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Article ; Online: Early puberty suppression and gender-affirming hormones do not alter final height in transgender adolescents.

Ciancia, Silvia / Klink, Daniel / Craen, Margarita / Cools, Martine

2023 Volume 189, Issue 3, Page(s) 396–401

Abstract: Background: Early puberty suppression (ePS; Tanner stages 2 and 3) through gonadotropin-releasing hormone agonists (GnRHas) and gender-affirming hormones (GAHs) interferes with growth and may impact final height (FH).: Aim: To investigate the impact ... ...

Abstract	Background: Early puberty suppression (ePS; Tanner stages 2 and 3) through gonadotropin-releasing hormone agonists (GnRHas) and gender-affirming hormones (GAHs) interferes with growth and may impact final height (FH). Aim: To investigate the impact of ePS and GAH on FH in trans boys and trans girls. Methods: Retrospective study, including 10 trans boys and 22 trans girls at FH. Bone age (BA) was determined at the start of ePS and at the start of GAH according to Greulich and Pyle; predicted adult height (PAH) was calculated according to Bayley and Pinneau's tables; target height (TH) was calculated as adjusted mean of maternal and paternal height. Target height, PAH, and BA were determined according to sex registered at birth (SRAB) and experienced gender (EG). Results: The age at the start of PS was 12.37 ± 0.74 years in trans boys and 13.10 ± 1.12 years in trans girls. Total height gain since the start of ePS in trans boys was 14.62 ± 4.08 cm, with 70% achieved before the start of GAH. In trans girls, it was 20.68 ± 7.66 cm, with 61% achieved before GAH. Target height for SRAB was the most accurate predictor for FH in both trans boys and girls: the difference with FH was 1.57 cm ± 3.1 (P = .168) and -0.98 cm ± 4.17 (P = .319), respectively. Also the difference between FH and PAH at the start of PS for SRAB was nonsignificant in both trans boys and girls (2.62 cm ± 3.79, P = .056 and -2.35 cm ± 5.2, P = .051, respectively). Conclusion: Early puberty suppression and GAH do not impact FH, supporting the safety of the treatment; however, trans adolescents achieve a FH in line with SRAB, rather than EG.
MeSH term(s)	Adult ; Infant, Newborn ; Male ; Female ; Adolescent ; Humans ; Transgender Persons ; Retrospective Studies ; Family ; Puberty, Precocious ; Puberty
Language	English
Publishing date	2023-09-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1093/ejendo/lvad125
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Article: Impact of gender-affirming treatment on bone health in transgender and gender diverse youth.

Ciancia, Silvia / Dubois, Vanessa / Cools, Martine

Endocrine connections

2022 Volume 11, Issue 11

Abstract: Both in the United States and Europe, the number of minors who present at transgender healthcare services before the onset of puberty is rapidly expanding. Many of those who will have persistent gender dysphoria at the onset of puberty will pursue long- ... ...

Abstract	Both in the United States and Europe, the number of minors who present at transgender healthcare services before the onset of puberty is rapidly expanding. Many of those who will have persistent gender dysphoria at the onset of puberty will pursue long-term puberty suppression before reaching the appropriate age to start using gender-affirming hormones. Exposure to pubertal sex steroids is thus significantly deferred in these individuals. Puberty is a critical period for bone development: increasing concentrations of estrogens and androgens (directly or after aromatization to estrogens) promote progressive bone growth and mineralization and induce sexually dimorphic skeletal changes. As a consequence, safety concerns regarding bone development and increased future fracture risk in transgender youth have been raised. We here review published data on bone development in transgender adolescents, focusing in particular on differences in age and pubertal stage at the start of puberty suppression, chosen strategy to block puberty progression, duration of puberty suppression, and the timing of re-evaluation after estradiol or testosterone administration. Results consistently indicate a negative impact of long-term puberty suppression on bone mineral density, especially at the lumbar spine, which is only partially restored after sex steroid administration. Trans girls are more vulnerable than trans boys for compromised bone health. Behavioral health measures that can promote bone mineralization, such as weight-bearing exercise and calcium and vitamin D supplementation, are strongly recommended in transgender youth, during the phase of puberty suppression and thereafter.
Language	English
Publishing date	2022-09-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2668428-7
ISSN	2049-3614
ISSN	2049-3614
DOI	10.1530/EC-22-0280
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Article ; Online: Germ cell cancer risk in DSD patients.

