New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.     

HRT, osteoporosis and regulatory authorities Quis custodiet ipsos custodes?

HRT has been widely used for the relief of menopausal symptoms and the prevention and treatment of post-menopausal osteoporosis. However, following the publication of the Women's Health Initiative (WHI) and the Million Women Study (MWS), regulatory authorities issued an urgent safety restriction on HRT use in preventing post-menopausal osteoporosis, recommending that it now be considered a second-line treatment. Are such recommendations justified? Treatments for osteoporosis, in women with increased future risk for fractures but who have not yet developed the disease, should prevent all types of osteoporotic fractures. Of the available therapies, none other than HRT has been clearly demonstrated to prevent hip fractures in such women. Thus, HRT should be recommended as first-line treatment for osteoporosis prevention. Potential risks of HRT, such as increased development of breast cancer and increased thromboembolism, have long been known. The WHI showed risks in less than 0.3% of women studied, and the MWS appears to have overestimated the risk of breast cancer. Thus, no new safety issues have been identified, and the regulatory authorities may have misinterpreted the data from these recent studies. When given for the correct indications, HRT is of major benefit to many women.     

Lessons to be learned from animal studies on hormones and the breast

The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women's Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.     

Breast cancer risk in the WHI study: the problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.     

Continuation of hormone replacement therapy in Slovenia: a prospective, randomized, controlled trial--1-year follow-up

OBJECTIVES: To evaluate the influence of educational intervention on the hormone replacement therapy (HRT) continuation rate in Slovenia after the publication of WHI results. METHODS: We enrolled 125 early postmenopausal women in a 12-month prospective, randomized, controlled, multicentric study in Slovenia. The study group women (n=62) attended educational lectures; the control group women (n=63) did not. Data were collected from three types of questionnaire: before starting HRT, at follow-up visits at 3, 6, 9 and 12 month, after the educational lecture (study group). The continuation rate was measured on the basis of women's self-reports. The results were analyzed according to the "intention-to-treat" principle. The Cox proportional hazard model was used for the final analysis. RESULTS: A gynecologist's suggestion, climacteric symptoms and quality of life were the prevailing reasons for starting HRT. The prevailing factors affecting continuation of HRT were: no or irregular previous OC use (hazard ratio 3.7), no educational lectures (hazard ratio 2.0) and climacteric disorders as the reason for start HRT (hazard ratio 2.1). In the women who discontinued HRT within the first 3 months, the fear of endometrial cancer, breast cancer and bleeding problems were statistically more significant than other factors (P=0.034). In the women who stopped HRT use within 6-12 months, the fear of breast and endometrial cancers increased substantially (P=0.002). CONCLUSIONS: Previous OC use and educational lectures on menopausal problems and HRT significantly improve the HRT continuation rate. The main reason for discontinuing HRT is fear of breast cancer, intensified by media.     

HRT and gynaecologic cancer after WHI: old stuff or new doubts?

Previous studies had shown that there is little concern about endometrial cancer risk with hormone replacement therapy (HRT), whereas the risk of ovarian cancer is still debated. A new paper based on the women's health initiative (WHI) study devoted to gynaecologic cancers has been published in the October 2003 issue of JAMA, leading to the conclusion that also for endometrial and ovarian cancer risk, as the first WHI publication did for breast cancer risk, the previous large studies have been confirmed. About follow-up the authors conclude that, "The increased burden of endometrial biopsies required to assess vaginal bleeding further limits the acceptability of this regimen." These conclusions deserve a thorough analysis and must be read in the light of the burden of available epidemiological and clinical data and of recommended clinical practice. In the WHI trial the use of continuous combined HRT has resulted in a considerable increase of both imaging and invasive exams, to investigate women with bleeding or spotting, but the findings of these exams have been invariably negative. As far as, all published studies agree on the fact that continuous combined HRT either has no effect or significantly reduces the risk of both endometrial hyperplasia and cancer, there should be no reason to close-watching endometrium of women using this regimen with a different strategy from that employed on any healthy woman.     

