Katherine is 53 with her last period about a year ago. She is complaining of severe hot flashes, night sweats and vaginal dryness. She wants to take hormonal therapy but is concerned about the increased risk of breast cancer seen in the Womens Health Initiative (WHI) Study with combination estrogen and progestin therapy. Her last periods before finally quitting were very heavy with cyclic breast tenderness. She wants relief from her hot flashes but doesn’t want to develop bleeding or breast tenderness.
Selective estrogen receptor modulators, commonly referred to as SERMs or estrogen agonists/antagonists, are estrogen-like compounds that may act as weak estrogen agonists and as estrogen antagonists, depending on the particular SERM and the target tissue. Selective estrogen receptor modulators have many clinical uses for postmenopausal women because of their ability to target and prevent or treat different diseases, including breast cancer and osteoporosis, and recently postmenopausal dyspareunia.
Selective estrogen receptor modulators available for postmenopausal women in the USA include tamoxifen and toremifene approved for prevention and treatment of breast cancer, raloxifene approved for prevention and treatment of osteoporosis and prevention of invasive breast cancer, and ospemifene approved for treatment of dyspareunia associated with postmenopausal vaginal atrophy. Tibolone, widely used around the world for relief of menopausal symptoms and prevention of bone loss, is not approved in the USA or Canada. Lasofoxifene prevents bone loss and improves vaginal atrophy but development has been placed on hold due to gynecologic concerns. Bazedoxefine is approved for prevention of osteoporosis in Europe. The first tissue selective estrogen complex (TSEC) approved in the USA is a pairing of conjugated equine estrogens with the SERM bazedoxefine for relief of hot flashes and prevention of bone loss. Many SERMs have been discontinued following phase III multicenter clinical trials due to adverse findings, including droloxifene, idoxifene, ormeloxifene and levormeloxifene.
An ideal SERM for postmenopausal women would be estrogenic on bone to prevent bone loss, relieve hot flashes with a neutral or estrogen antagonistic effect on the breast and endometrium to reduce cancer risks. To date, such a SERM has not been identified.
Selective estrogen receptor modulators are synthetic, non-steroidal hormones that show variable or mixed estrogen agonist or antagonist properties depending on specifics found at target tissue when they bind to the estrogen receptor.
Mechanism of action occurs through a conformational structure change at the receptor when the SERMS bind, with effects on transcription depending on different coactivators (CoA) or corepressors (CoR) which are involved in the regulation of target gene transcription. The shape of the ligands that bind to the estrogen receptors (ERs, ERα or ERβ) allows the complex to submit variable signals, which leads to the variable tissue activity . Although preclinical testing can suggest how a given SERM will behave in a given tissue, large clinical trials are needed to identify each SERM’s unique tissue-selective effects in postmenopausal women. Although SERMS in general are felt to be preventive of bone loss and antagonistic at the breast, each SERM must be tested for its effects on each tissue (targeted and non-targeted) for efficacy and safety.
The hope of SERMS for postmenopausal women is to allow individual care depending on specific estrogen agonist or estrogen antagonist effects desired in a given woman.
Tamoxifen is approved for prevention and treatment after breast cancer, and there is now good evidence from several prospective trials and a meta-analysis that it does decrease the incidence of recurrence, if used up to 10 years, of ER-positive breast cancer. Consequently, the American Society of Clinical Oncology (ASCO) [2, 3] has updated its guidelines for postmenopausal women with breast cancer who are hormone receptor-positive:
1. Take tamoxifen for 10 years.
2. Use an aromatase inhibitor for 5 years followed by tamoxifen for 5 years, then go back to aromatase inhibitor for up to another 5 years.
3. Take tamoxifen for 2–3 years followed by 5 years of an aromatase inhibitor.
Tamoxifen is not approved to prevent bone loss, but has been shown to be a partial agonist in bone with prevention of bone loss in postmenopausal (but not premenopausal) women at the lumbar spine and hip, although with less improvement in bone density than seen with hormone therapy.
Concerns about tamoxifen use include an increased risk of endometrial polyps, endometrial cancer (both adenocarcinoma of the endometrium and rare reports of mixed mesodermal sarcoma), venous thromboembolic events, pulmonary embolism and stroke in women over 50. The risk of endometrial cancer in postmenopausal tamoxifen users in the STAR trial was increased (RR 2.54), with an increase for women over 50 (RR 5.4), with higher risk seen with longer duration of use or prior endometrial thickening. The effect of tamoxifen on the vagina is mixed with some estrogenic effects but also adverse reports of dyspareunia, leukorrhea or vaginal dryness. Hot flashes have been reported as adverse events but reported bothersome enough to seek treatment only in 16%.
Toremifene is used for postmenopausal women as an adjunct in the treatment of advanced estrogen receptor-positive breast cancer and appears similar in effectiveness to tamoxifen in comparative trials . Although slightly less, endometrial cancer was seen (39% compared with 44.3%), this was not significantly less . Toremifene has an estrogen agonist effect on bone and lipid profiles.
Raloxifene is approved for prevention and treatment of osteoporosis and for the prevention of invasive breast cancer.
Effect on breast
Several studies have shown a protective effect of raloxifene with respect to recurrence of breast cancer, with an incidence of about 50% less cases of invasive estrogen-positive breast cancer. When compared with tamoxifen, raloxifene reduced invasive breast cancers as well but with fewer endometrial cancers, venous thromboembolism (VTE), pulmonary embolism and cataracts seen in STAR trial of women at high risk .
Raloxifene at 60 mg/day improved bone density at 3 years by 2.6% at lumbar spine and 2.1% at femoral neck (P < 0.001) with a significant reduction in new clinical vertebral fractures of 68% (absolute risk reduction of 1.3/1,000). At 3 years, the risk of vertebral fracture was reduced by 55% in women at high risk with T-scores of −2.5 SD or less at lumbar spine or hip, compared with a 30% reduction in women who had low T-scores and prior vertebral fracture . Raloxifene has thus shown beneficial effects on prevention of bone loss and in reducing vertebral fractures associated with postmenopausal osteoporosis although it did not show prevention of hip or non-vertebral fractures .
Effect on endometrium
Raloxifene has been tested up to 6 months with vaginal estrogen without proliferative effects on endometrium based on transvaginal ultrasound and endometrial biopsy, but in one study combined with oral estradiol, an increase in endometrial hyperplasia was seen. Studies combining raloxifene with systemic estrogen showed a benefit on quality of life, treatment satisfaction and vaginal dryness but in some, an increase in endometrial thickness was seen as soon as 3 months with endometrial proliferation and two cases of endometrial hyperplasia both after 24 weeks. Thus combining raloxifene with vaginal estrogen appears safe, but not combining it with systemic estrogen.
Ospemifene is a SERM that has been approved in the USA for treatment of dyspareunia due to postmenopausal atrophy. Several studies have shown beneficial effects on dyspareunia and positive changes on the vagina, with improvements in vaginal maturation index (increases of superficial and intermediate cells) compared with placebo, as well as improvements in vaginal pH .
Preclinical effect on ovariectomized rats and bone marker data in humans suggest an effect of ospemifene on prevention of bone density, but, unfortunately to date, ospemifene has not been evaluated in a large RCT for its effects on prevention of bone loss or whether it is neutral or antagonistic on the breast.