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PubMed1987

Contraceptive progestins and gonadotropin secretion in vitro.

In an in vitro bioassay using rat pituitary cell cultures the effect of contraceptive progestins was tested on basal and gonadotropin-releasing hormone (GnRH)-induced luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in vitro. Progestins diminished gonadotropin release in pituitary cells stimulated with GnRH, but did not alter basal values. This inhibitory effect was dose dependent in a range of 10(-10)-10(-5) M tested and the inhibitory action of most of the progestins examined was more potent than that of progesterone. The maximal reduction of LH and FSH values was by 60% of GnRH-induced control levels. Progestins also caused a shift in sensitivity of cells to GnRh (10(-12)-10(-6) M). When time dependence was investigated, some progestins potentiated GnRH effect on gonadotropins in pituitary cell cultures pre-incubated for a short time (4 h) with steroids. More prolonged pre-incubations from 23 to 71 h resulted in a progressive suppression of LH and FSH response to GnRH (10(-7) M). In order to examine intracellular effects, cells were pretreated with progestins and inositol phosphate metabolism was investigated. The data obtained in pituitary cells give evidence that polyphosphoinositide breakdown is potentially an early step in the action of GnRH on gonadotropin secretion by providing diacylglycerol and inositol phosphates. Addition of gonadotropin-releasing hormone to myo-2[3H]inositol-prelabeled rat pituitary cells in primary culture evoked a dose-dependent increase of the accumulation of [3H]inositol phosphates with a rise of inositol triphosphate, inositol diphosphate and inositol monophosphate within 1 min. Using one contraceptive progestin, gestoden, inositol phosphate production was inhibited by 80% compared to controls of GnRH-treated cells without the addition of steroids. The data obtained in this study suggest that this in vitro bioassay using rat pituitary cells is a useful tool in testing progestational compounds regarding their potency on gonadotropin release. In addition, these results show that one possible site of interference of progestins with GnRH-induced gonadotropin secretion may involve polyphosphoinositide breakdown.

Animals↗

PubMed1982

Progestins inhibit FSH-induced functional LH receptors in cultured rat granulosa cells.

The role of intraovarian progesterone in the control of follicular growth and development remains unclear. The presence of a rat ovary granulosa cell progesterone receptor suggests that progesterone has a direct effect on the follicles. We have previously reported that progestins inhibit FSH-stimulated estrogen production by cultured granulosa cells by inhibiting the FSH induction of the aromatase enzyme. We now report that progestins can inhibit another FSH action on rat granulosa cells; the induction of LH/hCG receptors. The concomitant administration of 10(-5) M R5020, a potent synthetic progestin, with 10 ng/ml FSH during a 2-day culture period inhibits the FSH induction of LH/hCG receptors by 75 +/- 6% (mean +/- S.E.) The progestin inhibition of the induction of LH/hCG receptors is not mediated by its inhibitory action on the induction of aromatase. Scatchard analysis indicates that progestin decreases the number of LH/hCG receptors per cell but has no effect on receptor affinity. Both R5020 and progesterone have a dose-dependent inhibitory effect on the FSH induction of LH/hCG receptors, causing a 30 and 85% decrease in receptor number at concentrations of 10(-6) and 10(-5) M, respectively. The concomitant administration of R5020 with FSH also leads to a significant decrease in the ability of LH to stimulate cAMP production, indicating that progestin is inhibiting the induction of 'functional' LH/hCG receptors. R5020 (10(-5) M) also inhibits by 90% the induction of LH/hCG receptors by cholera toxin and dibutyryl cAmP, indicating that the progestin effect is at a post-cAMP site. Since the induction of LH/hCG receptors by FSH is a necessary event in follicular maturation, these results offer another mechanism by which progestins, at high concentrations, can inhibit follicular growth and development.

Animals↗

PubMed1991

Progestin stimulation of thymidine kinase in the human breast cancer cell line T47D.

