Plasma Levels Of Adrenal Androgens Research Articles

Relationships of Urinary Adrenal Steroids at Age 8 Years with Birth Weight, Postnatal Growth, Blood Pressure, and Glucose Metabolism

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. 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. 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. 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.

Effects of metformin on adrenal steroidogenesis in women with polycystic ovary syndrome

Objective: To determine whether the administration of metformin, an insulin-sensitizing agent, is followed by changes in adrenal steroidogenesis in women with polycystic ovary syndrome (PCOS). Design: Prospective trial. Setting: Department of Obstetrics and Gynecology, University of Siena, Siena, Italy. Patient(s): Fourteen women with PCOS. Intervention(s): Blood samples were obtained before (−15 and 0 minutes) and after (15, 30, 45, and 60 minutes) the administration of ACTH (250 μg). Metformin then was given at a dosage of 500 mg three times a day for 30–32 days, at which time the pretreatment study was repeated. Main Outcome Measure(s): The adrenal androgen responses to ACTH before and after treatment with metformin. Result(s): Ovulation occurred in two women (14%) in response to metformin treatment. A significant reduction in basal concentrations of free testosterone and a significant increase in concentrations of sex hormone-binding globulin were observed. The administration of metformin was associated with a significant reduction in the response of 17α-hydroxyprogesterone, testosterone, free testosterone, and androstenedione to ACTH. The ratio of 17α-hydroxyprogesterone to progesterone, which indicates 17α-hydroxylase activity, and the ratio of androstenedione to 17α-hydroxyprogesterone, which indicates 17,20-lyase activity, were significantly lower after a month of metformin treatment, indicating a reduction in the activities of these enzymes. Conclusion(s): The administration of metformin to unselected women with PCOS led to a reduction in the adrenal steroidogenesis response to ACTH. This finding supports the hypothesis that high insulin levels associated with PCOS may cause an increase in plasma levels of adrenal androgens.

Early clinical experience with liarozole (Liazal) in patients with progressive prostate cancer.

Liarozole (Liazal) is the first retinoic acid (RA) metabolism blocking agent (RAMBA) in clinical practice. RAMBA therapy promotes differentiation and inhibits proliferation by increasing endogenous RA in tumours. Liarozole was investigated in two open-label pilot studies of 100 patients with progressive prostate cancer in relapse despite previous androgen ablation. Liarozole (150-300 mg twice daily, for > or = 1 month) produced > or = 50% reduction in prostate specific antigen (PSA) serum levels in 15 of 30 evaluable patients in study 1 (50%) and 10 of 55 patients in study 2 (18%). PSA responders had more marked reductions in prostatic acid phosphatase, alkaline phosphatase and symptom scores for bone pain and urological symptoms, and improved general well being. Plasma levels of adrenal androgens did not alter during chronic treatment with liarozole nor at adrenocorticotrophic hormone (ACTH) stimulation test. Liarozole did not alter plasma levels of adrenal androgens or cortisol. Cortisol response to ACTH stimulation was slightly blunted. Liarozole was generally well tolerated. Dermatological adverse events were probably related to increased intracellular RA. Liarozole appears to be a promising treatment option in prostate cancer.

The effect of flutamide on basal and ACTH-stimulated plasma levels of adrenal androgens in patients with advanced prostate cancer.

The effect of flutamide on basal and ACTH-stimulated plasma levels of adrenal androgens was investigated in 6 patients with untreated advanced prostate cancer, aged 52-75 yr. Flutamide was administered (250 mg three times daily) for 10 days; before and after treatment, a synthetic ACTH1-24 stimulation test (250 micrograms im, with blood sampling immediately before and 60 min after the stimulus) was performed. Basal plasma 17OH-pregnenolone (delta 5-17OHP), 170H-progesterone (delta 4-17OHP), androstenedione (A), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) were unchanged by flutamide treatment. In contrast, basal plasma testosterone (T) concentrations significantly increased (p less than 0.05). The response of cortisol delta 4-17OHP, delta 5-17OHP, A and DHEA to ACTH, as well as the ACTH-stimulated delta 5-17OHP/delta 4-17OHP, delta 5-17OHP/DHEA, delta 4-17OHP/A and DHEA/A ratios, were unchanged by flutamide treatment. These findings indicate that: a) Short-term flutamide administration enhances testicular steroidogenesis, via augmented LH pulse frequency; b) Adrenal steroidogenesis seems to be not affected by the drug, since ACTH-stimulated plasma levels of adrenal androgens and precursors/products ratios were unchanged.

Scintigraphic evidence of adrenal cortical dysfunction in the polycystic ovary syndrome.

The polycystic ovary syndrome (PCO) is frequently associated with elevated plasma levels of adrenal androgens and/or abnormal adrenal androgen responses to hormonal stimulation and suppression. Because of the overlap in the output of hormones between the adrenal glands and the ovaries, we measured adrenal iodocholesterol accumulation as an index of adrenocortical function in 11 women with PCO confirmed by laparoscopy or culdoscopy. All patients had normal dexamethasone suppression of plasma cortisol or urinary 17-hydroxycorticosteroid excretion. 6 beta-[131I]Iodomethylnorcholesterol (NP-59) adrenal scintiscans showed bilateral and excessive adrenal cortical uptake in PCO patients [0.46 +/- 0.08% (+/- SE) of the administered dose compared to 0.21 +/- 0.01% in a group of normal women; P less than 0.05]. The elevation of adrenal cortical NP-59 uptake in PCO was quantitatively similar to that in women with ACTH-dependent Cushing's syndrome (0.64 +/- 0.11%; P greater than 0.1). These data support the presence of abnormal adrenal cortical function in patients with PCO. The adrenal dysfunction of PCO most likely represents abnormal control of adrenal androgen production/secretion.

