Relationships of urinary adrenal steroids at age 8 years with birth weight, postnatal growth, blood pressure, and glucose metabolism

INTRODUCTION: Overactivity of the hypothalamic-pituitary-adrenal axis through a program set by early growth patterns is hypothesized to lead to central obesity, insulin resistance, and hypertension. We therefore examined links between adrenal steroid production and birth weight, rapid early growth, and body mass index (BMI), blood pressure, waist circumference, and resistance to insulin in early childhood through the action of adrenal steroids. METHODS: Timed overnight urine samples were collected in 461 children from a large representative birth cohort. In total 244 boys and 188 girls aged 8.2-8.4 yr completed the protocol. The excretion rates of individual steroids were measured to determine total androgen and cortisol metabolites. Indices of activity of 5alpha-androgen reduction of androgens and cortisol metabolites and 11beta-hydroxy steroid dehydrogenase activity were calculated. RESULTS: In both boys and girls, total urinary androgen and cortisol metabolites were positively related to current height, weight, BMI, and waist circumference. Girls had higher urine androgen metabolite levels and 5alpha-androgen indexes than boys, and in girls higher androgen metabolite excretion was associated with lower birth weight and faster postnatal weight gain. After adjustment for current BMI, total cortisol metabolites and 11beta-hydroxy steroid dehydrogenase index were not related to birth weight or postnatal weight gain in either sex. CONCLUSIONS: These data confirm early growth associations in this cohort seen with plasma levels of adrenal androgens at age 8 yr, at least in girls. Larger studies and follow-up during puberty are needed to exclude the possibility of programming of cortisol metabolism by early growth.     

Analysis of fecal glucocorticoids in the North Atlantic right whale (Eubalaena glacialis)

Very little is known about the endocrinology of the baleen whales. The highly endangered North Atlantic right whale (NARW; Eubalaena glacialis) is a good model species, because most NARW individuals are photo-identified with known histories. We used an 125I corticosterone assay, shown to reliably measure cortisol metabolites, to determine glucocorticoid metabolite concentrations in 177 NARW fecal samples collected between 1999-2004 in the Bay of Fundy, Canada. Fecal glucocorticoid metabolite concentrations varied significantly with sex and reproductive category, being highest in pregnant females (mean +/-SE: 238.14+/-74.37 ng/g) and mature males (71.6+/-11.36), intermediate in lactating females (39.33+/-5.82), and lower in non-reproducing females (23.11+/-4.25) and immature males (34.33+/-5.01) and females (14.0+/-0.41). One case also suggests that glucocorticoids rise markedly in response to severe entanglement in fishing lines. Whales with fecal glucocorticoid content over 100 ng/g (termed "high-cort" samples) were rare, and included most pregnant females, some mature males, a fatally entangled whale, and several very young animals. Glucocorticoid concentrations were highly correlated with androgen concentrations in males and pregnant females. We analyzed the elution profiles of glucocorticoid and androgen metabolites in 13 samples with high-performance liquid chromatography (HPLC) to determine the extent to which androgen metabolites cross-react with our glucocorticoid assay. Males, pregnant females, non-pregnant females, and "high-cort" whales each had distinctly different immunoreactive HPLC profiles of glucocorticoid and androgen metabolites. A major glucocorticoid metabolite was prominent in all "high-cort" whales including the fatally entangled whale. The major fecal androgen was not testosterone but was instead a more nonpolar steroid (possibly dihydrotestosterone), which may be diagnostic of males. Androgen metabolites showed only minor cross-reactivity to our glucocorticoid assay, having a slight influence on glucocorticoid results in particular individuals. We conclude that fecal glucocorticoid analysis appears to be a useful measure of adrenal activity and reproductive condition for NARW.     

Non-invasive methods to measure androgen metabolites in excrements of European stonechats,Saxicola torquata rubicola

Traditionally androgen concentrations are measured invasively in blood plasma. However, non-invasive methods to detect androgens are desirable, as this reduces interference with the natural behavior of the study species and multiple samples can be obtained relatively easy. The aim of this study was to validate a method to measure androgens non-invasively in excrements of male European stonechats (Saxicola torquata rubicola). Extracts of excrements of a male stonechat injected with [3H]testosterone ([3H]T) were chromatographically separated using high performance liquid chromatography (HPLC). The resulting HPLC fractions were then analyzed with a radioimmunoassay against testosterone (T-RIA). The results showed that the assay picked up major metabolites of [3H]T. The physiological relevance of excreted androgen metabolites was further validated by showing that injection of exogenous GnRH to seven males led to a significant increase in excreted androgen metabolites. In contrast, androgen metabolite levels of six saline-injected control males did not increase. Furthermore, excrements from nine males were collected from January until April to see whether the typical seasonal increase in testosterone levels can also be traced when measuring excreted androgen metabolites. As expected, there was a significant seasonal increase in androgen metabolite concentrations. Thus, the T-RIA measures androgen metabolites in droppings of male European stonechats and to our knowledge this study represents the first validation of a non-invasive androgen assay in a passerine bird.     