Our laboratory has previously reported that progestins stimulate growth of the human breast cancer cell line T47D. In an attempt to probe further into this stimulation, we are investigating progestin effects on thymidine kinase (EC 2.7.1.21), an enzyme known to be involved in growth regulation. This report relates our finding that progestins stimulate thymidine kinase activity, at physiological progestin concentrations, in a dose-responsive manner. Estradiol-17 beta also stimulates, but testosterone, hydrocortisone and aldosterone do not. The antiprogestin RU486 inhibits progestin stimulation, but also stimulates on its own. Maximal by 24 h, the progestin stimulation then falls off with time. Experiments with actinomycin D and cycloheximide suggest that the thymidine kinase stimulation depends on new RNA and protein synthesis. These data shed further light on progestin stimulation of the growth of human breast cancer. To our knowledge, this is the first report of progestin stimulation of thymidine kinase in human breast cancer cells.

Breast Neoplasms↗

PubMed1992

Effects of progestins on the proliferation of estrogen-dependent human breast cancer cells under growth factor-defined conditions.

The effect was studied of four different synthetic progestins (Org 30659, gestodene, 3-ketodesogestrel and levonorgestrel) on the proliferation of the 17 beta estradiol (E2)-dependent human breast cancer cell line MCF7. All progestins were found to stimulate proliferation, but only at high pharmacological dosages. Moreover, like estrogens the progestins at high concentrations synergistically stimulated MCF7 cell proliferation together with low concentrations of insulin. This stimulatory effect could be blocked by antiestrogens, but not by antiglucocorticoids and antiprogestins. This suggests that growth stimulation by these progestins (or their metabolites) occurs through crossreaction with the E2 receptor (ER). This is confirmed by the observation that the strong synthetic progestin Org 2058 does not stimulate proliferation. The absence of a progesterone receptor (PR)-mediated growth response seems not to be due to aberrant PR expression in these cells; 27,000 receptors (Kd 1.7 x 10(-10)M) per cell were present under growth-assay conditions. Growth stimulation by E2 in the absence or presence of insulin, is slightly inhibited or unaffected by the progestins, respectively. Our data do not support a role for the recently identified gestodene binding sites [Colletta et al., J. Steroid Biochem. 33 (1989) 1055-1061] in mediating gestodene effects on breast cancer cells: gestodene and 3-ketodesogestrel, a compound that does not bind to these gestodene binding sites, showed a similar biological activity. The effects of the progestins on the MCF7 breast cancer cell line, indicate that the use of these compounds at very high concentrations may be unfavourable, but do not support a role for them in directly stimulating breast tumor proliferation at the low progestin concentration which are reached in the serum in oral contraceptive users.

Analysis of Variance↗

PubMed1996

New insights in the molecular mechanism of progestin-induced proliferation of mammary epithelium: induction of the local biosynthesis of growth hormone (GH) in the mammary glands of dogs, cats and humans.

In contrast to the protective, anti-proliferative, action of progestins on the development of endometrium cancer, progestins may have local stimulatory and inhibitory effects on the proliferation of mammary epithelium. Until now there was no final molecular explanation of this discrepancy. Prolonged treatment of dogs with depot medroxyprogesterone acetate (DPMA) or with proligestone (PROL) results in enhanced plasma concentrations of growth hormone (GH), insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins, together with the development of benign mammary tumours. The stimulated plasma GH levels do not have the typical pulsatile secretion pattern, and are not sensitive to stimulation with GHRH or to inhibition with somatostatin. The autonomous secretion can be inhibited by the anti-progestin RUU-486. The source of progestin-induced plasma GH levels has been demonstrated to be the canine mammary gland where progestins induce the expression of the gene encoding GH. The expression of the GH gene is restricted to focal areas of hyperplastic epithelium as shown by immunohistochemistry, and is predominantly located in single positive epithelial cells with an intermediate position between luminal- and myo-epithelium. Progestin-induced fibroadenomatous changes in the mammary gland of cats are also associated with locally enhanced GH expression. In both normal, benign and malignant mammary tumours of humans GH mRNA expression has been demonstrated by RT-PCR. The presence of GH mRNA is associated with the presence of immunoreactive GH as shown by immunohistochemistry. Sequence analysis revealed 100% homology to the pituitary expressed GH gene. In malignant mammary tumours of humans and dogs GH expression is also found in specimens negative for progesterone receptors as measured by ligand binding. It is concluded that the gene encoding GH is expressed in the mammary gland of a variety of species, including man. This appears to represent a contribution to the molecular explanation of the action of progestins on proliferation of mammary epithelium. It needs, however, to be proven whether this local biosynthesis of GH in the mammary gland is the cause of the local stimulatory effect of progestins on the proliferation of mammary epithelium.

