Clomiphene citrate therapy for testosterone deficiency: a proposed clinical care pathway.

Abstract

Several testosterone (T) therapy options are currently available, including oral, intranasal, transdermal (gel, patches), intramuscular, and subcutaneous agents. The practice guidelines of some professional societies, including the American Urological Association and the European Association of Urology but not all international societies,1,2 suggest treating with aromatase inhibitors or selective estrogen receptor modulators for men with infertility. However, selective estrogen receptor modulators (ie, clomiphene citrate [CC]) may be a reasonable alternative for men experiencing low T with infertility or a wish to maintain their fertility.3 In clinical practice, CC—a nonsteroidal triphenylethylene derivative distantly related to diethylstilbestrol and a selective estrogen receptor modulator—is also used as an effective treatment for men with low T to improve T levels and T deficiency symptoms. CC is an oral agent that acts centrally. CC is a mixture of enclomiphene (62%), which is a trans isomer with pure antiestrogen effect, and zuclomiphene (38%), which is a cis isomer that has a mixed action with a predominant estrogen receptor agonistic property. It selectively binds to estrogen receptors primarily in the hypothalamus to produce a partial estrogen agonist effect resulting in an estrogenic negative feedback inhibition, thus increasing the hypothalamic gonadotropin-releasing hormone pulse frequency and, as a result, elevating luteinizing hormone (LH) secretion to stimulate the gonads to increase sexual hormones—for men, the Leydig cells to raise T levels.4 In vitro data have also suggested that CC has a pituitary site of action where it causes an increase in the gonadotropin response to gonadotropin-releasing hormone.5