The public debate surrounding the use of hormone therapy in the menopause has reached a polemic divide. Many see menopausal hormone therapy as a choice between the risk of one of two cancers. We learned many years ago that unopposed estrogen exposure would lead to a high incidence of endometrial hyperplasia and cancer in women with a uterus. We can prevent the increased incidence of endometrial cancer by the addition of a progestin; however, this comes at a price of increased breast cancer risk. These risks have caused many to abandon hormone therapy. Fortunately, new agents currently under the US FDA review may eliminate this dichotomy and allow for progestin-free hormone administration in all women, including those with an intact uterus.
Most women going through the transition to menopause experience at least some symptoms. In many, these symptoms reach a point where they are disruptive. Symptoms commonly include troubling hot flushes, disrupted sleep, cognitive changes and mood changes, which all appreciably affect quality of life. Vaginal dryness can make intercourse uncomfortable or difficult. Bone loss is all but inevitable. Early attempts to administer estrogens for symptom relief were successful; however, we eventually learned that in this population there was an unacceptably high rate of endometrial cancer.
Based on several randomized trials that have included a group of women with uteri receiving unopposed estrogen, a dose-responsive increase in endometrial cancer with estrogen use has been observed. In one study, women with an intact uterus were administered several doses of hormone therapy containing either estrogen alone or combination estrogen/progestin. All women in the study were scheduled to undergo an endometrial biopsy Citation[1]. Women using 0.625 mg of conjugated equine estrogens (CEEs) without a progestin had a rate of hyperplasia of 8% at 1 year. The effect was critically age dependent. Women aged 60 years and above had a 22% risk of endometrial hyperplasia in that time period. While lower doses showed a reduced risk compared with that of 0.625 mg, the risks were still over 3% at 1 year among women receiving a dose of 0.45 mg, and over 6% among women aged 60 years and above at that dose. The rate fell to below 1% among women using 0.3 mg; however, it still approached 3% in the older age group at this dose. Other studies have reported rates of 20% after 1 year of unopposed 0.625 mg of CEE Citation[2]. This rate rose dramatically by 3 years. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, 74 out of 119 subjects receiving unopposed estrogen for 3 years (62.2%) developed some type of endometrial hyperplasia and 41 out of 119 (34.4%) had complex hyperplasia or atypia Citation[3]. Subjects receiving unopposed estrogens were far more likely to develop hyperplasia than those receiving placebo (p < 0.001). Clearly, the use of unopposed estrogen, even at lower than conventional doses, is not an alternative for menopausal women with an intact uterus.
Endometrial cancer is prevented by the addition of progestins. Numerous trials, including large prospective randomized blind trials such as the Women’s Health Initiative (WHI) and PEPI, clearly demonstrate that progestins eliminate the estrogen-induced risk of endometrial cancer in women with a uterus Citation[2–4]. Unfortunately, progestins also increase the risk of breast cancer. The relative risk of breast cancer diagnosis in the WHI was 1.24 (adjusted 95% CI: 0.97–1.59) Citation[5,6]. While not unexpected, the renewed breast cancer publicity that accompanied reports from the WHI, coupled with the finding that there was no reduction in heart disease among women starting treatment remote from the menopause, led to a dramatic reduction in hormone therapy use. The recoil accompanying the report of the WHI results led to decreased hormone therapy use and was subsequently followed by an increase in menopausal symptomology, vaginal atrophy, bone loss and a diminished overall quality of life.
Interestingly, the use of estrogen alone in the WHI did not increase the risk of breast cancer Citation[7,8]. In women with a prior hysterectomy who were randomized to estrogen or placebo for an average of 7 years, the relative risk of breast cancer was 0.80 (95% CI: 0.62–1.04) in women who used estrogen alone. While this small trend toward risk reduction was not statistically significant, subsequent subgroup analysis demonstrated that women who were compliant with study medication (e.g., CEE) had a significant reduction in invasive breast cancer Citation[8]. The relative risk of breast cancer among compliant women using estrogen was 0.67 (95% CI: 0.47–0.97; p = 0.03) Women can safely use unopposed estrogen for at least 7 years without the worry of increased breast cancer risk.
