Psychopathological features and endocrine and metabolic profile in patients with functional hypothalamic amenorrhea

Functional hypothalamic amenorrhea (FHA) is a common and potentially reversible form of menstrual disorder due to suppression of the hypothalamic- pituitary-ovarian (HPO) axis [1]. Hypothalamic dysregulation of the reproductive system is accompanied by a decrease in the secretion of kisspeptin, gonadotropin releasing hormone (GnRH) and in the pulsatile secretion of gonadotropins [2]. This leads to impaired follicular growth, reduced estrogen secretion, and is ultimately manifested by the absence of cyclic changes in the endometrium with the development of amenorrhea. As early as 1946, Reifenstein E.C. defined FHA as a syndrome based on an “explicit or latent psychological disorder” negatively effecting the cyclic function of the reproductive system [3]. This was the reason to generate a hypothesis on the role of metabolic and mental stress in the FHA development [4, 5]. It was shown that restricted food intake, negative energy balance, and reduction of adipose tissue in patients with anorexia nervosa are accompanied by a decrease in the leptin level, increase in the ghrelin level, suppression of HPO axis with the FHA formation [6–8]. Mental stress can also disrupt the functioning of GnRH-neurons through overactivation of the hypothalamic-pituitary-adrenal system [6, 9, 10]. In 1972, Russel G. proposed a classification of stress triggers in psychogenic amenorrhea: extreme danger (war, famine), loss (death of a relative), severe mental disorders, and even such events as starting school, fear of pregnancy, etc. [11]. Later studies confirmed the assumption that FHA is often associated with events that are subjectively perceived as stressful [12]. According to Berga S. et al., women with FHA have excessive perfectionism, concern about other people’s opinions, low self-esteem, emotional lability, and excessive anxiety. In addition, subsyndromal manifestations of eating disorders are often observed in these patients [13–15]. Despite the fact that mental stress is an acknowledged factor in the FHA development, the available published data on the mental characteristics of women contributing to psychosocial maladjustment are understudied. In this regard, FHA patients often do not receive the necessary preventive mental health interventions and adequate management of existing disorders.

Тhe research objectives of the study was to assess the mental status of patients with functional hypothalamic amenorrhea (FHA) and the relationship of the mental status to the endocrine and metabolic profile.

Materials and Methods

The article presents the results of examination of 104 patients with FHA. The diagnosis was established based on clinical data (absence of menstruation periods for over six months), the results of hormonal examination and the absence of organic disorders of the hypothalamic-pituitary region according to magnetic resonance imaging (MRI).

The women aged 18 to 35 (mean age 25.75 ± 4.16 years) were included in the study. The body mass index (BMI) was calculated by the formula BMI = weight (kg) / height (m2), ranged from 16 to 34 kg/m2 and averaged 20.05 ± 1.9 kg/m2.

To diagnose FHA and differentiate it from other endocrinopathies, hormonal (LH, FSH, estradiol, AMH, total testosterone, globulin, sex steroids, prolactin, TTH, free T4, cortisol, leptin) and neurotransmitter (serotonin, epinephrine, noradrenine, dopamine) profiles were studied using the immunochemiluminescence method with the Immulite 2000 automatic analyzer (Siemens, USA). The “body composition” was evaluated using DEXA with the Total Body Tissue Quantification program on a Prodigy densitometer (Lunar, United States). The content of adipose tissue of less than 30% was regarded as a deficiency.

All patients gave voluntary informed consent for participation in clinical, laboratory and psychological examinations, during which they were interviewed by a psychiatrist in the form of a semi-structured clinical interview MINI6 (International Neuropsychiatric Interview), as well as some additional data on their medical history and personal characteristics were obtained.

The SPSS Statistics program (IBM Version 21) was used for the statistical analysis of the material. All data were presented as mean ± standard deviation (SD). The comparison of groups was carried out using the Mann-Whitney test. The results were considered statistically significant when error level of p <0.05 was reached.

Results

The average amenorrhea onset age was 22.1 ± 5.5 years, amenorrhea duration was 3.2 ± 3.1 years, while in 72% of patients it exceeded one year. An assessment of the data from the medical history showed that stress as the FHA cause was noted in 13% of patients, adherence to diet in 22%, and strenuous physical activity in 8%. In more than half of the cases (54%), a combination of factors was noted, and 3% of patients indicated a lack of association of the above factors with the FHA development.

Further assessment of mental status revealed various mental disorders in 97 (93.3%) patients with FHA (Table 1).

