BACKGROUND

Dehydroepiandrosterone (DHEA) replacement in sepsis has been advocated because of the sepsis-associated decrease in serum DHEA sulfate (DHEAS). However, experimental sepsis in rodents leads to down-regulation of DHEA sulfotransferase, which inactivates DHEA to DHEAS, theoretically resulting in higher DHEA levels.

OBJECTIVE

The objective of the study was to test whether serum DHEA and DHEAS are dissociated in septic shock and to determine their association with circulating cortisol in the context of severity of disease and mortality.

METHODS

This was a cross-sectional study consisting of 181 patients with septic shock, 31 patients with acute trauma, and 60 healthy controls.

METHODS

Serum cortisol, DHEA, and DHEAS were measured before and 60 min after ACTH stimulation.

RESULTS

Serum cortisol was increased and DHEAS was decreased in both septic shock and trauma patients (all P < 0.001). However, compared with healthy controls, DHEA was significantly increased in sepsis but decreased after trauma (all P < 0.001). In sepsis, neither cortisol nor DHEA increased significantly after ACTH. Most severely ill patients had higher cortisol (P = 0.069) and lower DHEA (P = 0.076) and a significantly higher cortisol to DHEA ratio (P = 0.004). Similarly, the cortisol to DHEA ratio was significantly increased in nonsurvivors of septic shock (P = 0.026), whereas survivors did not differ from controls (P = 0.322).

CONCLUSIONS

The observed dissociation of DHEA and DHEAS in septic shock contradicts the previous concept of sepsis-associated DHEA deficiency. Increased DHEA levels may maintain the balance between glucocorticoid- and DHEA-mediated immune and vascular effects. However, most severe disease and mortality is associated with an increased cortisol to DHEA ratio, which may represent a novel prognostic marker in septic shock.

BACKGROUND

Neurocognitive functioning may be impaired in the luteal phase of the menstrual cycle due to associated changes in hypothalamic-pituitary adrenal (HPA) axis function. This study examines the relationship between changes in neurocognition and HPA axis function in different phases of the menstrual cycle.

METHODS

Fifteen female volunteers, free from psychiatric history and hormonal medication were tested twice, during mid-follicular and late-luteal phases in a randomized, crossover design. Mood, neurocognitive function, and basal cortisol and dehydroepiandrosterone (DHEA) were profiled.

RESULTS

Relative to the follicular phase, verbal fluency was impaired in the luteal phase and reaction times speeded on a continuous performance task, without affecting overall accuracy. 'Hedonic' scores on the UWIST-MACL scale were decreased in the luteal phase. There was also evidence of changes in the function of the HPA axis, with 24 h urinary cortisol concentrations and salivary DHEA levels being significantly lower during the luteal phase.

CONCLUSIONS

These data suggest that luteal phase HPA axis function is lower than in the follicular phase in premenopausal healthy women. This putative biological difference may be important for our understanding of the aetiopathogenesis of menstrually related mood change and neurocognitive disturbance.

OBJECTIVE

To assess hypothalamic-pituitary-adrenocortical axis function in patients with rheumatoid arthritis (RA) not previously treated with glucocorticoids in relation to their inflammatory condition and in comparison to healthy controls.

METHODS

We evaluated, in 10 premenopausal patients with RA and 7 age matched controls, plasma dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and cortisol concentrations, together with inflammatory cytokine levels [interleukin 6 (IL-6) and IL-12], both in basal conditions and after stimulation with ovine corticotropin releasing hormone (oCRH) and with low dose intravenous (5 microg) adrenocorticotropic hormone (ACTH).

RESULTS

DHEA and DHEAS basal concentrations were found to be significantly lower (p<0.05) in premenopausal patients with RA than in controls. As expected, significantly higher basal levels of IL-6 and IL-12 (p<0.05) were found in patients with RA. After the low dose ACTH testing, the DHEA area under the curve value was found to be significantly lower (p<0.01) in patients than controls. Similar results, but without statistical significance, were observed after oCRH stimulation. DHEA levels at basal time showed a significant negative correlation with the erythrocyte sedimentation rate and platelet count, as well as with the Steinbrocker class of the disease (p<0.05). Normal plasma cortisol levels during oCRH and ACTH testing were found in patients with RA in spite of their inflammatory condition. After ACTH testing, IL-6 levels decreased significantly (p<0.05), whereas IL-12 levels were unchanged. No significant changes in IL-6 and IL-12 levels were found after oCRH testing.

