The scientific body of knowledge – Whose body does it serve? A spotlight on oral contraceptives and women’s health factors in neuroimaging

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Highlights

  • Sex hormones are powerful neuromodulators that shape brain structure and function.

  • Yet only 0.5% of neuroimaging articles consider endocrine-related health factors.

  • This oversight obscures basic knowledge and limits progress in women’s brain health.

  • 100 M women use oral contraception, yet we lack knowledge of its effects in the CNS.

  • The brain imaging community should prioritize women’s health research.

Abstract

Women constitute half of the world’s population, yet neuroscience research does not serve the sexes equally. Fifty years of preclinical animal evidence documents the tightly-coupled relationship between our endocrine and nervous systems, yet human neuroimaging studies rarely consider how endocrine factors shape the structural and functional architecture of the human brain. Here, we quantify several blind spots in neuroimaging research, which overlooks aspects of the human condition that impact women’s health (e.g. the menstrual cycle, hormonal contraceptives, pregnancy, menopause). Next, we illuminate potential consequences of this oversight: today over 100 million women use oral hormonal contraceptives, yet relatively few investigations have systematically examined whether disrupting endogenous hormone production impacts the brain. We close by presenting a roadmap for progress, highlighting the University of California Women’s Brain Initiative which is addressing unmet needs in women’s health research.

Section snippets

Brief review of sex hormone action in the central nervous system

Sex steroid hormones (androgens, estrogens, progestogens) are produced primarily by the gonads and coordinate the physiological changes that occur during puberty, the menstrual cycle, pregnancy, and menopause. Within the central nervous system, estrogen and progesterone receptors are expressed widely throughout the brain (McEwen, 2002, McEwen and Alves, 1999, Rossetti et al., 2016), with enriched expression in extra-hypothalamic regions such as the hippocampus and prefrontal cortex (PFC) (Almey

Identifying blind spots in human neuroimaging

While animal studies have documented the role of sex hormones in the brain for decades, human neuroimaging research has not kept pace. Given a groundswell of evidence that sex hormones regulate the structure and function of the mammalian brain, we sought to document the frequency with which human neuroimaging studies consider endocrine factors. We approached this in two ways. First, to capture a contemporary state of the field, we analyzed every empirical human neuroimaging paper (i.e.,

A spotlight on oral hormonal contraceptives

Perhaps one of the most striking illustrations of this oversight is neuroscience’s neglect with respect to one of the largest natural experiments in human history (Beltz and Moser, 2019): over the past half-century, women have used oral hormonal contraceptives without full knowledge of their influence on the central nervous system, as few rigorous human neuroimaging studies of oral hormonal contraception (OC) have been conducted. Here, we use OC to highlight the missed opportunities in our

A roadmap for the future: Harnessing new methodological and technological approaches to bolster women’s health research

Beyond OC, there are many other opportunities to expand research efforts to advance knowledge on women’s health in cognitive neuroscience. Below we propose three programmatic initiatives to aid in this pursuit. We describe “Big Data” approaches, including the University of California Women’s Brain Initiative, that are beginning to address unmet areas of women’s health research at the population level. Next, we describe innovations in methodological and computational approaches in human

Conclusion

Fifty years of basic science research has established a critical role for sex hormones in higher-order brain regions, including the hippocampus and prefrontal cortex. Yet, human brain imaging studies often overlook basic elements of endocrinology and women’s reproductive health. Moving forward, large-scale population-based studies, targeted dense-sampling studies, and translational research will provide novel insight into sex hormone action in the mammalian brain. Applying a women’s health lens

Funding

This work was supported by the Harvey L. Karp Discovery Award (CMT), the Brain and Behavior Research Foundation (EGJ), and the Hellman Family Fund (EGJ).

Acknowledgments

Thank you to Bridget Queenan and Michael J. Goard for helpful edits and feedback. We also thank Emily Cao and Bridget Bush for assistance with data collection.

References (150)

  • A.M. Clemens et al.

    Estrus-Cycle Regulation of Cortical Inhibition

    Curr. Biol.

    (2019)
  • T. De Bondt et al.

    Regional gray matter volume differences and sex-hormone correlations as a function of menstrual cycle phase and hormonal contraceptives use

    Brain Res.

    (2013)
  • T. De Bondt et al.

    Stability of resting state networks in the female brain during hormonal changes and their relation to premenstrual symptoms

    Brain Res.

    (2015)
  • L.N. Driscoll et al.

    Dynamic Reorganization of Neuronal Activity Patterns in Parietal Cortex

    Cell

    (2017)
  • S.J. Duff et al.

    A Beneficial Effect of Estrogen on Working Memory in Postmenopausal Women Taking Hormone Replacement Therapy

    Horm. Behav.

    (2000)
  • J.A. Dumas et al.

    Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

    Horm. Behav.

    (2010)
  • C.N. Epperson et al.

    Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women

    Psychoneuroendocrinology

    (2012)
  • A.M. Fortress et al.

    Epigenetic regulation of estrogen-dependent memory

    Front. Neuroendocrinol.

    (2014)
  • K.M. Frick et al.

