Genomic and non-genomic actions of progestogens in the breast.

Evidence is growing that progestogens may enhance breast cancer risk under hormone therapy in the postmenopause or hormonal contraception. However, differences may exist within the progestogen class and certain progestogens may have a higher potency in terms of breast cancer risk. The mechanism(s) by which these progestogens might influence breast cancer risk appear to be mediated via genomic and/or non-genomic effects triggered by activated progestogen receptors.

Nomegestrol acetate, a novel progestogen for oral contraception.

Nomegestrol acetate (NOMAC) is a potent, highly selective progestogen, which is structurally similar to 19-norprogesterone and characterized as a full agonist at the progesterone receptor, with no or minimal binding to other steroid receptors, including the androgen and glucocorticoid receptors. In animal models, NOMAC demonstrated moderate antiandrogenic activity and strong antiestrogenic activity. In clinical studies, the progestogen was associated with effective suppression of gonadotropic activity and ovulation in premenopausal women, and a neutral impact on hemostasis, lipids, and carbohydrate metabolism.

2-Methoxyestradiol--biology and mechanism of action.

In the last decade the endogenous estradiol metabolite, 2-methoxyestradiol (2ME), has gained more and more interest due to its marked anticancerogenic properties and possible cardiovascular benefits, as shown in numerous animal and experimental investigations. Some promising results in terms of the usage of 2ME as a therapeutic agent were obtained by various clinical studies in patients with breast cancer and prostate cancer. However, one main problem appears to be the bioavailability of 2ME, therefore new formulations are now in the test phase.

Why use of dienogest for the first contraceptive pill with estradiol?

Dienogest (DNG) has the essential properties of an effective progestogen for use in a new contraceptive pill using estradiol valerate as estrogenic component -- it inhibits ovulation and protects against endometrial proliferation. DNG is a derivative of norethisterone (NET), but has a cyanomethyl- instead of an ethinyl-group in C17 position which may offer a variety of benefits regarding hepatic effects. The similarity to NET is reflected in the high endometriotropy and in similar pharmacokinetics like short plasma half-live and high bioavailability.

[Contraception in women with special problems].

Thromboembolic, cardiovascular and cerebrovascular events are age-dependent. They are extremely rare in young women. In contrast to the progestogen-only pills, oral contraceptives (OC) increase the risk of venous thrombosis.

Progestogens and target tissues: vascular systems.

Progestogens were mostly used in hormone replacement therapy (HRT) in the postmenopause. Therefore, our knowledge about cardiovascular effects mainly originates from studies using HRT, whereby the progestogen effects were assessed according to clinical endpoints, metabolic effects and influence on vascular markers in vitro or in vivo, respectively. Furthermore, the progestogens can be characterised in terms of their partial receptor properties by specific experimental models.

The World Health Organization defines hormone replacement therapy as carcinogenic: is this plausible?

In June 2005 the World Health Organization's International Agency for Research on Cancer (IARC) classified combined hormone contraception and menopausal therapy as carcinogenic in humans. The IARC's function is to identify potential carcinogens associated with nutrition, environment and pharmaceutical products. They do not produce risk-benefit analyses for any country or population.

The use of hormone replacement therapy in patients after breast cancer.

Four prospective randomized studies and at least 15 observational studies investigating hormone replacement therapy (HRT) after breast cancer are available. Only the Hormonal replacement therapy After Breast cancer: Is iT Safe (HABITS) study shows an increased risk of relapse. This is probably associated with the relatively high number of patients with HRT treatment after estrogen receptor-positive cancers as well as to the preferred use of estrogen/progestin combined preparations.

Urinary phytoestrogen excretion of rats bearing methylnitrosourea-induced mammary carcinoma in response to treatment with 2-methoxyestradiol.

The effect of treating mammary tumor-bearing rats with 2-methoxyestradiol (2-MeE2) on the urinary excretion of 12 phytoestrogens was investigated and compared with the changes in urinary excretion of estradiol metabolites. Alterations of excretion were registered for isoflavonoids, lignans and coumestans. However, due to large variations statistical significant differences were found only for two lignans, i.

[Hormone replacement therapy for internal risk patients].

Using hormone replacement therapy (HRT), absolute and relative contradictions have to be considered, which are primarily classified according to a "worst case" scenario on the assumption of group effects, in order to satisfy forensic demands. However, in patients with severe complaints it make sense to apply HRT even at increased risk. To minimize the risk, a differentiated choice of the preparation especially in terms of progestin component and application mode is feasible apart from a general dose reduction.

Biochemical markers surrogating on vascular effects of sex steroid hormones.

The main mechanism of possible cardioprotection by estrogens appears to be a direct effect on the vasculature, resulting in an improvement of endothelial function and inhibition of atherogenesis. Numerous observational and experimental studies have demonstrated a positive correlation between estrogens and various biochemical markers surrogating direct vascular effects. In general, most markers are influenced in a similar way by oral and transdermal hormone therapy, although oral therapy may have a faster and more pronounced effect.

Smoking, estradiol metabolism and hormone replacement therapy.