However, these reassuring data on estrogen and breast cancer were of no benefit to women with a uterus. For women who need to oppose the uterine effects of estrogen with concomitant progestin use, the absolute increased risk of breast cancer diagnosis was found to be less than one in 1000 additional cases Citation[5,6]. This level of risk was sufficient to prevent women and their physicians from using hormone therapy. Alternative options to progestins for preventing endometrial hyperplasia have been proposed; however, there are currently no viable substitutes. Similarly, there is no evidence from adequately powered randomized trials to suggest that alternate progestins reduce breast cancer risk. Some evidence points towards breast cancer risk reduction with use of cyclic hormone regimens as opposed to continuous ones; however, the likely risk remains elevated to a significant degree Citation[9]. Currently, we must use a progestin to prevent the adverse endometrial effects of estrogens and accept a small but genuine increase in breast cancer risk. For some patients and their physicians, this risk may be unacceptable.
While we learned of dichotomy between estrogen and progestin in breast cancer risk, we also saw selective estrogen receptor modulators (SERMs) used for the treatment or prevention of breast cancer. Tamoxifen has long been used as breast cancer therapy and, more recently, based on large clinical trials, was approved by the FDA for use in breast cancer prevention Citation[10]. Subsequently, raloxifene was approved for use in breast cancer prevention as well Citation[11,12]. All SERMs have tissue-specific estrogen agonist or antagonist properties. In the breast, these agents generally prevent estrogen-induced breast cell proliferation. Some, but not all, SERMs are also estrogen antagonists in the uterus. Selected SERMs may be sufficiently antagonistic to counteract the estrogen stimulation of the uterine endometrium that leads to endometrial hyperplasia and cancer. Unfortunately, on their own, none have sufficient estrogen agonist properties in the brain to provide relief of menopausal symptoms.
Is it possible for SERMs be paired with estrogens to create a new class of drug with mixed tissue-specific agonist and antagonist properties? Recent findings suggest that such a combination may not only be possible, but that the right combination could have exciting therapeutic potential. The pairing of an estrogen with a SERM to create a new entity with unique properties has been termed a tissue-specific estrogen complex (TSEC) Citation[13]. Each of these heterogeneous compounds has a unique blend of estrogenic and anti-estrogenic properties depending on the tissue involved as well as the specific SERM used.
Empirical data from several clinical trials clearly demonstrate the effect of TSECs on endometrial cancer and hyperplasia. Tamoxifen use has been associated with the development of endometrial cancer when used for breast cancer treatment and should not be used with the addition of an estrogen. Raloxifene has been paired with estradiol a form of TSECs; unfortunately, raloxifene does not have sufficient anti-estrogenic properties in the uterus to prevent uterine cancer. Subjects who received raloxifene paired with estradiol developed endometrial hyperplasia and cancer Citation[14]. Raloxifene is not an appropriate compound for use in a TSEC.
In the uterine endometrium, the most anti-estrogenic SERM currently under development is bazedoxifene (BZA) Citation[15,16]. This SERM may therefore be beneficial when included in a TSEC; BZA would be expected to oppose the effects of estrogen on the uterus and prevent endometrial hyperplasia and cancer. BZA has undergone extensive testing in several large clinical trials where it has been paired with conjugated equine estrogens Citation[17–21]. The combination of conjugated equine estrogen and BZA was successful in reducing menopausal symptoms including hot flushes and sleeplessness Citation[21]. This combination also successfully prevented menopausal bone loss Citation[19]. Perhaps most importantly, BZA, when paired with conjugated estrogens in appropriate doses (CEE 0.45 mg and BZA 20 mg), prevented endometrial hyperplasia in a 2-year trial Citation[22]. While none of these studies were sufficiently powered to demonstrate protection against breast cancer, multiple SERMs have repeatedly demonstrated this effect. Furthermore, there was no increased risk of breast cancer in the BZA trials that have been conducted that involved over 3000 subjects. CEEs, as demonstrated in the WHI, do not increase breast cancer risk and SERMs generally have this property as well.
In the past, development of hormone therapy involved a balance between the risk of endometrial cancer imposed by estrogens and the alternative risk of breast cancer with the addition of a progestin. TSECs offer the potential of negating this dichotomy. If an appropriate dose of selected SERMs are used, TSECs prevent endometrial cancer. The use of estrogens without a progestin does not increase breast cancer risk. The addition of a SERM is very unlikely to lead to paradoxically increased breast cancer risk; indeed, it may even further reduce breast cancer risk. However, this hypothesis must be definitively tested in properly powered prospective clinical trials. We now have the prospect of a menopausal treatment that relieves symptoms and improves bone density while not increasing the risk of endometrial or breast cancer.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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