Psychosexual development of women with congenital adrenal hyperplasia

Women with congenital adrenal hyperplasia (CAH) (N = 31) and their unaffected sisters or female cousins (N = 15) participated in a study of psychosexual development. All participants were > or = 18 years of age (mean age, 25 years; range, 18-40). Comparisons were also made between the CAH women with the salt-wasting (SW) form of the disorder and those with simple virilization (SV). A psychosexual assessment protocol examined six variables: (1) sex assignment at birth (probands only); (2) recalled sex-typed behavior during childhood; (3) gender identity and gender role identification in adulthood; (4) relationship status; (5) sexual orientation in fantasy; and (6) sexual orientation in behavior. Salt-wasting status and sex assignment at birth were also ascertained for the CAH women who either refused to participate in the study (N = 10) or could not be traced (N = 13). Compared to the controls, the women with CAH recalled more cross-gender role behavior and less comfort with their sense of "femininity" during childhood. The two groups did not differ in degree of gender dysphoria in adulthood, although the probands showed more cross-gender role identification. Three of the nonparticipant probands were living, as adults, in the male social role (2 reared from birth as boys and 1 who changed from the female to the male social role during adolescence). The CAH women and the controls did not differ in relationship status (married/cohabiting vs. single). The CAH women had lower rates of exclusive heterosexual fantasy and fewer sexual experiences with men than the controls; however, the CAH women did not have more sexual experiences with women than the controls. Comparisons between the SW and SV revealed several differences: the SW were less likely to be assigned to the female sex at birth, recalled more cross-gender role behavior during childhood, were less likely to be married or cohabiting, and had lower rates of sexual experiences with men. The results were discussed in relation to the effects of prenatal androgens on psychosexual differentiation.     

Acute adrenal crisis complicating hypertensive congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency

In its classical form, congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is characterized by hypertension and abnormal sexual development. Suppression of ACTH secretion by means of administering glucocorticoids fulfills the therapeutic goal of reducing blood pressure and decreasing androgen production. The present report describes the case of a patient suffering from congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency who developed an acute adrenal crisis, unprovoked by stress, following interruption of glucocorticoid replacement therapy. It is suggested that patients on a suppressive dose of glucocorticoids for adrenal hyperplasia are at increased risk for acute adrenal insufficiency if therapy is interrupted, and that deoxycorticosterone (DOC) in the absence of a glucocorticoid is insufficient to prevent manifestations of adrenal crisis.     

Hormonal and genetic analysis of a patient with congenital adrenal hyperplasia

We describe a patient with signs and symptoms of virilization caused by 21-hydroxylase deficiency. The patient, a Hispanic woman, first sought medical attention at age 24, when she presented to a medical clinic with an uncomplicated urinary tract infection. At that time several signs of virilization were noted and she was referred to the endocrinology clinic. Evaluation revealed temporal balding, hyperpigmentation, acne, absent breast development, a muscular habitus, and clitoromegaly. Radiological studies revealed bilaterally enlarged adrenal glands and ovaries. Laboratory evaluation revealed markedly increased concentrations of 17-hydroxyprogesterone, androstenedione, and testosterone. The patient was diagnosed with congenital adrenal hyperplasia (CAH) and received hormone therapy. In her sister, encouraged to undergo testing for this autosomal recessive disorder, HLA testing demonstrated that certain haplotypes in this family were associated with CAH. The case highlights key steps in the laboratory diagnosis and genetics of CAH.     

