Abstract
Background
Classical Congenital Adrenal Hyperplasia (C-CAH) is a congenital disorder characterized by a loss of 21-hydroxylase enzymes. Consequently, androgen levels increase, resulting in varying degrees of psychological and physiological masculinization. This systematic review aims to examine existing research on females with C-CAH and identify challenges related to reproductive self-perception, mental health, and overall quality of life.
Methodology
This systematic review was conducted based on the PRISMA 2020 guidelines, studies were retrieved from PubMed, EBSCO, Science Direct, and ProQuest, and screened according to predefined eligibility criteria. Quality assessments of included studies were done using the Newcastle-Ottawa Scale (NOS) for case-control studies, adapted NOS for cross-sectional studies, and Risk of Bias in Non-randomized Studies of Intervention (ROBINS-I).
Results
Eleven studies determined to have low risk of bias involving 523 participants were included. All 11 studies addressed self-perception of reproductive health, evaluating gender and sexual-related issues, with outcomes such as atypical gender identity and sexual orientation, gender dysphoria, and sexual satisfaction impairment. Adverse perceptions and experiences related to virilized genitalia were commonly reported. Four studies examined mental health issues, comprising anxiety, social phobia, ADHD, sexual distress, and signs of depression. Finally, females with C-CAH have reduced QoL compared to healthy females, mainly due to impacted general health and pain.
Conclusion
Females with C-CAH demonstrated impaired reproductive self-perception, including sexual satisfaction and gender-related difficulties, alongside psychological concerns including anxiety, social phobia, and maladaptive coping behaviors, with reduced quality of life related to general health and pain.
Keywords: congenital adrenal hyperplasia, females, mental health, quality of life, self-perception, reproductive health
INTRODUCTION
Congenital Adrenal Hyperplasia (CAH) is a genetic disorder that causes deficiencies in the steroidogenic enzymes.1 The most common enzyme deficiency in CAH is 21-hydroxylase deficiency (21OHD) accounting for more than 90% of cases.1–3 21OHD is classified into two forms: classical and non-classical.1,4 Unlike the non-classical form (NC-CAH), the classical form (C-CAH) comprises the saltwasting and simple virilizing phenotypes and reflects a spectrum of residual 21OHD, rather than a complete loss of enzyme function, making CAH the most prevalent cause of genital virilization.5 Classical 21OHD occurs in approximately 1 out of every 15,000 births worldwide and is characterized by severe symptoms that include salt-wasting (SW) and ambiguous genitalia.1,2,5
The challenges CAH female patients face differ from those experienced by males.6 In addition to external genitalia virilization, elevated androgen exposure in XX individuals leads to progressive virilization and may influence both psychologically and physiologically, which may affect gender identity, and functionality of reproductive organs.7 Reports of females with C-CAH conveyed high atypical gender identity, gender dysphoria, cross-gender behaviors, as well as a variety of perceptions surrounding sexual dysfunctions such as sexual satisfaction impairment and stigma.8–11
Due to changes in reproductive health, CAH also affects a patient’s quality of life (QoL), potentially lowering quality of life in physical, psychological, and social QoL, such as concerns in romantic relationships, self-esteem, lower marriage rates, and infertility issues.12,13 In contrast, CAH female patients with positive social support and better understanding of their condition showed improvements in QoL.13,14 Mental health concerns, namely shame, secrecy, and stigma surrounding ambiguous genitalia in women with CAH can lead to increased psychiatric disorders, including anxiety disorders and depression.12
Considering the impacts that CAH potentially creates as addressed above, it is highly important to bring light towards psychological aspects of impacted patients as it is to medical aspects of this condition. Although psychosocial outcomes in the CAH population have been previously reported, existing studies are examined in isolation and have rarely been synthesized through a patient-centered lens that integrates reproductive self-perception, mental health, and quality of life. Existing reviews addressing similar topics included outdated studies, and while a previous systematic review discussed these aspects among males with CAH, none covered all three aspects in females.15 Therefore, this systematic review aims to address this gap by providing a comprehensive synthesis of reproductive self-perception, mental health, and quality of life outcomes among females with classical CAH.
METHODOLOGY
Search strategy
This systematic review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA 2020) guidelines. The study protocol was registered with PROSPERO (CRD420251058613). The PRISMA checklist is provided in (Supplemental Table 1). Published articles were searched across four databases, including PubMed, EBSCO, Science Direct, and ProQuest, from January 2015 to February 2024. The detailed search terms used are presented in (Table 1).
Table 1.
