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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gonadotroph adenomas may exhibit qualitative and quantitative defects in gonadotropin biosynthesis and secretion. Hypersecretion of immunoreactive FSH dimers by these adenomas occurs frequently; however, it has not been known whether this FSH is biologically active. Using the granulosa cell aromatase bioassay and a highly specific immunoradiometric assay for FSH, we studied the serum bioactivity and bio- to immunoactivity (B/I) ratios of 14 men with FSH-secreting adenomas and compared these values to those of 11 age-matched normal men. In addition, three adenoma patients received TRH (400 micrograms, iv). The mean basal serum FSH level (international units per L), as measured by both bio- and immunoassays, and the FSH B/I ratios were significantly higher (P less than 0.02, by Kolmogorov-Smirnov test) in the adenoma patients than in normal men (mean +/- SEM; adenoma patients: bioactivity, 68.8 +/- 10.4; immunoreactivity, 34.8 +/- 13.7; B/I ratio, 3.4 +/- 0.6; normal men: bioactivity, 5.8 +/- 1.2; immunoreactivity, 6.4 +/- 0.8; B/I ratio, 0.90 +/- 0.1). Both bio- and immunoactive FSH rose after TRH injection, resulting in maintenance of the B/I (mean +/- SEM; pre-TRH: bio-FSH, 63.7 +/- 22.4; immuno-FSH, 28.0 +/- 14.1; B/I ratio, 2.8 +/- 1.2; post-TRH: bio-FSH, 125.6 +/- 42.7; immuno-FSH, 45.8 +/- 21.8; B/I ratio, 3.5 +/- 1.6). When gonadotroph adenoma cells from three separate patients were cultured and their conditioned media (n = 3) studied, relatively large amounts of both bio- and immuno-FSH were detected. Furthermore, the major isoelectric profile of bio-FSH (pH 4.9-3.0) in the conditioned medium from two such adenomas was shown by chromatofocusing to be comparable to that of purified human pituitary FSH (pH 5.2-3.6). We conclude that gonadotroph adenomas in men secrete FSH that is biologically active, both basally and in response to TRH.
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PMID:Gonadotroph adenomas in men produce biologically active follicle-stimulating hormone. 211 91

CGS-16949A is a new orally active nonsteroidal aromatase inhibitor which is more than 100-fold more potent than aminoglutethimide. This compound is an imidazole derivative, and therefore, its possible effect on cytochrome P-450-dependent enzyme activities in the adrenal gland was evaluated. In vitro investigations with dispersed normal and hyperplastic human adrenocortical cells showed that CGS-16949A at 10(-7)-10(-6) M is a potent 11 beta-hydroxylase inhibitor, which inhibits ACTH-stimulated cortisol release to a similar extent as an equimolar concentration of metyrapone (IC50 for both compounds, 10(-7)-5 X 10(-7) M). Etomidate was a more potent 11 beta-hydroxylase inhibitor (IC50, approximately 10(-8) M), while 10(-7)-10(-6) M ketoconazole caused (via 17 alpha-hydroxylase inhibition) a similar inhibition of cortisol release as 10(-7) M CGS-16949A (IC50, 10(-7)-5 X 10(-7) M). The 11 beta-hydroxylase inhibition by CGS-16949A was accompanied by a dose-dependent increase in the release of precursor steroids by the adrenocortical cells in vitro, including deoxycortisol, 17-hydroxyprogesterone, and androstenedione. Aldosterone release was suppressed 50% by 10(-9) M CGS-16949A, while the IC50 for cortisol in the same cells was 10(-7) M. Aldosterone release by the dispersed adenoma cells obtained from a patient with primary aldosteronism was also significantly suppressed by CGS-16949A. We concluded that 1) the new nonsteroidal aromatase inhibitor CGS 16949A is an inhibitor of 11 beta-hydroxylase which is equipotent to metyrapone. At present it is unclear whether the compound at the dose that causes complete aromatase inhibition in vivo also affects stress-induced cortisol release in man. 2) CGS-16949A exerts a very potent inhibitory effect on normal aldosterone release (IC50, 10(-9) M) and on tumorous aldosterone secretion. CGS-16949A might, therefore, be a drug that can be used in the treatment of primary hyperaldosteronism.
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PMID:The new aromatase inhibitor CGS-16949A suppresses aldosterone and cortisol production by human adrenal cells in vitro. 255 May 11

