Basal Dehydroepiandrosterone Sulfate Research Articles

P-613 Association between basal androgen concentrations and number of follicles on the day of triggering final oocyte maturation in poor responders undergoing IVF; A prospective study

Abstract Study question Are basal androgen concentrations associated with the number of follicles on the day of triggering final oocyte maturation in poor responders undergoing in vitro fertilization (IVF)? Summary answer A significant negative association is present between (dehydroepiandrosterone sulfate) DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation. What is known already Studies in animals have shown that androgens promote early follicular development and granulosa cell proliferation, by augmenting follicle-stimulating hormone (FSH) receptor expression in granulosa cells. Several retrospective studies have evaluated the association between basal androgen concentrations and follicular development in normal and poor responders undergoing ovarian stimulation for IVF with conflicting results. Study design, size, duration This prospective study was performed between 02/2020 and 01/2022 in 103 poor responders according to the Bologna criteria. Androgens, including total testosterone, sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), Δ4-androstenedione and 17-OH progesterone (17-OHP), were measured at the initiation of ovarian stimulation, using the automated Elecsys immunoanalyser (Roche Diagnostics, Mannheim, Germany). Ovarian stimulation was performed using a fixed dose of 300 IU of recombinant gonadotrophins and gonadotrophin-releasing hormone (GnRH) analogues. Participants/materials, setting, methods Triggering of final oocyte maturation was performed in the presence of three follicles of ≥ 17mm. The primary outcome measure was the number of follicles ≥11mm on the day of triggering final oocyte maturation. The association between androgen concentrations and the number of follicles ≥11mm on the day of triggering was evaluated using generalized estimating equations, accounting for female age and body mass index (BMI). Values were expressed as coefficient (coef) or mean (95% confidence interval). Main results and the role of chance Female age was 41.9 (41.2-42.6) years, while BMI was 26.1 (24.9-27.3) kg/m2. The duration of ovarian stimulation was 10.3 (9.7-10.8) days and the total dose of gonadotrophins required was 3058 (2903-3213) IU. The number of follicles ≥11 mm on the day of triggering final oocyte maturation was 6.1 (5.3-7.0). The number of COCs retrieved was 3.9 (3.2-4.6), the number of MII oocytes was 3.4 (2.8-3.9) and the number of 2pn oocytes was 2.5 (2.1-2.8). No significant association was found between basal testosterone (coef: -0.008, -0.019 to + 0.003, p = 0.17), 17-OHP (coef: -0.044, -0.391 to + 0.303, p = 0.80), SHBG (coef: -0.002, -0.007 to + 0.002, p = 0.25) Δ4-androstenedione (coef: -0.101, -0.306 to + 0.104, p = 0.33) concentrations and the number of follicles ≥11mm on the day of triggering final oocyte maturation. In contrast, a significant negative association was found between basal DHEAS (coef: -0.011, -0.019 to -0.003, p = 0.007) concentrations and the number of follicles ≥11 mm on the day of triggering final oocyte maturation. Higher DHEAS concentrations were associated with the development of fewer follicles ≥11 mm. Limitations, reasons for caution This prospective study evaluated the association between basal androgen concentrations and the number of follicles on the day of triggering final oocyte maturation in poor responders stimulated with a fixed dose of recombinant FSH. However, the precision of the estimates could be increased by analyzing a larger study population. Wider implications of the findings DHEA supplementation in poor responders undergoing IVF has not been shown to improve ovarian response. Given the significant negative association between DHEAS concentrations and the number of follicles on the day of triggering final oocyte maturation, future studies on DHEA supplementation should consider basal DHEAS concentrations. Trial registration number N/A

Low DHEAS: A Sensitive and Specific Test for the Detection of Subclinical Hypercortisolism in Adrenal Incidentalomas.

