Menopause is not associated with increased psychiatric major morbidity, but some women experience psychological symptoms during perimenopause. Patient education, particularly instruction regarding the relationship between the brain and endocrine levels, is important. The clinical research does not consistently support the use of estrogen replacement to treat mood disorders.
Though menopause is not a time when women are at high risk of psychiatric illness, it may be a time of high psychological stress, and changes in hormone levels certainly play a role.
The menopause marks a major life transition for women, an end to the childbearing years and the cessation of the menses. For some it can be an ill-defined concept associated with fear, loss, and sinister connotations, while for others it can be a welcome end to menstruation and the fear of unwanted pregnancy. Many premenopausal women have concerns that they will experience mental instability, sudden signs of aging, and diminution of sexuality at this time.
Unfortunately, the menopause is also an ill-defined concept for many medical practitioners. The World Health Organization defines menopause as the cessation of the menses for 1 year. This definition is far removed from what most women are talking about when they refer to the symptoms of menopause, or “going through menopause.”
In fact, the term perimenopause, which is the time beginning immediately before the cessation of the menses and ending when the menses have been absent for 1 year, may be a more useful concept both for women and their practitioners. However, even many years before this stage, subtle changes in the female reproductive cycle may be noticeable. This is suggested by factors such as declining fertility with increasing maternal age, shortening of the follicular phase of the menstrual cycle, long cycles, and change in the pattern of menstrual bleeding. Although these normal changes may not be detectable by blood hormone measurements, they may be worrying for some women and warrant information sharing and explanation. Women are more likely to experience mood and anxiety symptoms during the years preceding the cessation of the menses than they are after menstruation has ceased.[2,3]
Large epidemiological studies have shown that the years usually associated with natural menopause, that is, 45 to 55, are not associated with increased psychiatric morbidity or more utilization of health services by women.[4-7] Women who used health services extensively before age 45 continue to do so between age 45 and 55.
The authors of several studies of smaller or more specific populations have suggested that certain individuals may be at greater risk of psychiatric morbidity during the perimenopausal years. There was a trend for increased risk for psychiatric morbidity in women who experience early menopause or surgical menopause. One study has shown high levels of psychiatric morbidity in women attending a menopause clinic. This group includes women who have a history of mood disorder, women who have had severe premenstrual mood instability and have met criteria for premenstrual dysphoric disorder, and women who have experienced psychiatric morbidity associated with other reproductive life events such as postpartum depression. However, even in this group the risk of an episode of major psychiatric illness associated with menopause is not high.
The fact that there does not appear to be an increased risk of major psychiatric disorder associated with menopause in large epidemiological studies does not rule out the possibility of mood, anxiety, and cognitive symptoms occurring. While these symptoms may not meet criteria for a major psychiatric disorder, either because of the timing of the symptoms (which may wax and wane) or because they consist of several isolated symptoms, they are still worrisome. Mood and cognitive disturbances common during perimenopause include mood swings, irritability, fatigue, a subjective sense of loss of memory, difficulty with word retrieval, decreased concentration, and decreased libido. These symptoms often occur in the absence of physical symptoms such as hot flushes (also referred to as “hot flashes”) or vaginal dryness. Women experiencing hot flushes may have restless sleep with night sweats, which will tend to worsen mood and cognitive symptoms. Women who have suffered from premenstrual dysphoric disorder often experience a worsening of their symptoms, with an increase in both the duration of the symptomatic time and an increase in symptom intensity. These changes may start as early as the late 30s, and are sometimes accompanied by night sweats and hot flushes, particularly in the luteal phase of the cycle. Hormone changes, including follicle-stimulating hormone level elevation, will usually not be detected in a woman with regular cycles despite these symptoms.
When addressing the issue of premenstrual symptoms with a patient, an explanation of the interaction between hormones and neurotransmitters is helpful. In particular, women need to know that their problems are not caused merely by ovarian dysfunction but by complex interactions between the higher centres of the brain, the hypothalamus, the pituitary, and the ovary, and the possible effects of circulating hormones on brain receptors.
The perimenopause is a time of increased hormonal instability. As ovarian function declines, hormone levels fluctuate, with occasional anovulatory cycles leading to temporarily high estrogen levels and related swings in the levels of luteinizing hormone and follicle-stimulating hormone. Eventually the hormone levels will decline, leading to the cessation of the menstrual cycle.
Female reproductive hormones do exert some effect on the brain neurotransmitter systems, particularly the serotonin and gamma amino butyric acid systems. The exact mechanisms are poorly understood and most studies have been done with animals. Estrogen has been reported to modulate serotonin, to increase tritiated imipramine binding in platelets, to increase serotonin presynaptic reuptake, modulate norepinephrine levels, decrease monoamine oxidase levels, affect dopamine turnover, increase brain excitability, affect endorphin levels, and possibly interact with gamma amino butyric acid. Progesterone has been reported to increase monoamine oxidase levels. In high doses, progesterone has an anesthetic effect and may decrease brain excitability by an interaction with the gamma amino butyric acid system.
