Mechanisms of sex steroids. Future developments

The discussion on the risks of hormone therapy supports the search for alternative drugs such as selective estrogen receptor modulators (SERMs). These compounds are suitable for special preventive goals, but cannot be expected to replace the use of estrogens in patients with estrogen deficiency. The development of selective progesterone receptor modulators (SPRMs) which has to resolve various problems, might be a promising approach. Hormone replacement therapy (HRT) with natural estrogens remains the measure of choice for treatment of symptoms caused by estrogen deficiency. Recent findings suggest that the additional progestogen which is used for the protection of the endometrium, plays a crucial role with regard to the risk of breast cancer and cardiovascular disease. As surrogate parameters cannot predict the extent of risks, suitable tools for the selection of progestogens with the least potential for causing adverse effects, are urgently needed. Experimental, clinical and epidemiological data suggest that the elevation in breast cancer risk is due to the proliferative effect of estrogens on breast tissue which is largely enhanced by progestogens. A short-term in vivo-test might be helpful for the evaluation of proliferative effects of estrogen-progestogen preparations. Similarly, a strictly standardized in vivo-test for the assessment of the atherogenic potential of estrogen-progestogen preparations might help to select the preparations with the lowest risk for ischemic diseases. The available data suggest that it is probably not the androgenic but the glucocorticoid activity of a progestogen which plays a role in the development of cardiovascular disease. Progestogens with glucocorticoid effects may up-regulate the thrombin receptor in the vessel wall which is involved in the development of atherosclerosis and stimulation of extrinsic coagulation.