Subclinical hypercortisolism (SH) occurs in 5% to 30% of adrenal incidentalomas (AIs). Common screening tests for adrenocorticotropin-independent hypercortisolism have substantial false-positive rates, mandating further time and resource-intensive investigations. To determine whether low basal dehydroepiandrosterone sulfate (DHEAS) is a sensitive and specific screening test for SH in AI. In total, 185 patients with AI were screened for adrenal medullary (plasma metanephrines) and cortical [1 mg overnight dexamethasone suppression test (ONDST), 24-hour urinary free cortisol (UFC), serum DHEAS, plasma renin, and aldosterone] hyperfunction. Positive ONDST [≥1.8 mcg/dL (≥50 nmol/L)] and/or UFC (more than the upper limit of reference range) results were further investigated. We diagnosed SH when at least 2 of the following were met: raised UFC, raised midnight serum cortisol, 48-hour dexamethasone suppression test (DST) cortisol ≥1.8 mcg/dL (≥50 nmol/L). 29 patients (16%) were diagnosed with SH. Adrenocorticotropin was <10 pg/mL (<2.2 pmol/L) in all patients with SH. We calculated age- and sex-specific DHEAS ratios (derived by dividing the DHEAS by the lower limit of the respective reference range) for all patients. Receiver operating characteristic curve analyses demonstrated that a ratio of 1.12 was sensitive (>99%) and specific (91.9%) for the diagnosis of SH. Cortisol following 1 mg ONDST of 1.9 mcg/dL (53 nmol/L) was a sensitive (>99%) screening test for SH but had lower specificity (82.9%). The 24-hour UFC lacked sensitivity (69%) and specificity (72%). A single basal measurement of DHEAS offers comparable sensitivity and greater specificity to the existing gold-standard 1 mg DST for the detection of SH in patients with AIs.

Heritability of serum dehydroepiandrosterone sulphate levels and pubertal development in 6∼18-year-old girls: a twin study

Background: Dehydroepiandrosterone sulphate (DHEAS), the most plentiful circulating adrenal hormone, may be considered as a marker of the onset of adrenarche and is involved in pubertal development and metabolic disorders.Aim: The objective of this study is to determine the genetic and environmental influences on the variation of basal DHEAS levels and pubertal development in pubertal girls.Subjects and methods: Three hundred and sixty twin girls aged 6–18-years were enrolled, consisting of 132 monozygotic pairs and 48 dizygotic pairs. Anthropometric and sexual characteristics were examined. Serum DHEAS was measured by RIA. Estimates of genetic and environmental components of variance were based on the theory of normal maximum likelihood in Mx package.Results: Serum DHEAS concentrations of PH-II and PH-III were significantly higher than Tanner stage PH-I (p < .05) and maintained higher levels in PH-IV ∼ V. Heritability of serum DHEAS estimated by model-fitting on data from 180-pairs of twins is 0.61 (0.52–0.70), the rest of the variance in DHEAS levels could be explained by unique environmental influences and age. The heritabilities of DHEAS in two pubertal sub-groups (PH-I and PH-II-V) are 0.82 (0.71–0.90) and 0.63 (0.52–0.74), respectively. The heritability index of menarche, breast development and pube development are 0.71, 0.35 and 0.45, respectively.Conclusions: Serum DHEAS concentrations of pubertal girls are mainly influenced by genetic factors, especially during the period of adrenarche. The results stress the importance of research into the genetic regulation of the endocrine regulators involved in adrenarche and related metabolic disorders in girls.

Central Adrenal Insufficiency Could Not Be Confirmed by Measurement of Basal Serum DHEAS Levels in Pubertal Children

Background: Central adrenal insufficiency (CAI) is due to a decrease of CRH and/or ACTH secretion. ACTH-dependent dehydroepiandrosterone sulphate (DHEAS) has been postulated as a possible marker of adrenal function in adult patients. Aims: To evaluate the usefulness of basal serum DHEAS determination to diagnose CAI in pubertal patients with a suspected diagnosis of CAI. Methods: Ninety-four pubertal patients suspected of having CAI were divided into two groups according to sufficient (group 1) or insufficient (group 2) low-dose ACTH test serum cortisol response. Concordance with low (<2.5th percentile) or normal (≥2.5th percentile) basal serum DHEAS levels for age and sex, respectively, was analysed. Results: Fifty patients (53.2%) in group 1 and 44 (46.8%) in group 2 were included. The median value of serum DHEAS levels in group 2 (0.7 µmol/l, interquartile range 0.44-1.49) was significantly lower than in group 1 (2.13 µmol/l, interquartile range 0.87-3.5; p < 0.03). Nevertheless, serum basal DHEAS levels as a diagnostic marker of CAI showed 39% sensitivity and 80% specificity. Conclusion: In pubertal patients, basal serum DHEAS levels do not seem to be a useful tool to diagnose either sufficiency or insufficiency of secondary adrenal function.

