Elsevier

Psychoneuroendocrinology

Volume 50, December 2014, Pages 167-180
Psychoneuroendocrinology

Hormonal treatment increases the response of the reward system at the menopause transition: A counterbalanced randomized placebo-controlled fMRI study

https://doi.org/10.1016/j.psyneuen.2014.08.012Get rights and content

Highlights

  • Hormonal treatment, relative to placebo, increased the response of the striatum and ventromedial prefrontal cortex during reward anticipation and at the time of reward delivery.

  • Our neuroimaging results bridge the gap between animal studies and human epidemiological studies of HT on cognition.

  • These findings establish a neurobiological foundation for understanding the neurofunctional impact of early HT initiation on reward processing at the menopause transition.

Summary

Preclinical research using rodent models demonstrated that estrogens play neuroprotective effects if they are administered during a critical period near the time of cessation of ovarian function. In women, a number of controversial epidemiological studies reported that a neuroprotective effect of estradiol may be obtained on cognition and mood-related disorders if hormone therapy (HT) begins early at the beginning of menopause. Yet, little is known about the modulatory effects of early HT administration on brain activation near menopause. Here, we investigated whether HT, initiated early during the menopause transition, increases the response of the reward system, a key brain circuit involved in motivation and hedonic behavior. We used fMRI and a counterbalanced, double-blind, randomized and crossover placebo-controlled design to investigate whether sequential 17β-estradiol plus oral progesterone modulate reward-related brain activity. Each woman was scanned twice while presented with images of slot machines, once after receiving HT and once under placebo. The fMRI results demonstrate that HT, relative to placebo, increased the response of the striatum and ventromedial prefrontal cortex, two areas that have been shown to be respectively involved during reward anticipation and at the time of reward delivery. Our neuroimaging results bridge the gap between animal studies and human epidemiological studies of HT on cognition. These findings establish a neurobiological foundation for understanding the neurofunctional impact of early HT initiation on reward processing at the menopause transition.

Introduction

Successful healthy brain aging has become one of the most crucial public health challenges of our time. Understanding how efficacious preventive pharmacological treatments modulate specific brain circuits, such as the reward system, is an integral part of rising to this challenge to improve our health and quality of life at old age. In women, menopause is accompanied by a drop of estradiol level, which may, in part, be responsible for cognitive impairments (Steiner et al., 2003). Although controversial studies reported that hormone therapy (HT) may prevent the deleterious effects of aging on cognition, and reduces the risks of dementia, including Alzheimer's disease, mild cognitive impairment and mood-related disorders (Henderson et al., 2005, Whitmer et al., 2011), others have found that initiation of HT more than a few years after menopause is associated with an unchanged or increased risk of dementia and age-associated cognitive decline (Resnick et al., 2006, Shumaker et al., 2003). The timing of initiation of HT relative to the onset of menopause has been proposed to be one important factor explaining part of the discrepant observations regarding a neuroprotective effect of HT (Sherwin, 2005, Sherwin, 2012, Daniel, 2013). According to the ‘critical time window period’ hypothesis, HT effectively decreases cognitive decline in aging women when it is initiated around the time of menopause, but this beneficial effect is not observed when HT is administered decades later. In humans, it is difficult to test this critical time window hypothesis and to study how sex steroid hormones affect the aging reward system because endocrine and neural senescence overlap in time and are mechanistically intertwined in complex feedback loops. Recent findings in younger early menopausal women reported that HT brought no significant benefit or harm to cognition 7 years later (Espeland et al., 2013). In contrast, animal models provide strong evidence for the critical window hypothesis, since 17β-estradiol (the major estrogen in most mammals, referred to as estradiol) replacement enhances cognitive functions when initiated immediately after ovariectomy, but not after a long period of ovarian hormone deprivation (Rocca et al., 2011, Daniel, 2013). Moreover, non-human primate studies have revealed that sequential HT reverses age-related prefrontal cortex (PFC) cognitive impairment in ovariectomized rhesus monkeys and that PFC synaptic attributes altered with aging are rescued by sequential HT (Hao et al., 2006).