Animals↗

PubMed2006

Progestins affect mechanism of estrogen-induced C-reactive protein stimulation.

PURPOSE: To determine whether the mechanisms of C-reactive protein production differ depending on the presence or absence of a progestin in the regimen. SUBJECTS AND METHODS: We examined data from the Postmenopausal Estrogen Progestin Intervention (PEPI) study, a 5-group (3 different combined estrogen-progestin regimens, conjugated equine estrogen-only, and placebo) randomized clinical trial. This substudy included 221 postmenopausal women assigned to active treatment groups who took at least 80% of pills and had stored plasma specimens available to assess 12-month changes in estrone, sex hormone binding globulin, interleukin (IL)-6, and C-reactive protein levels. RESULTS: All treatments resulted in increases in estrone, sex hormone binding globulin, and C-reactive protein at 12 months compared with baseline values. In all progestin-containing groups, 12-month change in IL-6 was positively correlated with 12-month change in C-reactive protein (r between 0.34 and 0.65, each P <.010). By contrast, in the conjugated equine estrogen-only group, 12-month change in IL-6 was negatively correlated with 12-month change in C-reactive protein (r value -0.31, P = .055). In adjusted models predicting 12-month C-reactive protein change, an interaction between change in IL-6 and treatment group was highly significant (P=.0008-P <.0001) for each of the progestin-containing groups compared with the conjugated equine estrogen-only group. In the conjugated equine estrogen-only group, the change in C-reactive protein per unit increase in IL-6 was -0.88, whereas in the progestin-containing groups it ranged from 1.46 to 2.85 (P <.0001 for each comparison with conjugated equine estrogen-only). CONCLUSION: Progestins in combination with conjugated equine estrogen potentiate the IL-6 (inflammatory)-mediated stimulation of C-reactive protein. These findings support the hypothesis that progestins plus estrogen, not estrogen alone, generate C-reactive protein through an inflammatory mechanism.

C-Reactive Protein↗

PubMed2006

Progestin inhibition of cell death in human breast cancer cell lines.

Previously, we have shown that progestins both stimulate proliferation of the progesterone receptor (PR)-rich human breast cancer cell line T47D and protect from cell death, in charcoal-stripped serum-containing medium. To lessen the variability inherent in different preparations of serum, we decided to further characterize progestin inhibition of cell death using serum starvation to kill the cells, and find that progestins protect from serum-starvation-induced apoptosis in T47D cells. This effect exhibits specificity for progestins and is inhibited by the antiprogestin RU486. While progestin inhibits cell death in a dose-responsive manner at physiological concentrations, estradiol-17beta surprisingly does not inhibit cell death at any concentration from 0.001 nM to 1 microM. Progestin inhibition of cell death also occurs in at least two other human breast cancer cell lines, one with an intermediate level of PR, MCF-7 cells, and, surprisingly, one with no detectable level of PR, MDA-MB-231 cells. Further, we have found progestin inhibition of cell death caused by the breast cancer chemotherapeutic agents doxorubicin and 5-fluorouracil. These data are consistent with the building body of evidence that progestins are not the benign hormones for breast cancer they have been so long thought to be, but may be harmful both for undiagnosed cases and those undergoing treatment.

Antibiotics, Antineoplastic↗

PubMed2003

Progestins and their effects on the breast.

