Hypothalamic Amenorrhea Research Articles

Chorioretinal biomarkers in hypothalamic amenorrhea

PurposeThe aim of our study was to evaluate changes in the retinal and choriocapillaris circulations in patients with hypothalamic amenorrhea.MethodsProspective, cross-sectional observational study on 25 patients (50 eyes) diagnosed with hypothalamic amenorrhea and 25 age-matched healthy women. Optical coherence tomography angiography (OCTA) was used to evaluate the vessel density (VD) of superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris VD layers in whole 6.4 × 6.4-mm image and in fovea grid-based image. In patients’ group, systemic parameters were collected: body mass index (BMI), endometrial rhyme thickness, follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, insulin, and cortisol.ResultsSCP and DCP did not show any statistical difference when comparing patients and controls (all p > 0.05). Differently, choriocapillaris VD in the whole region showed a non-significant tendency toward higher values in the patients group in both eyes (p = 0.038 for right eye [RE], p = 0.044 for left eye [LE]). Foveal choriocapillaris VD was higher in hypothalamic amenorrhea women vs. healthy controls (66.0 ± 2.4 vs. 63.7 ± 6.6%, p = 0.136 for RE; 65.0 ± 2.4 vs. 61.6 ± 7.0%, p = 0.005 for LE). Focusing on correlation with systemic parameters, SCP and DCP foveal density had a medium/high effect size with endometrial rhyme, along with DCP in the fovea area vs. cortisol and SCP in the whole area vs. FSH.ConclusionWhen comparing hypothalamic amenorrhea patients to healthy subjects, OCTA detected changes in the choriocapillaris layer, showing increased VD in the early stage of the systemic pathology, suggesting that microvascular “compaction” could be a first phase of hypoestrogenism adaptation.

Kisspeptin and neurokinin B neuroendocrine pathways in the control of human ovulation.

The roles of initially kisspeptin and subsequently neurokinin B pathways in the regulation of human reproduction through the control of GnRH secretion were first identified 20 years ago, as essential for the onset of puberty in both boys and girls. Within that short time we already now have the first licence for clinical use for a neurokinin antagonist in a related indication, for menopausal vasomotor symptoms. Between these two markers of the start and end of the reproductive lifespan, it is clear that these pathways underlie many of the aspects of the hypothalamic regulation of reproduction which had hitherto been enigmatic. In this review, we describe the data currently available from studies designed to elucidate the roles of kisspeptin and neurokinin B in human ovarian function, specifically the regulation of follicle development leading up to ovulation, and in the control of the mid-cycle GnRH/LH surge that triggers ovulation. These studies, undertaken with only very limited pharmacological tools, provide evidence that the neurokinin B pathway is important in controlling the hypothalamic contribution to the precise gonadotropic drive to the ovary that is necessary for mono-ovulation, whereas the switch from negative to positive estrogenic feedback results in kisspeptin-mediated increased GnRH secretion. Potential therapeutic opportunities in conditions characterised by disordered hypothalamic/pituitary function, polycystic ovary syndrome, and functional hypothalamic amenorrhoea, and in the induced LH surge that is a necessary part of IVF treatment are discussed.

The LH:FSH Ratio in Functional Hypothalamic Amenorrhea: An Observational Study.

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. 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. 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. 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.

Girls referred for amenorrhea: analysis of a patient series from a specialist center.

Among 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. Retrospective register study. Medical 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. Functional 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. Menstrual 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.

Characteristics of bone mineral density in patients with functional hypothalamic amenorrhoea and its association with reproductive hormones and body composition.

