Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00691 (EE2)
 7,802 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to investigate whether the amounts of progesterone (P) normally present at midcycle, when administered to normal women pretreated with estradiol benzoate (E2B), alter the release of LH and FSH. Twelve subjects (four groups of three) were studied during two menstrual cycles. On day 1 of both the initial (E2 control) and a subsequent (study) cycle, each subject received E2B im (2.5 micrograms/kg/12 h) for a total of seven injections. Twelve hours after the final injection, gonadotropin-releasing hormone (GnRH) was given. In the study cycle, P in oil was added to each of the last three injections of E2B in doses of 1.25 (group I), 2.5 (group II), or 5.0 (group III) mg/12 h, and in one group (IV) in graded doses of 1.25 2.5, and 5.0 mg/12 h. Estradiol levels were similar in both cycles, with a mean (+/- SE) of 271 +/- 3 pg/ml. During the interval of P administration, mean P levels rose gradually from 0.3 +/- 0.02 to 1.3 +/-0.12 ng/ml (mean +/- SE of all groups). In the study cycle, an FSH rise occurred in 8 of 12 subjects, while an LH surge greater than that in the E2 control cycle occurred in all but one subject. Peak levels of these surges usually occurred within 24 h of the initial P injection, which is similar to the relationship between the initial rise of P and the occurrence of peak gonadotropin levels at midcycle in normal women. The mean delta max of FSH and LH in subjects exhibiting gonadotropin rises approximated the magnitude of the gonadotropin increases observed normally at midcycle. In response to GnRH during the study cycle, the magnitude of the FSH rise was augmented in 6 of 12 subjects and of LH in 9 of 12, when compared to the E2 control cycles. These data suggest that P, in the presence of late follicular phase levels of E2, 1) augments the release of LH, 2) may induce the release of FSH, and 3) further modulates pituitary responsiveness to GnRH. The data are consistent with the hypothesis that the rising concentrations of E2 to which the hypothalamic-pituitary system is exposed for an appropriate duration serve to initiate the surge of LH at midcycle. This increased LH in turn, stimulates the production of P, which not only further augments the LH surge but, when coupled with E2, also can effect the midcycle FSH surge.
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PMID:Progesterone effects on gonadotropin release in women pretreated with estradiol. 12 95

A detailed study was undertaken in order to determine if a pituitary-half incubation system were a suitable model for the study of anterior pituitary response to estradiol and LHRH. Considerable variation in the gonadotropin content of randomized pituitary halves was observed. Much less variation was found in matched halves. During the initial thirty minutes incubation of pituitary halves, a large spontaneous release of gonadotropins was observed. Time course secretion studies indicated that by four hours incubation, in the presence of 50 ng/ml LHRH, cumulative secretion of LH and FSH had far exceeded that of controls. Elevations in both cumulative secretion and rate of secretion were evident within 15-30 minutes of incubation. Regardless of LHRH dose, only 2-4% of either gonadotropin was secreted. Estradiol in the range of 10, 100, 500, 1,000 and 50,000 pg/ml had no significant effect on pituitary response to LHRH or on basal release, tissue levels or total gonadotropin. Based on these results, it was concluded that while the pituitary-half incubation system may be suitable for studying LHRH induced gonadotropin secretion, it is apparently of insufficient sensitivity to allow the collection of meaningful data concerning the effects of estradiol alone on gonadotropin secretion or estradiol modulation of LHRH induced gonadotropin secretion.
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PMID:Evaluation of in vitro incubation systems for the study of gonadotropin release. 38 98

