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1.
E Perel D Daniilescu S Kindler L Kharlip D W Killinger 《The Journal of clinical endocrinology and metabolism》1986,62(2):314-318
The present study was designed to determine if stromal cells derived from human breast adipose tissue contain 5 alpha-reductase activity, and to study the effect of 5 alpha-reduced androgens on aromatase activity under basal and cortisol stimulated conditions. Stromal cells were prepared from breast adipose tissue obtained at the time of surgery from four patients. The cells were isolated after collagenase digestion and were cultured in alpha-minimum essential medium with 15% fetal calf serum. Studies were carried out between days 4 and 11 of the third subculture in the presence or absence of cortisol (10(-6) M). Metabolism of androstenedione (A) was studied over a period of 8 h after addition of medium containing 20 X 10(6) dpm (100 pM) [3H]A. The cells metabolized A to estrone (E1), testosterone (T), 5 alpha-androstane 3, 17-dione (5 alpha-A-dione), androsterone (AND), and dihydrotestosterone. On day 7 of culture, product formation expressed as percent conversion of A per 1 X 10(6) cells ranged as follows: E1, 0.02-0.13; T, 0.12-0.36; 5 alpha-A-dione, 2.05-9.91; and a fraction containing AND and dihydrotestosterone, 0.38-0.59. In the presence of cortisol the rate of cell growth was decreased by 25% to 50%. The formation of E1 increased 150- to 1500-fold and AND formation increased 2- to 8-fold. There was no consistent change in the formation of 5 alpha-A-dione and T. The addition of 5 alpha-A-dione (10(-6) M) to the culture medium at the time of assay resulted in greater than 90% inhibition of E1 formation under both basal and cortisol stimulated conditions. The studies indicate that adipose tissue is an important site for the formation of 5 alpha-reduced androgens. 相似文献
2.
E Perel D Daniilescu L Kharlip M E Blackstein D W Killinger 《Molecular and cellular endocrinology》1985,41(2-3):197-203
The conversion of androstenedione (A) to estrogens, testosterone (T) and 5 alpha-reduced metabolites was studied in different phases of cell growth in 4 lines of cultured human breast carcinoma cells. Aromatase activity was 10-fold greater in MD and DM than in MCF7 cells and was undetectable in ZR75 cells. Estrogen formation in MD and DM lines increased during the phase of exponential growth and decreased to 20% of maximum during confluence. 5 alpha-Reductase activity was determined by the formation of 5 alpha-androstane-3,17-dione (5 alpha-A-dione) and androsterone (AND), and was 5-fold greater in ZR75 cells than MD cells and 2-fold greater than in MCF7 cells. This activity was relatively constant during exponential growth and decreased during confluence. T accumulation was inversely related to 5 alpha-reductase activity. The MCF7 and ZR75 cells which contain estrogen receptors had the highest levels of 5 alpha-reductase activity while the MD line which lacks estrogen receptors had the lowest 5 alpha-reductase activity. The assessment of aromatase and 5 alpha-reductase activity in addition to estrogen and progesterone receptors may be helpful in predicting hormone sensitivity in human breast tumours. 相似文献
3.
K Noguchi 《Nippon Naibunpi Gakkai zasshi》1987,63(11):1330-1340
To evaluate the testosterone (T) 5 alpha-reductase activity in medial basal hypothalamus (MBH) and anterior pituitary gland of the adult male rat, whole homogenate of MBH or anterior pituitary glands was incubated with 14C-T in the presence of coenzymes under various experimental conditions. Major metabolites were 5 alpha-dihydrotestosterone (DHT), 5 alpha-androstane-3 alpha (beta), 17 beta-diol(3 alpha(beta)-diol) and delta 4 androstenedione. The activity of 5 alpha-reductase was expressed as the sum of the amount of DHT and 3 alpha(beta)-diol formed after incubation. The metabolites converted from T was separated and identified by thin layer chromatography and confirmed by recrystallization. The anterior pituitary gland possessed about four times higher 5 alpha-reductase activity compared with that in MBH. NADPH was essential for 5 alpha-reductase activity. They existed in microsomal fraction. They had same optimum temperature and almost same optimum pH. The Michaelis constant of the 5 alpha-reductase for T in MBH and anterior pituitary gland was 3.1 X 10(-7) M and 5.6 X 10(-7) M, respectively. These results suggest that 5 alpha-reduced metabolites of T, especially DHT have some physiologically significant roles in not only MBH but also anterior pituitary gland. Furthermore, it is noteworthy that 5 alpha-reductase in the anterior pituitary showed higher activity than that in MBH. 相似文献
4.
