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J. R. Pasqualini
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F. Lecerf
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ABSTRACT

The ultrastructural changes in the uterine epithelial cells of fetal and newborn guinea-pigs were examined by transmission electron microscopy after the administration of tamoxifen, oestradiol or a combination of tamoxifen and oestradiol.

Tamoxifen provoked a substantial alteration of the mitochondria and the rough endoplasmic reticulum with the formation of numerous vacuoles and secretory granules, indicating an enhancement of synthetic and secretory activities. The mixture of oestradiol and tamoxifen increased the effect and most organelles became irreversibly altered, particularly in the uteri of newborn animals after a long treatment.

It is concluded that, in addition to the agonistic oestrogen effects of tamoxifen on uterine growth, DNA and protein contents, tamoxifen also acts as an agonist on the ultrastructural changes of the uterine epithelial cells during the perinatal period of the guinea-pig.

J. Endocr. (1986) 110, 197–202

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J. R. PASQUALINI
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F. UHRICH
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A recent study has established that after simultaneous administration of [3H]corticosterone 21-sulphate (B-S) plus [14C]corticosterone (B), an important fraction of B-S was transformed into the glucuronides of the polar corticosterone metabolites (Pasqualini, 1967). These metabolites appeared in the urine mainly from 8 hr. after the administration of corticosterone and its 21-sulphate. In the previous study we suggested that most of this radioactive material represented hexahydro-derivatives of corticosterone. In the present investigations these results have been confirmed and the structure of the principal constituent of this fraction has been established.

Two healthy men each received i.v. a mixture of 20 μc [3H]B-S (s.a.: 0·1 μc/μg.) and 3·3 μc [14C]B (s.a.: 0·06 μc/μg.). The method of extraction from the urine and the fractionation procedure for the conjugated material have been described previously (Pasqualini, 1967). The urinary glucuronide fraction (0–4, 4–8 and 8–24 hr. collection after administration of the

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C. Sumida
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C. Gelly
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J. R. Pasqualini
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ABSTRACT

Progesterone receptor concentrations increased in fetal guinea-pig uterus in organ culture to as high as 13·15±1·22 pmol/mg DNA without any added steroid, although cytosol and nuclear oestrogen receptor levels were very low (0·41−1·92 pmol/mg DNA). Even after a 3-day exposure to 5×10−8 m-progesterone, which inhibits its own receptor (1·14±0·31 pmol/mg DNA), progesterone receptor levels rose to 8·58±1·39 pmol/mg DNA when progesterone was removed. This replenishment was inhibited by progesterone and 5α-dihydroprogesterone but was not affected by oestradiol, tamoxifen or dexamethasone. The incorporation of [3H]thymidine into nucleic acids was not decreased by progesterone so that its inhibition of its own receptor in the explants was not due to an inhibition of cell replication. Fetal uterine explants from oestrogen-primed fetuses, after an initial decrease in progesterone receptor, also showed a rise to 7 pmol/mg DNA on day 2 which could be decreased by exposure to progesterone and replenished by removal of this hormone (6–8 pmol/mg DNA), the entire process occurring without apparent oestrogen stimulation. Progesterone rather than oestradiol appears to be a key regulator of progesterone receptor synthesis in the fetal guinea-pig uterus, although oestradiol, along with other factors, may also be involved.

J. Endocr. (1985) 105,415–421

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J R Pasqualini
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G Chetrite
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E Le Nestour
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Abstract

Oestradiol (E2) is one of the most important factors supporting the growth and evolution of breast cancer; consequently, to block this hormone has been one of the main targets in recent years. The evaluation of oestrogens (oestrone, oestradiol and their sulphates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of oestrone sulphate (E1S) which is 15–25 times higher than in the plasma. Two main pathways are involved in the formation of oestrogens: the sulphatase pathway which transforms E1S into oestrone (E1), and the aromatase pathway which converts androgens into oestrogens. Comparative studies in breast cancer tissues show that the sulphatase pathway is 50–300 times more important than that of the aromatase pathway. Using intact cells and physiological concentrations of E1S (5 × 10−9 m) the conversion to oestradiol was very intense with the hormone-dependent (T-47D, MCF-7) breast cancer cells, but very little or no E2 was obtained with the hormone-independent (MDA-MB-231, MDA-MB-436) cells. However, when the latter cells were homogenized, the oestrone sulphatase became very intense. This contradiction in the comparison of the sulphatase activity of the intact cell and the homogenate of the hormone-independent cells can be explained by the presence of inhibitory factors or the absence of positive factor(s) involved in the enzyme activity, which could be related to the evolution of the cancer to hormone-independence. Testing different substances, it was proven that promegestone (R-5020), and danazol, as well as decapeptyl in the presence of heparin, are very active in inhibiting sulphatase activity in hormone-dependent breast cancer cells. Using reverse transcriptase-PCR it was possible to detect the presence of oestrone sulphatase mRNA in different mammary cancer cells. The expression of this mRNA is significantly higher in T-47D and MDA-MB-231 than in the other cell lines. A correlation of this mRNA with the enzymatic activities of oestrone sulphate was observed. The progestagen, R-5020, can significantly decrease the sulphatase mRNA in MCF-7 and T-47D cells. As this progestagen can also inhibit the enzyme itself, it is suggested that the decrease in sulphatase activity by antisulphatase agents in breast cancer cells is a complex mechanism involving not only the effect on the enzyme but also the transcriptional factor(s).

