Maturitas,
I (1979) 191-199 0 Elsevier/North-Holland Biomedical Press
LIFE STRESSES AND DEPRESSION
S. BALLINGER
191
IN THE MENOPAUSE
’, D. COBBIN 2, .I. KRIVANEK 2 and D. SAUNDERS 3
’ Department of Behavioural Sciences in Medicine, The University of Sydney, Sydney; 2 School of Behavioural Sciences, Macquarie University, Sydney; 3 Department of Obstetrics and G.ynaecology, The University of Sydney, Sydney, Australia (Received 19 September
1978, accepted 18 October 1978)
Research on the climacteric has largely concentrated on relationships between ovarian insufficiency, oestrogen deficiency, and climacteric symptoms. Little attention has been paid to those who have no symptoms. It is proposed, in addition to these relationships, that the life events of this period are significantly involved; and that resultant stress may contribute to oestrogen deficiency as opposed to physiologically normal postmenopausal oestrogen levels. In this preliminary study, two groups of women under conditions of relatively low stress and high stress were tested over a period of 15 mth. They were rated on the Hamilton Rating Scale for depression and anxiety and results were compared with the corresponding total urinary oestrogen output. The results, which suggest a significant relationship between stress related to depression and oestrogen levels in the menopause, are discussed and compared with differing life circumstances of the subjects.
INTRODUCTION
The postmenopause is increasingly defined in medical circles as a disease of oestrogen deficiency. Oestrogen levels are dramatically reduced, because adrenal, as well as ovarian function is decreased in the menopause [l]. Production of oestrogen is quite different from premenopausal production. After this time, neither ovaries nor adrenals secrete oestrogens directly. Instead a precursor, androstenedione, is secreted by the adrenals (and, to a lesser extent, the ovaries), and aromatized in peripheral fatty tissue to oestrone. This is the major oestrogen of the postmenopause [2-S]. The perimenopause is characterized by various symptoms - hot flushes, vaginal dryness, urethritis, depression, headaches, forgetfulness, anxiety, palpitations, insomnia, and many others - altogether loosely termed the “climacteric syndrome”. Recent informed medical concensus tends to attribute only hot flushes and vaginal atrophy to simple oestrogen deficiency, although there is concern about later manifestations that are apparently related to lack of oestrogen - particularly osteoporosis and ischaemic heart disease [ 61. Virtually all research on these symptoms has tacitly assumed a causal relationship between oestrogen deficiency and climacteric symptoms. However, Utian [7] reports Correspondence to: Susan Ballinger, Behavioural Sciences in Medicine, Blackburn Building, The University of Sydney, Sydney, Australia 2006.
192
there is virtually no published work relating specific symptoms to oestrogen level production or excretion. Much information on genesis and prevention of symptoms is derived from studies of treatment effects of oestrogens containing preparations. Little thought has been given to what constitutes an adequate physiological oestrogen level for non-reproductive women, or to the fact that many women suffer no symptoms except cessation of menses [8]. On the other hand, abundant research has shown the response to psychosocial stressors to be intricately involved in many diseases of Western civilization. Because stress is a complex phenomenon, research in the area is difficult, and the concepts. like those of the climacteric syndrome, are often nebulous. For this study, Selye’s [9] definition of stress is taken: a biological reaction to environmental pressures or stressors. Many women suffer increased environmental pressures around the time of the menopause. It symbolises the beginning of old age in a society where sexual desirability and social worth are strongly equated with youth, vitality and beauty. Major life changes occur at this time of life. The relief of losing the fear of conception, the joy of becoming a grandmother and the new freedom when children leave home, are balanced against a loss of former social role, loss of youth and, perhaps, tensions with a husband passing through a similar insecure stage of life. These changes in role and identity take place against a physiological background of sudden fluctuations in hormone levels. In this sense the perimenopause is analogous to puberty. Most symptoms which have been associated with the climacteric except hot flushes and vaginal dryness, are also symptoms of psychological duress [20]. Ballinger [lo,11 ] reports a number of studies showing that observed incidence of psychiatric morbidity may be positively correlated with the degree of climacteric symptomatic manifestation. Psychological stimuli have been shown to be the most potent of all stimuli affecting the pituitary adrenocortical system [12] and postmenopausal oestrogens have to a large extent an adrenal origin [ 131. It, therefore, seems reasonable to propose that an initiating factor of climacteric symptoms might be psychosocial stress. Interestingly, Keymolen et al. [3] found an unexpectedly low androstenedione production relative to cortisol in human adrenal cells in vitro; and Resko [ 141 found almost no androstenedione in the adrenal veins of rhesus monkeys under maximal endogenous ACTH production. This research suggests that when stress is great, oestrogen of adrenal origin drops to low levels. A new dimension to present knowledge of the enigma of the climacteric might, therefore, be gained by reversing the current medical model of ovarian insufficiency leading to symptoms. This study is based on a counter assumption that psychosocial stress plays a role in most climacteric symptoms, and also in oestrogen deficiency. A logical extension to this argument is that oestrogen levels produced from androstenedione, though lower than ovarian aestrogens, may be physiologically adequate for non-reproductive women. The women who fall into this category would tend to be those who experience relatively little environmental pressure during their peri- and postmenopause, and who tend not to present with symptoms. The aim of this preliminary study is to discover whether oestrogen levels are significantly lower in postmenopausal women under a great deal of psychosocial duress than in women of similar menopausal Status suffering relatively little such duress. Since differ-
