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Menopause: The Journal of The North American Menopause SocietyVol. 19, No. 9, pp. 949/951DOI: 10.1097/gme.0b013e3182651d8d * 2012 by The North American Menopause Society Depression and heavy bleeding during the menopausal transition:adjusting our gaze Researchpublishedduringthepastthreedecadeshas every1to2hours.Abnormalbleedingwasdefinedasmenstrual explored the relationship between mood and menstrual flow lasting more than 10 days; bleeding or spotting between bleeding. Investigators have established the relation- periods in more than 50% of the cycle; or menstrual flow usu- ship between cyclical mood symptoms and the menstrual cycle, ally lasting less than 2 days or more than 8 days and PMS characterizing perimenstrual symptoms, premenstrual syndrome (including two mood symptoms [such as changes in mood or (PMS), and premenstrual dysphoric disorder.1<3 Although each being anxious, jittery, or nervous] and one of five physical of these has been defined with respect to clusters of multiple symptoms [abdominal pain or cramps, breast pain, tenderness symptoms (such as mood and fluid retention), severity, and or swelling, weight gain or feeling bloated, back, joint, or interference with daily living, evidence supporting their rela- muscle pain, or severe headaches]) on the week before the onset tionship with endocrine fluctuation has been mixed. Data sup- of menses that interfered with work and/or home activities and port associations between levels of estradiol and progesterone ceased within a few days of menses onset. Findings from the and perimenstrual symptoms4,5 and fluctuations in these same SWAN MHS supporting a link between depression and heavy bleeding invite attempts to explain this relationship.
Additional evidence supports the persistence of these cycli- It is well established that rising levels of estradiol, in re- cal symptoms in women after the age of 40 years6 and as women sponse to FSH stimulation, induce the development of the approach menopause.7 Hypotheses relating entrainment of endometrial lining of the uterus. Progesterone levels increase mood symptoms to circamensual (menstrual cycle) rhythm have after ovulation and transform the endometrium in preparation been augmented by evidence supporting the relationships of for the implantation of a fertilized embryo. In the absence the same symptoms and symptom clusters to the context of of ovulation, progesterone levels remain low, and the endo- women’s lives, including their socialization about menstruation, metrium does not continue to develop and is shed with men- relationship and material stressors, and perceived stress.5,8<10 ses. Indeed, progesterone withdrawal is used therapeutically As the oldest of the baby boomers began to enter the menopausal transition, the gaze of many researchers refocused One of the perturbations that can suppress menses or ovula- on this birth cohort of women. Efforts to understand an in- tion is exposure to extreme stress. An early study of depression creasingly irregular menstrual rhythm and its relationship to and menorrhagia among adult women not yet experiencing the depressed mood once again examined levels of and variability menopausal transition (aged up to 42 y) linked depression to in hypothalamic-pituitary-ovarian (HPO) axis hormones.11<13 menorrhagia.15 Sixty percent of women experiencing menor- To date, there have been studies on the relationship of men- rhagia experienced a severely stressful event within a year opausal transition stages, estrogen, testosterone, and follicle- versus 40% of those without menorrhagia. Moreover, 50% of stimulating hormone (FSH) to depressed mood symptoms or those with menorrhagia had experienced a severe loss versus major depressive disorder. Evidence indicates that depression only 17% of those without menorrhagia. In addition, 78% of the during the menopausal transition was related to the level and women with menorrhagia experienced menorrhagia after the variability of estradiol12 and that the severity of depressed loss experience. The more recent Harvard Study of Women’s mood symptoms is greatest during the late menopausal tran- Moods and Cycles revealed that a lifetime history of phy- sition stage, when cycles vary by more than 60 days from one sical and sexual abuse was associated with elevated FSH cycle to the next.13 Moreover, depressed mood symptoms levels and low estradiol levels, suggesting that exposure to and major depressive disorder during the menopausal tran- violence, especially before adulthood, may lead to neuro- sition were related to a history of depression earlier in life and a history of PMS and postpartum depression.7,13 The impact of stress or shock on the endocrine system was Up until Bromberger et al14 published results from the described long ago by traditional Chinese medicine (TCM) Study of Women’s Health Across the Nation Mental Health scholars. Classic theory relates a feedback loop between the Study (SWAN MHS), there has been little, if any, attention to Heart* Qi (including emotions, much as western culture also the association between depression and menstrual characteris-tics, including heavy bleeding in women during perimenopause.
