Shifting Paradigms About Hormonal Risk Factorsfor Postmenopausal DepressionAge at Menopause as an Indicator of Cumulative LifetimeExposure to Female Reproductive HormonesHadine Joffe, MD, MSc; Joyce T. Bromberger, PhD The article by Georgakis et al in this issue of JAMA Psychiatry1
The implication is that prior and cumulative exposure to hor- is a meta-analysis of 14 observational studies addressing the mones has a sustained impact on the brain, increasing vulner- association of depression after menopause in women with both ability to depression years after these exposures. To date, most age at menopause and duration of the reproductive period. Age studies linking reproductive hormones to mood disturbance at menopause is used to esti- have conceptualized the association as concurrent or proxi- mate the duration of the re- mate. That is, the brain is concurrently or recently exposed to productive period because changes in reproductive hormones that provoke an adverse there is less variability in the mood response in susceptible women.4 This concept derives age range for menarche (within a 3-year window in 80% of from observations that mood changes occur during the im- girls)2 than for menopause (within a 7-year window for ap- mediate postpartum period when levels of estradiol and pro- proximately 80% of women).3 The meta-analysis concludes gesterone fall rapidly, during the premenstruum when mood that there is a small but statistically significant increased like- deteriorates in the context of fluctuating levels of estradiol and lihood of depression after menopause that is inversely asso- progesterone over the previous month, and during the peri- ciated with increasing age at menopause (odds ratio [OR], 0.98, menopause, when levels of estradiol vary widely. Other neu- in 13 studies) and increasing duration of the reproductive ral diseases linked with hormonal exacerbations (eg, catame- period (OR, 0.98, in 5 studies), which is defined as age at meno- nial epilepsy, migraines in pregnancy) are based on a similar pause (defined as 1 year after final menstrual period) minus temporal construct. Animal studies have demonstrated that age at menarche. This translates to a 2% reduction in risk for estradiol rapidly regulates neural activities through genomic each 2-year increase in menopausal age. Therefore, the older and nongenomic processes. Such observations provide a a woman is at the time of ovarian senescence and the greater mechanistic basis for the potential rapid neuromodulatory and the number of years between the age at menarche (first men- neuroprotective effect of estrogens on mood. Related to this ses) and at menopause (defined as final menstrual period or 1 concept is that the underlying hormonal milieu influences the year after final menstrual period), the lower the risk that she impact of female hormonal changes on mood. Clinical trial data will experience depression in her postmenopausal years.
showing that estrogen therapy improves mood in depressed Population-based studies show that the median age at the perimenopausal,5 but not postmenopausal,5women suggest final menstrual period is 52.5 years, and 90% of women have that depression in postmenopausal women is not hormon- their final menstrual period by age 56 years.3 The vast major- ally sensitive.
ity of the articles included in this meta-analysis were con- In contrast to the acute effects of reproductive hormones ducted in women whose average age was 55 years or older; the on mood in cycling women, the article by Georgakis et al high- average age was 60 years or older in half of the studies. In ad- lights a potential neuroprotective effect of gonadal steroids on dition, the average age for women in most studies was at least mood that is delayed and extends into the stable hypoestro- 5 years older than the average age at menopause that they re- genic and hypoprogestinemic environment of the postmeno- ported. Therefore, this meta-analysis does not address pause. Other nonpsychiatric diseases in postmenopausal depression associated with the gonadal steroid fluctuations women have similarly been linked with earlier age at meno- of the perimenopause or recent estradiol withdrawal of the pause. These include a greater risk for cardiovascular dis- immediate postmenopause. Rather, the analysis applies to ease, cognitive decline, and dementia among women who had depression in older women whose brains have not recently an artificially early surgical menopause or an earlier natural been exposed to estradiol or other reproductive hormones menopause. The current article adds postmenopausal depres- and for whom hormonal risk factors have previously been sion to that list, with findings that show similarly that the ef- considered less relevant.
fect of a slightly early natural menopause is small, while the Results of this study provide a novel paradigm for under- effect of premature menopause is much stronger. Mecha- standing the potential impact of central nervous system (CNS) nisms underlying the neuroprotective effect of an older age at exposure to female reproductive hormones and depression.
menopause are not fully elucidated and may vary between dis- (Reprinted) JAMA Psychiatry Published online January 6, 2016
Copyright 2016 American Medical Association. All rights reserved.
