Dehydroepiandrosterone Sulfate Responses Research Articles

Validation of an enzyme immunoassay for measurement of fecal dehydroepiandrosterone sulfate in gibbons and siamangs.

Monitoring wildlife stress levels is essential to ensure their quality of life in captivity or in the wild. One promising method to assess the stress response is the comeasurement of glucocorticoids (GC) and dehydroepiandrosterone sulfate (DHEAS), adrenal hormones involved in the modulation of the stress response. Although noninvasive methods to measure GCs have been validated in several species, only a few studies have validated DHEAS assays. The aims of this study were (1) to describe an enzyme immunoassay (EIA) to measure DHEAS levels, (2) to validate this assay for fecal samples in gibbons and siamangs, and (3) to test hormonal stability after one freeze-thaw cycle and over time at two freezer temperatures (-20°C and -80°C). Subjects included 32 gibbons and siamangs from U.S. zoological parks. The EIA was validated analytically by parallelism and accuracy tests, and biologically by confirming a DHEAS response 1-2 days after a stressful event (accident, vaccination, or transportation) in three individuals. In addition, fecal DHEAS levels in a pregnant female were above nonpregnant/nonlactating levels and declined progressively the following parturition. The hormonal stability experiments revealed no significant changes in fecal DHEAS levels after one freeze-thaw cycle. Hormonal levels in fecal extracts were stable for 2 months, regardless of the storage temperature, with no significant differences between -20°C and -80°C conditions. The EIA described has high sensitivity and it is suitable for fecal DHEAS measurement in gibbons and siamangs, with a potential to be applied to other species.

Attenuated DHEA and DHEA-S response to acute psychosocial stress in individuals with depressive disorders

BackgroundIn recent years, a relationship between depression and basal dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) levels has frequently been suggested, but responses of these adrenal steroids to psychosocial stress have not been examined in individuals with depressive disorders. In this study, we examined salivary DHEA, DHEA-S, and cortisol/DHEA response to the Trier Social Stress Test (TSST) in individuals with depressive disorders and in healthy controls to discover whether the responses of DHEA and DHEA-S to acute psychosocial stress could be a more sensitive marker of HPA dysfunction in depressive disorders. MethodsWe compared salivary cortisol, DHEA, DHEA-S, and cortisol/DHEA levels to the TSST tests between 38 individuals with depression and 43 healthy controls aged 18.4–25.9 years. Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II). Salivary samples were evaluated at four time points: the baseline (−10 time point), before the TSST started (0 time point), the end of the TSST (+20 time point), and the recovery (+50 time points). ResultsNo significant differences existed in the basal adrenal hormonal levels between subjects with depressive disorders and controls; however, at the end of TSST, attenuated DHEA and DHEA-S response was identified in subjects with depressive disorders compared to that found in healthy subjects. The differences in the DHEA and DHEA-S levels at the +20 time point, as well as the differences in the cortisol/DHEA at the +50 time point, exhibited negative correlations with depression severity. ConclusionAttenuated DHEA and DHEA-S response to acute psychosocial stress was identified in subjects with depressive disorders. These findings help us to discover the bi-directional relationship between depression and the hypothalamic-pituitary-adrenal (HPA) axis function, hence furthering our understanding of whether altered DHEA and DHEA-S response to psychosocial stress may be a more sensitive method than basal adrenal steroid analysis for detecting HPA axis dysfunction in depressive disorders. LimitationsAs this is a case control study, we could only draw the conclusion of the bi-directional relationship between the depression and the altered DHEA (S) response to stress, and could not identify whether depression was due to the HPA dysfunction, or vice versa. Prospective studies such as such as cohort studies or epidemiology experiments are needed to further test the cause of depression or HPA dysfunction; and the mechanisms responsible for altered DHEA and DHEA-S in response to acute psychosocial stress in individuals with depressive disorders are also needed to be clarified.