LC-MS analysis of androgen metabolites in serum and urine from east African chimpanzees (Pan troglodytes schweinfurthii)

Testosterone regulates a wide variety of behavioral and physiological traits in male vertebrates. It influences reproductive and aggressive behaviors and is used as a marker of gonadal activity. While testosterone is the primary biologically active male gonadal steroid in the blood, it is metabolized into a variety of related steroids when excreted via urine and feces. To monitor endocrinological profiles studies on wild-living animals primarily rely on non-invasively collected samples such as urine or feces. Since a number of androgen metabolites that are found in high concentrations in these matrices do not stem exclusively from gonadal production, but are also produced by the adrenal cortex, the metabolism and excretion pattern of testosterone and its characteristic metabolites have to be investigated. Here, we compare the levels of 11 androgens and their metabolites in serum and urine (after hydrolytic/solvolytic cleavage of conjugates) from female, and intact and castrated male chimpanzees to investigate whether they were of testicular or adrenal origin. For serum, significant differences in concentrations were found only for native testosterone. For urine, testosterone concentrations showed the largest differences between intact and castrated males, and intact males and females, while no differences were seen between females and castrated males. Epitestosterone levels revealed the same pattern. These differences in urinary concentrations could also be seen for 5α-androstane-3α,17β-diol (androstanediol), and less clearly for 5α-dihydrotestosterone (5α-DHT), etiocholanolone, and androsterone. In urine of males, significant correlations were found between the levels of testosterone and 5α-androstane-3α,17β-diol, as well as between testosterone and epitestosterone. Therefore, the clearest urinary markers of gonadal activity in male chimpanzees seems to be testosterone itself.     

The control of adrenocortical secretion in the brush-tailed possum, Trichosurus vulpecula

Circulating levels of corticosteroids and androgens have been studied in the brush-tailed possum (Trichosurus vulpecula) under conditions of tropic hormone stimulation. In both males and anestrous females, levels of androgen (considered to consist largely of testosterone) were elevated by 3 days of treatment with PMS. Further treatment with ACTH (Synacthen) subsequently reduced the level of testosterone in the females to values significantly below the control values, and in the male to a value intermediate between control and PMS stimulated levels. Levels of corticosteroid (considered to consist largely of cortisol) were unaffected by gonadotropin treatment, but significantly increased with ACTH. Dexamethasone treatment greatly decreased cortisol levels, but androgen levels were unaffected in both sexes.In vitro androgen production by the definitive adrenal cortex of the female was significantly decreased by dexamethasone pretreatment. Androgen production by a special hypertrophied adrenocortical zone was unaffected. Corticosteroid formation was reduced in both types of tissue.It is concluded that the adrenal cortex contributes to circulating testosterone levels in the female possum. This is supported by gonadotropin, whereas ACTH has a double effect of stimulating overall steroidogenesis, but switching the relative proportions of the steroids by decreasing the synthesis of androgen and stimulating the corticosteroid pathway. The possible physiological role for this phenomenon and the function of the special hypertrophied zone in the female adrenal cortex are discussed.     

Behavioral and hormonal effects of exogenous vasotocin and corticosterone in the green treefrog

