This is the first report of a male with 17alpha-hydroxylase deficiency resulting in male pseudohermaphroditism, ambiguous external genitalia, absence of male secondary sexual characteristics, and gynecomastia at puberty. Diagnosis was based on extensive studies of steroid metabolism including the following: low urinary excretion of 17-ketosteroids and 17-hydroxycorticoids which did not increase after ACTH; no response of very low plasma testosterone and dehydroepiandrosterone to adrenocorticotropin (ACTH) or chorionic gonadotropin; and low urinary aldosterone and plasma renin which increased after dexamethasone. Secretion rates of 17-hydroxylated steroids, cortisol (F) and 11-desoxycortisol (S), were very low while desoxycorticosterone (DOC) and corticosterone (B) secretion rates were increased sevenfold. Results expressed as milligrams per meter squared per day were as follows: F, 1.3; S, 0.023; DOC, 0.35; and B, 16 (mean normal values were F, 7.5; S, 0.26; DOC, 0.055, and B, 2.2). Plasma gonadotropins were markedly increased (FSH, 106; LH, 364 mIU/ml). Testicular biopsies revealed interstitial-cell hyperplasia and early spermatogenesis. Karyotype was 46/XY. Pedigree showed no other affected member. At laparotomy ovaries, uterus, and fallopian tubes were absent, vas deferens was incomplete, and prostate was present. External genitalia consisted of small phallus, bifid scrotum, third-degree hypospadias, and small vagina. At puberty there was no growth of body hair or phallic enlargement. Biopsy of marked gynecomastia showed both ducts and acini. Testosterone administration produced virilization. Sexual ambiguity demonstrates strong dependence of external genitalia on androgens for male differentiation. Suppression of Müllerian structures occurred despite female levels of testosterone indicating this step in male differentiation is not testosterone dependent. Pubertal breast development in this male supports the concept of femaleness during ontogeny unless counteracted by male factors. Diagnosis of other adrenocortical enzymatic deficiencies is excluded by the steroidal studies. The clinical response to testosterone excludes testicular feminization. Deficiency of 17-hydroxylation must be added to the cause of male pseudohermaphroditism.

BACKGROUND

The prevalence of erectile dysfunction (ED) and associated risk factors has been described in many countries, but there are still only a few studies from Asia.

OBJECTIVE

We investigated the prevalences of ED and premature ejaculation (PE) in Korean men and the impact of general health, lifestyle, and psychosocial factors on these conditions.

METHODS

To assess ED and PE, 1,570 Korean men aged 40-79 years were interviewed with a self-administered questionnaire on sexual function and the International Index of Erectile Function (IIEF)-5. In addition, blood chemistry was analyzed for each subject.

METHODS

The prevalences of ED and PE were obtained from self-reported ED, IIEF-5 scoring, EF (erectile function) domain scoring, and self-reported intravaginal ejaculatory latency time (IELT). The data were analyzed for the presence of risk factors and the relationship of general health, lifestyle, and psychosocial factors with ED.

RESULTS

The prevalences of ED among Korean men were 13.4% (self-reported ED) and 32.4% (IIEF-5 score <or= 17), and PE prevalences were 11% (IELT <or= 2-min) and 33.1% (IELT <or= 5-min). ED was more prevalent in the subject groups with older age, lower income, or lower education, and in subjects without a spouse. ED prevalence was positively associated with risk factors such as diabetes, hypertension, heart disease, psychological stress, and obesity. Levels of serum hemoglobin (Hb) A1c, triglycerides, testosterone, or <em>dehydroepiandrosterone</em> sulfate (DHEA-S) were significantly different between the ED and non-ED groups.

CONCLUSIONS

The prevalences of ED and PE in Korean men were 13.4% (self-reported ED) and 11% (IELT <or= 2-min), respectively. Risk factors and other socioeconomic and mental health factors were associated with ED prevalence. Biochemical factors such as HbA1c, triglycerides, testosterone, and DHEA-S were significantly related to ED prevalence.

