Klinefelter Syndrome

The study aims to carry out a translational analysis of the microbiome and metabolomics in patients suffering from non-obstructive azoospermia, with the aim of investigating prognostic factors predictive of the possible finding of spermatozoa following testicular pulp extraction and differences in blood and seminal level with the fertile population to identify etiopathogenic pathways of this condition. Furthermore, the study aims to assess if the blood and seminal alterations of infertile patients have similarities with the same fluids of elderly patients, validating from a metabolomic and microbiomic point of view the hypothesis of premature aging of infertile patients.

This is a Phase 3/4, open-label, multicenter study in approximately 100 males 12 to \< 18 years of age with primary or secondary hypogonadism (congenital or acquired). Each participant will be screened for eligibility within 28 days before receiving his first dose of study drug on Day 1. During the Screening period, each participant will have a full clinical examination with pubertal staging, including 2 separate serum total testosterone (TT) measurements obtained in the early morning, where the average (Cavg) will be considered baseline value. Each participant will be categorized as having primary or secondary hypogonadism prior to dosing on Day 1. Participants meeting all eligibility criteria will be assigned to a starting dose of XYOSTED based on their weight and Targeted Tanner Stage on Day 1. The Targeted Tanner Stage will be determined during Screening by an experienced pediatric endocrinologist. Participants will have dose adjustments during the study to achieve their Targeted Tanner Stage. Dose adjustments will be based on reviewing the TT concentration between doses (Cmid) by measuring serum TT 14 days after the administration of XYOSTED for participants receiving the Q4W schedule, 7 days after the administration of XYOSTED for participants who are on the Q2W schedule, and 4 days after administration of XYOSTED for participants on the Q1W schedule. Participants will be evaluated for further dose adjustments approximately every 3 months to achieve the desired targeted TT level. Following the 52-week primary study, participants may join a 24-month long-term safety extension study to continue the evaluation of XYOSTED in this population. Participants will return to the clinic at 6-month intervals for evaluation for clinical evaluations, and laboratory and pharmacokinetic assessments.

The objective of the biocollection is to respond to 3 scientific projects in MDS : Project 1: splicing anomalies in MDS with SF3B1 mutations : About 95% of the coding genes in humans are subjected to alternative splicing, a complex, highly regulated mechanism that diversifies the proteome by defining multiple proteins from a single gene. Deregulation of splicing is observed in many cancers and hemopathies (review Yoshida et al., 2014), especially in myelodysplastic syndromes More than half of MDS patients present an acquired mutation in a gene involved in the splicing of pre -RNA messengers. The SF3B1 gene (splice factor 3B subunit 1), which encodes a protein involved in the recognition of 3 'splice sites is the most frequently mutated gene in SMDs, at a frequency of 20-28% MDS, and up to 85% of myelodysplastic syndromes with crowned sideroblasts (Yoshida et al., 2011, Papaemmanuil et al., 2011). The functional consequences of the splicing abnormalities thus generated on the pathophysiology of MDS are far from clear. The transcriptome analyzes (by RNA-seq) carried out recently in various acquired pathologies that the most frequent variants of the SF3B1 gene lead to the formation of aberrant transcripts by the use of a 3 ' cryptic splicing site. The investigators seek to study the functional implications of SF3B1 mutations found in MDS patients in particular on the formation of sideroblasts in the crown. The investigators want to identify, by RNAseq, the aberrant junctions specifically expressed in the cells of MDS patients with mutated SF3B1, and which would affect transcripts of genes involved in iron metabolism or its regulation. For this, the investigators will use the cells obtained from the marrow of SMD SF3B1WT patients versus SF3B1K700E and collected in the Chromosomal Genetics laboratory, site of the CRB of the CHRU of Brest. The investigators will then analyze the functional repercussions associated with the presence of these aberrant junctions on the cells in culture of these same patients (detection of certain proteins, enzymatic analyzes, etc.). The collection of biological and clinical data from these patients of interest is essential for the interpretation of the results. This project is part of a more global approach to the study of the various splicing anomalies in this pathology. Project 2: splicing abnormalities in MDS with chromosomal abnormalities as 5q deletion : Chromosome 5 deletions are the most frequent structural