Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison*

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1 FERTILITY AND STERILITY Vol. 60, No.3, September The American Fertility Society Printed on acid-free paper in U. S. A. Cognitive and psychiatric correlates of functional hypothalamic amenorrhea: a controlled comparison* Donna E. Giles, Ph.D.t:!: Sarah L. Berga, M.D.t University of Pittsburgh, Pittsburgh, Pennsylvania Objective: To assess the association of cognitive function, emotional, and psychiatric history in women with functional hypothalamic amenorrhea compared with amenorrheic and eumenorrheic controls. Design: Each subject was medically evaluated for origin of amenorrhea or to establish eumenorrhea. Subjects completed a structured psychiatric interview and self-report questionnaires. Setting: Patients were recruited from a large reproductive endocrinology practice within a tertiary referral center. Patients/Participants: Consecutive patients who were eligible for the study were invited to participate. Eumenorrheic controls were recruited to match women with functional hypothalamic amenorrhea by age, sex, weight, and season. Main Outcome Measures: Cognitive measures assessed expectation of control, perfectionism, rigidity of ideas and concern about judgments of others (dysfunctional attitudes), coping ability, interpersonal and achievement functioning, and interpersonal dependence. Measures of mood and symptoms included both clinical and self-report scales. Psychiatric diagnoses were determined using Research Diagnostic Criteria and DSM Ill-R. Results: Women with functional hypothalamic amenorrhea endorsed more dysfunctional attitudes, had greater difficulty in coping with daily stresses, and tended to endorse greater interpersonal dependence than eumenorrheic women. Women with organic amenorrhea were statistically not different from either group but tended to report less dysfunctional attitudes and interpersonal dependence, although they displayed comparable difficulty in coping, compared with functional hypothalamic amenorrhea women. Women with functional hypothalamic amenorrhea more often had a history of psychiatric disorders, primarily mood disorders, than eumenorrheic women but were not different from women with organic amenorrhea. Conclusion: Women with functional hypothalamic amenorrhea showed increased cognitive dysfunction and psychiatric morbidity. Fertil Steril 1993;60: Key Words: Functional hypothalamic amenorrhea, amenorrhea, psychology, mood disorders, psychiatric illness Received December 21, 1992; revised and accepted May 11, * Supported in part by a grant to S.L.B. from the Magee-Women's Hospital Research Fund, Pittsburgh, Pennsylvania. t Department of Psychiatry. :I: Reprint requests: Donna E. Giles, Ph.D., Department ofpsychiatry, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, Pennsylvania Department of Obstetrics, Gynecology, and Reproductive Sciences. Women with functional hypothalamic amenorrhea typically do not present with obvious psychopathology (1). Yet direct examination reveals evidence of emotional, cognitive, or behavioral perturbations. For example, suppressed anxiety, heightened energy and activity, nonpathological compulsive characteristics, and idiosyncratic eating habits have been observed (2). Indeed, careful interviewing of a small series of normal weight women hospitalized for amenorrhea (n = 16) revealed that 31 % met criteria for major depression and 19% for generalized anxiety disorder (3). Although it is generally accepted that the proximate cause underlying functional hypothalamic 486 Giles and Berga Correlates of functional hypothalamic amenorrhea Fertility and Sterility

2 amenorrhea is reduced GnRH release (4, 5), mechanisms involved in initiation and maintenance of functional hypothalamic amenorrhea are poorly understood. External and intrapersonal stresses have been associated with functional hypothalamic amenorrhea (1, 2, 6, 7,8), and a biochemical correlate of stress, elevated 24-hour cortisol levels, has been documented (9-11). Cognitive, emotional, behavioral, and psychiatric precursors to functional hypothalamic amenorrhea that are consistent with a stress-arousal response have been suggested, but comparisons with appropriate control groups are not currently available. To assess the relative roles of cognitive function, emotional and psychiatric history in women with functional hypothalamic amenorrhea, we have controlled for cessation of menses and reduced estrogen and P concentrations by comparing women with functional hypothalamic amenorrhea with those with an organic form of amenorrhea. We have also included eumenorrheic women as a second control group. Our hypotheses were that cognitive and emotional differences, as well as differences in psychiatric history, would occur between women with functional hypothalamic amenorrhea and women with a clear organic origin to their amenorrhea, as well as between functional hypothalamic amenorrhea and eumenorrheic women. Data in this report were obtained as part of an investigation involving a 48-hour study of neuroendocrine parameters. Only the psychiatric