Bone mineral density (BMD) is typically reduced in patients with female athlete triad (FAT) and anorexia nervosa (AN). However, bone health in most patients with functional hypothalamic amenorrhoea (FHA), who may not suffer from severe energy deficiency, has not received adequate attention in clinical practice. This study aimed to investigate BMD and its association with clinical and endocrine features in individuals with FHA and to provide clinical evidence for improving bone loss and preventing osteoporosis in FHA. To assess the bone status of patients with FHA and investigate its association with various clinical and endocrinological characteristics. We retrospectively analysed 80 patients with FHA who attended the Obstetrics and Gynecology Hospital of Fudan University from January 2022 to March 2023. The levels of reproductive hormones, including luteinising hormone (LH), follicle-stimulating hormone, oestradiol (E2 )and total testosterone (TT), were examined at the time of initial diagnosis, and a body composition analyser was used to measure body fat percentage (BF%), lean body mass (LBM)and segmental muscle/fat. Dual-emission X-ray absorptiometry was used to measure lumbar spine BMDand femoral neck BMDin patients with FHA, and the Z score was calculated. The study cohort consisted of 80 female patients with FHA. The average age of the patients was 24.64 ± 6.02 years, and their body mass index (BMI) was 19.47 ± 2.86 kg/m2 . The duration of weight loss was 12 (6, 24) months, while the duration of oligo/amenorrhoea was 12 (4.5, 24) months. The mean degree of weight loss was 18.39 ± 9.53%. Low BMD were present in 15% of patients with FHA at the lumbar spine and/or femoral neck; 12.5% and 10% had low bone mass at the lumbar spine and femoral neck, respectively. The low bone mass group experienced a longer period of weight loss than the normal group [24 (16.5, 60) vs. 12 (4.5, 24) months, p = .037]. In addition, the abnormal group had a lower BMR (basal metabolic rate, BMR) [1158 ± 85 vs. 1231 ± 91 kcal/day, p = .011] and lower bone mineral content [2.15 ± 0.26 vs. 2.43 ± 0.31 kg, p = .009] than the normal group. Both LBMD and femoral neck BMD (Fn BMD) were positively correlated with BMI, BF%, LBM, and regional muscle/fat mass (all p < .05). There was also a positive correlation between LBMD and basal LH levels (p = .009) and waist-to-hip ratio (p = .034), whereas Fn BMD was positively correlated with TT levels (p = .029). Multiple linear regression analysis showed that LBM was positively associated with LBMD (β = .007, 95% confidence interval [CI] = 0.004-0.009, p < .001), while trunk muscle mass was positively associated with Fn BMD (β = .046, 95% CI = 0.013-0.080, p = .008). Fifteen percent of the patients with FHA exhibited low bone mass, a condition associated with prolonged weight loss. The basal LH and TT levels showed positive correlations with LBMD and Fn BMD, respectively. Meanwhile, BMR levels, BMI, BF%, and muscle mass were all positively correlated with LBMD and Fn BMD. Clinically, we should be attentive to suboptimal bone health in patients with FHA and take early screening, diagnosis and intervention measures, especially appropriate muscle mass gain, to prevent the onset of osteoporosis and fragility fractures in the long term.

The Role of Hormonal Imbalances in Amenorrhea

Amenorrhea, the absence of menstrual periods in women of reproductive age, is a multifaceted and clinically significant gynecological condition that can have various underlying causes and far-reaching implications for a woman’s overall health and well-being. This abstract provides a concise overview of amenorrhea, encompassing its classification, etiology, clinical presentation, and management. Amenorrhea can be categorized into two primary types: Primary and secondary. Primary amenorrhea refers to the absence of menstruation by the age of 16 years in the presence of normal secondary sexual characteristics, or by the age of 14 years with no signs of puberty. Secondary amenorrhea, on the other hand, is characterized by the cessation of regular menstruation for at least three cycles or six months in women with a history of regular menstruation. The etiology of amenorrhea is diverse and may be attributed to various factors including hormonal imbalances, structural abnormalities in the reproductive tract, excessive exercise, stress, and eating disorders. Polycystic ovary syndrome (PCOS) and hypothalamic amenorrhea are common hormonal causes, while Asherman’s syndrome and structural abnormalities in the uterus are anatomical factors contributing to amenorrhea. The clinical presentation of amenorrhea varies depending on its underlying cause but often includes symptoms such as changes in weight, hair growth patterns, and breast development. An accurate diagnosis requires a comprehensive evaluation, which may involve hormonal assays, imaging studies, and sometimes a biopsy. The management strategies for amenorrhea depend on this cause. Hormone therapy, lifestyle modifications, and surgical interventions are recommended to address hormonal imbalances, structural abnormalities, or other contributing factors. Psychosocial support and counseling play crucial roles in the management of amenorrhea, especially when related to eating disorders or psychological stress.