19-Nor-deoxycorticosterone is a newly recognized mineralocorticoid which has been associated with some forms of genetic, experimental, and human hypertension. To further examine this relationship, specific inhibitors of 19-nor-deoxycorticosterone biosynthesis must be developed. Since 19-hydroxylation is the pivotal step in both 19-nor-deoxycorticosterone biosynthesis and aromatization of androgens to estrogens, we evaluated an aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione on the inhibition of 19-hydroxylation in both rat and human adrenal mitochondria in vitro and 19-nor-deoxycorticosterone production and blood pressure in spontaneously hypertensive rats in vivo. Adrenal mitochondria from 48 male Sprague-Dawley rats and 1 patient with an aldosterone-producing adenoma were incubated in the presence of deoxycorticosterone substrate both with and without 4-hydroxyandrost-4-ene-3,17-dione. 4-Hydroxyandrost-4-ene-3,17-dione produced significant inhibition of 19-hydroxy-deoxycorticosterone production in both rat and human adrenal mitochondria, with a smaller and not significant inhibition of corticosterone and 18-hydroxy-corticosterone. 4-Hydroxyandrost-4-ene-3,17-dione given subcutaneously to spontaneously hypertensive rats lowered 19-nor-deoxycorticosterone by 69% and completely abolished hypertension compared to Wistar-Kyoto controls. These data demonstrate that 4-hydroxyandrost-4-ene-3,17-dione is a specific inhibitor of 19-hydroxylase, that it lowers 19-nor-deoxycorticosterone production and prevents hypertension in the spontaneously hypertensive rat. These studies reinforce the possible pathogenic significance of 19-nor-deoxycorticosterone in hypertension in spontaneously hypertensive rats.
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PMID:Selective 19-hydroxylase inhibition by an aromatase inhibitor, 4-hydroxyandrostenedione. 320 87

Bilateral tubular adenomas develop spontaneously in ovaries of WB X C57BL/6 F1-Sl/Slt mice after exponential loss of oocytes. We investigated the ability of this tumor to produce sex steroids. Incubation of tubular adenoma tissue with [3H] progesterone resulted in production of [3H]androstenedione and [3H]-testosterone. The amount of androgens produced by the tumor tissue was much greater than that produced by the normal ovarian tissue. The concentration of testosterone in the serum of the Sl/Slt mice bearing tubular adenomas, measured by radioimmunoassay, was about five times as high as the value in the serum of the congenic +/+ mice. Although incubation of the tumor tissue with [3H]androstenedione resulted in production of 3H-estrogens, the aromatase activity of the tumor tissue was about one-fifth of that of the normal ovarian tissue. Therefore, the major sex steroid secreted by tubular adenomas seemed to be testosterone. These endocrinological features of tubular adenomas were consistent with the following pathological features of the Sl/Slt mice with the tumors: (a) although the weight of uterus of the Sl/Slt mice was about one-half of the value observed in the +/+ mice, it decreased markedly after oophorectomy; and (b) submandibular glands of the Sl/Slt mice were significantly heavier than those of the +/+ mice.
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PMID:Production of androgens and estrogens by tubular adenomas which developed in ovaries of mutant mice of Sl/Slt genotype. 671 85

Ammonium perfluorooctanoate (C8) produced a dose-dependent increase in Leydig cell adenomas in Crl:CD BR (CD) rats fed 0, 30, or 300 ppm for 2 years. Administration of C8 to adult male CD rats, by gavage for 14 days, produced decreased serum and testicular interstitial fluid testosterone levels and increased serum estradiol levels. The C8-mediated decrease in the serum testosterone levels appeared to be due to a lesion at the level of the testis. These endocrine changes may play a role in the C8 induction of Leydig cell tumors. In the present work, C8 was examined for its ability to (1) directly affect Leydig cells in vitro using isolated Leydig cells from untreated rats and ex vivo using Leydig cells isolated from C8-treated rats, (2) affect testicular interstitial fluid hormone levels, and (3) induce aromatase activity. These studies were conducted to investigate the hypothesis that C8 produces an increase in estradiol by inducing cytochrome P450 XIX (aromatase), which converts testosterone to estradiol, and that the elevated estradiol levels ultimately produce Leydig cell hyperplasia and adenoma formation by acting as a mitogen or enhancing growth factor secretion. In the in vivo and ex vivo studies, adult male CD rats were gavaged with either 0 or 25 mg/kg/day C8 for 14 days. In addition to the ad libitum control, a second control group was pair-fed to the 25 mg/kg/day C8 group. In the in vitro and ex vivo studies, Leydig cells were isolated from testes of adult males by collagenase digestion followed by enrichment over Percoll gradients. A dose-dependent decrease in testosterone levels was observed in hCG-stimulated Leydig cells treated in vitro with C8 for 5 hr (IC50 approximately 200 microM). In contrast, ex vivo studies demonstrated an increase in testosterone production in hCG-stimulated Leydig cells from C8-treated rats when compared to Leydig cells isolated from either the ad libitum or pair-fed control rats. The in vitro data demonstrate that C8 directly inhibits testosterone release from Leydig cells, while the ex vivo data demonstrate that this inhibition is reversible.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of ammonium perfluorooctanoate on Leydig cell function: in vitro, in vivo, and ex vivo studies. 767 54

