title: Understanding the cognitive impact of the contraceptive estrogen Ethinyl Estradiol: tonic and cyclic administration impairs memory, and performance correlates with basal forebrain cholinergic system integrity.
abstract: Ethinyl Estradiol (EE), a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives, and is found in at least 30 different contraceptive formulations currently prescribed to women as well as hormone therapies prescribed to menopausal women. Thus, EE is prescribed clinically to women at ages ranging from puberty to reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection, modeling the daily rise and fall of serum EE levels with oral regimens. Study II also investigated the impact of low, medium and high doses of EE on the basal forebrain cholinergic system. The low and medium doses utilized here correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. We evaluate cognition using a battery of maze tasks tapping several domains of spatial learning and memory as well as basal forebrain cholinergic integrity using immunohistochemistry and unbiased stereology to estimate the number of choline acetyltransferase (ChAT)-producing cells in the medial septum and vertical/diagonal bands. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; tonic delivery of low EE, a dose that corresponds to the most popular doses used in the clinic today, did not impact cognition on any measure. Both medium and high injection doses of EE reduced the number of ChAt-immunoreactive cells in the basal forebrain, and cell population estimates in the vertical/diagonal bands negatively correlated with working memory errors.
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA.
authors: Sarah E
authors: SE
authors: Mennenga
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA.
authors: Julia E
authors: JE
authors: Gerson
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA.
authors: Stephanie V
authors: SV
authors: Koebele
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA.
authors: Melissa L
authors: ML
authors: Kingston
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA.
authors: Candy W S
authors: CW
authors: Tsang
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA.
authors: Elizabeth B
authors: EB
authors: Engler-Chiurazzi
authors: Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA; Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors: Leslie C
authors: LC
authors: Baxter
authors: Department of Psychology, Arizona State University, Tempe, AZ 85287, USA; Arizona Alzheimer's Consortium, Phoenix, AZ 85006, USA. Electronic address: Bimonte.Nelson@asu.edu.
authors: Heather A
authors: HA
authors: Bimonte-Nelson
mesh_terms: D000818:Animals; D066187:Basal Forebrain / Q000187:drug effects*; D059329:Cholinergic Neurons / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D003276:Contraceptives, Oral / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D003276:Contraceptives, Oral; D004997:Ethinyl Estradiol
keywords: Contraceptive; Ethinyl Estradiol; Hormone; Memory