Conversion Of Dehydroepiandrosterone Sulfate Research Articles

Steroid Sulfatase Stimulates Intracrine Androgen Synthesis and is a Therapeutic Target for Advanced Prostate Cancer.

Most patients with prostate cancer receiving enzalutamide or abiraterone develop resistance. Clinical evidence indicates that serum levels of dehydroepiandrosterone sulfate (DHEAS) and biologically active DHEA remain in the high range despite antiandrogen treatment. The conversion of DHEAS into DHEA by steroid sulfatase (STS) may contribute to sustained intracrine androgen synthesis. Here, we determine the contribution of STS to treatment resistance and explore the potential of targeting STS to overcome resistance in prostate cancer. STS expression was examined in patients and cell lines. In vitro, STS activity and expression were modulated using STS-specific siRNA or novel STS inhibitors (STSi). Cell growth, colony formation, androgen production, and gene expression were examined. RNA-sequencing analysis was conducted on VCaP cells treated with STSi. Mice were treated with STSis with or without enzalutamide to determine their effects in vivo. STS is overexpressed in patients with castration-resistant prostate cancer (CRPC) and resistant cells. STS overexpression increases intracrine androgen synthesis, cell proliferation, and confers resistance to enzalutamide and abiraterone. Inhibition of STS using siRNA suppresses prostate cancer cell growth. Targeting STS activity using STSi inhibits STS activity, suppresses androgen receptor transcriptional activity, and reduces the growth of resistant C4-2B and VCaP prostate cancer cells. STSis significantly suppress resistant VCaP tumor growth, decrease serum PSA levels, and enhance enzalutamide treatment in vitro and in vivo. These studies suggest that STS drives intracrine androgen synthesis and prostate cancer proliferation. Targeting STS represents a therapeutic strategy to treat CRPC and improve second-generation antiandrogen therapy.

Impairment of the Gnα11-controlled expression of claudin-1 and MMP-9 and collective migration of human breast cancer MCF-7 cells by DHEAS

Although dehydroepiandrosterone sulfate (DHEAS) constitutes the most abundant steroid in humans, in-depth investigations of its effects are rather scarce. We address here DHEAS effects on the estrogen receptor-positive metastatic human breast cancer cell line MCF-7. We focus on DHEAS-mediated signaling that might influence expression of claudin-1 and matrix metalloproteinase-9 (MMP-9), both known to be critical factors for migration and invasiveness of various cancers, including breast cancer cells.Physiological concentrations of DHEAS trigger persistent phosphorylation of Erk1/2 in MCF-7 cells. Exposure of these cells for 24 h to 1 μM DHEAS also leads to a significant reduction of claudin-1 expression that cannot be prevented by high concentrations of the steroid sulfatase inhibitor STX64, indicating that desulfation and further conversion of DHEAS to some other steroid hormone is not required for this action. In addition, exposure of MCF-7 cells to the same concentration of DHEAS completely abolishes MMP-9 expression and considerably impairs cell migratory behavior.Abrogation of Gnα11 expression by siRNA prevents the stimulatory effect of DHEAS on Erk1/2 phosphorylation, consistent with a G-protein-coupled receptor being involved in the DHEAS-induced signaling. Nevertheless, Gnα11 also has direct effects that do not depend on DHEAS; thus, when Gnα11 expression is suppressed, expression of claudin-1 and MMP-9 as well as cell migration are significantly reduced.This is the first report demonstrating direct involvement of DHEAS and Gnα11 in the regulation of claudin-1 and MMP-9 expression and migration of MCF-7 cells.

Dehydroepiandrosterone sulfate augments blood-brain barrier and tight junction protein expression in brain endothelial cells

Tight junctions (TJ) between brain endothelial cells are essential for formation and maintenance of the blood-brain barrier (BBB). Although loss of BBB integrity is associated with several neuropathological disorders, treatments that augment or stabilise the BBB are scarce. Here we show that physiological concentrations of dehydroepiandrosterone sulfate (DHEAS) stimulate the expression of the TJ proteins zonula occludens-1 (ZO-1) and claudin-3 in the brain-derived endothelial cell line bEnd.3 and promote TJ formation between neighbouring cells, demonstrated by augmented transendothelial resistance across cell monolayers. Silencing androgen receptor expression by siRNA does not prevent DHEAS-induced stimulation of ZO-1 expression, indicating that conversion of DHEAS into testosterone is not required for its actions. Suppression of Gnα11 expression by siRNA prevents DHEAS actions, pointing towards a G-protein-coupled receptor as being a mediator of the DHEAS effects. These results are consistent with the idea that DHEAS, acting as a hormone in its own right, supports the integrity of the BBB. The current findings might help in developing new strategies for the prevention or treatment of neurological disorders associated with BBB defects.

