Selective Estrogen Receptor Modulators

Introduction

The menopausal state is characterized by a decrease in ovarian production of estrogens resulting in an increase in the risk of osteoporosis, cardiovascular disease and Alzheimer’s disease ^(1,2,3). The majority of women can now expect to live well beyond the menopausal years increasing the likelihood that these conditions will be the cause of significant morbidity and mortality among this group. It is estimated that a woman’s risk of sustaining a hip fracture is between 11% and 18% ^{(4, 5)}. Furthermore, 36% of women 55 to 64 years old and 55% of women >75 years old are significantly disabled by cardiovascular diseases ⁽⁶⁾. Furthermore, half of these women will be severely disabled and 1 in 6 will die as a result of the hip fracture ⁽⁷⁾. Despite a growing body of evidence supporting the use of hormone replacement therapy (HRT) to prevent and treat some of these disorders, controversy regarding an increased risk in breast cancer and uterine cancer have fueled research into other treatment modalities such as selective estrogen receptor modulators (SERM). These compounds bind to and interact with estrogen receptors acting as estrogen agonists in some tissue and as estrogen antagonists in others. Ideally, these compounds would mimic the effect of estrogen on the skeleton, cardiovascular system and central nervous system, while having no estrogenic effect on the breast and reproductive system.

SERMs are a group of structurally diverse compounds with mixed agonist and antagonist activities, which include the triphenylethylenes, such as clomiphene (Serophene, Clomid), tamoxifen (Nolvadex) and toremifene (Fareston) and the benzothiophene derivatives such as raloxifene (Evista). SERMs that reduce postmenopausal bone loss, exert a beneficial effect on serum lipids and cardiovascular function and do not stimulate the endometrium and breast tissue are currently receiving the most attention. The exact mechanism of how SERMs exert tissue-selective effects is unknown, but their mechanism of action is currently under intense investigation as the distribution of estrogen receptors (ER) and their different roles in gene regulation is elucidated.

The Estrogen Receptor; Clomiphene

The estrogen receptor (ER) was first isolated in the 1960s ⁽⁸⁾. In 1996, a second ER, ERb, was cloned from rat prostate, which had a significant amount of homology to the original ER, now termed ERa ⁽⁹⁾. Even though conserved regions of ERa and ERb are homologous, there are various nonconserved regions, which may account for differences in action between the two receptors. It is hypothesized that individual SERMs may induce specific and unique changes in receptor conformations, accounting for their particular pharmacological properties ⁽¹⁰⁾. Alternatively, it has been proposed that ligand binding by a SERM or an estrogen will act differently at gene transcription-activating regions ⁽¹¹⁾. As the molecular pathways of function are identified there will be a better understanding of how SERM action and tissue selectivity is accomplished.

The mechanism of action of clomiphene to bind to and interact with estrogen receptors acting as an agonist in some tissue and an antagonist in others is a prototype of SERM compounds. Clomiphene has been used widely to initiate or augment ovulation by antagonizing estrogen’s action at the hypothalamus and pituitary, thereby accentuating the release of gonadotropins during the follicular phase. In addition to acting on the hypothalamus and pituitary, clomiphene may act directly on the ovary ⁽¹²⁾. Within the endometrium, cervical mucous-producing glands and in mammary tissue, clomiphene exerts an antiestrogenic effect.

Clomiphene is typically begun at a dose of 50 mg per day for 5 days. It is given in the follicular phase on days 3-7 or days 5-9 of a spontaneous menstrual cycle or induced withdrawal bleed. Follicular ultrasound measurements or urinary LH kits may be used to time intercourse or insemination. If ovulation does not occur with the 50-mg dose, the dose is then increased in increments of 50 mg. If ovulation does not occur with doses of 200 to 250 mg it is often necessary to move to other alternative treatments.

Tamoxifen

Tamoxifen was synthesized and developed in the 1960′s and first reported as a treatment for advanced breast cancer in the early 1970′s ^{(13, 14)}. Currently, tamoxifen is being used in patients with invasive tumors, as well as for adjuvant therapy to surgery, radiation and chemotherapy in earlier disease stages. In the adjuvant therapy of breast cancer, studies show that overall (25%) and disease-free (45%) survival is significantly improved versus no adjuvant therapy ⁽¹⁵⁾. Recently, 20 mg of tamoxifen daily was shown to decrease the incidence of breast cancer by 45% in women at high risk compared to placebo-treated controls ⁽¹⁶⁾. The optimum duration of therapy remains to be determined, however, tamoxifen is currently recommended for at least 5 years ⁽¹⁷⁾.

While primarily an estrogen antagonist, tamoxifen displays agonist properties in the skeleton, uterus and cardiovascular system. Women receiving adjuvant tamoxifen therapy for breast cancer were found to have reductions in total cholesterol, low density lipoprotein-cholesterol (LDL-C) and lipoprotein(a) while high density lipoprotein (HDL-C) and triglycerides were essentially unchanged ⁽¹⁸⁾. These findings were similar to results in studies using tamoxifen in healthy postmenopausal women ⁽¹⁹⁾. In addition, tamoxifen was found to preserve lumbar spine and femur neck bone mineral density (BMD) in postmenopausal breast cancer patients.

Overall, tamoxifen is well tolerated by patients. Side effects more commonly encountered with tamoxifen include hot flushes, nausea and vaginal dryness. Unfortunately, tamoxifen is also associated with an increased risk of endometrial cancer by as much as 6-fold over placebo ⁽¹⁷⁾. Tamoxifen stimulates proliferation of the endometrium increasing the risk of endometrial polyps (25%), hyperplasia (50%) and cancer (6%). The majority of studies do not show a higher histopathologic grade or worse prognosis than those of other breast cancer patients not treated with tamoxifen ^{(19, 20)}.