The effects of androgens and the androgen antagonist, flutamide, on the density of dendritic spine synapses in the CA1 subfield of the hippocampus were studied in gonadectomized male and female rats. Treatment of orchidectomized male rats with dehydroepiandrosterone (DHEA; 2 d, 1 mg/d sc) increased the density of CA1 spine synapses observed 2 d later, by 106%, without significantly affecting ventral prostate weight. The hippocampal response to DHEA was unaffected by blockade of intracerebral estrogen biosynthesis using the aromatase inhibitor, letrozole. By contrast, flutamide alone (2 d; 5 mg/d, sc) increased CA1 spine synapse density by 66%, whereas in combination the effects of flutamide and DHEA were additive rather than inhibitory. Additive effects on CA1 synapse density were also observed in males using combinations of flutamide with 5alpha-dihydrotestosterone (2 d, 500 microg/d, sc). At the same doses, flutamide had no effect on prostate weight and completely blocked the effects on the prostate of treatment with 5alpha-dihydrotestosterone. Treatment of ovariectomized females with DHEA increased CA1 spine synapse density to a level similar to that observed in the male. As in males, flutamide in females increased CA1 spine synapse formation and further augmented the response to DHEA. These results demonstrate that flutamide and DHEA have positive effects on hippocampal CA1 spine synapse density in both sexes. They also suggest that conventional measures of androgen agonist or antagonist activity, exemplified by ventral prostate growth, may not be indicative of effects on hippocampal CA1 synaptogenesis.

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels were determined in morning specimens from 659 fasting postmenopausal women who were not using estrogen therapy or antidiabetic medication. All women had concurrent oral glucose tolerance tests and measurements of body mass index (BMI) and waist-hip ratio (WHR). DHEA levels were weakly and inversely associated with BMI but not with WHR or glucose tolerance status. DHEAS levels were not associated with BMI but were positively associated with WHR, diabetes, and impaired glucose tolerance. In analyses adjusted for or stratified by WHR, the DHEAS association with abnormal carbohydrate tolerance was reduced but still independent of fat distribution. Because this was a cross-sectional study, it was not possible to determine whether DHEAS levels were raised by central obesity or vice versa. At a minimum, these data strongly suggest that the positive association of DHEAS with both central obesity and abnormal glucose tolerance does not support the thesis that DHEAS protect against diabetes or obesity in older women as had been suggested by animal studies.

It is currently believed that the postmenopausal ovary remains a gonadotropin-driven, androgen-producing gland. However, the adrenal contribution to circulating androgen levels may explain some conflicting results previously reported. In addition, the steroidogenic potential and gonadotropin responsiveness of the postmenopausal ovary have not been recently reassessed. Plasma T, bioavailable T, free T, androstenedione (Adione), and dehydroepiandrosterone sulfate levels were measured in postmenopausal or ovariectomized women with complete adrenal insufficiency, compared with women with intact adrenals. A stimulation human chorionic gonadotropin test (on d 0, 3, and 6) was performed in postmenopausal women with adrenal insufficiency. Dexamethasone was administered for 4 d in postmenopausal women with intact adrenals. Intraovarian T and androstenedione were also measured in homogenates of ovarian tissue from postmenopausal women. Immunocytochemistry was performed on postmenopausal ovaries and premenopausal controls to detect the presence of steroidogenic enzymes (P-450 aromatase, P-450 SCC, 3beta HSD, and P-450 C17) and gonadotropin receptors. Plasma androgen levels were below or close to the limit of the assay in all women with adrenal insufficiency. They were similar in postmenopausal and oophorectomized women with normal adrenals. No hormonal changes were observed after human chorionic gonadotropin injections in women with adrenal insufficiency. In contrast, a dramatic decrease of all steroids was observed after dexamethasone administration in postmenopausal women with intact adrenals. Intraovarian T and androstenedione levels were negligible in postmenopausal ovarian tissue. P-450 aromatase was absent from the 17 ovaries studied, and the enzymes for androgen biosynthesis were either absent (n = 13) or present in very low amounts (n = 4). In all the postmenopausal ovaries, FSH and LH receptors were completely absent. In the absence of adrenal steroids, postmenopausal women have no circulating androgens. This result is consistent with the immunocytochemical studies showing the almost constantly absent steroidogenic enzymes and LH receptors in the postmenopausal ovary. Thus, the climacteric ovary is not a critical source of androgens. The arrest of androgen secretion after menopause may impact significantly on women's health.

In earlier studies, the neural cell adhesion molecule, N-CAM, was found to inhibit the proliferation of rat astrocytes both in vitro and in vivo. To identify the gene targets involved, we used subtractive hybridization to examine changes in gene expression that occur after astrocytes are exposed to N-CAM in vitro. While the mRNA levels for N-CAM decreased after such treatment, the levels of mRNAs for glutamine synthetase and calreticulin increased. Since glutamine synthetase and calreticulin are known to be involved in glucocorticoid receptor pathways, we tested a number of steroids for their effects on astrocyte proliferation. Dexamethasone, corticosterone, and aldosterone were all found to inhibit rat cortical astrocyte proliferation in culture in a dose-dependent manner. RU-486, a potent glucocorticoid antagonist, reversed the inhibitory effects of dexamethasone. These observations prompted the hypothesis that the inhibition of proliferation by N-CAM might be mediated through the glucocorticoid receptor pathway. Consistent with this hypothesis, the inhibition of astrocyte proliferation by N-CAM was reversed in part by a number of glucocorticoid antagonists, including RU-486, dehydroepiandrosterone, and progesterone. In transfection experiments with cultured astrocytes, N-CAM treatment increased the expression of a luciferase reporter gene under the control of a minimal promoter linked to a glucocorticoid response element. The enhanced activity of this construct stimulated by N-CAM was abolished in the presence of RU-486. The combined data suggest that astrocyte proliferation is in part regulated by alterations in glucocorticoid receptor pathways.

