Analysis of the effects of eating and emotions on reproductive axis function in patients with functional hypothalamic amenorrhea

Abstract

Objective: To investigate the effects of eating and emotions on reproductive axis function in patients with functional hypothalamic amenorrhea (FHA).

Methods: A retrospective cohort study was conducted to summarize the clinical and endocrine characteristics of 58 patients with FHA at initial diagnosis and to follow up the recovery of ovulation and spontaneous menstruation in the patients to investigate these biochemical indicators and their effects on recovery outcomes.

Results: Among patients with FHA, 13.8% (8/58) and 15.5% (9/58) had above moderately severe depressive and severe anxiety symptoms respectively, and 25.9% (15/58) were at high risk for eating disorders. 34.5% (20/58) were included assessed as having recovered. The non-recovered group had higher scores on the Patient Health Questionnaire (PHQ-9) (p = .022) and higher scores on the Eating Attitude Test-26 (EAT-26) (p = .03) as well as bulimia and food preoccupation (p = .041). Follicle diameter >5 mm at initial diagnosis was an independent factor influencing recovery of reproductive axis function (odds ratio = 7.532; 95% confidence interval, 1.321–42.930; p = .023).

Conculsions: Mood disorders and a certain risk of eating disorders were present in FHA.These, together with weight loss, endocrine and follicle size, could influence the outcome.

Keywords:

• Functional hypothalamic amenorrhea
• eating disorder
• depression
• anxiety
• hypothalamic-pituitary-ovary axis

Introduction

Functional hypothalamic amenorrhea (FHA) is the most common cause of secondary amenorrhea [1], accounting for 15%–48% of all cases of amenorrhea [2]. As a condition of hypogonadotropic hypogonadism, FHA has adverse effects on women’s overall health, including anovulation, oligo-amenorrhea in short term, and infertility, increased risk of osteoporosis and cardiovascular disease in long-term hypoestrogenism. In addition, FHA is closely linked to female mental health [3].

The pathogenesis of FHA is considered to the inhibition of hypothalamus-pituitary-ovary (HPO) axis resulting from low body fat/weight, energy imbalance and stress. These factors typically interact to form a vicious cycle, and are principally seen in young women who dietary control and/or excessive exercise in order to lose weight or maintain low body weight, often complicated by eating disorders, depression and anxiety [4].

The inhibitive HPO axis is reflected in abnormalities in frequency and amplitude of GnRH secretion, as well as the retrogradation of LH pulse secretion to pubertal levels. Most patients with FHA have a basal LH between 1 and 3 mIU/mL [5], which leads to decreased estrogen levels and eventually amenorrhea [6].

The treatment mainly focuses on eliminating state of energy deficiency and stress caused by restricted eating and excessive exercise, and female hormone replacement is used to improve hypoestrogenism, protect the endometrium and prevent bone loss [7]. However, the recovery process for FHA is highly heterogeneous and influenced by many factors, including poor nutrition and refractory psychological conditions [8,9]. The prolonged inhibitive state of the HPO axis results in sustained low levels of estrogen and progesterone, stagnant follicular development, and failed ovulation or spontaneous menstruation [10], making the recovery of reproductive function difficult.

Our study had several strengths. This study focused the eating and psychological problems on patients with FHA who were not diagnosed with anorexia nervosa (AN), and summarized the differences and correlations of clinical and biochemical characteristics in patients with FHA between recovered and non-recovered groups. It also investigates the factors that potentially affect recovery outcomes. It can provide initial assessment of prognostic differences for patients with FHA, as well as personalized psychological interventions and appropriate diet and exercise guidance, which is of great clinical importance. However, our study was subject to certain limitations. Firstly, the size of sample was insufficient given that clinical heterogeneity observed among patients with FHA. Secondly, the recovery of ovulation and menstruation has probably not been observed during the limited follow-up period. Thirdly, the questionnaire and scales used in this study were for initial screening, which may introduce underlying risks in misdiagnosing both psychological and eating disorders. Therefore, it is necessary to include a larger number of study subjects and extend the follow-up period. Furthermore, a comprehensive and professional evaluation of patients with FHA should be conducted in collaboration with psychological specialists in the future.