Though these complex interactions presently have limited clinical application, it is important to realize that hormones are psychoactive, so it is possible that fluctuating hormone levels may cause women to experience subtle mood and cognitive changes. The greater frequency of symptoms during the years prior to the end of the menses and the reduction of symptoms once menopause has occurred suggest that emotional symptoms are related to changing hormone levels rather than low hormone levels. It is unclear why some women are more affected than others.
In North American culture, aging is regarded as abhorrent and something to be resisted with heroic efforts, including cosmetics, hair dyes, stringent diets, and even cosmetic surgery. In a culture whose female icons are still chosen largely for their appearance, menopause comes as an unwelcome marker of advancing years. In societies where aging is revered and brings an increase in status, menopausal symptoms may be less problematic.
A number of major life stressors frequently confront women during the years leading up to menopause. These include caring for aging or infirm parents and/or teenage children still at home, watching children leave home, juggling work and family responsibilities, dealing with financial concerns regarding retirement, and coping with other health issues. For some women these years may be seen as the last chance for a pregnancy. Women who have suffered from infertility or experienced perinatal loss may re-experience feelings of grief. At a time when women are dealing with changes in their bodies, and possibly hormone-induced emotional changes, they are also likely to be dealing with a large number of external stressors.
Since mild emotional symptoms occur in many women during the perimenopausal years, it is important to establish whether the symptoms are of sufficient severity and duration to constitute major depression, generalized anxiety disorder, or panic disorder. Worsening symptoms of premenstrual dysphoric disorder may be misdiagnosed as bipolar mood disorder. Asking the patient to keep a daily diary recording her symptoms and their severity may help with diagnostic clarification, and may have a mild therapeutic effect as the woman is able to regard her symptoms more objectively.
The data on the use of hormones for the treatment of mood symptoms are confusing and inconsistent. Most studies examining the therapeutic effect of estrogen have focused on depressive symptoms rather than on a clinical diagnosis of major depression. A recent meta-analysis of 26 studies on the effects of hormone replacement therapies (particularly estrogen) on mood found that estrogen, androgen, or estrogen and androgen in combination were effective in reducing depressive mood among nonclinically depressed perimenopausal and menopausal women. Progesterone had a much smaller effect, and when combined with estrogen reduced the positive effects of the estrogen. The most robust effect was noted with androgen, either alone or in combination with estrogen. Because different preparations of hormones and different dosages were used in different studies, it is not clear which, if any, is the most effective hormone preparation, in what dose it should be given, or how long it needs to be given to achieve positive effects on mood.
It is possible that hormone replacement may have a beneficial effect on mood by lessening the vasomotor symptoms of the menopausal years, thus improving sleep and overall well-being. An association between depressive symptoms and hot flushes was observed in an American study of 426 premenopausal and perimenopausal women, though this contradicts an earlier study from Sweden.
More recently a large double-blind study comparing placebo, estrogen only, and estrogen and progestin administered cyclically or continuously failed to show a significant difference between any of the groups on symptoms of anxiety, cognition, or affect.
Estrogen alone does not have a sufficient antidepressant effect to treat a major clinical depression. However, a recent study of depressed elderly women showed greater improvement in the group treated with estrogen replacement and the selective serotonin reuptake inhibitor fluoxetine than in the groups treated with estrogen alone or placebo. The authors suggest that estrogen may augment the antidepressant effect of fluoxetine in depressed elderly women. At present this must still be considered a topic for further research.
The effect of estrogen on memory and cognition has recently been a focus of interest. It has been suggested that postmenopausal women on estrogen replacement perform better on tests of cognitive skill than women not on estrogen replacement. Several studies[20,21] suggest that estrogen has a protective effect against the development of dementia. There is also one study showing that estrogen enhances memory in women with Alzheimer’s disease, although recent findings have not supported this.
In summary, there is currently little research to support the use of hormones in treating the mood symptoms of menopause, except for the secondary benefits that may occur as a result of improvement in vasomotor symptoms and the possibly related improvement in sleep. The effects of estrogen on cognition in menopausal women needs further study.
Major psychiatric disorders such as depression or panic disorder must be treated with the appropriate psychotropic medication. Many mood disorders related to reproductive life events in women respond well to treatment with selective serotonin reuptake inhibitors. It has been suggested that antidepressants may also lessen hot flushes, and a recent study has shown that the selective serotonin and noradrenaline reuptake inhibitor venlafaxine significantly reduced hot flushes in women with a history of breast cancer or fear of developing breast cancer.
Many women will attribute psychological symptoms to menopause. Clinicians must be aware that the woman’s distress is real, and take a careful history that includes life stressors, history of psychiatric illness, and family history of psychiatric illness. It is not helpful to order a follicle-stimulating hormone level then triumphantly announce to the woman that she is not in menopause, since her symptoms are more likely to occur in the years preceding menopause anyway.
