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Impaired neurodevelopment in preterm infants is caused by prematurity itself; however, hypoxia/ischemia, inflammation, and hyperoxia contribute to the extent of impairment. Because preterm birth is accompanied by a dramatic decrease in 17β-estradiol (E2) and progesterone, preliminary clinical studies have been carried out to substitute these steroids in preterm infants; however, they failed to confirm significantly improved neurologic outcomes. We therefore hypothesized that the persistently high postnatal production of fetal zone steroids [mainly dehydroepiandrosterone (DHEA)] until term could interfere with E2-mediated protection. We investigated whether E2 could reduce hyperoxia-mediated apoptosis in three immature glial cell types and detected the involved receptors. Thereafter, we investigated protection by the fetal zone steroids DHEA, 16α-hydroxy-DHEA, and androstenediol. For DHEA, the involved receptors were evaluated. We examined aromatases, which convert fetal zone steroids into more estrogenic compounds. Finally, cotreatment was compared against single hormone treatment to investigate synergism. In all cell types, E2 and fetal zone steroids resulted in significant dose-dependent protection, whereas the mediating receptors differed. The neuroprotection by fetal zone steroids highly depended on the cell type-specific expression of aromatases, the receptor repertoire, and the potency of the fetal zone steroids toward these receptors. No synergism in fetal zone steroid and E2 cotreatment was detected in two of three cell types. Therefore, E2 supplementation may not be beneficial with respect to neuroprotection because fetal zone steroids circulate in persistently high concentrations until term in preterm infants. Hence, a refined experimental model for preterm infants is required to investigate potential treatments., (Copyright © 2017 Endocrine Society.)

Estriol biosynthesis in human placenta requires the uptake of a fetal liver-derived estriol precursor, 16α-hydroxydehydroepiandrosterone sulfate (16α-OH DHEAS), by placental syncytiotrophoblasts at their basal plasma membrane (BM), which faces the fetal circulation. The aim of this work is to identify the transporter(s) mediating 16α-OH DHEAS uptake at the fetal side of syncytiotrophoblasts by using human placental BM-enriched vesicles and to examine the contribution of the putative transporter to estriol synthesis at the cellular level, using choriocarcinoma JEG-3 cells. Organic anion transporter (OAT)-4 and organic anion transporting polypeptide 2B1 proteins were enriched in human placental BM vesicles compared with crude membrane fraction. Uptake of [(3)H]16α-OH DHEAS by BM vesicles was partially inhibited in the absence of sodium but was significantly increased in the absence of chloride and after preloading glutarate. Uptake of [(3)H]16α-OH DHEAS by BM vesicles was significantly inhibited by OAT4 substrates such as dehydroepiandrosterone sulfate, estrone-3-sulfate, and bromosulfophthalein but not by cyclosporin A, tetraethylammonium, p-aminohippuric acid, or cimetidine. These characteristics of vesicular [(3)H]16α-OH DHEAS uptake are in good agreement with those of human OAT4-transfected COS-7 cells as well as forskolin-differentiated JEG-3 cells. Estriol secretion from differentiated JEG-3 cells was detected when the cells were incubated with 16α-OH DHEAS for 8 hours but was inhibited in the presence of 50 μM bromosulfophthalein. Our results indicate that OAT4 at the BM of human placental syncytiotrophoblasts plays a predominant role in the uptake of 16α-OH DHEAS for placental estriol synthesis.

The adrenal steroid dehydroepiandrosterone (DHEA) produces cancer-preventive, antiatherosclerotic, antidiabetic, immunomodulating, and anti-inflammatory effects in laboratory animals. The clinical use of DHEA is limited by its androgenicity. We have developed a synthetic congener of DHEA called fluasterone that, in animal tests, lacks the androgenicity, estrogenicity, and peroxisome-proliferating effects of DHEA but retains the cancer-preventive, antidiabetic, and anti-inflammatory efficacy. This report discusses how fluasterone ameliorates the development of joint inflammation in an adjuvant-arthritis model in Lewis rats.

We performed this study to investigate the hypothesis that insulin resistance plays a role in the pathogenesis of reproductive abnormalities in women with the polycystic ovary syndrome (PCOS). Twenty-five women with PCOS were enrolled in a double-blind randomized 3-month trial of two doses of the insulin-sensitizing agent, troglitazone, 21 of whom completed the study: 200 mg, n = 10; 400 mg, n = 11. Baseline hormonal parameters and glucose tolerance were compared with 12 age- and weight-matched ovulatory control women. There were no significant changes in body mass index during the study. Fasting (P < 0.01) and 2-h post-75-g glucose load insulin levels (P < 0.05), as well as integrated insulin responses to the glucose load, decreased (P < 0.05), and insulin sensitivity assessed by a frequently sampled iv glucose tolerance test increased significantly (P < 0.001) during troglitazone treatment. This was accompanied by significant decreases in the levels of nonsex hormone-binding globulin-bound testosterone (P < 0.01), dehydroepiandrosterone sulfate (P < 0.001), estradiol (P < 0.01), and estrone (P < 0.001). Stepwise regression analysis indicated that decreases in nonsex hormone-binding globulin testosterone levels were significantly correlated with decreases in integrated insulin responses to the glucose load (r2 0.44, P < 0.01). The only significant changes at the 200-mg troglitazone dose were an increase in insulin sensitivity (P < 0.05) and decreases in dehydro-epiandrosterone sulfate (P < 0.01) and estrone (P < 0.05) levels. At the 400-mg dose, in addition to the changes noted in the entire troglitazone treatment group, increases in the disposition index (the product of insulin sensitivity and secretion) achieved significance, as did decreases in androstenedione (P < 0.01) and LH (P < 0.05) levels and increases in sex hormone-binding globulin levels (P < 0.01). Two PCOS women had ovulatory menses. We conclude that 1) troglitazone improves total body insulin action in PCOS, resulting in lower circulating insulin levels; 2) insulin resistance, probably via hyperinsulinemia, results in a general augmentation of steroidogenesis and LH release in PCOS; and 3) insulin-sensitizing agents, such as troglitazone, may provide a novel therapy for PCOS.

It is known that lipoprotein(a) [Lp(a) is an independent risk factor for developing atherosclerosis, whereas the LpA-I particle of high density lipoprotein (HDL) is an antiatherogenic factor. The effects of androgen replacement therapy on lipid and lipoproteins have previously been reported in male hypogonadism. However, no study reported the effect of gonadotropin or testosterone treatment on Lp(a), LpA-I, or LpA-I;A-II levels in make hypogonadism. We, therefore, determined Lp(a), LpA-I, LpA-I:A-II, and other lipoprotein levels before and 3 months after treatment in 22 patients with idiopathic hypogonadotropic hypogonadism (IHH) and in 9 patients with Klinefelter's syndrome. All patients had been previously untreated for androgen deficiency. Plasma FSH, LH, PRL, testosterone (T), estradiol, and dehydroepiandrosterone sulfate levels were also determined before and 3 months after treatment. Patients with IHH were treated with hCG/human menopausal gonadotropin, whereas patients with Klinefelter's syndrome received T treatment. Three months after treatment, mean T levels role to low normal levels in both groups. Triglyceride, LpA-I:A-II, Lp(a), HDL cholesterol, HDL3 cholesterol, and apolipoprotein (apo) A-I concentrations did not change significantly after treatment, whereas total cholesterol, low density lipoprotein cholesterol, LpA-I, and HDL2 concentrations were significantly increased 3 months after treatment in both groups. The apo B concentration significantly increased in patients with klinefelter's syndrome, whereas no change was observed in the IHH group. Lp(a) concentrations were not related to all hormonal and clinical parameters in both groups. LpA-I concentrations were significantly and negatively correlated with free T (r = -0.80; P = 0.010) in patients with Klinefelter's syndrome and were not correlated with all hormonal and clinical parameters in the IHH group. The LpA-I:A-II concentration was only correlated with body mass index (r = -0.83; P = 0.005) in patients with Klinefelter's syndrome, whereas it was correlated negatively with dehydroepiandrosterone sulfate (r = -0.57; P = 0.005) in the IHH group.2 Overall, our study demonstrates that gonadotropin or T treatment has a complex effect on lipids and lipoproteins. This complexity will be resolved when sufficient large scale androgen treatment data are available for assessment of the long term outcome of androgen treatment. The increases in total cholesterol and low density lipoprotein cholesterol concentrations after treatments are the adverse effects of these treatments, whereas the increases in HDL2 and LpA-I concentrations and the lack of changes in Lp(a) are the beneficial effects. Gonadotropin or T treatment did not modify the Lp(a) concentration, indicating that it is not affected by the hormonal milieu in male hypogonadism. Our study also showed that LpA-I, but not LpA-I:A-II, particles could be modified by androgen replacement therapy.