Low level of basal testosterone: a significant risk factor for poor oocyte yield after ovulation induction.

The objective of this study was to further investigate the association of low androgen levels and poor ovarian response or negative pregnancy outcome in in vitro fertilisation treatment using a retrospective cohort study. Chinese women (n=1950) of relatively young age, with normal range of basal FSH and antral follicle count undergoing an in vitro fertilisation cycle were selected and testosterone and dehydroepiandrosterone sulfate levels were measured on Day 3 of the menstrual cycle before subsequent in vitro fertilisation treatment. The main outcome measures of the study were ovarian stimulation parameters and clinical pregnancy. Basal testosterone levels of poor responders and non-pregnant women were significantly lower than normal responders and pregnant women, respectively. Patients with low basal testosterone levels had significantly lower number of mature oocytes, cleavage-stage embryos, frozen embryos, lower fertilisation and pregnancy rates and required higher doses of gonadotrophins. Androgen levels had no correlation with early spontaneous abortion rates. Multivariable logistic analysis revealed that low basal testosterone (<0.88nmolL(-1)) was an independent risk factor for poor oocyte yield (odds ratio: 1.61; 95% confidence interval: 1.01-2.57; P=0.045). In conclusion, a low level of basal testosterone was a significant risk factor for poor oocyte yield after ovarian stimulation and might negatively influence pregnancy chances with in vitro fertilisation. Basal dehydroepiandrosterone sulfate levels were not predictive for poor ovarian response or negative pregnancy outcome in this population.

Do women with premenopausal-onset rheumatoid arthritis have relative insufficiency or imbalance of adrenocortical steroids?

Adrenocortical steroids may influence susceptibility to rheumatoid arthritis (RA). Serum levels of adrenocortical steroids in female RA patients not previously treated with glucocorticoids were reviewed in this paper, as were controlled cohort studies of predisease (pre-RA) and control (CN) women. Serum dehydroepiandrosterone sulfate (DHEAS) levels were lower in most reports of premenopausal-onset RA patients not treated with glucocorticoids and in the baseline levels in one cohort study of pre-RA females compared with CN subjects. The pre-RA versus CN cohort difference was confirmed in an independent laboratory. Basal DHEAS and cortisol levels correlated oppositely in pre-RA versus CN women, suggesting relative adrenocortical androgenic insufficiency in case subjects. Clinical observations of lower androstenedione levels in premenopausal RA patients were also reported in pre-RA versus CN subjects who had lower DHEAS and cortisol values. In summary, a minority of premenopausal-onset RA females had decreased adrenocortical androgenic steroid levels and exhibited an adrenal androgen-to-cortisol steroid imbalance.

Repeated Moderate Stress Stimulates the Production of Dehydroepiandrosterone Sulfate (DHEAS) and Reduces Corticosteroid Imbalance in Old Macaca Mulatta

Young (6-8 years) and old (21-30 years) Macaca mulatta females were subjected to gentle immobilization (2 h daily at 15.00) for 10 days. Blood specimens were collected before the exposure and 15, 30, 60, 120, 240 min and 24 h after the beginning of exposure on days 1, 3, and 10. The adrenocortical reaction to stress was maximum on day 1 in all animals. The increase of cortisol (F) and dehydroepiandrosterone sulfate (DHEAS) concentrations in young monkeys decreased on days 3 and 10, DHEAS drop being less pronounced in comparison with F, as a result of which F/DHEAS molar concentration ratio changed negligibly. In old monkeys the basal DHEAS levels were lower, while the F/DHEAS ratio was higher than in young animals. Repeated immobilizations inhibited F elevation on day 3, caused no changes in DHEAS reaction, led to increase of basal DHEAS levels and to a reduction of F/DHEAS ratio on days 2, 3, 4, 10, 11. Hence, chronic moderate stress stimulated the production of DHEAS and reduced the corticosteroid imbalance in old monkeys.