abnormalities in MDS and constitute a good prognostic entity if isolated or associated with an anomaly and poor prognosis if associated with more than 3 chromosomal abnormalities. Two genes located on chromosomes 5 encode proteins of a complex involved in the splicing of pre-messenger RNAs: the RBM22 gene (RNA Binding Motif Protein 22) and the SLU7 gene (SLU7 Homolog Splicing Factor). The investigators want to identify subgroups of patients with loss of these 2 genes or loss of RBM22 and conservation of SLU7. Does the loss of one or both genes play a role in the pathophysiogenesis of MDS with chromosome deletions and is it associated with worsening of the disease? Understanding these mechanisms could also have an impact on the therapeutic management of this pathology. The study of these chromosomal abnormalities associated with splicing abnormalities in MDS for the chromosomal genetics laboratory both from a diagnostic and research perspective. Several works carried out have given rise to numerous scientific publications with an international reading committee for several years. Project 3: Evolution of MDS in acute myeloid leukemia (AML) More than one third of patients with MDS progress to AML. The investigators want to focus on this group of patients and understand the clonal architecture of their malignant cells to detect new predictive markers of indolent or rapid disease progression.

The study aim is to evaluate whether testing embryos for chromosomal abnormalities (known as aneuploidy) can aid in embryo selection. If so, transfer of embryos that will fail to implant, miscarry or lead to birth of affected children, can be reduces. This would reduce the risk of miscarriage and increase the chance of healthy live birth per embryo transfer, which in turn would reduce the time and economical, physical and psychological cost associated with fertility treatment. The method of genetically testing embryos for aneuploidy is know as preimplantation genetic testing for aneuploidy (PGT-A). It entails testing a biopsy from preimplantation embryos generated from assisted reproductive technology (ART) from which DNA can be analyzed. Another potential source of embryonic DNA is the spent culture media, the media in which the embryo has grown since the egg was fertilized with the sperm. Previous research suggest that the media contains DNA shed from the embryo during development. Hence, this a potential non-invasive way of obtaining DNA for PGT-A. Both embryo biopsy and spent culture media will be assessed in the study. The study will be conducted as a prospective, blinded, prognostic cohort study in a cohort receiving preimplantation genetic testing for monogenic disorders (PGT-M). Hence, the study does not include an intervention, as data on aneuploidy is collected but not used to guide embryo selections and embryos are biopsied as part of standard care (PGT-M). Once clinical outcomes from embryo transfers has been collected from the study, the aneuploidy data will be assessed. Blinded towards the actual clinical outcome, predictions on whether each embryo would result in live birth or not will be made based on the aneuploidy results. Following prediction, actual clinical outcomes are revealed allowing calculation of predictive values. Predictive values will be calculated for PGT-A on embryos biopsies and spent culture media. Two predictive values will be assessed. The positive predictive value (PPV) and the negative predictive value (NPV). The PPV states how often an embryo predicted to result in live birth upon transfer actually did so. Numerous factors affect the chance of live birth besides aneuploidy, so while the PPV will never reach 100%, it should increase compared to the PPV of standard care (without testing for aneuploidy. The NPV states how often an embryo predicted not to result in live birth upon transfer actually also failed to do so. The NPV should be near 100 %, which would mean that all or almost all embryos that would have been deselected did not result in live birth. If the NPV is too low, it means that too many embryos capable of resulting in live birth are being discarded, disqualifying PGT-A for clinical use. With the predictive values assessed a proper evaluation of whether PGT-A should be used clinically can be made. A number of pre- and postnatal samples will be collected in the study to further validate PGT-A results. These include chorionic villus sampling, amniocentesis, Fetal cells isolated from maternal blood, products of conception and a DNA sample from the newborn. All of these samples can be consented to individually and as such are not required for participation in the study. Chorionic villus sampling and amniocenteses are only acquired if performed as part of routine care. The study is expected to include 540 transfers requiring the recruitment of approximately 220 patients. Recruitment is expected to take two years combined at the two centers in Denmark participating in the study.

