Abstract. The biological and morphological effects of cis-tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen, administered sc alone (100 μg/animal) or combined with estradiol (20 μg/animal) were studied in the uterus and vagina of the guinea pig. After 2 days treatment the values of the uterine wet weights (mg ± sd of 6–10 animals in each study) were as follows: non-treated animals (control): 142 ± 15; animals treated with cis-tamoxifen: 119 ± 4; N-desmethyltamoxifen: 280 ± 20; 4-hydroxytamoxifen: 268 ± 25. The values after long treatment were: 177 ± 30; 490 ± 65; 394 ± 36 and 581 ± 60, respectively. After short treatment the weights of the vaginas were: control: 99 ± 20; cis-Tamoxifen: 67 ± 2; N-desmethyltamoxifen: 153 ± 25; 4-hydroxytamoxifen: 166 ± 7; and after the long treatment: 155 ± 40; 660 ± 41; 467 ± 38 and 502 ±61, respectively. N-desmethyltamoxifen and 4-hydroxytamoxifen increased the progesterone receptors in the uterus after short treatment (P < 0.01) but not after 12 days treatment. On the other hand, there was no effect on progesterone receptor in the vagina after the short treatment but a very stimulatory effect after the long treatment. The morphological alterations after 12-days treatment indicate that the three tamoxifen derivatives in the two tissues studied provoke intense alterations in different organelles. In conclusion, it is suggested that the tamoxifen derivatives can act as real agonists in the uterus and vagina of the newborn guinea pig, and they do not block the effect provoked by estradiol.
F. Lecerf, B.-L. Nguyen and J. R. Pasqualini
J. R. Pasqualini, B.-L. Nguyen, C. Mayrand and F. Lecerf
Abstract. Tamoxifen (TAM) alone or combined with oestradiol (E2) or progesterone (P) was administered to newborn guinea pigs (2 days old) for a short (2 days) or a long (12 days) treatment period. TAM alone provoked a great stimulatory effect on uterine growth and DNA content and the effect was particularly intense after the long treatment. These actions were markedly enhanced when TAM was administered together with E2. Following short treatment, the values of the uterine wet weights (mg ± sd) were as follows: control animals, 142 ± 15; animals treated with TAM, 298 ± 53; E2, 335 ± 15; (TAM + E2), 362 ± 16. The values after the long treatment were 177 ± 30, 555 ± 93, 709 ± 117 and 1263 ± 222, respectively.
Histological studies showed that TAM provoked morphological changes in both the endometrium and the myometrium. The effects were particularly great on the height of the luminal epithelial cells and on the uterine glands. After 2 days of treatment with E2, TAM and P, the thickness of the luminal epithelium, which was 13.5 μm ± 1.5 in the control animals, increased as follows: TAM, 19 μm ± 1.7; E2, 20.3 μm ± 3.3; (TAM + E2), 30.5 μm ± 5; P, 12 μm ± 0.9 and (P + TAM), 19.7 μm ± 1.2. The values after the 12 day treatment were: controls, 20.8 μm ± 1.8; TAM, 27.4 μm ±2.1; E2, 32 ± 3; (TAM + E2), 43 μm ± 5; P, 17.8 μm ± 1.2 and (P + TAM), 23.6 μm ± 1.5. After the short treatment TAM doubled the number of specific progesterone binding sites. It is concluded that TAM acts as a real oestrogen agonist in the uterus of newborn guinea pigs.
J. R. Pasqualini, A. Lanzone, A. Tahri-Joutei and B. L. Nguyen
The biological effect of seven different oestrogen sulphates: oestrone-3-sulphate (E1-3-S), oestradiol-3-sulphate (E2-3-S), oestradiol-17-sulphate (E2-17-S), oestradiol-3,17-disulphate (E23,17-DS), oestriol-3-sulphate (E3-3-S), oestriol-17-sulphate (E3-17-S), oestriol-3,16,17-trisulphate (E3-3,16,17-TS), was studied in the foetal uterus of guinea pig (55–65 days of gestation) after sc administration for 3 consecutive days of each sulphate to the mother. On day 4, two response parameters were investigated, the uterotrophic effect and the action on the progesterone receptor. The monosulphates at the C3 position of the oestrogens (E1-3-S, E2-3-S and E3-3-S) provoked an increase in uterine weight of 1.9–2.4 times in relation to the non-treated animals. These oestrogen sulphates also very significantly stimulated the number of progesterone specific binding sites, 7–10 times in relation to the non-treated animals. On the other hand, when the sulphate was at C17 of the oestrogens (E2-17-S, E3-17-S, E2-3, 17-DS, E3-3,16,17-TS), very little or no effect on the foetal uterus was observed on the two parameters studied.
