Challenges Waiting for an Adult with DSD [Autosaved].pptx

Challenges waiting for adult with DSD

1. Challenges Waiting for an Adult with DSD JOURNAL CLUB PRESENTATION BY BELLO LAWAL DANCHADI AT Centre For Advanced Medical Research And Training, (CAMRET), UDUS. 1

2. Outline Article and journal description Introduction Aim of the paper Main challenges Summary Critical appraisal Conclusion References 2

3. Type of article : Narrative Review Authors: 2 Date of publication: December 6, 2022 Journal description: Journal name: Hormone Research in Paediatrics Publisher: Karger Journal Metrics: Impact factor: 2.6 CiteScore: 4.9 Number of citations: 5 Article and journal description 3

4. Introduction Disorders of Sex Development (DSD), a group of congenital conditions characterized by atypical development of chromosomal, gonadal, or anatomical sex ( Witchel , 2018) . These conditions can be associated with variations in genes, developmental programming, and hormones (Walia et al., 2018) . DSD can present in a variety of ways, including ambiguous genitalia, atypical chromosomal configurations, or discordance between genetic sex and phenotypic sex, this impacts human sex determination and differentiation ( Ouyang et al., 2022) . Individuals affected by these conditions might exhibit noticeable signs of ambiguity in external genitalia at birth, while others may present later with postnatal virilization, delayed/absent puberty, or infertility ( Witchel , 2018). 4

5. Introduction cont. 5 KEY LWPES : Lawson Wilkins Pediatric Endocrine Society ESPE : European Society for Pediatric Endocrinology LH: Luteinizing hormone GMD : Mixed gonadal dysgenesis AMH : Anti-mullerian hormone Adapted from García- Acero et al., 2020 LWPES AND ESPE proposed a classification system for DSD based on karyotyping analysis in 2006

6. Aim of the review The review aimed to addresses issues relating to transition of DSD care from the paediatric to adult care as well as health-related challenges in adulthood in DSD. 6

7. The main challenges Fig.1: The challenges regarding treatment of DSD in adulthood are similar regarding all three groups of DSD – XY DSD, XX DSD, and chromosomal DSD. 7

8. Transition care 8 Fig.2 . Transition from childhood and adolescence to adulthood involves patient- centred multidisciplinary care. Endocrinologists mostly take up a coordinating role of other specialities involved, such as geneticists, gynecologists, urologists/andrologists, psychologists, surgeons, cardiologists, dermatologists, neurologists, and ears nose throat specialists (ENT).

9. Transition care cont. Transition care for individuals with DSD is a critical phase that involves moving from pediatric to adult healthcare services. It is described as an interactive, structured, and ongoing process that spans several years, rather than a single event. It involves transferring not just treatment but also comprehensive information about the patient's medical history and psychosocial well-being . Transition to adult care is necessary as DSD impacts fertility and sexual life, may cause severe long-term comorbidities, and affects quality of life (Crouch & Creighton, 2014). 9

10. Transition care cont. Key tasks for effective transition care to fulfill include: Transfer information about pediatric care to ensure continuity. Ensure qualified and structured follow-up for the patient. Minimize long-term health issues associated with DSD. Educate and empower the patient to take responsibility for their health The transition process should continue even after moving to adult services, this helps to manage the challenges that may arise in later life ( Ouyang et al., 2022) . Despite structured transition programs, up to 50% of patients with DSD are lost to follow-up and do not continue their care after transitioning to adult services (Gleeson et al., 2013). A study of 50 adolescent girls with DSD during their transition revealed that 28% had urgent clinical needs, primarily psychological origin (Liao et al., 2010). 10

11. Fertility challenge Fertility challenge in adult individuals with DSD varies widely depending on the specific condition and the nature of the disorder. Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency experience significantly reduced fertility in both males and females. However, with optimal hormonal control, normal fertility can be achieved in both male and female patients with CAH. A recent survey highlighted that even DSD specialists have gaps in their understanding of fertility potential. This lead to inadequate counselling for patients and a demand for improved education on fertility preservation and counselling. 11

12. Fertility challenge cont. Patients with MRKH syndrome often suffer from infertility and may undergo experimental procedures like combined oocyte retrieval and vaginoplasty. This has been found feasible in a small group of 11 patients. Other experimental treatments being explored include the creation of a neovagina and uterus transplantation. There have also been case reports of patients with ovotesticular DSD achieving pregnancy, either spontaneously or following the removal of the ovotestis. Patients with 46, XY DSD face significant fertility challenges due to various factors, including gonadal dysregulation, gonadectomy due to increased tumor risk, anatomical barriers to functional sexual intercourse, and hormonal imbalance. Despite the challenges, there have been cases of successful pregnancies in patients with 46, XY DSD. 12