Cortisol Response To Low Dose Versus Standard Dose (Back-to-Back) Adrenocorticotrophic Stimulation Tests In Children and Adolescents With Thalassemia Major

Patients with thalassemia major(TM ), especially those with inadequate iron chelation, have high prevalence of endocrinopathies. Several studies reported a significant prevalence of subclinical “biochemical” adrenal insufficiency, ranging from 18–45%, in patients with thalassemia. This variability may be due to the different severity of TM, iron overload status, the test used for assessing adrenal function, and the cutoff value used to define subnormal cortisol response. The low dose (LD) 1-microg (ug) ACTH test follows the insulin tolerance test (ITT) has been shown to be more closely and more sensitive than the standard ACTH test in detecting more subtle insufficiency of the hypothalamic-pituitary-adrenal axis. Therefore the 1 ug ACTH test may be more appropriate for screening for secondary AI in TM patients. Measurements of serum dehydroepiandrosterone sulfate (DHEA-S) levels during LD simulation provide additional valuable information that improves the diagnostic accuracy of LDC in patients suspected to have central adrenal insufficiency (AI). The aim of this study was to compare cortisol and DHEA-S responses to LD and SD ACTH tests in patients with TM. Patients and Methods This cross-sectional controlled study was conducted at the Departments of Pediatrics and Hematology, Hamad Medical Center (HMC). 10 children and 13 adolescents (age 8 to 26 years ) were randomly recruited. They had been receiving blood transfusion at a regular basis every 4 wk. Iron chelation therapy was suboptimal in most of them. Patients were excluded if they had any other endocrine or systemic disease or drugs known to affect adrenal functions. 13 healthy children and adolescents with normal variant short stature served as controls. Serum cortisol and DHEA-S concentrations were determined in each subject before blood transfusion both in basal condition and after low dose (LD) (1 microgram) followed by standard dose (SD) (250 micrograms) respectively) with synthetic corticotrophin beta 1-24 ACTH (Synacthen Ciba). Normal controls were a group of 13 age and sex matched normal subjects. Results Using a peak total cortisol cutoff level of 550 nmol/L and increments of 200 ug above basal cortisol, AI was demonstrated in 8 patients after the LD ACTH and in 2 patients after SD ACTH test and in none of the controls. Using a peak total cortisol cutoff level of 420 nmol/L and increments of 200 ug above basal cortisol, AI was demonstrated in 5 patients after the LD ACTH and in 2 patients after SD ACTH test but none of controls. All patients with biochemical AI were asymptomatic with normal serum Na and K concentrations and no history suggestive of adrenal pathology. The peak cortisol concentrations in thalassemic patients with impaired adrenal function both after 1ug and 250 ug cosyntropin, ( 294 +/- 51 nmol/L and 307 +/- 58.6) were significantly lower than those with patients with normal ( 454 +/- 79.7 nmol/L and 546.1 +/- 92.2 nmol/L respectively) and controls (460.2 +/- 133.4 nmol/L and 554.3 +/- 165.8 nmol/L respectively). Adolescents but not children with TM had significantly lower peak cortisol concentration after SD cosyntropin test versus controls. Peak cortisol response to LD cosyntropin test was correlated significantly with peak cortisol response to SD in all patients (r = 0.83, p < 0.0001). In adolescents with thalassemia DHEA-S levels before and after LD ACTH stimulation were significantly lower and the cortisol/DHEA-S ratios significantly higher than controls. In conclusion, the use of LD ACTH test diagnoses more adrenal abnormalities versus SD ACTH in thalassemic patients. The relatively high prevalence of AI in thalassemic adolescents necessitates that these patients have to be investigated for AI before major surgery and those with impaired cortisol secretion should receive stress doses of corticosteroids during the stressful event. Disclosures: No relevant conflicts of interest to declare.

Perceived stress at work is associated with attenuated DHEA-S response during acute psychosocial stress