The importance of a supportive approach and careful explanation of the brain’s role in menopause cannot be overemphasized and will facilitate compliance with antidepressant medication if it is required.
Menopause is not a time of high risk for psychiatric illness, but may be a time of psychological stress for women. Some women will experience psychological symptoms during the perimenopausal years. The relationship between mood and female hormone changes is poorly understood. Patient education and support is important, particularly instruction that explains the relationship between the brain and endocrine events. The use of estrogen replacement to treat disturbances of mood is not consistently supported by clinical research. As with major psychiatric illness at any stage in life, psychiatric illness during menopause must be treated with appropriate psychotherapy and psychotropic medication.
2. McKinlay SM, Brambilla DJ, Posner JG, et al. The normal menopause transition. Maturitas 1992;14:103-115. PubMed Abstract
3. Stewart DE, Boydell K, Derzko C, et al. Psychologic distress during the menopausal years in women attending a menopause clinic. Int J Psychiatry Med 1992;22:213-220. PubMed Abstract
4. Hallstrom T, Samuelson S. Mental health in the climacteric: The longitudinal study of women in Gothenburg. Acta Obstet Gynecol Scand 1985;13:130-135. PubMed Abstract
5. Kaufert PA. A health and social profile of the menopausal woman. Exp Gerontol 1994;29:343-350. PubMed Abstract
7. McKinlay JB, McKinlay SM, Brambilla D, et al. The relative contributions of endocrine changes and social circumstances to depression in mid-aged women. J Health Soc Behav 1987; 28:345-363. PubMed Citation
8. Hay AG, Bancroft J, Johnstone EC, et al. Affective symptoms in women attending a menopause clinic. Br J Psychiatry 1994;164:513-516. PubMed Abstract
9. Stewart DE, Boydell K. Psychologic distress during menopause: Associations across the reproductive life cycle. Int J Psychiatry Med 1993;23:157-162. PubMed Abstract
12. Pearlstein TB. Hormones and depression: What are the facts about premenstrual syndrome, menopause, and hormone replacement therapy? Am J Obstet Gynecol 1995;173:646-653. PubMed Abstract
14. Zweifel JE, O’ Brien WH. A meta-analysis of the effect of hormone replacement therapy upon depressed mood. Psychoneuroendocrinology 1997;22:189-212. PubMed Abstract
15. Avis NE, Brambilla D, McKinlay SM, et al. A longitudinal analysis of the association between menopause and depression. Results from the Massachusetts Women’s Health Study. Ann Epidemiol 1994;4:214-220. PubMed Abstract
16. Furuhjelm M, Karlgren E, Carlstrom K. The effect of estrogen therapy on somatic and psychical symptoms in postmenopausal women. Acta Obstet Scand Gynecol 1984;63:655-661. PubMed Abstract
17. Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: Results from the Postmenopausal Estrogen/ progestin Interventions Trial. Obstet Gynecol 1998;92:982-988. PubMed Abstract
18. Schneider LS, Small GW, Hamilton SH, et al. Estrogen replacement and response to fluoxetine in a multicenter geriatric depression trial. Fluoxetine collaborative study group. Am J Geriatr Psychiatry 1997;5:97-106. PubMed Abstract
19. Wickelgren I. Estrogen stakes claim to cognition. Science 1997;276:675-678. PubMed Citation
20. Tang MX, Jacobs D, Stern Y, et al. Effect of estrogen during menopause on risk and age at onset of Alzheimer’s disease. Lancet 1996;348:429-432. PubMed Abstract
21. Paganini-Hill A, Henderson VW. Estrogen replacement therapy and risk of Alzheimer’s disease. Arch Intern Med 1996;156:2213-2217. PubMed Abstract
22. Henderson VW, Watt L, Buckwater JG, et al. Cognitive skills associated with estrogen replacement in women with Alzheimer’s disease. Psychoneuroendocrinology 1996;21:421-430. PubMed Abstract
23. Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: A randomized controlled trial. JAMA 2000;283:1007-1015. PubMed Abstract
24. Loprinzi CL, Kugler JW, Sloan JA, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: A randomized controlled trial. Lancet 2000;356:2059-2063. PubMed Abstract
Diana M. Carter, MB, CRCPC
Dr Carter is an associate clinical professor in the Department of Psychiatry, University of British Columbia, and consultant psychiatrist for the Reproductive Mental Health Program at BC’s Children’s Hospital and Women’s Health Care Centre and St. Paul’s Hospital.
Above is the information needed to cite this article in your paper or presentation. The International Committee
of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally
accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.
About the ICMJE and citation styles
The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.
An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.
BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:
- Only the first three authors are listed, followed by "et al."
- There is no period after the journal name.
- Page numbers are not abbreviated.
For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org