Bromberger et al defined heavy bleeding as passing clots larger *A capitalized organ name indicates the TCM physiological and/or anatomical than a dime; flooding or gushing; or heavy or very heavy flow concept of an organ. This differs from the biomedical physiological function of on the heaviest days of menstrual flow, changing protection Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
associates emotions and feelings with the heart) and the importance of the HPO-HPA axes in modulating both bleeding Kidney Qi (often related to biomedical functions of generat- ing estrogen and progesterone) via the Bao Mai (uterus ves- Yet another explanation for the relationship between de- sel) and the Bao Luo (uterus channel).17 Heart Qi is supposed pression and heavy bleeding involves the role of depression to descend, thus promoting timely ovulation and menses.
in shaping one’s outlook. Heavy vaginal bleeding is generally Shock or stress can disrupt this physiological function, causing regarded as a worrisome sign and is included as one of the Qi and Blood stagnation. Stagnation can lead to generation of warning signs for cancer. To a woman who is depressed or Heat, which may result in depression, anxiety, and/or heavy troubled by depression symptoms, heavy bleeding is both a bleeding (depending on the individual). Furthermore, this sign and a symptom that requires an appraisal of seriousness feedback loop between the Heart and the Kidneys involves and frequent attention to menstrual hygiene. Together, these several additional meridians (where Qi primarily flows), spe- contribute to a negative view of menses as a bodily function cifically the Conception, Governing, and Penetrating meridians.
and may be perceived as interfering with activities of daily The physiological function of these meridians and organs life. Heavy bleeding also is likely to rise quickly to con- closely parallels HPO axis physiology and anatomy. The path- scious awareness and to stimulate stress arousal and symptom ology of HPO can therefore be understood in both biomedical In the SWAN MHS cohort, other risk factors for heavy The plausibility of the relationship between depression bleeding included being in the early menopausal transition and menstrual bleeding is supported by the capacity of the stage, having had more pregnancies, a higher body mass index hypothalamic-pituitary-adrenal (HPA) axis to modulate HPO (BMI), and a history of fibroids. BMI has been implicated in axis functioning in ways that regulate reproductive func- the extraovarian production of estrogen and in perturbations tion, including suppressing ovulation and menstruation under of the HPO axis function.24 Still another pathway may involve stressful conditions.18 Thus, explanations for the association the effects of major depression on behavior, such as eating of depression with heavy bleeding could include stress- behavior, in turn increasing BMI, which is related to heavy induced effects on the HPA axis with perturbation of HPO axis functioning, resulting in both depressed mood and heavy Yet another explanation for the association of depressed mood with heavy bleeding can be found in the emergent view A second contributing factor could be the influence of the of depression as an illness with a myriad of correlates and menopausal transition on estradiol levels. In response to in- consequences, including inflammatory, hemostatic, and lipid creasing FSH levels, some women experience episodes of changes.25 Indeed, depression may also be regarded as a sig- hyperestrogenism, as described by Santoro et al,19 and these nal of physiological dysregulation, much as one regards heavy hyperestrogenemic episodes are associated with heavy bleed- vaginal bleeding. It is possible that both are indicators of ing. Variable levels of estradiol during these episodes, many underlying perturbations that are unrelated to one another, of which may be anovulatory, may also trigger depressed except through their contribution to allostatic load.26 mood through effects on neurotransmitters such as serotonin The complexities of the relationship between depression and norepinephrine.20 Women who are vulnerable to endocrine and heavy bleeding will be best addressed by conducting re- changes earlier in life, such as those experiencing PMS or search tracking women’s experiences during the reproduc- postpartum depression, may also be troubled by heavy bleed- tive life span and by incorporating a view spanning molecules ing during perimenopause. Of interest is that when women to the organism. Women who experience both depression undergo hysterectomy, with or without oophorectomy, they are and heaving bleeding during the menopausal transition will less likely to experience depressed mood than women who be served best by researchers redirecting our gaze from only perimenopause to mood and bleeding patterns that women Indeed, there may be multiple periods in the life span dur- experience throughout their reproductive life. Moreover, re- ing which hormonal dynamics increases vulnerability to both focusing our view of depression as a discrete mental illness depression and heavy bleeding. In addition to the postpartum into an expression of loss of complexity in a highly ordered period and the menstrual cycle, depressed mood becomes more dynamic state, as informed by systems biology, will expand prevalent among girls making the pubertal transition. Angold our understanding of depression and its myriad correlates.
