[Frontiers In Bioscience, Elite, 10, 1-14, January 1, 2018]

Centchroman: A safe reversible postcoital contraceptive with curative and prophylactic activity in many disorders

Ved P. Kamboj1, Suprabhat Ray1, Nitya Anand1

1Central Drug Research Institute, Lucknow, India

Table 1. Milestones and dates for development of Centchroman

Landmark milestones Dates
Design and synthesis of chroman CDRI 67/20 Jan 1967
Identification of the compound 67/20 as a potential oral contraceptive by testing in rodents, dogs and monkeys 1 year (1968)
Preclinical development including regulatory animal toxicity studies 2 ½ years (1970)
Centchroman brand name accorded to the Chroman contraceptive from Central Drug Research Institute 1971
Phase I Clinical Trial – Human safety studies 1 year (1972)
6-Months toxicity in rats and rhesus monkeys, mutagenicity and life-time carcinogenicity in mice and rats during dose ranging studies Phase IIA Clinical Trial: Proof of concept and dose ranging studies 5 years (1977)
Phase IIB Clinical Trial: Dose confirmation study 6 years (1983)
Phase III Multicenter clinical trial: 30 mg weekly dose 4 years (1987)
30 mg Biweekly for 3 months followed by 30 mg weekly from 13th month for as long as contraception is desired 2 years (1989)
Approval by DCGI for marketing as post-coital/weekly contraceptive pill 1 year (Nov 1990)
Licensed to Hindustan Latex Ltd now HLL Life Care Ltd 1991
Thiruvananthapuram and Torrent pharmaceuticals Ltd, Ahmedabad HLL Life Care marketed Centchroman as a biweekly-cum-weekly pill under the trade name “Saheli” 1991-present

Table 2. SERMs in clinical use

Compositions

Clomiphene

Triphenylethylene

Tamoxifene

Triphenylethylene

Raloxifene

Benzophenone

Centchroman (Ormeloxifene)

Triphenylethane

Biological Profile

Estrogen agonist in some tissues and antagonist in others
Estrogen antagonist on hypothalamus to release Gn and then FSH & LH from pituitary
Estrogen agonist on bone and CVS
No progestational, androgenic or antiandrogenic effect
No effect on adrenal or thyroid functions
Moderate estrogen and potent antiestrogen in rat uterus

Estrogen agonist on bone and CVS
Inhibits MCF-7 human mammary cells in vitro

Little estrogen and potent antiestrogen in rat uterus
Estrogen agonist on bone and CVS
Inhibits MCF-7 human mammary cells in vitro

Weak estrogen and potent antiestrogen in rat uterus
No effect on hypothalamus-pituitary-gonad axis
Estrogen agonist on bone and CVS
No progestational, antiprogestational, androgenic or antiandrogenic effect
No effect on adrenal or thyroid functions
Inhibits MCF-7 human mammary and other cancer cells in vitro

Regulatory Toxicity
Safe Affects liver, teratogen, carcinogen Reproductive, teratogenic and carcinogenic hazard Safe
Therapeutic Index
Excellent Narrow Excellent Excellent
Clinical Use
Used in sub-fertility and polycystic ovarian syndrome Used in metastatic breast cancer Used in post-menopausal osteoporosis, may be prophylactic in breast cancer and CVS Used as oral contraceptive, cure of DUB, mastalgia & fibroadenoma, indicated for breast cancer, prophylactic in osteoporosis and CVS
Clinical Side Effects
Common: Hot flushes, pelvic pain:Less frequent- Vomiting, trouble in sleeping, ovarian cancer, changes in vision Common: Amenorrhoea, fluid retention, hot flushes, vaginal discharge/hemorrhage, weight loss, : Less frequent- Increased risk of uterine cancer, stroke, vision problem, pulmonary embolism Common: Hot flushes, leg crumps Risk of blood clots, sudden vision changes, breathing confusion, headache, dizziness, nausea, vomiting, joint pain Delayed menstruation in about 8% menstrual cycles