Long-term somatic follow-up of prenatally treated children with congenital adrenal hyperplasia

Prenatal virilization of female fetuses is a serious symptom associated with severe congenital adrenal hyperplasia. In attempt to avoid sexual ambiguity, prenatal treatment of 21-hydroxylase deficiency was initiated in 1984, with the first Scandinavian case treated in 1985. Here we have studied the outcome of prenatal diagnosis and therapy of 44 at-risk pregnancies monitored during the years 1985-1995 in Scandinavia. Treated mothers and children were compared with matched controls. Compared to their elder affected sisters, all 5 girls with severe congenital adrenal hyperplasia who were treated until term showed little virilization. Only 1 required surgery for labial fusion. The majority of the 44 dexamethasone-treated fetuses demonstrated normal pre- and postnatal growth compared to matched controls. However, several adverse events such as failure to thrive and delayed psychomotor development, were reported among the treated infants. In addition, treated mothers reported more side-effects during pregnancy than did controls. A significant increase in weight gain was observed during early pregnancy when treatment was initiated, but this initial rapid weight gain declined during late pregnancy or when treatment was terminated. Thus, experience to date suggests that prenatal treatment of affected female fetuses is generally efficient in minimizing virilization of external genitalia. However, there is still a need to collect more data concerning possible rare unfavorable effects of this therapy on mother and child.     

Targeted disruption of StAR provides novel insights into congenital adrenal hyperplasia

To explore the function of StAR in a system that can be experimentally manipulated, and to develop a mouse model for the human disorder lipoid congenital adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to produce a mouse line deficient in StAR protein. Initially, StAR knockout mice were indistinguishable from wildtype littermates, except that all had female external genitalia. After birth, they showed signs of either respiratory distress or volume depletion and eventually died. Hormone assays confirmed severe defects in adrenal steroids, whereas hormones constituting the gonadal axis did not differ significantly from levels in wildtype littermates. Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, as visualized with oil red O stain. Lesser lipid deposits were observed in the steroidogenic compartment of the testis and none in the ovary. The sex-specific differences in gonadal involvement provide evidence for a two-stage model of the pathogenesis of StAR deficiency, with trophic hormone stimulation causing progressive accumulation of lipids within the steroidogenic cells which ultimately kills them. These StAR knockout mice provide a novel system in which to study StAR's essential roles in adrenocortical and gonadal steroidogenesis.     

Early hormonal influences on cognitive functioning in congenital adrenal hyperplasia.

Administered a cognitive test battery that emphasized spatial ability, verbal fluency, and perceptual speed and accuracy to 17 females (aged 12.7–23.2 yrs) and 8 males (aged 13–29.9 yrs) with congenital adrenal hyperplasia (CAH) and 13 normal female relatives (aged 11.4–31.1 yrs) and 14 unaffected male relatives (aged 12.5–28.8 yrs). In addition, 13 fathers and 15 mothers of CAH patients participated. Ss also completed the Progressive Matrices, a vocabulary test, and an early life activities questionnaire (ELAQ). Findings indicate that CAH females, as compared with normal females, showed significantly enhanced performance on hidden pattern, card rotation, and mental rotation tests of spatial ability. On the ELAQ, CAH females, relative to normal females, showed significantly lower frequencies of participation in activities involving verbal expression and a trend toward greater participation in spatial manipulation activities. However, differences between CAH females and normal females in early childhood activities did not account for observed differences in spatial ability, given the absence of a significant correlation between the spatial manipulation activity scale and spatial ability. There was an absence of reliable differences between male CAH patients and controls across spatial tasks. Results are consistent with an effect of pre- and perinatal androgenizing hormones on the development of spatial ability. (58 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mortality in patients with congenital adrenal hyperplasia: a cohort study

OBJECTIVE: To determine mortality in patients with congenital adrenal hyperplasia (CAH) compared with that in the general population. DESIGN: We identified 333 children with CAH, treated at several pediatric endocrinology departments in the United Kingdom since 1964, and monitored their mortality to mid 1996. Standardized mortality ratios were calculated, comparing mortality in the cohort with that in the general population, adjusted for sex, age, and calendar period. RESULTS: All-cause mortality in the cohort was 3 times that expected. Mortality was significantly increased at ages 1 to 4 years (standardized mortality ratio = 18.3) but not at older ages and was significantly increased in patients of Indian-subcontinent ethnicity (standardized mortality ratio = 20.4), particularly in girls. From case notes and death certificates, it appears that most deaths were caused by adrenal crisis, often after infection. CONCLUSIONS: Although survival of patients with CAH has greatly improved since steroid therapy has been used, this disease can still have fatal consequences. The high mortality rate in Indian ethnic girls may well reflect lack of parental acceptance and understanding of the disease, as well as of the action required when their child becomes acutely ill. Better communication with and education of parents of children with CAH, especially those from immigrant ethnic minorities, is important.     