It has previously been shown that increased nocturnal melatonin (MT) secretion exists in male patients with hypogonadotropic hypogonadism. However, little is known about the effects of gonadotropin and testosterone (T) treatment on early morning plasma MT levels in male hypogonadism. Also, the impact of gonadal steroids on plasma MT levels is an open question. We, therefore, determined early morning plasma MT levels at the same hour before and 3 months after treatment in 21 patients with idiopathic hypogonadotropic hypogonadism (IHH), 10 patients with primary hypogonadism, and 11 male controls. Plasma FSH, LH, PRL, T, and estradiol levels were also determined before and 3 months after treatment. Patients with IHH were treated with hCG/human menopausal gonadotropin, whereas patients with primary hypogonadism received T treatment. Short term treatments did not achieve normal T levels, although significant increases in T were observed in both groups. Plasma MT levels were measured by a RIA with a sensitivity of 10.7 pmol/L. Mean plasma MT levels before treatment were significantly higher in IHH (41.8 +/- 24.4 pmol/L) compared with those in the controls (21.7 +/- 10.8 pmol/L; P < 0.05). However, a slight, but not significant, increase in MT (34.2 +/- 21.1 pmol/L) was found in primary hypogonadism. Mean MT levels did not change significantly 3 months after the initiation of gonadotropin (41.7 +/- 22.8 pmol/L) or T (28.4 +/- 12.6 pmol/L) treatment in either IHH or primary hypogonadism, although a tendency for MT to decrease was observed in both groups. No correlation was found between MT and circulating FSH, LH, PRL, and gonadal steroids either before or after therapy. We conclude that male patients with IHH have increased early morning MT levels, although the pathophysiological mechanism is not clear. Furthermore, our study demonstrated that mean plasma MT levels are not influenced by short term gonadotropin or T treatment in male hypogonadism, although a longer time effect of gonadotropins or T treatment may not be excluded. The lack of correlation between plasma MT and circulating gonadal steroids before and after treatment suggests that there is no classic feedback regulation between the pineal gland and the testes.

Several aspects of the regulation of androgen secretion and plasma levels in males remain controversial. Among these, we cite the problem of whether the age-related decrease in testosterone (T) levels is an intrinsic aging phenomenon or is a sequel of previous illness, the mechanisms underlying the increase in sex hormone-binding globulin (SHBG)-binding capacity in aging men and the supranormal capacity observed immediately after a weight-reducing diet, and the role of insulin in the age-associated decrease in dehydroepiandrosterone (sulfate) [DHEA (DHEAS)] levels. To gain further insight into these issues, we investigated the influence of age, smoking, body mass index (BMI), serum albumin, insulin, GH, and insulin-like growth factor I (IGF-I) levels, respectively, on androgen levels and SHBG-binding capacity in a nonobese healthy population (n = 250) as well as in an obese population (n = 50) before and after weight loss. The influence of GH supplementation on SHBG, DHEAS, DHEA, and insulin levels was studied in a small group of men (n = 8) with isolated GH deficiency. In nonobese healthy men, age was inversely correlated with serum levels of all androgens studied (although total T levels stayed relatively stable until age 55 yr) as well as with albumin, GH, and IGF-I levels and positively correlated with BMI, insulin levels, and SHBG-binding capacity. Nevertheless, SHBG levels were significantly negatively correlated with insulin levels (P < 0.001) as well as with mean 24-h GH and IGF-I levels. Among possible confounding factors affecting (free) T [(FT)] levels in healthy men, smoking appeared to be accompanied by higher (F)T levels than those in nonsmokers. BMI increased with age, but although BMI was negatively correlated with T, FT, and SHBG, respectively, the age-dependent decrease in T levels persisted after correction for BMI. Data not corrected for BMI may, nevertheless, overestimate the age-associated decrease in T levels. The albumin concentration decreased with age, and if FT is the feedback regulator of plasma T levels, albumin concentration might be a codeterminant (although, evidently, less important than SHBG) of T levels and contribute to the age-associated decrease in T levels. In any case, albumin concentration is a codeterminant of DHEAS concentration. T, DHEA, and DHEAS levels were significantly correlated, but this correlation disappeared after controlling for age; hence, there is no evidence for an adrenal-gonadal interaction in men. In obese men, T, FT, and SHBG levels were significantly lower than those in the nonobese men and inversely correlated with BMI; DHEAS levels were slightly lower than those in the nonobese controls, but no significant correlation between DHEA or DHEAS, and insulin levels was observed. After a weight-reducing, protein-rich diet, resulting in a mean weight loss of +/- 15 kg, SHBG-binding capacity increased to normal values notwithstanding the fact that the subjects were still obese and that the insulin levels remained higher than those in the nonobese controls. Considering that after weight loss, GH and IGF-I levels remained lower than those in the nonobese controls, that adult men with isolated GH deficiency presented with higher SHBG levels than normal controls, which decreased to normal levels during GH substitution, and that elderly men have elevated SHBG levels notwithstanding high insulin levels, we suggest that the low GH and/or IGF-I levels might play a role in the elevated SHBG levels observed in both elderly males and obese men after a weight-reducing diet. As weight loss did not influence DHEAS levels notwithstanding an important decrease in insulin levels, our data do not support a role of insulin in the regulation of plasma DHEAS levels.

To assess its differential diagnostic value, dehydroepiandrosterone sulfate (DHEA-S) was measured in a nonselected cohort of 84 patients with incidentally detected adrenal tumors (incidentaloma). Of the 38 histologically confirmed cases, 6 of 12 patients with primary or metastatic malignant tumor of the adrenals and 7 of 14 patients with benign cortical adenoma had low DHEA-S levels. Thus, the sensitivity, specificity, and predictive value of a low DHEA-S level to indicate a benign adrenal tumor were 0.35, 0.50, and 0.60, and the values to indicate a cortical adenoma were 0.50, 0.67, and 0.47, respectively. Of the 14 cases of histologically confirmed benign cortical adenoma, 10 had signs of hormonal activity, but DHEA-S was suppressed in only 7 cases. Thus, the sensitivity, specificity, and predictive value of a low DHEA-S level to indicate clinically significant hormonal activity of a benign cortical adenoma were 0.60, 0.75, and 0.86, respectively. For comparison, 5 of 5 males and 2 of 5 females with metastatic carcinomatosis, but without involvement of the adrenals, also had low DHEA-S levels. The data clearly show that in nonselected cases of incidentaloma a suppressed DHEA-S level is not a good predictor of hormonal activity and that DHEA-S measurement may be valuable only after having ascertained the cortical origin and benign feature of the tumor.

The aim of this research was to study and compare the mechanism of action of interleukin (IL)-8, IL-1beta dehydroepiandrosterone sulphate (DHEA-S) and prostaglandin (PG)E2 on the cervix. Five equal groups of pregnant rabbits (n = 45) were tested by either placebo or tested drugs in the form of vaginal suppositories once daily for 3 days. The suppositories contained human recombinant IL-8 (100 ng), IL-1beta (200 ng), DHEA-S (10 mg) or PGE2 (1 mg). All rabbits were tested by one dose, two doses or three doses. Consistency, dilatation and water contents were estimated 24 h after the last dose of treatment. Leukocyte infiltration of the cervices was studied after staining the cervical tissue sections with antirabbit RT2 monoclonal antibodies. Relative collagen concentration was assessed after staining with Picrosirius Red. Collagenase, gelatinase and elastase activities were measured in 100 mg of homogenized cervical connective tissue. Water contents were significantly increased in all tested cervices. Neutrophil numbers were increased in IL-8 and IL-1beta groups after the second dose of treatment (P < 0.0005 and 0.001 respectively). In the PGE2 group, neutrophils were increased after the third dose of treatment, whereas in DHEA-S group no significant changes were observed. Collagen content was significantly decreased in IL-8, IL-1beta and PGE2 groups after the first dose of treatment (P < 0.004, and 0.005 and 0.03 respectively). In the DHEA-S group, the decrease in collagen content occurred after the third dose (P < 0.05). Collagenase activity was markedly increased in IL-8, IL-1, and DHEA-S groups after the second dose of treatment (P < 0.001, 0.003 and 0.007 respectively). No significant increase in collagenase activity was found in PGE2 group. Gelatinase activity was significantly increased in IL-8, IL-1beta, PGE2 and DHEA-S groups after the second dose of treatment (P < 0.008, 0.01, 0.003 and 0.05 respectively). Also, elastase activity was increased after the second dose of treatment in all groups (P < 0.001, 0.001, 0.001 and 0.006 respectively). Our data suggest that ripening of the cervix in rabbit can be initiated by different mechanisms. Cytokines play a vital role in cervical ripening, especially IL-8 and IL-1. IL-8 is one of the factors which could ripen the cervix in a manner similar to the physiological process at term.