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Opinion Editorial ease end points. Prolonged exposure to endogenous estra- reported scales that measure depressive symptom burden diol during the reproductive years certainly has cardiovascu- rather than a categorical depression diagnosis, (4) age at meno- lar and neurovascular benefits, but these effects are challenging pause and menarche are retrospectively self-reported, and (5) to disentangle from the potential benefits of end-organ expo- women who are either currently using or previously used sure to predictable fluctuations of estradiol across the cycle, hormone therapy are included. Use of hormone therapy con- intermittent progesterone exposure after ovulation occurs, or founds the analysis because the menstrual marker indicating its neurosteroid metabolites (eg, allopregnanolone).6 Alterna- the timing of natural menopause cannot be distinguished from tively, increasing duration of hypoestrogenism and hypopro- an exogenously induced withdrawal bleed of hormone therapy gestinism between an earlier menopause and the onset of de- with cyclic progesterone. Importantly, the implication that neu- pression with increasing age may result from an increased ral effects of reproductive hormones are responsible for the as- opportunity for depression.
sociation between these reproductive markers and post- Of note, studies of reproductive hormone effects in the brain menopausal depression risk does not take into account the assume that systemic levels of female reproductive hormones many other factors that might confound this association, each are a reliable proxy for CNS levels and that CNS levels are com- of which is independently associated with both risk for de- parable throughout all brain regions. However, evidence sup- pression and earlier menopause. These risk factors include porting this key assumption is limited. For example, CNS lev- sleep difficulties, stress, functioning in work and relation- els of the enzyme aromatase vary among cortical regions.7 As ships, and early-life adverse exposures (eg, socioeconomic dis- a result, estradiol can be produced tonically from steroid pre- advantage, childhood maltreatment).
cursors in some brain regions at levels sufficient to generate es- This meta-analysis is a commendable effort to expand tradiol's neuroprotective effects rather than relying solely on thinking about the role of lifetime exposure to reproductive widely varying levels of ovarian estradiol production. Other in- hormones in the occurrence of postmenopausal depression and direct mechanisms that may confer risk for subsequent depres- to shift our research focus to explore a new paradigm. The lit- sion include persistent perturbation of the hypothalamic- erature in this area would benefit from prospective studies that pituitary-adrenal axis, similar to the impact of early life stress investigate the incidence of diagnostically confirmed depres- on the hypothalamic-pituitary-adrenal axis, which precedes and sion episodes during and after the menopausal transition.
increases the risk for later onset of depression.
Given the small effect size and limitations of the studies used A significant limitation of this meta-analysis is that only in this analysis, more direct evidence supporting a sustained 2 studies controlled for past depression, the primary predic- and delayed neuroprotective effect of extended exposure to tor of subsequent depression. Other limitations are that (1) the estradiol, cyclic progestins, and their neurosteroid deriva- effect is very small, (2) study designs are primarily cross- tives is required to support use of hormonal therapy as a thera- sectional, precluding determination of the beginning of mood peutic approach to protecting against postmenopausal de- disturbance, (3) depression is defined primarily using self- ARTICLE INFORMATION R01MH082922 and U01AG012531 and Dr 3. Gold EB, Crawford SL, Avis NE, et al. Factors
Author Affiliations: Department of Psychiatry,
Bromberger's by grant U01AG012546.
related to age at natural menopause: longitudinal Brigham and Women's Hospital, Boston, Role of the Funder/Sponsor: The National
analyses from SWAN. Massachusetts (Joffe); Dana Farber Cancer Institutes of Health had no role in the preparation, Institute, Harvard Medical School, Boston, review, or approval of the manuscript; and decision 4. Payne JL, Palmer JT, Joffe H. A reproductive
Massachusetts (Joffe); Department of to submit the manuscript for publication.
subtype of depression: conceptualizing models and Epidemiology, University of Pittsburgh, Pittsburgh, Additional Contributions: Aleta Wiley, MPH,
moving toward etiology. Pennsylvania (Bromberger); Department of Department of Psychiatry, Brigham and Women's Psychiatry, University of Pittsburgh, Pittsburgh, Hospital, provided administrative support. She did 5. Joffe H, Petrillo LF, Koukopoulos A, et al.
not receive any compensation.
Increased estradiol and improved sleep, but not hot Corresponding Author: Hadine Joffe, MD, MSc,
flashes, predict enhanced mood during the Brigham and Women's Hospital, 75 Francis St, menopausal transition. BB232C, Boston, MA 02115 1. Georgakis MK, Thomopoulos TP, Diamantaras
Published Online: January 6, 2016.
A-A, et al. Association of age at menopause and 6. Gordon JL, Girdler SS, Meltzer-Brody SE, et al.
duration of reproductive period with depression Ovarian hormone fluctuation, neurosteroids, and Conflict of Interest Disclosures: Dr Joffe has
after menopause: a systematic review and HPA axis dysregulation in perimenopausal received research funding from Merck and meta-analysis [published online January 6, 2016].
depression: a novel heuristic model. Cephalon/Teva and is a consultant/advisor to JAMA Psychiatry. Mitsubishi-Tanabe, Merck, and Noven. No other 7. Biegon A, Kim SW, Alexoff DL, et al. Unique
disclosures were reported.
2. Chumlea WC, Schubert CM, Roche AF, et al. Age
distribution of aromatase in the human brain: in Funding/Support: Dr Joffe's time was supported
at menarche and racial comparisons in US girls.
vivo studies with PET and [N-methyl-11C]vorozole.
by National Institutes of Health grants JAMA Psychiatry Published online January 6, 2016 (Reprinted)
Copyright 2016 American Medical Association. All rights reserved.
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