Uterine Fibroids (UFs)?

(a.k.a. Uterine leiomyoma, myoma, fibromyoma, leiofibromyoma, fibroleiomyoma, and fibroma)

• Mainstream methods for treating uterine fibroids
• Alternative for treating uterine fibroids

What are Uterine Fibroids (UFs)?

Uterine fibroids are BENIGN i.e. non-cancerous), usually clusters of TUMORS in, on or within the uterine walls

Originate from and are composed of SMOOTH MUSCLE cells (myocytes) of the uterine wall's muscle layer (called the myometrium, the middle layer of the uterine wall used for contracting the uterus) and its accompanying connective tissue;

• It is RARE for benign uterine leiomyomas to progress to cancerous 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 of uterine fibroids

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, a pelvic ultrasound or a pelvic MRI.

Who gets uterine fibroids?

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 et al, 2003)
• More common in African-American women than Caucasian women - ~25% of white women and 50% of black women have symptomatic uterine fibroids. (Wise, 2005)
• 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 (Baird et al, 2007) (Flake et al, 2003)

What are the symptoms of uterine fibroids?

Not all UFs are symptomatic, but those that are can grow, causing:

• 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 rare) - called a leiomyosarcoma
• Infertility (rare)

What causes uterine fibroids?

Hormonal influences and growth factors are involved in UF growth and development:

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, necrotic or red (usually only during pregnancy).

Fibroid growth seems to depend on both estrogen and Progesterone hormones

Effects of Estrogen and Progesterone in Uterine FIbroids

UFs have altered collagen fibers

• UFs have excessive production of a disorganized but stable extracellular matrix (ECM) and altered collagen fibrils in the ECM - fibroid collagen fibers (bunches of fibrils) are short, widely dispersed and lying non-parallel, compared to well-packed and lying parallel in the myometrium (smooth muscle tissue of the uterus).
• 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. Integrins are changed in UFs.    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-β receptors. Conversely, reduced TGF-β expression yields reduced ECM production and fibroid shrinkage

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

• Increased profibrotic cytokines (E.g. IL-1, IL-6, interferon, TNF- α)  in UFs -  involved with inflammatory response, cytokines are 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

• >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 (i.e. mimic estrogen in the body). (Hodges et al, 2000)

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

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

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:

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

It is proposed 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

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

Mainstream treatments for symptomatic uterine fibroids

Or find: Alternative treatments for uterine fibroids

General Treatments

• Oral contraceptives - to help control heavy periods
• Intrauterine devices (IUDs) that release the synthetic hormone progestin - to help reduce heavy bleeding and pain
• Iron supplements - to prevent or treat anemia due to heavy periods
• Nonsteroidal anti-inflammatory drugs (NSAIDs) - E.g.ibuprofen for cramps or pain

Surgical Treatments

• A hysterectomy is frequently advised in the U.S. - especially if a woman does not intend to have children. In fact, leiomyoma are the predominant reason for a hysterectomy in premenopausal women (MerckManual)
• Myomectomy - This surgery removes the fibroids. It is often the chosen treatment for women who want to have children, because it usually can preserve fertility. More fibroids can develop after a myomectomy.
• Magnetic Resonance-Guided Focused Ultrasound - Magnetic Resonance guided Focused Ultrasound (MRgFUS), is a non-invasive intervention (requiring no incision) that uses high intensity focused ultrasound (HIFU) waves to ablate (destroy) tissue in combination with Magnetic Resonance Imaging (MRI), which guides and monitors the treatment.
• Hysteroscopic resection of fibroids(as outpatient) - when UFs are growing inside the uterus. A small camera/instruments are inserted through the cervix into the uterus to remove the UFs.
• Uterine artery embolization - procedure cuts off blood supply to the UF, causing it to die and shrink.

Anti-fibrotic therapies inhibit and reverse the fibrotic process

Affect a change in abnormal ECM by leiomyoma cells

• •  GONADOTROPIN-RELEASING HORMONE analogues
• •  Small studies indicate Progesterone receptor antagonists decrease uterine fibroid size
  •  Full Progesteronereceptor antagonist - Mifepristone (aka RU-486) was effective in a placebo-controlled pilot study. (Malartic et al, 2008)
  • Selective Progesterone receptor modulators - such as Progenta and Asoprisnil, have been under investigation; (Wilkens et al, 2009)

Malartic, C.; Morel, O.; Akerman, G.; Tulpin, L.; Desfeux, P.; Barranger, E. (2008). "La mifépristone dans la prise en charge des fibromes utérins". Gynécologie Obstétrique & Fertilité 36: 668.

