Is there still a role for SERMs in menopause management?

Selective Estrogen Receptor Modulators (SERMs) are non-hormonal compounds that can act as estrogen-agonist or antagonist according to the different target tissues. For instance, a SERM may be an estrogen agonist on bone tissue and, conversely, a potent estrogen antagonist on breast tissue [1]. The concept of SERM arises from the recognized existence of a spectrum of action from agonist-to-antagonist activity in nature. In other words, the same hormone can exert an agonist or antagonist function under different conditions in different cell types. Estrogen receptors (ERs), and their signaling system, are important targets found in bone tissue, as clearly demonstrated by the effects observed under aromatase inhibitors (AIs), on one hand, and hormone therapy (HT), SERMs, and Tissue Selective Estrogen Complex (TSEC), on the other hand.

As for SERMs, a well-known first-generation SERM is tamoxifene (TAM): it can be used in preventing breast cancer (BrCa) in high-risk women and treating ER-positive BrCa patients, due to its antiestrogenic action on mammary cells [2]. TAM also has an agonist activity on bone tissue.

The most important SERMs currently available for the management of menopausal related disturbances are Raloxifene (RLX), Bazedoxifene (BZA) – particularly useful for their action on bone – and Ospemifene – indicated for vaginal health.

RLX (at a daily dose of 60 mg) is a second-generation non-steroidal benzothiophene SERM that binds to ERs, reducing bone resorption without stimulating the breast or the uterus. RLX is able to increase vertebral and hip bone mineral density (BMD) and decrease bone turnover markers (BTMs), thus significantly reducing the relative risk of vertebral fracture [3], but not that of non-vertebral fracture. Interestingly, due to its antiestrogenic effect, the use of RLX in postmenopausal women is associated with an important decrease of BrCa risk. More specifically, after 4 years of follow-up, the incidence of BrCa (invasive or non-invasive) with RLX was reduced by 62% compared to the placebo (MORE Trial), and, after 8 years of RLX treatment, the incidence of ER-positive BrCa was decreased by 76% [4]. Moreover, RLX resulted similar to TAM in reducing the risk of invasive BrCa [5].

BZA (at a daily dose of 20 mg) is a third-generation SERM, containing in its molecule an indolic-based core. BZA showed to increase vertebral and hip BMD and reduce BTMs (e.g. osteocalcin, C-telopeptide and N-telopeptide) with significant differences versus placebo [6]; additionally, BZA reduced vertebral fracture risk in postmenopausal osteoporotic women [6]. Differently, in comparison to RLX, BZA also reduces the risk of non-vertebral fracture in a post-hoc analysis of high-risk patients. BZA shows an antiestrogenic effect on breast tissue, but it is also characterized by a potent antiestrogenic effect at the endometrial level.

The endometrial antiestrogenic action of BZA was crucial in the development of the so-called TSEC, in which BZA (20 mg) is combined with conjugated equine estrogen (CEE: 0.45 mg). TSEC is a progestin-free HT, that is effective for the treatment of menopausal complaints and the prevention of osteoporosis, without stimulating the breast or endometrium [7]. In particular, TSEC improves hot flushes and quality of life of postmenopausal women, and does not increase the risk of endometrial hyperplasia, venous thromboembolism, stroke and coronary artery disease for up to 2 years of administration [7]. Besides, TSEC does not increase mammographic density (a marker of BrCa risk) or breast tenderness and, nowadays, there is no evidence of an increased risk of BrCa [7]. Overall, these data suggest that TSEC can have a better breast-related safety profile than other traditional HTs. In fact, in TSEC, the tissue-selectivity of action of a SERM that replaces the progestin normally used in other HTs, is a primary mechanism that counteracts the possible negative effects of estrogens, and thus maintaining the benefits of a classic HT.

Ospemifene (at a daily dose of 60 mg) is a SERM that can improve vulvo-vaginal atrophy (VVA), ameliorate dyspareunia [8], increase vaginal superficial cells and decrease vaginal pH, without producing endometrial and breast stimulation. Additionally, ospemifene has a neutral action on the cardiovascular system. Overall, all these effects of ospemifene favor a significant improvement of sexual function and quality of life of postmenopausal women affected by VVA. Interestingly, ospemifene can be also used to treat VVA in women with a previous diagnosis of BrCa, after the completion of the active treatment course (including adjuvant therapy).

In summary, several clinical gynecological conditions that affect postmenopausal women may require the use of different SERMs (alone or in association with estrogens) including: (a) women with menopausal symptoms and/or at risk of osteoporosis (TSEC); (b) women with osteoporosis at high risk of BrCa (RLX); (c) women suffering from VVA as the most bothersome problem (ospemifene); and (d) women without menopausal symptoms but at risk of osteoporosis (RLX, BZA).

In conclusion, SERMs are compounds with important tissue-specific activities. The ability of a SERM to behave as an agonist or an antagonist according to the target tissue provides an important opportunity to individualize treatment strategies in postmenopausal women through a wide range of options.

Disclosure statement

No potential conflict of interest was reported by the author(s).