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The largest-to-date randomized trial (Women's Health Initiative) comparing the effects of hormone replacement therapy (HRT) and a placebo concluded that the continuous use of an oral combination of conjugated equine estrogens (CEE) and medroxy-progesterone acetate (MPA) increases the risk of breast cancer. This conclusion may not apply to women taking other estrogen and progestin formulations, as suggested by discrepancies in the findings of in vitro studies, epidemiological surveys and, mostly, in vivo studies of human breast epithelial cell proliferation showing opposite effects of HRT combining CEE plus MPA or estradiol plus progesterone. To evaluate the risk of breast cancer associated with the use of the latter combination, commonly prescribed in France, a cohort including 3175 postmenopausal women was followed for a mean of 8.9 years (28 367 woman-years). In total, 1739 (55%) of these women were users of one type of estrogen replacement with systemic effect during at least 12 months, any time after the menopause, and were classified as HRT users. Among them, 83% were receiving exclusively or mostly a combination of a transdermal estradiol gel and a progestin other than MPA. Some 105 cases of breast cancer occurred during the follow-up period, corresponding to a mean of 37 new cases per 10 000 women/year. Using multivariate analysis adjusted for the calendar period of treatment, date of birth and age at menopause, we were unable to detect an increase in the relative risk (RR) of breast cancer (RR 0.98, 95% confidence interval (CI): 0.65-1.5) in the HRT users. The RR of breast cancer per year of use of HRT was 1.005 (95% CI 0.97-1.05). These results do not justify early interruption of such a type of HRT, which is beneficial for quality of life, prevention of bone loss and cardiovascular risk profile, without the activation of coagulation and inflammatory protein synthesis measured in users of oral estrogens.

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.

One-hundred and fifty hirsute women (68 with type I or II polycystic ovary syndrome and 82 with idiopathic hirsutism) were treated for periods of 6 to 48 months with oral cyproterone (CPA), a drug with peripheral antiandrogenic, antigonadotrophic and progestative properties, and 17 beta-estradiol given percutaneously to ensure estrogenic impregnation. CPA was administered in daily doses of 50 mg from day 5 to day 25 of the menstrual cycle, and E 2 (3 mg/day) from day 16 to day 25. The dramatic regression of hirsutism observed after 3 to 6 months of treatment was paralleled by a marked decrease of plasma testosterone and delta 4-androstenedione levels and a decrease of the androgen-dependent skin testosterone 5 alpha-reductase. The CPA-percutaneous E 2 combination also has contraceptive properties. Beside its remarkable therapeutic effectiveness, it has the advantages of avoiding the adverse reactions reported with higher doses of CPA and the metabolic and vascular effects of synthetic estrogen administered orally.

Twenty hirsute women were treated with 50 mg cyproterone acetate orally, administered from the 5th to the 25th day of the menstrual cycle, along with 3 mg 17 beta-estradiol administered percutaneously from days 16-25. Percutaneously administered 17 beta-estradiol was used rather than ethinylestradiol in order to avoid the side effects of oral administration of synthetic estrogens. From a clinical point of view there was a dramatic improvement of hirsutism after 3-6 months of treatment. Biologically, plasma testosterone decreased markedly (P < 0.01) from 64.6 +/- 24.2 ng/dl (n = 20) to 25.2 +/- 11.8 (n = 20), 26.1 +/- 16.6 (n = 16), and 13.3 +/- 10.8 ng/dl (n = 14) after 3, 6, and 9 months of treatment. There was also a significant decrease in delta 4-androstenedione from 251.0 +/- 110.2 ng/dl to 129.9 +/- 66.5, 114.2 +/- 45.8, and 62.0 +/- 21.5 ng/dl after the same periods. From these results it may be assumed that this therapeutic combination has an antigonadotropic effect, as confirmed by the decrease in plasma estradiol, FSH, and LH and the absence of a significant progesterone level in all cases. Plasma and urinary cortisol, lipids, and hepatic tests remained normal. The good clinical and biological tolerance of this treatment makes it interesting to consider for use in the management of hirsutism.