Plasma dehydroepiandrosterone sulfate (DHEA-S) and testosterone levels both decline with age in healthy men. Features of the metabolic syndrome also show age-related deteriorations. We examined the relative contribution of age and declining androgen levels to features of the metabolic syndrome in men. In a sample of 130 nonsmoking men from the Quebec Family Study, we tested the hypothesis that age-related decreases in DHEA-S and testosterone levels would explain most of the variance in alterations of the metabolic profile associated with aging. As expected, we found that plasma DHEA-S and testosterone levels were negatively associated with age. Significant negative correlations were found between androgen levels and adiposity measures, body fat distribution, and metabolic risk variables. Statistical control for age eliminated correlations with DHEA-S, whereas age-adjusted associations between testosterone and most adiposity and metabolic variables remained significant. The percentage frequency of men characterized by 3 or more features of the metabolic syndrome increased with decreasing testosterone (8.9%-44.2%, chi2 = 15.89, P < .0005 ) and DHEA-S levels (8.9%-41.5%, chi2 = 13.02, P < .005). Logistic regression analyses showed that men in the upper tertile of testosterone levels had a lower risk of being characterized by 3 or more features of the metabolic syndrome (odds ratio = 0.24, P < .04) independent of age, whereas tertiles of DHEA-S levels were not related to the metabolic syndrome independent of age. In conclusion, results suggest that age per se is an important correlate of the associations between DHEA-S and metabolic variables, whereas the association of plasma testosterone levels to features of the metabolic syndrome appears to be independent of age.

OBJECTIVE

To explain why adrenal androgens rise with increasing adiposity during childhood, the role of body mass index (BMI), leptin and IGF-I was studied. We also tested whether these parameters contribute to inducing premature adrenarche (PA).

METHODS

In a cross-sectional study, 26 prepubertal obese children were compared with a group of 26 prepubertal children of normal weight, and 30 children under observation for PA were compared with 30 healthy children, matched for gender, bone age and BMI.

METHODS

Relative contributions of BMI standard deviation scores (SDS) and height SDS, as well as unbound leptin and IGF-I, to the levels of androgens, dehydroepiandrosterone sulfate (DHEAS) and Delta4-androstenedione (AD) were investigated by means of stepwise regression models. Logarithms of all hormones were standardised for age using residuals of a simple regression analysis, labelled by the suffix '(res)'.

RESULTS

In the obese children, height SDS, IGF-I(res,) DHEAS(res) (all P<0.05), leptin(res) (P<0.01), and AD(res) (P=0.07) were higher than in the controls, and covariates were correlated with each other (leptin(res) versus BMI SDS r=0.71, IGF-I(res) versus height SDS r=0.61). In the stepwise regression analysis of control and obese children, BMI SDS explained 26% and leptin(res) explained 12% of the variability of DHEAS(res), but this percentage remained at 26% when both variables were simultaneously introduced into the model. In contrast, IGF-I(res) and BMI SDS alone each accounted for 15% of the variability of AD, and their joint influence accumulated to explain 28% of the variability of AD(res). In PA, neither BMI SDS nor leptin(res) were correlated with the increased androgens.

CONCLUSIONS

Before the onset of gonadal activity in obese and control children, DHEAS levels, to some extent, are explained by BMI and leptin, while IGF-I in addition to BMI in part accounts for AD levels. Enhanced adrenal androgen secretion in children with PA, however, may be explained by parameters other than leptin or BMI.

BACKGROUND

Little information is available on androgens in obese children, and it is unknown whether these hormones change after weight loss.

OBJECTIVE

The objective of this study was to compare androgens between obese and normal-weight children and to study the effect of weight loss on androgens.

METHODS

The design was a cross-sectional comparison between obese and normal-weight children separated according to pubertal stage and longitudinal 1-yr follow-up study in obese children participating in a weight-loss intervention.

METHODS

The setting of this study was a primary care facility.

METHODS

A total of 273 obese and 79 lean children (aged 4-14 yr) were studied, including a subgroup of 155 obese children for the longitudinal study.