and psychological data will be described in detail here. Subjects MATERIALS AND METHODS A total of 23 women participated in this study: 9 with functional hypothalamic amenorrhea, 6 with an organic form of amenorrhea, and 8 who were eumenorrheic. All women were interviewed regarding reproductive status, number of pregnancies and births, history of use of exogenous hormones, and history of menstrual cycle patterns. Only women between the ages of 18 and 39 years were included in this study. Exclusion criteria were the following: concurrent medical or neurological disease; > 10 hours of exercise per week; running> 10 miles per week; and a lifetime history of eating disorders. Both women with functional hypothalamic amen- 0rrhea and women with an organic form of amenorrhea presented with a chief complaint of amenorrhea. The diagnosis of functional hypothalamic amenorrhea was established by excluding organic etiologies, i.e., hyperprolactinemia, thyroid and adrenal disease, premature ovarian failure, panhypopituitarism, hyperandrogenic anovulation, and diabetes (12). Women with functional hypothalamic amenorrhea were also required to be within 90% to 110% of ideal body weight (IBW). The mean ± SE LH pulse frequency of women with functional hypothalamic amenorrhea was significantly less than that of the eumenorrheic group: 7.2 ± 2.6 versus 13.5 ± 0.9, respectively (t 16 = 3.20, P = 0.006). The organic causes of amenorrhea for women included PRL-secreting pituitary microadrenoma (n = 4), isolated gonadotropin deficiency with anosmia (n = 1), and hyperandrogenic anovulation (n = 1). Eumenorrheic women were age- and seasonmatched to the functional hypothalamic amenorrhea group and were within 90% to 110% of IBW. To be considered eumenorrheic, women were required to have a history of menstrual cycle intervals of 27 to 31 days. Midluteal P level was required to be >25 nmoljl in a cycle preceding the study and during the menstrual cycle in which the data were obtained. The mean midluteal P level in the cycle under study was 38.0 ± 3.3 nmoljl. Procedures All subjects were interviewed using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) (13) to ascertain lifetime history of psychiatric disorder. The SADS-L is a structured diagnostic interview designed to provide current and lifetime diagnoses based on Research Diagnostic Criteria (14) and DSM Ill-R. It has been used extensively in clinical psychiatric research. This instrument assesses major psychiatric syndromes including major and minor depression, mania and hypomania, schizophrenia, panic disorder, phobic disorder, generalized anxiety disorder, somatization disorder, obsessive compulsive disorder, alcohol and substance abuse, psychosis, and antisocial personality disorder. Lifetime history of eating disorders was also explicitly assessed. The interview was supplemented by detailed questions regarding onset and offset of psychiatric disorders relative to menstrual dysfunction, weight loss and weight gain, and exercise history. Measures designed to refine our understanding of relevant cognitions, coping strategies, interpersonal dependence and mood were administered and included the following: Dysfunctional Attitude Scale. The 40-item Vol. 60, No.3, September 1993 Giles and Berga Correlates of functional hypothalamic amenorrhea 487

3 Dysfunctional Attitude Scale (15) measures cognitive domains related to expectation of control, perfectionistic performance standards, belief in the likelihood of a desired outcome, rigid ideas about events that should occur, and concern about the judgments of others. Each item is rated on a 7 -point scale anchored by "totally agree" through "neutral" to "totally disagree". Scores range from 40 to 280. Higher scores indicate more dysfunctional beliefs. Self-Control Scale. The 36-item Self-Control Scale (16) assesses learned resourcefulness or ability to cope. There are four dimensions: cognitive strategies, problem solving, delay of gratification, and self-efficacy expectations. Each item is rated on a 6-point scale indicating the extent to which the item is characteristic of personal behavior. Lower scores indicate greater difficulty coping. Sociotroph Autonomy Scale. The 60-item Sociotroph Autonomy Scale (17) measures cognitive domains of interpersonal and achievement functioning. The 30 items in the Sociotroph scale reflect concern with disapproval by others and efforts to secure attachment to others. The 30 items in the Autonomy scale reflect achievement orientation, concern with the possibility of personal failure, and maximization of control over the environment. All items are scored on a 5-point scale defined by the percentage of time that the statement applies to the subject: 0%, 25%, 50%, 75%, 100%. Higher scores indicate greater presence of the trait. Personal Attitude Survey. The 48-item Personal Attitude Survey (18) is designed to measure interpersonal dependency, a complex of thoughts, beliefs, feelings, and behaviors that revolve around the need to associate closely with, interact with, and rely on valued other people. Three domains of interpersonal dependency are assessed: emotional