Vasotocin (AVT) promotes courtship in a wide range of vertebrates. However, this effect is not independent of steroid hormones. For example, androgens may work in concert with AVT and corticosterone (CORT) may work to oppose AVT action. In frogs, AVT promotes calling, and in some species, CORT inhibits calling. In addition, androgens are known to modulate AVT in the brain, and CORT may depress androgen secretion. Previous work in amphibians has suggested that AVT promotes courtship by overcoming a CORT-mediated stress response. Possible behavioral and hormonal interactions among AVT, CORT, and androgens were investigated in wild, free-living green treefrogs (Hyla cinerea). Saline, AVT, CORT, or a combination of AVT and CORT were administered to calling males, and several measures of spontaneous calling were evaluated for 1.5 h following injection. Plasma testosterone, dihydrotestosterone, and CORT were also measured. Saline-injected males had low CORT levels, and AVT and CORT injection elevated plasma CORT levels. AVT increased the likelihood of calling, but, in males who did call, AVT did not influence latency to call or how often they were observed calling. Very few saline-injected males resumed calling after injection, and therefore a CORT effect was only detectable in AVT-injected males. CORT inhibited calling in AVT-injected males only at the highest dose of CORT (40 microg); lower levels of CORT were unsuccessful at inhibiting AVT-induced calling. AVT appeared to have a specific effect on calling motivation. Further, the data suggest that disinhibition of a CORT response is not the primary mechanism by which AVT increases calling. In addition, CORT injection reduced endogenous androgen levels. Finally, endogenous androgens were negatively correlated with latency to begin calling, suggesting that they may have a positive effect on calling. These data indicate that AVT has positive effects on calling but provide only weak evidence that CORT inhibits courtship in this species.     

Effects of gonadal androgens and oestrogens on adrenal androgen levels

OBJECTIVE The physiological role of adrenal androgens In humans remains unclear. Furthermore, there are few data on the relation between sex steroids and adrenal androgen production. We have assessed the effects of sex steroid hormone administration on adrenal androgen levels, by studying a large group of transsexual patients. DESIGN A non-randomized intervention. SETTING A university teaching hospital. PATIENTS Thirty-one male-to-female and 22 female-to-male transsexual patients. MEASUREMENTS Plasma levels of adrenal androgens were measured in a group of male-to-female and female-to-male transsexual patients both before and during cross-gender hormone treatment. This treatment involves administration of testosterone esters to women and of ethlnyloestradiol and cyproterone acetate to men. RESULTS High dose sex steroid administration had marked effects on adrenal androgens levels, which decreased by 27–48% in males treated with ethinyloestradiol and increased by 23–70% in females treated with testosterone. CONCLUSION We conclude that administration of high doses of testosterone and oestradiol exert opposing effects on adrenal androgen production.     

11-Oxygenated androgens in female teleosts: prevalence,abundance, and life history implications

Although 11-ketotestosterone (11-KT) has been found in blood of females of several diadromous fish species, the importance, abundance, and prevalence of this and related 11-oxygenated androgens in females have not been investigated. To address this issue and to determine whether the differences among androgen profiles relate to specific life history strategies, particularly diadromous migrations, fish (males and females) of around 30 species were sampled and 5 androgens were measured by radioimmunoassay. Levels of 17beta-estradiol and cortisol were also determined to evaluate ovarian and interrenal activity at the time of sampling. Testosterone (T) was the predominant androgen in most sexually recrudescent females. Only in female eel and sturgeon were 11-oxygenated androgens present in levels as high as, or higher than, those of T, although substantial amounts were also found in blood of mullet and salmonids. 11-KT was generally the most abundant 11-oxyandrogen, levels being higher than those of 11beta-hydroxytestosterone or 11beta-hydroxyandrostenedione. It is concluded that 11-oxygenated androgens are quantitatively minor steroids in most female fish. There was no convincing evidence to support the notion that the presence of 11-oxygenated androgens in blood is an adaptation specific to migratory fishes.     

Endocrine effects of the podophyllotoxine derivative drug CPH 82 (Reumacon) in patients with rheumatoid arthritis

CPH 82 is a non-steroid antirheumatic drug containing two benzylidenated podophyllotoxin glucosides with no affinity for the glucocorticoid receptor. Treatment with CPH 82 as single drug therapy significantly decreased serum and urinary cortisol and cortisol metabolites, serum adrenal androgens and urinary androgen metabolites, plasma ACTH and serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and increased serum levels of sex hormone-binding globulin (SHBG). Significant positive correlations were found between serum TNF-alpha and plasma ACTH and between serum IL-6 and TNF-alpha on the one hand and serum and urinary cortisol and cortisol metabolites on the other. The initial action of CPH 82 on adrenal steroidogenesis may be a reduction in cytokine levels due to the drugs' antiinflammatory effect. This causes decreased ACTH stimulation, resulting in a reduced adrenocortical steroid secretion. Accumulation of the drug in the adrenal cortex may also affect adrenal steroidogenesis. The elevated SHBG levels may be caused by a weak estrogenic activity of the drug.     