    Mechanisms underlying the rapid effects of estradiol and progesterone on hippocampal memory consolidation in female rodents

    Horm. Behav.

    (2018)
  • K.M. Frick et al.

    Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females

    Physiol. Behav.

    (2018)
  • D. Fuhrmann et al.

    Adolescence as a Sensitive Period of Brain Development

    Trends Cogn. Sci.

    (2015)
  • L.AM. Galea et al.

    Beyond sex differences: short and long-term implications of motherhood on women’s health

    Curr. Opin. Physiol.

    (2018)
  • L.A.M. Galea et al.

    The promises and pitfalls of sex difference research

    Front. Neuroendocrinol.

    (2020)
  • L.A.M. Galea et al.

    Why estrogens matter for behavior and brain health

    Neurosci. Biobehav. Rev.

    (2017)
  • L.A.M. Galea et al.

    Relations of hippocampal volume and dentate gyrus width to gonadal hormone levels in male and female meadow voles

    Brain Res.

    (1999)
  • U.J. Gaspard et al.

    Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel

    Contraception

    (1983)
  • M. Gingnell et al.

    Oral contraceptive use changes brain activity and mood in women with previous negative affect on the pill—a double-blinded, placebo-controlled randomized trial of a levonorgestrel-containing combined oral contraceptive

    Psychoneuroendocrinology

    (2013)
  • E.M. Gordon et al.

    Precision Functional Mapping of Individual Human Brains

    Neuron

    (2017)
  • C. Gratton et al.

    Functional Brain Networks Are Dominated by Stable Group and Individual Factors, Not Cognitive or Daily Variation

    Neuron

    (2018)
  • E. Hampson

    A brief guide to the menstrual cycle and oral contraceptive use for researchers in behavioral endocrinology

    Horm. Behav.

    (2020)
  • E. Hampson et al.

    Estradiol concentrations and working memory performance in women of reproductive age

    Psychoneuroendocrinology

    (2013)
  • E.G. Jacobs et al.

    The middle-aged brain: biological sex and sex hormones shape memory circuitry

    Curr. Opin. Behav. Sci.

    (2018)
  • A.M. Kaufman et al.

    A Role for the Locus Coeruleus in Hippocampal CA1 Place Cell Reorganization during Spatial Reward Learning

    Neuron

    (2020)
  • R.K. Lenroot et al.

    Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging

    Neurosci. Biobehav. Rev.

    (2006)
  • N. Lisofsky et al.

    Hippocampal volume and functional connectivity changes during the female menstrual cycle

    NeuroImage

    (2015)
  • N. Lisofsky et al.

    Hormonal contraceptive use is associated with neural and affective changes in healthy young women

    NeuroImage

    (2016)
  • R. Louw-du Toit et al.

    Comparing the androgenic and estrogenic properties of progestins used in contraception and hormone therapy

    Biochem. Biophys. Res. Commun.

    (2017)
  • R. Mahmoud et al.

    Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms

    Front. Neuroendocrinol.

    (2016)
  • C.J. Merz et al.

    Oral contraceptive usage alters the effects of cortisol on implicit fear learning

    Horm. Behav.

    (2012)
  • S. Mizutani et al.

    Pharmacoepidemiological characterization of drug-induced adverse reaction clusters towards understanding of their mechanisms

    Comput. Biol. Chem.

    (2014)
  • E.R. Montoya et al.

    How Oral Contraceptives Impact Social-Emotional Behavior and Brain Function

    Trends in Cognitive Sciences

    (2017)
  • C. Panzer et al.

    Impact of oral contraceptives on sex hormone-binding globulin and androgen levels: a retrospective study in women with sexual dysfunction

    J. Sex. Med.

    (2006)
  • N. Petersen et al.

    Oral contraceptive pill use and menstrual cycle phase are associated with altered resting state functional connectivity

    NeuroImage

    (2014)
  • B. Pletzer et al.

    Menstrual cycle and hormonal contraceptive use modulate human brain structure

    Brain Res.

    (2010)
  • M. Abbassi-Ghanavati et al.

    Pregnancy and Laboratory Studies: A Reference Table for Clinicians

    Obstet. Gynecol.

    (2009)
  • B. Abler et al.

    Neural Correlates of Erotic Stimulation under Different Levels of Female Sexual Hormones

    PLOS ONE

    (2013)
  • Z. Amin et al.

    Effect of Estrogen-Serotonin Interactions on Mood and Cognition

    Behav. Cogn. Neurosci. Rev.

    (2005)
  • K. Arélin et al.

    Progesterone mediates brain functional connectivity changes during the menstrual cycle—a pilot resting state MRI study

    Front. Neurosci.

    (2015)
  • A. Balogh et al.

    LH, FSH, estradiol and progesterone levels after discontinuation of hormonal contraception

    Acta Univ. Palacki. Olomuc. Fac. Med.

    (1981)
  • A.M. Beltz et al.

    Ovarian hormones: a long overlooked but critical contributor to cognitive brain structures and function

    Ann. N.Y. Acad. Sci.

    (2020)
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