To characterize the differential aging response in gonadotropin secretion that occurs before menopause, we assessed pulsatile LH and serial FSH, estradiol (E2), and progesterone (P) concentrations in aging women across the menstrual cycle. We conducted 96 daytime studies during the follicular, midluteal, and late luteal phases of the same menstrual cycle in 32 volunteers, aged 40-50 yr (n = 16) and 19-39 yr (n = 16). Mean cycle length was shorter in the older women (26 +/- 0.4 vs. 27.6 +/- 0.6 days; P = 0.02), but mean plasma E2 and P values were similar in the two age groups. Mean plasma FSH was higher in the older group on all 3 study days. For LH, an age difference was observed during the late luteal phase, when mean plasma LH and pulse amplitude were higher in women over 40 yr of age (mean LH, 6.4 +/- 0.7 vs. 3.0 +/- 0.5 IU/L (P = 0.002); mean amplitude, 4.0 +/- 0.5 vs. 2.8 +/- 0.2 IU/L (P = 0.03)]. Pulse frequency was higher in the older group, but not different from that in younger women on all study days. When the subjects aged 35-39 yr were analyzed as a third age group (n = 8), age effects for mean LH persisted, and pulse frequency was higher in the group over 40 yr of age vs. women under age 35 yr (n = 8) in both the follicular phase (7.1 +/- 0.4 us. 5.6 +/- 0.8; P = 0.03) and late luteal phase (5.8 +/- 0.7 vs. 4.4 +/- 0.3; P = 0.03). Although highly variable, individual patterns of gonadotropin secretion in the women over age 40 yr included a sustained elevation in the FSH/LH ratio as well as a failure to demonstrate slow frequency, high amplitude LH pulses in the midluteal phase. In conclusion, 1) the age-related increase in FSH concentrations in ovulatory women, although more pronounced, is associated with phase-dependent enhancement of pulsatile LH secretion; 2) the higher LH concentrations are brought about by changes in both pulse frequency and amplitude; and 3) these age effects preempt overt reductions in cyclic E2 or P concentrations.

Forty normally ovulating women aged 25-38 years from one private and two university in vitro fertilization (IVF) centres were used in this randomized, double-blind, parallel, placebo-controlled study to explore the effect of recombinant human growth hormone (GH) on follicular fluid (FF) levels of steroid hormones, particularly androgens. All the women had tubal factor infertility and were classified as poor responders with at least two previously performed and failed IVF treatments in which less than five oocytes had been retrieved following ovarian hyperstimulation. Growth hormone (GH 0.1 IU/kg body wt per day) or placebo was given as pretreatment during down-regulation with gonadotropin-releasing hormone agonist and during stimulation with human menopausal gonadotropin (hMG) according to the randomized protocol. Follicular fluid concentrations of steroids were measured and changes related to the levels of insulin-like growth factor I (IGF-I) and IGF binding proteins 1 and 3 and to the mode of GH administration. Pretreatment with GH, i.e. administration of GH before hMG stimulation only, caused significantly elevated follicular fluid concentrations of estrone, testosterone and dehydroepiandrosterone (DHEA) and higher values for markers of aromatase activity (ratios between estrone and androstenedione and between estradiol-17 beta and androstenedione) than in the placebo group, as well as in the two groups receiving GH during hMG stimulation. The highest values for markers of steroid sulfatase activity (ratios between DHA and DHEA sulfate and between unconjugated and conjugated estrone) were found in the patients pretreated with GH. Positive correlations were found between follicular fluid IGF-I and IGF binding protein 3 on the one hand and androgens on the other. This study showed that the administration of adjuvant GH to women who were poor responders to gonadotropins alters the endocrine/paracrine ovarian response to gonadotropins.

Serum cortisol concentrations are increased in fasted or malnourished human subjects. The dynamic mechanisms underlying this adaptive response have been investigated in eight normal men by analyzing serum cortisol concentrations measured in blood obtained at 5-min intervals over 24 h on a control (fed) day and on the fifth day of a fast (water only) assigned in randomized order. A multiple parameter deconvolution method was used to simultaneously resolve endogenous cortisol secretion and half-life. Five days of fasting induced a 1.8-fold increase in the 24-h endogenous cortisol production rate (fed, 2504 +/- 308; fasted, 4528 +/- 488 nmol/L distribution volume; P < 0.006). This enhanced cortisol production rate was accounted for by a 1.6-fold increase in the mass of cortisol secreted per burst (fed, 115 +/- 12.1; fasted, 183 +/- 17.3 nmol/L; P < 0.02). Cortisol secretory event amplitudes (maximal rates of cortisol release attained within a burst) increased in seven of eight men, and mean secretory burst durations remained unchanged by fasting. Moreover, the number of computer-resolved cortisol secretory bursts per 24 h (fed, 22 +/- 1.4; fasted, 25 +/- 2.0; P = NS) and the interburst interval (fed, 65 +/- 4.0; fasted, 57 +/- 4.4 min) did not change significantly during a 5-day fast. The calculated half-life of endogenous cortisol was not significantly altered by fasting (fed, 108 +/- 9.7; fasted, 129 +/- 11 min). There was no significant change in the nyctohemeral pattern of varying adrenocortical secretory burst frequency in response to fasting. However, the mean (mesor) mass of glucocorticoid secreted per burst over 24 h rose significantly in response to fasting. In addition, by cosinor analysis, maximal serum cortisol concentrations occurred (95% confidence intervals) between 0930-1334 h in the fed state and between 1116-1612 h in the fasted state (P < 0.04). Fasting augmented the mesor (average value about which the diurnal rhythm oscillates; P < 0.0008 compared with fed state) and the amplitude (P < 0.04) of the 24-h serum cortisol concentration profile. Linear regression analysis disclosed a significant inverse relationship between mean serum cortisol and GH concentrations in fasted men (r = -0.76; P < 0.02). In conclusion, the present data indicate that starvation-induced enhancement of cortisol secretion in young healthy men is mediated by an increased glucocorticoid secretory burst mass, rather than changes in secretory burst frequency or duration or in cortisol half-life. In addition, fasting modifies the diurnal secretory pattern of cortisol by delaying maximal serum concentrations to the early afternoon. The inverse relationship between serum cortisol and GH responses to fasting suggests differential regulation of the corticotropic and somatotropic axis by the metabolic stress of fasting and/or feedback interactions between these two axes when they are both activated.

Previous reports of a correlation between serum dehydroepiandrosterone sulfate (DHEAS) and testosterone in both men and women have led to the suggestion that adrenal and gonadal secretion are related. In the present study, the correlation of DHEAS with testosterone and free testosterone (FT) in both normal men and women was tested. Androstenedione, estradiol, sex hormone binding globulin (SHBG), and insulin were also measured and their correlations determined. All correlations were controlled for age and body mass index. In the men in the study, DHEAS did not correlate with testosterone or FT but correlated strongly with androstenedione. In the women, DHEAS correlated strongly with testosterone, FT, and androstenedione; androstenedione in turn correlated strongly with testosterone and FT. DHEAS showed no correlations with estradiol, SHBG, or insulin in the men or women. The lack of a correlation between DHEAS and testosterone in normal men is consistent with the independent secretion of these hormones by the adrenal and testis, respectively. The finding of a strong DHEAS-testosterone correlation in normal women may be explained by parallel adrenal secretion in response to trophic stimuli, i.e., without invoking an adrenal-gonadal interaction.

We previously found that a remarkable number of patients with adrenal incidentaloma display partially autonomous cortisol secretion. The amount of hypercortisolism is insufficient to give clinical expression, but enough to inhibit, in some cases, normal adrenal tissue. Other researchers found with high frequency a partial deficiency of 21-hydroxylase. The aim of the present study was to make a combined evaluation of these aspects of adrenal steroidogenesis. Twenty patients (6 men and 14 women, aged 25-74 yr; median, 59 yr) with incidentally discovered adrenal masses were studied. All had an adrenal adenoma histologically proven or diagnosed on the basis of size (< or = 4.0 cm in all but 1) and computed tomography picture (hypodense homogeneous mass with well defined margins). The following parameters were used to evaluate the ACTH-cortisol axis: overnight 1-mg dexamethasone suppression (4 nonsuppressors), ovine CRH stimulation (blunted ACTH-cortisol response in 2 cases), circadian serum cortisol rhythm (blunted night/day ratio in 4 and increased 24-h mean in 1), and 24-h urinary free cortisol excretion (always within the normal range). Three patients had 2 concomitant alterations, and 5 had a single abnormality. Partial deficiency of 21-hydroxylase was assumed in 6 patients who showed an exaggerated 17-hydroxyprogesterone response to ACTH, with a peak value of more than 10 ng/mL (> 30 nmol/L), according to New's nomogram. No abnormalities of the ACTH-cortisol axis were found in these patients, with the exception of low amplitude cortisol rhythm in 1 case. Therefore, 2 distinct patterns, dysregulated and partially autonomous cortisol secretion, on the one hand, and reduced 21-hydroxylase activity, on the other, can be found in a high number of patients bearing an adrenal incidentaloma. They appear mutually exclusive, and the differentiation by endocrine testing is quite clear. Serum dehydroepiandrosterone sulfate was below the third percentile in 13 of 20 patients and could represent a specific marker of cortical adenomas. This finding was evenly distributed among patients with subclinical hypercortisolism or partial enzymatic defect; therefore, low serum dehydroepiandrosterone sulfate is not readily attributable to suppressed ACTH secretion, which actually occurs in only some patients with subclinical hypercortisolism.