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) have been suggested to play a protective role during acute psychosocial stress, because they act as antagonists to the effects of the stress hormone cortisol. This study aims to investigate whether prolonged psychosocial stress, measured as perceived stress at work during the past week, is related to the capacity to produce DHEA and DHEA-S during acute psychosocial stress. It also aims to investigate whether prolonged perceived stress affects the balance between production of cortisol and DHEA-S during acute psychosocial stress. Thirty-six healthy subjects (19 men and 17 women, mean age 37 years, SD 5 years), were included. Perceived stress at work during the past week was measured by using the Stress-Energy (SE) Questionnaire. The participants were divided into three groups based on their mean scores; Low stress, Medium stress and High stress. The participants underwent the Trier Social Stress Test (TSST) and blood samples were collected before, directly after the stress test, and after 30 min of recovery. General Linear Models were used to investigate if the Medium stress group and the High stress group differ regarding stress response compared to the Low stress group. Higher perceived stress at work was associated with attenuated DHEA-S response during acute psychosocial stress. Furthermore, the ratio between the cortisol production and the DHEA-S production during the acute stress test were higher in individuals reporting higher perceived stress at work compared to individuals reporting low perceived stress at work. There was no statistical difference in DHEA response between the groups. This study shows that prolonged stress, measured as perceived stress at work during the past week, seems to negatively affect the capacity to produce DHEA-S during acute stress. Given the protective functions of DHEA-S, attenuated DHEA-S production during acute stress may lead to higher risk for adverse effects on psychological and physiological health, particularly if stress exposure continues.

Acute and chronic stress increase DHEAS concentrations in rhesus monkeys

Most studies on the stress-responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis have focused on glucocorticoids, while few studies have investigated the adrenal secretion of dehydroepiandrosterone sulfate (DHEAS), which is unique to primates. Monkeys were chair-restrained for 2h per day for seven consecutive days, and blood samples were collected upon placement in the chair, and at 15, 30, 60 and 120 min later. Like cortisol, DHEAS concentrations increased throughout the initial session of chair restraint (acute stress). Unlike the cortisol response, which decreased after repeated exposure to the stressor, the DHEAS response was sustained throughout the seventh session of restraint (chronic stress) and response to the seventh session of restraint did not differ from the DHEAS response to the initial session. Like cortisol, DHEAS concentrations showed a diurnal rhythm with higher concentrations in the morning compared to the evening and a decrease in response to dexamethasone (DEX) administration. After repeated exposure to the stressor, the suppression of DHEAS in response to dexamethasone was more complete, suggesting an increase in negative feedback sensitivity. These data show that DHEAS concentrations increase in response to both acute and chronic (repeated) stress and provide another measure of HPA activity that parallels cortisol during acute responses to stress but diverges in chronic or repeated stress.

Evaluation of the hypothalamic–pituitary–adrenal axis in untreated patients with polymyalgia rheumatica and healthy controls

Objective: To explore the hypothalamic–pituitary–adrenal (HPA) axis in polymyalgia rheumatica (PMR).Subjects and methods: This study was carried out on 13 female patients with PMR who were diagnosed according to the criteria of Chuang et al (Ann Intern Med 1982;97:672–80) and 10 healthy female subjects in the Department of Physical Medicine and Rehabilitation, Erciyes University Medical School. In the patient and control groups, basal cortisol, adrenocorticotrophic hormone (ACTH), 17α‐hydroxyprogesterone (17‐OHP), 11‐deoxycortisol (11‐S), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A), prolactin (PRL), and thyroid stimulating hormone (TSH) levels were measured. Cortisol, 17‐OHP, 11‐S and A responses after the low‐dose (1 µg) ACTH stimulation test and cortisol and DHEAS responses after the dexamethasone suppression test were detected. We also measured acute phase reactants including C‐reactive protein (CRP) and erythrocyte sedimentation rate (ESR).Results: Age and sex characteristics were similar in both patient and control groups. The levels of basal hormones including cortisol, ACTH, 17‐OHP, 11‐S, DHEAS, A, prolactin and TSH and cortisol and DHEAS levels after the low‐dose dexamethasone suppression test were not significantly different between the patient and control groups. However, cortisol/CRP and ACTH/CRP ratios were significantly lower in the patient group. Cortisol and DHEAS responses after the low‐dose dexamethasone suppression test were not significantly different between the patient and control groups. Cortisol response after the 1 µg ACTH stimulation test was significantly lower in the patients than in the control group, but there were no significant differences in 17‐OHP, 11‐S and A responses between the patients and controls. Correlation analysis showed that there was a negative correlation between peak cortisol levels after the ACTH stimulation test and disease duration, and also a positive correlation between cortisol levels after the low‐dose dexamethasone suppression test and acute phase reactants including CRP and ESR.Conclusion: A significant low cortisol response to ACTH stimulation was detected in the patients with PMR. In addition, a negative correlation after the 1 µg ACTH stimulation test between peak cortisol levels and disease duration was detected. These findings may indicate hypoactivation in the HPA axis.

