Mammalian sulfotransferases (EC 2.8.2) are involved in many important facets of steroid hormone activity and metabolism. In this study, Arabidopsis AtST4a and AtST1 were identified and characterized as brassinosteroid sulfotransferases that appear to be involved in different aspects of hormone regulation. The two proteins share 44% identity in amino acid sequence, and belong to different plant sulfotransferase families. AtST4a was specific for biologically active end products of the brassinosteroid pathway. The enzyme sulfated brassinosteroids with diverse side-chain structures, including 24-epibrassinosteroids and the naturally occurring (22R, 23R)-28-homobrassinosteroids. AtST4a belongs to a small subfamily of sulfotransferases having two other members, AtST4b and -c. Among the three recombinant enzymes, only AtST4a was catalytically active with brassinosteroids. Transcript expression of AtST4 subfamily members was largely specific to the root. AtST4b- and -c transcript levels were induced by treatment with trans-zeatin, while AtST4a was repressed under the same conditions, supporting a divergent function of AtST4a. Co-regulation of AtST4b and -c correlated with their location in tandem on chromosome 1. AtST1 was stereospecific for 24-epibrassinosteroids, with a substrate preference for the metabolic precursor 24-epicathasterone, and exhibited catalytic activity with hydroxysteroids and estrogens. To gain more insight into this dual activity with plant and mammalian steroids, enzymatic activities of human steroid sulfotransferases toward brassinosteroids were characterized. The dehydroepiandrosterone sulfotransferase SULT2A1 displayed catalytic activity with a selected set of 24-epibrassinolide precursors, including 24-epicathasterone, with specific activities comparable to that measured for the endogenous substrate dehydroepiandrosterone. The comparable activity profiles of AtST1 and SULT2A1 suggest a similar architecture of the acceptor-binding site between the two enzymes, and may potentially reflect a common ability to conjugate certain xenobiotics.

Dehydroepiandrosterone (DHEA) and its sulfate derivative DHEA-S are neurosteroids, produced in the brain, and neuroactive steroids, produced in the adrenals and affecting the brain. We compared the ratios of serum cortisol/DHEA or DHEA-S in schizophrenia patients with normal subjects, and determined the correlation of these ratios with psychopathology and distress. Early morning plasma concentrations of DHEA, DHEA-S, and cortisol were determined by radioimmunassay in 40 medicated schizophrenia inpatients, and 15 healthy subjects with similar age and sex distribution. Subjects were assessed for psychopathology using the Positive and Negative Syndrome Scale (PANSS) and the Montgomery and Asberg Depression Rating Scale (MADRS), anxiety, anger, emotional and somatic distress levels. Schizophrenia inpatients demonstrated significantly higher levels of state and trait anxiety, anger expression index, emotional and somatic self-reported distress scores. Cortisol/DHEA and cortisol/DHEA-S ratios were significantly higher in schizophrenia patients than in healthy comparison subjects. Both ratios correlated positively with age and duration of illness; cortisol/DHEA-S ratio also showed positive association with age of illness onset. When age, illness duration and age of onset were controlled, cortisol/DHEA-S ratio significantly correlated with severity of depression (MADRS, r=0.33, p=0.048), state and trait anxiety (r=0.43, p=0.008 and r=0.40, p=0.014, respectively), trait anger (r=0.41, p=0.012), angry temperament (r=0.46, p=0.004), anger expression index (r=0.36, p=0.033), and hostility (r=0.42, p=0.010). No significant association was found between these ratios and severity of psychopathology, and type or dosage of antipsychotic agents. Thus, elevated cortisol/DHEA and/or cortisol/DHEA-S ratios in schizophrenia patients are positively associated with higher scores for anxiety and anger, depression and hostility, age and age of onset/duration of illness, but are independent of severity of psychopathology (PANSS) and antipsychotic treatment.