All patients with FHA were classified into four groups depending on the prevailing mental disorder: 36 (34.6%) patients with eating disorders (EDs), 14 (13.5%) with bipolar spectrum disorders (BSDs), 21 (20.2%) diagnosed with depressive episodes or recurrent depression (depression), 26 (25.0%) with anxiety disorders (ADs). The fifth group included 7 (6.73%) women with no current mental disorders (NMDs). Four of them had mental disorders in the past and showed signs of dissimulative behavior. Among patients with ED, 38.9% were diagnosed with typical anorexia nervosa, 44.4% had atypical form of anorexia nervosa, 13.9% had typical form of bulimia nervosa, 2.8% showed atypical form of bulimia nervosa.

It is worth noting that a large number of personality anomalies were detected; at least 47 patients had them. In 63.8% of cases, an emotionally unstable personality disorder was diagnosed. At the same time, however, anxiety was detected in 10.6% of patients, schizoid personality disorders in 8.5%, dependent in 10.6%, and anancastic personality disorders in 6.4%. The psychopathological analysis of the condition of the examined patients showed perfectionism, hypersocial attitudes and insufficient sex role differentiation as inherent to vast majority. In some cases, distinct psychological masculinization was observed. Clinical and anamnestic data of patients with FHA are shown in Table 2.

In patients with ED, an earlier FHA development and a tendency to a greater loss of body weight were observed in comparison with patients from other groups.

Body weight loss in past medical history was noted in 75% of the examined patients and was typical for 83.3% of patients with EDs, 85.7% with depression, 57.1% with BSDs, 69.2% with ADs, and 57.1% of patients without identified mental pathology.

As shown in Table 2, at the time of inclusion there were no differences in the mean values of height, body weight and BMI. BMI of less than 18.5 kg/m2 was detected in 24% of patients, among them the share of ED patients was 44%, AD - 24%, depression - 16%, BSD - 12%, patients without identified psychopathologies composed 4%.

Analysis of the hormonal profile by the levels of gonadotropins, TTH, prolactin, and estradiol did not reveal significant differences among patients with different mental disorders. The level of cortisol was higher in the ED and BSD groups (p = 0.002). The lowest serotonin level was typical for patients with depression (p = 0.003) (Table 3).

Despite the fact that mean leptin levels did not significantly differ among the groups, hypolepthinemia (less than 4.8 ng/ml) was detected in 79.8% of patients with FHA. The frequency of hypoleptinemia did not significantly differ among the groups (p = 0.446): ED - 83.3%, BSD - 71.4%, depression – 76.2%, AD - 88.5%, in patients without identified mental pathology it was 57.1%.

Given the high incidence of weight loss and hypolepthinemia in past medical history, the body composition was evaluated. The percentage of adipose tissue in patients with FHA ranged from 10.7 to 36.8% and averaged 24.6 ± 6.7%. Normal adipose tissue (over 30%) was observed in 24% of patients, a slight deficit (20–30%) in 51.9% of patients, moderate deficiency (less than 20%) in 24%, among which the proportion of ED patients was 44%, with BSD - 28% (p = 0.03). There were no statistical differences in the average indicators of the adipose tissue percentage among patients with various mental disorders (p = 0.226). The rate of adipose tissue deficiency of less than 20% was five times more frequent in BSD group and three times more often in ED group compared with patients with depression or ADs (Fig. 1).

Discussion

Analysis of the literature data showed that the researchers focus mainly on menstrual disorders accompanied by anorexia nervosa, whereas only few investigations show the data on FHA in the presence of BSDs, depression or ADs. According to Reynolds-May et al., in BSD patients, the FHA frequency associated with stressful events or strenuous physical activity composes 22%, it is not statistically different from the FHA frequency in women without BSDs [16]. In another study conducted on a sample of women from North Korea, the FHA frequency in women with depression is two to four times higher than in the total population [17]. The authors point out that even in the absence of FHA, the frequency of oligomenorrhea among patients with depression reaches аs much as 34.2%. However, there are no evaluations of the features of the endocrine and metabolic status of patients with FHA in the presence of mental pathologies.

Psychiatric examination as part of the present study allowed us to identify mental disorders in 93.7% of patients with FHA. According to the data obtained, every third patient had EDs, every fourth patient had ADs, and every fifth had depressive disorders. BSDs were less common. These data are partially consistent with the results of Giovanni A. Fava, who in 1984 showed that 28% of patients with FHA showed depressive disorders, and 22% of women had generalized ADs [18].

