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Hindawi Publishing CorporationInternational Journal of Pediatric EndocrinologyVolume 2010, Article ID 191520, 11 pagesdoi:10.1155/2010/191520Review ArticleCongenital Adrenal Hyperplasia: Classification ofStudies Employing Psychological EndpointsStephanie A. Stout, Margarita Litvak, Natashia M. Robbins, and David E. SandbergDivision of Child Behavioral Health, Department of Pediatrics & Communicable Diseases, University of Michigan,1500 E. Medical Center Drive, Ann Arbor, MI 48109-5318, USACorrespondence should be addressed to David E. Sandberg, dsandber@med.umich.eduReceived 18 April 2010; Revised 7 July 2010; Accepted 30 July 2010Academic Editor: John FuquaCopyright © 2010 Stephanie A. Stout et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.Psychological outcomes in persons with congenital adrenal hyperplasia (CAH) have received substantial attention. Theobjectives of this paper were to (1) catalog psychological endpoints assessed in CAH outcome studies and (2) classify theconceptual/theoretical model shaping the research design and interpretation of CAH-related psychological effects. A total of 98original research studies, published between 1955 and 2009, were categorized based on psychological endpoints examined aswell as the research design and conceptual model guiding analysis and interpretation of data. The majority of studies (68%)investigated endpoints related to psychosexual differentiation. The preponderance of studies (76%) examined a direct relationship(i.e., inferring causality) between prenatal androgen exposure and psychological outcomes. Findings are discussed in relation tothe observed imbalance between theoretical interest in the role of prenatal androgens in shaping psychosexual differentiation anda broader conceptual model that examines the role of other potential factors in mediating or moderating the influence of CAHpathophysiology on psychological outcomes in both affected females and males. The latter approach offers to identify factorsamenable to clinical intervention that enhance both health and quality of life outcomes in CAH as well as other disorders of sexdevelopment.1. IntroductionCongenital adrenal hyperplasia (CAH) comprises a family ofautosomal recessive disorders involving impaired synthesisof cortisol. In 21-hydroxylase deficiency (21-OH CAH),the most common form comprising as many as 95% ofnew cases, excessive adrenal androgen biosynthesis resultsin masculinization of the genitals of 46, XX offspring [1].Similar to other chronic pediatric conditions, CAH hasdrawn the attention of clinical researchers interested inthe psychological sequelae of the condition and factorscontributing to variability in both physical health and qualityof life outcomes of affected persons.Hormone replacement in CAH is imperfect and doesnot mimic physiologic secretion. According to the 2002Consensus Statement on 21-Hydroxylase Deficiency [2], thegoal of treatment is the minimization of adrenal sex hormoneand glucocorticoid excess, while simultaneously preventingpremature or inappropriate virilization, optimizing growthand adult height, and preserving potential fertility. Becauseof the masculinizing effects of prenatal androgen excess onthe genitalia, 21-OH CAH in 46, XX is now categorized asa disorder of sex development (DSD) [3]. According to the2006 Consensus Statement on the Management of Intersex,DSD are “congenital conditions in which development ofchromosomal, gonadal, or anatomic sex is atypical” [3](p. e488). Both the CAH and DSD consensus statementsrecognize the stress on patient and family associated witha chronic life-threatening illness and, in the case of girlsand women affected with CAH, the added burden ofatypical genital anatomy. The DSD consensus statement alsonotes that cultural and social factors modulate outcomesin affected persons and, therefore, recommends that theseinfluences be taken into account in clinical care and researchdesign. The statement charges clinicians and researchers toexamine a wide range of psychological endpoints including
