Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women

Shumaker, Sally A.; Legault, Claudine; Rapp, Stéphen R.; Thal, Leon J.; Wallace, Robert B.; Ockene, Judith K.; Hendrix, Susan L.; Jones, Beverly N.; Assaf, Annlouise R.; Jackson, Rebecca D.; Kotchen, Jane Morley; Wassertheil‐Smoller, Sylvia; Wactawski‐Wende, Jean

doi:10.1001/jama.289.20.2651

Cited by 1,864 publications

(610 citation statements)

References 85 publications

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“…This fits well with the fact that ERa and ERb act in opposition to each other in their control of a number of physiological and behavioral processes (Gustafsson, 2006;Ogawa et al, 2004). Elucidating the involvement of estrogens and their receptors in aspects of social cognition will prove especially useful as the 'baby boom' generation ages and an increasing number of women are placed on hormone replacement therapy (Shumaker et al, 2003).…”

Section: Overall Conclusionsupporting

confidence: 65%

Differential Effects of Estrogen Receptor Alpha and Beta Specific Agonists on Social Learning of Food Preferences in Female Mice

Clipperton

Spinato

Chernets

et al. 2007

Neuropsychopharmacol

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There is an evolutionary advantage to learning food preferences from conspecifics, as social learning allows an individual to bypass the risks associated with trial and error individual learning. The social transmission of food preferences (STFP) paradigm examines this advantage. Females in the proestrus and diestrus phases of the estrous cycle show a prolonged preference for the demonstrated food relative to estrus and ovariectomized females. Additionally, both estrogen receptor alpha (ERa) and estrogen receptor beta (ERb) knockout mice show impaired social recognition, which suggests that both receptors may be involved in other types of socially dependent learning, including the STFP. The present study investigated the effect of the ERa selective agonist PPT (1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole) and the ERb selective agonist WAY-200070 (7-Bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol) on the STFP. Results showed that ovariectomized (ovx) mice treated with PPT failed to learn the socially acquired preference, while WAY-200070-treated ovx mice showed a two-fold prolonged preference for the food eaten by their demonstrator. The effects of PPT on the socially acquired food preference cannot be explained by effects on the total food intake of the groups or on the type of interaction with the demonstrator mouse. The effects of WAY-200070 may be partially due to effects on Submissive Behavior. The higher WAY-200070 doses produced prolonged preferences similar to those seen previously in intact female mice during the proestrus and diestrus phases. This suggests that the estrous cycle's effects on social learning may be due to the action of ERb on Submissive Behavior, or to ERb countering that of ERa.

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Section: Overall Conclusionsupporting

confidence: 65%

Differential Effects of Estrogen Receptor Alpha and Beta Specific Agonists on Social Learning of Food Preferences in Female Mice

Clipperton

Spinato

Chernets

et al. 2007

Neuropsychopharmacol

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“…Recent findings from the Women's Health Initiative (WHI) and Women's Health Initiative Memory Study (WHIMS) have shown that the risk of diagnosis of dementia in women taking conjugated equine estrogen (CEE) alone and CEE and medroxyprogesterone actate (MPA) was twice that of women in the placebo group (Shumaker et al 2004;Shumaker et al 2003). However, the WHI study was not designed as a study of cognition and was primarily a study of cardiovascular prevention, thus the women were older than is typical for postmenopausal hormone therapy.…”

Section: Introductionmentioning

confidence: 99%

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: Evidence for the critical period hypothesis

Dumas

Hancur-Bucci

Naylor

et al. 2008

Hormones and Behavior

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Estradiol has been shown to interact with the cholinergic system to affect cognition in postmenopausal women. This study further investigated the interaction of estradiol and cholinergic system functioning on verbal memory and attention in two groups of healthy younger (ages 50-62) and older (ages 70-80) postmenopausal women. Twenty-two postmenopausal women were randomly and blindly placed on 1 mg of 17-beta estradiol orally for one month then 2 mg for two months or matching placebo pills after which they participated in three anticholinergic challenge sessions when verbal memory performance was assessed. Subjects were administered either the antimuscarinic drug scopolamine (SCOP), the antinicotinic drug mecamylamine (MECA) or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another three months and repeated the challenges. Results showed that estradiol pretreatment significantly attenuated the anticholinergic drug-induced impairments on a test of episodic memory (the Buschke Selective Reminding test) for the younger group only, while estradiol treatment impaired performance of the older group. The results suggest that younger subjects may experience more cholinergic benefit from estradiol treatment than older subjects, supporting the concept of a critical period for postmenopausal estrogen use.

