Related individuals with different androgen receptor gene deletions.

We have identified different members of one family affected by androgen insensitivity syndrome who have deletions of different exons of the X-linked androgen receptor (AR) gene. Two affected (XY) siblings have a deletion of exon E of the AR gene and their affected (XY) aunt has a normal exon E, but a deletion of exons F and G of the same gene. The mother and maternal grandmother of the children both carry the exon E deletion, but not the exon F, G deletion. Both deletions are 5 kb in length and have one breakpoint within a 200-bp region in intron 5; however, they extend in opposite directions. The probability that these two different deletions have arisen at random is extremely low, but the cause of this intriguing phenomenon remains to be found.

Defective nuclear accumulation of androgen receptors in disorders of sexual differentiation.

Nuclear transfer of androgen receptors (AR) and glucocorticoid receptors (GR) was determined in cultured genital skin fibroblasts from 10 normal controls and eight patients with abnormalities of the external genitalia. In whole cell studies, cultures were incubated for 20 min at 37 degrees C with [3H]methyltrienolone (3H-R1881) or tritiated dexamethasone, and specific binding was determined in whole cell, cytoplasmic, and crude nuclear fractions. Between normal and affected fibroblasts no difference was seen in cellular levels of GR, or in cytoplasmic and nuclear distribution of GR. In normal fibroblasts, cytoplasmic binding of 3H-R1881 represented 56%, and crude nuclear binding 44%, of total binding; in fibroblasts from five of the eight patients similar values (cytoplasmic 55% and nuclear 44%) were seen for 3H-R1881 binding. In fibroblasts from the other three patients no decrease in total cellular levels of AR were seen; nuclear compartmentalization, however, was much lower (approximately 20%) than in other cultures. In vitro reconstitution studies, combining 3H-R1881-loaded cytosol with naive nuclei, lead us to suggest that the defect in nuclear compartmentalization lies at the level of the nuclear acceptor site rather than the cytoplasmic binder in affected cells. We interpret the data to suggest that defective nuclear binding of AR complexes may be involved in a proportion of cases of abnormal development of the external genitalia.

Differences in proteins synthesized by fibroblasts from normal individuals and patients with complete testicular feminization.

Patterns of protein synthesis by genital skin fibroblasts from three unrelated normal individuals and three unrelated patients with complete testicular feminization were compared to two-dimensional gel electrophoresis. cell lines were maintained in monolayer culture and pulse labeled with [35S]methionine. Cells were lysed in 9 M urea, and aliquots of 20 microliters subjected to isoelectric focussing and polyacrylamide gel electrophoresis followed by autoradiography. Gels of control fibroblasts showed two proteins (mol wt approximately 45,000, approximately 85,000; pKi approximately 5.0) markedly more prominent than on gels from affected fibroblasts. This pattern was unaltered by prior exposure to dihydrotestosterone, suggesting differences in constitutive proteins of the fibroblast cells. Parallel studies demonstrated a marked reduction in the ability of fibroblasts from patients with complete testicular feminization to bind androgens in vitro compared with those of normal individuals. The relationship between these proteins, androgen receptors, and androgen insensitivity requires further investigation.

Living with congenital adrenal hyperplasia in Vietnam: a survey of parents.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) has the potential to place an enormous burden on families in resource-poor countries, and the aim of this survey was to provide more specific insights into the difficulties faced by families living with CAH in Vietnam. It is hoped that this information will be used to ensure that future efforts to reduce the burden of CAH are as effective, sustainable and appropriate as possible. DESIGN AND METHODS: A questionnaire-based needs assessment survey was offered to parents of children with CAH who were attending the Annual CAH Support Group Meeting held at the National Hospital of Pediatrics (NHP) in Hanoi, Vietnam, on 10th June 2005. RESULTS: Fifty-three families responded to the questionnaire. Information pertaining to the purchase and use of medication to treat CAH, access to medical care, surgical treatment for girls, and a wide range of parental concerns was collected. CONCLUSIONS: This survey highlights the heavy burden that CAH places on families in Vietnam, and provides significant insights into various initiatives that could well help ease this suffering. In particular, efforts must be made to ensure essential medication is affordably available, communication of important messages to parents is enhanced, local support groups encouraged, and early diagnosis and medical treatment of CAH optimized so as to reduce morbidity and mortality.

Quality of life and gender role behavior in disorders of sexual differentiation in India.