METHODS

The intervention program was an outpatient 1-yr intervention program based on exercise, behavior, and nutrition therapy (high-carbohydrate low-fat diet).

METHODS

The outcome measures included testosterone and dehydroepiandrosterone sulfate (DHEAS) at baseline and 1 yr later.

RESULTS

The obese prepubertal children and the obese pubertal girls showed significantly (P < 0.01) higher testosterone and DHEAS levels, whereas obese pubertal boys did not significantly differ in androgens from their lean counterparts. Significant correlations with body mass index were demonstrated in multivariate regression analyses for DHEAS in all children and for testosterone in prepubertal children and in pubertal girls. The obese prepubertal children and obese girls losing substantial weight showed a significant (P < 0.05) decrease in their testosterone concentrations.

CONCLUSIONS

Moderately increased testosterone and DHEAS levels were found in obese prepubertal children and in obese pubertal girls, whereas androgen concentrations did not differ between obese and normal-weight pubertal boys. Weight loss induced a decrease in testosterone in obese prepubertal children and pubertal girls pointing to a reversible increase of androgens.

OBJECTIVE

To update practice guidelines for the therapeutic use of androgens in women.

METHODS

A Task Force appointed by the Endocrine Society, American Congress of Obestricians and Gynecologists (ACOG), American Society for Reproductive Medicine (ASRM), European Society of Endocrinology (ESE), and International Menopause Society (IMS) consisting of six experts, a methodologist, and a medical writer.

METHODS

The Task Force commissioned two systematic reviews of published data and considered several other existing meta-analyses and trials. The GRADE methodology was used; the strength of a recommendation is indicated by a number "1" (strong recommendation, we recommend) or "2" (weak recommendation, we suggest).

METHODS

Multiple e-mail communications and conference calls determined consensus. Committees of the Endocrine Society, ASRM, ACOG, ESE, and IMS reviewed and commented on the drafts of the guidelines.

CONCLUSIONS

We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable. We recommend against the general use of T for the following indications: infertility; sexual dysfunction other than hypoactive sexual desire disorder; cognitive, cardiovascular, metabolic, or bone health; or general well-being. We recommend against the routine use of dehydroepiandrosterone due to limited data concerning its effectiveness and safety in normal women or those with adrenal insufficiency. We recommend against the routine prescription of T or dehydroepiandrosterone for the treatment of women with low androgen levels due to hypopituitarism, adrenal insufficiency, surgical menopause, pharmacological glucocorticoid administration, or other conditions associated with low androgen levels because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk. Evidence supports the short-term efficacy and safety of high physiological doses of T treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder. Importantly, endogenous T levels did not predict response to therapy. At present, physiological T preparations for use in women are not available in many countries including the United States, and long-term safety data are lacking. We recommend that any woman receiving T therapy be monitored for signs and symptoms of androgen excess. We outline areas for future research. Ongoing improvement in androgen assays will allow a redefinition of normal ranges across the lifespan; this may help to clarify the impact of varying concentrations of plasma androgens on the biology, physiology, and psychology in women and lead to indications for therapeutic interventions.

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) are the major circulating steroid hormones in humans, and their levels progressively decline with age. Epidemiological studies suggest that DHEA/DHEAS concentrations may be inversely related to cardiovascular risk, but disagreement exists on this issue. Preliminary studies show that DHEA regulates vascular function, but few data have been published on the mechanisms. We show that DHEA administration to human endothelial cells triggers nitric oxide synthesis, due to enhanced expression and stabilization of endothelial nitric oxide synthase (eNOS). Additionally, DHEA rapidly activates eNOS, through a nontranscriptional mechanism that depends on ERK1/2 MAPK, but not on phosphatidylinositol 3-kinase/Akt. DHEA is not converted to estrogens or androgens by endothelial cells, and its genomic and nongenomic effects are not blocked by antagonists of the estrogen, progesterone, glucocorticoid, or androgen receptors, suggesting that DHEA acts through a specific receptor. Oral DHEA administration to ovariectomized Wistar rats dose-dependently restores aortic eNOS levels and eNOS activity, confirming the effects of DHEA in vivo. Our present data suggest that DHEA may have direct genomic and nongenomic effects on the vascular wall that are not mediated by other steroid hormone receptors, leading to eNOS activation and induction.

OBJECTIVE

To investigate if testosterone levels are higher in patients with preeclampsia compared to normotensive pregnant patients.

METHODS

The levels of serum total and free testosterone, dehydroepiandrosterone sulfate, androstenedione and sex hormone binding globulin were estimated in 28 patients during the third trimester of pregnancy with established preeclampsia and 25 normotensive women.