Influence of lifestyle factors on menstrual disorders

Menstrual disorders, including dysmenorrhea, amenorrhea, and premenstrual syndrome (PMS), significantly impact the quality of life of many women. These disorders can be influenced by various lifestyle factors such as diet, physical activity, stress, body weight, and substance use. This review examines the existing literature on the impact of these lifestyle factors on menstrual health. Nutrient deficiencies and imbalanced diets, especially those low in magnesium, vitamin B6, and vitamin D, are associated with increased severity of PMS and dysmenorrhea. Conversely, diets rich in fruits, vegetables, and whole grains are linked to more regular menstrual cycles. Regular physical activity is beneficial, often reducing menstrual pain and promoting cycle regularity. However, excessive exercise, particularly in athletes, can lead to energy deficits and hypothalamic amenorrhea. Stress is another crucial factor, with chronic stress elevating cortisol levels and disrupting the hypothalamic-pituitary-ovarian axis, leading to irregular cycles and exacerbated PMS symptoms. Body weight also plays a significant role; both obesity and being underweight can disrupt hormonal balance, with obesity leading to excess estrogen and heavy bleeding, and low body weight resulting in reduced estrogen production and amenorrhea. Substance use, including high intake of alcohol and caffeine, is linked to an increased risk of PMS and irregular cycles, while smoking exacerbates dysmenorrhea and accelerates menopause. Addressing these lifestyle factors through balanced nutrition, regular physical activity, effective stress management, and maintaining a healthy body weight is essential for improving menstrual health and overall well-being. Further research is needed to fully understand the complex interactions between lifestyle factors and menstrual health.

The role of KNDy neurons in human reproductive health.

In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

Prevalence of functional hypothalamic amenorrhea in a cohort of women referred because of polycystic ovary syndrome.

In this unselected population of women referred to a center specialized in gynecologic endocrinology for suspicion of PCOS, a minimum rate of misdiagnosed FHA patients of about 2% was found. It is necessary to evaluate reliable markers for the differential diagnosis between PCOS and FHA to avoid incorrect treatment, which might lead to negative long-term effects in women with undiagnosed FHA.

Gene-environment interaction in functional hypothalamic amenorrhea.

Functional hypothalamic amenorrhea (FHA) is a common cause of amenorrhea and chronic anovulation in adolescent girls and young women, diagnosed after excluding other organic causes. It is commonly associated with calorie restriction, excessive physical exercise, and psychosocial stress. These stressors alter the pulsatile secretion of gonadotropin-releasing hormone, leading to a chronic condition of hypoestrogenism and significant health consequences. Recent evidence has highlighted a genetic predisposition to FHA that could explain interindividual variability in stress response. Indeed, not all women experience FHA in response to stress. Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism have been identified in women with FHA, suggesting that these mutations may contribute to an increased susceptibility of women to the trigger of stress exposure. FHA appears today as a complex disease resulting from the combination of genetic predisposition, environmental factors, and epigenetic changes. Furthermore, the genetic background of FHA allows for the hypothesis of a male counterpart. Despite the paucity of data, preliminary findings indicate that an equivalent condition of FHA exists in men, warranting further investigation. This narrative review aims to summarize the recent genetic evidence contributing to the pathophysiology of FHA and to raise awareness on a possible male counterpart.

The Role of Irisin throughout Women's Life Span.

Since its discovery, much attention has been drawn to irisin's potential role in metabolic and reproductive diseases. This narrative review summarizes and updates the possible role played by this fascinating molecule in different physiological (puberty and menopause) and pathological (polycystic ovary syndrome (PCOS), functional hypothalamic amenorrhea (FHA), endometriosis, and gestational diabetes) conditions that can affect women throughout their entire lives. Irisin appears to be an important factor for the hypothalamic-pituitary-gonadal axis activation, and appears to play a role in the timing of puberty onset. Serum irisin levels have been proposed as a biomarker for predicting the future development of gestational diabetes (GDM). Its role in PCOS is still controversial, although an "irisin resistance" mechanism has been hypothesized. In addition to its impact on metabolism, irisin also appears to influence bone health. Irisin levels are inversely correlated with the prevalence of fractures in postmenopausal women. Similar mechanisms have also been postulated in young women with FHA. In clinical settings, further controlled, prospective and randomized clinical trials are needed to investigate the casual relationship between irisin levels and the conditions described and, in turn, to establish the role of irisin as a prognostic/diagnostic biomarker or a therapeutic target.

