2020, VOL. 36, NO. 7, 567–568
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 antag-
onist according to the different target tissues. For instance, a
SERM may be an estrogen agonist on bone tissue and, con-
versely, a potent estrogen antagonist on breast tissue . The
concept of SERM arises from the recognized existence of a spec-
trum of action from agonist-to-antagonist activity in nature. In
other words, the same hormone can exert an agonist or antagon-
ist function under different conditions in different cell types.
Estrogen receptors (ERs), and their signaling system, are import-
ant 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 tamox-
ifene (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 . TAM also has
an agonist activity on bone tissue.
The most important SERMs currently available for the man-
agement 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 sig-
nificantly reducing the relative risk of vertebral fracture , but
not that of non-vertebral fracture. Interestingly, due to its anties-
trogenic effect, the use of RLX in postmenopausal women is
associated with an important decrease of BrCa risk. More specif-
ically, 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% .
Moreover, RLX resulted similar to TAM in reducing the risk of
invasive BrCa .
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. osteocal-
cin, C-telopeptide and N-telopeptide) with significant differences
versus placebo ; additionally, BZA reduced vertebral fracture
risk in postmenopausal osteoporotic women . 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 character-
ized 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 . In particular,
TSEC improves hot flushes and quality of life of postmenopausal
women, and does not increase the risk of endometrial hyperpla-
sia, venous thromboembolism, stroke and coronary artery disease
for up to 2 years of administration . 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 . Overall, these data suggest that TSEC
can have a better breast-related safety profile than other trad-
itional 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
Ospemifene (at a daily dose of 60 mg) is a SERM that can
improve vulvo-vaginal atrophy (VVA), ameliorate dyspareunia
without producing endometrial and breast stimulation.
Additionally, ospemifene has a neutral action on the cardiovas-
cular system. Overall, all these effects of ospemifene favor a sig-
nificant improvement of sexual function and quality of life of
postmenopausal women affected by VVA. Interestingly, ospemi-
fene 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 osteopor-
osis (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.
No potential conflict of interest was reported by the author(s).
Stefano Lello http://orcid.org/0000-0002-1616-9105
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Stefano Lello Anna Capozzi and Giovanni Scambia
Department of Woman and Child Health, Policlinico Gemelli
Foundation-IRCCS, Rome, Italy
Received 2 June 2020; accepted 4 June 2020
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