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2025-06-29

Caring for individuals with a difference of sex development (DSD): a Consensus Statement

EXPERT CONSENSUS DOCUMENT

Caring for individuals with a difference of sex development (DSD): a Consensus Statement

Martine Cools, Anna Nordenstrom, Ralitsa Robeva, Joanne Hall, Puck Westerveld, Christa Fluck, Birgit Kohler, Marta Berra, Alexander Springer, Katinka Schweizer & Vickie Pasterski on behalf of the COST Action BM1303 working group 1

Nature Reviews Endocrinology volume 14, (2018)

Abstract

The term differences of sex development (DSDs; also known as disorders of sex development) refers to a heterogeneous group of congenital conditions affecting human sex determination and differentiation. Several reports highlighting suboptimal physical and psychosexual outcomes in individuals who have a DSD led to a radical revision of nomenclature and management a decade ago. Whereas the resulting recommendations for holistic, multidisciplinary care seem to have been implemented rapidly in specialized paediatric services around the world, adolescents often experience difficulties in finding access to expert adult care and gradually or abruptly cease medical follow-up. Many adults with a DSD have health-related questions that remain unanswered owing to a lack of evidence pertaining to the natural evolution of the various conditions in later life stages. This Consensus Statement, developed by a European multidisciplinary group of experts, including patient representatives, summarizes evidence-based and experience-based recommendations for lifelong care and data collection in individuals with a DSD across ages and highlights clinical research priorities. By doing so, we hope to contribute to improving understanding and management of these conditions by involved medical professionals. In addition, we hope to give impetus to multicentre studies that will shed light on outcomes and comorbidities of DSD conditions across the lifespan.

最強やっと出た・・・(´;ω;`)。

2018-11-04

Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development.

J Clin Endocrinol Metab. 2018 Nov 1. doi: 10.1210/jc.2018-01866. [Epub ahead of print]

Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development.

Batista RL1, Inácio M2, Arnhold IJP1, Gomes NL1, Faria JA Jr1, de Moraes DR1, Costa EMF1, Domenice S1, de Mendonca BB1.

Author information ブラジル

Abstract

Background:

In 46,XY DSD patients, several factors may affect psychosexual development, leading to gender identity discrepancy and gender change later in life. Prenatal sexual steroid exposure and external genital virilization are considered to influence human psychosexual development, but it is not completely understood yet.

Methods:

A total of 144 individuals (18-60 years) with a clinical/molecular diagnosis of 46,XY DSD from a single tertiary center were enrolled. Psychosexual outcomes (gender role, gender identity, and sexual orientation) were assessed using questionnaires and psychological test. The Sinnecker score was used for genital virilization measurement. Prenatal androgen exposure was estimated according to 46,XY DSD etiology.

Results:

We found a positive association between prenatal androgen exposure and male psychosexual outcomes. On the other hand, prenatal estrogen exposure, age of gonadectomy, and the degree of external genital virilization did not influence any psychosexual outcome. There was 19% (n = 27) of gender change, which was associated with prenatal androgen exposure (p < 0.001) but not with the external genitalia virilization. The median age of gender change was 15 years, but most of the patients reported the desire for gender change earlier.

Conclusions:

Prenatal androgen exposure influenced psychosexual development in 46,XY DSD favoring male psychosexuality in all psychosexual outcomes, while the degree of external genital virilization did not influence these outcomes. The organizational effect of sexual steroids on psychosexuality at puberty appears to be weak in comparison with the prenatal effects. Prenatal androgen exposure also influenced on female-to-male gender change frequency. All 46,XY DSD conditions with prenatal androgen exposure must be following for gender issues in their management.

2018-10-21

Long-term healthcare of people with disorders of sex development: Predictors of pubertal outcomes of partial androgen insensitivity syndrome.

EBioMedicine. 2018 Oct 15. pii: S2352-3964(18)30438-9. doi: 10.1016/j.ebiom.2018.10.026. [Epub ahead of print]

Long-term healthcare of people with disorders of sex development: Predictors of pubertal outcomes of partial androgen insensitivity syndrome.

Fukami M1.

Author information 日本

1Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan. Electronic address: fukami-m@ncchd.go.jp.

Abstract

Partial androgen insensitivity syndrome (PAIS) is a relatively common type of 46, XY disorders of sex development (DSD) caused by hypomorphic mutations in the androgen receptor gene (AR) [6]. Patients with PAIS typically present with hypomasculinized external genitalia at birth [6]. The median external masculinization score (EMS) of neonates with PAIS is around 5–7 (typical female- and male-type genitalia correspond to scores 0 and 12, respectively) [5], causing difficulties in sex assignment of many cases.


Partial androgen insensitivity syndrome (PAIS) is a relatively common type of 46, XY disorders of sex development (DSD) caused by hypomorphic mutations in the androgen receptor gene (AR) [6]. Patients with PAIS typically present with hypomasculinized external genitalia at birth [6]. The median external masculinization score (EMS) of neonates with PAIS is around 5–7 (typical female- and male-type genitalia correspond to scores 0 and 12, respectively) [5], causing difficulties in sex assignment of many cases. Moreover, PAIS tends to be associated with poor clinical outcomes: PAIS patients more frequently require multiple surgeries and exhibit insufficient masculinization in adulthood than patients with similar genital abnormalities at birth but no AR mutations [5]. Since degrees of pre- and post-natal masculinization are highly variable among PAIS patients [5,6], personalized management is necessary for each case. In this regard, outcome prediction for children with PAIS is essential for the decision-making of clinicians and patients' parents; however, no reliable biomarkers for long-term outcomes of PAIS have been documented.

