Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ketoconazole, an orally-active, broad spectrum mycotic agent, was shown to inhibit in vitro human placental microsomal aromatase but was without effect on 3 beta-hydroxysteroid dehydrogenase-isomerase (3 beta-HSD-I) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activities. The Km of placental aromatase for testosterone was 30 +/- 1.1 nmol/l (mean +/- SEM, n = 6). Inhibition (determined by Lineweaver-Burk plot) was non-competitive with respect to substrate with a Ki value of 3.0 +/- 1.4 mumol/l (mean +/- SEM, n = 6). Ketoconazole was without effect on the 3 beta-HSD-I and 17 beta-HSD activities when using [3H] pregnenolone and [3H] oestradiol, respectively, as substrates. Since ketoconazole is known to inhibit cytochrome P-450-dependent enzyme reactions, the results of the present study support the contention that cytochrome P-450 is involved in the aromatisation process.
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PMID:Effect of ketoconazole on placental aromatase, 3 beta-hydroxysteroid dehydrogenase-isomerase and 17 beta-hydroxysteroid dehydrogenase. 302 21

Follicular fluid estradiol, progesterone, testosterone, and androstenedione levels were compared in 2 groups of spontaneously ovulatory women undergoing ovulation induction with human menopausal gonadotropin (hMG; which contains equal amounts of LH and FSH) or human urinary FSH (huFSH). The results were correlated with the ratios of embryo cleavage and pregnancy. Although significantly more FSH [1268 +/- 38 (+/- SEM) vs. 953 +/- 38 IU; P less than 0.05] was required for equivalent hyperstimulation in hMG compared to huFSH cycles, the number of oocytes retrieved and fertilized and the number of embryos transferred were similar for the 2 ovulation induction protocols. Forty-two follicles from 21 women stimulated with hMG and 38 follicles from 15 women stimulated with huFSH were examined and found to be representative of the total cohort of aspirated follicles. Follicular fluid estradiol and progesterone levels were similar, but hMG-stimulated follicles contained significantly more testosterone [7.83 +/- 0.52 (+/- SEM) vs. 6.30 +/- 0.42 ng/ml; P less than 0.03] and less androstenedione (24.4 +/- 3.6 vs. 37.8 +/- 5.0 ng/ml; P less than 0.03) than did huFSH-stimulated follicles. Embryonic cleavage rates were similar for all fertilized oocytes from both hMG- and huFSH-stimulated cycles, although pregnancy rates were significantly higher in huFSH cycles (40% vs. 9.5%; P less than 0.05). In addition, aromatase activity, progesterone production, and [125I]hCG-binding activity were compared in granulosa-luteal cells isolated from some of these women. Cells from 21 follicles from 9 women stimulated with hMG and 24 follicles from 9 women stimulated with huFSH were studied. There were no significant differences in aromatase activity, progesterone production, or [125I]hCG binding. Thus, the presence or absence of exogenous LH during ovulation induction with FSH has little direct effect on granulosaluteal cell function. However, the presence of LH during ovulation induction with FSH does appear to alter thecal androgen metabolism, resulting in higher testosterone and lower androstenedione levels in follicular fluid. Such a shift in androgen milieu may impair oocyte development and successful implantation.
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PMID:Ovulation induction with human menopausal gonadotropin compared to human urinary follicle-stimulating hormone results in a significant shift in follicular fluid androgen levels without discernible differences in granulosa-luteal cell function. 309 55

