therefore, has be­come, “Does long-term use of HRT increase the risk of breast cancer, and, if so, how soon after use has begun does risk increase?”

In this review, I summarize the evidence that endogenous estrogen and replacement hormones are causally related to breast cancer. I then ask questions that must be addressed to improve the information available to women to help them in decision making about the use of postmeno­pausal hormones.

REPRODUCTIVE EVENTS AND BREAST CANCER RISK

Reproductive events have long been known to be related to the risk of breast cancer (7). The rate of breast cancer in postmenopausal women is largely determined by the timing and number of births. When age at menopause is included, the accumulated cell divisions relate directly to the risk of breast cancer (8). Specifically, late age at menarche, early age at first pregnancy, higher number of term pregnancies, and early meno­pause are associated with lower risk of breast can­cer. Although age at menopause has remained relatively constant over time, in the past 150 years we have moved from a population-wide repro­ductive profile of low breast cancer risk to a much higher population average profile (menarche is earlier, ‘first birth is later, and the number of children has declined substantially). These societal changes continue to drive the rates of breast can­cer higher.

Oral contraceptives (OCs) have been widely used over the past 30 years. The combined data from studies relating use of OCs to risk of breast cancer show no long-term relation after cessation of use, although current users are at increased risk (9).  This lack of long-term adverse effects, in large part, is consistent with the background hor­mone levels and menstrual characteristics of pre­-menopausal women who are having a regular monthly cycle of estrogen and progesterone. Use of OCs brings the population to a common cycle length of 28 days, which is also the average for nonusers of OCs. Thus, regular monthly cell pro­liferation in the breasts of both users and nonusers of OCs is on average the same, and the long-term risk of breast cancer is on average the same for both groups of women.

Against this background of risk, how does the use of postmenopausal hormones modify risk; Both oral estrogen replacement and transdermal estrogen raise serum estradiol levels to those found in pre-menopausal women who are in the early follicular phase of the menstrual cycle (10,11).  This should be considered in relation to the en­dogenous hormone levels of postmenopausal women.

Obesity is positively related to reproductive hormone levels among postmenopausal women,(12-14) reflecting a biologic function of fat cells, which metabolize androgens to estrogens. For ex­ample, mean estradiol concentrations among a sample of participants in the Nurses’ Health Study were 4.7 pg/ml for women with body mass index (BMI) <21 kg / m2 and 10.0 pg / ml for women with BMI >29 kg / m2 (13).  Lean post­menopausal women have both lower estrogen levels and lower age-specific incidence of post­menopausal breast cancer (15-17).  Obesity is also positively related to risk of breast cancer mortal­ity (18,19). This relation persists after controlling for stage at diagnosis and other known modifiers of survival,19 a finding consistent with a role for es­trogen as a later promoter of breast cancer.

Tamoxifen, which acts as an anti-estrogen in the breast, significantly reduces breast cancer mor­tality among breast cancer patients (20) and also re­duces the incidence of breast cancer among women at higher risk than average (21).

Further evidence for the role of estrogen in fa­cilitating breast cancer growth is the success of oophorectomy in the treatment of breast cancer (20).  Ovarian ablation reduces mortality by 26% among women under age 50 at diagnosis of breast cancer, although this is no longer recommended therapy for breast cancer.

Taken together, these data indicate that higher levels of estrogen among postmenopausal women are associated with increased incidence of breast cancer and that higher levels after di­agnosis lead to poorer survival.

HORMONE LEVELS AND BREAST CANCER RISK

Few studies have assessed prospectively the risk of breast cancer according to the blood lev­els of hormones. The results have varied, perhaps because of difficulty in measuring hormone lev­els in postmenopausal women (22).   In a follow-up study that identified 130 women diagnosed with incident breast cancer, Toniolo et al. (23) showed a positive relation between estradiol levels and breast cancer. The follow-up of the Study of Os­teoporotic Fractures also showed a strong rela­tion between hormone levels among women who were not using postmenopausal hormones and subsequent risk of breast cancer (24).  Comparing ex­treme quartiles of estrone levels, Cauley et aJ.24 observed a relative risk (RR) of 3.2 (95% Cl 1.4-7.0) for women in the highest quartile. Simi­lar data were found on the island of Guernsey (25) and in the Nurses’ Health Study,(26) the largest prospective study to date. In the Nurses’ Health Study, among women who had never used post­menopausal hormones, the RR comparing the highest versus the lowest quartile of estrone showed a significant fourfold increase in risk. Other prospective studies either agree with this relation, although the number of cases is small, (27-29) or have failed to find such an association but are statistically compatible with an in­creasing risk with higher hormone levels(30,31)

The data from prospective studies have been combined in a systematic review and quantitative analysis by Thomas et al.,(32) who note that there is no substantial heterogeneity in results among the prospective studies. These authors observed a statistically significant higher risk of breast can­cer among women with higher levels of serum estradiol.

Androgens have also been reported to be associated with increased risk of breast cancer in some (28,30) but not a11 (31,33) prospective studies ad­dressing this relation. In two of the larger prospective studies, the findings were mixed (25,33). Although the data in the study by Zeeniuch-­Jacquotte et al.,(33) with 81 cases, showed a statistically significant positive relation between testosterone levels and risk when adjusted only for age, once other hormones were controlled for (e.g., estradiol and percent sex hormone-binding globulin [SHBG]-bound estradiol), the results showed no statistically significant dose-response, and the RR comparing highest versus lowest quartile of testosterone was not significant (RR = 1.2,95% Cl 0.4-3.5). In a smaller study with only 24 cases, Berrino et al. (28) did not see a compara­ble effect when they controlled for total estradiol, and Thomas et al., (25) with 61 cases in their prospective study, observed that the statistically significant positive relation between testosterone and the risk of breast cancer became null after controlling for estradiol. A similar finding was reported by Hankinson et a1.,(26) based on the Nurses’ Health Study. Taken together, these data suggest that testosterone may have an indirect effect through estrogens rather than being an independent risk factor. Additional data are re­quired to confirm this.

In conclusion, growing evidence supports a positive relation between blood levels of estro­gens and the risk of breast cancer, with up to a fourfold increase in risk between extreme quar­tiles of estradiol. This association is stronger than that between cholesterol and CHD, suggesting that estrogen levels may serve as a clinical indicator of breast cancer risk once laboratory meth­ods to measure estrogens are adequately standardised and once the best estrogen fraction to predict risk is identified (22).  With such data and the availability of new products that act as specific antiestrogens at the breast, screening and treatment may mimic the approach to heart disease, where cholesterol-lowering drugs have become a standard preventive strategy.

