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GSE Uterine fibroids and their treatment

Uterine Fibroids (UFs)

(Uterine leiomyoma, myoma, fibromyoma, leiofibromyoma, fibroleiomyoma, and fibroma)

What are Uterine Fibroids (UFs)?

OVERVIEW

BENIGN (i.e. non-cancerous), usually multiple TUMORS originate from and are composed of SMOOTH MUSCLE cells (myocytes) of the uterine wall's muscle layer (myometrium, the middle layer of the uterine wall used for contracting the uterus) and its accompanying connective tissue;

–   It is rare for uterine leiomyomas to progress to leiomyosarcomas (1.7 women per 100,000 women are diagnosed annually with uterine sarcoma, which includes leiomyosarcoma)

National Cancer Institute

Vary in size - from microscopic to very large (can weigh several pounds).

Fibroids are often described by their location in the uterus:

✔ Myometrial - in the muscle wall of the uterus

✔ Submucosal - just under the surface of the uterine lining

✔ Subserosal - just under the outside covering of the uterus

✔ Pendunculated - occurring on a long stalk on the outside of the uterus or inside the cavity of the uterus

Called DIFFUSE uterine leiomyomatosis - when there are too many fibroids to count.

Diagnosis

Diagnosis can be wrong - pelvic examination may show an irregularly shaped, lumpy, or enlarged uterus, but in obese women it is difficult to diagnose fibroids, which may be mistaken for:

✔ Pregnancy

✔ Ovarian tumors

✔ Inflammation of the fallopian tubes

✔  Uterine adenomyosis (a condition in which the uterine lining grows into the muscle wall of the uterus)

 

Fibroids can be confirmed - by a transvaginal ultrasound, ar pelvic ultrasound or a pelvic MRI.

Who gets Uterine Fibroids (UFs)?

UFs are the most common pelvic tumor in females, typically found during the mid- to late-reproductive years

–   Uterine fibroid incidence rate is 70% by age 50 in U.S. white women and 80% in African-American women - with a staggering half of reproductive age U.S. women having fibroids. Typically affects women over 30, but not under 20;

Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in balack and white women: ultrasound evidence. Am J Obstet Gynecol 2003; 188: 100-107

–   More common in African-American women than Caucasian women - ~25% of white women and 50% of black women have symptomatic uterine fibroids.

Wise, L., Palmer, J., Bernard, H., Stewart, E., Rosenberg, L., (2005) Age-Specific Incidence rates for Self-Reported Uterine Leiomyomata in the Black Women's Health Study Obstet Gynecol 105(3): 563-568

–   More common in overweight women - perhaps because of increased estrogen from adipose aromatase enzyme activity that converts the androgens ANDROSTENEDIONE and Testosterone to estrogens

 

–   UFs often have a growth spurt before menopause –and then become quiescent

–   Higher UF incidence in women who have not given birth or had early menarche or have a UF history in first degree relatives

–   Smokers have LESS risk of UFs

–   Physical activity seems to protect against having UFs

Flake GP, Andersen J, Dixon D.Review Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health Perspect. Environ Health Perspect. 2003 Jun; 111(8):1037-54. PubMed

Baird DD, et al. (2007) Association of physical activity with development of uterine leiomyoma. Am. J. Epidemiol. (2007) 165 (2): 157-163. Study

Properties / Causes of Uterine Fibroids (UFs)?

During a woman's menstruating years, UFs typically continue to grow slowly

Large fibroids may outgrow their blood supply and degenerate - described as hyaline, myxomatous, calcific, cystic, fatty, red (usually only during pregnancy), or necrotic.

Fibroid growth seems to depend on both estrogen and Progesteronehormones:

 

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

–   Fibroid cells can make their own estrogen and have more estrogen and Progesteronereceptors (to respond to these hormones) than normal uterine muscle cells

–    Progesteroneseems to have a dominant role by INCREASING mitotic rates in fibroids in the secretory phase of the menstrual cycyle - The Progesteroneantagonist mifepristone INHIBITS fibroid growth lending support to the dominant role of Progesterone. One theory is that Progesteroneupregulates EGF and TGF-βexpression. However, Progesteronealso 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. 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 fall of Progesteronepostpartum.

–   Fibroids express higher levels of aromatase the enzyme which catalyzes conversion of androgens to estrogens.

Walker CL, Stewart EA Uterine fibroids: the elephant in the room. Science. June 10, 2005; 308.