Many women receiving hormone replacement therapy (HRT) smoke; in the Women's Health Initiative (WHI), one of the largest interventional studies on HRT to date and which recently had to be discontinued, 50% of the 8,500 women on HRT had smoked before or continued to smoke during the study. Remarkably, there is little knowledge about the impact smoking has on the efficacy and side effects of HRT. However, it has been proven that, depending on the type, duration and intensity of nicotine consumption, smoking can reduce or completely cancel the efficacy of orally administered estrogens.

Inhibitory effect of statins on the proliferation of human breast cancer cells.

Objective: Long-term hormone therapy in the postmenopause is associated with a moderate increase in cardiovascular and breast cancer risk. Of great concern, therefore, is the question of how women with menopausal symptoms and enhanced cardiovascular risk can be treated. Evidence is growing that an estrogen/statin combination may be a good choice, since this combination seems to elicit additive beneficial effects on the lipid profile and on the vasculature.

Effect of hormone therapy on BP in normotensive and hypertensive postmenopausal women.

High blood pressure (BP) ranks as the greatest risk factor for cardiovascular disease. The increased cardiovascular risk determined in recent interventional studies has led the health authorities in some countries to re-ignite the discussion about whether hypertension should be listed as a contraindication for hormone replacement therapy (HRT). We reviewed papers published since 1960 and listed in MEDLINE, EMBASE and Biosis, on studies that monitored the course of BP during HRT.

Estrogens acting as cardiovascular agents: direct vascular actions.

In vitro experiments and in vivo studies indicate that estrogens exert various beneficial effects on the vascular wall. In the present review the recent literature and the results of our own studies on this topic are summarized. By modulating the synthesis of nitric oxide, prostacyclin and endothelin and blocking calcium channels estrogens positively affect the vasotonus.

Chemotherapy of breast cancer-additive anticancerogenic effects by 2-methoxyestradiol?

2-Methoxyestradiol (2ME) is an endogenous estradiol metabolite, which acts antiproliferative in various tumor cell lines independent of the hormone receptor status. We investigated whether combinations of 2ME with various chemotherapeutic or endocrine compounds may result in an additive effect on the proliferation of human breast cancer cells. The breast cancer cell lines MCF-7 (receptor-positive), BM (receptor-negative) and a MCF-7 line transfected with the aromatase gene were used.

Hormone therapy after endometrial cancer.

Endometrial carcinoma is listed among the absolute contra-indications to hormone therapy. After all the existing opinions so far, hormone therapy after FIGO stage I or II endometrial cancer is still thought of as a possibility, and up to now the continuous combined oestrogen/progestogen replacement therapy would be recommended. However, until today, only observational studies have been put forward.

Hormone therapy after endometrial cancer.

Endometrial carcinoma is listed under the absolute contraindications to hormone therapy (HT). According to current opinion, HT after stage I or II is still considered an option, and continuous combined oestrogen/progestogen replacement therapy (CCEPT) would be recommended. However, up to now, only observational studies have been put forward.

Class-specific pro-apoptotic effect of statins on human vascular endothelial cells.

Neonangiogenesis represents an important step in tumor development and propagation. Statins may have anticancerogenic potential by blocking vascular endothelial cell growth. The antiproliferative effect of four statins on human endothelial cells was compared, concomitantly delineating a possible pro-apoptotic process.

Endogenous estradiol metabolism during treatment with oral contraceptives.

Objective: Recent clinical studies indicate that an increase in D-ring estradiol metabolites over A-ring metabolites may be a risk factor for breast cancer. The present work was aimed to investigate the effect of oral contraceptives (OC) on the endogenous estradiol metabolism in premenopausal women.

Methods: Two studies were conducted, firstly comparing 2 different progestins, i.

Effects of oxytocin outside pregnancy.

For a long time, oxytocin was regarded as a pregnancy hormone released by the hypophysis to stimulate labour and milk ejection. In the present survey, data have been collected from the literature to show the spectrum of the hitherto known functions of oxytocin outside pregnancy. It is now known that oxytocin receptors can occur almost ubiquitously in the organism, that oxytocin is also formed outside of the brain and that oxytocin has functions in a number of organs.

[Estrogen-dependent neoplasia - what is the significance of estradiol metabolites].

Estradiol can be metabolized to substances eliciting different, partly opposite effects even at low concentrations as shown in own investigations, e. g., regarding (anti)angiogenic actions.

Effect of statins combined with estradiol on the proliferation of human receptor-positive and receptor-negative breast cancer cells.

Objective: Combination of a statin plus estrogen may reveal benefits on the cardiovascular system in postmenopausal women by additively ameliorating both the lipid profile and vascular function. Long-term therapy with estrogens, however, is associated with an increase of breast cancer risk. In contrast, evidence is accumulating that statins may inhibit carcinogenesis because of their central action on important cellular functions.

Statins and direct vascular actions.

Statins can exert many pleiotropic effects beyond their cholesterol-lowering action. These effects mainly influence the vascular wall and may modulate beneficially endothelial function, atherogenesis and atherosclerotic plaque stability. Recent data suggest a possible positive effect of statins on prevention of osteoporosis and cancerogenesis.