Methods

Study design and subjects

We conducted a retrospective cohort study analysis of 58 patients who were diagnosed with FHA by the Reproductive Endocrinology Outpatient Clinic from January 2020 to January 2023. The 2017 Endocrine Society Guidelines (USA) were adopted as a reference to indicate the diagnostic criteria we used for individuals with FHA: 1) anatomical abnormalities or organic pathology; 2) a menstrual cycle interval that persistently exceeded 45 days and/or amenorrhea for three months or more; and 3) a medical history of weight loss or eating disorder, excessive exercise, psychological stress, or other triggers before amenorrhea. A diagnosis of FHA was then considered if the above three criteria were met.

We excluded patients with acute/chronic inflammation or trauma, a definite tumor, immune disease. Patients must not have taken hormones in the past 3 months, and they had to sign a written informed consent form. This study was approved by the Ethics Committee.

Collection of clinical data upon initial diagnosis:

1. Collection of medical history, eating attitude and emotion evaluations:

During initial diagnosis, a dedicated staff queried and recorded the medical history and detailed the patient’s age, menstrual history—including age at menarche, menstrual cycle length and regularity before oligo-amenorrhea, disease duration, past history of menstrual cycle-regulating drugs (e.g. progesterone alone or sequential combination therapy of estrogen and progesterone), weight-change status, dietary/exercise habits and mental stress, and history of other psychological and nutritional diseases and treatment.

Patient health questionnaire-9 (PHQ-9) [11] and generalized anxiety disorder-7 (GAD-7) [12] were applied to screen patients for symptoms of depression and anxiety. Each item was divided into four grades based on frequency. The scoring method employed in this study was: not at all = 0, several days = 1, more than half of the days = 2, and nearly every day = 3. A higher score indicated more severe depressive and anxiety symptoms. We distinguished among mild depression (5–9 scores), moderate depression (10–14 scores), moderately severe depression (15–19 scores), severe depression (20–27 scores); mild anxiety (5–9 scores), moderate anxiety (10–14 scores), severe anxiety (15–21 scores).

The eating attitudes test [13] (EAT-26) was used for self-evaluation of eating attitudes. This scale contained 26 questions in total, and each item was divided into six grades based on frequency. The scoring method used in this study was: always = 3; usually = 2; often = 1; and sometimes, rarely, or never = 0. A higher score indicated a greater deviation from normal in an individual’s eating attitudes and behavior. If the total score was ≥ 20, the subject was considered at high risk for eating disorder (ED).

A Chinese researcher revised the EAT-26 scale into a 19-item eating attitude questionnaire for the Chinese population [14], including four factors: dieting, bulimia and food preoccupation, perception of food contents, and compensatory behavior. Item scores for the four factors in the original EAT-26 were calculated, as was the total EAT-26 score.

1. Reproductive endocrine hormone test:

Venous blood was collected on the 3rd to 5th of menstrual cycle (no time restriction on patients with amenorrhea) from all subjects during the initial diagnosis and follow-up period. Serum was stored at −20 °C for hormonal measurements after isolation. A chemiluminescent method was used to measure concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), Estradiol (E₂), progesterone (P), total testosterone (TT).

1. Gynecological ultrasound:

All study subjects underwent transvaginal or transrectal gynecological ultrasound by a dedicated staff during the follicular phase (no time restriction on patients with amenorrhea). Ovarian volume (0.5 × length × breath × thickness) was calculated, while endometrial thickness and follicle size as well as number on each side were recorded.

After all of the above clinical data were collected, and a designed staff reviewed and entered them into database.

Treatment follow-up process and review-examination items:

1. Treatment follow-up process:

Patients were educated about the etiology of FHA at the initial outpatient visit. During the follow-up period without any recovery of menstruation and ovulation, all patients were encouraged to engage in self-lifestyle interventions to improve dietary attitudes, eating habits, and increase energy intake and/or decrease energy expenditure by reducing exercise. Personalized hormone replacement therapy was administered, according to the endometrial thickness and endocrine status. During the treatment period, patients were instructed to record their basal body temperatures daily and their weight-changes and observe the presence of withdrawal bleeding spontaneous menstruation after medication.

