Mental health outcomes among individuals with 46,XY disorders of sex development: A systematic review

Abstract

This review summarizes research on the mental health outcomes of genetic males with a disorder of sex development (46,XY DSD). Databases were systematically searched, yielding 19 studies included in this review. Results varied widely, with mental health outcomes ranging from very poor to similar to comparison groups. A small number of studies demonstrated that patients with hypospadias or complete androgen insensitivity syndrome reported better mental health than patients with other 46,XY (DSD) diagnoses. Future studies should include larger samples of patients within a similar developmental stage, display results separately by DSD diagnosis and gender identity, and consider the potential impact of medical/surgical events on their mental health.

Keywords

46,XY DSD disorders of sex development mental health psychological outcomes

Disorders of sex development (DSD) refer to a wide variety of conditions in which there is atypical congenital development of the chromosomal, gonadal, and/or anatomical sex (Hughes et al., 2006). Individuals with DSD are a heterogeneous group, with great variability in physical, hormonal, and genetic characteristics, including degree of atypical genital development (Meyer-Bahlburg, 2017). DSD are classified by karyotype (i.e. 46,XY DSD, 46,XX DSD, and sex chromosome DSD such as 45,X) and are further differentiated based on descriptive terms and/or diagnosis.

DSD in genetic males (also referred to as 46,XY DSD) can broadly be categorized into three types (Hughes et al., 2006): (1) variations in androgen synthesis or action, (2) variations of testicular development, and (3) other variations. Among the different 46,XY DSD, the most common is androgen insensitivity syndrome (Parisi et al., 2007), affecting approximately two to five out of 100,000 people who are genetically male (Genetics Home Reference, 2019). In this condition, androgen receptors’ response to circulating androgens in the body is diminished; therefore, androgens cannot influence male development as they typically would. In addition, patients with androgen insensitivity syndrome have high levels of anti-Müllerian hormone, which inhibits the development of female internal reproductive structures including the fallopian tubes, uterus, and cervix (Kusumi et al., 2017). Individuals with complete androgen insensitivity syndrome (CAIS) generally have a female phenotype (i.e. female external genital development, breasts, and distribution of adipose tissue in the hips and thighs) and are assigned and reared female despite having an XY karyotype and male internal gonads (Beale and Creighton, 2016). In contrast, individuals with partial androgen sensitivity syndrome (PAIS) have varying degrees of genital ambiguity and are reared male or female depending on the degree of under-masculinization of the genitalia (Wisniewski and Mazur, 2009). Other 46,XY DSD diagnoses include 5α-reductase (5α-RD) deficiency, 17β-hydroxysteroid dehydrogenase (17β-HSD) deficiency, and gonadal dysgenesis (GD). A description of 46,XY DSD diagnoses and their corresponding classification types are provided in Table 1.

Table 1.

Classification and description of different 46,XY DSD conditions.

Diagnosis	Cause	Gonadal function	Possible physical characteristics
Variations in androgen synthesis or action
CAIS	AR gene mutations resulting in no sensitivity to androgens	Androgen production; AMH production	Female external genitalia and secondary sex characteristics, testes, absent uterus
PAIS	AR gene mutations resulting in partial sensitivity to androgens	Androgen production; AMH production	Ambiguous external genitalia, underdevelopment of male secondary sex characteristics
5α-RD	Steroid 5α-reductase 2 (SRD5A2) gene mutations resulting in underproduction of DHT	Testosterone production; AMH production	Ambiguous/female external genitalia, development of some male secondary sex characteristics
17β-HSD	Hydroxysteroid 17β dehydrogenase 3 (HSD17B3) gene mutations	Underproduction of testosterone; AMH production	Ambiguous/female external genitalia, development of some male secondary sex characteristics
LCH	LHCGR gene mutations	Underdevelopment of Leydig cells in testes; underproduction of testosterone; AMH production	Ambiguous external genitalia (i.e. micropenis, hypospadias, or bifid scrotum)
Variations of testicular development
Complete GD	Mutations of genes involved in testis development (e.g. SRY, SOX9, WT1, SF1)	Complete gonadal dysgenesis; undetectable production of AMH	Female external genitalia, presence of uterus, streak gonads
Partial GD	Mutations of genes involved in testis development (e.g. SRY, SOX9, WT1, SF1)	Partial gonadal dysgenesis, underproduction of AMH	Ambiguous external genitalia with or without Müllerian structures, regression of testicular tissue on one or both sides
Ovotesticular DSD	Many associated (including SRY gene mutations)	Varies (e.g. ovarian tissue may be normal while testicular tissue may be dysgenetic); underproduction of AMH	Ambiguous external genitalia, presence of both ovarian and testicular tissues (e.g. ovotestes)
Other variations
Severe hypospadias	Unknown	Mostly male-typical	Penile anomalies (i.e. urinary opening is below the glans, rather than the tip, of the penis)
Cloacal exstrophy	Unknown	Mostly male-typical	Penile anomalies (i.e. bifid, underdeveloped, or entirely absent), development of some male secondary sex characteristics, imperforate anus

DSD: disorder of sex development; CAIS: complete androgen insensitivity syndrome; PAIS: partial androgen insensitivity syndrome; AR: androgen receptor; 5α-RD: 5α-reductase deficiency; DHT: dihydrotestosterone; 17β-HSD: 17β-hydroxysteroid dehydrogenase deficiency; LCH: Leydig cell hypoplasia; LHCGR: luteinizing hormone/choriogonadotropin receptor; GD: gonadal dysgenesis; AMH: anti-Müllerian hormone; SRY: sex-determining region Y; SOX9: SRY-like box 9; WT1: Wilms tumor 1; SF1: steroidogenic factor 1.