Dehydroepiandrosterone Sulfate Stimulates Expression of Blood-Testis-Barrier Proteins Claudin-3 and -5 and Tight Junction Formation via a Gnα11-Coupled Receptor in Sertoli Cells.

Dehydroepiandrosterone sulfate (DHEAS) is a circulating sulfated steroid considered to be a pro-androgen in mammalian physiology. Here we show that at a physiological concentration (1 μM), DHEAS induces the phosphorylation of the kinase Erk1/2 and of the transcription factors CREB and ATF-1 in the murine Sertoli cell line TM4. This signaling cascade stimulates the expression of the tight junction (TJ) proteins claudin-3 and claudin-5. As a consequence of the increased expression, tight junction connections between neighboring Sertoli cells are augmented, as demonstrated by measurements of transepithelial resistance. Phosphorylation of Erk1/2, CREB, or ATF-1 is not affected by the presence of the steroid sulfatase inhibitor STX64. Erk1/2 phosphorylation was not observed when dehydroepiandrosterone (DHEA) was used instead of DHEAS. Abrogation of androgen receptor (AR) expression by siRNA did not affect DHEAS-stimulated Erk1/2 phosphorylation, nor did it change DHEAS-induced stimulation of claudin-3 and claudin-5 expression. All of the above indicate that desulfation and conversion of DHEAS into a different steroid hormone is not required to trigger the DHEAS-induced signaling cascade. All activating effects of DHEAS, however, are abolished when the expression of the G-protein Gnα11 is suppressed by siRNA, including claudin-3 and -5 expression and TJ formation between neighboring Sertoli cells as indicated by reduced transepithelial resistance. Taken together, these results are consistent with the effects of DHEAS being mediated through a membrane-bound G-protein-coupled receptor interacting with Gnα11 in a signaling pathway that resembles the non-classical signaling pathways of steroid hormones. Considering the fact that DHEAS is produced in reproductive organs, these findings also suggest that DHEAS, by acting as an autonomous steroid hormone and influencing the formation and dynamics of the TJ at the blood-testis barrier, might play a crucial role for the regulation and maintenance of male fertility.

Tumor necrosis factor inhibits conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA in rheumatoid arthritis synovial cells: A prerequisite for local androgen deficiency

Use of anti-tumor necrosis factor (anti-TNF) antibody therapy in rheumatoid arthritis (RA) has expanded our understanding of possible mechanisms by which this treatment reduces inflammation. Beyond its effects on local immune responses, anti-TNF treatment may also modulate the local hormone supply. Because androgens are thought to inhibit immune responses, their presence in inflamed tissue is an additional important antiinflammatory factor. We investigated conversion of the ubiquitous dehydroepiandrosterone sulfate (DHEAS), the biologically inactive precursor of DHEA, to the androgen DHEA in mixed synovial cells from patients with RA and patients with osteoarthritis (OA), making use of thin-layer chromatography and phosphorimaging. Using immunohistochemical analysis, we detected the key enzyme, steroid sulfatase. DHEAS-to-DHEA conversion in synovial cells from patients with RA was significantly lower than that in synovial cells from patients with OA (mean +/- SEM 3.3 +/- 0.5% versus 6.0 +/- 0.9% of applied (3)H-DHEAS per 10(6) synovial cells; P = 0.042). In RA, but not in OA, the level of converted (3)H-DHEA was inversely correlated with the density of synovial macrophages (for RA, R(rank) = -0.725, P = 0.005; for OA, R(rank) = 0.069, P not significant [NS]) and T cells (for RA, R(rank) = -0.621, P = 0.024; for OA, R(rank) = 0.247, P NS). Double immunohistochemistry analysis revealed that steroid sulfatase was located mainly in synovial macrophages but was also observed in fibroblasts. Neutralization of TNF largely up-regulated the conversion of DHEAS to DHEA in RA, but not in OA. A similar neutralizing effect was observed with polyclonal human immunoglobulins; this effect is most probably mediated via TNF neutralization at low TNF concentrations. These data indicate that TNF inhibits the conversion of DHEAS to DHEA in RA synovial cells. Because androgens are antiinflammatory mediators, TNF-induced inhibition of the local androgen supply is a supplementary proinflammatory factor. Consequently, anti-TNF strategies may also exert their positive effects by increasing tissue androgens.