It is concluded that in addition to the control of aromatase, specific inhibition of oestrone sulphatase with antisulphatase agents can open new possibilities in breast cancer treatment.

Journal of Endocrinology (1996) 150, S99–S105

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C. SUMIDA
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C. GELLY
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J. R. PASQUALINI
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The responsiveness of the uterus of the guinea-pig to oestrogen treatment was studied in the fetal and perinatal periods. Twenty-four hours after one dose of 1 mg oestradiol/kg body wt to the pregnant guinea-pig, there was no significant increase in uterine wet weight of the fetus but a sevenfold increase in the concentration of progesterone receptors. In the perinatal period, doses of 1,10 and 100 μg oestradiol led to as much as an 80% increase in uterine wet weight after 24 h in both 2- and 7-day-old guinea-pigs. On the other hand, levels of progesterone receptors in newborn animals showed a smaller increase (twofold) than that which occurred in the fetal uterus. In both fetal and newborn guinea-pigs, total oestradiol-receptor concentrations (both available and occupied binding sites) decreased significantly after treatment with oestradiol. It was concluded that the hormonal effect of oestradiol on progesterone-receptor synthesis can be expressed in the fetus and to an even greater extent than in the perinatal period over the same period of time. In the fetus, this response can be distinguished from the overall uterotrophic effect of oestradiol.

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C. GELLY
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C. SUMIDA
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A. GULINO
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J. R. PASQUALINI
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The concentrations of unconjugated oestradiol-17β and oestrone have been measured by radioimmunoassay in the plasma of fetal, newborn and immature guinea-pigs. In fetal plasma, the values of oestradiol ranged from 15 to 50 pg/ml with no significant variations with gestational age except for an abrupt increase at the very end of gestation (148 pg/ml). Low concentrations of oestradiol were also found postnatally (from not detectable to 31 pg/ml) as well as in maternal plasma (22 pg/ml). The values of oestrone were consistently higher in all plasma regardless of age (43–164 pg/ml).

Oestrogen concentrations were also determined in the fetal uterus, lung, kidney and brain and were found to be as much as 60 times higher (per g tissue) than in plasma, especially in the fetal uterus which contained four to five times more than the other tissues. These data correlated well with a 20–90 times greater uptake of [3H]oestradiol by the fetal uterus compared with the other tissues after in-vivo administration of [3H]oestradiol to the fetuses. The selective retention of oestradiol was probably due to the presence of specific oestradiol binding in these fetal tissues, particularly in the uterus whose binding was 60–120 times higher than in the other fetal tissues. Thus, the levels of oestrogen in the circulation of fetal guinea-pigs are low, but the fetal uterus is capable of maintaining a higher concentration which may be important physiologically since oestradiol has been shown to evoke a biological response in the fetal guinea-pig uterus.

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J. R. PASQUALINI
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F. DUTTER
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M. F. JAYLE
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SUMMARY

After the oral administration of tritiated 3β,21-dihydroxypregn-5-en-20-one (21-hydroxypregnenolone) to a normal subject, 40% of the radioactivity was excreted during the first 24 hr. The disulphate fraction which contained mainly 21-hydroxypregnenolone 3,21-disulphate, accounted for 62 % of the total radioactivity. The monosulphate fraction accounted for 6·8% of the total radioactivity. In the glucosiduronic acid fraction (8·7%) 21-hydroxypregnenolone, tetrahydrodeoxycorticosterone and allotetrahydrodeoxycorticosterone were detected.

After the simultaneous oral and intravenous administration of inert and tritiated 3β,17α,21-trihydroxypregn-5-en-20-one (17α,21-dihydroxypregnenolone) only 25·7% of the radioactivity was excreted in the first 24 hr. The monosulphate fraction, accounting for 64% of the total radioactivity, contained 3β,17α,20ξ,21-tetrahydroxypregn-5-en-20-one, dehydroepiandrosterone and 17α,21-dihydroxypregnenolone. In the glucosiduronic acid fraction (15%), 17β,21-dihydroxypregnenolone, tetrahydro-11-deoxycortisol, allotetrahydro-11-deoxycortisol, aetiocholanolone and androsterone were detected.

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