Addressing Postmenopausal Estrogen Deficiency: A Position Paper of the American Council on Science and Health

Sander Shapiro, MD

In This Article

Physiology of Reduced Estrogen Production

The most common perceivable and physiologically detectable events associated with onset of menopause are the occurrence of hot flashes and body sweats. These vasomotor complaints may begin several years before menopause and usually last for 2-5 years beyond that landmark event. Infrequently, they are experienced by women over 60 years of age.[35] As many as 70% of American women experience these symptoms, to some degree, while only 20% of Japanese women report them.[11,36,37] Most European surveys on incidence produce rates similar to those reported in the United States.[38,39] The rather substantial difference between surveys from Eastern and Western countries remains unexplained. Cultural influences on perceptions and attitudes as well as biologic factors such as diet have been offered as possible reasons for the discrepancy.[40]

The characteristics of a hot flash have been described heterogeneously and are quite variable from individual to individual.[36] Generally, flashes are experienced as transient warm feelings that start on the upper body or face, spread centripetally, and last less than 2 minutes. They are accompanied by tachycardia and may be immediately followed by perspiration that is sometimes profuse. Episodes are usually more frequent during waking hours but can awaken a person multiple times each night. A pituitary luteinizing hormone pulse accompanies each flash.[41] Objective findings during each episode include a drop in skin electrical resistance, an increase in peripheral blood flow, and a rise in skin temperature. Peripheral vasodilatation and sweating often lead to a fall in core temperature with subsequent vasoconstriction, chills, and shivering.[42] These events have caused physiologists to suspect that both labile hypothalamic thermoregulatory and peripheral vascular response mechanisms are at the etiologic center of this phenomenon.[43,44] The precipitating event that affects the hypothalamus is estrogen withdrawal. Appearance and extent of symptoms is directly related to the serum concentration of postmenopausal estrogen.[45] Age of the individual does not relate to incidence of this type of vasomotor instability, as young women who are oophorectomized experience these symptoms at about the same rate as older women.[46]

Recognition of the temporal relationship between menopause and ovarian atresia is of long standing. It formed the basis for the early 20th century hypothesis that gradually falling levels of an ovarian product might be the primary initiator of vasomotor flushing. Supporting this belief was the observation that an increase in frequency and intensity of hot flashes resulted from an abrupt loss of the ovarian agent, as happens following oophorectomy.[47] This hypothesis was finally sustained when pure samples of various estrogens became available and were shown to abolish menopausal vasomotor symptoms. Additional support for the central role of estrogen withdrawal came from the observation that prepubertal girls and adult women with ovarian agenesis, both of whom have low serum estrogen levels, are unencumbered by hot flashes. Further evidence is provided by the observation that once exposed to estrogen, women with ovarian agenesis experienced hot flashes following cessation of administration.[48]

More recently, the mechanistic role of LH pulses as a requirement for initiation of each hot flash has been pondered. The finding that flashes continue to occur in women whose capacity to secrete LH has been inhibited by long-acting gonadotropin agonist administration has established that this pituitary agent does not trigger flashes. Similar findings have been noted in hypophysectomized women. Mechanistic studies have also substantially ruled out menopausally elevated levels of FSH and the absence of inhibin as primary initiators of menopausal vasomotor instability.[49] Hence, the cellular site and underlying mechanisms that cause hot flashes remain undetermined.

Prospective studies of perimenopausal women do not provide data to demonstrate that they experience an increase in psychological or physical problems other than vasomotor complaints and diminished vaginal lubrication.[11,50] Convincing evidence has not been developed to support claims for the occurrence of more frequent or intense psychiatric problems during this period.[51] The oft enunciated 19th century view that menopause is associated with nervous irritability and hysterical states does not bear up to scrutiny through comparative testing.[19,52] However, when vasomotor complaints become severe, there can be sufficient sleep deprivation to induce irritability, tiredness, and difficulty with concentration.[53] Also, test instruments designed to detect clinical depression have been found to provide mean numerical scores among perimenopausal women that, while not consistent with overt depression, do decrease significantly after estrogen treatment.[54]