POSTMENOPAUSAL HORMONE USE AND BREAST CANCER RISK

Correlates of use

Traditionally, the use of postmenopausal hor­mones has been for relief of menopausal symp­toms, where their efficacy is unquestioned. More recently, their use has been advocated to reduce the risk of CHD and osteoporosis (34).  Mounting ev­idence suggests that women with menopausal symptoms have lower estrogen levels at menopause than women without symptoms (35-38).  Women who are lean at menopause are more likely to report hot flashes (35) and to use post­menopausal hormones (39).  In addition, bone density is typically lower in women when they be­gin using postmenopausal hormones than in those who choose not to use hormones, although bone density is not the only factor in the decision to use or not to use hormones (40).  Together, this evidence points to the likelihood that women who use postmenopausal hormones are, on av­erage, at lower risk of breast cancer at the time of menopause than women who do not use hor­mones, which should lead to an underestimate of the adverse effects of postmenopausal hormones.

In addition to these biologic correlates of hor­mone use, women who use hormones have been noted to be of higher socioeconomic status and to consume more alcohol, (41,42) factors that are asso­ciated with increased risk of breast cancer. Likewise, women who take postmenopausal hor­mones may have higher rates of mammography, which would lead to a higher reported incidence of breast cancer. These factors should cause over-­estimation of the underlying biologic relation be­tween use of hormones and risk of breast can­cer (43).  However, such factors can be controlled in analysis.

Only some of these apparent sources of bias can be controlled in data analysis. Many are not measured in the majority of epidemiologic stud­ies of hormone use and the risk of breast cancer. Therefore, it is possible that confounding by in­dication selection bias is induced by the un­measured correlate of hormone use that results in women at lower risk of breast cancer being more likely to use postmenopausal hormones Such confounding by indication would lead to a biased estimate of the relation between use of hor­mones and risk of breast cancer. This may in part, explain the observation, in the American Cancer Society study, of lower breast cancer mortality among women who have ever used post­menopausal hormones than among women who never used-hormones (44).

In addition, women who have menopause at an earlier age are more likely to use post­menopausal hormones (45) and to use them for longer durations, as are those who undergo sur­gical menopause (46).  Because early menopause is associated with a substantially lower risk of breast cancer (47,48), users of hormones again are on average at lower risk of breast cancer than non-users of the same age, once other risk factors are controlled for. The approach to statistical con­trol for age at menopause in three age categories (<47, 47-52, >52), as in previous analyses of the Nurses’ Health Study, (49) does not give an unbi­ased estimate of the relationship. Further illus­tration of this bias is seen in the collaborative re­analysis of epidemiologic studies (6). When the Oxford investigators assessed the potential mag­nitude of risk underestimation in previous re­ports of epidemiologic data that can be attributed to incomplete analytic control for the time since menopause, they found a profound impact – underestimating the strength of the association. They noted that the estimated annual increase in the risk of breast cancer associated with the duration of use of replacement hormones was 0.8% per year (p = 0.10) if no correction was made, as compared with an increase in risk of 2.3% per year (p = 0.0002) when full statistical control was implemented. The combined reanalysis excluded from analysis women with a hysterectomy who did not have a bilateral oophorectomy, as their age at menopause would be unknown. This fur­ther reduces error in the estimation of the asso­ciation between hormones and breast cancer (50).

The adverse effects of postmenopausal hor­mones will likely have been underestimated in individual epidemiologic studies that compare hormone users with nonusers. The combined reanalysis uses statistical techniques to remove some of the inherent biases in previous analyses. The majority of studies of hormone use do not use measures of bone density or menopausal symptoms as markers of hormone levels, and few ????

IMPLICATIONS FOR WOMEN WHO USE POSTMENOPAUSAL HORMONES

On the basis of this review, it is evident that postmenopausal hormones cause breast cancer. Long-term use substantially increases the risk of this cancer, which is the most common malig­nancy in’ women.  Given this causal relation and consistent evidence that hormone replacement reduces the risk of osteoporosis, and several other major illnesses, how do we best present the data so that women can make informed choices? How do we view this problem from a public health perspective?

Several issues pertain to the application of such data to clinical practice, Glasziou and Irwig (73) sug­gest that one needs to assess the underlying risk and potential benefits of any clinical therapy as it is applied to the individual patient. Such an as­sessment requires sound estimates of the risk of heart disease and osteoporosis to begin with, as well as the risk of breast cancer. That is, although results from a randomized trial may indicate the absolute magnitude of an association (either ben­eficial or adverse), the trade off at the individual level is not answered by the trial results for an outcome, such as total mortality, but is dependent on the risk profile of the woman, To this formula, I believe we must add the individual’s fear or con­cern about the diseases considered, as is recom­mended for broader risk-benefit or cost-effec­tiveness considerations where quality-adjusted life years are used as an outcome (74).  The need to separate short-term benefits from long-term is­sues remains paramount.  Relief of vasomotor flushes, sleep disruption, and the like are clear benefits of short-term therapy,

Age-specific mortality from cancer exceeds that from heart disease through age 70 among women in the United States, The age-adjusted mortality from cancer has been higher than that for heart disease among women since 1990 (75).   In 1995, the age-adjusted mortality from heart disease was 104 deaths per 100,000 women and from cancer 110 deaths per 100,000 women.  Among white women, the difference was greater (heart disease 95, cancer 109). As a measure of the burden of cancer, it is noted that the average years of life lost per death is 11.8 for heart disease and 19.5 for breast cancer (76).  Cancer has a major impact on women, and breast cancer is the leading cancer diagnosis, Age-specific data are informative.

Table 1.  Death Rate per 100 000 women.  United States 1995

Age (years) Breast Heart Disease
25 – 34 2.7 5.6
35 – 44 15.0 17.1
45 – 54 41.4 56.0
55 – 64 69.8 193

Source:  Health United States, 1996 – 1997

Deaths from malignant neoplasm of the breast for females and from disease of the heart in 1995 are summarised in Table 1.  Death rates are comparable for breast cancer mortality and heart disease up to age 54.

Further complicating considerations of trade-off of risk and benefits is the increase in risk of endometrial cancer and the growing evidence that use of postmenopausal hormones is associated with a lower risk of colon cancer.  This association is now observed in numerous case-control and prospective cohort studies.

To the data on the burden of cancer we might add that the apparent absence of lifestyle practices that can be modified easily to reduce the risk of breast cancer further heightens fear of this cancer. Contrast this with heart disease for which we have a wide range of behavioural or clinical options that can reduce risk, many with fewer potential side effects than the increase in the risk of breast cancer caused by use of postmenopausal hormones. These options include greater physical activity (77), avoidance of weight gain (78), aspirin (79), vitamin E (80), folate (81), cholesterol lowering drugs, and treatment of high blood pressure for example, a daily multivitamin reduces the risk of heart disease by some 25% (81) and has the added benefit of reducing risk of colon cancer (82) without any evident adverse effects.