CONCLUSIONS

The abnormal androgen concentrations observed during testing in patients with RA might support the implication of adrenal androgens in the immune/inflammatory cytokine mediated mechanisms involved in the pathophysiology and clinical aspects of RA.

BACKGROUND

Dehydroepiandrosterone sulfate (DHEAS) is an endogenously produced sex steroid that has been hypothesized to have anti-aging effects. Low DHEAS levels are associated with mortality in older men, but the relationship between DHEAS levels and mortality in women is not clearly defined.

METHODS

The relationship between serum DHEAS level and 5-year mortality was analyzed in a cohort of 539 disabled women aged 65-100 years enrolled in the Women's Health and Aging Study I (WHAS I). Using Cox proportional hazard models, we calculated multivariate-adjusted mortality risks by DHEAS quartiles and by DHEAS continuously, allowing for a nonlinear relationship. We also examined cause-specific mortality.

RESULTS

We found a U-shaped relationship between DHEAS level and mortality. After adjusting for multiple covariates, women in the top and bottom DHEAS quartiles had a more than 2-fold higher 5-year mortality than did those in the middle quartiles (hazard ratio, 2.15; 95% confidence interval [CI], 1.17-3.98 for the top quartile and 2.05; 95% CI, 1.27-3.32 for the bottom quartile, each compared to the third quartile). Women with higher DHEAS levels tended to have greater cancer mortality, whereas those with lower DHEAS tended to have greater cardiovascular mortality.

CONCLUSIONS

Disabled older women with either low or high levels of DHEAS are at greater risk for death than are those with intermediate levels. More research is needed to determine if targeted dehydroepiandrosterone supplementation would provide clinical benefit to disabled older women.

The immune system interacts with the hypothalamo-pituitary-adrenal axis via so-called glucocorticoid increasing factors, which are produced by the immune system during immune reactions, causing an elevation of systemic glucocorticoid levels that contribute to preservation of the immune reactions specificities. Previous results from our laboratory had already shown an altered immuno-neuroendocrine dialogue via the hypothalamo-pituitary-adrenal axis in autoimmune disease-prone chicken and mouse strains. In the present study, we further investigated the altered glucocorticoid response via the hypothalamo-pituitary-adrenal axis in murine lupus. We established the circadian rhythms of corticosterone, dehydroepiandrosterone-sulfate, adrenocorticotropic hormone and melatonin, as well as the time response curves after injection of interleukin-1 of the first three parameters in normal SWISS and lupus-prone MRL/MP-fas(Ipr) mice. The results show that lupus-prone MRL/ MP-fas(Ipr) mice do not react appropriately to changes of the light/dark cycle, circadian melatonin rhythms seem to uncouple from the light/dark cycle, and plasma corticosterone levels are elevated during the resting phase. Diurnal changes of dehydroepiandrosterone-sulfate and adrenocorticotropic hormone were normal compared to healthy controls. These data indicate that MRL/ MP-fas(Ipr) mice not only show an altered glucocorticoid response mediated via the hypothalamo pituitary adrenal axis to IL-1, but are also affected by disturbances of corticosterone and melatonin circadian rhythms. Our findings may have implications for intrathymic T cell development and the emergence of autoimmune disease.

To evaluate serum adrenal steroid concentrations in preterm infants, 17-hydroxyprogesterone (17-OHP), 17-hydroxypregnenolone, 11-deoxycortisol, cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione, 18-hydroxycorticosterone, and aldosterone values were determined in 9 sick and 13 healthy premature infants. Serum steroid concentrations were compared to previously reported data from healthy full-term infants. 17-OHP, 11-deoxycortisol, and aldosterone values were higher in sick preterm infants than in healthy preterm infants. Compared to healthy full-term infants, the premature infants-had significantly higher 17-hydroxypregnenolone, 17-OHP, and DHEA sulfate concentrations. Cortisol values were not different between the sick and healthy preterm infants and were similar to full-term values. Aldosterone values were also similar between the premature and the full-term infants. The findings of elevated steroid precursors in preterm infants and low cortisol levels in stressed sick preterm infants may indicate a relative immaturity of adrenal enzyme activity and inadequate adrenal reserve for stress.

