Disorders of Sex Development-Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation.

Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary 'male' pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.

Environmental Impacts on Male Reproductive Development: Lessons from Experimental Models.

BACKGROUND: Male reproductive development in mammals can be divided into a gonadal formation phase followed by a hormone-driven differentiation phase. Failure of these processes may result in Differences in Sex Development (DSD), which may include abnormalities of the male reproductive tract, including cryptorchidism, hypospadias, infertility, and testicular germ cell cancer (TGCC). These disorders are also considered to be part of a testicular dysgenesis syndrome (TDS) in males. Whilst DSDs are considered to result primarily from genetic abnormalities, the development of TDS disorders is frequently associated with environmental factors. SUMMARY: In this review, we will discuss the development of the male reproductive system in relation to DSD and TDS. We will also describe the experimental systems, including studies involving animals and human tissues or cells that can be used to investigate the role of environmental factors in inducing male reproductive disorders. We will discuss recent studies investigating the impact of environmental chemicals (e.g., phthalates and bisphenols), lifestyle factors (e.g., smoking) and pharmaceuticals (e.g., analgesics) on foetal testis development. Finally, we will describe the evidence, involving experimental and epidemiologic approaches, for a role of environmental factors in the development of specific male reproductive disorders, including cryptorchidism, hypospadias, and TGCC. KEY MESSAGES: Environmental exposures can impact the development and function of the male reproductive system in humans. Epidemiology studies and experimental approaches using human tissues are important to translate findings from animal studies and account for species differences in response to environmental exposures.

Protein Ingestion in Reducing the Risk of Late-Onset Post-Exercise Hypoglycemia: A Pilot Study in Adolescents and Youth with Type 1 Diabetes.

Dietary protein causes dose-dependent hyperglycemia in individuals with type 1 diabetes (T1D). This study investigated the effect of consuming 50 g of protein on overnight blood glucose levels (BGLs) following late-afternoon moderate-intensity exercise. Six participants (3M:3F) with T1D, HbA1c 7.5 ± 0.8% (58.0 ± 8.7 mmol/mol) and aged 20.2 ± 3.1 years exercised for 45 min at 1600 h and consumed a protein drink or water alone at 2000 h, on two separate days. A basal insulin euglycemic clamp was employed to measure the mean glucose infusion rates (m-GIR) required to maintain euglycemia on both nights. The m-GIR on the protein and water nights during the hypoglycemia risk period and overnight were 0.27 ± 043 vs. 1.60 ± 0.66 mg/kg/min (p = 0.028, r = 0.63) and 0.51 ± 0.16 vs. 1.34 ± 0.71 mg/kg/min (p = 0.028, r = 0.63), respectively. Despite ceasing intravenous glucose infusion on the protein night, the BGLs peaked at 9.6 ± 1.6 mmol/L, with a hypoglycemia risk period mean of 7.8 ± 1.5 mmol/L compared to 5.9 ± 0.4 mmol/L (p = 0.028) on the water night. The mean plasma glucagon levels were 51.5 ± 14.1 and 27.2 ± 10.1 ng/L (p = 0.028) on the protein and water night, respectively. This suggests that an intake of protein is effective at reducing the post-exercise hypoglycemia risk, potentially via a glucagon-mediated stimulation of glucose production. However, 50 g of protein may be excessive for maintaining euglycemia.

The Challenges of Being Physically Active: A Qualitative Study of Young People With Type 1 Diabetes and Their Parents.

BACKGROUND: Benefits of physical activity are well recognized for youth with type 1 diabetes mellitus (T1DM), but being active is challenging. In this study, we aimed to investigate the challenges experienced by adolescents, their parents and young adults with T1DM when they are physically active. METHODS: Six focus groups involving adolescents (13 to 18 years old, n=14) and young adults (19 to 25 years old, n=7) and 4 focus groups with parents (n=14) of the adolescents (13 to 18 years) were established. Data were analyzed using content analysis. RESULTS: Adolescents and young adults with T1DM identified challenges of unpredictability, knowledge, trust and stigma when they were physically active. Parent challenges were specifically unpredictability and trust. CONCLUSIONS: Interventions are needed that provide adolescents and young adults with T1DM and parents of adolescents with T1DM more in-depth information about managing physical activity in a manner that enhances their perceived competence and builds autonomy. Interventions can also target peer and community support.