To determine whether hyperprolactinemic women with menses are at risk for the development of osteopenia and to define the effects of PRL excess and estrogen deficiency on bone mass in amenorrheic women, spinal and radial bone densities were measured in 25 hyperprolactinemic women (13 with amenorrhea and 12 with regular menstrual periods) and 11 women with hypothalamic amenorrhea. The degree of hyperprolactinemia was comparable in the hyperprolactinemic women with and without menstrual periods [mean, 55 +/- 18 (+/- SD) and 57 +/- 16 micrograms/L, respectively]. The mean spinal bone density in the hyperprolactinemic amenorrheic women (148 +/- 26 mg/K2HPO4.cm3) was significantly lower (P less than 0.01) than that in 19 normal women (178 +/- 21 mg/K2HPO4.cm3), and 6 of the former group had values greater than 2 SD below normal. However, the mean spinal bone density in the eumenorrheic hyperprolactinemic women (171 +/- 22 mg/K2HPO4.cm3) was similar to that in the normal women and was significantly greater (P less than 0.05) than that in the hyperprolactinemic amenorrheic women. The mean spinal bone density in the women with hypothalamic amenorrhea (128 +/- 24 mg/K2HPO4.cm3) and normal PRL levels was also significantly (P less than 0.001) lower than that in normal women or hyperprolactinemic euenorrheic women. Six of the women with hypothalamic amenorrhea had bone density measurements greater than 2 SD below normal. The spinal bone density values were similar in the amenorrheic women with or without hyperprolactinemia. The mean radial bone density in the hyperprolactinemic women with amenorrhea (0.69 +/- 0.03 g/cm2) was comparable to that in the women with hypothalamic amenorrhea (0.69 +/- 0.05 g/cm2), and both groups had significantly (P less than 0.05) lower values than normal women (0.72 +/- 0.03 g/cm2). Radial bone density was normal in the hyperprolactinemic eumenorrheic women. The mean serum estradiol level in the hyperprolactinemic amenorrheic women (120 +/- 90 pmol/L) was significantly (P less than 0.05) lower than that in the hyperprolactinemic eumenorrheic women measured during the follicular phase of their cycles (240 +/- 180 pmol/L) and was comparable to that in the women with hypothalamic amenorrhea (80 +/- 40 pmol/L). Multiple comparisons of clinical variables, serum hormone concentrations, and bone mass demonstrated a significant correlation (P = 0.0125) between bone density and serum dehydroepiandrosterone sulfate levels, which suggests a role for endogenous androgens in the maintenance of premenopausal bone mass.(ABSTRACT TRUNCATED AT 400 WORDS)

Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM;>> 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.

Evidence suggests that adult cancer risk of hormonally related tumors may be influenced by the in utero environment, and most speculation on the biological mechanism has focused on the hormonal component. Epidemiological studies investigating the biological nature of pregnancy and maternal factors associated with offspring's cancer risk have relied on maternal hormone measurements. The degree to which maternal hormone levels represent the fetal environment, however, is not widely known. Pregnancy estrogen, androstenedione, testosterone, dehydroepiandrosterone (DHEA), and DHEA-sulfate concentrations were measured in maternal and mixed umbilical cord sera from 86 singleton pregnancies. Spearman correlations between maternal and cord hormone levels generally ranged between 0.2 and 0.3. The correlation was 0.26 for estriol, the estrogen of highest concentration in pregnancy, and 0.27 for estradiol, the most biologically active estrogen. The correlations between mother and offspring for the estrogens and DHEA appeared similar for males and females, whereas there was a suggestion that the maternal-umbilical cord correlations for other androgens varied in magnitude by fetal sex, and all correlations appeared higher in pregnancies lasting <38 weeks compared with longer gestational lengths, although these stratified findings may have been attributable to chance. These data show a moderate degree of correlation in hormone concentrations between the maternal and fetal circulation. Studies using maternal hormone concentrations as a proxy for the fetal environment should consider the misclassification resulting with the use of this marker.

