Recent Position and Scientific Statements

In January of 2010 the North American Menopause Society (NAMS) published a position statement on the use of estrogen and progestogen in postmenopausal women.¹  Working closely with NAMS, the Endocrine Society, followed with its own scientific statement in July of the same year.²  The NAMS position statement considered only the use of prescription estrogen and estrogen/ progestogen products while the Endocrine Society statement was boader in scope, adressing  postmenopausal hormone use in general-- including,  where relevant, evidence regarding testosterone, raloxifene and tibolone  (an estrogen formulation currently in use in Europe but not available in the United States).  Both societies employed rigorous methodologies involving comprehensive literature reviews, peer reviews of statements based on those reviews, and consensus by panels of leading experts. Both societies also sought to maintain the principles of evidence-based medicine by giving randomized controlled trials the most weight, and, in descending order,  “meta-analyses, cohort studies, case-control studies and collective wisdom (or observational studies)” ^2(p.S8) respectively less weight.

It soon became clear to both societies that very few studies of hormone therapy in post- menopausal women met evidence-based criteria for highest levels of evidence. In fact, The Women’s Health Initiative (WHI) is cited in both statements as providing, for some questions, “the only large, relatively long-term RCTs to date of postmenopausal women using HT [hormone therapy-which includes both estrogen only (ET) and combined estrogen-progestogen therapy (EPT)].” ^1(p.243)  This study, however,  also had design limitations in that participants had an average age of 63 with only 3.5% of participants being between the ages of 50-54—the average age range for the onset of menopause, and the time when women and their physicians are most likely to be weighing the pros and cons of HT.¹ Also, because WHI participants were,  on average approximately 10 years older than women at the onset of menopause, they had a longer time to accumulate risk factors and comorbidities—thereby lowering the threshold for experiencing potential adverse events as a result of HT. In addition, evidence from WHI was limited by the fact that only oral conjugated estrogen (CE) and oral medroxyprogesterone acetate (MPA) were used—making information about other formulations and routes of administration a matter of extrapolation, and not direct observation/measurement.

For these reasons, both NAMS and the Endocrine Society balanced the methodological rigor of WHI data with observational studies which, though less technically rigorous, were more relevant to the population of women for whom hormone replacement is typically being considered.^1,2

 back to top

Estrogen-progestogen (EPT)

North American Menopause Society

In terms of breast cancer, the WHI found that women using estrogen-progestogen therapy for 5 or more years had an increased risk of breast cancer—at a rate of 8 per 10,000 women using EPT for ≥ 5 years.¹ Still unresolved was the question of whether continuous vs. sequential use of progestogen impacted outcome. According, to NAMS, some observational studies indicated a greater risk with a continuous regimen. It was also unknown if these results would apply to forms of progestogen other than MPA.1
The NAMS position statement discussed a reanalysis of the WHI data that looked at the effect of the length of time between onset of menopause and beginning EPT—an interval referred to as “gap time.”  Interestingly, it was found that

Those starting EPT shortly after menopause experienced an increased risk of breast cancer over the next 5 years, whereas those with a gap time of greater than 5 years did not. The French E3N (a prospective cohort study on French women that examined the potential relationship between pre- and post-menopausal breast cancer occurrence) also reported a greater risk of breast cancer in those women with a short as opposed to a long gap time.^1(p.247)

Endocrine Society

Pre WHI

The Endocrine Society provided some historical background about the data that was available on hormone therapy.²   They discussed the fact that the practice of prescribing progestogen with estrogen for menopausal women with an intact uterus did not really begin until the mid to late 1980’s. Prior to that, most menopausal women were prescribed estrogen alone. Before the publication of the initial WHI results in 2002, the only real data available on estrogen-progestogen was from a collaborative meta-analysis that looked at the association between HRT and breast cancer. Although 51 studies were pooled and contained data on a total of 67,370 women, only 12% were on an estrogen-progestogen combination—not enough for the authors of the collaborative meta-analysis to reach any definitive conclusions.

WHI

In their discussion of the randomized WHI trial, the Endocrine Society noted the trial’s major methodological flaws to be 1) that the high dropout rate in both the group using estrogen and progestogen, and in the placebo group undermined the statistical power of the study; 2) that the women in the trial were not representative of the women who are typically candidates for, and actually are prescribed, hormone therapy and 3) that pre-trial hormone use on the part of participants influenced results. The original results of the WHI showed an absolute excess breast cancer risk of 4 per 100 women taking combined HR. This risk, however, was not found among the women in the study who had never used hormone therapy in the past “(non-prior users”).²  Data from WHI was reanalyzed in 2006 and again in 2008. In the 2008 reanalysis, it was found that

 

only 17% (n=952) of women in the RCT commenced MHT within 5 yr of final menses, and 22 breast cancers were observed, giving a RR of 1.77 (CI, 1.07-2.93) for gap times of less than 5 yr. In contrast, the RR was 0.99 (CI, 0.74-1.31) for gap times of 5 or more years according to data based on 92 breast cancers in a total of 4498 women with gap times of 5 yr to more than 15 yr…..It should be noted…that the RR of 1.77 in the women with a gap of less than 5 yr suggests the possibility that the risk with E+P is actually higher than initially reported in the WHI. ^2(p.21)

 

back to top

Post WHI

In looking at studies conducted after the WHI study, the Endocrine Society found that almost all reported that breast cancer risk among women taking both estrogen and progestogen was higher than among those taking estrogen only.

Breast Cancer Severity

In the October 20, 2010 issue of JAMA, Chlebowski et al. published the results of a follow up study of women who participated in WHI.³ They found, in direct contrast to most previously published observational studies, that breast cancers associated with combined estrogen-progesterone use were more invasive and more likely to be associated with death than breast cancers in women who had received placebo.
 