RESULTS

No statistically significant differences were noted between the two groups regarding the maternal age, gestational age, body mass index (BMI) haematocrit and neonatal sex. The mean+/-S.D. total testosterone and free testosterone levels were significantly higher (p < 0.01) in the group with preeclapsia compared to the control group. The values of DHEA-S, androstenedione and sex hormone binding globulin were lower in the group with preeclampsia but the difference did not reach statistical significance.

CONCLUSIONS

The levels of total and free testosterone appear to be higher in patients with preeclampsia compared to normotensive pregnant women during the third trimester of pregnancy. This difference could indicate an involvement of testosterone in the pathophysiology of preeclampsia and stimulates research in the potential role of anti-androgens in the management of preeclampsia.

We have examined the effect of androst-5-ene-3 beta,17 beta-diol (delta 5-diol) and its precursors, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone 3 beta-sulfate (DHEAS), on the growth of the estrogen-sensitive human breast cancer cell line, ZR-75-1. While the cell number was increased up to 4-fold by maximal concentrations of estradiol, delta 5-diol maximally stimulated cell proliferation by approximately 3-fold. Since the half-maximal stimulation achieved by delta 5-diol is observed at 2.5 nM and the normal range of plasma concentrations of this steroid in women is 1 to 3 nM, it is most likely that the stimulatory effect of delta 5-diol has physiological significance. DHEA and DHEAS were much less effective than delta 5-diol in stimulating the proliferation of ZR-75-1 cells, the maximal effect on cell number being 75% at the maximal dose used, namely 10 microM. The mitogenic effects of estradiol and delta 5-diol were competitively inhibited by the antiestrogen LY156758 (keoxifene), while the effects of DHEA and DHEAS were completely abolished by the antiestrogen. The effects of DHEA and delta 5-diol on cell proliferation are not likely to be mediated via their conversion to estrone or estradiol, since androstenedione had no effect, while testosterone and dihydrotestosterone decreased cell number by about 20%. The number of specific progesterone binding sites was increased 3.7-, 3.2-, and 2.0-fold by delta 5-diol, DHEA, and DHEAS, respectively. The relative potency of the C19-delta 5-steroids to increase the number of progesterone-specific binding sites was comparable to their ability to stimulate cell proliferation. Direct competition experiments performed with intact cells in monolayer culture showed that, under conditions of minimal metabolism, only delta 5-diol could significantly compete with estradiol for cellular estrogen-specific binding sites with an apparent dissociation constant of 11 nM, thus suggesting that physiological concentrations of C19-delta 5-steroids of adrenal origin could exert an estrogenic stimulation of breast tumor growth without involvement of the aromatase pathway. The present data suggest not only that estrone derived from androstenedione could play a role in estrogen-sensitive breast cancer in women but that delta 5-diol could well be the most important estrogen in breast cancer in women.

Hormonal effects of Tribulus terrestris (TT) were evaluated in primates, rabbit and rat to identify its usefulness in the management of erectile dysfunction (ED). TT extract was administered intravenously, as a bolus dose of 7.5, 15 and 30 mg/kg, in primates for acute study. Rabbits and normal rats were treated with 2.5, 5 and 10mg/kg of TT extract orally for 8 weeks, for chronic study. In addition, castrated rats were treated either with testosterone cypionate (10mg/kg, subcutaneously; biweekly for 8 weeks) or TT orally (5mg/kg daily for 8 weeks). Blood samples were analyzed for testosterone (T), dihydrotestosterone (DHT) and dehydroepiandrosterone sulphate (DHEAS) levels using radioimmunoassay. In primates, the increases in T (52%), DHT (31%) and DHEAS (29%) at 7.5mg/kg were statistically significant. In rabbits, both T and DHT were increased compared to control, however, only the increases in DHT (by 30% and 32% at 5 and 10mg/kg) were statistically significant. In castrated rats, increases in T levels by 51% and 25% were observed with T and TT extract respectively that were statistically significant. TT increases some of the sex hormones, possibly due to the presence of protodioscin in the extract. TT may be useful in mild to moderate cases of ED.

To study the influence of excess body weight on vertebral postmenopausal bone loss, 155 healthy early postmenopausal women were divided into 2 groups according to their body mass index (BMI = weight/height2) and prospectively followed over a mean 31-month period. Spinal (L2-L4) bone mineral density was measured by dual photon absorptiometry. The annual rate of vertebral bone loss (percentage) was significantly reduced (-0.54 +/- 1.1% vs. -1.46 +/- 1.6%; P < 0.05) in the overweight group (BMI,>> or = 25; n = 40) compared to that in the normal weight group (BMI, < 25; n = 115). At baseline, a significant decrease in the urinary calcium/creatinine ratio was observed in the overweight group, which suggested a decrease in bone turnover. A significant correlation was found between the annual rate of bone loss and the BMI (r = 0.21; P < 0.05), but not the body weight. The positive correlation between vertebral postmenopausal rate of bone loss and BMI was confirmed after adjustment for age and time since menopause. Moreover, plasma dehydroepiandrosterone sulfate levels were higher in the high BMI group than in the normal BMI group (P < 0.05). We conclude that within the first years after menopause, moderate excess body weight significantly reduces vertebral postmenopausal bone loss. This effect is probably related to excess adipose tissue through increased conversion of estrogen from adrenal precursors and/or increased production of adrenal androgens.

