Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

Koebele, Stephanie V.; Bimonte-Nelson, Heather A.

doi:10.1016/j.yhbeh.2015.06.009

Cited by 33 publications

(25 citation statements)

References 248 publications

(325 reference statements)

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“…To add complexity to this puzzle, what is optimal for one woman may not have the same effect in another woman (for review, see Koebele & Bimonte-Nelson, 2015). Our findings provide further insight into the window of opportunity for hormone therapy by revealing that the age at the onset of the menopause transition matters for memory outcomes.…”

Section: Discussionmentioning

confidence: 99%

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory

Koebele

Mennenga

Hiroi

et al. 2017

Hormones and Behavior

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Cognitive changes that occur during mid-life and beyond are linked to both aging and the menopause transition. Studies in women suggest that the age at menopause onset can impact cognitive status later in life; yet, little is known about memory changes that occur during the transitional period to the post-menopausal state. The 4-vinylcyclohexene diepoxide (VCD) model simulates transitional menopause in rodents by depleting the immature ovarian follicle reserve and allowing animals to retain their follicle-deplete ovarian tissue, resulting in a profile similar to the majority of perimenopausal women. Here, Vehicle or VCD treatment was administered to ovary-intact adult and middle-aged Fischer-344 rats to assess the trajectory of cognitive change across time with normal aging and aging with transitional menopause via VCD-induced follicular depletion, as well as to evaluate whether age at the onset of follicular depletion plays a role in cognitive outcomes. Animals experiencing the onset of menopause at a younger age exhibited impaired spatial memory early in the transition to a follicle-deplete state. Additionally, at the mid- and post- follicular depletion time points, VCD-induced follicular depletion amplified an age effect on memory. Overall, these findings suggest that the age at the onset of menopause is a critical parameter to consider when evaluating learning and memory across the transition to reproductive senescence. From a translational perspective, this study illustrates how age at menopause onset might impact cognition in menopausal women, and provides insight into time points to explore for the window of opportunity for hormone therapy during the menopause transition period. Hormone therapy during this critical juncture might be especially efficacious at attenuating age- and menopause- related cognitive decline, producing healthy brain aging profiles in women who retain their ovaries throughout their lifespan.

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“…Over the years, there have been numerous review articles underscoring the importance of these factors (Gibbs and Gabor, 2003; Brinton, 2004; Bimonte-Nelson et al, 2010; Rocca et al, 2011; Maki, 2012; Sherwin, 2012; Acosta et al, 2013; Chisholm and Juraska, 2013; Fischer et al, 2014; Luine, 2014; Koebele and Bimonte-Nelson, 2015; McCarrey and Resnick, 2015). The present study adds to the growing consensus that clarity gained from understanding the impact of these parameters is critical for providing information to offer unique and tailored treatment options for women.…”

Section: Discussionmentioning

confidence: 99%

Benefits of Hormone Therapy Estrogens Depend on Estrogen Type: 17β-Estradiol and Conjugated Equine Estrogens Have Differential Effects on Cognitive, Anxiety-Like, and Depressive-Like Behaviors and Increase Tryptophan Hydroxylase-2 mRNA Levels in Dorsal Raphe Nucleus Subregions

et al. 2016

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Decreased serotonin (5-HT) function is associated with numerous cognitive and affective disorders. Women are more vulnerable to these disorders and have a lower rate of 5-HT synthesis than men. Serotonergic neurons in the dorsal raphe nucleus (DRN) are a major source of 5-HT in the forebrain and play a critical role in regulation of stress-related disorders. In particular, polymorphisms of tryptophan hydroxylase-2 (TpH2, the brain-specific, rate-limiting enzyme for 5-HT biosynthesis) are implicated in cognitive and affective disorders. Administration of 17β-estradiol (E2), the most potent naturally circulating estrogen in women and rats, can have beneficial effects on cognitive, anxiety-like, and depressive-like behaviors. Moreover, E2 increases TpH2 mRNA in specific subregions of the DRN. Although conjugated equine estrogens (CEE) are a commonly prescribed estrogen component of hormone therapy in menopausal women, there is a marked gap in knowledge regarding how CEE affects these behaviors and the brain 5-HT system. Therefore, we compared the effects of CEE and E2 treatments on behavior and TpH2 mRNA. Female Sprague-Dawley rats were ovariectomized, administered either vehicle, CEE, or E2 and tested on a battery of cognitive, anxiety-like, and depressive-like behaviors. The brains of these animals were subsequently analyzed for TpH2 mRNA. Both CEE and E2 exerted beneficial behavioral effects, although efficacy depended on the distinct behavior and for cognition, on the task difficulty. Compared to CEE, E2 generally had more robust anxiolytic and antidepressant effects. E2 increased TpH2 mRNA in the caudal and mid DRN, corroborating previous findings. However, CEE increased TpH2 mRNA in the caudal and rostral, but not the mid, DRN, suggesting that distinct estrogens can have subregion-specific effects on TpH2 gene expression. We also found differential correlations between the level of TpH2 mRNA in specific DRN subregions and behavior, depending on the type of behavior. These distinct associations imply that cognition, anxiety-like, and depressive-like behaviors are modulated by unique serotonergic neurocircuitry, opening the possibility of novel avenues of targeted treatment for different types of cognitive and affective disorders.

