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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. [ABSTRACT FROM AUTHOR]

Purpose: Functional hypothalamic amenorrhea (FHA) is characterized by an estrogen deficiency which in turn can cause vascular dysfunction. The aim of this study is to evaluate any changes in the chorio-retinal circulation in patients affected by FHA. 24 patients with FHA and 24 age-matched controls underwent a gynecological evaluation and an OCT angiography (OCTA) to study chorio-retinal vascularization. Results: OCTA in FHA patients showed an increase in vessel density in the choriocapillaris (CC) layer (both in the fovea area, at 5% p value = 0.037 and in the whole area, at 5% p value = 0.028) and an increase in vascular density in the deep fovea (DVP) (at 10% p value = 0.096) in the whole district compared to controls. Simple linear regressions show a significant negative association between CC vessel density and insulin (p = 0.0002) and glucose values (p = 0.0335) for the fovea district and a negative association between DVP vessel density and endometrial thickness (at 10%, p value: 0.095) in the whole district. Conclusion: Our study shows that CC vessel density is increased in women affected by FHA. This could represent a compensation effort to supply the vascular dysfunction caused by estrogen deficiency. We also found an increasing trend in vascular density in DVP associated with the decrease of endometrial thickness, an indirect sign of estrogenization. Considering that these changes occur in absence of visual defects, they could be used as a biomarker to estimate hypoestrogenism-induced microcirculation changes before clinical appearance. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea (FHA) is one of the most common causes of secondary amenorrhea, resulting in anovulation and infertility, and is a low estrogen state that increases the risk of cardiovascular disease and impairs bone health. FHA is characterized by acquired suppression of physiological pulsatile gonadotropin‐releasing hormone (GnRH) release by the hypothalamus in the absence of an identifiable structural cause, resulting in a functional hypogonadotropic hypogonadism. FHA results from either decreased energy intake and/or excessive exercise, leading to low energy availability and weight loss—often in combination with psychological stress on top of a background of genetic susceptibility. The hypothalamic neuropeptide kisspeptin is a key component of the GnRH pulse generator, tightly regulating pulsatile GnRH secretion and the downstream reproductive axis. Here, we review the physiological regulation of pulsatile GnRH secretion by hypothalamic kisspeptin neurons and how their activity is modulated by signals of energy status to affect reproductive function. We explore endocrine factors contributing to the suppression of GnRH pulsatility in the pathophysiology of FHA and how hypothalamic kisspeptin neurons likely represent a final common pathway through which these factors affect GnRH pulse generation. Finally, we discuss the therapeutic potential of kisspeptin as a novel treatment for women with FHA. [ABSTRACT FROM AUTHOR]

Objective of the study: to optimize the treatment of stress-induced amenorrhea by non-hormonal medication therapy combined with phytotherapy alongside psychological counseling. Materials and methods. A total of 106 women of reproductive age with stress-induced amenorrhea were examined, receiving psychological counseling and medication therapy. The patients were randomized into three groups: 34 patients received Vitex agnus castus extract BNO 1095, 35 women were prescribed a preparation containing magnesium citrate and vitamin B6, and 37 participants received a combination of both treatments for six months. Results. After six months menstrual cycles were restored in 22 (64.71%) women who received Vitex agnus castus, in 19 (55.88%) patients who received magnesium citrate, and in 29 (78.4%) patients who received combined treatment. This was accompanied by the normalization of gonadotropic function of the pituitary gland, steroidogenic function of the ovaries, and endometrial thickness. Conclusions. Stabilization of the mental state and reduction of anxiety levels are key etiological interventions and essential conditions for restoring menstrual cycle regularity in patients with stress-induced amenorrhea. The mild dopaminergic support in the form of standardized Vitex agnus castus extract BNO 1095 (Cyclodynon) helps to restore hormonal balance and the menstrual cycle in women with stress-induced amenorrhea, especially when combined with magnesium supplements and psychological counseling. The obtained data allow to recommend this treatment regimen as first-line therapy for women with stress-induced amenorrhea to preserve and restore reproductive function that is especially relevant in the conditions of the military conflict in Ukraine [ABSTRACT FROM AUTHOR]

Background: For years, bone mineral density (BMD) has played a key role in assessing bone health, but the trabecular bone score (TBS) is emerging as an equivalent measure. However, BMD alone may not fully measure bone quality or predict osteoporosis risk. To evaluate the usefulness of TBS and BMD in estimating the risk of bone fracture in young women with FHA, this study examined the association between metabolic parameters and bone quality, which was measured using TBS and BMD. Methods: We analyzed the association of metabolic factors with tests assessing bone quality—TBS and BMD. Patients were checked for BMI, measured body fat, and determined serum glucose levels and insulin levels in a 75g glucose load test. Spearman correlation analysis was used. Results: Significant positive correlations were found between BMD and age (p < 0.001) and body fat (p < 0.001), as well as between TBS values and BMI (p < 0.001) and TBS and percent body fat (p < 0.001). Of the variables analyzed in the multivariate analysis, the only independent predictor of higher bone mineral density in the lumbar spine was found to be higher values of the trabecular bone index in the same segment (p < 0.001). Conclusions: The use of TBS provides a simple tool for estimating the risk of bone damage. Ultimately, early screening, diagnosis and treatment of patients with FHA may help prevent osteoporosis and fragility fractures in the long term. [ABSTRACT FROM AUTHOR]