No Evidence for Hepatic Conversion of Dehydroepiandrosterone (DHEA) Sulfate to DHEA: In Vivo and in Vitro Studies

Dehydroepiandrosterone (DHEA) sulfate (DHEAS) is the most abundant steroid in the human circulation and is thought to be the circulating hydrophilic storage form of DHEA. It is generally accepted that DHEA and DHEAS inter-convert freely and continuously via hydroxysteroid sulfotransferases and steroid sulfatase and that only desulfated DHEA can be converted downstream to sex steroids. Here we analyzed DHEA/DHEAS interconversion in vivo and in vitro. We administered oral DHEA (100 mg) and iv DHEAS (25 mg) to eight healthy young men, resulting in similar increases in serum DHEAS compared with baseline. However, although DHEA administration significantly increased serum DHEA (P < 0.05), no such increase was observed after DHEAS. Similarly, DHEA but not DHEAS was converted downstream to androstenedione, estrone, and androstanediol glucuronide. The striking absence of conversion of DHEAS to DHEA was mirrored by our in vitro findings in HepG2 cells, revealing dose-dependent conversion of DHEA (0.1-2 mum) to DHEAS but no conversion of DHEAS (0.1-2 mum). These results clearly illustrate a lack of hepatic conversion of DHEAS to DHEA, challenging the concept of free interconversion of DHEA and DHEAS. DHEAS does not seem to represent a circulating storage pool for DHEA regeneration, and therefore serum DHEAS is unlikely to reflect bioavailable DHEA.

The Early Dehydroepiandrosterone Sulfate Rise of Adrenarche and the Delay of Pubarche Indicate Primary Ovarian Failure in Turner Syndrome

Girls with Turner syndrome provide the first human model in which adrenal puberty (adrenarche) takes place without gonadal puberty. A wide range of serum dehydroepiandrosterone sulfate (DHEAS) concentrations has been observed, ranging from normal to very elevated. This study attempted to determine whether the course of adrenarche and pubarche is independent of ovarian function. A total of 867 serum DHEAS estimates were made over time in 111 girls with Turner syndrome. Puberty began spontaneously in 22 of these girls, whereas 45 had primary ovarian failure (POF). Serum DHEAS levels were compared with those of 322 healthy girls 3 to 17 years of age. POF was defined as a lack of spontaneous breast development and at least 1 follicle-stimulating hormone (FSH) level of 50 IU/L or higher before estrogen replacement therapy. Age-related serum concentrations of DHEAS were significantly higher in girls with Turner syndrome than in control girls from ages 7 to 17 years. Those with POF had significantly higher age-related levels than did girls experiencing spontaneous puberty at ages 9 to 15 years. Adrenarche occurred at a median age of 8.3 years in girls with POF, compared with 10.5 years for girls with spontaneous puberty and 11 years in normal girls. In both groups with Turner syndrome, mean DHEAS levels correlated closely with mean FSH and luteinizing hormone levels. Pubarche was delayed in girls with POF despite their high serum DHEAS levels. Puberty occurred more than 4.5 years after adrenarche, at a median age of 13 years, in girls with Turner syndrome, whereas in girls with spontaneous puberty, the interval was 1.4 years and the median age at pubarche was 11.9 years. These findings indicate that normally timed adrenarche depends on gonadal function. Normal pubarche represents the conversion of DHEAS to active androgens in the ovaries. Premature adrenarche and pubarche in an otherwise healthy girl may be the first clinical sign of functionally defective ovaries.

