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Progesterone receptor membrane component-1 (PGRMC1) in breast cancer tissue has been suggested to predict a worse prognosis. The aim of this study was to assess for the first time whether PGRMC1 expressed in cancer tissue is associated with PGRMC1 blood concentrations and whether both are correlated with clinical tumour characteristics known to predict a worse outcome.In total, 201 patients with invasive breast cancer and 65 with benign breast disease (control group) were recruited. PGRMC1 blood concentrations were measured by a recently developed ELISA, PGRMC1 in breast cancer tissue was assessed by immunohistochemistry, and the correlation between the two was calculated. Receiver-operating characteristic (ROC) curve analysis was used to assess area under the curve (AUC). Furthermore, PGRMC1 was correlated with tumour characteristics such as tumour diameter, tumour grade and metastatic status, and with known blood tumour markers.AUC for the breast cancer group was 0.713, which was significantly higher than in the control group (p0.01). Blood PGRMC1 concentrations had a strong (positive) correlation with tissue PGRMC1 expression (p0.01) but were not associated with serum tumour markers CEA, CA125, CA153 and TPS. Tissue PGRMC1, ER and cancer stage were positively associated with blood PGRMC1 (p0.05).As PGRMC1 expression levels in cancer tissue were significantly correlated with PGRMC1 in blood, and because concentrations in blood were also positively associated with breast tumour characteristics known to predict a worse prognosis, PGRMC1 may be valuable as a new tumour marker and may be superior to known tumour markers such as CEA, CA125, CA153 and TPS.

Objectives A few observational studies have suggested that progesterone and dydrogesterone may have a lower risk of breast cancer than other progestogens. In our earlier xenograft animal experiments, progesterone did not stimulate breast tumors. The aim of this study was to test dydrogesterone for the first time. The study also evaluated the effects of PGRMC1 on proliferation with progestogens. Methods (1) In-vitro study. The proliferative effects of dydrogesterone and of progesterone were assessed in vitro using T47D cells transfected with PGRMC1 or empty vector in the presence or absence of estradiol. Additionally, to find the strongest proliferator for inclusion as a comparator in the xenograft animal study, norethisterone, levonorgestrel, desogestrel, dienogest, drospirenone, nomegestrol, and cyproterone acetate were tested. Methods (2) Xenograft main study. PGRMC1-transfected or empty-vector T47D and MCF7 xenotransplants were each treated with four different hormonal preparations: E2+placebo; E2+dydrogesterone; E2+progesterone; E2+norethisterone. A total of 112 castrated mice were randomly allocated to the 16 groups. This was thus a prospective, randomized, blinded, placebo-controlled four-arm study (45–50 days) with the two T47D and two MCF7 xenografts. Tumor volumes were monitored twice weekly. Results (1) In-vitro study. The strongest proliferation was with norethisterone, but only with PGRMC1-transfected cells. There was significant proliferation with dydrogesterone, but not with progesterone in the absence of estradiol. However, no increase in proliferation was achieved by adding dydrogesterone to estradiol compared with the proliferation induced with estradiol alone, in contrast to norethisterone. Results (2) Xenograft main study. There was significantly faster tumor growth with norethisterone + E2 than with E2+placebo in T47D and MCF7 PGRMC1 xenografts, but not with dydrogesterone + E2 or progesterone + E2. There was less tumor growth in empty-vector xenografts, without between-group differences. Conclusion PGRMC1 increases the breast-cell proliferation effects of certain progestogens, including dydrogesterone, in contrast to progesterone, but not during estradiol-induced proliferation, either in vitro or in a xenograft animal model, in contrast to norethisterone. Thus the proliferative potency of dydrogesterone may be similar to that of progesterone. Clinical studies in women overexpressing PGRMC1 are recommended.