Estrogen replacement has been demonstrated to be an effective treatment for hot flashes.[36,55] The reduction in frequency and severity is time dependent, requiring from 4-6 weeks for maximum effect. After this length of therapy, alterations in quantifiable sleep parameters can also be expected. The oral dose of conjugated estrogen that is most frequently effective is 0.625 mg/day. Higher doses are sometimes required. However, when 1.25 mg is inadequate, the initial diagnosis must be questioned. There is rarely a substantive difference in response when other routes (transdermal, intramuscular) or estrogen formulations are prescribed.

Almost contemporaneous with the onset of flushing, some women begin to experience dyspareunia and vaginitis. These signs are thought to result from a decrease in vaginal lubrication and a change in pH.[7] Later events include restricted blood flow, epithelial atrophy, and loss of connective tissue elasticity. Since sexual interest can remain high (over 50% of peri- and postmenopausal women) these physiologic changes are unwelcome.[56] Preventing their appearance or inducing their reversal can usually be accomplished by administration of the same systemic estrogen doses as are given for vasomotor symptoms.[57] When direct vaginal application of estrogen cream is undertaken, therapeutic serum levels of the hormone are usually attained. Local estrogen delivery systems have recently become commercially available for the treatment of vaginal atrophy. They provide sustained hormone release without causing an appreciable rise in serum estrogen concentration or the induction of systemic events.

Estrogens contribute to the maintenance of many tissues and their metabolic activities. When estrogen levels fall toward the end of the perimenopause, two distinguishable kinds of change take place. One includes a group of rather abrupt and directly observable events, including vasomotor flushing. The other comprises a larger, diverse group of more slowly developing processes whose observable consequences reach threshold status only years after ovarian estrogen output has fallen. Outwardly, the late changes seem indistinguishable from other degenerative events related to aging. In the past, there was nothing that directly connected them to the temporally distant menopause. However, by mid-20th century, their collective relationship to an absence of estrogen stimulation had become evident. Simultaneously, the sequelae of these physiologic degenerative processes began to draw clinical attention. This conjunction fostered the concept that postmenopausal women were in a state of chronic estrogen deficiency which, in turn, provided the rationale for long-term ERT. Those organ systems that are considered to be most profoundly affected by limited postmenopausal estrogen levels are the cardiovascular, skeletal, genitourinary, and central nervous system (CNS).

Cardiovascular Disease. Cardiovascular disease is the most common cause of death among women in the United States.[58] Deaths due to coronary heart disease are less frequent than in men at all ages and are extremely infrequent before the advent of menopause.[59] Postmenopausal coronary heart disease rises in women, paralleling the increase seen in men as they age. Women who undergo premature menopause are at greater coronary risk than menstruating women of similar age.[60] These observations suggest that estrogens play a significant role in delaying the onset of cardiovascular disease in women. They also support the hypothesis that by replacing estrogens after menopause, substantial reductions in the incidence of cardiovascular disease can be obtained. A number of specific direct and indirect estrogen effects are thought to potentially contribute to this favorable outcome.[61]

Estrogens exert a major influence on lipoprotein metabolism. Hepatocytes produce more high-density lipoprotein (HDL) and catabolize more low-density lipoprotein (LDL) when under estrogen stimulation. This induces a serum lipid profile that is less favorable to atheroma formation. When estrogen levels fall the ratio of HDL to LDL changes, adversely resulting in an increased rate of atherosclerosis production.[62] Estrogen administration after menopause will maintain a favorable lipoprotein profile.[63] ERT can alter hepatic protein production profiles that may then influence cardiovascular risk by changing intravascular coagulation characteristics. In addition, estrogens have several direct effects on blood vessel metabolism that are favorable.[61,63,64] These include their antioxidant activity, which protects endothelial cells from injury, and their capacity to inhibit myointimal proliferation after vascular injury.[65] Numerous other estrogen-induced effects, some that involve nonclassical (nongenomic) steroid mechanisms, have also been proposed.[62,66] All are potential inhibitors of cardiovascular disease. However, the fractional contribution of these mechanisms to the overall result brought on by estrogen is unknown.[67] At present, conjecture places one third of an estrogen's favorable overall effect on cardiovascular disease in its influence on lipoprotein profiles.[60,68,69]