Background: In functional hypothalamic amenorrhea (FHA), luteinizing hormone and follicle-stimulating hormone levels show high interindividual variability, which significantly limits their diagnostic value in differentiating FHA from polycystic ovary syndrome (PCOS). Our aim was to profile the LH:FSH ratio in a large sample of patients with well-defined FHA. Methods: This observational study included all consecutive patients with FHA presenting to the Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna, between January 2017 and August 2023. The main parameters of interest were the LH level, the FSH level, and the LH:FSH ratio. In a subgroup analysis, we compared the LH:FSH ratio of patients with PCO morphology (PCOM) on ultrasound with that of patients without PCOM. Results: A total of 135 patients were included. Only a minority of patients revealed FSH and LH levels ≤ 2.0 mIU/mL (13% and 39%, respectively). Most patients (81.5%) had an LH:FSH ratio ≤ 1.0, while a minority (2.2%) had a ratio ≥ 2.1. The LH:FSH ratio was similar in patients with and without PCOM. Conclusion: In a well-defined FHA sample, the LH:FSH ratio was ≤ 1 in most patients. The LH:FSH ratio may prove useful in distinguishing FHA from PCOS but needs further investigation. [ABSTRACT FROM AUTHOR]

Context Endothelial dysfunction is a preclinical cardiovascular disease (CVD) marker. Due to various neuroendocrine aberrations, functional hypothalamic amenorrhea (FHA) may be a sex-specific risk factor for CVD in young women. Objective To investigate endothelial function in women with FHA, compared with eumenorrheic controls and recently menopausal women. Methods We performed a cross-sectional analysis among women with FHA (n = 30), eumenorrheic controls (n = 29), and recently menopausal women (n = 30). FHA was defined as amenorrhea ≥3 consecutive months, estradiol <50 pg/mL, follicle-stimulating hormone (FSH) < 10 mIU/mL, and luteinizing hormone (LH) < 10 mIU/mL, excluding other etiologies. Participants were recruited through obstetrics and gynecology referrals, social media advertising, and review of electronic health records. Preclinical CVD was measured using EndoPAT 2000 to calculate reactive hyperemic index (RHI). RHI ≤1.67 indicates endothelial dysfunction. Results Mean estradiol levels in women with FHA, as compared with eumenorrheic controls and recently menopausal women, were 29.0 ± 18.1, 46.4 ± 15.7, and 10.9 ± 14.4 pg/mL (P <.0001), respectively. Women with FHA had lower insulin (P =.0095) and higher cortisol (P =.0004) compared with controls. RHI was significantly lower in women with FHA compared with eumenorrheic controls and recently menopausal women (1.8 ± 0.5 vs 2.2 ± 0.5 vs 2.2 ± 0.6, respectively; P =.008), and 35% of women with FHA had RHI ≤1.67, consistent with endothelial dysfunction. Conclusion These results demonstrate endothelial dysfunction in 1 out of 3 young women with FHA. FHA may be a contributor to preclinical CVD, and it is not explained by hypoestrogenemia alone. [ABSTRACT FROM AUTHOR]

Neurokinin B (NKB) belongs to the tachykinin family of proteins who's regulation is essential for proper function of the reproductive system. It has been shown that patients with functional hypothalamic amenorrhea (FHA) exhibit decreased levels of serum kisspeptin. As kisspeptin secretion is regulated by NKB signaling, it is reasonable to suspect that patients with FHA will also have abnormal NKB secretion. To assess NKB levels in patients with FHA and to determine whether NKB signaling is affected in these patients. We hypothesized that decreased NKB signaling is a factor contributing to the development of the FHA. A total of 147 patients with FHA and 88 healthy age-matched controls were enrolled. Baseline blood samples were drawn from both groups to measure serum concentrations of NKB, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), prolactin (PRL), thyroid-stimulating hormone (TSH), free thyroxine (fT4), cortisol, dehydroepiandrosterone sulfate (DHEA-S), testosterone (T), glucose, and insulin. Mean serum NKB levels were found to be decreased significantly in the FHA group when compared with the control group (628.35 ± 324.92 vs. 721.41 ± 337.57 ng/L, respectively p = 0.002). No statistical difference was observed in NKB-1 levels within the FHA group when selecting for normal and decreased body mass index. Patients with FHA were found to have decreased serum NKB concentrations when compared to healthy controls. Abnormal NKB secretion is likely a key factor contributing to development of FHA. [ABSTRACT FROM AUTHOR]

ObjectiveAmong adolescents, amenorrhea is a common reason for medical consultation. Despite the variety of underlying etiologies, the prevalence of the causes is incompletely understood. This study aimed to assess the demographic and etiological factors among patients with amenorrhea treated in a single specialist unit of adolescent gynecology.DesignRetrospective register study.MethodsMedical records of 438 girls evaluated for primary or secondary amenorrhea in a single tertiary care center between 2015 and 2019 were retrospectively reviewed. In all, 423 patients—171 with primary amenorrhea and 252 with secondary amenorrhea—were included in the study. Data on underlying conditions, anthropometric variables, and selected hormonal markers were analyzed.ResultsFunctional hypogonadotropic hypogonadism was the most frequent reason for primary (56%) and secondary (78%) amenorrhea. It was mostly explained by lifestyle-related functional hypothalamic amenorrhea caused by disordered eating, intense exercise, energy deficiency, psychological stress, and their combinations.ConclusionMenstrual pattern is a significant indicator of overall health and well-being among adolescent girls and young women. Functional reasons behind primary and secondary amenorrhea are important to recognize. Treatment often requires long-term lifestyle modifications. The frequency of functional causes also implies that most amenorrhea cases are preventable.