OBJECTIVE

To determine if dehydroepiandrosterone (DHEA) has clinical benefits in patients with systemic lupus erythematosus (SLE).

METHODS

Ten female patients with mild to moderate SLE and various disease manifestations were given DHEA (200 mg/day orally) for 3-6 months. The patients were given other medications as clinically indicated, and followed with respect to overall disease activity and specific outcome parameters.

RESULTS

After 3-6 months of DHEA treatment, indices for overall SLE activity including the SLEDAI (SLE Disease Activity Index) score and physician's overall assessment were improved, and corticosteroid requirements were decreased. Of 3 patients with significant proteinuria, 2 showed marked and 1 modest reductions in protein excretion. DHEA was well tolerated, the only frequently noted side effect being mild acneiform dermatitis.

CONCLUSIONS

DHEA shows promise as a new therapeutic agent for the treatment of mild to moderate SLE. Further studies of DHEA in the treatment of SLE are warranted.

The effects of pregnancy on cognition and mood were examined using a repeated-measures design. Nineteen women, average age 33, were tested with a comprehensive neuropsychological battery during their last 2 months of pregnancy and again within 2 months of delivery. Blood samples were obtained from all subjects and assayed for a variety of steroid hormones implicated in cognitive and mood functioning. Most participants also completed several self-report measures of mood. In comparison with performance after delivery, women showed significantly more impairment in aspects of verbal memory during pregnancy and also tended to report more negative mood states. Memory deficits were not explained by mood disturbances. No hormone assayed consistently related to cognitive performance during pregnancy. During pregnancy, higher levels of progesterone (P) were associated with greater mood disturbances and higher levels of dehydroepiandrosterone (DHEA) with better mood. After delivery, testosterone (T) was strongly and consistently associated with greater reported mood disturbances. Our results confirm a peripartal memory deficit, which cannot be explained by the dramatic rise in circulating steroid hormones, or by mood status during pregnancy. Steroidal hormones, namely P, DHEA and T, appear to play a role in mood disturbances during, and after, pregnancy. Studies beginning earlier in pregnancy and continuing for an extended period of time after delivery are needed to confirm and expand these observations.

OBJECTIVE

To investigate the incidence and type of endocrine abnormalities in critical care patients with traumatic brain injury (TBI) and to examine their relationships to possible predisposing factors.

METHODS

Prospective study.

METHODS

General intensive care unit in a university hospital.

METHODS

Thirty-four TBI patients (27 men, 7 women), having a mean age of 37+/-16 years, were studied after weaning from mechanical ventilation.

METHODS

Baseline endocrine assessment was carried out by measuring cortisol, corticotropin, dehydroepiandrosterone sulfate, free thyroxine, thyrotropin (TSH), testosterone, oestradiol, follicle stimulating hormone (FSH), luteinizing hormone, prolactin, growth hormone and insulin-like growth factor I. Dynamic evaluation was performed by human corticotropin releasing hormone and growth hormone releasing hormone in all patients. Male patients underwent additional investigation with gonadotropin-releasing hormone. Severity of neurological derangement was graded according to Glasgow Coma Scale (GCS), Marshall Computerized Tomographic Classification and intracranial pressure (ICP) levels.

RESULTS

Eighteen of the 34 patients (53%) had an abnormal result in at least one hormonal axis tested, with cortisol hyporesponsiveness and gonadal dysfunction being equally common, affecting 24% of patients. Endocrine abnormalities were associated with a higher brain CT-scan classification score ( p=0.02). The GCS on admission correlated positively with baseline FSH (r=0.37, p=0.03), peak FSH (r=0.41, p=0.03), testosterone (r=0.44, p=0.02) and TSH (r=0.39, p=0.03). There were no relations between ICP(max) and any baseline or dynamic hormone measurements.

CONCLUSIONS

Patients with TBI receiving critical care show changes in their neuroendocrine responses, which depend upon clinical and radiological measures of head injury severity. Most common abnormalities include cortisol hyporesponsiveness and hypogonadism.