Epithelial-stromal interactions in the regulation of rat ventral prostate function: identification and characterization of pathways for androgen metabolism in isolated cell types.

Androgen metabolism plays a significant role in the androgen regulation of prostate cell function. In this report the various pathways for androgen metabolism in primary cultures of rat ventral prostate epithelial and stromal cells were identified and characterized by in vitro whole cell assays, using HPLC. Confluent cultures of both cell types were incubated with supraphysiological concentrations (50 nM) of tritiated androgens (testosterone, 5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha(and 3 beta), 17 beta-diols, and delta 4-androstene-3,17-dione), and the metabolites were analyzed at several time points over a 24-h period. The metabolism studies indicated that 5 alpha-reductase activity, the oxidative reactions of 3 alpha-, 3 beta-, and 17 beta-hydroxysteroid oxidoreductases, and the reductive reaction of 3 beta-hydroxysteroid oxidoreductase were expressed at significantly higher levels in epithelial cells compared to stromal cells. The reductive reactions of 3 alpha- and 17 beta-hydroxysteroid oxidoreductases were similar in both cell types. In contrast, stromal cells exhibited substantially higher levels of 6 alpha/7 alpha-hydroxylase activity. In addition, stromal cells were capable of metabolizing 5 alpha-dihydrotestosterone directly to a new unidentified polar androgen metabolite (HO5 alpha-DHT). Overall, epithelial cells were approximately 29 times more capable than stromal cells of forming the biologically active androgen 5 alpha-dihydrotestosterone. Conversely, stromal cells were more capable of forming biologically inactive polar androgen metabolites.     

Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: in vivo and in vitro studies

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACTH-dependent Cushing's syndrome. In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-normal baseline cortisol, normal suppression of cortisol after dexamethasone administration, and ACTH levels that were not suppressed and did stimulate after CRH administration. The elevated urinary free cortisol excretion, in conjunction with an atypical cortisol diurnal rhythm, raised the possibility of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which was abolished by prior octreotide administration. Notably, substantial amounts of adrenal androgens were also secreted after food consumption. Removal of the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tumor revealed an adrenocortical adenomatous nodule originating from the inner zona reticularis, consisting mainly of compact cells. A steroidogenic secretory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in vitro from tumor cells cultured in the presence of GIP. The in vitro secretory response to GIP was higher for the adrenal androgen DHEA, compared with cortisol. The expression of the GIP receptor in tumor cells, but not in the adjacent normal adrenal, was demonstrated by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androgen oversecreting adrenocortical nodule with the unusual presentation of hirsutism and not the typical clinical signs of Cushing's syndrome. It is of note that food intake in this patient provoked a substantial increase in both adrenal androgen and cortisol levels that, together with the histological appearance of this nodule, was compatible with a zona reticularis-derived tumor. Thus, aberrant expression of the GIP receptor does not exclusively involve cells of a zona fasciculata phenotype, as previously reported, but may also occur in other types of differentiated adrenocortical cells.     

Non-invasive assessment of adrenocortical function in the male African elephant (Loxodonta africana) and its relation to musth

