Gender development and sexuality in disorders of sex development.

Understanding psychological development in individuals with disorders of sex development (DSD) is important for optimizing their clinical care and for identifying paths to competence and health in all individuals. In this paper, we focus on psychological outcomes likely to be influenced by processes of physical sexual differentiation that may be atypical in DSD, particularly characteristics related to being male or female (those that show sex differences in the general population, gender identity, and sexuality). We review evidence suggesting that (a) early androgens facilitate several aspects of male-typed behavior, with large effects on activity interests, and moderate effects on some social and personal behaviors (including sexual orientation) and spatial ability; (b) gender dysphoria and gender change occur more frequently in individuals with DSD than in the general population, with rates varying in relation to syndrome, initial gender assignment, and medical treatment; and (c) sexual behavior may be affected by DSD through several paths related to the condition and treatment, including reduced fertility, physical problems associated with genital ambiguity, social stigmatization, and hormonal variations. We also consider limitations to current work and challenges to studying gender and sexuality in DSD. We conclude with suggestions for a research agenda and a proposed research framework.

Cognitive function in congenital adrenal hyperplasia.

Cognition in patients with CAH has not been as well studied as other aspects of psychologic function. Nevertheless, it is possible to make some conclusions and to offer a number of hypotheses for further study (Table 1). First, patients with CAH do not seem to have an overall intellectual advantage as a direct consequence of the disease. The high IQs reported in some groups of patients with CAH are also reported in their siblings and probably reflect sampling bias. Second, it is possible that, on average, patients with salt-wasting CAH have lower overall ability than patients with the simple-virilizing form, but both groups are well within the normal range, and there is considerable variability among both groups. Third, the evidence to date does not confirm that patients with CAH are more likely to have diagnosable learning disabilities when compared with their unaffected relatives, but this issue has not been well studied with the appropriate psychoeducational assessments. It is unlikely that patients with CAH are at substantially increased risk for frank learning disabilities, but they may be likely to have problems in specific areas. Fourth, females with CAH seem to have enhanced spatial ability as a result of exposure to high levels of androgens early in development. The neural substrate of this advantage is unknown but a subject of active research. It is unclear whether when compared with their unaffected siblings, females with CAH are better in other abilities that are typically performed best by males or worse in abilities typically performed best by females. Fifth, it is likely that patients with CAH have other cognitive changes as a consequence of disease characteristics (besides androgens) and of the treatment of the disease. Some evidence suggests that patients with CAH are more likely to have white-matter brain changes produced by the disease and its treatment. This has not been well studied but should be because of the potential clinical implications. It is reasonable to hypothesize that there will be cognitive changes that reflect effects of undertreatment (e.g., ACTH effects on attention) and other changes that reflect effects of overtreatment (e.g., glucocorticoid effects on memory). Some of these effects may be transient, reflecting acute brain changes, whereas others may become chronic as a result of permanent brain changes with repeated exposure. There is need for continuing study of cognition in patients with CAH. Such studies will provide basic information about hormonal effects on cognition and the neural mechanisms that mediate those effects. They will also provide important clinical information to guide psychologic and medical treatment of patients.

Behavioral effects of prenatal versus postnatal androgen excess in children with 21-hydroxylase-deficient congenital adrenal hyperplasia.

Systematic behavioral studies show that females with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) are masculinized and defeminized in several ways; compared to their sisters, they play more with boys' toys, are more likely to use aggression when provoked, and show less interest in infants. We studied the extent to which these behavioral changes could be attributed to high levels of androgens in the prenatal vs. postnatal periods in 23 girls with CAH, aged 3-12 yr. Sex-atypical behavior was significantly associated with degree of inferred prenatal, but not postnatal, androgen excess; marked boy-typical play was associated with severe salt-wasting CAH, early age at diagnosis, and moderate genital masculinization at birth, but not with bone age advance, concurrent or cumulative high levels of 17-hydroxyprogesterone, or accelerated growth velocity in early childhood. Aggression and interest in infants were not consistently associated with indicators of prenatal or postnatal androgen excess, probably because those behaviors were measured less reliably than was toy play. The results are consistent with the idea that behavioral masculinization in girls with CAH results from high levels of androgens during fetal development and not in postnatal life.

Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia.

