Raloxifene and/or estradiol decrease anxiety-like and depressive-like behavior, whereas only estradiol increases carcinogen-induced tumorigenesis and uterine proliferation among ovariectomized rats
Open accessAbstract
Controversy surrounds the efficacy and safety of 17beta-estradiol (E2)-mimetic therapies to women for treatment of menopausal symptoms. An important question is the nature of the trophic actions of E2-mimetics in the brain for behavioral processes versus in the periphery for beneficial effects related to osteoporosis, or unwanted proliferative effects in the reproductive tissues, such as mammary glands and uterus. Of recent interest are the effects of selective estrogen receptor modulators, which can have tissue specific actions, for these processes. In the present study, the effects were determined of E2 alone, or co-administered with a selective estrogen receptor modulator, raloxifene, for anxiety-like, depression-like, and trophic peripheral effects in ovariectomized rats that were exposed to a chemical carcinogen (7,12-dimethylbenz(a)anthracene), or not. Once per week, rats were administered vehicle, E2 (0.09 mg/kg) and/or raloxifene (1 mg/kg) subcutaneously 44-48 h before testing in a positive control, E2-dependent behavior (lordosis), depression (forced swim test), and anxiety (elevated plus maze) behavioral assays. In addition to behavioral endpoints, incidence and number of tumors, and tumor, pituitary gland, and uterine weight 14 weeks after carcinogen-exposure, and weekly hormone treatments, were analyzed. Rats administered 7,12-dimethylbenz(a)anthracene had an increased number and size of tumors, compared with vehicle treatment. E2 + raloxifene increased the number of tumors. Administration of E2 or E2 +raloxifene, but not raloxifene alone, increased pituitary and uterine weight, compared with vehicle administration. E2 or E2 + raloxifene, but not raloxifene alone, also increased the incidence of lordosis and reduced the depression-like behavior in the forced swim test (i.e. decreased time spent immobile) compared with vehicle administration. However, administration of E2 or raloxifene reduced anxiety behavior in the elevated plus maze (i.e. increased time spent on the open arms of the maze), compared with vehicle treatment. Together these data show that E2 and/or raloxifene can have some effects to alter the behavior of ovariectomized rodents, depending upon the task. As well, E2, with or without raloxifene, can also have clear trophic actions in peripheral tissues, such as carcinogen-induced tumors, uterus, and pituitary glands.
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An estrogen modified feedback mechanism may act at the pituitary level.
“An estrogen modified feedback mechanism may act at this level (Popovics et al., 2011;Walf and Frye, 2010).”
From RETRACTED: Long term toxicity of a Roundup herbicide and a Roundup-tolerant genetically modified maize (2012) · cites this paper as Walf and Frye, 2010
An estrogen-modified feedback mechanism may act at this level.
“An estrogen-modified feedback mechanism may act at this level [65,66].”
From Republished study: long-term toxicity of a Roundup herbicide and a Roundup-tolerantgenetically modified maize (2014) · cites this paper as [66]
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- Authors
- Walf, A. A., & Frye, C. A.
- Affiliations
- State University of New York (US)
- University at Albany, State University of New York (US)
- Corresponding author
- Frye, Cheryl Anne
- Venue
- Behavioural Pharmacology
- Published
- 2010-05
- Volume
- 21
- Issue
- 3
- Pages
- 231-240
- ISSN
- 0955-8810 (ISSN-L)
- PMC
- PMC2885355
- OpenAlex
- W2029917525
- Cited by
- 34
- References
- 64
- Citations by year
- 2026: 1 · 2023: 2 · 2021: 1 · 2019: 3 · 2018: 3 · 2017: 3 · 2015: 4 · 2014: 4 · 2012: 4
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Behavioural Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- National Institute of Mental Health (R01MH067698)
- Congressionally Directed Medical Research Programs
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- raloxifene, estradiol, selective estrogen receptor modulators, anxiety-like behavior, depression-like behavior, 7,12-dimethylbenz(a)anthracene, uterine proliferation, pituitary weight, ovariectomy, menopausal symptoms
- MeSH terms
- Animals, Anxiety, Behavior, Animal, Carcinogens, Depression, Disease Models, Animal, Drug Interactions, Estradiol, Estrogens, Female, Neoplasms, Ovariectomy, Regression Analysis, Sexual Behavior, Animal, Swimming, Time Factors, Uterus, 9,10-Dimethyl-1,2-benzanthracene, Maze Learning, Rats, Long-Evans, Raloxifene Hydrochloride, Cell Proliferation, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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