Details of search terms used for every database
| No. | Database | Keywords |
|---|---|---|
| 1. | PubMed | (“congenital adrenal hyperplasia”[Title/Abstract] OR “CAH”[Title/Abstract] OR “adrenogenital syndrome”[Title/Abstract]) AND (“women”[Title/Abstract] OR “female”[Title/Abstract] OR “girl”[Title/Abstract]) AND (“psychological”[Title/Abstract] OR “distress”[Title/Abstract] OR “stress”[Title/Abstract] OR “quality of life”[Title/Abstract] OR “qol”[Title/Abstract] OR “emotional”[Title/Abstract] OR “mental disorder”[Title/Abstract] OR “social stigma”[Title/Abstract] OR “lived experience”[Title/Abstract] OR “satisfaction”[Title/Abstract] OR “empower*”[Title/Abstract] OR “attitude*”[Title/Abstract] OR “coping*”[Title/Abstract] OR “network”[Title/Abstract] OR “isolation”[Title/Abstract] OR “relation*”[Title/Abstract] OR “stigma*”[Title/Abstract] OR “social adaptation”[Title/Abstract]) |
|
| ||
| 2. | Science Direct | (“congenital adrenal hyperplasia”[Title/Abstract] OR “CAH”[Title/Abstract]) AND (“women”[Title/Abstract]) AND (“psychological”[Title/Abstract] OR “stress”[Title/Abstract] OR “quality of life”[Title/Abstract] OR “mental disorder”[Title/Abstract] OR “social stigma”[Title/Abstract] OR “social adaptation”[Title/Abstract]) |
|
| ||
| 3. | EBSCOHost | AB (congenital adrenal hyperplasia or CAH or adrenogenital syndrome) AND AB (women or female or girl) AND AB (psychological or distress or stress or quality of life or qol or emotional or mental disorder or social stigma or lived experience or satisfaction or empower or attitude or coping or network or isolation or relation or stigma or social adaptation) |
|
| ||
| 4. | ProQuest | (abstract(congenital adrenal hyperplasia) OR abstract(CAH) OR abstract(adrenogenital syndrome)) AND (abstract(women) OR abstract(female) OR abstract(girl)) AND (abstract(psychological) OR abstract(distress) OR abstract(stress) OR abstract(quality of life) OR abstract(qol) OR abstract(emotional) OR abstract(mental disorder) OR abstract(social stigma) OR abstract(lived experience) OR abstract(satisfaction) OR abstract(empower) OR abstract(attitude) OR abstract(coping) OR abstract(network) OR abstract(isolation) OR abstract(relation) OR abstract(stigma) OR abstract(social adaptation)) |
Eligibility criteria
All original articles addressing QoL, mental health, or selfperception of reproductive health including but not limited to their gender identity and their feelings surrounding stigma about their condition or their condition itself, of female patients with classical 21OHD were included. Quantitative, qualitative or mixed methods studies were eligible for inclusion with no age restrictions. Case reports, review articles, protocol studies, irretrievable full texts, and articles published in languages inaccessible to the review team were excluded. Studies without data of interest, studies discussing mixed genders and not displaying separate results, studies with males only, and studies investigating disorders of sexual development or CAH without separate outcomes for classical 21OHD were further excluded.
Study selection and data extraction
Duplicate studies were removed prior to screening. Titles and abstracts of all studies were initially screened based on eligibility criteria prior to full-text assessment. Three independent reviewers (WJT, JVS and MN) assessed retrieved full-text articles of selected studies, with any conflicts resolved through the fourth and sixth author (AFL, LAP). Data were extracted based on a predetermined tabular sheet consisting of (a) authors and year of publication, (b) study location and design, (c) subject population: sample size, and age range or mean age ± SD, (d) comparison group, and (e) study outcomes as described in the eligibility criteria. Extracted data were synthesized.
Quality assessment
Two independent reviewers (JVS and MN) assessed the risk of bias and quality of included studies using the Newcastle-Ottawa Scale (NOS) for case-control studies and adapted NOS for cross-sectional studies from previously published literature.16 One non-randomized experimental study was assessed using the Risk of Bias in Non-randomized Studies of Intervention (ROBINS-I) and visualized as traffic light plot through the RobVis website.17 Any disagreements were resolved by the first author (WJT).
RESULTS
A total of 783 studies were identified across all databases. Prior to screening, 288 duplicates were removed, and the remaining 495 studies were screened based on title and abstract. Reviewers obtained 29 studies for full-text assessment and ultimately included 11 studies for qualitative synthesis.9,13,18–26 The screening process is summarized as a PRISMA flowchart and presented in (Figure 1).
Figure 1.
A PRISMA 2020 flowchart for literature search and screening.
The characteristics and outcomes of the 11 included studies were extracted, comprising a total of 523 participants. An overview of the study characteristics is presented in Table 2. The majority of selected studies were conducted in the United States, followed by the United Kingdom, Turkey, Austria, and India. All included studies were peer-reviewed original articles that comprise a total of 800 samples, including female patients with classical CAH as the focus of study, and a variety of control groups.
Table 2.