ences in levels of endogenous oestrogens between “low-stressed” and “high-stressed” postmenopausal women have not been demonstrated to date, it is a necessary first step towards testing a postulated causal relationship between stress and oestrogen deficiency. A major problem was to define and discover two populations of postmenopausal women with as great a difference as possible between levels of stress. Anxiety and depression, both reactions to environmental stressors, were found by Ballinger [ 111 to be the most common psychological problems among menopausal women. Since time did not allow for the complexity of selective procedures necessary to distinguish differing severities of anxiety from a general population, it was decided for the purposes of this study to define the “high-stressed” population as women with a diagnosis of clinical depression. Stress and depression are not equated, but it is assumed that the syndrome of clinical depression contains a significant stress component; stressors being the environmental repercussions of suffering from a depressive disease, such as admission to a psychiatric unit and separation from the family. Normal distribution of the occurrence of the menopause falls mainly into a lo-yr span - from ti5-55 yr of age. Climacteric symptoms are broadly taken to be those which occur within a IO-yr span, before and after actual cessation of menses. Since the hypothesis of this study is concerned with oestrogen production following ovarian involution, subjects were chosen during the second half of this IO-yr period. Subjects (1) Ten women who were within 5 yr of the date of their last period, and who did not consider themselves to be suffering undue emotional stress. Their ages ranged from 4955 yr. (2) Ten female inpatients of a psychiatric clinic, all with a diagnosis of clinical depression. The mean criteria for diagnosis used by psychiatrists at the clinic were: depressed mood, guilt, insomnia, decreased productivity, and diurnal variation. Seven had had a natural menopause within the last 5 yr. Three had had hysterectomies but retained their ovaries. Each of the latter women had experienced hot flushes within the last 5 yr, which was taken as evidence of ovarian involution. The age range of this group was 47-55 yr. All subjects, therefore, were within 5 yr of the date of their last period, or evidence of cyclic ovarian secretion. None had taken any form of exogenous oestrogen for at least 2 yr prior to the onset of testing. All were parous. The mean body weight of the highstress group was 72.6 kg, and the low-stress group 59.3 kg. MATERIAL
AND METHOD
All subjects underwent 3 informal unstructured interviews at 3-monthly intervals. The first interview for the depressed group was held in the psychiatric clinic as soon as possible after admission. All other interviews excepting 1 readmission were held in the homes of the subjects. Wherever possible, 2 independent female raters interviewed the women. About 24 h prior to each interview the subjects were given 2000-ml plastic bottles for 24-h urine specimens. 10 ml of glacial acetic acid were added as a preservative. Interviews were held at some time during the 24-h urine collection.
194
At each interview, the subjects were rated on the Hamilton Rating Scale (HRS) for depression [ 151. This scale has been found a reliable and valid indicator of both severity of depressive symptoms and changes in depression over time [ 16,171, and since Carroll et al. [18] found the HRS capable of differentiating between psychiatric inpatients and patients in general practice, it was considered valid for women who were not clinically depressed. Of the 21 items in the HRS, 6 comprise a subscale for measuring anxiety. Urine samples were refrigerated for up to 48 h, then frozen to await assay. The J.B. Brown semi-automatic partitioning extractor model 2A was used to measure total urinary oestrogens fluorometrically [ 191. No drug has been encountered which interferes in the fluorometric method. The inter-assay variation, expressed as a mean ratio, is 1.22 k 0.3 1 (n = 199); and the intra-assay variation is 0.95 + 0.21 (n = 24) for non-pregnant women. The method is sensitive.enough to measure oestrogens in the range O-5 pg per 24 h with a mean ratio intra-assay variation of 0.72 [21]. RESULTS
Over the 3 interviews mean oestrogen values for the 2 groups are shown in Fig. 1. Comparable data for the HRS scores are shown in Fig. 2. A loge transformation was performed on the oestrogen data to meet the assumption of homogeneity of variance. No tranformation was required with the HRS data. The multivariate analysis of variance for the data shown in Fig. 1 is presented in Table 1. The results indicate that total urinary oestrogen levels were significantly lower TABLE I Analysis of variance for total urinary oestrogens. * Source
SS
DF
MS
F coeff
I (1979) 191-199 0 Elsevier/North-Holland Biomedical Press
LIFE STRESSES AND DEPRESSION
S. BALLINGER
191
IN THE MENOPAUSE
’, D. COBBIN 2, .I. KRIVANEK 2 and D. SAUNDERS 3
’ Department of Behavioural Sciences in Medicine, The University of Sydney, Sydney; 2 School of Behavioural Sciences, Macquarie University, Sydney; 3 Department of Obstetrics and G.ynaecology, The University of Sydney, Sydney, Australia (Received 19 September
1978, accepted 18 October 1978)
Research on the climacteric has largely concentrated on relationships between ovarian insufficiency, oestrogen deficiency, and climacteric symptoms. Little attention has been paid to those who have no symptoms. It is proposed, in addition to these relationships, that the life events of this period are significantly involved; and that resultant stress may contribute to oestrogen deficiency as opposed to physiologically normal postmenopausal oestrogen levels. In this preliminary study, two groups of women under conditions of relatively low stress and high stress were tested over a period of 15 mth. They were rated on the Hamilton Rating Scale for depression and anxiety and results were compared with the corresponding total urinary oestrogen output. The results, which suggest a significant relationship between stress related to depression and oestrogen levels in the menopause, are discussed and compared with differing life circumstances of the subjects.