The goal of this study was to examine the relation of early androgen exposure to sex-typed activities and interests in adolescence. Participants aged 9-19 years included 24 girls and 18 boys with congenital adrenal hyperplasia (CAH) and 16 unaffected sisters and 24 unaffected brothers who served as controls. Using standardized questionnaires, adolescents reported on their participation in sex-typed activities and interest in sex-typed occupations, and parents reported on the adolescents' activities. As hypothesized, girls with CAH showed sex-atypical preferences: increased interest in male-typical activities and careers and reduced interest in female-typical activities and careers compared to the unexposed control girls. These results extend findings of sex-atypical play in young girls with CAH and suggest that the sex-atypical activities and interests of females with CAH reflect direct effects of androgens on the developing brain rather than social responses to virilized genitalia. These results also suggest that population sex differences in activities and interests arise in part from sex differences in early androgens.

Neuropsychological follow-up in neonatal screening: issues, methods and findings.

There are several ongoing studies of psychological outcome in children identified through neonatal screening with phenylketonuria, congenital hypothyroidism or congenital adrenal hyperplasia. These studies document the reduction in mental retardation, learning difficulties and behaviour problems associated with neonatal screening. They also describe other behavioural changes resulting from these disorders. Some behavioural changes are transient or preventable with early diagnosis and treatment, whereas some appear to be irreversible, reflecting permanent brain effects of abnormalities associated with the disease. Despite the variety of disorders studied, there are commonalities in approach and issues, including a developmental neuropsychological perspective resulting in behavioural assessments specific to the disorder and its likely manifestations, a recognition that behaviour may change across time in association with brain development and an understanding of the neural mechanisms underlying the behavioural changes. Assessments go beyond IQ, and include specific intellectual abilities, social behaviour, temperament, behaviour problems and identity. Behavioural changes are related to specific characteristics of the disease and its treatment, including the timing of exposure to abnormal hormones and/or neurotransmitters, the severity of the disease, and the age at initiation and adequacy of treatment. These studies provide information about the ways in which hormones and neurotransmitters affect the development and ongoing function of the brain, and an understanding of the ways in which neonatal screening results in improved psychological outcome. They also provide models for psychological follow-up of other disorders detected through neonatal screening.

Sex differences in right hemisphere tasks.

We tested the hypothesis that sex differences in spatial ability and emotional perception are due to sex differences in intrahemispheric organization of the right hemisphere. If the right hemisphere is differently organized by sex-primarily specialized for spatial ability in men, but primarily specialized for emotional perception in women-then there should be a negative correlation between spatial ability and emotional perception within sex, and the greatest disparity between abilities should be found in people with characteristic arousal of the right hemisphere. Undergraduate men (N = 86) and women (N = 132) completed tests of Mental Rotation, Surface Development, Profile of Nonverbal Sensitivity, Progressive Matrices, and Chimeric Faces. Although the expected pattern of sex differences was observed, there was no evidence for the hypothesized negative correlation between spatial ability and emotional perception, even after statistical control of general intelligence.

Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia.

OBJECTIVE: To assess results of newborn screening for 21-hydroxylase-deficient congenital adrenal hyperplasia (CAH) in Texas over 6 years of screening 1.9 million infants. METHODS: In 1989, CAH was incorporated into the ongoing Texas Newborn Screening Program, which requires two screens on each newborn. 17-Hydroxyprogesterone was assayed, without extraction, by radioimmunoassay of blood collected from heel sticks onto filter paper collection cards. Infants with elevated levels of 17-hydroxyprogesterone were referred for evaluation, and those considered to have CAH were studied with respect to disease characteristics. Data were collected by pediatric endocrinologists using standardized forms that included type of CAH, results of laboratory tests, treatment regimen, disease symptoms and signs, and, for girls, degree of genital virilization. RESULTS: The incidence of classic CAH in Texas is 1:16 008, with a ratio of salt-wasting to simple-virilizing of 2.7:1. A majority of infants detected were undiagnosed until screened, despite signs of salt-wasting or ambiguous genitalia. It was difficult to differentiate salt-wasting from simple-virilizing CAH in infants who were identified before the onset of adrenal insufficiency or electrolyte abnormalities. A substantial number of infants with nonclassic (NC) CAH also were detected. Not all infants were detected on the initial screen; 14% of infants with classic CAH and 87% with NC CAH were detected on the second routine screening test. CONCLUSIONS: Our findings confirm the benefits of newborn screening for CAH and the importance of a second screening test, and suggest that programs for newborn CAH screening must consider complex issues in diagnosis and treatment. These results also confirm that CAH is a continuum of disorders, rather than a disorder with discrete subtypes. In addition, the difficulties in differentiating CAH subtypes in newborns, and thus deciding appropriate treatment, and the high incidence of NC CAH suggest that standard diagnostic criteria and treatment regimens for CAH may need modification. Where screening exists, physicians will encounter more cases of CAH than in the past.