The enormous variability in DSD presents specific challenges for both patients and providers that may be related to psychological difficulties in this population. Because DSD are rare, especially when each diagnosis is considered in isolation, many medical providers have limited experience managing these conditions. As such, many patients are reluctant to see new providers or providers who do not specialize in DSD, which often results in medical care that is insufficient or inadequate (Meyer-Bahlburg, 2017). Further, mental health providers with expertise in managing DSD are scarce, and their priorities often include issues such as helping parents in joint decision-making regarding gender assignment and possible genital surgery (Siminoff and Sandberg, 2015), in coping with stress and uncertainty about the consequences of these decisions (Crissman et al., 2011), and in fostering acceptance of their child if they develop an unexpected gender expression/identity, or sexual orientation (Meyer-Bahlburg, 2017). Although these are important issues to discuss with parents, patients’ own psychological concerns need to be addressed.

Common problems reported by individuals with 46,XY DSD include coping with traumatic treatment experiences and feelings of being abnormal (Schweizer et al., 2009). Diamond and Watson (2004) found that those with CAIS and PAIS also struggled with issues such as secrecy, shame, concerns with infertility, their own identity, and how to resolve personal questions of masculinity and femininity. Some individuals with DSD report that they experience gender dysphoria, do not feel entirely male or female, or do not feel that they belong on the male–female gender binary at all; such feelings were found to be associated with lower self-esteem and psychological well-being (Kreukels et al., 2018). In addition, individuals with DSD may face anticipated or experienced stigmatization about their diagnosis in medical settings and other social environments (Meyer-Bahlburg, 2017) and dissatisfaction with their body and sex life (Schönbucher et al., 2010).

It appears that having a DSD can be accompanied by a wide range of psychologically relevant concerns. There is already a wealth of quantitative research examining psychological outcomes in individuals with DSD, but studies have largely focused on psychosexual development, including gender dysphoria and satisfaction with gender assignment (e.g. de Vries et al., 2007; Furtado et al., 2012; Schweizer et al., 2014), sexual functioning (e.g. Lee et al., 2012; Schönbucher et al., 2010), and quality of life (e.g. Amaral et al., 2015; Wisniewski and Mazur, 2009). Studies that have examined mental health outcomes specifically have primarily investigated women with a 46,XX condition called congenital adrenal hyperplasia (CAH; e.g., Berenbaum et al., 2004; Engberg et al., 2015; Falhammar et al., 2014), as this is the most prevalent DSD condition. As such, the purpose of this review is to synthesize current research on the mental health outcomes of individuals with 46,XY DSD of any age, reared female or male. Such a review may be useful in informing the development of treatment approaches that target the psychological well-being of this population.

Method

Inclusion and exclusion criteria

Inclusion criteria for this systematic review were as follows: (1) empirical studies published in a peer-reviewed journal that employed quantitative methods, (2) samples that included individuals with 46,XY DSD of any age, and (3) outcome measure(s) of mental health (e.g., psychological distress, internalizing symptoms, suicidality). Articles were excluded if (1) they did not include original quantitative results published in a peer-reviewed journal (e.g., review papers, meta-analyses, qualitative studies, case reports, unpublished dissertations, editorials, meeting abstracts), (2) they were not written in English, and (3) the sample included participants with other DSD (e.g., CAH) and did not present results separately by DSD diagnosis.

Search strategy

MEDLINE, PsycINFO, and CINAHL databases were systematically searched in November 2019 using the following search terms: (disorders of sex development or disorders of sex differentiation or intersex or 46,XY DSD or androgen insensitivity syndrome or 5α-reductase-2 deficiency or 17β-hydroxysteroid dehydrogenase-3 deficiency or Leydig cell hypoplasia or gonadal dysgenesis or hypospadias) and (mental health or mental illness or mental disorder or psychopathology or psychological outcomes or psychological distress or psychological symptoms or psychological adjustment or psychological well-being or internalizing symptoms or depression or anxiety or suicid*). Search expanders were selected to apply related words and search within the full text of articles. Filters were applied to include peer-reviewed journal articles written in English and to exclude dissertations. The reference lists of journal articles and review papers retrieved by the search were manually screened to identify additional relevant articles that were not found by the electronic searches. Articles were initially screened by title and abstract for relevance; relevant articles were then full-text-reviewed for compliance with the previous inclusion and exclusion criteria.

A flow diagram detailing study selection is shown in Figure 1. The initial database search yielded 495 articles published between 1944 and 2019, and an additional eight articles were found by screening reference lists of journal articles and review papers. All article titles and abstracts were screened, resulting in 39 articles that were full-text-reviewed by the author for eligibility. A total of 19 studies were eligible according to inclusion and exclusion criteria and included in this systematic review.

Figure 1.

Four-phase flow diagram detailing study selection.

Data extraction

Following a thorough review of each article, the author extracted the following data: country in which the study was conducted, total sample size, age information of the 46,XY DSD group and of the total sample when applicable, specific DSD diagnoses of the 46,XY DSD group and of the total sample when applicable, information about the comparison group(s), measure(s) of mental health, and key findings.