reliance on others, social self-confidence, and autonomy. A 4-point scale is rated, varying from "not characteristic of me" (1) to "very characteristic of me" (4). Higher scores indicate greater presence of the characteristic. Hamilton Rating Scale for Depression. The Hamilton Rating Scale for Depression (19) is the preeminent clinical rating scale for assessing depressive severity. Traditionally, the first 17 of 24 items are used in the tabulation of symptom frequency and severity. Items relate to mood, self-reproach, sleep disturbance, psychomotor activity, somatic and psychological anxiety, loss of interest, loss of appetite, decreased libido, loss of insight, and hypochondriacal concerns. Scores of 7 or less are considered to be within normal limits, and scores of 14 or greater reflect clinically significant depression. Beck Depression Inventory. The Beck Depression Inventory (20) is considered the standard in self-report measures of depression. There are 21 items consisting of graded statements with scores ranging from 0 to 3. Six items relate to vegetative symptoms, and 15 relate to cognitions and mood. Scores of 10 or higher indicate clinically significant depression. Data Analysis To accommodate the diversity of cognitive and mood domains assessed, multivariate analyses of variance were used to test for differences among domains using group as the major factor. The statistic to determine significance was Roy's Greatest Root. Identified domains were cognitive content (Dysfunctional Attitude Scale and Self-Control Scale) and interpersonal dependence (Sociotroph Autonomy Scale and Personal Attitude Survey). Mood and symptoms (Hamilton Rating Scale for Depression and Beck Depression Inventory) were assessed using univariate analysis of variance procedures. Duncan's post hoc tests were used to test for differences when the F ratio after the multivariate test was statistically significant. To assess psychiatric history, we tabulated the frequency of psychiatric disorder by group. In view of the small sample size, we calculated relative risk estimates of psychiatric illness between groups. RESULTS Demographic and Clinical Data Demographic and clinical data for women with functional hypothalamic amenorrhea, organic amenorrhea, and eumenorrhea are presented in Table 1. There were no differences in age (F[2, 22] = 2.06, P = 0.15), height (F[2, 22] = 1.18, P = 0.33), or education (F[2, 22] = 0.58, P = 0.57) among the groups. There were significant group differences in weight (F[2, 22] = 10.13, P = ). Duncan's post hoc test revealed that women with organic amenorrhea weighed significantly more than women with functional hypothalamic amenorrhea and eumenorrheic women. There were no differences between functional hypothalamic amenorrhea and eumenorrheic women. Exercise and Diet History Among women with functional hypothalamic amenorrhea, seven of nine reported regular weekly 488 Giles and Berga Correlates of functional hypothalamic amenorrhea Fertility and Sterility

4 Table 1 Sample Description* Functional hypothalamic Organic amenorrhea amenorrhea Eumenorrhea (n = 9) (n = 6) (n = 8) Probability Age (y) 27.8 ± ± ± Height (in) 63.2 ± ± ± Weight (lb) ± ± ± Education (y) 15.2 ± ± ± * Values are means ± SD. exercise. The mean ± SD amount of exercise was 5.1 ± 1.7 hours per week (range, 2.5 to 7.5 h/wk). Type of exercise ranged from aerobic (no more than 4 h/wk) to isotonic exercise such as working with resistance-based exercise equipment. Five of 9 women reported weight loss within a year of disturbed menstrual function, varying from mild (e.g., 2.7 to 4.5 kg) to gradual weight loss of 11 kg. This 11-kg weight loss occurred in one subject only; she she maintained 90% to 110% IBW throughout. All women were within 90% to 110% IBW body weight before and after weight loss. Two of six women in the organic amenorrhea group reported regular exercise (mean, 6.0 ± 2.1 h/ wk). Another two reported only incidental exercise, and two reported no regular exercise. One organic amenorrhea patient reported menstrual irregularities concurrent with exercise of 8 h/wk 2 years before her diagnosis of organic amenorrhea. One of eight normal control subjects reported regular exercise of approximately 1.5 h/wk. No other normal control women reported regular exercise and all reported stable weight for at least 3 years. Psychological, Mood, and Symptom Measures Summary of the scale scores for cognitive content, interpersonal dependence, mood and symptom measures in the three groups are presented in Table 2. The multivariate F ratio associated with cognitive content (Dysfunctional Attitude Scale [DAS] and Self-Control Scale [SCS]) was statistically significant in the three groups (F[2, 20] = 5.28, P = 0.028). Univariate tests indicated that DAS scores (F[2, 22] = 4.33, P = 0.027) discriminated among the groups, with a trend for differences in SCS scores (F[2, 22] = 3.15, P = 0.065). The pattern of these discriminations varied with the scale. Women with functional hypothalamic amenorrhea endorsed more dysfunctional attitudes than eu- menorrheic women; women with organic amenorrhea were not different from