1. Review-examination items:

At the first, third, and sixth months after treatment (and every three months thereafter), a follow-up consultation was carried out at the Reproductive Endocrinology Department to monitor the changes in ovulation, weight gain, and menstruation. Reproductive-hormone laboratory tests and ultrasound were individually implemented every three to six months, and the recovery outcomes were recorded.

The follow-up was completed in June 2023. The above data and information were collected and completed and statistical analysis was performed by a designated staff.

Recovery evaluation and grouping:

1. Ovulation resumption was confirmed by the biphasic change in basal body temperature or the presence of a dominant follicle, or the formation of corpus luteum on ultrasound.

2. Regular spontaneous menstruation was observed at least three times after treatment.

Patients were assessed to achieve recovery of reproductive function if any one of the aforementioned criteria was met. Meanwhile, they were divided into two groups: the recovered and non-recovered groups.

Statistical methods

IBM SPSS Statistics 26.0 software was applied for collation and statistical analysis. Measures that conform to a normal distribution are described by x ± s, and those that are not normally distributed are described by M(P25, P75). Normality was tested by the Shapiro–wilk test and chi-square by the F-test. When analyzing data that is normally distributed or approximately normally distributed, the independent samples t-test is used to compare means between two groups if the variance is homogeneous. If the variance is not homogeneous, the approximate t-test should be used. The Mann–Whitney U test was used to compare data between two groups with skewed distribution. Count data were presented as cases (%) and group comparisons were conducted using the χ² test. Spearman correlation analysis was used to perform correlation analysis. A two-sided test with a test level of α = 0.05 was conducted. The recovery outcomes were analyzed using multivariate logistic regression to determine the effect of the various clinical biochemical characteristics.

Results

Basic characteristics

Table 1 shows the condition of all patients with FHA during initial diagnosis.

Table 1. Weight-loss condition, PHQ-9, GAD-7 and EAT-26 scores in patients with FHA.

Item			Value
Age (years), mean ± SD			23.29 ± 5.27
Disease duration (months), M (P25, P75)			10 (4, 24)
Weight-loss duration (months), M (P25, P75)			12 (6, 24)
Magnitude of weight loss (%), M (P25, P75)			20.0 ± 9.7
Weight-loss speed (%/month), M (P25, P75)			1.25 (0.64, 2.29)
BMI before weight loss (kg/m^2), mean ± SD			21.52 ± 2.32
BMI change during disease onset (kg/m^2), M (P25, P75)			3.95 (2.47, 5.88)
Cause of weight loss, n (%)	Dietary control alone Exercise alone Diet combined with exercise Psychological stress alone		15 (25.9)
			3 (5.2)
			28 (65.5)
			2 (3.4)
PHQ-9 (scores), M (P25, P75)			7 (4, 11)
GAD-7 (scores), M (P25, P75)			6 (3, 12)
EAT-26 (scores), M (P25, P75)			11 (5, 20)
High risk of eating disorders, n (%)			15 (25.9)
Severity, n (%)/moderate		Depressive symptoms	Anxiety symptoms
	Absent	18 (31.0)	23 (39.7)
	Mild	20 (34.5)	18 (31.0)
	Moderate	12 (20.7)	8 (13.8)
	Moderately severe/severe	8 (13.8)	9 (15.5)

BMI: body mass index; PHQ-9: Patient health questionnaire-9; GAD-7: Generalized anxiety disorder-7; EAT-26: Eating attitude test-26.

Comparison of clinical and endocrine characteristics in recovered and non-recovered groups

The recovered group comprised 34.5% (20/58) of the subjects, while the non-recovered group comprised 65.5% (38/58).

1. There were no significant differences in age, disease duration, weight loss duration, magnitude, speed of weight loss, follow-up duration, and BMI changes during disease onset and recovery. While the non-recovered group had significantly higher scores in the PHQ-9 (p = .022), total EAT-26 score (p = .03), and bulimia and food preoccupation score (p = .041) (Table 2).