Results

Table 2 provides an overview of the 19 studies, including author information, country, sample characteristics displayed separately for the 46,XY DSD group when possible, and comparison groups. Among the 19 studies reviewed, mental health was assessed by self-report measures, psychodiagnostic interviews, a registry study, and presence of suicidality. The measures used and a summary of findings from each study are reported in Table 3.

Table 2.

Summary of studies examining mental health in individuals with 46,XY DSD.

Reference	Country	N	Age	DSD diagnoses	Comparison group
Berg et al. (1982)	Sweden	34	Total Range = 21–35 M = 27.2	46,XY Hypospadias (n = 34)	Male controls who had an appendectomy matched by age and time of operation
Brinkmann et al. (2007)	Germany	38	46,XY group Range = 21–63 M = 36.0 Total Range = 19–63 M = 30.6	46,XY (n = 27) CAIS (n = 5) PAIS (n = 6) 5α-RD/17β-HSD (n = 5) GD (n = 11) Other CAH (n = 11)	None
Butwicka et al. (2015)	Sweden	9262	Total <37 years	46,XY Hypospadias (n = 9262)	Controls matched by birth year and country of birth
D’Alberton et al. (2015)	Italy	43	Total Range = 18–57 M = 31.5	46,XY CAIS (n = 34) 5α-RD (n = 4) GD (n = 1) LCH (n = 1) Unknown (n = 3)	46,XX healthy females matched by age and education
de Neve-Enthoven et al. (2016)	Netherlands	121	46,XY female genitalia group Range = 15–49 Median = 24 Total Range = 14–60 Median = 26	46,XY female genitalia (n = 36) CAIS (n = 22) GD (n = 14) 46,XY or 46,XX atypical genitalia (n = 85) PAIS (n = 7) 17β-HSD (n = 8) GD (n = 11) Hypospadias (n = 6) LCH (n = 3) Hypomasculinization (n = 3) 17,20 LD (n = 1) NR5A-1 (n = 1) CAH (n = 42) Ovotesticular DSD (n = 3)	Dutch general population
Fliegner et al. (2014)	Germany	60	CAIS group Q₂₅ = 31, Q₇₅ = 49 Median = 39	46,XY CAIS (n = 11) Other MRKHS (n = 49)	None
Hines et al. (2003)	UK	22	Total >15 years M = 27.4	46,XY CAIS (n = 22)	Controls matched by sex-of-rearing, age, and race
Johannsen et al. (2006)	Denmark	70	CAIS group Range = 18–56 Median = 35 Virilized females group Range = 22–55 Median = 39 GD group Range = 25–30 Median = 30	46,XY (n = 30) CAIS (n = 11) Virilized females (n = 16) GD (n = 3) Other CAH (n = 40)	Controls matched by age and education
Khorashad et al. (2018)	Iran	61	CAIS group Range = 5–28 M = 18.3 5α-RD group Range = 5–29 M = 19.5 Total Range = 5–29 M = 17.4	46,XY (n = 39) CAIS (n = 19) 5α-RD (n = 20) Other CAH (n = 22)	Iranian general population (aged 15–64) Iranian general population (aged 6–18)
Kleinemeier et al. (2010)	Germany, Austria, Switzerland	60	46,XY complete androgen effects, female group M = 14.3 46,XY partial androgen effects, female group M = 14.5 46,XY partial androgen effects, male group M = 14.5 Total M = 14.5	46,XY complete, female (n = 7) CAIS (n = 4) GD (n = 3) 46,XY partial, female (n = 18) PAIS (n = 5) 17β-HSD (n = 3) GD (n = 5) LH receptor defect (n = 2) Other (n = 3) Hypospadias (n = 1) Unknown (n = 1) 46,XY partial, male (n = 6) PAIS (n = 1) 17β-HSD (n = 1) Hypospadias (n = 2) Unknown (n = 2) Other (n = 29) CAH (n = 27) Aromatase deficiency (n = 2)	German adolescents (aged 13–16)
Mazur et al. (2004)	USA	5	Total Range = 29–34 M = 32.0	46,XY PAIS (n = 3) Kallmann syndrome (n = 1) Unknown (n = 1)	None
Mureau et al. (1997)	Netherlands	189	Adolescents (n = 116): Range = 9–18 M = 14.4 Adults (n = 73): Range = 18–38 M = 25.6	46,XY Hypospadias (n = 189)	Male controls treated for an inguinal hernia matched by age
Örtqvist et al. (2019)	Sweden	167	Total Range = 19–54 M = 34.0	46,XY Hypospadias (n = 167)	Swedish general population matched by age
Schützmann et al. (2009)	Germany	37	46,XY group Range = 17–60 M = 33.2 Total Range = 16–60 M = 30.5	46,XY (n = 26) CAIS (n = 5) PAIS (n = 6) 5α-RD (n = 3) 17β-HSD (n = 2) GD (n = 10) Other CAH (n = 11)	Women without sexual/physical abuse Women with sexual or physical abuse Women with both sexual and physical abuse
Schweizer et al. (2017)	Germany	69	Total Range = 16–60 M = 33.0	46,XY (n = 45) CAIS (n = 13) PAIS (n = 12) 5α-RD (n = 3) 17β-HSD (n = 4) GD (n = 12) LCH (n = 1) Other (n = 24) CAH (n = 21) GD (n = 2) Ovotesticular DSD (n = 1)	None
Slijper et al. (1998)	Netherlands	59	Total (age at onset of psychopathology) Range = 2–27 M = 13.4	46,XY (n = 33) CAIS (n = 12) PAIS (n = 8) GD (n = 2) Cloacal exstrophy (n = 4) LCH (n = 2) 17 KRD (n = 2) RGS (n = 1) Transversal penis (n = 1) True hermaphroditism (n = 1) Other (n = 26) CAH (n = 18) GD (n = 7) True hermaphroditism (n = 1)	None
van de Grift et al. (2018)	Germany, France, Netherlands, Poland, Sweden, UK	1040	46,XY group M = 28.8 Total M = 32.4	46,XY (n = 267) CAIS (n = 71) PAIS (n = 35) GD (n = 103) Hypospadias (n = 25) Steroid synthesis conditions (n = 18) Ovotesticular DSD (n = 5) Unknown (n = 10) Other (n = 773) CAH (n = 226) Klinefelter syndrome (n = 225) Turner syndrome (n = 322)	None
Wang et al. (2009)	China	130	Total M = 26.2	46,XY Hypospadias (n = 130)	Chinese general population (aged 24–35)
Wang et al. (2010)	China	130	Total M = 26.2	46,XY Hypospadias (n = 130)	Chinese general population (aged 24–35)

