Progesterone is also thought to play a role in fibroid growth. More specifically, clinical studies suggest progesterone facilitates the growth of fibroids. For example, fibroid size increases during treatment with synthetic progesterones. Combination GnRH agonist and progesterone therapy has been shown to have no effect on uterine volume, in contrast to GnRH agonist therapy alone which has been shown to reduce uterine volume. The observation that fibroids regress with the antiprogesterone agent, RU-486, further supports the role of progesterone as a promoter of fibroid growth.

Histologically, fibroids from patients treated with progesterone show more cellular growth than those from patients without progesterone therapy. Biochemically, fibroids have higher progesterone receptor concentrations than normal myometrium. Together, these data suggest that progesterone also enhances fibroid growth.