One objective of this paper was to catalog studies of CAH which included psychological endpoints. A total of 98 original studies published between 1955 and 2009 formed the dataset for our analysis. The majority of investigations (68% of total) examined endpoints related to psychosexual differentiation (i.e., gender identity, gender role, or sexual orientation). Classic 21-OH in females has long served as a human model for the study of early androgen exposure effects on the developing brain. This focus accounts for the fact that affected males, assumed to be exposed to a relatively typical prenatal androgen milieu [19
], are underrepresented in CAH psychological outcome studies.
A number of potential problems emerge as a consequence of this arguably unbalanced research portfolio. For example, there is the risk that the emphasis on gender-role behavior in girls and women may be misinterpreted by consumers of this research (including healthcare providers, patients, and their families) as gender-atypical behavior being a significant source of concern rather than an observation primarily of theoretical importance [120
]. Recent reports in the lay media [121
], as well as an essay published on an authoritative bioethics website [120
], suggest that this risk is, in fact, real. At the center of the current controversy is the practice of prescribing dexamethasone (dex) to pregnant women at risk for carrying a female fetus with CAH. Prenatal dex has been shown to diminish the degree of masculinization of female genitalia which may obviate the perceived need for genital surgery [124
]. Research findings reported at a recent conference [125
] suggest that this same treatment is associated with a similar reduction in the masculinization of behavior. The media and bioethicists interpreted interest in the gender outcome as indicating that the investigators believed that the gender behavior of these girls is a legitimate target for clinical intervention.
An overemphasis on gender-related outcomes has also been associated with a relative scarcity of studies investigating endpoints that relate more directly to improving clinical care. Previous work suggests that both the physical sequelae of the condition and modulation of circulating corticosteroids can affect psychological outcomes. For example, studies examining the influence of hirsutism, acne, short stature, or deep voice [87
] on outcomes such as body image [40
] provide information of potentially great relevance to clinical care, but such studies are relatively scarce. Furthermore, little attention is directed towards the effects of suboptimal hormone replacement therapy on emotional reactivity in male and female CAH patients. Studies have consistently found dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, particularly increases in corticotropin-releasing hormone (CRH), to be related to symptoms of depression, anxiety, panic, and posttraumatic stress disorder [126
]. Similarly, relatively little consideration has been given to the fact that adrenal medulla function is also compromised in 21-OH CAH, resulting in decreased production of epinephrine. Plasma epinephrine and metanephrine concentrations are substantially lower in patients with CAH than in unaffected individuals, especially in those individuals who had been hospitalized for adrenal crisis [127
]. Although apparently not life threatening, this deficiency may result in decreased endurance during long-term physical stress [128
]. This aspect of adrenal function clearly warrants further study because of implications not only for the physical health of the CAH-affected person but also for their health-related quality of life.
In addition to the restricted focus on endocrine abnormalities in CAH as predictors of outcomes, relatively little consideration has been given to social contextual factors (e.g., ethnic, religious, or familial environments [28
]) in which intuition and a large body of evidence from the pediatric psychology literature [130
] suggest exerting strong and lasting effects on the development of children. In the case of CAH, factors to consider include family adaptation to the birth and parenting of a child with a rare life-threatening chronic illness, decision-making regarding genital surgery in girls and its timing and possible decisional regret, to name only a few. Our review also revealed that relatively little attention has been directed toward constructs that may exert profound and lasting effects on the persons and their social relationships; examples include the development of a distorted body image and feelings of shame and fear of disclosure of medical information [30
]. This gap in theory-driven research makes it difficult to develop evidence-based psychosocial interventions to prevent or ameliorate predictable negative sequelae of CAH at different stages of development. Progress in this respect will be greatly facilitated through the development of health-related quality of life questionnaires that focus on issues specific to and shared by patients with CAH and other disorders of sex development and their families, which are not otherwise covered by generic health-related quality of life measures [132
The second objective of this paper was to characterize the conceptual/theoretical models guiding individual studies. For many, the underlying conceptual model had to be inferred from the selection of control/comparison groups, the statistical analysis employed, or through the investigators' interpretation of the data. The majority of studies implicitly or explicitly posited a direct effect of prenatal CAH pathophysiology (i.e., elevated androgens) on the developing brain, and this tendency was most notable for studies examining gender-role behavior and cognitive function. However, even in the case of other psychosexual endpoints, where the evidence for organizational effects of prenatal androgens on the developing brain (i.e., gender identity and sexual orientation) has not been established, investigators rarely articulated (let alone statistically tested) for moderating or mediated effects. Instead, data analysis and interpretation suggested that the investigators assumed a causal rather than correlational relationship between CAH hormonal abnormalities and psychological outcomes.
The current paper also showed that the majority of studies (76%) were quantitative, employing standardized measures to assess behavior in predetermined domains. Relatively few studies employed qualitative or mixed methods. Findings from several of these suggest the promise of this approach in identifying areas of particular relevance to clinical care. A poignant example comes from a qualitative study by May and colleagues [43
]. It was reported that a lower percentage of women with CAH masturbated compared with women in a diabetes control group. Explanations given by CAH participants were illuminating. One participant described masturbation as a necessary medical procedure rather than one performed for sexual pleasure: “ [masturbation was necessary] to keep it [the vagina] open. I have done so, everybody does, I used to have to, I would explore-what had [the surgeons] done? Even now, I've never thought about it for enjoyment” (p.484). Regardless of the generalizability of this observation, it suggests a direction for investigations examining the effects of medical examinations and procedures that may influence sexual experiences. In the same way, knowledge of patient subjective experiences such as these can directly inform the model of clinical care, for example, referral for sex therapy [3
An implication of this paper is the need for larger sample sizes in order to test moderated and mediated models of CAH effects with adequate statistical power. Because CAH is a rare disease, the development of multisite collaborations is essential to progress. An example of such collaboration is Euro DSD, a consortium supported by the European Union [133
]. As already noted, a broadened research agenda that includes assessment of psychological outcomes directly relevant to patients' lives will hopefully spur efforts in the development of well-informed psychosocial interventions.
Finally, two aspects of the methodology of this paper should be kept in mind: first, there is a possibility that some eligible studies were missed despite our best efforts to be complete. Because studies were identified using both Medline and PsychINFO databases, we do not believe that the addition of missed articles would fundamentally alter any of our findings or conclusions. Accuracy in categorization of studies according to the underlying conceptual model is more problematic. We made every effort to seek reliability in the process but expect that others, attempting the same task, might generate a somewhat different result than that summarized in . Here also, we do not expect that a reclassification of individual studies will fundamentally alter the conclusion that the majority of research on psychological endpoints in CAH arises from a direct effect model. Nonetheless, it should be noted that studies published in this special issue, but beyond the cutoff year for this paper (2009), hint at increased interest in the use of qualitative methods and examination of family contextual variables (e.g., [134
This paper will hopefully serve to encourage investigators to design new studies that attempt to model some degree of the complexity of the lives of children, adolescents, and adults (both women and men) with CAH and their families. Such approaches are firmly established in other areas of health research [136
]. Because the theoretical framework for studying psychological outcomes of persons with DSD other than CAH is similarly focused on the putative action of androgens on sex-dimorphic brain development and psychosexual differentiation [137
], it is perhaps obvious, but nonetheless worth mentioning, that all that has been stated in this paper regarding the CAH research agenda potentially applies to all other conditions currently categorized as DSD.