Reproduction
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Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
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We previously published the DexFEM trial, which showed that in women with heavy menstrual bleeding (HMB), oral dexamethasone reduces menstrual blood loss. Here, we report a pharmacodynamic analysis exploring the likely mechanism for this effect. We studied oral dosing with dexamethasone during the mid-luteal phase of two menstrual cycles (1.5 mg daily, 5 days) in five women with HMB (six recruited aged 41–50 years, one withdrew before treatment). Steroid hormones were profiled in serum and endometrium by liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that following oral dosing, dexamethasone reached the endometrium and that, compared to the preceding control cycle, cortisol (active), cortisone (inactive) and intermediate 11-deoxycortisol were reduced in all samples assessed, both endometrial (n = 4) and serum (n = 5). Concentrations of androgens, androstenedione and testosterone were reduced in serum but not in all tissue samples. This proof-of-concept pharmacodynamic study supports the inference that dexamethasone is effective in HMB by altering endometrial glucocorticoid concentrations.
Significance statement
New treatments are needed for HMB, a debilitating symptom experienced by many women. The association previously found between local endometrial glucocorticoid deficiency and HMB stimulated research into the role for glucocorticoids in the physiological process of menstruation. We report a proof-of-concept experimental medicine study profiling steroids in endometrial biopsies, demonstrating that dexamethasone administered orally penetrates the endometrium and is associated with changes in circulating endogenous steroid profiles (glucocorticoids and androgens) and in glucocorticoids in the endometrium. Dexamethasone thus has potential utility to modify glucocorticoid profiles and endometrial steroids in those with HMB. These findings augment the results of the recently reported adaptive clinical trial we conducted, also in women with HMB, showing that oral dexamethasone reduces menstrual blood loss.
French Institute of Health and Medical Research (INSERM; UMR-S 1185),
Department of Pediatric Endocrinology and Diabetes and Adolescent Medicine, Paris-Saclay Hospital,
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Reference Center for Rare Pituitary Diseases, Bicêtre Hospital,
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Department of Molecular Genetics, Pharmacogenetics and Hormonology, AP-HP Bicêtre Hospital,
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French Institute of Health and Medical Research (INSERM; UMR-S 1185),
Department of Pediatric Endocrinology and Diabetes and Adolescent Medicine, Paris-Saclay Hospital,
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French Institute of Health and Medical Research (INSERM; UMR-S 1185),
Department of Pediatric Endocrinology and Diabetes and Adolescent Medicine, Paris-Saclay Hospital,
Reference Center for Rare Genital Diseases, Bicêtre Hospital,
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We previously observed that continuous subcutaneous gonadotropin infusion (CSGI) in infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty.
Objective
To describe the early adolescence outcome of boys treated during the first year of life.
Methods
In this retrospective cohort study, we describe eleven boys with CHH aged 12 years (11.5–14.6) treated at the age of 4.5 months (2.0–11) with CSGI. As a retrospective control cohort, we report testicular function of 12 untreated boys with CHH aged 12 years (12–15.9).
Results
In response to CSGI, serum testosterone and inhibin B levels increased from 0.03 ng/mL (0–0.07) to 2.25 ng/mL (1.12–3.86) and from 73 (11–173) to 401 (185–727) pg/mL, respectively. The testicular volume increased from 0.50 mL (0.5–1) to 1.50 mL (0.7–3). Orchidopexy was performed in 4/11 patients. Between end of CSGI and early adolescence period, testicular volume in the treated group decreased from 1.5 mL (0.7–3) to 1.05 mL (0.7–2.36) (P = 0.024) and differed from that in untreated boys (0.3 mL (0.13–1.3); reference range (mL) for the Tanner stage (0.5–4.7)). Concerning hormonal status, hormone levels were higher in the treated group than in untreated group: serum AMH and inhibin B levels in treated patients decreased from 1028 pmol/L (550–1750) and 356 (185–727) pg/mL at neonatal period to 331 pmol/L (85–479) and 68 pg/mL (19–239), respectively, at early adolescence and differed from those in untreated patients (57.5 (30–169) and 8 pg/mL (<5–37), respectively (P < 0.001)).
Conclusion
We report the first long-term follow-up of boys with CHH treated with CSGI in infancy. Our results have shown that the CSGI treatment resulted in higher inhibin B, AMH levels and testicular volume, which had some persisting effects lasting until early adolescence age. Follow-up should be continued until the end of puberty to assess spermatogenesis.