Wilkens, J; Williams, AR; Chwalisz, K; Han, C; Cameron, IT; Critchley, HO (2009). "Effect of asoprisnil on uterine proliferation markers and endometrial expression of the tumour suppressor gene, PTEN". Human reproduction (Oxford, England) 24(5): 1036-44 PubMed

Alternative methods to treat uterine fibroids

Anti-estrogen therapies

High levels of estrogen are considered an element of uterine fibroids

There are various tactics to use to improve estrogen balance in the body:

How to reduce estrogen in the body

• Aromatase inhibitors used to reduce fibroids (Malartic, 2008) - The effect is believed to be partially due to (i) Lowering ovarian production and systemic estrogen levels and (ii) Inhibiting locally overexpressed aromatase in fibroids.  Aromatase inhibitors have also been used experimentally in treatment of endometriosis - which indicated that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.
• Phytoestrogens - compete for receptors with endogenous estrogens; isoflavones daidzein and genistein are found in soy, but have been found to worsen fibroids when consumed in too high amounts. Lignans found in flaxseed.
• I3C in cruciferous vegetables - promotes formation of less potent estrogen metabolites (Minich & Bland, 2007)
• Reduce caffeine intake - to <500 mg / day (e.g.  2 cups coffee / day)
• Reduce alcohol consumption to 1 drink / day
• Increase fiber - helps remove excess estrogen from GI tract aiding excretion; reduces enterohepatic estrogen recirculation and/or shields estrogen absorption;
• Consume anti-inflammatory omega-3 fats and reduce inflammatory omega-6 fats  to reduce estrogen production
•  Iodine has a critical role in maintaining the body's estrogen balance and can reduce uterine fibroids.  Based on a controlled clinical trial with 1,365 women, 4mg daily of molecular iodine quickly resolves fibrocystic breast disease(FBD) - Iodine makes breast lumps and cysts disappear usually within only two months for most women. Iodine can similarly reduce uterine fibroids - one of the first conventional medical treatments for severe fibroids was to "paint"the uterus with iodine.

The primary aromatase promoter in leiomyomata tissues in non-Asian U.S. women is the inflammatory prostaglandin PGE2 (Imir et al, 2007)

Omega-3 fat reduces release of growth hormone - which promotes formation / growth of fibroids

Myoma is associated with beef and ham consumption, whereas high intake of green vegetables seems to have a protective effect (Chiaffarino et al, 1999)

 

Iodine -"The Universal Medicine"

Vitamin D3 decreases fibroid cell size and disrupts the formation of fibroid muscle cells

Vitamin D3 is typically deficient in many populations today - E.g. Elderly, office workers, African Americans

• D3 treatment has been shown to inhibit leiomyocyte proliferation at physiological doses - Leiomyomas widely express the vitamin D receptor.
• Vitamin D decreases mitogenic activity of INSULIN and IGF-1
• Active metabolites of CALCITRIOL (Active form of Vitamin D) down-regulate epidermal growth factor receptors (EGFRs) known to be active in mitogenic pathways in uterine leiomyomas. Down-regulation of these receptors shown to decrease growth / differentiation of tumor cells
• Risk of developing uterine fibroids in American black women REDUCED with just increased daily servings of "vitamin D-added" milk.
• Research shows that physiological doses of vitamin D have significant growth-inhibiting effect on leiomyomata cells (Blauer et al, 2009)

Vitamin D - "The Sunshine Vitamin"

Bioflavonoids reduce risk of malignant tumors

There is an inverse association between bioflavonoid intake and risk of malignant tumors - reported biological activities include:

• Induce apoptosis
• Cell cycle arrest
• Antiproliferative
• Anti-inflammatory
• Antioxidant protection against oxidative stress
• Anti-estrogenic

Asian women consume a lot of bioflavonoids and have lower incidence of hormonally dependent solid tumors - E.g. breast cancer in Asian women is 4-6 times lower than in American women, and several generations after migration to America they line up with the American statistics, suggesting an environmental rather than a genetic influence. Asian women consume a lot of soy-based foods, containing bioflavonoids that show up in blood and urine samples at significantly elevated levels.

"Bioflavonoids are . . . found in legumes, nuts, onions, apple, broccoli, red wine, grreen tea, cocoa powder, and dark chocolate. The best known anti-tumor flavonoids are epigallocatechin gallate (EGCG) from green tea, genistein (from soy and red clover), curcumin (from turmeric), silibin (from milk thistle), quercetin (from many yellow vegetables such as onions), and resveratrol (from grapes and red wine)."