Functional luteinizing hormone/chorionic gonadotropin receptors in human adrenal cortical H295R cells.

Previous studies have suggested that activation of normal human adrenal and adrenal tumor luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptors results in an increased secretion of steroid hormones. Since it is not feasible to test this suggestion on normal human adrenal cells, we used human adrenal cortical carcinoma H295R cells, which are similar in some respects to normal adrenal cortical cells. These cells contained LH/hCG receptor transcripts and receptor protein that can bind (125)I-hCG in a hormone-specific manner. Culturing the cells with highly purified hCG resulted in a time- and dose-dependent significant increase in dehydroepiandrosterone sulfate (DHEAS) secretion as compared with the controls. The DHEAS response was hormone as well as steroid specific. Since hCG treatment did not increase DHEA secretion, we suspected that the hCG might increase DHEA sulfotransferase (ST). Consistent with this possibility, hCG treatment increased steady-state DHEA-ST mRNA levels. The hCG effects require its receptors, as inhibition of their synthesis by treatment with antisense phosphorothioate oligodeoxynucleotides (ODN) made from the LH/hCG receptor sequence resulted in loss of DHEA-ST and DHEAS responses. The findings that 1) hCG treatment increased cAMP levels and activated protein kinase A (PKA), 2) 8-bromo cAMP mimicked hCG, and 3) blocking PKA activation prevented hCG as well as 8-bromo cAMP from increasing both DHEA-ST mRNA and DHEAS levels suggested that cAMP/PKA signaling was involved in the hCG actions. In conclusion, H295R cells contain LH/hCG receptors, which are coupled to increasing DHEAS secretion through upregulating the ST enzyme mRNA level. This action is mediated by the cAMP/PKA signaling pathway. These findings support the concept that adrenal function in normal and pathological conditions could be influenced by LH and hCG.

The prevalence of late onset congenital adrenal hyperplasia in hirsute women from Central Anatolia.

Late onset congenital adrenal hyperplasia (LO CAH) can be seen in association with polycystic ovary syndrome (PCOS) or idiopathic hirsutism (IH). The study aimed to find out the prevalence of LO CAH in Central Anatolia among hirsute women. Sixty-three patients with hirsutism were evaluated to determine the frequency of LO CAH by comparing them with their age and body mass index matched 28 healthy controls. Of those 63 hirsute women, 43 were diagnosed as PCOS, and 20 were diagnosed as IH. Following basal hormonal evaluation, all subjects underwent ACTH stimulation test and ACTH stimulated 17-hydroxyprogesterone (17-OH P), 11-desoxycortisol (11-DOC), cortisol (F), and dehydroepiandrosterone sulfate (DHEA-S) levels were determined in all subjects. ACTH stimulated 17-OH P, 11-DOC, and DHEA-S levels did not differ between groups. However, stimulated F levels were found to be higher in hirsute women (p<0.001). Six out of 63 (9.52%) patients with hirsutism met the criterion for 21 hydroxylase deficiency. We found no subject presumed to have 11-beta hydroxylase deficiency, but one subject in control group (3.57%) and two patients among PCOS subjects (4.65%) had exaggerated DHEA-S response which was suggestive of mild 3-beta hydroxysteroid dehydrogenase deficiency. In conclusion, the most frequent form of LO CAH seems to be due to 21 OH deficiency among women with PCOS and IH in Central Anatolia. Mild 3-beta HSD deficiency may also be an underlying cause for hirsutism and it may be seen without any clinical presentation. Adrenal hyperactivity is likely to be the main reason of hyperandrogenemia in women with hirsutism.

