Antiestrogens and Selective Estrogen Receptor Modulators (SERMS)

ANTIESTROGENS AND SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS)

Two nonsteroidal compounds clomiphene citrate and tamoxifen citrate previously grouped as estrogen antagonists have been in use since 1970s, but their differing antagonistic and agonistic actions depending on species, target organ and hormonal background could not be explained. The recent discovery of two estrogen receptors (ERs) and that ligand binding could change their configuration in multiple ways allowing interaction with different coactivators and corepressors in a tissue specific manner has paved the way for development of compounds with unique profile of agonistic and antagonistic actions in different tissues. These drugs have been designated ‘selective estrogen receptor modulators’ and two new compounds Raloxifene and Ormeloxifene have been marketed. It has been demonstrated that the conformation of ER after binding tamoxifen or raloxifene is different from that after binding estradiol.

Antiestrogens

Clomiphene Citrate

It binds to both ERα and ERβ and acts as a pure estrogen antagonist in all human tissues, but the recemate displays weak agonistic action in rats. It induces Gn secretion in women by blocking estrogenic feedback inhibition of pituitary. The amount of LH/FSH released at each secretory pulse is increased. In response, the ovaries enlarge and ovulation occurs if the ovaries are responsive to Gn. Antagonism of peripheral actions of estrogen results in hot flushes. Endometrium and cervical mucus may be modified.

The chief use of clomiphene is in sterility due to failure of ovulation: 50 mg once daily for 5 days starting from 5th day of cycle. Treatment is given monthly. Conception occurs in many women who previously were amenorrhoeic or had anovular cycles. If 1–2 months treatment does not result in conception—the daily dose may be doubled for 2–3 cycles (max 200 mg/day). The antiestrogenic effect of clomiphene on developing follicle, endometrium or cervical mucus can be counterproductive. Luteal phase dysfunction has also been blamed for therapeutic failures. Addition of menotropins or chorionic gonadotropin on the last 2 days of the course improves the success rate.

Clomiphene is well absorbed orally, gets deposited in adipose tissue and has long t½ of ~6 days. It is largely metabolized and excreted in bile.

Adverse Effects

Polycystic ovaries, multiple pregnancy, hot flushes, gastric upset, vertigo, allergic dermatitis. Risk of ovarian tumour may be increased.

Other Uses

To aid in vitro fertilization Clomiphene given with Gns causes synchronous maturation of several ova—improves their harvesting for in vitro fertilization.

Oligozoospermia: In men also clomiphene increases Gn secretion → promotes spermatogenesis and testosterone secretion. For male infertility— 25 mg daily given for 24 days in a month with 6 days rest for upto 6 months has been recommended. However, success rates are low.

CLOMID, FERTOMID, 25, 50 mg tab. CLOFERT, CLOME 25, 50, 100 mg tab.

Fulvestrant

It is the first member of a distinct class of ER ligands called ‘selective estrogen receptor down regulators’ (SERDs) or ‘pure estrogen antagonists’ that has been introduced for the treatment of metastatic ER positive breast cancer in postmenopausal women which has stopped responding to tamoxifen. In contrast to tamoxifen, it inhibits ER dimerization so that ER interaction with DNA is prevented and receptor degradation is enhanced. The ER is thus down regulated resulting in more complete suppression of ER responsive gene function. This along with its higher affinity for the ER probably accounts for its efficacy in tamoxifen resistant cases.

Fulvestrant is administered as monthly i.m. injections; is slowly absorbed and has an elimination t½ of more than a month.

Selective Estrogen Receptor Modulators (SERMs)

Tamoxifen Citrate

Though chemically related to clomiphene, it has complex actions; acts as potent estrogen antagonist in breast carcinoma cells, blood vessels and at some peripheral sites, but as partial agonist in uterus, bone, liver and pituitary. Inhibition of human breast cancer cells and hot flushes reflect antiestrogenic action, while the weak estrogen agonistic action manifests as stimulation of endometrial proliferation, lowering of Gn and prolactin levels in postmenopausal women as well as improvement in their bone density.

A decrease in total and LDL cholesterol without any change in HDL and triglyceride level reflects estrogenic action. Similar to estrogen HRT, it increases the risk of deep vein thrombosis by 2–3 times.