Assessment of Adrenal Functions in Patients with Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease and extrarenal manifestations may be observed in many organ systems. Hypothalamus-pituitary-adrenal axis was not evaluated extensively in patients with ADPKD. We aimed to evaluate this axis in these patients. Twenty two patients with ADPKD and 27 healthy subjects were enrolled. Basal dehydroepiandrosterone sulfate (DHEAS) levels and cortisol and DHEA responses to low dose short adrenocorticotropin stimulation test were assessed. Correlation analyses of these parameters with glomerular filtration rates (GFR), renal volumes and pain characteristics in patients with ADPKD were performed. Patients with ADPKD had higher basal cortisol levels (12.1 ± 3.4 vs. 9.6 ± 4.3 μg/dL, p=0.033), and higher basal cortisol/DHEAS ratios (0.073 ± 0.05 vs. 0.045 ± 0.02, p=0.015) compared to controls. None of the subjects had inadequate response to adrenocorticotropin stimulation. Patients with ADPKD had lower delta cortisol (absolute increase between peak and basal) levels (10.3 ± 2.8 vs. 12.6 ± 4.2 μg/dL, p=0.026) compared to controls. Subgroup analysis showed that significant differences existed only between female patients and female controls. There was no significant correlation between cortisol levels and renal volumes or GFR. A significant correlation was found only between delta cortisol and pain frequency in female patients. Patients with ADPKD had higher basal cortisol levels, higher basal cortisol/DHEAS ratios and lower delta cortisol levels compared to controls, indicating promptly stimulated zona fasciculata function. Further studies are needed to confirm these results and to investigate possible underlying mechanisms.

The Effects of Galantamine Hydrobromide Treatment on Dehydroepiandrosterone Sulfate and Cortisol Levels in Patients with Chronic Fatigue Syndrome

ObjectiveMental fatigue, cognitive disorders, and sleep disturbances seen in chronic fatigue syndrome (CFS) may be attributed to cholinergic deficit. A functional deficiency of cholinergic neurotransmission may cause the hypothalamic-pituitary-adrenal axis hypoactivity seen in CFS. Therefore, we investigated the alterations in stress hormones such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in CFS patients before and after 4-week administration of galantamine hydrobromide, a selective acetylcholinesterase inhibitor, and aimed to investigate whether there are any relationships between the probable hormonal changes and cholinergic treatment.MethodsBasal levels of cortisol and DHEAS were measured in 29 untreated CFS patients who were diagnosed according to Centers for Disease Control (CDC) criteria and in 20 healthy controls. In the patient group, four weeks after 8 mg/d galantamine hydrobromide treatment, cortisol and DHEAS levels were measured again. After the treatment 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according to the reduction in their Newcastle Research Group ME/CFS Score Card (NRG) scores.ResultsImportant findings of this study are lower pre-and post-treatment cortisol levels and in all CFS patients compared to controls (F=4.129, p=0.049; F=4.803, p=0.035, respectively); higher basal DHEAS values and higher DHEAS/cortisol molar ratios which were normalized following four weeks' treatment with 8 mg/d galantamine hydrobromide in the treatment-respondent group (F=5.382, p=0.029; F=5.722, p=0.025, respectively).ConclusionThe findings of the decrease in basal DHEAS levels and DHEAS/cortisol molar ratios normalizing with galantamine treatment may give some support to the cholinergic deficit hypothesis in CFS.

Dehydroepiandrosterone Sulfate in the Assessment of the Hypothalamic-Pituitary-Adrenal Axis

