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Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging

Award Number: R01AG028084
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2007
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging - The broad goal of our continued program of research is to decipher the cognitive and brain effects of transitional and surgical variants of menopause, including optimizing cognitive aging by discovering efficacious hormone therapy (HT) options in the context of menopause variations seen in women. This incorporates determining memory and brain changes as transitional menopause ensues when ovaries are undergoing follicular depletion, as well as the optimal parameters for interventions subsequent to transitional and surgical menopause variants. Menopause has been associated with cognitive decline and increased dementia risk. However, factors driving these outcomes, and which HT parameters alter effects, are undetermined. Importance is underscored given that most women are living at least one-third of their lives in a menopausal state encompassed by numerous variations (with or without a uterus, follicular deplete ovaries, or HT). In the current grant period, we had 23 publications; using the rat model, we showed that transitional menopause detrimentally impacted memory, that effects were most pronounced during perimenopause when follicles were undergoing early depletion, that higher androstenedione levels were associated with worse memory outcomes, and that short-term hysterectomy (uterus removal) alone impaired memory. We found that progesterone impaired memory, and that these effects were modulated by the GABAergic system. We also showed that several clinically-used synthetic progestins impaired memory, and identified one that enhanced memory: Levonorgestrel (Levo). When taking oral contraceptives or HT, a woman with a uterus must include a progestin along with estrogens to offset estrogen-induced hyperplasia. Thus, we performed an individual versus combination study, and showed that 17β-estradiol (E2) and Levo each enhanced memory when given alone, but impaired memory when given in combination. We also found that E2- induced cognitive benefits were associated with cholinergic integrity, building on literature showing estrogen- cholinergic interactions. This renewal addresses critical questions stemming from these collective findings. Aim 1 tests whether varied E2 regimens attenuate memory impairments associated with the perimenopausal transition, and assesses novel progestins that are anti-androgenic or have minimal androgenicity, with a goal to find options that do not reverse beneficial E2 effects on cognition and the brain. Aim 2 determines how variations in menopause type, including hysterectomy, impact cognition and the brain, testing effects of a temporal window, age, and follicular depletion state. Aim 3 defines how menopause variants and clinically-used HTs interact with candidate neurotransmitter systems in mechanistic detail, systematically examining GABAergic signaling and cholinergic circuitry. We combine behavioral, physiological, and neurobiological approaches in the framework of a blinded and randomized animal model research program to disentangle the complexity of menopause variants and HT opportunities for neurocognitive enhancement, extrapolating directives explicitly from the clinic.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	15	6/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVENUE STE 204	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	15	5/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $321,558 )
2022	2022	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	004	15	7/11/2022	NON-COMPETING CONTINUATION	$321,558
2022	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	003	11	3/23/2022	COMPETING CONTINUATION	$84,930
2022	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	001	11	10/20/2021	COMPETING CONTINUATION	-$89,261
2022	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	10	10/20/2021	NON-COMPETING CONTINUATION	$89,261
2022	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	002	10	3/23/2022	NON-COMPETING CONTINUATION	-$84,930
														Subtotal = $321,558

Issue Date FY: 2021 ( Subtotal = $323,323 )
2021	2021	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	14	6/3/2021	NON-COMPETING CONTINUATION	$323,323
														Subtotal = $323,323

Issue Date FY: 2020 ( Subtotal = $319,849 )
2020	2020	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	13	5/20/2020	NON-COMPETING CONTINUATION	$319,849
														Subtotal = $319,849

Issue Date FY: 2019 ( Subtotal = $321,666 )
2019	2019	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	002	12	5/27/2019	NON-COMPETING CONTINUATION	$321,666
2019	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	001	11	5/16/2019	COMPETING CONTINUATION	$89,261
2019	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	10	5/16/2019	NON-COMPETING CONTINUATION	-$89,261
														Subtotal = $321,666

Issue Date FY: 2018 ( Subtotal = $322,586 )
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	001	11	8/23/2018	COMPETING CONTINUATION	$300,591
2018	2018	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	002	11	8/30/2018	COMPETING CONTINUATION	$21,995
2018	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	10	8/21/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $322,586

Issue Date FY: 2017 ( Subtotal = $391,866 )
2017	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	000	9	5/12/2017	SUPPLEMENT FOR EXPANSION	$29,906
2017	2017	ARIZONA STATE UNIVERSITY	660 S MILL AVE STE 312	TEMPE	AZ	85281	MARICOPA	USA	Aging Research	001	10	6/23/2017	NON-COMPETING CONTINUATION	$361,960
														Subtotal = $391,866

Issue Date FY: 2016 ( Subtotal = $320,245 )
2016	2016	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	9	5/27/2016	EXTENSION WITH OR WITHOUT FUNDS	$320,245
														Subtotal = $320,245

Issue Date FY: 2015 ( Subtotal = $311,995 )
2015	2015	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	8	5/14/2015	NON-COMPETING CONTINUATION	$311,995
														Subtotal = $311,995

Issue Date FY: 2014 ( Subtotal = $318,968 )
2014	2014	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	7	5/26/2014	NON-COMPETING CONTINUATION	$318,968
														Subtotal = $318,968

Issue Date FY: 2013 ( Subtotal = $320,337 )
2013	2013	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	002	6	8/15/2013	COMPETING CONTINUATION	$320,337
2013	2011	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	001	5	8/13/2013	NON-COMPETING CONTINUATION	$0
2013	2011	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	5	7/11/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $320,337

Issue Date FY: 2011 ( Subtotal = $256,093 )
2011	2011	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	5	7/22/2011	NON-COMPETING CONTINUATION	$256,093
														Subtotal = $256,093

Issue Date FY: 2010 ( Subtotal = $266,620 )
2010	2010	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	4	7/19/2010	NON-COMPETING CONTINUATION	$266,620
														Subtotal = $266,620

Issue Date FY: 2009 ( Subtotal = $347,934 )
2009	2009	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	001	3	9/11/2009	SUPPLEMENT FOR EXPANSION	$78,538
2009	2009	ARIZONA STATE UNIVERSITY	P.O. BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	3	7/21/2009	NON-COMPETING CONTINUATION	$269,396
														Subtotal = $347,934

Issue Date FY: 2008 ( Subtotal = $324,937 )
2008	2008	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	2	7/21/2008	NON-COMPETING CONTINUATION	$269,581
2008	2008	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	001	2	9/18/2008	SUPPLEMENT FOR EXPANSION	$55,356
														Subtotal = $324,937

Issue Date FY: 2007 ( Subtotal = $278,686 )
2007	2007	ARIZONA STATE UNIVERSITY	BOX 873503	TEMPE	AZ	85287	MARICOPA	USA	Aging Research	000	1	8/21/2007	NEW	$278,686
														Subtotal = $278,686

Grand Total All Awards = $4,746,663

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Variations in Hormones During Menopause: Effects on Cognitive and Brain Aging

Award Number: R01AG028084

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2007

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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