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“…Estrogens have been shown to have beneficial effects on a myriad of body systems, including cardiovascular, bone, and brain health. However, estrogens’ actions are complex, and often exert beneficial effects only when given at a fitting dose, through the ideal route of administration, and with appropriate timing and duration of the treatment [30–32]. In the early 2000’s, findings from the Women’s Health Initiative Memory Study (WHIMS) challenged the tenet that estrogen-containing HT has protective effects against global cognitive decline, mild cognitive impairment, and probable dementia risks when the large, double-blind, placebo-controlled clinical trials indicated that some forms of HT increase the risk of probable dementia development when administered post-menopause [33–36].…”

Section: 1 the Human Menopause Transitionmentioning

confidence: 99%

Modeling menopause: The utility of rodents in translational behavioral endocrinology research

2016

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The human menopause transition and aging are each associated with an increase in a variety of health risk factors including, but not limited to, cardiovascular disease, osteoporosis, cancer, diabetes, stroke, sexual dysfunction, affective disorders, sleep disturbances, and cognitive decline. It is often challenging to systematically evaluate the biological underpinnings associated with the menopause transition in the human population. For this reason, rodent models have been invaluable tools for studying the impact of gonadal hormone fluctuations and eventual decline on a variety of body systems. While it is essential to keep in mind that some of the mechanisms associated with aging and the transition into a reproductively senescent state can differ when translating from one species to another, animal models provide researchers with opportunities to gain a fundamental understanding of the key elements underlying reproduction and aging processes, paving the way to explore novel pathways for intervention associated with known health risks. Here, we discuss the utility of several rodent models used in the laboratory for translational menopause research, examining the benefits and drawbacks in helping us to better understand aging and the menopause transition in women. The rodent models discussed are ovary-intact, ovariectomy, and 4-vinylcylohexene diepoxide for the menopause transition. We then describe how these models may be implemented in the laboratory, particularly in the context of cognition. Ultimately, we aim to use these animal models to elucidate novel perspectives and interventions for maintaining a high quality of life in women, and to potentially prevent or postpone the onset of negative health consequences associated with these significant life changes during aging.

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“…These adverse effects are especially robust when an abrupt hormone loss occurs, such as that associated with ovariectomy (Ovx; the surgical removal of the ovaries). Ovarian hormone loss is associated with a decline in cognitive function both in humans (Nappi et al, 1999; Rocca et al, 2007; Sherwin, 2003) as well as in animal models (Daniel, 2013; Frick, 2015; Koebele and Bimonte-Nelson, 2015; Korol and Pisani, 2015; Luine, 2014). Animal models have provided an excellent framework to elucidate the effects of ovarian hormones on the brain and behavior.…”

Section: On the Role Of Midlife Changes In Ovarian Hormones Gonadmentioning

confidence: 99%

“…Indeed, tonic administration of estrone, a weaker metabolite of 17β-estradiol, failed to impact ChAT+ neurons in the rat basal forebrain (Engler-Chiurazzi et al, 2012), and the synthetic estrogen used in oral contraceptives, ethinyl estradiol, decreased the number of ChAT+ neurons in the basal forebrain following chronic administration in an Ovx rat model (Mennenga et al, 2015a). These diverse effects of estrogens on one system highlight the complexity of estrogens’ actions in the brain, and underscore the importance of taking multiple factors into account when assessing estrogens’ effects on the brain and other body systems, such as type of estrogen, dose, route of administration, and timing of administration (for review, see Koebele and Bimonte-Nelson, 2015). …”

Section: Aging Ovarian Hormones and Altered Neural Systemsmentioning

confidence: 99%

The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory

Koebele

Bimonte-Nelson

2017

Experimental Gerontology

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Female mammals undergo natural fluctuations in sex steroid hormone levels throughout life. These fluctuations span from early development, to cyclic changes associated with the menstrual or estrous cycle and pregnancy, to marked hormone flux during perimenopause, and a final decline at reproductive senescence. While the transition to reproductive senescence is not yet fully understood, the vast majority of mammals experience this spontaneous, natural phenomenon with age, which has broad implications for long-lived species. Indeed, this post-reproductive life stage, and its transition, involves significant and enduring physiological changes, including considerably altered sex steroid hormone and gonadotropin profiles that impact multiple body systems, including the brain. The endocrine-brain-aging triad is especially noteworthy, as many paths meet and interact. Many of the brain regions affected by aging are also sensitive to changes in ovarian hormone levels, and aging and reproductive senescence are both associated with changes in memory performance. This review explores how menopause is related to cognitive aging, and discusses some of the key neural systems and molecular factors altered with age and reproductive hormone level changes, with an emphasis on brain regions important for learning and memory.

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Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

Cited by 33 publications

References 248 publications

Cognitive changes across the menopause transition: A longitudinal evaluation of the impact of age and ovarian status on spatial memory

Benefits of Hormone Therapy Estrogens Depend on Estrogen Type: 17β-Estradiol and Conjugated Equine Estrogens Have Differential Effects on Cognitive, Anxiety-Like, and Depressive-Like Behaviors and Increase Tryptophan Hydroxylase-2 mRNA Levels in Dorsal Raphe Nucleus Subregions

Modeling menopause: The utility of rodents in translational behavioral endocrinology research

The endocrine-brain-aging triad where many paths meet: female reproductive hormone changes at midlife and their influence on circuits important for learning and memory

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