In this study we partition the phenotypic correlations between body fat measures and serum levels of hormones with known, or suspected, lipolytic effects into their genetic and environmental components. Using variance decomposition techniques, we are able to estimate the pleiotropic effects of genes and/or shared environmental factors that give rise to the phenotypic correlations previously reported between these traits. We used data from a large sample of randomly ascertained Mexican-American families living in San Antonio, TX. Data were available for 582 individuals in 26 pedigrees. Levels of sex hormone-binding globulin, dehydroepiandrosterone sulfate, insulin, insulin-like growth factor I, total T4, and total T3 were assayed. The measures of body fat accumulation and topography included body mass index, subscapular/triceps ratio, and relative fat patterning index. The results of this analysis demonstrate that significant phenotypic correlations among these traits can arise from three underlying conditions: 1) entirely from shared genetic effects (pleiotropy), 2) entirely from shared random environmental effects, or 3) a combination of both effects. However, we also show that it is possible for significant genetic and environmental correlations to interact in such a way as to produce a phenotypic correlation that itself would not be considered significant.

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

The aim of this study was to investigate the relationship between plasma insulin levels, peripheral insulin sensitivity and androgen secretion in ten patients with polycystic ovary syndrome and in six obese women as compared with six normal-weight control subjects. During a euglycemic-hyper-insulinemic clamp no significant change of testosterone, androstenedione or dehydroepiandrosterone sulfate plasma levels was observed in the two groups of patients or in the control subjects; insulin sensitivity was clearly reduced and was similar in polycystic ovary patients and in obese women, in spite of the different plasma androgen levels. A long-term (5 months) androgen suppression with the gonadotropin-releasing hormone agonist leuprolide was not able to improve significantly the insulin sensitivity. These results demonstrate that the short-term hyperinsulinemia achieved with the clamp technique does not affect androgen secretion and that insulin resistance, measured with the same technique, is not influenced by long-term suppression of plasma androgen levels in polycystic ovary syndrome.

To assess the effect of weight reduction on serum dehydroepiandrosterone (DHEA)-sulfate, insulin, and glucose, these parameters were assessed in 18 men and 29 women before and after weight loss achieved by a 2-month 1000-1400 kcal diet. Men and women did not differ at baseline with respect to age, body mass index (BMI), or serum insulin and glucose, but serum DHEA-sulfate was almost 2-fold higher in women than men (5.4 +/- 0.5 vs. 2.8 +/- 0.2 mumol/L; P < 0.001). During the diet, men and women experienced similar reductions in BMI of 3.5 kg/m2 and 3.2 kg/m2, respectively. Fasting serum insulin fell by 38% in men and 33% in women, and did not differ between sexes at the diet's end (135 +/- 7 vs. 156 +/- 8 pmol/L; P = NS). Serum glucose fell slightly in both men and women, but did not differ between sexes. Weight loss in men was associated with a 125% rise in serum DHEA-sulfate from 2.8 +/- 0.2 to 6.3 +/- 0.3 mumol/L (P < 0.0001). In contrast, serum DHEA-sulfate did not change with weight loss in women (P = 0.35). Serum DHEA-sulfate at the end of the diet did not differ between men and women (6.3 +/- 0.3 vs. 5.2 +/- 0.5 mumol/L; P = 0.10). Hence, dietary weight loss accompanied by equivalent reductions in body mass index and serum insulin between sexes was associated with a marked rise in serum DHEA-sulfate in men, whereas in women serum DHEA-sulfate did not change. Although speculative, these findings are consistent with the idea that insulin acts in a sex-specific fashion to reduce circulating DHEA-sulfate in men only.

We have recently demonstrated that estrogen reduced the responsivity of the baboon fetal adrenal gland to ACTH with respect to the formation of dehydroepiandrosterone (DHA) and therefore have proposed that a regulatory system exists for feedback control of estrogen on fetal adrenal androgen production. Because the maternal adrenal also provides DHA and DHA sulfate (DHAS) for placental estrogen synthesis, we determined whether an estrogen-androgen feedback system is operative in the maternal-placental unit. Serum DHA/DHAS and cortisol concentrations were determined by RIA in maternal blood samples obtained at 1- to 2-day intervals from intact baboons untreated (n = 4) or treated sc with estradiol benzoate (n = 3, beginning with 1 mg/day and increasing by 1 mg each day) on days 150 to 184 (term); from animals in which fetal adrenal DHA and DHAS were eliminated by fetectomy on day 100 (n = 4); and from fetectomized baboons treated with estradiol on day 130 to term (n = 3). Maternal serum DHA and DHAS levels increased (P < 0.001) in controls between day 80 and term to means +/- SE of 46.8 +/- 2.4 nmol/L and 0.507 +/- 0.048 mumol/L, respectively, on days 150-184. Estrogen increased serum estradiol concentrations by 78% to 14.50 +/- 0.84 nmol/L and decreased (P < 0.001) DHA and DHAS to 17.2 +/- 1.3 nmol/L and 0.246 +/- 0.015 mumol/L, respectively, on days 150 to 184. After fetectomy, serum estradiol decreased to a level that was 5% of controls, and maternal DHA increased (P < 0.01) to 75.2 +/- 4.8 nmol/L. Estrogen treatment after fetectomy increased mean maternal serum estradiol concentration to 12.15 +/- 0.37 nmol/L and reduced (P < 0.01) DHA and DHAS to 11.9 +/- 0.7 nmol/L and 0.102 +/- 0.005 mumol/L. In contrast, serum cortisol levels were not altered in baboons by estrogen treatment. The estrogen-induced decrease in maternal DHA/DHAS levels reflected a decline in adrenal production; the MCRs (liters/day) of DHA and DHAS in three nonpregnant baboons were similar before (414 +/- 119 and 29.3 +/- 5.6, respectively) and after (359 +/- 66 and 30.4 +/- 3.4, respectively) estradiol treatment, which decreased (P < 0.05) serum DHA and DHAS levels by more than 90%. On the basis of these results and our previous observations in fetal baboons, we propose that a negative feedback system exists in utero whereby placental product estrogen regulates maternal and fetal adrenal C19-steroid production to maintain a physiologically normal balance of estrogen biosynthesis during primate pregnancy.

Sex hormones play a major role in determining the risk of cardiovascular disease. While several studies have shown that reduced sex hormone-binding globulin is associated with an atherogenic pattern of lipoproteins and increased glucose concentrations in premenopausal women, little data are available examining the association of sex hormone-binding globulin and sex hormones with cardiovascular risk factors in postmenopausal women, a group with high rates of cardiovascular disease. The investigators hypothesized that in postmenopausal women decreased sex hormone-binding globulin and increased testosterone would be associated with an atherogenic pattern of cardiovascular risk factors. The sex hormone-binding globulin, total and free testosterone, estrone, and dehydroepiandrosterone sulfate (DHEA-SO4) in 253 postmenopausal women who were not taking hormones were measured in a population-based study, the Beaver Dam Eye Study (Beaver Dam, Wisconsin, 1988-1990). Sex hormone-binding globulin was significantly inversely correlated with body mass index (r = -0.53, p 0.001), glycosylated hemoglobin (r = -0.34, p < 0.001), and diastolic blood pressure (r = -0.25, p < 0.001), and positively correlated with high density lipoprotein cholesterol (HDL cholesterol) (r = 0.31, p < 0.001), and HDL cholesterol/total cholesterol (r = 0.31, p < 0.001). Total (r = -0.20, p < 0.01) and free (r = -0.14, p < 0.05) testosterone were significantly inversely correlated with HDL cholesterol/total cholesterol ratio. Total testosterone concentrations were also significantly positively correlated with total cholesterol (r = 0.15), body mass index (r = 0.16), and systolic (r = 0.17) and diastolic (r = 0.18) blood pressures (all p < 0.01). DHEA-SO4 was not associated with any of the metabolic variables, while estrone was inversely associated only with the HDL cholesterol/total cholesterol ratio (r = 0.13, p < 0.05). The authors conclude that increased androgenization in postmenopausal women is associated with atherogenic changes in cardiovascular risk factors.

