Regulation of the expression and activity by progestins of a member of the SOX gene family of transcriptional modulators.
(9/878)
The mammalian testis-determining gene Sry and the related Sox genes define a family of transcriptional regulators widely expressed during embryogenesis. Tightly controlled temporal profiles of expression are a feature of the Sox gene family and may be required for initiation of a cascade of gene expression, yet the molecular mechanisms that control Sox gene expression are unknown. We now show that human SOX4 is expressed in the normal breast and in breast cancer cells. In these cells SOX4 is a progesterone-regulated gene, the expression of which is increased by progestins, leading to a marked increase in SOX-mediated transcriptional activity. Treatment of T-47D breast cancer cells with the synthetic progestin ORG 2058 directly increased SOX4 transcription, resulting in a 4-fold increase in SOX4 mRNA levels within 4 h of treatment. No effect of ORG 2058 was noted on other SOX genes measured, nor were other hormone-regulated HMG box proteins detected in this system, suggesting that the observed ability of progestin to increase SOX mRNA expression was confined to SOX4. The increase in SOX4 transcription was reflected in increased SOX4 protein expression, as progestin treatment of T-47D cells transfected with a SOX-responsive reporter resulted in a marked increase in reporter gene expression. Progesterone is essential for normal development and differentiation of the female reproductive system, plays an essential role in regulating growth and differentiation of the mammary gland and is required for opposing the proliferative effects of estrogen in specific cell types. The detection of SOX4 expression in the normal and malignant breast and the demonstration that SOX4 expression is under progesterone control suggests that changes in SOX4 gene expression may play a role in commitment to the differentiated phenotype in the normal and malignant mammary gland. (+info)
Exposure to female hormone drugs during pregnancy: effect on malformations and cancer.
(10/878)
This study aimed to investigate whether the use of female sex hormone drugs during pregnancy is a risk factor for subsequent breast and other oestrogen-dependent cancers among mothers and their children and for genital malformations in the children. A retrospective cohort of 2052 hormone-drug exposed mothers, 2038 control mothers and their 4130 infants was collected from maternity centres in Helsinki from 1954 to 1963. Cancer cases were searched for in national registers through record linkage. Exposures were examined by the type of the drug (oestrogen, progestin only) and by timing (early in pregnancy, only late in pregnancy). There were no statistically significant differences between the groups with regard to mothers' cancer, either in total or in specified hormone-dependent cancers. The total number of malformations recorded, as well as malformations of the genitals in male infants, were higher among exposed children. The number of cancers among the offspring was small and none of the differences between groups were statistically significant. The study supports the hypothesis that oestrogen or progestin drug therapy during pregnancy causes malformations among children who were exposed in utero but does not support the hypothesis that it causes cancer later in life in the mother; the power to study cancers in offspring, however, was very low. Non-existence of the risk, negative confounding, weak exposure or low study-power may explain the negative findings. (+info)
Risk of endometrial cancer following estrogen replacement with and without progestins.
(11/878)
BACKGROUND: Unopposed estrogen replacement therapy (i.e., estrogen without progestins) increases the risk of endometrial cancer. In this study, we examined the endometrial cancer risk associated with combined estrogen-progestin regimens currently in use, since the safety profiles of these regimens have not been clearly defined. METHODS: We conducted a nationwide population-based, case-control study in Sweden of postmenopausal women aged 50-74 years. We collected information on use of hormone replacement from 709 case patients with incident endometrial cancer and from 3368 control subjects. We used unconditional logistic regression to calculate odds ratios (ORs) as estimates of relative risks. All individual comparisons were made with women who never used the respective hormone replacement regimens. RESULTS: Treatment with estrogens alone was associated with a marked duration- and dose-dependent increase in the relative risk of endometrial cancer. Five or more years of treatment had an OR of 6.2 for estradiol (95% confidence interval [CI] = 3.1-12.6) and of 6.6 for conjugated estrogens (95% CI = 3.6-12.0). Following combined estrogen-progestin use, the association was considerably weaker than that for estrogen alone; the OR was 1.6 (95% CI = 1.1-2.4) after 5 or more years of use. This increase in risk was confined to women with cyclic use of progestins, i.e., fewer than 16 days per cycle (most commonly 10 days per cycle [OR = 2.9; 95% CI = 1.8-4.6 for 5 or more years of use]), whereas continuous progestin use along with estrogens was associated with a reduced risk (OR = 0.2; 95% CI = 0.1-0.8 for 5 or more years of use). CONCLUSION: The risk of developing endometrial cancer is increased after long-term use of estrogens without progestins and with cyclically added progestins. Continuously added progestins may be needed to minimize the endometrial cancer risk associated with estrogen replacement therapy. (+info)
Effects of progestogens on thrombosis and atherosclerosis.