Background Recent investigations have indicated that hormone therapy may increase the risk of breast cancer (BC), and the addition of synthetic progestins may play a critical role in this. Several studies have pointed out the important role of progesterone receptor membrane component 1 (PGRMC1) in the development of BC, especially with hormone therapy using progestins. Although the deregulation of microRNA-181a (miR-181a) is often associated with human BC, the effect of miR-181a on PGRMC1 expression during hormone therapy has not been investigated. Methods Cell viability assay and apoptosis assay were performed to investigate the pro-BC effect of progestin (norethisterone, NET) and anti-BC effect of miR-181a on MCF-7 cells. Quantitative RT-PCR and Western blot analysis were used to evaluate gene expressions in the NET-treated MCF-7 cells. Results NET dose-dependently increased BC cell viability and this effect was accompanied by increased expression of PGRMC1. Overexpression of miR-181a strongly reduced the cell viability of MCF-7 cells, mainly through increased apoptosis, which was evidenced by substantially increased gene expression of pro-apoptosis factors such as BAX and CASPASE 9 in miR-181a overexpressed cells. Importantly, miR-181a abrogated NET-stimulated cell viability and PGRMC1 expression. Conclusions We provide evidence that miR-181a promotes MCF-7 cell apoptosis. Moreover, miR-181a suppressed NET-provoked cell viability and PGRMC1 expression in MCF-7 cells. These data may suggest a therapeutic strategy of using miR-181a to reduce BC risk in progestin hormone replacement therapy.

During menopausal hormone therapy (MHT) a possible increase in breast cancer risk is thought to depend mainly on the progestogen component. In vitro studies have shown that the progesterone receptor membrane component 1 (PGRMC1) is important for tumor proliferation induced by progestogens. The primary aim of this study was to compare for the first time the natural progestogen, progesterone (P), with a synthetic progestogen, norethisterone (NET), using a xenograft model.MCF7 cells, transfected with PGRMC1 plasmid or empty vector, were injected into nude mice and estradiol (E2) pellets were implanted. After 12days, NET or P or placebo pellets were implanted. Tumor volumes in all groups (6 mice/group) were monitored for 6-7 weeks. Immunohistochemical expression of PGRMC1 and KI-67 was assessed. These experiments were repeated using T47D cells.Compared with the control condition, E2 and sequential E2/NET combination increased xenograft tumor growth with MCF7 and T47D cells that transgenically expressed PGRMC1 (p0.01); progesterone did not increase growth. Breast cancer cells transfected with empty vectors did not respond to either progestogen. Comparing KI-67 and PGRMC1 expression, the Pearson correlation was r=0.848, p=0.002.E2 plus NET increases tumor growth in human breast cancer cells overexpressing PGRMC1, but there is no change with progesterone. To our knowledge, this is the first comparison of both progestogens in vivo using nude mice, which are frequently used in xenograft models. Clinical trials are needed to determine whether women with overexpression of PGRMC1 are at increased risk of breast cancer if NET instead of progesterone is used in MHT.

Dienogest (DNG) is a 19-nortestosterone derivative (a C-19 progestogen) with a cyanomethyl instead of an ethinyl group at the C-17 position, which may make the compound elicit fewer hepatic effects than other C-19 nortestosterone derivatives. Its similarity to norethisterone is reflected in its high endometrial efficacy, which could explain the high stability of the menstrual cycle women achieve when they use DNG in combination with ethinyl estradiol (EE) or with estradiol valerate (E2V). Its strong endometrial efficacy underlies the use of DNG (on its own) to treat endometriosis, and gives it antiproliferative and anti-inflammatory effects in the treatment of endometriotic lesions. Properties derived from its C-19 derivative structure include its short plasma half-life, of about 10h (which means the drug is not accumulated), and its high oral bioavailability, of more than 90%. However, DNG also has some of the properties of typical of progesterone derivatives, including a lack of effect on the metabolic and cardiovascular systems, and considerable antiandrogenic activity, the latter increased by its lack of affinity to the sex-hormone binding globulin (SHBG), in contrast to other C-19 progestogens. DNG has no glucocorticoid and no antimineralocorticoid activity. It also has no antiestrogenic activity, which suggests that it should not antagonize estradiol's beneficial effects. This is important for its use in the treatment of endometriosis, because, due to DNG's low gonadotropic activity, E2 levels are not decreased to zero, in contrast to treatments with gonadotropin-releasing hormone (GnRH) analogues. This maintenance beneficial E2 effects is of particular importance for the general tolerability of the first contraceptive pill to use E2V instead of EE, although clinical endpoint studies are still ongoing. These studies are expected, on the basis of its pharmacology, to demonstrate the cardiovascular safety of the new pill.