Introduction: Functional Hypothalamic Amenorrhea (FHA) has been associated with excessive-chronic stress, eating disorders, and weight loss. A common feature is the increased serum cortisol, but its measurement has many limitations. Currently, salivary cortisol (SC) has been proposed as a more sensitive and adequate index. Aim: To investigate the SC alterations through a 24-h period and the possible correlation with the severity of stress in women with FHA. Methods: Between July 2019 and March 2021, 12 FHA women and 12 healthy controls of comparable age were included. Psychological, eating, and physical abnormalities were evaluated by applying equivalent validated self-questionnaires. Results: No significant differences were found between FHA women and healthy individuals with respect to morning (8:00 am) serum cortisol and ACTH (522.5 ± 162.2 vs 442 ± 138.5 nmol/l; p = 0.204 and 37 ± 44.8 vs 17.4 ± 10.8 pg/ml; p = 0.186, respectively). Women with FHA had statistically significant higher morning SC compared to control subjects (21.8 ± 5.9 nmol/l vs 12.8 ± 3.8 nmol/l; p < 0.001), while no significant differences were found regarding the afternoon (4:00 pm) and midnight (12:00 am) SC. A significant positive correlation was found between morning SC and morning serum cortisol (rho = 0.532; p = 0.007), EAT-26 (rho = 0.527; p = 0.008) and HADS-Anxiety score (rho = 0.471; p = 0.02). Additionally, a significant negative correlation between morning SC and BMI was observed (rho = −0.53; p = 0.009). Conclusion: Compared to serum cortisol, SC seems to express better the hypercortisolemic state of women with FHA and correlates well with the underlying contributing factors. Larger studies are needed in order to confirm these results and validate the optimal SC cut-off value associated with the development of FHA. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea (FHA) is a non-organic reversible chronic endocrine disorder characterized by an impaired pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This impaired secretion, triggered by psychosocial and metabolic stressors, leads to an abnormal pituitary production of gonadotropins. As LH and FSH release is defective, the ovarian function is steadily reduced, inducing a systemic hypoestrogenic condition characterized by amenorrhea, vaginal atrophy, mood changes and increased risk of osteoporosis and cardiovascular disease. Diagnosis of FHA is made excluding other possible causes for secondary amenorrhea, and it is based upon the findings of low serum gonadotropins and estradiol (E2) with evidence of precipitating factors (excessive exercise, low weight, stress). Treatments of women with FHA include weight gain through an appropriate diet and physical activity reduction, psychological support, and integrative approach up to estrogen replacement therapy. If no spontaneous ovarian function is restored, assisted reproductive technologies may be used when pregnancy is desired. Because subjects with FHA are hypoestrogenic, the use of low-dose estrogens has been proposed as a putative treatment to positively modulate the spontaneous restart of gonadotropin secretion, counteracting the blockade of the reproductive axis triggered by stress acting through the neuroendocrine pathways at the basis of positive feedback of estrogens. The mechanism through which low-dose estrogens acts is still unknown, but kisspeptin-secreting neurons may be involved. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder can cause severe and prolonged amenorrhea in women. Since the beginning of the war in Ukraine, there has been an increased number of visits for the medical care of female military servicewomen and displaced women with this problem. The objective: to perform a comprehensive study of the characteristics of the hormonal levels of the hypothalamic-pituitaryovarian axis and the stress hormone cortisol, as well as to analyze the presence of autoantibodies to ovarian tissue in women with secondary amenorrhea caused by posttraumatic stress disorder. Materials and methods. The levels of hypothalamic-pituitary-ovarian hormones (follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol, progesterone, free testosterone and anti-Mullerian hormone (AMH), as well as cortisol (urine), autoantibodies to ovarian tissue from 54 military servicewomen and displaced women with amenorrhea caused by posttraumatic stress disorder (main group). 35 (64.8%) women (the 1st subgroup) were diagnosed with functional hypothalamic amenorrhea (FHA), 19 (35.2%) patients (the 2nd subgroup) were diagnosed with premature ovarian failure (POF). The control group included 23 women of reproductive age (18–37 years), who were in a state of psychological comfort and had no menstrual cycle disorders. Results. As a result of the study, a significant (p<0.05) decrease of all pituitary-ovarian hormones was found in women with FHA, except for free testosterone and AMH. In patients with POF, there was an increased concentration of pituitary hormones and a decreased amount of estradiol by 2.2 times, progesterone by 3.9 times, and AMH by 21.0 times compared to the control group. A 1.5-fold increase in prolactin level in patients with POF compared to the indicator of the control group is noteworthy. The presence of autoantibodies in the group with POF was detected in 26.3% of cases (in the group of women with FHA – only in 2.9% of cases; p<0.05), which may be a manifestation of polyglandular autoimmune syndrome. In both examined subgroups of the main group, a probable increased cortisol concentration in daily urine was determined (by 2.0 times in the 1st subgroup and by 2.1 times in the 2nd subgroup compared to the control), which indicates a stressogenic dysfunction of the adrenal glands. Conclusions. Posttraumatic stress disorder can have an irreversible pathological effect on the reproductive system of women. In women with stressogenic functional hypothalamic amenorrhea there is a deep depression of the hypothalamic-pituitaryovarian axis with preserving the follicular ovarian apparatus. In women with premature ovarian failure (POF) with long-term stress, there is a sharp depletion of the ovarian reserve. The presence of autoantibodies to ovarian tissue indicates the involvement of the immune system in the pathogenetic chain of development of amenorrhea, the severity of the lesion and the higher speed of the follicle atresia process by POF. [ABSTRACT FROM AUTHOR]