Significance statement
Minipuberty is known to be of some importance for future fertility but is usually absent in infants with hypogonadotropic hypogonadism. CSGI treatment in minipuberty period can mimic this hormonal activation. We describe here the natural course at early adolescence of boys treated with CSGI during their first year of life. The effects shown in the study were higher inhibin B levels and larger testicular volume in patients treated by CSGI treatment, which had some persisting effects lasting until early adolescence period. Follow-up should be continued until the end of puberty to assess spermatogenesis in these patients.
Glickman Urological & Kidney Institute, Cleveland Clinic Foundation,
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The 47,XYY syndrome, or Jacobs syndrome, is a chromosomal disorder affecting approximately one in 1000 male births. While often asymptomatic or mildly expressed, it is associated with various physical, cognitive and behavioral features. Early studies erroneously linked the condition to aggressive behavior and elevated testosterone levels, largely based on incarcerated populations. Recent evidence contradicts this, showing testosterone levels in 47,XYY individuals are typically normal or lower than in 46,XY males. This systematic review and meta-analysis of 362 patients examine hormonal, testicular and fertility outcomes in 47,XYY syndrome. Findings reveal significantly lower testosterone levels and elevated luteinizing hormone and follicle-stimulating hormone, indicating impaired gonadal function. While testicular volumes are often normal, many patients exhibit reduced size and a notable proportion experience oligozoospermia or azoospermia. These outcomes highlight the need for counseling regarding infertility and hormonal imbalances. This review dispels the myth of 47,XYY as a ‘super-male syndrome’, emphasizing the complexity of hormonal, testicular and psychological factors. It underscores the importance of early diagnosis and a multidisciplinary approach to address endocrine and reproductive health. Regular monitoring for hypogonadism and consideration of assisted reproductive technologies are recommended to support affected individuals.
Pediatrics and Neonatology Unit, Santo Stefano Hospital, AUSL Toscana Centro,
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Department of Health Sciences, University of Florence, Florence, Italy
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Objective
Gonadal dysfunction is a major late complication after cancer diagnosis and treatment. We aimed to study the prevalence of premature ovarian insufficiency (POI) and the potential reduction of ovarian reserve in a cohort of adolescent and young adult (AYA) patients undergoing cancer treatments, evaluating ovarian function and reserve markers. We also aimed to analyze how these markers are related to each other and to treatment-related risk factors.
Methods
We performed a retrospective study, including all female AYA patients undergoing cancer treatment during childhood or adolescence, who visited our pediatric gynecology outpatient clinic between January 1, 2018, and August 30, 2023. Serum levels of anti-Mullerian hormone (AMH) and follicle-stimulating hormone (FSH), antral follicle count (AFC) and mean ovarian volume were evaluated. The correlations between these markers and how their alterations are related to treatment-related risk factors were analyzed.
Results
The prevalence of POI in 95 patients was 18.9%. A significant positive correlation was observed between AMH levels and both AFC and ovarian volume. AMH was the most reliable serum marker for ovarian function in terms of POI. Independent risk factors for ovarian dysfunction in relation to all the markers analyzed were hematopoietic stem cell transplantation (HSCT) and high doses of alkylating agents (≥6000 mg/m2).
Conclusion
Gonadal dysfunction and infertility are quite common in AYA patients undergoing cancer treatment. High-dose alkylating agents and HSCT are the independent risk factors. AMH and FSH values, AFC and mean ovarian volume provide different but consistent information for closely monitoring patients after cancer treatment.
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Department of Breast Surgery, Henan Provincial People’s Hospital,
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Department of Breast Surgery, Henan Provincial People’s Hospital,
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Background
Ethylene oxide (EO) is an environmental chemical widely used in industry and has been related to various conditions such as dyslipidemia and metabolic syndrome. However, it is not clear what effect EO has on sex hormones. This paper aims to investigate the connection between EO exposure and sex hormones.
Methods
EO exposure was assessed by measuring blood levels of hemoglobin adducts of EO (HbEO). Based on the National Health and Nutrition Examination Survey (NHANES) 2013–2016 dataset, we assessed linear and nonlinear associations between HbEO and sex hormone levels using weighted multivariate linear regression analyses and weighted generalized additive modeling approaches. We further calculated the threshold effect using a two-piecewise linear regression model. In addition, we performed subgroup analyses.