Other health advantages of postmenopausal hormones relate to the prevention of osteoporosis. The burden of this condition is carried primarily by older women, thus placing great demand for prevention strategies that do not increase the risk of breast cancer, which has a higher incidence than osteoporotic fractures before age 70. Growing evidence suggests that  selective estrogen receptor modulators may offer protection against osteoporotic fractures by increasing bone density (83).  It is likely that these agents will also offer substantial protection against breast cancer (reported at the National Osteoporosis Foundation Meeting in Washing­ton, DC, in June 1997). Given the causal relation between estrogen and breast cancer, we must rapidly assess the risk-benefit profiles of these newer agents and develop a knowledge base suf­ficient to counsel women who are making choices among the many options for relief of menopausal symptoms and for long-term use to prevent chronic diseases. The use of low-dose estrogens to prevent osteoporosis, although potentially having less adverse effect on the risk of breast cancer, has not been shown to limit this impor­tant adverse effect. Data are urgently needed.

From a public health perspective, we must con­sider the underlying distribution of other risk fac­tors for chronic conditions. The proportion of breast cancers and osteoporotic hip fractures in a population of hormone users will depend on the age distribution of that population. Historic trends indicate that heart disease has declined among women and men over the past 20 years (84).  Hence, the trade off of chronic conditions is not static but reflects a secular trend whereby cancer deaths exceed heart disease deaths among white women and will do so among black women in the near future if current trends continue. Based on the follow-up of women in the Nurses’ Health Study whose reproductive histories, age at menarche, parity, and age at menopause reflect those of their birth cohort, even long-term use of postmenopausal hormones looks good from the population perspective (85).  Women who used post­menopausal hormones for 10 or more years had a 20% reduction in mortality that was statistically significant, contrasting with a mortality reduction of 44% for users of less than 5 years. Among these women with 10 or more years of use, the mor­tality from breast cancer was 1.43 (95% Cl = 0.82-2.48). The mortality benefit of hormones was most pronounced among women who were at higher risk for cardiovascular disease. There was no significant reduction in mortality among women at low risk for cardiovascular disease. However, to achieve a reduction in mortality within the population, some women will pay the price of breast cancer that they would not other­wise have developed. That is, some women ex­perience a disadvantage as a result of our trying to improve the overall population’s health. Thus, the· public health benefit and the individual choices may differ. Further work is needed to im­prove our understanding and communication of these considerations, to quantify the change in trade off with duration of use of hormones, and to determine the factors

References:

  1. Moolgavkar SH, Day NE, Stevens RC. Two-stage model for carcinogenesis: Epidemiology of breast can­cer in females. J Natl Cancer Inst 1980;65:559.
  2. Rosner B, Colditz CA. Extended mathematical model of breast cancer incidence in the Nurses’ Health Study.J Natl Cancer Inst 1996;88:359.
  3. Burch J, Byrd B Effects of long-term administration of estrogen. Ann Surg 1971;174:414.
  4. Steinberg KK, Thaker SB, Smith SJ, et id. A meta-­analysis of the effect of estrogen replacement therapy on the risk of breast cancer. JAMA 1991;265:1985.
  5. Steinberg KK, Smith SJ, Thacker SB, Stroup OF. Breast cancer risk and duration of estrogen use: The role of study design in meta-analysis. Epidemiology 1994; 5:415.
  6. Collaborative Croup on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacemen1 ther­apy. Combined reanalysis of data from 51 epidemio­logical studies involving 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047.
  7. Lane-Claypon JE. A further report on cancer of the breast, with special reference to its associated an­tecedent conditions. London: Ministry of Health, 1,)2()
  8. Rosner B, Colditz C. Extended mathematical model of breast cancer incidence in the Nurses’ Health Study. J Natl Cancer lnst 1996;88:359.
  9. Collaborative Croup on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53,297 women with breast cancer and 100,239 women with­out breast cancer from 54 epidemiologic studies Lancet 1996;347:1713.
  10. Blohm PL, Hammond CB. Oral estrogen replacement In: Adashi EY, Rock JA. Rosenwaks Z, eds. Reproductive endocrinology, surgery, and technology Philadelphia: Lippincott-Raven, 1996: 1797.
  11. Adashi EY. Transdermal estrogen replacement. In:  Adashi EY, Rock J A, Rosenwaks Z, eds. Reproductive endocrinology, surgery, and technology. Philadelphia: Lippincott-Raven, 19%:1783.
  12. Key TJ, Pike MC. The role of estrogens and progestogens in the epidemiology of and prevention of breast cancer. Eur J Cancer Clin Oncol 1988;24:2′).
  13. Hankinson SE, Willett WC, Manson JE, et al.  Alcohol height, and adiposity in relation to estrogen and pro­lactin levels in postmenopausal women. J Natl Can­cer Inst 1995;87:1297.

Thomas HV, Key TJ, Allen OS, el al. Reversal of relation between body mass index and endogenous estrogens??????

HRT-HOW SAFE IS IT?

Professor W J Serfontein
MSc, PhD (Leiden)

How safe is currently used oestrogen drugs and what are the alternatives?

How safe is it?

Many women’s health problems revolve around distorted hormone production patterns in which oestrogen and progesterone play a prominent role. Oestrogen refers to a group of female hormones produced mainly in the ovaries, with estradiol, estriol and estrone the most prominent members. The most important role of oestrogen is in the development of female sexual characteristics and in the regulation of female reproductive functions.

It also has strong growth-stimulating functions which may affect a variety of tissues including breast tissue. The broad role that oestrogen plays in female physiology is indicated by the fact that there are more than 300 different types of oestrogen receptors in the female body that can be activated by oestrogen. This means that many different functions in a woman’s body respond to oestrogen and that fluctuating oestrogen levels such as may occur during the menopause will be felt throughout the body.

Beginning already in the late thirties, but especially as a woman approaches the menopause, oestrogen production in the ovaries begins to decline, affecting many bodily functions. As the menopause approaches menstruation becomes less regular, sexual function declines and changes occur in the appearance and texture of the skin and hair.

Many women suffer severe mood swings, hot flushes and night sweats, and many other symptoms may appear including changes in the vaginal epithelium (thinning and drying out) which adversely affect libido and sexual function. Any form of oestrogen replacement therapy (ERT) or hormone replacement. Premarin, estradiol patches, vaginal creams, etc. improve many of these symptoms. Because oestrogen when taken alone stimulates growth in many tissues, including the uterine lining and breast (and therefore may increase the risk of cancer in these tissues), women with an intact uterus are usually advised to use a combination of oestrogen with a synthetic progestin since, theoretically, the progestin activity in this type of preparation suppresses this tendency. This procedure is widely used and has become known as hormone replacement therapy (HRT).

HRT involves both serious risks as well as undoubted advantages, especially for the middle-aged woman. Oestrogens as such promote youthful cell division in the many organs that have oestrogen receptors, and in this manner they protect against some of the effects of ageing. Some of the anti-ageing benefits of oestrogen include enhanced moistness of skin and vaginal tissues, less thinning of vaginal membranes, enhanced libido, reduced menopausal symptoms, an increased sense of wellbeing, improved immune function, improved memory and neurological function and many others. There can therefore be no question about the advantages of oestrogen per se. The important questions are: how safe are currently used oestrogen drugs, and are there perhaps other forms of oestrogen that are safer while still retaining the many advantages associated with oestrogen therapy?