No evidence for hepatic conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA – in vivo and in vitro studies

No evidence for hepatic conversion of dehydroepiandrosterone sulfate (DHEAS) to DHEA – in vivo and in vitro studies

The Early Dehydroepiandrosterone Sulfate Rise of Adrenarche and the Delay of Pubarche Indicate Primary Ovarian Failure in Turner Syndrome

Pubarche without thelarche has been taken as clinical evidence that adrenarche is independent of gonadarche in females. This study examines whether the course of adrenarche [rise of serum dehydroepiandrosterone sulfate (DHEAS)] and pubarche (Tanner stage PH2) is independent from ovarian function. Serum DHEAS levels (n = 867) were longitudinally measured in 111 girls with Turner syndrome between 1990 and 2002. Of these, 22 had spontaneous puberty onset (Tanner stage B2), and 45 had primary ovarian failure (POF). Serum DHEAS levels were assayed by chemiluminescence and compared with those of healthy girls (n = 322; age range, 3-17 yr in both groups). Between the ages of 7 and 17 yr, girls with Turner syndrome had significantly higher age-related DHEAS levels than normal girls (P </= 0.02). Moreover, in the 9- to 15-yr-old girls, DHEAS levels were significantly higher in girls with Turner syndrome and POF than in Turner syndrome girls with spontaneous puberty onset (P </= 0.02). This discrepancy was caused by an earlier adrenarche (DHEAS levels reaching 1.1 micro mol/liter) in Turner syndrome girls with POF, which occurred at a median age of 8.3 yr (80% confidence interval, 6.5-10.4 yr) vs. 10.5 yr (8.6-12.2) and 11.0 yr (8.9-12.6) in Turner syndrome girls with spontaneous puberty onset and normal girls, respectively (P = 0.003). In contrast, pubarche was delayed in Turner syndrome girls with POF [median age, 13.0 yr (80% confidence interval, 10.6-15.0) vs. 11.9 yr (10.5-13.2) in Turner syndrome girls with spontaneous puberty onset (P = 0.02) and 11.6 yr (10.6-12.5) in normal girls]. Primary gonadal failure in Turner syndrome is associated with an earlier onset of adrenarche, but delayed pubarche. These data demonstrate that normal timing of adrenarche is dependent on gonadal function and suggest that normal pubarche is the clinical manifestation of the ovarian conversion of DHEAS to active androgens.

Conversion of dehydroepiandrosterone sulfate at physiological plasma concentration into estrogens in MCF-7 cells

Metabolism of dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and androstene-3,17-dione (Δ 4) was performed at their physiological plasma concentrations in MCF-7 cell cultures (1 μM, 10 and 2 nM, respectively). Final metabolic products of these steroids were separated by HPLC-radioactive flow detection and identified by LC/MS or MS/MS. Typical and specific mass fragmentation spectra identified the presence of estrone (E 1), 17β-estradiol (E 2), Δ 4, DHEA, 5-androstene-3β,17β-diol (Δ 5), and testosterone as principal DHEAS metabolites. Other steroids, such as androstenedione, androsterone, and DHEA fatty acid esters at very low concentrations (from pM to nM), were also obtained after steroid incubation. This highly specific method allowed us to conclude whether a metabolite and enzymatic activity of interest were present in MCF-7 cells or not. We also showed that DHEAS at its physiological plasma concentration may be converted into estrogens and estrogen-like compounds in breast cancer cells. The estrogenic action of DHEAS on breast cancer cells was also measured by bioluminescence in a stably transfected human breast cancer MCF-7 cell line with a reporter gene that allowed expression of the firefly luciferase enzyme under the control of an estrogen regulatory element.

Accelerated Conversion of Dehydroepiandrosterone Sulfate to Estrogen in a Patient with Crow-Fukase Syndrome and Diabetes Mellitus

About 28% of patients with the Crow-Fukase syndrome exhibit glucose intolerance which may be induced by low serum levels of dehydroepiandrosterone (DHEA). We report a patient with the Crow-Fukase syndrome who exhibited non-insulin dependent diabetes mellitus (NIDDM) worsened prior to admission. He received the DHEA sulfate (DHEA-S) infusion test to evaluate aromatase activity. This patient exhibited an increase in aromatase activity measured by the conversion of the intravenously loaded DHEA-S to estrogen, and low serum levels of DHEA and DHEA-S. These abnormalities returned to nearly normal during the administration of prednisolone, 60 mg per day. No adverse effect on his diabetes was observed during the corticosteroid treatment. Five control patients with diabetes but without the Crow-Fukase syndrome showed no increase in the conversion of DHEA-S to estrogen, which suggests that aromatase activity is normal in diabetes.The increase in aromatase activity in our patient may have led to a low serum concentration of DHEA that in turn caused glucose intolerance and a deterioration of the diabetes prior to admission. Glucocorticoid therapy may be beneficial in Crow-Fukase syndrome to improve the distorted metabolism of DHEA with no adverse effect on the diabetes.