The normal response to a single 0.25-mg dose of ACTH-(1-24) is not well established in infancy or childhood. We report the adrenal steroidogenic responses of 17-hydroxypregnenolone (17OH Preg), 17-hydroxyprogesterone (17OH Prog), 11-deoxycortisol, cortisol, deoxycorticosterone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione (A'dione), and testosterone in 102 healthy children who were divided into 5 groups: group 1 (less than 1 yr old; n = 22), group 2 (1-5 yr old; n = 22), group 3 (6-12 yr old; n = 15), group 4 (early-midpuberty; n = 21), and group 5 (late puberty; n = 22). Baseline and stimulated levels of 17OH Preg were significantly higher in group 1 infants than in group 2 children (P less than 0.01). Baseline levels of 17OH Prog increased in late puberty (P less than 0.01). Baseline and stimulated levels of DHEA rose in late puberty (group 5 vs. group 3, P less than 0.01). DHEA levels in late pubertal females were higher than those in their male counterparts (P less than 0.01). DHEA sulfate levels did not change after ACTH administration in any age group. Baseline and stimulated levels of A'dione rose significantly before the onset of puberty in female children (group 2 vs. group 3, P less than 0.01). The calculated ratio of 17OH Preg/17OH Prog in group 1 was significantly higher than that in other groups of children (P less than 0.01). The calculated, baseline DHEA/A'dione ratio was higher in group 1 than in older children (P less than 0.01). Stimulated ratios were higher in late pubertal females than in males (P less than 0.01). In both sexes baseline and stimulated ratios of 17OH Prog/deoxycorticosterone increased in puberty, such that late pubertal children had higher levels than prepubertal children (P less than 0.01). These data confirm the need for interpretation ACTH stimulation test data to be based upon age- and sex-specific norms.

This article is an invited report of a symposium sponsored by the Division for Drug Metabolism of the American Society for Pharmacology and Experimental Therapeutics held at Experimental Biology 2003 in San Diego, California, April 11-15, 2003. Several members of the cytochrome P450 (P450) superfamily are induced after exposure to a variety of chemical signals, and we have gained considerable mechanistic insight into these processes over the past four decades. In addition, the expression of many P450s is suppressed in response to various endogenous and exogenous chemicals; however, relatively little is known about the molecular mechanisms involved. The goal of this symposium was to critically examine our current understanding of molecular mechanisms involved in transcriptional suppression of CYP genes by endogenous and exogenous chemicals. Specific examples were drawn from the following chemical categories: polycyclic and halogenated aromatic hydrocarbon environmental toxicants, inflammatory mediators, the endogenous sterol dehydroepiandrosterone and peroxisome proliferators, and bile acids. Multiple molecular mechanisms are involved in transcriptional suppression, and these processes often involve rather complex cascades of transcription factors and other regulatory proteins. Mechanistic studies of CYP gene suppression can enhance our understanding of how organisms respond to xenobiotics as well as to perturbations in endogenous chemicals involved in maintaining homeostasis.

Androgens have been implicated in increasing ovarian cancer risk; however, results from prospective studies have been inconclusive. The authors examined whether plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate were associated with risk of epithelial ovarian cancer in a nested-case control study, using data from three prospective cohort studies: the Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), and the Women's Health Study (WHS). The present analysis comprised 224 cases (161 from the NHS/NHSII and 63 from the WHS) and 603 controls (matched at a ratio of 1:3 for the NHS/NHSII and 1:2 for the WHS), with follow-up of up to 14 years. Women ranged in age from 34 years to 72 years (mean age = 56 years). The authors did not observe any associations between plasma androgen levels and risk of ovarian cancer. For example, comparing the top quartile with the bottom quartile, the relative risk was 0.74 (95% confidence interval: 0.44, 1.25; p-trend = 0.34) for testosterone and 0.76 (95% confidence interval: 0.45, 1.30; p-trend = 0.65) for androstenedione. There was a suggestion that dehydroepiandrosterone and dehydroepiandrosterone sulfate were inversely associated with ovarian cancer risk among postmenopausal women (for top quartile vs. bottom, relative risks were 0.65 and 0.70, respectively). Overall, these results do not support a positive association between circulating androgen levels and ovarian cancer risk.

OBJECTIVE

To determine whether longterm therapy (up to 1 year) with the weakly androgenic adrenal steroid dehydroepiandrosterone (DHEA) is feasible and beneficial in patients with mild to moderate systemic lupus erythematosus (SLE).

METHODS

In a prospective, open label, uncontrolled longitudinal study 50 female patients (37 premenopausal, 13 postmenopausal) with mild to moderate SLE were treated with oral DHEA 50-200 mg/day.