FSH bioactivity was measured by means of FSH-dependent aromatase activity (conversion of androgen substrate to estradiol). Assay sensitivity was optimized by the use of immature (7-10 days old) rats as Sertoli cell donors, serum-free medium for incubation, phosphodiesterase inhibitor (methylisobutylxanthinine), serial dilution of FSH in medium containing 1% BSA, delayed addition of FSH for 72 h after cell plating, and 19-hydroxyandrostenedione (2.5 X 10(-6) M) as the aromatizable androgen substrate. The method consisted of subjecting the decapsulated immature rat testes to a 2-step collagenase dispersion, plating the cells in medium [Dulbecco's Modified Eagle's Medium-Ham's F-10 (1:1)] containing growth factors and methylisobutylxanthinine for 72 h, adding increasing doses of FSH to the standard curve or small volumes of serum to the test vials as well as 19-hydroxyandrostenedione for 24 h, and measuring estradiol by RIA in dilutions of the medium. Using NIAMDD human (h) FSH-2 as the bioassay standard, the useful range of the assay was 0.01-5.0 ng/ml. Specificity was determined by the addition of graded doses of hLH, hTSH, ACTH, hGH, hPRL, and hCG. The minor degree of FSH bioactivity observed in a few hormone preparations was accounted for by the degree of FSH contamination in them. Mean intra- and interassay coefficients of variation were 9% and 11%, and the index of precision was 0.049. This bioassay was used to determine the bioactive FSH content of pituitary extracts, tissue culture media, elutions from columns, and isoelectrically focused samples. More importantly, small quantities of human sera gave responses parallel to the standard curve in a minimum of two dilutions. The bio- to immunoreactive ratios, expressed as the mean +/- SEM (NIAMDD-hFSH-2), were 0.66 +/- 0.2 in boys (n = 6), 0.78 +/- 0.2 in pubertal girls (n = 6), 1.18 +/- 0.2 in men (n = 13), 1.24 +/- 0.1 in postmenopausal women (n = 30), 1.94 +/- 0.3 in the follicular phase (n = 19), 6.2 +/- 1.4 in the ovulatory phase (n = 19), and 1.6 +/- 0.4 in the luteal phase (n = 19) of the normal menstrual cycle. These results indicate that the bio- to immunoreactive hFSH ratio in the circulation, is dependent upon the hormonal milieu of the subject.
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PMID:An improved in vitro bioassay for follicle-stimulating hormone (FSH): suitable for measurement of FSH in unextracted human serum. 311 17

One-third of the cases of breast cancer in postmenopausal women are hormone-dependent and the lesions regress upon treatment with antiestrogens or inhibition of estrogen biosynthesis. In these patients, estrogens are synthesized in extraglandular tissues from adrenal precursors and re-enter plasma to produce estrone levels of 52 +/- 6.5 pg/ml (mean +/- SEM) and estradiol concentrations of 13.1 +/- 0.7 pg/ml. However, the fact that the levels of estrogen in breast tumor tissue are an order of magnitude higher than plasma levels suggested the possibility of in situ estrogen production. To address this possibility, we measured several enzymes involved in estradiol biosynthesis in human tumors. Forty-eight of 61 tumors contained aromatase (estrogen synthetase) activity ranging from 5-80 pg/gm protein per hour. By comparison, the levels of estrone sulfatase were 10(6) higher, ranging from 0.8-125 micrograms/gm protein per hour. Because the sulfatase enzyme was of lower affinity (i.e., Km = 27 microM) than that of aromatase (i.e., 0.027 microM), the amount of estrogen formed under conditions of similar substrate concentrations was compared and found to be 10-fold higher via the sulfatase enzyme. In 41 additional tumors, the 17 beta-hydroxysteroid dehydrogenase enzyme, catalyzing the conversion of estrone to estradiol, was uniformly present. To test the biologic relevance of the estrone sulfate to estrone to estradiol pathway, estrogen-dependent nitrosomethylurea rat mammary tumors were grown in soft agar in the presence of estrone sulfate. Concentrations of estrone sulfate of 10(-6) microM significantly (p less than 0.01) stimulated colony formation in this system in which 75.5-98.6% of estrone sulfate was converted to estrone and 0.2 to 6% to estradiol. These data support the hypothesis that mammary carcinomas can synthesize estradiol in situ from circulating estrogen precursor and that local conversion is biologically important. On the basis of comparative data, the estrone sulfate to estrone to estradiol pathway is quantitatively more important than that involving androstenedione to estrone to estradiol.
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PMID:Enzymatic control of estrogen production in human breast cancer: relative significance of aromatase versus sulfatase pathways. 352 46

The conversion of testosterone to estradiol by aromatase and to dihydrotestosterone by 5 alpha-reductase was measured in the medial basal hypothalamus of starved and control male rats. Activities of both enzymes were significantly reduced in starved animals. Aromatase activity was 18.2 +/- 2.3 versus 29.8 +/- 5.7 fmol E2/mg protein/90 min (mean +/- SEM, P less than 0.02) and 5 alpha-reductase was 4.95 +/- 0.35 versus 5.96 +/- 0.30 pmol DHT/mg protein/90 min (P less than 0.02) for starved and control animals respectively. The results indicate that hypothalamic metabolism of testosterone is decreased during starvation. Therefore the increased sensitivity of the T-LH feedback described earlier in starved rats [4] cannot be explained by changes in central testosterone metabolism.
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PMID:Testosterone metabolism in the medial basal hypothalamus of the starved male rat. 358 55

The luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH (LHRHa) inhibits rat testicular testosterone secretion. To determine whether LHRHa decreases serum testosterone concentrations solely by inhibiting gonadotropin secretion or, in addition, by influencing directly testicular testosterone biosynthesis, we examined the effects of LHRHa on the activities of 5 key testicular steroidogenic enzymes. Thirty hypophysectomized, hOG treated rats were given either LHRHa (1 micrograms sc/day) or saline during 7 days. The LHRHa treated animals exhibited a significant decrease of serum testosterone when compared to the control group (498 +/- 37 ng/dl vs 2044 +/- 105 ng/dl, mean +/- SEM, P less than 0.001). 17-Hydroxyprogesterone serum levels were also decreased in the LHRHa treated rats (61 +/- 6 ng/dl vs 93 +/- 7 ng/dl, P less than 0.005), while serum progesterone levels were similar in both groups of animals. These changes in steroid concentrations were associated with decreases in the microsomal enzyme activities of 17-hydroxylase (37 +/- 9 vs 654 +/- 41 pmol/mg protein/min, P less than 0.001), 17,20-desmolase (103 +/- 9 vs 522 +/- 47 pmol/mg protein/min, P less than 0.001), 3 beta-hydroxysteroid dehydrogenase (1.7 +/- 0.02 vs 4.1 +/- 0.1 nmol/mg protein/min, P less than 0.001), aromatase (95 +/- 7 vs 228 +/- 6 pmol/mg protein/min, P less than 0.001) and 17-ketosteroid reductase (167 +/- 9 vs 290 +/- 18 pmol/mg protein/min, P less than 0.01) in the LHRHa treated animals. These findings indicate that LHRHa can inhibit directly rat testicular testosterone biosynthesis.
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PMID:Direct effect of the luteinizing hormone releasing hormone analog D-Trp6-Pro9-Net-LHRH on rat testicular steroidogenesis. 639 51

Recently, we identified a human follicular fluid protein(s) (FP) which inhibited human menopausal gonadotropin (hMG)-induced rat ovarian weight gain and FSH-induced aromatase. Here, we assessed FP activity from ovulatory patients who were either untreated (n = 7) or received clomiphene (n = 9; 150 mg/day on cycle days 5-9) or hMG (n = 6; 150 IU/day on cycle day 3). Aspirations were performed when one follicular diameter exceeded 20 mm. FP activity was expressed as the percent inhibition of porcine granulosa cell aromatase activity at three concentrations of extracted follicular fluid (range, 1250-10 micrograms; extrapolated to 50 micrograms). Patients receiving hMG or clomiphene had multiple follicles greater than 16 mm in diameter (3.83; 2.66/patient, respectively), while untreated patients had 1 each. FP activity was 14.1 +/- 5.3% (mean +/- SEM) inhibition for untreated, 18.0 +/- 3.4% inhibition for hMG-treated, and 13.7 +/- 5.3% inhibition for clomiphene-treated patients. Follicular fluid estradiol levels from untreated patients (2590 +/- 1221 ng/ml) were greater than estradiol concentrations from hMG-treated (356 +/- 55 ng/ml; P less than 0.01) or clomiphene-treated (1317 +/- 344 ng/ml; P less than 0.05) patients. Progesterone follicular fluid levels were 9.84 +/- 3.3, 5.18 +/- 61, and 11.3 +/- 2.3 micrograms/ml for untreated, hMG-treated, and clomiphene-treated patients, respectively (P less than 0.05). A similar relationship was present with 17-hydroxyprogesterone (untreated, 1.6 +/- 0.2 micrograms/ml; hMG-treated, 0.76 +/- 0.1 micrograms/ml; clomiphene-treated, 2.16 +/- 0.3 micrograms/ml; P less than 0.05). Androstenedione and testosterone follicular fluid levels were similar in all groups (78.9 +/- 23 and 7.09 +/- 2.14 ng/ml, respectively). Untreated patients had a positive correlation between FP and follicular fluid estradiol (r = 0.689; P less than 0.01) and inhibin activity (r = 0.654; P less than 0.05), and a negative correlation between follicular fluid progesterone levels (r = 0.622; P less than 0.05). Patients treated with hMG had a significant negative correlation between FP activity and follicular fluid progesterone levels (r = 0.756; P less than 0.005) and a biphasic correlation with follicular fluid 17-hydroxyprogesterone (r2 = 0.853; P less than 0.0025). Clomiphene-treated patients had biphasic correlations between follicular fluid estradiol and 17-hydroxyprogesterone levels (r2 = 0.853 and P less than 0.0025, and r2 = 0.637 and P less than 0.025, respectively). These findings indicate that the FP activity of the dominant follicle correlates with its state of differentiation, as described by intrafollicular estradiol, progesterone, 17-hydroxyprogesterone levels and inhibin activity. These relationships are in part dependent upon gonadotropin stimulation.
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PMID:Activity of a human follicular fluid protein(s) in spontaneous and induced ovarian cycles. 641 55