An overview of included study characteristics
| Studies (year) | Location | Study design | Sample size | Age range (years) / mean (SD) | Comparison group |
|---|---|---|---|---|---|
| Schernthaner-Reiter et al. (2019)9 | Austria | Cross-sectional | 35 females | 35.1 (12.3) | NC-CAH |
| Kanhere et al. (2015)13 | United States | Cross-sectional | 89 patients with CAH | NR | None |
| Gangaher et al. (2016)18 | India | Cross-sectional | 22 females | 3.5-32 | Female reared as male |
| Endendijk et al. (2016)19 | United States | Cross-sectional | 54 girls | 10-13 | NC-CAH |
| Meyer-Bahlburg et al. (2018)20 | United States | Cross-sectional | 62 women* | 18-51 | None |
| Meyer-Bahlburg, Reyes-Portillo et al. (2017)21 | United States | Cross-sectional | 62 women* | 18-51 | None |
| Dwiggins et al. (2020)22 | United States | Case-control study | 36 patients with classic CAH; 27 control women | 19-67 | Unaffected relatives |
| Spencer et al. (2021)23 | United Kingdom | Cross-sectional | 43 girls and 38 boys with CAH; 41 girls and 31 boys control† | 4-11.93 | Unaffected relatives |
| Doktur et al. (2021)24 | Turkey | Cross-sectional | 27 girls and 18 boys | 6-18 | Male |
| Hines et al. (2016)25 | United Kingdom | Non-randomized experimental | 43 girls and 38 boys with CAH; 41 female and 31 male controls† | 4-11 | Unaffected relatives |
| Meyer-Bahlburg, Khuri et al. (2017)26 | United States | Cross-sectional | 62 women* | 18-51 | None |
| Summary | 523 |
Meyer-Bahlburg, Khuri et al., Meyer-Bahlburg et al., and Meyer-Bahlburg, Reyes-Portillo et al., were conducted using the same study population.
Spencer et al., and Hines et al., were conducted using the same study population.
NC-CAH – Non-classical congenital adrenal hyperplasia
Nine studies were cross-sectional studies, with one casecontrol study, and one non-randomized experimental study. Based on the NOS, seven studies were classified as low-risk studies and three as high-risk (Tables 3 and 4). The non-randomized study was classified to have a moderate risk of bias based on ROBINS-I (Figure 2).
Table 3.
Modified Newcastle-Ottawa scale quality assessment of cross-sectional studies
| Author (year) | Selection | Comparability | Outcome | Results | ||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||
| Case representative | Sample size | Non-respondents | Ascertainment | Outcome assessment | Statistical test | |||
| Schernthaner-Reiter et al. (2019) | ★ | ☆ | ☆ | ★ | ★☆ | ★ | ★ | High risk |
| Kanhere et al. (2015) | ★ | ☆ | ★ | ★ | ★★ | ★ | ★ | Low risk |
| Gangaher et al. (2016) | ★ | ★ | ★ | ★ | ★☆ | ★ | ☆ | Low risk |
| Endendijk et al. (2016) | ★ | ☆ | ★ | ★ | ★★ | ★ | ★ | Low risk |
| Meyer-Bahlburg et al. (2018) | ★ | ☆ | ★ | ★ | ★☆ | ★ | ☆ | High risk |
| Meyer-Bahlburg, Reyes-Portillo et al. (2017) | ★ | ☆ | ★ | ★ | ★★ | ★ | ☆ | Low risk |
| Spencer et al. (2021) | ★ | ☆ | ★ | ★ | ★★ | ★ | ★ | Low risk |
| Doktur et al. (2021) | ★ | ★ | ★ | ★ | ★★ | ★ | ★ | Low risk |
| Meyer-Bahlburg, Khuri et al. (2017) | ★ | ☆ | ★ | ★ | ★☆ | ★ | ☆ | High risk |
The amount of stars indicates the number of points one study can achieve within each category. A black star (★) indicates that the study has earned a point, while a white star (☆) means that the study failed to earn a point.
Table 4.
Newcastle-Ottawa scale quality assessment of case-control studies
| Author (year) | Selection | Comparability | Outcome | Results | |||||
|---|---|---|---|---|---|---|---|---|---|
|
|
|
||||||||
| Representativeness | Selection | Definition | Demonstration | Ascertainment | Same Method | Non-response | |||
| Dwiggins et al. (2020) | ★ | ★ | ★ | ★ | ★ | ★★ | ★ | ☆ | Low risk |
The amount of stars indicates the number of points one study can achieve within each category. A black star (★) indicates that the study has earned a point, while a white star (☆) means that the study failed to earn a point.
Figure 2.
Risk of Bias in Non-randomized Studies of Intervention (ROBINS-I) quality assessment.
This paper investigates three main domains: (1) selfperception of reproductive health including gender identity, sexual orientation, sexual satisfaction, gendertypical preferences, and perceptions surrounding patients’ genital appearance, (2) mental health, and (3) quality of life, with all outcomes summarized in (Table 5).
Table 5.