Regulation of macrophage dehydroepiandrosterone sulfate metabolism by inflammatory cytokines.

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.

Conversion of Dehydroepiandrosterone Sulfate (DHEA-S) to Estrogens and Testosterone in Young Non-Pregnant Women

Conversion of Dehydroepiandrosterone Sulfate (DHEA-S) to Estrogens and Testosterone in Young Non-Pregnant Women

Competitive studies with dehydroepiandrosterone sulfate and 16 alpha-hydroxydehydroepiandrosterone sulfate in cultured human choriocarcinoma JEG-3 cells: effect on estrone, 17 beta-estradiol, and estriol secretion.

The estradiol (E2) to estriol (E3) ratio during human pregnancy depends on fetal liver hydroxylation of fetal adrenal dehydroepiandrosterone sulfate (DHEAS) and conversion by the trophoblast of DHEAS and 16 alpha-hydroxy-DHEAS (16 OH-DHEAS) to estrone (E1), estradiol (E2), and estriol (E3), respectively. It is not known whether the conversion of DHEAS into E1 and E2 influence the conversion of 16OH-DHEAS into E3 and vice versa. To examine this question, we studied these interactions in human choriocarcinoma JEG-3 cells. In serum-free medium (Dulbecco's Modified Eagle's Medium), JEG-3 cells secreted hCG [27 +/- 3 (+/- SEM) ng/mg cellular protein X 24 h] and progesterone (22 +/- 2.5), but neither C-19 nor C-18 steroids. The addition of DHEAS resulted in secretion of E1 and E2; at a concentration of 500 ng DHEAS/ml, the secretion of E1 (1 +/- 0.16) and E2 (11 +/- 3.1) was maximal, while E3 remained undetectable. The addition of 1000 ng 16 OH-DHEAS/ml resulted in maximum E3 secretion (13 +/- 1.8), while E1 and E2 remained undetectable. The addition of increasing concentrations of DHEAS to cultures exposed to 1000 ng 16OH-DHEAS/ml caused a decrease in E3 secretion and increased secretion of E1 and E2. Conversely, addition of increasing concentrations of 16OH-DHEAS in cultures exposed to 500 ng DHEAS/ml resulted in inhibition of E1 and E2 secretion and increased E3 secretion. A concentration of 16OH-DHEAS that inhibited the conversion of DHEAS into E1 and E2 neither altered the intracellular to extracellular steroid ratios (approximately 0.1) nor reduced the secretion of DHEA, androstenedione, and testosterone. The inhibitory effect of 16OH-DHEAS was minimal at low DHEAS concentrations (favoring the secretion of E1 and E2) and was greatly enhanced at concentrations of DHEAS that induced maximum E1 and E2 secretions. The results indicate that in trophoblastic cells, the metabolism of DHEAS can modulate E3 secretion, and the metabolism of 16OH-DHEAS can modulate the secretion of E1 and E2; and this regulatory mechanism appears to take place at the level of the aromatase system.

Kinetic studies on the formation of estrogens from dehydroepiandrosterone sulfate by human placental microsomes.