Background The epidemics of obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis are increasing worldwide. Non-alcoholic fatty liver disease (NAFLD), for a long time unnoted in the metabolic field, is becoming recognized as a condition possibly involved in the pathogenesis of these diseases. Support for this hypothesis emerges from studies revealing that NAFLD precedes the manifestation of the metabolic derangements. NAFLD includes the whole spectrum from non-evolutive simple steatosis to progressive non-alcoholic steatohepatitis (NASH) with/without cirrhosis and hepatocellular carcinoma in individuals without relevant alcohol consumption. NAFLD is a relevant issue in public health owing to its' epidemiologic burden. It represents the most common chronic liver disease in the general population and is expected to increase in the future as a result of an ageing population, the improving control of other major causes of chronic liver disease and the epidemics of obesity and diabetes. The prevalence of NAFLD varies according to age, gender and ethnicity. In the general population, the prevalence of NAFLD is about 25% and the incidence is of two new cases/100 people/year. 2-3% of individuals in the general population will suffer from NASH. Furthermore, up to 15-20% of patients with NASH may develop cirrhosis and 30-40%of these patients who develop cirrhosis may suffer from liver-related mortality. NAFLD is tightly associated with the metabolic syndrome. The metabolic syndrome is a condition characterized by a cluster of alterations including glucose intolerance/ insulin resistance, abdominal obesity, atherogenic dyslipidemia (low concentrations of high density lipoprotein- cholesterol and high concentrations of triglycerides), elevated blood pressure, a proinflammatory and a prothrombotic state. It increases morbidity and mortality, especially due to cardiovascular disease. The prevailing hypothesis for NAFLD pathogenesis is the 'two-hit' model, with insulin resistance and hyperinsulinemia playing essential roles. Insulin resistance and hyperinsulinemia have a plethora of effects on hepatic lipid metabolism and can lead to accumulation of excess triglycerides in hepatocytes. The progression to NASH entails a 'second hit', which is believed to be due to oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, resulting in inflammation (producing NASH) and fibrosis. Currently, the only accepted treatment for NAFLD regardless of stage is lifestyle modifications. These include weight loss by a combination of decreased caloric intake and increased physical activity. Study rationale Many patients worldwide are suffering from type 2 diabetes with steeply rising numbers predicted for the next decades. Although much progress can be seen in the field of diabetic research and new treatment modalities, new approaches have to be found to cure the disease and underlying risk factors. As men and women show sex specific differences especially in risk factors of T2DM, a sex- and gender-sensitive approach might be considered. Sex hormones might play an important role in the development and possibly the treatment of T2DM. In women higher but in men lower than normal testosterone concentrations predispose for a higher diabetes risk making evident that sex hormones and sex hormone equilibrium are relevant in disease progression. Especially in men low testosterone levels have deteriorating effects on glucose levels, which is aggravated in obesity as aromatization of testosterone to estrogen is enhanced. Due to this mechanism changes in energy homeostasis are reported which lead to changes in lipid accumulation, as described for visceral obesity. Testosterone deficiency is related to increases of visceral fat accumulation. Furthermore testosterone deficiency is associated with the development of non alcoholic fatty liver disease (NAFLD), a well known risk factor for progression of metabolic syndrome (MEtSy), T2DM and cardiovascular disease. Thus, testosterone replacement might be a successful way in hypogonadal men to treat obesity and counteract the further progression of MEtSy, T2DM or cardiovascular disease mainly driven by visceral fat accumulation and NAFLD and are able to improve quality of life. Testosterone and changes in metabolism: Whether low testosterone levels have direct effects on hyperglycaemia or testosterone deficiency is caused by chronic diseases such as type 2 diabetes is not yet fully understood and needs further clarification. Studies are showing that the link between hypogonadism and the metabolic syndrome is bidirectional. On the one hand MetSy and obesity are associated with a higher risk of hypogonadism in the future but on the other hand low testosterone levels and SHBG levels are strong predictors for the development of MetSy and T2DM. It is further hypothesized that hypoandrogenism is an early marker for disturbances in glucose metabolism. Many studies proved that low testosterone levels may aggravate hyperglycaemia and also may deteriorate other metabolic parameters such as insulin levels and sensitivity, lipid levels, hepatic, myocardial and visceral fat content or body composition in general. Just recently the ADA recommends to test for testosterone deficiency (morning testosterone levels) in all men with T2DM with symptoms or signs of hypogonadism, which are decreased sexual desire or erectile dysfunction. Treatment in asymptomatic men is controversial. Supplementation of testosterone in diabetic men with hypogonadism was reported to increase insulin sensitivity and to significantly reduce HbA1c, which