Nowadays, when the available scientific data on the in vivo effects of progestins on mammary gland tissue remain controversial, it is of utmost importance to establish adequate criteria to evaluate their actions. One of the reasons for this situation is that a variety of progestins have been studied using a number of different study designs. In addition, data relating to the effects of progestins on breast tissue have been interpreted differently from country to country. Recent data indicate that some progestins clearly oppose the favourable effects of estrogens on a number of important metabolic processes, e.g. influencing insulin-like-growth-factor (IGF)-1 serum levels. IGF-1 is a mitogenic and antiapoptotic peptide involved in growth regulation of breast epithelial cells. Circulating IGF-1 exerts endocrine action, it regulates growth hormone secretion by a negative feedback mechanism. In the past few years, both laboratory investigations and epidemiologic studies provided strong evidence that the IGF-1/growth hormone axis is involved in human cancer risk [Maturitas 29 (1998) 61; Horm. Res. 51 (1999) 34; Eur. J. Cancer 36 (2000) 1224; Maturitas 41 (2002) 299] Some progestins also have effects on the enzymes in breast tissue that are responsible for the local synthesis of estradiol. Thus, whilst progestins without androgenic action have been found to markedly inhibit these enzymes, an equivalent degree of inhibition is not achieved with testosterone-derivatives. Therefore, special attention should be paid to the various partial actions of the different progestins and their effects on breast tissue. Furthermore, factors such as the duration of breast tissue exposure to progestin activity, the influence of different regimens on protective apoptotic mechanisms in the breasts, as well as dose levels and the degree of mammary gland tissue differentiation throughout treatment, should also be considered.

Apoptosis↗

PubMed2004

A comparison of the central effects of different progestins used in hormone replacement therapy.

OBJECTIVE: To evaluate the central effect exerted by different progestins used for hormone replacement therapy. METHODS: Randomised, placebo-controlled study. One hundred-twenty postmenopausal women on continuous hormonal replacement therapy with transdermal estradiol (50 microg per day) associated, for 10 days every 28 days, with four different progestins: dydrogesterone (DYD; 10 mg per day; n = 20), medroxyprogesterone acetete (MPA; 10 mg per day; n = 20), nomegestrol acetate (NMG; 5 mg per day; n = 20) or norethisterone acetate (NETA; 10 mg per day; n = 20). Other 40 women, 10 for each treatment group, were used as controls and were monitored for a single cycle of 28 days during the administration of transdermal estradiol plus placebo. Morning basal body temperature (BBT) was monitored for 28 days. Anxiety, by the state-trait anxiety inventory, and depression, by the self-evaluation depression scale of Zung, were evaluated just prior to and in the last 2 days of the 10-day progestins adjunct. RESULTS: All progestins except DYD increased (P < 0.0001) BBT by 0.3-0.5 degrees C. Anxiety was decreased by DYD (- 2.3 + 1.1; P < 0.01) and MPA (- 1.5 + 0.5; P < 0.01), but not by NMG or NETA. Depression did not significantly increase during progestins and actually decreased during MPA (- 3.0 + 0.7; P < 0.01). Only the effect of DYD on anxiety and that of MPA on depression were significant versus the control group (P < 0.05 ). CONCLUSIONS: Different progestins exert different central effects. DYD has the peculiarity of not increasing BBT and of decreasing anxiety, which is also decreased by MPA. Depression is not negatively affected by the tested progestins and it may be ameliorated by MPA. The present data may help to individualise the progestin choice of hormone replacement therapy.

Administration, Cutaneous↗

PubMed2003

Mechanisms involved in the evolution of progestin resistance in human endometrial hyperplasia--precursor of endometrial cancer.