How safe are HRT and ERT?
The commonly used oestrogen and progestin drugs have well documented side-effects apart from increased cancer risk, which are serious and unpleasant enough to make many women reluctant to use them or discontinue using them, often at a time when they are most needed. These side-effects include increased tendency to form blood clots, gallstones, fibroids, weight gain and headaches.

However, there are also more serious side-effects associated with the commonly used HRT drugs such as estradiol and estrone (Premarin).1 It has been known for a long time that these forms of oestrogen are associated with a significantly increased risk of endometrial and breast cancer. Recent studies have not only confirmed this, they have also defined the magnitude of the risk more precisely. One study2 found that the increased cancer risk associated with the use of oestrogen alone is 34%, while the risk increases to 54% when oestrogen is combined with progestin. A more recent study published in the Journal of the American Medical Association3 found that the cancer risk increases 10% for every 5 years on oestrogen therapy, with an even higher risk when oestrogen is combined with progestin. One significant finding of several of these studies is that the cancer risk increases with the time spent on oestrogen therapy and that the risk is further increased when oestrogens are combined with progestins. In spite of the convincing evidence of increased cancer risk associated with the use of these oestrogens and progestins, it is still standard medical practice to prescribe HRT for women during and after the menopause.

The standard response to concerns about the cancer risk is that the risk is relatively small and that the other advantages associated with the use of oestrogens outweigh the possible risk. These statements are now both questionable. The risk is not small – it may vary from 34% increased risk to 100% or more. Various studies have found that if a woman is on oestrogen therapy for 5 years or more, her chances of developing breast cancer increase from 1.7 to 2 times.4 One Swedish study5 found that under these circumstances the breast cancer risk is doubled.

Among the other arguments in favour of HRT as it is currently used is the assumed reduced risk of osteoporosis and heart attack. The former assumption is only partly true and the latter is not true. Bone density is determined by the balanced activity of two types of bone cells: osteoclasts that constantly break down bone, and osteoblasts that remodel new bone. Oestrogens suppress osteoclastic activity, thus suppressing the rate at which bone is broken down, but they have no effect on osteoblastic activity. There are no oestrogen receptors on osteoblasts. For this reason, oestrogen therapy is initially beneficial for a period of 7 – 10 years. The protective effect wanes and women who had been on HRT were found to lose bone faster when HRT was stopped than those who had not been on HRT.6 Since HRT has to be stopped at some stage because of increased cancer risk, it has been shown that whether a woman had been on HRT during her menopausal years makes no difference to her bone density in later life when the danger of osteoporosis is greatest.7 HRT therefore has only temporary advantages at best.8

The fact that oestrogen is not a major role player in osteoporosis is further supported by the well-known fact that osteoporosis starts at age 30 at a stage when oestrogen levels are still high.

The latest well-designed studies have shown that HRT provides no heart benefits for women and that it may actually increase the risk. One recent study9 found that oestrogen is no better than placebo for preventing heart disease and the use of HRT was associated with a 23% increase in heart attack deaths. The result of this study is diametrically opposed to those of numerous epidemiological studies which have found that women on HRT have a lower incidence of heart attacks, and these studies are often quoted in favour of HRT. The argument is that even if the cancer risk is increased by HRT, the overall death risk would be very much reduced since the incidence of heart attack deaths among women is nine times greater than the incidence of cancer. Dr R Atkins was the first to point out that the epidemiological studies were basically flawed for a very interesting reason.10                       these epidemiological studies were by their very nature unreliable because identical groups were not compared. The studies compared women who, of their own choosing, were taking HRT with other groups of women who were not taking HRT, again on the basis of their own choice or that of their doctors. Many menopausal women who are not in good health for various reasons (diabetes, obesity, high blood pressure) find that their symptoms are aggravated by HRT and therefore avoid it. These are also the women mostly likely to have a heart attack. On the other hand, those who do not have these problems are more likely to use HRT because of its many other benefits referred to above. They are also less likely to have a heart attack. In this manner a serious bias is introduced into the test populations, which is responsible for a serious distortion of the results in favour of those taking HRT.

Before taking additional oestrogens in the form of supplements we should also consider the problem of oestrogen dominance. We also need to consider the nature of the oestrogen receptor and to determine the possible advantages of using ‘weaker’ oestrogens or others that have been modified in such a manner that they do not activate the undesirable aspects of the action of oestrogens, such as excessive growth stimulation which may lead to cancer.

Oestrogen dominance: progesterone
Oestrogen and progesterone are two very important hormones that fluctuate according to a distinct pattern during the normal female monthly cycle. In many respects these two hormones have opposing effects in the body, and for the maintenance of optimal health it is necessary to maintain a certain balance between the two hormones. This balance may be distorted if additional quantities of oestrogens are taken without considering the progesterone status of the patient. This phenomenon is referred to as oestrogen dominance. It can be caused by increased levels of oestrogens caused by overproduction and/or supplementation or by a deficiency of progesterone. It can also be aggravated by the huge load of environmental oestrogens present in our environment. Hence the practice of using oestrogens such as Premarin in combination with synthetic progestins.

These are ‘progesterone-mimickers’ which are produced synthetically. They are therefore drugs and not natural substances and as such have side-effects not associated with natural progesterone. They also have some (but certainly not all) of the desirable properties of natural progesterone which unfortunately cannot be used in oral supplements due to rapid breakdown in the liver. For this reason it is more effective and safer to take progesterone topically in the form of a progesterone cream.

Some of the side-effects associated with oestrogen dominance include face puffiness, excessive uterine bleeding, night-time feet swelling and PMS symptoms. Oestrogen dominance is particularly relevant in the menopausal and postmenopausal woman in whom natural progesterone may decline to very low levels. If oestrogens are given to these patients in the form of supplements, the problems associated with oestrogen dominance may be expected to develop.

By using the usual oestrogen plus synthetic progestin combination present in most HRT formulae more problems may be created as pointed out by Dr Robert Atkins in his book.10 This combination will promote weight gain tendencies in most women as a result of its effects on the common insulin-related disorders (raised triglycerides, cholesterol and blood pressure) resulting from the consumption of refined carbohydrates. These food artefacts cause chronically elevated blood sugar levels associated with chronically elevated insulin levels, which in turn are inter alia responsible for elevated triglycerides, diabetic tendencies, high blood pressure and weight gain. These effects are aggravated by HRT. The oestrogen component in HRT formulae suppresses glucagon secretion, the one hormone capable of controlling elevated insulin levels which are at the core of the problem. It has been shown that estradiol (a common component in HRT formulae) depresses glucagon secretion, which then leads to elevated insulin levels resulting in blood lipid elevations with attendant undesirable consequences, including the tendency to gain weight.11 Many women on HRT will confirm that this is a real problem. It is also a good reason why the postmenopausal woman should pay careful attention to her diet and reduce or preferably completely eliminate refined carbohydrates.