was also reported in a long time observational study including men with T2DM with an amelioration of glycemic control as well as other cardiovascular and cardiometabolic parameters. Furthermore, total and LDL cholesterol, as well as lipoprotein a were lowered, and body composition, libido, and sexual function improved, whereas frequencies of adverse events (AEs) or serious AEs between groups were comparable after 6 months of transdermal testosterone application. These results were corroborated by a systematic review including five RCTs with 350 diabetic hypogonadal men showing improvements in fasting glucose, fasting insulin, HbA1c and triglyceride levels. In a recent study depression was found to have confounding effects with alleviated success in reduction in waist circumference, weight, and body mass index as well as improvements in glycaemic control in men with psychiatric disorders. Testosterone is an important regulator of central and peripheral adipose tissue and shows many inhibitory effects such as triglyceride uptake in fat tissue or lipoprotein lipase activity, as well as a higher lipolytic activity triggered by β-adrenergic receptors. An RCT found that in men with hypogonadism subcutaneous fat mass decreases, lean mass and insulin sensitivity increase and the expression of insulin signaling genes is upregulated after testosterone treatment. Furthermore, inflammatory parameters as well as FFA decrease after testosterone treatment. Interestingly in this study a decrease in hepatic lipids in the treatment group was found, which was not significant in a 24 weeks treatment period. However, treatment groups were inhomogenous regarding baseline hepatic lipid content, the lipid content was relatively low for a collective of subjects with T2DM and the treatment period was relatively short. Another recent RCT found significant reductions in HOMA-IR, HbA1c by 0.94 +- 0.88% and an increase in flow-mediated dilatation, which indicates improved endothelial function in a hypogonadal male population with obesity and diabetes. Testosterone and cardiovascular risk: The influence of testosterone on cardiovascular risk factors is not well investigated as prospective data are widely missing but evidence shows that testosterone application in men does not increase cardiovascular risk. Furthermore androgen deficiency is associated with a higher risk in cardiovascular mortality. Recent epidemiological data suspect testosterone replacement therapy to increase cardiovascular risk. However, FDA experts find that data is insufficient to make clear suggestions and that there is a need for clinical trials assessing safety of testosterone replacement in people at high risk for cardiovascular risk, like older men, men with T2DM or obesity. After this FDA statement a retrospectively assessed observational study with over 80000 male veterans with documented low total testosterone levels was published reporting a reduction of all cause mortality, myocardial infarction and stroke in men with testosterone replacement therapy. A reduction of MACE was also reported in a further study in male subjects with low testosterone levels substituted to normal levels compared to those with persistent low levels. Men with high testosterone levels had similar MACE risk but a trend for higher stroke risk. Especially in an obese population with T2DM and hypogonadism the mortality and morbidity caused by coronary artery disease is expected to be high, as CAD is the leading cause of death in subjects with T2DM and often progresses asymptomatic until an infarction or sudden cardiac death occur. Recent conducted MPI (=myocardial perfusion imaging) studies in T2DM patients have shown higher prevalence of abnormal MPI, with more extensive ischemia, compared with subjects without T2DM. The DIAD trial did not show any benefit in prevention of cardiac events comparing MPI screening at regular intervals with a non-screened diabetic population up to nearly 5 years. However, it remains uncertain whether asymptomatic patients with type 2 diabetes benefit from revascularization after the identification of inducible ischemia, as was suggested in a prior retrospective database analysis and a small randomized pilot study. Currently in obese men with hypogonadism and T2DM it is largely unknown whether testosterone replacement has any effects on cardiac perfusion. According to appropriate use criteria (AUC) for the detection a risk assessment of stable ischemic heart disease MPI is a potential diagnostic method to detect CHD at stages of high global coronary artery disease risk \[42\]. According to NCEP ATP III criteria, the recommended tool of the AUC, the patient collective of TEST2FUNC featuring male subjects with hypogonadism, diabetes mellitus, overweight/obesity, hypertension and dyslipidemia are at high risk for coronary heart disease, as diabetes is seen as a CHD risk equivalent and confers to a high risk of new CHD within 10 years. Study objective: This study wants to investigate the direct effects of intramuscular testosterone replacement versus placebo in changing the intrahepatic fat content, myocardial fat content, visceral and abdominal fat content as well as pancreatic fat content of poorly controlled men suffering from T2DM and secondary hypogonadism. Furthermore, the effects of testosterone on glycaemic control and cardiovascular safety will be investigated. The effect of testosterone on cardiac perfusion will be tested in this high risk collective. For studying long-term effects, an open-label extension of the study by an additional 2 years is intended.

