The oestrogen receptor familiar to researchers for longer is known as ‘ER-alpha’. In 1995, J.-Ă. Gustafsson discovered another oestrogen receptor, the ER-beta (ER-ß). Both are localised within the nucleus. Such nuclear receptors can be activated by low-molecular-weight substances such as oestrogens and structurally similar molecules, e.g. isoflavones, or by synthetic active ingredients. A precondition to activation of the receptors is that these substances pass through the membranes of their target cells, continuing through the cytoplasm of the cells to the nuclei, where they bond covalently with the receptors in the nuclei. They then form a ligand-receptor complex. Once activated by a ligand, ER-α causes ‘cellular activity in the broadest sense’, including proliferation and inflammation; this can result in an increased risk of mutations and the oncogenesis to which this can lead.

ER-ß, on the other hand, once activated by a ligand, provides for ‘calming’, for anti-proliferative and anti-inflammatory effects and hence for an option to protect against cancer through targeted activation of this receptor using suitable substances. This dimension also gives rise to treatment possibilities of the kind already seen with the oestrogen receptor-beta agonist tamoxifen.

When it encounters ER-alpha, 17-beta oestradiol (E2) can stimulate mitosis and promote inflammation and angiogenesis. If, however, ER-beta predominates in the tissues, then the same stimulant, oestrogen, inhibits mitosis and has anti-inflammatory and antiangiogenic effects. Thus, the same substance can have two different effects, depending on the receptor constellation in the tissues.

The best evidence for the chemopreventive effect of the oestrogen receptor beta is provided by tamoxifen, referred to above, which prevents the tissue against further proliferation via the selective effect on the beta receptor in the breast.

Soya isoflavones are natural ER-ß agonists. They selectively stimulate ER-ß and promote ER-ß expression in tissues as well.

There are not only the different receptors ER-ß and ER-α, but there are also different metabolites of E2. Today, we know that the oestradiol, progesterone and testosterone are only precursors, i.e. precursor steroids. From these precursors, each organ can then assemble the hormone it needs in its own local situation.

The metabolism of oestradiol was presented for the first time at the major cancer congress (Conference of the National Cancer Institute) in Bethesda, Maryland, in 1998. It is evident that the original oestradiol can be hydroxylated at a different place in the molecule; this diversifies the effectiveness of the hormone in different directions.

The human body accomplishes this with other hormones in different organs as well. This has long been known and accepted for testosterone. In the prostate, it is hydroxylated further into dihydrotestosterone, which ultimately exerts the stimulative effect on the prostate gland. Progesterone, too, is transformed into other metabolites in the brain, such as allopregnanolone, which also has a highly differentiated task to perform. The situation with oestrogen is similar. It has three different highways available to it that it pursues following release from the ovary or following oral administration (Fig. 22.2).