Hormone use and patient concerns after the findings of the Women's Health Initiative

OBJECTIVE: To assess behaviors and concerns related to hormone therapy after the findings of the Women's Health Initiative (WHI). DESIGN: A survey was mailed to a random sample of 1,200 women identified through the pharmacy database as taking one of two estrogen + progestogen therapies (EPT) during the 6-month period before the publication of WHI findings. Questions included hormone use history, changes in usage, an assessment of symptoms, symptom changes, health behavior changes, use of alternative therapies, and demographics. RESULTS: The response rate was 70%, with women in their 60s and those receiving hormone therapy for 5 or more years were more likely to respond (P < 0.05). The majority had started hormones for symptom relief (69%) and expected to continue use. Many reported discontinuation (63%) or modifying their medication (18%). Half of these women stopped then restarted, the other half changed products. Women in their 50s were more likely to remain on hormones than older women (P < 0.01), and those taking ethinyl estradiol and norethindrone acetate were more likely to remain on their medication than those on conjugated estrogens (43% vs 29%, P < 0.01). Little change was reported in exercise and 19% increased their calcium intake. Patient concerns fell into five major categories: long-term effects, symptom control, breast cancer risk, bone health, and cognitive function. CONCLUSIONS: Women seem to be heeding the warnings about hormones but remain concerned about the potential long-term sequelae and symptom control. More research is needed to identify safer approaches to symptom relief and to address the concerns expressed.     

Prior hormone therapy and breast cancer risk in the Women's Health Initiative randomized trial of estrogen plus progestin

OBJECTIVES: To assess the extent to which prior hormone therapy modifies the breast cancer risk found with estrogen plus progestin (E+P) in the Women's Health Initiative (WHI) randomized trial. METHODS: Subgroup analyses of prior hormone use on invasive breast cancer incidence in 16,608 postmenopausal women in the WHI randomized trial of E+P over an average 5.6 years of follow-up. RESULTS: Small but statistically significant differences were found between prior HT users and non-users for most breast cancer risk factors but Gail risk scores were similar. Duration of E+P use within the trial (mean 4.4 years, S.D. 2.0) did not vary by prior use. Among 4311 prior users, the adjusted hazard ratio (HR) for E+P versus placebo was 1.96 (95% confidence interval [CI]: 1.17-3.27), significantly different (p=0.03) from that among 12,297 never users (HR 1.02; 95% CI: 0.77-1.36). The interaction between study arm and follow-up time was significant overall (p=0.01) and among never users (p=0.02) but not among prior users (p=0.10). The cumulative incidence over time for the E+P and placebo groups appeared to cross after about 3 years in prior users, and after about 5 years in women with no prior use. No interaction was found with duration (p=0.08) or recency of prior use (p=0.17). Prior hormone use significantly increased the E+P hazard ratio for larger, more advanced tumors. CONCLUSION: A safe interval for combined hormone use could not be reliably defined with these data. However, the significant increase in breast cancer risk in the trial overall after only 5.6 years of follow-up, initially concentrated in women with prior hormone exposure, but with increasing risk over time in women without prior exposure, suggests that durations only slightly longer than those in the WHI trial are associated with increased risk of breast cancer. Longer-term exposure and follow-up data are needed.     

Issues to debate on the Women's Health Initiative: failure of estrogen plus progestin therapy for prevention of breast cancer risk

