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Biomedical subjects

G Emons

Publications and source records attributed to G Emons.

108 records · Page 6Linked to original sources
PubMed1984

Biphasic modulation of pituitary sensitivity to GnRH by oestrogens: the effects of A- and D-ring substitution on LH release in cultured pituitary cells.

The sensitizing effect of oestrogens on GnRH-stimulated LH release was evaluated in pituitary cells from adult female rats, cultured for 2 days in the presence of 10(-13) to 10(-6) M concentrations of oestradiol and selected A- and D-ring modified oestrogens. With almost all steroids tested, bell-shaped dose-response curves with comparable LH-maxima but different ED max values were obtained for the LH response to a submaximal GnRH stimulus (5 X 10(-10) M). Maximal LH response to 5 X 10(-10) M GnRH were found at the following oestrogen concentrations: oestradiol and 4-hydroxyoestradiol = 10(-11) M; 2-methyloestradiol = 10(-9) M; 2-hydroxyoestradiol = 10(-8) M; with 4-methyloestradiol no significant maximum was observed. When cells were pretreated with 10(-13), 10(-11) and 10(-9) M oestradiol, or 4-hydroxyoestradiol, or 2-hydroxyoestradiol, and exposed to increasing concentrations of GnRH (10(-11) to 10(-7) M), an almost 10-fold decrease in the ED50 for GnRH was observed after pretreatment with 10(-11) M oestradiol and 4-hydroxyoestradiol. With 2-hydroxyoestradiol at this concentration, the sensitizing effect was much less pronounced. Increasing the steroid concentration to 10(-9) M slightly decreased the effect of oestradiol and 4-hydroxyoestradiol, whereas it increased the effect of 2-hydroxyoestradiol. Thus, at the target cell 4-hydroxyoestradiol has the same potency as oestradiol, while 2-hydroxyoestradiol is significantly less active. The sensitizing effect of oestradiol is only slightly decreased by the presence of a methyl group in position 2, but is markedly reduced by a methyl group in position 4. Our results also demonstrate the high sensitivity of the pituitary to oestrogen-induced enhancement of GnRH-stimulated gonadotrophin release, as well as the decrease of the positive effect at high oestrogen concentrations. The bell-shaped dose-response curves for oestrogen action should be taken into account when evaluating the effects of oestrogens and their derivatives upon gonadotrophin release from the pituitary gland.

Animals↗
PubMed1984

Effects of continuous infusions of 4-hydroxyoestradiol and oestradiol on plasma LH-levels in the ovariectomized ewe.

Ovariectomized ewes were infused over a period of 12 h at constant rates with different doses of the catecholoestrogen 4-hydroxyoestradiol (4-OHE2) or the primary oestrogen oestradiol (E2) via a catheter placed in the right atrium. Blood samples were drawn every hour for a total period of 48 h starting 1 h before the beginning of the steroid infusion. Luteinizing hormone (LH), 4-OHE2 and E2 concentrations were measured in these samples by specific radioimmunoassays. Infusions of low doses E2 (0.5 microgram/h) or 4-OHE2 (2 micrograms/h) caused only a suppression of LH-secretion. At doses of 1 microgram E2/h or 5 micrograms 4-OHE2/h this negative effect was followed by inconsistent elevations of plasma LH. Beyond this threshold dose, E2 at infusion rates of 2, 5 and 10 micrograms/h and 4-OHE2 at infusion rates of 10, 25 and 50 micrograms/h produced the negative effect and massive LH-surges. At still higher infusion rates (E2: 20 micrograms/h, 4-OHE2: 100 micrograms/h) lower elevations of plasma LH levels were observed. 4-OHE2 had to be infused at 4-5 times higher rates than E2 to obtain comparable plasma concentrations of either oestrogen. Under this condition the effects of 4-OHE2 and E2 were similar indicating that 4-OHE2 has the same potency as E2 at central target sites.

Animals↗
PubMed1983

Metabolic clearance rates of catechol estrogens in rats.

MCRs of the catechol estrogens 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2) and of the parent estrogen 17 beta-estradiol (E2) were determined in rats. Long term ovariectomized Wistar rats were infused with the steroids at a constant rate for 3 days via a catheter placed in the abdominal aorta. Blood samples were drawn discontinually by retroorbital puncture, and the serum concentrations of E2, 4-OHE2, and 2-OHE2 were measured by RIA. Steady state was reached within 24 h of infusion. Mean serum MCRs were calculated to be 740 +/- 117 ml/h for E2, 2700 +/- 1000 ml/h for 4-OHE2, and 8300 +/- 1700 ml/h for 2-OHE2. Thus, the MCRs of the catechol estrogens were definitely higher than the MCR of E2 resulting in an apparent ratio of 1:4:11 (E2:4-OHE2:2-OHE2).

