The Selective Testicular Effects of Certain Bis-(Dichloroacetyl) Diamines

Beyler, A. L.; Potts, Gordon O.; Coulston, F.; Surrey, Alexander R.

doi:10.1210/endo-69-4-819

Cited by 47 publications

(16 citation statements)

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“…Full recovery to normal seminiferous tubule diameters was attained after 42 days of WIN treatment followed by 42 days of withdrawal. These ndings conform to the seminiferous tubule diameter reductions in the rat (Beyler et al 1961, Heller et al 1961, Drobeck & Coulston 1962, Kar et al 1966 and in the mouse (Singh & Dominic 1995).…”

Section: Discussionsupporting

confidence: 82%

Short-term effects of N'N-bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446) on the testes, selected sperm parameters and fertility of male CBA mice

Brooks

Horst

2003

Lab Anim

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SummaryN'N-bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446), the most potent of the diamines and one of the least amoebicidal agents, was shown to exert a speci c effect on the testes of CBA mice, while the Leydig cells were unaffected. Spermatogenesis was severely affected after a 42-day treatment period with 125 mg WIN 18446=kg body weight. Large multinucleated cells, vacuolization and the absence of sperm within the testes were evident in most seminiferous tubules. After 15 days of withdrawal of WIN 18446, there was a slight recovery of spermatogenesis and after withdrawal of 42 days a marked recovery of spermatogenesis. The normality or abnormality of this spermatogenic cycle could be evaluated using the semi-quantitative Stages program. There was a signi cant decrease in the diameters of seminiferous tubules of WIN 18446 treated mice, however an almost complete recovery was evident after 42 days of withdrawal of WIN 18446. A signi cant decrease in sperm concentration and sperm morphology was observed for the WIN 18446 treated mice. Various sperm motion parameters were assessed for the different treatment groups and compared to the control group. The female and male fertility indices were assessed and compared for the different treatment groups. Complete recovery of the above-mentioned parameters was evident after 42 days of withdrawal from WIN 18446, and this con rms its potential as a possible contraceptive for animal populations.

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Section: Discussionsupporting

confidence: 82%

Short-term effects of N'N-bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446) on the testes, selected sperm parameters and fertility of male CBA mice

Brooks

Horst

2003

Lab Anim

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“…Over fifty years ago, the oral administration of WIN 18,446 was shown to completely and reversibly inhibit spermatogenesis in man (74–76). Unfortunately, subjects taking WIN 18,446 experienced a “disulfiram reaction” consisting of nausea, vomiting, palpitations and sweating, when they took WIN 18,446 and drank alcohol.…”

Section: Experimental Male Contraceptivesmentioning

confidence: 99%

Male contraception

Amory

2016

Fertility and Sterility

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NARRATIVE ABSTRACT Although female contraceptives are very effective at preventing unintended pregnancy, some women cannot use them due to health conditions or side effects, leaving some couples without effective contraceptive options. In addition, many men wish to take active responsibility for family planning. Thus, there is a great need for male contraceptives to prevent unintended pregnancy, of which 80–90 million occur annually. At present, effective male contraceptive options are condoms and vasectomy, which are not ideal for all men. Therefore, efforts are under way to develop novel male contraceptives. This paper will briefly review the advantages and disadvantages of condoms and vasectomies, and then discuss the research directed towards the development of novel methods of male contraception.

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“…This compound was initially being developed as an amebicide (Berberian et al, 1961), but was noted to cause marked impairment of spermatogenesis in rodents, without significant effects on other tissues (Coulston et al, 1960). Follow‐up investigations in dogs and rhesus monkeys demonstrated that oral administration of WIN 18,446 led to a complete arrest of spermatogenesis in testicular biopsies (Beyler et al, 1961; Heller et al, 1963). Notably, WIN 18,446 had no effect on serum testosterone concentrations, implying that the mechanism by which WIN 18,446 suppressed spermatogenesis was not hormonal in nature.…”

mentioning

confidence: 99%

Suppression of Spermatogenesis by Bisdichloroacetyldiamines Is Mediated by Inhibition of Testicular Retinoic Acid Biosynthesis

Amory

Müller

Shimshoni

et al. 2010

Journal of Andrology

118

108

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The bisdichloroacetyldiamine WIN 18,446 reversibly inhibits spermatogenesis in many species, including humans; however, the mechanism by which WIN 18,446 functions is unknown. As retinoic acid is essential for spermatogenesis, we hypothesized that WIN 18,446 might inhibit retinoic acid biosynthesis from retinol (vitamin A) within the testes by inhibiting the enzyme aldehyde dehydrogenase 1a2 (ALDH1a2). We studied the effect of WIN 18,446 on ALDH1a2 enzyme activity in vitro, and on spermatogenesis and fertility in vivo, in mature male rabbits for 16 weeks. WIN 18,446 markedly inhibited ALDH1a2 enzyme activity in vitro with an IC50 of 0.3 μM. In vivo, the oral administration of 200 mg/kg WIN 18,446 to male rabbits for 16 weeks significantly reduced intratesticular concentrations of retinoic acid, severely impaired spermatogenesis, and caused infertility. Reduced concentrations of intratesticular retinoic acid were apparent after only 4 weeks of treatment and preceded the decrease in sperm counts and the loss of mature germ cells in tissue samples. Sperm counts and fertility recovered after treatment was discontinued. These findings demonstrate that bisdichloroacetyldiamines such as WIN 18,446 reversibly suppress spermatogenesis via inhibition of testicular retinoic acid biosynthesis by ALDH1a2. These findings suggest that ALDH1a2 is a promising target for the development of a reversible, nonhormonal male contraceptive.

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The Selective Testicular Effects of Certain Bis-(Dichloroacetyl) Diamines

Cited by 47 publications

References 0 publications

Short-term effects of N'N-bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446) on the testes, selected sperm parameters and fertility of male CBA mice

Short-term effects of N'N-bis(dichloroacetyl)-1,8-octamethylenediamine (WIN 18446) on the testes, selected sperm parameters and fertility of male CBA mice

Male contraception

Suppression of Spermatogenesis by Bisdichloroacetyldiamines Is Mediated by Inhibition of Testicular Retinoic Acid Biosynthesis

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