Hormone dependence of breast tissue estradiol and progesterone interaction.
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17-Hydroxysteroid Dehydrogenases↗
Biomedical subjects
F Kuttenn
Publications and source records attributed to F Kuttenn.
Antiestrogen action of progesterone in breast tissue.
This review analyzes recent data from international literature concerning the antiestrogen action of progesterone and progestins at the level of mammary cells in culture from either breast cancer lines or normal breast obtained from reduction mammoplasties. Most data indicate that progesterone and progestins have a strong antiestrogen effect on breast cell appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell differentiation dependent of progesterone receptor.
Animals↗
[Antiestrogen action of progesterone in the breast].
This review analyzes recent data from international literature concerning the antiestrogen action of progesterone, progestins and the antiprogesterone RU 486 at the level of mammary cells in culture from either breast cancer lines or normal breast obtained from reduction mammoplasties. Most data indicate that progesterone, progestins and even RU 486 have a strong antiestrogen effect on breast cell appreciated by the decrease of estradiol receptor content, the decrease of cell multiplication and the stimulation of 17 beta-hydroxysteroid activity which may be considered as a marker of breast cell differentiation dependent of progesterone receptor.
Animals↗
[Androgen insensitivity syndromes].
The syndromes of androgen resistance illustrate a special field of endocrinology, that is pathology of target-tissues. These syndromes are responsible for male pseudohermaphroditism and provoke in XY subjects, with a normal testicular androgen secretion, abnormalities in the phenotype with all the possibilities from an "idealistically" female phenotype in the testicular feminization syndrome to an almost normal male phenotype in the mildest forms of the incomplete syndrome. Understanding of these syndromes has strongly benefited of progress in biochemistry and molecular biology concerning the mechanism of action of androgens. On the other hand, understanding androgen mechanism expanded markedly from parallel clinical observation and biochemical investigation permitted by methodological progress: plasma hormones assays, 5 alpha-reductase and androgen receptor qualitative and quantitative determinations. The complete form of the testicular feminization syndrome seems to be due--in most cases--to an absence of the androgen receptor whereas the incomplete forms of the syndrome are related either to insufficient amount or qualitative alteration of the receptor or to a defect of 5 alpha-reductase, the key-enzyme which transforms testosterone to its active metabolite dihydrotestosterone in androgen target-cells. In some cases (approximately equal to 10%) the mechanism of androgen insensitivity could not be identified. The abnormality might be downstream the receptor at various possible steps = binding of the complex androgen-receptor to the chromatin, transcription or post-transcription process. These cases can be useful models for understanding the ultimate steps of the androgen mechanism of action.
Androgen-Insensitivity Syndrome↗
Antiestrogen action of progesterone in breast tissue.
In normal breast, estrogen stimulates growth of the ductal system, while lobular development depends on progesterone. Thus, estrogen and progesterone, when secreted in an adequate balance, permit the complete and proper development of the mammary gland. Progesterone may also have an antagonistic activity against estradiol, mediated through a decrease in the replenishment of the estrogen receptor, and also through increased 17 beta-hydroxysteroid dehydrogenase which leads to accelerated metabolism of estradiol to estrone in the target organ. Thus, it can be inferred that long periods of luteal phase defect leading to an unopposed estrogen effect on the breast might promote breast carcinogenesis.
17-Hydroxysteroid Dehydrogenases↗
Effects of estradiol and promegestone on human breast cell cultures. An ultrastructural study.
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.
Breast↗
Estradiol/progesterone interaction in normal and pathologic breast cells.
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.
17-Hydroxysteroid Dehydrogenases↗
Contribution of plasma androstenedione to 5 alpha-androstanediol glucuronide in women with idiopathic hirsutism.