INTRODUCTION
The postmenopause is increasingly defined in medical circles as a disease of oestrogen deficiency. Oestrogen levels are dramatically reduced, because adrenal, as well as ovarian function is decreased in the menopause [l]. Production of oestrogen is quite different from premenopausal production. After this time, neither ovaries nor adrenals secrete oestrogens directly. Instead a precursor, androstenedione, is secreted by the adrenals (and, to a lesser extent, the ovaries), and aromatized in peripheral fatty tissue to oestrone. This is the major oestrogen of the postmenopause [2-S]. The perimenopause is characterized by various symptoms - hot flushes, vaginal dryness, urethritis, depression, headaches, forgetfulness, anxiety, palpitations, insomnia, and many others - altogether loosely termed the “climacteric syndrome”. Recent informed medical concensus tends to attribute only hot flushes and vaginal atrophy to simple oestrogen deficiency, although there is concern about later manifestations that are apparently related to lack of oestrogen - particularly osteoporosis and ischaemic heart disease [ 61. Virtually all research on these symptoms has tacitly assumed a causal relationship between oestrogen deficiency and climacteric symptoms. However, Utian [7] reports Correspondence to: Susan Ballinger, Behavioural Sciences in Medicine, Blackburn Building, The University of Sydney, Sydney, Australia 2006.
192
there is virtually no published work relating specific symptoms to oestrogen level production or excretion. Much information on genesis and prevention of symptoms is derived from studies of treatment effects of oestrogens containing preparations. Little thought has been given to what constitutes an adequate physiological oestrogen level for non-reproductive women, or to the fact that many women suffer no symptoms except cessation of menses [8]. On the other hand, abundant research has shown the response to psychosocial stressors to be intricately involved in many diseases of Western civilization. Because stress is a complex phenomenon, research in the area is difficult, and the concepts. like those of the climacteric syndrome, are often nebulous. For this study, Selye’s [9] definition of stress is taken: a biological reaction to environmental pressures or stressors. Many women suffer increased environmental pressures around the time of the menopause. It symbolises the beginning of old age in a society where sexual desirability and social worth are strongly equated with youth, vitality and beauty. Major life changes occur at this time of life. The relief of losing the fear of conception, the joy of becoming a grandmother and the new freedom when children leave home, are balanced against a loss of former social role, loss of youth and, perhaps, tensions with a husband passing through a similar insecure stage of life. These changes in role and identity take place against a physiological background of sudden fluctuations in hormone levels. In this sense the perimenopause is analogous to puberty. Most symptoms which have been associated with the climacteric except hot flushes and vaginal dryness, are also symptoms of psychological duress [20]. Ballinger [lo,11 ] reports a number of studies showing that observed incidence of psychiatric morbidity may be positively correlated with the degree of climacteric symptomatic manifestation. Psychological stimuli have been shown to be the most potent of all stimuli affecting the pituitary adrenocortical system [12] and postmenopausal oestrogens have to a large extent an adrenal origin [ 131. It, therefore, seems reasonable to propose that an initiating factor of climacteric symptoms might be psychosocial stress. Interestingly, Keymolen et al. [3] found an unexpectedly low androstenedione production relative to cortisol in human adrenal cells in vitro; and Resko [ 141 found almost no androstenedione in the adrenal veins of rhesus monkeys under maximal endogenous ACTH production. This research suggests that when stress is great, oestrogen of adrenal origin drops to low levels. A new dimension to present knowledge of the enigma of the climacteric might, therefore, be gained by reversing the current medical model of ovarian insufficiency leading to symptoms. This study is based on a counter assumption that psychosocial stress plays a role in most climacteric symptoms, and also in oestrogen deficiency. A logical extension to this argument is that oestrogen levels produced from androstenedione, though lower than ovarian aestrogens, may be physiologically adequate for non-reproductive women. The women who fall into this category would tend to be those who experience relatively little environmental pressure during their peri- and postmenopause, and who tend not to present with symptoms. The aim of this preliminary study is to discover whether oestrogen levels are significantly lower in postmenopausal women under a great deal of psychosocial duress than in women of similar menopausal Status suffering relatively little such duress. Since differ-