Evidence for a heterozygote advantage in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

21-Hydroxylase deficiency is one of the most common inherited disorders, with carrier frequencies of approximately 10% in all world populations studied to date. The high prevalence of the mutant gene is probably due to a flanking pseudogene serving as a reservoir for mutations. Despite the potential for a high rate of de novo mutations, a founder effect for specific gene conversions is observed in most populations. We hypothesized that there was a survival advantage to 21-hydroxylase heterozygotes, and here we report endocrinological and molecular investigations to test this hypothesis. We defined 28 carriers and 22 mutation-negative controls by molecular genotyping and determined ACTH-stimulated adrenal hormone responses. We found significantly elevated cortisol responses in the carriers compared to controls (30 min cortisol levels: normal, 24.2 +/- 4.6 micrograms/dL; carrier, 28.1 +/- 4.2 micrograms/dL; P < 0.005). Cortisol has a crucial role in maintaining homeostasis, influencing differentiation, suppressing inflammation, and effecting cross-talk among the immune, nervous, and endocrine systems. The brisk cortisol response we have documented in carriers of 21-hydroxylase may enable a rapid return to homeostasis in response to infectious, inflammatory, or other environmental stresses and may protect from inappropriate immune responses, such as autoimmune diseases.     

Molecular and clinical characterization of Korean patients with congenital lipoid adrenal hyperplasia

The (Na,K)ATPase is responsible for generating the ionic gradients and membrane potentials by the exchange of intracellular Na+ for K+. It has been recently shown that (Na,K)ATPase is involved in the exocytic pathway of basic fibroblast growth factor (bFGF), although it is not known that bFGF is secreted to the outside of cell through direct interaction with (Na,K)ATPase. To understand the role for (Na,K)ATPase in the secretory pathway of bFGF, we have sought to identify the cytoplasmic domains of the alpha 1 isoform of (Na,K)ATPase interacting with bFGF by yeast two-hybrid system. We have also investigated the interaction between the alpha 2 isoform of (Na,K)ATPase and bFGF to find out whether the interaction is isoform-specific. We found that none of the cytoplasmic domains of (Na,K)ATPase isoforms interacted with bFGF. The result suggests that the interaction between bFGF and (Na,K)ATPase might be indirect, thus requiring other proteins which are involved in the formation of protein complexes for the interaction, although we cannot exclude the possibility that the interaction requires the element of the whole alpha subunit structure that was not present in the isolated alpha subunit cytoplasmic domains.     

New developments in congenital lipoid adrenal hyperplasia and steroidogenic acute regulatory protein

To date, studies of patients with lipoid CAH have shown the indispensable role of StAR in the production of steroids by adrenal gland and gonads. Lipoid CAH is the first and so far only inborn disorder of steroid hormone synthesis and metabolism that is not caused by a defective steroidogenic enzyme but rather by a defect in cholesterol transport.     

Androgen-related effects on peripheral glucose metabolism in women with congenital adrenal hyperplasia