Abnormal adrenal response is often observed in girls with precocious adrenarche (1). We studied the adrenal response in 112 girls with idiopathic true central precocious puberty (CPP) at early stages of puberty compared to that in 21 girls with normal puberty (controls). The aims of this study were to determine the prevalence of abnormal adrenal response at early stages of puberty, the possible correlation of abnormal adrenal response with pubertal signs at onset of puberty and with plasma androgen levels, and a possible association with the activity of the hypothalamic-pituitary-gonadal (HPG) axis. All participants underwent a combined i.v. adrenocorticotropic hormone (ACTH)-gonadotropin-releasing hormone (GnRH) test at Tanner stage 2-3: 62 of the CPP girls before and 50 during treatment with GnRH analog. The stimulated levels of 17-hydroxypregnenolone (17OHPreg) and the stimulated 17OHPreg/17-hydroxyprogesterone ratio were analyzed and compared to previously reported norms. The result revealed three patterns of adrenal response: normal (17OHPreg < or = 24 nmol/l and 17OHPreg/17OHP ratio < or = 7) in 50/112 (44.6%) CPP patients and 17/21 (80.9%) controls; exaggerated (17OHPreg > 24 nmol/l, 17OHPreg/17OHP ratio < or = 7) in 50/112 (44.6%) CPP patients and 3/21 (14.3%) controls; and non-classical 3 beta-hydroxysteroid dehydrogenase deficiency (17OHPreg > 24 nmol/l and 17OHPreg/17OHP ratio > 7) in 12/112 (10.8%) CPP patients and 1/21 (4.8%) controls. The clinical features at onset of puberty were comparable in all girls with the CPP in spite of the different adrenal response patterns.(ABSTRACT TRUNCATED AT 250 WORDS)

Exaggerated adrenal response (ExAR), i.e. hypersecretion of both 17-hydroxypregnenolone (170HPreg) and 17-hydroxyprogesterone(17OHP) in response to adrenocorticotropic hormone (ACTH) stimulation, is frequently found in women with polycystic ovary (PCO) syndrome who had precocious adrenarche. In an earlier study we found an abnormal adrenal response in girls with idiopathic true central precocious puberty (CPP) at early stages of puberty. On follow-up it was noted that a significant number of girls with CPP develop PCO-like syndrome at a relatively young age. The aim of the present study was to determine if there is an association between ExAR and early PCO in girls with a history of CPP. Included were 49 girls with a history of CPP, 34 of whom were treated with gonadotropin-releasing hormone (GnRH) analog. All 49 were evaluated at full maturity, at ages 12.5-14 years, 0.5-4 years after menarche or resumption of menses. Of the 49 girls, 20 had at least 3/4 clinical signs of PCO (irregular menses, hirsutism, acne and obesity) and were defined as PCO-like+, whereas 29 did not fulfil the criteria and were considered PCO-like-. Girls with a definite enzyme deficiency were excluded from the study. All participants underwent a combined iv ACTH-GnRH test at early follicular phase. The PCO-like+ girls all revealed ExAR, i.e. an elevated stimulated 17OHPreg of 63.4 +/- 9.6 nmol/l (normal 28.6 +/- 9.2 nmol/l) and a normal stimulated 17OHPreg/17OHP ratio of 7.1 +/- 1.8 (normal 6.2 +/- 2.7), whereas all the PCO-like- had a normal adrenal response (30.0 +/- 8.7 and 5.3 +/- 2.0 nmol/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Menstrual dysfunction is common among athletes with very low body mass, such as long distance runners and dancers, and is usually associated with hypothalamic dysfunction. The purpose of this study was to investigate the menstrual status of swimmers, in whom exercise is nonweight bearing and thinness is, thus, not essential. Questionnaires recording the menstrual history of 69 young competitive swimmers (aged 16.4 +/- 0.5) were compared to those of 279 age-matched controls. Age of menarche (M) was significantly (P < 0.005) delayed among swimmers (13.8 +/- 0.2 yr) compared to controls (13.0 +/- 0.1 yr). Eighty-two percent of swimmers had menstrual irregularities after M compared to 40% of control, with longer duration of these irregularities (16 vs. 4 months; P < 0.005). A subset of 24 swimmers was studied further for body composition, pubertal stage, and reproductive hormone levels. Estradiol levels were normal in all post-M swimmers (273 +/- 20 pmol/L) and higher than average in pre-M (383 +/- 44 pmol/L). FSH levels were normal in all subjects (10.7 +/- 1.6 IU/L), LH was mildly elevated (17.1 +/- 1.2 IU/L), and the LH/FSH ratio was 1.7. Levels of dehydroepiandrostenedione sulfate and androstenedione, but not testosterone, were higher than average in all groups of swimmers. The results of this study indicate that female competitive swimmers are vulnerable to delayed puberty and menstrual irregularities, but the associated hormonal profile is very different from the hypothalamic amenorrhea described in dancers and runners. We, therefore, suggest a different mechanism for reproductive dysfunction in swimmers that is associated not with hypoestrogenism, but, rather, with mild hyperandrogenism. A distinction among the various types of athletic amenorrhea should be made based on hormonal profiles with attention to their weight and somatotype.

As so many variables can affect obesity (age, genetics, health status), new directions, other than reducing or altering diet, are being pursued in controlling obesity in our society. Both dehydroepiandrosterone (DHEA) and GH have reported antiobesity effects; thus, the possible interaction of these hormones was investigated in genetically lean, obese, and meat-type cross-bred male pigs (boars) administered implants that released 0, 2, or 4 mg/day recombinant porcine GH (pGH) for 42 days. Subcutaneous fat was determined by measurement of back fat depth at 2-week intervals, and blood samples were obtained 0, 7, 14, 28, and 42 days post-implant. The weight of perinephrenic fat, an index of abdominal fat, was obtained at death. The obese line had higher DHEA/DHEA sulfate (DHEA-SO4) serum concentrations than the lean and cross-bred boars. Treatment with pGH reduced sc and perinephrenic fat in all lines at both doses (P < 0.01). There was no relationship between day 42 concentrations of DHEA/DHEA-SO4 and indexes of obesity. Concentrations of DHEA/DHEA-SO4 were decreased by pGH treatment (P < 0.01) by days 7-14 in all genetic lines. Concentrations of insulin-like growth factor I, insulin-like growth factor II, and insulin were increased with pGH treatment in all lines (P < 0.01). The a priori hypothesis that increases in these peptides would stimulate gonadal steroidal synthesis (as demonstrated in vitro) and result in elevated DHEA/DHEA-SO4 concentrations and reduced obesity was not supported by pGH-induced decreases in DHEA/DHEA-SO4. Insulin concentrations were elevated 7-14 days postimplant in all lines (P < 0.01), then declined in the later stages of the trial. Insulin concentrations and DHEA/DHEA-SO4 concentrations were inversely related (r = -0.59; P < 0.05); this may indicate that with elevated insulin levels, DHEA/DHEA-SO4 is decreased and has a limited opportunity to affect obesity. Although the administration of DHEA may reduce obesity, the lipolytic action of pGH does not appear to be through increased circulating concentrations of DHEA/DHEA-SO4.

Androgenic stimulation of sebaceous glands is an important factor in the development of acne. We examined 36 females (aged 14-34 years), selected because none had received oral contraceptives, anti-androgen therapy, or systemic antibiotics during the previous year, or isotretinoin therapy, prior to their participation in the study. Subjects were divided into groups on the basis of acne severity, as follows: physiological, mild and moderate. Only two patients had polycystic ovaries on ultrasound examination. Seven patients had irregular menses; none had evidence of hirsutism. We found that the severity of acne, based on the acne grade, was highly correlated with the inflammatory lesion count, and less correlated with the sebum excretion rate. Either acne grade or inflammatory lesion count could be related to some of the five androgenic hormone determinants; free testosterone (TESTOS), delta 4 androstenedione (DELTA 4), sex hormone binding globulin (SHBG), dehydroepiandrostenedione sulphate (DHEAS) and dihydrotestosterone (DHT). Multiple linear regression analysis determined the best model for predicting ACNE scores as involving DELTA 4 and DHEAS (positive effects), and SHBG (negative effect), P < 0.005, R2 = 0.36). In none of the patients were the levels of DHEAS or SHBG outside the normal range. The findings in the two patients with polycystic ovaries did not differ significantly from those in the remainder of the patients.

Insulin concentration correlates negatively with sex hormone-binding globulin (SHBG) in adults, although the age at which this relationship develops is unknown. The present study assesses this relationship in a cohort of European, Maori, South Asian, and Pacific Islands neonates from 125 normal and 35 pregnancies complicated by diabetes. Maternal glycemia was assessed with a 3-h 100-g oral glucose tolerance test with fasting glucose and fructosamine concentrations determined at 36-38 weeks. Umbilical cord blood was taken for insulin, C peptide, fructosamine, SHBG, sex hormone, and insulin-like growth factor I (IGF-I) measurements, and neonatal anthropometry was measured 24 h after delivery. Babies from pregnancies complicated by diabetes were heavier, fatter, hyperinsulinemic (90.4 vs. 130.6 pmol/L, respectively; P < 0.01), with similar SHBG (44.0 +/- 6.5 vs. 44.2 +/- 12.0) and sex hormone levels and higher IGF-I concentrations (57.1 +/- 24.2 vs. 70.1 +/- 37.1; P < 0.05). There were no ethnic differences in cord SHBG, sex hormones, or IGF-I. SHBG correlated negatively with cord insulin concentrations [males, -0.31 (P < 0.01); females, -0.35 (P < 0.001)], birth weight [males, -0.25 (P < 0.05); females, -0.36 (P < 0.001)] and other measures of neonatal size. In both normal pregnancies and those complicated by diabetes, cord IGF-I correlated with cord C peptide levels [0.32 (0.32 (P < 0.001) and 0.42 (P < 0.05), respectively] and neonatal size, but only in normal babies was there a correlation between IGF-I and insulin [0.43 (P < 0.001) and 0.10] or SHBG [-0.28 (P < 0.01) and -0.01]. These data confirm that relationships between insulin concentration and SHBG are present at birth and are likely to be physiological.