Page 2 2International Journal of Pediatric Endocrinology“sexual function, and social and psychosexual adjustment,mental health, quality of life, and social participation” [3] (p.e493).1.1. Psychological Endpoints in CAH. Much of what isknown about the psychological development of personsaffected with CAH (particularly females) stems from researchfocused on elucidating the influence of atypical sex hor-mone exposure during steroid-sensitive periods of braindevelopment [4–6]. Prenatal androgen excess associated withmasculinization of the genitalia is believed to influence thedevelopment of regions of the brain responsible for sexdifferences in behavior across a wide range of mammalianspecies, including humans [7–9]. Accordingly, CAH has beenutilized as a model for testing hormonal hypotheses relatedto the influence of early androgen exposure on behaviorsexhibiting sex-related variability, in particular psychosexualdifferentiation (i.e., gender identity, gender role, and sexualorientation) and sex differences in neurocognitive function.Although the rate at which females with CAH experiencegender dysphoria is significantly higher than in the generalpopulation, the large majority of females with CAH reared asgirls develop a feminine gender identity and do not expressfeelings of gender dysphoria [10]. With regard to genderrole (i.e., behaviors that differ in frequency or level betweenmales and females that are promoted by social learning [11]),affected girls prefer toys and activities characterized as maletypical [12, 13], are more likely to report the use of physicalaggression in conflict situations [14], and are less interestedin marriage, motherhood, and physical appearance [15] thanunaffected girls. In the case of sexual orientation, affectedwomen are more likely to have experienced homosexualfantasies or behavior than their unaffected relatives [16,17]. Consistent with theories regarding the role of earlyandrogens in the development of sex differences in cognitivefunction, girls with CAH exhibit enhanced spatial reasoningcompared with unaffected siblings [18]. The apparent biastoward utilizing CAH as a model to test hormonal theoriesfor the origins of sex differences in human behavior can beinferred from the relative scarcity of psychological outcomestudies in CAH males. Affected males are of less interest inthis regard because prenatal androgen levels in males arethought to fall within the normal range [19, 20] and becausegendered behavior of boys with CAH appears typical [8].In contrast to extensive research on gender-related phe-nomena, there has been relatively limited research addressingpsychosocial adaptation in either females or males. Thesestudies generally fail to show that CAH patients exhibitan increased incidence of psychopathology relative to thegeneral population [21–23].1.2. Conceptualization of the Effects of CAH on Psycho-logical Outcomes. There are several ways to conceptualizethe influence of CAH on psychological endpoints [24,25]. The simple or direct effect model involves a singlepredictor (A) directly related to a single outcome (C). Thepotential influence of other variables is not considered inthis model. An example of a direct effect model appliedto behavioral outcomes would be a study comparing thesexual orientation of affected women to that of an unaf-fected female control group. An increased frequency ofhomosexuality or bisexuality has typically been attributedto the influence of prenatal androgen exposure on braindevelopment [16, 17, 26]. Because other variables potentiallyimpacting the endpoint of sexual orientation have not beenformally examined or incorporated into the data-analyticstrategy, prenatal androgen exposure, by default, becomesan appealing interpretation in light of animal experimentalresearch [6–8]. However, this simplest of conceptual modelsdoes not reflect the view that sexual orientation in CAHwomen is likely multifactorially determined [27].When the relationship between predictor and outcome isthought to be either buffered or intensified by another factor,then a more suitable model than one depicting a direct effectis one that tests for moderation. A moderator is a qualitative(e.g., sex, form of CAH, salt wasting vs simple virilizing,family’s ethnic background) or quantitative (e.g., age, serumtestosterone levels) variable that influences the directionand/or strength of the relationship between predictor andoutcome variables. In other words, moderation occurs whenone variable affects the relationship between two othervariables such that the impact of the predictor (A) on theoutcome (C) varies according to the level or value of themoderator (B). For example, gender assignment in 46, XXCAH appears to be moderated by the country in whichthe patient receives care. A comprehensive review of genderassignment decisions in Western industrialized countriesshows that the vast majority of 46, XX CAH patients havebeen reared as girls [10], while 46, XX CAH patients in morepatriarchal societies (e.g., Turkey) have a higher rate of malegender assignment [28].Finally, there are mediation models in which the mediatorvariable serves to clarify the nature of the relationshipbetween the predictor and outcome [25]. Rather thanhypothesizing a direct causal relationship between the pre-dictor and outcome variables, a mediation model posits thatthe predictor (A) influences another variable (B) which,in turn, is more directly responsible for the outcome (C).Potential examples of mediated effects of CAH on sexualbehavior include studies examining the outcomes of genitalsurgery [29, 30]. In these reports, reduced genital sensitivityand dissatisfaction or anxiety about genital appearance wereidentified as factors accounting for decreased sexual activityand pregnancy rates. The effect is not directly the conse-quence of having CAH but is mediated through experiencesor consequences associated with its management.Although incorporating a moderator or mediator in theconceptual model helps sharpen our understanding of therelationship between predictor and outcome, the researchermust secure a larger sample size to ensure adequate statisticalpower to demonstrate the influence of either [31, 32].Because CAH is a relatively rare disease (1 in 15,000 births,only half of whom are 46, XX), problems arising from thelarger sample size requirement may be remedied throughmulticenter studies.The objective of the current paper is two-fold: first,to catalog studies of psychological endpoints assessed in
Page 3 International Journal of Pediatric Endocrinology3CAH outcome studies and, second, to categorize these intodomains and subdomains. This objective’s importance flowsfrom the consensus statement on DSD [3] which drewattention to the need to broaden the range of psychologicaloutcomes investigated and attended to in clinical care.Second, it aims to classify the conceptual model (implicitlyor explicitly) applied to account for CAH-related effects onpsychological endpoints.2. Materials and Methods2.1. Study Eligibility Criteria. Original research studies pub-lished in English between 1955 and 2009 were included inthis paper if study participants included persons affectedwith 21-OH CAH (regardless of age or sex) and psycholog-ical variables (broadly defined) were measured. Literaturereviews and research studies focusing on CAH pathophys-iology that did not examine psychological endpoints wereexcluded. Similarly, studies were excluded if data fromparticipants with varying medical diagnoses were combinedsuch that results for participants with CAH could not beisolated.Using the electronic databases OVID/Medline andPsycINFO, searches were performed by combining termsused to identify CAH with those likely to capture thebroadest possible range of psychological endpoints (SeeTable 1). In OVID/Medline, the Medical Subject Heading(MeSH) “Adrenal Hyperplasia, Congenital,” which encom-passes “Adrenogenital Syndrome,” was combined with theMeSH terms “Adjustment, Psychological” (capturing theterms behavior, adaptive; coping behavior; adaptation,psychologic; coping skills; psychological adaptation; psy-chological adjustment), “Stress, Psychological” (comprisinganguish, emotional stress, life stress, mental suffering, andsuffering), and the terms of psychosexual development;gender; gender identity; gender role; sexuality; sexual behav-ior; sexual dysfunction; sexual dysfunction, psychological;self-concept; body image; individual adjustment; qualityof life; fertility; conception; personality inventory; careerchoice; religion; spirituality; psychopathology; mental dis-orders; cognition; interpersonal relations; marriage; socialadjustment; social support; as well as results from thecombinations of family + psychology, family + attitude,family + adjustment, and family + behavior. In the case ofsearches performed on the PsycINFO database, the terms“congenital adrenal hyperplasia,” “adrenogenital syndrome,”and “intersex” were paired with the psychosocial terms listedabove. These procedures yielded a total of 98 articles.2.2. Classification of Psychological Endpoints and ConceptualModel. Two raters (SS and ML) used study summary formsto reliably classify psychological endpoints assessed andresearch design used in each study. Psychological endpointswere classified into major domains and further dividedinto subdomains to achieve greater specificity (Table 1).Given that several studies examined multiple psychologicalendpoints, the tabled numbers exceed the total number ofstudies reviewed. Although most domain and subdomainlabels are self-explanatory, the Psychological Factors subdo-mains warrant further explanation. Studies that employedstandardized measures based on diagnostic criteria of theAmerican Psychiatric Association Diagnostic and Statisti-cal Manual [116] were categorized within the subdomainPsychopathology. Those studies examining behavioral andemotional symptoms, apart from diagnosable syndromes,were categorized as Behavioral/Emotional Functioning. Withregard to the endpoint Health-Related Quality of Life,only those studies which utilized questionnaires designedspecifically to assess this construct [117] were classifiedin this subdomain. Reproduction comprised two subdo-mains: studies which