2. The recovered group had significantly higher basal levels of LH and FSH at the time of initial diagnosis of FHA. The recovered group had significantly higher basal levels of LH and FSH at the time of initial diagnosis of FHA. Additionally, the proportion of follicles with diameter >5 mm at initial diagnosis was also significantly higher in the recovered group. There were no differences in the remaining characteristics (Table 2).

Table 2. Comparison of clinical, endocrine and ultrasound characteristics between the two groups.

Item	Recovered group (n1 = 20)	Non-recovered group (n2 = 38)	t/z/χ^2	P
Age (years), mean ± SD	24.1 ± 6.07	22.9 ± 4.83	0.844	.403
Disease duration (months) M (P25, P75)	6 (4.12)	12 (4.24)	−0.801	.423
Weight loss duration (months) M (P25, P75)	12 (6.24)	12 (6.24)	−0.058	.954
Magnitude of weight loss (%) mean ± SD	18.75 ± 9.60	20.13 ± 9.80	−0.517	.608
Speed of weight loss (%/months) M (P25, P75)	1.25 (0.60, 2.70)	1.17 (0.67, 2.29)	−0.131	.896
Follow-up duration (months) M (P25, P75)	15.0 (8.3, 21.5)	16.0 (7.5, 30.0)	−0.221	.825
BMI change during disease onset (kg/m^2), M (P25, P75)	3.48 (2.40, 5.93)	4.05 (2.47, 5.88)	−0.417	.677
BMI change during recovery (kg/m^2) M (P25, P75)	1.61 (0.88, 3.53)	1.69 (0.64, 3.18)	−0.033	.974
PHQ-9 (scores) M (P25, P75)	5.00 (2.25, 7.75)	9.00 (4.00, 14.00)	−2.296	.022
GAD-7 (scores), M (P25, P75)	4.50 (2.00, 8.75)	6.50 (4.00, 13.00)	−1.437	.151
EAT-26 (scores), M (P25, P75)	8.50 (4.00, 11.75)	14.5 (6.75, 25.75)	−2.170	.03
Bulimia and food preoccupation M (scores) (P25, P75)	1.0 (0.0, 2.0)	2.0 (0.0, 4.0)	−2.041	.041
LH (mIU/mL) M (P25, P75)	1.69 (0.24, 3.19)	0.28 (0.01, 0.69)	−2.546	.011
FSH (mIU/mL) M (P25, P75)	5.97 (1.31, 8.17)	1.16 (0.31, 4.33)	−2.716	.007
E2 (pmol/mL) M (P25, P75)	116.56 (39.16, 161.11)	87.00(51.00, 165.74)	−0.351	.726
TT (nmol/L) M (P25, P75)	1.48 ± 0.83	1.25 ± 0.80	1.699	.095
Ovarian volume (mL) M (P25, P75)	5.10 (4.30, 7.57)	4.36 (3.52, 6.40)	−1.471	.141
Follicular diameter > 5 mm, n(%)	16 (80.0)	16 (42.1)	7.608	.006

BMI: Body mass index; PHQ-9: Patient health questionnaire-9; GAD-7: Generalized anxiety disorder-7; EAT-26: Eating attitude test-26 LH: luteinizing hormone; FSH: follicle stimulating hormone; E2: estradiol; TT: total testosterone.

Correlation between basal LH levels and magnitude of weight loss with BMI change during disease onset

Spearman correlation analysis showed that baseline LH levels and magnitude of weight loss with FHA (r = −0.361, p = .005) were negatively correlated with BMI change during disease onset (r = −0.341, p = .009). In the non-recovered group, there was a correlation between basal LH levels and the magnitude of weight loss (r = −0.343, p = .035) with BMI change during disease onset (r = −0.358, p = .027), which was not observed in the recovered group (Table 3).

Table 3. Correlation between basal LH level and magnitude of weight loss with change in BMI.

Group	Magnitude of weight loss		BMI change during disease onset
	R	P	R	P
All FHA (n = 58)	−0.361	.005	−0.341	.009
Recovered group (n1 = 20)	−0.288	.218	−0.191	.419
Non-recovered group (n2 = 38)	−0.343	.035	−0.358	.027

FHA: functional hypothalamic amenorrhea; BMI: body mass index.