To confirm that plasma delta 4 androstenedione (delta 4) is the main precursor for 5 alpha-androstane-3 alpha, 17 beta-diol glucuronide (Adiol G) in patients with idiopathic hirsutism (IH), delta 4 was cutaneously applied to five normal women and five women with IH. Several parameters of androgen metabolism were assayed basally and throughout the studies. Those included plasma delta 4, testosterone, and dihydrotestosterone as well as urinary Adiol G and testosterone glucuronide excretion. Under basal conditions plasma testosterone, delta 4, and dihydrotestosterone did not differ significantly between the two groups of subjects. Urinary Adiol G excretion was significantly higher (P less than 0.01) in IH patients [123 +/- 36 (SE) micrograms/24 h] than in the normal women group (45 +/- 20 micrograms/24 h). After percutaneous administration of delta 4, plasma delta 4 increased in both groups by nearly 600% and there was a 300% increase in Adiol G excretion in IH patients (336 +/- 57 micrograms/24 h), whereas only a 50% increase occurred in normal women (65 +/- 17 micrograms/24 h). We postulate that plasma delta 4 may be the main precursor accounting for the increased production of urinary Adiol G in women with IH, in whom hirsutism may be due to a high 5 alpha-reductase activity. Indeed, 5 alpha-reductase as measured in vitro in pubic skin was significantly higher in hirsute patients (224 +/- 66 fmol/mg skin X h) than in normal women (45 +/- 15 fmol/mg skin X h).
Adolescent↗
Progestin effect on cell proliferation and 17 beta-hydroxysteroid dehydrogenase activity in normal human breast cells in culture.
In contrast to cancer cell lines, normal human breast epithelial cells are infrequently studied. Such cells, now routinely cultured in our laboratory from tissue obtained at the time of reduction mammoplasty, were used to study the actions of estradiol (E2), the progestin promegestone (R5020), and the antiprogesterone RU486 on cell growth and progesterone-dependent 17 beta-hydroxysteroid dehydrogenase (E2DH) activity, which is considered good marker of epithelial differentiation as well as progesterone dependency. The studies were carried out using secondary cultures to assure equal initial cell distribution. Cell growth was estimated daily by a histometric method providing a growth index and DNA assay. E2 stimulation of cell growth was not found when the cells were grown in our usual culture medium, but E2 dose-dependent growth stimulation occurred in medium minimally supplemented with serum (1%), insulin; and epidermal growth factor. R5020 inhibited cell growth and stimulated E2DH activity in a dose-dependent manner. RU486 behaved as a pure but low potent progestin agonist concerning E2DH stimulation, but as an agonist with partial antagonist properties concerning cell growth inhibition. In conclusion, E2 stimulated proliferation of human breast epithelial cells in culture, whereas the progestin R5020 inhibited cell multiplication and favored differentiation. The antiprogesterone RU486 had a biphasic effect acting both as progestin agonist and partial antagonist.
17-Hydroxysteroid Dehydrogenases↗
[Hormonal modulation in disseminated lupus erythematosus: the preliminary results with danazol and cyproterone acetate].
In an open prospective study, we have tested clinical efficacy and tolerance of two antigonadotropic drugs, that is danazol (D) and cyproterone-acetate (CA). This study was performed in 11 female patients ranging in age from 19 to 47 years, who suffered from midly-active SLE, during 12 therapeutic periods on the whole (that is 6 for each drug), the minimum period of which was one year. Because of side-effects, D had to be early withdrawn in 2 patients, whereas (the) AC appeared to be well-tolerated in all of them. On the whole, 16 clinical exacerbations of DLE were observed during the 12 months pre-treatment period, versus 9 exacerbations during the 12 months treatment period (p less than 0.05, Wilcoxon test), whereas the average dose of prednisone was reduced from 9.6 to 3.5 mg/day. A dramatic improvement was then observed in 3 patients suffering from mucous ulcerations. Increased plasma testosterone level without any change in estradiol level was observed in patients treated with D. Conversely, plasma estradiol decreased without any change in testosterone level in patients treated with CA. Both drugs induced reduction in plasma sex-hormone binding protein. These preliminary results suggest that D and CA may both reduce lupus disease activity, in parallel with an hormonal environment modification, towards a lower estrogen-androgen balance, along with a better tolerance as for CA.
Adult↗
[HLA antigens and different clinical forms of 21-hydroxylase deficiency in the French population].
HLA associations with 21-OH deficiency were studied on respectively 109 and 60 congenital and late onset French index cases. Significant negative associations were found with antigens B8: congenital forms; B5, DR3: late onset. Significant positive associations were observed with A3, Bw47 (A3 Cw6 Bw47 DR7): congenital forms; B40: salt-wasting form; B5: simple virilizing form; Aw33, B14, DR1, DR2, DRw6 (Aw33 B14 DR1): late onset form. Among late onset patients not bearing B14 antigens significant positive associations were observed with B12 and B35.