Role of the hippocampus in sex differences in verbal memory: memory outcome following left anterior temporal lobectomy.

The authors examined the neural and cognitive bases for sex differences in verbal memory in 57 patients who underwent left anterior temporal lobectomy (ATL) for the treatment of intractable seizures. On the California Verbal Learning Test (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1987), women recalled more words than men both before and after surgery, regardless of the extent of hippocampal damage. Extent of hippocampal sclerosis was related to memory loss in both men and women. Women's superiority in verbal memory appears to result in part from their use of an efficient encoding strategy. Women were more likely than men to use semantic clustering both before and after ATL, and sex differences in word recall were attenuated after scores were adjusted for semantic clustering. There was no effect of ATL on semantic clustering. Taken together, these results suggest that sex differences in verbal memory are not due to differences in the integrity of the left hippocampus.

Early androgen effects on aggression in children and adults with congenital adrenal hyperplasia.

Males are more likely than females to show aggressive behavior across species, ages, and situations, and these differences may be partly influenced by early hormones. We studied aggression in three samples of subjects with congenital adrenal hyperplasia (CAH), who were exposed to high levels of androgen in the prenatal and early postnatal periods. Controls were siblings and first cousins similar in age. In Sample 1, adolescents and adults completed the Multidimensional Personality Questionnaire (MPQ), which includes an Aggression scale. In Sample 2, adolescents and adults completed the MPQ and a paper-and-pencil version of Reinisch's Aggression Inventory. In Sample 3, parents rated the aggression of children aged 3-12, using a modification of Reinisch's Inventory. In all three samples, control males had higher aggression scores than control females. Further, as predicted, females with CAH had higher aggression than control females, but the difference was significant only in adolescents and adults. These results suggest that early androgens contribute to variability in human aggression.

Sex-typed play in opposite-sex twins.

To examine possible prenatal hormonal influences on sex-typed play, we compared girls with a boy co-twin to girls with a girl co-twin and girls with an older brother. In opposite-sex dizygotic twin pairs, the uterine environment may allow transfer of testosterone from the male to the female fetus. Singletons with an older brother provide a control for shared social environment. Girls aged 3 to 8 years (N = 91) were observed playing with sex-typed toys, and mothers completed questionnaires about the child's activities. Contrary to expectation, girls with a boy co-twin did not spend more time playing with boys' toys than girls with a girl co-twin or girls with an older brother. Although these results might suggest that normal variations in hormones do not contribute to within-sex variations in childhood activities, they combine with other work to suggest factors to consider in evaluating hormonal influences on human behavior, including level and timing of exposure.

Evaluating the empirical support for the role of testosterone in the Geschwind-Behan-Galaburda model of cerebral lateralization: commentary on Bryden, McManus, and Bulman-Fleming.

The main tenet of the GBG model relates to the prenatal action of testosterone. Anomalies in cerebral dominance, immune functioning, abilities, and neural crest development are hypothesized to correlate with each other because all result from high levels of prenatal testosterone. Studies directly evaluating the effect of testosterone on these traits do not validate the model: sex ratios and animal studies suggest that testosterone has a protective, rather than facilitatory, effect on autoimmune diseases; individuals with high levels of early testosterone do not have elevated rates of left-handedness or learning disabilities. These findings reinforce Bryden et al.'s conclusions that there is little empirical support for the GBG model, and that it is wise to consider other theories in evaluating data derived from the model.

Family study of schizophrenia and personality.

The purpose of this study was to determine whether the abnormal characteristics observed in relatives of schizophrenics represent variations in normal personality. Relatives (N = 340) of patients with schizophrenia, affective disorder, and medical or surgical conditions were personally interviewed about psychiatric symptoms and completed the Multidimensional Personality Questionnaire. Relatives who were themselves ill had elevated scores on some scales. Relatives of schizophrenics had normal scores on all personality scales, but relatives of affectively ill probands differed from other relatives on Well-Being and measures of Negative Emotionality. When schizophrenic probands were subtyped by symptoms, relatives of emotionally blunted schizophrenics were found to have slightly lower scores on Social Closeness than did relatives of controls. Overall, these results suggest that schizophrenia is unrelated to normal personality.

