P. Mauvais-Jarvis

Studies on clinical, hormonal and pathological correlations in breast fibroadenomas

This study was undertaken to determine if the observation made in vito in women with benign breast diseases of an abnormal hormonal status characterized by an unopposed ovarian estrogenic secretion was correlated in vitro with an abnormal concentration of cytosolic estradiol receptors (ER) in breast tissue. Plasma progesterone (P) measured throughout the menstrual cycle in 84 women for all the patients (11.7+ or -2.8 ng/ml) were significantly lower (P 20 fmol/mg of protein; ll cases) was also found to have the highest cell proliferation; whereas the 49 patients with the lowest ER concentration (< 7 fmol/mg of protein) showed an important stromal reaction. In 28 cases where ER binding site levels varied from 7-20 fmol the cellular density was intermediate between both groups. The presence of positive ER protein in fibroadenomas where the epithelial cellularity was most important emphasized the role of E2 in cellular multiplication and hyperplasia. The in vivo E2-P imbalance in all patients studied indicated that this was the primary cause favoring development of benign dystrophy in mammary glands.

Oral micronized progesterone: Bioavailability pharmacokinetics, pharmacological and therapeutic implications — A review

Progesterone (P), the natural hormone, binds to its specific receptors to induce specific progestational effects. In addition to this binding, P is able to interfere with the binding sites of other steroids. Therefore the natural hormone exhibits an anti-estrogenic activity, and anti-androgenic activity and also exerts anti-mineralocorticoid effects. For a long time progesterone could not be used in clinical applications because of a rapid liver inactivation after oral administration. An oral micronized preparation of progesterone is now available which produces adequate plasma and tissue levels of progesterone. The preparation reproduces the anti-estrogenic effect of the natural hormone on the endometrium at the dose of 200 mg daily. It also reproduces the anti-mineralocorticoid effect and has no androgenic action. No side effects have been reported as far as lipids profile, coagulation factors and blood pressure are concerned. Therefore oral micronized progesterone appears suitable for hormonal replacement therapy in various areas, essentially postmenopause therapy, premenstrual syndrome, correction of irregular cycles and pregnancy maintenance.

17β-estradiol dehydrogenase (E2DH) activity in T47D cells

Abstract Activity of NAD-dependent 17β-hydroxysteroid dehydrogenase (E2DH), the enzyme which converts estradiol (E2) into its less active metabolite estrone (E1), has been previously characterized in normal human breast cells in culture and in benign and malignant breast tumors. E2DH activity is far greater in epithelial cells than in fibroblasts. Moreover, it is progesterone dependent in epithelial cells. It was therefore interesting to explore E2DH in the progesterone receptor (PR)-rich T47D cell line as a possible marker of hormone dependence in breast cancer cells. In T47D cells, transformation of [ 3 H]E2 to E1 is limited. The metabolism seems to be preferentially oriented in the way E1 → E2 in these cells. However, in the presence of the cofactor NAD the conversion of E2 into E1 increases. Moreover, treatment of T47D cells in culture by the progestin R5020 stimulates E2 to E1 conversion 2- to 3-fold. Stimulation of E2DH (E2 → E1) activity reflects both the presence and the operability of PR. This observation underlines the possible interest of E2DH assay in parallel to estradiol receptor and PR to evaluate hormone-dependence of breast cancer.

Selective venous catheterization in the evaluation of hyperandrogenism

Retrograde bilateral ovarian-adrenal vein catheterization was carried out in 16 patients with plasma testosterone levels exceeding 1.4 ng/ml (4.85 nmol/l). While pelvic ultrasonography and computerized axial tomographic scan failed to locate the androgen-producing ovarian tumors, catheterization led to a diagnosis of occult ovarian tumor in 5 patients, based on the observation of an abnormally-high and unilateral ovarian-peripheral vein testosterone gradient, which was subsequently confirmed histopathologically. In one case, unilateral elevation of the adrenal-peripheral vein testosterone gradient was found, complementing the ultrasonographic finding of an adrenal mass and confirming the diagnosis of a virilizing adrenal tumor. In the other 10 patients, gradient analysis ruled out an androgen-producing tumor, leading to the identification of nontumoral hyperandrogeny, such as a severe form of the polycystic ovary syndrome in the 6 premenopausal patients and of ovarian stromal and hilus cell hyperplasia in the 4 menopausal patients. In conclusion, appropriate indication of selective catheterization may considerably reduce the need for exploratory surgery and may help in selecting the adequate surgical approach.

Long‐term follow‐up of 246 hyperprolactinemic patients

Background. We wanted to evaluate the very long‐term effects of bromocriptine on prolactin (PRL) levels and pituitary tumor size in a large cohort of hyperprolactinemic patients.