In vitro effects of an aromatase inhibitor on 5 alpha-reductase activity in human hypertrophic prostatic tissue 总被引:1,自引:0,他引:1
S Zoppi M Cocconi A Natali A Costantini M Serio L Martini M Motta 《The Journal of clinical endocrinology and metabolism》1986,63(1):269-271
To determine the effects of 4-hydroxy-4-androstene-3,17-dione (4-OH-A) on the in vitro conversion of testosterone (T) to 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone, DHT), 5 alpha-androstan-3 alpha, 17 beta-diol and 5 alpha-androstan-3 beta, 17 beta-diol (diols), human benign hypertrophic prostatic (BPH) tissue was incubated with 4-14C-T as substrate, in the presence of 4-OH-A (10(-8) to 10(-6) M); the amounts of the 5 alpha-reduced metabolites formed were quantitated. The effects of 4-OH-A were compared with those of 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza-5 alpha-androstan-3-one (4-MA), a known inhibitor of the 5 alpha-reductase. In the absence of 4-OH-A and 4-MA, human BPH tissue converted T to DHT and the diols readily. Both 4-OH-A and 4-MA induced significant and dose-related decreases in the formation of both DHT and the diols. The degree of inhibition induced by the different concentrations of 4-OH-A and 4-MA were 31, 41, 72% and 57, 87, 97%, respectively. The decreased formation of the diols was a consequence of the decreased availability of DHT (the immediate precursor of the diols) and was not due to direct effects of the inhibitors on the 3-hydroxysteroid dehydrogenases; both 4-OH-A and 4-MA were totally unable to modify the conversion of DHT to the diols, when 4-14C-DHT was used as substrate. Thus, 4-OH-A inhibits the process of 5 alpha-reduction of T in BPH tissue. This molecule might represent a potential new agent for the prevention and/or treatment of human BPH. 相似文献
5.
M Fujimoto 《Nippon Naibunpi Gakkai zasshi》1989,65(6):585-602
Cyproterone acetate(CA), a well-known competitive antiandrogen, has been used for the treatment of precocious puberty, prostatic adenocarcinoma, hirsutism and hypersexuality. However, there have been some reports of troublesome gynecomastia developing during the use of this drug. It was, therefore, of interest to investigate the effect of CA on peripheral aromatization, since it is the major source of circulating estrogens in men. Our recent studies of aromatase activity in human skin fibroblasts demonstrated that the skin is an important site of extraglandular aromatase activity in men and suggested that these cells might provide a valuable new system in which to study the enzyme. Estrogen formation was assayed by the [3H]H2O technique, after 3h incubation of the cells with androstenedione. The initial experiment was designed to test the effect of CA (10(-8) to 10(-5) M) on baseline aromatase activity during a 12h preincubation in the presence of fetal bovine serum (FBS). Baseline aromatase activity was not affected by the presence of CA, whereas medroxyprogesterone acetate, a similar synthetic progestogen, induced a 2-fold stimulation of aromatase activity at a concentration of 10(-5) M. In cells preincubated with dexamethasone (DEX) in the presence of FBS, aromatase activity was stimulated markedly. When the cells were preincubated in the medium containing FBS with DEX (2.5 X 10(-7) M) in the presence of CA (10(-7) to 10(-4) M), DEX-stimulated levels of aromatase activity were inhibited by CA in a dose-dependent fashion. A competitive binding assay using [3H]DEX, showed that CA was able to compete with DEX for glucocorticoid receptor and the relative binding affinity of CA was approximately 50 times less than DEX. This suggested that the inhibitory effect of CA was due to competition with DEX for receptor binding. Aromatase activity was also stimulated by (Bu)2cAMP (1mM) in the absence of FBS. The stimulatory effect of (Bu)2 cAMP was maximal after 12-24h of preincubation, and this level was maintained for 60h. Similar to the DEX stimulation, stimulation of aromatase activity by (Bu)2cAMP required both RNA and protein synthesis, since the stimulatory effect of (Bu)2cAMP was abolished by co-preincubation with cycloheximide or actinomycin D. When CA was present during either the 12h preincubation or assay incubation, no difference was found in the (Bu)2cAMP-stimulated levels of aromatase activity. On the other hand, the non-aromatizable androgen dihydrotestosterone (DHT) (10(-8) to 10(-6) M) inhibited the stimulation of aromatase activity by (Bu)2cAMP in a dose-dependent fashion.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
6.