(12/878)
In contrast with past practice, current hormone replacement usually includes a combination of oestrogens and progestogens. In this article, we review the effect of progestins on haemostasis and in the development of atherosclerosis. Second-generation progestogens produce minor haemostatic changes, and in lipid metabolism they decrease the synthesis of triglycerides and very low density lipoproteins (VLDL) and stimulate hepatic lipoprotein lipase. In combination, progestogens modify the effect of oestrogens on hepatic metabolism, endothelium and platelets. Several new progestins (known as third-generation) have less effect on lipid profiles. In vessel walls, animal studies have shown that progestogens are able dose-dependently to inhibit the beneficial effect of oestrogen without significant changes in lipid concentrations. The endothelium-dependent vasoconstrictor effect of progestogens on the arterial wall has been also evaluated. Large epidemiological studies show a two-fold increase in risk of venous thromboembolism with the use of third-generation progestins. Regarding the risk of myocardial infarction, no definite evidence is yet available with the use of third-generation progestins. The clinical consequence is therefore that second-generation progestins are the first choice in prescription for first-time users. (+info)
Effects of progestins on cardiovascular diseases: the haemostatic system.
(13/878)
The effect of progestin-only therapy on the haemostatic system has mainly been studied in premenopausal women. Although these studies are difficult to compare, most authors agree that there is no consistent pattern of effects on haemostasis. Oestrogen-progestin combinations have been extensively studied in pre- (combined oral contraceptives) and postmenopausal women (sequential and continuous combined hormone replacement therapy), but mostly with emphasis on the effects of oestrogens. Comparative studies into the differential effects of progestins in combined preparations are scarce. Based on these studies, there is evidence for modifying effects of progestins on oestrogen-induced changes, particularly on fibrinogen, factor VII and the fibrinolytic system. The modifying effects appear to vary among certain progestins, the variation being most likely due to differential effects on lipid metabolism. The clinical interpretation of steroid-induced effects on the haemostatic system is difficult. Retrospective analyses linking certain patterns of haemostatic regulation to the risk of venous or arterial vascular diseases are subject to bias, and no interventional studies are yet available. In the absence of such prospective studies and well-designed comparative studies, the available data do not support the notion of a superiority of certain progestins with regard to cardiovascular risks of combined preparations. (+info)
The differential effects of oestrogens and progestins on vascular tone.
(14/878)
The purpose of this paper is to present reported findings of the effects of ovarian steroids on vascular tone. The medical literature was reviewed for relevant contributions. Oestrogen replacement therapy in postmenopausal women is associated with a reduction in mortality from coronary artery disease. Many different cellular actions have been described which help explain the cardioprotective effects of oestrogens, and among these are effects on vascular tone. Oestrogens induce vasodilation through mechanisms involving the arterial endothelium and through endothelial-independent actions. Progestins have varying effects on arterial tone, including induction of vascular smooth muscle relaxation as well as induction of smooth muscle constriction. The effects of oestrogens and progestins on vascular tone are clinically meaningful. Pathophysiological arterial conditions, including angina pectoris and migraine headaches, have been associated with oestradiol deficiency and improvement has been associated with oestradiol replacement. Women with coronary artery disease show improved arterial vasodilator responses after oestradiol treatment which can be reduced by the addition of progestin treatment. Androgens are also vasoactive. Study of the effects of ovarian hormones on vascular tone has become an important area for basic and clinical research. (+info)
Aortic plaque size and endometrial response in cholesterol-fed rabbits treated with estrogen plus continuous or sequential progestin.