DSD: disorder of sex development; CAIS: complete androgen insensitivity syndrome; PAIS: partial androgen insensitivity syndrome; 5α-RD: 5α-reductase deficiency; 17β-HSD: 17β-hydroxysteroid dehydrogenase deficiency; GD: gonadal dysgenesis; LCH: Leydig cell hypoplasia; 17,20 LD: 17,20 Lyase deficiency; NR5A-1: NR5A-1 gene mutation; LH receptor defect: luteinizing hormone receptor defect; 17 KRD: 17-ketoreductase deficiency; RGS: rudimentary gonadal syndrome; CAH: congenital adrenal hyperplasia; MRKHS: Mayer–Rokitansky–Küster–Hauser Syndrome.

Table 3.

Measures and summary of findings in studies examining mental health in individuals with 46,XY DSD.

Reference	Measures	Summary of findings
Berg et al. (1982)	Clinical interview (assessed psychiatric symptoms and general mental health during childhood and adulthood)	More psychiatric symptoms in childhood (enuresis, extreme shyness, and neurotic symptoms) and adulthood (depressiveness) than comparison group
Brinkmann et al. (2007)	BSI–Global Severity Index	15 of 27 patients (55.6%) reported clinically relevant psychological distress
Butwicka et al. (2015)	Information extracted from the National Patient Register (diagnoses of psychiatric disorders)	Increased risk of ADHD, autism spectrum disorder, intellectual disability, and other emotional/behavioral disorders with onset in childhood among those with hypospadias, especially for those with more severe forms of hypospadias
D’Alberton et al. (2015)	ABCL	More anxious/depressive symptoms, withdrawal behavior, thought problems, attention problems, and aggressive behavior than comparison group; 31% of patients’ total scores were in the pathological range
de Neve-Enthoven et al. (2016)	ASR	Less anxiety problems than comparison group (no other differences on DSM-5 oriented, syndrome, and substance use scales); median scores were in the normal range
Fliegner et al. (2014)	BSI—Depression Scale	4 of 11 patients (35.4%) reported clinically relevant depression
Hines et al. (2003)	PGWBS	Psychological well-being did not differ from comparison group
Johannsen et al. (2006)	Clinical interview (previous contacts with mental health providers, previous suicidal thoughts/attempts, present psychopharmacological treatment)	More previous suicidal thoughts in virilized females group than comparison group; no differences on previous contacts with mental health providers and present psychopharmacological treatment
	SCL-90-R	Lower somatization, depression, and anxiety scores in CAIS group than in comparison group (not statistically significant); no other differences in somatization, depression, and anxiety
Khorashad et al. (2018)	SCID-IVK-SADS	85.0% of 5α-RD and 57.9% of CAIS patients had at least one lifetime Axis I disorder; more mental health issues than comparison groups in both age groups
Kleinemeier et al. (2010)	SDQ	Emotional symptoms, conduct problems, hyperactivity/inattention, peer-relationship problems, and prosocial behavior did not differ from comparison group
Mazur et al. (2004)	BSI–Global Severity Index	2 of 5 patients (40.0%) reported clinically relevant psychological distress
Mureau et al. (1997)	CBCLYSRASR	Withdrawal, somatic complaints, anxiety/depression, social problems, thought problems, attention problems, delinquent behavior, and aggressive behavior did not differ from comparison group for adolescents or adults
Örtqvist et al. (2019)	MINICPRS–Self-Rating Scale for Affective Syndromes	7 of 33 patients (21.2%) reported current or previous psychiatric symptoms (this proportion did not differ from comparison group); ADHD, depression, anxiety, and obsessive-compulsive disorder symptoms did not differ from comparison group
Schützmann et al. (2009)	BSIPresence of self-harming behavior, suicidal thoughts, and suicide attempts	16 of 26 patients (61.5%) reported clinically relevant distress; 5 of 26 patients (19.2%) reported self-harming behavior; 15 of 26 patients (57.7%) reported suicidal thoughts; 2 of 26 patients (7.7%) reported suicide attempts
Schweizer et al. (2017)	BSI–Global Severity IndexPresence of suicidal thoughts	31 of 45 patients (68.9%) reported clinically relevant distress; 25 of 44 patients (56.8%) reported lifetime suicidal thoughts
Slijper et al. (1998)	Semi-structured diagnostic interview (with parents and patients separately)	17 of 33 patients (51.5%) had at least one DSM-IV diagnosis and/or gender identity disorder
van de Grift et al. (2018)	HADS	Mean anxiety and depression scores did not reach clinical significance
Wang et al. (2009)	SDSSAS	More depression/anxiety than comparison group; patients with proximal hypospadias and patients who had >1 procedure reported more depression/anxiety than patients with distal hypospadias and patients who had a single procedure
Wang et al. (2010)	SDSSAS	More depression/anxiety than comparison group; patients who completed surgery before age 10 reported lower depression/anxiety than patients who completed surgery after age 10

