Reproduction
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ANZAC Research Institute, University of Sydney, Concord Hospital,
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ANZAC Research Institute, University of Sydney, Concord Hospital,
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Objective
Androgen insensitivity syndrome (AIS) due to androgen receptor (AR) mutations creates a spectrum of clinical presentations based on residual AR function with the mildest impairment creating mild AIS (MAIS) whose undefined molecular mechanism and subtle clinical features leave it less understood and underdiagnosed.
Design
In silico modeling and in vitro androgen bioassay of the mutated AR are used to identify its structural and physiological mechanism. Clinical features and responses to high-dose testosterone treatment of three cases of MAIS across a six-generation family pedigree are described.
Methods
Structural and dynamic in silico molecular modeling and in vitro yeast-based androgen bioassays of the mutant AR are employed. Three cases of MAIS with consistent (gynecomastia and micropenis) and variable (infertility) clinical features across generations are reported, and the effects of high-dose testosterone treatment are studied.
Results
The missense AR exon 8 mutation (nucleotide aga → gga, p.R872G arginine to glycine), known to cause an increased ligand dissociation rate in mutant AR in binding assays, was analyzed. Modeling shows that the mutation weakens the closure energy of the ‘lid’ of the ligand-binding pocket, allowing easier ligand dissociation from the binding site but with unimpaired in vitro androgen bioactivity. High-dose testosterone treatment for 3 years in one young man caused increased virilization and height growth but was ineffective for treating micropenis. Genetic counseling allowed effective prediction of MAIS risks in progeny for carrier and noncarrier sisters.
Conclusions
The differential diagnosis and clinical management of MAIS is reviewed. The novel molecular mechanism of an AR ligand-binding domain mutation in MAIS may be present in other cases of MAIS.
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Purpose
Our study aimed to assess the relationship between serum adipokines and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS) and explore the predictive value of adipokines on IR in PCOS.
Methods
This was a prospective cross-sectional study. 154 women with PCOS were included from July 2021 to September 2022 who underwent gonadal steroid hormone measurement, lipid profile, oral glucose tolerance test and homoeostasis model assessment (HOMA)-IR. Adiponectin (APN), leptin and secreted frizzled-related protein (Sfrp5) were measured by immunoturbidimetry and enzyme-linked immunosorbent assay. Women with PCOS were categorised based on the presence of IR.
Results
Women with PCOS with IR (n = 99) had significantly lower APN level and APN-to-leptin ratio (A/L ratio) than those without IR (n = 55), whereas serum levels of leptin and Sfrp5 were similar between the two groups. In multivariable linear regression analysis, serum log (APN) and log (A/L ratio) were associated with log (HOMA-IR), and the association was statistically significant after adjusting for body mass index and free androgen index. The area under the receiver operating characteristic curve (95% CI) for APN and A/L ratio was 0.726 (0.644–0.807; P < 0.001) and 0.660 (0.569–0.751; P < 0.01), respectively, with cutoff values of 5.225 mg/L (Youden index ¼ 0.364) and 1.438 mg/L (Youden index ¼ 0.265).
Conclusion
Our study demonstrated that serum APN was negatively related to IR. Serum APN may be useful as a clinical marker for IR in women with PCOS. Our findings warrant further investigations into the function of APN in the pathogenesis of IR in women with PCOS.
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Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education of the People’s Republic of China, Hefei, Anhui, China
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Graphical abstract
The potential protective mechanisms of MT on hepatic OS in PCOS. MT could lead to a decrease in autophagy, presenting a decrease of LC3 and an increase of P62 in the PCOS liver. Increased P62 could reduce Nrf2 ubiquitination and increase its nuclear translocation and activation through direct interaction with Keap1. Thus, MT ultimately activated the Keap1-Nrf2 pathway, promoting nuclear Nrf2 expression to reduce hepatic OS.
Abstract
The elevated level of hepatic oxidative stress (OS) in polycystic ovary syndrome (PCOS) is one of the important causes of liver abnormalities. Therefore, decreasing the level of hepatic OS in PCOS is beneficial in reducing the risk of PCOS-related liver diseases. Melatonin (MT) is recognized as a potent antioxidant. Nevertheless, the efficacy of MT in alleviating hepatic OS associated with PCOS is yet to be established, and the precise mechanisms through which MT exerts its antioxidant effects remain to be fully elucidated. The aim of this study was to explore the potential mechanisms by which MT reduces hepatic OS in PCOS. First, we detected elevated OS levels in PCOS samples. Subsequently, with MT pretreatment, we discovered that MT could significantly diminish the levels of OS, liver triglycerides, total cholesterol, alanine aminotransferase, and aspartate aminotransferase, while concurrently ameliorating mitochondrial structural damage in the PCOS liver. Furthermore, we identified elevated autophagy levels in the liver of PCOS rats and an inhibition of the Keap1–Nrf2 pathway. Through MT pretreatment, the expression of LC3 was significantly decreased, while the Keap1–Nrf2 pathway was activated. Our study showed that MT could affect the Nrf2 pathway dependent on the P62/LC3 autophagy pathway, thereby attenuating hepatic OS in PCOS. These findings offer novel insights and research avenues for the study of PCOS-related liver diseases.