Despite evidence that estrogens have beneficial effects on arterial health and the wide use of these steroids to inhibit the development of coronary heart disease, therapeutic efficacy remains in question. Almost every observational study published to date has found a lower risk of coronary heart disease in postmenopausal women who were taking ERT as compared with those who were not.[70] In aggregate, these findings suggest that estrogen replacement is responsible for a reduction in the relative risk of death from coronary heart disease to 0.70, with some individual studies doing considerably better.[68] Studies that included a progestin in the therapeutic regimen produced similar reductions. The large number and variable design used in these studies make it unlikely that these results were produced by some unidentified confounding factor.[71] Nevertheless, controversy remains primarily because of the limited amount of information available from randomized, prospective studies.

Recently, skepticism has been heightened by findings from the only large-scale, blinded, placebo-controlled trial yet to be published.[72] In that study, women with preexisting acute coronary disease were put on an estrogen-progestin or placebo regimen for 4 years. Overall, the number of coronary events in the two study limbs was the same. However, there was an increase in the number of clinical adverse events among estrogen users during the trial's first year. Furthermore, a prospective, randomized trial that employed sequential coronary angiography to evaluate women with documented coronary artery disease failed to demonstrate any substantive differences between those who were or were not on an HRT regimen.[73] Thus, while these results seem contrary to those of several nonrandomized trials and may not be indicative of future results, they do provide a note of caution.[58,74]

Osteoporosis. Osteoporosis is defined as a loss of normal bone micro-architecture and density that leads to structural fragility. The cellular processes that cause this deterioration are intrinsic to the general process of aging. In women, a more rapid diminution of bone mineral density is superimposed upon this slow loss during the 5-10 years immediately following menopause.[75] Among persons of limited peak bone density, age-related bone loss results in a greater risk of fracture -- common sites being vertebral bodies, wrists, and hips. Clinical measurements of bone density have established a threshold for substantially increased fracture risk at 2.5 standard deviations below the mean density found in young adults.[76] Women are more likely to cross this threshold then men, accounting for 80% of all hip fractures. Women who are big boned, darkly pigmented, or have higher postmenopausal estrogen levels are less likely to experience fractures.[77] Cigarette smokers and those who have had a limited calcium intake during their reproductive years are more susceptible.

Osteoporosis plays a significant role in most of the 1.5 million annual fractures that occur in the United States.[78] It was the first chronic medical problem recognized to result from long-term estrogen deficiency.[79] In recent years, the identification of estrogen receptors within bone cells and the realization that estrogens play an influential role in cellular bone remodeling activity have begun to provide a basic understanding of the mechanisms by which postmenopausal women rapidly lose bone density.[80]

Chronic estrogen administration during and following menopause has been shown to substantially reduce the rate of osteoporotic bone loss and decrease the incidence of both hip and vertebral fractures by about 50%.[81] ERT can also improve bone density measurements in osteoporotic women.[82] However, once estrogen administration ceases, the rate of bone mineral density decline returns to that of untreated women during the immediate postmenopausal period. Treatment intervals, routes of administration, and dosages have varied among the many favorably reported studies. On average, it takes from 5-10 years of ERT before a significant difference in fracture incidence can be demonstrated.[83] An improvement in bone density can be demonstrated after as short a therapy interval as 6 months. The effective dose of conjugated estrogens has been found to be as low as 0.3 mg/day.[84] However, most studies have found a dose of 0.625 mg to be more widely effective. Other forms of oral estrogen seem to be equally efficacious and, because the action is directly upon the target tissue, route of administration does not seem to matter.[85] Since little, if any, protection from fracture is gained with short-term estrogen replacement and because rapid bone deterioration resumes after estrogen withdrawal, therapy should be planned as a long-term activity. Moreover, once substantial loss of trabecular micro-architecture has occurred, estrogen-induced stabilization and/or increased bone density are thought less likely to diminish fracture risk.[86,87]

