Clomiphen Resistance -Why clomiphene does not work in all cases of WHO Class II anovulation?

Biological rationale for the variability in the response to clomiphene treatment.

Know your drug: CC  & Tamoxifene:-Do you have a feeling that ingested drug (for instance CC )  strictly consumed as per your prescription is not working due to associated hepatic abnormality in PCO women ?? Do you think like that?? If U don’t belive that then please note that in some cases CC resiatnce is not due to wrong drug selection , neither poor drug complinece ,but CC resitance is in a fair no of cases is due to pts  genetic characteristics in  liver because research has shown  that 8 and 12 times lower concentrations of plasma CC in subjects with non-functional CYP2D6 alleles. Let me explain whyCC don’t work in some cases of PCO and this come to a surprise.  -Since clomiphene shares structural similarities with tamoxifen, which is predominantly bioactivities by the polymorphic cytochrome P450 (CYP) 2D6, researcher systematically explored clomiphene metabolism and action in vitro and in vivo by pharmacogenetics, -kinetic and -dynamic investigations. Human liver macrodomes were incubated with clomiphene citrate and nine metabolites were identified by mass spectrometry and tested at the oestrogen receptor for their antagonistic capacity. (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed strongest inhibition of the oestrogen receptor activity with 50% inhibitory concentrations of 2.5 and 1.4 nm, respectively. CYP2D6 has been identified as the major enzyme involved in their formation using recombinant CYP450 isotypes as confirmed by inhibition experiments with CYP monoclonal antibodies. Researchers correlated the CYP2D6 genotype of 30 human liver donors with the microsomal formation rate of active metabolites and observed a strong gene-dose effect. A healthy female volunteer study  too confirmed in vitro data that the CYP2D6 polymorphism substantially determines the formation of the active clomiphene metabolites. Comparison of the Coax of (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene showed 8 and 12 times lower concentrations in subjects with non-functional CYP2D6 alleles. Researchers added that results highlight (E)-4-hydroxyclomiphene and (E)-4-hydroxy-N-desethylclomiphene as the active clomiphene metabolites, the formation of which strongly depends on the polymorphic CYP2D6 enzyme. Researchers , therefore very rightly provide first evidence of a biological rationale for the variability in the response to clomiphene treatment.