Background: Psychological factors have been found to be associated with functional hypothalamic amenorrhea (FHA); however, their role in the onset or persistence of FHA is still understudied. The study aims to assess the associations of psychological factors with the presence vs the absence of FHA. Methods: A systematic literature search has been conducted across the major databases (PubMed, PsycINFO, Scopus, and Embase) to explore the psychological factors associated with FHA. The search was limited to English-written articles published from 2000 onwards. Articles were selected based on stringent inclusion/ exclusion criteria. After data extraction, meta-analysis and meta-synthesis were conducted. Results: Of 349 retrieved articles, eight studies were included. Findings indicate that the main psychological factors associated to FHA seem to be depression and eating attitudes, especially drive for thinness. FHA women present higher levels of anxiety, sleep disorders, dysfunctional attitudes, and alexithymia. The metaanalysis on drive for thinness revealed that the pooled MD across the studies was statistically significant both in the fixed 0.63 (95% CI: 0.31–0.95) and random model 0.70 (95% CI: 0.13–1.26). Likewise, as for depression, the pooled MD across the studies was statistically significant both in the fixed 0.60 (95% CI: 0.36–0.84) and random model 0.61 (95% CI: 0.20–1.01). Discussion: Findings showed the association of psychological factors and FHA and recognized their involvement in the persistence of the disorder. A multidisciplinary approach should involve a collaborative process between gynecologists, clinical psychologists, and psychiatrists, from diagnosis to treatment. Longitudinal studies should be implemented with a comparison/control group or by including clinical psychologists in the psychological assessment and study design. [ABSTRACT FROM AUTHOR]

BackgroundPsychological factors have been found to be associated with functional hypothalamic amenorrhea (FHA); however, their role in the onset or persistence of FHA is still understudied. The study aims to assess the associations of psychological factors with the presence vs the absence of FHA.MethodsA systematic literature search has been conducted across the major databases (PubMed, PsycINFO, Scopus, and Embase) to explore the psychological factors associated with FHA. The search was limited to English-written articles published from 2000 onwards. Articles were selected based on stringent inclusion/exclusion criteria. After data extraction, meta-analysis and meta-synthesis were conducted.ResultsOf 349 retrieved articles, eight studies were included. Findings indicate that the main psychological factors associated to FHA seem to be depression and eating attitudes, especially drive for thinness. FHA women present higher levels of anxiety, sleep disorders, dysfunctional attitudes, and alexithymia. The meta-analysis on drive for thinness revealed that the pooled MD across the studies was statistically significant both in the fixed 0.63 (95% CI: 0.31–0.95) and random model 0.70 (95% CI: 0.13–1.26). Likewise, as for depression, the pooled MD across the studies was statistically significant both in the fixed 0.60 (95% CI: 0.36–0.84) and random model 0.61 (95% CI: 0.20–1.01).DiscussionFindings showed the association of psychological factors and FHA and recognized their involvement in the persistence of the disorder. A multidisciplinary approach should involve a collaborative process between gynecologists, clinical psychologists, and psychiatrists, from diagnosis to treatment. Longitudinal studies should be implemented with a comparison/control group or by including clinical psychologists in the psychological assessment and study design.

Background: Functional hypothalamic amenorrhea (FHA) is a chronic endocrine disorder caused by the abnormal pulsatile secretion of neurohormones in the hypothalamus. Secretion of GnRH is regulated by kisspeptin/neurokinin B/dynorphin (KNDy) neurons. These neurons produce, among other neurohormones, neurokinin B (NKB) which regulates the coordinated stimulation or inhibition of GnRH secreting neurons. Aim of the study: Assessment and comparison of serum NKB in patients with FHA at baseline, and following 6 months of estrogen-progestagen therapy. Materials and methods: Fifty-five patients with functional hypothalamic amenorrhea were included in the study group. Serum concentrations of neurokinin B (NKB), follicle stimulating hormone (FSH), luteinizing hormone (LH), 17-β-estradiol (E2), prolactin (PRL), cortisol, testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), thyroid-stimulating hormone (TSH), free thyroxine (fT4), fasting glucose and insulin, as well as lipid profile were measured at baseline. At the time of diagnosis, patients with FHA were prescribed a course of 2 mg 17-β-estradiol and 10 mg dydrogesterone for duration of 6 months. Serum NKB was then reassessed following treatment at 6 months. Results: At baseline, the FHA group was found to have a decreased serum NKB concentration when compared to a healthy control group. Following 6 months of sequential estrogen-progestogen hormone therapy, this study did not find any statistically significant difference in serum NKB concentration in the treatment arm compared to baseline. Conclusions: For the first time, NKB secretion has been studied in patients with FHA. A significantly lower level of serum NKB was observed in these patients at baseline, when compared to a control group. After 6 months of combination estrogen-progesterone therapy, no significant changes in NKB levels were observed in these patients. These findings, for the first time in the literature, provide insight into the perceived benefit of HRT, calling into question its benefit in addressing the underlying etiopathogenetic contributors of FHA. These new findings may contribute to more targeted and appropriate treatment of such patients in the future. [ABSTRACT FROM AUTHOR]

