Absence of fibroids before puberty and low prevalence after menopause

Uterine fibroids are typically found in the reproductive years, with peak incidence around 40 and involution after menopause. There are exceptions where the tumors continue to grow after menopause, but no case has been reported of uterine fibroid before puberty. This profile has led to the assumption that estrogen is the main feeder of uterine leiomyomas . The high prevalence of the disease in the last premenopausal years, when anovulatory cycles are more frequent and progesterone levels may decrease , also implies a greater role of estradiol than progesterone in fibroid pathogenesis. A more accurate analysis of clinical and translational evidence, however, has revealed that progesterone action is required for the full development and proliferation of leiomyoma cells and that estrogen is also necessary, but especially to increase tissue sensitivity to progesterone by increasing the availability of PR .

Local expression of ER and PR

ER is abundantly expressed in uterine leiomyomas, which ensures considerable responsiveness to the circulating estrogens ( Fig. 1 ). Whether the tumors are richer in ER than the surrounding myometrium is still debatable, with some studies showing such a difference whereas others do not . Regarding PR, studies using various designs and molecular approaches have found increased expression levels in leiomyomas compared to matched myometrial samples . Interestingly, the expression of PR increases with the woman’s age and with the number of tumors, but it is lower in women experiencing severe bleeding and dysmenorrhea .

Effects of menopause hormone therapy

Whether estrogen and/or progesterone are essential to sustain fibroid cell renewal and tumor growth is a matter of several lines of investigation, including clinical trials of menopause hormone therapy. In a group of 37 postmenopausal women with uterine fibroids measured by ultrasound and using continuous combined hormone therapy, a mean increase of 8% in tumor diameter was observed after 3 years of treatment , suggesting that the combination of estrogen and progestogen rescues fibroid growth from the effect of menopausal ovarian quiescence. However, only hysterectomized women can receive isolated estrogen to treat menopausal symptoms; therefore, this clinical model cannot resolve the question of whether estrogen stimulation alone is sufficient to maintain leiomyoma growth. Studies of postmenopausal women with uterine fibroids receiving only progesterone or a progestogen are not available, probably because there is no indication for such therapy if the woman is postmenopausal and not on estrogen therapy. Moreover, a body of evidence indicates that estrogen is essential for inducing PRs and allows PR ligands to act on their target cells.

Changes during pregnancy

During gestation, uterine leiomyomas may be expected to grow in response to the very high levels of circulating estrogens and progesterone of placental origin. This hypothesis has been confirmed in early pregnancy , but not in the later stages , despite the steady increase of sex steroid levels throughout gestation. Therefore, protective mechanisms must be present at least in those fibroids that fail to grow during pregnancy. In addition, multiple pregnancies are associated with a lower risk of developing uterine fibroids. The reason for this apparent paradox might be due to myometrium differentiation during pregnancy , making the tissue less susceptible to the action of growth factors and to the genetic mutations that trigger the pathogenesis of the disease.

Risk association with combined contraceptives and progestin-only contraceptives

The possible increase or reduction of fibroid risk attributable to current or past use of hormone contraceptives has been evaluated in observational studies of different designs and mixed interventions, which produced inconsistent results . The Nurses’ Health Study II included 318,712 person-years of follow-up and 2943 cases of uterine leiomyoma diagnosed by ultrasound or hysterectomy. The relative risk of uterine leiomyomata was 1.03 (0.93–1.15) for past users and 0.80 (0.67–0.94) for current users of oral contraceptives. This analysis did not consider different types of progestogens or non-oral hormone contraceptives. Nevertheless, the large number of participants and the prospective cohort design make this study reliable in suggesting a minimum, if any, effect of combined contraceptive use on the risk of uterine fibroids.

In a long-term, multicenter randomized controlled trial comparing levonorgestrel-releasing intrauterine system (LNG-IUS) versus copper intrauterine device (IUD), the former was a protective factor against the development of uterine leiomyomas . Short-term therapeutic trials (reviewed by Kim et al. ) have suggested, although with some inconsistency, that the LNG-IUS may also contribute to reduce fibroid size. The mechanisms of such protective effect of levonorgestrel are unclear and contrast with the anabolic effect of progesterone on leiomyoma cells.

Effects of gonadotropin-releasing hormone analogs and antagonists

The blockade of pituitary gonadotropin release with gonadotropin-releasing hormone (GnRH) analogs or antagonist is an effective strategy to control fibroid symptoms and arrest their growth . Although the inhibitory effect of these peptides might be related to their direct action on GnRH receptors in the uterus or via downregulation of gonadotropin levels reducing the direct stimulus of gonadotropins on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) receptors within the leiomyomas , the most probable explanation for the effectiveness of this therapy is ovarian blockade and the consequent decrease in circulating estradiol and progesterone levels. In a 2-year clinical trial, the involution of uterine volume observed in women treated with GnRH analog was reversed by add-back therapy with oral norethindrone in a high-dose, continuous regimen, but not with the combination of estrogen plus low-dose, cyclic norethindrone . Another randomized, placebo-controlled trial using magnetic resonance imaging showed that GnRH analog treatment reduced total uterine volume and leiomyoma volume within 12 weeks of treatment, while medroxyprogesterone acetate add-back therapy reversed the effect of GnRH on total uterine volume, but not on leiomyoma volume . These studies indicate that blocking the pituitary–ovary axis is a powerful means of inducing uterine fibroid regression, but they fail to demonstrate unequivocally that estradiol and/or progesterone withdrawal are the major mechanisms behind this therapeutic effect in vivo.