13. Fertility in patients with DSDs 13

14. Cardiovascular and Metabolic Health Issues Patients with DSD, such as CAH, face an increased risk of metabolic disturbances and compromised cardiovascular health, including obesity, altered blood pressure profiles, impaired glucose tolerance, diabetes, and hyperlipidemia. Metabolic comorbidities in patients with CAH are most likely due to suboptimal lifelong glucocorticoid (GC) replacement therapy rather than the disease itself. Studies have reported that individuals with 46, XY DSD exhibit increased body fat mass, elevated levels of total and LDL cholesterol, and higher HOMA-IR, primarily due to androgen receptor dysregulation. Additionally, some individuals with 46, XY DSD have an increased risk of cardiac anomalies, such as those associated with GATA4 variants. 14

15. Cardiovascular and Metabolic Health Issues cont. The high cardiovascular risk is one of the main factors contributing to increased morbidity and mortality in patients with Turner syndrome (TS). TS and KS patients face increased cardiovascular morbidity due to cardiometabolic risk factors such as insulin resistance, diabetes mellitus, dyslipidemia, and central obesity. Growth hormone and hormone replacement therapy (HRT) have been reported to benefit cardiovascular outcomes in TS and KS patients by lowering blood pressure and improving lipid profiles. Testosterone replacement therapy (TRT) in KS patients with low testosterone or high gonadotropins has shown favorable effects on body composition, reducing overall and abdominal fat mass. 15

16. Tumor risk Patients with DSD, especially those with a Y chromosome, are at increased risk for gonadal neoplasia, this risk varies with age, gonad location, and genetic predisposition. The highest risk for germ cell cancers is seen in 46, XY patients with all forms of gonadal dysgenesis (GD). Complete GD carries the highest risk, but patients with mixed GD also have an elevated risk for germ cell tumors like gonadoblastoma, which can develop into dysgerminoma or seminoma. Patients with conditions due to mutations in early gonadal differentiation, such as androgen insensitivity syndrome or SRY and WT1 mutations, are at an increased risk for gonadal germ cell cancers. 16

17. Tumor risk cont. Gonadectomy is typically recommended to prevent these malignancies, but deciding which patients should undergo surgery and when remains challenging. The need for appropriate screening tools to detect potential tumors early is essential to prevent long-term consequences. Regular monitoring and discussions about the necessity of gonadectomy are crucial components of care for patients at risk. 17

18. Bone Health Bone health is compromised in DSD patients due to hormonal imbalances, both androgen and estrogen deficiencies play a role in this reduced bone health. Other factors contributing to impaired bone health in DSD patients are low vitamin D status, lack of physical exercise, concomitant diseases or medication, and genetic influence. Patients with CAH are particularly affected by the negative impact of suboptimal GC treatment on bone mineral density. One of the primary effects of androgen dysregulation in 46, XY DSD patients is the reduction of bone mineral density (BMD), particularly following gonadectomy. In patients with Complete Androgen Insensitivity Syndrome (CAIS), significantly increases the risk of early-onset osteoporosis. 18

19. Bone Health cont . Patients with TS and KS are at high risk for osteopenia and osteoporosis in up to 40% of cases due to ovarian insufficiency and low testosterone levels respectively as well as genetic modifications. There is a need for screening and early intervention to prevent long-term complications such as fractures and osteoporosis, as some studies indicated that bone health issues may begin in childhood or adolescence rather than only after puberty. TRT combined with vitamin D supplementation has been shown to effectively increase BMD. This highlights the importance of addressing hormonal deficiencies to improve bone health outcomes. 19

20. Psychological and Neurocognitive Challenges and QoL Individuals with DSD often experience psychological challenges, including anxiety, depression, and issues related to body image and identity. These challenges can significantly impact their overall quality of life. Studies indicate that the quality of life in patients with DSD can be good, particularly when they receive adequate and l ife-long medical care for their physical and mental health challenges. Access to specialized care at tertiary centers with multidisciplinary case management is associated with better QoL outcomes. Patients with chromosomal DSD, such as Turner Syndrome (TS), often have neurocognitive impairments. Those with TS and KS are at higher risk for ADHD and social competence issues. 20