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“…Although some of these studies used the same hormone formulation [conjugated estrogens (Premarin) with medroxyprogesterone acetate (MPA; Provera)], many did not determine or subdivide the type of progestin used (9-14), raising the possibility that the apparent discrepancies in outcomes are due to the differences in cellular responses induced by different progestins. Such concerns have been underscored by the termination of the combined regimen arm of the Women's Health Initiative trial (11,12,15).In earlier work, we found that 17␤-estradiol (E 2 ) and progesterone (P 4 ), but not MPA, exerted neuroprotection against glutamate neurotoxicity (16). Not only was MPA an ineffective neuroprotectant, it attenuated E 2 -induced neuroprotection when coadministered (16).…”

mentioning

confidence: 98%

“…Because progestins are added to HRT to prevent hyperplasia of the endometrium (7) and resulting uterine cancer (8), possible impacts of progestins need to be determined. Numerous studies have found contradictory effects of estrogen͞ progestin use and breast cancer (9), coronary heart disease (10), and cognition (11,12). Although some of these studies used the same hormone formulation [conjugated estrogens (Premarin) with medroxyprogesterone acetate (MPA; Provera)], many did not determine or subdivide the type of progestin used (9-14), raising the possibility that the apparent discrepancies in outcomes are due to the differences in cellular responses induced by different progestins.…”

mentioning

confidence: 99%

Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling

Nilsen

Brinton

2003

Proc. Natl. Acad. Sci. U.S.A.

227

157

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The impact of progestins on estrogen-inducible mechanisms of neuroprotection was investigated. Previously, we showed that estrogen and progesterone are neuroprotective against excitotoxicity, whereas the synthetic progestin medroxyprogesterone acetate (MPA; Provera) is not. Here, we demonstrate that 17␤-estradiol (E 2) and progesterone (P4) treatment of hippocampal neurons attenuated the excitotoxic glutamate-induced rise in intracellular calcium concentration. Although MPA had no effect alone, MPA completely antagonized E 2-induced attenuation of intracellular calcium concentration. Activation of extracellular receptor kinase (ERK) is required for estrogen-induced neuroprotection and calcium regulation. Paradoxically, E 2, P4, and MPA all elicited similar rapid and transient activation of ERK, presenting a contradiction between the dependence on ERK for gonadal hormone-induced neuroprotection and the lack of neuroprotection induced by MPA. Subcellular analysis of ERK demonstrated that the phospho-ERK signal is transduced to the nucleus only by E 2 and P4, not by MPA. These results indicate that the profile of nuclear translocation of ERK is consistent with the neuroprotective profile. Further, the E 2-induced nuclear translocation of ERK was blocked by coadministration of MPA. Results of this study reveal that nuclear ERK induction by ovarian steroids is predictive of the neuroprotective effects of estrogen and progestin treatments, revealing a hitherto unrecognized divergence of progestin signaling through the src͞ MAPK pathway. These results have much broader implications encompassing the impact of progestins on estrogen-mediated effects in multiple tissues. The recent results from the Women's Health Initiative trial, which used MPA as the progestinal agent, indicate that differences between progestin formulations are crucial to health outcomes in women.N eurologic benefits of estrogen replacement therapy in humans include reversal of estrogen deficiency-induced memory dysfunction and reduced risk of Alzheimer's disease (AD) (1-5). Recently, the Cache County Study confirmed a reduced risk of AD in elderly women on hormone replacement therapy (HRT) (6). Because progestins are added to HRT to prevent hyperplasia of the endometrium (7) and resulting uterine cancer (8), possible impacts of progestins need to be determined. Numerous studies have found contradictory effects of estrogen͞ progestin use and breast cancer (9), coronary heart disease (10), and cognition (11,12). Although some of these studies used the same hormone formulation [conjugated estrogens (Premarin) with medroxyprogesterone acetate (MPA; Provera)], many did not determine or subdivide the type of progestin used (9-14), raising the possibility that the apparent discrepancies in outcomes are due to the differences in cellular responses induced by different progestins. Such concerns have been underscored by the termination of the combined regimen arm of the Women's Health Initiative trial (11,12,15).In earlier work, we found that 17␤-estradiol (E 2...

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Estrogen Plus Progestin and the Incidence of Dementia and Mild Cognitive Impairment in Postmenopausal Women

Cited by 1,864 publications

References 85 publications

Differential Effects of Estrogen Receptor Alpha and Beta Specific Agonists on Social Learning of Food Preferences in Female Mice

Differential Effects of Estrogen Receptor Alpha and Beta Specific Agonists on Social Learning of Food Preferences in Female Mice

Estradiol interacts with the cholinergic system to affect verbal memory in postmenopausal women: Evidence for the critical period hypothesis

Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling

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