Association with anovulatory states

A cohort study of African-American women tested whether self-reported polycystic ovary syndrome (PCOS) was a risk factor for uterine leiomyomata. The study included 275 PCOS cases and 23,300 controls (a prevalence of 1.17%, which is six times lower than the prevalence of PCOS in unselected populations by the most strict diagnostic criteria) and found a positive association between both conditions with an incidence rate ratio of 1.65. Considering the current understanding of the role of estrogen and progesterone in leiomyoma growth, it is reasonable to hypothesize that PCOS women would be at a lower risk of developing uterine leiomyomas due to their typical anovulatory phenotype with reduced progesterone levels. However, the authors recognize that the method of PCOS detection in this study is subjected to imprecision, if not bias, due to self-report and variable diagnostic criteria used by the attending physicians . Nevertheless, they suggest that insulin resistance, hyperinsulinemia, and excess LH might be putative mechanisms to explain the direct association between PCOS and leiomyomas in this population.

Effects of selective ER modulators and selective PR modulators

The use of high-dose raloxifene for 4 weeks before hysterectomy in postmenopausal women reduced uterine volume and fibroid dimension, decreased cell proliferation, and reduced antiapoptotic marker levels in the leiomyoma tissue . As the patients were hypoestrogenic, the effects of raloxifene cannot be ascribed to competition with endogenous estradiol. The authors suggest that raloxifene might act as an ER antagonist and thereby decrease the concentrations of growth factors within the fibroids .

Mifepristone, asoprisnil, and ulipristal are selective PR modulators that have been shown in clinical trials to inhibit fibroid growth (reviewed by Bulun ). These compounds act specifically through the PR, albeit not only by competition with natural progesterone for receptor binding, but also by alternative mechanisms of post-receptor signaling.

Absence of fibroids before puberty and low prevalence after menopause

Uterine fibroids are typically found in the reproductive years, with peak incidence around 40 and involution after menopause. There are exceptions where the tumors continue to grow after menopause, but no case has been reported of uterine fibroid before puberty. This profile has led to the assumption that estrogen is the main feeder of uterine leiomyomas . The high prevalence of the disease in the last premenopausal years, when anovulatory cycles are more frequent and progesterone levels may decrease , also implies a greater role of estradiol than progesterone in fibroid pathogenesis. A more accurate analysis of clinical and translational evidence, however, has revealed that progesterone action is required for the full development and proliferation of leiomyoma cells and that estrogen is also necessary, but especially to increase tissue sensitivity to progesterone by increasing the availability of PR .

Local expression of ER and PR

ER is abundantly expressed in uterine leiomyomas, which ensures considerable responsiveness to the circulating estrogens ( Fig. 1 ). Whether the tumors are richer in ER than the surrounding myometrium is still debatable, with some studies showing such a difference whereas others do not . Regarding PR, studies using various designs and molecular approaches have found increased expression levels in leiomyomas compared to matched myometrial samples . Interestingly, the expression of PR increases with the woman’s age and with the number of tumors, but it is lower in women experiencing severe bleeding and dysmenorrhea .

Effects of menopause hormone therapy

Whether estrogen and/or progesterone are essential to sustain fibroid cell renewal and tumor growth is a matter of several lines of investigation, including clinical trials of menopause hormone therapy. In a group of 37 postmenopausal women with uterine fibroids measured by ultrasound and using continuous combined hormone therapy, a mean increase of 8% in tumor diameter was observed after 3 years of treatment , suggesting that the combination of estrogen and progestogen rescues fibroid growth from the effect of menopausal ovarian quiescence. However, only hysterectomized women can receive isolated estrogen to treat menopausal symptoms; therefore, this clinical model cannot resolve the question of whether estrogen stimulation alone is sufficient to maintain leiomyoma growth. Studies of postmenopausal women with uterine fibroids receiving only progesterone or a progestogen are not available, probably because there is no indication for such therapy if the woman is postmenopausal and not on estrogen therapy. Moreover, a body of evidence indicates that estrogen is essential for inducing PRs and allows PR ligands to act on their target cells.

