CLOMID HAS GOT A BRIGHT SIDE AND A DARK SIDE. WHAT DO WE REALLY KNOW AFTER ALL THESE YEARS? EVIDENCE FOR TOXICITY.
R. Wiehle G. K. Fontenot. Research and Development, Repros Therapeutics Inc, The Woodlands, TX.
OBJECTIVE: Clomid has been approved in women with PCOS/ovulation induction. In men it is used off-label to increase testosterone or to relieve symptoms of androgen abuse.
Clomid is a mixture of two isomers: zuclomiphene and enclomiphene. The former is a weak estrogen agonist and the latter is a strong estrogen antagonist.
Repros Therapeutics is developing enclomiphene for elevating endogenous testosterone in men with secondary hypogonadism.
DESIGN: We have administered each isomer of clomid to mice, both chronically and acutely, in an attempt to determine the relative differences.
MATERIALS AND METHODS: Enclomiphene and zuclomiphene were separated from clomiphene as pure mono-isomers. Mice were administered each isomer chronically (90 days) then tissues were examined histologic. In a mouse ADME, pigmented mice were acutely administered each of the 14C-labelled isomers. Tissue and fluid distribution were followed up to 45 days.
RESULTS: In animals chronically administered each isomer, zuclomiphene had pernicious effects on the male reproductive tract (testes, epididymis, and seminal vesicles) and the kidney. Significant reduction in size of testes with testicular degeneration was seen, including Leydig cell loss with absence of sperm in the seminiferous tubules and reduction in size of the epididymis, seminal vesicles and kidneys.
In the ADME study, for 47 tissues assessed, 97.5% of the 14C-enclomiphene seen at 4 hours was lost by 24 hours. In contrast, only 40.8% of the 14C-zuclomiphene seen at 4 hours was lost. Zuclomiphene was retained selectively. Among those that accumulated zuclomiphene that seen in the blood were the pigmented portions of the eye, the brain, adrenal gland, the kidneys and the testes.
CONCLUSIONS: We infer that zuclomiphene accumulates in excess over enclomiphene. Human studies have suggested this as well. We concede that the antagonist effects of enclomiphene can overwhelm effects of zuclomiphene when used chronically, however the extreme high build-up of the agonist isomer may have lasting effects.
These results justify the case for a monoisomeric preparation and the development of Enclomiphene citrate, for clinical use in men with secondary hypogonadism to increase testosterone. It is interesting to speculate whether clomiphene citrate would have been granted FDA approval given the differences between its constitutive isomers.
R. Wiehle G. K. Fontenot. Research and Development, Repros Therapeutics Inc, The Woodlands, TX.
OBJECTIVE: Clomid has been approved in women with PCOS/ovulation induction. In men it is used off-label to increase testosterone or to relieve symptoms of androgen abuse.
Clomid is a mixture of two isomers: zuclomiphene and enclomiphene. The former is a weak estrogen agonist and the latter is a strong estrogen antagonist.
Repros Therapeutics is developing enclomiphene for elevating endogenous testosterone in men with secondary hypogonadism.
DESIGN: We have administered each isomer of clomid to mice, both chronically and acutely, in an attempt to determine the relative differences.
MATERIALS AND METHODS: Enclomiphene and zuclomiphene were separated from clomiphene as pure mono-isomers. Mice were administered each isomer chronically (90 days) then tissues were examined histologic. In a mouse ADME, pigmented mice were acutely administered each of the 14C-labelled isomers. Tissue and fluid distribution were followed up to 45 days.
RESULTS: In animals chronically administered each isomer, zuclomiphene had pernicious effects on the male reproductive tract (testes, epididymis, and seminal vesicles) and the kidney. Significant reduction in size of testes with testicular degeneration was seen, including Leydig cell loss with absence of sperm in the seminiferous tubules and reduction in size of the epididymis, seminal vesicles and kidneys.
In the ADME study, for 47 tissues assessed, 97.5% of the 14C-enclomiphene seen at 4 hours was lost by 24 hours. In contrast, only 40.8% of the 14C-zuclomiphene seen at 4 hours was lost. Zuclomiphene was retained selectively. Among those that accumulated zuclomiphene that seen in the blood were the pigmented portions of the eye, the brain, adrenal gland, the kidneys and the testes.
CONCLUSIONS: We infer that zuclomiphene accumulates in excess over enclomiphene. Human studies have suggested this as well. We concede that the antagonist effects of enclomiphene can overwhelm effects of zuclomiphene when used chronically, however the extreme high build-up of the agonist isomer may have lasting effects.
These results justify the case for a monoisomeric preparation and the development of Enclomiphene citrate, for clinical use in men with secondary hypogonadism to increase testosterone. It is interesting to speculate whether clomiphene citrate would have been granted FDA approval given the differences between its constitutive isomers.
