Mood and Menopause

Lorraine Dennerstein, MBBS, PhD, DPM, FRANZCP

Disclosures

April 14, 2004

Editorial Collaboration

Medscape &

There has been much controversy over the relationship between menopause and women's mental health. Earlier psychiatric terminology had a special term, "involutional melancholia," to refer to depression presenting in women in association with the menopausal years.[1] These midlife years also coincide with other stressors for women, including their children reaching the developmental stage of independence and leaving home, ill health of elderly parents, health problems for the spouse or for women themselves, confrontation with aging, and need to re-evaluate life expectations and goals, work stressors, and so on. As well, it was not clear whether chronologic aging predisposed women to depression.

Mood problems are known to be among the 3 most common problems reported to specialist menopause clinics.[2] They are also reported in association with other phases of exogenous and endogenous change in ovarian steroid hormones. The greatest sense of well-being has been found to occur during the follicular and ovulatory phases of the menstrual cycle.[3] The majority of reproductive-age women report that symptoms of tension and depression increase in the premenstruum.[4] Some of these women find the symptoms problematic enough to seek medical intervention.[4] A small minority of women (< 5%) in the peak reproductive phase experience severe cyclical premenstrual depression and meet criteria for premenstrual dysphoric disorder.[5] Depressive mood changes (and adverse effects on sexual functioning) are reported to be among the most frequent symptoms cited by women for ceasing the oral contraceptive pill.[6] Women presenting for treatment of mood complaints associated with the menstrual cycle are more likely to report adverse mood experience with oral contraceptives.[4] There has also been increasing concern about the high prevalence of minor and major depression in pregnancy and postnatally.[7] An association between premenstrual mood complaints and experience of postnatal depression has been reported,[7] and PMDD and lifetime experience of depression have been correlated.[4,5] Thus, these findings suggest a strong link between underlying ovarian steroid changes and depression.

The menopausal transition is characterized by underlying endocrine changes. Using annually collected hormone measures from participants in the Melbourne Women's Midlife Health Project, Burger and colleagues[8] have shown that follicle-stimulating hormone (FSH) levels begin to rise during the early menopausal transition. During this phase, estradiol levels are highly variable and may increase in some women. The rise in FSH seems to be driven by a decrease in the level of inhibin B[9] and, to some extent, estradiol.[9] Not all cycles will be ovulatory, and women report menstrual irregularity. The late menopausal transition (characterized by amenorrhea of 3 to 11 months' duration in the Melbourne study) coincides with the steepest decline in estradiol levels and a corresponding steep increase in FSH.[8] FSH levels stabilize at an elevated level during the early postmenopause, while estradiol levels stabilize at low levels during the same phase. Women's experience of bothersome hot flashes increases significantly during the late menopausal transition.[10] Bothersome hot flashes reach their highest frequency during the first 2 years after the final menstrual period and then slowly decline. Burger and colleagues[11] have also shown that total testosterone levels did not change with the menopausal transition or over 8 years of follow-up. However, the amount of bioavailable testosterone (free testosterone index [FTI]) increased as a result of a corresponding decrease in sex hormone-binding globulin.[11] Dehydroepiandrosterone sulphate (DHEAS) was not affected by the menopausal transition, but showed a steady decline with age.[11]

So how do mood problems associated with depressive symptoms or major depressive disorder relate to the endocrine changes of the menopausal transition? Or are the mood problems presented in clinics more likely to relate to chronologic aging, health problems, or the many other stressors listed above? Clinical experience is based on a small proportion of self-selecting women who may not be representative of most women's experience.[12]

A number of research methodologies are used to explore the relationship between depressive mood and menopause. Longitudinal population-based studies that include concomitant measures of mood, menstrual cycle frequency, and hormones are the most suited research methodologies to reveal what proportion of women will experience depression in relation to underlying endocrine changes and the menopausal transition. These rich sources of data can also be used to indicate the roles of hormonal change relative to aging, psychosocial factors, health and lifestyle factors, and to aid clinicians by highlighting risk factors for depression.