Low Basal Androstenedione Levels Plus Augmented 17α-Hydroxyprogesterone and Low Dehydroepiandrosterone Sulfate Responses to Adrenocorticotropic Hormone Stimulation in Patients with Adrenal Incidentaloma

To investigate the androstenedione, 17a-hydroxyprogesterone (17-OHP), and dehydroepiandrosterone sulfate (DHEAS) basal levels and responses to adrenocorticotropic hormone (ACTH) in patients with adrenal incidentalomas in order to determine which enzyme defects are present. In a study group of 23 patients (18 women and 5 men who ranged in age from 16 to 70 years) with incidentally discovered asymptomatic adrenal masses, ACTH stimulation was performed to evaluate the secretory responses of 17-OHP and DHEAS. The same test was performed in 15 age- and sex-matched control subjects. Of the 23 patients, 16 (70%) had a 17-OHP peak >30 nmol/L. The 17-OHP response to ACTH stimulation was significantly higher in patients with adrenal incidentalomas than in control subjects (P<0.001). Fourteen patients had basal DHEAS levels below the 3rd percentile of the control group (1.4 +/- 0.1 mmol/L). The mean stimulated DHEAS level was 1.7 +/- 0.2 mmol/L (range, 0.8 to 4.1) in patients with incidentalomas and 4.2 +/- 0.4 mmol/L (range, 1.8 to 5.6) in the control group (P<0.001). In 13 patients, stimulated DHEAS levels were low in association with high 17-OHP levels. Basal ACTH levels did not differ significantly between patients (8.14 +/- 1.2 pmol/L) and control subjects (8.73 +/- 0.7 pmol/L). Basal androstenedione levels were significantly lower in patients (1.9 +/- 0.3 nmol/L) than in control subjects (5.7 +/- 2.5 nmol/L) (P<0.001). No significant correlation was found between 17-OHP levels and tumor size. Enzyme defects may have an important role in adrenal incidentalomas. Two possible explanations for the observed abnormalities of steroid metabolism in patients with incidentalomas are that (1) the incidentalomas are true primary tumors that have aberrant steroid metabolic pathways or (2) such patients have underlying congenital adrenal hyperplasia that leads, over time, to development of pseudotumors. To assess these two possibilities, we need further studies such as genetic investigations, postoperative test results, and evidence relating the size of the adrenal mass to steroid-suppressible treatment.

Mechanisms of androgen deficiency in human immunodeficiency virus-infected women with the wasting syndrome.

Although prior studies suggest reduced androgen levels in women with acquired immune deficiency syndrome wasting, little is known regarding the regulation of adrenal and ovarian androgen secretion in such patients. We investigated ovarian and adrenal function in 13 human immunodeficiency virus-infected women with acquired immune deficiency syndrome wasting and 21 age- and body mass index-matched healthy control subjects studied in the early follicular phase. Subjects received hCG (5000 U, im) on d 1 and Cosyntropin (0.25 mg, i.v.) on d 3 after dexamethasone (1 mg, orally, at 2400 h) pretreatment on d 2. At baseline, human immunodeficiency virus-infected subjects demonstrated significantly reduced T [18 +/- 2 vs. 25 +/- 2 ng/dl (0.6 +/- 0.1 vs. 0.9 +/- 0.1 nmol/liter); P = 0.02], free T [1.5 +/- 0.1 vs. 2.4 +/- 0.2 pg/ml (5.3 +/- 0.5 vs. 8.3 +/- 0.6 pmol/liter); P = 0.001], androstenedione [119 +/- 6 vs. 162 +/- 14 ng/dl (4.16 +/- 0.20 vs. 5.66 +/- 0.48 nmol/liter); P = 0.02], and dehydroepiandrosterone sulfate [0.96 +/- 0.17 vs. 1.55 +/- 0.19 microg/ml (2.6 +/- 0.5 vs. 4.2 +/- 0.5 micromol/liter); P = 0.047] levels compared with the control subjects. T [8 +/- 2 vs. 6 +/- 2 ng/dl (0.3 +/- 0.1 vs. 0.2 +/- 0.1 nmol/liter); P = 0.48], free T [0.5 +/- 0.2 vs. 0.4 +/- 0.1 pg/ml (1.7 +/- 0.7 vs. 1.5 +/- 0.5 pmol/liter); P = 0.85], 17 hydroxyprogesterone [0.5 +/- 0.2 vs. 0.7 +/- 0.2 microg/liter (1.6 +/- 0.6 vs. 2.0 +/- 0.6 nmol/liter); P = 0.63], and androstenedione [-1 +/- 12 vs. 8 +/- 11 ng/dl (-0.03 +/- 0.42 vs. 0.28 +/- 0.39 nmol/liter), P = 0.61] responses to hCG were not different between the groups. Cortisol responses were increased and dehydroepiandrosterone sulfate responses were decreased in the human immunodeficiency virus-infected vs. control subjects after ACTH stimulation. The ratio of DHEA to cortisol was significantly decreased at 60 (71 +/- 11 vs. 107 +/- 10; P = 0.02) and 90 (63 +/- 8 vs. 102 +/- 9; P = 0.004) min post-ACTH in the human immunodeficiency virus-infected patients compared with control subjects. Baseline urinary free cortisol levels were not different between the groups [36 +/- 9 vs. 36 +/- 5 microg/24 h (99 +/- 26 vs. 100 +/- 13 nmol/d)]. The DHEA to cortisol ratio correlated with the CD4 count (r = 0.67; P = 0.01). These data demonstrate significant shunting of adrenal steroid metabolism away from androgenic pathways and toward cortisol production in human immunodeficiency virus-infected women with the wasting syndrome. In contrast, our data suggest intact ovarian androgen responsivity to hCG stimulation. Further studies of the mechanism of adrenal steroid shunting and the efficacy of androgen replacement in human immunodeficiency virus-infected women are necessary.