It has been well documented that a significant proportion of chronic anovulatory patients have elevated levels of dehydroepiandrosterone sulfate (DHEAS) and luteinizing hormone (LH) and normal levels of adrenocortiocotropic hormone (ACTH). We tested the hypothesis that the zones of human adrenal cortex that secrete DHEAS may contain LH/human chorionic gonadotropin (hCG) receptors. In situ hybridization showed the presence of hybridization signals representing LH/hCG receptor mRNA transcripts in the zona reticularis. Immunocytochemistry demonstrated that the zona reticularis also contained LH/hCG receptor protein. The receptor transcripts and receptor protein are also present in the deeper layer of the zona fasciculata which can also secrete DHEAS. Double immunostaining revealed that LH/hCG receptors are present in the same cells that contain cytochrome P450 side chain cleavage enzyme, suggesting that the receptor containing cells are steroidogenic. These findings may potentially explain higher DHEAS levels in chronic anovulatory women who have normal ACTH and elevated LH levels.

Frailty is characterized by vulnerability to acute stressors and is a consequence of decline in overall function and physiologic reserves. An estimated 7% of the US population older than 65 years and 30% of octogenarians are frail. The domains to define frailty include mobility, strength, balance, motor processing, cognition, nutrition, endurance, and physical activity. Pathophysiologic pathways leading to frailty involve a multisystem cascade that includes neuroendocrine dysfunction with lower insulin-like growth factor and dehydroepiandrosterone sulfate and an altered inflammatory milieu with increased levels of C-reactive protein, interleukins, tumor necrosis factor alpha, and abnormal coagulation. Frailty predicts death and heralds the transition to disability in general populations. As the population with coronary artery disease shifts toward older patients, physicians must consider the role of frailty in their patients. This review will enable clinicians to recognize frailty and consider its relevance in their daily practice. We also elaborate on reasons to consider frailty in older adults with cardiovascular disease and focus on its early identification, on referral to specialists, and on care after serious cardiac events.

There is accumulating evidence that a deficiency in brain-derived neurotrophic factor (BDNF) plays a critical role in the pathophysiology of depression. This is in line with the postulate that low BDNF levels in serum are associated with depression. However, the regulation of maternal BDNF serum levels in the perinatal period, and its relationship to maternal depression is unknown. In this study, serum BDNF concentrations were measured in 40 pregnant (follow-up: 30th and 37th week of gestation, 1 week and 8 weeks after childbirth) and 40 non-pregnant women (20-40 years old). The Edinburgh Postnatal Depression Scale (EPDS) was assessed in all subjects at all time points. Maternal serum levels of BDNF were markedly decreased, both before and after childbirth (median: <30% of non-pregnant controls). BDNF correlated with decreased Serotonin (5-HT) levels in serum (r>0.6 and p<0.001 at all time points). In contrast, there was no association with altered estrogen, progesterone, dehydroepiandrosterone or cortisol concentrations in serum. There were significantly higher cortisol levels in cases of maternal depression (EPDS scores>9 points) than in cases without depression. There was a trend to a decrease of BDNF and 5-HT levels in cases of maternal depression (as compared to cases without depression), but this was not significant. In conclusion, we demonstrate that women display markedly decreased BDNF serum levels before and after childbirth. This phenomenon might reflect an increased risk for the development of mood disorders in the perinatal period. However, the individual serum concentration of BDNF alone did not predict maternal depression in our study.

Dehydroepiandrosterone (DHEA) and its sulfate ester are major secretory products of the human adrenal. Serum DHEA concentrations decline with advancing age and DHEA supplementation in elderly people has been advertized as anti-aging medication. However, such claims are based on experiments in rodents with a fundamentally different DHEA physiology. In humans, DHEA is a crucial precursor of sex steroid biosynthesis and exerts indirect endocrine and intracrine actions following conversion to androgens and estrogens. In addition, it acts as a neurosteroid via effects on neurotransmitter receptors in the brain. DHEA has considerable effects on mood, well-being and sexuality in patients with adrenal insufficiency, and also in those with mood disorders. However, subjects with a physiological, age-related decline in DHEA secretion show little benefit from DHEA administration. Future research should focus on DHEA treatment for adrenal insufficiency, and DHEA administration in both patients receiving chronic glucocorticoid treatment and women with androgen deficiency.