We report on a 19-year-old man with adrenocortical adenoma producing an excessive amount of estrogen. Determination of aromatase activity of the carcinoma tissue revealed its marked enhancement compared with that of 3 normal adrenal glands and the adipose tissue. The enhanced activity of aromatase was mainly responsible for the overproduction of estrogen in the adrenocortical carcinoma of our case.
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PMID:Aromatase activity in an estrogen-producing adrenocortical carcinoma in a young man. 785 54

Oestrogen producing adrenocortical tumours are extremely rare. We report a 65-year-old woman who presented with abnormal vaginal bleeding, with no significant abnormalities in her uterus or ovaries, who was found to have a right adrenal mass by radiological examination. Excessive secretion of oestrogens from the tumour was demonstrated by adrenal venous sampling. Basal levels of corticosteroids were within normal limits. Adrenalectomy was performed and pathological examination revealed an adrenocortical adenoma measuring 5.5 cm in its greatest dimension, in which both clear and compact tumour cells were observed. Oestrogen levels normalized following the removal of the adrenal mass. Tissue concentrations of oestrone and oestradiol in the tumour were 6.9 (69.5 pmol/g wet tissue weight) and 34.6 (93.6 pmol/g wet tissue weight)-fold greater respectively than those of adjacent non-neoplastic adrenal cortex. Aromatase activity in the tumour tissue determined by the 3H-water method was 118.6 pmol/h/mg protein, equivalent to that of a full-term human placenta. Immunohistochemical analysis of aromatase demonstrated immunoreactivity in the tumour cells, especially in compact cells, but not in adjacent non-neoplastic adrenal cells. This is the first reported case of an oestrogen producing adrenocortical adenoma in which aromatase in the tumour cells was documented.
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PMID:Oestrogen producing adrenocortical adenoma: clinical, biochemical and immunohistochemical studies. 897 64

The tritium water release assay, originally described for the analysis of aromatase activity in placental tissue, was used to estimate aromatase activity in breast tissue samples. The lower activity in this tissue necessitates longer incubation times and thus optimization of the assay conditions. To prevent oxidative and proteolytic inactivation of aromatase, dithiothreitol and albumin were added to the incubation mixture. Extra NADPH, cofactor in the aromatase reaction, also improved reaction rate in placental incubations, but after approximately 120 min activity rapidly decreased. Inhibitors gradually produced during the incubation could explain this phenomenon. Quantitative gas chromatography-mass spectrometry (GC-MS) analyses of testosterone, oestradiol, oestrone and androstenedione after incubation with non-labelled androstenedione proved that a substantial amount of the substrate is converted into testosterone. Qualitative GC-MS steroid profiling of the incubation mixture demonstrated the presence of hydroxylated oestradiol and hydroxylated testosterone, produced during incubation, which could have caused partial aromatase inhibition. The adjusted assay was used to analyse 84 breast tissue samples, histologically classified as normal, adenoma or carcinoma. Aromatase activity was found in 56% of all samples and ranged from 0.6 to 26 pmol oestrogen/g protein per hour. Aromatase positivity was found in 80% of the normal samples, 56% of the adenoma samples and 48% of the carcinoma samples. Although carcinoma samples were less often aromatase positive than normal tissue samples (chi2 = 4.80; P < 0.050) there was no difference in absolute aromatase activity. Because no less than approximately 50% of the carcinomas contained aromatase activity and because of the non-routine character of the assay we conclude that it is justified to start aromatase inhibition therapy without previous knowledge of the aromatase status.
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PMID:Optimization of a classical aromatase activity assay and application in normal, adenomatous and malignant breast parenchyma. 901 Mar 22