Endothelial Dysfunction and Cardiovascular Health: Endothelial dysfunction is characterized by impaired endothelium-dependent vasodilation, which is a critical factor in the development and progression of cardiovascular diseases. The endothelium, the thin layer of cells lining blood vessels, plays a pivotal role in vascular health by regulating blood flow, coagulation, and immune function. When the endothelium is not functioning properly, it can lead to a range of cardiovascular conditions, including atherosclerosis, hypertension, and erectile dysfunction (ED). Erectile Dysfunction and Endothelial Dysfunction: ED is often an early marker of endothelial dysfunction and cardiovascular diseases. Vasculogenic ED, in particular, is linked to poor endothelial health, where impaired blood flow to the penile tissue results in the inability to achieve or maintain an erection. This condition shares common risk factors with other cardiovascular diseases, such as diabetes, hypertension, and hyperlipidemia, highlighting the interconnected nature of endothelial health and ED. Hormonal Therapy and Endothelial Function: Testosterone therapy (T therapy) is commonly used to treat hypogonadism in men, a condition characterized by low testosterone levels. Hypogonadism itself is associated with an increased risk of cardiovascular diseases, and testosterone therapy has been shown to have varying effects on endothelial function. While some studies suggest that testosterone may improve endothelial health, others indicate potential risks, necessitating further research to clarify its impact. Current Gaps in Knowledge: Prevalence of Endothelial Dysfunction in Young Men with ED: While the association between endothelial dysfunction and ED is established, there is a need for precise data on the prevalence and extent of endothelial dysfunction specifically in young men with vasculogenic ED. Understanding this prevalence can inform targeted treatment strategies. Impact of PDE5 Inhibitors on Endothelial Function: Phosphodiesterase type 5 (PDE5) inhibitors are a first-line treatment for ED, known to improve erectile function by enhancing blood flow. However, their direct impact on endothelial function over time remains underexplored, particularly in terms of long-term cardiovascular outcomes. Effects of Testosterone Therapy on Endothelial Health: The influence of testosterone therapy on endothelial function in hypogonadal men is not well understood. There is conflicting evidence on whether testosterone therapy confers cardiovascular benefits or risks, necessitating comprehensive studies to determine its effects.