Dehydroepiandrosterone (DHEA), an adrenal cortex hormone secreted in large quantities in humans, protects cells of the clonal mouse hippocampal cell line HT-22 against the excitatory amino acid glutamate (5 mM), and amyloid beta-protein (2 microM) toxicity in a dose-dependent manner with optimum protection obtained at 5 microM concentration of DHEA. The protective effects of DHEA appear to be specific in that other related steroids and metabolites of DHEA, such as 5-androstene-3beta,17beta-diol, etiocholan-3alpha-ol-17-one, etiocholan-3beta-ol-17-one, testosterone, and 5alpha-androstane-3, 17-dione, offered no protection even at 50 microM concentrations. In addition, using immunocytochemical techniques, we observed that 20 hr of treatment with 5 mM glutamate remarkably increased glucocorticoid receptor (GR) nuclear localization in neuronal cells. Interestingly, 5 microM DHEA treatment for 24 hr, followed by 5 mM glutamate treatment for 20 hr almost completely reversed the copious nuclear localization of GR observed by glutamate treatment alone. Results obtained suggest that DHEA protects hippocampal neurons, at least in part, by its antiglucocorticoid action via decreasing hippocampal cells nuclear GR levels.

OBJECTIVE

Aims of this study were 1) to assess sexual function and endocrine profile among fertile type 1 diabetic women during the follicular and luteal phases of the menstrual cycle, 2) to compare these results with those obtained among healthy fertile women who served as control subjects, and 3) to explore the correlations between sexual function and endocrine milieu among patients and control subjects during the follicular and luteal phases of the menstrual cycle.

METHODS

Fifty fertile women with type 1 diabetes and 47 healthy control subjects completed a semistructured medical interview and filled in self-administered validated instruments to evaluate sexual function, depression, and sexual distress. Venous blood samples were drawn to measure glycated hemoglobin and an endocrine profile during either the follicular or the luteal phase of the menstrual cycle.

RESULTS

Type 1 diabetic women had decreased sexual function and increased sexual distress compared with control subjects during the luteal, but not the follicular, phase of the menstrual cycle. During the follicular phase, patients had lower estrogenic basal tone, lower "weak" androgen (namely Delta4-androstenedione and dehydroepiandrosterone sulfate) production, and lower free-triiodothyronine and free-thyroxine levels compared with control subjects. During the luteal phase, total testosterone levels were higher in patients than control subjects, while 17beta-estradiol and progesterone levels were lower in patients than control subjects.

CONCLUSIONS

Among type 1 diabetic women, sexual function and sexual distress vary according to the phase of the menstrual cycle. This finding may have implications on the clinical assessment of sexual function in type 1 diabetic women.

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands--yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15 × 10(-36)), SULT2A1 (rs2637125; p = 2.61 × 10(-19)), ARPC1A (rs740160; p = 1.56 × 10(-16)), TRIM4 (rs17277546; p = 4.50 × 10(-11)), BMF (rs7181230; p = 5.44 × 10(-11)), HHEX (rs2497306; p = 4.64 × 10(-9)), BCL2L11 (rs6738028; p = 1.72 × 10(-8)), and CYP2C9 (rs2185570; p = 2.29 × 10(-8)). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.

BACKGROUND

The simultaneous, rapid and reliable measurement of a wide steroid panel is a powerful tool to unravel physiological and pathological hormone status. Clinical laboratories are currently dominated by high-throughput immunoassays, but these methods lack specificity due to cross-reactivity and matrix interferences. We developed and validated an isotopic dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) method for the simultaneous measurement of cortisol, corticosterone, 11deoxycortisol, androstenedione, deoxycorticosterone (DOC), testosterone, 17OHprogesterone, dehydroepiandrosterone (DHEA) and progesterone in serum, and compared it to routine immunoassays employed in our laboratory. We also established adult reference intervals in 416 healthy subjects.

METHODS

0.9 ml of serum were spiked with labelled internal standards (IS) and extracted on C18 cartridges. Eluate was injected into a two-dimensional LC-system, purified in a perfusion column and separated on a C8 column during a 21 min gradient run. Analytes were revealed by atmospheric pressure chemical ionization (APCI) followed by multiple reaction monitoring (MRM) analysis.