A genetic study of dehydroepiandrosterone sulfate measured before and after a 20-week endurance exercise training program: The HERITAGE Family Study

Familial aggregation and possible major gene effects were evaluated for the baseline serum dehydroepiandrosterone sulfate (DHEAS) level and the change in DHEAS in response to a 20-week exercise training program in a sample of 481 individuals from 99 Caucasian families who were sedentary at baseline and who participated in the HERITAGE Family Study. Baseline DHEAS levels were not normally distributed, and were therefore logarithmically transformed and adjusted for the effects of age and sex prior to genetic analysis. The DHEAS response to training was computed as the simple difference, post-training minus baseline, and was adjusted for the baseline DHEAS level, age, and sex. Maximal (genetic and familial environmental) heritabilities (using a familial correlation model) reached 58% and 30% for the baseline and the response to training, respectively. Our estimate for the baseline is generally in agreement with previous reports, suggesting that the magnitude of the familial effect underlying this phenotype in these sedentary families is similar to that in the general population. However, segregation analysis showed no evidence for a multifactorial familial component in data for either the baseline or the response to training. Rather, a major additive gene controlling the baseline was found. For the response to training in the complete sample, transmission of the major effect from parents to offspring was ambiguous, but in a subset of 56 "responsive" families (with at least 1 family member whose response to training was greater than 1 standard deviation) this major effect was Mendelian in nature. The putative major genes accounted for 50% and 33% of the variance for the baseline and the response to training, respectively. The novel finding in this study is that the baseline DHEAS level and the change in DHEAS in response to training may be influenced by major gene effects.

Value of buserelin testing in the evaluation of hirsute women.