Is there any relationship between nutrition, stress, physical exercise and amenorrhea?

Amenorrhea is the absence or abnormal cessation of the menstrual cycle. Functional hypothalamic amenorrhea (FHA) is one of the most common and least studied forms of secondary (hypothalamic) amenorrhea that occurs after adaptation failure in response to mental, social and metabolic irritants. At there are no common threshold values of potential irritants and markers of efficacy for female patioents with FHA. Methods of diagnostics, treatment and prevention of FHA stay still not personalized, but empirical. The most promising solution of present problem is combination of nutritive and mental correction among females with FHA. Also, the most promising step is searching and studying of omics (genomic, epigenomic, transcriptomic, proteomic and metabolomic) markers of hypothalamic–hypophysial-gonadal axis disruption. This review shows the association between amenorrhea and stress, changes in nutrition or weight, excessive physical activity, and the COVID-19 pandemic. The literature was searched in Russian and English languages in eLibrary, MEDLINE, and Scopus databases mainly for the last decade. Due to the insufficient study of the chosen topic, sources dating back to the 1990s were also selected.

Quantifying the variability in the assessment of reproductive hormone levels

To quantify how representative a single measure of reproductive hormone level is of the daily hormonal profile using data from detailed hormonal sampling in the saline placebo-treated arm conducted over several hours. Retrospective analysis of data from previous interventional research studies evaluating reproductive hormones. Clinical Research Facility at a tertiary reproductive endocrinology centre at Imperial College Hospital NHS Foundation Trust. Overall, 266 individuals, including healthy men and women (n = 142) and those with reproductive disorders and states (n = 124 [11 with functional hypothalamic amenorrhoea, 6 with polycystic ovary syndrome, 62 women and 32 men with hypoactive sexual desire disorder, and 13 postmenopausal women]), were included in the analysis. Data from 266 individuals who had undergone detailed hormonal sampling in the saline placebo-treated arms of previous research studies was used to quantify the variability in reproductive hormones because of pulsatile secretion, diurnal variation, and feeding using coefficient of variation (CV) and entropy. The ability of a single measure of reproductive hormone level to quantify the variability in reproductive hormone levels because of pulsatile secretion, diurnal variation, and nutrient intake. The initial morning value of reproductive hormone levels was typically higher than the mean value throughout the day (percentage decrease from initial morning measure to daily mean: luteinizing hormone level 18.4%, follicle-stimulating hormone level 9.7%, testosterone level 9.2%, and estradiol level 2.1%). Luteinizing hormone level was the most variable (CV 28%), followed by sex-steroid hormone levels (testosterone level 12% and estradiol level 13%), whereas follicle-stimulating hormone level was the least variable reproductive hormone (CV 8%). In healthy men, testosterone levels fell between 9:00 am and 5:00 pm by 14.9% (95% confidence interval 4.2, 25.5%), although morning levels correlated with (and could be predicted from) late afternoon levels in the same individual (r2 = 0.53, P<.0001). Testosterone levels were reduced more after a mixed meal (by 34.3%) than during ad libitum feeding (9.5%), after an oral glucose load (6.0%), or an intravenous glucose load (7.4%). Quantification of the variability of a single measure of reproductive hormone levels informs the reliability of reproductive hormone assessment.

Prolactin levels in functional hypothalamic amenorrhea: a retrospective case–control study