Although many phase III clinical trials evaluate the quality of life as a secondary endpoint, male sexuality remains a neglected topic in oncology research. In light of the long-term efficacy of new-generation anticancer treatments for ANSCLC (i.e. targeted therapies and immunotherapy), there is a paucity of data about any detrimental effect on fertility and sexuality that could complicate the therapy proposal, especially in young patients. The aim of this trial is to assess incidence of endocrine toxicity and sexual dysfuction in male patients receiving active treatment for ANSCLC

Background and Rationale: Testicular and ovarian failure, often called 'gonadal failure,' occurs when the testes or ovaries lose their ability to produce gametes. Both lead to reduced fertility and hormonal deficiencies, significantly impacting an individual's health and quality of life. Conventional treatments such as hormone replacement therapy (HRT) help alleviate symptoms but do not restore fertility. Surgical options (testicular sperm retrieval, ultrasound-guided egg retrieval) are found to be helpful for some. However, they are not uniformly successful 11. Surgeries (testicular biopsies) always carry risks such as risk of bleeding or infection and lack of guaranteed success 12. Clinicians are exploring less invasive alternatives like stem cell-based therapies, including adipose-derived stem cells (ADSCs) and exosomes. Stem cells or stem cell-derived exosome therapy offers a promising regenerative approach for restoring gonadal function by enhancing tissue repair, stimulating folliculogenesis or spermatogenesis, modulating hormonal balance, and improving overall reproductive potential in individuals with testicular or ovarian failure. This study assesses the safety and efficacy of intra-gonadal (testicular or ovarian) stem cells or stem cell-derived exosome injection for patients with testicular and ovarian failure who have not responded to conventional treatments. ADSC therapy has been studied in humans for related conditions like ovarian insufficiency and POF (Premature ovarian failure)6. It has shown encouraging results in repairing damaged tissues and improving hormonal function, showing early successes that provide hope for its potential. This research assumes even greater importance in the UAE, where donor sperm and eggs are not permitted due to religious and legal restrictions 13. Testing the safety and long-term efficacy of ADSC therapy for gonadal failure in the UAE could provide a groundbreaking, culturally appropriate solution for individuals facing reproductive challenges, giving them new opportunities for treatment and a renewed sense of hope. The Bioscience Institute, a DHA-approved facility, will provide the stem cells or stem cell-derived exosomes under an existing Memorandum of Understanding (MOU) with the First IVF Clinic and Day Surgery Center. The stem cells or stem cell-derived exosomes will be extracted and produced in an off-site laboratory (Bioscience Institute) and undergo sterility, cell count, and viability check before being prepared for administration back into the patient. The manufacturing process follows CGTP. The cells will be injected directly into the testes and ovaries under anesthesia. Study Objectives * Primary Objective: 1\. To evaluate the safety and efficacy of intraovarian or intratesticular injections of stem cells or stem cell-derived exosomes in restoring gonadal function, as measured by hormonal changes (testosterone, estradiol, FSH, AMH) and reproductive capacity from baseline to post-treatment. * Secondary Objectives: 1. Assess gonadal tissue regeneration using imaging techniques. 2. Monitor long-term treatment effects at follow-up points 3. Document any adverse events or complications related to stem cell or exosome therapy, such as fibrosis, infection, or immune reactions. 4. Evaluate functional outcomes such as spermatogenesis in men (via semen analysis) and ovarian follicular activity in women (via antral follicle count and menstrual cycle regularity). 