RESULTS

Of the four immunoassays compared with the ID-LC-MS/MS method, only the results of ElecsysE170 for cortisol, testosterone in males and progesterone>1 ng/ml were in agreement with ID-LC-MS/MS. ElecsysE170 for testosterone in females and progesterone<1 ng/ml, Immulite2000 for androstenedione, DSL-9000 for DHEA and 17OHP Bridge for 17OHprogesterone, respectively, showed poor agreement. Reference intervals and steroid age and fertility related fluctuations were established.

CONCLUSIONS

Our ID-LC-MS/MS method proved to be reliable and sensitive in revealing steroid circulating concentrations in adults and in highlighting the limits of routine immunoassays at low concentrations.

OBJECTIVE

The objective of this study was to identify systemic diseases associated with hyposalivation and xerostomia and develop evidence-based management recommendations for hyposalivation/xerostomia.

METHODS

Literature searches covered the English language medical literature from 1966 to 2005. An evidence-based review process was applied to management studies published from 2002 to 2005.

RESULTS

Several systemic diseases were identified. From studies published 2002 to 2005, 15 were identified as high-quality studies and were used to support management recommendations: pilocarpine and cevimeline are recommended for treating hyposalivation and xerostomia in primary and secondary Sjögren's syndrome (SS). IFN-alpha lozenges may enhance saliva flow in primary SS patients. Anti-TNF-alpha agents, such as infliximab or etanercept, are not recommended to treat hyposalivation in SS. Dehydroepiandrosterone is not recommended to relieve hyposalivation or xerostomia in primary SS. There was not enough evidence to support any recommendations for the use of local stimulants, lubricants, and protectants for hyposalivation/xerostomia. However, professional judgment and patient preferences may support the use of a specific product for an individual patient.

CONCLUSIONS

These evidence-based management recommendations should guide the clinician's management decisions for patients with salivary dysfunction related to systemic disease. Future treatment strategies may include new formulations of existing drugs, e.g., local application of pilocarpine. Recent discoveries on gene expression and a better understanding of the etiopathogenesis of SS may open new treatment options in the future.

Androgens may contribute to higher cardiovascular risk in men via deleterious effects on vascular endothelial cells (EC). We examined the effects of androgens on male human umbilical vein EC (EA.hy926) in culture. [(3)H]Thymidine incorporation assays showed that after 24-h serum deprivation, testosterone (T) (but not dehydroepiandrosterone nor 17beta-E2) induced significant dose-dependent decreases in DNA synthesis (10-16% at 1-100 nmol/liter); the AR antagonist flutamide (100 nmol/liter) abolished this effect of T. After 48-h serum deprivation, typical apoptotic DNA patterns were detected in agarose gels, and the number of floating cells indicative of severe damage was significantly greater after T treatment for 48 and 72 h (13.7 +/- 0.5% and 30.2 +/- 2.5%, respectively) than the control values (9.7 +/- 1.05% and 23.7 +/- 3.0%). Analysis of attached cells by annexin V-fluorescein isothiocyanate/propidium iodide staining showed that after 48-h serum deprivation, T significantly increased the number of cells in the early (16.0 +/- 1.1%) and late (8.3 +/- 0.3%) stages of apoptosis compared with control (6.8 +/- 1.0% and 4.0 +/- 0.2%, respectively); such increases in apoptosis-related damage were also observed, to a lesser degree, in serum-enriched culture. Western blotting showed that B cell leukemia/lymphoma-2 protein (Bcl-2) expression decreased significantly in serum-deprived EC treated with T. Thus, T reduces DNA synthesis and enhances apoptosis after serum deprivation in EC, possibly related to reduced Bcl-2 expression.

BACKGROUND

Investigation of a possible effect of metformin on androgen levels in pregnant women with polycystic ovary syndrome (PCOS).

METHODS

A prospective, randomized, double-blind, placebo-controlled pilot study was conducted. Forty pregnant women with PCOS received diet and lifestyle counselling and were randomized to either metformin 850 mg twice daily or placebo. Primary outcome measures were changes in serum levels of dehydroepiandrosterone sulphate, androstenedione, testosterone, sex hormone-binding globulin, and free testosterone index. Secondary outcome measures were pregnancy complications and outcome. Two-tailed t-tests and chi2-tests were used.