BACKGROUND: Successful treatment of endometrial hyperplasia with progestins is commonly accompanied by the finding of an inactive or suppressed endometrium after therapy. However, approximately 30% of the endometrial hyperplasia cases do not respond to progestins and hyperplastic glands persist. The Fas/FasL system is known to play a role in tissue remodeling as a result of changes in menstrual hormone levels. The aims of this study are to examine Fas/FasL expression in endometrial hyperplasia of pre- and postprogestin treatment samples and to study the Fas/FasL regulation in vitro with Ishikawa cells after progestin stimulation. DESIGN: Pre- and posttreatment paraffin-embedded endometrial hyperplasia tissue samples from 26 women were examined by immunohistochemistry for changes in Fas/FasL expression related to the administration of progestins. Among 26 patients, 18 were successfully treated with progestins and 8 failed treatment. Fas/ FasL positivity was defined by the presence of 10% or more immunoreactive epithelial cells in each specimen. In positive cases, a percentage or an immunoscore of immunoreactive cells was given by counting 500 cells. Cell viability was evaluated by the MTT assay. The in vitro effects of progesterone on Fas/FasL expression and apoptosis in Ishikawa cells were examined by using Western blot and TUNEL assays, respectively. RESULTS: Fas immunoreactivity was present in 4/26 (15%) preprogestin cases with an average of 16% of the epithelial cells expressing Fas. FasL was expressed in 21/26 (80%) pretreatment cases with an average of 42% of the hyperplastic glandular cells being positive. In postprogestin cases, an increase of Fas expression (14/18, 77%) with an average of 47% stained cells was seen in responders (P < 0.001), while FasL was found in 16/18 (89%) responders with an average of 65% of cells positive (P = 0.587). In nonresponders, no significant changes in Fas/FasL expression were detected compared to pretreatment samples. With in vitro Ishikawa cells, a slight increase (10-20%) of Fas and FasL protein expression was detected after 24 h of progesterone treatment, but a more significant increase (220-343%) of both Fas and FasL expression was found after 48 h of withdrawing progesterone, which parallels apoptotic activity. CONCLUSIONS: The Fas/FasL system may be involved in the development of endometrial hyperplasia. Part of the molecular mechanisms of progestin therapy for endometrial hyperplasia is through upregulation of Fas/FasL expression. Dysregulation of Fas/FasL expression in hyperplastic endometrium may be part of the molecular mechanisms for nonresponders to progestin treatment. Intermittent, rather than continuous, progestin treatment may be more effective clinically for the treatment of endometrial hyperplasia.

Adult↗

PubMedDate not supplied

Progestins in the menopause.

While the benefits of progestin use in hormone replacement therapy (HRT) are well recognised as far as endometrial protection is concerned, their risks and drawbacks have generated controversial articles. The data related to the progestin effect on breast tissue has been interpreted differently from country to country. However it has been admitted that, according to the type of progestin used, the dose and duration of its application, a predominant antiproliferative effect is observed in the human breast cells. As far as breast cancer risk is concerned, most epidemiological studies do not suggest any difference between the estrogens given alone or combined to progestins in HRT. When the cardiovascular risk factors are considered, some molecules with a higher androgenic potency than others, attenuate the beneficial effects of estrogens on the lipid profile and the vasomotion as well. On the other hand, other progestins devoid of androgenic properties do not exert these deleterious effects. The epidemiological data does not suggest any negative effect of the progestins administered together with estrogens on cardiovascular morbidity or mortality. However, recent results suggest that in women with established coronary heart disease (CHD), HRT may not protect against further heart attacks, when the progestin selected possesses androgenic properties. Complying with the classic contra indications of HRT and selecting molecules devoid of estrogenic, androgenic, or glucocorticoid effect should allow a larger use of the progestins without any major drawback.

Breast↗

PubMed2001

Cyclin D1 overexpression induces progestin resistance in T-47D breast cancer cells despite p27(Kip1) association with cyclin E-Cdk2.