Cools, Martine

Annales d'endocrinologie

2014 Volume 75, Issue 2, Page(s) 67–71

Abstract: The risk of germ cell cancer is elevated in many DSD patients, although not to the same extent. A number of risk factors have been identified recently, but their interplay and relative impact is currently not fully clear. Until the advent of reliable ... ...

Abstract	The risk of germ cell cancer is elevated in many DSD patients, although not to the same extent. A number of risk factors have been identified recently, but their interplay and relative impact is currently not fully clear. Until the advent of reliable screening tools for the detection of pre-invasive cancer lesions, managing germ cell tumour risk focuses on the question if and when to perform biopsy or gonadectomy in most patients and how to interpret the histological findings.
MeSH term(s)	Biomarkers, Tumor/genetics ; Chromosomes, Human, Y ; Disorders of Sex Development/complications ; Early Detection of Cancer ; Genetic Counseling ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Male ; Neoplasm Proteins/genetics ; Neoplasms, Germ Cell and Embryonal/diagnosis ; Neoplasms, Germ Cell and Embryonal/etiology ; Neoplasms, Germ Cell and Embryonal/surgery ; Neoplastic Syndromes, Hereditary/epidemiology ; Neoplastic Syndromes, Hereditary/genetics ; Orchiectomy ; Risk ; Testicular Neoplasms/diagnosis ; Testicular Neoplasms/etiology ; Testicular Neoplasms/surgery ; Testis/embryology ; Testis/pathology
Chemical Substances	Biomarkers, Tumor ; Neoplasm Proteins
Language	English
Publishing date	2014-05
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	299-9
ISSN	2213-3941 ; 0003-4266
ISSN (online)	2213-3941
ISSN	0003-4266
DOI	10.1016/j.ando.2014.04.003
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Article ; Online: Working towards convergence of the clinical management of differences of sex development/intersex conditions and the human rights framework: A case study.

Cools, Martine / Verhagen, Emmanuelle / Hoebeke, Piet / Van Hoecke, Eline / Cannoot, Pieter

Clinical endocrinology

2023

Abstract: Objective: Medical treatments that aim to modify the appearance of the genitals in children who are born with a difference of sex development/intersex (DSD/I*) condition are highly controversial. Human Rights bodies worldwide have argued that such ... ...

Abstract	Objective: Medical treatments that aim to modify the appearance of the genitals in children who are born with a difference of sex development/intersex (DSD/I) condition are highly controversial. Human Rights bodies worldwide have argued that such treatments are conflicting with the child's right of personal autonomy and should be legally restricted to the unique situation where the child's physical health is in danger. Design:* We here review the current status of legal initiatives in Europe that have addressed the issue of medical treatments in minors who have a DSD for which they have not been able to give personal informed consent due to their young age. Patients: The management of a 3 years old child who has congenital adrenal hyperplasia (CAH) and grows up with atypical-looking genitals is discussed. Results: In spite of extensive psychosocial support to the child and family from birth onwards, and good medical control of CAH, the child develops signs of emotional distress, suspected to be attributable to the genital difference. Our discussions include perspectives from the multidisciplinary DSD team caring for the child, a human rights specialist, and an intersex activist. From our discussions, we conclude that with evolving medical care, new ethical and human rights challenges are raised. A truly holistic human rights approach should not only consider physical but also mental health and psychosocial and psychosexual adaptation of the child to the medical condition, when reflecting on the acceptability of medical treatments in minors for which no personal informed consent can be obtained due to their young age. In addition it is paramount to include the meaningful participation of the child in the clinical management at the earliest possible stage. Conclusions: Continued convergence of clinical management and the human rights framework can be realised based on constructive discussions involving all stakeholders, and with the best interest of the child - and adult that they will become - as a common goal.
Language	English
Publishing date	2023-12-07
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	121745-8
ISSN	1365-2265 ; 0300-0664
ISSN (online)	1365-2265
ISSN	0300-0664
DOI	10.1111/cen.15002
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Article: Individuals with numerical and structural variations of sex chromosomes: interdisciplinary management with focus on fertility potential.