An overview of included studies and outcomes of investigated domains
| Studies (year) | SPRH | QoL | Mental health |
|---|---|---|---|
| Schernthaner-Reiter et al. (2019) | More identified as homosexual (p = 0.062) Higher sexual satisfaction (p = 0.636) | Lower sexual distress (p = 0.063) | |
| Kanhere et al. (2015) | Showed cross-gender behavior (51.8%) Dissatisfaction with genital appearance Childhood and adult perceptions are in accordance (p = 0.02) |
Reduced QoL | |
| Gangaher et al. (2016) | Higher rate of gender dysphoria. | Showed subsyndromal depression | |
| Endendijk et al. (2016) | More cross-gender behavior (p <0.05) Higher masculine gender identity (p >0.05) | ||
| Meyer-Bahlburg et al. (2018) | Adverse emotion and experiences. Showed homosexuality. Dissatisfaction with genital appearance. |
Showed substance abuse | |
| Meyer-Bahlburg, Reyes-Portillo et al. (2017) | Doubts on current gender identity. Adverse emotions and experiences. |
||
| Dwiggins et al. (2020) | Less likely to be heterosexual (p = 0.013). Changed gender identity. Lower sexual satisfaction (p = 0.017). |
Reduced QoL (p <0.05) | |
| Spencer et al. (2021) | More cross-gender behavior (p <0.001). | ||
| Doktur et al. (2021) | Higher rate of gender dysphoria (p = 0.23). More cross-gender behavior (18.5%). |
Higher rate of anxiety disorder (p = 0.22) Higher rate of social phobia (p = 0.33) Lower rate of ADHD (p = 0.052) |
|
| Hines et al. (2016) | Reduced female-type preferences (p <0.10). | ||
| Meyer-Bahlburg, Khuri et al. (2017) | Adverse emotions and experiences. Dissatisfaction with genital appearance. |
SPRH – Self-perception of Reproductive Health; QoL – Quality of Life; ADHD – attention-deficit/hyperactivity disorder
DISCUSSION
Self-perception of reproductive health
All included studies addressed diverse issues in relation to sex, gender identity and perceptions surrounding patients’ genital appearance. Three studies acknowledged that female patients with C-CAH are overall more likely to have atypical sexual orientation.9,20,22 Dwiggins et al., showed significant differences compared to healthy females, with a higher proportion of participants reporting bisexual or homosexual orientation. Similarly, the study of Schernthaner-Reiter et al., also demonstrated slightly higher homosexual gender identity among females with C-CAH compared with females with NC-CAH. Some participants from Meyer-Bahlburg et al.,’s interview revealed that frequent misgendering made them restrict their sexual life to women partners only. Dwiggins et al., also reported significantly lower sexual satisfaction compared to healthy controls because of a higher number of reconstructive surgeries done due to the severity of the condition. In contrast, in the study of Schernthaner-Reiter et al., NC-CAH females reported higher sexual satisfaction albeit by non-statistically significant levels. Beyond sexual orientation, five studies reported effects on gender identity; some manage to make adjustments and find comfort in their current gender identity, whereas experience gender dysphoria.18,19,21,22,24 No atypical gender identity or gender dysphoria was reported among control groups.19,22,24 Females with NC-CAH demonstrated only slightly higher masculine gender identity scores, likely reflecting lower prenatal androgen exposure and less severe genital virilization. Gangaher et al., reported that participants reared as female have higher rates of gender dysphoria and dissatisfaction with their female identity, compared to those reared as male.18 In interviews conducted by Meyer-Bahlburg, Reyes-Portillo et al., some participants reported that parental and societal stigma contributed to doubts about being female; however, open discussions regarding their condition helped alleviate those concerns.21
Three studies examining the relationship between prenatal androgen exposure and gender-typed behaviors demonstrate consistent findings.19,23,25 Girls with C-CAH exhibited significantly more male-typical preferences and behaviors than unaffected girls and girls with NC-CAH, whereas boys with C-CAH did not differ from unaffected boys. Consistent with these findings, Kanhere et al., reported that many affected girls preferred male-typical play activities. However, a substantial proportion expressed neutral preferences regarding playmates, suggesting that environmental influences such as sibling gender, may also contribute to behavioral development.
Overall, females with C-CAH demonstrated greater masculinization across several sexual- and gender-related domains. They were more likely to report same-sex attraction, male-typical preferences and behaviors, dissatisfaction with female gender identity, and gender dysphoria than control groups. These findings support the role of prenatal androgen exposure and virilization in shaping psychosexual development. Non-significant findings in some studies may reflect limited statistical power resulting from relatively small and unequal sample sizes. Nevertheless, these observations are consistent with findings reported more than two decades ago, despite the inclusion of a small number of participants whose diagnosis of classical 21OHD was not confirmed.27 Likewise, a study comparing C-CAH to other androgen excess disorders also showed significantly higher homosexuality and lower sexual satisfaction in C-CAH females.28
This review also highlights the perceptions and experiences of females with C-CAH regarding their condition, particularly their genital appearance. According to the three of four studies addressing this topic, there is a relatively high occurrence of affected females who demonstrate dissatisfaction towards their genital appearance, wishing they looked better or wanting a different genital appearance.13,20,26 In two of the three interview-based studies by Meyer-Bahlburg et al., participants described their genitalia as abnormal, different, or strange and reported feelings of fear and discomfort related to their appearance.20,26 Across all three interview studies, many participants expressed discomfort when their genitalia were visible to others, particularly during medical examinations, sexual activity, changing clothes in the presence of other women, or wearing swimwear. Negative self-perceptions were often compounded by stigma and reactions from others, contributing to feelings of nervousness, avoidance, shame, and secrecy that may adversely affect mental health. Dissatisfaction with genital appearance and genital selfconsciousness may also contribute to impaired sexual satisfaction, and potentially influence gender identity and sexual orientation, as supported by previous research demonstrating significant associations among these factors.29
Taken together, females with C-CAH experience challenges related to sexuality, gender identity, and perceptions of virilized genitalia that are closely interconnected. Variability in outcomes likely reflects the influence of multiple biological and environmental factors, including prenatal androgen exposure, parental support, sibling sex, societal attitudes, and stigma. Medical interventions, such as genital reconstructive surgery and hormone replacement therapy, may also influence these outcomes. Consequently, supportive family environments and appropriate psychosocial care are important in helping affected individuals cope with gender- and sexuality-related concerns.