provided documentation of either thefrequency of pregnancy or frequency with which CAH-affected women carried the pregnancy to term were classifiedunder Conception; all other measured outcomes dealingwith reproductive function were classified under FertilityStatus. Studies examining psychological factors that couldnot reliably be classified within another domain/subdomainwere listed as “Other.” Examples of outcomes falling intothis category included parental attitudes toward genderassignment [33, 34] or reactions to genital anomalies [28].Reviewers also categorized studies based on their inter-pretation of the underlying conceptual model guiding studydesign and data analysis; that is, direct, mediated, ormoderated. This aspect of the paper was complicated by thefact that investigators neither specified nor formally testedthe fit of specific conceptual models according to acceptedstatistical practice (e.g., [24, 25, 32]) leaving it to the raters toinfer the type of model guiding the research. Disagreementsbetween raters were resolved by consensus involving thesenior author (DES).Finally, studies were also categorized as employing quan-titative, qualitative, or mixed-methods (i.e., involving a com-bination of both quantitative and qualitative methodologies)[118] approaches. Quantitative research primarily uses adeductive process to test prespecified concepts, constructs,and hypotheses that make up a theory. The aim is to classifyfeatures, count them, and construct statistical models inan attempt to explain observed phenomena. In contrast,qualitative research primarily uses an inductive process toformulate theory. Qualitative research methods commonlyinvolve detailed analysis of data such as transcripts frominterviews. This approach is fundamentally more subjective,for example, by describing a problem or condition from thepoint of view of those experiencing it [119].3. Results3.1. Classification of Psychological Endpoints. Of the 98articles reviewed, 67 (68%) studied endpoints were classifiedin the Psychosexual Differentiation domain. The majoritywithin this domain included an assessment of Gender Role(n = 46, 46%), followed by Gender Identity (n = 27, 27%)and Sexual Orientation (n = 28, 29%) (Table 1). The nextmost frequently investigated endpoints were categorized inthe domain of Psychological Factors (n = 28 studies, 29%).The remaining domains and subdomains are summarized
Page 4 4International Journal of Pediatric EndocrinologyTable 1: Classification of psychological endpoints by domain and subdomain†.Domain (# Studies)Subdomain (# Studies)ReferencesPsychosexual Differentiation (67)Gender role (46)[4, 5, 12–17, 22, 26, 28, 33–88]Gender identity (27)Sexual orientation (27)Psychological Factors (30)Self-concept (18)[5, 21–23, 28, 30, 33, 40–42, 49, 51, 55, 57, 65, 69, 71, 72, 74, 81, 86, 87, 89–96]Behavioral/emotionalfunctioning (11)Psychopathology (10)Health-related quality of life (5)Sexuality (25)Sexual function (2)[16, 26, 29, 30, 38, 40, 41, 43, 50, 52, 65, 69–72, 81–84, 87, 89, 97–100]Sexual activity (17)Social Adaptation (25)Social functioning (12)[14, 17, 21, 23, 38, 40, 41, 46, 52, 55, 56, 69–72, 81, 82, 84, 87, 89, 90, 93, 97, 98, 100]Cohabitation/marriage (15)Cognitive Function (23)[4, 28, 35, 48, 53, 55, 57, 64, 67, 98, 101–113]Reproduction (10)Fertility status (7)[40, 50, 52, 70, 85, 87, 89, 94, 114, 115]Conception (8)Other (8)[28, 33, 34, 40, 71, 82, 87, 89]Education/Occupation (7)[51, 65–67, 87, 92, 100]†Individual studies examined multiple endpoints; numbers of studies within domain/subdomain therefore exceed the total number of studies reviewed (N =98).in Table 1. Studies employing quantitative methods alonecomprised 76% of the reviewed literature, 18% were classi-fied as qualitative, and 6% were applied to a combination ofquantitative and qualitative strategies, that is, mixed methods(not shown in Table).3.2. Classification of Conceptual Models. Seventy three of 98studies (74%) interpreted the psychological outcome as adirect consequence of CAH pathophysiology (Table 2). Forexample, masculinized gender-role behavior and neurocog-nitive profiles in affected girls are commonly explained interms of a direct effect of excess prenatal androgen exposureon brain development in affected girls (e.g., [35, 36, 101]).The majority of studies within the domains of PsychosexualDifferentiation (57 of 67), Psychological Factors (21of 30),Cognitive Function (22 of 23), Social Adaptation (19 of 25),Sexuality (13 of 25), Reproduction (8 of 10), and all studiesexamining Education/Occupation (7) endpoints applied adirect effect conceptual model.A minority of reviewed studies (15 of 98, 15%) examinedthe possibility that a third variable moderated the asso-ciation between CAH and the outcome variable. Studieswhich