The study was designed to investigate the influence of androgens on peripheral glucose metabolism in women with congenital adrenal hyperplasia (CAH). Nine normal women and seven women with CAH were studied (4 with the classical form of 21-hydroxylase deficiency [C 21-OH] and 3 with nonclassical 21-hydroxylase deficiency [NC 21-OH]). The study was performed using the forearm model combined with local indirect calorimetry. The insulin level reached 30 minutes after glucose ingestion was significantly greater (p < .05) in patients with CAH. The patients with C 21-OH had elevated androstenedione (A) and testosterone (T) and low DHEA-S and presented a 35% greater insulin response to a glucose stimulus than the control group, area under the curve (AUC) of 9457 +/- 887 vs 6989 +/- 833 microU/ml.3 hours. Patients with NC 21-OH had slightly elevated T, A and DHEA-S and presented an insulin response that was similar to the control group, AUC = 7208 +/- 1935 microU/ml.3 hours. Despite the greater muscle mass of the patients with CAH the forearm glucose uptake during the three hours of the study was lower in these patients than in normal women (CAH = 100.9 +/- 10.0 vs control group = 132.5 +/- 21.2 mg/100 ml forearm). The ratio of insulin response to the increment of forearm glucose uptake over a period of 3 h was significantly higher in patients with CAH (control group = 59.6 +/- 6.5 vs CAH = 98.6 +/- 19.4 microU.ml-1/mg.100 ml forearm-1, p < 0.05). These results suggest that insulin sensitivity is decreased in patients with CAH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cerebral lateralization and cognitive functioning in patients with congenital adrenal hyperplasia.

A battery of tests was administered to 17 patients with congenital adrenal hyperplasia (CAH) and 17 normal controls to investigate the effect of prenatal androgen exposure on cerebral lateralization and cognitive performance. Individuals were compared on measures of hand preference, verbal and performance IQ, and temporal processing asymmetry. A higher incidence of left-handedness was found among CAH participants. CAH individuals exhibited higher performance IQs as opposed to verbal IQs. Temporal processing asymmetries were investigated using an auditory gap detection task. Measures of reaction time and response error revealed a right-ear, therefore left-hemisphere, advantage for gap detection. This right-ear advantage did not differ between CAH individuals and controls. Results partially support the hypothesis that prenatal androgen exposure causes a shift in cerebral lateralization toward right-hemisphere dominance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Congenital adrenal hyperplasia

A clinical spectrum, varying from prenatal onset to postnatal onset of symptoms, exists in all hyperandrogenic forms of congenital adrenal hyperplasia (CAH). Postnatal onset hyperandrogenic symptoms such as premature pubarche, clitoromegaly, hirsutism, menstrual disorders and infertility are well known manifestations of CAH due to 21-hydroxylase deficiency, 3 beta-hydroxysteroid dehydrogenase deficiency or 11 beta-hydroxylase deficiency. These hyperandrogenic symptoms of CAH are clinically indistinguishable from other causes of hyperandrogenism. The molecular data has proven the genetic basis for the phenotypic variability of CAH disorders. Specific hormonal criterion(a) defined by the molecular proof of the disorder should aid in discriminating between symptomatic patients due to CAH and other causes, and between those with mild and severe CAH disorders. Prevalence of the hyperandrogenic forms of CAH, as well as pubertal maturation and reproductive function in women with hyperandrogenic forms of CAH, are discussed.     

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.     

Problems in diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

A number of biochemical tests have been utilized to assist the diagnosis of steroid 21-hydroxylase deficiency. The specificity and accuracy of plasma 17-hydroxyprogesterone assays are important. A profile of steroids in urine by gas chromatography and mass spectrometry is the definitive test. Molecular biology is not practical for the diagnosis of a new case. The ACTH stimulation test for detection of heterozygotes is a poor discriminant. Fertility in patients with congenital adrenal hyperplasia may be due to excess of progesterone as well as of androgens. Gene amplification offers the best approach in molecular biology for the prenatal diagnosis of 21-hydroxylase deficiency.     

Testicular histopathology in congenital lipoid adrenal hyperplasia: a light and electron microscopic study

During the 1980s, interest was shown in North America as to how Intensive Care Nurses use their work time, in response to a shortage of trained nurses. These studies were developed to investigate the amount of nursing time that could be saved by computerised recording systems. Similar pressures are now present in the United Kingdom, but there are no published work load studies of Intensive Care Nurses. This study used a five category tool to examine the work load of nurses in a cardiothoracic ICU. The methodology was designed so that comparison could be made with the earlier American studies. The 36 nurses studied spent 41% of their time in direct nursing care, 22% in patient assessment, 19% in clerical duties, 11% in time outside the unit and 7% in non-nursing duties. These findings were compared with the North American studies. Similarities were found which give some support to the reliability and validity of the tool.