Progesterone, in the form of a topical cream, is relatively harmless and should be seriously considered as part of any hormone replacement programme.

Environmental oestrogens
The patient who decides to take extra oestrogens in the form of HRT should consider the impact that the huge quantities of environmental oestrogens have on the total oestrogen load to which we are daily exposed in the form of oestrogenic chemicals present in some plastics and pesticides, many of which have an additive effect. These are thought to be responsible for the drastic decline in fertility and sperm counts in the Western world as well as the increase in incidence of certain oestrogen-related cancers (breast, cervix and testes) and other oestrogen-related diseases such as endometriosis, ovarian cysts and fibroids. We need a lot more information before we will be able to appreciate fully the health consequences of these man-made chemicals. In the meantime, there is little doubt that they contribute to the general problem of oestrogen dominance.

The nature of the oestrogen receptor
Many biologically active molecules such as oestrogens and other hormones are essentially chemical messengers which prompt cells that have receptors for them to perform certain functions, such as to grow. This function is performed by occupying receptors on the cell surface which ‘receive’ the messages and then pass them on for execution. In this sense receptors may be compared with a computer keyboard. Organs with cells in them that have the particular receptor may therefore be expected to react to the message. In this manner oestrogens react with receptors in different organs such as the brain, breast, gut and skin and many others with oestrogen receptors. This explains the wide range of biological effects that oestrogens have in the human body.

Some receptors are very specific, they can only be occupied by one specific type of molecule, while others such as the oestrogen receptor are more spacious, allowing them to accommodate more than one type of molecule on their surface. When a molecule occupies a receptor (‘keyboard’) it may activate certain specific ‘keys’ on the surface which initiate certain graded cellular responses in the particular organ. Thus when a ‘strong’ oestrogen such as estradiol occupies the oestrogen receptor, it will cause a strong growth response, while a ‘weaker’ oestrogen such as a phyto-oestrogen may elicit a much weaker response. Other molecules, such as tamoxifen or indole-3-carbinol, may prompt no growth response although they have occupied the receptor, thus preventing active oestrogen molecules from occupying it (‘receptor blockage’). One of the most important messages that oestrogens deliver to many cells is to divide and multiply (the grow signal). That is why oestrogens are so important in pregnancy but at the same time dangerous in the cancer patient.

Up to 70% (and possibly many more) of all breast cancers have oestrogen receptors on their cells which means that increased circulating oestrogen levels in these patients (such as may result from conventional HRT) will tend to stimulate cancerous growths. Some oestrogens produced in the body, such as the ones mostly used in HRT formulations (estradiol and estrone), fit the oestrogen receptors perfectly, thus enabling them to stimulate all oestrogen-related functions maximally, including that of growth and multiplication. Weaker oestrogens such as estriol (also produced in the body) or certain isoflavone plant oestrogens fit the oestrogen receptor site reasonably well, but in so doing they only elicit a weak growth signal while still activating other more desirable oestrogen functions such as the suppression of menopausal symptoms. Also, having occupied the oestrogen receptors, these ‘weaker’ oestrogens may prevent stronger oestrogens such as estradiol from occupying the same receptor site, thus preventing them from exerting their growth-stimulating properties. This very incomplete and elementary discussion of receptor function nevertheless allows us to understand, at a molecular level, why weaker oestrogens such as the ones mentioned may be effectively used to replace the more dangerous strong oestrogens as components in a HRT programme.

Alternatives to conventional HRT
Several strategies exist by means of which the advantages of oestrogen therapy may be largely retained while at the same time reducing the disadvantages such as excessive growth stimulation which may stimulate cancerous growths. The following possibilities exist:

  • the use of phyto-oestrogens such as soya isoflavones which have oestrogenic activity
  • the use of ‘weak’ endogenous oestrogens such as estriol
  • the use of hormone precursors such as dehydroepiandrosterone (DHEA) and pregnenolone
  • The use of bio-identical oestrogen and progesterone creams.

No one alternative will suit all patients equally well. The patient, in consultation with her doctor, must decide which one is the most suitable in her particular case.
These alternatives will be discussed in more detail in the next issue of the Journal.

NIH Stops Estrogen-Alone Arm of WHI: A Newsmaker Interview with Jacques Rossouw, MD

Laurie Barclay, MD

Medscape Medical News 2004. © 2004 Medscape

March 4, 2004 — Editor’s Note: On March 2, the National Institutes of Health (NIH) instructed 11,000 women enrolled in the estrogen-alone group of the Women’s Health Initiative (WHI) to stop taking study medications and to begin the follow-up phase of the study. After a review of data from approximately seven years of follow-up, the NIH concluded that in that time frame, estrogen alone does not affect heart disease or breast cancer risk, while increasing stroke risk and decreasing hip fracture risk. These results would not be likely to change even if the estrogen trial continued to its planned completion in 2005, according to the NIH.

The increased risk of stroke with estrogen alone was similar to that for estrogen plus progestin, which prompted investigators to stop that part of the trial in July 2002. The WHI was split as to whether the estrogen-alone study medications should be stopped or whether they should be continued, provided that a letter was sent to the subjects clearly informing them of the stroke risks and other findings. On Feb. 2, the NIH decided to stop the estrogen-alone part of the trial.

To learn more about the clinical implications of these findings, Medscape’s Laurie Barclay interviewed Jacques Rossouw, MD, National Heart, Lung, and Blood Institute project officer of the WHI.

Medscape: What are the main findings from the WHI estrogen-alone group at the seven-year point?

Dr. Rossouw: The NIH stopped the study drugs in the estrogen-alone trial in the interest of safety after finding an increased risk of stroke and no effect — neither an increase or a decrease — on risk of coronary heart disease. The increased risk for stroke was similar to that found in the trial of estrogen plus progestin, where the excess risk amounted to eight additional strokes per year for every 10,000 women on estrogen. After an average of seven years in the trial, there was no apparent increase in the risk for breast cancer. As expected, there was a decreased risk of hip fractures. It should be noted that all of these risks and benefits were small, in absolute terms, as might be expected in a trial of healthy women who have low rates of disease to start with.

Medscape: Why was the WHI Data and Safety Monitoring Board (DSMB) split on their recommendation to stop the trial, and why did the NIH elect to stop it?

Dr. Rossouw: The DSMB was split on whether the trial should stop, or should continue with a clear message to participants about the risk for stroke. NIH stopped the study after a thorough and thoughtful review of the DSMB recommendation, and after considering every possible argument for continuing or for stopping. In the end, the NIH decided that the continuing risk for stroke was not acceptable in a prevention trial of healthy women, given that there was no benefit for heart disease. In the judgment of NIH, enough data had been collected to come to some conclusions about the risks and benefits of estrogen alone. It seemed unlikely that there would be any increase in scientific knowledge if the trial continued for one more year, and in any event the risk of stroke outweighed any possible gain.