Animals↗
PubMed1983

Pharmacological effects of 2- and 4-methyloestradiol as a probe to test the biological importance of 2- and 4-hydroxylation of oestrogens (catecholoestrogen-formation).

2-Methyloestradiol, 4-hydroxy-2-methyloestradiol and 4-methyloestradiol were synthesized and infused sc into long-term ovariectomized rats by means of osmotic minipumps. The effects on uterine growth and gonadotrophin release were tested and compared to oestradiol or vehicle alone. 2-Methyloestradiol and 4-hydroxy-2-methyloestradiol, steroids in which the 2-hydroxylation is selectively blocked, definitely increased uterine weight (dry and wet), decreased morning LH and increased evening LH serum levels. 4-Methyloestradiol, a compound which cannot be 4-hydroxylated in vivo, was inactive in the model used. It is assumed that 4-hydroxylation constitutes an essential step in the expression of oestrogenicity of primary oestrogens, whereas 2-hydroxylation does not.

Animals↗
PubMed1982

Pharmacokinetics of free catecholestrogens and catecholestrogen benzoates.

To provide a definite basis for studies on the biological effects of exogenously administered catecholestrogens, the time courses of the concentrations of these estrogens in serum, pituitary and CNS-tissues were studied in male rats after s.c. injection of either 150 microgram of 4-hydroxyestradiol or 2-hydroxyestradiol (dissolved in 200 microliter sesame oil/ethanol/ascorbic acid; 97.5/2.5/0.1; vol/vol/wt) or equimolar amounts of 4-hydroxyestradiol 3, 4-dibenzoate or 2-hydroxyestradiol 2,3-dibenzoate (dissolved in 200 microliter sesame oil). The injection of free catecholestrogens resulted in bolus-like elevations of the serum and tissue concentrations of the respective compound (max. values up to 9 ng/ml, half-life below 1 h) whereas the injection of catecholestrogen benzoates gave lower (max. values about 1 ng/ml) but prolonged elevations (half-life approx. 24 h and 32 h for 4-OHE2 and 2-OHE2) of the respective free catecholestrogen.

Animals↗
PubMed1982

Radioimmunoassay for 4-hydroxyestrone 4-methyl ether in human urine.

4-Hydroxyestrone 4-methyl ether (4-OHE1 4-Me) was converted to its 17-(O-carboxymethyl)oxime and then coupled to bovine serum albumin. The injection of this steroid-protein conjugate into rabbits induced the formation of antibodies with high specificity and affinity for 4-OHE1 4-Me. With this antiserum a radioimmunoassay was developed which allowed the measurement of 4-OHE1 4-Me with a lower limit of detection of 6 pg/tube. Using a simple and practicable method for the hydrolysis and purification of urine, the excretion rates of 4-OHE1 4-Me were reliably measured in healthy human subjects: male children 0.1 microgram/24 h, female children 0.2 micrograms/24 h, men (20-45 years) 0.7 micrograms/24 h, men (greater than 50 years) 0.5 micrograms/24 h, women, follic. 0.5 micrograms/24 h, periov. 0.6 micrograms/24 h, luteal 0.6 micrograms/24 h, women pregn., first trim. 2.3 micrograms/24 h, sec. trim. 2.9 micrograms/24 h, third trim. 5 micrograms/24 h, women postmenop. 0.5 micrograms/24 h. These urinary excretion rates of 4-OHE1 4-Me are significantly lower than those of 4-hydroxyestrone. Comparing the ratios 4-OHE1 4-Me/4-hydroxyestrone with those of 2-hydroxyestrone 2-methyl ether/2-hydroxyestrone, it becomes obvious that endogenous 4-hydroxyestrogens are methylated in vivo to a much lesser extent than the isomeric 2-hydroxyestrogens, a finding which could partly explain why 4-hydroxyestrogens have higher biologic potencies than their 2-hydroxylated isomers

Estrogens, Catechol↗
PubMed1982

Induction of ovulation in immature female rats by a single injection of 4-hydroxyoestradiol-dibenzoate.