Taking into account the heterogeneity of the identified mental pathologies, it seemed appropriate to assess its relationship with the endocrine and metabolic status of patients with FHA. It turned out that the cortisol level was significantly higher in the groups of women with EDs and BSDs. The serotonin level was significantly lower in the group of patients with depression, which is confirmed by numerous studies and it determines the high efficacy of monoamine oxidase inhibitors in patients with FHA and depression [19]. No significant differences were found in the levels of gonadotropins and estradiol. This suggests that the degree of suppression of the hypothalamic-pituitary system does not depend on the type of mental disorder and is likely to be due to other mechanisms. Therefore, FHA should be considered in terms of the theory of the body metabolic adaptation as a response to the resulting energy deficit.

The results of the study showed that body weight loss was observed in the past medical history in 75% of patients, while the rate of body weight loss, total percentage of the lost body weight reached maximum in ED patients. However, body weight loss was observed not only in ED patients, but also in other forms of mental disorders. It can be assumed that the mechanisms of weight loss and the formation of FHA in these categories of patients differ. For example, it is known that in EDs, in particular anorexia nervosa, body weight loss is associated with deliberate restriction of food intake and excessive physical activity, whereas there is no consensus regarding the mechanisms of weight loss during depression and ADs. Given that loss of appetite is characteristic of ADs, and anergy (decrease or loss of ability to be active) and angedonia (decrease or loss of ability to feel pleasure) are typical symptoms of depression, it can be assumed that these symptoms reflect the inadequate nutritional status of the patients with FHA and anxiety and depressive disorders [20].

The HPO system regulation is believed to depend primarily on the content of adipose tissue. In the study, adipose tissue deficiency (less than 30%) was characteristic of 76% of patients, and the average content of adipose tissue did not differ among the groups. However, when considering the degree of adipose tissue deficiency, it was found that a decrease in adipose tissue (less than 20%) was observed in 24% of patients and was characteristic mainly of patients with ED and BSD. The frequency of expressed reduction in adipose tissue in patients with BSD may result from the high proportion of comorbid anorexia nervosa. It is noteworthy that in 24% of patients, FHA persisted despite the absence of adipose tissue deficiency.

It is known that the functioning of the reproductive system depends on the adequate secretion of kisspeptin in the arcuate nuclei of the hypothalamus, the expression level of which depends on the energy balance. The leptin hormone is the link between the kisspeptinergic system and the energy balance, and its sufficient level is determined by the content of adipose tissue [21]. However, according to the metabolic adaptation theory, even with normal BMI and adipose tissue in patients with FHA, a negative energy balance can be observed, accompanied by a decrease in leptin levels, which was confirmed by a number of studies [22]. Karen K. Miller and M.P. Warren noted that in the absence of differences in BMI and adipose tissue content in patients with FHA, compared with the control group, the leptin level was significantly lower [23, 24]. The decrease in leptin levels turned out to be associated with inadequate nutrition. This is confirmed by the results of a previous study, in which 91.7% of patients with FHA were deficient in carbohydrate intake, and in 50% of cases there was a decrease in the total caloric intake in the diet [25].

Hypoleptinemia is known to be characteristic of patients with anorexia nervosa and is associated with low BMI and decreased adipose tissue; however, data on hypoleptinemia in patients with BSD, depression and generalized ADs are inconsistent and are represented by single studies. Experimental work confirms the role of stress hormones (cortisol and catecholamines) in the regulation of leptin levels [26]. It was shown that short-term stress leads to an increase in the level of leptin in blood, while the chronic stress, on the contrary, to persistent hypoleptic fever. In the study of Deuschle et al., a high rate of hypoleptinemia was shown in patients with prolonged depression. However, according to the authors, hypoleptic fever in patients with depression was caused not so much by the pathophysiological neuroendocrine mechanisms of development of depressive disorder, as by the restrictive type of nutrition accompanied by loss of appetite and anergy [27].

Conclusion

Thus, the results of a comprehensive examination of patients allow us to conclude that 93.7% of patients with FHA, without any significant differences in the endocrine and metabolic status, suffer from mental disorders in the form of EDs, BSDs, depression, and ADs. Their manifestation is probably realized together with inadequate strategies for overcoming psychological problems, maladaptive personality traits, and chronic stress. The above mentioned disorders in most patients may be accompanied by a restrictive type of nutrition, excessive physical activity, loss of appetite, apathy, anergy and angedonia, with subsequent development of energy deficit which results in a decrease in adipose tissue and hypoleptinemia. This leads to the suppression of the kisspeptinergic system, the suppression of GnRH synthesis, gonadotropins, and the development of amenorrhea (Fig. 2).

These findings suggest that the FHA problem is multidisciplinary. Patients need a comprehensive examination, including consultation not only with gynecologists, but also psychiatrists, to identify and subsequently correct latent psychiatric problems, which will increase the effectiveness of treatment.