Genitourinary Disease. Hypoestrogenism during the perimenopause can result in the rather abrupt onset of dyspareunia. This is thought to be primarily the consequence of decreased vaginal secretions and the resultant lack of coital lubrication. Over longer intervals, more profound alterations in genitourinary anatomy and physiology occur. Studies in laboratory animals have demonstrated genitourinary sensitivity to estrogens. Estrogen receptors have been identified in the human urinary tract as well as in the various tissues of the internal genitalia.[88] After menopause, atrophic changes gradually occur in the urethra, periurethral connective tissue, and genital mucosa. A correlation has been shown between atrophic urogenital conditions and decreased sexual well being.[89] These changes are associated with urinary incontinence in more than 15% of the non-nursing home population who are over 60 years of age.[90] At present, however, the degree to which estrogen deficiency changes contribute to either urge or stress incontinence is unknown. Clearly, estrogens have a direct effect on urogenital tissues and are capable of inducing measurable improvements in several urodynamic parameters. Definitive studies that might establish the relative importance of estrogen deficiency among the several known causative factors for incontinence are lacking. Only the positive experiences from estrogen replacement studies are available to support the contention that a hormone deficiency contributes to age-related genitourinary symptomatology.

Meta-analysis of the available studies addressing estrogen therapy (as of 1994) for stress incontinence shows that while significant subjective improvement was found, a decrease in the quantity of urine loss was not demonstrable.[91] More recently, a single, large, controlled study of stress incontinence (inadvertent urine loss following an abrupt increase in intra-abdominal pressure) failed to obtain positive results from estrogen therapy.[92] On the other hand, studies evaluating estrogen therapy for urge incontinence (inadvertent urine loss associated with a sensation of voiding urgency) have been slightly more positive.[93] This has led one observer to suggest that the benefits of estrogen in some stress incontinence trials have actually been due to the presence of a mixed-type incontinence among members of the study groups.[94] A more substantive positive claim can be made for inhibition of recurrent cystitis and improved sexual function in postmenopausal women. Here, evidence strongly supports the use of either local or systemic estrogen therapy.[95]

CNS Deterioration. Among the faculties affected by aging, mentation stands out. Only minor quantifiable deterioration is experienced during middle age, while more severe decrements frequently occur in those who are over age 65.[96] Memory and learning capacity normally degenerate modestly in old age. When the decline is severe enough to interfere with daily affairs it is called dementia. This form of incapacity becomes increasingly prevalent after 70, and by age 80, new cases appear in the population with the same frequency as myocardial infarction.[97,98] Alzheimer's disease accounts for two thirds of all dementia, occurring in about 40% of the population that is over 80 years of age.[97] An association between estrogens, menopause, and cognition has long been postulated.[99] However, relatively little attention was directed toward the influence of estrogens on CNS activity until the last 2 decades. During this interval, persuasive evidence has been developed suggesting that estrogens promote neural cell growth, alter CNS function, and protect the system against toxins.

Work on ovariectomized rodents has demonstrated that estrogens enhance synapse formation within the cerebellum, hippocampus, and other CNS structures.[100,101] These synapses have been shown to actively transmit neural signals.[102] In the forebrain, estrogens stimulate production of choline acetyltransferase, which promotes production of the neurotransmitter acetylcholine.[103] A deficit in acetylcholine reduces memory, while estrogens can raise levels of the transmitter and prevent cognitive loss. Estrogens also act as an antioxidant, reducing the toxicity of several free radical producers; one of which, beta amyloid, accumulates in the brain of Alzheimer's patients.[104,105] In addition, estrogens have been shown to enhance synaptic sprouting through an apolipoprotein-dependent mechanism.[106]

These biochemical/molecular findings have provided a biological rationale upon which to explore the possible relationship between postmenopausal estrogen therapy and cognition. Two provocative questions have come under clinical investigation: Can ERT influence the modest general decline in age-related mental function? and Can ERT inhibit the onset and/or the progression of Alzheimer's dementia? Definitive answers are not currently available, but initial observations have shown sufficient promise to encourage more rigorous, ongoing study.