Medscape: What were the effects on cognitive impairment in women older than 65 years?

Dr. Rossouw: A subset of women over the age of 65 participated in the WHI Memory Study (WHIMS), and of course this trial also ended at the same time. Preliminary data suggest that for the WHIMS participants who were on estrogen alone compared to the women who were taking the placebo, there was a trend toward increased risk of probable dementia and/or mild cognitive impairment.

Medscape: Given animal models and earlier studies, are you surprised by these findings?

Dr. Rossouw: In the years since WHI was designed, considerable knowledge has accumulated from other clinical trials of hormones, both estrogen alone and estrogen plus progestin, to prevent heart disease. Most of these trials had surrogate outcomes, like changes in coronary angiograms rather than clinical outcomes, and most of them enrolled women who already had evidence of heart disease or stroke. With the exception of one study using carotid intima-media thickness as an outcome, these trials failed to show benefit in terms of changes in arteries, or for the clinical outcomes of coronary heart disease and stroke, and in some instances there was evidence of harm in the first year or two after starting the study drug.

The primary prevention WHI trial of estrogen plus progestin showed no overall benefit for CHD, and a statistically significant increase in risk during the first year. These results were very similar to those found in the earlier Heart and Estrogen/Progestin Study (HERS), which was a secondary prevention trial in women with existing heart disease. So, the data from the primary prevention WHI trial of estrogen alone adds to a growing body of evidence that hormones, whether estrogen alone or estrogen plus progestin, are not useful for the prevention of heart disease in postmenopausal women.

The animal models and laboratory studies examined effects of hormones on a much earlier stage of atherosclerosis than that prevalent in women in their fifties, most of whom likely have existing, albeit subclinical, atherosclerosis, and therefore it is uncertain whether their results apply to the average woman starting postmenopausal hormones. The observational studies have inherent flaws such as differences in women who take hormones compared to those that do not, and the inability of some of these studies to include CHD events in the first year or two after starting hormones — which is when most of the excess CHD events occurred in the clinical trials. Nonetheless, the hypothesis that younger women who start hormones at the age of menopause may have a more benign outcome is worthy of further study.

Medscape: Are there any data concerning the effects of the equine estrogen used in this study compared with natural estrogens or related compounds?

Dr. Rossouw: Some of the trials noted above used estradiol rather than conjugated equine estrogens, and the results for CHD and stroke were similar to that found in the WHI in that estradiol did not retard the progression of coronary atherosclerosis or prevent strokes. In a trial of estradiol in women who had a prior stroke, the overall risk of stroke was not affected but there was some evidence of increased risk of more severe strokes and also an increased risk of strokes in the first year after starting estradiol. The single trial of estradiol in women with normal carotid arteries did find some regression of carotid intima-media thickness compared to placebo in the subset who were not on statins. Those that were on statins showed regression of carotid intima-media thickness, but no further improvement for the subset on both statins and estradiol. One way of interpreting these results is that both statins and estradiol were effective, but that they do not act in an additive manner. So, given the choice and the proven benefits of statins compared to the risks of estrogen, statins are a better choice for preventing atherosclerosis.

Medscape: Should women who have been taking estrogen alone follow any special preventive measures to decrease their stroke risk?

Dr. Rossouw: The NIH press statement and letters to participants are intended to notify WHI study participants that they should stop their study pills, and are not intended to cause any change in clinical practice. The complete data will be published in a peer-reviewed journal in the next two months, [after which] the [U.S. Food and Drug Administration] FDA and the professional bodies will consider whether changes in practice guidelines are needed. In the meantime, the FDA guidance is that if hormones are used, they should be used at the lowest dose and for the shortest possible period. Measures to reduce stroke risk are no different for hormone users than nonusers, and of course include due attention to all the risk factors, especially high blood pressure.

Medscape: At this point, what are the primary indications for estrogen-alone therapy?

Dr. Rossouw: According to the FDA, the indications for estrogen-only therapy are the treatment of moderate to severe hot flashes and night sweats, the treatment of vulvovaginal atrophy (but topical estrogen is preferred), and the prevention of osteoporosis. For osteoporosis prevention [with] estrogen and estrogen plus progestin, the FDA advises that the need for treatment must be clearly established, and that other treatments must first be carefully considered. In other words, hormones are no longer a first-line treatment for the prevention of osteoporosis.

Medscape: Are additional studies planned?

Dr. Rossouw: Within WHI, the participants in both the hormone trials will be followed at least [until] 2007 to see whether the effects observed during the trial dissipate, or whether an increased risk of breast cancer [in the estrogen-alone trial] emerges in later years. The WHI investigators will continue to analyze and publish the data, including data on subgroups that might be at higher or lower risks of stroke and other health conditions. Laboratory studies are being conducted to try to explain the findings, for example, to find out whether there are any markers of risk that would allow physicians to identify women who are at particularly high risk.

Medscape: How should physicians advise their patients concerning the risks and benefits of hormone therapy?

Dr. Rossouw: The NIH concurs with the guidance from the FDA, which is that hormone use should be limited to the treatment of moderate to severe menopausal symptoms, vulvovaginal atrophy, and prevention of osteoporosis (as a second-line drug). In addition, hormones should be used at the lowest dose and for the shortest time needed to obtain the desired effect. The need for hormones should be reconsidered at regular intervals, and attempts made to discontinue such use when no longer needed.

Reviewed by Gary D. Vogin, MD

The Effect of Hormone Replacement Therapy on Recall Rate in the National Health Service Breast Screening Programme

J C Litherland, A J Evans and A R M Wilson

Breast Screening Training Centre, Nottingham City Hospital, Nottingham, UK.

Purpose: Hormone replacement therapy (HRT) can lead to an increase in the density of breast parenchyma on mammography and to the development of mammographically visible cysts and fibroadenomas. These changes may obscure features indicative of benign processes or mimic those of a carcinoma on screening mammography.  This study was designed to assess the effect of HRT usage on the recall rate of women attending for routine breast screening.  Method: Details of HRT usage were taken from 5 699 consecutive women aged 49-64 attending for breast screening. Mammograms were read without knowledge of HRT usage and recall for assessment details collected. Result: A significant fall in recall rate was seen between the prevalent and incident screens in women not taking HRT (p<0.016). This fall was not present in women taking HRT. The recall rate for the incident screen on women on HRT was 37% higher than that for women who did not take HRT; however the positive predictive value for cancer of recall was lower at 3.7% compared to 12.9%.  Conclusion: These results indicate that the recall rate for incident screening is likely to be higher in women on HRT. This increase in assessment will lead to increased cost, and anxiety in the screened population. LItherland, J.C., Evans, A.J. & WIlson, A.R.M. (1997) Clinical Radiology 52, 276-279. The Effect of Hormone Replacement Therapy on Recall Rate in the National Health Service Breast Screening Programme.