Conscious unrestrained rats were stimulated through chronically-implanted electrodes in the median eminence-arcuate (ME-ARC), medial preoptic area (MPOA), amygdala (AMYG) or caudateputamen area of the brain on diestrus-2 of a 4-day estrous cycle or diestrus-3 of a 5-day cycle. Each rat was repeatedly tested after returning to normal cycles according to the following procedure: stimulation at current levels of 25, 50 or 100 muA (biphasic pulses), injection of 1 or 3 mug estradiol benzoate or 1 mg progesterone, and injection of the same hormones 24 h before stimulation at 50 muA. Indirect evidence of advanced ovulation, judged by the pattern of vaginal smears, was obtained depending on the current and site of stimulation: 25 muA was subthreshold for all brain areas, 50 muA was threshold for the ME-ARC and AMYG, and 75-100 muA was very effective in the ME-ARC, but could not be tested in the MPOA or AMYG due to abnormal behavior. Histological studies of the ovary revealed premature luteinization of some follicles and occasional advancement of ovulation. Pseudopregnancy-length diestrus often followed ovulation or advanced ovulation. This event was produced by a lower threshold current of 25 muA in the ME-ARC and MPOA. A current of 50 muA was maximally effective in the ME-ARC, but less so in the MPOA and AMYG; 75-100 muA caused successive periods of pseudoprengancy-length diestrus in the ME-ARC group. It is concluded that specificity of neural circuits from the AMYG to LHRH neurons is questionable since stimuli which led to reproductive changes also produced seizure activity. But stimuli producing no abnormal behavior in conscious rats clearly altered reproductive cycles when applied to the ME-ARC, and in the MPOA produced mino changes in cycles. Estradiol facilitated the effect of stimulation on early appearance of leucocytes in the vaginal smear in the estrous cycle and pseudopregnancy-length diestrus; contrarily, progesterone, in a few cases, inhibited both effects.
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PMID:Estrous cycles after electrical stimulation of the brain in conscious rats: effect of current strength, estradiol benzoate and progesterone. 55 3

The direct effect of steroids on rat pituitaries, as reflected by their response to the hypothalamic gonadotropin-releasing hormone (GnRH), was studied in rats. Also, the modulating effect of steroids was investigated in women with primary amenorrhea due to hypothalamic failure. In the human cases, the pituitary was considered as not being regulated by endogenous gonadotropin-releasing hormones and any steroidal effects could be ascribed as being exerted directly on the pituitary gland without being mediated via the hypothalamus. The ovaries of these patients were capable of steroid secretion when stimulated by exogenous gonadotropins. The response to GnRH was evaluated prior to and at different phases of the cycles of ovarian stimulation. Techniques used in the in vitro rat studies are described. Estradiol had a dual effect depending on the dose. Progeste rone had no effect on the base level secretion of either luteinizing hormone (LH) or follicle stimulating hormone (FSH) or on the stimulatory effect of GnRH. However, the addition of progesterone to estradiol counteracted the sensitizing effect of estradiol. In the human cases, dynamic stimulating tests were done to localize the origin of the hormon al insufficiency and to exclude pituitary and ovarian unresponsiveness t o appropriate stimuli. None responded to clomiphene citrate but all had a pituitary response to GnRH and an ovarian response to human menopausal gonadodtropins. In Phase 1 in the absence of ovarian steroids, GnRH evoked an increase in both LH and FSH. In Phase 2, when the endogenous level of estradiol was high, GnRH did not induce FSH release. Elevation of LH secretion was prolonged and reached higher values at the time of increase in the plasma progesterone. In Phase 3, the luteal phase, GnRH failed to elicit either LH or FSH release. It seemed that estrogen sensitized the pituitary to respond to GnRH with a selective augmentatio n of LH secretion. Therefore, it is thought that steroids can modulate pituitary responsiveness to hypothalamic stimuli.
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PMID:The effect of sex steroids on pituitary responsiveness to gonadotropin releasing hormone. 110 Sep 6

Gonadal steroids act at the pituitary to regulate gonadotropin-releasing hormone (GnRH) receptor number and the responsiveness of gonadotropes to GnRH and can act at post-receptor sites to modulate Ca(2+)-mediated and protein kinase C-mediated signal-transducing pathways. However, such effects have been seen in the mixed cell population of primary cell cultures and may involve indirect effects on cells other than gonadotropes. Here, steroid effects on a recently described gonadotrope-derived cell line (alpha T3-1 cells) have been assessed. In these cells estradiol, progesterone, testosterone and corticosterone all exerted trophic effects. Estradiol increased [3H]thymidine incorporation with an EC50 of 10(-12) to 10(-11) M and this effect was blocked by keoxifene, an estrogen receptor antagonist. Estradiol also reduced binding of [125I]buserelin (EC50 approximately 10(-11) M), an effect which appears to reflect a reduction in GnRH receptor number rather than a change in Kd. Estradiol also shifted the dose-response curve for GnRH-stimulated inositol phosphate (IP) accumulation rightward, increasing the EC50 for this GnRH effect by approximately 20-fold. Accordingly estradiol acts directly upon alpha T3-1 cells not only to reduce GnRH receptor number, but also to reduce the efficiency of coupling of residual GnRH receptors to second messenger generation.
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PMID:Estradiol regulates gonadotropin-releasing hormone receptor number, growth and inositol phosphate production in alpha T3-1 cells. 133 8