The peripheral aromatization ([rho]BM) of androstenedione (A) and testosterone (T) was measured before and after administration of the aromatase inhibitor 10-(2 propynyl)estr-4-ene-3,17-dione (MDL-18,962) to five mature female baboons, Papio annubis. The measurements were made by infusing [3H]androstenedione/[14C]estrone or [3H]testosterone/[14C]estradiol for 3.5 h and collecting blood samples during the infusions and all urine for 96 h from the start of the infusion. Blood samples were analyzed for radioactivity as infused and product steroids, and the data were used to calculate MCRs. An aliquot of the pooled urine was analyzed for the glucuronides of estrone and estradiol and used to calculate the [rho]BM. MDL-18,962 was administered as a pulse in polyethylene glycol-400 (1-5 ml) either iv or via gastric tube 30 min before administration of the radiolabeled steroids. Control studies were done with and without polyethylene glycol-400 administration. When MDL-18,962 was given iv at 4 mg/kg, the aromatization of A was decreased 91.8 +/- 0.9% from the control value of 1.23 +/- 0.13% to 0.11 +/- 0.01%. At the same dose, aromatization of T was decreased 82.0 +/- 7.1%, from a control value of 0.20 +/- 0.03% to 0.037 +/- 0.018%. When MDL-18,962 was given iv at doses of 0.4, 0.1, 0.04, and 0.01 mg/kg, the values for aromatization of A were 0.16 +/- 0.03%, 0.18 +/- 0.06%, 0.37 +/- 11%, and 0.65 +/- 0.09%, respectively. The administration of MDL-18,962 via gastric tube at 4 mg/kg as a pulse decreased the aromatization of A from 1.35 +/- 0.06% to 0.43 +/- 0.12%, an inhibition of 67.2 +/- 10.7%. When administered via gastric tube daily for 5 days at 4 mg/kg, the aromatization of A fell from 1.35 +/- 0.06% to 0.063 +/- 0.003%, an inhibition of 84.4 +/- 0.5%. The MCRs of A and estrone were not altered by any dose of MDL-18,962 regardless of the mode of administration, but there was an increase in the MCRs of T and estradiol at the only dose (4 mg/kg, iv) at which these steroids were infused. The interconversions between the androgens and between the estrogens were not altered by the administration of MDL-18,962 at 4 mg/kg, iv. The enzyme-activated inhibitor MDL-18,962 is an effective inhibitor of [rho BM] in female baboons and could prove to be a useful therapeutic agent in treating estrogen-dependent breast cancer. 相似文献
7.
Ovarian homogenates from 10-150-day-old rats were incubated with [3H]progesterone and NADPH. Also, ovarian homogenates from 28-day-old rats were incubated for 5-180 min with either [14C]progesterone, [3H]5alpha-pregnane-3,20-dione or [14C]progesterone plus [3H]5alpha-pregnane-3,20-dione. Following incubation, radioactive metabolites were isolated, identified, and measured by column and paper chromatography, with derivative formation and recrystallizations to constant specific activity. Prepubertal ovaries (10, 20, and 28 days of age) converted 15-60% of progesterone to C21-17-hydroxysteroids and C19-steroids. At 40 and 150 days of age (postpubertal), the formation of these steroids decreased to less than 2%. At 10 and 150 days of age, the major C19-steroids formed from progesterone were androstenedione and testosterone. At 20 and 28 days of age, however, no accumulation of these C19-delta4-3ketosteroids was found (less than 0.1% of each), at which time the conversion of progesterone to 5alpha-reduced C19-steriods, such as androsterone and 5alpha-androstane-3alpha,17beta-diol, reached 30%. In ovaries of 28-day-old rats, the results from incubation studies for the detection of metabolic pathways indicated two biosynthetic pathways leading to 5alpha-reduced C19-steroids, one from progesterone via 5alpha-reduced C21 steroids, such as 3alpha-hydroxy-5alpha-pregnan-20-one and 3alpha,17alpha-dihydroxy-5alpha-pregnan-20-one, and a second via 17-hydroxyprogesterone, androstenedione, and testosterone. It seems that the active 5alpha-reduction of C19-delta4-3-ketosteroids and the formation of 5alpha-reduced C19-steroids by the pathway through 5alpha-reduced C21-steroids, are present in the ovaries of older prepubertal rats and may be the biological significance. 相似文献
8.