Vascular aging is the term that describes the structural and functional disturbances of the vasculature with advancing aging. The molecular mechanisms of aging-associated endothelial dysfunction are complex, but reduced nitric oxide (NO) bioavailability and altered vascular expression and activity of NO synthase (NOS) enzymes have been implicated as major players. Impaired vascular relaxation in aging has been attributed to reduced endothelial NOS (eNOS)-derived NO, while increased inducible NOS (iNOS) expression seems to account for nitrosative stress and disrupted vascular homeostasis. Although eNOS is considered the main source of NO in the vascular endothelium, neuronal NOS (nNOS) also contributes to endothelial cells-derived NO, a mechanism that is reduced in aging. Pharmacological modulation of NO generation and expression/activity of NOS isoforms may represent a therapeutic alternative to prevent the progression of cardiovascular diseases. Accordingly, this review will focus on drugs that modulate NO bioavailability, such as nitrite anions and NO-releasing non-steroidal anti-inflammatory drugs, hormones (dehydroepiandrosterone and estrogen), statins, resveratrol, and folic acid, since they may be useful to treat/to prevent aging-associated vascular dysfunction. The impact of these therapies on life quality in elderly and longevity will be discussed.

Women with diminished ovarian reserve often respond poorly to controlled ovarian stimulation resulting in retrieval of fewer oocytes and reduced pregnancy rates. It has been proposed that pre-IVF Dehydroepiandrosterone (DHEA) adjuvant therapy may improve ovarian response and pregnancy rates in women with diminished ovarian reserve. This meta-analysis aims to investigate efficacy of DHEA as an adjuvant to improve ovarian response and IVF outcome in women with diminished ovarian reserve. Electronic databases were searched under the following terms: (DHEA) and (diminished ovarian reserve) and/or (poor response). Studies were included if they reported at least one of the following outcomes; clinical pregnancy rate, number of oocytes retrieved, miscarriage rate. We identified 22 publications determining effects of DHEA in clinical trials. Only 3 controlled studies were eligible for meta-analysis. There was no significant difference in the clinical pregnancy rate and miscarriage rates between women pre-treated with DHEA compared to those without DHEA pre-treatment (RR 1.87, 95% CI 0.96-3.64; and RR 0.59, 95% CI 0.21-1.65, respectively). The number of oocytes retrieved (WMD -1.88, 95% CI -2.08, 1.67; P < 0.001) was significantly lower in the DHEA group. In conclusion, based on the limited available evidence from a total of approximately 200 IVF cycles, there are insufficient data to support a beneficial role of DHEA as an adjuvant to controlled ovarian stimulation in IVF cycle. Well-designed, randomised controlled trials as well as more exact knowledge about DHEA mechanisms of action are needed to support use of DHEA in standard practice for poor-responders.

Dehydroepiandrosterone 3-sulfate and other neurosteroids are synthesized in the CNS and peripheral nervous system where they may modulate neuronal excitability by interacting with ligand-gated ion channels. For this modulatory activity, neurosteroids have to be locally released from either neurons or glial cells. We here identify the integral membrane protein ABCC11 (multidrug resistance protein 8) as an ATP-dependent efflux pump for steroid sulfates, including dehydroepiandrosterone 3-sulfate, and localize it to axons of the human CNS and peripheral nervous system. ABCC11 mRNA was detected in human brain by real-time polymerase chain reaction. Antibodies raised against ABCC11 served to detect the protein in brain by immunoblotting and immunofluorescence microscopy. ABCC11 was preferentially found in the white matter of the brain and co-localized with neurofilaments indicating that it is an axonal protein. Additionally, ABCC11 was localized to axons of the peripheral nervous system. For functional studies, ABCC11 was expressed in polarized Madin-Darby canine kidney cells where it was sorted to the apical membrane. This apical sorting is in accordance with the localization of ABCC11 to the axonal membrane of neurons. Inside-out plasma membrane vesicles containing recombinant ABCC11 mediated ATP-dependent transport of dehydroepiandrosterone 3-sulfate with a Km value of 21 microM. This transport function together with the localization of the ABCC11 protein in vicinity to GABAA receptors is consistent with a role of ABCC11 in dehydroepiandrosterone 3-sulfate release from neurons to sites of dehydroepiandrosterone 3-sulfate-mediated receptor modulation. Our findings may provide a basis for the characterization of mutations in the human ABCC11 gene and their linkage with neurological disorders.