21. Psychological and Neurocognitive Challenges and QoL Patients with 46, XY DSD face increased psychiatric risks due to the loss of androgen effects on brain development which is associated with higher rates of depression, addiction, and eating disorders. Suicidal thoughts have been reported to present in at least 45% of patients with DSD at least once in their lifetime, especially virilized females. Studies on the impact of estrogen therapy on neurocognitive development in TS patients have shown mixed results. Some studies suggest improvements in cognitive functions, while others indicate no significant impact. 21

22. Sexuality The dsd-LIFE study found that sexual activity among individuals with DSD is significantly lower compared to the general population, With 31–59% of patients reported that they had not engaged in sexual activity in the past 12 months. This was particularly pronounced in XY DSD patients living in the male-gender role ( Kreukels et al., 2019) . Many study participants expressed dissatisfaction with their sex lives with the lowest satisfaction reported by XY DSD patients living in a female gender role, Androgen supplementation has been proposed as an alternative to estrogens for gonadectomized women with CAIS and sexual dysfunction. 22

23. Sexuality cont. Hormonal treatments, such as androgen supplementation for women with complete androgen insensitivity syndrome (CAIS), have been proposed to address sexual dysfunction. However, hormonal treatments alone are not sufficient; psychological aspects and the effects of hormone replacement therapy (HRT) on overall health, including bone health, must also be considered. Individuals with DSD often experience delays in sexual development, with many reporting later sexual debuts and establishing sexual relationships later in life. This can contribute to feelings of isolation and dissatisfaction regarding their sexual experiences Comprehensive multidisciplinary care that includes psychological support, sexual health education, and counseling to improve sexual health outcomes and overall quality of life for individuals with DSD is essential. 23

24. Summary The heterogeneous nature of DSD conditions, can lead to variable clinical features and long-term outcomes. Optimizing fertility potential is a significant challenge, often requiring early intervention and collaboration among various specialists, including endocrinologists and urologists. Patients frequently face stigma, discrimination, and difficulties in social relationships, which can contribute to mental health issues and affect their overall well-being. Some DSD patients may experience neurocognitive impairments, impacting their social competence and cognitive abilities, which can further complicate their health management. A coordinated, multidisciplinary approach is essential to address the diverse needs of DSD patients, involving various healthcare professionals and support systems. There is need for a prospective longitudinal study to fully understand the effect of long-term consequences caused by DSD. 24

25. Critical appraisal 25 Lack of information Not a challenge rather a management strategy No detail explanation Not a challenge rather a treatment option No explanation/limited data

26. Critical appraisal Strengths: Title: Challenges Waiting for an Adult with DSD Short, Interesting and reflect their findings Abstract: Precise and well structured. Introduction: Concise: A brief background, justification and summary of the findings. Body of the paper: The paper provides a thorough explanations of the selected challenges faced by individuals. 26 Limitations: Classify transition care as challenge Limited data on neurological issues No data on concomitant diseases, Meaning of most abbreviations not stated. Lack longitudinal studies that provide deeper insights into the long-term effects of DSD.

27. References Witchel , S. F. (2018). Disorders of sex development. Best Practice and Research: Clinical Obstetrics and Gynaecology , 48 , 90–102. https://doi.org/10.1016/j.bpobgyn.2017.11.005 Walia, R., Singla, M., Vaiphei , K., Kumar, S., & Bhansali, A. (2018). Disorders of Sex Development: A Study of 194 Cases. Endocrine Connections , 7 (2), 364–371. https://doi.org/10.1530/ec-18-0022 Ouyang, Y., Tan, S., Yu, Y., Luo, B., Yin, W., & Luo, L. (2022). Gonadal tumor and malignancy in 118 patients with disorders of sex development with Y chromosome. International Journal of Gynecology & Obstetrics , 158 (2), 285–288. https://doi.org/10.1002/ijgo.13974 Crouch NS, Creighton SM. Transition of care for adolescents with disorders of sex development. Nat Rev Endocrinol. 2014;10(7):436–42 Liao LM, Tacconelli E, Wood D, Conway G, Creighton SM. Adolescent girls with disorders of sex development: a needs analysis of transitional care. J Pediatr Urol. 2010;6(6):609–13. Kreukels BPC, Cohen- Kettenis PT, Roehle R, van de Grift TC, Slowikowska-Hilczer J, Claahsen -van der Grinten H, et al. Sexuality in adults with differences/disorders of sex development (DSD): findings from the dsd -LIFE study. J Sex Marital Ther . 2019;45(8): 688–705. Silberbach M, Roos-Hesselink JW, Ander- sen NH, Braverman AC, Brown N, CollinsRT , et al. Cardiovascular health in turner syndrome: a scientific statement from the American heart association. Circ Genom Precis Med. 2018;11(10):e000048 27

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