Search

SummaryObjective The objective of this study was to determine the aetiological spectrum of disorders of sex development (DSD) in a large cohort of underprivileged and undiagnosed patients from Indonesia. Methods A total of 286 patients with atypical external and/or internal genitalia were evaluated using clinical, hormonal, molecular genetic and histological parameters. Results The age (years) at presentation was 0–0·5 in 41 (14·3%), >0·5–12 in 181 (63·3%) and >12 in 64 cases (22·4%). 46,XY DSD was most common (68·2%, n = 195), 46,XX DSD was found in 23·4% (n = 67) and sex chromosomal DSD in 8·4% (n = 24). In 61·2% of 46,XX DSD patients, 17·9% of 46,XY DSD patients and all sex chromosome DSD patients (29·4% in total), a final diagnosis was reached based on genetic or histological gonadal tissue evaluation. 17-hydroxyprogesterone and androstenedione levels were the most distinctive parameters in 46,XX DSD patients. In 46,XY DSD, diagnostic groups were identified based on the external masculinization score: androgen action disorder (AAD), unknown male undermasculinization (UMU), and gonadal dysgenesis (GD). LH, FSH and testosterone levels were most informative especially in the older age group. HCG tests were of no additional value as no patients with androgen synthesis disorders were found. Hormonal profiles of patients with sex chromosome DSD and a Y-chromosome sequence containing karyotype showed high levels of LH and FSH, and low levels of AMH, inhibin B and testosterone compared with the normal male range. Gene mutations were found in all patients with CAH, but in only 24·5% and 1·8% of patients with AAD and UMU. In 32% of 46,XY GD patients, copy number variants of different genes were found. Conclusion A stepwise diagnostic approach led to a molecularly or histologically proven final diagnosis in 29·4% of the patients. The most informative parameters were serum levels of 17-hydroxyprogesterone and androstenedione in 46,XX DSD patients, and serum LH, FSH and testosterone levels in 46,XY DSD patients.

Objective Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment. Methods Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow-up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone-binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist–hip ratio, and body composition measures (dual energy X-ray absorptiometry). Results Non-SHBG-bound testosterone was significantly decreased in survivors with BMI ≥ 30 kg/m2 (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P = 0.015), high fat percentage (10.0 vs. 11.2, P = 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P = 0.020). Survivors with high fat percentage (≥25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: β −34%, P = 0.041). Conclusion Obesity is associated with gonadal dysfunction in male CCS, independent of the irreversible effect of previous cancer treatment. Randomized controlled trials are required to evaluate whether weight normalization could improve gonadal function, especially in obese survivors with potential other mechanisms than lifestyle causing their obesity.

BACKGROUND Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown. METHODS The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP. RESULTS In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells. CONCLUSIONS Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth. Prostate 73: 1636–1650, 2013. © 2013 Wiley Periodicals, Inc.

Summary Context Premature pubarche (PP) is reported in children with Prader–Willi Syndrome (PWS). Pubarche is preceded by adrenarche – an increase in serum levels of adrenal androgens, most specifically dehydroepiandrosterone sulphate (DHEAS). Objectives To assess DHEAS levels, the age at and progression of pubarche and the prevalence of PP in children with PWS. Design/Patients In the Dutch PWS Cohort Study, 120 children (6 months–17 years) are prospectively followed. Their age at onset of pubarche and various pubic hair stages and prevalence of PP were determined. Serum DHEAS levels were assessed in 97 children. Results Median serum DHEAS levels were significantly higher in children with PWS than in healthy age-matched controls at ages 3–6 years (girls: P = 0·004 and boys: P = 0·010) and 6–10 years (girls: P = 0·045 and boys: P = 0·001). Age and gender significantly influenced DHEAS levels in children with PWS. The median [P10–P90] age at onset of pubarche in children with PWS was significantly younger than in healthy peers, 9·04[6·75–11·84] years in PWS girls (P