This study was designed to test the ability of 2- and 4-hydroxyoestrogens to induce ovulations and the formation of corpora lutea in immature female rats. To this end 25 day old animals received a single injection of different doses of either 4-hydroxyoestradiol-dibenzoate (10, 25, 50 micrograms) or 2-hydroxyoestradiol-dibenzoate (25, 250 micrograms) or oestradiol-benzoate (10, 25, 60 micrograms). On day 31 the ovaries were checked for corpora lutea. 4-Hydroxyoestradiol-dibenzoate and oestradiol-benzoate in doses of 50 or 25 micrograms significantly increased the number of animals with corpora lutea whereas animals treated with 10 micrograms of either steroid did not differ significantly fron the respective vehicle groups. 2-Hydroxyoestradiol-dibenzoate, even at the high dose of 250 micrograms did not show a significant effect. This is the first demonstration that a catecholoestrogen - 4-hydroxyoestradiol - can induce ovulation. As its potency in doing so is similar to that of oestradiol and as 4-hydroxyoestradiol can be formed in neuroendocrine tissues from primary oestrogens, we conclude that this catecholoestrogen might play a role in the regulation of ovulation.

Animals↗
PubMed1981

Effects of catecholestrogens on luteinizing hormone levels in long tem ovariectomized adult rats.

The long term ovariectomized adult rat was used to test the effects of exogenous estradiol, 4-hydroxyestradiol, and 2-hydroxyestradiol on LH secretion. To this end, different doses of estradiol 3-benzoate, 4-hydroxyestradiol 3,4-dibenzoate, and 2-hydroxyestradiol 2,3-dibenzoate were injected daily at 0800 h, and the LH serum levels were measured on 4 experimental days. At a dose of 1 micrograms/day, estradiol benzoate lowered LH secretion, beginning 48 h after the first injection (morning of day 2), and induced a characteristic LH surge 10 h later. 4-Hydroxyestradiol dibenzoate at the same dose produced less suppression of LH on the morning of day 3, but caused a comparable and highly significant surge on the same evening. Higher doses (3 and 10 micrograms/day) resulted in the same pattern seen with estradiol benzoate. 2-Hydroxyestradiol dibenzoate at comparable doses had no effect. Only extremely high doses (129 micrograms/day) caused slight suppression of tonic LH secretion 72 h after the first injection, and inconsistent LH elevations occurred on the same evening. It is concluded that in this model, catecholestrogens act as estrogens with respect to LH suppression and release, with 4-hydroxyestradiol being a potent estrogen and 2-hydroxyestradiol a weak estrogen.

Animals↗
PubMed1981

4-Hydroxyestradiol-17 beta and 4-hydroxyestradiol-17 alpha: comparative studies on central and peripheral effects of two epimeric catecholestrogens.

4-Hydroxyestradiol-17 beta and 4-hydroxyestradiol-17 alpha (5 or 20 microgram/d) were continuously s.c. infused for 3 days into ovariectomized adult rats. The serum levels of either epimer were virtually identical when the same dose was administered. 4-Hydroxyestradiol-17 beta significantly altered body and uterus weight and LH serum levels (negative and positive effects) at both doses tested. 4-Hydroxyestradiol-17 alpha showed no effects even at the 20 microgram/d dose. As both epimers have similar affinities for catechol O-methyltransferase, but their potencies regarding effects on lH serum levels differ markedly, it is concluded that the interaction of catecholestrogens with this enzyme is not essential for their effects on LH release.

Animals↗
PubMed1981

Effect of low doses of continuously administered catecholoestrogens on peripheral and central target organs.

Osmotic minipumps containing low doses of either 4-hydroxyoestradiol or 2-hydroxyoestradiol2) were sc implanted for 152 h (6 1/3 day) into immature male and female rats. At the end of the test period the animals were killed and the uterine weight, the vaginal opening, the gonadotrophin serum levels and the gonadal weight monitored. The following results were obtained: 1) a significant increase in the uterine weight and a consistent vaginal opening were observed after 4-hydroxyoestradiol but not after 2-hydroxyoestradiol treatment, 2) LH-levels increased after 2-hydroxyestradiol but not after 4-hydroxyoestradiol; the increase was, however, not significant, 3) FSH-levels and gonadal weights were lowered by 4-hydroxyoestradiol treatment in male animals only; 2-hydroxyoestradiol had not effect on FSH-levels in both sexes, 4) in no instance an antioestrogenic effect of either catecholoestrogen was observed. It is concluded that 4-hydroxyoestrogens - using the above paradigm - have a significant importance on uterine growth and vaginal opening but (on day 6) no role of LH-release, whereas 2-hydroxyoestrogens may increase LH levels (on day 6) but are nearly ineffective with respect to peripheral parameters.

Animals↗
PubMed1981

Radioimmunoassay for 4-hydroxyoestrone in human urine.

