Comparison of the biological effects of tamoxifen and a new antioestrogen (LY 117018) on the immature rat uterus

1983 ◽  
Vol 99 (3) ◽  
pp. 447-453 ◽  
Author(s):  
A. E. Wakeling ◽  
K. M. O'Connor ◽  
E. Newboult
Keyword(s):  
Biological Effects ◽  
Prior Treatment ◽  
Uterine Weight ◽  
Rat Uterus ◽  
Immature Rat ◽  
Uterine Growth ◽  
High Doses

The uterotrophic and antiuterotrophic activities of tamoxifen and 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- <2-(1-pyrrolidinyl) ethoxyphenyl ketone (LY 117018) in the immature rat uterus have been evaluated. The antioestrogens were administered alone, concurrently or sequentially with or without oestradiol. LY 117018 administered alone was less uterotrophic (oestrogenic) than tamoxifen. At high doses, when administered concurrently with oestradiol, LY 117018 was more antiuterotrophic (antioestrogenic) than tamoxifen. When uterine growth was maximally stimulated by prior treatment with oestradiol, tamoxifen and LY 117018 were equally effective in reducing uterine weight. However, when uterine growth was induced with a dose of oestradiol producing an oestrogenic effect equivalent to that of tamoxifen (but less than that produced by LY 117018) LY 117018 was more effective than tamoxifen in reversing the uterotrophic effect of oestradiol. In animals pretreated with LY 117018 a further increase in uterine weight occurred on treatment with tamoxifen. The increase in uterine weight after tamoxifen was progressively reversed by increasing doses of LY 117018. The hypothesis that tamoxifen and LY 117018 may act by different mechanisms, based on the apparent failure of LY 117018 to antagonize the uterotrophic action of tamoxifen, is not supported by these studies.

Antioestrogenic and antitumour activities of a series of non-steroidal antioestrogens

1983 ◽  
Vol 99 (3) ◽  
pp. 455-464 ◽  
Author(s):  
A. E. Wakeling ◽  
B. Valcaccia
Keyword(s):  
Tumour Growth ◽  
Partial Agonist ◽  
Low Doses ◽  
Agonist Activity ◽  
Rat Uterus ◽  
Immature Rat ◽  
Partial Agonist Activity ◽  
Uterine Growth ◽  
Progressive Growth ◽  
High Doses

The relative oestrogenic and antioestrogenic activities in the immature rat uterus of the antioestrogens tamoxifen, trioxifene, 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- <2-(1-pyrrolidinyl) ethoxyphenyl ketone (LY 117018) and 6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl p- <2-(1-piperidinyl) ethoxyphenyl ketone (LY 139481) were compared. The efficacy of these compounds in inhibiting the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary carcinomas was also measured. Tamoxifen and trioxifene were equipotent antioestrogens (ED50 =dose required to produce 50% reduction in oestradiol-stimulated uterine growth = 0·1 mg/kg); both compounds also demonstrated a maximal partial agonist (uterotrophic) effect of 40% that of oestradiol. LY 117018 and LY 139481 were less potent antioestrogens (ED50 = 0·7 and 0·25 mg/kg respectively) than tamoxifen but both compounds were also less oestrogenic (partial agonist activities 20 and 10% respectively compared with oestradiol). The differences in partial agonist activity were reflected by differences in maximum antioestrogenic effects. High doses of tamoxifen or trioxifene produced 60% inhibition of oestradiol-induced uterine growth whereas LY 117018 (80% inhibition) and LY 139481 (90% inhibition) were both more antioestrogenic because of their reduced partial agonist activity. In rats bearing DMBA-induced mammary tumours tamoxifen was the most effective inhibitor of tumour growth. In tamoxifen-treated animals only 7% (8/111) of hormone-dependent tumours showed progressive growth, compared to 60% in controls. The other antioestrogens were less effective; in trioxifene-treated animals 42% (18/43) of tumours continued to grow during treatment. Similarly, for LY 117018, 39% (14/36) and for LY 139481, 26% (10/38) of tumours showed progression. High doses of trioxifene and LY 117018 were markedly less efficacious than low doses. The increased separation between oestrogenic and antioestrogenic activity in the rat uterus, exemplified by LY 117018 and LY 139481 compared to tamoxifen and trioxifene, did not lead to increased antitumour efficacy.

