Why can estrogen therapy increase the risk of uterine cancer without progestin?

Estrogen therapy can increase the risk of uterine cancer because estrogen acts to build and maintain the endometrium, the lining of the uterus. By stimulating the growth of these cells, estrogen increases the size, weight, and cell number of the uterine lining.1

When estrogen is administered without progesterone (or a synthetic progestogen like progestin), the endometrium is exposed to unopposed estrogen stimulation. This creates a hormonal imbalance where estrogen levels are consistently higher than progesterone levels. Without the counterbalancing effects of progesterone, which helps regulate and shed the uterine lining, this continuous stimulation can lead to the development of hyperplasias—benign growths that have the potential to progress into malignant tumors. Consequently, medical approaches often combine estrogen with a progestin to mitigate this risk and protect the uterine lining.21