Abstract
Purpose: To review the long-term data associated with taking hormone replacement therapy (HRT) and the controversial outcomes.
Data sources: A literature review was conducted via Pub Med. The relevant search terms included hormone replacement therapy, breast cancer, cancer mortality, and health risks. The accessed publications were in English and not limited by publication date.
Conclusions: There have been numerous studies evaluating the risks and benefits from taking HRT. While there is potentially an increased risk of breast cancer from long-term estrogen/progestin therapy and a perceived benefit from estrogen therapy alone, the findings remain controversial.
Implications for practice: Physicians and nurses should actively engage in constructive discourse with their patients regarding the efficacy and side effects associated with extended HRT use. The dialogue should specifically address the patients’ clinical profile, attendant risks, and medical alternatives of which they could potentially avail themselves.
Keywords: hormone replacement therapy; estrogen; progestin; breast cancer
Introduction
Breast cancer is the most common female malignancy in the United States, afflicting 281,500 women in 2020, of whom 43,600 will ultimately succumb to disease progression [1]. Fortunately, nearly two-thirds of breast cancer patient cases are diagnosed at a localized stage, wherein the 5-year survival rate is auspicious.
Age is a prominent risk factor for developing breast cancer and women, ages 45 to 75, are the most vulnerable demographic [2]. Additional risk factors include ovarian hormones, the presence of BRCA1/2 gene mutations, reproductive history, and previous chest irradiation [3,4]. Since ovarian hormones are particularly essential to cellular regulation, hormone therapy has been frequently implicated in the manifestation of breast cancer [5,6]. Nevertheless, since the 1970’s, approximately 600 million women from western countries have used hormone therapy [7].
Hormone therapy, encompassing conjugated estrogens alone, or in combination with progestin, is primarily indicated to attenuate menopausal complications (e.g., vasomotor symptoms)), forestall cognitive impairment and avert cardiovascular disease [8,9]. However, there have been several randomized clinical trials and observational studies that have impugned the safety of this treatment because of the alleged relationship with breast cancer incidence and mortality [7,10-12].
The Women’s Health Initiative (WHI) initially reported on the controversial benefits and potential complications inherent in hormone therapy in their 2002 landmark study [11]. The trial comprised 16,608 healthy postmenopausal women with a uterus who underwent treatment with conjugated quine estrogens (0.625 mg/d) and medroxyprogesterone acetate (2.5 mg/d) or placebo for a median duration of 7.2 years. The hormone therapy group was associated with more breast cancer-related deaths compared to the place group (2.6 vs 1.3 per 10,000 women annually), resulting in clinical trial cessation. In 2004, the WHI evaluated 10,739 postmenopausal women with a prior hysterectomy, aged 50-79 years, who underwent either conjugated equine estrogen (0.625 mg/d) or placebo. This study was also prematurely closed due to the elevated risk of stroke in the hormone therapy group although interestingly, the results suggested a possible decreased incidence in breast cancer [12].
In the Million Women Study, 1,084,110 women from the United Kingdom, ages 50–64 years, reported their use of hormone therapy (estrogen alone or progestin-estrogen) and were surveilled to ascertain the corresponding breast cancer incidence and mortality [10]. The results indicated that women who underwent estrogen-only or estrogen-progestogen had a 1.3-fold risk or 2-fold risk of developing breast cancer, respectively. Following the results from WHI and UK trials, the use of hormone therapy declined significantly [13]. Consequently, from 2001 to 2004, an 8.6% decrease in breast cancer incidence was reported for women, 50 years or older [14].
In 2017, updated follow-up data from the WHI clinical studies were released [15]. There were 7489 deaths throughout the treatment and surveillance periods and all-cause mortality was 27.1% for the women who underwent hormone therapy vs 27.6% in the placebo group (i.e., neither estrogen-alone nor in combination with medroxyprogesterone acetate was associated with an increased risk of cancer mortality). Accordingly, the North American Menopause Society subsequently revised its guidelines [16]; hormone therapy was recommended for women who were younger than 60 or within 10 years of menopause, especially if they were at higher risk for bone loss or fracture.
In 2019, a prolonged review of the WHI trials indicated that estrogen-alone had a countervailing effect on breast cancer incidence, compared to the increased risk of breast cancer from estrogen/progestin therapy [17]. There was a 23% reduction in breast cancer for the postmenopausal woman who received estrogen therapy- alone, whereas the risk of breast cancer and breast cancer-related death was increased by 29% for the women treated with estrogen/progestin, an effect that transcended 10-years of discontinued use.
Conclusion
Hormone therapy was routinely used in the 1990’s to attenuate menopausal symptoms and currently, greater than 40% of women in the United States are prescribed this treatment [18]. Despite the recently updated findings from the WHI study [17], an epidemiological study conducted in the United Kingdom for nearly 30 years, reported that of the 108,647 postmenopausal woman who developed breast cancer, 51% had been treated with hormone therapy [7]. Intriguingly, the elevated risk encompassed all types of hormone therapy, particularly combined estrogen/progestin, which was further compounded by extended treatment.
Estradiol heightens the risk of breast cancer in postmenopausal women and similarly, preclinical studies have demonstrated that progestin engendered progenitor cells in both human and breast cancer cells [6,19]. Estrogen and progesterone levels significantly decline following menopause; and hormone therapy-induced blood estrogen levels are associated with an increased incidence of estrogen receptor positive breast cancer, especially in women with a higher body mass index [19]. Accordingly, even if estrogen-alone is presumably safe and estrogen/progestin either theoretically accords a countervailing or detrimental effect [15,17], the persistent inclusion of these two agents, independently or collectively, should be considered when evaluating a woman’s lifetime risk for developing breast cancer.
The combined results from the aforesaid hormone therapy trials are varied, and thus, confound an unequivocal approach to treating menopausal symptoms. Conversely, when endeavoring to assess the risks associated with hormone therapy, we recognize the disadvantages of untreated vasomotor symptoms, which can impair quality of life and reduce work productivity [15,20]. Perhaps, before initiating hormone therapy, the physician and patient should thoughtfully engage in a discourse that incorporates the individual’s clinical symptoms and attendant risk profile.