5. Compare the effects of stem cells vs. stem cell-derived exosomes in improving gonadal function and hormone levels. Study Design and Objectives This open-label, single-arm, pilot observational study will serve as a preliminary investigation into the use of adipose-derived stem cells (ADSCs) or stem cell-derived exosomes for treating gonadal failure in both men and women. The study's primary focus will be on assessing safety and feasibility, while also gathering initial efficacy data to support future large-scale trials. Study Population The study will enroll 60 adults (30 males, 30 females) aged 20 to 50 years diagnosed with gonadal failure, including testicular failure, hypogonadism, ovarian insufficiency, or premature ovarian failure (POF). Participants must have failed or experienced suboptimal responses to conventional treatments, such as hormone replacement therapy (HRT), testosterone replacement therapy (TRT), or assisted reproductive technologies (ART). Recruitment will take place at First IVF Clinic, Dubai, where participants are actively receiving evaluation and treatment for gonadal failure. The inclusion and exclusion criteria will ensure that the study targets individuals most likely to benefit from therapy while prioritizing patient safety. Sample Size Rationale A sample size of 60 participants was selected based on the exploratory nature of the study. The primary objective is to assess the feasibility, safety, and preliminary efficacy of stem cell or exosome therapy while providing sufficient data to inform the design of future, larger trials. Given the clinic's patient population, recruiting 60 participants over the planned two-year study period is considered achievable. Study Procedures 1. Informed Consent Participants will receive detailed information about the study, including its risks and potential benefits, and will provide written consent prior to enrollment. 2. Baseline Assessments Before treatment, participants will undergo comprehensive baseline testing, including: Hormonal blood tests (Testosterone, Estradiol, FSH, AMH) Ultrasound imaging (AFC for ovaries, testicular volume for testes) Semen analysis (for male participants, if applicable) Medical history review and general health evaluation 3. Therapeutic Administration For ADSCs: ADSCs will be harvested via minimally invasive liposuction from the participant's own adipose tissue. The cells will be processed, purified, and prepared for injection into the ovaries (females) or testes (males). For Exosomes: Exosomes will be derived from stem cells, isolated, and purified before administration. The injections will follow the same procedure as stem cell therapy, ensuring targeted delivery into the gonads. Injection Procedure: Ovarian injections: Administered via direct intraovarian injection. Testicular injections: Administered via direct intratesticular injection in rete testis. 4. Follow-Up Monitoring Participants will be monitored immediately post-injection for any adverse reactions and will return for regular follow-ups at 3, 6, 9, and 12 months to assess: Data Collection and Analysis Collected data will be analyzed to evaluate primary and secondary outcomes. Primary Outcome: Hormonal level changes from baseline to 12 months post-treatment. Secondary Outcomes: Changes in gonadal tissue structure (AFC, testicular volume). Functional improvements (spermatogenesis, menstrual cycle regulation). Incidence of adverse events (infection, fibrosis, immune response). Surgical sperm retrieval and Egg retrieval success Ethical Considerations This study will adhere to strict ethical standards for clinical research. Ethics Committee Review: The protocol will be reviewed and approved by an independent ethics board. Informed Consent: Participants will have full autonomy to decide on participation and may withdraw at any time without affecting their standard medical care. Confidentiality: All patient data will be anonymized and stored securely to ensure privacy. Expected Outcomes This study aims to provide early evidence on the safety and potential efficacy of stem cell or exosome therapy for gonadal failure. If successful, participants are expected to show: Improvements in hormone levels and reproductive function. Gonadal tissue regeneration, restoring follicular activity or spermatogenesis. Minimal adverse effects, confirming safety and feasibility. The findings from this study will help guide future, larger-scale trials and contribute to the development of regenerative therapies for gonadal failure, offering a novel and culturally appropriate solution for fertility preservation in the UAE.

GALAXY is a registry research study that plans to learn more about individuals with X\&Y variations (also called sex chromosome aneuploidies) through collecting information from medical records.This includes genetic tests, imaging, medications, and more for hundreds of patients seen at a number of clinics across the US. The purpose of the GALAXY Registry is to collect and store this information with the overall goal to improve health outcomes in individuals with X\&Y variations and the care they receive.