Estradiol stimulates c-myc proto-oncogene expression in normal human breast epithelial cells in culture

The proto-oncogene c-myc is involved in the stimulation of cell proliferation, and its expression is known to be stimulated by estradiol (E2) in human breast cancer cell lines and various non-cancerous E2-dependent tissues. However, little information is currently available concerning its expression and regulation in normal human breast tissue. We therefore studied c-myc expression and hormone modulation in normal human breast epithelial (HBE) cells in culture, routinely obtained in our laboratory and which remain hormone-dependent. On these normal HBE cells, E2 induced a biphasic increase in c-myc mRNA level, with a first peak as early as 30 min, and a secondary increase after 2 h of treatment; this stimulation was dose-dependent, with an optimal concentration of 10 nM E2. Its primary action is probably at the transcriptional level since the half-life of c-myc mRNA measured in the presence of actinomycin D (12 +/- 3 min) was not modified by E2 treatment. In addition, E2 stimulation of c-myc mRNA does not require protein synthesis since it was not suppressed by cycloheximide treatment. Western blot studies of c-myc protein in HBE cells revealed the same biphasic pattern of stimulation, with a first peak after 60 min and a second one after 2 h of E2 treatment. In conclusion, the c-myc proto-oncogene is expressed in normal HBE cells, as in breast cancer cells. Moreover, E2 stimulates c-myc expression which, therefore, may partly mediate the growth-promoting effect of E2.

Progesterone receptors in breast fibroadenomas

Abstract Cytosol progesterone receptors (P-R) were measured in breast fibroadenomas from 88 women, and their levels were compared to the tumor epithelial cell density and estradiol receptor levels (E-R). Three groups of fibroadenoma were distinguished: type I with a high epithelial cell density (n= 18), type III (n = 46) with low epithelial cell density and extensive fibrosis, and type II with cell density intermediate between the two other groups (n = 24). Whereas E-R levels correlated well with cellular density, P-R levels were elevated in group I and absent in group III, but in contrast to E-R, the low P-R levels observed in group II could not be only explained by cellular density. Since P-R is an estrogen-dependent protein and an hormonal marker, its decrease in type II fibroadenoma might be interpreted as reflecting a rapid decrease in hormone dependence.

Effect of 4-hydroxytamoxifen isomers on growth and ultrastructural aspects of normal human breast epithelial (HBE) cells in culture

In the search for a breast cancer prevention strategy which would avoid undesirable effects of orally administered tamoxifen, the percutaneous administration of the highly active metabolite 4OHTamoxifen (4OHTam) has been proposed. Percutaneous 4OHTam penetrates the skin to reach breast tissues. It, thus, avoids the hepatic first pass effect, and offers an optimal local/systemic effect. However, trans-4OHTamoxifen can spontaneously isomerize into the cis-isomer, which may have estrogen agonist action. The aim of this study was to examine the effect of cis-4OHTam on normal human breast epithelial (HBE) cells in culture. Spontaneous isomerization of trans- into cis-4OHTam occurred within 24-48h, but stabilized rapidly at a trans/cis ratio of 70/30, whether in stock solution, culture medium or cultured cells. The cis-4OHTam did not stimulate HBE cell growth according to histometric cell counts and scanning electron microscopy analysis, but inhibited E(2)-induced cell growth, albeit two to three times less than trans-4OHTam. In conclusion, spontaneous isomerization of trans- to cis-4-OHTam is limited and 4OHTam retains a marked antiestrogenic effect. It may prove to be a useful alternative to tamoxifen in breast cancer prevention, especially if administered percutaneously.

Risk factors for breast fibroadenoma in young women

In a case-control study, 178 women diagnosed with fibroadenoma (FA) between 1976 and 1982 were compared with 178 age-matched controls in order to assess the risk factors for FA. Women who had a previous diagnosis of breast disease were excluded. The odds ratios (OR) of FA were calculated for different risk factors of breast disease from bivariate analysis as well as multivariate regression analysis. The highest ORs were found for a previous premenstrual mastalgia before first childbirth and a familial history (FH) of breast cancer (BC). Oral contraceptive (OC) use before a first full-term pregnancy (FFTP) does not modify this risk. Also current use of standard oral contraceptives (SOC) containing 50 micrograms of ethinyl estradiol per pill appeared to be protective and the correlation with FA was negative. These findings underline: (a) the predictive value of premenstrual mastalgia for the subsequent development of breast disease; (b) only current high-dose OC use is protective.

Hormonal replacement therapy in menopausal women with a history of hyperprolactinemia.

Hyperprolactinemia is involved in almost 30% of infertility problems. At the onset of menopause, prolactin levels often decrease; however, no data are available regarding the course of hyperprolactinemia after menopause with hormonal replacement therapy (HRT). A retrospective study was undertaken in our department to evaluate the potential role of estrogens in women with a history of hyperprolactinemia. Twenty-two patients, with hyperprolactinemia before menopause, were followed-up. Group I included 11 patients who withdrew bromocriptine treatment when menopause was confirmed. These patients were placed on HRT with no other medication administered. HRT was a combination of percutaneous estradiol gel and an oral progestin. Group II included 7 women treated by bromocriptine before menopause and after menopause concomitantly with HRT. Group III included 4 patients who did not receive HRT or other treatments once menopause was diagnosed. The mean serum prolactin level was unchanged in Group I (22.8±21.7 before and 22.8 ±16.1 ng/ml after HRT) while it increased but not significantly from 8.1 ±5.2 to 16.0±11.7 ng/ml in Group II. The mean duration of HRT was 42.8±23.8 (7–81) and 37.3±31.0 (6–99) months in Group I and II respectively. In Group III patients, PRL levels decreased spontaneously from 61.2±39.8 to 33.0±34.7 ng/ml. In conclusion, in this population of menopausal patients with a history of moderate hyperprolactinemia, HRT did not seem to affect plasma prolactin levels.