Many studies have focused on effects of HT on disease outcomes, such as increase risk of heart attack, breast cancer or coronary artery disease, but little is known about the effects of HT on the human brain. Indeed, there are limited studies of sequential HT intervention at the functional brain level around menopause and it is unknown how the reward system, involved in motivation and hedonic behavior, is modulated by HT at perimenopause. Achieving an understanding of how the reward circuit changes with HT administration is of public health importance given that HT continues to be widely prescribed for managing menopausal symptoms. This brain system is known to show reduced BOLD response and lower number of dopaminergic receptors with aging (Dreher et al., 2008, Wong et al., 1988) and there are strong links between decline in striatal dopamine activity and cognitive dysfunctions as age increase (Volkow et al., 1998). Moreover, interventions that enhance dopamine activity enhance working memory capacity in aged monkeys (Castner and Goldman-Rakic, 2004), suggesting possible beneficial effects on performance and quality of life in healthy aging. A better understanding of these hormonal influences also has crucial implications for understanding sex-related differences on prevalence, course and treatment response characteristics of neurological and neuropsychiatric disorders in which dopaminergic abnormalities play a prominent role.

From a neuroanatomic point of view, there are reasons to believe that HT may modulate the reward circuitry near menopause. Indeed, ovarian steroids have widespread neurophysiological effects, including on the dopaminergic system, and estrogen and progesterone receptors are densely present along rodents’ midbrain dopaminergic neurons and other components of the reward system, such as the striatum (McEwen, 2002, Brailoiu et al., 2007, Laflamme et al., 1998). A number of preclinical data attest to a neuroregulatory role of estradiol on the reward system. For example, estrogen facilitates the effect of amphetamine or apomorphine on dopamine release and locomotor activity in rats unilaterally lesioned by 6-hydroxydopamine (Becker and Cha, 1989), and this activity is responsive to natural fluctuations in estradiol and is increased during late proestrus and early estrus (Becker et al., 1982). Although recent neuroimaging data demonstrate neuroregulatory effects of sex steroid hormones in young women on the reward system and on brain regions engaged in processing emotions, the evidence of these influences were indirect because estrogen and progesterone are simultaneously present in women of reproductive age (Dreher et al., 2007, Goldstein et al., 2005, Andreano and Cahill, 2010, Ossewaarde et al., 2011, Alonso-Alonso et al., 2011). In contrast, menopause provides a unique model to study how naturally low endogenous baseline estradiol levels influence reward-related functions and how HT may restore these functions.

Here, we investigated how HT, a sequential administration of 17β-estradiol followed by progesterone, influenced activity of the reward system in a carefully selected group of women at the end of the menopause transition, using a counterbalanced, randomized, crossover, double-blind and placebo-controlled fMRI design study (Fig. 1). We chose to initiate HT early in this group of women (the time between the last menses and HT initiation was less than a year) to maximally take advantage of a possible beneficial effect of HT on the reward system. Importantly, none of the women had ever taken HT before inclusion in the study. Each woman with a loss of ovarian hormones function was scanned once after a placebo period and once after HT. The order of the scans was counterbalanced across women. In each treatment condition, women performed an event-related fMRI reward task consisting in viewing four types of slot machines varying monetary reward probability of being rewarded 20€ or 0€. They simply had to press one of four specific response buttons corresponding to each slot machine at the time of their presentation and at the time of outcome delivery.

Because previous fMRI studies in young participants have documented that distinct reward anticipation- and outcome-processing phases are associated with differential patterns of ventral striatal and ventromedial prefrontal cortex activity (Dreher et al., 2006), we hypothesized that HT could restore or increase activity of these reward-related brain areas.

Section snippets

Subjects

Fifteen healthy, right-handed non-smoking perimenopausal caucasian women were recruited through advertizement in local newspapers. Two of them were excluded from the analyses because of problems encountered during scanning. The mean age of the thirteen remaining women was 52.3 ± 2.2 years old (range 48–55 y.o.). Women were all at the end of their menopause transition (8.7 ± 1.3 months after the last menstrual period) at the time of the first scan. The menopause transition, also called

Estradiol levels and clinical ratings

On the day of inclusion in the study (i.e. before HT or placebo treatment), plasma estradiol level was 28 ± 22.3 pmol/L, confirming women's perimenopausal status (Burger et al., 1999). This baseline level was significantly lower than under HT (173 ± 36.4 pmol/L) (t = 3.93, P < 0.005) and did not differ from placebo level (20.6 ± 0.7 pmol/L) (P = 0.22). As expected, when directly comparing estradiol concentrations on the two scanning days, HT increased plasma estradiol levels under HT (173 ± 36.4 pmol/L) as