Findings concur that although the majority of women do not become depressed with the menopausal transition, some women may be vulnerable to depression.[13] Identifying which women are at risk for depression is important for clinicians, as these women may need extra support during the menopausal transition.[13]

Nancy Woods, PhD, and colleagues, from the University of Seattle,[14,15,16] presented findings from the population-based Seattle Healthy Women's Study. In 1990, 508 women were recruited and followed annually using the Center for Epidemiologic Studies Depression Scale (CES-D). Using cluster analysis modeling of intra-individual change, 9 different patterns were identified. The most prevalent pattern was of low scores over time (n = 79). Only 1 of the groups (n = 30) showed scores rising from low to high over time. Women with a history of sexual assault/abuse were over-represented among those who had chronic depressed mood (high CES-D scores) throughout the follow-up, confirming the association between sexual abuse and poor mental health. There was no overall indication of depression coinciding with a particular menopausal phase.[15,16]

Ellen Freeman, MD,[17,18] and colleagues from the University of Pennsylvania used random telephone dialing to find a population sample of women aged 35 to 45 for the Penn. Ovarian Aging Study. Healthy women (n = 436) who were experiencing regular menstrual cycles were enrolled in the study. Assessments were conducted every 8 months. Two blood samples for hormone estimations were taken at each assessment period (in the early follicular phases of women's cycles). These investigators used the CES-D to quantify depressed mood and clinical criteria for assessment of major depression. Dr. Freeman presented results from the first 5 years of the study.

The Penn. study (and the Seattle study) are among the few to evaluate women from the time of late reproductive stage as they transit into the menopause. Interestingly, these authors report that as women enter the early menopausal transition, CES-D scores increase even after adjusting for other factors. The risk for new depression was maximal in the early phase of the menopausal transition. The highest CES-D scores (high scores indicate increasing depressed mood) appeared to coincide with the late menopausal transition. However, as most of the sample had not reached their final menstrual period at the time of analysis, it may be premature for this study to yet determine pattern of change over the menopausal transition.

Dr. Freeman found that CES-D scores did not correlate in a linear way with estradiol levels, but there was a significant association using cubic or quadratic statistical methods. She interpreted this as indicating that depressed mood is linked to changes in estradiol rather than to actual level. Freeman reports that symptoms of depressed mood resolve as women age and as women become postmenopausal.[17,18] Earlier history of depression, and of premenstrual syndrome, significantly increased the risk of being diagnosed with major depressive disorder during the 5 years of the study. Other risk factors for the development of depression were poor sleep, lack of paid employment, and African-American ethnicity. Her findings thus corroborate earlier reports from the Melbourne Women's Midlife Health Project that depressed mood lessens as women pass through the transition and become postmenopausal and highlight the importance of premorbid depression and problematic premenstrual mood complaints as predictors of later depression.[13] The Melbourne study had reported that although depressed mood was not directly related to menopausal phase or hormone levels, women were more susceptible to becoming depressed in response to stressors occurring while they were in the menopausal transition.[13]

Peter Schmidt, MD, and David Rubinow, MD, from the National Institutes for Mental Health, presented an elegant series of studies that demonstrated that some women are rendered vulnerable to depression by the hormonal changes of the menopausal transition.[19] These co-investigators prospectively evaluated an asymptomatic group of 29 women, following each woman from premenopause until 6 to 12 months after her last menses for an average of 5 years. In the 24 months surrounding the final menstrual period, 9 episodes of depression occurred in 8 women, suggesting that this phase known to coincide with maximal hormonal change may represent a vulnerability phase for mood change for these women.[20] The investigators also conducted a double-blind, randomized, placebo-controlled trial of estradiol (50 micrograms [mcg]/day) in 34 perimenopausal women presenting with recent-onset minor or major depression coinciding with menstrual irregularity and increased gonadotropin levels. Depression was evaluated at baseline, 3 weeks, and 6 weeks into therapy. A beneficial effect of estradiol on mood was found both in women with and without hot flashes.[21] This study thus is the first to demonstrate the efficacy of estradiol in perimenopausal depression. An earlier randomized controlled trial had demonstrated that ethinyl estradiol 50 mcg/day could significantly improve depressed mood scores in surgically menopausal women, even after allowing for the effect of alleviation of hot flashes.[22]

In a separate study, Schmidt and Rubinow reported experimentally inducing hypogonadism in younger women with a GnRH agonist and then adding back estradiol or progesterone to produce physiologic levels similar to those of reproductive functioning.[19] Notably, the investigators failed to find any adverse effect on mood of the induced hypogonadism but did find adverse effect on sexual functioning (measured by the Derogatis Inventory of Sexual Functioning). This adverse effect on sexual functioning was not restored by estradiol alone, suggesting that other hormones such as testosterone (also produced by functioning ovaries) may need to be replaced to restore sexual functioning.

