{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T08:59:16Z","timestamp":1772355556789,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2004,7,20]],"date-time":"2004-07-20T00:00:00Z","timestamp":1090281600000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Birth Defects Research Pt B"],"published-print":{"date-parts":[[2004,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>BACKGROUND:<\/jats:bold> Lasofoxifene is a nonsteroidal selective estrogen receptor modulator (SERM) developed for the treatment of postmenopausal osteoporosis. The purpose of these studies was to evaluate the effects of lasofoxifene on the postnatal development, behavior, and reproductive performance of offspring of female rats given lasofoxifene during organogenesis and lactation. <jats:bold>METHODS:<\/jats:bold> Two range\u2010finding studies were conducted to determine the effects of lasofoxifene at doses from 0.01\u201310\u2009mg\/kg on parturition and lactation in pregnant rats and on the early postnatal development of the offspring, and to optimize the dosing regimen. Maternal milk and plasma were sampled for concentrations of lasofoxifene on Lactation Days 4, 7, and 14. In the pre\u2010 and postnatal development study, lasofoxifene was administered to pregnant and lactating rats by oral gavage at dose levels of 0.01, 0.03, and 0.1\u2009mg\/kg on Gestation Days 6\u201317 and Lactation Days 1\u201320. Maternal body weight and food consumption were measured throughout pregnancy, and body weight was measured throughout lactation. Parturition was monitored closely. The F<jats:sub>1<\/jats:sub> offspring were measured for viability, body weight, anogenital distance, the appearance of postnatal developmental indices and reflex behaviors, sensory function, in an age\u2010appropriate functional observational battery, motor activity, auditory startle, passive avoidance, and the Cincinnati Water Maze. The F<jats:sub>1<\/jats:sub> generation was assessed for reproductive function, and the F<jats:sub>2<\/jats:sub> offspring were measured for body weight and viability throughout the lactation period. <jats:bold>RESULTS:<\/jats:bold> In the range\u2010finding studies, indications of maternal toxicity included decreased body weight and food consumption, increased length of gestation, prolonged parturition, dystocia, and increased offspring mortality at birth. Concentrations of lasofoxifene in maternal plasma were similar to those in milk, increased with increasing dose, and remained consistent over a 10\u2010day period. In the pre\u2010 and postnatal development study, maternal body weights and food consumption were decreased in all treated groups during gestation. Length of gestation was increased, parturition was prolonged, and dystocia was noted in the dams in the 0.1\u2009mg\/kg group. There was increased pup mortality in the F<jats:sub>1<\/jats:sub> litters in the 0.1\u2009mg\/kg group and all treated groups had decreased offspring body weights beginning at 1 week of age, continuing into the postweaning period and, for the F<jats:sub>1<\/jats:sub> males, into adulthood. Female F<jats:sub>1<\/jats:sub> offspring in the 0.03 and 0.1\u2009mg\/kg groups had increased body weights as adults. There were delays in the age of appearance of preputial separation in the males in the 0.1\u2009mg\/kg group and vaginal opening in the females in all treated groups. Body temperature was decreased by &lt;0.5\u00b0C after weaning for male and female offspring in the 0.1\u2009mg\/kg group. The sensory, behavioral, and functional measures, including the tests of learning and memory, were unaffected by treatment. Mating success was lower for the F<jats:sub>1<\/jats:sub> animals in the 0.1\u2009mg\/kg group, but there were no effects on the reproductive parameters. Mating, reproduction, and maternal behavior of the F<jats:sub>1<\/jats:sub> animals in the 0.01 and 0.03\u2009mg\/kg groups and the survival and body weights of the F<jats:sub>2<\/jats:sub> offspring in all treated groups through Postnatal Day 21 were unaffected by treatment. <jats:bold>CONCLUSION:<\/jats:bold> The maternal findings in this study were related to the pharmacologic activity of lasofoxifene. Inhibition of growth of the F<jats:sub>1<\/jats:sub> offspring after perinatal exposure to lasofoxifene was observed, but there were no significant effects on the sensory, behavioral, or functional measures, including learning and memory. There were no effects on the F<jats:sub>2<\/jats:sub> generation. The findings are consistent with those reported for at least one other SERM. The findings of this study do not suggest increased risk for the primary indication of use in postmenopausal women. <jats:italic>Birth Defects Res B<\/jats:italic> 71:171\u2013184, 2004. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/bdrb.20013","type":"journal-article","created":{"date-parts":[[2004,7,20]],"date-time":"2004-07-20T15:08:59Z","timestamp":1090336139000},"page":"171-184","source":"Crossref","is-referenced-by-count":13,"title":["Pre\u2010 and postnatal development studies of lasofoxifene, a selective estrogen receptor modulator (SERM), in Sprague\u2013Dawley rats"],"prefix":"10.1002","volume":"71","author":[{"given":"Walter P.","family":"Weisenburger","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan R.","family":"Hagler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa S.","family":"Tassinari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2004,7,20]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"116","article-title":"90\u2010day feeding and one\u2010generation reproduction study in Crl:CD BR rats with 17 beta\u2010estradiol","volume":"44","author":"Biegel LB","year":"1998","journal-title":"Toxicol Sci"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/jappl.1997.83.2.477"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0890-6238(98)00006-9"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20008"},{"key":"e_1_2_7_6_1","first-page":"155","article-title":"Effects of dietary 17 beta\u2010estradiol exposure on serum hormone concentrations and testicular parameters in male Crl:CD BR rats","volume":"44","author":"Cook JC","year":"1998","journal-title":"Toxicol Sci"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7280692"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0031-9384(89)90010-3"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo-97-4-898"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0361-9230(86)90103-6"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/neu.480180204"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.10-04-01286.1990"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod64.3.927"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4530(90)90018-5"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/0278-6915(88)90123-8"},{"key":"e_1_2_7_16_1","volume-title":"Nonparametric statistical methods","author":"Hollander M","year":"1973"},{"key":"e_1_2_7_17_1","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1210\/endo.139.4.5902","article-title":"Effects of CP\u2010336, 156, a new, nonsteroidal estrogen agonist\/antagonist, on bone, serum cholesterol, uterus, and body composition in rat models","volume":"139","author":"Ke HZ","year":"1998","journal-title":"Endocrinology"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/endo.141.4.7408"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2001.16.4.765"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1095\/biolreprod17.2.298"},{"key":"e_1_2_7_21_1","first-page":"R400","article-title":"Energy balance in ovariectomized rats with and without estrogen replacement","volume":"238","author":"Laudenslager ML","year":"1980","journal-title":"Am J Physiol"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(78)90309-8"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(87)91574-5"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2826.2000.00425.x"},{"key":"e_1_2_7_25_1","volume-title":"The hippocampus as a cognitive map","author":"O'Keefe J","year":"1978"},{"key":"e_1_2_7_26_1","volume-title":"The hippocampus","author":"Olton DDS","year":"1983"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20010"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm980048b"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdrb.20009"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/41.2.199"},{"key":"e_1_2_7_31_1","unstructured":"United States Food and Drug Administration.1994.International Conference on Harmonization: guideline on detection of toxicity to reproduction for medicinal products: availability notice Federal Register; 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