Accepted for publication 6 August 1996

Hormone replacement therapy (HRT) is now widely used to relieve menopausal symptoms and for the prevention of osteoporosis [1,2]. However, it is also known to be associated with breast parenchymal changes which may be apparent on .mammograms.  Increases in background density, both focal and generalised, and the appearance of mass lesions representing cysts and fibroadenomas have been described previously in women taking HRT (3-7).  The changes can mimic malignancy and so are likely to lead to recall for further assessment when they are detected on routine screening mammograms.  The use of HRT could therefore lead to increased recall rates with the associated resource implications and an increase in anxiety for women who are disease free. This study was designed to ascertain the number of women taking HRT in our screening population and assess the effect this has on the recall fate for these women compared with those not taking HRT.

The details of screening recalls and the results of further assessment were collected. The results of FNA, core biopsy and surgery were also collected. Results were analysed using the chi-squared test.

Discussion

Hormone replacement therapy is now widely used for the relief of menopausal symptoms and many women within the age range invited for screening on the NHSBSP will be taking HRT regularly. Breast parenchymal patterns are known to change as women get older with a significant fall in density with increasing age (8).

However the use of HRT has been demonstrated to diminish this trend in some women [3] but also to lead to the development of a dense glandular pattern in breasts which were previously of low density, (fig 1). Changes may be bilateral and generalized (4) or focal and asymmetric, often representing cysts and fibroadenomas which may increase in size when a women takes HRT (5-7) (Fig 2).  It has been suggested that these changes  may lead to a decrease in sensitivity for detecting carcinoma on mammograms [5,6], and specificity for carcinoma will also decrease when women are recalled for assessment because of developing densities and enlarging masses which in reality represent benign changes. False positive results have resource implications as well as causing anxiety for the women involved [9].

Our study demonstrates a significant fall in recall rate between the prevalent and incident round for women who were not taking HRT. This is to be expected as films from previous screens are available for comparison making the: detection of any suspicious change easier. In spite of similar mean ages in the groups, there is no equivalent fall in the recall rate between the prevalent and incident rounds for women on HRT; in fact the recall rate in the incident round is 37% higher than that for women who are not on HRT. This may reflect the fact that these women are more likely to have changing parenchymal patterns because of their HRT. Pronounced changes in parenchymal patterns may also explain the trend to increased recall of women who started their HRT within the last 36 months, rather than before the previous screen. It is of note that the prevalent round recall rate for women on HRT is non­-significantly lower than that for women not on HRT. This may be because denser glandular breasts in women on HRT lead to decreased sensitivity for masses within the breast, and hence a lower recall rate. At incident screening, conversely, the further development of density leads to an increase in recall rate.

The benefits of HRT are well known, including the relief of menopausal symptoms. However we need to be aware of the drawbacks of a treatment which is so widely used. Discussion about the link between HRT and breast cancer continues [10]. The results of our assessments did not demonstrate any significant difference in outcome between the groups of women; our study is not large enough to comment on any relationship between HRT and breast cancer. However it does demonstrate a non ­significant decrease in the positive predicted value for carcinoma in the recalled women on HRT compared to those not on HRT which may indicate that women on HRT are more likely to be assessed for benign lesions. The significant decrease in recall rate seen after the first screen in women not on HRT is not seen in women on HRT, and this is also likely to lead to an increased number of recall assessments for well women on HRT with an associated increased use of resources and heightened level of anxiety for such women and their families.  A larger study would be needed to demonstrate a significantly increased recall rate for women on HRT compared to those not taking HRT.

References

  1. Daly E, Gray A, Barlow D et al Measuring the impact of menopausal symptoms on quality of life. British Medical Journal 1993;307:836-910
  2. Felson DT, Zhang Y, Hannan MT et al. The effect of postmenopausal estrogen therapy on bone density in elderly ·women. New England Journal of Medicine 1993;329:1I41-II46.
  3. Kaufman Z,  Garstin WM, Heyes R et al The mammographic parenchymal patterns of women on hormone replacement therapy. Radiology 1991,43.389-392.
  4. Berkowitz JE, Gatewood OMB, Goldblum LE et al. Hormone replacement therapy: mammographic manifestations.Radiology 1990, 199-201
  5. Stomper PC, van Voorhis BJ, Ravnikar VA et al.. Mammographic changes associated with postmenopausal hormone replacement therapy a longitudinal study. Radiology 1990;174-487-490.
  6. Cyrlak D, Wong CH. Mammographic changes in postmenopausal women undergoing hormone replacement therapy.American Journal of Radiology 1993;161:1177-1183.
  7. Doyle GJ, McLean L. Unilateral increase in mammographic density with hormone replacement therapy. Clinical Radiology 1994;49: 50-51.
  8. van GiIs CH, Otten JDM, Verbeek ALM et al. Short communication:  Breast parenchymal patterns and their changes with age. British Journal of Radiology 1995;68: I 133-1135.
  9. Lidbrink E, Elfving, FriselI J et al. Neglected aspects of false positive findings of mammography in breast cancer screening: analysis of false positive cases from the Stockholm trial. British Medical 10llmal 1996;312:273-276.
  10. McPherson K. Breast cancer and hormonal supplements in post-menopausal women. British Medical Journal 1995;311:699-700.

IF THIS DOES NOT CONVINCE ANYBODY THAT ESTROGEN CAUSES BREAST CANCER, AND THEN NOTHING WILL! (It shocked us that our prescriptions may be causing 25% of breast cancers in our patients)

Regional Changes in Hormone Therapy Use and Breast Cancer Incidence in California from 2001 to, 2004

Robbins AS, Clarke CA (Public Health Inst, Sacramento, CA; Northern California Cancer Ctr, Fremont; Stanford Univ School of Medicine, CA)

J Clin Oncol 25:3437-3439, 2007

Purpose—Recently, an unprecedented 1 -year 7% decrease in the overall incidence of invasive female breast cancer in the United States was reported. It has been suggested that the decrease resulted from the mass cessation of estrogens-progestin hormone therapy (EPHT) in 2002. We took advantage’ of California’s unique population-based cancer surveillance resources to assess whether regional changes in breast cancer incidence                     observed between 2001 and 2004, correlated with regional changes in EPHT use between 2001 and 2003.

Methods.—we obtained state-wide cancer registry and California Health Interview Survey (CHIS) EPHT data for almost 3 million non-Hispanic white women age 45-74 years,

residing in California’s 58 counties. We examined trends in the age-adjusted incidence of in-evasive female breast cancer and compared these with trends in the use of EPHT, after grouping all California counties into three groups based on EPHT use in 2001. We also examined CHIS data on trends in screening mammography.