Office for Rare Conditions, University of Glasgow, Glasgow, UK
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Office for Rare Conditions, University of Glasgow, Glasgow, UK
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Background
There is a paucity of information on health-related quality of life (HRQoL) outcomes in parents and children with conditions affecting sex development. The objective of this study was to develop short forms of HRQoL questionnaires which consist of a 63-item and 25-item parent self-report (PSR) and parent proxy-report (PPR), respectively, optimizing use in routine clinical settings.
Methods
Short questionnaires were developed following exploratory factor analysis using raw data from 132 parents. Long and short PSRs were completed by 24 parents of children with conditions affecting sex development, with a median age of 3.6 years (range 0.1, 6.6); 21 (88%) were boys, and 11 (46%) had proximal hypospadias. A subset of 19 parents completed both long and short PPRs.
Results
Item selection, based on factor loadings of >0.8 and expert consultation, produced short PSRs and PPRs containing 16 and 7 items, respectively. There was no statistically significant difference in 11 out of 12 (92%) scales on the PSR and 4 out of 5 (80%) scales on the PPR when comparing short and long questionnaire scores. The short and long questionnaires took <1 min and 5 min to complete, respectively. Eighteen parents (75%) reported that the time taken to complete the short questionnaires was acceptable; 10 (42%) preferred short questionnaires. Ten (42%) versus 6 (25%) stated a preference for completing the short versus long questionnaires.
Conclusion
The short versions were largely representative of the long questionnaires and are acceptable for evaluating psychosocial distress in young children and their caregivers. Further psychometric validation of the short forms is warranted.
Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Unit of Endocrinology, Diabetes Mellitus and Metabolism, ARETAIEION University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Introduction
To investigate whether synthetic (s) glucocorticoids (GCs) administered between the 24th and the 34th gestational weeks in pre-term labor might precipitate labor, studies on sGCs administration were reviewed. The physiology of endogenous glucocorticoid-related increase in fetal–maternal circulation and its association with labor, followed by a scoping review of studies on exogenous sGCs administered for fetal lung maturation and the timing of labor, were included.
Materials and methods
The methodology of systematic reviews was followed. MEDLINE, Cochrane Library, and Google Scholar databases were searched until October 2023, for original studies investigating the administration of sGCs in pregnancies risking pre-term labor. Duplicates were removed, and 1867 abstracts were excluded as irrelevant. Six controlled and four non-controlled studies were included. The index group consisted of 6001 subjects and 7691 controls in the former, while in the latter, the index group consisted of 2069 subjects.
Results
In three out of the six controlled studies, gestational age at labor was significantly lower in sGC-treated women than in controls, while in three studies, gestational age at labor was lower in sGC-treated women than in controls, with a trend toward statistical significance. In one study, gestational age at labor was significantly lower in controls than in sGC-treated women. In the non-controlled studies, the majority of women delivered less than 1 week from the day of sGC administration.
Conclusions
In this scoping review, studies lack homogeneity. However, in the controlled studies, a pattern of earlier labor emerges among sGC-treated pregnant women. The use of multiple courses of antenatal sGCs appears to be associated with precipitated labor. Their use should be carefully weighed. Carefully designed trials should examine this ongoing scientific query.
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Background
The data on Leydig cell hypoplasia (LCH) resulting from biallelic Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) inactivating variants is limited to case series.
Methods
We aim to describe our patients and perform systematic review of the patients with LHCGR inactivating variants in the literature. Detailed phenotype and genotype data of three patients from our centre and 85 (46,XY: 67; 46,XX: 18) patients from 59 families with LHCGR-inactivating variants from literature were described.
Results
Three 46,XY patients (age 6–18 years) from our center, with two reared as females, had two novel variants in LHCGR. Systematic review (including our patients) revealed 72 variants in 88 patients. 46,XY patients (n = 70, 56 raised as females) presented with pubertal delay (n = 41) or atypical genitalia (n = 17). Sinnecker score ≥3 (suggesting antenatal human chorionic gonadotropin (hCG) inaction) was seen in 80% (56/70), and hCG-stimulated testosterone was low (<1.1 ng/mL) in 77.4% (24/31), whereas puberty/postpubertal age, high luteinizing hormone (LH) (97.6%, 41/42) and low (<1.0 ng/mL) basal testosterone (94.9%, 37/39) was observed in most. Follicle stimulating hormone was elevated in 21/51 of these patients. Variants with <10% receptor function were exclusively seen in cohorts with Sinnecker 4/5 (10/15 vs 0/5, P = 0.033). 46,XX patients (n = 18) presented with oligo/amenorrhea and/or anovulatory infertility and had polycystic ovaries (7/9) with median LH of 10 IU/L (1.2–38).
