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22.11 Mortality
A new analysis from the Women’s Health Initiative (WHI) randomized trials
examined all-cause and cause-specic mortality during the intervention and post-
intervention follow-up periods (total cumulative follow-up of 18years) [77]. The
primary outcome measure was all-cause mortality in the two pooled trials and in
each trial individually. There was no link between MHT and all-cause mortality
in the overall study population (ages 50–79) in either trial. However, there was a
trend toward lower all-cause mortality among the younger women in both trials. In
women aged 50–59, there was a statistically signicant 31% lower risk of mortality
in the pooled trials among women taking active MHT compared with those taking
placebo, but no reduction in mortality with MHT among older women (P for trend
by age=0.01) [77].
22.12 Conclusions
Hormone therapy continues to have an important clinical role in the management
of menopausal symptoms. Currently available evidence does not support the use of
MHT for chronic disease prevention. However, the absolute risks of adverse events
in younger women are much lower than in older women, and the quality-of-life ben-
ets are likely to outweigh the risks for many women who seek treatment for symp-
toms in early menopause. Given the lack of validated primary prevention strategies
other than lifestyle changes for younger women (<60years), MHT is considered a
good strategy—taking into account current knowledge thereof—for reducing the
risk of osteoporosis fractures in menopausal women and for reducing the frequency
of CHD and general mortality of women in their sixth decade (or in the 10years
since onset of the menopause), unless there are specic contraindications.
In conclusion, our understanding of the benets and risks of MHT has advanced
substantially. The guidance for physicians and women should reect this evolu-
tion and emphasize the individualization and shared decision-making that facilitates
appropriate decisions regarding the use of MHT.
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© Springer Nature Switzerland AG 2019
F. R. Pérez-López (ed.), Postmenopausal Diseases and Disorders,
https://doi.org/10.1007/978-3-030-13936-0_23
S. Palacios (*)
Instituto Palacios de Salud y Medicina de la Mujer, Madrid, Spain
e-mail: spalacios@institutopalacios.com
23
Selective Estrogen Receptor Modulators
(SERMs): State of theArt
SantiagoPalacios
23.1 Introduction
During and after menopause, women may experience various symptoms, such as
vasomotor symptoms and genitourinary syndrome associated with menopause,
attributable to the decrease in estrogen levels, with the consequent physiological
changes [1]. In addition, there has been shown to be a strong link between decreased
estrogen levels and loss of bone mass with the consequent risk of osteoporosis and
fracture [2].
Hot ushes affect 50–82% of women undergoing menopause [3], and 40–50%
have vaginal atrophy [4]. In addition, more than 40% of women have low bone mass
between the ages of 50 and 60 [5].
Estrogen therapy at menopause is considered the number one treatment for both
hot ushes and vulvovaginal atrophy, and most scientic societies consider estro-
gen therapy to be a very effective treatment for the prevention and/or treatment of
osteoporosis [2, 6–8].
But estrogen therapy, even local, has its contraindications. After any gyneco-
logical or hormone-dependent cancer, it is preferable to start with non-hormonal
therapies [8]. On the other hand, in general, concerns about the possible stimulating
effects of systemic estrogen on the breast and endometrium as well as other nega-
tive effects of long-term estrogen treatment may be a barrier to its use [9]. Another
important point is that adherence to drugs prescribed for long-term conditions is
often poor [10, 11].
Therefore, the search for an alternative to estrogen therapy, both systemic and
local, has proved necessary. Selective estrogen receptor modulators have been used
for more than 30years and have made it possible to avoid many of the side effects of
estrogens. The possibility of them being used for the therapeutic purpose of treating
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osteoporosis and vulvovaginal atrophy has been investigated. The result of this is the
emergence of various selective estrogen receptor modulators (SERMs) with different
applications, ranging from the prevention and treatment of breast cancer to the pre-
vention and treatment of osteoporosis or even dyspareunia and vulvovaginal atrophy.