Are schizophrenia and affective disorder related? preliminary data from a family study.

OBJECTIVE: Most investigators presume that schizophrenia and affective disorder are separate diseases. Others have proposed alternatives to this Kraepelinian view. These alternatives were addressed by preliminary analyses of data from a family study of psychopathology. METHOD: The authors identified 1,895 first-degree relatives of 166 patients with DSM-III schizophrenia, 71 patients with affective disorder, and 85 medical comparison probands; 949 relatives were blindly diagnosed. RESULTS: The risks for schizophrenia and affective disorder (unipolar melancholia and bipolar disorder combined) were significantly higher in the relatives of the schizophrenic probands and the relatives of the probands with affective disorder than in the relatives of the comparison probands. The morbid risk for nonmelancholic depressions was not significantly higher. Among the relatives of the schizophrenic probands, the risk for affective disorder was highest among the relatives of the patients with "core" schizophrenia, who were younger at illness onset, had chronic illness, had severe emotional blunting, and showed few affective features. CONCLUSIONS: Despite limitations, these preliminary analyses, consistent with other studies, suggest some familial relationship between schizophrenia and severe forms of affective disorder.

Sex differences in spatial ability in children.

There is considerable evidence that sex differences in spatial ability exist in adults, with males outperforming females at every age after puberty. It is difficult, however, to find sex differences in children younger than 13. This is due in part to the lack of adequate measures of spatial ability for use with children. We report the use of spatial tests for children that are similar to those that have shown large sex differences in adults and may be measuring ability comparable to adult spatial ability. Four tests of mental rotation and spatial visualization were given to two samples of children. The first sample consisted of 81 children (39 males and 42 females) aged 9 to 12 years. The second sample consisted of 42 children (21 males and 21 females) aged 9 to 13 years. Sex differences of .4-.6 standard deviations were found on three tests in both samples. These results indicate that sex differences in spatial ability can be found in preadolescents if appropriate tests are used. Measurement of these abilities in children facilitates the investigation of possible biological and sociocultural contributors to the sex differences in spatial ability.

The nature of emotional blunting: a factor-analytic study.

To investigate the components of emotional blunting, we factor-analyzed an emotional blunting scale, and examined the relationships between the derived factors and several clinical variables in two patient samples. Two factors were identified, corresponding to "lack of emotional expression" and "avolition". The "avolition" factor was strongly related to clinical improvement after treatment. Discriminant analyses indicated that schizophrenics could be differentiated from manics by emotional expression and from depressives by avolition. Scores on two shorter scales derived from the factors were also highly predictive of clinical improvement and diagnosis. These results indicate that emotional blunting can be differentiated into two easily measured components which may have different clinical significance.

alpha 1-Adrenergic receptor binding in the spontaneously hypertensive rat.

Increased sympathetic outflow from the central nervous system to the periphery may contribute to the initiation of hypertension in spontaneously hypertensive rats (SHR). As this alteration in sympathetic activity may be mediated in part by alpha-adrenergic receptors in the central nervous system, the current study examined alpha 1-adrenergic receptors in various brain areas of SHR and normotensive Wistar-Kyoto control rats (WKY). The alpha 1-adrenergic receptor number and apparent affinity constants of brain sections of both young prehypertensive animals (4 weeks old) and mature hypertensive animals (12 weeks old) were studied with the alpha 1-adrenergic receptor antagonist [3H]WB-4101 to label the alpha-adrenergic receptor. Five brain regions were studied: rostral hypothalamus, caudal hypothalamus, locus ceruleus, nucleus tractus solitarius, and frontal cortical poles. In comparison to normotensive controls, mature hypertensive rats had a significantly greater density (p less than 0.05) of the alpha 1-adrenergic receptors in the rostral hypothalamus (+11%), caudal hypothalamus (+25%), and frontal cortical poles (+20%). Significantly greater (p less than 0.05) alpha 1-adrenergic receptor density was found in the rostral hypothalamus (+27%), caudal hypothalamus (+60%), and locus ceruleus (+39%) of the young prehypertensive SHR compared with age-matched WKY. These results indicate the presence of altered adrenergic receptor systems in the brains of genetically hypertensive animals and suggest that changes in the receptor systems take place during establishment of the hypertension.