Mental health
Four studies included in this review examined mental health outcomes and have been summarized in (Figure 3).9,18,20,24 Although statistically insignificant, the elevated rates in anxiety disorders and social phobia showed by Doktur et al., are described as a cause of the lower selfesteem in female patients with C-CAH. The findings in this study are consistent with other studies included in this review, which reported reduced self-esteem among participants who experienced stigma from peers, partners, or even health professionals due to their masculinized behavior, atypical genitalia, or chronic medication use., which may increase their susceptibility to psychiatric disorders.20,21,26 The findings related to attention-deficit/hyperactivity disorder (ADHD) were generally consistent with population-based studies showing a higher prevalence of ADHD among males.30 The lack of statistical significance may reflect insufficient statistical power due to the small sample size rather than a true absence of association. Alternatively, it may indicate that males and females with CAH experience comparable psychological burdens related to chronic disease management and long-term treatment. The findings regarding sexual distress were supported by other studies included in this review.9,18,20 Although C-CAH is considered to be more severe than the non-classical form, the study showed a lower distress in females with C-CAH. Sexual distress is often found in female patients with C-CAH as a consequence of their dissatisfaction and negative self-perceptions due to their severely impaired sexual function. However, factors other than disease severity may contribute to these outcomes. For example, genitoplasty has been associated with impaired sexual function in some studies, yet most females with C-CAH in the study by Schernthaner-Reiter et al., had undergone reconstructive surgery, whereas those with NC-CAH generally had not. These findings suggest that reconstructive surgery may alleviate some aspects of sexual distress in selected patients. This interpretation is supported by similar studies showing high level of satisfaction after corrective surgery, allowing patients to live free from the ‘intersex individual’ label, resulting in reduced distress.31,32
Figure 3.
Mental health implications of C-CAH in female patients.
The distress caused by peer pressures and stigma was further supported by one sample from Gangaher et al., examining psychological aspects in females with CAH. Though the aim of the study was not specifically to measure mental health, it reported attempted self-harm performed by one participant as a result of being ridiculed by her peers. Moreover, interviews done by Meyer-Bahlburg et al., showed a shift in behavior where one patient distanced herself from men due to her impaired sexual function and inability to meet both her and her partner’s sexual needs. She experienced feelings of hopelessness, leading her to avoid relationships with men and, instead, turn to alcohol. She also inquired whether the interviewer had identified substance abuse or addiction among other females with C-CAH.
Generally, these findings suggest that females with C-CAH have several mental health problems, mainly anxiety disorders, social phobia, sexual distress and present coping mechanisms like self-harm, self-isolation, and substance abuse which are often signs of depression. These outcomes are likely influenced by both biological factors, including hormonal imbalances, and psychosocial factors, such as stigma and concerns about social acceptance. Genitoplasty may contribute positively to psychological well-being in some individuals (Figure 3).
However, given that only four studies addressed mental health outcomes, and one relied primarily on qualitative interviews, further research is needed to better characterize the psychological challenges faced by females with C-CAH and to identify appropriate supportive interventions.
Quality of life
Patients with CAH face lifelong physical and psychosocial challenges that can significantly impact their quality of life (QoL).33 The chronic nature of CAH necessitates lifelong treatment, frequent healthcare visits, and ongoing management of reproductive and sexual health concerns, all of which may adversely affect psychosocial wellbeing. Concerns regarding fertility, transmission of the condition to offspring, and long-term health outcomes may further contribute to reduced QoL.34 Overall, CAH appears to have a greater impact on females than males, largely due to excess androgen exposure and its associated consequences.33 Untreated female patients may experience hirsutism, acne, voice deepening, anovulation, and menstrual irregularities, ambiguous genitalia, precocious puberty, obesity, and short stature in adulthood.33,34 Greater degrees of virilization, particularly with the classical form of CAH, have been associated with a lower quality of life.33
Studies by Dwiggins et al., and Kanhere et al., evaluated quality of life in females with C-CAH using a 36-item Short Form Survey (SF-36) questionnaire which measures eight health-related quality of life (HRQoL) domains including physical functioning, role limitations due to physical health, role limitations due to emotional problems, energy/fatigue, emotional well-being, social functioning, pain, and general health perception. Both studies showed lower QoL across all domains compared to healthy controls, particularly in general health and pain, with increased dyspareunia and pelvic pain likely contributing to these findings.13,22 Urinary dysfunction had minimal impact on QoL, though patients with clitorectomies reported worse control.35 Importantly, family support, positive childhood experiences, and broader psychosocial support were associated with better QoL outcomes in early adulthood. This may partly explain why differences in some SF-36 domains were not statistically significant. Thus, the quality of life in female patients with C-CAH are multifactorial. However, these findings should be interpreted cautiously because only two studies examined QoL outcomes, both of which had relatively small sample sizes. Furthermore, important confounding factors, including surgical history, degree of virilization, hormonal control, and mental health status, may have influenced the reported outcomes.