OBJECTIVE: Culture-specific tools to assess longterm psychosocial outcomes for patients with disorders of sexual differentiation are scant. We conducted a study to develop tools for evaluating gender role behavior and health related quality of life for Indian adolescent patients with intersex disorders. We also studied factors important to parents while deciding sex of rearing for their baby. METHODS: A 29-item gender role behavior questionnaire and an 18-item health related quality-of-life questionnaire were administered to 82 healthy controls, 13 patients with intersex disorders and 18 patients with type 1 diabetes mellitus. Internal consistency was checked by Cronbach's alpha and test-retest reliability using intra-class correlation coefficient. Responses of 28 parents to a questionnaire on factors affecting the decision of sex of rearing were recorded on a 5-point Likert scale in order of importance. RESULTS: Cronbach's alpha was 0.92 and 0.75, and intra-class correlation coefficient 0.76 and 0.75, for the gender role behavior and quality-of-life questionnaires respectively, indicating a high degree of internal consistency and stability. The mean composite scores for healthy girls on the gender role behavior questionnaire (82.5 +/- 8.7) differed significantly from that for healthy boys (53.2 +/- 7.1, p <0.001). Factors important to parents while making decisions for sex of rearing were appearance of the genitalia, medical advice, ability to bear children and economic independence. CONCLUSIONS: We have created valid tools to study gender role behavior and quality of life in adolescent patients with intersex disorders in India. We have also identified in a quantitative way the factors of greatest importance to parents while deciding sex of rearing. These results have direct utility in the management of patients with intersex disorders in India and other similar cultures.

Health related quality of life and psychological outcome in patients treated for craniopharyngioma in childhood.

UNLABELLED: Patients with craniopharyngioma are at risk for many adverse effects related to the tumour's invasive behaviour and its proximity to many vital structures. Profound psychosocial problems, memory impairment, pituitary and hypothalamic dysfunction in addition to the physical handicap of visual loss are frequently recognized sequelae of craniopharyngioma treatment. OBJECTIVES: To examine health related quality of life (QoL) and psychological outcomes of patients treated for craniopharyngioma at the Royal Children's Hospital, Melbourne, between January 1980 and September 2003. PATIENTS: Seven (17.4%) of 46 (26 male) had died. Thirty-nine remained, of whom 30 were contactable. Eighteen of 30 (8 male), mean age 21.2 +/- 6.7 years, agreed to evaluation, of whom 16/18 (88.9%) had three or more pituitary hormone deficiencies, 11/18 had visual impairment and 9/18 obesity. MEASUREMENTS: The Adult GH-Deficient Assessment (AGHDA) and Psychological General Well-Being (PGWB) questionnaires were employed to assess quality of life in patients and age- and sex-matched healthy controls. Additional psychological assessment, including intellectual and academic skills, emotional function, and adaptive behaviour, had been undertaken in 12 patients at a previous time. RESULTS: High levels of physical morbidity and psychological disability were described. The General Health score of patients was significantly worse than for controls on PGWB (p = 0.025), anxiety was higher in those who had surgery alone (p = 0.008) and subjective QoL associated with GHD using AGHDA was lower (p = 0.006). Few craniopharyngioma survivors (18/30) were available for evaluation, demonstrating difficulties in attempts to assess this complex group. The discrepancy between results of objective and subjective measures of QoL is discussed in terms of adaptation to illness, disabilities and changed perception of life fulfilment. CONCLUSIONS: Craniopharyngioma and its treatment result in significant, complex medical, social, psychological and emotional difficulties. The degree of global disability is not reflected in subjective QoL reports for this group, highlighting the need for careful selection of assessment instruments.

Fasting ghrelin levels are not elevated in children with hypothalamic obesity.

Morbid obesity is a common problem after damage to the hypothalamus. Hypothalamic dysfunction is also thought to underlie the obesity that is typical of Prader-Willi syndrome. Elevated fasting levels of the appetite-stimulating hormone ghrelin have been reported in Prader-Willi syndrome. The aim of this study was to determine whether fasting ghrelin levels are increased in children with hypothalamic obesity. Fasting total ghrelin levels were compared in three groups: normal-weight controls (n = 16), obese controls (n = 16), and patients with hypothalamic obesity (n = 16). Obese children had lower fasting total ghrelin levels than normal controls, but there was no difference between the fasting total ghrelin level in obese controls and children with hypothalamic obesity (P = 0.88). These data suggest that it is unlikely that an elevation in fasting total ghrelin is responsible for the obesity that occurs after hypothalamic damage. Therapeutic interventions aimed at reducing fasting total ghrelin may prove ineffective in controlling weight gain in this group.