RESULTS

DHEA therapy was associated with increases in the serum levels of DHEA, DHEA sulfate, and testosterone and, for those patients who continued DHEA, with decreasing disease activity measured by SLE Disease Activity Index score (p < 0.01), patient global assessment (p < 0.01), and physician global assessment (p < 0.05), compared to baseline. Concurrent prednisone doses were reduced (p < 0.05). These improvements were sustained over the entire treatment period. Thirty-four patients (68%) completed 6 months of treatment and 21 patients (42%) completed 12 months. Mild acneiform dermatitis was the most common adverse event (54%). Pre and postmenopausal women experienced similar efficacy and adverse effects from DHEA.

CONCLUSIONS

DHEA was well tolerated and appeared clinically beneficial, with the benefits sustained for at least one year in those patients who maintained therapy.

Steroids synthesized de novo from cholesterol in the brain are generally called neurosteroids. We have recently demonstrated, using biochemical and molecular biological methods, that certain structures in the quail brain possess cytochrome P450 side-chain cleavage enzyme (P450scc) and 3beta-hydroxysteroid dehydrogenase/Delta(5)-Delta(4)-isomerase (3beta-HSD) and produce pregnenolone, pregnenolone sulfate and progesterone. To clarify the biosynthetic pathway of neurosteroids in the avian brain, therefore, we examined the expression of messenger RNA (mRNA) encoding for the enzyme cytochrome P450 17alpha-hydroxylase/c17,20-lyase (P450(17alpha,lyase)), which converts pregnenolone to dehydroepiandrosterone via 17alpha-hydroxypregnenolone or progesterone to androstenedione via 17alpha-hydroxyprogesterone. RT-PCR analysis followed by Southern hybridization indicated the expression of P450(17alpha,lyase) mRNA in the brain of sexually mature birds without a clear-cut sex difference. Employing biochemical techniques combined with HPLC analysis, the conversion of progesterone to 17alpha-hydroxyprogesterone was also found in brain slices of the mature male. P450(17alpha,lyase) mRNA was detected in various brain regions, but there was a clear regional difference in the expression. The expressions of P450(17alpha,lyase) mRNA in the diencephalon and mesencephalon were significantly higher than those in the cerebrum and cerebellum, unlike 3beta-HSD mRNA, which showed no regional difference in the expression. In situ hybridization revealed the cellular localization of P450(17alpha,lyase) mRNA. The cells expressing P450(17alpha,lyase) mRNA were detected several diencephalic and mesencephalic regions, such as the preoptic area, the anterior hypothalamus, the dorsolateral thalamus, the optic tectum and the ventral midbrain. The expression was also localized in the septum, the hyperstriatum accessorium, and the ventral portions of the archistriatum in the telencephalon. Cerebellar Purkinje cells also expressed P450(17alpha,lyase) mRNA. These results suggest that the avian brain possesses P450(17alpha,lyase) as well as P450scc and 3beta-HSD in both sexes. The expression of P450(17alpha,lyase) in the avian brain may be region-dependent.

Although much research focuses on hormones during gestation, little is known about the actual hormone concentrations within the fetal surroundings. The aim of this study was to combine all available oestrogen, androgen, sex hormone-binding globulin (SHBG), anti-Müllerian hormone (AMH), inhibin, gonadotrophin and dehydroepiandrosterone sulphate (DHEAS) concentrations during gestation and post partum into graphical representations reporting weighted mean hormone values. A systematic search was performed in Pubmed and Embase from inception to March 2012. Studies were evaluated by two reviewers; manuscripts were included if the actual hormone concentrations were reported together with the gestational age at time of sampling. A total of 97 articles were found eligible for this review. Maternal serum oestrogens, inhibin A, SHBG, androstenedione and testosterone rise during gestation, which is followed by a rapid decline in the post-partum period. For AMH and DHEAS, an inverse relationship is found, while gonadotrophin concentrations are negligible during gestation. For girls cord blood oestriol and post-partum FSH concentrations are higher, while for boys cord blood FSH and neonatal testosterone, inhibin B, LH and AMH concentrations are higher. In conclusion, longitudinally measured endocrine data during gestation and in the peri- and post-natal period are lacking, especially for twin pregnancies.