If estrogen replacement has any effect on the modest, age-related declination in women's cognition, it is likely to be in specific functional areas. This is because some components of cognition, such as primary and remote memory, do not show any change with age, while others, such as new information recall, do decline.[107,108] From the limited studies carried out to date, there is only modest evidence to suggest ERT improves specific types of cognitive performance; principally verbal learning.[109] However, methodologic problems and a diversity of findings among the available studies have led to the recommendation that more rigorous investigations be carried out.[110,111]

A small group of studies that addressed cognitive function in women already affected by Alzheimer's disease showed consistent positive evidence for an estrogen effect. These efforts suggested that estrogen replacement in standard therapeutic doses can improve verbal IQ, comprehension, memory, and some but not all other measures of dementia.[110,112] A recent, larger study, however, failed to support the hypothesis that 1 year of estrogen administration is effective in limiting the progression of mild to moderate Alzheimer's disease.[113]

More substantive evidence can be mustered for estrogens' capacity to inhibit the onset of Alzheimer's disease.[110] In both case control and cohort studies, the relative risk of developing Alzheimer's disease was between 0.3 and 0.7, suggesting that a reduced incidence of 50% might be obtained with long-term ERT.[110,114] In one of these studies, evidence was accumulated that showed a greater effect when estrogen dosage was in the high rather than low therapeutic range.[115] The efficacy of progestin or androgen addition to estrogen therapy has not been determined for either age-related cognition or Alzheimer's dementia.

Sexual Drive. The relative extent to which cultural and biological factors influence sexual activity is not well established. Libido, a significant component of sexual activity, is thought to be primarily a cognitive phenomenon. In women it begins to wane during the early perimenopause, decreasing more rapidly some years after menopause. Nevertheless, most healthy 70-year-olds engage in sexual intercourse, and a substantial proportion of postmenopausal women express regret at their loss of libido.[116,117] Studies of postmenopausal women have shown that estrogen-reversible, atrophic genital tract changes substantially influence sexual activity but that ERT does not alter libido. Premenopausal women lose libido rapidly after oophorectomy. Reversal does not come from estrogen replacement but does when testosterone is provided.[118] In these patients, androgen administration produced an increase in sexual fantasies, sexual desire, and arousal during intercourse but did not alter the number of orgasms or the frequency of intercourse.[118,119] Thus, by extrapolation one might suppose that androgens play a major role in postmenopausal loss of libido. This hypothesis remains in question, however, because ovarian testosterone production and serum testosterone concentrations do not fall substantially in the immediate postmenopausal period.[120] Only a small number of postmenopausal women with intact ovaries have been evaluated for an androgen effect on libido.[121] These studies have not, unambiguously, supported the many positive anecdotal experiences of clinicians in the field.[117] This lack of support for androgen therapy is important, as the commonly used therapeutic doses (1.25-2.5 mg/day) are capable of adversely altering estrogen-induced lipid profiles during ERT.

Uterus. Estrogens induce hypertrophy of the myometrium and proliferation of the endometrium. With chronic exposure, the endometrium becomes prone to carcinomatous degeneration.[122] Reduction of endometrial mitotic activity occurs during the luteal phase of each ovulatory cycle as a result of progesterone exposure. This progesterone effect is the mechanism by which the estrogen-driven propensity toward neoplasia is held in check during the reproductive years. Recognition, during the early 1970s, that a substantial increase in endometrial cancer accrued (relative risk, 2-8) to women either currently or previously on estrogen-only replacement regimens dampened enthusiasm for chronic postmenopausal ERT.[123] The observation that iatrogenic estrogen-induced malignancy was more likely to be identified at an early stage failed to mollify.[124] Addition of a progestin to ERT regimens became almost mandatory for prophylaxis in those women possessing a uterus. This scheme proved effective in limiting the incidence of endometrial cancer and may actually have reduced its rate below that found in non-estrogen users.[125] Addition of a progestin (usually medroxyprogesterone acetate, 10 mg/day) for 12 or more days of each cycle effectively lowered the epithelial proliferation rate to that of the midluteal phase, but it also caused cyclic bleeding in at least 50% of those taking ERT.[126,127] Since this was an inconvenience and a major reason that many women abandoned therapy, new protocols incorporating progestins came into vogue (see Figure 3). Today, almost all postmenopausal women taking estrogen also take a progestin; ERT has become HRT except for those women who are ex-uteri.