BSI: Brief Symptom Inventory; ADHD: attention-deficit/hyperactivity disorder; ABCL: Achenbach Adult Behavior Checklist; ASR: Achenbach Adult Self-Report; PGWBS: Psychological General Well-Being Scale; SCID-IV: Structured Clinical Interview for DSM-IV; K-SADS: Kiddie Schedule for Affective Disorders and Schizophrenia; SDQ: Strengths and Difficulties Questionnaire; CBCL: Achenbach Child Behavior Checklist; YSR: Achenbach Youth Self-Report; MINI: Mini-International Neuropsychiatric Interview; SCL-90-R: Hopkins Symptom Checklist; HADS: Hospital Anxiety and Depression Scale; SDS: Self-Rating Depression Scale; SAS: Self-Rating Anxiety Scale; CAIS: complete androgen insensitivity syndrome; 5α-RD: 5α-reductase deficiency; CPRS: Comprehensive Psychopathological Rating Scale; DSM: diagnostic and statistical manual of mental disorders.

Self-report measures

A variety of instruments were used to measure global distress, internalizing symptoms, and other psychological problems, including the Adult Behavior Checklist, Adult Self-Report, Child Behavior Checklist, and Youth Self-Report from the Achenbach System of Empirically Based Assessment (ASEBA; Achenbach and Rescorla, 2003), Brief Symptom Inventory (BSI; Derogatis, 1992), Comprehensive Psychopath-ological Rating Scale (CPRS; Svanborg and Åsberg, 1994), Hopkins Symptom Checklist (SCL-90-R; Derogatis, 1977), Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith, 1983), Psychological General Well-Being Scale (PGWBS; Depuy, 1984), Self-Rating Depression Scale (SDS; Zung, 1965), Self-Rating Anxiety Scale (SAS; Zung, 1971), and the Strengths and Difficulties Questionnaire (SDQ; Goodman et al., 1998).

Global distress

Seven studies examined global distress as an outcome. Four of these studies reported the proportion of patients with a variety of 46,XY DSD diagnoses whose overall distress level fell into the pathological range based on the Global Severity Index score from the BSI. One study conducted in the United States indicated that 2 of 5 female-identified patients (40.0%) reported clinically relevant psychological distress (mean age of sample = 32.0; Mazur et al., 2004) and three studies from Germany found that 15 of 27 patients (55.6%; mean age of sample = 36.0; 92% female-identified; Brinkmann et al., 2007), 16 of 26 patients (61.5%; mean age of sample = 33.2; 88% female-identified; Schützmann et al., 2009), and 31 of 45 patients (68.9%; mean age of sample = 33.0; 89% female-identified; Schweizer et al., 2017) reported clinically relevant distress.

Lower rates of global distress were found in a study conducted in Italy by D’Alberton et al. (2015) that administered the ASEBA to female-identified patients with a variety of 46,XY DSD diagnoses (mean age = 31.5). In this study, approximately 31 percent of patients had a total score that fell in the borderline or pathological range; patients’ median total score was significantly higher than the score of healthy female controls, but was still in the normal range. De Neve-Enthoven et al. (2016) also measured global distress using the ASEBA among female-identified patients in the Netherlands with CAIS or GD with congenitally female external genitalia (median age = 24.0). Their results showed that patients’ median total score was in the normal range and did not significantly differ from the score of the comparison group (Dutch general population). In another study conducted in the Netherlands by Mureau et al. (1997), boys/adolescents (mean age = 14.4) and men (mean age = 25.6) with hypospadias had mean total problem scores on the ASEBA that did not significantly differ from a group of male controls who were treated for a hernia.

Internalizing symptoms

Depression and anxiety were examined in 12 studies. Two studies conducted in Germany reported on the proportion of patients whose depression scores fell in the pathological range on the BSI: 4 of 11 female-identified patients with CAIS (35.4%; median age of sample = 39) in Fliegner et al. (2014) and 12 of 26 patients (46.2%; mean age of sample = 33.2; 88% female-identified) in Schützmann et al. (2009) reported clinically relevant depression. Schützmann et al. (2009) also found that 9 of 26 patients (34.6%) reported clinically relevant anxiety.

Three articles found that patients with 46,XY DSD reported higher levels of internalizing symptoms than the reference group. In D’Alberton et al. (2015), female-identified patients in Italy with a variety of 46,XY DSD diagnoses (mean age = 31.5) reported more anxious/depressive symptoms on the ASEBA compared to healthy female controls. In a study in China, men with hypospadias (mean age = 26.2) reported more depression and anxiety than a comparison group of healthy male controls on the SDS and SAS (Wang et al., 2009, 2010). Further, these results suggested that patients with proximal (vs. distal) hypospadias, patients who had multiple procedure (vs. a single procedure), and patients who completed surgery after age 10 (vs. before age 10) reported more depression and anxiety.