To our knowledge, this is the first systematic review to comprehensively examine reproductive self-perception, mental health, and quality of life among females with C-CAH. Our findings manage to bring emphasis on those aspects that are often overseen, providing insights useful for determining the most suitable care tailored to specific challenges encountered by females with C-CAH. However, there are certain limitations in this review. The included studies are highly heterogeneous in outcome measurements and patient demographics, limiting direct comparisons and the strength of the conclusions. Nevertheless, such heterogeneity is expected, given the rarity of the condition.
Limitations
This systematic review has several limitations that should be considered when interpreting the findings. First, the included studies generally involved small and unequal sample sizes, reflecting the rarity of classical CAH but nonetheless limiting the generalizability of the results to the broader CAH population. Second, substantial heterogeneity was present across the included studies in terms of outcome measures, study populations, age ranges, and comparison groups. Variations in assessment instruments, along with differences in patient demographics and clinical characteristics, limited direct comparisons across studies and hindered the synthesis of definitive conclusions. Given this heterogeneity, we did not perform a meta-analysis and instead synthesized the findings narratively. In addition, the evidence base was dominated by crosssectional studies conducted largely in Western settings and focused primarily on adolescents and adults. This does not imply that these age groups are inherently less well adjusted; rather, psychosocial concerns are more readily identified and reported during adolescence and adulthood, and clinic-based recruitment may preferentially capture individuals experiencing distress. Consequently, well-adjusted females with CAH and good clinical control may be underrepresented. Moreover, most studies compared females with CAH to healthy controls rather than examining differences within the CAH population, for instance, disease severity, treatment history, or adequacy of hormonal control, which may introduce selection bias and limit clinical interpretability. Consequently, the findings should be interpreted cautiously, and future research using standardized outcome measures, more diverse and representative cohorts, and within-CAH comparisons is warranted to improve comparability, external validity, and clinical relevance.
CONCLUSION
Females with C-CAH demonstrated impaired selfperception of reproductive health in several domains, including reduced sexual satisfaction, dissatisfaction with genital appearance, doubts regarding gender identity, and gender dysphoria. They also appeared to be more vulnerable to mental health problems, particularly anxiety disorder, social phobia, and social distress, alongside behaviors suggestive of maladaptive coping, such as selfisolation, self-harm, and substance abuse. In addition, females with C-CAH generally showed lower quality of life, especially in the domains of general health and pain, including dyspareunia and pelvic pain. The multifactorial nature of these issues highlights the need for broad and coordinated support from families, local communities, and healthcare professionals. Considering the heterogeneity and small number of included studies, future research should prioritize longitudinal designs, and the inclusion of more diverse and well-adjusted CAH populations, and standardized outcome measures. Further comparative analyses within CAH subgroups, considering disease severity, hormonal control, surgical history, sex of rearing, and sociocultural context, are also essential to better inform individualized and multidisciplinary care for females with C-CAH.
Funding Statement
Funding Source None.
Statement of Authorship
All authors certified fulfillment of ICMJE authorship criteria.
CRediT Author Statement
WJT: Conceptualization, Methodology, Validation, Acquisition of data, Formal analysis, Interpretation, Writing – original draft preparation, Writing – review and editing, Visualization, Final approval of manuscript, Project administration; MN: Conceptualization, Methodology, Validation, Acquisition of data, Formal analysis, Interpretation, Writing – original draft preparation, Writing – review and editing, Visualization, Final approval of manuscript; JVS: Conceptualization, Methodology, Validation, Acquisition of data, Formal analysis, Interpretation, Writing – original draft preparation, Writing – review and editing, Visualization, Final approval of manuscript; AFL: Conceptualization, Methodology, Validation, Acquisition of data, Formal analysis, Interpretation, Writing – original draft preparation, Writing – review and editing, Visualization, Final approval of manuscript; SRW: Conceptualization, Methodology, Validation, Acquisition of data, Formal analysis, Interpretation, Writing – original draft preparation, Writing – review and editing, Visualization, Final approval of manuscript; LAP: Conceptualization, Methodology, Validation, Acquisition of data, Formal analysis, Interpretation, Writing – original draft preparation, Writing – review and editing, Visualization, Final approval of manuscript, Supervision.
Data Availability Statement
Datasets generated and analyzed are included in the published article.
Author Disclosure
The authors declared no conflict of interest.