We have investigated the ability of dehydroepiandrosterone (DHEA) to alter the production of interleukin-2 (IL-2) and to bind to a specific binding complex in antiCD3 epsilon activated T cells. Binding activity correlated with the presence of a specific DHEA binding complex in the cytosol and nuclei of DHEA-responsive T-cell hybridomas, as well as in CD4+ and CD8+ cells isolated from peripheral lymph nodes of normal mice. Scatchard analysis determined that intact lymphocytes and cytosolic fractions contained high affinity binding for [3H]DHEA (approx. 2.6 nM) with 1000-7000 binding sites existing per cell. Five of the T-cell hybridomas tested both responded to DHEA treatment with increased production of IL-2 and also contained specific high affinity [3H]DHEA binding. Four additional T-cell hybridomas were found to contain no specific [3H]DHEA binding and were also unresponsive to DHEA influences on IL-2 production. Sucrose density gradients demonstrated a 3-4s [3H]DHEA binding complex in high salt and a 7-8s binding complex in low salt. Specific binding was inhibited by preincubation of the cytosol fractions with either trypsin or chymotrypsin, or by heating to 60 degrees C for 1 h (less than 15% of control). [3H]DHEA binding was unaffected by preincubation of the cytosol fractions with ribonuclease, deoxyribonuclease, or phospholipase A. The DHEA-protein complexes bound to DNA-cellulose with the amount of binding being slightly increased by preincubation at 25 degrees C as compared to 4 degrees C. As expected, [3H]DHEA binding was inhibited by the addition of unlabeled DHEA, but was also modestly inhibited by dihydrotestosterone and cortisol. Binding of DHEA was unaffected by progesterone, dexamethasone, estradiol, androsterone, DHEAS, and beta-etiocholanolone at all concentrations tested. DHEA was incapable of inhibiting the binding of [3H]DHT to the androgen receptor or [3H]dexamethasone to the glucocorticoid receptor. Collectively, these findings suggest that murine T cells contain a specific DHEA receptor. We believe that DHEA is a steroid hormone that is directly involved in the regulation of IL-2 production by both normal and some T-cell hybridomas.

A specific and sensitive radioimmunoassay for measuring unconjugated plasma dehydroepiandrosterone (DHA) has been developed and the results expressed in ng/100 ml. Mean values +/-1 SD were in mixed cord blood 593.3 +/- 186.5 in 21 females and 712.7 +/- 190.9 in 18 males. During the first day of life the peripheral plasma concentration of DHA was 917.6 +/- 317.8 in 22 female and 922.65 +/- 290 in 17 male neonates. During the first month of age, DHA levels decreased significantly and then more progressively throughout the first year of life. Mean levels observed between the first and 6th month of life were 147.1 +/- 53.6 in 15 girls and 151.6 +/- 62.7 in 28 boys. Between 6 and 12 months of age mean DHA levels were 90.9 +/- 43.3 and 68.14 +/- 30.9 in 11 girls and 24 boys, respectively. In 250 normal children, plasma DHA levels were very low between 1 to 6 years of age, but rising progressively thereafter without any sex difference long before any clinical sign of puberty. A circadian rhythm parallel to that of cortisol was observed as early as 5 years of age. Acute and chronic stimulation of ACTH confirmed the adrenal origin of DHA, while the results of hCG stimulation test and fluoxymesterone suppression test assessed the testicular participation to the DHA production.

To determine the effect of ketoconazole, a nonestrogenic antifungal agent, in patients with metastatic prostatic cancer 13 patients with symptomatic stage D2 prostatic cancer were administered 400 mg. ketoconazole orally every 8 hours. By 24 hours of treatment serum testosterone had decreased to the castrate level and the adrenal androgens, androstenedione and dehydroepiandrosterone, also had decreased significantly. By 1 week of treatment clinical response was evident in all patients. Pain was improved and serum prostatic acid phosphatase levels had decreased significantly, and by 1 month prostatic acid phosphatase had reached the normal range. The patients have been followed for 3 to 10 months without relapse. Side effects were few. Because of the ease of administration, rapidity of action, and decrease of adrenal and testicular androgen levels, as well as the relative lack of side effects, ketoconazole may prove to be an important new drug in the treatment of prostatic cancer.