ences in levels of endogenous oestrogens between “low-stressed” and “high-stressed” postmenopausal women have not been demonstrated to date, it is a necessary first step towards testing a postulated causal relationship between stress and oestrogen deficiency. A major problem was to define and discover two populations of postmenopausal women with as great a difference as possible between levels of stress. Anxiety and depression, both reactions to environmental stressors, were found by Ballinger [ 111 to be the most common psychological problems among menopausal women. Since time did not allow for the complexity of selective procedures necessary to distinguish differing severities of anxiety from a general population, it was decided for the purposes of this study to define the “high-stressed” population as women with a diagnosis of clinical depression. Stress and depression are not equated, but it is assumed that the syndrome of clinical depression contains a significant stress component; stressors being the environmental repercussions of suffering from a depressive disease, such as admission to a psychiatric unit and separation from the family. Normal distribution of the occurrence of the menopause falls mainly into a lo-yr span - from ti5-55 yr of age. Climacteric symptoms are broadly taken to be those which occur within a IO-yr span, before and after actual cessation of menses. Since the hypothesis of this study is concerned with oestrogen production following ovarian involution, subjects were chosen during the second half of this IO-yr period. Subjects (1) Ten women who were within 5 yr of the date of their last period, and who did not consider themselves to be suffering undue emotional stress. Their ages ranged from 4955 yr. (2) Ten female inpatients of a psychiatric clinic, all with a diagnosis of clinical depression. The mean criteria for diagnosis used by psychiatrists at the clinic were: depressed mood, guilt, insomnia, decreased productivity, and diurnal variation. Seven had had a natural menopause within the last 5 yr. Three had had hysterectomies but retained their ovaries. Each of the latter women had experienced hot flushes within the last 5 yr, which was taken as evidence of ovarian involution. The age range of this group was 47-55 yr. All subjects, therefore, were within 5 yr of the date of their last period, or evidence of cyclic ovarian secretion. None had taken any form of exogenous oestrogen for at least 2 yr prior to the onset of testing. All were parous. The mean body weight of the highstress group was 72.6 kg, and the low-stress group 59.3 kg. MATERIAL
AND METHOD
All subjects underwent 3 informal unstructured interviews at 3-monthly intervals. The first interview for the depressed group was held in the psychiatric clinic as soon as possible after admission. All other interviews excepting 1 readmission were held in the homes of the subjects. Wherever possible, 2 independent female raters interviewed the women. About 24 h prior to each interview the subjects were given 2000-ml plastic bottles for 24-h urine specimens. 10 ml of glacial acetic acid were added as a preservative. Interviews were held at some time during the 24-h urine collection.
194
At each interview, the subjects were rated on the Hamilton Rating Scale (HRS) for depression [ 151. This scale has been found a reliable and valid indicator of both severity of depressive symptoms and changes in depression over time [ 16,171, and since Carroll et al. [18] found the HRS capable of differentiating between psychiatric inpatients and patients in general practice, it was considered valid for women who were not clinically depressed. Of the 21 items in the HRS, 6 comprise a subscale for measuring anxiety. Urine samples were refrigerated for up to 48 h, then frozen to await assay. The J.B. Brown semi-automatic partitioning extractor model 2A was used to measure total urinary oestrogens fluorometrically [ 191. No drug has been encountered which interferes in the fluorometric method. The inter-assay variation, expressed as a mean ratio, is 1.22 k 0.3 1 (n = 199); and the intra-assay variation is 0.95 + 0.21 (n = 24) for non-pregnant women. The method is sensitive.enough to measure oestrogens in the range O-5 pg per 24 h with a mean ratio intra-assay variation of 0.72 [21]. RESULTS
Over the 3 interviews mean oestrogen values for the 2 groups are shown in Fig. 1. Comparable data for the HRS scores are shown in Fig. 2. A loge transformation was performed on the oestrogen data to meet the assumption of homogeneity of variance. No tranformation was required with the HRS data. The multivariate analysis of variance for the data shown in Fig. 1 is presented in Table 1. The results indicate that total urinary oestrogen levels were significantly lower TABLE I Analysis of variance for total urinary oestrogens. * Source
SS
DF
MS
F coeff
