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Biomedical subjects

P Ball

Publications and source records attributed to P Ball.

At least 127 records · Page 7Linked 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

Neonatal defeminization of the luteinizing hormone release mechanism by catecholestrogens: different potencies of 2- and 4-hydroxyestradiol.

Female rats were neonatally treated with estradiol-17 beta-benzoate or the long-acting dibenzoate esters of the isomeric catecholestrogens, 2-hydroxyestradiol-17 beta and 4-hydroxyestradiol-17 beta. Estrogen benzoates were administered subcutaneously from day 1 to 5 of life at doses of 0.05, 0.10, 0.50 and 1.00 micrograms/day. All rats were ovariectomized as adults and, 4 weeks later, the luteinizing hormone (LH) response to progesterone (2.5 mg) was tested after priming with estradiol-17 beta-benzoate (20 micrograms). At a dose of 0.5 micrograms/day, estradiol-17 beta-benzoate and 4-hydroxyestradiol-17 beta-dibenzoate were equally effective in neonatally defeminizing the LH surge mechanism. In contrast, up to a dose of 1.00 micrograms/day, 2-hydroxyestradiol-17 beta-dibenzoate did not interfere with the LH response in adult life. In the pituitary gland and uterus of the neonatally defeminized rats estrogen responsiveness of cytosolic progestin receptor induction was unimpaired. Moreover, in the uterus of these rats nuclear translocation of cytosolic progestin receptors was intact.

Animals↗
PubMed1983

Identification of 6 alpha- and 7 alpha-hydroxyestrone as major metabolites of estrone and estradiol in porcine uterus.

Polar metabolites extracted from the effluents of viable porcine uterine strips superfused with either 6,7-3H-estrone or 6,7-3H-estradiol were identified as a 1:1 mixture of 6 alpha-hydroxyestrone and 7 alpha-hydroxyestrone by paper chromatography in various systems, derivatization and crystallizations to a constant specific activity. The hydroxylated compounds are the only derivatives detected after estrone superfusion. The major metabolite of estradiol released in short-time experiments is estrone followed by its 6 alpha- and 7 alpha-hydroxylated derivatives.

Animals↗
PubMed1983

Induction of cytosolic progestin binding sites by catecholestrogens in rat pituitary gland and uterus: different potencies of 2- and 4-hydroxyestradiol.

The ability of catecholestrogens to induce cytosolic progestin binding sites in the hypothalamus, pituitary gland, and uterus of ovariectomised-adrenalectomised rats was demonstrated by the increase in high-affinity [3H]promegestone binding sites (KD 1.39, 0.50, and 0.54 nM, respectively) following a single subcutaneous injection (26.4 micrograms/animal) of the 3.4-dibenzoate ester of 4-hydroxyestradiol. The affinity and the time course of induction of these binding sites were very similar to those after a single injection of an equivalent dose (20 micrograms/animal) of estradiol 3-benzoate, exhibiting maximal receptor levels after 44 h. Widely differing efficacies in the induction of progestin binding sites were observed between the dibenzoate esters of 2- and 4-hydroxyestradiol. 2-Hydroxyestradiol 2,3-dibenzoate was ineffective in the pituitary gland up to a dose of 132 micrograms/animal, whereas 4-hydroxyestradiol dibenzoate was equipotent to estradiol benzoate, showing a maximal induction of progestin binding sites at single doses in the range of 13.2-26.4 micrograms/animal (equivalent to 10-20 micrograms of estradiol benzoate). As compared to the pituitary gland, the uterus was much more sensitive to the systemic administration of estrogen benzoates. At single doses in the range of 1.32-6.6 micrograms/animal (equivalent to 1-5 micrograms of estradiol benzoate), 4-hydroxyestradiol dibenzoate induced maximal levels of progestin receptors, and even 2-hydroxyestradiol dibenzoate, when given at a high dose (132.4 micrograms/animal, equivalent to 100 micrograms of estradiol benzoate), produced a slight increase in progestin binding sites.

Adrenalectomy↗
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

Tetracycline resistance determinants from groups A to D vary in their ability to confer decreased accumulation of tetracycline derivatives by Escherichia coli.

The ability of four genetically distinct plasmid-located tetracycline resistance determinants (TetA, B, C and D) to confer decreased accumulation of tetracycline and some of its analogues by Escherichia coli K12 was examined. Accumulation of oxytetracycline, tetracycline, demethylchlorotetracycline, 6-demethyl-6-deoxy-5-hydroxy-6-methylene-tetracycline, chlorotetracycline, doxycycline and 6-demethyl-6-deoxytetracycline was examined by fluorescence spectroscopy. The determinants varied in their ability to promote decreased accumulation of tetracyclines, defined as an R+/R- fluorescence ratio of less than 0.85. Plasmid pIP7 (TetA) caused reduced accumulation of only oxytetracycline, tetracycline and chlorotetracycline, but plasmid pDU301 (TetB) promoted reduced accumulation of all the compounds tested except 6-demethyl-6-deoxytetracycline. The TetC determinant of pBR322 caused decreased uptake of five derivatives, but not doxycycline or 6-demethyl-6-deoxytetracycline. Plasmid RA1 (TetD) encoded reduced accumulation of oxytetracycline, tetracycline, 6-demethyl-6-deoxy-5-hydroxy-6-methylenetetracycline and chlorotetracycline. In general, the resistance determinants were more efficient in promoting decreased accumulation of hydrophilic tetracyclines. These accumulation studies provide a satisfactory method for the phenotypic identification of Tet resistance determinants.

Drug Resistance, Microbial↗
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↗
PubMed1982

[Diagnosis and therapy of hirsutism].

In ten of 12 patients with non-progressive hirsutism a pathologic pattern of androgens was assessed by hormone determinations. Using a new test procedure increased androgen production could be tentatively associated with an impaired function of either ovaries or adrenals. Androgen-producing tumors could be excluded. With differential therapy (progestins, estrogens, corticosteroids, antiandrogens) pathologic androgen serum levels subsided already prior to antiandrogen medication. Definite clinical success was, however, observed only it antiandrogen therapy. As long-term therapy a low-dose antiandrogen-estrogen combination proved valuable.

17-Hydroxycorticosteroids↗