Stress has well-known effects on adrenal glucocorticoid secretion, and chronic elevation of glucocorticoids can have detrimental effects on the brain. Dehydroepiandrosterone (DHEA), an androgen precursor synthesized in the adrenal glands or the brain itself, has anti-glucocorticoid properties, but little is known about the role of DHEA in the stress response, particularly in the brain. Here, we measured the effects of acute restraint on circulating corticosterone (CORT) and DHEA levels in wild song sparrows. Blood was collected from either the brachial or jugular vein. In songbirds, jugular plasma is enriched with neurally synthesized steroids, and therefore, jugular plasma is an indirect index of the neural steroidal milieu. Subjects were sampled during four times of year: breeding, molt, early nonbreeding, and mid-nonbreeding. Baseline CORT and DHEA levels showed similar seasonal changes; both steroids were elevated during the breeding season. Baseline CORT and DHEA levels were similar in jugular and brachial plasma. Acute stress had robust effects on CORT and DHEA that were season specific and vein specific. For CORT, during the molt, stress increased jugular CORT more than brachial CORT. For DHEA, during the breeding season, stress decreased jugular DHEA but not brachial DHEA. During the molt, stress increased jugular DHEA but not brachial DHEA. Acute stress did not affect brachial DHEA. These data suggest that acute stress specifically affects the balance between DHEA synthesis and metabolism in the brain. Furthermore, these results suggest that CORT and DHEA are locally synthesized in the brain during molt, when systemic levels of CORT and DHEA are low.

Dehydroepiandrosterone sulfate levels have been inversely related with cardiovascular mortality in men, but findings have been inconsistent, and there are few data in women. We examined the relationship between baseline circulating dehydroepiandrosterone sulfate levels and subsequent all-cause and cardiovascular mortality in 963 men and 1171 women, 65-76 yr old, surveyed in 1991-1995, and followed up until August 2000 (when 296 deaths had occurred). All-cause and cardiovascular disease mortality rates were highest in the lowest dehydroepiandrosterone sulfate quartile in men; and thereafter, rates did not differ significantly in the upper three quartiles. This pattern remained after excluding those with previous history of cardiovascular disease and, in multivariate analyses, was independent of age, cigarette smoking habit, systolic blood pressure, body mass index, blood cholesterol, and steroid use. There was no significant association of dehydroepiandrosterone sulfate and mortality in women. The multivariate adjusted relative risks for all-cause mortality by sex-specific increasing quartile of dehydroepiandrosterone sulfate were 1.00, 0.66 (95% confidence interval, 0.44-1.01), 0.70 (0.46-1.07), 0.73 (0.48-1.10), respectively, for men and 1.00, 0.71 (95% confidence interval, 0.41-1.24), 0.97 (0.58-1.62), and 1.14 (0.69-1.88), respectively, for women. In older men and women, there is no consistent relationship between dehydroepiandrosterone sulfate and all-cause or cardiovascular mortality. The highest mortality rates were observed in the lowest quartile in men, but the highest rates were in the highest quartile in women.

The rat brain accumulates pregnenolone (P) as the unconjugated steroid, the sulfate ester (S) and fatty acid esters (L). P + PS do not disappear from rat brain after combined adrenalectomy (adx) and castration (orx). PL does not serve a source of P after adx + orx. P is metabolized by several rat brain regions to progesterone and to PL. Brain microsomes contain the acyl-transferase which converts P to PL using endogenous substrates. Brain P and dehydroepiandrosterone (D) undergo a prominent circadian variation with their acrophases at the beginning of the dark span. The circadian variation of brain D persists after adx + orx. The monkey brain (Macaca fascicularis) also accumulates P and D. Adrenal suppression with dexamethasone for 4 days does not decrease the concentrations of brain P and 3rd ventricle CSFP and D. The concentrations of brain D are decreased to a much smaller extent than plasma D. D inhibits the aggressive behavior of castrated male mice exposed to lactating female intruders. This is not the case for DS or androst-5-ene-3 beta, 17 beta-diol. The D analog 3 beta-methyl-androst-5-en-17-one, which is not estrogenic and cannot be metabolized to testosterone or estradiol, is as active as D in inhibiting the aggressive behavior of castrated mice.

BACKGROUND

Hirsutism in women is usually caused by benign adrenal or ovarian disorders, but it can also be caused by adrenal carcinoma. The most effective way to identify such carcinomas is not known.

METHODS

We measured serum and urinary steroids before and after the administration of 3 mg of dexamethasone per day for five days in 14 hirsute women with histologically proved adrenal tumors (12 adrenal carcinomas and 2 adrenal adenomas) and in 73 women with hirsutism of non-neoplastic origin.