Conclusion
In summary, this study comprehensively characterizes LHCGR variants, revealing genotype-phenotype correlations and informing clinical management of LCH. In 46,XY LCH patients, pubertal LH inaction is uniform with variable severity of antenatal hCG inaction. Few mutant LHCGR have differential actions for LH and hCG.
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Prenatal stress can lead to the programming of the neuroendocrine system in male offspring, disrupting the hypothalamic testicular axis and adversely affecting the reproductive health of male offspring. This study aimed to determine the long-term effects of prenatal stress on the KISS1 system in male offspring and the effects on reproductive function in male offspring. Sixteen pregnant females were divided into a prenatal control group (PC, n = 8) and a prenatal stress group (PS, n = 8). The PS group was modeled with chronic unpredictable mild stress (CUMS) from day 1 of gestation to full-term delivery. Differences between the two groups in various maternal parameters, including glucocorticoid secretion, litter size, and the effects of male offspring birth weight, the KISS1 system, and reproductive function, were determined. Male offspring of PS dams had lower birth weights compared to prenatal controls.KISS1 gene expression is reduced at birth and in adult PS offspring, and its receptor KISS1-R protein is similarly reduced in PS offspring at birth and adulthood. In adulthood, PS male offspring show significantly reduced sex hormone production, altered testicular morphology, reduced maturation of their supporting cells, and decreased expression of connexin 43 (CX43), leading to an altered sperm microenvironment and reduced sperm quality. In conclusion, prenatal stress leads to adverse changes in the KISS1 system in male offspring and decreased reproductive function.
Laboratory of Biotechnology, Environment, Food, and Health, Faculty of Sciences Dhar El Mahraz, Sidi Mohammed Ben Abdellah University, Fez, Morocco
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Background
Differences/disorders of sex development (DSD) encompass a wide range of conditions. Their clinical spectrum and etiological diagnosis have not been reported in Moroccan patients.
Aims
The study aims to highlight the clinical spectrum, etiological diagnosis, and management of patients with DSD.
Subjects and methods
This is a retrospective study of all patients diagnosed with DSD under the age of 18 years, who were referred to the Pediatric Endocrinology Department and the Medical Genetics Laboratory at HASSAN II University Hospital of Fez between June 2018 and June 2023.
Results
Out of 57 patients, 54.4% (n = 31) were diagnosed with 46,XX DSD, the most common type, while 45.6% (n = 26) had 46,XY DSD. Patients with 46,XX DSD presented earlier than those with 46,XY DSD, at a median age of 0.08 years and 0.96 years, respectively. The most commonly reported complaint was atypical genitalia. At the first presentation, the sex of rearing was already assigned to 26 males and 27 females. All patients with 46,XX DSD were diagnosed with congenital adrenal hyperplasia (CAH) at a median age of diagnosis of 0.92 years. Of these, 11 patients were raised as males. Disorders of androgen action or synthesis were more common in XY patients (69.2%). The consanguinity rate was 46.5%, and there were 19 cases with a positive family history, with 10 siblings having died.
Conclusion
DSD are not rare in Morocco. Overall, CAH remains the most frequent DSD etiology. Molecular genetic analyses are needed to determine the accurate etiological distribution of DSD, especially in XY patients.
Department of Performance and Image-enhancing Drugs Research, Android Health Clinic, Utrecht, the Netherlands
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Department of Internal Medicine, Spaarne Gasthuis, Haarlem, the Netherlands
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Department of Performance and Image-enhancing Drugs Research, Android Health Clinic, Utrecht, the Netherlands
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Erythrocytosis, or elevated hematocrit, is a common side effect of testosterone therapy (TTh) in male hypogonadism. Testosterone stimulates erythropoiesis through an initial rise in erythropoietin (EPO), the establishment of a new EPO/hemoglobin ‘set point’, and a parallel decrease in the master iron regulator protein hepcidin, as well as several other potential mechanisms. Evidence shows an increased thrombotic risk associated with TTh-induced erythrocytosis. Several guidelines by endocrine organizations for the treatment of male hypogonadism recommend against starting TTh in patients presenting with elevated hematocrit at baseline or stopping TTh when its levels cannot be controlled. Besides dose adjustments, therapeutic phlebotomy or venesection is mentioned as a means of reducing hematocrit in these patients. However, evidence supporting the efficacy or safety of therapeutic phlebotomy in lowering hematocrit in TTh-induced erythrocytosis is lacking. In light of this dearth of evidence, the recommendation to lower hematocrit using therapeutic phlebotomy is notable, as phlebotomy lowers tissue oxygen partial pressure (pO2) and eventually depletes iron stores, thereby triggering various biological pathways which might increase thrombotic risk. The potential pros and cons should therefore be carefully weighed against each other, and shared decision-making is recommended for initiating therapeutic phlebotomy as a treatment in patients on TTh who present with increased hematocrit.
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Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond–Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18–6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46–18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3–14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0–8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2–17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57–14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32–11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09–13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57–14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.