Double-blind controlled trial of azathioprine in children with newly diagnosed type I diabetes.

A double-blind controlled trial of azathioprine (2 mg.kg-1.day-1) was conducted with 49 patients aged 2-20 yr (mean 10.8 yr) who had newly diagnosed type I (insulin-dependent) diabetes. Patients were randomly assigned to receive either azathioprine (n = 24) or placebo (n = 25) for 12 mo, beginning within the 20-day period after diagnosis. Baseline clinical and metabolic characteristics did not differ between the two groups. No patient experienced complete remission, defined as restoration of normal carbohydrate tolerance without other treatment. Partial remission, defined as good metabolic control (hemoglobin A1c less than or equal to 7.9%, preprandial blood glucose less than or equal to 8 mM with an insulin dose of less than 0.5 U.kg-1.day-1), occurred in 10 placebo (40%) and 7 azathioprine (29%) patients at 6 mo and in 4 placebo (16%) and 4 azathioprine (17%) patients at 12 mo (differences not significant). Fasting plasma C-peptide was significantly greater in the azathioprine-treated group at 3 and 6 mo, but this difference was not sustained. C-peptide responses to a standard meal and the frequency of islet cell and insulin antibodies did not differ between the two groups over the 12-mo period. Azathioprine caused no significant side effects. We conclude that in the dosage used, and despite early effects on endogenous insulin secretion, azathioprine alone does not influence the remission phase in children with newly diagnosed type I diabetes.

Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3.

INTRODUCTION: Array comparative genomic hybridisation (array CGH) is a powerful method that detects alteration of gene copy number with greater resolution and efficiency than traditional methods. However, its ability to detect disease causing duplications in constitutional genomic DNA has not been shown. We developed an array CGH assay for X linked hypopituitarism, which is associated with duplication of Xq26-q27. METHODS: We generated custom BAC/PAC arrays that spanned the 7.3 Mb critical region at Xq26.1-q27.3, and used them to search for duplications in three previously uncharacterised families with X linked hypopituitarism. RESULTS: Validation experiments clearly identified Xq26-q27 duplications that we had previously mapped by fluorescence in situ hybridisation. Array CGH analysis of novel XH families identified three different Xq26-q27 duplications, which together refine the critical region to a 3.9 Mb interval at Xq27.2-q27.3. Expression analysis of six orthologous mouse genes from this region revealed that the transcription factor Sox3 is expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus. DISCUSSION: Array CGH is a robust and sensitive method for identifying X chromosome duplications. The existence of different, overlapping Xq duplications in five kindreds indicates that X linked hypopituitarism is caused by increased gene dosage. Interestingly, all X linked hypopituitarism duplications contain SOX3. As mutation of this gene in human beings and mice results in hypopituitarism, we hypothesise that increased dosage of Sox3 causes perturbation of pituitary and hypothalamic development and may be the causative mechanism for X linked hypopituitarism.

Predictors of change in the neuropsychological profiles of children with type 1 diabetes 2 years after disease onset.

OBJECTIVE: To identify type 1 diabetes-related predictors of change in the neuropsychological profiles of children over the first 2 years of the illness. RESEARCH DESIGN AND METHODS: Children (n = 116) aged 3-14 years were assessed soon after diagnosis and re-evaluated 2 years later to examine relationships between illness variables, such as age of onset and metabolic control history, and changes in neuropsychological status over the first 2 years of type 1 diabetes. RESULTS: Illness variables were significant predictors of change in neuropsychological test scores within 2 years of onset of type 1 diabetes. Age of onset of type 1 diabetes predicted negative change on Performance Intelligence Quotient, whereas both recurrent severe hypoglycemia and chronic hyperglycemia were associated with reduced memory and learning capacity. CONCLUSIONS: These results suggest that the relationship between metabolic control and neuropsychological risk is nonlinear in that children with either recurrent severe hypoglycemia or chronically elevated blood sugars exhibit negative changes in their neuropsychological profiles. Onset of type 1 diabetes very early in life adds another dimension of risk, particularly affecting the acquisition of visuospatial skills.

Neuropsychological profiles of children with type 1 diabetes 6 years after disease onset.

