SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

• Are anti-estrogen drugs.
• Provides beneficial effect of estrogen & also antagonizes its adverse effects.

MOA:

• Acts both as estrogen agonists & antagonists.

As estrogen agonist in bone & blood:

• Reduces bone resorption & improves lipid profile in blood.

As estrogen antagonist in endometrium, breast & liver:

• Increases breast Ca. risk & predisposes to thromboembolism.
• Antagonistic actions are of more significant.

Drugs:

• Tamoxifen, toremifene, doloxifen, ospemifene, bazedoxifene, clomiphene, fulvestrant, tibolone, raloxifene, ormeloxifene (Centchroman)

Drug groups/subcategories:

Selective estrogen receptor degrader/down-regulator (SERD):

• Fulvestrant

Selective tissue estrogen activity regulators (STEAR):

• Tibolone

Non-steroidal SERM:

• Ormeloxifene (Centchroman)

Overall clinical uses:

• All drugs are used for breast carcinoma.
• Treats both early stage & metastatic breast carcinoma – Particularly estrogen receptor (+ve) breast Ca.
• As chemopreventive drug for breast Ca.
• In osteoporosis.

General adverse effects:

• Transient flare-up reactions.
• Estrogenic adverse effects.

Specific SERM’s toxicities – 

• Menopausal symptoms, fluid retention, thromboembolism, increased endometrial cancer incidence.

Drug description:

1^st drug group: Selective estrogen receptor degrader/down-regulator (SERD):

A.) Tamoxifen:

MOA:

• Acts as antagonist to estrogen receptors in breast.

Drug actions:

• Decreases risk of contralateral breast cancer.

Uses:

• Primary prevention of breast cancer in high-risk women.

Adverse effects:

• Hot flushes
• Vaginal discharge/bleeding
• Menstrual irregularities
• Endometrial hyperplasia
• Cataracts
• Tumor flare.
• Hepatotoxicity
• Thromboembolic events (rare)

B.) Fulvestrant:

• 1^st FDA approved agent in new drug class “selective estrogen receptor down-regulator (SERD)”.
• Are pure ER antagonist.
• Administered intramuscularly, at monthly intervals.
• Safer than SERMs.
• Faster onset & long duration.
  • Both due to pure ER antagonism.

Uses:

• Tamoxifen-resistant breast Ca.
• Hormone receptor-positive metastatic breast Ca. in postmenopausal women.
• (Progressed despite antiestrogen therapy).

Comparison with tamoxifen:

• Binds to estrogen receptor (ER) with 100 times more affinity than tamoxifen.
• Inhibits its dimerization & its degradation –> Results in ER “downregulation”.
• Abolishes ER-mediated transcription –> Suppresses expression of estrogen-dependent genes.
• Hence, is efficient against tamoxifen-resistant breast cancer.

Adverse effects:

• Nausea, asthenia & pain (most common).
• Vasodilation (hot flushes)
• Headache.

C.) Ospemifene:

Uses:

• Treating moderate to severe dyspareunia (pain during sexual intercourse).
• (Dyspareunia – Due to vulvar vaginal atrophy during menopause).

MOA:

• Effect similar to estrogen.
• Builds vaginal epithelium & increases vaginal wall thickness → Reduces dyspareunia.

Adverse effect:

• Thickens endometrium → Causing unusual bleeding & endometrial cancer.
• Boxed warning.

D.) Clomiphene:

MOA: 

• Estrogen antagonistic action in hypothalamus.
• Reduces feedback inhibition of GnRH secretion.

Uses:

• Treatment of anovulatory infertility – By increasing GnRH release.
• DOC for Stein Leventhal syndrome.

Major adverse effect:

• Hyperstimulation syndrome (polycystic ovarian disease) & multiple pregnancies.
• Alopecia, vertigo, allergic dermatitis, gastric upset, breast soreness, heavy menses and increased risk of ovarian tumor.

E.) Raloxifene:

• Beneficial effects on lipid profile, breast & endometrium.
• Major adverse effect: Increased thromboembolism predisposition.
• Uses: Particularly useful for osteoporosis in postmenopausal women.

F.) Bazedoxifene:

Uses:

• Treats (moderate to severe) vasomotor symptoms during menopause.
• Prevention of postmenopausal osteoporosis in combination with estrogen.

2^nd drug category: Selective tissue estrogen activity regulators (STEAR):

• Compounds with estrogenic activity, tissue-selective mode of action & regulate ligand levels.

A.) Tibolone:

• Considered as hormone replacement therapy (HRT) designer.
• Used for preventing vasomotor symptoms & osteoporosis in menopause.

3^rd drug category: Non-steroidal SERM:

A.) Centchroman (ormeloxifene):

• Developed at CDRI India.
• Used as non-hormonal oral contraceptive (Saheli).
• Dose: 30mg
• Approved for dysfunctional uterine bleeding (DUB) treatment. 

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