Juul, Anders / Gravholt, Claus H / De Vos, Michel / Koledova, Ekaterina / Cools, Martine

Frontiers in endocrinology

2023 Volume 14, Page(s) 1160884

Abstract: Diagnosis and management of individuals who have differences of sex development (DSD) due to numerical or structural variations of sex chromosomes (NSVSC) remains challenging. Girls who have Turner syndrome (45X) may present with varying phenotypic ... ...

Abstract	Diagnosis and management of individuals who have differences of sex development (DSD) due to numerical or structural variations of sex chromosomes (NSVSC) remains challenging. Girls who have Turner syndrome (45X) may present with varying phenotypic features, from classical/severe to minor, and some remain undiagnosed. Boys and girls who have 45,X/46,XY chromosomal mosaicism may have Turner syndrome-like features and short stature; therefore, unexplained short stature during childhood requires karyotype analysis in both sexes, particularly if characteristic features or atypical genitalia are present. Many individuals with Klinefelter syndrome (47XXY) remain undiagnosed or are only diagnosed as adults due to fertility problems. Newborn screening by heel prick tests could potentially identify sex chromosome variations but would have ethical and financial implications, and in-depth cost-benefit analyses are needed before nationwide screening can be introduced. Most individuals who have NSVSC have lifelong co-morbidities and healthcare should be holistic, personalized and centralized, with a focus on information, psychosocial support and shared decision-making. Fertility potential should be assessed individually and discussed at an appropriate age. Oocyte or ovarian tissue cryopreservation is possible in some women who have Turner syndrome and live births have been reported following assisted reproductive technology (ART). Testicular sperm cell extraction (TESE) is possible in some men who have 45,X/46,XY mosaicism, but there is no established protocol and no reported fathering of children. Some men with Klinefelter syndrome can now father a child following TESE and ART, with multiple reports of healthy live births. Children who have NSVSC, their parents and DSD team members need to address possibilities and ethical questions relating to potential fertility preservation, with guidelines and international studies still needed.
MeSH term(s)	Male ; Female ; Humans ; Turner Syndrome/diagnosis ; Turner Syndrome/genetics ; Turner Syndrome/therapy ; Klinefelter Syndrome/diagnosis ; Klinefelter Syndrome/genetics ; Klinefelter Syndrome/therapy ; Semen ; Mosaicism ; Sex Chromosomes
Language	English
Publishing date	2023-05-05
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1160884
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Article ; Online: Ovotesticular Difference of Sex Development: Genetic Background, Histological Features, and Clinical Management.

Syryn, Hannes / Van De Vijver, Koen / Cools, Martine

Hormone research in paediatrics

2021 Volume 96, Issue 2, Page(s) 180–189

Abstract: Background: Ovotesticular disorder/difference of sex development (DSD) refers to the co-presence of testicular and ovarian tissue in one individual. Childhood management is challenging as there are many uncertainties regarding etiology, gonadal function, ...

Abstract	Background: Ovotesticular disorder/difference of sex development (DSD) refers to the co-presence of testicular and ovarian tissue in one individual. Childhood management is challenging as there are many uncertainties regarding etiology, gonadal function, and gender outcome. Summary: Ovotesticular DSD should mainly be considered in 46,XX children with atypical genitalia and normal adrenal steroid profiles. Various underlying genetic mechanisms have been described. Histological assessment of ovotestes requires expert revision and has many pitfalls. Neonatal sex assignment is essential, but as gender outcome is unpredictable, this should be regarded as provisional until a stable gender identity has developed. Therefore, it is crucial not to perform any irreversible medical or surgical procedure in affected individuals until adolescents can give their full informed consent. Gonadal function mostly allows for spontaneous pubertal development; however, fertility is compromised, especially in boys. Specific long-term outcome data for ovotesticular DSD are lacking but can be extrapolated from studies in other DSD populations. Key messages: Management of ovotesticular DSD has changed in recent years, prioritizing the child's future right for autonomy and self-determination. The benefits and pitfalls of this new approach have not been documented yet and require intensive monitoring on an international scale.
MeSH term(s)	Infant, Newborn ; Child ; Adolescent ; Humans ; Male ; Female ; Ovotesticular Disorders of Sex Development/genetics ; Ovotesticular Disorders of Sex Development/therapy ; Ovotesticular Disorders of Sex Development/pathology ; Gender Identity ; Genitalia/pathology ; Sexual Development/genetics ; Genetic Background ; Disorders of Sex Development/genetics ; Disorders of Sex Development/therapy
Language	English
Publishing date	2021-09-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2537278-6
ISSN	1663-2826 ; 1663-2818
ISSN (online)	1663-2826
ISSN	1663-2818
DOI	10.1159/000519323
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Article ; Online: Update on the Pathophysiology and Risk Factors for the Development of Malignant Testicular Germ Cell Tumors in Complete Androgen Insensitivity Syndrome.