Use of Continuous Glucose Monitoring Trends to Facilitate Exercise in Children with Type 1 Diabetes.

Diabetes care during exercise frequently requires interruptions to activity and adds extra challenges particularly for young individuals with type 1 diabetes (T1D). This study investigated the use of a carbohydrate (CHO) intake algorithm based on continuous glucose monitoring (CGM) trends during physical activity. Children with T1D diagnosed for >1 year, ages 8-12 years, with a glycated hemoglobin of <10% were recruited into a randomized crossover study. They attended two similar mornings of fun-based physical activity and adhered to either a CHO intake algorithm based on CGM trends (intervention) or to standard exercise guidelines (consumption of 0.5 g CHO/kg/h when glucose <8 mmol/L) (control). Outcome measures included events such as exercise interruptions, CHO intake, and hypoglycemia events and percentage time spent in different sensor glucose ranges. Fourteen children completed the study. No episodes of significant hypoglycemia (sensor glucose level <3.0 mmol/L) occurred in either arm. Mean CHO intake was the same in both arms, 0.3 ± 0.2 g/kg/h. However, the intervention algorithm resulted in fewer CHO intake events per day: rate [95% confidence interval] 2.4 [1.6-2.3] versus 0.9 [0.4-1.5], P < 0.001, and exercise interruptions: 7.2 [5.9-8.8] versus 1.4 [0.8-2.1], P < 0.001, compared with control. There was no evidence of a difference in percentage time in range (3.9-10 mmol/L) and percentage time spent high between study arms. Both control and intervention protocols prevented significant hypoglycemia. Using a CHO intake algorithm based on CGM trends resulted in fewer CHO intake events and fewer interruptions to exercise. Use of this algorithm may reduce the burden of diabetes management with potential to facilitate activity in young people with T1D.

Exercise Management for Young People With Type 1 Diabetes: A Structured Approach to the Exercise Consultation.

Regular physical activity during childhood is important for optimal physical and psychological development. For individuals with Type 1 Diabetes (T1D), physical activity offers many health benefits including improved glycemic control, cardiovascular function, blood lipid profiles, and psychological well-being. Despite these benefits, many young people with T1D do not meet physical activity recommendations. Barriers to engaging in a physically active lifestyle include fear of hypoglycemia, as well as insufficient knowledge in managing diabetes around exercise in both individuals and health care professionals. Diabetes and exercise management is complex, and many factors can influence an individual's glycemic response to exercise including exercise related factors (such as type, intensity and duration of the activity) and person specific factors (amount of insulin on board, person's stress/anxiety and fitness levels). International guidelines provide recommendations for clinical practice, however a gap remains in how to apply these guidelines to a pediatric exercise consultation. Consequently, it can be challenging for health care practitioners to advise young people with T1D how to approach exercise management in a busy clinic setting. This review provides a structured approach to the child/adolescent exercise consultation, based on a framework of questions, to assist the health care professional in formulating person-specific exercise management plans for young people with T1D.

Prolonged exposure to acetaminophen reduces testosterone production by the human fetal testis in a xenograft model.

Most common male reproductive disorders are linked to lower testosterone exposure in fetal life, although the factors responsible for suppressing fetal testosterone remain largely unknown. Protracted use of acetaminophen during pregnancy is associated with increased risk of cryptorchidism in sons, but effects on fetal testosterone production have not been demonstrated. We used a validated xenograft model to expose human fetal testes to clinically relevant doses and regimens of acetaminophen. Exposure to a therapeutic dose of acetaminophen for 7 days significantly reduced plasma testosterone (45% reduction; P = 0.025) and seminal vesicle weight (a biomarker of androgen exposure; 18% reduction; P = 0.005) in castrate host mice bearing human fetal testis xenografts, whereas acetaminophen exposure for just 1 day did not alter either parameter. Plasma acetaminophen concentrations (at 1 hour after the final dose) in exposed host mice were substantially below those reported in humans after a therapeutic oral dose. Subsequent in utero exposure studies in rats indicated that the acetaminophen-induced reduction in testosterone likely results from reduced expression of key steroidogenic enzymes (Cyp11a1, Cyp17a1). Our results suggest that protracted use of acetaminophen (1 week) may suppress fetal testosterone production, which could have adverse consequences. Further studies are required to establish the dose-response and treatment-duration relationships to delineate the maximum dose and treatment period without this adverse effect.