either group. In contrast, functional hypothalamic amenorrhea women tended to report less ability to cope than eumenorrheic women but were not different from women with organic amenorrhea. Women with organic amenorrhea tended also to report less ability to cope than eumenorrheic women. The multivariate comparison associated with scales measuring interpersonal dependence (Sociotroph Autonomy Scale and Personal Attitude Survey) was not significant at the traditional probability level (F[5, 17] = 2.21, P = 0.10). Evaluation of univariate effects indicated that to the extent that differences were suggested, they were due to elevated scores on the Sociotroph subscale for the functional hypothalamic amenorrhea group. This suggests that these women reported greater concern with disapproval by others and greater efforts to secure attachments than either comparison group (F[2, 22] = 2.53, P = 0.11). Presence of current mood disturbances or psychiatric symptoms (Hamilton Rating Scale for Depression and Beck Depression Inventory) were not different among the three groups. Univariate analyses indicated that clinically rated mood and symptoms (Hamilton Rating Scale for Depression) did not discriminate among the groups (P = 0.18), but that self-report of mood and symptoms (Beck Depression Inventory) suggested greater distress in amenorrheic women (P = 0.08). None of these mean scores were in the clinically significant range. Two of nine functional hypothalamic amenorrhea women had Hamilton Rating Scale for Depression scores> 7, and 3 had Beck Depression Inventory scores > 10. These scores are outside the normal range. One of six women with organic amenorrhea had an Hamilton Rating Scale for Depression score greater than 7, and 3 had Beck Depression Inventory scores > 10. None of the normal control women had Hamilton Rating Scale for Depression Vol. 60, No.3, September 1993 Giles and Berga Correlates of functional hypothalamic amenorrhea 489

5 Table 2 Psychological, Mood, and Symptom Measures* Cognitive content Dysfunctional attitudes Coping ability (SeS) Interpersonal dependence Sociotrophy Autonomy Emotional reliance Social confidence Autonomy Mood Hamilton Rating Scale Beck Inventory Functional hypothalamic amenorrhea (n = 9) ± ± ± ± ± ± ± ± ± 4.9 Organic Normal amenorrhea control (n = 6) (n - 8) Probability ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± or Beck Depression Inventory scores outside the normal range. Lifetime History of Psychiatric Disorder By criteria, women with current or lifetime history of eating disorders were excluded from this sample. Among the nine women with functional hypothalamic amenorrhea, three (33.3%) reported lifetime histories of psychiatric disorders. All three reported disorders consistent with affective dysregulation (Major Depression, Minor Depression Labile Personality Disorder), and one also reported clinically significant anxiety (Generalized Anxiety Disorder). In the organic amenorrhea group, three of six (50%) patients reported lifetime histories of psychiatric disorders. Two women (33.3%) reported evidence of affective dysregulation (Dysthymic Disorder, Adjustment Disorder with mixed emotional features), and one reported a phobic disorder. Only one of eight women (12.5%) in the eume~orrheic group reported a psychiatric history, Major Depression. The relative risk for lifetime affective disturbance was identical when functional hypothalamic amenorrhea women were compared with women with organic amenorrhea (1:1). The relative risk for affective dysregulation was 2.7 when functional hypothalamic amenorrhea women were compared with normal controls. These differences were not significant in this small sample by Fisher's exact test. DISCUSSION This study provides preliminary evidence from a controlled comparison that selected cognitive parameters discriminate women with functional hypothalamic amenorrhea from amenorrheic and eumenorrheic controls. Women with functional hypothalamic amenorrhea were more likely to endorse dysfunctional attitudes and tended to endorse greater interpersonal dependence, as expressed in need for social sanction, compared with age- and weight-matched eumenorrheic women and women with organic amenorrhea. Women with either a functional or an organic basis to amenorrhea reported similar difficulty in coping with daily stresses, suggesting that amenorrhea, regardless of origin, is associated with a compromise in stress-response mechanisms. Moreover, upon careful examination, women with either functional or organic amenorrhea tend toward greater risk for lifetime psychiatric disorders, most often mood dysregulation, than eumenorrheic women. Women with functional hypothalamic amenorrhea reported more regular exercise and mild weight loss, associated in time with menstrual disturbances. Neither the amount of exercise nor the amount of weight loss, with the exception of one patient, was appreciable by clinical standards. Although we cannot rule out these differences between the groups as fundamental to menstrual dysregulation in the functional hypothalamic amen- 0rrhea group, we suggest that these differences underscore our finding of increased reactivity or vulnerability to mild stress, whether that stress is of a physiological or psychological nature. A study is to be initiated that will provide a more definitive test of this hypothesis by specifically recruiting eumenorrheic women who are matched in exercise regimens. Sample sizes were small in this preliminary 490 Giles and Berga Correlates of functional hypothalamic amenorrhea Fertility and Sterility