Several studies on hormone replacement therapy (HRT) in the USA have been published. They revealed that the risk of breast cancer is increased with HRT more than with estrogen alone (ERT). A progestin has been given with each dose of ERT, as was the case in the Women's Health Initiative (WHI) study. The results of studies in Europe show similar trends. The increased risk of breast cancer in the WHI study was significantly higher only in women who had used HRT for several years before entering the study. The study was non-blind in 3444 cases, i.e. 40.5% of women in the estrogen plus progestin group and 6.8% in controls. If the women in the HRT group had more mammographic examinations it could change the validity of the results of the study. Estradiol-containing drugs have now been added to the list of carcinogens and the packages of these drugs have warning labels. The results of the WHI study do not support this labelling. The results of the WHI study show that the administration of HRT increases the risks of stroke and pulmonary embolism. It is reasonable to think that in the case of bleeding, at least at weekends in nursing homes (when staff levels may be low) patients were immobilized in their beds. Immobilization among women on HRT could have been more dangerous than the HRT itself. Progestins need to be delivered to the endometrium in a manner that will have the least effect on the breast. Systemic administration can be replaced by releasing progestin locally in the uterine cavity. Endometrial protection with a levonorgestrel-releasing intra-uterine system (IUS) is well tolerated. The high hepatic concentrations of estrogens given orally could be avoided by transdermal administration. New studies should be planned to reflect the situation in clinical practice. The time to start HRT in healthy menopausal women is between the ages of 45 to 55 years.     

The effect of the duration of progestin use on the occurrence of endometrial cancer in postmenopausal women.

OBJECTIVE: Women who have ever used estrogen replacement therapy (ERT), even at a low dose, have an increased incidence of endometrial cancer. The addition of a progestin to ERT reduces the incidence of endometrial cancer. The duration of progestin administration is more important than the dose. DESIGN: A MEDLINE review of the literature was performed using the search terms endometrial cancer, epidemiology, and hormone replacement therapy (HRT). RESULTS: Women who have ever used ERT have an increased incidence of endometrial cancer. The use of HRT for more than 5 years, with a progestin use of <10 days per cycle, has a relative risk = 1.8. Continuous combined HRT, or sequential or cyclic HRT with >10 days of progestin per cycle, appears to decrease the incidence of endometrial cancer to that found in nonusers of HRT. CONCLUSIONS: The use of HRT in postmenopausal women with a uterus reduces the incidence of endometrial cancer. The duration of progestin administration should be 14 days or more per cycle based on recent epidemiologic data.     

Population attributable risk of modifiable risk factors associated with invasive breast cancer in women aged 45–69 years in Queensland,Australia

Objectives

To quantify the population attributable risk of key modifiable risk factors associated with breast cancer incidence in Queensland, Australia.

Study design

Population attributable fractions (PAFs) for high body mass index (BMI), use of hormone replacement therapy (HRT), alcohol consumption and inadequate physical activity were calculated, using prevalence data from a representative survey of women attending mammographic screening at BreastScreen Queensland in 2008 and relative risk estimates sourced from published literature. Attributable cancers were calculated using ‘underlying’ breast cancer incidence data for 2008 based on Poisson regression models, adjusting for the inflation of incidence due to the effects of mammographic screening.

Main outcome measures

Attributable burden of breast cancer due to high body mass index (BMI), use of hormone replacement therapy (HRT), alcohol consumption and inadequate physical activity.

Results

In Queensland women aged 45–69 years, an estimated 12.1% (95% CI: 11.6–12.5%) of invasive breast cancers were attributable to high BMI in post-menopausal women who have never used HRT; 2.8% (95% CI: 2.7–2.9%) to alcohol consumption; 7.6% (95% CI: 7.4–7.9%) to inadequate physical activity in post-menopausal women and 6.2% (95% CI: 5.5–7.0%) to current use of HRT after stratification by BMI and type of HRT used. Combined, just over one quarter (26.0%; 95% CI: 25.4–26.6%) of all invasive breast cancers in Queensland women aged 45–69 years in 2008 were attributable to these modifiable risk factors.

Conclusions

There is benefit in targeting prevention strategies to modify lifestyle behaviours around BMI, physical activity, HRT use and alcohol consumption, as a reduction in these risk factors could decrease invasive breast cancer incidence in the Queensland population.     

Reduced breast cancer incidence in women treated with subcutaneous testosterone,or testosterone with anastrozole: A prospective,observational study

Objectives

There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estrogen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.

Study design

This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anastrozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.

Results

Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women's Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).

Conclusion

T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by maintaining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer.