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

The development of well tolerated, potent, specific, and nontoxic aromatase inhibitors for the treatment of postmenopausal women with estrogen-dependent breast cancer has been a major goal of recent studies. The third generation inhibitors now under investigation are nearly 10,000-fold more potent than first generation compounds. Currently available RIAs for plasma estradiol lack sufficient sensitivity to measure levels during aromatase inhibition and, thus, to assess drug potency precisely. The availability of an ultrasensitive bioassay for estradiol provided the opportunity to accurately assess the potency of a new third generation triazole aromatase inhibitor, letrozole (CGS 20267). We used this assay to measure estradiol levels in 14 women with metastatic breast cancer given letrozole at doses of 100 micrograms to 5.0 mg/day over a 12-week period. The lack of differences between doses and sampling times allowed pooling of data. Basal estradiol levels of 7.2 +/- 1.9 pmol/L (mean +/- SEM, 1.95 +/- 0.52 pg/mL) fell to 0.26 +/- 0.11 pmol/L (0.07 +/- 0.03 pg/mL) during the first 6 weeks of therapy and to 0.48 +/- 0.18 pmol/L (0.13 +/- 0.05 pg/mL) during the second 6 weeks of therapy. Although plasma estradiol levels measured by RIA were significantly correlated with levels measured by bioassay (r = 0.79; P < 0.01), the degree of suppression assessed by the bioassay (95 +/- 2% after 6 weeks) was greater than that determined by the RIA (81 +/- 4%), presumably due to improved ability to measure very low estradiol levels. We conclude that plasma estradiol is suppressed by letrozole to lower levels than previously observed, with equivalent suppression at all doses studied. A slight, although not statistically significant, rebound in estradiol levels occurs during the second 6 weeks of therapy compared to the first 6 weeks. Maximum inhibition of aromatase is achieved at letrozole doses as low as 100 micrograms.
 ...
PMID:Use of ultrasensitive recombinant cell bioassay to measure estrogen levels in women with breast cancer receiving the aromatase inhibitor, letrozole. 767 8

This study investigated the influence of the aromatase inhibitor 4-hydroxyandrostenedione (4OHA, formestane), given orally, on peripheral aromatase activity and plasma oestradiol (E2) levels in post-menopausal women with advanced breast cancer. The aim was to establish whether an optimal dose could be identified that had a pharmacological effectiveness comparable with that of parenteral 4OHA. A total of 13 post-menopausal women were studied before treatment and after a minimum of 4 weeks on treatment with one or more of the following doses: 125 mg once daily (od), 125 mg b.i.d. (bd) and 250 mg od. In all, seven aromatase studied were performed at 125 mg od; four, at 125 mg bd; and ten, at 250 mg od. Three patients were studied at all doses. E2 was measured concurrently and was available at all dose increments for seven patients. Given at doses of 125 mg od, 125 mg bd and 250 mg od, treatment with formestane inhibited in vivo aromatisation by 62.3% +/- 9.5%, 70.0% +/- 5.1% and 57.3% +/- 5.3%, respectively (mean +/- SEM). Corresponding values for plasma E2 suppression were 30.7% +/- 6.5%, 43.4% +/- 4.5% and 42.9% +/- 6.7%, respectively. Thus, apart from a somewhat better suppression of plasma E2 levels by the two higher doses as compared with 125 mg od, no significant difference in the degree of aromatase inhibition or plasma E2 suppression was observed. The suppression of E2 by oral 4OHA at 125 mg bd or 250 mg od approaches that achieved by the recommended parenteral schedule of 250 mg fortnightly, but inhibition of aromatase at this dose was substantially inferior. The findings are consistent with a hypothesis that 4OHA given orally may cause substantial plasma oestrogen suppression during part of the day, but neither the od nor the bd regimens investigated in the present study were capable of producing optimal aromatase inhibition.
 ...
PMID:The effects of oral 4-hydroxyandrostenedione on peripheral aromatisation in post-menopausal breast cancer patients. 778 Nov 47

Pilot studies in boys with abnormalities of puberty have suggested that both gonadotropin and sex steroid responses to GnRH agonist undergo characteristic maturational changes. However, it is not known how the pattern of hormonal secretory responses to GnRH agonist changes during normal puberty. Therefore, we have assessed the responses of normal boys at various stages of pubertal development to a single dose of the GnRH agonist nafarelin. Baseline LH, FSH, testosterone (T), estradiol (E2), and steroid intermediates, including 17-hydroxyprogesterone, increased during puberty. LH responses peaked at 3 h in prepubertal (P1; n = 8) and midpubertal (P2; n = 4) boys, at 12 h in late pubertal (P3; n = 8) boys, but earlier (0.5-1 h) in adults (P4; n = 10). LH levels remained high for 24 h in P3-P4. Indexes of both the readily releasable and reserve pools of pituitary LH increased significantly with advancing pubertal stage (P < 0.003). FSH responses differed among groups only at 24 h. Nafarelin stimulated T significantly in groups P2 < P3 < P4. The maximal responses of T were 0.54 +/- 0.25 (+/- SEM), 8.7 +/- 2.9, 18.5 +/- 1.0, and 15.3 +/- 1.4 nmol/L in these respective groups (by analysis of variance, F = 40.5; P < 0.001). However, nafarelin did not stimulate E2 significantly until late puberty; the maximal E2 responses to nafarelin treatment were 17.9 +/- 5.9, 26.7 +/- 8.7, 318 +/- 71.3, and 329 +/- 17.4 pmol/L in P1, P2, P3, and P4 (F = 18.3; P < 0.001). In contrast to E2, most intermediate steroids measured increased significantly in response to nafarelin in stages P2-P4. We conclude that a single dose of the GnRH agonist nafarelin stimulates gonadotropin secretion in normal prepubertal and pubertal males; it also stimulates gonadal steroid production in pubertal males. Pubertal maturation of gonadotrope function appears to involve mainly increases in both the readily releasable and reserve pools of LH. The findings that late pubertal boys had LH responses similar to those of men, but greater T and lesser 17-hydroxyprogesterone outputs are compatible with their pituitary-testicular axis operating at a less down-regulated state than that of adults. The apparently isolated failure of E2 to increase in response to nafarelin in early puberty suggests that maturation of aromatase activity normally does not become appreciable until late puberty. These findings suggest that a single dose of GnRH agonist may provide a simple means of assessing the maturation of the neuroendocrine-testicular axis.
 ...
PMID:Maturation of the normal pituitary-testicular axis, as assessed by gonadotropin-releasing hormone agonist challenge. 820 Sep 35

Transforming growth factor alpha (TGF alpha) is implicated as a paracrine growth factor in the regulation of human granulosa cell function. To investigate this further, we have examined the actions of TGF alpha on the basal and follicle-stimulating hormone (FSH)-stimulated aromatase activity of human granulosa cells to determine how this growth factor influences oestrogen biosynthesis in the follicle. Granulosa cells from women having in-vitro fertilization during untreated or gonadotrophin-stimulated cycles were cultured for 1-6 days in the presence or absence of FSH or TGF alpha at a range of doses. Aromatase activity, expressed as oestradiol production, was determined after culture during a 3 h test period. After 2 days, TGF alpha (1-300 ng/ml) decreased basal and FSH-stimulated aromatase activity in a dose-dependent manner (ED50 = 3 ng/ml). In contrast, after 4 days, TGF alpha enhanced both basal and FSH-stimulated aromatase activity. Repeated experiments revealed a consistent pattern of inhibition on day 2, which was more marked in the presence of FSH (reduction by 30.6 +/- 9.1%, mean +/- SEM; n = 14; P < 0.01), and stimulation on day 4 in both the absence (increased by 61.4 +/- 20.6%, mean +/- SEM; n = 6; P < 0.05) and presence of FSH (increased by 36.0 +/- 15.2%, mean +/- SEM; n = 8; P < 0.05). The results provide further evidence that TGF alpha is a paracrine factor in the control of oestrogen biosynthesis, but the actions can be either inhibitory or stimulatory depending on the duration of exposure.
 ...
PMID:Time-dependent effects of transforming growth factor alpha on aromatase activity in human granulosa cells. 856 69

This report concerns the evaluation of various estrogens, estrone (El), estradiol (E2), and estrone sulfate (E1S), as well as E1S-sulfatase and aromatase activities in pre- and postmenopausal women with breast cancer. The levels (in picomoles per g; mean +/- SEM) of the various estrogens in the breast tissue from premenopausal patients (n = 11) are: El, 1.4 +/- 0.5; E2, 1.2 +/- 0.6; and E1S, 1.2 +/- 0.3. In postmenopausal patients (n = 23), the values are, respectively, 1.0 +/- 0.4, 1.4 +/- 0.7, and 3.3 +/- 1.9. These concentrations of estrogens in the tumors of postmenopausal patients are significantly higher than those found in plasma. The activity of E1S-sulfatase in both pre- and postmenopausal patients was 50-200 times higher than that of aromatase. E1S-sulfatase and aromatase activities are significantly higher in post-menopausal than in cycling patients. It is concluded that despite the low levels of circulating estrogens in postmenopausal patients, the tissue concentrations of these steroids are several-fold higher than those in plasma, suggesting tumor accumulation of these estrogens. The physiopathology and clinical significance of these high levels of the various estrogens (E1, E2, and E1S) as well as sulfatase and aromatase activities in postmenopausal patients with breast cancer is yet to be explored.
 ...
PMID:Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. 863 51