Tamoxifen is the standard hormonal treatment of breast cancer in both pre and postmenopausal women, though aromatase inhibitors are gaining prominence. In early cases it is given as postmastectomy adjuvant therapy, while in advanced cases it is a constituent of palliative treatment. Response rates are high in ERpositive breast carcinomas, but some ERnegative tumours also respond suggesting additional nonhormonal mechanism of action. It is also effective following surgery in cancer of male breast.

Based on large epidemiological studies which have shown 45% reduction in the incidence of ERpositive breast cancer, it has been approved for primary prophylaxis of breast cancer in highrisk women. Recurrence rate in ipsilateral as well as contralateral breasts is reduced by tamoxifen, but benefits of prophylactic therapy beyond 5 years are not proven; outcomes may even be worse.

Improvement in bone mass due to antiresorptive effect, and in lipid profile are the other benefits of tamoxifen therapy. However, endometrial thickening occurs and risk of endometrial carcinoma is increased 2–3 fold.

Tamoxifen is effective orally; has a biphasic plasma t½ (10 hours and 7 days) and a long duration of action. Some metabolites of tamoxiphen are more potent antiestrogens. The drug is excreted primarily in bile.

Dose 10–20 mg BD. TAMOXIFEN, MAMOFEN, TAMODEX 10, 20 mg tabs.

Male infertility: May be used as alternative to clomiphene.

Side Effects

Hot flushes, vomiting, vaginal bleeding, vaginal discharge, menstrual irregularities, increased risk of venous thromboembolism.

Dermatitis, anorexia, depression, mild leucopenia and ocular changes are infrequent.

It is much less toxic than other anticancer drugs.

Toremifene It is a newer congener of tamoxifen with similar actions, uses and adverse effects.

Raloxifene

This SERM is an estrogen partial agonist in bone and cardiovascular system, but an antagonist in endometrium and breast. It has high affinity for both ERα and ERβ, and has a distinct DNA target the ‘raloxifene response element’ (RRE).

Several long term multicentric studies have convincingly shown that raloxifene prevents bone loss in postmenopausal women; bone mineral density (BMD) may even increase by 0.9– 3.4% over years in different bones, particularly the lumbar vertebrae. The risk of vertebral fracture is reduced to half, but not that of long bones except ankle.

In postmenopausal women raloxifene reduces LDL cholesterol, probably by upregulating hepatic LDL receptors. In contrast to estrogen HRT there is no increase in HDL and triglyceride levels. Follow up studies have shown that raloxifene reduces the risk of breast cancer by 65%, though the protection was confined to ERpositive breast cancer.

Raloxifene does not stimulate endometrial proliferation and there is no increase in the risk of endometrial carcinoma. It does not relieve vasomotor symptoms of menopause; rather hot flushes may be induced in some women.

Raloxifene is absorbed orally but has low bioavailability due to extensive first pass glucuronidation. The t½ is 28 hours and major route of excretion is faeces.

Side Effects

Hot flushes, leg cramps are generally mild; vaginal bleeding is occasional. The only serious concern is 3fold increase in risk of deep vein thrombosis and pulmonary embolism. However, similar risk attends estrogen HRT.

Raloxifene is a first line drug for prevention and treatment of osteoporosis in postmenopausal women; Ca2+ and vit D supplements enhance the benefit; bisphosphonates are the other first line drugs. It has no use in men.

Dose: 60 mg/day;

BONMAX, RALOTAB, ESSERM 60 mg tab.

Ormeloxifene

A distinct new SERM which acts as estrogen antagonist in breast and uterus. It suppresses endometrial proliferation by regulating their ER. Excessive uterine bleeding with anovular cycles occurring near menopause is normalized. However, vaginal epithelium and cervical mucus are not altered. It may have contraceptive property.

Ormeloxifene is approved for treatment of dysfunctional uterine bleeding. Side effects are nausea, headache, fluid retention, weight gain, rise in BP and prolongation of menstrual cycles.

Dose: 120 mg twice weekly for 2–3 months, followed by 60 mg weekly for another 3 months. SEVISTA 60 mg tab.