Evidence suggests that hyperinsulinemic insulin resistance may increase serum levels of ovarian androgens and reduce sex hormone-binding globulin (SHBG) levels in humans. The present study was conducted to assess the effect of administration of the biguanide metformin, a drug commonly used in the treatment of diabetes mellitus, on androgen and insulin levels in 24 hirsute patients. The patients selected for the study were obese, with a body mass index higher than 25 kg/m2 and high fasting insulin (> 90 pmol/L) and low SHBG levels (< 30 nmol/L). All patients were given a low calorie diet (1500 Cal/day) and randomized for either metformin administration at a dose of 850 mg or a placebo, twice daily for 4 months, in a double blind study. In the placebo group, diet resulted in a significant decrease in body mass index (30.8 +/- 1.0 vs. 32.7 +/- 1.5 kg/m2; P < 0.0001), fasting insulin (127 +/- 11 vs. 156 +/- 14 pmol/L; P < 0.01), non-SHBG-bound testosterone (0.19 +/- 0.02 vs. 0.28 +/- 0.03 nmol/L; P < 0.02), androstenedione (5.8 +/- 0.5 vs. 9.0 +/- 1.1 nmol/L; P < 0.03), and 3 alpha-diolglucuronide (8.6 +/- 1.1 vs. 11.7 +/- 1.9; P < 0.005) plasma concentrations and a significant increase in the glucose/insulin ratio (0.047 +/- 0.005 vs. 0.035 +/- 0.003; P < 0.001) and plasma concentrations of SHBG (26.0 +/- 3.3 vs. 19.1 +/- 1.9 nmol/L; P < 0.001) and dehydroepiandrosterone sulfate (8.7 +/- 1.5 vs. 8.4 +/- 1.3; P < 0.05). Beneficial effects of diet were not significantly different in the patients who were given metformin instead of placebo. These results confirm that weight loss induced by a low calorie diet is effective in improving hyperinsulinemia and hyperandrogenism in obese and hirsute women. With our study design, metformin administration had no additional benefit over the effect of diet.

Hypogonadotropic hypogonadism (IGD) and constitutional delayed puberty (DP) share a common pathophysiologic process, i.e. GnRH deficiency. Both conditions are heterogenous and exhibit different grades of GnRH deficiency. To discern whether these disorders of GnRH deficiency are associated with altered melatonin secretion profiles, we compared untreated young males IGD (n = 7) and DP (n = 7) to normal pubertal male controls (n = 6). Serum samples for melatonin, LH, and prolactin concentrations were obtained every 15 min from 1900 h to 0700 h in a controlled light-dark environment with simultaneous sleep recordings. Mean (+/- SD) darktime nocturnal melatonin levels were significantly higher in IGD (259 +/- 73 pmol/L) and DP (217 +/- 29 pmol/L) compared with 182 +/- 69 pmol/L in controls (P < 0.02). So were the mean (+/- SD) peak melatonin levels (410 +/- 117, 327 +/- 97 and 298 +/- 95 pmol/L in IGD, DP, and controls, respectively (P < 0.05). Integrated nocturnal melatonin secretion values (AUC) were also higher in IGD and DP (168 +/- 45 and 134 +/- 28) compared with 119 +/- 45 pmol/min.1 x 10(3) in controls (P < 0.02). The time of melatonin peak and the time of onset of the nocturnal melatonin rise were observed earlier in IGD and DP. Light-time mean (+/- SD) serum melatonin levels were similar in all three groups. No correlations were found between melatonin and LH levels, nor between melatonin and prolactin levels. These data indicate that melatonin secretion is increased in male patients with GnRH deficiency. The lack of correlations between melatonin and LH suggest that circulating sex steroids, rather than LH, modulate melatonin secretion in a reverse fashion.

In a previous study we demonstrated that, in children affected with isolated GH deficiency, an acute high-dose human recombinant GH (hrGH) treatment increases the 11-deoxycortisol and induces an IGF-I responsiveness to ACTH. The aim of the present study was to reevaluate, in the same children, the adrenal and IGF-I responsiveness to ACTH after a chronic replacement-dose GH therapy. Ten children (seven males and three females, mean age 7 years) affected with isolated GH deficiency underwent a synthetic ACTH 1-17 test before and after sc administration of human recombinant GH at a dose of 0.6 UI/kg/week for 3 months. After therapy, the 11-deoxycortisol responsiveness to ACTH significantly decreased compared with that observed after acute treatment (P < 0.001), and so it returned to baseline. No differences were detected in the responsiveness to ACTH of cortisol, dehydroepiandrosterone-sulphate, D4-androstenedione, and 17-hydroxyprogesterone. On the other hand, the chronic treatment induced an IGF-I responsiveness to ACTH (P < 0.001). In conclusion, our study demonstrates that, in isolated GH deficiency, replacement doses of hrGH do not modify the adrenal steroid basal levels or its responsiveness to ACTH, whereas both replacement and high doses of hrGH induce an IGF-I responsiveness to ACTH.

This study was undertaken to evaluate the role of thyroid hormones in fibrocystic breast disease. The concentrations of thyroid-stimulating hormone (TSH), thyroxine (T4), free T4 and free triiodothyronine (T3) were determined in serum of 50 women with fibrocystic breast disease without macrocysts (cysts of over 3 mm diameter) and in the serum and breast cyst fluid (BCF) of 60 women with fibrocystic breast disease and macrocysts. Possible relationships between thyroid hormones and estradiol, dehydroepiandrosterone sulfate, testosterone, progesterone and 17-hydroxyprogesterone in the BCF also were analyzed. Serum thyroid hormone levels did not differ between the two groups. Free T3 levels were higher in BCF than in serum (p < 0.001), whereas T4, free T4 and TSH concentrations were lower in BCF as compared to serum (p < 0.001). Cysts were divided according to their K+/Na+ ratio because a ratio above 3 represents a predictor of malignant transformation. Free T3 concentrations were higher in BCF than in serum, in both low K+/Na+ cysts and in cysts with a K+/Na+ ratio above 3; those cysts with a high K+/Na+ ratio had the highest free T3 concentration. Free T3 in cysts correlated positively to the K+/Na+ ratio (r = 0.831; p < 0.001). Multiple linear regression analysis demonstrated that the concentration of free T3 in BCF was predicted statistically by the positive regression coefficient for the estradiol concentration. No candidate variable was included in the model to predict concentrations of TSH, free T4 or T4 in BCF. These data suggest an important role of free T3 in the physiology of fibrocystic breast disease.

The 24-h mean plasma concentration of total testosterone (T) was measured in 33 healthy, regularly cycling, nonobese women between 21 and 51 yr of age. Percent free T was measured in 17 of them. Plasma dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were measured in 24 of them, and the DHEA-to-T and DHEAS-to-T ratios were calculated. It was found that the concentration of total T showed a steep decline with age; the regression equation was: T (nanomoles per L) = 37.8 x age-1.12 (r = -0.54; P < 0.003). According to this equation, the expected T concentration of a woman of 40 would be 0.61 nmol/L, about half that of a woman of 21 (1.3 nmol/L). The percent free T did not vary significantly with age, so free T concentration likewise showed a steep decline with age. The DHEA-to-T and DHEAS-to-T ratios were both age invariant, clearly because the levels of DHEA and DHEAS also decline steeply with age, as previously reported.

To determine whether a reduction in insulinemia would be associated with a rise in serum dehydroepiandrosterone (DHEA) sulfate in insulin-resistant men, 29 middle-aged (30-59 yr old) and 28 elderly (60-80 yr old) hypertensive men were enrolled into a single blind, placebo-controlled study, in which benfluorex was administered to improve insulin sensitivity and reduce circulating insulin. Men in each age group received either benfluorex (150 mg) or placebo three times daily for 6 weeks, and fasting serum insulin, glucose, DHEA, DHEA sulfate, and cortisol were determined before and after treatment. Glucose tolerance was also assessed by an oral glucose tolerance test. Benfluorex treatment lowered diastolic and systolic blood pressures and improved glucose tolerance in both age groups. In middle-aged men, benfluorex (n = 12) reduced both the area under the curve for glucose (AUCGLUCOSE; from 977 +/- 27 to 814 +/- 27 mmol/L.min; P = 0.0001) and the AUCINSULIN (from 78.1 +/- 7.9 to 44.5 +/- 5.7 nmol/L.min; P < 0.0001) during the oral glucose tolerance test. In elderly men, benfluorex (n = 15) also reduced both the AUCGLUCOSE (from 1100 +/- 60 to 864 +/- 26 mmol/L.min; P < 0.0001) and the AUCINSULIN (from 88.9 +/- 5.6 to 44.8 +/- 5.8 nmol/L.min; P < 0.0001). Concurrent with the reduction in insulinemia, benfluorex treatment was associated with rises in both serum DHEA sulfate and unconjugated DHEA. In middle-aged men, serum DHEA sulfate and DHEA rose from 6.80 +/- 0.75 to 10.52 +/- 1.02 mumol/L (P < 0.015) and from 13.69 +/- 1.95 to 22.78 +/- 2.90 nmol/L (P < 0.03), respectively. In elderly men, serum DHEA sulfate and DHEA rose from 5.16 +/- 0.67 to 8.36 +/- 1.21 mumol/L (P < 0.015) and from 8.47 +/- 0.99 to 22.61 +/- 3.24 nmol/L (P < 0.0005), respectively. In neither middle-aged nor elderly men did serum cortisol change with benfluorex treatment. Neither glucose tolerance nor serum DHEA, DHEA sulfate, or cortisol levels changed in either middle-aged (n = 17) or elderly (n = 13) men treated with placebo. We conclude that benfluorex treatment lowers blood pressure, improves glucose tolerance, reduces the glucose-stimulated insulin response, and increases serum DHEA and DHEA sulfate in both middle-aged and elderly men.(ABSTRACT TRUNCATED AT 400 WORDS)