Nesfatin-1 plays an important role in regulating metabolism, appetite, gut motility, and eating behavior. It is suspected that abnormalities in nesfatin-1 secretion may be involved in the development of anorexia nervosa, and as such, this study aims to investigate the "circumstances of" nesfatin-1 in patients with functional hypothalamic amenorrhea (FHA). One hundred and forty-seven patients with FHA were enrolled to the present study. A control group consisting of 88 healthy, age-matched subjects was used. Both study and control groups had blood samples drawn to establish baseline serum concentrations of luteinizing hormone, follicle-stimulating hormone, estradiol, prolactin, thyroid-stimulating hormone, fT4, morning cortisol, dehydroepiandrosterone sulfate, testosterone, glucose, and insulin. Nesfatin-1 was also measured with the use of enzyme-linked immunosorbent assay. Patients with FHA were found to have a significantly decreased concentration of serum nesfatin-1 when compared to healthy controls (6.21 ± 4.79 vs. 8.64 ± 6.63 respectively, p = 0.005). No statistically significant difference in nesfatin-1 levels was found between patients with normal and decreased BMI in the FHA group. Significant positive correlation was observed between serum nesfatin-1 concentration and 17-β-estradiol, while a significant negative correlation was observed between serum nesfatin-1 concentration and patient age, fasting glucose, and HDL levels. This is the first known study to examine nesfatin-1 concentration in the context of clinical FHA. Patients with FHA were found to have decreased serum nesfatin-1 concentrations. This finding may prove instrumental in our future approach managing patients with FHA. [ABSTRACT FROM AUTHOR]

Anti-Müllerian hormone (AMН) is a glycopeptide of the transforming growth factors β-family, used in many medical fields. Understanding of the biological role of AMH at norm and at pathology such as polycystic ovary syndrome (PCOS) is expanding. This review includes the literature analysis on the synthesis and biological role of AMH in women and men; factors influencing its level; possibilities and limitations of clinical use of AMH in pediatric endocrinology/urogynecology, reproductive medicine, diagnosis of PCOS and other dyshormonal conditions, oncofertility programs and diagnosis of genital tumors. Effects of AMH in women: inhibiting the entry of primordial follicles into growth, control of follicle sensitivity to follicle-stimulating hormone, participation in the selection of the dominant follicle, inhibition of aromatase activity in granulosa cells of the follicle, regulation of the gonadotropic generator of gonadotropic releasing hormone. AMH is an important component of predicting the response to ovulation stimulation in infertile women, diagnosis of nonclassical forms of PCOS, premature ovarian failure to the development of amenorrhea, other hormonal diseases, granulosa cell tumors, decisions about the possibility of maintaining reproductive function after cancer treatment. Currently, AMH cannot be used as a tool for individualized prediction of the age of menopause, fertility. It is not recommended to decide on the use of cryotechnologies based only on the AMH level. Evolution of laboratory estimation of АМН as an important factor of impact on clinical and scientific application of research is also considered. Despite significant improvements in the technical characteristics of test systems for determining the AMH level, there are limitations in the use of this diagnostic marker due to the lack of standardization. This shortcoming can be overcome by following principles: do not base important clinical decisions only at the AMH level, and use this indicator in conjunction with other laboratory parameters and clinical data; adhere to the consistent use of one automated test system until the introduction of the standard in laboratory practice.

The aim of the study is to present the problem of functional hypothalamic amenorrhea, taking into account any disease and treatment, diagnosis, and consequences of this disease. We searched PubMed (MEDLINE) and included 38 original and review articles concerning functional hypothalamic amenorrhea. Functional hypothalamic amenorrhea is the most common cause of secondary amenorrhea in women of childbearing age. It is a reversible disorder caused by stress related to weight loss, excessive exercise and/or traumatic mental experiences. The basis of functional hypothalamic amenorrhea is hormonal, based on impaired pulsatile GnRH secretion in the hypothalamus, then decreased secretion of gonadotropins, and, consequently, impaired hormonal function of the ovaries. This disorder leads to hypoestrogenism, manifested by a disturbance of the menstrual cycle in the form of amenorrhea, leading to anovulation. Prolonged state of hypoestrogenism can be very detrimental to general health, leading to many harmful short- and long-term consequences. Treatment of functional hypothalamic amenorrhea should be started as soon as possible, and it should primarily involve lifestyle modification. Only then should pharmacological treatment be applied. Importantly, treatment is most often long-term, but it results in recovery for the majority of patients. Effective therapy, based on multidirectional action, can protect patients from numerous negative impacts on fertility, cardiovascular system and bone health, as well as reducing mental morbidity.