In most target tissues of the female genital tract, an adequate cell differentiation can be obtained with the successive and synergistic action of estradiol (E2) and progesterone (P), essentially because the progesterone receptor (PR) synthesis implicates the previous action of E2 via its E2 receptor (ER). In normal breast, E2 stimulates the growth of the ductal system whereas the development of acini depends on P secretion. In other words, when E2 plus P are secreted by the ovaries in balanced proportions, the two hormones permit a complete and harmonious development of the mammary gland. The antiestrogenic activity of P is carried out through the decrease of ER resynthesis and stimulation of 17 beta-hydroxysteroid dehydrogenase enzyme activity, which transforms E2 into its less active metabolite estrone (E1) in the target cells. These biochemical events are well documented concerning the endometrium. They have also been observed in normal mammary cells in primary cultures as well as in breast fibroadenomas with high epithelial cellularity. Moreover, data from literature indicate that E2 could be both a direct and indirect factor of cell multiplication in cancerous cell lines. P as well as progestins have the opposite effect. Recent results from this laboratory indicate that E2 and P also have antagonistic effects on the cell multiplication of normal human mammary cells in primary culture. Therefore, the hypothesis that a lack of P during a long period of the female genital like could be a factor in the promotion of breast cancer must be considered.

The results of exploration of the corpus luteum in 125 patients with benign breast disease are analysed. In 109 patients, plasma oestradiol and progesterone were measured at various times during the hyperthermic phase of the menstrual cycle. The results obtained were compared with those obtained in normal women explored during the same phase of the cycle. The average daily values for plasma progesterone obtained in this group of 109 patients was significantly lower than that found in the normal women, whilst there was no change in oestradiol levels. In addition, 16 patients were studied daily throughout the period of hyperthermia. In 8 cases, there the hyperoestrogenism, with or without progesterone insifficiency of the corpus luteum. In all, secretory imbalance of the corpus luteum with a tendency to relative or absolute hyperoestrogenism was a constant finding in women with benign breast disease.

Effects of estradiol (E2) and promegestone (R 5020) were tested on primary cultures of epithelial human breast cells prepared from surgical specimens of reduction mammoplasty. Comparative morphological studies were performed by means of transmission and scanning electron microscopy in cells without any hormonal adjunction and in those previously treated with E2 or E2 + R 5020. The results were as follows: In basal medium used as control the majority of epithelial cells, although well-differentiated, remained flat with few microvilli, well-developed Golgi apparatus and rough endoplasmic reticulum, was obvious. R 5020 added with E2 increased differentiation of epithelial cells covered with scarce long and branched microvilli, but reduced the turn-over of young cells. E2 seemed to generate more active proliferation of cells. R 5020 inhibited this effect and induced a higher differentiation of mammary epithelial cells.

Percutaneous administration of estradiol (E2) is a new substitutive treatment for postmenopausal women. In order to compare hepatic action of percutaneous E2 with that of conjugated estrogens, 18 postmenopausal women were allocated at random to receive one of these two types of natural estrogens for 21 days. Eight patients (group I) received conjugated estrogens orally, 1.25 mg daily. Ten patients (group II) were told to apply percutaneous E2 ointment, 5 gm (i.e., 3 mg of E2), each evening on the abdominal skin. E2, estrone (E1), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and several markers of estrogen action were evaluated before and after treatment. Both types of treatment were biologically effective, as indicated by the decrease in plasma gonadotropins and the increase in estrogen levels. However, conjugated estrogens produced a greater increase in E1 than in E2; hence, the E2/E1 ratio was 0.57 in group I, whereas it was approximately 1 in group II. Plasma renin substrate increased significantly (by 180%) in group I but not in group II. In the same way, conjugated estrogens produced a modest (12%) but significant decrease in antithrombin III, whereas there was no variation with percutaneous E2. Sex steroid-binding protein was the most sensitive parameter for the hepatic action of estrogen, and increased by 18.66% with percutaneous E2 and by 150% with conjugated estrogens. Plasma triglycerides tended to increase in group I and to decrease in group II, but not significantly. Therefore, percutaneous administration of of E2, in contrast to conjugated estrogens, can produce plasma levels of estrogens closer to those observed in the follicular phase and less alterations in protein synthesis. This lesser toxicity may be explained partially by the route of administration, since with percutaneous administration of E2, the steroid bypasses the liver.