Study Description: Gonadal tissue cryopreservation will be evaluated in individuals with Turner Syndrome, galactosemia, post-menarcheal adolescents with recent premature ovarian insufficiency, and children/adolescents conditions associated with POI and with diminished ovarian reserve (DOR) who have contraindication to ovarian stimulation as well as those with diminished ovarian reserve who did not respond to ovarian stimulation, and individuals with variations in sex characteristics (VSD or differences in sex development, DSD) including those with Turner syndrome with Y chromosome material and those with conditions that require high risk gonadotoxic therapy. Objectives: Primary Objectives: After initial evaluation of number and quality of follicles/gametes, the remaining tissue will be utilized to perform research regarding mechanisms of follicle/gametes loss in the included conditions. a. We will perform next generation sequencing on the tissue collected from study participants and ovaries from cadaveric organ donors on cardiopulmonary support. Additionally, some ovarian tissue from patients undergoing gonadotoxic therapy will function as controls. Hypothesis: next generation sequencing from tissue obtained from gonads in individuals with these conditions will differ significantly from that of controls. Such differences may allow for further hypothesis development regarding the underlying mechanism of follicle loss and/or dysfunction in individuals with these conditions. Secondary Objective: This protocol is designed to evaluate the feasibility (meaning a reasonable expectation of future fertility based on the anatomy, histology, and physiology of fresh gonadal tissue as well as the effects after freezing and thawing) of gonadal tissue cryopreservation (GTC) for fertility preservation in children with increased risk of loss of gonadal function due to underlying genetic conditions including Turner syndrome or galactosemia and post-menarcheal adolescents with a recent development of premature ovarian insufficiency (POI) or children/adolescents with conditions associated with POI and presenting with diminished ovarian reserve (based on laboratory findings of low AMH (\<1.0 ng/mL) and/or mildly elevated FSH (\>10 U/L) or those who do not respond to ovarian stimulation for oocyte cryopreservation due to lower follicle counts) or individuals with variations in sex characteristics. 1. The feasibility GTC as a fertility preservation option in these individuals will be evaluated through evaluation of number and quality of follicles/gametes found in the tissue prior to freezing and after thawing. 2. Lack of follicles/gametes in the gonadal tissue will confirm that GTC is not a viable option for fertility preservation for these populations. 3. An attempt to correlate laboratory and imaging markers with follicle/gamete presence and number will be made. b. Hypothesis: Young individuals with Turner syndrome, variations of sex characteristics, classic galactosemia and adolescents with recent POI, and children/adolescents with underlying conditions associated with POI presenting with DOR harbor populations of follicles/gametes which may be preserved through gonadal tissue cryopreservation for future fertility. There will be a variety of follicular findings which will correlate with patient s anti-Mullerian hormone (AMH), age and underlying condition. c. Depending on their underlying condition, individuals with VSC will have gametes (follicles and/or spermatogonia). d. Loss of follicles with cryopreservation and thawing will be similar to that of non-affected individuals. Tertiary Objectives: Research regarding inhibition and activation of follicles within the tissue will be undertaken. 1. Tissue will be treated with known inhibitors and activators and next generation sequencing will be performed in order to assess gene expression before and after treatment. 2. To create a national database of human ovarian tissue of individuals who are undergoing OTC in order to elucidate short and long term outcomes including complication and reproductive health parameters. Hypothesis: Primordial follicles within gonadal tissue in individuals with these conditions may be inhibited from activating. Such techniques may allow for a decrease in follicle loss with freezing and thawing as well as possible future development of novel treatments to prevent accelerated follicle loss in individuals and adolescent affected by these conditions. Promoting follicle activation prior to re-implantation of the tissue may improve the possibility of achieving pregnancy after tissue re-implantation Endpoints: Primary Endpoints: 1. Tissue for research: Next generation sequencing will be performed on tissues of affected individuals and compared to age matched controls: patients who undergo GTC for solid organ tumors far from the reproductive system or cadaveric organ donors on cardiopulmonary support. This will allow for specific cellular type comparisons within the ovary and exploratory research regarding possible mechanisms of follicle loss in these populations. 2. Next generation sequencing on fresh compared to frozen and thawed tissue. This will assess what transcription changed occur due to the freezing process. Secondary Endpoint: 1. Evaluation of density and quality of follicles/gametes in the gonads of individuals with increased risk of loss of gonadal function due to underlying genetic conditions including Turner syndrome or galactosemia and post-menarcheal adolescents with a recent development of premature ovarian insufficiency (POI) or children/adolescents with conditions associated with POI and presenting with diminished ovarian reserve (based on laboratory findings of low AMH (\<1.1 ng/mL) and mildly elevated FSH (10-25 U/L) or those who do not respond to ovarian stimulation for oocyte cryopreservation due to lower follicle counts) or individuals with variations in sex characteristics. 2. Correlation of follicle/gamete density and quality with markers such as age, AMH, condition. 3. Comparison of hormone levels such as AMH, FSH, LH, and Estradiol between patients and controls. 4. Long term data regarding surgical complications Tertiary Endpoint: -Evaluate changes in single next generation sequencing in tissue before and after treatment with primordial follicle inhibitors and activators. The remaining tissue will be cryopreserved for future experiments.