It has been recently reported that many hirsute women are affected with functional ovarian hyperandrogenism (FOH)-a term that encompasses the heterogeneous polycystic ovary syndrome- and show an abnormal ovarian steroidogenic response to gonadotropin-releasing hormone (Gn-RH) agonists. The aims of the present study were to determine the prevalence of FOH by the assessment of 17-hydroxyprogesterone (17-OHP) response to the Gn-RH agonist buserelin, to correlate these abnormal responses to other parameters suggestive of PCOS, and to assess the possible adrenal origin of hyperandrogenism. Therefore, in 33 consecutive women with hirsutism serum LH, FSH, 17-OHP, dehydroepiandrosterone sulfate (DHEA-S), androstenedione (A), cortisol levels were evaluated in basal conditions and after the administration of buserelin (0.5 mg sc) and ACTH (tetracosactide 0.25 mg iv). Two patients were affected with a non classic congenital adrenal hyperplasia (CAH)-21OH deficiency. In 5 other women ACTH test caused a rate increase 17-OHP (30-0)/30 min > 19 nmol/L/min (0.25 +/- 0.03; mean +/- SE), suggesting the possible existence of heterozygote non classic CAH-21OH. One patient showed a DHEA-S response to ACTH (from 10.3 to 17.2 mumol/L), which was compatible with late-onset 3 beta-Hydroxy-delta 5 steroid dehydrogenase deficiency. Out of the 25 patients with normal responsiveness to ACTH, 11 women (group A) showed higher 17-OHP and A levels, in comparison to normal women, both in basal conditions (17-OHP = 4.18 +/- 0.72 vs 1.74 +/- 0.34 nmol/L, p < 0.005; A = 11.8 +/- 1.2 vs 6.0 +/- 0.7 nmol/L, p < 0.05) and after buserelin (17-OHP = 15.61 +/- 1.31 vs 6.96 +/- 0.9 nmol/L; A = 19.0 +/- 1.9 vs 7.5 +/- 0.8 nmol/L; p < 0.001). In 6 of these 11 patients basal and buserelin-stimulated LH levels were higher than in normals. The remaining 14 patients (group B) showed normal baseline and buserelin-stimulated 17-OHP and A concentrations. In this group only 2 patients had high basal and stimulated LH levels. An augmented LH/FSH ratio was present in 5 and 1 cases of groups A and B, and polycystic ovaries at ultrasonography were observed in 7 and 8 cases of groups A and B, respectively. It is to note that an abnormal 17-OHP response to buserelin was present also in 3 of the 5 patients with abnormal 17-OHP rise after ACTH test, suggesting an adrenal and ovarian cause of hyperandrogenism. In conclusion, an abnormal response to one or both stimulation test was present in 57% of cases: an adrenal origin of hirsutism was detected in 15%, a combined adrenal and ovarian origin was found in 9% and an ovarian cause was present in 33%. Buserelin testing is an useful means to reveal the presence of FOH.

Re-examination of the effect of hCG on plasma levels and renal excretion of dehydroepiandrosterone sulfate in healthy males

To reinvestigate the effect of hCG on circulating and urinary dehydroepiandrosterone sulfate (DHEAS), a hCG stimulation test (5000 IU administered i.m. at 8.30 h on 3 consecutive days) was performed in 6 healthy males (aged 24 to 35 years). Blood specimens and 24-h urine samples were collected immediately before the first and directly after the last hCG administration. Contrary to previous findings in normal men, the present study revealed significant DHEAS responses after testicular stimulation with hCG: plasma DHEAS increased from 7.9 ± 2.3 to 9.6 ± 2.2 μmol/L ( P < 0.05) and urinary DHEAS from 5.7 ± 3.6 to 9.3 ± 5.2 μmol/day ( P < 0.05). There was also a marked rise ( P < 0.05) in the urinary excretion of total 17-ketosteroid sulfates. Clear increases of unconjugated plasma dehydroepiandrosterone as well as of circulating and renally excreted androstenedione and testosterone definitely confirmed an adequate Leydig cell stimulation. Significant post-hCG changes were additionally observed for plasma and urinary 3α-androstanediol glucuronide (149% and 79% increases, respectively) and for urinary cortisol (21% decrease). Significant correlations were found for the post-hCG percent increases of plasma androstenedione versus plasma DHEAS ( r = 0.86) and for the percent increases of plasma testosterone versus urinary DHEAS ( r = 0.98), indicating that the extent of gonadal androgen elevations in the circulation of normal men is a determinant of DHEAS increases in blood or urine. These findings provide an explanation for the frequently observed sex differences for DHEAS in adults. In addition, the data suggests that the DHEAS rise during puberty in boys could possibly be modulated by the secretory activity of the testes.

Disparate effects of insulin reduction with diltiazem on serum dehydroepiandrosterone sulfate levels in obese hypertensive men and women.