In contrast, five studies found no significant differences in depression or anxiety scores between patients with different 46,XY DSD conditions and healthy controls. These studies examined internalizing symptoms among female-identified patients with CAIS, GD, or some degree of virilization in Denmark (median age = 36.6; Johannsen et al., 2006), female-identified patients with CAIS in the United Kingdom (mean age = 27.4; Hines et al., 2003), patients with a variety of 46,XY DSD conditions in Germany, Austria, and Switzerland (mean age = 14.5; 81% female-identified; Kleinemeier et al., 2010), boys/adolescents (mean age = 14.4) and men (mean age = 25.6) with hypospadias in the Netherlands (Mureau et al., 1997), and men with hypospadias in Sweden (mean age = 34.0; Örtqvist et al., 2019). Another study conducted across Germany, France, the Netherlands, Poland, Sweden, and the United Kingdom found no differences in depression or anxiety between patients with various 46,XY DSD diagnoses (mean age = 28.8; 65% female-identified) and those with other DSD conditions such as CAH (van de Grift et al., 2018). Interestingly, two studies found that female-identified patients in Denmark with CAIS (median age = 36.6; Johannsen et al., 2006) and female-identified patients in the Netherlands with congenitally female external genitalia (median age = 24; de Neve-Enthoven et al., 2016) actually reported fewer internalizing symptoms than did healthy controls.

Psychodiagnostic interviews

Four studies assessed for psychopathology in participants with 46,XY DSD using psychodiagnostic interviews. In Iran, Khorashad et al. (2018) assessed lifetime episodes of psychopathology in adults and children with CAIS and 5α-RD (mean age = 18.9) using the Structured Clinical Interview for DSM-IV (SCID; First et al., 1997) and the Kiddie Schedule for Affec-tive Disorders and Schizophrenia (K-SADS; Lauth et al., 2010). All of the patients with CAIS identified as female, while 55 percent of patients with 5α-RD identified as male and 45 percent identified as female. They found that 85.0 percent of participants with 5α-RD and 57.9 percent of participants with CAIS had at least one lifetime Axis I disorder. Participants among these two groups were diagnosed with gender identity disorder not otherwise specified, affective disorders, and anxiety disorders. No participants were diagnosed with adjustment disorders, attention-deficit and disruptive disorders, substance-related disorders, eating disorders, or psychotic disorders. Khorashad et al. (2018) also found that, among both adults and children, the DSD groups had significantly more mental health issues than comparison groups (Iranian general population).

In a study conducted in the Netherlands by Slijper et al. (1998), diagnoses were made based on semi-structured psychiatric interviews with children with a variety of 46,XY DSD diagnoses and their parents separately, in line with the diagnostic criteria from the DSM-IV. The majority of children were assigned female at birth, with the exception of one patient with PAIS and one with GD. They found that 17 of 33 children with 46,XY DSD (51.5%) had at least one DSM-IV diagnosis. Diagnoses included depressive neurosis (18.2%), sexual problems not otherwise specified (18.2%), gender identity disorder (15.2%), mental retardation (12.1%), oppositional defiant disorder (12.1%), anxiety disorder (3.0%), and attention-deficit/hyperactivity disorder (ADHD) (3.0%).

In a study conducted in Sweden by Örtqvist et al. (2019), 21 percent of men with hypospadias (mean age = 34.2) reported current or previous psychiatric symptoms on the MINI (Sheehan et al., 1998), a proportion that did not significantly differ from a group of age-matched healthy controls. Patients reported having affective symptoms most frequently (15% having at least one mood disorder). The proportion of patients with psychiatric symptoms did not differ by severity of hypospadias (21% mild, 20% mid, and 25% proximal cases). Affective symptoms, anxiety symptoms, and suicide risk were reported more frequently among the men with hypospadias compared to the comparison group, but this difference did not reach statistical significance.

Berg et al. (1982) also administered a clinical interview to men with hypospadias (mean age = 27.2) in Sweden, assessing for psychiatric symptoms and general mental health during childhood and adulthood. Their results showed that patients with hypospadias reported having more neurotic symptoms, extreme shyness, and enuresis during childhood compared to male controls who had an appendectomy. When asked about adulthood, 11.8 percent of patients reported psychiatric symptoms that interfered with daily life and another 29.4 percent reported minor symptoms. Men with hypospadias reported more psychiatric symptoms in adulthood than the comparison group, with the most notable difference in depressiveness.

Registry study

Butwicka et al. (2015) conducted a registry study in Sweden, extracting information on diagnoses of psychiatric disorders among men with hypospadias <37 years old from the National Patient Register. They reported that the lifetime prevalence of any psychiatric disorder was 9.7 percent for men with hypospadias compared to 7.6 percent for healthy male controls. Men with hypospadias were more likely to be diagnosed with ADHD, autism spectrum disorder, intellectual disability, and other emotional/behavioral disorders with onset in childhood compared to the control group. Furthermore, patients with more severe hypospadias were at greater risk of intellectual disability, other emotional/behavioral disorders, and autism spectrum disorder.