Estrogen–androgeri interaction: selective inhibition of estrogen-induced uterine peroxidase by testosterone and 5α-dihydrotestosterone

1983 ◽  
Vol 61 (7) ◽  
pp. 779-783 ◽  
Author(s):  
Peter H. Jellinck ◽  
Andrew Affleck ◽  
Anne-Marie Newcombe
Keyword(s):  
Estrogen Receptor ◽  
Low Dose ◽  
Combined Treatment ◽  
Selective Inhibition ◽  
Time Intervals ◽  
Rat Uterus ◽  
Immature Rat ◽  
Uterine Growth ◽  
Nuclear Estrogen Receptor ◽  
Glucose 6 Phosphate Dehydrogenase

The effect of testosterone (T) and dihydrotestosterone (DHT) on the induction of peroxidase and glucose-6-phosphate dehydrogenase (G6PDH) in the immature rat uterus by estradiol (E2) was investigated. T (0.5–12.5 mg/rat) given on 3 successive days produced a large increase in uterine weight but, in contrast to E2, did not induce peroxidase or significantly augment uterine G6PDH. However, this androgen, even at a very low dose (50 μg/rat three times), inhibited the induction of peroxidase without a corresponding effect on G6PDH when given concurrently with E2 and was more effective than DHT. Inhibition by androgen was also observed when diethylstilbestrol was used to stimulate uterine growth. Combined treatment with E2 (3 μg/rat) and T (3 mg/rat) produced a cytosolic and nuclear estrogen receptor pattern in the uterus similar to that observed with E2 alone after various time intervals. The results speak against a direct inhibitory action or T on E2-induced uterine peroxidase via the estrogen receptor and confirm the lack of aromatization of T to E2 in the immature rat. Possible mechanisms for modifying the action of estrogens by androgens are discussed, particularly in the light of E2-induced eosinophilia. It is proposed that steroid hormones can interact in several ways and that uterine peroxidase provides a useful indicator to study steroid hormone action.

EFFECT OF EQUOL ON OESTROGEN RECEPTORS AND ON SYNTHESIS OF DNA AND PROTEIN IN THE IMMATURE RAT UTERUS

1980 ◽  
Vol 85 (2) ◽  
pp. 291-297 ◽  
Author(s):  
B. Y. TANG ◽  
N. R. ADAMS
Keyword(s):  
Subcutaneous Injection ◽  
Female Rats ◽  
Receptor Complex ◽  
Oestrogen Receptors ◽  
Rat Uterus ◽  
Immature Rat ◽  
Nuclear Binding ◽  
Uterine Growth ◽  
Wet Weight

In immature, 3-week-old female rats, 5 mg equol given by subcutaneous injection increased uterine wet weight 24 h later to the same degree as did 5 μg oestradiol-17β. At this dose there was more receptor complex binding to the nucleus in the equol-injected rats than in the rats injected with oestradiol-17β even after 6 h. However, the equol–receptor complex that bound to the nucleus was more extractable with 0·3 m-KC1. In the equol-injected rats the duration of uterine growth was shorter and there was less receptor replenishment and synthesis of protein and DNA than in the rats injected with oestradiol-17β 30 h after either injection. It was concluded that equol is a weakly oestrogenic compound which is antagonistic to oestradiol-17β by competing with oestradiol–receptor complex for nuclear binding and yet fails to initiate the replenishment of oestrogen receptors effectively in the cytoplasm.

Comparative pharmacology of oestrogens and catechol oestrogens: actions on the immature rat uterus in vivo and in vitro

1982 ◽  
Vol 94 (1) ◽  
pp. 91-98 ◽  
Author(s):  
S. Franks ◽  
N. J. MacLusky ◽  
F. Naftolin
Keyword(s):  
Histological Examination ◽  
Target Organ ◽  
Peripheral Target ◽  
Uterine Weight ◽  
Rat Uterus ◽  
Immature Rat ◽  
In Vivo Effects

The effects of primary and catechol oestrogens on the uterus of the immature rat were compared. Because differences between the in-vivo and in-vitro oestrogenic actions of catechol oestrogens on the secretion of LH had been observed, their effects on a peripheral target organ, the uterus, were examined under similar conditions. In-vivo effects were assessed by measurement of uterine weight, induction of uterine cytoplasmic progestogen receptors, and by histological examination. In-vitro actions were determined by measurement of oestrogen-specific induced protein. It was found that the uterotrophic effects in vivo of 4-hydroxyoestradiol were indistinguishable from those of oestradiol whereas 2-hydroxyoestradiol was only weakly oestrogenic and 2-hydroxyoestrone had no effect. However, in vitro, 2-hydroxyoestradiol was as effective as 4-hydroxyoestradiol or oestradiol in stimulating synthesis of uterine induced protein, and 2-hydroxyoestrone, although less potent than oestradiol, had a significant effect. These results were consistent with the observed effects on the secretion of LH. The differences between in-vivo and in-vitro uterotrophic properties of catechol oestrogens can be explained on the basis of known pharmacokinetic factors.