In EBioMedicine, Lek and colleagues introduce their findings about outcome predictors of PAIS [4]. The authors performed a prospective long-term follow-up study on 27 patients with molecularly confirmed PAIS. The authors also investigated the residual activity of each mutant AR protein by in vitro assays. The results suggested that the pubertal outcomes of PAIS patients do not parallel to the predicted activities of the mutant proteins. Instead, the outcomes were correlated with EMS at birth. Specifically, all patients with EMS ≥ 5 at birth subsequently exhibited spontaneous puberty and frequently developed normal adult male-type external genitalia, while 33% and 83% of patients with EMS < 5 at birth did not show spontaneous puberty and satisfactory adult genitalia, respectively. These results highlighted the usefulness of EMS as clinical parameters of PAIS. Since EMS can be easily obtained from all neonates suspected to have PAIS, these findings would facilitate decision-making in clinical practice. From the viewpoint of basic research, the paper revealed limitations of current in vitro methods in the functional assessment of hypomorphic mutations in AR.

In their paper, Lek et al. also pointed out two unsolved issues that need to be addressed in future studies. First, it remains unknown whether blood hormone values can be used as biomarkers for pubertal outcomes of PAIS. In this regard, previous studies have shown that PAIS occasionally underlies testicular dysfunction, in addition to androgen resistance in peripheral tissues [5]. Indeed, elevated blood levels of FSH and/or blunted responses of testosterone to human chorionic gonadotropin stimulation have been reported in multiple patients with PAIS [5]. Testicular dysfunction of these patients was assumed to result from maldescent of the testis or insufficient androgen action in the developing testis [5]. Since testicular dysfunction further attenuates suboptimal masculinization caused by androgen resistance, hormonal evaluation of children with PAIS may provide information about future phenotypes. Second, Lek et al. did not examine somatic mosaicism of AR mutations, which has previously been reported in multiple patients with PAIS [3]. The lack of genotype-phenotype correlation in this cohort may be ascribed to somatic mosaicism, because mosaicism can modify phenotypic severities of the patients. Furthermore, Lek et al. mentioned that current in vitro assays may not be sensitive enough to detect mild functional impairment of AR mutations. In this regard, novel methods for the functional assessment of AR mutants, such as quantification of APOD mRNA in genital skin fibroblasts, have recently been developed [2]. In future studies, detection of mosaicism and the use of novel assay methods would help to clarify precise genotype-phenotype correlation of PAIS.

An important issue that also needs to be addressed is psychological outcomes of PAIS patients. Currently, there are no parameters to predict long-term gender identity in children with DSD including PAIS [1]. The lack of reliable predictors for gender development raises difficulty in sex-assignment of neonates. Indeed, PAIS patients have a risk of gender incongruousness in adulthood. In addition, PAIS has been linked to a relatively high risk of gynecomastia, cardiovascular diseases, glucose intolerance, and osteoporosis [5]. Thus, biomarkers for these complications also need to be established.

Altogether, the study by Lek et al. [4] provided useful information for the long-term healthcare of DSD. Yet, further studies are necessary to determine reliable predictors of various health issues of PAIS. To this end, international registries and study groups for DSD have been launched recently (for example, I-DSD registry, https://www.i-dsd.org/) [1]. Such research networks enable scientists to collect longitudinal data of a large number of patients, and are therefore expected to promote personalized management for patients with DSD including PAIS.

2018-10-17

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

EBioMedicine. 2018 Oct 10. pii: S2352-3964(18)30406-7. doi: 10.1016/j.ebiom.2018.09.047. [Epub ahead of print]

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices.

Lek N1, Tadokoro-Cuccaro R2, Whitchurch JB3, Mazumder B3, Miles H2, Prentice P2, Bunch T2, Zielińska K2, Metzler V4, Mongan NP4, Heery DM3, Hughes IA5.

Author information イギリス

Abstract

BACKGROUND:

PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment.

METHODS:

We collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth <5 and ≥ 5 (EMS in normal males is 12; median EMS in PAIS is 4·7) and pubertal outcomes compared.

FINDINGS:

Only 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p = .03). Only 1/6 patients (17%) with EMS <5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ≥5 (p = 0·01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume ≥ 15 ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function.

INTERPRETATION:

In PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty.



FUND: European Commission Framework 7 Programme, NIHR Cambridge Biomedical Research Centre, BBSRC DTP.
Copyright © 2018. Published by Elsevier B.V.

KEYWORDS:
Androgen insensitivity; Androgen receptor; External masculinisation score; Gynaecomastia; Mutation; Puberty outcome; Reporter assays; Sex assignment; in silico modelling

2018-09-02

Psychosocial and psychosexual aspects of disorders of sex development.

Best Pract Res Clin Endocrinol Metab. 2010 Apr;24(2):325-34. doi: 10.1016/j.beem.2009.11.005.

Psychosocial and psychosexual aspects of disorders of sex development.

Cohen-Kettenis PT

Author information
Department of Medical Psychology, VU University, PO Box 7057, 1007 MB Amsterdam, The Netherlands. pt.cohen-kettenis@vumc.nl

Abstract

Psychosocial aspects of the treatment of disorders of sex development (DSDs) concern gender assignment, information management and communication, timing of medical interventions, consequences of surgery, and sexuality. Although outcome is often satisfactory, a variety of medical and psychosocial factors may jeopardise the psychological development of children with DSDs. This sometimes results in the desire to change gender later in life. The clinical management of gender dysphoria in individuals with DSD may profit from methods and insights that have been developed for gender dysphoric individuals without DSD. In DSD care, clinical decisions are often made with long-lasting effects on quality of life and should be based on empirical evidence. Yet, such evidence (e.g., regarding gender assignment, information management and timing of surgery) is largely non-existent. DSD-specific protocols and educational materials need to be developed to standardise and evaluate interventions in order to facilitate decision making of professionals and individuals with DSD and enhance psychosocial care in this area.

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