Aims: It has been suggested that schizophrenic patients are more vulnerable to stress than healthy persons, and that stressors can trigger a psychotic episode or worsen symptoms. The biological system often studied in relation to stress is the hypothalamic–pituitary–adrenal (HPA) axis, which controls the release of cortisol. We investigated whether the diurnal basal activity of the HPA axis differed between young male patients with schizophrenia and healthy controls. Methods: Twenty-seven male patients (mean age 22 ± 5 years) and 38 healthy male control subjects (mean age 22 ± 3 years) were included in the present study. Saliva was sampled at five time points during the day: directly after awakening, 30 min thereafter, and at 12.00 hours, 16.00 hours and 22.00 hours. Results: The cortisol concentration decreased significantly more during the day in the patient group thanin the control group. Patients also showed a significantly decreased area under the curve with respect to the increase, again indicating that the cortisol concentrations decreased more during the day in patients than in controls. Both the morning increase and the area under the curve with respect to the increase were significantly negatively correlated with negative symptom severity. Conclusions: Patients with schizophrenia showed a different daytime sensitivity of the HPA axis. Our findings further suggest that an increase in negative symptom severity is related to a decreased HPA axis sensitivity.

Summary Background Mutations in CYP21A2 lead to deficiency of 21-hydroxylase and can have either severe or moderate effects on phenotype, which can be prevented by early treatment. We studied long-term effects of this deficiency on phenotype in patients who had not been treated for prolonged periods and correlated these phenotypes with the mutations found in our patients. Objective To assess the correlation between genotype and phenotype in untreated patients with 21-hydroxylase deficiency. Design Subjects with 21-hydroxylase deficiency were selected from a large population of Indonesian patients with disorders of sexual differentiation. CYP21A2 mutations in these patients were correlated with their phenotype in terms of genital development and steroid hormone levels. Patients Fifteen 46,XX patients with ages between 1 and 33 years, of whom 12 had never been treated before. Measurements Mutations in CYP21A2, genital phenotype and steroid hormone levels. Results We found in all patients CYP21A2 mutations which affect enzyme activity, with a relatively high allele frequency of R356W (40%), I172N (20%) and IVS2 - 1A > G (13%). Clitoris length was directly correlated with levels of testosterone, but not with age. The phenotype was not always concordant with the genotype: different phenotypes (mild to severe virilization) were found in sibling pairs with the mutations IVS2 - 13A > G or I172N. The high frequency of homozygous mutants for R356W in patients aged from 1 to 11 years old is remarkable, as this mutation has been described only in salt-wasting patients. In our study, this mutation caused a urogenital sinus in three out of seven cases, whereas in the remaining cases the labia were at least partially fused. This mutation caused severe virilization with remarkably high serum levels of renin. We found one novel substitution in intron 2 (IVS2 - 37A > G), containing the branch site, which is likely to affect the CYP21-enzyme. Two additional intron 2 substitutions were discovered, which are supposed to affect the 21-hydroxylase (i.e. IVS2 + 33A > C and IVS2 + 67C > T). Conclusion We conclude that a correlation exists between the concentration of androgens and the extent of virilization. However, there was no clear correlation between genotype and phenotype, except for the mutation R356W.

Summary Objective To investigate whether levels of endogenous hormones, in particular circulating oestrogens and SHBG, are associated with cognition in healthy postmenopausal women. Design Cross-sectional study. Patients Four hundred and two healthy postmenopausal women aged 50‐74 years between 8 and 30 years after menopause, none taking oestrogen. Measurements Serum concentration of oestradiol, oestrone, and sex hormone binding globulin (SHBG) determined by immunoassay. Cognition assessed using the mini-mental state examination questionnaire (MMSE). Results In this group, 149 individuals had a MMSE score < 27, while only 89 individuals had a MMSE score < 26, indicating a relatively healthy population with regard to cognitive ability. Cognition decreased with age, time since menopause and blood pressure, and was better with higher age at menopause. Serum oestrogens and SHBG levels were not related to age, age at menopause, or time since menopause, and oestrogen levels were positively associated with blood pressure. After adjustment for mean arterial pressure and SHBG, the frequency of mild cognitive impairment decreased significantly with higher oestradiol and oestrone serum levels [ORs Q5 vs. Q1: 0·41 (95% CI 0·20 ‐ 0·84) and 0·51 (95% CI 0·20 ‐ 0·99) for oestradiol and oestrone, respectively]. Conclusions Postmenopausal women with higher remaining circulating oestradiol levels appear less likely to suffer from cognitive impairment. This effect is independent of age at menopause, time since menopause and BMI. These findings support the hypothesis that endogenous oestrogens may protect against cognitive decline with ageing.