Cools, Martine / Looijenga, Leendert

Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation

2017 Volume 11, Issue 4, Page(s) 175–181

Abstract: Prophylactic gonadectomy in young adult women with complete androgen insensitivity syndrome (CAIS) to avoid development of an invasive testicular germ cell tumor (TGCT) is currently advised in most centers. However, women with CAIS increasingly question ... ...

Abstract	Prophylactic gonadectomy in young adult women with complete androgen insensitivity syndrome (CAIS) to avoid development of an invasive testicular germ cell tumor (TGCT) is currently advised in most centers. However, women with CAIS increasingly question the need of this procedure. In order to provide optimal counseling and follow-up of these women, insight in the mechanisms underlying TGCT development in androgen insensitivity syndrome (AIS), data regarding the incidence of TGCT in AIS adults specifically, and an overview of existing and novel screening tools for in situ and invasive neoplastic lesions are crucial. The current knowledge regarding these topics is revised in this paper.
Language	English
Publishing date	2017
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2253672-3
ISSN	1661-5433 ; 1661-5425
ISSN (online)	1661-5433
ISSN	1661-5425
DOI	10.1159/000477921
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Article ; Online: Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development.

Kouri, Chrysanthi / Sommer, Grit / Martinez de Lapiscina, Idoia / Elzenaty, Rawda Naamneh / Tack, Lloyd J W / Cools, Martine / Ahmed, S Faisal / Flück, Christa E

EBioMedicine

2024 Volume 99, Page(s) 104941

Abstract: Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained.: Methods: We ... ...

Abstract	Background: Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods: We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/SF-1 variants, identified through the I-DSD registry and a research network. Findings: Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF-1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. Interpretation: The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as-yet-unknown factors. Funding: Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.
MeSH term(s)	Infant, Newborn ; Humans ; Female ; Mutation ; Steroidogenic Factor 1/genetics ; Retrospective Studies ; Phenotype ; Sexual Development/genetics
Chemical Substances	Steroidogenic Factor 1 ; NR5A1 protein, human
Language	English
Publishing date	2024-01-01
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104941
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Zs.A 7090: Show issues

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Article ; Online: Multidisciplinary Approach to the Child with Sex Chromosomal Mosaicism Including a Y-Containing Cell Line.

Debo, Bauke / Van Loocke, Marlies / De Groote, Katya / De Leenheer, Els / Cools, Martine

International journal of environmental research and public health

2021 Volume 18, Issue 3

Abstract: Children born with sex chromosomal mosaicism including material derived from the Y chromosome may present with a broad phenotypical spectrum. Both boys and girls can present with Turner features and functional health problems typically associated with ... ...

Abstract	Children born with sex chromosomal mosaicism including material derived from the Y chromosome may present with a broad phenotypical spectrum. Both boys and girls can present with Turner features and functional health problems typically associated with Turner syndrome, but the presence of Y-chromosomal material can modify some aspects of the condition. We retrospectively analyzed the results of our cohort of 21 individuals (14 boys, 7 girls) with sex chromosomal mosaicism including Y-derived material followed at Ghent University Hospital according to our local multidisciplinary Turner surveillance protocol. Results were compared with literature data, focusing on similarities and differences between girls and boys with this condition. Age at diagnosis was lower in boys compared to girls but the difference was not significant. Short stature is a key feature of the condition both in girls and boys, but skeletal maturation may be different between groups. The effects of growth-hormone therapy remain unclear. Cardiac (33%), ear-nose- throat (ENT) (77.8%) and renal (28.6%) problems were as prevalent in boys as in girls from our cohort, and did not differ from literature data. In line with literature reports, a significant difference in the presence of premalignant germ cell tumors between males (0%) and females (42.9%) was found (
MeSH term(s)	Cell Line ; Child ; Female ; Growth Hormone ; Humans ; Male ; Mosaicism ; Retrospective Studies ; Turner Syndrome/epidemiology ; Turner Syndrome/genetics
Chemical Substances	Growth Hormone (9002-72-6)
Language	English
Publishing date	2021-01-21
Publishing country	Switzerland
Document type	Journal Article
ISSN	1660-4601
ISSN (online)	1660-4601
DOI	10.3390/ijerph18030917
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Article ; Online: A European Network for the Investigation of Gender Incongruence in adolescents.