PurposeFunctional hypothalamic amenorrhea (FHA) is due to hypothalamic dysregulation. Literature lacks data about prolactin in FHA women, although both prolactin levels and FHA are associated with stress. Moreover, polycystic ovarian morphology is common in FHA and there is an association between FHA and polycystic ovary syndrome. Thus, the aim of this study was to assess prolactin levels in FHA patients and controls with a special focus on factors influencing prolactin levels, that could be considered as “sensors” of the hypothalamic–pituitary dysregulation.MethodsIn a retrospective cohort study, 140 women with clearly defined FHA were compared to 70 healthy, normally ovulating women matched for age. The main outcome parameter was prolactin. Factors associated with prolactin levels > 12 µg/L were tested using a multivariable binary logistic regression model.ResultsThe median prolactin level was 11.5 µg/L (interquartile range, IQR 7.5–14.4), which was similar to the control group (median 10.7, IQR 8.3–14.5; p = 0.065). Only two women had hyperprolactinemia (prolactin > 25 µg/L; 1.4%). In a multivariable binary logistic regression model eating disorder (odds ratio, OR 0.206; p = 0.040), excessive exercise (OR 0.280; p = 0.031) and TSH (OR 1.923; p = 0.020) were significantly associated with prolactin levels > 12 µg/L.ConclusionWomen with FHA have similar prolactin levels to healthy age-matched individuals. Eating disorders and excessive exercise where associated with prolactin levels < 12 µg/L, in contrast to TSH.

Патофизиологические механизмы функциональной гипоталамической аменореи и синдрома поликистозных яичников у девушек репродуктивного возраста

Secondary oligo-/amenorrhea occurs in 3–5% of women of reproductive age. The two most common causes are polycystic ovary syndrome (PCOS) (2–13%) and functional hypothalamic amenorrhea (FHA) (1–2%). The goal of this literature review was to study and systematize data from foreign relevant l studies on the topic as differences in the pathophysiological mechanisms of FHA and PCOS. The topic touched upon is important and requires analysis due to the difficulty of understanding and the still unclear pathophysiology of FHA and PCOS. This review examines the mechanisms of ovarian dysfunction in PHA and PCOS as the main causes of menstrual cycle disorders.

Gonadotropin and Ovarian Hormone Monitoring: Lateral Flow Assays for Clinical Decision Making

FSH, estrogen and progesterone testing are widely utilized in clinical practice. Lateral flow assays (LFAs) are cost-effective tools used for diagnosing infectious diseases, pregnancy, and substance testing. The focus of this narrative review is the potential for the wider utilization of listed hormone LFAs. A search was conducted with PubMed, Google Scholar and Wiley online libraries using keywords without any limitation on the publication date; animal studies were excluded. Clinical guidelines for the related conditions were included. According to published data, E3G and PdG are used to determine ovulatory cycles and can be utilized for research purposes to establish the normal range of menstrual cycles, as there is currently disagreement among guidelines. FSH measurement in blood samples is utilized to predict oocyte yield in assisted cycles and to differentiate women with premature ovarian insufficiency from hypothalamic amenorrhea, and can be replaced with more convenient urine testing. PdG was tested to assess the risk of pregnancy complications, specifically miscarriage and ectopic pregnancy, and might become a screening tool for miscarriage in the future. PMS, PMDD and ovarian carcinogenesis could be extensively studied using LFAs to gain a better understanding of the biology behind these conditions. Before implementing these LFAs into clinical practice, the reproducibility of progesterone assays should be evaluated. The results are critical for treatment decisions, and universally recognized standards for estradiol measurement should be developed.

Body weight variation is not an independent factor in the determination of functional hypothalamic amenorrhea in anorexia nervosa

ObjectiveFunctional hypothalamic amenorrhea (FHA) is one of the foremost manifestations in anorexia nervosa (AN), but a subset of patients have menses despite marked weight loss and underweight. The aim of our study was to investigate parameters potentially influencing FHA in AN.Design and methodsIn this observational retrospective study, we selected 114 female patients with AN who completed a 12 months semi-residential rehabilitation program and a subsequent 12 months outpatient follow-up. We divided our sample into three groups: “Group 0” patients who experienced FHA and recovered their menses, “Group 1” persistent FHA, “Group 2” never experienced FHA, and looked for clinical and hormonal correlations.ResultsAt the enrollment, the BMI was higher in Group 2 than in Group 1 (p = 0.0202), but the last follow-up weight was higher in Group 1 (p < 0.0001) despite persistent amenorrhea. At logistic regression, the higher BMI at which patients experienced amenorrhea was the main prediction factor for persistent FHA. Notwithstanding comparable leptin levels at admission, they improved significantly at discharge only in Groups 0 and 2 (p = 0.0054 and p = 0.0104, respectively). FT3 at admission was significantly higher in Group 2 than in Group 0 (p = 0.0249).ConclusionsFHA does not correlate strictly with body weight variations in AN patients, indicating a multifactorial origin, likely including an individual predisposition. Higher FT3 levels identify patients who continue having menses at extremely low BMI. AN patients with persistent FHA constitute a subgroup in whom estroprogestins should be considered after significant weight recovery to prevent prolonged tissue hypoestrogenism.

