Clomiphene citrate: mechanism(s) and site(s) of action—a hypothesis revisited

It has now been 28 years since the synthesis of clomiphene citrate (CC) by Dr. Frank P. Palopoli,l, 2 then a synthetic chemist with the William S. Merrell Company.However, despite intense basic and clinical research and a cumulative bibliography now approaching 8000 contributions, the mechanism(s) and site(s) of action of CC have only been partially clarified.This knowledge gap is particularly striking in view of the widespread and highly successful use of CC worldwide.Indeed, the clinical utility of CC has recently been further enhanced through its introduction as a primary agent in the management of luteal phase dysfunction 3 and its application in the area of in vitro fertilization. 4It is the intent of this presentation to critically explore the current hypothesis underlying the mechanism(s) and site(s) of action of CC and to propose its expansion and modification in keeping with recently accumulated experimental data.