RESULTS

Maternal androgen levels were unaffected by metformin treatment in pregnant women with PCOS. While none of the 18 women in the metformin group experienced a severe pregnancy or post-partum complication, seven of the 22 (32%) women experienced severe complications in the placebo group (P = 0.01).

CONCLUSIONS

Metformin treatment did not reduce maternal androgen levels in pregnant women with PCOS. In the metformin-treated group we observed a reduction of severe, pregnancy and post-partum complications. Metformin treatment of pregnant PCOS women may reduce complications during pregnancy and in the post-partum period.

Treatment outcome in congenital adrenal hyperplasia is often sub-optimal due to hyperandrogenism, treatment-induced hypercortisolism, or both. We previously reported better control of linear growth, weight gain, and bone maturation in a short term cross-over study of a new four-drug treatment regimen containing an antiandrogen (flutamide), an inhibitor of androgen to estrogen conversion (testolactone), reduced hydrocortisone dose, and fludrocortisone, compared to the effects of a control regimen of hydrocortisone and fludrocortisone. Twenty-eight children have completed 2 yr of follow-up in a subsequent long term randomized parallel study comparing these two treatment regimens. During 2 yr of therapy, compared to children receiving hydrocortisone, and fludrocortisone treatment, children receiving flutamide, testolactone, reduced hydrocortisone dose (average of 8.7 +/- 0.6 mg/m2 x day), and fludrocortisone had significantly (P < or = 0.05) higher plasma 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels. Despite elevated androgen levels, children receiving the new treatment regimen had normal linear growth rate (at 2 yr, 0.1 +/- 0.5 SD units), and bone maturation (at 2 yr, 0.7 +/- 0.3 yr bone age/yr chronological age). No significant adverse effects were observed after 2 yr. We conclude that the regimen of flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone provides effective control of congenital adrenal hyperplasia with reduced risk of glucocorticoid excess. A long term study of this new regimen is ongoing.

The human hydroxysteroid sulfotransferase (SULT) family is comprised of two subfamilies, SULT2A1 and SULT2B1. We characterized the substrate specificity, in vitro biochemical properties, and tissue distribution patterns of human SULT2B1a and SULT2B1b. In contrast to the wide substrate specificity of SULT2A1, SULT2B1a and SULT2B1b specifically catalyzed the sulfonation of 3beta-hydroxysteroids with high catalytic efficiency. Both SULT2B1 enzymes also sulfonated dihydrotestosterone. In vitro studies revealed that the biochemical properties of SULT2B1a and SULT2B1b were not significantly different from each other. However, tissue expression analysis suggested that they are differentially regulated. In contrast to the limited tissue distribution of SULT2A1, SULT2B1 was detected in a variety of hormone-responsive tissues including placenta, ovary, uterus, and prostate. The catalytic activity toward dehydroepiandrosterone and dihydrotestosterone, biologically important androgens, coupled with expression in prostate suggests that SULT2B1 may play a novel regulatory role that protects against the mitogenic effects of androgens.

Allopregnanolone is the best characterized among neurosteroids, and its role in the control of neuroendocrine axes has attracted increasing interest recently. However, there is no available information about circulating levels of allopregnanolone during infancy, childhood and puberty. We studied two groups of children: 1) those aged between 0 and 2 y (n = 72), and 2) those aged between 6 and 18 y, at different Tanner's stages (n = 82). In each of these patients, serum allopregnanolone, progesterone, cortisol, and dehydroepiandrosterone levels were evaluated after informed consent; allopregnanolone was measured by RIA after acid extraction on cartridge. There was no significant variation of serum allopregnanolone levels either in male and female children during the first 2 y of life. Furthermore, although serum dehydroepiandrosterone levels showed a significant decrease, inversely correlated with age of the children (p < 0.01), serum cortisol and progesterone levels showed a significant age-related increase during the first 2 y of life. Cortisol and allopregnanolone levels were positively correlated (p < 0.01). During puberty, we observed a progressive increase in serum allopregnanolone levels in both boys and in girls, which were higher at Tanner' s stage IV-V (0.7+/-0.01 nM; mean +/- SEM) than at stages I-II (0.32+/-0.02 nM; p < 0.01); mean levels were significantly higher at puberty than in the first 2 y of life (p < 0.01). Furthermore, during puberty, serum progesterone and dehydroepiandrosterone levels also increased progressively with age in both boys and girls. Allopregnanolone and dehydroepiandrosterone levels were positively correlated throughout puberty. The present results indicate that serum allopregnanolone levels do not change during the first 2 y of life but increase during pubertal development, suggesting that this steroid may be involved in the adaptive neuroendocrine mechanisms related to puberty.