We studied a unique group of rams that would not mate with estrous ewes during extensive testing for sexual behavior. The same rams courted males in preference to females in 30-min sexual preference tests and were classified as male-oriented (n = 6). We compared the following endocrine profiles: systemic steroid concentrations, the capacity of the testes to biosynthesize 17 alpha-hydroxyprogesterone and testosterone from 3H-progesterone in vitro, and the levels of brain aromatase activity (AA) in male-oriented rams vs. rams that were proven breeders and designated as female-oriented (n = 7). After the last behavioral test, sera were collected, and males in each experimental group were killed. Brains and testes were obtained for subsequent determinations of AA and measurements of steroidogenic enzyme activity. All dissections and subsequent assays were performed without knowledge of experimental group assignments. Serum concentration of testosterone (T), dihydrotestosterone (DHT), androstenedione, estrone (E1), and estradiol-17 beta (E2) were determined by RIA. AA was quantified by a 3H2O assay validated for neural tissue of the ram. We studied frontal, parietal and cingulate cortex, cerebellum, hippocampus, olfactory bulb, septum, amygdala, infundibulum-median eminence, and preoptic area (POA). Serum T, E1, and E2 concentrations of female-oriented subjects were significantly higher (p < 0.05) than those in male-oriented subjects (SEM: 1559 +/- 228, 46 +/- 2, and 15 +/- 3 pg/ml vs. 874 +/- 196, 40 +/- 2, and 8 +/- 1 pg/ml serum, respectively). DHT and androstenedione concentrations in the systemic circulation did not differ between groups. Likewise, biosynthesis of labeled T and 17 alpha-hydroxyprogesterone from 3H-progesterone by testicular homogenates in vitro was significantly higher (p < 0.05) in female-oriented than in male-oriented subjects (28.8 +/- 8.1 vs. 12.1 +/- 2.3 mumol.h-1.mg protein-1 for T and 416.9 +/- 100.8 vs. 186.3 +/- 30.7 mumol.h-1.mg protein-1 for 17 alpha-hydroxyprogesterone). The highest level of AA was found in the POA, which was significantly greater in female-oriented than in male-oriented rams (472 +/- 34 vs. 296 +/- 24 fmol 3H2O.h-1.mg protein-1, p < 0.05). AA in other brain areas did not differ between experimental groups. Our data suggest that the testes of the male-oriented ram have reduced capacity for T production. In other species, T controls in situ estrogen formation not only by providing substrate for aromatization but also by up-regulating P450arom mRNA in the POA. Because the POA is part of a neural circuitry that mediates male sexual behavior in many species, we hypothesize that the capacity for aromatization influences sexual orientation of these rams.
 ...
PMID:Endocrine correlates of partner preference behavior in rams. 879 66

Leukaemia inhibitory factor (LIF) is a 43 kDa glycoprotein with a remarkable range of biological actions in different tissue systems. LIF improves the rate of fertilization of mouse oocytes in vitro and up-regulates aromatase enzyme. We postulated that LIF may be an important modulator of ovarian function and may also improve embryo quality in humans. Follicular fluid samples from patients undergoing in-vitro fertilization (IVF) and embryo transfer (n = 123), from women undergoing ovarian stimulation (n = 4) and from women undergoing laparoscopy for tubal ligation during their follicular phase (n = 3) were used. Follicular fluid LIF, oestradiol, and progesterone were measured and embryo quality was assessed. Granulosa-lutein cells were cultured for 3 days in Ham's F-12:Dulbecco's modified Eagle's medium (DMEM). Ovarian stromal cells, isolated by enzymatic dispersion of ovarian tissue, were also cultured in the same medium. Following experimental treatments, LIF mRNA and protein concentrations were quantified. The concentration of LIF was 0.8 +/- 0.3 (mean +/- SEM) pg/ml in pre-human chorionic gonadotrophin (HCG) follicular fluid samples and 13.0 +/- 1.1 pg/ml in post-HCG follicular fluid samples (P < 0.05). LIF levels were undetectable in three follicular fluid samples obtained during unstimulated follicular phase. There was a correlation between follicular fluid LIF and follicular fluid oestradiol concentrations (r = 0.36; P = 0.0001) and the number of grade I embryos (r = 0.62; P = 0.01). LIF mRNA and the protein were expressed constitutively but in low amounts in the ovarian stromal cell cultures. The concentrations of LIF mRNA as well as protein were increased by interleukin (IL)-1alpha and tumour necrosis factor alpha (TNF alpha) in a time- and concentration-dependent manner. Purified granulosa-lutein cells expressed low amounts of LIF mRNA and protein which were not significantly increased by IL-1alpha or TNF alpha. Our findings suggest that HCG stimulates the expression of LIF in follicular fluid. Both granulosa-lutein and ovarian stromal cells express the LIF mRNA and produce the protein. Modulation of LIF in these cells may play an important role in the physiology of ovulation and early embryo development.
 ...
PMID:Leukaemia inhibitory factor expression in human follicular fluid and ovarian cells. 1010 12