The aim of this paper is to briey compare the pharmacology of different SERMs
and provide a detailed review of the available clinical data on their effects. The
relevant English-language articles, published between 1985 and 2018, were rst
identied through a PubMed database search with the search string “selective estro-
gen receptor modulator or SERM.” Furthermore, a specic review has been made
of each individual SERM.
23.2 Selective Estrogen Receptor Modulators
SERMs are compounds with a molecular structure different from that of steroids.
They share their selective binding to estrogen receptors (ER) with steroids and pro-
duce an estrogen agonist or antagonist effect depending on the target cell and hor-
monal environment. They have been developed with the aim of producing specic
positive estrogenic effects on some target tissues, but with negative or neutral estro-
genic effects on other tissues [12].
They were rst known as antiestrogens and developed for the treatment of breast
cancer. The four best known SERMs are tamoxifen, raloxifene, bazedoxifene, and
ospemifene, wherein tamoxifen is currently being used for the prevention and treat-
ment of breast cancer, both raloxifene and bazedoxifene for the treatment of osteo-
porosis, and ospemifene for dyspareunia or vulvovaginal atrophy. Therefore, the
main aim of the pharmacological development of SERMs is to increase the benet/
risk ratio compared to estrogen therapy in the prevention and treatment of several
highly prevalent, chronic, postmenopausal diseases that are associated with this
state of estrogen deciency.
Tamoxifen, a drug that was introduced more than 40years ago for the treat-
ment of hormone-dependent breast cancer, has been considered an antiestro-
gen for decades because of its blocking action on the binding of endogenous
estrogens to the estrogen receptor (ER) of neoplastic breast cells. However, sev-
eral studies suggest that tamoxifen may have a protective action on bone tissue
(estrogen agonist) [13]. Raloxifene is the rst SERM approved for preventing
and treating osteoporosis [14]. In addition, raloxifene is as effective as tamoxi-
fen in reducing the risk of breast cancer in postmenopausal women [15] and
does not signicantly affect the risk of cardiovascular disease [16]. Bazedoxifene
has been shown to be effective in reducing vertebral and, in a high-risk group,
non-vertebral fractures [17]. Finally, the rst SERM, ospemifene, has recently
been approved in the USA and Europe for the treatment of dyspareunia in the
USA and for patients with vulvovaginal atrophy who are not eligible for estrogen
treatment in Europe [18].
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This class of drugs has enormous potential in the primary and secondary preven-
tion of various types of estrogen-dependent tumors, postmenopausal osteoporosis,
and vulvovaginal atrophy.
23.3 SERM Classification
There is an extensive list of compounds that can be considered SERMs for which
results are available in either invitro or invivo animal cell models and in human
experiments. There are more than 60 molecules already described with a SERM
pharmacological prole [19]. Table23.1 provides a summary of the main SERM
groups classied according to chemical structure [20]. But they could also be
divided by generations (Table23.2) [21]. Certain phytoestrogens, such as genistein
and daidzein, also appear to have a SERM-type pharmacological prole. There are
currently three main chemical classes of SERM approved for clinical use: triphe-
nylethylene derivatives, such as tamoxifen and ospemifene, used to treat and pre-
vent breast cancer and vulvovaginal atrophy, respectively, and clomiphene to induce
Class Examples
Triphenylethylenes Tamoxifen
Clomiphene
Droloxifene
Fispemifene
GW-5638
Idoxifene
MDL-103,323
Miproxifene
Ospemifene
Toremifene
Benzothiophenes Raloxifene
Arzoxifene
LY-117018
Indoles Bazedoxifene
Pipendoxifene
Naphthalenes Lasofoxifene
Trioxifene
Benzopyrans EM-800
Acolbifene
Levormeloxifene
Ormeloxifene
NNC 45-0781 and derivatives
SP-500263
Table 23.1
Classication of
SERMs
23 Selective Estrogen Receptor Modulators (SERMs): State of theArt
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