Evidence suggests that amelioration of hyperinsulinemic insulin resistance in men with calcium channel blockers of the dihydropyridine class is associated with a fall in serum insulin and a rise in serum dehydroepiandrosterone sulfate (DHEA-S) concentrations. The present study was conducted to determine whether 1) the nondihydropyridine calcium channel blocker diltiazem also reduces circulating insulin levels in humans, and 2) a reduction in circulating insulin with a calcium channel blocker is associated with a rise in serum DHEA-S concentrations in women as well as men. Ten obese hypertensive men and 13 obese hypertensive postmenopausal women were studied. Subjects were assessed at baseline and after the oral administration of diltiazem (60 mg, three times daily) for 18 days. Diltiazem treatment was associated with reductions in fasting serum insulin levels in both the men (from 91 +/- 14 to 56 +/- 12 pmol/L; P < 0.03) and women (from 92 +/- 20 to 48 +/- 9 pmol/L; P = 0.05). Serum glucose levels did not change in either group. In men, concurrent with the fall in serum insulin levels, serum DHEA-S levels rose from 4.05 +/- 1.06 to 6.91 +/- 1.32 mumol/L (P < 0.04), and serum DHEA levels rose from 14.4 +/- 3.0 to 24.3 +/- 4.6 nmol/L (P = 0.05) with diltiazem treatment, whereas serum cortisol did not change. In contrast, diltiazem administration in the women was not associated with any change in serum DHEA-S, DHEA, or cortisol levels. These observations suggest that the action of calcium channel blockers to lower fasting serum insulin levels is not specific for the dihydropyridine class and applies to both men and women. Furthermore, the finding of a sex-based disparity in DHEA-S and DHEA responses to insulin reduction suggests that the metabolism of these steroids may be regulated differently in men than in women.

Serum androgens in hyperinsulinemic Pima Indian and obese Caucasian women and their response to short-term insulin infusion

Insulin resistance and its attendant hyperinsulinemia has been linked with hyperandrogenism. Insulin resistance is characteristic of the Pima Indians of the Gila River Indian community in central Arizona. Serum androgens, testosterone and dehydroepiandrosterone sulfate (DHEA-S) were quantitated at baseline and in response to low- and high-dose insulin infusion in 11 obese, hyperinsulinemic Pima Indian and 10 obese, hyperinsulinemic Caucasian women and were compared with baseline androgens in 16 nonobese Caucasian women. While there was no significant testosterone or DHEA-S response to short-term insulin infusion in either Pimas or obese Caucasians, both these groups had higher baseline testosterone concentrations (67 +/- 6.5 ng/dl in the Pimas, 55 +/- 5.9 ng/dl in the obese Caucasians) as compared with the nonobese Caucasians (28 +/- 2 ng/dl; p < 0.001). Baseline DHEA-S concentrations were not significantly different in the three groups. Given the hyperinsulinemic status of both the Pimas and the obese Caucasians, the finding of higher testosterone concentrations in these subjects as compared with nonobese Caucasians supports a role for insulin in ovarian androgen production and demonstrates that hormonal interactions that may be operating in obese hyperinsulinemic Caucasian subjects also operate in obese, hyperinsulinemic Pima Indians.

The prevalence and significance of elevated dehydroepiandrosterone sulfate levels in anovulatory women

One hundred nineteen euprolactinemic anovulatory infertility patients who were being evaluated for induction of ovulation with clomiphene citrate were studied to determine the prevalence of increased adrenal androgen (AA) secretion in this group. Fifty percent of these patients exhibited increased AA secretion, as evidenced by an elevated serum dehydroepiandrosterone sulfate (DHEA-S) level. Seventy-seven percent of these women with elevated levels of DHEA-S were nonhirsute . Twenty-six patients with elevated serum DHEA-S levels underwent adrenocorticotropic hormone (ACTH) stimulation tests in order to determine a possible mechanism(s) for the increase in DHEA-S. Plasma ACTH, as well as total, low-density lipoprotein, and high-density lipoprotein cholesterol were also measured. These levels were normal and did not correlate with the elevated levels of DHEA-S. Seven of 16 patients (34%) had exaggerated responses of serum DHEA-S and of 17-OH pregnenolone to ACTH stimulation. In six of these seven patients, our data suggested the occurrence of a mild deficiency of 3 beta-ol dehydrogenase-isomerase. All of these six patients were considered to have polycystic ovary syndrome. While these data do not explain the increased AA secretion in the majority of patients with elevated levels of DHEA-S, we suggest that serum DHEA-S is frequently elevated in anovulatory infertile patients.