The practice of hormone therapy (HT) witnessed a widespread application
in the 1980s to control menopausal symptoms. In the 1990s, the
speculation about HT’s cardiovascular protective effect and bone loss
prevention potential in the postmenopausal period increased its use. The
lack of evidence about the risks and benefits of HT has led the Women’s
Health Initiative (WHI) group to conduct a series of randomized clinical
trials aiming to answer some of these questions. The WHI Hormone Therapy
trials included 27,347 women who were followed during the treatment. The
subjects were randomized to take oral estrogen plus progestin or
placebo, and women with prior hysterectomy were randomized to receive
oral estrogen alone or placebo 1
The outcomes of this randomized clinical trial published by the WHI
abruptly changed the prescription of HT. The study aimed to evaluate the
risks and benefits of HT; however, it was interrupted precociously due
to the adverse effects. The study showed an increased relative risk of
breast cancer (BC) development after an average use of combined HT for
five years. The BC risk rate was 1.26 (CI 1.00–1.59) after an average
of 5.2 years, and the risk raised to 2.3 (CI 1.12–3.94) when the use
was extended to ten years. Thus, the WHI study indicated that the risks
exceeded the benefits of combined HT usage after an average time of 5.2
years, despite the all-cause mortality being not affected in the study.
One limitation of the study was the evaluation of only one combined
hormonal therapy regimen, i.e., the conjugated equine estrogen 0.625
mg/d associated with 2.5 mg/d medroxyprogesterone acetate1. Nevertheless, despite this limitation of the study
and the lack of specific mortality information, there was an
unquestionable change-over after the WIH study. The 13 years of
cumulative follow-up just corroborate these findings1.
Another WHI publication assessed the use of estrogen alone in
postmenopausal women who had undergone a hysterectomy. The primary
outcome found was also the incidence of invasive BC; however, there was
a decrease in the hazard ratio (HR) value to 0.77 (CI 0.59–1.01),
suggesting a reduction in the risk of BC. Unfortunately, the study had
to be interrupted due to an increased risk of cerebral vascular disease.
The reduction in BC risk had no statistical significance according to
this data. However, further investigation is warranted.1
These publications encouraged discussions regarding the risks and
benefits of the use of HT, a topic that has been widely studied since
then. It raised new questions, such as which type and duration of
therapy and age of onset were related to the increased risk of BC. A
recent meta-analysis answered some of these questions. The use of
combined HT for five years in postmenopausal women, regardless of the
age of onset, showed an increase in the risk of BC. Further, while
evaluating the different types of therapies, no statistically
significant differences between the estrogen therapies were observed.
All HTs, except those given via vaginal route, increased the relative
risk of BC.2
Remarkable data were presented at the ”San Antonio Breast Cancer
Symposium 2019” on the WHI Hormone Therapy trials. This 20-year
follow-up of combined therapy group(>=5years) in
postmenopausal women confirmed the increased BC incidence and associated
mortality (incidence BC HR: 1.29; CI 1.14 - 1.47; p< 0.001 and
mortality after BC HR:1.29; CI 1.02-1.63, p 0.03). Mortality related to
BC development in HT users was not assessed in previous literature,
probably, due to shorter follow-ups. The second group of hysterectomized
women using estrogen alone showed new data that resulted in a reduced
incidence (HR: 0.77; CI 0.65-0.92; p=0.005) and mortality for BC (HR:
0.56; CI 0.34-0.92; p=0.005). Further studies are still needed to
clarify this evidence, although, these impactful data on mortality come
from a randomized clinical trial. 3
The decreased risk of BC using estrogen alone in postmenopausal women
might be due to an increase in estrogen-induced apoptosis in the breast
cells 4. The key point for estrogen-induced apoptosis
is the selection of cell populations that can survive prolonged estrogen
deprivation, comparable to long-standing menopause, and become sensitive
to this apoptotic mechanism. These cells survive estrogen deprivation
due to the activation of different types of receptors, and estradiol can
bind to the receptors and trigger apoptosis 4. The WHI
hormone therapy trial selected women aged 50 – 79 years at baseline,
many of whom probably have been in menopause for more than five
years1. Therefore, we can hypothesize that this trial
may have selected patients with long-standing menopause (with cells
sensitive to this apoptotic mechanism) who were being benefited from the
estrogen-induced apoptotic death of breast cells, thereby reducing the
risk of BC.
The complexity of estrogen and BC is not completely understood. Another
important randomized placebo-controlled trial, the International Breast
Cancer Intervention Study I ( IBIS I), showed an extended protection
period of tamoxifen for BC risk in women deemed to be at an increased
risk of developing BC with a hazard ratio of 0.69 (CI 0.53–0.91). The
five-year use of 20 mg tamoxifen, a selective estrogen receptor
modulator with antiestrogenic effects in the breast, reduced the
incidence of BC in high-risk women5. So, there are
trials that show that estrogen can protect from BC in some cases;
however, medication with antiestrogenic effect has also demonstrated
efficacy in BC prevention 3,5.
An interesting fact related to the effect of estrogen on breast cancer
is the pathophysiology of HT in transgenders. Studies have demonstrated
that testosterone therapy decreases the risk of BC in female to male
transgenders, regardless of mastectomy. This probably is due to a
decrease in estradiol-induced tissue proliferation resulting from a
decrease in the expression of estrogen receptors and increase in the
induction of epithelial breast cells apoptosis. All these alterations
might prevent the effects of estradiol on inducing BC development6. It can be hypothesized that the basis for BC
prevention lies on the estrogen receptors. Consequently, the decrease in
estrogen receptors in breast induced by testosterone may lead to a
reduction in BC cases in transgenders. The role of progesterone in this
topic is still unknown. Despite these encouraging findings, further
studies are required to assess the real effect of the therapy on this
population and to understand the pathophysiology.
The rational use of HT is strongly based on evidence from randomized
clinical studies related to the topic. Therefore, the gynecologist
should provide information to their patients individually about benefits
and adverse events, especially the risk of BC. It is important to note
that the well-established time for safely using HT is five years. There
is no evidence for the use of estrogen alone just for the prevention of
BC in healthy postmenopausal hysterectomy patients. Therefore, the
gynecologists must be updated regarding the use of HT unless these
topics are fully understood. There is no doubt that the risk of BC
should be individually discussed with the patients before initiation of
HT, considering other individual risk factors for BC and other
pathologies.
Acknowledgments: We thank all the doctors and students that were
involved in
this commentary.
Disclosure of interest: The authors have no financial conflicts of
interest to disclose. This research did not receive any specific grant
from funding agencies in the public, commercial, or not-for-profit
sectors.
Contribution to authorship:
Gustavo dos Santos Raupp - Substantial contributions to conception and
design*.
Alessandra Borba Anton de Souza - Substantial contributions to
conception and design; critical review of the intellectual content;
final approval of the version to be published*.
Martina Lichtenfels - Critical review of the intellectual content
Antonio Luiz Frasson - Critical review of the intellectual content;
final approval of the
version to be published.
* both authors contributed equally to the paper
References
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https://www.whi.org/about/SitePages/WHI%20Findings.aspx
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