Under the protection of ascorbic acid a 4-hydroxyoestrone-bovine serum albumin conjugate was prepared containing intact 4-hydroxyoestrone as determined by gas chromatography-mass spectrometry. Using this antigen, antibodies with high affinity and specificity for 4-hydroxyoestrone were raised in rabbits. An assay procedure for the determination of 4-hydroxyoestrone in human urine and the assessment of its reliability are described. The following urinary excretion rates were found: male children 0.29 microgram/24 h, men (less than 50 microgram/24 h, men (20-40 years) 1.6 microgram/24 h, men (less than 50 years) 1.8 microgram/24 h, women, follic, 2.0 microgram/24 h, pre-ov. 5.3 microgram/24 h, luteal 2.4 microgram/24 h, women, pregnant, first trim. 30.0 microgram/24 h, second trim. 64.0 microgram/24 h, third trim. 48.0 microgram/24 h, women, post-men. 1.5 microgram/24 h. Thus the amounts of 4-hydroxyoestrone excreted in human urine are about 1/3 to 1/10 of those of 2-hydroxyoestrone. During the menstrual cycle the excretion rates of 4-hydroxyoestrone are in the same order of magnitude as those of oestradiol and show a clear-cut pre-ovulatory peak.

Adult↗
PubMed1980

4-hydroxyestrone, isolation and identification in human urine.

Portions of pregnancy and midcycle urines were submitted to hot acid hydrolysis, extracted with benzene/ethyl acetate and the extracts washed with ascorbic acid buffer. From the remaining organic phase the catecholestrogens were removed with borate buffer and further purified on Sephadex LH-20 columns. After derivatisation 4-hydroxyestrone was separated from the isomeric 2-hydroxyestrone peak were identical with that of authentic 4-hydroxyestrone. After treatment of the extracts with sodium borohydride 4-hydroxyestradiol-17 beta was identified by GC-MS. By the addition of trace amounts of tritiated 4-hydroxyestrone a recovery of 40% was calculated. On the basis of this recovery and the peak heights of the gas chromatograms an excretion of 4 microgram (midcycle) and 40 microgram (pregnancy) of 4-hydroxyestrone/24 h was estimated.

Chromatography, Ion Exchange↗
PubMed1979

Radioimmunoassay for 2-methoxyoestrone in human plasma.

A bovine serum albumin conjugate of 2-methoxyoestrone was used for the preparation of highly specific antibodies in rabbits. Cross-reactivity for catecholoestrogens and monophenolic steroids was below 0.3%. Only 2-methoxyoestradiol cross-reacted with 44%. An assay procedure for the determination of unconjugated and conjugated 2-methoxyoestrone in human plasma is described. The following mean plasma concentrations (pg/ml) were found (unconjugated/conjugated): children 61/1130, young men 74/1320, elderly men 109/1260, cycling women 131/1040, post-menopausal women 102/1420, and pregnant women 3980/5850.

Adolescent↗
PubMed1978

Radioimmunoassay of 2-hydroxyestrone.

Under the protection of ascorbic acid a 2-hydroxyestrone bovine serum albumin conjugate was prepared containing intact 2-hydroxyestrone as determined by gas chromatographymass spectometry. Using this antigen highely specific antibodies were raised in rabbits. Cross-reactivity for 2-hydroxyestradiol and 2-hydroxyestriol was 26 and 4.5%, respectively. An assay procedure of 2-hydroxyestrone in human plasma is described. Using special precautions the assay allows the determination of 2-hydroxyestrone in plasma samples of women (50-95 pg/ml), pregnant women (105-220 pg/ml), men (45-65 pg/ml) and children(20-40 pg/ml).

Adult↗
PubMedDate not supplied

Docetaxel is effective in the treatment of metastatic endometrial cancer.

BACKGROUND: Systemic treatment of endometrial carcinoma with distant metastases is currently performed, inter alia, with anthracyclines, platinum, paclitaxel, if osfamid or progestins. This is the first report presenting experience in treatment of metastatic endometrial carcinoma with docetaxel. CASE REPORT: A 69-year-old women with adenocarcinoma of the endometrium was treated with primary combined radiotherapy. Two years later disseminated bilateral pulmonary metastases were detected and the patient was submitted to chemotherapy with epirubicin. After three cycles of chemotherapy with epirubicin examinations revealed metastatic progression. Thus, chemotherapy was changed to docetaxel. RESULTS: After three cycles of chemotherapy with docetaxel examinations revealed remission of the described pulmonary metastases more than 50%. A further three cycles of chemotherapy with docetaxel lead to continuing shrinkage of the detectable metastases to less than 25% of the original size. Because of various side effects, like increasing fatigue and asthenia, uncomfortable acral paresthesia and allergic skin reactions, the patient refused to continue chemotherapy. CONCLUSION: We conclude that docetaxel may be an active agent in patients with metastatic endometrial cancer, but care should be taken to minimize side-effects.

Adenocarcinoma↗