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Rabe T et al.  
Selective Estrogen Receptor Modulators – an Update
(Joint Statement by the German Society for Gynecological Endocrinology and Reproductive Medicine [DGGEF] and the German Professional Association of Gynecologists [BVF])

Journal für Reproduktionsmedizin und Endokrinologie - Journal of Reproductive Medicine and Endocrinology 2015; 12 (4): 287-317

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Keywords: bazedoxifeneclomifeneindicationsmode of actionormeloxifeneospemifeneraloxifeneselective estrogen receptor modulatorsSERMstamoxifenetoremifene

Selective estrogen receptor modulators (SERMs) are a heterogeneous group of non-steroidal substances with both estrogenic and anti-estrogenic properties. Mode of action: Competitive binding to estrogen receptors (ER) with conformational changes of the receptor and involvement of tissue-specific co-activators and co-repressors, resulting in tissue-dependent, anti-estrogenic or estrogenic effects. Apart from the genomic activity via estrogen receptors in the nucleus, non-genomic effects via membrane-bound estrogen receptors have also been described.
Indications: The indications are substance-specific and include the treatment of breast cancer (tamoxifene) osteoporosis (raloxifene, bazedoxifene), infertility (clomifene), vaginal dryness (ospemifene), dysfunctional uterine bleeding (ormeloxifene) as well as hormone replacement therapy (bazedoxifene in combination with conjugated estrogens) and contraception (ormeloxifene). In addition, tamoxifene and raloxifene have marketing authorization is some countries for prevention of breast cancer in women at increased risk of breast cancer.
“Ideal SERM“: substance showing desired estrogenic and anti-estrogen effects, yet without its drawbacks.
Characteristics of SERMs (in alphabetical order):
Compounds with marketing authorization:
Bazedoxifene (Indole derivative): Bazedoxifene has been approved in Europe as a stand-alone treatment for the treatment of osteoporosis (brand name Conbriza®). It has not been approved in the US as a stand-alone treatment.
“Tissue Selective Estrogen Complex (TSEC)”: Combination with conjugated estrogens: Bazedoxifene plus conjugated estrogens is indicated in the US (tradename Duavee®) for the treatment of moderate to severe vasomotor symptoms associated with menopause and the prevention of postmenopausal osteoporosis. In Europe (where the tradename is Duavive®), the approved indication is the treatment of estrogen deficiency symptoms in postmenopausal women with a uterus (with at least 12 months since the last menses) for whom treatment with progestin-containing therapy is not appropriate.
Clomifene (Triphenylethylene derivative): Treatment of ovarian dysfunction (infertility). Ospemifene: FDA registration for treatment of moderate or severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause; EU-registration for moderate or severe symptoms of vulvo-vaginal atrophy.
Ormeloxifene used in India for contraception and treatment of dysfunctional uterine bleeding. Raloxifene (Benzothiophene derivative) used for treatment and prevention of osteoporosis in postmenopausal women and in some countries (including the USA) for breast cancer prevention in high risk women. Raloxifene has no marketing authorization for this indication in Europe. The VTE risk is increased, similar to HRT. Death due to stroke was increased in the RUTH study (secondary prevention study), but not in the MORE or CORE studies (osteoporosis treatment and extension studies).
Tamoxifene (triphenylethylene derivative) is licensed for adjuvant use in women with primary or metastasized breast cancer and in some countries for the primary prevention of breast cancer. Tamoxifene is an antiestrogen, used (20 mg/day) in women who have estrogen receptor-positive (ER+) breast cancer. Unfortunately, resistance to tamoxifene is common in women with metastatic disease. Possible side effects include an increased risk of endometrial cancer and, like with all SERMs, an increased risk of VTE. An increased risk of stroke has been observed in the NSABP-1 study (RR1.42), but this was not statistically significant. Some antidepressants (SSRIs) abolish the effect of tamoxifene.
Toremifene (citrate) (also a triphenylethylene derivative) has EU marketing authorization for first line endocrine treatment of hormone-dependent meta static breast cancer in postmenopausal patients. Fareston is not recommended for patients with estrogen receptor negative tumors. According to the US license, Fareston is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.
Compounds whose development has been suspended:
Arzoxifene: Development for use in osteoporosis and breast cancer prevention suspended
Droloxifene: Development suspended
EM 800: Development suspended
Lasofoxifene (= desmethyl dihydro analogue of nafoxidine): FDA registration for osteoporosis refused in 2005. In 2009 EU marketing authorization for the treatment of osteoporosis. Marketing authorization is no longer valid as a result of the “Sunset Clause”. The rights to lasofoxifene have recently been acquired by Sermonix Pharmaceuticals LLC with a view to restarting the development.
Idoxifene: Development suspendedLevormeloxifene: Development suspended
Pipendoxifene: Development for the treatment of postmenopausal women with metastatic breast cancer has been suspended
Compounds in development:
Afimoxifene: Studies are being conducted in mastalgia and breast cancer.
Future aspects:
– Further research on active metabolites of above mentioned SERMs
– New indications for the use of SERMs: e.g. osteoarthritis, schizophrenia, postmenopausal vascular disease, increased lipid levels, virus infections (ebola), cryptococcal infections.
– New types of application may be vaginal ring, intrauterine devices, vaginal tablets.
– Selective estrogen receptor downregulators: Alternative choice to SERMs. These pure estrogen antagonists lead to a down-regulation of the estrogen receptors.
An already registered product is fulvestrant (Faslodex®) which is indicated for the treatment of postmenopausal women with estrogen receptor positive, locally advanced or metastatic breast cancer for disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on therapy with an anti-estrogen (like tamoxifene).
– Multiple metabolites of tamoxifene as norendoxifen, 4,4’-dihydroxy-tamoxifene, endoxifene, N-desmethyl-tamoxifene, N-desmethyl-4’-hydroxy-tamoxifene, tamoxifene-N-oxide, 4’-hydroxy-tamoxifene, N-desmethyl-droloxifene, 4-hydroxy-tamoxifene can be used in women with breast cancer, based on their aromatase inhibition activity. Most of all, norendoxifene may be able to serve as a potent and selective lead compound in the development of improved therapeutic agents.
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