et al’s22 study of girls in Tanner stages II and III revealed Such an integrative view prompts scientists to recognize that that depression was explained by changing estrogen levels. Of seemingly single phenotypic entities can have multiple etio- added interest was that morning salivary cortisol levels were logic and/or pathological processes.27 This integrative view is 20% higher in Tanner stage II+ girls versus boys. Tanner stages emblematic in TCM. Any given symptom is seen only in II and III are the periods in pubertal development when the relationship to other symptoms. For this reason, women with prevalence of depression increases markedly in young girls, heavy menses may be diagnosed and treated differently ac- but not in boys. In addition to changing estradiol levels during cording to the cluster of symptoms and signs presented.28 the menopausal transition,23 cortisol levels rise during the late Moreover, taking a broader view of the phenomena reminds menopausal transition stage, tracking with the rise of estrogen us that the defining feature of healthy functioning is the ca- levels during the same stage.24 These relationships suggest the pacity to respond to unpredictable stimuli29 and that disease * 2012 The North American Menopause Society Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.
is an expression of loss of complexity in a highly ordered 12. Freeman E, Sammel M, Lin H, Nelson D. Associations of hormones and menopausal status with depressed mood in women with no history of dynamic state.30 The symptom patterns discussed here are depression. Arch Gen Psychiatry 2006;63:375-382.
thus likely to be local expressions of far-reaching global 13. Woods NF, Smith-DiJulio K, Percival DB, Tao EY, Mariella A, Mitchell ES. Depressed mood during the menopausal transition and early post-menopause: observations from the Seattle Midlife Women’s Health Study.
Menopause 2008;15:223-232.
Financial disclosure/conflicts of interest: None reported.
14. Bromberger JT, Schott LL, Matthews KA, et al. Association of past and recent major depression and menstrual characteristics in midlife: Study ofWomen’s Health Across the Nation. Menopause 2012;19:959-966.
15. Harris T. Disorders of menstruation. In: Brown GW, Harris TO, eds. Life Events and Illness. New York, NY: Guilford, 1989:261-294.
16. Allsworth JE, Zierler S, Krieger N, Harlow BL. Ovarian function in late reproductive years in relation to lifetime experiences of abuse. Epidemi- 17. Maciocia G. Obstetrics & Gynecology in Chinese Medicine, 1st ed. New York, NY: Churchill Livingstone; 1998.
18. Berga SL. Stress and ovarian function. Am J Sports Med 1996;24:S36-S37.
19. Santoro N, Brown JR, Adel T, Skurnick JH. Characterization of reproduc- 1. Woods NF, Mitchell ES, Lentz M. Premenstrual symptoms: delineating tive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab symptom clusters. J Womens Health (Larchmt) 1999;8:1053-1062.
2. Freeman EW, Halberstadt SM, Rickels K, Legler JM, Jin H, Sammel 20. Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L.