When measured in vitro using human placental microsomal preparations, the aromatization of 16alpha-hydroxytestosterone to estriol and androstenedione to estrone and estradiol proceeds at almost identical initial rates. Important differences between 16alpha-hydroxytestosterone and adrostenedione aromatization are evident, however. While substantial findings have implicated cytochrome P-450 in placental aromatization, the aromatizaiton of androstenedione is insensitive to CO although it is competitively inhibited by metyrapone. 16alpha-Hydroxytestosterone aromatization, in contrast, is inhibited 50-60% by CO and is strongly inhibited by metyrapone. 16alpha-hydroxytestosterone aromatization is strongly inhibited in a competitive manner by androstenedione, while 16alpha-hydroxytestosterone has essentially no effect on androstenedione aromatization, althogh at very high 16alpha-hydroxytestosterone concentrations (65 muM) and subsaturating androstenedione concentrations, 16alpha-hydroxytestosterone appears to noncomptitively inhibit androstenedione aromatization. The apparent Km for the aromatization of androstenedione is 95 nM and for 16alpha-hydroxytestosterone, 7 muM. Both androstenedione and 16alpha-hydroxytestosterone cause type I spectral perturbations associated with binding to cytochrome P-450 when added to placental microsomes; however, the deltaA390-420 is twice as great in response to saturating amounts of androstenedione than in response to 16alpha-hydroxytestosterone. If androstenedione is added to 16alpha-hydroxytestosterone, the same spectral change as that caused by androstenedione alone is expressed. The apparent spectral dissociation constant for androstenedione is 93 nM while for 16alpha-hydroxytestosterone it is 11muM; both essentially the same as the comparable apparent Kms for aromatization. The evidence suggests the presence of two aromatase P-450's in human placenta. 相似文献
9.
Short term androgen production by rat ovarian follicles and long term steroidogenesis by thecal explants in culture 总被引:1,自引:0,他引:1
To characterize the aromatizable and 5 alpha-reduced androgens produced by developing ovarian follicles, small antral (SA) and preovulatory (PO) follicles, theca and granulosa cells were incubated for 4 h with or without 8-bromo-cAMP and androstenedione. In addition, thecal explants were cultured for 10 days with or without ovine LH (oLH) to determine if the hormone-induced changes in androgen synthesis by developing follicles could be mimicked in vitro. Short term incubations of SA and PO follicles, theca and granulosa cells in medium alone resulted in limited accumulation of androgen [testosterone, 5 alpha-androstan-17 beta-ol-3-one (DHT), 5 alpha-androstan-3 alpha, 17 beta-diol (3 alpha diol), and androsterone], as determined by RIA. In the presence of 8-bromo-cAMP, PO follicles produced large quantities of testosterone (3 ng), DHT (1 ng), 3 alpha diol (15 ng), and androsterone (14 ng), while SA follicles accumulated much less androgen (0.69, 0.05, 1.23, and 1.3 ng, respectively). In the presence of androstenedione and 8-bromo-cAMP, both SA and PO follicles and theca produced large amounts of aromatizable and 5 alpha-reduced androgens. SA and PO granulosa cells required the presence of the substrate androstenedione to produce androgens, primarily testosterone and 3 alpha diol. Therefore, progesterone, androstenedione, and 5 alpha-reduced androgens were used to monitor LH action on thecal cell function in culture. Small antral theca cultured in basic culture medium alone (containing 10% fetal calf serum) displayed an increased ability to accumulate androstenedione by day 6, approximately 3 times that observed on day 2. However, a 5-fold further increase in androstenedione accumulation was observed by day 6 for SA theca cultured in the presence of oLH. Maintenance of progesterone accumulation by SA theca throughout the culture period also was dependent on the presence of LH. In contrast, androstenedione accumulation by PO theca required the presence of LH in the culture medium, while progesterone accumulation in these cultures did not. Little or no 5 alpha-reduced androgen accumulated in the media of SA and PO theca cultured in basic culture medium alone. However, SA and PO theca cultured with oLH accumulated approximately 1 ng androsterone by day 10. We conclude that 1) SA and PO follicles, theca and granulosa cells possess the enzymes required to produce large amounts of 3 alpha diol and androsterone; 2) low concentrations of oLH are required to stimulate SA thecal steroidogenesis and to maintain PO thecal androstenedione accumulation in culture.(ABSTRACT TRUNCATED AT 400 WORDS) 相似文献
10.
W H Cleland C R Mendelson E R Simpson 《The Journal of clinical endocrinology and metabolism》1985,60(1):174-177
Adipose tissue is the principal site of estrogen formation in postmenopausal women; with advancing age as well as with increased body weight, there is an increase in the fractional conversion of circulating androstenedione to estrone. We have studied the effects of aging as well as body weight on aromatase activity of adipose tissue specimens taken from 50 women of various ages and weights. Since aromatase activity of adipose tissue is detectable primarily in stromal cells, these cells were incubated with [1-3H]androstenedione (150 nM), and estrogen formation was assayed by measuring the incorporation of tritium into [3H]water. The aromatization rate, when normalized on the basis of equal numbers of cells, increased with increasing age (P less than 0.03; r = 0.43). In contrast, when expressed as a function of body weight, no change in aromatase activity of adipose stromal cells were found. Aromatization of androstenedione by cells from young women who had undergone oophorectomy was not increased compared with that of cells from young women with normal ovarian function, indicating that the onset of menopause per se and the accompanying increase in circulating gonadotropin levels were not causative factors in the increased aromatase activity of adipose stromal cells. We conclude, therefore, that increased estrone production associated with aging may result from an increase in the specific activity of the aromatase enzyme in adipose stromal cells and is not affected by changes in gonadotropin concentrations associated with menopause. On the other hand, the increase in estrogen formation as a function of obesity is probably due to increased numbers of adipose cells, rather than to an increase in the specific activity of aromatase in those cells. 相似文献
11.
The purpose of the present investigation was to characterize and determine what hormones affect the activity of aromatase in human fetal hepatocytes maintained in primary monolayer culture. The major product of aromatization of androstenedione was estrone sulfate. Optimal conditions for assay of aromatase activity in fetal liver cells were determined. The apparent Km for androstenedione was 50 nM. Aromatase activity was stimulated by glucocorticoids in the presence of fetal calf serum. The concentration of dexamethasone required for half-maximal stimulation was 10(-8) M, similar to the concentration required for half-maximal binding to glucocorticoid receptors. This action of dexamethasone was inhibited by cortisol 21-mesylate, a glucocorticoid antagonist. Aromatase activity was also stimulated by (Bu)2cAMP and cholera toxin, and was inhibited by fetal calf serum. This effect of fetal calf serum was mimicked by epidermal growth factor. However, epidermal growth factor did not mimic the permissive action of serum to stimulate aromatase activity by dexamethasone. In these respects, the regulation of aromatase activity of human fetal hepatocytes is similar to that of human adipose stromal cells. A polycyclic hydrocarbon, benzo(a)pyrene, which causes induction of aryl hydrocarbon hydroxylase activity in fetal hepatocytes, inhibited the stimulation of aromatase activity by dexamethasone. Of a number of hormones tested, including glucagon, insulin, angiotensin II, ACTH, hCG, GH, PRL, and T3, only glucocorticoids were effective in stimulating aromatase activity of human fetal hepatocytes. These results emphasize the complex and multiparameter nature of the regulation of aromatase activity in this as in other tissues. 相似文献
12.