The Authors have been showed the utility of LHRH analogues in the treatment of PCO disease, through hormonal dosages and echographic examination made before, during and after the therapy both with Enantone depot, CPA and EE2, and with only CPA and EE2 of control cases. The association of analogue to traditional therapy has determined a more speedy reduction of haematic levels of LH, T free, DHEA-S, than the ones we have found in control case, an evident reduction (50%) of pilonidal growth and an important improvement of acne and seborrhea.
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PMID:LHRH analogues and PCO disease: validity of the use of enantone depot in the treatment of the disease. 134 54

The purpose of this study was to investigate the combined effect of bromocriptine (Brc) and clomiphene citrate (Cl) treatment on 40 patients with normoprolactinemic amenorrhea who failed to respond to Cl alone. The ovulation rate in this treatment was 57.3% (23/40) in the 40 cases, 55.6% (99/178) in 178 cycles; the pregnancy rate was 26.7%. This treatment was effective in 14 of 21 women with polycystic ovary-like syndrome (66.7%). Among those women who responded to treatment, prolactin (PRL) and LH levels were significantly decreased. Estradiol and progesterone levels were significantly increased in the patients who responded. Before treatment, the responsiveness of LH to LHRH among responders to Brc/Cl therapy was significantly higher than among the nonresponders. After treatment, the LH-releasing response following a conjugated estrogen injection in the patients who responded to the treatment was significantly greater than that in the patients who did not respond. The results suggest that the therapeutic effect of this treatment may be primarily due to the restoration and improvement of the impaired hypothalamo-pituitary axis.
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PMID:Combined therapy with bromocriptine and clomiphene citrate for patients with normoprolactinemic amenorrhea. 135 38

The present work was carried out to study the in vitro effects of mammalian gonadotropin-releasing hormone (mGnRH) on Rana esculenta and Triturus carnifex testis production of prostaglandin F2 alpha (PGF2 alpha) and sex steroid hormones during the prereproduction, reproduction, and postreproduction periods. In R. esculenta, testicular PGF2 alpha release was lower during postreproduction, and mGnRH increased PGF2 alpha in prereproduction and reproduction. Androgens were higher during prereproduction, and mGnRH induced an androgens increase in prereproduction and reproduction. In T. carnifex testicular PGF2 alpha release was lower during reproduction, and mGnRH increased PGF2 alpha in prereproduction and reproduction. Androgens were higher in reproduction and lower in postreproduction, and mGnRH induced an androgens increase in reproduction. Estradiol-17 beta release was higher in postreproduction, and mGnRH induced an estradiol decrease in reproduction and an increase in postreproduction. These results seem to indicate the involvement of PGF2 alpha in the testicular reproductive activity, and a similar mGnRH mechanism of action, both in R. esculenta and in T. carnifex. In addition, taken together with previous studies, they seem to suggest that the relationship found between mGnRH and PGF2 alpha or sex steroids could be widespread in amphibians.
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PMID:Mammalian GnRH involvement in prostaglandin F2 alpha and sex steroid hormones testicular release in two amphibian species: the anuran water frog, Rana esculenta, and the urodele crested newt, Triturus carnifex. 139 18