Correlation between basal LH and E₂ levels and EAT-26, PHQ-9 and GAD-7 during disease onset

Spearman correlation analysis did not show that the basal LH levels or E₂ were correlated with EAT-26, GAD-7 and PHQ-9 during disease onset in the patients with FHA (Table 4).

Table 4. Correlation between basal LH and E2 levels and EAT-26, PHQ-9 and GAD-7 during disease onset.

Item	LH		E2
	R	P	R	P
EAT-26	−0.054	.685	−0.066	.629
PHQ-9	−0.200	.132	−0.017	.900
GAD-7	−0.208	.117	−0.149	.274

LH: luteinizing hormone; FSH: follicle stimulating hormone; E₂: estradiol; PHQ-9: Patient health questionnaire-9; GAD-7: Generalized anxiety disorder-7; EAT-26: Eating attitude test-26.

Multiple logistic regression analysis of factors that affect recovery outcomes in patients with FHA

The multivariate logistic regression analysis included weight loss, the state of eating and emotions, basal LH and FSH levels, and the presence of ovarian follicles >5 mm in diameter at initial diagnosis. We found that follicle with diameter >5 mm during initial diagnosis showed statistical significance in the recovery outcomes of patients with FHA (OR =7.532; 95% CI, 1.321–42.930; p = .023) (Table 5).

Table 5. Multivariate logistic regression analysis of factors that affect recovery outcomes in patients with FHA.

Variable	B	Standard error of B	Wald χ^2 value	P	OR	95% CI of OR
						Lower limit	Upper limit
Magnitude of weight loss (%)	10.540	15.616	0.456	.499	38127.453	0.000	7.472 × 10^17
BMI change during disease onset (kg/m^2)	−0.328	0.637	0.265	.607	0.720	0.207	2.509
PHQ-9 (scores)	−1.114	0.138	0.681	.409	0.893	0.681	1.169
GAD-7 (scores)	0.120	0.124	0.927	.336	1.127	0.883	1.438
EAT-26 (scores)	−0.001	0.057	0.000	.989	0.999	0.894	1.117
Bulimia and food preoccupation	−0.228	0.267	0.726	.394	0.796	0.471	1.345
LH (mIU/mL)	0.149	0.155	0.927	.336	1.161	0.857	1.572
FSH (mIU/mL)	−0.025	0.166	0.023	.878	0.975	0.705	1.349
Follicle with diameter > 5 mm during initial diagnosis	2.019	0.888	5.170	.023	7.532	1.321	42.930

BMI: body mass index; PHQ-9: Patient health questionnaire-9; GAD-7: Generalized anxiety disorder-7; EAT-26: Eating attitude test-26; LH: luteinizing hormone; FSH: follicle stimulating hormone.

Discussion

It is acknowledged that the pathogenesis of FHA is intimately associated with low energy availability (LEA) [15]. The female athlete triad (FAT) of ‘amenorrhea, osteoporosis, and eating disorder’ caused by excessive energy consumption [16] and anorexia nervosa (AN) due to restrictive energy intake [17] are typical types of long-term LEA. Due to strict physique requirements, some athletes involved in esthetic sports may suffer from eating disorders [18], while cognitive impairment, depression, anxiety and obsessive-compulsive disorder are more common in AN [19].

ED refers to a constellation of symptoms that include abnormal eating behavior and excessive preoccupation with food, body weight and body shape, most commonly manifested in AN, bulimia nervosa (BN) and binge eating disorder (BED) [20].

Seventy percent of patients with ED have comorbid psychiatric disorders, and the most common psychiatric disorders are anxiety (53%) [21]. Depressive symptoms comprise the most common mood disorder in 75%–85% of patients with AN and 80%–90% of patients with BN [22]. Menstrual disorders are common physical symptoms in patients with ED [23], amenorrhea is present in 66%–84% of patients with AN, oligomenorrhea is present in 36%–64% of patients with BN.

13.8% of patients with FHA in our study had above moderately severe depressive symptoms at initial diagnosis, 15.5% had severe anxiety symptoms, and 25.9% were at high risk for ED.