References
- 1.Witchel SF. Congenital adrenal hyperplasia. J Pediatr Adolesc Gynecol. 2017;30(5):520–34. PMID: PMCID: DOI: 10.1016/j.jpag.2017.04.001 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia—Current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2021;43(1):91–159. PMID: PMCID: DOI: 10.1210/endrev/bnab016 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Elfekih H, Abdelkrim AB, Marzouk H, et al. Congenital adrenal hyperplasia due to 11-Beta-hydroxylase deficiency in a Tunisian family. Pan Afr Med J. 2020;36:226. PMID: PMCID: DOI: 10.11604/pamj.2020.36.226.24270 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kurtoğlu S, Hatipoğlu N.. Non-classical congenital adrenal hyperplasia in childhood. J Clin Res Pediatr Endocrinol. 2017;9(1):1–7. PMID: PMCID: DOI: 10.4274/jcrpe.3378 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nermoen I, Husebye ES, Myhre AG, Løvås K.. Classic congenital adrenal hyperplasia. Tidsskr Nor Laegeforen. 2017;137(7):540–3. PMID: DOI: 10.4045/tidsskr.16.0376 [DOI] [PubMed] [Google Scholar]
- 6.Alemany M. The roles of androgens in humans: Biology, metabolic regulation and health. Int J Mol Sci. 2022;23(19):11952. PMID: PMCID: DOI: 10.3390/ijms231911952 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Simeoli C, de Angelis C, Delli Veneri A, et al. Severe impact of late diagnosis of congenital adrenal hyperplasia on gender identity, sexual orientation and function: Case report and review of the literature. Front Genet. 2022;13:902844. PMID: PMCID: DOI: 10.3389/fgene.2022.902844 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Spencer D, Pasterski V, Neufeld S, et al. Prenatal androgen exposure and children’s aggressive behavior and activity level. Horm Behav. 2017;96:156–65. PMID: PMCID: DOI: 10.1016/j.yhbeh.2017.09.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Schernthaner-Reiter MH, Baumgartner-Parzer S, Egarter HC, et al. Influence of genotype and hyperandrogenism on sexual function in women with congenital adrenal hyperplasia. J Sex Med. 2019;16(10):1529–40. PMID: DOI: 10.1016/j.jsxm.2019.07.009 [DOI] [PubMed] [Google Scholar]
- 10.Seneviratne SN, Jayarajah U, Gunawardana S, Samarasinghe M, de Silva S. Gender-role behaviour and gender identity in girls with classical congenital adrenal hyperplasia. BMC Pediatr. 2021;21(1):262. PMID: PMCID: DOI: 10.1186/s12887-021-02742-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Dessens AB, Slijper FME, Drop SLS. Gender dysphoria and gender change in chromosomal females with congenital adrenal hyperplasia. Arch Sex Behav. 2005;34(4):389–97. PMID: DOI: 10.1007/s10508-005-4338-5 [DOI] [PubMed] [Google Scholar]
- 12.Malouf MA, Inman AG, Carr AG, Franco J, Brooks LM. Health-related quality of life, mental health and psychotherapeutic considerations for women diagnosed with a disorder of sexual development: Congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2010; 2010:253465. PMID: PMCID: DOI: 10.1155/2010/253465 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kanhere M, Fuqua J, Rink R, Houk C, Mauger D, Lee PA. Psychosexual development and quality of life outcomes in females with congenital adrenal hyperplasia. Int J Pediatr Endocrinol. 2015;2015:21. PMID: PMCID: DOI: 10.1186/s13633-015-0017-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Bachelot A, Vialon M, Baptiste A, et al. Impact of transition on quality of life in patients with congenital adrenal hyperplasia diagnosed during childhood. Endocr Connect. 2017;6(7):422–9. PMID: PMCID: DOI: 10.1530/EC-17-0094 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Daae E, Feragen KB, Nermoen I, Falhammar H. Psychological adjustment, quality of life, and self-perceptions of reproductive health in males with congenital adrenal hyperplasia: A systematic review. Endocrine. 2018;62(1):3–13. PMID: PMCID: DOI: 10.1007/s12020-018-1723-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Herzog R, Alvarez-Pasquín M, Díaz C, Barrio J, Estrada J, Gil A.. Are healthcare workers’ intentions to vaccinate related to their knowledge, beliefs and attitudes? A systematic review. BMC Public Health. 2013; 13:154. PMID: PMCID: DOI: 10.1186/1471-2458-13-154 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. PMID: PMCID: DOI: 10.1136/bmj.i4919 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Gangaher A, Jyotsna V, Chauhan V, John J, Mehta M. Gender of rearing and psychosocial aspect in 46 XX congenital adrenal hyperplasia. Indian J Endocrinol Metab. 2016;20(6):870–7. PMID: PMCID: DOI: 10.4103/2230-8210.192922 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Endendijk JJ, Beltz AM, McHale SM, Bryk K, Berenbaum SA. Linking prenatal androgens to gender-related attitudes, identity, and activities: Evidence from girls with congenital adrenal hyperplasia. Arch Sex Behav. 2016;45(7):1807–15. PMID: PMCID: DOI: 10.1007/s10508-016-0693-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Meyer-Bahlburg HFL, Khuri J, Reyes-Portillo J, Ehrhardt AA, New MI. Stigma associated with classical congenital adrenal hyperplasia in women’s sexual lives. Arch Sex Behav. 2018;47(4):943–51. PMID: DOI: 10.1007/s10508-017-1003-8 [DOI] [PubMed] [Google Scholar]