Functional hypothalamic amenorrhea (FHA) is a non-organic reversible chronic endocrine disorder characterized by an impaired pulsatile secretion of the gonadotropin-releasing hormone (GnRH) from the hypothalamus. This impaired secretion, triggered by psychosocial and metabolic stressors, leads to an abnormal pituitary production of gonadotropins. As LH and FSH release is defective, the ovarian function is steadily reduced, inducing a systemic hypoestrogenic condition characterized by amenorrhea, vaginal atrophy, mood changes and increased risk of osteoporosis and cardiovascular disease. Diagnosis of FHA is made excluding other possible causes for secondary amenorrhea, and it is based upon the findings of low serum gonadotropins and estradiol (E2) with evidence of precipitating factors (excessive exercise, low weight, stress). Treatments of women with FHA include weight gain through an appropriate diet and physical activity reduction, psychological support, and integrative approach up to estrogen replacement therapy. If no spontaneous ovarian function is restored, assisted reproductive technologies may be used when pregnancy is desired. Because subjects with FHA are hypoestrogenic, the use of low-dose estrogens has been proposed as a putative treatment to positively modulate the spontaneous restart of gonadotropin secretion, counteracting the blockade of the reproductive axis triggered by stress acting through the neuroendocrine pathways at the basis of positive feedback of estrogens. The mechanism through which low-dose estrogens acts is still unknown, but kisspeptin-secreting neurons may be involved.

Functional hypothalamic amenorrhea is a state of reversible hypogonadism common in adolescents and young women that can be triggered by energy deficit or emotional stress or a combination of these factors. Energy deficit may be a consequence of (i) reduced caloric intake, as seen in patients with eating disorders, such as anorexia nervosa, or (ii) excessive exercise, when caloric intake is insufficient to meet the needs of energy expenditure. In these conditions of energy deficit, suppression of the hypothalamic secretion of gonadotrophin-releasing hormone (with resulting hypoestrogenism) as well as other changes in hypothalamic-pituitary function may occur as an adaptive response to limited energy availability. Many of these adaptive changes, however, are deleterious to reproductive, skeletal, and neuropsychiatric health. Particularly, normoestrogenemia is critical for normal bone accrual during adolescence, and hypoestrogenemia during this time may lead to deficits in peak bone mass acquisition with longstanding effects on skeletal health. The adolescent years are also a time of neurological changes that impact cognitive function, and anxiety and depression present more frequently during this time. Normal estrogen status is essential for optimal cognitive function (particularly verbal memory and executive function) and may impact emotion and mood. Early recognition of women at high risk of developing hypothalamic amenorrhea and its timely management with a multidisciplinary team are crucial to prevent the severe and long-term effects of this condition. [ABSTRACT FROM AUTHOR]

The two most frequent causes of secondary amenorrhea are polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhea (FHA). Despite several studies showing differences in hormonal profile between these groups, the differential diagnosis remains challenging, in particular between FHA women with polycystic ovarian morphology (FHA-PCOM) and PCOS patients without hyperandrogenism (phenotype D, PCOS-D). In a retrospective case-control study, 58 clearly defined patients with FHA-PCOM were compared to 58 PCOS-D patients, matched 1:1 for age and BMI. Significantly higher levels of LH, estradiol, testosterone, and a higher luteinizing hormone (LH): follicle stimulating hormone (FSH) ratio as well as lower sexual hormone binding globulin (SHBG) levels were found in PCOS-D patients (p< 0.05). Optimized cut-off values for the prediction of FHA-PCOM were calculated by the Youden index. The highest sensitivity was found for an estradiol serum level <37.5 pg/mL (84.5%, 95% confidence interval, CI: 72.6-92.6), whereas a LH : FSH ratio <0.96 had the highest specificity (94.8, 95% CI: 85.6-98.9). A linear discriminant analysis including testosterone, SHBG and LH was able to correctly classify 87.9% of FHA-PCOM patients (bootstrap 95% CI: 80.2 - 94.0%). In conclusion, this model including serological parameters could be an easy and reliable tool to distinguish between FHA-PCOM and PCOS-D patients, especially in situations where the clinical profile is not obvious. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea is a state of reversible hypogonadism common in adolescents and young women that can be triggered by energy deficit or emotional stress or a combination of these factors. Energy deficit may be a consequence of (i) reduced caloric intake, as seen in patients with eating disorders, such as anorexia nervosa, or (ii) excessive exercise, when caloric intake is insufficient to meet the needs of energy expenditure. In these conditions of energy deficit, suppression of the hypothalamic secretion of gonadotrophin-releasing hormone (with resulting hypoestrogenism) as well as other changes in hypothalamic-pituitary function may occur as an adaptive response to limited energy availability. Many of these adaptive changes, however, are deleterious to reproductive, skeletal, and neuropsychiatric health. Particularly, normoestrogenemia is critical for normal bone accrual during adolescence, and hypoestrogenemia during this time may lead to deficits in peak bone mass acquisition with longstanding effects on skeletal health. The adolescent years are also a time of neurological changes that impact cognitive function, and anxiety and depression present more frequently during this time. Normal estrogen status is essential for optimal cognitive function (particularly verbal memory and executive function) and may impact emotion and mood. Early recognition of women at high risk of developing hypothalamic amenorrhea and its timely management with a multidisciplinary team are crucial to prevent the severe and long-term effects of this condition.