In the symposium "Sexuality of Menopausal Women," Dr. Jeanne Leventhal Alexander, MD, presented a comprehensive evidence-based review of double-blind, randomized, controlled trials of the effects of estradiol or testosterone on female sexual functioning in naturally or surgically menopausal women.[23] This literature review included only those studies that had a measure of sexual functioning, were randomized, had placebo or drug comparison, and included naturally or surgically menopausal women in their sample. Dr. Alexander described the various methodologic issues that influenced the interpretation of the trials. These included sample size, power, validity of measures, and assessment of endocrine aspects. The review[23] found evidence for positive effects of estradiol on general sexual functioning and specifically on sexual desire, enjoyment, arousal, orgasm, vaginal dryness and dyspareunia, and feelings of attractiveness. Additional incremental beneficial effects of testosterone to those of estradiol were found on frequency of sexual activity, satisfaction with frequency of sexual activity, pleasure with sexual activity, pleasure with masturbation, sexual desire, and general sexual functioning. These results indicate a role for estradiol for acquired female sexual dysfunction affecting naturally menopausal or surgically menopausal women. Testosterone may have an additional role for those postmenopausal women with demonstrated testosterone insufficiency who have not responded to estradiol alone or premenopausal women after hysterectomy or oophorectomy for whom estradiol replacement is not sufficient.

No discussion of possible benefits of hormones such as estrogen or testosterone would be relevant for clinicians without consideration of risks of their use. The Women's Health Initiative (WHI) study, carried out in an older sample of largely asymptomatic women (mean age = 63.3 years), utilized a randomized, double-blind, placebo design to assess the effects of continuous combined hormone therapy (conjugated equine estrogens 0.625 mcg/day and medroxyprogesterone acetate 2.5 mcg/day). The WHI trial was discontinued after a mean of 5.2 years of follow-up because of significant increase in coronary heart disease, stroke, pulmonary embolism, and breast cancer, while there was a significant reduction found for vasomotor symptoms, hip fractures, and bowel cancer.[24] A later report from the WHI Memory Study, an arm of WHI that assessed cognitive functioning, found a higher risk of probable dementia in those women taking the combined estrogen progestin therapy.[25] More recently, the arm of WHI in hysterectomized women, which entailed use of unopposed conjugated equine estrogens, was discontinued because of the increased risk of stroke, although there was apparently no significantly increased risk of breast cancer found in this study. The results of the WHI trial may not necessarily pertain to other forms of estrogen use or mode of administration, particularly when given to younger symptomatic women around the time of menopause. There has been less evaluation of the risks of use of testosterone in women.

Consequently, with our present state of knowledge, clinicians are advised to prescribe hormones only for short-term relief of symptoms (< 5 years). The research described above indicates that estradiol may modulate mood in some women, but with the attendant risks for prescription of estradiol and the likely doses needed to affect mood, antidepressants such as selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors remain the treatment of choice for major depressive disorder. Evidence is growing that estradiol, and possibly testosterone, may be useful in the management of female sexual dysfunction associated with the menopause. Both hormones are likely needed when sexual dysfunction occurs after bilateral oophorectomy. We await more information on the risks and benefits of these hormones from large randomized controlled trials of testosterone/estrogen therapy currently under way.

References
  1. Burrows GD, Dennerstein L. Depression and suicide in middle age. In: Howells JG, ed. Modern Perspectives in the Psychiatry of Middle Age. New York, NY: Brunner/Mazel; 1981:220 250.