Results
In men, HbEO levels showed a U-shaped relationship with total testosterone (TT) and sex hormone binding globulin (SHBG), with inflection points ln(HbEO) (natural logarithmic transformed value of HbEO) of 4.12 and 3.78 pmol/g Hb, respectively. HbEO levels in women showed an inverted U-shaped relationship with TT, with an inflection point ln(HbEO) of 4.54 pmol/g Hb. However, to the right of the inflection point, the relationship between HbEO and TT was not statistically significant (β = −0.09, 95%CI −0.21, 0.03). Female HbEO levels were negatively correlated with estradiol (β = −0.11, 95%CI −0.19, −0.03). In addition, we found a positive correlation between HbEO and SHBG in women with a body mass index (BMI) <25 (β = 0.12, 95%CI 0.04, 0.20, P for interaction = 0.007).
Conclusions
EO exposure leads to altered sex hormone levels in the general US population, and further research is required in the future to validate our findings.
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Background
The aim is to develop age-specific anti-Müllerian hormone (AMH) screening criteria for polycystic ovary syndrome (PCOS) to facilitate early detection and diagnosis of the condition and subsequently evaluate the screening criteria.
Methods
A retrospective analysis was performed on patient data from Hangzhou Women’s Hospital between July 2021 and August 2024. The use of restricted cubic spline analysis helped identify age-related inflection points, which were crucial for segmenting the patient population. Statistical analysis was conducted using SPSS software, and the receiver operating characteristic curve was employed to determine the area under the curve, optimal AMH screening thresholds, sensitivity, specificity, Youden index, correct diagnosis rate, positive predictive value and negative predictive value. The established age-related AMH screening criteria for PCOS were then validated using a separate validation group. The consistency of the PCOS age-related AMH screening test with the 2003 Rotterdam PCOS diagnostic criteria was assessed using the kappa statistic.
Results
The derived age-specific AMH screening thresholds for PCOS are as follows: ≥6.93 ng/mL (20–27 years old), ≥5.06 ng/mL (28–30 years old) and ≥4.19 ng/mL (31–39 years old).
Conclusion
The age-stratified AMH screening criteria demonstrated high sensitivity, specificity and accuracy in identifying PCOS, indicating a strong predictive value. However, the development of more robust and universally applicable diagnostic criteria for PCOS will require additional multicenter, prospective clinical trials for further validation.
Department of Andrology, West China Second University Hospital of Sichuan University,
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education,
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Department of Andrology, West China Second University Hospital of Sichuan University,
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education,
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Department of Andrology, West China Second University Hospital of Sichuan University,
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education,
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Department of Andrology, West China Second University Hospital of Sichuan University,
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education,
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Graphical abstract
Role of anti-Müllerian hormone (AMH) in male development and fertility prediction. (A) AMH levels in normal development, constitutional delay of growth and puberty (CDGP) and central hypogonadotropic hypogonadism (CHH) models. In normal males, AMH declines with puberty; in CDGP and CHH, AMH is normal or slightly elevated or abnormally low, indicating delayed or impaired pubertal progression. (B) AMH as a predictor of successful sperm retrieval (SSR) in idiopathic non-obstructive azoospermia. Lower AMH levels (<2.6 ng/mL) correlate with higher SSR in microdissection testicular sperm extraction.
Abstract
Anti-Müllerian hormone (AMH), a biomarker secreted by Sertoli cells in the testes, has emerged as a critical indicator of male reproductive function with significant clinical application potential. AMH reflects Sertoli cell activity and plays a pivotal role across different stages of male gonadal function. First, in prepubertal males, AMH levels are crucial for assessing testicular development and the progression of puberty, with delayed or insufficient AMH secretion often being associated with disorders such as delayed puberty. Second, in reproductive-age males, AMH serves as an important biomarker for evaluating spermatogenic capacity, particularly in cases of idiopathic non-obstructive azoospermia. In these patients, AMH levels can help predict the success of testicular sperm extraction, thereby influencing fertility treatment strategies. This review explores the physiological mechanisms of AMH and its diagnostic and prognostic significance in both delayed puberty and fertility disorders in reproductive-age males. While AMH shows great promise in the management of hypogonadism, further research is needed to validate its clinical utility and refine treatment protocols for optimizing patient outcomes.