Adult male elephants periodically show the phenomenon of musth, a condition associated with increased aggressiveness, restlessness, significant weight reduction and markedly elevated androgen levels. It has been suggested that musth-related behaviours are costly and that therefore musth may represent a form of physiological stress. In order to provide data on this largely unanswered question, the first aim of this study was to evaluate different assays for non-invasive assessment of adrenocortical function in the male African elephant by (i) characterizing the metabolism and excretion of [3H]cortisol (3H-C) and [14C]testosterone (14C-T) and (ii) using this information to evaluate the specificity of four antibodies for determination of excreted cortisol metabolites, particularly with respect to possible cross-reactions with androgen metabolites, and to assess their biological validity using an ACTH challenge test. Based on the methodology established, the second objective was to provide data on fecal cortisol metabolite concentrations in bulls during the musth and non-musth condition. 3H-C (1 mCi) and 14C-T (100 microCi) were injected simultaneously into a 16 year old male and all urine and feces collected for 30 and 86 h, respectively. The majority (82%) of cortisol metabolites was excreted into the urine, whereas testosterone metabolites were mainly (57%) excreted into the feces. Almost all radioactive metabolites recovered from urine were conjugated (86% 3H-C and 97% 14C-T). In contrast, 86% and >99% of the 3H-C and 14C-T metabolites recovered from feces consisted of unconjugated forms. HPLC separations indicated the presence of various metabolites of cortisol in both urine and feces, with cortisol being abundant in hydrolysed urine, but virtually absent in feces. Although all antibodies measured substantial amounts of immunoreactivity after HPLC separation of peak radioactive samples and detected an increase in glucocorticoid output following the ACTH challenge, only two (in feces against 3alpha,11-oxo-cortisol metabolites, measured by an 11-oxo-etiocholanolone-EIA and in urine against cortisol, measured by a cortisol-EIA) did not show substantial cross-reactivity with excreted 14C-T metabolites and could provide an acceptable degree of specificity for reliable assessment of glucocorticoid output from urine and feces. Based on these findings, concentrations of immunoreactive 3alpha,11-oxo-cortisol metabolites were determined in weekly fecal samples collected from four adult bulls over periods of 11-20 months to examine whether musth is associated with increased adrenal activity. Results showed that in each male levels of these cortisol metabolites were not elevated during periods of musth, suggesting that in the African elephant musth is generally not associated with marked elevations in glucocorticoid output. Given the complex nature of musth and the variety of factors that are likely to influence its manifestation, it is clear, however, that further studies, particularly on free-ranging animals, are needed before a possible relationship between musth and adrenal function can be resolved. This study also clearly illustrates the potential problems associated with cross-reacting metabolites of gonadal steroids in EIAs measuring glucocorticoid metabolites. This has to be taken into account when selecting assays and interpreting results of glucocorticoid metabolite analysis, not only for studies in the elephant but also in other species.     

Effects of growth hormone administration on dehydroepiandrosterone sulphate, androstenedione, testosterone and Cortisol metabolism during nutritional repletion

This study evaluated whether pharmacological doses of recombinant human growth hormone (hGH) influences androgen or cortisol metabolism during nutritional repletion following prolonged illness. Stable hospitalized adults (three males, seven female) receiving constant calorie and protein intake were studied. An initial control week was followed by a treatment period during which hGH (10 mg/day s.c.) was administered daily. Prior to hGH treatment, serum and 24-h urinary concentrations of dehydroepiandrosterone sulphate (DS) were below the normal range; serum androstenedione and testosterone concentrations were within the lower limit of normal. In contrast, serum cortisol (F) and 24-h urinary F excretion were normal. During hGH treatment, nitrogen balance became positive and plasma insulin-like growth factor I (IGF-I) concentrations rose five to seven-fold. However, serum DS, androstenedione, testosterone and F, and urinary F excretion did not change, while 24-h urinary DS excretion fell significantly. Growth hormone administration markedly stimulated protein anabolism but did not increase the low concentrations of circulating androgens or alter the disassociation between adrenal androgen and F release in stable hospitalized males and females. Thus, hGH does not appear to function as a cortical adrenal androgen stimulating hormone (CASH) or regulate adrenal cortisol or gonadal androgen release in this clinical setting.     

Androgen and androgen metabolite levels in serum and urine of East African chimpanzees (Pan troglodytes schweinfurthii): comparison of EIA and LC-MS analyses

The primary male androgen testosterone (T) is often used as an endocrinological marker to investigate androgen-behaviour interactions in males. In chimpanzees and bonobos, studies investigating the relationship between T levels and dominance rank or aggressive behaviour have revealed contradictory results. The immunoassays used in these studies were originally developed for the measurement of steroids in serum. Their application to non-invasively collected samples, however, can lead to methodological problems due to cross-reacting metabolites, which might occur in urine or faeces but not in blood. The overall aim of this study, therefore, is to clarify whether a T enzyme immunoassay (EIA) is an applicable method to monitor testicular function in adult male chimpanzees. To estimate the impact of cross-reacting androgens on the used T EIA, we compared the results of an EIA measurement with a set of androgen metabolite levels measured by LC–MS. In urine from male chimpanzees, cross-reactivities appear to exist mainly with T and its exclusive metabolites, 5α-dihydrotestosterone (5α-DHT) and 5α-androstanediol (androstanediol). Both urinary and serum T levels of male chimpanzees were significantly higher than female T levels when measured with the T EIA, indicating a reliable measurement of testicular androgens and their exclusive metabolites with the used EIA. In urine from female chimpanzees, the comparison between LC–MS and T EIA results indicated a higher impact of cross-reactions with adrenal androgen metabolites. Therefore, the investigation of urinary T levels in female chimpanzees with a T EIA seems to be problematic. Overall our results show that a T EIA can be a reliable method to monitor testicular function in male chimpanzee urine and that LC–MS is a valuable tool for the validation of immunoassays.     