Estradiol and triphenylethylene antiestrogen actions have been studied extensively in breast cancer cell lines. However, their effects are still poorly understood on normal human breast cells. We have developed a culture system of normal human breast epithelial (HBE) cells. It has been shown previously that cultured HBE cells were hormone dependent and well adapted for the study of hormone/antihormone actions. However, until now, no data were available on estradiol receptor (ER) in HBE cells. In this study, the presence of ER was demonstrated by (a) whole-cell biochemical assay on breast cells after enzymatic tissue dissociation and (b) an immunocytochemical method using an anti-ER monoclonal antibody both on enzymatically dissociated cells and on 8-day cultured cells. Immunostaining was nuclear and cell positivity was heterogeneous. However, the percentage of positive cells and staining intensity were far greater in the presence of estradiol in the culture, indicating estradiol stimulation of ER. Moreover, HBE cells were used to study the action on cell growth of estradiol versus trans-tamoxifen (TAM), trans-4-hydroxytamoxifen (trans-4OHTAM), and cis-4-hydroxytamoxifen (cis-4OHTAM) alone or added to estradiol. Cell growth was estimated daily by a histometric method and by DNA assay at the end of the 7-day study. When the medium was minimally supplemented with human serum (1%), estradiol stimulated cell growth in a dose-dependent manner at concentrations varying from 10(-9) to 10(-7) M. TAM and trans-4OHTAM clearly inhibited mammary cell division when estradiol was added to the medium and, to a lesser extent, in the absence of estradiol. This inhibitory effect was dose dependent. trans-4OHTAM was 100 times more active than trans-TAM. cis-4OHTAM also clearly inhibited breast cell division at 10(-7) and 10(-6) M concentrations but was 3-fold less efficient than trans-4OHTAM. In conclusion, (a) the presence and estradiol dependence of ER have been demonstrated in HBE cells, which constitute a fruitful model for the study of hormone/antihormone actions, and (b) in these normal cells, estradiol stimulates growth, whereas TAM and the 4OHTAM isomers are potent inhibitors of cell multiplication, as they are in breast cancer cell lines in culture.

Estimations of estradiol, progesteron and other biochemical analyses support the hypothesis of a relative unopposed hyperestrogenism as cause of benign breast diseases. Additional factors are insufficient luteal phases combined with hyperprolactinemia or transient prolactin pulses. Progestagen treatment applied either topically or both orally and topically can correct the imbalance and perhaps prevent breast cancer.

In most target cells of the female genital tract, adequate cell differentiation is obtained via the successive and synergistic actions of estradiol (E2) and progesterone (P). This mainly due to the fact that progesterone receptor (PR) synthesis involves the prior action of estradiol through its receptor (ER). In normal breast, E2 stimulates the growth of the ductal system whereas lobular development depends on progesterone secretion. In other words E2 + P, when secreted in an adequate balance, permit the complete and proper development of the mammary gland. On the other hand progesterone may also have an antagonistic action against E2. The antiestrogen activity of progesterone is mediated through a decrease in the replenishment of E2 receptor and the synthesis of 17 beta-hydroxysteroid dehydrogenase, which leads to an accelerated metabolism of E2 to E1 in the target organ itself. These biochemical events, which have been well documented in the endometrium, have also been shown in cultures of normal breast epithelial cells as well as in differentiated fibroadenomas with high cellular density. In addition, data from the literature show that E2 added to human breast cells increases cell multiplication by means, eventually, of the synthesis of growth factors. Progesterone and progestins have a reverse effect. Data from our laboratory indicate that in normal cultured cells E2 and progestins are also antagonists with regard to cell multiplication. From these different data, it is postulated that in human beings, long periods of a luteal-phase defect leading to an unopposed estrogen effect might be a promoter of carcinogenesis in the breast.

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.Methods: We conducted a retrospective cohort study in the Department of Endocrinology from Necker Hospital in Paris, France. Two hundred and forty-six patients consulted primarily for menstrual disorders, with diagnosis of hyperprolactinemia. Patients were followed-up for 99.9+/-3.6 months. One hundred and ninety-one were treated with bromocriptine, 32 underwent surgery, and 23 received no treatment.Results: The mean initial plasma PRL level was 135.0+/-20.2 ng/ml. Presence of an adenoma was detected in 60% of our patients and comprised a microadenoma in 64% of cases. Compared to oligomenorrheic women, amenorrheic patients had significantly higher levels of PRL and larger pituitary tumor size. In the bromocriptine group, PRL levels decreased from 99.6+/-7.9 to 20.0+/-1.5 ng/ml (p=0.00001). The medical treatment was associated with disappearance of the adenoma in 45% of the women and with stabilization of pituitary tumor size in 40% of patients. Surgery led to disappearance of the adenoma in almost all cases, but failed to definitively cure hyperprolactinemia.Conclusion: In this large-scale retrospective study, the medical treatment of mild hyperprolactinemia was shown to be effective and sufficient after 9 years of follow-up. [ABSTRACT FROM AUTHOR]