The role of dehydroepiandrosterone-sulfate (DHEA-S) in assessing the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected insufficiency is uncertain. The objective of the study was to prospectively evaluate the diagnostic value of DHEA-S on HPA function in consecutive patients with suspected HPA insufficiency with and without pituitary lesions at a tertiary referral center. In 70 consecutive patients, insulin tolerance test was accompanied by measurement of basal DHEA-S. Assessment of HPA axis was based on peak cortisol response in insulin tolerance test (normal > or = 550 nmol/liter). To account for the age and gender dependency of DHEA-S, a z-score was calculated using age- and gender-specific reference values of the assay. Individuals with HPA insufficiency had significantly lower z-scores than those with normal HPA function (-1.66 vs. -0.62, P < 0.0001). In individuals up to 30 yr of age, a z-score of -2.0 had 100% sensitivity and specificity regarding HPA function [area under receiver operating characteristics (ROC) curve 1.00], whereas z-scores proved less useful in older individuals. In individuals with pituitary macroadenoma, a z-score below -2.0 had 100% specificity to predict HPA insufficiency (area under ROC curve 0.82). In the absence of a pituitary adenoma, the diagnostic value of the z-score was reduced (area under ROC curve 0.71). Individuals with HPA insufficiency have lower z-scores for DHEA-S than those with normal HPA function. There is evidence that a z-score could be of diagnostic value in assessing HPA integrity, especially in younger patients and patients with pituitary macroadenoma, but further studies are needed to consolidate these findings.

Hypothalamic–pituitary–adrenal axis activity, dehydroepiandrosterone sulphate and their relationships with aggression in early and late alcohol withdrawal

The study aims at investigating the relationship between hypothalamic–pituitary–adrenal (HPA) axis alterations and aggression level in alcoholic patients during early and late alcohol withdrawal. Serum levels of basal cortisol and dehydroepiandrosterone sulphate (DHEAS) were measured three times, and cortisol and DHEAS response to dexamethasone twice during the early and late withdrawal periods in alcohol dependent males ( n = 30) and once in healthy control males ( n = 20). Abnormal cortisol non-suppression response to dexamethasone in dexamethasone suppression test (DST) was observed in some proportion of the patients in early withdrawal, which normalized in late withdrawal. The study revealed reduced basal DHEAS levels and reduced DHEAS response to dexamethasone in late withdrawal. When the patients were assessed in two separate groups as high- and low-aggressives, in the high-aggression group abnormality in DST was observed during both early and late withdrawal periods, in the low-aggression group it was observed only in early withdrawal. While basal DHEAS levels were low in the high-aggression group only in early withdrawal, it was reduced in the low-aggression group during late withdrawal period. Some alterations of the HPA axis during alcohol withdrawal might be associated not only with alcohol use per se but also with aggressivity tendency of alcoholic patients.

Low serum allopregnanolone levels in girls with precocious pubarche

Allopregnanolone, a neuroactive steroid, increases during pubertal development and high concentrations are present in subjects with precocious puberty. The aim of the present study was to evaluate serum allopregnanolone levels in girls with precocious pubarche (PP). Basal gonadotropins and steroid hormones were assessed in 17 girls with PP, 22 girls with central precocious puberty (CPP), 25 girls with normal puberty at the same pubertal stage of CPP ones, and 17 prepubertal girls. Adrenocorticotropin hormone (ACTH) and gonadotropin-releasing hormone (GnRH) stimulation tests were performed in all subjects with PP, and in 12 out of 22 with CPP. All girls with normal puberty underwent to GnRH test, while ACTH test was performed in 17 out of 25. Basal dehydroepiandrosterone sulfate (DHEAS) concentrations resulted significantly higher in PP and normal pubertal girls than in prepubertal ones. Allopregnanolone, gonadotropins and estradiol levels were significantly lower in PP group with respect to CPP ( P < 0.05), while they were comparable among PP, normal pubertal and prepubertal groups. After ACTH administration, allopregnanolone concentrations significantly increased in all groups ( P < 0.05). After GnRH stimulation, its levels significantly increased in CPP and normal pubertal controls ( P < 0.05), while no incremental rise was found in PP girls. In conclusion, our study shows that in girls with PP basal and GnRH-stimulated levels of allopregnanolone are significantly lower than in CPP girls. These data suggest that this neurosteroid may be considered a new marker of pubertal development.

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.