MD. Core symptoms that discriminate premenstrual syndrome. J Womens Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry 2004;61:62-70.
3. Endicott J, Amsterdam J, Eriksson E, et al. Is premenstrual dysphoric 21. Gibson CJ, Joffe H, Bromberger JT, et al. Mood symptoms after natural disorder a distinct clinical entity? J Womens Health (Larchmt) 1999;8: menopause and hysterectomy with and without bilateral oophorectomy among women in midlife. Obstet Gynecol 2012;119:935-941.
4. Woods NF, Lentz MJ, Mitchel ES, Heitkemper MM, Shaver J, Henker R.
22. Angold A, Costello EJ, Erkani A, Worthman CM. Pubertal changes in Ovarian steroids and premenstrual symptoms: a comparison of group hormone levels and depression in girls. Psychol Med 1999;29:1043-1053.
differences and intra-individual patterns. Res Nurs Health 2007;30: 23. Randolph J, Zheng H, Sowers MR, et al. Change in follicle-stimulating hormone and estradiol across the menopausal transition: effect of age at 5. Freeman EW, Frye CA, Rickels K, Martin PA, Smith SS. Allopreg- the final menstrual period. J Clin Endocrinol Metab 2011;96:746-754.
nanolone levels nand symptom improvement in severe premenstrual syn- 24. Woods NF, Smith-DiJulio K, Percival DB, Mitchell ES. Cortisol levels drome. J Clin Psychopharmacol 2002;22:516-520.
during the menopausal transition and early postmenopause: observa- 6. Woods N, Lentz M, Mitchell ES, Heitkemper M, Shaver J. PMS after 40: tions from the Seattle Midlife Women’s Health Study. Menopause 2009; persistence of a stress-related symptom pattern. Res Nurs Health 1997;20: 7. Freeman EW, Sammel MD, Rinaudo PJ, Sheng L. Premenstrual syn- 25. Matthews KA, Schott LL, Bromberger JT, Cyranowski JM, Everson-Rose drome as a predictor of menopausal symptoms. Obstet Gynecol 2004;103: SA, Sowers M. Are there bidirectional associations between depressive symptoms and C-reactive protein in midlife women? Brain Behav Immunol 8. Woods N, Lentz M, Mitchell E, Heitkemper M, Shaver J, Henker R.
Perceived stress, physiologic stress arousal, and premenstrual symptoms: 26. Mc Ewen BS. Physiology and neurobiology of stress and adaptation: group differences and intra-individual patterns. Res Nurs Health 1998;21: central role of the brain. Physiol Rev 2007;87:873-904.
27. Ahn AC, Tewari M, Poon C, Phillips RS. The clinical applications of a 9. Woods NF, Lentz MJ, Mitchell ES, Shaver J, Heitkemper M. Luteal systems approach. PLoS Med 2006;3:e209.
phase ovarian steroids, stress arousal, premenses perceived stress and pre- 28. Maciocia G. The Foundations of Chinese Medicine: A Comprehensive menstrual symptoms. Res Nurs Health 1998;21:129-142.
Text for Acupuncturists and Herbalists, 1st ed. New York, NY: Churchill 10. Woods NF, Mitchell ES, Lentz MJ. Social pathways to premenstrual symptoms. Res Nurs Health 1995;18:1-13.
29. Goldberger AL. Complex systems. Proc Am Thorac Soc 2006;3:467-472.
11. Bromberger JT, Schott LL, Kravitz HM, et al. Longitudinal change in 30. Varela M, Ruiz-Esteban R, de Juan MJM. Chaos, fractals, and our con- reproductive hormones and depressive symptoms across the menopausal cept of disease. Perspect Biol Med 2010;53:584-595.
transition; results from the Study of Women’s Health Across the Nation 31. Bell I, Koithan M. Models for the study of whole systems. Integr Cancer (SWAN). Arch Gen Psychiatry 2010;67:598-607.
Copyright 2012 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.

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