Estrogen alone

North American Menopause Society
 

For women taking estrogen alone, WHI showed no increase in the incidence of breast cancer after an average of 7.1 years.¹ In fact, there was a non-statistically significant decrease in invasive breast cancer (6 fewer cases per 10,000 women) overall. However, post hoc analysis did show statistical significance in the decrease in three subgroups.

Fewer breast cancers with localized disease were diagnosed in the ET group than in the placebo group (HR, 0.69; 95% CI, 0.51-0.95); a similar reduction was found for ductal carcinomas (HR, 0.71; 95% CI, 0.52-0.99); and a larger, significant reduction was observed in a 6-month follow-up when the women were no longer using ET (HR, 0.67; 95% CI, 0.47-0.97). When ET was extended beyond 10 to 15 years in observational studies, breast cancer risk seemed to increase.^1(p.247)

Endocrine Society

Pre WHI

Because estrogen was largely prescribed without progesterone prior to the late1980’s, there is considerable data on the effects of estrogen alone even before the WHI trial. The Endocrine Society discussed the results of the 1997 collaborative meta-analysis, mentioned above, which reported on the analysis of pooled data from 51 studies that included a total of 67,370 women.  There were 4460 women on whom information about the type of hormone they were receiving was available. 80% were receiving estrogen alone. In these women, no increase in breast cancer risk was seen when estrogen use was less than five years. After five years, relative risk (RR) was increased to 1.34 ± 0.09—but only in women with a BMI of less than 25 kg/m². ²

Five out of nine cohort studies published after the collaborative meta-analysis reported increased breast cancer risk in women taking estrogen alone for more than five years compared with women taking no estrogen.  In general, these studies found that the longer the estrogen use, the higher the risk. The estrogen-associated risks were higher among women with higher risk profiles for breast cancer to begin with. As in the collaborative meta-analysis, women with lower BMIs were found to be at greater risk than women with higher BMIs.²

^{back to top}

WHI and post WHI

In contrast to the above findings, conclusions based on WHI data, as we have seen, seemed to indicate a decrease in breast cancer risk among estrogen users. Although this was at first thought to represent an “outlier finding,” it was later found to be due to gap time discrepancies. In a pattern similar to that found with estrogen and progesterone,

Starting E alone more than 5 yr after onset of menopause (long gap time) was associated with a significant reduction in breast cancer risk (RR, 0.58; CI, 0.36-0.93) whereas starting immediately after menopause (short gap time) was not (RR 1.12; CI, 0.39-3.21) in patients who had not received prior MHT.^2(p.S19)

The Endocrine Society reported seven other studies showing similar reductions in breast cancer risk in certain subsets of women taking estrogen alone and emphasized the need  for more studies examining the influence of gap time on breast cancer risk.²

The conclusions of the Endocrine Society on the risk of using estrogen alone were as follows:

Existing data suggest no increased risk of breast cancer (and likely a reduction in risk) when E alone is used for less than 5 yr in women starting MHT several years after onset of menopause (i.e. long gap time). Those with a short gap time experience a 3% increase in RR of breast cancer per year of use. From SEER (Surveillance, Epidemiology and End Results) data, a woman between ages of 50 and 54 has a 13.0 per 1000 chance of developing breast cancer over 5 yr. Therefore, in women starting estrogen within 5 yr of menopause (i.e. short gap time), attributable risk would represent 2.59 per 1000 per 5 yr (if the WHI RCT is used for calculations), a relatively small excess risk. ^2(p.S20)

How long does it take after discontinuation for risk to diminish?

Although the Endocrine Society stated that the risk of breast cancer among women taking both estrogen, and estrogen plus progestogen, returns to the baseline risk for non-users within 3-5 years after discontinuation, the more recent follow-up study by Chlebowski et al.,3 suggested that the long-term effects, particularly of estrogen and progestogen, may manifest years later and that there is, in fact, no “safe window” in which to take estrogen and progestogen.^3,4

back to top

Conclusion

An abbreviated and partial answer to Dr. Van Hook’s question is that treatment with estrogen alone is associated with less risk of breast cancer than is the combination of estrogen plus progestogen. There are, however, a large number of variables that need to be considered in any discussion of hormone therapy.  Among these are patient age, body mass index (BMI), length of time between onset of menopause and beginning HT (gap time), formulation of hormone, route of administration, continuous vs. intermittent administration (for estrogen-progestogen), length of time HT is prescribed, and any underlying breast cancer risk that may exist. If one were to try to summarize the evidence regarding estrogen alone, it would be that estrogen alone does not contribute to breast cancer risk in women already at low risk for the disease, and may even lower risk. The caveats are that estrogen alone should not be used in women with an intact uterus, or for more than five years, and should be ideally started five or more years after the onset of menopause--by which point vasomotor and other menopausal symptoms--the main reasons women seek treatment,  have largely subsided in a large percentage of women.

Dr. Van Hook’s question addresses breast cancer alone, only one of many potential risks/benefits associated with postmenopausal hormone therapy. In addition to relief of menopausal symptoms, other risks/benefits include  coronary heart disease, alterations in lipid profile, stroke, venous thromboembolism, diabetes, osteoporosis, lung cancer, cognitive status, arthritis, genitourinary health and cancers of the endometrium, colon, lung, and ovaries. Hormone therapy may decrease risk in one arena while increasing it in another. The risk-benefit balance is very different for different individuals, and also changes with time within the same individual. Decisions about hormone therapy must, as with any complex medical decision, be made on a case by case basis with full consideration of all the potential moderating factors.