adopted this approach targeted endpoints classifiedas Psychosexual Differentiation (8), Cognition (6), Sexuality(2), Psychological Factors (2), and Social Adaptation (2).For example, Berenbaum [37] demonstrated that effects ofCAH on sex-typed play activities and interests were restrictedto affected girls. The statistical interaction between sex ofpatient and type of play and interests constitutes evidence ofa moderating variable. Across all studies, the moderator vari-able most frequently considered was participant’s biologicalsex (13 of 15, 87%) (Table 2).A slightly higher proportion of studies (29 of 98, 30%)adopted a mediation model (i.e., consideration that all ora portion of the influence of CAH on the outcome wasmediated through another variable). Studies attending to thepossibility of mediated effects tracked endpoints in the fol-lowing domains: Psychosexual Differentiation (18), Sexuality(11), Psychological Factors (7), Social Adaptation (5), Other(4 articles examining family response to CAH and deepnessof voice), Reproduction (3), and Cognition (1). For example,Zucker and colleagues [38] reported that for both womenwith CAH and their unaffected relatives, higher self-reportedsexual arousability positively predicted relationship status,level of sexual attraction to men in fantasy, greater likelihoodof heterosexual behavior, and more sexual experiences withmen. The only statistically significant predictor of sexualarousability (for both CAH women and unaffected relatives)was lifetime sexual experiences with men. In other words,what differentiated CAH and healthy women was the amountof sexual experience by the time of study participation,whether or not they had CAH. Accordingly, if controlgroup participants for any reason had more limited sexualexperience, then they also would have been expected toshow reduced sexual arousability. In this context, “sexualexperience” is conceptualized as mediating the influence ofCAH on sexual arousability.Other examples of studies allowing for mediated effectsincluded Hall et al. [39] and Slijper [88]; both introduced acontrol group comprised of comparably-aged patients withdiabetes to control for “very similar life experiences thataccompany their respective chronic illnesses: regular outpa-tient attendances, daily medication, decompensation duringintercurrent illnesses, potentially life-threatening crises, andadverse impact on family life, schooling, and social life” [39].
Page 5 International Journal of Pediatric Endocrinology5Table 2: Summary of conceptual models applied to study of psychological endpoints†.Conceptual ModelNumber of StudiesReferencesDirect Effect73[4, 5, 12–17, 21–23, 26, 28, 35, 36, 38, 40–42, 44, 46–48, 50, 51, 53–56, 58–61, 64–70, 72–80, 83, 84, 86, 87, 89, 90, 92–94, 97, 98, 100, 101, 103–107, 110–115]Mediating29[16, 30, 33, 34, 38–40, 43–45, 49, 50, 52, 56, 57, 62, 63, 71, 74, 80–82, 85, 88, 91, 95, 96, 99, 102]Moderating15[4, 5, 12, 29, 37, 53, 54, 58, 75, 89, 93, 103, 108, 109, 111]†Individual studies examined multiple endpoints; numbers of studies within domain/subdomain therefore exceed the total number of studies reviewed (N =98).A total of 7 of 98 studies (7%) incorporated a control groupcomprised of chronically ill participants.4. DiscussionOne objective of this paper was to catalog studies of CAHwhich included psychological endpoints. A total of 98original studies published between 1955 and 2009 formedthe dataset for our analysis. The majority of investigations(68% of total) examined endpoints related to psychosexualdifferentiation (i.e., gender identity, gender role, or sexualorientation). Classic 21-OH in females has long served asa human model for the study of early androgen exposureeffects on the developing brain. This focus accounts forthe fact that affected males, assumed to be exposed toa relatively typical prenatal androgen milieu [19, 20], areunderrepresented in CAH psychological outcome studies.A number of potential problems emerge as a consequenceof this arguably unbalanced research portfolio. For example,there is the risk that the emphasis on gender-role behaviorin girls and women may be misinterpreted by consumers ofthis research (including healthcare providers, patients, andtheir families) as gender-atypical behavior being a significantsource of concern rather than an observation primarily oftheoretical importance [120]. Recent reports in the lay media[121–123], as well as an essay published on an authoritativebioethics website [120], suggest that this risk is, in fact,real. At the center of the current controversy is the practiceof prescribing dexamethasone (dex) to pregnant women atrisk for carrying a female fetus with CAH. Prenatal dexhas been shown to diminish the degree of masculinizationof female genitalia which may