In vivo steroid regulation of aromatase and 5 alpha-reductase in goldfish brain and pituitary 总被引:1,自引:0,他引:1
The full expression of testosterone (T) actions in neuroendocrine tissues requires aromatization and 5 alpha-reduction to estradiol (E2) and 5 alpha-dihydrotestosterone (DHT), respectively. Recently, we documented striking changes in aromatase and 5 alpha-reductase during the annual reproductive cycle of goldfish (Carassius auratus). To investigate possible regulatory effects of sex steroids, goldfish were implanted with hormone-filled silastic capsules for 2-5 weeks. Conversion of [3H]androstenedione to estrone or 5 alpha-androstanedione by homogenates of anterior hypothalamus/preoptic area, remaining telencephalon, and whole pituitary (PIT) was used to estimate aromatase and 5 alpha-reductase, respectively. Gonadosomatic index and plasma E2, T, and DHT were monitored as an index of reproductive status and capsule effectiveness. In reproductively inactive fish in which plasma steroids and aromatase were basal (October), E2 or T increased aromatase activity in brain of both sexes but stimulated activity in PIT of females only; DHT was not effective. In a subsequent experiment initiated close to the spawning peak and prior to the seasonal decline in plasma steroids and brain aromatase (April), T increased or maintained brain aromatase in a time-dependent manner. 5 alpha-Reductase activity was unaffected by steroid treatment in both reproductively active and inactive fish. These results indicate that variations in circulating steroids are responsible, at least in part, for changes in brain aromatase during the annual reproductive cycle of goldfish and provide the first evidence for steroid control of pituitary aromatase. The steroid specificity of the induction suggests that an estrogen receptor mechanism is involved.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
13.
The possible modulatory role of the sympathetic nervous system on testosterone aromatization and 5 alpha reduction by rat pineal gland was examined in vitro. NE (10 microM) added to pineal organ cultures increased by 72% the conversion of [14C]testosterone into estradiol and depressed by 39 and 53% that into the 5 alpha-reduced metabolites 5 alpha-dihydrotestosterone (5-DHT) and 5 alpha-androstanediol (5 alpha-diol). Both effects of NE were negated by the addition of the beta-adrenoceptor antagonist propranolol but not by the alpha-adrenoceptor antagonist phentolamine. Dibutyryl cAMP (0.1 mM) mimicked the effect of NE on pineal [14C]testosterone metabolism; it also mimicked the NE-induced inhibition of [14C]progesterone reduction to 5 alpha-pregnanedione and 3 alpha-hydroxy-5 alpha-pregnan-20-one by rat pineal gland explants. At the end of the dark phase of the daily photoperiod, pineal aromatization of testosterone was significantly higher, and 5 alpha reduction lower, than in rats killed at noon. Pineal glands obtained from rats subjected to superior cervical ganglionectomy 12 h earlier exhibited increased conversion of [14C]testosterone into estradiol, and depressed synthesis of 5 alpha-reduced metabolites, as compared with their respective sham-operated controls. 3 days after ganglionectomy a diminished testosterone aromatization was found. These results suggest that the increased release of NE from pineal sympathetic nerve endings stimulates testosterone aromatization and inhibits 5 alpha reduction via a beta-adrenoceptor. 相似文献
14.
Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro 总被引:2,自引:0,他引:2
The role of androgen in aromatase induction/activation by follicle-stimulating hormone (FSH) was studied in cultured granulosa cells from estrogen-pretreated, immature rat ovaries. Aromatase activity was measured in washed cell monolayers after a 48-h culture in medium containing hFSH and/or various sex steroids or their analogues. Culture with hFSH (100 ng/ml) plus 10(-7) M testosterone (T) stimulated aromatase activity to a level similar to that of granulosa cells from preovulatory follicles in the cyclic adult on the morning of proestrus. But if T was omitted, or replaced by estrogen (DES) or progesterone (P), the response to hFSH was at least 90% lower. The abilities of T, androstenedione, five nonaromatizable 5 alpha-reduced androgens, an aromatase reaction intermediate (19-hydroxyandrostenedione), and a pharmacological competitive aromatase inhibitor (delta 1-testoloalactone) to stimulate the aromatase response to hFSH were proportionate to their stimulatory effects on P production during the culture. By both criteria T was the most potent androgen while 19-hydroxyandrostenedione and delta 1-testololactone were completely inactive. The stimulatory effect of 10(-7) M T on the aromatase response to FSH was inhibited by the nonsteroidal antiandrogen SCH 16423 (ID50 = 3.6 x 10(-6) M). These results indicate that granulosa cell aromatase induction/activation by hFSH is an androgen receptor-regulated process in vitro. 相似文献
15.
