Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in male rats

Cappon, Gregg D.; Horimoto, Masao; Hurtt, Mark E.

doi:10.1002/bdrb.20008

Cited by 10 publications

(4 citation statements)

References 54 publications

(79 reference statements)

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“…In both the cyclicity and the implantation studies, lasofoxifene reduced body weight, body weight gain, and food consumption. This was an expected finding based on observations from SERMs raloxifene (Hoyt et al, 1998;Clarke et al, 1998), tamoxifen (Tucker et al, 1984;Wallen et al, 2001), Mer-25 (Gray and Wade, 1981), and from lasofoxifene-treated males (Cappon et al, 2004). Lasofoxifene-induced reductions in food consumption and body weight are believed to be pharmacologically-mediated, with receptor saturation likely occurring at all doses.…”

Section: Discussionsupporting

confidence: 53%

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Terry

Cappon

Hurtt

et al. 2004

Birth Defects Research Pt B

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BACKGROUND: Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM). With high affinity to the a and b human estrogen receptors and greater potency than other SERMs, lasofoxifene is potentially a superior treatment for postmenopausal osteoporosis. In light of the known effects of estrogen-modulating compounds on female reproductive indices, two studies were conducted to evaluate the effects of lasofoxifene on female rat cyclicity, reproduction, and parturition. METHODS: One study evaluated effects of lasofoxifene on estrous cyclicity, and the second study assessed effects on implantation and parturition. In the cyclicity study, lasofoxifene was administered to female rats at doses of 0.1, 0.3, and 1.0 mg/kg/day for 14 consecutive days. After treatment, there was a 3-week reversibility phase followed by a mating phase. In the implantation study, lasofoxifene was administered to pregnant female rats at doses of 0.01, 0.03, and 0.1 mg/kg/day for 7 consecutive days (gestation day [GD] 0-6). Some animals were euthanized on GD 21, and the remainder of the group was allowed to deliver the F 1 generation. Several developmental indices were evaluated in the F 1 pups through post-natal day (PND) 21. RESULTS: In the cyclicity study, all lasofoxifenetreated females were anestrous by Study Day 7 (1.0 mg/kg) or 9 (0.3 and 0.1 mg/kg). The reversibility phase resulted in restoration of normal estrous cycles by the end of 1 (0.1 mg/kg) or 2 weeks (0.3 and 1.0 mg/kg). During the mating phase, no adverse effects occurred in pregnancy success or reproductive parameters. In the implantation study, all doses of lasofoxifene increased pre-and post-implantation losses, increased gestation length, and reduced litter size. None of the developmental parameters measured on the

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Section: Discussionsupporting

confidence: 53%

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Terry

Cappon

Hurtt

et al. 2004

Birth Defects Research Pt B

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“…36 Also, there are studies in which any change of the testis and epididymis weights were not observed, while the reproductive toxic effects were shown to be induced. [37][38][39][40] According to our results, relative testis and epididymis weights did not change with ZNS administration. It can be stated that the reproductive toxic effect findings obtained with ZNS administration were not accompanied by the changes of the relative organ weights.…”

Section: Discussionsupporting

confidence: 45%

Reproductive toxic effects and possible mechanisms of zonisamide in male rats

et al. 2019

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Zonisamide (ZNS) is an anticonvulsant which is used to treat the symptoms of epilepsy. Although it is frequently used during reproductive ages, studies that investigated the effects of ZNS on reproductive system are limited. Therefore, we aimed to assess the effects of ZNS on male reproductive system by oral administration to rats in 25, 50, and 100 mg/kg doses for 28 days. After the exposure period, sperm concentration, motility, morphology, and DNA damage, as biomarkers of reproductive toxic effects, were determined, and histopathological examination of testis was performed. In addition, levels of the hormones that play a role in the regulation of reproductive functions, such as follicle-stimulating hormone, luteinizing hormone (LH), and testosterone were measured and the levels of oxidative stress biomarkers that take part in the reproductive pathologies such as catalase, superoxide dismutase, glutathione, and malondialdehyde, were determined. Reproductive toxic effects related to ZNS administration were shown by the significant decrease of sperm concentration and normal sperm morphology in ZNS groups. Additionally, pathological findings were observed in the testicular tissues of ZNS-administered groups dose dependently. In addition, serum LH and testosterone levels were significantly decreased in the ZNS groups. Decreased catalase activities and increased malondialdehyde levels in ZNS groups were evaluated as oxidative stress findings in the testis tissue. It could be expressed that ZNS administration induced dose-dependent reproductive toxic effects in rats, and pathological findings associated with the reproductive system could be the result of that hormonal changes and testicular oxidative stress, which in turn might be considered as possible mechanisms of male reproductive toxicity.

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“…Clomiphene or tamoxifen have been the most used antiestrogen agents for the treatment of male infertility [138][139][140][141][142][143]; on the contrary the new generation of selective ER modulators does not show significant changes in male fertility [147,148]. Tamoxifen represents the first line treatment for men affected by idiopathic oligozoospermia as recommended by the World Health Organization (WHO) (2000) [137].…”

Section: Clinical and Therapeutical Implicationmentioning

confidence: 99%

Estrogens in males: what have we learned in the last 10 years?

et al. 2005

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Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in male rats

Abstract: The changes in male fertility and reproductive tissue weights after exposure to lasofoxifene are consistent with those previously described for estrogen receptor-modulating compounds.

Cited by 10 publications

References 54 publications

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Reproductive toxicity assessment of lasofoxifene, a selective estrogen receptor modulator (SERM), in female rats

Reproductive toxic effects and possible mechanisms of zonisamide in male rats

Estrogens in males: what have we learned in the last 10 years?

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