Progestins and potassium.

T he bulletins from the nation’s therapeutic frontiers continue to read like the casualty reports from a lost war. At least once or twice a year, yet another pharmaceutical company or regulatory agency or biomedical journal releases yet another melancholic communiqué on the terrible effects of a drug that previously had been thought to be the greatest advance in medicine since aspirin or penicillin. We have had the demise of inotropic drugs for heart failure, of NEP-ACE inhibitors and COX-2 inhibitors, to mention but a few of the more spectacular pieces of bad news. However, none could have been more surprising, and impacted more people, than the story of hormone replacement therapy (HRT). Menopausal symptoms can be grim, and it made perfect sense to replace the hormonal deficit with exogenous hormones, estrogen and progestin. The enthusiasm for HRT was greatly enhanced by the results of observational studies, which suggested that either estrogen alone or in combination with progesterone seemed to improve many measures of cardiac and vascular health, including serum lipids and endothelial function, not to mention the prevention of osteoporosis and its damaging clinical consequences. There was also the tantalizing evidence that these agents slowed the decline in cognitive function and might help prevent Alzheimer disease. Because of all of the perceived benefits, it is no great surprise that by the mid-1990s HRT was the most frequently prescribed drug in the United States, in spite of some lingering worries about breast and endometrial cancer and venous thromboembolism. Then came the large and well-designed randomized clinical trials, the Heart and Estrogen/progestin Replacement Study (HERS) and the Womens Health Initiative (WHI), which showed, to everyone’s astonishment, that HRT actually increased cardiovascular risk. Since then there has been intense activity in the drug development world to find new estrogen and progestin analogs that are both effective and safe, and with a little bit of luck would carry through on the early promise of cardiovascular protection. One of these agents is drospirenone (DRSP), a novel progestin, that has been developed, in combination with 17-estradiol (E2), for