We have recently cloned the mRNA encoding KGF from canine prostate and produced recombinant canine KGF (rcKGF) which specifically acts on cultured canine prostatic epithelial cells (CCPECs) which possess KGF receptors (Canatan et al., 1996; DNA Cell Biol. 15:247). In the present study, the effect of rcKGF on aromatase activity in CCPECs from young (6-month-old) and mature (3-year-old) dogs was examined. Release of 3H2O from labeled substrate was used as the indicator of aromatase activity. CCPECs were pulsed with [1-beta-3H]-androstenedione (1 microCi/ml, 6 hr). The amounts of 3H2O released into culture medium were measured (dpm) and total cellular proteins were determined. Aromatase activity was expressed as 3H2O dpm/mg cellular protein (mean +/- SEM). The basal level of aromatase activity in CCPECs from mature dogs was approximately 4 times higher (p < 0.05) than that in cells from young dogs. Aromatase activity in CCPECs from mature dogs increased in a dose-dependent manner upon treatment with rcKGF. Interestingly, rcKGF, at any of the concentrations tested, had no significant effect on aromatase activity in CCPECs from young dogs. These results are the first to indicate that aromatase activity is affected by KGF in mature CCPECs, suggesting that KGF may be involved indirectly in the etiology of benign prostatic hyperplasia by increasing aromatase activity and thus increasing aromatization of androgens. Aromatase induction by KGF may explain, at least in part, the increased aromatization of androgens observed in aged dogs. The exact mechanism of how KGF induces aromatase activity in CCPECs is needed to be addressed further.
 ...
PMID:Differential effect of keratinocyte growth factor (KGF) on aromatase activity in cultured canine prostatic epithelial cells. 943 Aug 21

The conversion of androgens to estrogens by CYP19 (cytochrome P450AROM, aromatase) is an important step in the mechanism of androgen action in the brain. CYP19 expression has been demonstrated in various animal species, but studies in human postnatal brain tissue are lacking. Therefore, we investigated CYP19 mRNA expression in human temporal lobe tissues. We studied biopsy materials removed at neurosurgery from 34 women, 32 men and 10 children with temporal lobe epilepsy. Quantification of CYP19 mRNA was achieved by nested competitive reverse transcription-PCR. CYP19 mRNA concentrations did not differ significantly between women (2.6 +/- 0.6 arbitrary units, aU; mean +/- SEM) and men (1.6 +/- 0.3 aU) nor between cerebral cortex tissue (2.0 +/- 0.4 aU) and subcortical white matter tissue of adults (2.4 +/- 0.7 aU), but they were significantly lower in cerebral cortex specimens of children (0.9 +/- 0.6 aU) than in those of adults (p < 0.02). In conclusion, CYP19 mRNA is expressed in the temporal lobe of children and adults. CYP19 mRNA concentrations are significantly lower in specimens of children than in those of adults.
 ...
PMID:Expression of CYP19 (aromatase) mRNA in the human temporal lobe. 953 40

In this study the effect of recombinant human follicle stimulating hormone (rFSH) on oestradiol production by human granulosa-lutein cells was examined in long-term culture, in the presence or absence of androgens. Cells were harvested at the time of follicular aspiration after ovarian hyperstimulation for in-vitro fertilization and cultured for 9 days. Granulosa cells were capable of secreting oestradiol spontaneously even without androgen and gonadotrophin support. Basal oestradiol secretion was relatively high and variable (421.3 +/- 159.3 pg/ml, mean +/- SEM, n = 13) on the first day and decreased gradually to 16.7 +/- 3.1 pg/ml on day 9. Addition of androgens (testosterone or androstenedione) to the incubation medium enhanced dose-dependently basal oestrogen production on days 5, 7 and 9. The androgen/oestrogen conversion rate remained constantly high during the culture, even without rFSH. After pre-incubation for 3 days, addition of rFSH resulted in a dose- and time-dependent increase in granulosa-lutein cell oestrogen production in the absence of exogenous androgens. Testosterone supplementation caused considerably higher basal oestradiol concentrations, however rFSH failed to further stimulate the oestrogen release from granulosa-lutein cells, suggesting that these cells cultured in vitro possess high aromatase activity even without rFSH support.
 ...
PMID:Oestradiol production by luteinized human granulosa cells: evidence of the stimulatory action of recombinant human follicle stimulating hormone. 968 70


<< Previous 1 2 3 4 5 Next >>