Since 1989, 45 patients [pts; 26 females and 19 males, aged 19-79 yr (median, 58)] bearing incidentally discovered adrenal masses were studied. The aim of the study was to verify the prevalence of hormone activity in clinically silent adrenal masses. Endocrine work-up included determination of urinary catecholamines and their metabolites, measurement of PRA and aldosterone levels in clino- and orthostatic posture, and basal and dynamic [dexamethasone (dex) suppression and ovine CRH stimulation] evaluation of hypothalamic-pituitary-adrenal axis. The most frequent finding was the reduction of dehydroepiandrosterone sulfate (DHEA-S) levels below the third percentile of controls in 19 (42%) pts. DHEA-S levels were significantly lower in pts than in controls [68 (range, 5-1000) vs. 208 (34-326) micrograms/dL; 1.8 (0.1-27.1) vs. 5.6 (0.9-8.8) mumol/L; P < 0.001]. Three pts (7%) had high 24-h mean serum cortisol levels, and 6 (14%) had blunted day-night amplitude of cortisol rhythm. Defective dex suppressibility was found in 15% of pts vs. 8% of controls (P < 0.05). ACTH and cortisol responses to ovine CRH did not significantly differ between pts and controls, although blunted ACTH responses were found in 22% of the cases. The above-mentioned endocrine alterations could be accounted for by autonomous cortisol secretion by the adrenal nodule at a rate not sufficient to give clinical expression, but able to inhibit to some extent the hypothalamic-pituitary-adrenal axis. These results indicate that silent cortisol hypersecretion is frequently observed in pts with adrenal incidentaloma even if progression to overt Cushing's syndrome seems unlikely. Indeed, the size of the mass and the hormone pattern remained substantially unchanged in 9 pts followed up for 12 months. From merely a cost/benefit ratio, the evaluation of DHEA-S levels and dex suppression has sufficient sensitivity to identify the occurrence of silent hypercortisolism.

High levels of dehydroepiandrosterone sulfate (DHEAS) have been associated with decreased risks of cardiovascular disease. The authors analyzed DHEAS in plasma collected at baseline among 169 participants in the Physicians' Health Study who subsequently had a myocardial infarction and 169 matched controls. The mean prediagnostic plasma DHEAS levels between cases (p = 0.33) (mean, 3.54 mumol/liter; standard deviation, 2.30) and controls (mean, 3.61 mumol/liter; standard deviation, 2.16) did not differ significantly. The relative risk was 1.04 (95 percent confidence interval 0.42-2.60) comparing extreme quintiles after adjustment for several coronary risk factors. In conclusion, these findings do not support the hypothesis that elevated plasma DHEAS is associated with a decreased risk of coronary disease in men, but a small to moderate association cannot be excluded.

To assess the significance of the serum dehydroepiandrosterone sulfate (DHEAS) concentration as a parameter of the individual hormonal milieu, two different groups of subjects were studied: DHEAS levels were determined 3 times at 6-month intervals in 47 elderly hospitalized women, aged 71-94 yr (group 1), and 6 times over 2 consecutive weeks in 10 healthy male volunteers, aged 24-30 yr (group 2). For reference, serum cortisol (F) levels were determined concomitantly. In each group and on each sampling occasion, the subjects were ranked according to their DHEAS or F values. The stability over time of the ranking was much higher for DHEAS than for F; estimated concordance coefficients were 92% (group 1) and 88% (group 2) for DHEAS vs. 51% (group 1) and 49% (group 2) for F. We conclude that due to a comparatively low within- to between-subject variability ratio, DHEAS is a highly specific individual marker.

The relationships of cigarette smoking, age, relative weight, and dietary intake to serum dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), androstenedione, cortisol, 3-alpha-androstanediol, 3-alpha-androstanediol-glucuronide, testosterone, albumin-bound testosterone, free testosterone, dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) were examined cross-sectionally in 1241 randomly sampled middle-aged U.S. men. Compared with nonsmokers and independent of relative weight (body mass index) and age, cigarette smokers had increased serum levels of DHEA (18% higher, P = 0.0002), DHEAS (13% higher, P = 0.0007), cortisol (5% higher, P = 0.01), androstenedione (33% higher, P = 0.0001), testosterone (9% higher, P = 0.009), DHT (14% higher, P = 0.004), and SHBG (8% higher, P = 0.004). Androstenedione, total plasma testosterone, albumin-bound testosterone, DHT, and SHBG decreased with increasing relative weight. Age was positively associated with serum SHBG and negatively associated with albumin-bound testosterone, DHEA, and DHEAS. An association was found between alcohol intake and DHEA (r = 0.15; P = 0.0001), cortisol (r = 0.10; P = 0.0007), and 3-alpha-androstanediol-glucuronide (r = 0.08; P = 0.0004). Cortisol was the only hormone that was associated with carbohydrate intake (r = -0.09; P = 0.002). The only hormones associated with dietary lipids were DHT (for vegetable fat, r = 0.07; P = 0.02), cortisol (for total fat, r = 0.08; P = 0.007), and SHBG (for animal fat, r = -0.06; P = 0.05). In addition, SHBG was positively associated with dietary (r = 0.07; P = 0.008) and crude (r = 0.08; P = 0.007) fiber. These data suggest that serum adrenal steroid and sex hormone concentrations in middle-aged men are more influenced by cigarette smoking, age, and obesity than by dietary intake; however, serum adrenal steroids were influenced by alcohol intake.

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.

Transforming growth factor-beta 1 (TGF beta 1) has been reported to have a strong inhibitory effect on the specific function of adrenal cells of several species. In the present study, we examined the effects of TGF beta 1 on cultured human fasciculata-reticularis cells. TGF beta 1 alone had no effect on ACTH receptor messenger ribonucleic acid (mRNA) levels and was unable to reduce the strong stimulatory effects of ACTH on its own receptor. However, TGF beta 1 enhanced angiotensin-II type 1 receptor mRNA and binding sites. Treatment with TGF beta 1 increased significantly the levels of 3 beta-hydroxysteroid dehydrogenase mRNA, reduced those of cytochrome P-450 17 alpha-hydroxylase mRNA, and had no effect on cholesterol side-chain cleavage cytochrome P-450 mRNA. Whatever the experimental condition, TGF beta 1 did not reduce basal or ACTH-stimulated cortisol production, but the production of dehydroepiandrosterone sulfate of TGF beta 1-treated cells was always decreased. The effects of TGF beta 1 on 3 beta-hydroxysteroid dehydrogenase mRNA and dehydroepiandrosterone sulfate were opposite the change observed at the time of adrenarche. As adrenal cells express TGF beta 1 mRNA, it is tempting to postulate that a local diminution of TGF beta 1 might be involved in adrenarche. Our findings also illustrate the specific species differences and, therefore, the caution to extrapolate to humans the results observed in other species.

Obesity offers protection against osteoporosis in older women. The mechanisms are not well understood, but relate in part to increased aromatization of adrenal androgens to estrone in peripheral fat and muscle tissue. Two hundred and one white and 77 black women previously reported to be free of skeletal disease and to have normal bone mass had measurements of total body bone mineral (TBBM), fat mass (TBFM), and lean mass (TBLM) performed by dual energy x-ray absorptiometry. Serum estrone, androstenedione, and dihydroepiandrostenedione sulfate were measured on the same day. Body weight, body mass index, TBFM, and TBLM were all significantly higher in the black women. However, proportionately, there were no differences in body composition between the two groups. This suggests that the black women were not more obese despite their greater body mass index, and that future studies on the health impact of obesity in older black women should take this into consideration. Despite the greater TBFM and TBLM in the black women and no difference in serum androstenedione levels, the serum estrone level was not higher in the black women, and the higher bone mass in blacks was not related to serum estrone. In both ethnic groups, TBBM was significantly related to body weight (white, r = 0.80; black, r = 0.85; P < 0.001 for both). Both TBFM and TBLM were significantly related to TBBM in both ethnic groups. Serum estrone was significantly related to all measures of body mass in the white women, but to no measures of body mass in the black women, indicating apparent differences in the metabolism of estrone between older white and black women.