Adrenal androgen excess is found in adult female rhesus monkeys previously exposed to androgen treatment during early gestation. In adulthood, such prenatally androgenized female monkeys exhibit elevated basal circulating levels of dehydroepiandrosterone sulfate (DHEAS), typical of polycystic ovary syndrome (PCOS) women with adrenal androgen excess. Further androgen and glucocorticoid abnormalities in PA female monkeys are revealed by acute ACTH stimulation: DHEA, androstenedione and corticosterone responses are all elevated compared to responses in controls. Pioglitazone treatment, however, diminishes circulating DHEAS responses to ACTH in both prenatally androgenized and control female monkeys, while increasing the 17-hydroxyprogesterone response and reducing the DHEA to 17-hydroxyprogesterone ratio. Since 60-min post-ACTH serum values for 17-hydroxyprogesterone correlate negatively with basal serum insulin levels (all female monkeys on pioglitazone and placebo treatment combined), while similar DHEAS values correlate positively with basal serum insulin levels, circulating insulin levels may preferentially support adrenal androgen biosynthesis in both prenatally androgenized and control female rhesus monkeys. Overall, our findings suggest that differentiation of the monkey adrenal cortex in a hyperandrogenic fetal environment may permanently upregulate adult adrenal androgen biosynthesis through specific elevation of 17,20-lyase activity in the zona fasciculata-reticularis. As adult prenatally androgenized female rhesus monkeys closely emulate PCOS-like symptoms, excess fetal androgen programming may contribute to adult adrenal androgen excess in women with PCOS.

OBJECTIVE

Stiripentol (STP) is currently an efficient drug for add-on therapy in infantile epilepsies because it improves the efficacy of antiepileptic drugs (AEDs) through its potent inhibition of liver cytochromes P450. In addition, STP directly reduces seizures in several animal models of epilepsy, suggesting that it might also have anticonvulsive effects of its own. However, its underlying mechanisms of action are unknown.

METHODS

We examined the interactions of STP with gamma-aminobutyric acid (GABA) transmission by using patch-clamp methods in CA3 pyramidal neurons in the neonatal rat.

RESULTS

STP markedly increased miniature inhibitory postsynaptic current (mIPSC) decay-time constant in a concentration-dependent manner. The prolongation of mIPSC duration does not result from an interaction with GABA transporters because it persisted in the presence of GAT-1 inhibitors (SKF-89976A and NO-711). An interaction with benzodiazepine or neurosteroid binding sites also was excluded because STP-mediated increase of decay time was still observed when these sites were initially saturated (by clobazam, zolpidem, or pregnanolone) or blocked (by flumazenil or dehydroepiandrosterone sulfate), respectively. In contrast, saturating barbiturate sites with pentobarbital clearly occluded this effect of STP, suggesting that STP and barbiturates interact at the same locus. This was directly confirmed by using outside-out patches, because STP increased the duration and not the frequency of opening of GABAA channels.

CONCLUSIONS

At clinically relevant concentrations, STP enhances central GABA transmission through a barbiturate-like effect, suggesting that STP should possess an antiepileptic effect by itself.

The relationships between plasma insulin, insulin-like growth factor I (IGF-I) and dehydroepiandrosterone sulfate (DHEAS) concentrations in normal subjects have not been defined. We performed iv glucose tolerance tests on 102 normal subjects, aged 5-20 yr. The subjects were divided into 4 groups according to pubertal stage (Tanner): A, stage 1 (n = 22); B, stages 2 and 3 (n = 17); C, stages 4 and 5 (n = 20); and D, adult, greater than 17 yr (n = 43). The basal plasma IGF-I and insulin concentrations and incremental 0-60 min insulin areas in response to glucose rose significantly throughout puberty (P less than 0.001 for all parameters) and declined to prepubertal levels by the third decade of life. There was a strong positive correlation between log fasting plasma insulin vs. log plasma IGF-I (r = 0.625; P less than 0.001) and log incremental 0-60 min insulin areas vs. log plasma IGF-I (r = 0.572; P less than 0.001). Plasma DHEAS concentrations were measured in groups A-C (n = 59); these also rose throughout puberty. There was strong correlations between log plasma DHEAS and log basal or stimulated (incremental 0-60 min areas) insulin responses (P less than 0.001). To assess the relationship between plasma DHEAS and insulin before puberty, we analyzed the data from group A separately. Plasma DHEAS concentrations tended to be higher in children 9 yr of age or older than in those less than 9 yr old, whereas basal and stimulated plasma insulin levels were similar. We found no correlation between log plasma insulin (fasting or stimulated responses) and log plasma DHEAS concentrations in group A (P greater than 0.05). In conclusion, we found a strong relationship between plasma insulin and IGF-I throughout childhood and puberty and during adult life. This finding suggests that insulin may be important for normal growth during childhood. There was no correlation between plasma insulin and DHEAS concentrations in prepubertal children, which suggests that adrenarche does not influence insulin levels.