- 21.Meyer-Bahlburg HFL, Reyes-Portillo JA, Khuri J, Ehrhardt AA, New MI. Syndrome-Related Stigma in the General Social Environment as Reported by Women with Classical Congenital Adrenal Hyperplasia. Arch Sex Behav. 2017;46(2):341–51. PMID: DOI: 10.1007/s10508-016-0862-8 [DOI] [PubMed] [Google Scholar]
- 22.Dwiggins M, Brookner B, Fowler K, Veeraraghavan P, Gomez-Lobo V, Merke DP. Multidimensional aspects of female sexual function in congenital adrenal hyperplasia: A case-control study. J Endocr Soc. 2020;4(11):bvaa131. PMID: PMCID: DOI: 10.1210/jendso/bvaa131 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Spencer D, Pasterski V, Neufeld SAS, et al. Prenatal androgen exposure and children’s gender-typed behavior and toy and playmate preferences. Horm Behav. 2021;127:104889. PMID: PMCID: DOI: 10.1016/j.yhbeh.2020.104889 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Doktur H, Tanidir C, Güneş H, et al. Gender dysphoria and psychiatric disorders in children and adolescents with congenital adrenal hyperplasia. Acta Endocrinol (Buchar). 2021;17(3):365–71. PMID: PMCID: DOI: 10.4183/aeb.2021.365 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Hines M, Pasterski V, Spencer D, et al. Prenatal androgen exposure alters girls’ responses to information indicating gender-appropriate behaviour. Philos Trans R Soc Lond B Biol Sci. 2016;371(1688):20150125. PMID: PMCID: DOI: 10.1098/rstb.2015.0125 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Meyer-Bahlburg HFL, Khuri J, Reyes-Portillo J, New MI. Stigma in medical settings as reported retrospectively by women with congenital adrenal hyperplasia (CAH) for their childhood and adolescence. J Pediatr Psychol. 2017;42(5):496–503. PMID: PMCID: DOI: 10.1093/jpepsy/jsw034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hines M, Brook C, Conway GS. Androgen and psychosexual development: Core gender identity, sexual orientation, and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH). J Sex Res. 2004;41(1):75–81. PMID: DOI: 10.1080/00224490409552215 [DOI] [PubMed] [Google Scholar]
- 28.Kępczyńska-Nyk A, Kuryłowicz A, Nowak A, Bednarczuk T, Ambroziak U.. Sexual function in women with androgen excess disorders: classic forms of congenital adrenal hyperplasia and polycystic ovary syndrome. J Endocrinol Invest. 2021;44(3):505–13. PMID: PMCID: DOI: 10.1007/s40618-020-01332-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Schick VR, Calabrese SK, Rima BN, Zucker AN. Genital appearance dissatisfaction: Implications for women’s genital image selfconsciousness, sexual esteem, sexual satisfaction, and sexual risk. Psychol Women Q. 2010;34(3):394–404. PMID: PMCID: DOI: 10.1111/j.1471-6402.2010.01584.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Mowlem FD, Rosenqvist MA, Martin J, Lichtenstein P, Asherson P, Larsson H. Sex differences in predicting ADHD clinical diagnosis and pharmacological treatment. Eur Child Adolesc Psychiatry. 2019; 28(4):481–9. PMID: PMCID: DOI: 10.1007/s00787-018-1211-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Akhtar N, Hayat Z, Bari A. Female pseudo hermaphroditism: Late onset congenital adrenal hyperplasia. J Ayub Med Coll Abbottabad JAMC. 2018;30(3):458–62. PMID: [PubMed] [Google Scholar]
- 32.Tschaidse L, Quinkler M, Claahsen-van der Grinten H, et al. body image and quality of life in women with congenital adrenal hyperplasia. J Clin Med. 2022;11(15):4506. PMID: PMCID: DOI: 10.3390/jcm11154506 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Shafaay EA, Aldriweesh MA, Aljahdali GL, et al. The clinical characteristics and quality of life of 248 pediatric and adult patients with congenital adrenal hyperplasia. Front Endocrinol. 2023; 14:1122435. PMID: PMCID: DOI: 10.3389/fendo.2023.1122435 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Johannsen TH, Ripa CPL, Mortensen EL, Main KM. Quality of life in 70 women with disorders of sex development. Eur J Endocrinol. 2006;155(6):877–85. PMID: DOI: 10.1530/eje.1.02294 [DOI] [PubMed] [Google Scholar]
- 35.Frisén L, Nordenström A, Falhammar H, et al. Gender role behavior, sexuality, and psychosocial adaptation in women with congenital adrenal hyperplasia due to CYP21A2 deficiency. J Clin Endocrinol Metab. 2009;94(9):3432–9. PMID: DOI: 10.1210/jc.2009-0636 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Datasets generated and analyzed are included in the published article.