We report results from 2 years of therapy with the long-acting form of the gonadotropin-releasing hormone (GnRH) analog leuprolide acetate, which was previously reported in short-term trials to be efficacious in the treatment of central precocious puberty. Thirteen girls and two boys, aged 1.9 to 9.7 years, who satisfied clinical criteria including GnRH-stimulated luteinizing hormone (LH) greater than 10 IU/L (mean radioimmunoassay LH, 29.1 +/- 5.54 IU/L), received depot leuprolide, 6 to 15 mg intramuscularly every 4 weeks. Estradiol (or testosterone), insulin-like growth factor I, and GnRH-stimulated gonadotropins were obtained at baseline, at 2 months, and at 6-month intervals with bone age determinations. Pubertal progression ceased in all patients, and menses did not occur. Mean increase in height during therapy was 5.77 +/- 2.0 cm/yr. Predicted adult height increased over baseline by 5.52 +/- 1.16 cm at 18 months. Mean estradiol values in the girls declined from 3.3 +/- 0.6 to 0.60 +/- 0.03 ng/dl, with no overlap of baseline and treatment values. The mean basal LH value was unchanged by therapy; mean basal and peak LH values for all follow-up GnRH stimulation tests were 4.05 +/- 0.57 and 4.95 +/- 0.70 IU/L, respectively. Basal and peak follicle-stimulating hormone (FSH) values were suppressed from 4.10 +/- 0.62 and 10.06 +/- 1.34 IU/L, respectively, to generally undetectable levels (< 1). Comparison with untreated control patients suggested that basal LH did not completely return to prepubertal levels, whereas FSH levels were suppressed below prepubertal levels. Estradiol, FSH, and LH levels reached their nadir by 2 months; in contrast, mean serum levels of insulin-like growth factor I progressively declined from +0.57 +/- 0.19 SD score to -0.06 +/- 0.22 SD score at 24 months. Two girls were withdrawn from the study because of reactions at injection sites, with apparent sterile abscess formation in one patient. This study provides evidence that (1) long-term treatment with depot leuprolide is characterized by immediate and sustained laboratory and clinical suppression, (2) GnRH-stimulated LH and random FSH and estradiol concentrations are useful laboratory measures of efficacy, and (3) the progressive increase in predicted adult height is temporally associated with decreased serum levels of insulin-like growth factor I and striking deceleration of bone age advancement.
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PMID:Two-year results of treatment with depot leuprolide acetate for central precocious puberty. 834 41

We have investigated the effects of steroids on the intracellular calcium ion concentration [Ca2+]i in chicken granulosa cells obtained from the two largest preovulatory follicles of laying hens. [Ca2+]i was measured in cells loaded with the Ca(2+)-responsive fluorescent dye fura-2. The resting [Ca2+]i in these cells was 100 +/- 5 nM. There was an immediate (i.e. less than 5 sec) 4- to 8-fold increase in [Ca2+]i in all of the 76 cells examined after the addition of 10(-7) M estradiol-17 bdta. Estradiol-17 beta was effective between 10(-10)-10(-6) M. Estradiol-17 alpha, estrone, and estriol (10(-8)-10(-6) M) were as effective as estradiol-17 beta, but the progestins, pregnenolone, and progesterone, and the androgens, testosterone, androstenedione, or 5 alpha-dihydrotestosterone were ineffective at concentrations up to 10(-5) M. The prompt estradiol-17 beta-induced [Ca2+]i spike was not affected by incubating the cells in Ca(2+)-free medium containing 2 mM EGTA or by pretreating them with the Ca2+ channel blockers lanthanum (1 mM), cobalt (5 mM), methoxyverapamil (D600; 50 microM), or nifedipine (20 microM). The estrogen-triggered [Ca2+]i surge was also not affected by pretreating the cells with the conventional estrogen receptor antagonist tamoxifen (10(-5) M), or the RNA and protein synthesis inhibitors actinomycin D (1 microgram/ml) and cycloheximide (1 microgram/ml), but was abolished by pretreating the cells with inhibitors of inositol phospholipid hydrolysis, neomycin (1.5 mM) and U-73,122 (2.5 microM). The closely related, but inactive, compound U-73,343 (1 microM) did not affect the estrogen-triggered [Ca2+]i surge. Estradiol-17 beta (10(-7) M), but not progesterone (10(-5) M), also triggered a large [Ca2+]i surge in pig granulosa cells, which, like the [Ca2+]i surge in chicken granulosa cells, was almost immediate, transient, and unaffected by incubation in Ca(2+)-free medium or pretreatment with methoxyverapamil (D600; 50 microM), lanthanum (1 mM), or tamoxifen (10(-5)M). However, granulosa cells from immature rats primed with diethylstilbestrol or PMSG did not respond to estradiol-17 beta, even at concentrations as high as 10(-5) M, although they promptly generated a [Ca2+]i transient upon exposure to LHRH (10(-5) M). These results suggest that estrogens almost instantaneously trigger the release of Ca2+ from intracellular stores which may be mediated through phosphoinositide breakdown. The striking rapidity of this estrogen-induced internal Ca2+ mobilization is consistent with the activation of a cell surface receptor which is different from the conventional slowly acting, gene-stimulating nuclear estrogen receptor.
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PMID:A new, nongenomic estrogen action: the rapid release of intracellular calcium. 150 65


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