Metabolism of dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA) occurs within specific anatomical compartments in vivo through the actions of the enzyme DHEAS sulfatase. This enzymatic activity facilitates the conversion of hydrophilic DHEAS to the hydrophobic species DHEA, which can then be further metabolized to other steroid hormones. High levels of DHEAS sulfatase reside in tissues where the biological activity of DHEA or its downstream metabolites regulate cellular function. Therefore, control over the activity of DHEAS sulfatase may represent an important regulatory process for the production of DHEA and its metabolites. Homogeneous populations of macrophages from normal mice were found to effectively convert DHEAS to DHEA in vitro. DHEAS sulfatase activity could be markedly depressed after exposure of these cells to a variety of nonspecific macrophage activators [i.e. zymosan, polyinosine/cytosine, heat-killed bacteria, or bacterial lipopolysaccharide (LPS)]. Inhibition of DHEAS metabolism was found to require protein synthesis, because temporary abrogation of protein synthesis with cycloheximide eliminated the ability of LPS to depress the conversion of DHEAS to DHEA. Additionally, exposure of LPS-nonresponsive macrophages to supernatants derived from LPS-treated BALB/c macrophages inhibited their ability to convert DHEAS to DHEA. Potent inhibition of sulfatase activity could be achieved by directly exposing murine macrophages to interferon-alpha (IFN alpha), IFN beta, or tumor necrosis factor-alpha, but not interleukin-1, interleukin-6, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta, platelet-derived growth factor, or the T-cell product IFN gamma. Our results indicate that macrophage metabolism of DHEAS to DHEA is down-regulated after cellular activation. Furthermore, inhibition of DHEAS sulfatase activity appears to be mediated through the actions of the inflammatory cytokines tumor necrosis factor-alpha and IFN alpha/beta.

In order to investigate the pathological characteristics of polycystic ovaries diagnosed by transvaginal ultrasound (TVS) in patients with polycystic ovarian syndrome (PCOS) and to investigate the relationship between morphological and endocrine changes in the ovaries, 32 PCOS patients with bilateral polycystic ovaries (> 10 cysts) detected by TVS were studied; 20 ovulatory women served as controls. Ovarian tissues from wedge resection were examined histologically. A comparative histological and TVS study of ovarian morphology was made, and the relationship between the number of small cysts and the endocrine profile was examined. The position and size of small cysts on TVS agreed with those observed histologically. There was a significant correlation between the number of small cysts on TVS and the number of atretic follicles with hypertrophied and luteinized inner theca cells, and thickened ovarian capsules. Numerous atretic follicles and thickened ovarian capsules were observed in 97 and 64% of ovaries respectively, from PCOS patients. In patients with PCOS, a significant positive correlation was noted both between the number of small cysts and delta 4-androstenedione (ASD), and between ASD and the luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio. Furthermore, testosterone, ASD and the number of small cysts on TVS were significantly higher in PCOS patients with ovarian thickened tunica compared to PCOS patients without ovarian thickened tunica. TVS images of ovaries in patients with PCOS correlated with the histopathological and endocrine features. It is suggested that an increase in intra-ovarian small cysts leads to increased production of ovarian androgen, in turn influencing the secretion of gonadotrophin, and is correlated with ovarian capsular thickness.

In 70 healthy obese subjects (37 men and 33 premenopausal women; aged 27-51 yr; body mass index, 28-38 kg/m2), associations between the initial amount of visceral fat and sex hormone levels were studied as well as between changes that occurred in response to a 4.2 mJ/day deficit diet for 13 weeks. Magnetic resonance imaging was used to quantify the visceral fat depot. In women, an abundance of visceral fat was significantly associated with diminished levels of sex hormone-binding globulin and free 17 beta-estradiol/free testosterone (T) ratio and to elevated levels of free T after adjustment for age and total fat mass. In men, no significant relationships could be found between visceral fat accumulation and any of the sex hormones. Mean total fat loss was 11.3 +/- 3.3 (+/- SD) kg. In women, loss of visceral fat was significantly related to rises in the sex hormone-binding globulin level and the free 17 beta-estradiol/free T ratio independent of total fat loss, whereas in men, only the association between visceral fat loss and increased estrone level reached statistical significance. In conclusion, in obese premenopausal women, visceral fat predominance seems to be related to a relatively increased androgenicity. In obese men, sex steroid levels appear not to depend on the amount of visceral fat. In obese women, but not in obese men, visceral fat loss seems to be accompanied by a relative reduction in androgenicity.

The association of obesity and hypertestosteronaemia with elevated insulin concentration and dyslipidaemia was studied in 15 non-obese and 15 obese, hypertestosteronaemia patients; 14 non-obese and 10 obese, normotestosteronaemic subjects served as controls. Data were subjected to multivariate analysis. Enhanced body mass index (BMI kg/m2) resulted in a significant elevation of basal insulin (b-Ins), glucose-stimulated (delta) insulin (del-Ins), triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL), and LDL/high density lipoprotein (HDL) ratio, and in a significant reduction of HDL. Furthermore, it was shown that BMI was positively correlated with TG, VLDL, LDL and LDH/HLD ratio, and negatively correlated with HDL in the normotestosteronaemic groups. Hypertestosteronaemia was associated with a significant increase of del-Ins, VLDL and LDL/HDL ratio, and with a significant decrease of HDL concentration. Testosterone was directly associated with del-Ins and LDL/HDL ratio, and inversely related to HDL in the non-obese groups. Summation effects of obesity and hypertestosteronaemia were found for del-Ins and VLDL. The data suggest that obesity and hypertestosteronaemia are independently and jointly associated with insulin resistance and dyslipidaemia, indicating an increased risk for coronary heart disease. The highest risk rate was found in obese hypertestosteronaemic patients. Serum testosterone may be a useful marker in detecting metabolic disorders connected with cardiovascular risk.

Evidence suggests that hyperinsulinemic insulin resistance may reduce serum levels of the adrenal steroid dehydroepiandrosterone (DHEA) sulfate in humans. This study was conducted to assess the influence of physiological concentrations of insulin on serum adrenal steroid levels by lowering circulating insulin in nondiabetic men through the administration of the biguanide metformin. A total of 28 nondiabetic men were studied. The study group consisted of 16 obese and hypertensive men, and the control group of 12 nonobese and normotensive men. The men were studied at baseline and after the oral administration of 500 mg metformin, 3 times daily, for 21 days. Metformin administration resulted in significant reductions in serum insulin levels and concurrent increases in serum DHEA sulfate levels in both groups of men. The mean fasting serum DHEA sulfate concentration rose by 48% in the obese hypertensive men (from 5.9 +/- 0.8 to 8.7 +/- 0.7 mumol/L; P < 0.02) and by 80% in the nonobese normotensive men (from 3.5 +/- 0.5 to 6.3 +/- 0.9 mumol/L; P < 0.05). When the results from both groups were combined, changes in serum DHEA sulfate levels (i.e. day 21 value minus day 0 value) correlated positively with baseline fasting serum insulin levels (r = 0.44; P = 0.02; n = 28). Moreover, changes in fasting serum DHEA sulfate levels correlated inversely with changes in fasting serum insulin levels (r = -0.38; P < 0.05; n = 28). These findings lend further credence to the idea that insulin acts as a physiological regulator of DHEA sulfate metabolism and lowers circulating DHEA sulfate concentrations in men.

There is little information about the plasma concentrations of 3 beta-hydroxy-delta 5-steroids (delta 5-steroids) in untreated patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. To further study the delta 5 pathway, we measured plasma levels of delta 5- and delta 4-steroids in 21 adult patients with different degrees of 21-hydroxylase deficiency (11 salt-wasters, 5 simple virilizers, and 5 patients with the nonclassical form of the disease). In all patients, investigations were performed after withdrawal of steroid treatment for at least 10 days. In addition, catheterization of gonadal and adrenal veins was performed in two salt-wasting male patients displaying bilateral testicular tumors to study adrenal secretion of delta 5- and delta 4-steroids. In one of them, surgical resection of the intratesticular adrenal rests gave the opportunity to measure 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity. In all untreated patients, an increase in plasma delta 4-steroids was observed. In contrast, although plasma levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not significantly modified in simple virilizers, a paradoxical decrease in all delta 5-steroids was observed in salt-wasters. Catheterization of the adrenal veins confirmed the decrease in delta 5-steroids, particularly DHEA and DHEAS. The androstenedione/DHEA ratio was increased in all patients proportionally to the severity of the disease, suggesting an increase in adrenal 3 beta HSD. In vitro analysis of 3 beta HSD activity showed a 4-fold increase in intratesticular adrenal tissue compared to that in normal adrenals. A positive correlation between the androstenedione/DHEA ratio and plasma ACTH levels was observed, suggesting a long term stimulatory effect of ACTH on 3 beta HSD. Angiotensin-II could have an additive effect on ACTH-induced 3 beta HSD activity.