Psychogenic factors are known to have an effect on the neuroendocrine activity of the HPO axis [24], which elevates cortisol levels, inhibits the activity of GnRH neurons, and decreases the frequency of LH pulses, leading to lower estrogen levels.

In our study, no correlation was found between PHQ-9 or GAD-7 scores and basal LH or estrogen levels. But we found that the basal LH level was negatively correlated with magnitude of weight loss and change in BMI in patient with FHA. Previous research has demonstrated that basal LH is a sensitive indicator of energy deficiency [25]. And the relationship between LH levels and energy availability is dose-dependent [26]. It is assumed that a greater degree and/or duration of energy deficit results in a greater degree of weight loss and change in BMI, while also leading to lower basal LH levels and greater inhibition of the HPO axis.

It is proposed that there are complex interactions between stress, LEA and activation of the HPA axis, which together affect the inhibition of LH. In addition, there are individual differences in susceptibility to stressors that are influenced by genetic factors, including variants in GnRH neuron migration-related fibroblast growth factor receptor 1, dynein receptor 2 and Kallmann syndrome-related KAL1 [27].

We followed up and discovered that the recovered group had significantly lower PHQ-9 and EAT-26 scores at initial diagnosis compared to the non-recovered group, indicating that the severity of depressive symptoms and eating disorders during disease onset may affect the recovery outcome. A previous study suggested that patients with FHA have milder eating and emotional disorders, and cognitive impairment compared to the ‘rigid cognitive behavior’ of AN [28], which are relatively easier to correct and can benefit recovery.

We also found that the ‘bulimia and food preoccupation’ factor in EAT-26 was significantly higher in the non-recovered group compared to the recovered group. Patients with BED also experience menstrual dysfunction with lifetime incidence rates of 10.4% for amenorrhea and 33.7% for oligomenorrhea [29]. We suspect that recurrent irregular eating behaviors of binge eating and purging form a vicious cycle that may exacerbate mood disorders; and patients with bulimia have a tendency to consume high carbohydrate foods, potentially affecting metabolism. Previous study results showed that BED was associated with obesity and polycystic ovary syndrome (PCOS) [30], and other studies showed that ‘FHA with underlying characteristics of PCOS’ [31,32]. Therefore, further research should focus on the changes of endocrine and metabolism in FHA with bulimic behavior, particularly those who do not experience menstrual recovery despite rapid weight and body fat gain [33].

Our study revealed that the non-recovered group had significantly lower basal LH and FSH levels at initial diagnosis than the recovered group. Additionally, it discovered that the presence of follicle diameters >5 mm was the independent factor influencing recovery outcomes. It is indicated that severe LH inhibition during disease onset results in greater stagnation of follicular development at the stage of 1–4 grade, which prevents selection and dominance from occurring [34], making recovery more difficult.

Earlier studies have suggested that the highest BMI before weight loss and the BMI during amenorrhea were strong predictors of the target body weight during recovery [8]. However, we found no differences in weight loss duration, magnitude, or speed, or in BMI changes during disease onset and recovery between the two groups. It is important to consider factors other than weight changes, such as mood and endocrine status, when treating patients with FHA.

In this study we only performed EAT-26, PHQ-9 and GAD-7 in patients at the initial diagnosis, without repetitive evaluation the follow-up stage. Additionally, the sample size should be expanded, and the follow-up duration should be prolonged to allow for the study of other factors that influence the recovery of reproductive function in FHA.

As the important trigger of FHA, eating and mood disorders can jointly affect endocrine activities in the HPO axis, which may impact the recovery outcomes of patients. Furthermore, endocrine and ultrasound characteristics during disease onset were associated with recovery, while follicle size was an independent influencing factor. There is a suggestion that more attention should be paid to eating and mood disorders in people with FHA and that routine screening should be undertaken.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Obstetrics and Gynecology Hospital of Fudan University (approval number: 2023-123). All participants agreed to participate in the study and provided informed written consent.

Acknowledgements

We want to acknowledge all the staffs for their participation in this research.

Declaration of interest statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data collected during the current study are not publicly available but are available from the corresponding author upon reasonable request.