A Cross-Sectional Study of Dehydroepiandrosterone Sulfate in Prepubertal Children with Myelomeningocele

Objective: To assess biochemical characteristics of adrenarche in patients with myelomeningocele (MMC), we examined serum levels of dehydroepiandrosterone sulfate (DHEAS) in prepubertal MMC patients. Patients and Methods: The study included a total of 54 prepubertal patients with MMC and shunted hydrocephalus: 13 patients (2 m, 11 f; aged 4.6–10.1 years, mean 8.1 ± 0.4) with isolated pubarche (Tanner stage PH 2–4, B1 or testes volume ≤3 ml) and 41 prepubertal MMC patients without pubarche (17 m, 24 f; aged 2.0–11.9 years; mean 6.8 ± 2.5). DHEAS levels were measured directly by chemiluminescence immunoassay (Nichols, USA). Auxological data (supine length, body mass index (BMI), arm span) and bone age (BA) were recorded. Results(mean ± SD): Basal DHEAS levels correlated with chronological age (CA) (r = 0.32, p < 0.05), BA (r = 0.65, p < 0.01; n = 23), BMI (r = 0.54, p < 0.01) and pubic hair stage (PH1 vs. PH2–4, r = 0.49, p < 0.01). 10/11 patients aged 2–4 years had DHEAS levels in the normal range, whereas 18/40 (45.0%) of the 5- to 9-year-old patients showed elevated levels (>+2 SDS). Ten patients with isolated pubarche (10/13; 2 m, 8 f; CA 8.3 ± 1.5 years) and 9 patients without pubarche (9/41; 6 m, 3 f; CA 6.9 ± 2.1 years) had elevated DHEAS levels (+6.34 and +4.05 SDS, respectively). The values correlated with BA/CA ratio (p < 0.05, n = 23). There was a trend to higher BMI SDS levels in patients with elevated DHEAS levels. Conclusion: Our data show an early and increased activation of adrenal androgen secretion in MMC patients.

Ovulation After Glucocorticoid Suppression of Adrenal Androgens in the Polycystic Ovary Syndrome Is Not Predicted by the Basal Dehydroepiandrosterone Sulfate Level

Adrenal androgen (AA) excess, primarily in the form of dehydroepiandrosterone sulfate (DHEAS), affects over 50% of women with the polycystic ovary syndrome (PCOS). Nonetheless, it is unclear what role AA excess plays in the PCOS-associated oligo-ovulation. We have hypothesized that AAs are important in the maintenance of the ovulatory dysfunction of women with PCOS and AA excess, which can be improved by glucocorticoid suppression. To test our hypothesis we prospectively studied 36 unselected women, ages 18-40 yr, with PCOS; i.e. oligomenorrhea (cycles > 35 days in length), and clinical/ biochemical evidence of hyperandrogenism (i.e. hirsutism and/or hyperandrogenemia), after the exclusion of related disorders. After informed consent, all patients underwent an acute ACTH-(1-24) stimulation test, measuring androstenedione, dehydroepiandrosterone (DHEA) and cortisol (F), and were then treated with dexamethasone 0.5 mg/day for four cycles. Ovulatory function was assessed before and during treatment using a basal body temperature calendar and day 22-24 progesterone (P4) levels. If patients were anovulatory (P4 4 ng/mL); and of the remaining, 10 (28%) had only one, five (14%) had two, and three (8%) had three ovulatory cycles. There were no significant differences either in physical features, basal hormones, adrenal response to ACTH stimulation, or hormonal levels at the end of treatment, between those women ovulating and those not. Finally, there were no differences in ovulatory response to dexamethasone therapy between women with (n = 14) and without (n = 22) DHEAS excess (i.e. DHEAS > 2750 ng/mL). In conclusion, the data from this prospective study do not suggest that continuous dexamethasone suppression results in consistent ovulation in any PCOS patient, regardless of basal DHEAS levels. Furthermore, this treatment is associated with significant side-effects, notably weight gain. Finally, these data suggest that, while AA may be an important risk factor for PCOS, once the syndrome is established, they play a limited role in the associated ovulatory dysfunction.