Results.—in 2001, there were large regional differences in EPHT use and breast cancer incidence. From 2001 to 2004 incidence declined in all the counties in a linier relationship with reductions in EPHT use.

The smallest EPHT reductions coincided with the smallest reductions in breast cancer. The largest reductions in EPHT use coincided with the largest drop in breast cancer figures. Between 2001 and 2003, CHIS data did not show any significant change in the proportion of women who reported hav¬ing a mammogram in the previous 2 years.

Conclusion.—these data support the hypothesis that changes in Estrogens-progestin hormone therapy use in 2002 may be responsible for significant declines in breast cancer incidence between 2002 and 2003 and sustained through 2004.

“Coincident with the announcement of the Women’s Health Initiative in 2002, the use of EPHT dropped dramatically.

Breast cancer incidence in the United States started to drop at the same time.

An implication is that the former caused the latter.2 the authors of the present study addressed the relationship between EPHT use and invasive breast cancer in a clever and interesting way. They obtained county-specific data about breast cancer incidence and EPHT use for nearly 3 million non-Hispanic white women 45 to 74 years old living in California. They assigned all of California’s counties to 1 of 3 groups based on level of EPHT use in 2001 (low, medium, or high) and assessed the use of EPHT within each group in 2003.

They found that EPHT use dropped to about 6% in all 3 groups.

The higher the use of EPHT in 2001, the greater the drop in both EPHT use and breast cancer incidence.

Moreover, these findings evince a linear relationship. The authors do not say so explicitly, but their data suggest that EPHT use prior to 2002 may have accounted for as much as 25% of the breast cancers among women in this age group, which is consistent with the data reported in the Surveillance, Epidemiology, and End Results (SEER) database. As in other studies, 2 these authors found no appreciable decrease in screening mammography use that might account for a drop in breast cancer incidence during the period in question.”

  1. A. Berry, PhD

Cancer Research Professor of Biostatistics, Anderson Cancer Centre,

REFERENCES:

  1. Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007; 356:1670-1674.

Berry DA, Ravdin PM. Breast cancer trends: a marriage between clinical trial evidence and epidemiology. J  Nat. Cancer Inst. 2007 99:1139-1141.

“WE SHOULD ALWAYS BE HUMBLED WHEN WE THINK OF WHAT WE DO NOT KNOW ABOUT THE FEMALE REPRODUCTIVE CYCLE.

WE STILL HAVE NO UNDERSTANDING OF THE MECHANISM THAT MAKES ONE GRAAFIAN FOLLICLE IN ONE OF THE OVARIES OF A NORMAL WOMAN MATURATE AND OVULATE EACH MONTH. THIS IS A BAFFLING PROBLEM.

UNTIL WE KNOW THAT MECHANISM THAT SELECTS ONE GRAAFIAAN FOLLICLE, OUT OF PERHAPS HUNDREDS OF THOUSANDS, TO MATURATE EACH MONTH, WE STILL HAVE TO PROCEED WITH CAUTION ON ANY LONG-TERM HORMONAL TREATMENT OF THE HUMAN FEMALE”.

CHARLES DODDS (INVENTOR 1st SYNTHETIC OESTROGEN – DES )

This comes from the inventor of the first synthetic estrogen way back in 1938.Shortley after this he warned that estrogen causes breast cancer in his laboratory rats, and it might be the same in human females!!!   He was right, but the warning fell on deaf ears. (Ie.ears plugged with dollars}

HRT prescriptions linked to 25% of breast cancers in California

(CORRESPONDENCE TO SAMJ)

To the Editor: I am a breast radiologist, running a multidisciplinary breast care centre together with two surgeons and a practitioner in oncology. We add about 90 – 100 new cancer cases to our files annually.

I am amazed to see how we doctors persist in our old ways of prescribing medicine and how reluctant we are to change, despite recent data. Our medical history is flawed with mistakes that sometimes took hundreds of years to correct (400 years to admit that vitamin C prevents scurvy, decades to admit that Semmelweis was right in washing hands and that bloodletting had no benefit). It took the USA’s Food and Drug Administration (FDA) 37 years to ban diethylstilbestrol, after the first synthetic oestrogen caused vaginal cancer in female babies.

Despite many colleagues criticising the composition of the Women’s Health Initiative (WHI) study1 on hormones, it nevertheless had a major impact on breast cancer figures. Women became scared, stopped their prescriptions, and then … breast cancer figures tumbled – for the first time in 30 years2 – and in the 1970s also dropped after the scare of oestrogen causing endometrial cancer.3

The Stanford University Group could find no other cause of the unprecedented drop – other than women stopping their HRT prescriptions.4,5 A calculation by Donald A Berry, Cancer Research Professor of Biostatistics, Anderson Cancer Center, shocked us: that 25% of breast cancers in California before 2002 could have been caused by HRT prescriptions.6 Which means that we, well-meaning doctors, caused cancer in our patients. This was 67 years after Dr Charles Dodds (inventor of the first synthetic oestrogen, diethylstilbestrol) and Dr Boris Shimkin warned that it caused cancer in their laboratory rats and that we did not know what the long-term effect might be on the human female!7

It is high time that our patients should be informed about the side-effects of prescription drugs and encouraged to make their own decisions, irrespective of whether the drug is thalidomide, Vioxx or HRT. After all, hormones are misused in a non-disease state like the menopause. How long will it take us to discard the financial gains, to admit that we are harming many of our patients, and to start changing our prescription habits?

A J Carstens

Eastleigh Breast Care Centre

Moreleta Park

Pretoria

drcarstens@breastcare.co.za

 

  1. Writing Group for the Women’s Health Initiative Investigators. Risk and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 88: 321-333.
  2. Ravdin PM, Cronin KA, Howlander N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med 2007; 356(16): 1670-1674.
  3. Smith DC, Ross MD, Donovan PD, et al. Association of exogenous estrogen and endometrial carcinoma. N Engl JMed 1975; 293(23): 1259-1262.
  4. Regional Changes in Hormone Therapy Use and Breast Cancer Incidence in California from 2001 to 2004. J Clin Oncol 2007; 25: 3437-3439.
  5. The decrease in breast cancer incidence in 2003 in the United States N Eng J Med 2007; 356: 1671-1674.
  6. Robbins AS, Clarke CA. Regional changes in hormone therapy use and breast cancer incidence in California from 2001 to 2004. J Clin Oncol 2007; 25(23): 3437-3439.
  7. Shimkin MB, Grady H. Carcinogenic potency of stilbestrol and estrone on strain C3H mice. J Natl Cancer Inst 1940; 1: 119-128.

Did you know?

  • About 1/15 hospital admissions are due to adverse drug reactions (ADR’s)1
  • ADR’s account for about 100 000 deaths annually in the USA alone

 

 Breakdown of the 1035 new drugs approved by the FDA between 1989 and 2000 (NIHCM 2002)