Presence of suicidality

Data on suicidality were collected in three studies. Schweizer et al. (2017) assessed suicidal ideation among patients in Germany with a variety of 46,XY DSD diagnoses (mean age = 33.0) by asking whether the patients ever had thoughts about ending their life. They found that 25 of 44 patients with 46,XY DSD (56.8%) reported lifetime suicidal ideation (data from one patient with CAIS were missing). Suicidal thoughts were present among five of seven patients with PAIS who identified as female (71.4%) and among one of five patients with PAIS who identified as male (20.0%). Further, suicidal thoughts were reported among 8 of 12 patients with CAIS (66.7%), 6 of 12 patients with GD (50.0%), 2 of 3 patients with 5α-RD (66.7%), 2 of 4 patients with 17β-HSD (50.0%), and the individual with Leydig cell hypoplasia (LCH), all of whom identified as female.

Via interview, Johannsen et al. (2006) collected information on whether female-identified patients in Denmark with various 46,XY DSD diagnoses (median age = 36.6) had previous suicidal thoughts and/or suicide attempts, previous contacts to psychologists/psychiatrists/ psychiatric departments, and present psychopharmacological treatment. They found that the virilized females group (43.8%), but not the CAIS (10.0%) or GD (0.0%) groups, reported higher rates of previous suicidal thoughts than healthy controls (12.9%). They did not find differences between any of the DSD groups and the healthy controls on previous suicide attempts, previous contacts with mental health providers, or present psychopharmacological treatment.

Schützmann et al. (2009) asked patients in Germany with a variety of 46,XY DSD diagnoses (mean age = 33.2; 88% female identified) to indicate whether they had ever engaged in self-harming behavior, had thoughts to end their life, or had ever attempted to end their life. They found that 5 of 26 patients (19.2%) reported self-harming behavior at some point. The rate of self-harming behavior in the 46,XY DSD group was significantly higher than in the comparison group of women without sexual/physical abuse, but did not significantly differ from rates in the comparison groups of women with sexual and/or physical abuse. Suicidal thoughts were more prevalent; 15 of 26 patients (57.7%) reported that they had thoughts to end their life at some point. The rate of suicidal thoughts in the 46,XY DSD group was comparable to the rates of women with sexual or physical abuse, but was higher than the rates of women without abuse and lower than the rates of women with both sexual and physical abuse. Finally, they found that 2 of 26 patients (7.7%) reported that they had attempted to end their life at some point. This rate of suicide attempts was not significantly different than the rate of any comparison groups (women with and without sexual/physical abuse).

Discussion

The purpose of this review was to summarize the current research on mental health outcomes of individuals with 46,XY DSD, as the literature on psychological outcomes in individuals with DSD has mainly centered on gender dysphoria and satisfaction with gender assignment, sexual functioning, and quality of life, or has limited their samples to those with CAH. Overall, mental health outcomes, including global distress, internalizing symptoms, diagnoses of psychiatric disorders, and presence of suicidality, varied considerably across studies with outcomes ranging from very poor to similar to comparison groups.

Many different self-report instruments were administered to patients, perhaps contributing to conflicting results across studies. Studies that used the BSI subscales and Global Severity Index reported that a high proportion of patients were experiencing clinically relevant depression (35%–46%; Fliegner et al., 2014; Schützmann et al., 2009) and overall psychological distress (between 40% and 69%; Mazur et al., 2004; Schweizer et al., 2017). Further, three articles showed that patients with 46,XY DSD reported higher depression and anxiety compared to healthy controls on the Achenbach Adult Behavior Checklist (ABCL; D’Alberton et al., 2015) and on the SDS and SAS (Wang et al., 2010; Wang et al., 2009). In contrast, patients did not appear to be as impaired or distressed in other studies. Those that used the ASEBA or HADS, which also have cut-off scores indicating clinical significance, reported that mean/median subscale scores (including anxiety, depression, etc.) and total problem scores of patients with 46,XY DSD fell in the normal range (D’Alberton et al., 2015; de Neve-Enthoven et al., 2016; van de Grift et al., 2018). In addition, studies that administered the ASEBA, PGWBS, SCL-90-R, SDQ, and CPRS reported that participants with 46,XY DSD did not differ from healthy controls on their indicators of mental health (de Neve-Enthoven et al., 2016; Hines et al., 2003; Johannsen et al., 2006; Kleinemeier et al., 2010; Mureau et al., 1997; Örtqvist et al., 2019).

Results were more consistent for suicidality. Two studies found that over half of patients with various 46,XY DSD diagnoses had thought about ending their life at some point (Schützmann et al., 2009; Schweizer et al., 2017). Johannsen et al. (2006) found a similar rate of suicidal ideation among virilized females (44%), but a much lower rate among those with CAIS (10%) and GD (0%). The rates of suicidal ideation reported in this review are extremely high; the lifetime prevalence of suicidal ideation in a probability representative sample from six European countries was approximately 8% (Bernal et al., 2007). Regarding previous suicide attempts, individuals with 46,XY DSD were no more likely to have attempted to take their own life at some point than healthy controls (Johannsen et al., 2006) or women with and without sexual/physical abuse (Schützmann et al., 2009).

Several studies measured mental health by examining psychiatric symptoms and disorders rated by clinicians, which provided useful information about how many individuals with 46,XY DSD met criteria for at least one DSM diagnosis. Khorashad et al. (2018) found that 85% of patients with 5α-RD and 58% of those with CAIS had at least one lifetime Axis I disorder, while Slijper et al. (1998) found that 52% of children with 46,XY DSD had at least one DSM-IV diagnosis. Both studies found that affective disorders and gender identity disorder were among the most common diagnoses. Three other studies focused on men with hypospadias specifically, revealing that 21–41 percent of patients reported current or previous psychiatric symptoms (Berg et al., 1982; Örtqvist et al., 2019), and the lifetime prevalence of any psychiatric disorder was 10 percent (Butwicka et al., 2015). These results, compared to those of the other studies in this review, did not provide as much insight into the degree to which these participants felt impaired or distressed by their psychological symptoms.