Using microsomes isolated from term human placentae kinetic analyses of each of the enzymes involved in estrogen synthesis from dehydroepiandrosterone sulfate have been carried out and the following parameters were found: sulfatase, Michaelis-Menten constant (Km) = 16,000 +/- 5,000 nM, maximum velocity (Vm) = 2.0 +/- 0.5 nmol X min-1 X mg protein-1; 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), Km = 15 +/- 3 nM, Vm = 1.8 +/- 0.4 nmol X min-1 X mg protein-1; aromatase, Km = 14 +/- 4 nM, Vm = 0.12 +/- 0.02 nmol X min-1 X mg protein-1. From these values one can predict that, theoretically, the rate-limiting enzyme in estrogen synthesis from dehydroepiandrosterone sulfate (DS) should change from the sulfatase at low concentrations of substrate to the aromatase at higher concentrations. In order to test this hypothesis we developed a system which allowed the formation of estrogens from DS, dehydroepiandrosterone, and androstenedione to be measured and the appropriate intermediates to be isolated. The sulfatase was found to be rate limiting at concentrations of DS below 2 microM and the aromatase was found to be rate limiting at higher concentrations. These data may explain why previous perfusion studies of human placentae indicated the sulfatase was the rate-limiting enzyme in estrogen synthesis yet in vitro studies found that it was the aromatase. Steroids previously shown to inhibit the 3 beta-HSD were examined for their ability to inhibit the formation of estrogens from DS. Although 3 beta-HSD activity was markedly inhibited this had little effect on the overall conversion of DS to estrogens, until high concentrations of inhibitors were used. The data also underline the importance of studying enzyme systems rather than single enzymes when studying steroid synthesis.

Placental Steroid Synthesis from DHEAS During Dexamethasone Therapy

Maternal glucocorticoid treatment affects estrogen synthesis by decreasing estrogen precursors. Whether glucocorticoid has any effect on the placental conversion of estrogen precursors to estrogen is not known. A study was therefore undertaken to investigate the effect of 100 mg of intravenously administered dehydroepiandrosterone sulfate (DHEAS) on estradiol (E2), estriol (E3), and testosterone (T) serum levels. The test was conducted for 5 hours in 10 women treated with intramuscular dexamethasone and in 8 controls during the last trimester of pregnancy. The initial E2 and E3 serum concentrations were lower in women treated with dexamethasone than in controls, while T serum levels did not display any difference. Following the injection of DHEAS there was a significant increase in E2, with maximal levels reached between 1 and 3 hours after injection in both groups. Maximal levels of E2 were equal for both groups. There was no change in E3 levels after DHEAS administration in the nontreated group, while the increase in the dexamethasone group was significant. A significant rise in T, with maximal levels reached at 1 hour after infusion, was similar in both groups. It is concluded that maternal dexamethasone does not inhibit the conversion of DHEAS either to E2 in the placenta or to E3 and T.

The contribution of plasma dehydroepiandrosterone sulfate to testosterone in a virilized patient with an arrhenoblastoma.

ABSTRACT The conversion of dehydroepiandrosterone sulfate (DS) to testosterone (T) and the DS production rate were quantified preand postoperatively in a virilized 32-yr-old female with an arrhenoblastoma. Additionally, at the time of operation, the tumor was isolated and perfused with DS-4-14C and T-7α-3H and the venous effluent collected. Preoperatively, the maximum quantity of plasma T derived from circulating DS was 640 μg/day. Postoperatively, this figure was found to be 310 7mu;g/day. The preoperative DS production rate was 80 mg/day, with the postoperative production rate falling to 15.5 mg/day. Labeled DS perfused through the tumor was not converted to T, testosterone sulfate or androstenedione. A small conversion of DS to dehydroepiandrosterone was noted. It is concluded that the conversion of circulating DS to T by the tumor itself was not an important factor in the genesis of this patient's virilism. Likewise, the peripheral conversion of circulating DS to T did not appear to be significant in ...

Steroidal and gonadotropin evaluation of a patient with a feminizing tumor of the adrenal gland. In vivo and in vitro studies.

ABSTRACT Steroidal metabolism was studied both in vivo and in vitro in a patient with a feminizing adrenocortical tumor. In vivo studies showed increased plasma S and urinary excretion of THS, whereas in vitro studies showed decreased cortisol synthesis and an increased amount of 11-desoxycortisol and 11-desoxycorticosterone, confirming an 11β-hydroxylase defect. This tumor also produced large quantities of estrogens. Production rates of estradiol-17β and estriol were 557 and 128 μg/day, respectively. No in vivo conversion of dehydroepiandrosterone sulfate to estrogens could be demonstrated. Elevated values of urinary gonadotropins by mouse uterine weight bioassay and at the same time normal serum levels for FSH and LH by radioimmunoassay were found. To our knowledge, such a feminizing adrenocortical tumor is unique in that, although the evidence is circumstantial, these results most probably represent the production of a biologically active but immunologically nonreactive gonadotropin by the tumor.