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

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

ESTROGEN Dominance

–   Having estrogen receptors, fibroids tend to enlarge during the reproductive years and shrink after menopause

 

UFs have excessive production of disorganized but very stable extracellular matrix (ECM) / Altered collagen fibrils – collagen fibers are short, widely dispersed and lying non-parallel in fibroids, compared to well-packed and lying parallel in the myometrium. It is the abnormal and overproduced ECM that causes UF expansion , and not the slowly proliferating fibroid cells.UF tumors contain decreased/disrupted matrix metalloproteinases (MMPs) and more proteins in their ECM, such as collagen subtypes, proteoglycans, fibronectin, matrix glycoproteins and matricellular proteins (in particular thrombospondin-1 (TSP-1), which activates TGF- β and has a role in angiogenesis. The ECM binds cytokines and growth factors ready for action in the vicinity of the UF.

–   The stability of this allbeit disorganized ECM requires therapeutic interventions that address ECM dissolution in addition to inhibiting cell proliferation

UFs involve growth factors:

–   Transforming Growth Factors-β1 and β3 (TGF- β1,TGF- β3) - have a central role in UF enlargement, in that they stimulate production/deposition of ECM and are acknowledged as important growth factors in fibrotic disease. E.g. Fibroids have more concentrated TGF-βreceptors. Conversely, reduced TGF-βexpression yields reduced ECM production and fibroid shrinkage

–   Other growth factors acting on myometrial cells –  epidermal growth factor (EGF), Insulin-Like Growth Factor (IGF), platelet-dericed growth factor (PDGF), vascular endothelial growth factor (VEGF)

Increased profibrotic cytokines (E.g. IL-1, IL-6, interferon, Tumor Necrosis Factor-α(TNF- α)) - Cytokines involved with inflammatory response are changed in UFs, produced when growth factors act on target tissue

UFs grow at different rates even in the same woman and with different growth-rate patterns in white and African-American women

Integrins are changed in UFs

 

>50% of UFs are asymptomatic (i.e. have no symptoms) - ~70% of women by age 45 will be diagnosed with UFs, but only a fraction of those will cause problems or require treatment.

Merck Manual

Organochlorine pesticides stimulate leiomyomata cell proliferation in animals organochlorines are xenoestrogens that mimic estrogen in the body

Hodges LC, Bergerson JS, Hunter DS, Walker CL. Estrogenic effects of organochlorine pesticides on uterine leiomyoma cells in vitro. Toxicol Sci. 2000 Apr;54(2):355–364. PubMed

Symptomatic Uterine Fibroids

When fibroids are symptomatic, they can grow and cause:

✔ Heavy and painful menstruation; bleeding between periods; longer-lasing periods

✔ Painful sexual intercourse

✔ Urinary frequency and urgency

✔ Pelvic pain / pressure;

✔ Abdominal fullness, gas, constipation

✔ Pregnancy complications (rare) – increased blood flow and ESTROGEN levels during pregnancy may cause UFs to grow, but return to normal size after delivery. Insufficient room in uterus may require early delivery; C-section may be needed if UFs block birth canal or cause wrong positioning of baby; may cause heavy bleeding immediately after giving birth.

Other complications of fibroids include:

✔ A pedunculated fibroid can become twisted and cause a kink in the blood vessels feeding the tumor - may need surgery;

✔ Anemia - may be severe with heavy bleeding

✔ Urinary tract infections - pressure from the fibroid can prevent bladder emptying fully;

✔ Malignant change (extremely uncommon) - called a leiomyosarcoma

✔ Infertility (rare)

Generally accepted effects of Estrogen and Progesteronein UFs

Estrogen and Progesteronehave the following effects:

 

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).

It is believed that:

✔ Estrogen is growth-promoting by up-regulating IGF-1, EGFR, TGF-β1;

✔ Progesteroneis thought to promote the growth of leiomyoma via up-regulation of EGF, TGF-β1 and TGF-β3

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

✔ Progesteroneis thought to counteract growth of leiomyoma by downregulating IGF-1.

✔ Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium - TGIF is a potential repressor of anti-proliferative TGF-β pathways in myometrial cells.

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

P53:

▪Increases expression of the anti-apoptotic factor PCP4

▪Antagonizes PPAR-gamma signaling

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

–   Other hormones

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

In PREmenopausal fibroids the  ER-ß, ER-α and Progesteronereceptors are found over-expressed – compared to only ER-ß in POSTmenopausal fibroids (which are rare)

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

–    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, 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

Aromatase and 17ß-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids - indicating that fibroids can convert circulating androstenedione into ESTRADIOL

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

–    Aromatase over-expression in uterine leiomyoma tissue is particularly pronounced in African-American women

Ishikawa, H.; Reierstad, S.; Demura, M.; Rademaker, A. W.; Kasai, T.; Inoue, M.; Usui, H.; Shozu, M. et al. (2009). "High Aromatase Expression in Uterine Leiomyoma Tissues of African-American Women". Journal of Clinical Endocrinology & Metabolism 94 (5): 1752.

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

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