Long-term growth inhibition, arrest in G(1) phase and reduced activity of both cyclin D1-Cdk4 and cyclin E-Cdk2 are elicited by progestin treatment of breast cancer cells in culture. Decreased cyclin expression, induction of p18(INK4c) and increased association of the CDK inhibitors p21(WAF1/Cip1) and p27(Kip1) with cyclin E-Cdk2 have been implicated in these responses. To determine the role of decreased cyclin expression, T-47D human breast cancer cells constitutively expressing cyclin D1 or cyclin E were treated with the progestin ORG 2058. Overexpression of cyclin E had only a modest effect on growth inhibition. Although cyclin E expression was maintained during progestin treatment, cyclin E-Cdk2 activity decreased by approximately 60%. This was accompanied by p27(Kip1) association with cyclin E-Cdk2, indicating that both cyclin E down-regulation and p27(Kip1) recruitment contribute to the decrease in activity. In contrast, overexpression of cyclin D1 induced progestin resistance and cell proliferation continued despite decreased cyclin E-Cdk2 activity. Progestin treatment of cyclin D1-overexpressing cells was associated with increased p27(Kip1) association with cyclin E-Cdk2. Thus the ability of cyclin D1 to confer progestin resistance does not depend on sequestration of p27(Kip1) away from cyclin E-Cdk2, providing evidence for a critical function of cyclin D1 other than as a high-capacity "sink" for p27(Kip1). These data indicate that regulation of cyclin D1 is a critical element of progestin inhibition in breast cancer cells and suggest that breast cancers overexpressing cyclin D1 may respond poorly to progestin therapy.

Animals↗

PubMed1999

Biological effects of progestins in breast cancer.

Developments in the synthesis of different progestins have opened up new possibilities for the biological effects and therapeutic uses of these compounds. The actions of progestins are a function of their structure, affinity to the progesterone receptor or to other steroid receptors, the target tissue considered, the biological response, the experimental conditions, dose, and metabolic transformation. Data on the action of progestins in breast cancer patients are very limited. A positive response with the progestins medroxyprogesterone acetate and megestrol acetate has been obtained in postmenopausal patients with advanced breast cancer. However, extensive information on the effect of progestins was obtained in in vitro studies using hormone-dependent and hormone-independent human mammary cancer cell lines. It was demonstrated that in hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, medrogestone, promegestone) as well as tibolone, are potent sulfatase-inhibitory agents. Progestins may also be involved in the inhibition of the mRNA of this enzyme. In another series of studies, it was also demonstrated that various progestins are very active in inhibiting the 17 beta-hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently, it has been observed that promegestone or medrogestone stimulates the sulfotransferase for the formation of estrogen sulfates. Clinical trials of these enzymatic effects on the formation and transformation of estradiol in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.

17-Hydroxysteroid Dehydrogenases↗

PubMed2001

Biological effects of progestins in breast cancer.

The action of progestins is derived from many factors: structure, affinity for the progesterone receptor or for other steroid receptors, the target tissue considered, the biological response, the experimental conditions, the dose and metabolic transformation. The proliferative response to progestins in human breast cancer cells is contradictory: some progestins inhibit, others stimulate, have no effect at all, or have a dual action. For instance, medroxyprogesterone acetate has a stimulatory effect on breast cancer cells after a short period of treatment, but this effect becomes inhibitory when treatment is prolonged. It has been demonstrated that, in hormone-dependent breast cancer cells, various progestins (nomegestrol acetate, medrogestone, promegestone) are potent sulfatase inhibitory agents. The progestins can also involve the inhibition of the mRNA expression of this enzyme. In another series of studies it was also demonstrated that some progestins are very active in inhibiting 17beta-hydroxysteroid dehydrogenase for the conversion of estrone to estradiol. More recently it was observed that the progestins promegestone and medrogestone stimulate sulfotransferase for the formation of estrogen sulfates. Consequently, the action of progestins in blocking estradiol formation via sulfatase, or in stimulating the effect on sulfotransferase activity, can open interesting and new possibilities in clinical applications in breast cancer.

17-Hydroxysteroid Dehydrogenases↗

PubMed1999

Risk of endometrial cancer following estrogen replacement with and without progestins.

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.

Adenocarcinoma↗

PubMed1996

Progestin represses human connexin43 gene expression similarly in primary cultures of myometrial and uterine leiomyoma cells.