RESULTS

All the women with adrenal tumors had elevated basal serum concentrations of testosterone or dehydroepiandrosterone sulfate, as compared with 36 of the 73 women with non-neoplastic hirsutism (sensitivity, 100 percent; 95 percent confidence interval, 77 to 100; specificity, 50 percent; 95 percent confidence interval, 38 to 62). After the administration of dexamethasone, serum dehydroepiandrosterone sulfate concentrations and urinary 17-ketosteroid excretion decreased to values similar to those in normal women in all the women with non-neoplastic hirsutism, but in none of the 12 with adrenal tumors who were tested. All the women who did not have adrenal tumors had serum cortisol concentrations below 3.3 micrograms per deciliter (90 nmol per liter) after dexamethasone administration, whereas in all 12 patients tested who had tumors the values were higher. The suppression of serum dehydroepiandrosterone sulfate and cortisol and urinary 17-ketosteroid excretion excluded the likelihood of adrenal tumors with a sensitivity of 100 percent (95 percent confidence interval, 74 to 100) and a specificity of 100 percent (95 percent confidence interval, 89 to 100).

CONCLUSIONS

Among women with hirsutism, an adrenal tumor is unlikely if the patient has normal basal serum concentrations of testosterone and dehydroepiandrosterone sulfate. In women in whom these concentrations are elevated, a tumor is unlikely if the serum concentration of dehydroepiandrosterone sulfate and urinary 17-ketosteroid excretion are in the normal basal range and the serum cortisol concentration is less than 3.3 micrograms per deciliter after the administration of dexamethasone.

BACKGROUND

Retrospective research suggests smokers with posttraumatic stress disorder (PTSD) lapse more quickly after their quit date. Ecological momentary assessment (EMA) research is needed to confirm the presence of early smoking lapse in PTSD and form conceptualizations that inform intervention.

METHODS

Smokers with (n = 55) and without (n = 52) PTSD completed alarm-prompted EMA of situational and psychiatric variables the week before and after a quit date, and self-initiated EMA following smoking lapses. Blood samples at baseline and on the quit date allowed assessment of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA(S)).

RESULTS

PTSD was related to shorter time to lapse (hazard ratio [HR] = 1.677, 95% CI: 1.106-2.544). Increased smoking abstinence self-efficacy was related to longer time to lapse (HR = 0.608, 95% CI: 0.430-0.860). Analyses of participants' real-time reports revealed that smokers with PTSD were more likely to attribute first-time lapses to negative affect ( = 5.412, p = .020), and trauma reminders (Fisher's exact p = .003**). Finally, the quit date decrease in DHEA(S) was related to shorter time to lapse (HR = 1.009, 95% CI: 1.000-1.018, p < .05).

CONCLUSIONS

Results provide evidence of shorter time to first smoking lapse in PTSD, and add to evidence that early lapse occasions are more strongly related to trauma reminders, negative affect, and cravings in smokers with PTSD.

It is well established that sulfated steroids regulate synaptic transmission by altering the function of postsynaptic neurotransmitter receptors. In recent years, evidence from several laboratories indicates that these agents also regulate glutamatergic synaptic transmission at the presynaptic level in an age-dependent manner. In developing neurons, pregnenolone sulfate (PREGS) increases the probability of glutamate release, as evidenced by an increase in the frequency of AMPA receptor-mediated miniature excitatory postsynaptic currents and a decrease in paired-pulse facilitation. In hippocampal slices from postnatal day 3-5 rats, this effect is mediated by an increase in Ca(2+) levels in the axonal terminal that depends on presynaptic NMDA receptors. This is followed by delayed potentiation of postsynaptic AMPA receptor currents. Importantly, depolarization of postsynaptic neurons, inhibition of hydroxysteroid sulfatase activity and acute exposure to ethanol mimics the effect of exogenous PREGS application. This developmental form of synaptic plasticity cannot be observed in slices from rats older than postnatal day 6, when presynaptic NMDA receptors are no longer expressed in CA1 hippocampal region. Both in the CA1 hippocampal region and the dentate gyrus of more mature rats, PREGS, dehydroepiandrosterone sulfate and hydroxysteroid sulfatase inhibitors increase paired-pulse facilitation, without affecting basal glutamate release probability. This effect depends on activation of sigma(1)-like receptors and G(i/o) and involves a target in the release machinery that is downstream of residual Ca(2+). These presynaptic actions of sulfated steroids could play important roles in physiological processes ranging from synapse maturation to learning and memory, as well as pathophysiological conditions such as fetal alcohol spectrum disorder.