Leydig cell adenomas are observed frequently in studies evaluating the chronic toxicity of chemical agents in laboratory animals. Doubts have been raised about the relevance of such responses for human risk assessment, but the question of relevance has not been evaluated and presented in a comprehensive manner by a broad group of experts. This article reports the consensus conclusions from a workshop on rodent Leydig cell adenomas and human relevance. Five aspects of Leydig cell biology and toxicology were discussed: 1) control of Leydig cell proliferation; 2) mechanisms of toxicant-induced Leydig cell hyperplasia and tumorigenesis; 3) pathology of Leydig cell adenomas; 4) epidemiology of Leydig cell adenomas; and 5) risk assessment for Leydig cell tumorigens. Important research needs also were identified. Uncertainty exists about the true incidence of Leydig cell adenomas in men, although apparent incidence is rare and restricted primarily to white males. Also, surveillance databases for specific therapeutic agents as well as nicotine and lactose that have induced Leydig cell hyperplasia or adenoma in test species have detected no increased incidence in humans. Because uncertainties exist about the true incidence in humans, induction of Leydig cell adenomas in test species may be of concern under some conditions. Occurrence of Leydig cell hyperplasia alone in test species after lifetime exposure to a chemical does not constitute a cause for concern in a risk assessment for carcinogenic potential, but early occurrence may indicate a need for additional testing. Occurrence of Leydig cell adenomas in test species is of potential concern as both a carcinogenic and reproductive effect if the mode of induction and potential exposures cannot be ruled out as relevant for humans. The workgroup focused on seven hormonal modes of induction of which two, GnRH agonism and dopamine agonism, were considered not relevant to humans. Androgen receptor antagonism, 5 alpha-reductase inhibition, testosterone biosynthesis inhibition, aromatase inhibition, and estrogen agonism were considered to be relevant or potentially relevant, but quantitative differences may exist across species, with rodents being more sensitive. A margin of exposure (MOE; the ratio of the lowest exposure associated with toxicity to the human exposure level) approach should be used for compounds causing Leydig cell adenoma by a hormonal mode that is relevant to humans. For agents that are positive for mutagenicity, the decision regarding a MOE or linear extrapolation approach should be made on a case-by-case basis. In the absence of information about mode of induction, it is necessary to utilize default assumptions, including linear behavior below the observable range. All of the evidence should be weighed in the decision-making process.
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PMID:Leydig cell hyperplasia and adenoma formation: mechanisms and relevance to humans. 913 29

Dopamine agonists are known to increase the incidence of Leydig cell hyperplasia/adenomas when administered to rats over periods of 1-2 years. We have examined the early changes in factors affecting luteinizing hormone (LH)-controlled signal transduction pathways and steroidogenesis in Leydig cells in vitro after chronic oral administration of one of these dopamine agonists, Mesulergine (CU327-085) (N-(1-6,dimethylergolin-8a-yl)-N',N'-dimethylsulphamide hydrochloride) to Sprague-Dawley (SD) rats. Eight-week-old rats were given this dopamine agonist (2 mg/kg body wt/day) in food for 1, 5, or 12 weeks. The Leydig cells from control and treated rats were purified by elutriation and density gradient centrifugation. The dopamine agonist treatment was found to decrease the specific binding of 125I-human chorionic gonadotrophin (hCG) binding to the Leydig cells: a decrease was detected as early as 1 week after treatment and was more pronounced after 5 and 12 weeks. This was found to be due to a decrease in the LH/hCG receptor numbers and not to a decrease in LH/hCG-receptor binding affinity. Both basal and LH-stimulated cAMP and testosterone production were also decreased; cAMP production was decreased by approximately 50% by all concentrations of LH added whereas testosterone production was only decreased with submaximum stimulating concentrations of LH. The formation of testosterone in response to dibutyryl cAMP was also decreased by approximately 50%, indicating additional lesions in the signal transduction pathway. The addition of the cell permeant 22R-hydroxycholesterol (22R) demonstrated that testosterone but not pregnenolone production was decreased by treatment with the dopamine agonist, thus indicating that the 17 alpha-hydroxylase/C17-20 lyase may have been inhibited. Supporting evidence for this was found because the dopamine agonist also increased aromatase activity in the Leydig cells and thus the potential to produce estrogens; previous studies have shown that estradiol is an inhibitor of the 17-20 lyase enzyme. The addition of the dopamine agonist directly to the Leydig cells did not inhibit cAMP production or testosterone production except at high concentrations. It is concluded that treatment of rats with the dopamine agonist indirectly (i.e., via the pituitary) affects Leydig cell function resulting in a rapid decrease in LH receptors and cAMP and testosterone production. Aromatase activity is increased and thus the capacity to produce estrogens. These early changes in the signal transduction pathways and steroidogenesis may be involved in the Leydig cell hyperplasia/adenoma formation that subsequently occurs.
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PMID:Effect of a dopamine agonist on luteinizing hormone receptors, cyclic AMP production and steroidogenesis in rat Leydig cells. 965 71


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