(15/878)
ERT is associated with a reduced incidence of coronary risk and cardiac events in postmenopausal women, but increases the risk of endometrial hyperplasia and carcinoma. Combined estrogen and progestin therapy protects the endometrium; however, its effects on heart disease risk factors are not completely known. In our study, 56 ovariectomized New Zealand White rabbits in 7 groups received a 0.5% cholesterol diet for 12 weeks. Controls were not treated with hormones. All other animals received (per kilogram body weight per week) intramuscular injections of either 0.3 mg estrogen (estradiol valerate) alone, 8.3 mg progestin (hydroxyprogesterone caproate) alone, estrogen and progestin continuously in 3 different dosages (0.3 and 8.3 mg; 1 and 8.3 mg; or 1 and 2.8 mg; estrogen and progestin, respectively), or 1 mg estrogen with 25 mg progestin sequentially in 2-week cycles. Eight non-ovariectomized animals served as further controls for endometrial analysis. Morphometric analysis of plaque size in the aortic arch showed that estrogen monotherapy, and the 3 combined therapies with 1 mg estrogen, significantly reduced intimal thickening (P<0.05). The application of progestin alone had no effect on plaque size. The endometrium was enlarged by 3-fold after estrogen treatment, and was decreased by half after progestin treatment, compared with control uteri (P<0.05). In all groups with combined hormone regimens, endometrial size was not significantly different from control uteri. However, these uteri showed more inflammatory reactions, especially when higher doses of hormones were given. In this animal model, doses of progestin that are able to successfully reduce the proliferative effect of estrogen on endometrium do not diminish the desirable antiatherosclerotic properties of estrogen. (+info)
Conversion of mammalian 3alpha-hydroxysteroid dehydrogenase to 20alpha-hydroxysteroid dehydrogenase using loop chimeras: changing specificity from androgens to progestins.
(16/878)
Hydroxysteroid dehydrogenases (HSDs) regulate the occupancy and activation of steroid hormone receptors by converting potent steroid hormones into their cognate inactive metabolites. 3alpha-HSD catalyzes the inactivation of androgens in the prostate by converting 5alpha-dihydrotestosterone to 3alpha-androstanediol, where excess 5alpha-dihydrotestosterone is implicated in prostate disease. By contrast, 20alpha-HSD catalyzes the inactivation of progestins in the ovary and placenta by converting progesterone to 20alpha-hydroxyprogesterone, where progesterone is essential for maintaining pregnancy. Mammalian 3alpha-HSDs and 20alpha-HSDs belong to the aldo-keto reductase superfamily and share 67% amino acid sequence identity yet show positional and stereospecificity for the formation of secondary alcohols on opposite ends of steroid hormone substrates. The crystal structure of 3alpha-HSD indicates that the mature steroid binding pocket consists of 10 residues located on five loops, including loop A and the mobile loops B and C. 3alpha-HSD was converted to 20alpha-HSD by replacing these loops with those found in 20alpha-HSD. However, when pocket residues in 3alpha-HSD were mutated to those found in 20alpha-HSD altered specificity was not achieved. Replacement of loop A created a 17beta-HSD activity that was absent in either 3alpha- or 20alpha-HSD. Once loops A and C were replaced, the chimera had both 3alpha- and 20alpha-HSD activity. When loops A, B, and C were substituted, 3alpha-HSD was converted to a stereospecific 20alpha-HSD with a resultant shift in k(cat)/K(m) for the desired reaction of 2 x 10(11). This study represents an example where sex hormone specificity can be changed at the enzyme level. (+info)