Several N-hydroxy metabolites of carcinogenic arylamines and heterocyclic amines were examined as substrates for bioactivation by human liver sulfotransferases (STs). Among the N-hydroxy derivatives studied, N-hydroxy-2-acetylaminofluorene, N-hydroxy-2-aminofluorene, N-hydroxy-4,4'-methylene-bis(2-chloroaniline), N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and N-hydroxy-2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole were each metabolically activated by 3'-phosphoadenosine-5'-phosphosulfate-dependent human liver STs. No ST-mediated DNA binding of N-hydroxy-2-amino-3-methylimidazo[4,5-f]quinoline or N-hydroxy-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline was detected under our assay conditions. In the 12 human hepatic cytosols studied, the extent of 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding of the N-hydroxy derivatives were all significantly correlated with levels of thermostable phenol ST (TS-PST) activity but not with thermolabile phenol ST or dehydroepiandrosterone ST activities. The propensity of these N-hydroxy arylamines and N-hydroxy heterocyclic amines to serve as selective substrates for human TS-PST was further confirmed by inhibition with 2,6-dichloro-4-nitrophenol and by thermostability studies. N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and N-hydroxy-4,4'-methylene-bis(2-chloroaniline) were also used as substrates to study ST-dependent metabolic activation in other human tissue preparations. 3'-phosphoadenosine-5'-phosphosulfate-dependent DNA binding activity was detected in human liver and colon cytosols but not in pancreas, larynx, or urinary bladder epithelial cytosols. Since the TS-PST appears to be expressed polymorphically in human populations, the finding that human TS-PST is capable of metabolically activating N-hydroxy metabolites of several carcinogenic arylamines and heterocyclic amines suggests that TS-PST may have an important role in determining interindividual susceptibility to these environmental and dietary carcinogens.

Many vertebrate species exhibit alternative phenotypes (or morphs), in which one sex displays phenotypic variation equal to or greater than the variation between the sexes. Males in such species typically display differences in reproductive strategies and morphology. Steroid hormones such as testosterone are known modulators of reproductive behavior and morphology and therefore are obvious candidates for the mediation of phenotypic differences between morphs. We conducted a year-round study in the white-throated sparrow (Zonotrichia albicollis) that exhibits alternative phenotypes in plumage coloration and behavior in both sexes: during the breeding season, white-striped males and females are more aggressive and have higher song rates than tan-striped individuals. At the beginning of the breeding season, free-living white-striped males had higher plasma testosterone concentrations than tan-striped males. However, this finding might have been due to different social experiences because captive male morphs sampled at similar times of year did not differ in testosterone concentrations. Captive white-striped males had larger testis and cloacal protuberance sizes than tan-striped males, which might be related to the divergent mating strategies of the morphs. Male morphs showed similar increases in luteinizing hormone following injections of gonadotropin-releasing hormone, but white-striped males showed larger increases in testosterone, indicating differences between morphs in gonadal testosterone production. Females had low concentrations of testosterone, and morphs did not differ. Plasma dehydroepiandrosterone (DHEA) concentrations were elevated in both sexes and morphs during the breeding and non-breeding seasons. These data do not support the hypothesis that testosterone activates behavioral differences between alternative phenotypes in the white-throated sparrow. Alternative testable hypotheses include hormonal effects during early development and direct genetic effects.

Our previous kinetic analyses have shown that rat organic anion transporter 1 (rOat1; Slc22a6) and rOat3 (Slc22a8) are responsible for the renal uptake of p-aminohippurate and pravastatin, respectively. In this study, their contribution to the renal uptake of organic anions and nucleoside derivatives was examined by investigating the uptake by rOat1- and rOat3-expressing cells and kidney slices. Transfection of rOat1 resulted in an increase of the uptake of temocaprilat (Km = 0.56 microM), 2,4-dichlorophenoxyacetate (2,4-D; Km = 10 microM), and 3'-azido-3'-deoxythymidine (AZT; Km = 43 microM). rOat3-expressing cells showed significant uptake of temocaprilat (Km = 1.4 microM), estrone sulfate (Km = 5.3 microM), dehydroepiandrosterone sulfate (DHEAS; Km = 12 microM), and benzylpenicillin (PCG; Km = 85 microM). All the test compounds were accumulated in kidney slices in a carrier-mediated manner, although the saturable components of AZT and acyclovir were small. The Km of 2,4-D uptake by kidney slices was comparable with that of rOat1, and the corresponding values of DHEAS and PCG were similar to those of rOat3. The uptake of estrone sulfate and temocaprilat by kidney slices consisted of two saturable components, with the Km values of their high-affinity components being similar to those for rOat3 (estrone sulfate), and rOat1 and rOat3 (temocaprilat), respectively. These results suggest that the renal uptake of 2,4-D is mainly accounted for by rOat1 and the uptake of PCG and DHEAS by rOat3, and rOat3 is partly involved in the renal uptake of temocaprilat and estrone sulfate.