Differences of Bone Mineral Density by Characteristics of Sports in Amenorrheic Athletes.

Hypothalamic amenorrhea leads to a hypoestrogenic state, causing decreased bone mineral density (BMD), while strong impact loading on bone has been shown to increase BMD. The purpose of this study is to compare BMD in female athletes based on menstrual status and their sports/events by impact loading characteristics. BMD at the lumbar spine was measured by dual-energy X-ray absorptiometry and hormone level. The subjects were classified into four groups and BMD and hormone levels were compared among the four groups, which were divided into amenorrheic athletes (AAs) and eumenorrheic athletes (EAs). This study recruited 410 female athletes (164 in the AAs and 246 in the EAs), 55 athletes in non-impact sports, 123 in low-impact sports, 141 in multidirectional sports, and 91 in high-impact sports. In the AAs group, BMD Z-score was lowest in low-impact sports (Z-score: -1.53 [-1.76, -1.30]), and was highest in high-impact sports (Z-score: 0.02 [-0.34, 0.38]). In multidirectional and high-impact sports, BMD Z-score in the AAs group did not show results lower than the average for non-athletes. When screening female athletes for low BMD, it is important to evaluate the risk of low BMD based on the impact loading characteristics of their sports/events, in addition to the menstrual state.

OR17-06 Clinical And Mechanistic Insight For The Therapeutic Potential Of Intranasal Kisspeptin Administration To Treat Reproductive Disorders In Humans

Abstract Disclosure: E.G. Mills: None. M. Swedrowska: None. V. Delli: None. K. Chachlaki: None. M. Silva: None. L. Decoster: None. G. Ternier: None. L. Thurston: None. M. Phylactou: None. B. Patel: None. L. Yang: None. S.A. Clarke: None. B. Muzi: None. E.C. Alexander: None. M. Choudhury: None. P. Bech: None. A. Abbara: None. B. Forbes: None. P. Giacobini: None. V. Prevot: None. A.N. Comninos: None. W.S. Dhillo: None. Background: Kisspeptin is a key regulator of hypothalamic GnRH neurons with emerging potential to treat reproductive, psychosexual and bone disorders. However, current therapeutic application is limited to the subcutaneous or intravenous routes, which presents significant barriers to further development. Alternative delivery routes could overcome this and capitalise on the clinical utility of kisspeptin-based therapeutics. Herein, we comprehensively examine the translational potential of intranasal kisspeptin administration for the first time using a series of human, rodent and pharmaceutical studies. Methods:Human studies: Healthy men (n=12) and a patient group of women with Hypothalamic Amenorrhoea (HA) (n=5) completed a randomised, double-blind, crossover, placebo-controlled study investigating the acute effects of intranasal kisspeptin-54 administration (doses 3.2-25.6nmol/kg [healthy men] and 12.8nmol/kg [women with HA] vs 0.9% saline placebo). Plasma kisspeptin and serum reproductive hormones were measured every 15mins for 4hrs. Thereafter, we conducted rodent studies in adult C57BL/6J male mice to elucidate the possible mechanism by which intranasal kisspeptin induces reproductive hormone release, using intranasal administration of fluorescently-tagged kisspeptin-54 and a series of c-Fos experiments. From a medicines development perspective, we undertook pharmaceutical studies to evaluate the chemical stability of kisspeptin-54 in solution for nasal delivery in real-time. Results:Human studies: in healthy men, intranasal kisspeptin dose-dependently increased plasma kisspeptin at doses 6.4-25.6nmol/kg (p&amp;lt;0.01 for all doses vs placebo), with the maximal rises achieved within 15-30 minutes. Correspondingly, intranasal kisspeptin acutely and potently increased serum LH at doses 6.4-25.6nmol/kg (p&amp;lt;0.01 all doses vs placebo) with maximal rises at 30 minutes. Likewise, in women with HA, intranasal kisspeptin acutely increased plasma kisspeptin (p=0.004 vs placebo) and serum LH (p=0.004 vs placebo). Animal studies: To provide mechanistic insight, we demonstrate in male mice that GnRH neurons located in the olfactory bulb express kisspeptin receptors and that intranasal administration of fluorescently-tagged kisspeptin-54 binds to the olfactory epithelium. Pharmaceutical studies: Kisspeptin-54 in 0.9% saline remained within pharmaceutically accepted limits for stability for up to 60 days at 4°C demonstrating realistic pharmaceutical potential. Conclusion: We identify robust clinical effects and provide mechanistic and pharmaceutical data for intranasal delivery as a novel, non-invasive, safe and effective kisspeptin administration route for the management of common reproductive disorders that would be far preferable to patients and clinicians and so transform the ongoing rapid development of kisspeptin-based therapeutics. Presentation: Saturday, June 17, 2023