-    James H. Segars, author of the book Fibroids

Quercetin, EGCG, Curcumin, Silibrinin - (In berries, tea, grapes, olive oil, dark chocolate, walnuts, citrus):

• Inhibits IGF-1 signaling
• Anti-estrogenic - Estrogen receptor antagonist
• Alters cell cycle

Resveratrol (In red wine, grape, berries, dark chocolate, also peanuts (not recommended because of common fungal content); produced in plants in response to injury or fungal/ bacterial presence)

• Induces apoptosis
• Anti-estrogenic -Weak estrogen receptor agonist / antagonist
• Decreases collagen production

Resveratrol study-reported properties include:

• Anti-proliferative - mainly as a preventative; Decreases growth and increases death of fibroid cells in vitro;
• Cardio-protective
• Anti-diabetic
• Neuroprotective -possibly by chelating copper
• Reduces opioid tolerance -by increasing NMDA receptors
• Anti-inflammatory
• Antiviral activity

Curcumin (spice) - decreases growth and increases death of fibroid cells in vitro. Curcumin inhibited uterine leiomyoma cell proliferation by inducing apoptosis, and inhibited production of the ECM component fibronectin. (Malik et al, 2009; Kenji et al, 2011; )

Licorice (contains flavonoid isoliquiritigenin) - decreases growth and increases apoptosis of fibroid cells in vitro.

Green Tea (epigallocatechin gallate) - decreases growth of fibroid cells in vitro.

Retinoic acid

GI tract health strongly linked to uterine fibroid growth

Gastrointestinal problems (e.g. leaky gut syndrome, candida (yeast), intestinal bacterial overgrowth and gut inflammation) can indirectly lead to:

• Abnormal growth factor expression
• Excess estrogen
• Immune dysfunction.
• Toxic heavy metals can lead to abnormal bacterial growth in the gut and breakdown of the mucosal lining in the intestines. (Nikolaus, 2011)

Female support herbs

There is supportive evidence that vitex, yarrow and capsella buras-pastoris can reduce menstrual bleeding and PMS symptoms.

Vitex agnus-castus (Vitex, Chaste Tree, Chasteberry)

• Typical extract doses significantly inhibit PROLACTIN secretion - (basal and TRH-stimulated) - presumed to be via dopaminergic effects. At low doses, such as might have been used in previous centuries for suppression of sexual desire, it inhibits activation of DOPAMINE 2 receptor by competitive binding, causing a slight increase ▲  in release of PROLACTIN. In higher concentrations, as in modern extracts, the binding activity is sufficient to reduce ▼  the release of PROLACTIN. A study found that treatment of 20 healthy men with higher doses of Vitex agnus-castus was associated with a slight reduction of PROLACTIN levels, whereas lower doses caused a slight increase as compared to doses of placebo. (Merz et al, 1996)

  • A decrease of PROLACTIN influences levels of FOLLICLE-STIMULATING HORMONE (FSH) and estrogen in women, and Testosterone in men.

  • Chemical analysis of vitex agnus-castus has isolated the following compounds - flavonoids, alkaloids, diterpenoids, Vitexin, Casticin and steroidal hormone precursors, some of which are believed to affect the pituitary gland explaining its effects on hormone levels.

Blauer M, Rovio PH, Ylikomi T, Heinonen PK. (May 2009) Vitamin D inhibits mypmetrial and leimyoma cell proliferation in vitro. Fertility and Sterility. 91(5):1919-1925

Chiaffarino et al (Oct 1999) Diet and Uterine Myomas, Obstetrics and Gynecology 94(3):395-8  PubMed

Imir AG, Lin Z, Yin P, et al, (May 2007) Aromatase expression in uterine leiomyomata is regulated primarily by proximal promotors 1.3/II/. J. Clin Endocrinol Metab.; 92(5):1979-1982.

Malartic, C.; Morel, O.; Akerman, G.; Tulpin, L.; Desfeux, P.; Barranger, E. (2008). "La mifépristone dans la prise en charge des fibromes utérins". Gynécologie Obstétrique & Fertilité 36: 668.Link

Malik M , Mendoza M Payson M,  Catherino W.H. (May 2009) Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression Fertility and Sterility. Volume 91, Issue 5, Supplement , Pages 2177-2184, Abstract

Merz, PG; Gorkow C, Schrödter A, Rietbrock S, Sieder C, Loew D, Dericks-Tan JS, Taubert HD (1996). "The effects of a special Agnus castus extract (BP1095E1) on prolactin secretion in healthy male subjects". Exp Clin Endocrinol Diabetes 04 (6): 447-53. Link

Minich DM, Bland JS (June 2007) A Review of the clinical efficacy and safety of cruciferous vegeatable phytochemicals. Nutrition Revei ws.; 65(6):259-267.

Kenji Tsuiji et al (July 2011) Inhibitory effect of curcumin on uterine leiomyoma cell proliferation.Gyn. Endocrinolgy, Vol. 27, No. 7 , Pages 512-517 Abstract

Nikolas Hedberg (2011) Renew Your Health Naturally  Link

 

References

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

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

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

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. PubMed

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

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