OBJECTIVE: To describe neuropsychological profiles and their relationship to metabolic control in children with type 1 diabetes 6 years after the onset of disease. RESEARCH DESIGN AND METHODS: Children with type 1 diabetes (n = 90), aged 6-17 years, who had previously been assessed soon after diagnosis and 2 years later, were reevaluated 6 years after the onset of disease. Their neuropsychological profiles were compared with those of individuals in a community control group (n = 84), who had been assessed at similar intervals. Relationships between illness variables, such as age at the onset of disease and metabolic control history, and neuropsychological status were also examined. RESULTS: Six years after onset of disease, children with type 1 diabetes performed more poorly than control subjects on measures of intelligence, attention, processing speed, long-term memory, and executive skills. Attention, processing speed, and executive skills were particularly affected in children with onset of disease before 4 years of age, whereas severe hypoglycemia was associated with lower verbal and full-scale intelligence quotient scores. CONCLUSIONS: Neuropsychological profiles of children with type 1 diabetes 6 years after the onset of disease are consistent with subtle compromise of anterior and medial temporal brain regions. Severe hypoglycemia, particularly in very young children, is the most plausible explanation for neuropsychological deficits, but the contributory role of chronic hyperglycemia warrants further exploration.

Neuropsychological complications of IDDM in children 2 years after disease onset.

OBJECTIVE: To compare the neuropsychological profiles of children with IDDM with a community control group at two time points: 3 months after disease onset and 2 years after the baseline assessment. RESEARCH DESIGN AND METHODS: A total of 123 children (age 3-14 years) with recent IDDM onset were compared with 129 community control subjects, stratified for age and sex, on standardized measures of general intelligence, attention, speed of processing, memory, learning, executive skills, and behavioral adjustment soon after diagnosis and 2 years later. Exclusion criteria were premorbid evidence of central nervous system disease or trauma, or English not spoken in the home. RESULTS: There were no differences between children with IDDM and control subjects on any measure at the initial assessment 3 months after disease onset. Two years later, children with IDDM tended to show a less positive change, relative to control subjects, in their standardized scores on measures of general intelligence, and significantly so on the vocabulary (P < 0.01) and block design (P < 0.05) subtests. Multivariate group differences were also apparent on speed of processing (P < 0.05) and learning (P < 0.01) subtests, reflecting smaller developmental gains in the children with IDDM when compared with control subjects. CONCLUSIONS: The findings are consistent with previous reports, suggesting that IDDM is associated with an increased risk of mild neuropsychological dysfunction. The skills most affected in this cohort were information processing speed, acquisition of new knowledge, and conceptual reasoning abilities. Clinicians and educators should be made aware of the risk of specific neuropsychological deficits in children with IDDM.

The methyltrienolone binding protein of human placenta requires nicotinamide adenine dinucleotide cofactor(s) for steroid binding.

The methyltrienolone binding protein (MTBP) found in human placental cytosol was found to require a low molecular weight modulator for steroid binding activity. Purification and characterization of the modulating activity showed that NAD+ is the endogenous substance responsible for activating MTBP to a form capable of steroid binding. The hierarchy of potency of exogenously added nucleotides is NADH greater than NAD+ = NADPH = NADP+. An investigation of the tissue distribution of human MTBP demonstrated that MTBP binding activity was present in placenta and chorion but absent from amnion and umbilical cord. Preliminary studies showed that rat, mouse, and rabbit placenta do not contain MTBP and suggest that MTBP may be a species-specific protein.

Studies on human sexual development. VI. Concentrations of unconjugated dehydroepiandrosterone, estradiol, and estriol in amniotic fluid throughout gestation.

Concentrations of unconjugated dehydroepiandrosterone, estradiol, and estriol were measured in samples of amniotic fluid from uneventful pregnancies of 9-40 weeks conceptual age. There was no apparent influence of fetal sex upon the levels of these steroids. Dehydroepiandrosterone concentrations rose slightly from 9-20 weeks, and then showed little further change. Estradiol concentrations declined slightly from 9-20 weeks; after 32 weeks gestation, there was a 2-fold rise to term. Estriol levels rose in almost exponential fashion throughout gestation.

Studies on human sexual development. V. Concentrations of testosterone, 17-hydroxyprogesterone and progesterone in human amniotic fluid throughout gestation.

