Tag Archive for: clomiphene citrate

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Article of the Week: Differential effects of ENC & ZUC on reproductive tissues in male mice

Every Week the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Gregory Fontenot, discussing his paper.

If you only have time to read one article this week, it should be this one.

Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice

Gregory K. Fontenot, Ronald D. Wiehle and Joseph S. Podolski

 

Repros Therapeutics Inc., The Woodlands, TX, USA

 

Objectives

To determine, in a chronic dosing study, the oral toxicity potential of the test substances, enclomiphene citrate (ENC) and zuclomiphene citrate (ZUC), when administered to male mice by oral gavage.

Materials and Methods

Mice were divided into five treatment groups. Group I, placebo; Group II, 40 mg/kg body weight/day ENC; Group III, 4 mg/kg/day ENC; Group IV, 40 mg/kg/day ZUC; Group V, 4 mg/kg/day ZUC. Serum samples and tissues were obtained from each mouse for analysis and body weights were measured.

FebAOTW2

Results

In this chronic dosing study in mice, profound effects on Leydig cells, epididymis, seminal vesicles, and kidneys were seen, as well as effects on serum testosterone, follicle-stimulating hormone and luteinising hormone levels that were associated with ZUC treatment only. Treatment with the isolated enclomiphene isomer had positive effects on testosterone production and no effects on testicular histology.

Conclusions

The present study suggests that an unopposed high dose of zuclomiphene can have pernicious effects on male mammalian reproductive organs. The deleterious effects seen when administering ZUC in male mice, justifies the case for a monoisomeric preparation and the development of ENC for clinical use in human males to increase serum levels of testosterone and maintain sperm counts.

Editorial: When two and two don’t make four

Many drugs are chiral, i.e. the enantiomers (isomers) cannot be superimposed on their mirror images. It has long been known that if a drug is chiral, then in biological terms, the isomers invariably differ in activity [1]. One isomer may specifically interact with a cell receptor to produce the desired outcome while the other might have no useful application or might have an unwanted pharmacological or even a toxicological effect through some other interaction.

In the clear-cut example where one isomer of a chiral compound is ‘good’ and the other ‘bad’, there is obvious benefit from developing the drug as the single isomer to enhance its safety and tolerability. The paper in the present issue of BJUI by Fontenot et al. [2] on the differential activity of the enantiomers of clomiphene elegantly exemplifies this in terms of potential toxicity.

Since 1992 the US Food and Drugs Administration and the European Medicines Agency have required manufacturers to research and characterize each enantiomer in all drugs proposed to be marketed as a mixture. The assumption was that a mixture may not manifest clinically as a simple algebraic summation of the biological characteristics of the individual components. From that date, production of new racemates (mixture of enantiomers) ceased to be a rational commercial option and instead became a high-risk route for pharmaceutical companies.

With respect to the enantiomers of clomiphene, it was undoubtedly the differential toxicological profile [2], coupled with relative primary activity as oestrogen antagonists [3], that resulted in the prioritization of Enclomiphene for late stage clinical development. It is this isomer that forms the basis of the submission to the regulatory authorities for the treatment of secondary hypogonadism.

The present paper in some ways reinforces what we already knew; isomers can have differential activity. What is unusual is that what is presented is not pharmacological evidence but clear-cut differences in toxicological profile.

The research raises a specific issue in relation to the treatment of secondary hypogonadism. In general, patients with secondary hypogonadism require restoration of normal testosterone levels while preserving fertility. As such, the use of exogenous testosterone for replacement can be counter-productive as there is a well-documented negative impact on spermatogenesis [4]. As an alternative, ‘off-label’ clomiphene is relatively widely proffered. Assuming approval, Enclomiphene would provide an attractive alternative to its racemic ‘parent’.

Overall, the present paper is a useful reminder of what we think we know; that is, that all racemates are likely to manifest the characteristics of both component enantiomers.

Michael G. Wyllie
Global Pharma Consulting Ltd, Banbury, UK

 

Conflict of Interest

The author is an independent director on the board of Repros Therapeutics.

 

References

 

Video: Effects of clomiphene citrate isomers on mouse reproductive tissues

Differential effects of isomers of clomiphene citrate on reproductive tissues in male mice

Gregory K. Fontenot, Ronald D. Wiehle and Joseph S. Podolski

 

Repros Therapeutics Inc., The Woodlands, TX, USA

 

Objectives

To determine, in a chronic dosing study, the oral toxicity potential of the test substances, enclomiphene citrate (ENC) and zuclomiphene citrate (ZUC), when administered to male mice by oral gavage.

Materials and Methods

Mice were divided into five treatment groups. Group I, placebo; Group II, 40 mg/kg body weight/day ENC; Group III, 4 mg/kg/day ENC; Group IV, 40 mg/kg/day ZUC; Group V, 4 mg/kg/day ZUC. Serum samples and tissues were obtained from each mouse for analysis and body weights were measured.

Results

In this chronic dosing study in mice, profound effects on Leydig cells, epididymis, seminal vesicles, and kidneys were seen, as well as effects on serum testosterone, follicle-stimulating hormone and luteinising hormone levels that were associated with ZUC treatment only. Treatment with the isolated enclomiphene isomer had positive effects on testosterone production and no effects on testicular histology.

Conclusions

The present study suggests that an unopposed high dose of zuclomiphene can have pernicious effects on male mammalian reproductive organs. The deleterious effects seen when administering ZUC in male mice, justifies the case for a monoisomeric preparation and the development of ENC for clinical use in human males to increase serum levels of testosterone and maintain sperm counts.

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