Objective Sensitivity to glucocorticoids differs between individuals, partially due to genetic variation in the glucocorticoid receptor (GR) gene. We studied the sequence alteration of a previously described intronic BclI polymorphism of the GR gene, and investigated whether there was an association with sensitivity to glucocorticoids and anthropometric parameters in a group of healthy elderly individuals. Design and measurements In study group 1, two overnight dexamethasone suppression tests (DSTs) were performed: with 1 mg dexamethasone, and 2.5 years later with 0.25 mg dexamethasone. Anthropometric parameters were measured in a larger population (study group 2), as well as in a third study group, in which we also measured body composition by dual-energy X-ray absorbtiometry (DEXA) scans. Subjects Groups 1 and 2, respectively, 191 and 1963 male and female participants of the Rotterdam study, a population-based study in Dutch elderly. Study group 3: 370 elderly males (mean age 77.8 +/- 0.2 years) from Zoetermeer, the Netherlands. Results We identified the BclI restriction site polymorphism as a C/G substitution in intron 2, 646 nucleotides downstream from exon 2. After both 1 mg and 0.25 mg DST, heterozygous (CG) and homozygous G-allele carriers (GG) had lower cortisol levels than CC-carriers (P = 0.01 and P = 0.02, respectively). In study group 2, we found a lower body mass index (BMI; P = 0.006) and waist-hip ratio (WHR; P = 0.02) in G-allele carriers. In study group 3, again we found a lower BMI (P = 0.05) in G-allele carriers. No differences were found in fat mass. However, lean mass tended to be lower in G-allele carriers (P = 0.07). Conclusions We characterized a BclI-RFLP (restriction fragment length polymorphism) of the GR gene as a C/G polymorphism in intron 2 of which the G-allele was associated with hypersensitivity to glucocorticoids. This resulted in a lower BMI in older individuals in general, while our study in elderly males suggests that the lower BMI is probably due to a greater loss of lean mass during the ageing process.

For a long time oestrogens in the human male have been regarded as a mere by-product of testosterone synthesis. Only since the description of an oestrogen-resistant man (Smith et al ., 1994) has it been fully realized that oestrogens play an import role in bone homeostasis, cardiovascular health and pituitary–gonadal interactions in men. Due to a disruptive homozygous oestrogen receptor alpha (ER α ) mutation, this man was virtually insensitive to oestrogens which lead to osteoporosis, unfused epiphyses resulting in linear growth into adulthood, increased gonadotrophin levels and evidence of premature atherosclerosis (Sudhir et al ., 1997a) and endothelial dysfunction (Sudhir et al ., 1997b). Additionally, there was low viability of sperm and glucose intolerance with acanthosis nigrans. Two adult aromatase-deficient men showed, besides undetectable oestrogen levels, low bone mass, unfused epiphyses, increased gonadotrophins and a unfavourable lipid profile (Morishima et al ., 1995; Carani et al ., 1997). Earlier, Korach (1994) described similar observations in ER α knockout mice. Heterozygous mice exhibited no obvious phenotypic abnormalities. Homozygous male mice proved to be infertile, showing smaller testes with dysmorphic seminiferous tubules and a sperm count of less than 10% compared to normal mice. Finally, bone mineral density was 20–25% lower in male and female mutants compared to wild-type animals. These reports indicate that oestrogens also play a central role in several metabolic processes in men. The interrelation between testosterone and oestrogen biosynthesis makes it difficult to separate their respective biological effects. Therefore, it is not unlikely that biological effects formerly attributed to testosterone actually represent effects of oestrogens. In light of the observations in oestrogen-resistant or -deficient males, and because of the wealth of evidence for the role of oestrogens in the (patho)physiology of bone and lipid metabolism, cardiovascular disease and the hypothalamo–pituitary– gonadal axis in women, this review will discuss these areas, focusing on the clinical importance of oestrogens in males.