Functional differentiation in steroidogenesis of two types of luteal cells isolated from mature human corpora lutea of menstrual cycle 总被引:2,自引:0,他引:2
A Ohara T Mori S Taii C Ban K Narimoto 《The Journal of clinical endocrinology and metabolism》1987,65(6):1192-1200
Enriched small and large cell fractions were prepared from mature corpora lutea from 15 women in the midluteal phase by enzymatic dissociation, followed by Percoll gradient centrifugation. The steroidogenic function of each cell type was assessed by measuring the gonadal steroids released into the incubation medium. The large cell fraction was estimated to be 97% pure, with minimal contamination by small cells, whereas the small cell fraction was approximately 68% pure, being contaminated with 10% large cells and 22% nonsteroidogenic cells. In the unstimulated state, large cells were approximately 2-fold more potent in progesterone formation and aromatase activity, but only half as potent in androstenedione and testosterone formation as an equal number of small cells. When stimulated with hCG, the small cells responded with significant increases in progesterone, androstenedione, and testosterone release, but the large cells did not. Both cell types secreted estrone and 17 beta-estradiol in the presence of androgen substrate, but the addition of FSH significantly stimulated aromatization only in large cells. Thus, small and large human luteal cells have steroidogenic properties similar to those exhibited by follicular thecal and granulosa cells, respectively. 相似文献
16.
Oestrogen formation from androstenedione in human bone 总被引:2,自引:0,他引:2
BACKGROUND AND OBJECTIVE Peripheral aromatization of testosterone and androstenedione Is the principal source for circulating oestrogens In men and In castrated and post-menopausal women. Since human bone is a target organ for androgens and oestrogens, aromatase activity was assessed In human sponglosa obtained from patients who were undergoing orthopaedic surgery. DESIGN AND PATIENTS In Initial experiments for assessing aromatization, oestrogen formation from 1,2,6,7-3H-androstenedlone was compared with the release of trltlated water from 1β-3H-androstenedlone. Since the rates of enzyme activity were similar with the two methods, rates of oestrogen formation were determined under standardized conditions with the trltlated water generation technique In bone specimens obtained from 4 men and 11 post-menopausal women. RESULTS The apparent Km of the aromatase ranged between 6 and 50 nm (20.4 ± 3.9; mean ± SEM), values In the range of those reported for human placental mlcrosomes. The maximum velocity (Vmax) of the aromatase activity ranged between 0-14 and 1.23 nmol/g DNA/h. CONCLUSIONS Oestrogens formed in human bone may play a physiological role In steroid hormone action in this tissue. 相似文献
17.
Clinical and biochemical parameters of androgen action in normal healthy Caucasian versus Chinese subjects. 总被引:7,自引:0,他引:7
D P Lookingbill L M Demers C Wang A Leung R S Rittmaster R J Santen 《The Journal of clinical endocrinology and metabolism》1991,72(6):1242-1248
Stimulation of androgen-sensitive hair follicles is mediated by dihydrotestosterone (DHT), which is formed in these tissues by 5 alpha-reduction of testosterone. A possible mechanism for increased body hair in some human populations might, therefore, be an increase in 5 alpha-reductase activity, resulting in elevated tissue levels of DHT. If present, this finding could have other important clinical implications, since the 5 alpha-reductase enzyme is pivotal in the pathophysiology of prostatic disease. To explore differences in clinical and biochemical parameters of androgen action, we conducted a study of 184 caucasian and Chinese subjects in whom we evaluated chest hair density and serum levels of androgen precursors and 5 alpha-reduced androgen metabolites. Differences in chest hair density were most notable in the men, in whom comparative mean chest hair scores (using a scale of 0-4) were 3.0 vs. 0.8 (P less than 0.0001), caucasian vs. Chinese. Levels of 5 alpha-reduced androgen products were also strikingly higher in the caucasian vs. Chinese subjects. Serum 3 alpha-androstanediol glucuronide levels (nanomoles per L) were 34.7 +/- 2.4 vs. 19.7 +/- 0.9 (P less than 0.001) for the men and 21.5 +/- 3.2 vs. 9.4 +/- 0.6 (P less than 0.001) for the women, and serum levels of androsterone glucuronide (nanomoles per L) were 179 +/- 26 vs. 107 +/- 7 (P less than 0.01) for the caucasian vs. Chinese men and 173 +/- 23 vs. 81 +/- 9 (P less than 0.001) for the women. Serum levels of total and bioavailable testosterone did not differ between the racial groups, but serum levels of the precursor androgens, dehydroepiandrosterone sulfate and androstenedione, were significantly higher in the caucasian vs. Chinese men, but not in the women. We conclude that increased serum levels of 5 alpha-reduced androgen metabolites in caucasians vs. Chinese subjects provide circumstantial evidence for a racial difference in 5 alpha-reductase activity and suggest a mechanism for the increased body hair observed in the caucasian men. Increased levels of precursor androgens may also play a role. 相似文献
18.