Adrenal Hyperplasia, Congenital↗
[Estradiol-progesterone interaction in normal and pathological human breast cells].
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.
17-Hydroxysteroid Dehydrogenases↗
[Endocrine markers in benign breast diseases].
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.
Breast↗
trans-4-Hydroxytamoxifen concentration and metabolism after local percutaneous administration to human breast.
trans-4-Hydroxytamoxifen (4-OHTAM), a very active metabolite of the antiestrogen tamoxifen, was percutaneously administered to the affected breast of nine patients before surgery for breast cancer in order to evaluate 4-OHTAM absorption through the skin and its subcellular localization and metabolism. After percutaneous administration of 80 muCi, [3H]-4-OHTAM was detected in breast tissue. It was especially concentrated in tumor tissue and nuclear and cytosolic fractions, in which it remained unmetabolized except for limited isomerization from the trans to the cis form. In contrast to breast tissue, concentrations of radioactivity remained low in plasma but with a high proportion of metabolites. In another experiment [3H]tamoxifen was percutaneously administered over the breast of 3 patients, resulting in tissue retention weaker and shorter than after [3H]-4-OHTAM. In addition [3H]-4-OHTAM was administered to either breast or abdominal skin; the appearance of radioactivity in plasma and urine was delayed after administration to the breast in comparison with administration to the abdomen. It therefore appears that 4-OHTAM passes through the skin and is concentrated in receptor structures of breast tissue, thus avoiding the hepatic metabolism subsequent to p.o. administration. We suggest that local percutaneous administration of this active antiestrogen could be useful in the treatment of hormone-dependent benign breast diseases.
Administration, Topical↗
Late-onset adrenal hyperplasia in hirsutism.
We studied the incidence of late-onset adrenal hyperplasia as a cause of hirsutism, its association with the major histocompatibility complex, and its clinical expression. Twenty-four of 400 women seen because of hirsutism were found to have late-onset adrenal hyperplasia, diagnosed on the basis of a high plasma level of 17-hydroxyprogesterone, and its marked increase after ACTH stimulation. The degree of hirsutism varied widely. Plasma antigen levels were high, especially the level of androstenedione, whereas 5 alpha-reductase activity, considered to be a good index of peripheral androgen utilization, showed frequent normal or low values. The 24 patients were genotyped, along with 84 family members, and plasma hormones were measured in the family members. We found a high correlation between late-onset adrenal hyperplasia and HLA antigens B14 and Aw33. Similar biologic profiles were observed in the patients and those of their siblings who were HLA identical (n = 9), confirming that late-onset adrenal hyperplasia is linked to the histocompatibility complex. These nine siblings had no hirsutism. We therefore conclude that the role of skin sensitivity to androgens is important in determining the clinical expression of this disorder.
17-alpha-Hydroxyprogesterone↗
Hormonal modulation in systemic lupus erythematosus. Preliminary clinical and hormonal results with cyproterone acetate.
We prospectively studied the effects of hormonal modulation using the antigonadotropic drug, cyproterone acetate (CA), in 7 female patients who had moderately active systemic lupus erythematosus. CA was taken orally at a mean daily dose of 50 mg for 21-33 months by 6 patients (9 months by the seventh patient) without any side effects. The number of clinical lupus exacerbations during CA treatment was lower than that during the corresponding pretreatment period (15 of 170 patient-months versus 27 of 156 patient-months; P less than 0.05), despite a reduction in the daily maintenance dose of corticosteroids or antimalarial drugs. Mean plasma testosterone levels were low initially and remained unchanged (0.66 +/- 0.31 to 0.59 +/- 0.23 nmoles/liter), whereas plasma estradiol decreased markedly (from 0.6 +/- 0 38 to 0.11 +/- 0.03 nmoles/liter), resulting in a significant reduction in the estradiol:testosterone ratio (from 1.19 +/- 0.68 to 0.23 +/- 0.12) and in the plasma concentration of the sex hormone-binding protein. Thus, cyproterone acetate induced improvement in clinical lupus activity in parallel with the expected lower estradiol:testosterone balance.
Adult↗
HLA associations in 21-hydroxylase deficiency (congenital and late-onset adrenal hyperplasia) in France.
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Adrenal Glands↗