Protocols for administering estrogen and progestin during HRT: the light boxes represent days of estrogen intake; the dark boxes represent days of progestin intake.

Venous System. Ever since epidemiologic studies suggested a relationship between the amount of estrogen in oral contraceptive pills and an increase in the rate of venous thrombosis, there has been concern that a similar effect might result from postmenopausal ERT. The mechanisms by which oral contraceptives increase venous thrombosis are not entirely clear, but it is generally believed that the effect is mediated by estrogen-induced changes in the metabolism of multiple plasma coagulation factors. Despite substantially lower estrogen doses during postmenopausal therapy than are used for contraception, an increase in the rate of venous thrombosis does appear to exist.[128,129] The relative risk has been found to increase with the amount of orally administered hormone (using conjugated estrogen: 0.3 mg, RR = 2.1; 0.625 mg, RR = 3.3; 1.25 mg, RR = 6.9).[128] Nevertheless, postmenopausal baseline rates of venous thrombosis are so low (1.3 per 100,000 women years) that these occurrences have little impact on overall mortality rates.

Because estrogens' overall effect on coagulation is most likely the cumulative result of many metabolic alterations in hepatic protein metabolism, use of transdermal rather than oral hormone has been suggested as a means of limiting direct liver stimulation and thereby minimizing coagulation problems. However, when the "first pass" effect of orally administered hormones on hepatic coagulation factors has been evaluated and compared with routes that initially bypass the liver, uniform alterations have not been found[130,131,132]; nor has data accumulated to show that avoidance of an oral dose, first-pass effect can prevent the increase in venous thrombosis during ERT. Further study is required in order to ascertain whether avoiding first-pass hepatic exposure can limit venous thrombosis. Coincidently, the degree to which absence of a first-pass effect might diminish those benefits derived from altered HDL/LDL concentrations will need to be determined. Furthermore, it is not clear whether the addition of progestins to estrogen replacement regimens influences venous thrombosis rates.

Colon. There have been a number of observational studies suggesting that estrogen inhibits the development of colon cancer among postmenopausal women.[133,134] The relative risk for estrogen users, as compared with nonusers, in these studies varies from 0.5 to 0.7 for women of the same age. For past users, rates returned to those of nonusers 5 years after discontinuing estrogen intake.[135] Because the large bowel is not ordinarily thought of as an estrogen target, it has been suggested that altered hepatic bile output might be the mechanism by which cancer induction is inhibited.[136] However, there is growing evidence that large-bowel mucosa actually is an estrogen-sensitive tissue. Steroid hormone receptors have been found in normal colonic mucosa as well as in colonic adenocarcinoma, and some physiologic activities of the colon are known to be modified during the menstrual cycle.[137,138] With women accounting for almost half of the 100,000 new colon cancers appearing in the United States each year, a potential reduction in incidence of 50% would have a considerable impact on the overall mortality statistics of postmenopausal women. But, because the vitality of this estrogen action diminishes rapidly with cessation of therapy, chronic administration would be required in order to obtain full benefit. Prospective, randomized trials are needed to confirm the observational evidence of this estrogen-produced benefit and to establish its effect on mortality rates. Trials that include nonoral routes of administration will also be needed if the impact of first-pass hepatic influences is to be determined.