Hyperestronemia may be central to the development of polycystic ovary syndrome. The present study was designed to examine whether increased availability of androstenedione or increased aromatase closely associated with adiposity, plays the dominant role in the development of hyperestronemia. We measured plasma androstenedione, estrone and the estrone/androstenedione ratio (an indirect index of peripheral aromatase activity), in 141 patients with idiopathic hirsutism and in 88 patients with polycystic ovary syndrome. Estrone levels were higher in polycystic ovary syndrome, 250.4 +/- 129 (mean +/- standard deviation) than in idiopathic hirsutism, 210.6 +/- 119 pmol/l, p less than 0.05. Plasma androstenedione levels were higher in polycystic ovary syndrome, 8.24 +/- 3.5, than in idiopathic hirsutism, 7.1 +/- 1.7 nmol/l, p less than 0.0025. However, the estrone/androstenedione ratio was similar in the two groups. In all patients who smoked, androstenedione was higher, 8.14 +/- 3.22 than in nonsmokers, 6.99 +/- 2.96 nmol/l, p less than 0.005. Smokers had a lower body mass index, 23.9 +/- 2.3, than non-smokers 25.6 +/- 4.8 kg/m2, p less than 0.025. However, estrone levels were similar in smokers and in non-smokers. These data indicate that elevated estrone is more closely related to increased availability of androstenedione than to increased aromatase activity. While cigarette smoking appears to increase androstenedione levels, it may inhibit aromatase activity either directly or indirectly because of an associated reduction in adiposity. However, since the relative frequency of polycystic ovary syndrome and idiopathic hirsutism was similar in smokers and non-smokers, smoking did not appear to reduce estrone bioactivity as had been claimed. 相似文献
19.
S W Lamberts H A Bruining H Marzouk J Zuiderwijk P Uitterlinden J J Blijd W H Hackeng F H De Jong 《The Journal of clinical endocrinology and metabolism》1989,69(4):896-901
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. 相似文献
20.
We previously reported no difference in progesterone (P4) secretion from the granulosa layer of the largest follicle (F1) of the domestic hen regardless of the maturity of the F1 follicle. However, coincubation of the granulosa and thecal layers resulted in inhibition of P4 secretion from the less mature F1, but not from the more mature F1. The goal of this study was to determine if estradiol (E2) and androgens secreted by the thecal layer suppress P4 production by the granulosa cells. We removed the granulosa layer from less mature F1 follicles and dispersed granulosa cells (1 x 10(5)) were incubated (3 h) in triplicate with one of these treatments: control, E2, testosterone (T), androstenedione (A), and dihydrotestosterone (DHT; at concentrations of 1 x 10(-7), 1 x 10(-6), and 1 x 10(-5) M), LH (100 ng) as well as LH plus E2, T, A, and DHT at the same concentrations. P4 secretion was measured in the medium and cells, and the experiment was replicated seven times. We found a dose-related suppression of basal and LH-stimulated P4 production by all steroids. In a second experiment (n = 3-5), we tested the specificity of the androgens in suppressing P4 production by granulosa cells by using the aromatase inhibitor 7-(4'-amino)phenylthio-4-androstene-3,17-dione. This compound did not reduce the effectiveness of T in suppressing P4 production. Finally in Exp 3 (n = 4-7), E2 and T were tested individually and in combination at concentrations of 1 X 10(-8)-1 X 10(-5) M. We found a possible synergistic effect, in that the combination of E2 plus T suppressed P4 to a greater degree than either steroid alone. Our results indicate that 1) E2 and androgens suppress basal and LH-stimulated P4 production by granulosa cells in a dose-related manner; 2) androgen suppression of P4 production is not mediated by aromatization to estrogen; and 3) the suppressive effects of E2 and androgens may be synergistic. We conclude that E2 and androgens secreted by the thecal layer may regulate P4 production by the granulosa layer. 相似文献