The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin, one of the earlier forms of estrogen to be introduced.[86][87] From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Studies in the 1975 and thereafter demonstrated that in the absence of a progestogen, unopposed estrogen therapy with Premarin resulted in an 8-fold increased risk of endometrial cancer.[86] After this, sales of Premarin plummeted for a few years.[86] However, it was shown by the early 1980s that the addition of a progestogen to estrogen therapy could mitigate the risk of endometrial hyperplasia and cancer in women with intact uteruses.[86] This led to the development of combined estrogen–progestogen therapy who had not undergone hysterectomy, most typically with a combination of Premarin and Provera (CEEs and MPA, respectively), and in the birth of the modern concept of what is referred to as "hormone replacement therapy".[86]