Concentrations of unconjugated testosterone, 17-hydroxyprogesterone (170HP) and progesterone were measured by radioimmunoassay in amniotic fluid (AF) specimens from normal pregnancies of 9-40 weeks gestation. In two-thirds of samples from pregnancies with male fetuses. AF testosterone exceeded the upper limit found in female samples, with minimal overlap in the 12-18 week period of gestation. Although AF testosterone levels associated with male and female fetuses were both significantly lower toward term, the sex-difference persisted. Between 9-19 weeks gestation, fetal sex was also found to influence AF 170HP, a steroid thought to be predominantly of placental and fetal adrenal origin; in this case, female levels exceeded male. Awareness of the influence of sex and gestation upon AF concentrations of these steroids is an important prerequisite for their application to the prenatal diagnosis of endocrine disease (e.g., congenital adrenal hyperplasia). There was no sex difference in AF progesterone concentrations at 12-18 weeks gestation. The median progesterone concentration at 34-40 weeks was higher with female fetuses, but this difference may be related to a difference in gestational age between AF samples obtained from male and female fetuses.

Abnormal androgen receptor binding affinity in subjects with Kennedy's disease (spinal and bulbar muscular atrophy).

We have investigated androgen-binding properties of the androgen receptor (AR) in cultured suprapubic skin fibroblasts from six subjects with Kennedy's disease (X-linked spinal and bulbar muscular atrophy). Binding of the synthetic androgen methyltrienolone (R1881) was measured in a monolayer assay, and Scatchard analysis was performed to determine the total number of binding sites and the apparent binding affinity (Kd) of the AR for androgen. Five of the six subjects investigated had an abnormal apparent binding affinity, with Kd values ranging from 0.34-11.7 nmol/L, more than 2 SD from the mean of the normal range (0.19 +/- 0.06 nmol/L). In this group of six patients, there was a significant correlation between the AR Kd and the severity of testicular atrophy and gynecomastia. The number of CAG repeats in the expanded region of exon A of the AR gene was determined in all subjects from whom suprapubic skin fibroblasts were cultured and an additional 12 subjects with Kennedy's disease. In the total group of 18 subjects investigated, there was a trend for an increasing number of CAG repeats associated with decreasing age at onset of different symptoms; however, this correlation was not statistically significant. Thus, we report for the first time a quantitative abnormality of the AR apparent binding affinity in subjects with Kennedy's disease, which appears to be related to the severity of the symptoms of androgen insensitivity.

Serum gonadotropin, sex steroid, and immunoreactive inhibin levels in the first two years of life.

To characterize the changes in serum immunoreactive inhibin (INH) in the first 2 yr of life, blood samples were obtained from 46 boys (age range, 61-659 days) and 37 girls (76-666 days) undergoing minor surgery for nonendocrine related conditions. Serum levels were compared with those of simultaneously measured FSH, LH, and either testosterone (T) or estradiol (E2). In the boys, the levels of all 4 hormones fell progressively with age up to about 300 days, with a minor fall only in the second year. FSH (0.7-1.4 IU/L) was initially at the lower adult male limit, while LH (3.2-5.0 IU/L) was at the midrange. T levels (2.2-3.3 nmol/L) were in the adult female range, while INH (200-820 U/L) was in the midrange for men. In the youngest girls, FSH levels (12-26 IU/L) were frequently above the upper limit of normal for the adult follicular phase, but fell to approximately 2.0 IU/L after 300 days. LH levels (0.5-3.5 IU/L) were at the lower adult normal limit and changed little with age, while E2 levels in the youngest girls (280-550 pmol/L) were in the midfollicular range, but were generally less than 10 pM at more than 200 days. INH levels (175-260 U/L) were in the low adult range initially, but the majority were undetectable over 200 days. In the boys, significant negative correlations were observed for all 4 hormones with age, while FSH, LH, and T were positively correlated with INH. In the girls, there were weaker negative correlations of the 4 hormones with age, but no significant correlations between the gonadotropins and INH. E2 was strongly correlated with INH. Thus, the previously described early postnatal activation of the hypothalamo-pituitary-gonadal axis involves INH as well as the se steroids and gonadotropins. FSH levels in young girls were strikingly high, and INH levels were much higher in boys than girls. The low INH levels in girls may contribute to the elevated FSH seen during the period of neonatal gonadal activation.

Bone mineral density and body composition in congenital adrenal hyperplasia.