Adrenocorticotropin-stimulated adrenal androgen secretion in anorexia nervosa: impaired secretion at low weight with normalization after long-term weight recovery

Adrenal androgen secretion is decreased in patients with anorexia nervosa. To assess the reversibility of the decreased secretion with recovery of body weight, we measured ACTH-stimulated adrenal androgen levels at different stages of recovery. Basal plasma GH and somatomedin-C levels also were measured, because both have been proposed as potential stimuli for adrenal androgen secretion. When studied at low body weight [58 +/- 3% (+/- SEM) ideal BW], women with anorexia nervosa had decreased ACTH-stimulated levels of dehydroepiandrosterone (DHA), DHA sulfate (DHAS), and androstenedione and decreased DHA to cortisol, DHAS to cortisol, and androstenedione to cortisol ratios compared to normal women. Women who had recently completed a refeeding program (within 2-4 weeks, 81 +/- 2% ideal BW) had an increased somatomedin-C level compared to low weight patients, but similar ACTH-stimulated adrenal androgen levels. Long term weight-recovered women (86 +/- 4% ideal BW, recovery for more than 6 months, with resumption of menses), however, had significant increases in ACTH-stimulated DHA and DHAS levels and DHA to cortisol and DHAS to cortisol ratios, and their hormone levels and ratios were not different from those in normal women. GH levels fell during weight recovery, although the values in the three patient groups did not differ significantly. We conclude that the recovery of adrenal androgen secretion while GH levels were falling provides evidence against a direct effect of GH as a stimulus for adrenal androgen secretion. The recovery of somatomedin-C before the recovery of adrenal androgens, however, and the positive correlation between plasma somatomedin-C and the integrated level of plasma DHAS (r = 0.50; P less than 0.02) are consistent with the hypothesis that somatomedin-C is a stimulus for adrenal androgen secretion.     

Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus

BACKGROUND: In rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), patients demonstrate low levels of adrenal hormones. OBJECTIVE: To investigate whether increased renal clearance and daily excretion contribute to this phenomenon. METHODS: Thirty patients with RA, 32 with SLE, and 54 healthy subjects (HS) participated. Serum and urinary levels of cortisol, cortisone, 17-hydroxyprogesterone (17OHP), androstenedione, dehydroepiandrosterone (DHEA), and DHEA sulphate (DHEAS) were measured. RESULTS: Clearance of DHEAS and DHEA was lower in patients than in HS, and clearance of androstenedione was somewhat higher in patients than in HS, but daily excretion of this latter hormone was low. Clearance of cortisol, cortisone, and 17OHP was similar between the groups. The total molar amount per hour of excreted DHEA, DHEAS, and androstenedione was lower in patients than HS (but similar for cortisol). Serum DHEAS levels correlated with urinary DHEAS levels in HS and patients, whereby HS excreted 5-10 times more of this hormone than excreted by patients. Low serum levels of adrenal androgens and cortisol in patients as compared with HS were confirmed, and proteinuria was not associated with changes of measured renal parameters. CONCLUSIONS: This study in patients with RA and SLE demonstrates that low serum levels of adrenal androgens and cortisol are not due to increased renal clearance and daily loss of these hormones. Decreased adrenal production or increased conversion or conjugation to downstream hormones are the most likely causes of inadequately low serum levels of adrenal hormones in RA and SLE.     

Subnormal plasma adrenal androgen levels in men with uremia

The 24-h mean plasma concentrations of 8 hormones were measured in 11 men with chronic uremia and 32 normal men. Our findings confirm previous reports of subnormal levels of testosterone, T3, and T4 and elevated levels of LH, PRL, and cortisol. In addition, we observed a new finding: markedly subnormal levels of the adrenal androgens dehydroisoandrosterone (DHA) and DHA sulfate. The mean DHA level in the patients was 164 +/- 46 (SD) ng/dl, compared with 320 +/- 124 in age-matched controls (P < 0.0001); the geometric mean DHA sulfate level was 40 micrograms/dl (95% confidence limits, 11-113) in the patients and 76 micrograms/dl (95% confidence limits, 26-214) in age-matched controls (P = 0.005). The depression of adrenal androgen levels in the face of elevated cortisol levels suggests a biosynthetic block in the adrenal cortex at the step where the C-19 and C-21 pathways diverge, namely the removal of the 2-carbon side chain by C-17, 20-lyase. If a similar defect were present in the testes, it could account for the diminished synthesis of testosterone, which is a further metabolite of DHA in the testes.     

