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Uterine fibroids and their treatment

Estrogen and Progesterone generally promote uterine fibroid growth

It's the "free" hormone levels that count

Some researchers maintain that serum estrogen and Progesterone levels are unchanged by UFs - however, these serum levels are only meaningful if their free levels have been measured, which is not usually the case.

 

Overall effects of Estrogen and Progesterone:

i)  Mitogenic effect on leiomyoma cells.   Encourages cell division/mitosis;

ii)  Act by influencing (directly and indirectly) a large number of:

-   Growth factors.   Usually a protein or steroid hormone capable of stimulating cellular growth, proliferation and cellular differentiation (less specialized cell becomes a more specialized cell type).

Estrogen Dominance.   A dominance of estrogen over other hormones is a recognized problem of today, due to dietary and environmental changes.

ESTROGEN Dominance

 

Effects of estrogen on uterine fibroid growth

Fibroids make a lot of estrogen

Fibroid cells can make their own  ESTRADIOL  and the conversion enzymes to make it are over-expressed in fibroids - Fibroids express higher levels of aromatase and can convert circulating androstenedione into ESTRADIOL via the enzymes Aromatase and 17ß-hydroxysteroid dehydrogenase  (Walker & Stewart, 2005; Shozu, 2004)

-   Aromatase over-expression in uterine leiomyoma tissue is particularly pronounced in African-American women (Ishikawa et al, 2009)

-   LEPTIN (the “appetite suppressor” hormone) has also been shown to increase aromatase expression

 

Fibroids have a lot of Estrogen receptors

Fibroid cells have more estrogen receptors (to respond to estrogen) than normal uterine muscle cells

Having estrogen receptors, fibroids tend to enlarge during the reproductive years and shrink after menopause - In PREmenopausal fibroids the  ER-ß, ER-α (and Progesterone) receptors are found over-expressed - compared to only ER-ß in POSTmenopausal fibroids (which are rare) (Strissel et al, 2007)

A special ER-α genotype was found correlated with incidence and size of fibroids - Higher prevalence of this genotype in black women may also explain higher incidence of fibroids in Afro-American women. Most studies found that other different phenotypes in ER and Pr gene encodings are not correlated with incidence of fibroids in Caucasian populations (Alhendy, 2006)

 

Believed that Estrogen is growth-promoting by up-regulating:

•   IGF-1, EGFR, TGF-β1 - Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium (In myometrial cells,TGIF is a potential repressor of anti-proliferative TGF-β pathways).

•  Cytokines - signaling molecules secreted by nervous system glial cells and many immune system cells for intercellular communication.

•  Apoptotic factors - TGF-ß3 and PDGF, promotes aberrant survival of leiomyoma cells by down-regulating the tumor-suppressor protein p53.

•   Other hormones

Effects of Progesterone on uterine fibroid growth

Uterine fibroids have more Progesterone receptors (to respond to Progesterone) than normal uterine muscle cells.

•  Progesterone is thought to promote the growth of leiomyoma via up-regulation of EGF, TGF-β1 and TGF-β3

•  Progesterone is thought to promote the survival of leiomyoma via up-regulation of Bcl-2 expression and down-regulating TNF-α.

•  Progesterone is thought to counteract growth of leiomyoma by downregulating IGF-1.

A recent study emphasized the anomaly whereby >72% of women who were pregnant (or recently postpartum) have > 50% regression of pre-existing fibroids - One explanation points to the postpartum fall of Progesterone.

Progesterone seems to have a dominant role by INCREASING mitotic rates in fibroids in the luteal phase  of the menstrual cycyle (2nd half of cycle when corpus luteum secretes a lot of Progesterone) -  the drug mifepristone, a Progesterone antagonist, INHIBITS fibroid growth lending support to Progesterone's dominant role. One theory is that Progesterone upregulates EGF and TGF-β expression. However, Progesterone also REDUCES the growth factor IGF-1 in vitro and INHIBITS MMPs, which activate growth factors and degrade extra cellular matrix (ECM), affecting ECM assembly and deposition, and so counters UF enlargement.

 

Other notes

Actions of estrogen and Progesterone are modulated by the “cross-talk” between themselves and PROLACTIN -  which controls the expression of their respective nuclear receptors.

Rarely, leiomyomas progress to leiomyosarcomas and evolve to a hormone-non-responsive state - since many sarcomas have markedly reduced or no steroid hormone receptors

 

References

Alhendy, A.; Salama, S. (2006). "Ethnic distribution of ESTROGEN receptor-αpolymorphism is associated with a higher prevalence of uterine leiomyomas in black Americans". Fertility and Sterility 86 (3): 686 PubMed

Shozu, M.; Murakami, K.; Inoue, M. (2004). "Aromatase and Leiomyoma of the Uterus". Seminars in Reproductive Medicine 22 (1): 51. PubMed

Strissel, P.; Swiatek, J.; Oppelt, P.; Renner, S.; Beckmann, M.; Strick, R. (2007). "Transcriptional analysis of steroid hormone receptors in smooth muscle uterine leiomyoma tumors of postmenopausal patients". The Journal of Steroid Biochemistry and Molecular Biology 107(1-2): 42-47. . PubMed

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