University of Belgrade – Faculty of Biology, Institute of Physiology and Biochemistry “Ivan Djaja”, Department of General Physiology and Biophysics, Center for Laser Microscopy,
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School of Medicine, University of Belgrade,
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Laboratory for Experimental Psychology, Faculty of Philosophy, University of Belgrade,
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LIRA laboratory, Faculty of Philosophy, University of Belgrade,
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Endocrine-disrupting chemicals are significant contributors to various detrimental conditions, mechanistically disrupting the endocrine system and causing adverse health effects. Mounting evidence suggests they can induce multigenerational and transgenerational effects, yet awareness among individuals remain insufficient. This study aimed to assess the knowledge, attitudes and ways of informing mothers in Serbia about endocrine disruptors based on information from 190 women in Serbia. The research was conducted using a survey consisting of multiple-choice questions comprising: the first part aimed to collect sociodemographic data, the second part related to knowledge and attitudes about endocrine disruptors, and the third part focused on the sources of information about endocrine disruptors. Cronbach’s alpha was used to check for scale reliability, and Pearson correlation was used to test the relations between interval variables. ANOVA was employed to test for group differences. The results indicated that mothers in Serbia do not have adequate knowledge about endocrine disruptors (potential sources, categories of substances and alternatives) nor confidence in their ability to mitigate exposure to endocrine disruptors. Also, the estimation of the health risks of exposure to endocrine disruptors was perceived as high, and the mothers thought that they should get additional information about endocrine disruptors before pregnancy. Although with several limitations (i.e. mothers were recruited among those with higher education and mainly from urban areas), the study results highlight the necessity for enhanced maternal education in Serbia regarding endocrine disruptors. Health professionals are deemed most suitable for providing this education, given the respondents' high level of trust in them.
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Objective
Individuals with a difference of sex development (DSD) face complex medical and psychosocial challenges, which can make it difficult to provide care tailored to their needs and in line with guidelines. The DSDCare project in Germany regularly evaluates the quality of care for people with DSD, focusing on patient satisfaction as a key indicator of care quality.
Design
Nationwide, longitudinal, multicentre observational study in Germany, including people with DSD.
Methods
Since May 2021, ten specialised DSD centres have been recruiting individuals with DSD and collecting patient-related medical data in a registry. Participants and legal guardians, in the case of minors, complete a questionnaire about satisfaction with care using the Y/CHC-SUN questionnaire. Both medical and self-reported data were merged and analysed descriptively.
Results
Between May 2021 and December 2023, 141 adults and 232 parents completed the questionnaire. Of these, 81.9% of adults and 86.4% of parents reported being ‘very’ or ‘extremely satisfied’ with their healthcare. Satisfaction scores in the dimensions ‘doctor’s behaviour’ and ‘patient-centred care’ were very high for both adults and parents, while the dimensions ‘clinical environment’, ‘diagnosis/information’ and ‘coordination’ were rated slightly lower. Some participants expressed unmet needs for DSD training, psychological counselling, contact with self-advocacy groups and, in the case of adults, nutritional counselling.
Conclusion
Individuals with DSD treated at specialised DSD centres in Germany report high satisfaction with their care. The next step is to ensure that all individuals with DSD have access to a specialised centre to where their care needs can be met.
Significance statement
Several international guidelines provide recommendations for the management of individuals with DSD. Previous studies examining the evolution of management practices in response to these guidelines have concluded that while some are being implemented, others are not, with notable regional variations. In addition, there is limited understanding of satisfaction with care from the perspective of adults and, in particular, from parents of children with DSD, which is a key indicator of quality of care. Consequently, our study focused on patient-related outcomes and experiences, as well as on identifying unmet needs to enhance the quality of care for individuals with DSD in Germany.
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NIHR, Imperial Biomedical Research Centre,
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Background
Semen analysis is the standard test for evaluating male fertility. However, it may not address all aspects of male infertility. This review explores the role of leukocyte elastase (LE) as a possible biomarker for male fertility by evaluating 28 corresponding studies.
Objectives
We aimed to explore how LE levels in semen relate to sperm quality and pregnancy outcomes.
Methods
This systematic review followed PRISMA guidelines and included studies from PubMed, Medline, Embase and Scopus (March 22–25, 2024) using the keywords ‘elastase’, ‘sperm’ and ‘semen’. Out of 897 identified articles, 334 were screened, leading to 90 full-text reviews. We included 28 studies reporting sperm parameters linked to LE and excluded non-English articles, reviews and animal studies. Data collected included study details, methods, population, LE levels, sperm characteristics and pregnancy outcomes. A narrative synthesis was used because of differing study designs. Quality assessment, using the National Heart, Lung, and Blood Institute tool, rated 21 studies medium quality, 6 high and 1 low.
Results
Only a limited number of studies reported a correlation between LE levels and sperm parameters, with no significant link to sperm concentration. Overall, we did not identify a strong association between LE levels and pregnancy or fertilization rates.
Conclusions
Although LE serves as a marker for seminal leukocyte concentration, its link to sperm quality and fertility outcomes remains weak and inconsistent. Based on current evidence, LE does not appear to be a reliable diagnostic marker for male infertility. Future studies should focus on standardizing LE measurement techniques and exploring its interaction with other semen parameters to clarify its role in male fertility.