Tamoxifen also increases the risk of thromboembolic events such as deep venous thrombosis and pulmonary embolism ⁽²¹⁾. The incidence of thromboembolism was 0.9 percent for tamoxifen treated patients compared with 0.2 percent for placebo-treated patients. The increased risk of thromboembolic disease has not been elucidated but may be similar to that of estrogen. Because of the risks of endometrial cancer and thromboembolic events tamoxifen use is restricted to women with breast cancer or those in high-risk groups.

Raloxifene

Raloxifene, a benzothiophene, was initially investigated as a treatment for breast cancer based on preliminary studies showing that it binds to both ERa and ERb with high affinity and has antagonist activity within the breast ^(22,23). In clinical trials, raloxifene has been shown to have beneficial effects on bone and serum lipids and lipoproteins without stimulating the endometrial lining of the uterus. A dose of 60 mg per day has similar antiresorptive effects as compared to 0.625 mg of conjugated estrogen ⁽²⁴⁾. There was a decrease bone turnover markers of 23% in serum levels of bone-specific alkaline phosphatase and a decrease of 15% in osteocalcin. In a more recent study, raloxifene was found to increase bone density at the hip and spine by 2%⁽²⁵⁾. Results from the Multiple Outcomes of Raloxifene Evaluation (MORE) revealed that therapy with 60 or 120 mg/day for 2 years was associated with approximately 50% reduction in the risk of asymptomatic and symptomatic vertebral fractures compared with calcium and vitamin D therapy plus placebo alone ⁽²⁶⁾. Findings also revealed a 2 to 3% increase in BMD above baseline at the spine and hip and a reduction in the markers of bone metabolism. No significant effect was found in the risk for nonvertebral fractures.

The beneficial effects of raloxifene on serum lipids have shown a significant reduction from baseline in LDL-C and total-C. HDL-C and triglycerides levels were not significantly affected. In a 6-month randomized, placebo and HRT-control trial raloxifene at doses of 60 and 120mg/day decreased LDL-C by 11%, similar to that of conjugated HRT ⁽²⁶⁾. However, raloxifene lowered lipoprotein(a) less than HRT and increased HDL-C2 (high density lipoprotein cholesterol 2 subfraction) only 15 to 17% as compared to 33% with HRT. Evidence suggests that increases in HDL-C2 may correlate with a cardiovascular protective effect ⁽²⁷⁾. Furthermore, raloxifene did not change levels of plasminogen activator inhibitor-a (PAI-1) as compared to HRT. Based on these studies, raloxifene exerts a favorable effect on serum lipids however physicians should not assume that SERMs have cardioprotective effects solely based on their estrogen-like effects on lipids. In fact, results of a study of raloxifene in menopausal monkeys showed no cardioprotective effect ⁽²⁸⁾.

One particular advantage of raloxifene is the lack of proliferative effect on endometrial tissue. Data has shown that raloxifene has minimal effects on the uterus and causes no significant changes in the histologic appearance of the endometrium. Two six-month studies involving a total of 969 postmenopausal women showed no difference in endometrial thickness than women receiving placebo ⁽²⁹⁾. Another short-term study found no evidence of endometrial proliferation as measured by endometrial biopsies after eight weeks of treatment with doses of 200 to 600mg/day ⁽³⁰⁾. Short-term trials appear to support that raloxifene does not stimulate the endometrial lining, however it is unclear whether raloxifene provides long-term protection against endometrial cancer.

Adverse effects reported by women treated with raloxifene have included hot flushes (24.6 percent versus 18.3 percent for placebo) and leg cramps (5.9 percent versus 1.9 percent for placebo) ⁽²⁶⁾. There was no significant uterine bleeding or breast tenderness as compared to continuous or cyclic HRT. The risk of thromboembolic events has also been reported with raloxifene and is more likely to occur during the first four months of treatment ⁽³¹⁾. Due to the risk of thromboembolism it has proposed that raloxifene be discontinued 72 hours before surgery and until the patient is fully ambulatory.

Other SERMs

Other SERMs currently being investigated in clinical trials are droloxifene and idoxifene, triphenyethylene derivatives. Droloxifene is currently being evaluated as a treatment for breast cancer as well as for the prevention of postmenopausal osteoporosis. It has a greater affinity for the estrogen receptor than tamoxifen and has less agonist and more antagonist activity at the uterus ⁽³²⁾. In the breast tissue droloxifene has antiestrogenic effect and preserves bone density by reducing the formation of osteoclasts in the bone marrow through apoptosis of mononuclear precursors ⁽³³⁾.

Idoxifene is also being studied for the treatment of advanced breast cancer. Idoxifene has an estrogen receptor binding affinity that is twice that of tamoxifen, but a less potent antiestrogen⁽³⁴⁾.

SERMs are a class of drugs that help to reduce the risk of osteoporosis and breast cancer and improve serum lipids. These medications have obvious advantages over HRT however more research and development is needed before this therapy becomes mainstay. Many women who initiate HRT commonly cite relief from menopausal symptoms such as hot flushes and night sweats. The currently available SERMs do not alleviate such symptoms and may even exacerbate some limiting their use. There is also no data to address long-term safety and efficacy questions. At this time HRT remains the treatment of choice for osteoporosis and coronary heart disease prevention while SERMs offer an alternative to only a select group of women.

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