On the other hand, due to the loss of inactivation of EE by 17β-HSD in the endometrium (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison. This is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium. The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol, in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).