The purpose of this study was to assess whether replacement doses of glucocorticoid hormones administered to patients with congenital adrenal hyperplasia (CAH) cause changes in body composition, including either generalized or regional osteoporosis. In 21 patients with 21-hydroxylase deficiency we measured height, body mass index, lean mass, fat mass, and whole body and regional bone mineral density (BMD). We measured the same parameters in 21 age- and sex-matched control patients. The CAH group (aged 8-32 yr) showed significantly reduced mean height compared with both standard data (P = 0.0015) and the control group (P = 0.009). There were no significant differences in mean body mass index between the CAH group and the standard data (P = 0.13) or the control group (P = 0.87). CAH males had significantly higher fat/lean mass ratios than control males (P = 0.005). There were no significant differences in whole body mean bone mineral apparent density values between the CAH and control groups (P = 0.39). There were, however, significant differences in whole body BMD z scores between the CAH and control groups and the reference data (P = 0.027 and P = 0.004, respectively). No significant differences were observed between the total CAH and control groups with respect to spinal bone mineral apparent density; however CAH males had significantly lower mean adjusted spinal BMD than the male controls (P = 0.02). We conclude that although replacement therapy with glucocorticoid and mineralocorticoid hormones in our group of CAH patients may not be optimal with regard to longitudinal growth, it is not deleterious in terms of general bone mineralization. It may decrease spinal BMD in CAH males. We also conclude that the relevance of Hologic reference data for BMD to an Australian population is uncertain, and there is a need for Australian standard data.

Variable androgen receptor levels in infertile men.

Labeled methyltrienelone was used to determine androgen receptor (AR) levels in cultured pubic skin fibroblasts in 40 infertile men with primary seminiferous tubule disorders and 18 normal men. LH pulse patterns and mean serum LH levels were also determined by blood sampling at 10-min intervals for 6 h. The infertile men and the normal men had similar mean receptor levels [mean, 28.1 +/- 2.0 (+/- SEM) and 24.8 +/- 1.8 fmol/mg protein, respectively]. However, 5 men with chromosomal disorders had a higher mean AR level (41.3 +/- 6.2 fmol/mg protein) than the normal men, and 5 of the remaining infertile men (14.2%) had receptor levels that were less than the minimum value in normal men. In men with idiopathic oligospermia, 19.0% had low receptor levels. Although mean serum FSH and testosterone levels were similar in the infertile men with low AR levels and in the normal men, mean LH levels were significantly elevated in this group (7.1 vs. 3.6 IU/L), the higher values being a result of increased LH pulse amplitude (mean, 5.6 vs. 2.8 IU/L). The LH-testosterone product (an index of androgen resistance) was also elevated in these men. When infertile men with low AR levels were matched with infertile men with normal receptor levels, the mean LH values were significantly elevated in the former, as was the LH-testosterone product. Testosterone values were similar in the two groups of men. After excluding subjects with chromosomal disorders, there were no significant correlations between AR levels and other indices of androgen action, such as semen volume, seminal fructose, or sex hormone-binding globulin levels. We conclude that AR levels are higher in patients with severe testicular failure associated with X-chromosome disorders. Also, AR defects were found in 19.0% of infertile men with idiopathic oligospermia. Finally, elevation of mean LH levels in men with seminiferous tubule disorders may reflect resistance to androgen action.

Adrenocortical function in hyperprolactinemic women.

To study the effects of prolactin (PRL) on adrenocortical function in humans, dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), androstenedione (delta) and testosterone (T) were measured in serum obtained from 35 hyperprolactinemic women with galactorrhea and amenorrhea before and after treatment with bromocriptine-induced fall in mean PRL levels from 82 +/- 8 (SE) to 14 +/- 2 ng/ml (n = 39, P less than 0.0005), DHAS fell from 322 +/- 21 to 237 +/- 21 microgram/dl (n = 39); P less than 0.0005), DHA fell from 492 +/- 47 to 378 +/- 30 ng/dl (n = 39; P less than 0.01) while T (n = 16) and delta (n = 13) levels were unchanges (44 +/- 4 vs. 49 +/- 4 ng/dl and 280 +/- 55 vs. 236 +/- 40 ng/dl, respectively). In addition, 4 women were infused iv with 25 microgram synthetic ACTH over 4 h and serial blood samples drawn while hyperprolactinemic, and again 2-4 months later following normalization of PRL levels by bromocriptine. Although pre-infusion levels of DHAS were lower when PRL levels were normalized, no significant differences in responses of circulating DHAS, DHA, T, cortisol and 17-hydroxyprogesterone concentrations were detected between the two infusions. Since DHAS is virtually an exclusive product of the adrenal cortex, and since high PRL levels appear to inhibit ovarian steroid production, the findings suggest that hyperprolactinemia selectively stimulates adrenocortical androgen production.