6 investigation, yet several points can be made. Our findings underscore the importance of a control group of women with amenorrhea. Although there were cognitive characteristics that may be specific to women with functional hypothalamic amenorrhea, some differences that were apparent when those with functional hypothalamic amenorrhea were compared with eumenorrheic women were mitigated when the general effects of amenorrhea were taken in account. Second, the diagnosis of functional hypothalamic amenorrhea was definitive, determined not only by excluding other disorders but by measuring LH pulse frequency (12). Women with functional hypothalamic amenorrhea truly had a functional amenorrhea because excessive exercise, weight loss, and active psychiatric disorders were ruled out. Third, the clinical interview was supplemented by careful and systematic documentation of exercise and diet/weight history, with specific emphasis on changes within a year of menstrual dysfunction. Our view of our findings is that there is evidence that women with functional hypothalamic amenorrhea may be sensitive at central and neuroendocrine levels to the stress of living and that this sensitivity is mediated by cognitive characteristics. Nevertheless, sample sizes are small, power to detect differences was reduced, and our findings could have been influenced by outlier responses. Variability in measures between women with functional hypothalamic amenorrhea and normal controls were comparable, however, indicating that outlier responses did not occur in our groups. Some measures did not distinguish between differing origins of amenorrhea, and scores for all measures were not in the pathological range, suggesting that these characteristics are relatively subtle. We cannot exclude the possibility that amenorrhea, regardless of origin, may mediate cognitive dysfunction. More definitive evaluation, such as would be found in prospective follow-up of at-risk women or more direct manipulation of the environment, as could be done in an animal model, would provide clearest evidence for causal connections. Appropriate caution must be maintained in generalizing the present findings. Animal studies suggest that psychosocial stress can cause reproductive dysfunction. Central neuronal systems, including those that release corticotropin-releasing hormone, are activated and, in turn, eventuate in the disruption of the hypothalamic secretion of GnRH (21, 22). We have hypothesized that women with functional hypothalamic amenorrhea may be sensitive to the stresses of living because of certain cognitive characteristics. The present data are consistent with this hypothesis. Assuming that the present findings are replicated in additional studies, this information has treatment implications. If certain cognitive features predispose women to the stresses of daily living, it should be possible to alter these outlooks, attitudes, and expectations with psychological interventions designed to address these processes. This, in turn, would be expected to reverse the activation of the central cascade mediating the inhibition of GnRH secretion, lessen hypercortisolemia, and eventually lead to the spontaneous resumption of menses. It is important to determine if psychological interventions are efficacious in reversing functional hypothalamic amenorrhea because at the present time the only treatment options are to provide hormone replacement if pregnancy is not desired and ovulation induction if it is. Neither of these approaches results in a spontaneous resumption of menses, and neither reverses the central and neuroendocrine processes that mediate functional hypothalamic amenorrhea (23-25). Acknowledgments. We thank Jan Markert, R.N., Kelly Prescott, R.N., and Holly Koff, R.N., Magee-Womens Hospital, Pittsburgh, for assistance in subject recruitment. We thank the following from Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania: Nancy Hoffman, M.Ed., for carefulpsychiatric evaluation of a subset of subjects; JoAnn Matthews, B.A., for data entry and assistance with data analyses; and Ms. Janice B. Davis for typing the manuscript. REFERENCES 1. Berga SL, Girton LG. The psychoneuroendocrinology of functional hypothalamic amenorrhea. Psychiatr Clin North Am 1989;12: Shanan J, Brzezinski A, Sulman FG. Active coping behavior, anxiety and cortical steroid excretion in the prediction of transient amenorrhea. Behav Sci 1965;10: Fava G, Trombini G, Grandi S, Bernardi M, Pasqualievangelisti L, Santarsiero G. Depression and anxiety associated with secondary amenorrhea. Psychosomatics 1984; 25: Reame NE, Sauder SE, Case GD, Kelch RP, Marshall JC. 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