The mechanism by which progestin represses the expression of the human connexin43 (cx43) gene was analyzed in primary cultures of human myometrial cells, and for comparison, in primary cultures of uterine leiomyoma cells. Within 24 h, the levels of connexin43 (Cx43) protein in primary cells treated with progestin were reduced to about 50% of that in untreated cells, and these levels were maintained for up to 120 h. A plateau in the reduction of Cx43 protein levels was reached at progestin concentrations of 50-100 nM. No significant difference was found in a comparison of progestin-mediated reduction of Cx43 protein in autologous myometrial and leiomyoma primary cultures. Levels of cx43 mRNA levels also decreased to about 50% in myometrial and leiomyoma cells within hours after treatment with progestin, and these new levels were maintained for up to 48 h. Nuclear run-on transcription analysis showed that 100 nM progestin partially repressed transcription of the cx43 gene in both myometrial and leiomyoma primary cultures. The amount of decrease in cx43 transcription in cells treated with progestin was paralleled by a corresponding decrease in cytoplasmic cx43 mRNA levels. Progesterone receptor (PR)-mediated transcription was also determined to be similar in the two types of primary cells as evidenced by transient expression assays. Thus progestin down-regulates the expression of the human cx43 gene primarily by repressing transcription of the gene in myometrial cells, and it acts similarly in leiomyoma cells.

Cells, Cultured↗

PubMed1999

Aortic plaque size and endometrial response in cholesterol-fed rabbits treated with estrogen plus continuous or sequential progestin.

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.

17-alpha-Hydroxyprogesterone↗

PubMed1985

The antiprogestin RU38 486: receptor-mediated progestin versus antiprogestin actions screened in estrogen-insensitive T47Dco human breast cancer cells.

Despite the theoretical promise of synthetic antiprogestational agents as anticancer agents, experimental tools, midcycle contraceptives, and implantation inhibitors, none has been available for either basic or clinical studies. However, a candidate antiprogestin, RU38 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(1-propynl)estra-4,9 -dien-3-one], has recently been described that has antiprogestational and antiglucocorticoid activities in early clinical trials. Its mechanisms of action are unclear. Furthermore, development of this drug underscores an old bioassay problem: that biological screening of progestins and antiprogestins is complex because of the physiological requirement that progestational effects must be superimposed upon an estrogenized system. This has made it difficult to distinguish among progestational, antiprogestational, and antiestrogenic properties of unknown agents. Here we describe the use of T47Dco human breast cancer cells to circumvent these problems. T47Dco cells are rich in progesterone receptors (PR), but are resistant to estrogens and antiestrogens. Their PR are estrogen-independent, and this permits progestins to be studied in an estrogen-free system. We have used these cells to assess the receptor-binding properties and the biological actions of RU38 486. Since RU38 486 absorbs UV at approximately 300 nm, this wavelength was used to covalently photolink the drug to PR in situ. Like the synthetic progestin R5020, low concentrations (10 nM) of [3H]RU38 486 bind two PR subunits in nuclei of T47Dco; glucocorticoid receptors are not bound. RU38 486 has a high affinity for PR in vitro (Kd approximately 2 nM at 0-4 C), and in intact cells, low concentrations (6-8 nM) transform more than 95% of PR to a high affinity nuclear binding state. In contrast to progesterone, the compound is not metabolized, so that it chronically (3-6 days) suppresses PR replenishment. These biochemical properties of RU38 486 are typical of synthetic progestins, but distinguish it from pure glucocorticoids. To bioassay RU38 486, we have measured growth and insulin receptors, since in T47Dco, physiological concentrations of progestins inhibit proliferation and increase the number of cell surface insulin-binding sites. Like progestins, RU38 486 is growth inhibitory; unlike progestins, it fails to stimulate insulin receptors and partially blocks their stimulation by R5020. Thus, RU38 486 has dual progestin agonist/antagonist actions depending on the biological response measured.

Affinity Labels↗