Human breast carcinomas contain aromatase, the enzyme necessary for the conversion of androgens to estrogens. If present in sufficient amounts, aromatase could catalyze the synthesis of estrogens from plasma steroid precursors and produce high breast cancer tissue concentrations. To determine the biological importance of tumor aromatase, we validated a specific and highly sensitive 3H-labeled water release assay for aromatase and used this to quantitate the amount of estrogen synthesized in vitro in breast tumors. As proof of assay validity, the [3H] water release assay detected 22.7 +/- 0.09 (+/- SEM) pmol/g . h estrogen formed vs. 24.7 pmol/g . h with the direct product isolation assay. Of 61 human breast tumors studied, 48 contained measurable aromatase activity, ranging from 5-70.5 pmol estrone formed/g . h. Three aromatase inhibitors (aminoglutethimide, testololactone, and 4-hydroxyandrostenedione) blocked this activity at concentrations similar to those affecting aromatase activity in other tissues. If biologically important, the estrogen formed locally from aromatase would be expected to stimulate production of the progesterone receptor. Under these circumstances, a positive correlation of progesterone receptor and local estrogen production should be found. In contrast, no significant correlation between aromatase activity and progesterone receptor level was observed (r = -0.27; P = NS). In addition, no correlation between estrogen receptor content and aromatase activity was detected. Finally, the amount of aromatase activity present in most tumors was insufficient to produce biologically meaningful saturation of estrogen receptors. These observations suggested that aromatase, while present in the majority of breast cancer tissues, may only be biologically important in those few tumors with very high aromatase activity.
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PMID:Biological significance of aromatase activity in human breast tumors. 663 Apr 10

In six healthy subjects serum oestradiol was selectively decreased by administering an aromatase activity inhibitor, hydrotestolactone (HT). After HT administration serum oestradiol (Oe2) decreased from 18.7 +/- 2.3 (SEM) to 6.7 +/- 0.6 pg/ml whereas testosterone (T) and dihydrotestosterone (DHT) blood levels were not modified. These oestradiol changes were associated with a significant increase in serum LH and FSH concentrations (P less than 0.001). The administration of tamoxifen, an oestrogen antagonist, to 5 subjects caused a sharp increase in LH and FSH levels (P less than 0.001). Oe2 was unchanged after the treatment with tamoxifen, whereas T levels were significantly higher. The sum of these data suggests that oestradiol under physiological conditions plays a specific role in the feedback mechanism of gonadotrophin release.
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PMID:Direct evidence in men for a role of endogenous oestrogens on gonadotrophin release. 678 50

The metabolism of androstenedione (A) by the placenta in late pregnancy and the early puerperium was studied. The metabolic clearance rate of A (MCR-A) was increased in pregnant women, 2,825 +/- 207 L/24 hr (mean +/- SEM), compared to 2,020 +/- 140 L/24 hr in nonpregnant women of similar body weight. The immediate puerperal MCR-A was 2,538 +/- 50 L/24 hr. Therefore, approximately 10% of maternal plasma A was cleared by the placenta. In the latter half of pregnancy, the extent of conversion of maternal plasma A through estradiol formation, (rho)AE2, was increased, whereas in the immediate puerperium it was normal, 0.018. Moreover, 90% of aromatase activity was attributed to the placenta in late pregnancy. From these data, we computed that the placental clearance rate of A through estradiol (PCAE2) from whole blood was 497 +/- 41 ml/min in women with a single fetus and 691 +/- 102 ml/min in women with twin fetuses. Thus, it appears that the PCAE2 is a sensitive index of maternal-placental perfusion.
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PMID:Placental clearance rate of maternal plasma androstenedione through placental estradiol formation: an indirect method of assessing uteroplacental blood flow. 731 14


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