obviate the perceived needfor genital surgery [124]. Research findings reported at arecent conference [125] suggest that this same treatment isassociated with a similar reduction in the masculinizationof behavior. The media and bioethicists interpreted interestin the gender outcome as indicating that the investigatorsbelieved that the gender behavior of these girls is a legitimatetarget for clinical intervention.An overemphasis on gender-related outcomes has alsobeen associated with a relative scarcity of studies investigat-ing endpoints that relate more directly to improving clinicalcare. Previous work suggests that both the physical sequelaeof the condition and modulation of circulating corticos-teroids can affect psychological outcomes. For example, stud-ies 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 clinicalcare, but such studies are relatively scarce. Furthermore,little attention is directed towards the effects of suboptimalhormone replacement therapy on emotional reactivity inmale and female CAH patients. Studies have consistentlyfound dysregulation of the hypothalamic-pituitary-adrenal(HPA) axis, particularly increases in corticotropin-releasinghormone (CRH), to be related to symptoms of depression,anxiety, panic, and posttraumatic stress disorder [126]. Sim-ilarly, relatively little consideration has been given to the factthat adrenal medulla function is also compromised in 21-OH CAH, resulting in decreased production of epinephrine.Plasma epinephrine and metanephrine concentrations aresubstantially lower in patients with CAH than in unaffectedindividuals, especially in those individuals who had beenhospitalized for adrenal crisis [127]. Although apparentlynot life threatening, this deficiency may result in decreasedendurance during long-term physical stress [128, 129]. Thisaspect of adrenal function clearly warrants further studybecause of implications not only for the physical health of theCAH-affected person but also for their health-related qualityof life.In addition to the restricted focus on endocrine abnor-malities in CAH as predictors of outcomes, relatively littleconsideration has been given to social contextual factors(e.g., ethnic, religious, or familial environments [28]) inwhich intuition and a large body of evidence from the pedi-atric psychology literature [130, 131] suggest exerting strongand lasting effects on the development of children. In the caseof CAH, factors to consider include family adaptation to thebirth and parenting of a child with a rare life-threateningchronic illness, decision-making regarding genital surgeryin girls and its timing and possible decisional regret, toname only a few. Our review also revealed that relativelylittle attention has been directed toward constructs that mayexert profound and lasting effects on the persons and theirsocial relationships; examples include the development ofa distorted body image and feelings of shame and fear ofdisclosure of medical information [30, 41, 42, 89]. Thisgap in theory-driven research makes it difficult to developevidence-based psychosocial interventions to prevent orameliorate predictable negative sequelae of CAH at differentstages of development. Progress in this respect will be greatlyfacilitated through the development of health-related qualityof life questionnaires that focus on issues specific to and
Page 6 6International Journal of Pediatric Endocrinologyshared by patients with CAH and other disorders of sexdevelopment and their families, which are not otherwisecovered by generic health-related quality of life measures[132].The second objective of this paper was to character-ize the conceptual/theoretical models guiding individualstudies. For many, the underlying conceptual model hadto be inferred from the selection of control/comparisongroups, the statistical analysis employed, or through theinvestigators’ interpretation of the data. The majority ofstudies implicitly or explicitly posited a direct effect ofprenatal CAH pathophysiology (i.e., elevated androgens) onthe developing brain, and this tendency was most notablefor studies examining gender-role behavior and cognitivefunction. However, even in the case of other psychosexualendpoints, where the evidence for organizational effects ofprenatal androgens on the developing brain (i.e., genderidentity and sexual orientation) has not been established,investigators rarely articulated (let alone statistically tested)for moderating or mediated effects. Instead, data analysisand interpretation suggested that the investigators assumeda causal rather than correlational relationship between CAHhormonal abnormalities and psychological outcomes.The current paper also showed that the majority ofstudies (76%) were quantitative, employing standardizedmeasures to