Selective Estrogen Receptor Modulators (SERMs)

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:

1st 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:

  • 1st 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.

2nd 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.

3rd 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. 

Exam Important

  • Selective estrogen receptor modulator (SERM’s) are anti-estrogen drugs.
  • SERM’s exerts estrogen agonistic actions in bone & blood, by reducing bone resorption & improving lipid profile in blood.
  • Estrogen antagonistic actions of SERM’s are on endometrium, breast & liver.
  • SERM’s increases breast Ca. risk & predisposes to thromboembolism.
  • Drugs included under SERM’s are Tamoxifen, toremifene, doloxifen, ospemifene, bazedoxifene, clomiphene, fulvestrant, tibolone, raloxifene, ormeloxifene (Centchroman).
  • Fulvestrant is an anti-estrogen drug, under category “selective estrogen receptor degrader/down-regulator (SERD)”.
  • Tibolone is an anti-estrogen drug, under category “Selective tissue estrogen activity regulators (STEAR)”.
  • Ormeloxifene (Centchroman) is an anti-estrogen drug, under category “Non-steroidal SERM”, which can also be used as an oral anticoagulant.
  • SERM’s are used for treating both early stage & metastatic breast carcinoma, particularly estrogen receptor (+ve) breast Ca.
  • Tamoxifen acts as antagonist to estrogen receptors in breast.
  • Tamoxifen is used for primary prevention of breast cancer in high-risk women.
  • Hot flushes, vaginal discharge/bleeding, menstrual irregularities & endometrial hyperplasia are all adverse effects of Tamoxifen.
  • Fulvestrant is the 1st FDA approved agent in new drug class “selective estrogen receptor down-regulator (SERD)”.
  • Fulvestrant is a pure ER antagonist, with faster onset, long duration & safer than SERMs.
  • Fulvestrant is useful in treatment of tamoxifen-resistant breast Ca & hormone receptor-positive metastatic breast Ca. in postmenopausal women.
  • Fulvestrant compared with tamoxifen, binds to estrogen receptor (ER) with 100 times more affinity than tamoxifen.
  • Clomiphene exhibits estrogen antagonistic action in hypothalamus, by reducing feedback inhibition of GnRH secretion.
  • Clomiphene is used for anovulatory infertility treatment, by increasing GnRH release.
  • DOC for Stein Leventhal syndrome is Clomiphene.
  • Hyperstimulation syndrome (polycystic ovarian disease) & multiple pregnancies are major adverse effects of Clomiphene.
  • Ospemifene is used for dyspareunia treatment, during menopause.
  • Ospemifene builds vaginal epithelium & increases vaginal wall thickness, thus reduces dyspareunia.
  • Raloxifene is particularly useful for osteoporosis in postmenopausal women.
  • Bazedoxifene treats vasomotor symptoms during menopause & prevents postmenopausal osteoporosis in combination with estrogen.
  • Selective tissue estrogen activity regulators (STEAR) includes compounds with estrogenic activity, tissue-selective mode of action & regulate ligand levels.
  • Tibolone, a STEAR drug is considered as hormone replacement therapy (HRT) designer.
  • Tibolone prevents vasomotor symptoms & osteoporosis in menopause.
  • Non-steroidal SERM includes Centchroman (ormeloxifene) developed at CDRI India, used as non-hormonal oral contraceptive (Saheli).
  • Centchroman (ormeloxifene) is approved for dysfunctional uterine bleeding (DUB) treatment.
Don’t Forget to Solve all the previous Year Question asked on SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Module Below Start Quiz

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this:
Malcare WordPress Security