FRI408 Metabolic Hormone- And Energy-related-factors Are Associated With The Pulsatile LH Secretion Response To Short-term Energy Restriction In Healthy Women

Abstract Disclosure: S. Shekhar: None. J. Tessa Tonleu: None. E.D. Brown: None. C. Okigbo: None. L. Helen: None. A.E. Kim: None. B. Purse: None. D. Zaccaro: None. S.J. Soldin: None. K. Hirsch: None. A. Smith-Ryan: None. J.E. Hall: None. Introduction: Functional hypothalamic amenorrhea is characterized by reproductive dysfunction in a deficient energy state mediated through suppressed secretion of pulsatile GnRH. We investigated the relationship between metabolic, appetite, energy, body composition and attitude variables with LH pulse frequency responses. Methods: Two 5-day dietary interventions were administered to nineteen regularly cycling, healthy women (mean age (SD): 23.36 (2.08) y) with unchanged exercise in the early follicular phases of two menstrual cycles. The neutral energy availability diet (NEA, 45 kCal/kg*LBM/d, ±0%) was followed by a deficient energy availability (DEA, -55%) intervention. On enrollment, we administered the following questionnaires: almost perfect, perceived stress, dysfunctional attitude, eating attitudes, exercise (IPAQ), appetite, and palatability. Resting energy expenditure (REE), maximum oxygen uptake (VO2 max) and body composition were assessed at baseline. After each intervention, blood was sampled every 10 min for LH and metabolic hormones (thyroid hormones, GH, cortisol, glucose, insulin, leptin, and orexin) was measured at varying intervals (0800 — 1600hrs). Outcomes included 1) DEA LH pulse frequency expressed as an absolute number (LHPF), 2) change from NEA (αLHPF) and 3) % change from NEA (%αLHPF). Principal components (PC) analysis tested the association between predictor variables separated into relevant domains. As expected from the degree of energy restriction, LHPF decreased in response to DEA in ∼53% of women (‘responders’, n=10) for whom PC analysis was separately performed. Results: For the entire group, the PC for energy expenditure domain highlighted VO2 max and REE and was significantly associated with αLHPF (p=0.04) and %αLHPF (p=0.05). There was no relationship between metabolic or thyroid hormone, or body composition domains with DEA LHPF, αLHPF and %αLHPF. In responders, the fasting metabolic domain primarily consisted of insulin and leptin and was associated with αLHPF (p=0.008) and %αLHPF (p=0.08). The thyroid domain, which was a primary composite of T3, reverse T3 and T4 had a trend of association with DEA LHPF (p=0.06) and %αLHPF (p=0.05). The metabolic domain primarily consisted of samples from the across-the-day growth hormone and cortisol and was associated with αLHPF (p=0.05) and %αLHPF (p=0.049). There was no association between attitude, anthropometry, or energy domains and outcome variables in this subgroup. Conclusion: Our data suggest that in normal women higher resting energy expenditure and a greater degree of fitness predict a greater inhibitory effect of energy restriction on the reproductive axis. In those who demonstrate this inhibition, the degree of response to ER can be predicted by the fasting metabolic (insulin and leptin) and thyroid domains. Presentation: Friday, June 16, 2023