Breast. Biologists became aware that breast tissue was sensitive to estrogen almost simultaneously with their recognition that estrogens influence genital tract tissues. Shortly thereafter, estrogens' tumorigenic influence on breast tissue was established and its role in maintaining neoplastic growth determined. This information induced oncologists to attempt therapeutic manipulations of systemic estrogen levels in women with breast cancer. It also stimulated epidemiologists to investigate the influence that estrogen exposure might have on breast cancer incidence. Resulting investigations showed that women exposed to intrinsic estrogens for longer time periods, as is the case with early onset of menarche or late onset of menopause, experienced higher rates of breast cancer.[139,140] Additionally, it was noted that there was a decrease in the breast cancer incidence rate following menopause, no matter what the age of onset, and suggested that this decrease could be a result of the coincident fall in serum estrogen concentrations.[141] All of these findings suggest that an excess of exposure to estrogens during the woman's ovulatory years is associated with an increased risk of breast cancer.

Despite these and many other observations linking estrogen to breast metabolism and neoplasia, the relationship between estrogen use in postmenopausal therapy and breast cancer remains unclear. To date there are only limited, conflicting data sets concerning whether short-term ERT (< 5 years) alters the incidence of breast cancer. For longer therapeutic intervals, the study data, which are derived almost exclusively from observational investigations, are less ambiguous. The results of these studies lack consistency, with some showing no difference in incidence while others demonstrate increases in relative risk and a few contrarily suggest the existence of a protective effect. However, analysis of 51 epidemiologic studies involving 52,000 women with and 110,000 women without breast cancer sheds substantial light on the issue.[142] The evaluators, while recognizing the potential for selection bias in these studies, concluded that there was an increase in relative risk when women between 50 and 70 years of age took ERT for more than 5 years. They estimated that after 15 years of therapy, the risk was about 1.25 times that for nonusers: an increase that would add 12 cases per 1000 women to the base rate of 45 cases per thousand over the same time interval.

Some evidence suggests that the addition of a progestin to estrogen may confer a greater increase in breast cancer risk than the use of estrogen alone.[142,143] In a recent case-control study, combination HRT was associated with a 24% increase in breast cancer risk over nonusers (statistically significant), whereas unopposed estrogen was associated with a 6% increase that was not statistically significant.[144]

This increase may, however, not be of a comparable type disease to that found in women who are not taking estrogens.[145] For example, breast cancer with a favorable histology has been found to be 2.65 times more likely among HRT users than nonusers.[146] Fairly consistent evidence has been developed showing that the prognosis for neoplastic breast disease contracted while on ERT is better than that for disease contracted without estrogen use.[146,147,148] Consistent data exploring whether route, amount, and type of estrogen administered alter these incidence figures have not been developed. There is also a dearth of information to support the contention that women with a family history of breast cancer experience a greater change in relative risk by taking estrogen than do women without a positive family history.

Once a woman stops ERT, her relative risk appears to return to that of a nonuser within 2-5 years.[142] More conclusive information about the impact of ERT on breast cancer incidence presently does not exist. When, in about 5 years, data from randomized trials become available, a clearer picture of this critical aspect of ERT may emerge. At present, most authoritative analysts favor the concept that chronic estrogen therapy probably does result in a slight increase in the relative risk of breast cancer.[149,150,151] Their individual interpretations of the significance that this increase imparts to the therapy's overall clinical value vary immensely. Because breast cancer affects a large fraction of the female population, small changes in its incidence will produce a large change in the number contracting the disease. Thus, an individual's (investigator, clinician, patient) view of breast cancer's medical impact will substantially influence their appreciation for the overall value that may be gained from ERT.[152]

Survivors of breast cancer experience the same estrogen deficiency problems as other postmenopausal women. Their rising numbers make the question of efficacy for postcancer ERT extremely cogent. Unfortunately, convincing study data that either support or denigrate the use of estrogen in the post-breast cancer patient are not available. Nor are there any studies that demonstrate a worse prognosis for women who take estrogens after breast cancer.[153]


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