Ovulation After Glucocorticoid Suppression of Adrenal Androgens in the Polycystic Ovary Syndrome Is Not Predicted by the Basal Dehydroepiandrosterone Sulfate Level

Ovulation After Glucocorticoid Suppression of Adrenal Androgens in the Polycystic Ovary Syndrome Is Not Predicted by the Basal Dehydroepiandrosterone Sulfate Level

The contributions of oestrogen and growth factors to increased adrenal androgen secretion in polycystic ovary syndrome

Adrenal hyperandrogenism is prevalent in many women with polycystic ovary syndrome (PCOS), although the expression of this enhanced secretion may be heterogeneous. Since no single factor acts in isolation, this study was performed to assess the influence of oestradiol (total and unbound), insulin, insulin-like growth factor (IGF)-I, IGF-II and the binding proteins IGFBP-I, and IGFBP-3, on basal and adrenocorticotrophic hormone (ACTH) stimulated adrenal androgen secretion in 25 women with PCOS and 10 matched ovulatory controls. Women with PCOS exhibited elevations of all androgens as well as unbound oestradiol, insulin and non-IGFBP-1 bound IGF-I. Positive correlations were noted between oestrogen and basal and ACTH stimulated delta 5 adrenal androgens. Serum IGF-I was only correlated with basal dehydroepiandrosterone sulphate (DHEA-S), while insulin exhibited a strong correlation with the delta 4 pathway and androstenedione formation in particular. This correlation was also confirmed by dividing the PCOS group into those women with and without hyperinsulinaemia. The activity of 17,20 lyase favouring androstenedione was increased in the hyperinsulinaemic women. By multivariate analyses, body mass index did not influence these findings. Although there are inherent difficulties in making major conclusions based on correlative analyses, it is suggested that oestrogen may have a greater influence on enhancing delta 5 adrenal androgen secretion, and insulin a greater effect on the delta 4 pathway. In turn, the relative importance of these influences may contribute to the heterogeneous nature of adrenal hyperandrogenism in PCOS.

Regulation of steroidogenesis by insulin-like growth factors (IGFs) in adult human adrenocortical cells: IGF-I and, more potently, IGF-II preferentially enhance androgen biosynthesis through interaction with the IGF-I receptor and IGF-binding proteins.

Although the effect of insulin-like growth factors (IGFs) in fetal adrenocortical cells has been investigated extensively, the role of the IGF system in the adult human adrenal gland remains unclear. In the present study we investigated the effect of recombinant human IGF-I and IGF-II on cortisol, dehydroepiandrosterone sulfate (DHEA-S) and cAMP synthesis in adult human adrenocortical cells in primary culture. Both IGFs stimulate basal as well as adrenocorticotropin (ACTH)-induced steroid secretion in a time- and dose-dependent fashion. While both IGFs (6.5 nM) induced only a moderate 2-fold increase in basal cortisol output after 48 h, the effect on basal DHEA-S secretion was significantly stronger, with a 2.7- and 3.7-fold stimulation by IGF-I and IGF-II respectively. Similarly, IGF-II enhanced ACTH-induced cortisol and DHEA-S secretion more potently than IGF-I. In dose-response experiments, the maximum stimulation of ACTH-induced DHEA-S secretion was induced by 1.6 nM IGF-I (2-fold increase) or IGF-II (2.9-fold increase), while the maximum response of cortisol secretion was elicited only at 13 nM IGF-I (2-fold increase) or IGF-II (2.5-fold increase). This resulted in a significant shift of the DHEA-S dose-response curves to the left, indicating a relative selective stimulation of androgen biosynthesis by physiologically low concentrations (0.4-3.2 nM) of IGF-II, and less potently by IGF-I. At all doses tested, the steroidogenic effect of IGF-II was significantly stronger than the effect of IGF-I. Although both IGF receptors are present in adult human adrenocortical cells, the steroidogenic effect of IGF-II is mediated through the IGF-I receptor, since [Arg54,55]IGF-II, which only binds to the IGF-I receptor, was equipotent with native IGF-II, whereas [Leu27]IGF-II, which preferentially binds to the type II IGF receptor, did not show any effect. In addition, [des1-3]IGF-I, which exhibits only minimal binding to IGFBPs, was significantly more potent than native IGF-I in stimulating adrenal steroid biosynthesis, and elicited almost the same maximum stimulatory effect as IGF-II and [des1-6]IGF-II. By Western ligand blotting of conditioned medium it was shown that adult human adrenocortical cells secrete various IGF-binding proteins (IGFBPs), which are induced differentially by treatment with ACTH. In conclusion, these results demonstrate that: (1)IGF-II stimulates basal as well as ACTH-induced DHEA-S and cortisol secretion from adult human adrenocortical cells more potently than IGF-I; (2) both IGFs predominantly stimulate androgen biosynthesis; (3) the steroidogenic effect of IGF-I and IGF-II is mediated through interaction with the IGF-I receptor; (4) the different steroidogenic potency of IGF-I and IGF-II might be explained by interaction of these ligands with locally produced IGFBPs. These data indicate that the IGF system plays an important role in the regulation of the differentiated function of adult human adrenocortical cells.