In 104 normal boys, aged 7 to 14 years (bone ages 5 to 15 years), plasma dehydroepiandrosterone (DHEA) rose from 52.7 at 7 years, to 112.0 ng/100 ml at 10 years. A further rise occurred at 12 years (188 ng/100 ml). In relation to the bone age, DHEA increased from a mean plasma level of 31.1 at a bone age of 5 years to 77.1 ng/100 ml at one of 7 years. Further increases were observed with mean values of 163.2 at a bone age of 11 years, and of 221.2 at a bone age of 12 years, with a maximum of 333.4 ng/100 ml at bone ages of 14-15 years. The first significant increase of plasma testosterone (T) was noted at a bone age of 12 years (54.8 ng/100 ml). The major rise of T was preceded by the rise of plasma LH and was accompanied by the rise of plasma FSH. Plasma DHEA and T were also measured in 123 normal girls, ages 6 to 13 years (bone ages 5 to 15 years). DHEA rose significantly from a mean level of 44.7 at 6 years, to 80.9 ng/100 ml at 8 years, with further increases between 9 and 10 years and between 10 and 11 years. In relation to bone age, DHEA increased significantly from a mean plasma concentration of 30.9 at a bone age of 5 years, to that of 58.6 ng/100 ml at 7 years. Further increases were observed with values of 191.1 at a bone age of 10 years and 485.6 ng/100 ml at a bone age of 13 years. The first significant rise of testosterone (T) occurred at 10 years of both chronological and bone age. DHEA rose before the increase of gonadotropins. The major rise of T at a bone age of 10 years occurred concurrently with increases in plasma FSH and LH. Low levels of DHEA were observed in Addison's disease. In hypogonadotropin hypogonadism and in anorchia, DHEA levels were normal, suggesting that DHEA is produced primarily in the adrenal gland. In seven girls with early adrenarche, plasma concentrations of DHEA were in the upper range of normal values, whereas T levels were within the normal range. Conversely in girls with late adrenarche, plasms DHEA was lower than normal but T was within the normal limits. The elevation of DHEA prior to the first signs of puberty suggests that DHEA may play a role in the maturation of the hypothalamic-hypophysealgonadal axis. However, the mechanism that triggers the secretion of DHEA is not known.

This study examined associations between medications prescribed to control children's problem behaviors and levels of, and diurnal variation in, salivary cortisol (C), testosterone (T), and dehydroepiandrosterone (DHEA). Saliva was collected in the morning, midday, and afternoon from 432 children ages 6-13 years. Relative to a no-medication comparison group, children taking (1) antipsychotics had higher DHEA levels and flat C diurnal rhythms, (2) Ritalin or Adderall had flat T diurnal rhythms, (3) Concerta had higher T and DHEA levels, (4) antidepressants had flat DHEA diurnal rhythms, and (5) hypotensives had flat DHEA diurnal rhythms and higher T levels. Medications prescribed to control children's problem behaviors should be monitored in studies of the endocrine correlates and consequences of developmental psychopathology.

OBJECTIVE

To investigate whether circulating levels of sex hormones are associated with urological symptoms, using data from the Boston Area Community Health (BACH) Survey.

METHODS

BACH used a multistage stratified-cluster approach to randomly sample 5506 adults aged 30-79 years in Boston, MA, USA. Anthropometric measures, lifestyle and psychosocial factors, comorbidities and urological symptoms were obtained using a questionnaire administered by an interviewer. Serum testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), dihydrotestosterone (DHT) and oestradiol (E2) levels were measured, and bioavailable testosterone (BT) was calculated in 1899 men (538 Black, 651 Hispanic and 710 White). Regression analysis was used to investigate the relationships between androgen levels and American Urological Association symptom index (AUA-SI), lower urinary tract symptoms (LUTS) >> or = 8 on the AUA-SI), urinary incontinence (UI), dribble and hesitancy.