assess behavior in predetermined domains. Rel-atively few studies employed qualitative or mixed methods.Findings from several of these suggest the promise of thisapproach in identifying areas of particular relevance toclinical care. A poignant example comes from a qualitativestudy by May and colleagues [43]. It was reported that a lowerpercentage of women with CAH masturbated comparedwith women in a diabetes control group. Explanations givenby CAH participants were illuminating. One participantdescribed masturbation as a necessary medical procedurerather than one performed for sexual pleasure: “ [mas-turbation was necessary] to keep it [the vagina] open. Ihave done so, everybody does, I used to have to, I wouldexplore-what had [the surgeons] done? Even now, I’ve neverthought about it for enjoyment” (p.484). Regardless of thegeneralizability of this observation, it suggests a direction forinvestigations examining the effects of medical examinationsand procedures that may influence sexual experiences. In thesame way, knowledge of patient subjective experiences suchas these can directly inform the model of clinical care, forexample, referral for sex therapy [3].An implication of this paper is the need for larger samplesizes in order to test moderated and mediated models ofCAH effects with adequate statistical power. Because CAHis a rare disease, the development of multisite collaborationsis essential to progress. An example of such collaborationis Euro DSD, a consortium supported by the EuropeanUnion [133]. As already noted, a broadened research agendathat includes assessment of psychological outcomes directlyrelevant to patients’ lives will hopefully spur efforts in thedevelopment of well-informed psychosocial interventions.Finally, two aspects of the methodology of this papershould be kept in mind: first, there is a possibility thatsome eligible studies were missed despite our best effortsto be complete. Because studies were identified using bothMedline and PsychINFO databases, we do not believe thatthe addition of missed articles would fundamentally alter anyof our findings or conclusions. Accuracy in categorizationof studies according to the underlying conceptual model ismore problematic. We made every effort to seek reliabilityin the process but expect that others, attempting the sametask, might generate a somewhat different result than thatsummarized in Table 2. Here also, we do not expect that areclassification of individual studies will fundamentally alterthe conclusion that the majority of research on psycholog-ical endpoints in CAH arises from a direct effect model.Nonetheless, it should be noted that studies published inthis special issue, but beyond the cutoff year for this paper(2009), hint at increased interest in the use of qualitativemethods and examination of family contextual variables(e.g., [134, 135]).This paper will hopefully serve to encourage investigatorsto design new studies that attempt to model some degreeof the complexity of the lives of children, adolescents, andadults (both women and men) with CAH and their families.Such approaches are firmly established in other areas ofhealth research [136]. Because the theoretical framework forstudying psychological outcomes of persons with DSD otherthan CAH is similarly focused on the putative action ofandrogens on sex-dimorphic brain development and psycho-sexual differentiation [137–139], it is perhaps obvious, butnonetheless worth mentioning, that all that has been statedin this paper regarding the CAH research agenda potentiallyapplies to all other conditions currently categorized as DSD.AcknowledgmentsThe project described was supported in part by Award no.R01HD053637 from the Eunice Kennedy Shriver NationalInstitute of Child Health and Human Development. Thecontent is solely the responsibility of the authors and doesnot necessarily represent the official views of the EuniceKennedy Shriver National Institute of Child Health andHuman Development or the National Institutes of Health.The authors thank Tom Mazur for encouraging them toprepare this paper as well as the research staff who assistedwith its preparation, including Bijal Bhavsar, Kerrie Gillespie,and David Nguyen. Finally, they thank Melissa Gardner forcomments on the paper.References[1] P. W. Speiser and P. C. White, “Congenital adrenal hyper-plasia,” New England Journal of Medicine, vol. 349, no. 8, pp.776–788, 2003.[2] Joint LWPES/ESPE CAH Working Group, “Consensus state-ment on 21-hydroxylase deficiency from the Lawson WilkinsPediatric Endocrine Society and the European Society forPaediatric Endocrinology,” Journal of Clinical Endocrinologyand Metabolism, vol. 87, no. 9, pp. 4048–4053, 2002.[3] P. A. Lee, C. P. Houk, S. F. 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