Changes during pregnancy

During gestation, uterine leiomyomas may be expected to grow in response to the very high levels of circulating estrogens and progesterone of placental origin. This hypothesis has been confirmed in early pregnancy , but not in the later stages , despite the steady increase of sex steroid levels throughout gestation. Therefore, protective mechanisms must be present at least in those fibroids that fail to grow during pregnancy. In addition, multiple pregnancies are associated with a lower risk of developing uterine fibroids. The reason for this apparent paradox might be due to myometrium differentiation during pregnancy , making the tissue less susceptible to the action of growth factors and to the genetic mutations that trigger the pathogenesis of the disease.

Risk association with combined contraceptives and progestin-only contraceptives

The possible increase or reduction of fibroid risk attributable to current or past use of hormone contraceptives has been evaluated in observational studies of different designs and mixed interventions, which produced inconsistent results . The Nurses’ Health Study II included 318,712 person-years of follow-up and 2943 cases of uterine leiomyoma diagnosed by ultrasound or hysterectomy. The relative risk of uterine leiomyomata was 1.03 (0.93–1.15) for past users and 0.80 (0.67–0.94) for current users of oral contraceptives. This analysis did not consider different types of progestogens or non-oral hormone contraceptives. Nevertheless, the large number of participants and the prospective cohort design make this study reliable in suggesting a minimum, if any, effect of combined contraceptive use on the risk of uterine fibroids.

In a long-term, multicenter randomized controlled trial comparing levonorgestrel-releasing intrauterine system (LNG-IUS) versus copper intrauterine device (IUD), the former was a protective factor against the development of uterine leiomyomas . Short-term therapeutic trials (reviewed by Kim et al. ) have suggested, although with some inconsistency, that the LNG-IUS may also contribute to reduce fibroid size. The mechanisms of such protective effect of levonorgestrel are unclear and contrast with the anabolic effect of progesterone on leiomyoma cells.

Effects of gonadotropin-releasing hormone analogs and antagonists

The blockade of pituitary gonadotropin release with gonadotropin-releasing hormone (GnRH) analogs or antagonist is an effective strategy to control fibroid symptoms and arrest their growth . Although the inhibitory effect of these peptides might be related to their direct action on GnRH receptors in the uterus or via downregulation of gonadotropin levels reducing the direct stimulus of gonadotropins on luteinizing hormone (LH) and follicle-stimulating hormone (FSH) receptors within the leiomyomas , the most probable explanation for the effectiveness of this therapy is ovarian blockade and the consequent decrease in circulating estradiol and progesterone levels. In a 2-year clinical trial, the involution of uterine volume observed in women treated with GnRH analog was reversed by add-back therapy with oral norethindrone in a high-dose, continuous regimen, but not with the combination of estrogen plus low-dose, cyclic norethindrone . Another randomized, placebo-controlled trial using magnetic resonance imaging showed that GnRH analog treatment reduced total uterine volume and leiomyoma volume within 12 weeks of treatment, while medroxyprogesterone acetate add-back therapy reversed the effect of GnRH on total uterine volume, but not on leiomyoma volume . These studies indicate that blocking the pituitary–ovary axis is a powerful means of inducing uterine fibroid regression, but they fail to demonstrate unequivocally that estradiol and/or progesterone withdrawal are the major mechanisms behind this therapeutic effect in vivo.

Association with anovulatory states

A cohort study of African-American women tested whether self-reported polycystic ovary syndrome (PCOS) was a risk factor for uterine leiomyomata. The study included 275 PCOS cases and 23,300 controls (a prevalence of 1.17%, which is six times lower than the prevalence of PCOS in unselected populations by the most strict diagnostic criteria) and found a positive association between both conditions with an incidence rate ratio of 1.65. Considering the current understanding of the role of estrogen and progesterone in leiomyoma growth, it is reasonable to hypothesize that PCOS women would be at a lower risk of developing uterine leiomyomas due to their typical anovulatory phenotype with reduced progesterone levels. However, the authors recognize that the method of PCOS detection in this study is subjected to imprecision, if not bias, due to self-report and variable diagnostic criteria used by the attending physicians . Nevertheless, they suggest that insulin resistance, hyperinsulinemia, and excess LH might be putative mechanisms to explain the direct association between PCOS and leiomyomas in this population.

Effects of selective ER modulators and selective PR modulators

The use of high-dose raloxifene for 4 weeks before hysterectomy in postmenopausal women reduced uterine volume and fibroid dimension, decreased cell proliferation, and reduced antiapoptotic marker levels in the leiomyoma tissue . As the patients were hypoestrogenic, the effects of raloxifene cannot be ascribed to competition with endogenous estradiol. The authors suggest that raloxifene might act as an ER antagonist and thereby decrease the concentrations of growth factors within the fibroids .

Mifepristone, asoprisnil, and ulipristal are selective PR modulators that have been shown in clinical trials to inhibit fibroid growth (reviewed by Bulun ). These compounds act specifically through the PR, albeit not only by competition with natural progesterone for receptor binding, but also by alternative mechanisms of post-receptor signaling.