OBJECTIVE A recent report showing disappointingly low sensitivity and specificity for the oral high dose dexamethasone test in the differential diagnosis of Cushing's syndrome prompted us to re-evaluate the results obtained in our centre using the continuous 7-hour intravenous dexamethasone suppression test for this purpose. PATIENTS 105 patients with ACTH–dependent Cushing's syndrome were included in this study; 78 with Cushing's disease, 8 with ectopic ACTH-secreting tumours and 19 were classified as ‘of unknown aetiology’. RESULTS In 74/78 (94.9%) of patients with Cushing's disease and in 3/8 (37.5%) patients with the ectopic ACTH syndrome, a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values was achieved in the continuous 7-hour intravenous dexamethasone suppression test. Using a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values as the cut-off value, the sensitivity and specificity of the continuous 7-hour intravenous dexamethasone suppression test for the diagnosis of Cushing's disease in patients with ACTH–dependent Cushing's syndrome were 94.9% and 62.5%, respectively. CONCLUSIONS In patients with ACTH–dependent Cushing's syndrome with a plasma cortisol decrease > 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test, additional localizing investigations such as bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy should be performed when no clearly discernible pituitary adenoma is observed on MRI studies. Patients with ACTH–dependent Cushing's syndrome with a plasma cortisol decrease

OBJECTIVE The prediction of relapse during the early months after transsphenoidal surgery for Cushing's disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation. PATIENTS From a retrospective series of 77 consecutive primary pituitary operations for Cushing's disease 29 patients, who also had a metyrapone test at 14 days postoperatively, were selected. Median follow-up was 35 months (range: 8–118 months). MAIN OUTCOME MEASURES Early postoperative: fasting morning serum cortisol, 24-hour urinary cortisol excretion, serum 11-deoxycortisol after 6 × 750 mg metyrapone. Remission was defined as a fasting morning serum cortisol 350 nmol/l after metyrapone. Seventeen patients met the criteria for early remission. Four of these patients had serum 11-deoxycortisol levels between 150 nmol/l and 350 nmol/l after metyrapone. Three of these 4 patient’s experienced a relapse of Cushing's disease during follow-up. In the 13 patients with a serum 11-deoxycortisol 150 nmol/L is found after metyrapone are at a high risk for relapse of Cushing's disease.

SUMMARY To quantify the role of endogenous oestrogen activity in osteoporosis we measured relative metacarpal cortical area (RCA), body mass, serum oestrone, oestradiol, androstenedione, and sex hormone binding globulin (SHBG) in 746 postmenopausal women aged 53 to 76 years, sampled from the general population. The occurrence of fractures and the rate of loss of RCA (delta-RCA) were determined over the previous 9 years. Both RCA and delta-RCA were significantly related to body mass, serum oestrone, oestradiol, and SHBG. The influence of the first three variables appeared to be bone preserving, whereas the latter appeared to be bone wasting. Serum oestradiol, SHBG and body mass proved to have an independent relationship with RCA in multivariate regression analysis. The relationship to delta-RCA was statistically independent for serum SHBG only. Serum androstenedione was unrelated to either RCA or delta-RCA. In the total study population, body mass, serum oestrone, oestradiol and SHBG were not related to the occurrence of fractures over the previous 9 years. In the subgroup of 249 elderly women, aged 65-76 years, SHBG levels were significantly higher for women with type I osteoporotic fractures (vertebral and forearm fractures) as compared to controls. The results suggest a bone wasting influence of SHBG in postmenopausal women, possibly resulting in an increased risk of type I osteoporotic fractures in elderly women.