It is concluded that oestrogen (oestrone, oestradiol, oestriol) sulphates in position C3 can be involved in the biological response to the hormone and it is suggested that the effect is carried out after the hydrolysis of the sulphate. On the other hand, sulphates in C17 are not hydrolysed and no significant biological effects were observed in the uterine growth or in the progesterone receptor.
B.-L. Nguyen, R. Hatier, G. Jeanvoine, M. Roux, G. Grignon and J. R. Pasqualini
Abstract. The effect provoked by estradiol after administration to pregnant rats (1 mg per day) was studied in fetal and newborn uteri and ovary. Estrogen receptors are found in the fetuses of non-treated animals. Their number (in fmol/mg DNA, ± sd) in the fetal uterus (total sites, cytosol + nuclei) was at the age of 18 days: 63 ± 15; at 20 days 101 ± 13; and in the 24-h-old newborn; 415 ± 120. The respective values in the ovary were: 105 ± 25; 520 ± 60 and 410 ± 190. Estradiol stimulated significantly the progesterone receptor in the fetal uterus at 20 days old. The progesterone receptor (in fmol/mg DNA, ± sd) which was 97 ± 17 in the non-treated animals, increased to 790 ± 90 in the E2-primed animals. Newborns, 24-h-old, had no detectable progesterone receptor, but in the E2-treated animals the value increased to 1210 ± 120. In the fetal ovary of non-treated animals, progesterone receptor at the age of 18 days is: 90 ± 19; at 20 days 132 ± 47, and in the newborns 260 ± 67; in the E2-treated animals, the values are respectively 330 ± 49; 865 ± 78 and 1280 ± 307. In the fetal uteri of E2-treated animals, histological and ultrastructural studies showed an increase in the size of the uterine horn, the height of the epithelial cells, and stromal cell differentiation. It is suggested that, as was extensively demonstrated in the fetal compartment of the guinea-pig, the machinery for estrogen responses operates also during fetal development of the rat.
L Nguyen, P Niccoli-Sire, P Caron, D Bastie, B Maes, G Chabrier, O Chabre, V Rohmer, P Lecomte, JF Henry and B Conte-Devolx
OBJECTIVE: The aim of this prospective study is to update our knowledge of the chronology of pheochromocytoma occurrence in multiple endocrine neoplasia type 2 (MEN 2), and to better manage MEN 2 patients after the genetic diagnosis. DESIGN: Eighty-seven non-index gene carrier MEN 2 patients were included in this prospective study: 84 patients with MEN 2A (from 52 families) and 3 with MEN 2B (from 3 families). METHODS: Medullary thyroid carcinoma (MTC) was diagnosed by measuring plasma calcitonin in basal conditions or after pentagastrin stimulation. The search for pheochromocytoma consisted of clinical evaluation, 24 h determination of urinary catecholamines and adrenal imaging. The mean age at genetic diagnosis of MEN 2 was 14.0+/-7.0 years, the mean duration for the follow-up was 7.6+/-2.8 years. RESULTS: All 87 patients had a MTC detected at the same time as the genetic diagnosis was made. Urinary catecholamine measurements led to the diagnosis of pheochromocytoma and a combination of imaging techniques enabled the correct localization of both unilateral or bilateral adrenal involvement. Pheochromocytoma was detected simultaneously with MTC in only seven patients, and seven others were detected throughout the follow-up. Of the 14 patients with pheochromocytoma, 11 had bilateral involvement: nine were initially bilateral and two became so during follow-up. CONCLUSION: This study demonstrates that in MEN 2, MTC is the lesion which appears earliest. Pheochromocytoma develops later during the evolution of the disease, and necessitates regular clinical and biological monitoring throughout follow-up. Determination of urinary and/or plasma catecholamines and metanephrines should be performed to detect pheochromocytoma. Imaging techniques lead to the detection of both unilateral and bilateral pheochromocytoma, thus making video-assisted laparoscopic adrenalectomy possible.