Inhibition of basal and adrenocorticotropin-stimulated plasma levels of adrenal androgens after treatment with an antiandrogen in castrated patients with prostatic cancer.

The basal plasma levels of cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and testosterone were studied in 20 patients with advanced prostatic cancer receiving combined treatment with an LHRH agonist and an antiandrogen [5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2 4-imidazolidinedione]. After 60 days of combined antihormonal therapy, plasma levels of testosterone decreased from 5.44 +/- 0.44 (SEM) to 0.136 +/- 0.052 ng/ml (2.5% of control). Somewhat unexpectedly, the plasma concentrations of the adrenal androgens DHEA and DHEA-S were reduced to 45 +/- 7 and 64 +/- 4% of control, respectively. The maximal reduction in plasma adrenal androgen levels occurred between 2 and 4 weeks of treatment. Whereas the increase in serum cortisol, 17-hydroxypregnenolone, and 17-hydroxyprogesterone concentrations 2 1/2 h after the injection of 0.25 mg human ACTH 1-24 was not affected by the combined treatment, the increment of DHEA and androstenedione after the same stimulus was reduced from 3.1 +/- 0.98 and 0.73 +/- 0.11 to 1.48 +/- 0.5 and 0.31 +/- 0.05 ng/ml, respectively. The reduced levels of serum DHEA and DHEA-S were not due to the LHRH agonist by itself, since similarly low levels of serum DHEA and DHEA-S were found in patients surgically castrated and receiving the same antiandrogen. These data suggest that treatment with an antiandrogen in castrated men inhibit the formation of adrenal androgens due to a blockade at the level of 17, 20-desmolase. The efficiency of the new combined antihormonal therapy (castration and antiandrogen) aimed at complete androgen neutralization in prostate cancer is thus further facilitated.

Effect of human growth hormone on adrenal androgens in children with growth hormone deficiency.

The effect of human growth hormone (hGH) on adrenal androgen secretion was assessed in 7 patients (5 males, 2 females) with GH deficiency but normal ACTH-cortisol function. Patients ranged in age from 9 5/12 to 14 8/12 years (median 12 years). Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and urinary excretion of 17-ketosteroids (17-KS) and free cortisol were determined before, during short-term (2 U/day X 3) and after long-term (6 months) treatment with hGH. No significant change was noted in the plasma concentration or urinary excretion of steroids during the short-term administration of hGH. Despite a significant increase in growth velocity during 6 months of hGH therapy (8.2 vs. 4.5 cm/year, p less than 0.01), the plasma concentrations of DHEA-S and the urinary 17-KS and free cortisol levels were unchanged. These results fail to substantiate a role for hGH in the physiologic control of adrenal androgen secretion. Thus, the low plasma levels of adrenal androgens sometimes seen in GH-deficient patients are not due to the absence of GH per se.

Effect of induced hyperprolactinemia on the plasma levels of C19 steroids in humans

In order to investigate the relationship between the increment of plasma prolactin (PRL) levels and the change of plasma levels of PRL, DHEA-S, cortisol, aldosterone and 17 alpha OH delta 5-P were quantified by respective RIA in patients treated with TRH parenterally or with sulpiride orally. The results were as follows: During the infusion of TRH, plasma levels of PRL reached the maximal values within 30 min and then declined gradually in spite of continued TRH stimulation. Sulpiride given orally for 12 consecutive days in the luteal phase of the menstrual cycle caused a significant increase in the plasma PRL level. This increase was higher than that obtained in the experiment during the follicular phase. No significant change in the plasma level of 17 alpha OH delta 5-P was observed TRH sulpiride administration. In 3 out of 9 cases, plasma DHEA-S levels were elevated significantly on day 13 to 14 of the experimental course. These results indicate that the responsiveness of plasma levels of adrenal androgens to the raised plasma PRL level requires a certain period of time in the hyperprolactinemic state in the human female.

Plasma levels of adrenal androgens before and throughout puberty

Plasma levels of androstenedione,dehydroepiandrosterone, dehydroepiandrosterone sulphate (DHA-S), and testosterone (T), were measured (RIA after chromatographic separation) before and throughout puberty in 90 normal subjects and 235 children with various endocrine and growth disorders. In normal prepubertal boys, but not in girls, plasma levels of androgens rise significantly after the age of 6 years. The only sex differences are for DHA-S in the age range 1-6 and for T after 6 years. All values increase throughout puberty. In a longitudinal study (177 determinations in 39 hypopituitary patients), two distinct populations with either normal or low levels were found. In growth delay, levels are normal for bone age (BA), but not for chronological age (CA). In precocious puberty and simple obesity levels are high for CA, but normal for BA. It appears that plasma levels of adrenal androgens are a helpful tool in growth and puberty disorders.