scholarly journals INFLUENCE OF ESTROGEN ON THE ELECTROLYTE PATTERN OF THE IMMATURE RAT UTERUS

1940 ◽  
Vol 132 (1) ◽  
pp. 1-9 ◽  
Author(s):  
N.B. Talbot ◽  
Oliver H. Lowry ◽  
E.B. Astwood
Keyword(s):  
Rat Uterus ◽  
Immature Rat

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

1981 ◽  
Vol 96 (4) ◽  
pp. 470-474 ◽  
Author(s):  
Peter Ball ◽  
Günter Emons ◽  
Ulrich Gethmann
Keyword(s):  
Serum Levels ◽  
Female Rats ◽  
Low Doses ◽  
Vaginal Opening ◽  
Uterine Weight ◽  
Central Target ◽  
Male And Female Rats ◽  
Target Organs ◽  
Uterine Growth ◽  
Lh Release

Abstract. Osmotic minipumps containing low doses of either 4-hydroxyoestradiol or 2-hydroxyoestradiol2) were sc implanted for 152 h (6⅓ 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-hydroxyoestradiol 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 no 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 on LH-release, whereas 2-hydroxyoestrogens may increase LH levels (on day 6) but are nearly ineffective with respect to peripheral parameters.

Effects of estrogen and progesterone on thymidine kinase activity in the immature rat uterus

1983 ◽  
Vol 145 (6) ◽  
pp. 711-715 ◽  
Author(s):  
Shinobu Sakamoto ◽  
Akio Abe ◽  
Hideki Kudo ◽  
Noriko Yamada ◽  
Keiko Seki ◽  
...  
Keyword(s):  
Thymidine Kinase ◽  
Kinase Activity ◽  
Thymidine Kinase Activity ◽  
Rat Uterus ◽  
Immature Rat

Inhibition of Estradiol-17ß-Induced Uterine Growth by Δ1, 9α Fluoro-17 Hydroxycorticosterone

1956 ◽  
Vol 186 (3) ◽  
pp. 468-470 ◽  
Author(s):  
Joseph T. Velardo
Keyword(s):  
Double Bond ◽  
Ovariectomized Rat ◽  
Albino Rats ◽  
Inhibiting Activity ◽  
Uterine Weight ◽  
Uterine Growth ◽  
Growth Inhibiting

Adult, albino rats of the Charles River strain, 100 days of age, weighing 190–210 gm, were bilaterally ovariectomized, and 1 week later were placed on experiments to ascertain the influence of Δ1, 9α fluoro-17-hydroxycorticosterone (ΔFF) on estradiol-17ß-induced uterine growth. The results indicate that ΔFF when administered in a daily dosage up to 0.20 mg for 3 days did not modify the weight of the uterus of the ovariectomized rat, whereas 3 daily dosages of 0.10 µg estradiol-17ß effected an increase of approximately 85% in uterine weight. When 0.05–0.20 mg ΔFF was injected daily, but at different sites, with 0.10 µg estradiol-17ß for the 3-day period, the response of the uterus to estradiol-17ß was markedly reduced from the estradiol-17ß-induced increase of 85% to 52% on the lowest dosage of ΔFF down to 24% on the highest dose (0.20 mg) of ΔFF. These experiments further indicate that the inhibition of estradiol-17ß-induced uterine growth could be partially reversed by increasing the dosage of estradiol-17ß. Comparatively, data at hand suggest that ΔFF > 9αFlF > compound F > compound E > Δ1E and Δ1F in inhibiting 0.10 µg estradiol-17ß on the uterus and the vagina of the ovariectomized rat. Moreover, the incorporation of an additional double bond in ring A (Δ1) and flourine atom in the 9α position of compound F enhances the uterine growth inhibiting activity of compound F. Of the numerous glucocorticoids and mineralocorticoids tested for ability to inhibit estradiol-17ß, ΔFF is by far the most efficacious.

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