Only some of these studies reported results separately for each 46,XY DSD diagnosis, rather than grouping all patients with 46,XY DSD together. Interestingly, patients with CAIS, the most common type of 46,XY DSD (Parisi et al., 2007), appeared to have better psychological well-being than patients with other 46,XY DSD diagnoses in some, but not all, studies. In Hines et al. (2003), those with CAIS did not differ from healthy controls in overall psychological well-being, and in de Neve-Enthoven et al., (2016) and Johannsen et al. (2006), those with CAIS actually reported fewer psychological problems than healthy controls on some indicators. Although results were mixed, it could be that some individuals with CAIS have better mental health than those with other 46,XY DSD diagnoses because they generally have female (vs. ambiguous) genitalia and develop typical female secondary sex characteristics (Beale and Creighton, 2016). As such, these individuals may be less likely to struggle with common psychologically relevant concerns among those with different DSD, including traumatic treatment experiences and feelings of being different (Schweizer et al., 2009), as well as dissatisfaction with their body and sex life (Schönbucher et al., 2010). However, we know that some people with CAIS find it difficult to cope with the discrepancy of being a woman with an XY karyotype and male internal gonads (Diamond and Watson, 2004); perhaps it is these individuals who have poorer mental health compared to their CAIS counterparts.

Results also suggested that, for the most part, the mental health of patients with hypospadias did not significantly differ from comparison groups (Butwicka et al., 2015; Mureau et al., 1997; Örtqvist et al., 2019), and that mental health outcomes may be worse among those with more severe hypospadias (Wang et al., 2009). Hypospadias is usually surgically corrected early in life to achieve “normal” appearance of the penis, the ability to urinate in the standing position, and later sexual functioning (e.g. Mureau et al., 1997). As such, the lasting effects of these surgical corrections may explain why mental health outcomes among patients with hypospadias were similar to comparison groups, and that those with hypospadias that are more difficult to correct may experience more psychological problems. Another explanation may be that, unlike some other 46,XY DSD conditions, hypospadias is generally not visible to others (Mureau et al., 1997) or associated with gender dysphoria (Sandberg et al., 1995).

This review should be interpreted in light of several limitations. First, patients were categorized differently in each study; some studies merged patients with 46,XY DSD and other types of DSD in the same group. As such, the article was either excluded from the review altogether, or findings from that particular group were not included. More data on mental health outcomes in individuals with 46,XY DSD therefore exist but could not be examined here. Another methodological challenge is that, although the majority of patients in this review identified as female (with the exception of those with hypospadias), some studies examined patients with different gender identities but did not present findings separately by gender. This prevented the investigation of mental health outcomes in patients with 46,XY DSD who identify as male versus female. Other limitations included the risk of selection bias in most of the included studies, such that more well-adjusted patients may have been more likely to participate, as well as publication bias, such that studies with null findings are less likely to be published. The conflicting findings reported in this review may partially be explained by these limitations, in addition to the wide variation in measures that were used to assess mental health outcomes.

In addition, this review included patients within a wide age range (children to adults) with no association to a particular developmental stage or medical/surgical event. Further, patients likely differed in the quality of medical care received as well as access to mental health services. With the exception of three articles, all of the studies included in this review were conducted in Western countries, which has cultural implications that may affect the validity and generalizability of results. Future studies should include larger samples of patients with 46,XY DSD within a similar developmental stage, display results separately by diagnosis and gender identity, and consider the potential impact of medical/surgical events relevant to their condition on their mental health.

The small number of studies included in this review illuminates the need for further research on mental health outcomes in 46,XY DSD. Although results varied widely across studies, with mental health outcomes ranging from very poor to similar to comparison groups, it is clear that some individuals with 46,XY DSD experience a great deal of psychological distress and suicidal ideation. Currently, these patients may receive medical treatments, including surgery and hormonal therapies, to manage their conditions (Meyer-Bahlburg, 2017). However, this review supports the consensus statement on the management of DSD, which states that a more holistic approach to treatment that includes mental health care is needed to address all of these patients’ needs (Hughes et al., 2006). Currently, culturally sensitive psychological interventions developed for this population are absent from the literature, despite an abundance of issues specific to DSD that clinicians could work on with patients. For example, it may be helpful for clinicians to discuss with patients their specific DSD diagnosis and the potential impact it has on their identity, provide problem-solving strategies to assist them in making difficult medical decisions, identify ways that patients can cope with anticipated or experienced stigma associated with their condition, or increase self-compassion and positive body image. Intervention efforts are clearly needed to help many individuals with different DSD conditions improve their mental health outcomes.

Footnotes

Acknowledgements

The author gratefully acknowledges Sarah Whitton, PhD, and Kristen Jastrowski Mano, PhD, from the University of Cincinnati for their helpful feedback on earlier versions of this manuscript.

Declaration of conflicting interests

The author declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Lisa M Godfrey

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Mental health outcomes among individuals with 46,XY disorders of sex development: A systematic review

Abstract

Keywords

Method

Inclusion and exclusion criteria

Search strategy

Data extraction

Results

Self-report measures

Global distress

Internalizing symptoms

Other psychological problems

Psychodiagnostic interviews

Registry study

Presence of suicidality

Discussion

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

ORCID iD

References