Boogers, Lidewij S / Wiepjes, Chantal M / Staphorsius, Annemieke S / Klink, Daniel T / Ciancia, Silvia / Romani, Alessia / Stolk, Tessa H R / van den Boogaard, Emmy / Steensma, Thomas D / de Vries, Annelou L C / van Trotsenburg, A S Paul / den Heijer, Martin / Fisher, Alessandra D / Cools, Martine / Hannema, Sabine E

The journal of sexual medicine

2024 Volume 21, Issue 4, Page(s) 350–356

Abstract: Background: Knowledge regarding the effects and side effects of gender-affirming hormone therapy (GAHT) in adults is rapidly growing, partly through international research networks such as the European Network for the Investigation of Gender ... ...

Abstract	Background: Knowledge regarding the effects and side effects of gender-affirming hormone therapy (GAHT) in adults is rapidly growing, partly through international research networks such as the European Network for the Investigation of Gender Incongruence (ENIGI). However, data on the effects of puberty suppression (PS) and GAHT in transgender and gender diverse (TGD) youth are limited, although these data are of crucial importance, given the controversies surrounding this treatment. Aim: We sought to present a detailed overview of the design of the ENIGI Adolescents study protocol, including the first baseline data. Methods: The ENIGI Adolescents study is an ongoing multicenter prospective cohort study. This study protocol was developed by 3 European centers that provide endocrine care for TGD adolescents and were already part of the ENIGI collaboration: Amsterdam, Ghent, and Florence. Outcomes: Study outcomes include physical effects and side effects, laboratory parameters, bone mineral density, anthropometric characteristics, attitudes toward fertility and fertility preservation, and psychological well-being, which are measured in the study participants during PS and GAHT, up to 3 years after the start of GAHT. Results: Between November 2021 and May 2023, 172 TGD adolescents were included in the ENIGI Adolescents protocol, of whom 51 were assigned male at birth (AMAB) and 121 were assigned female at birth (AFAB); 3 AFAB participants reported a nonbinary gender identification. A total of 76 participants were included at the start of PS, at a median (IQR) age of 13.7 (12.9-16.5) years in AMAB and 13.5 (12.4-16.1) years in AFAB individuals. The remaining 96 participants were included at start of GAHT, at a median (IQR) age of 15.9 (15.1-17.4) years in AFAB and 16.0 (15.1-16.8) years in AMAB individuals. At the time of this report the study was open for inclusion and follow-up measurements were ongoing. Clinical implications: In response to the rising demand for gender-affirming treatment among TGD youth, this ongoing study is fulfilling the need for prospective data on the effects and safety of PS and GAHT, thus providing a foundation for evidence-based healthcare decisions. Strengths and limitations: This study has a strong multicenter, prospective design that allows for systematic data collection. The use of clinical and self-reported data offers a broad range of outcomes to evaluate. Nevertheless, the burden of additional measurements and questionnaires may lead to withdrawal or lower response rates. Few participants with a non-binary gender identity have been included. Conclusion: With the ENIGI Adolescents study we aim to create a comprehensive dataset that we can use for a wide range of studies to address current controversies and uncertainties and to improve healthcare for TGD adolescents.
MeSH term(s)	Adult ; Infant, Newborn ; Humans ; Male ; Female ; Adolescent ; Gender Identity ; Transgender Persons/psychology ; Prospective Studies ; Gender Dysphoria/drug therapy ; Gender Dysphoria/psychology ; Research Design
Language	English
Publishing date	2024-03-01
Publishing country	Netherlands
Document type	Multicenter Study ; Journal Article
ZDB-ID	2251959-2
ISSN	1743-6109 ; 1743-6095
ISSN (online)	1743-6109
ISSN	1743-6095
DOI	10.1093/jsxmed/qdae014
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