The two most frequent causes of secondary amenorrhea are polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhea (FHA). Despite several studies showing differences in hormonal profile between these groups, the differential diagnosis remains challenging, in particular between FHA women with polycystic ovarian morphology (FHA-PCOM) and PCOS patients without hyperandrogenism (phenotype D, PCOS-D). In a retrospective case-control study, 58 clearly defined patients with FHA-PCOM were compared to 58 PCOS-D patients, matched 1:1 for age and BMI. Significantly higher levels of LH, estradiol, testosterone, and a higher luteinizing hormone (LH): follicle stimulating hormone (FSH) ratio as well as lower sexual hormone binding globulin (SHBG) levels were found in PCOS-D patients (p< 0.05). Optimized cut-off values for the prediction of FHA-PCOM were calculated by the Youden index. The highest sensitivity was found for an estradiol serum level

Essential hyperandrogenism seems to be overrepresented in female elite athletes. This applies to mild forms such as polycystic ovary syndrome, as well as rare differences/disorders of sex development (DSD). The reason is likely a selection bias since there is increasing evidence that androgens are beneficial for athletic performance by potent anabolic effects on muscle mass and bone mass, and stimulation of erythropoiesis. XY DSD may cause a greatly increased production of testosterone in the male range, that is, 10 to 20 times higher than the normal female range. The established regulations concerning the eligibility of female athletes with severe hyperandrogenism to compete in the female classification remain controversial. The most common cause of menstrual disorders in female athletes, however, is probably an acquired functional hypothalamic disturbance due to energy deficiency in relation to energy expenditure, which could lead to low bone mineral density and increased risk of injury. This condition is particularly common in endurance and esthetic sports, where a lean body composition is considered an advantage for physical performance. It is important to carefully evaluate endocrine disturbances and menstrual disorders in athletes since the management should be specific according to the underlying cause. [ABSTRACT FROM AUTHOR]

Aim. To investigate the usefulness of differential diagnostic criteria of functional hypothalamic amenorrhea (FHA) related to energy deficiency and stress. Materials and methods. There were provided clinical and laboratory examination of 56 patients with FHA associated with stressful events (group 1) and 64 patients with FHA on the background of eating disorders (group 2), including assessment of adipose tissue, determination of leptin level, adipose tissue index and differential index. Results. Patients of group 2 were distinguished by a more significant deficiency of body mass index, total body fat, and leptin levels in comparison with patients of group 1. The differential index [AUC=0.907 (0.84-0.97)] turned out to be the most informative indicator in the differential diagnosis of various forms of FHA, its threshold value was 21.4, the least informative - body mass index [AUC=0.78 (0.71-0.87)]. Conclusion. The differential index can be considered as an informative differential diagnostic criterion for various forms of FHA.

Hypothalamic-pituitary-gonadal (HPG) axis suppression in exercising women can be caused by low energy availability (EA), but the impact of a real-world, multistressor training environment on reproductive and metabolic function is unknown. This study aimed to characterize reproductive and metabolic adaptation in women undertaking basic military training. A prospective cohort study in women undertaking 11-month initial military training (n = 47) was carried out. Dynamic low-dose 1-h gonadotrophin-releasing hormone (GnRH) tests were completed after 0 and 7 mo of training. Urine progesterone was sampled weekly throughout. Body composition (dual X-ray absorptiometry), fasting insulin resistance (homeostatic modeling assessment 2, HOMA2), leptin, sex steroids, anti-M€ullerian hormone (AMH), and inhibin B were measured after 0, 7, and 11 mo with an additional assessment of body composition at 3 mo. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responses were suppressed after 7mo (both P < 0.001). Among noncontraceptive users (n = 20), 65% had regular (23-35 days) cycles preenrollment, falling to 24% by 7mo of training. Of women in whom urine progesterone was measured (n = 24), 87% of cycles showed no evidence of ovulation. There was little change in AMH, LH, and estradiol, although inhibin B and FSH increased (P < 0.05). Fat mass fluctuated during training but at month 11 was unchanged from baseline. Fat-free mass did not change. Visceral adiposity, HOMA2, and leptin increased (all P < 0.001). HPG axis suppression with anovulation occurred in response to training without evidence of low EA. Increased insulin resistance may have contributed to the observed pituitary and ovarian dysfunction. Our findings are likely to represent an adaptive response of reproductive function to the multistressor nature of military training. [ABSTRACT FROM AUTHOR]