Nomegestrol acetate (NOMAC) is a 19-norprogesterone derivative with high biological activity at the progesterone receptor, a weak anti-androgenic effect, but with no binding to estrogen, glucocorticoid or mineralocorticoid receptors. At dosages of 1.5 mg/day or more, NOMAC effectively suppresses gonadotropic activity and ovulation in women of reproductive age. Hemostasis, lipids and carbohydrate metabolism remain largely unchanged. In normal and cancerous human breast cells, NOMAC has shown favorable effects on estrogen metabolism. Like natural progesterone (but in contrast to some other synthetic progestogens), it does not appear stimulate the proliferation of cancerous breast cells. While there has been some experience of the use of NOMAC in combination with estrogens as a hormone replacement therapy, most of the data on the compound are reported in the context of its inclusion as a component of a new contraceptive pill comprising 2.5 mg NOMAC combined with 1.5 mg estradiol. Because of its strong endometrial efficacy, and due to its high antigonadotropic activity and long elimination half-life (about 50 h), the contraceptive efficacy of the new pill is maintained even when dosages are missed. Furthermore, for the first time with a monophasic 24/4 regimen containing estradiol, cyclical stability can be achieved comparable with that obtained using pills containing ethinyl estradiol and progestogens like levonorgestrel or drospirenone. The addition of NOMAC to estradiol means that the beneficial effects of estrogen are not lost, which is of especial importance in relation to the cardiovascular system. On the basis both of its pharmacology and of studies performed during the development of the NOMAC/estradiol pill, involving some 4000 women in total, good long-term tolerability can be expected for NOMAC, although its safety profile is still to be fully ascertained, as the clinical endpoint studies are yet to be completed.

Women at middle age have decreased fertility and their pregnancies are higher risk. Combined oral contraceptives (COC) are effective but confer increased risk of age-related diseases, especially cardiovascular diseases. These risks are lower, however, with progestogen-only pills (POP). Therefore, other than the levonorgestrel intrauterine device (LNG-IUD), POP are usually the first choice, even though they do often lead to bleeding problems, which are already frequent in the perimenopause. However, the main risk of COC, venous thromboembolism, seems not to be relevant in (non-hospitalized) Chinese women and perhaps also other Asian women. COC may therefore be in fact a better choice than POP for these groups. In contrast to POP and IUDs, they have a variety of benefits especially important for middle-aged women, including a large decrease of the risk of ovarian, endometrial and colorectal cancer, an improvement in bleeding irregularities, a reduction of climacteric symptoms and some protection against bone loss. Further research is needed into individualized and safe contraception that takes into account ethnicity, as well as other factors.

Several medicinal products containing progesterone are in widespread use orally for protection of the endometrium during concurrent oestrogen treatment, and injections or vaginally for support of luteal function during assisted reproduction. These indications have been established in extensive clinical testing programmes. In addition, the results of recent studies and meta-analyses suggest that vaginal progesterone is an effective method for preventing premature births in singleton pregnancies in women with a shortened cervix. In US, 17α-hydroxyprogesterone caproate is licensed to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. There is insufficient evidence from scientific studies to substantiate the transdermal application of progesterone. In particular, these preparations should not be used to oppose the effects of oestrogen on the endometrium, because even with low doses of estradiol a reliable progestogenic effect to protect the endometrium has not been proved. On the other hand, the application of transdermal progesterone preparations alone is not known to pose any risks to health.

The questionnaires were available in both paper-based and electronic form and comprised demographic data; health data including, climacteric symptoms, bone health, pelvic floor, sexuality and medication use. It was used for data collection Questionnaire MUMENESP and Women Sexual Function validated in Spanish. The study was carried out at the outpatient clinics of the departments of gynecology of public and private institutions throughout Spain in the routine clinical setting. Results