  2. Sarrel P, Whitehead M. Sex and menopause: Defining the issues. Maturitas. 1985;7:217-224. Abstract

  3. Dennerstein L, Gotts G, Brown JB, Morse CA, Farley TMM, Pinol A. The relationship between the menstrual cycle and female sexual interest. Psychoneuroendocrinology. 1994;19:293-304. Abstract

  4. Dennerstein L, Morse CA, Varnavides K. Premenstrual tension and depression is there a relationship? J Psychosom Obstet Gynaecol. 1988;8:45 52.

  5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Washington, DC: APA Press; 1994. 715-718.

  6. Dennerstein L. Psychosexual effects of hormonal contraception. Gynaecology Forum. 1999;4,3:13-16.

  7. Dennerstein L, Lehert P, Riphagen F. Post partum depression risk factors. J Psychosom Obstet Gynaecol. 1989;10:53-67.

  8. Burger H, Dudley E, Hopper J, et al. Prospectively measured levels of serum FSH, estradiol and the dimeric inhibins during the menopausal transition in a population-based cohort of women. J Clin Endocrinol Metab. 1999:84;4025-4030. Abstract

  9. Burger HG, Cahir N, Robertson BM, et al. Serum inhibins A & B fall differentially as FSH rises in perimenopausal women. Clin Endocrinol. 1998;48:809-813.

  10. Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG. A prospective population-based study of menopausal symptoms. Obstet Gynecol. 2000;96:351-358. Abstract

  11. Burger HG, Dudley EC, Cui J, Dennerstein L, Hopper JL. A prospective longitudinal study of serum testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin levels through the menopause transition. J Clin Endocrinol Metab. 2000;85:2832-2838. Abstract

  12. Morse C, Smith A, Dennerstein L, Green A, Hopper J, Burger H. The treatment-seeking woman at menopause. Maturitas. 1994;18,3:161-173.

  13. Dennerstein L, Lehert P, Burger H, Dudley E. Mood and the menopausal transition. J Nerv Ment Dis. 1999;187:685-691. Abstract

  14. Woods NF, Mariella A, Mitchell ES. Depressed mood during the menopausal; transition and beyond. Program and abstracts from the 2nd World Congress of Women's Mental Health; March 7-10, 2004; Washington, DC. Abstract S19-3-024.

  15. Woods NF, Mariella A, Mitchell ES. Patterns of depressed mood across the menopausal transition: approaches to studying patterns in longitudinal data. Acta Obstet Gynecol Scand. 2002;81:623-632. Abstract

  16. Woods NF., Mitchell ES. Anticipating menopause. Observations from the Seattle Midlife Women's Health Study. Menopause. 1999;6:167-173. Abstract

  17. Freeman EW, Sammel MD, Liu L, Gracia CR, Nelson DB, Hollander L. Hormones and menopausal status as predictors of depression in women in transition to menopause. Arch Gen Psychiatry. 2004;61:62-70. Abstract

  18. Freeman EW, Sammel MD, Liu L, Nelson DB. Hormones and depression in the transition to menopause. Program and abstracts from the 2nd World Congress of Women's Mental Health; March 7-10, 2004; Washington, DC. Abstract S18-1-033.

  19. Schmidt PJ, Roca CA, Rubinow DR. Estradiol, the perimenopause and depression. Program and abstracts from the 2nd World Congress of Women's Mental Health; March 7-10, 2004; Washington, DC. Abstract S18-1-032.

  20. Schmidt PJ, Haq NA, Rubinow DR. A longitudinal evaluation of the relationship between reproductive status and mood in perimenopausal women. Am J Psychiatry; in press.

  21. Schmidt P, Nieman L, Danaceau MA, et al. Estrogen replacement in perimenopause-related depression: a preliminary report. Am J Obstet Gynecol. 2000;183:414-420. Abstract

  22. Dennerstein L, Burrows GD, Hyman G, Sharpe K. Hormone therapy and affect. Maturitas. 1979;1:247 259.

  23. Alexander JL, Kotz K, Dennerstein L, Davis S. What do the randomized control trials tell us about the treatment of libido in the symptomatic postmenopausal woman? Program and abstracts from the 2nd World Congress of Women's Mental Health; March 7-10, 2004; Washington, DC. S19-3-011.

  24. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288:321-333. Abstract

  25. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. JAMA. 2003;289:2651-2662. Abstract

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