Discussion

The present study is the first to investigate the effects of sequential estradiol plus progesterone administration on the reward system at the end of the menopause transition. It bridges research preclinical studies on the role of estradiol on the dopaminergic system with women epidemiological studies of HT on cognition. Taking an experimental cognitive neuroscience approach is necessary and important to understand the impact of sex-steroid hormones substitution on specific neural systems. One

Contributors

J.T. performed research (scanning of subjects and behavioral analysis) and wrote a first draft of the manuscript. Author E.M. and J.T. performed the fMRI statistical analysis. Author H.D. performed the hormonal measures. Author J.T. and M.P. recruited the women and M.P. assessed them clinically before inclusion in the study. Author J-C D. designed the study, wrote the protocol, managed the literature searches and wrote the manuscript. All authors contributed to and have approved the final

Role of the funding source

This research was funded by research grants to J-C D. from the Medical Research Foundation (FRM no. DLC20060206409) and the LABEX Cortex (ANR-11-LABX-0042) of Université de Lyon, within the program Investissements d’Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR). The funding source was not involved in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Conflict of interest statement

The authors report no conflict of interest and no financial relationship with commercial interests.

Acknowledgements

This research was funded by research grants from the Medical Research Foundation (FRM no. DLC20060206409) and was performed within the framework of the LABEX ANR-11-LABEX-0042 of Université de Lyon, within the program Investissements d’Avenir (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR). We thank the staff of CERMEP—Imagerie du Vivant for helpful assistance with data collection.

We thank the staff from the Neuroimaging Center CERMEP (http://www.cermep.fr/cermep_en.php

References (57)

  • D.S. Reddy

    Neurosteroids: endogenous role in the human brain and therapeutic potentials

    Prog. Brain Res.

    (2010)
  • W.A. Rocca et al.

    Oophorectomy, menopause, estrogen treatment, and cognitive aging: clinical evidence for a window of opportunity

    Brain Res.

    (2011)
  • R.L. Sanchez et al.

    A second tryptophan hydroxylase isoform, TPH-2 mRNA, is increased by ovarian steroids in the raphe region of macaques

    Brain Res. Mol. Brain Res.

    (2005)
  • G. Sescousse et al.

    Common and specific neural structures processing primary and secondary rewards: a quantitative voxel-based meta-analysis

    Neurosci. Biobehav. Rev.

    (2013)
  • T. Shafir et al.

    Postmenopausal hormone use impact on emotion processing circuitry

    Behav. Brain Res.

    (2012)
  • B.B. Sherwin

    Estrogen and memory in women: how can we reconcile the findings?

    Horm. Behav.

    (2005)
  • M. Steiner et al.

    Hormones and mood: from menarche to menopause and beyond

    J. Affect. Disord.

    (2003)
  • G.L. Anderson et al.

    Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial

    JAMA

    (2004)
  • J. Bayer et al.

    Differential modulation of activity related to the anticipation of monetary gains and losses across the menstrual cycle

    Eur. J. Neurosci.

    (2013)
  • J.B. Becker et al.

    The role of dopamine in the nucleus accumbens and striatum during sexual behavior in the female rat

    J. Neurosci.

    (2001)
  • A. Berent-Spillson et al.

    Early menopausal hormone use influences brain regions used for visual working memory

    Menopause (New York, NY)

    (2010)
  • K.F. Berman et al.

    Modulation of cognition-specific cortical activity by gonadal steroids: a positron-emission tomography study in women

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

    (1997)
  • E. Brailoiu et al.

    Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system

    J. Endocrinol.

    (2007)
  • H.G. Burger et al.

    Prospectively measured levels of serum follicle-stimulating hormone, estradiol, and the dimeric inhibins during the menopausal transition in a population-based cohort of women

    J. Clin. Endocrinol. Metab.

    (1999)
  • S.A. Castner et al.

    Enhancement of working memory in aged monkeys by a sensitizing regimen of dopamine D1 receptor stimulation

    J. Neurosci.

    (2004)
  • J.C. Dreher et al.

    Neural coding of distinct statistical properties of reward information in humans

    Cerebral Cortex

    (2006)
  • J.C. Dreher et al.

    Menstrual cycle phase modulates reward-related neural function in women

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

    (2007)
  • J.C. Dreher et al.

    Age-related changes in midbrain dopaminergic regulation of the human reward system

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

    (2008)
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