Uterine fibroids and risk of hypertension: Implication of inflammation and a possible role of the renin‐angiotensin‐aldosterone system

Haan and colleagues1 reported a crosssectional study on the association between uterine fibroids (UF), hypertension, and asymptomatic organ damage. The major question that arises from this study is, Are UF directly linked to hypertension or is hypertension or some related factors involved in the onset or growth of fibroids? Uterine fibroids are benign tumors of the muscle layer of uterus, affecting about 70% of women by age 50 years, even if only 30% of patients are symptomatic and request treatment.2 UF can be considered a fibrotic disease starting with an invasion of inflammatory cells at the level of the uterus or alternatively by an increase of resident fibrotic cells.3 It is well known that the female genital tract is less reactive to inflammation and autoimmunity and this pattern allows spermatozoa to exert their reproductive function still maintaining a full protection against microbial invasion. The pathogenesis of UF involves a genetic predisposition influenced by the effect of several hormones. Both estradiol and progesterone have a role in the normal development of uterine mucosa and in the preparation of the uterus for pregnancy, but their involvement in hypertension risk is not proven. High amounts of estrogens can produce hypertension, as reported for some contraceptives, but these associations do not induce UF development or increase their volume. The hypertension caused by contraceptives has been related to the increase of angiotensinogen and activation of reninangiotensinaldosterone system (RAAS) or to a direct effect of estradiol at the kidney level producing sodium retention. A previous study has shown that the risk of hypertension in UF is not influenced by hysterectomy with ovarian conservation and on the contrary hysterectomy is associated with longterm increase of cardiovascular risk.4 These studies are consistent with an extra uterine mechanism underlying the association of hypertension and UF. Progesterone may play an important role in UF development, stimulating cellular proliferation and fibroid growth.5 Fibroids express elevated levels of both types of progesterone receptors (PR), PRα and PRβ, compared to the surrounding myometrium.6 These findings suggest a certain role of progesterone and PR in UF pathogenesis but not in hypertension, progesterone being a mineralocorticoid receptor (MR) antagonist. Uterine fibroid size is significantly reduced in response to the PR antagonist mifepristone (RU486) or to the selective PR modulator ulipristal acetate, which are also effective at controlling uterine bleeding and reducing collagen deposits.7 Ulipristal does not have antialdosteronic properties like progesterone and for this reason it is effective in ameliorating UF volume, but it is not effective in reducing the cardiovascular risk and hypertension.