Differences in blood levels of androgens in female talapoin monkeys related to their social status

Serum testosterone and androstenedione levels were lower in the subordinate female talapoin monkeys of four social groups than either dominant or intermediate-ranking females. This was found in both intact or ovariectomized (oestrogen-treated) animals, which suggests that androgen from the adrenals contributed to this rank-related endocrine effect. These differences disappeared when the females were housed singly, levels in all animals becoming similar to those in subordinates in the group cage. There were no rank-related differences in progesterone levels during either the follicular or luteal phase of the cycle in intact females, or in those of ovariectomized females of different rank, but cortisol was highest in dominant group-living animals in these experiments. Significant correlations were found between androgen levels in group-living females and the amount of sexual interest shown in them by males; the amount of aggressive interaction involving each female did not correlate with her androgen levels. Social rank is defined according to the direction, not the amount, of aggression. These findings suggest that the social hierarchy regulates androgen levels in these female monkeys; there may also be effects on the ability of females to respond to their own, or to administered, androgen. Similar findings have been made previously in male talapoins. Since androgens fill a critical role in the sexual behaviour of both sexes in primates, this may be a neuroendocrine mechanism of general significance relating behaviour to social rank.     

Handling during pregnancy in the blue fox (Alopex lagopus): the influence on the fetal pituitary-adrenal axis

Previous studies revealed that handling is a stressor for farmed blue foxes. The present study was designed to examine the effects of a 1-min daily handling stress applied to pregnant blue fox vixens on the function of the fetal pituitary-adrenal system. Plasma concentrations of adrenocorticotropin hormone (ACTH), cortisol, and progesterone, adrenal content of cortisol and progesterone, in vitro adrenal production of these steroids and response to ACTH, and adrenal weights were measured in control (C; n = 73) and stressed (S; n = 58) fetuses. The ACTH levels were lower in stressed fetuses than in the controls (C: males, 128.6 +/- 6.1 pg/ml; females, 165.9 +/- 6.1 pg/ml; S: males, 122.3 +/- 5.4 pg/ml; females, 145.0 +/- 8.1 pg/ml; P < 0.05). In contrast, increased plasma cortisol concentrations in both sexes were demonstrated in stressed compared with control fetuses (C: males, 9.2 +/- 0.4 ng/ml; females, 9.2 +/- 0.4 ng/ml; S: males, 11.8 +/- 0.7 ng/ml; females, 13.2 +/- 0.7 ng/ml; P < 0.00001). The same difference was observed in plasma progesterone concentrations (C: males, 1.54 +/- 0.07 ng/ml; females, 1.49 +/- 0.10 ng/ml; S: males, 1.86 +/- 0.11 ng/ml; females, 1.74 +/- 0.10 ng/ml; P < 0.01). Prenatal stress did not change the baseline adrenal production of cortisol but prevented the cortisol response to ACTH in female fetuses and decreased the progesterone production in both sexes. Additionally, prenatally stressed fetuses of both sexes had significantly lower adrenal weights than controls (C: males, 9.4 +/- 0.3 mg; females, 9.5 +/- 0.4 mg; S: males, 8.1 +/- 0.3 mg; females, 8.2 +/- 0.4 mg; P < 0.001). These results indicate that prenatal handling stress induces a dysregulation of the pituitary-adrenal axis in the fetus and suggest that increased plasma glucocorticoids in the stressed dam can cross the placenta and influence the fetal hypothalamicpituitary-adrenal axis.     

Primary intracranial HCG-producing germinoma in a boy with congenital adrenal hyperplasia

A primary intracranial HCG-producing tumour was studied in an 8 year old boy with congenital adrenal hyperplasia. The case provided a unique opportunity to study the sequential changes in serum and urinary androgens and HCG as measured by radioreceptor assay for HCG and by radioimmunoassay for HCG using antisera raised against the hormone specific for the beta subunit of HCG. Plasma concentrations of HCG, measured by the radioreceptor assay, closely correlated with the biologic activity of his tumour, as measured by serum testosterone concentration. This case demonstrates that precocious puberty in any child, including one with a known androgen disorder such as congenital adrenal hyperplasia, warrants through investigation.