Effects of transforming growth factor-β on human fetal adrenal steroid production

Transforming growth factor-β (TGF-β) was found to inhibit basal and ACTH-stimulated steroid production by cultured human fetal adrenal cells. The inhibitory effects of TGF-β were both time and dose-dependent. Inhibition of basal dehydroepiandrosterone sulfate (DS) production usually was noted only after 3 or more days of treatment with ≥ 0.1 ng TGF-β/ml. The inhibitory effects of l ng/ml TGF-β on ACTH-stimulated DS production were more striking than those on cortisol production by both fetal zone and neocortical cells. TGF-β also was found to interfere with DS and cortisol production by fetal zone cells in response to forskolin and dibutyryl cAMP. TGF-β interfered with ACTH stimulation of cytochrome P450 17α mRNA in fetal zone and neocortex cells. These results are suggestive that TGF-β differentially inhibits DS and cortisol production by human fetal adrenal cells and that the site of TGF-β action on steroidogenesis may be distal to the generation of cAMP. Such results, along with those of others, are suggestive that TGF-β may play an autocrine/paracrine role in the human adrenal.

Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production.

We examined the regulation of steroid production in fetal zone cells from midgestation (16-21 weeks) human fetal adrenal glands to elucidate the mechanism by which these cells secrete large quantities of dehydroepiandrosterone sulfate (DHAS) and little cortisol in response to ACTH. Our underlying hypothesis is that estrogen and insulin-like to ACTH. Our underlying hypothesis is that estrogen and insulin-like growth factor-II (IGF-II) modulate the steroidogenic response of fetal zone cells to ACTH, driving steroid production toward DHAS rather than cortisol. We also hypothesize that the effects of IGF-II and estrogen on steroidogenesis are achieved by modulating the expression of key enzymes in the steroidogenic pathway. Basal cortisol secretion by cultured fetal zone cells was below the limit of assay sensitivity (< 0.54 pmol/10(5) cells.24 h), whereas basal DHAS secretion was 210.8 +/- 41.0 pmol/10(5) cells.24 h (mean +/- SE). ACTH-(1-24) increased the secretion of cortisol to 228.96 +/- 6.75 pmol/10(5) cells.24 h and that of DHAS to 2039.8 +/- 121.7 pmol/10(5) cells.24 h. Neither IGF-II nor estradiol (E2) affected basal (no added ACTH) steroid secretion by fetal zone cells. IGF-II increased ACTH-stimulated cortisol and DHAS secretion by fetal zone cells in a dose-dependent fashion. In contrast, E2 at high concentrations (1-10 mumol/L) decreased ACTH-stimulated cortisol production to basal levels, but increased ACTH-stimulated DHAS production 1.5- to 2-fold. Combinations of IGF-II (100 ng/mL) and E2 (1 mumol/L) increased ACTH-stimulated cortisol and DHAS secretion by 1.5- to 2-fold compared with control values. However, compared with cultures exposed to IGF-II alone, inclusion of E2 decreased ACTH-stimulated cortisol secretion by about 60% and increased ACTH-stimulated DHAS secretion by about 50%. IGF-II increased the abundance of ACTH-stimulated mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha hydroxylase/17,20 lyase P450 (P450c17), and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In addition, IGF-II increased the abundance of mRNA encoding P450c17 under basal conditions, but did not affect the basal expression of P450scc or 3 beta HSD. E2 had no effect on basal expression of these steroidogenic enzymes, but increased the abundance of ACTH-stimulated mRNA encoding P450scc and P450c17. The abundance of mRNA encoding 3 beta HSD was not affected by E2. The effect of IGF-II and E2 in combination on steroidogenic enzyme mRNA abundance was not different from that of IGF-II alone. These data indicate that IGF-II increases ACTH-stimulated steroid production in fetal zone cells by increasing the expression of key steroidogenic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)