RESULTS

Of all subjects, 19% reported LUTS, 6% UI, 9% dribble and 4% hesitancy. Testosterone, BT and DHEAS levels were inversely related to the AUA-SI (P = 0.009, <0.001 and <0.001, respectively); SHBG values and the AUA-SI were positively correlated (P < 0.001). Adjusting for age, BT and DHEAS levels had negative relationships with the AUA-SI; BT and DHEAS levels were negatively related to LUTS and SHBG was positively related to LUTS (both P < 0.001); after age adjustment, only LUTS and DHEAS remained related, and only the relationship between dribble and E2 remained significant; no hormone levels were related to hesitancy.

CONCLUSIONS

Circulating levels of sex hormones are generally not significant predictors of urological symptoms in men after adjusting for age. The pathophysiology of LUTS is complex and probably includes factors other than circulating sex steroid levels.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation/mental retardation syndrome with an estimated incidence among individuals of European ancestry of 1 in 20000 to 1 in 30000. It is caused by inactivity of the enzyme 7-dehydrosterol-delta(7)-reductase, which catalyses the terminal transformation in cholesterol synthesis. Patients show not only an increased level of 7-dehydrocholesterol in blood and tissues, but also increased 8-dehydrocholesterol because of the presence of an active delta(8)-delta(7) isomerase. A major consequence of these biochemical abnormalities is the alteration of normal embryonic and fetal somatic development causing postnatal abnormalities of growth, learning, language and behavior. While deficient cholesterol during early development is the primary cause of central nervous system (CNS) abnormalities and retardation, we questioned whether neurosteroids could also be involved since they can have a profound influence on behavioral characteristics. Disordered neurosteroidogenesis would be expected in SLOS and could be caused by a deficiency in classical neurosteroid synthesis secondary to cholesterol deficiency, or by synthesis from 7- and 8-dehydrocholesterol of novel neurosteroids with delta(7) or delta(8) unsaturation which may have altered activity compared with conventional neurosteroids. In particular we sought analogues of dehydroepiandrosterone sulfate, pregnenolone sulfate and the pregnanolone epimers. We targeted urine from post-pubertal females, as this type of sample would be most likely to yield identifiable amounts of the pregnanolone metabolites of progesterone. Analysis by GC/MS of urinary steroids excreted by post-pubertal females confirmed the presence of neurosteroid-like compounds in SLOS patient's urine. Even though the new neuroactive steroids identified were unlikely to have been formed in the brain, it is likely that mechanisms for their synthesis are operable in this organ.

OBJECTIVE

A progressive decrease in androgen production is common in males after middle age. The resulting clinical picture has been erroneously named male menopause or andropause. A more appropriate designation is androgen decline in the aging male (ADAM). The syndrome is characterized by alterations in the physical and intellectual domains that correlate with and can be corrected by manipulation of the androgen milieu. We review the epidemiological aspects of aging and endocrinological manifestations of ADAM, and provide recommendations for treatment and monitoring of these patients.

METHODS

We performed MEDLINE, Pubmed, Current Contents and Pharmaceutical Abstracts searches of relevant peer reviewed publications on andropause, male climacteric, adult hypogonadism and aging. In addition, conference proceedings were researched to provide a more complete review of the literature. Information was scrutinized and collated, and contributory data were reviewed and summarized.

RESULTS

ADAM is a clinical entity characterized biochemically by a decrease not only in serum androgen, but also in other hormones, such as growth hormone, melatonin and dehydroepiandrosterone. Clinical manifestations include fatigue, depression, decreased libido, erectile dysfunction, and alterations in mood and cognition.

CONCLUSIONS

The onset of ADAM is unpredictable and its manifestations are subtle and variable, which has led to a paucity of interest in its diagnosis and treatment. Urological practice commonly includes a large proportion of men older than 50 years. Therefore, it is important for urologists to recognize the manifestations of and be familiar with evaluations necessary to document ADAM as well as its treatment and monitoring.