{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T20:17:17Z","timestamp":1760300237856,"version":"3.37.3"},"reference-count":74,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T00:00:00Z","timestamp":1559692800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Avagacestat, a gamma (\u03b3)-secretase inhibitor that was in development for treatment of Alzheimer\u2019s disease, produced ovarian granulosa-thecal cell tumors in rats and dogs and a glomerulopathy with profound proteinuria in female rats. This report describes the results of follow-up investigative studies, including the use of ovariectomized (OVX) rats, to further characterize these findings and determine their mechanism(s). Ovarian proliferative changes in rats likely resulted from: (1) inhibition of Notch signaling pathways regulating ovarian follicular differentiation\/development, characterized microscopically as altered ovarian cyclicity and\/or ovarian follicular degeneration; (2) subsequent disruption of the hypothalamic-pituitary-ovarian axis due to ovarian atrophy with decreases in serum estrogen and progesterone (as low as 0.45\u00d7 and 0.21\u00d7 controls, respectively); and (3) chronic gonadotropin stimulation and pituitary hypertrophy\/hyperplasia in response to the absence of negative feedback. Gonadotropin stimulation in rats was confirmed by increases in serum follicle-stimulating hormone (up to 7.75\u00d7 controls) and luteinizing hormone (up to 5.84\u00d7). A similar nongenotoxic mechanism was likely responsible for the ovarian findings in dogs although changes in serum hormone levels were not detected. The dose- and time-dependent glomerulopathy with progression to chronic progressive nephropathy in female rats appears to be a direct effect of avagacestat and was not ameliorated with coadministration of 17\u03b2-estradiol or an antihypertensive (enalapril) and was not present in control OVX rats. In contrast, adrenocortical hypertrophy in female rats was considered secondary to ovarian changes based on the absence of this finding in avagacestat-treated OVX rats and no increase in adrenocorticotropic hormone staining in the pituitary.<\/jats:p>","DOI":"10.1093\/toxsci\/kfz129","type":"journal-article","created":{"date-parts":[[2019,5,31]],"date-time":"2019-05-31T07:09:36Z","timestamp":1559286576000},"page":"98-116","source":"Crossref","is-referenced-by-count":3,"title":["Investigations on the Relationship Between Ovarian, Endocrine, and Renal Findings in Nonclinical Safety Studies of the \u03b3-Secretase Inhibitor Avagacestat"],"prefix":"10.1093","volume":"171","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0211-9665","authenticated-orcid":false,"given":"Frank J","family":"Simutis","sequence":"first","affiliation":[{"name":"Drug Safety Evaluation, Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas P","family":"Sanderson","sequence":"additional","affiliation":[{"name":"Drug Safety Evaluation, Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary D","family":"Pilcher","sequence":"additional","affiliation":[{"name":"Drug Safety Evaluation, Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J","family":"Graziano","sequence":"additional","affiliation":[{"name":"Drug Safety Evaluation, Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,6,4]]},"reference":[{"key":"2019091012173905200_kfz129-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/REP-14-0449","article-title":"A link between Notch and progesterone maintains the functionality of the rat corpus luteum","volume":"149","author":"Accialini","year":"2015","journal-title":"Reproduction"},{"key":"2019091012173905200_kfz129-B2","doi-asserted-by":"crossref","first-page":"S311.","DOI":"10.1016\/j.jalz.2011.05.905","article-title":"The gamma-secretase inhibitor BMS-708163 causes dose-dependent reductions in CSF A\u03b240 levels in patients with mild-to-moderate Alzheimer\u2019s disease (AD)","volume":"7(Suppl.)","author":"Albright","year":"2011","journal-title":"Alzheimers Dement."},{"key":"2019091012173905200_kfz129-B3","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1124\/jpet.112.199356","article-title":"Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat","volume":"344","author":"Albright","year":"2013","journal-title":"J. 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