Purpose: Functional hypothalamic amenorrhea (FHA) occurs in response to exaggerated stressors with or without body weight loss. Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH and kisspeptin is one of them. Our study aimed to evaluate the putative temporal coupling between kisspeptin and GnRH-induced LH pulsatile secretion. Methods: In total, 71 patients with FHA were selected for this study. All patients undergo to a pulsatility study for LH and kisspeptin evaluation (120 min, sampling every 10 min), and to an endocrine evaluation for prolactin (PRL), estradiol (E2), androstenedione (A), 17-hydroxy-progesterone (17OHP), TSH, fT3, fT4, insulin, cortisol and testosterone (T), glucose, total cholesterol, triglycerides. Results: Our data demonstrated kisspeptin and LH pulsatile secretions and that both hormones are co-secreted and temporally coupled at time 0 (p < 0.05). When patients were subdivided in hypo-LH (≤3 mIU/ml, n = 58) and normo-LH (>3 mIU/ml, n = 13), more insights were observed on the specific correlations of metabolic and hormone profiles with pulsatility indexes of LH and kisspeptin. Conclusions: Our study demonstrated the presence of a distinct kisspeptin episodic secretion in patients with FHA, and showed the temporally coupling of kisspeptin with LH secretory episodes thus supporting that though in amenorrhea, the reproductive axis is still relying on kisspeptin to drive GnRH discharge. In addition, correlations among hormonal data sustain the hypothesis that stress-induced compensatory events are the main direct and indirect promoters of the reproductive blockade in patients affected by FHA. [ABSTRACT FROM AUTHOR]

Purpose: To ascertain the role of deranged eating behaviours (DEBs) in the development of functional hypothalamic amenorrhoea (FHA) and the reciprocal role of psychopathological traits on both disorders.Methods: A prospective case-control study was conducted spanning the period January 2016 to April 2018. Forty-one consecutive FHA females and 86 healthy controls were recruited. We assessed the DEBs and other FHA predisposing factors via self-reported questionnaires. Possible correlations amongst the variables were examined using the Spearman's correlation coefficient (rho), whilst multivariate logistic regression was carried out to identify independent predictors of DEBs.Results: Mean scores on Eating Attitudes Test-26 (EAT-26) were significantly higher in females with FHA (p < 0.0001). Women with FHA were characterised by significantly higher scores at the sub-scale items of dieting (p = 0.03) and bulimia and food preoccupation (p < 0.001) compared to healthy controls. Significant difference was also observed between the mean scores of the two groups in all other questionnaires: State-Trait-Anxiety-Inventory (STAI) (p < 0.0001), Multidimensional Body-Self-Relations Questionnaire (MBSRQ) (p < 0.0001) and International Physical Activity Questionnaire (IPAQ) (p = 0.004). EAT-26 scores were positively correlated with scores on STAI (ρ = 0.26, p = 0.04), MBSRQ (ρ = 0.79, p < 0.0001) and IPAQ (ρ = 0.35, p = 0.03). High scores on IPAQ and STAI were correlated with a 12.2-fold (p = 0.008) and 4.3-fold (p = 0.04) increased risk for high scores on EAT-26 respectively.Conclusions: DEBs may occur in FHA populations at a higher frequency compared to the general population. Anxiety and overweight preoccupation may underlie and independently contribute to development and maintenance of both DEBs and FHA. This evidence may have future implications for both screening and interventions that target DEBs and other psychological factors. [ABSTRACT FROM AUTHOR]

Background: Functional hypothalamic amenorrhea is common among female athletes and may be difficult to treat. Restoration of menses (ROM) is crucial to prevent deleterious effects to skeletal and reproductive health. Objectives: To determine the natural history of menstrual disturbances in female college athletes managed with nonpharmacologic therapies including increased dietary intake and/or decreased exercise expenditure and to identify factors associated with ROM. Study Design: A 5-yr retrospective study of college athletes at a major Division I university. Methods: 373 female athletes' charts were reviewed. For athletes with menstrual disturbances, morphometric variables were noted. Months to ROM were recorded for each athlete. Results: Fifty-one female athletes (19.7%) had menstrual disturbances (14.7% oligomenorrheic, 5.0% amenorrheic). In all, 17.6% of oligo-/amenorrheic athletes experienced ROM with nonpharmacologic therapy. Mean time to ROM among all athletes with menstrual disturbances was 15.6 ± 2.6 mo. Total absolute (5.3 ± 1.1 kg vs. 1.3 ± 1.1 kg, p < .05) and percentage (9.3% ± 1.9% vs. 2.3% ± 1.9%, p < .05) weight gain and increase in body-mass index (BMI; 1.9 ± 0.4 kg/m2 vs. 0.5 ± 0.4 kg/m2, p < .05) emerged as the primary differentiating characteristics between athletes with ROM and those without ROM. Percent weight gain was identified as a significant positive predictor of ROM, OR (95% CI) = 1.25 (1.01, 1.56), p < .05. Conclusions: Nonpharmacologic intervention in college athletes with menstrual disturbances can restore regular menstrual cycles, although ROM may take more than 1 yr. Weight gain or an increase in BMI may be important predictors of ROM. [ABSTRACT FROM AUTHOR]

Functional hypothalamic amenorrhea (FHA) is characterized by the low levels of serum gonadotropin and estrogen in young women, in which the organic lesion of hypothalamus and hypophysis has been excluded. FHA has negative effects on the cardiovascular system, skeletal system, reproductive system and mental health of patients. Many factors may induce FHA, such as excessive exercise, nutritional deficiencies, dieting, and mental stress, or the combination of those factors. The treatment of FHA should be comprehensive, including the increased weight, the reduced strenuous -exercise, gonadotropin releasing hormone pulse therapy, hormone replacement therapy and cognitive behavioral therapy. The research progress of functional hypothalamic amenorrhea is reviewed. [ABSTRACT FROM AUTHOR]