Uterine Fibroids

Uterine Fibroids

1 Overview

Summary and Quick Facts

  • Uterine fibroids are abnormal growths of the uterus that can cause symptoms like pelvic pain and prolonged menstrual bleeding. Importantly, fibroids are not cancer, and they typically do not become cancerous. In fact, most women will have some uterine fibroids at some point in their lives and experience little to no symptoms.
  • This protocol covers causes of and conventional treatments of uterine fibroids, as well as dietary and lifestyle considerations associated with lower fibroid risk and what emerging medical approaches appear promising. Several dietary supplements that may compliment conventional treatments are covered, as well.
  • Strategies in this protocol, in conjunction with appropriate medically supervised treatment, can provide a comprehensive approach to ensure uterine health.
  • Green tea has been shown in clinical trials to help ease symptoms associated with fibroids, and low vitamin D levels have been linked to fibroids in several observational studies.

Uterine fibroids are noncancerous growths of the smooth muscle within the uterine wall. They are the most common benign pelvic tumor in women. Up to 75% of women will have uterine fibroids at some point during their lives, with the majority causing no symptoms and occurring during the reproductive years. Fortunately, natural integrative interventions such as green tea may help ease symptoms associated with fibroids.

Risk Factors for Uterine Fibroids

  • Higher estrogen and progesterone levels
  • Higher body weight and body mass index (BMI)
  • Ethnicity (African-American women have a 3-fold greater risk as compared to Caucasian women)
  • Women with a first-degree relative with uterine fibroids have a 2.5-fold increased chance of developing fibroids themselves

Symptoms Associated with Uterine Fibroids

Uterine fibroids often do not cause noticeable signs or symptoms, but may present with the following:

  • Heavy, prolonged menstrual bleeding
  • Pelvic pain or fullness
  • Increased urinary frequency or incontinence

Conventional Medical Treatments

For fibroids that require intervention, treatment can be approached medically or surgically.

  • Drugs (gonadotropin-releasing hormone agonists, anti-progestogen therapy, tranexamic acid, non-steroidal anti-inflammatory drugs [NSAIDs])
  • Minimally-invasive procedures (uterine artery embolization, endometrial ablation, and magnetic resonance-guided focused ultrasound surgery)
  • Surgical procedures (hysterectomy and myomectomy)

Note: A surgical procedure known as uterine power morcellation involves shredding uterine tissue into smaller pieces so that it may be removed through laparoscopic surgery. Life Extension reported on the dangers of this procedure in its July 2014 issue and on the FDA’s lack of oversight and insufficient protection of women from this procedure.

Natural Therapies for Uterine Fibroids

Lifestyle and Dietary Changes:

  • Consume greater quantities of vegetables, fruits, and dairy products with an emphasis on lower glycemic index foods
  • Exercise at least seven hours per week

Integrative Interventions:

  • Green Tea and EGCG: Epigallocatechin gallate (EGCG), a polyphenol found in green tea, was found to significantly reduce fibroid volume and symptoms.
  • Vitamin D: Women with lower serum levels of vitamin D are more likely to develop uterine fibroids.
  • Curcumin: Curcumin has been shown to inhibit fibroid cell growth.
  • Cimicifuga racemosa (Black Cohosh) Extract: Black cohosh has been found to help decrease fibroid size in women with menopausal symptoms and fibroids.

2 Introduction

Uterine fibroids, also called uterine leiomyomas, are noncancerous growths of the uterus. They are the most common benign pelvic tumor in women (Eltoukhi 2014; Bulun 2013; Mitwally 2013; Mayo Clinic 2014a; Stine 2014; Hodge 2007). Although very controversial, with some sources stating definitively that uterine fibroids do not transform into cancer, other data suggest a very rare risk for transformation (Clement 1993).

In a US study with women age 35 to 49 years, the incidence of uterine fibroids by age 35 was 60% among African-American women, increasing to greater than 80% by age 50, whereas Caucasian women showed an incidence of 40% by age 35 and almost 70% by age 50 (Day Baird 2003). Up to 75% of women will have uterine fibroids at some point during their lives, though they often do not cause symptoms (Ferri 2014; Mayo Clinic 2014a).

Symptoms associated with uterine fibroids include heavy, prolonged menstrual bleeding; pelvic pain, pressure, or fullness; frequent urination or incontinence; constipation; infertility; and back or leg pain (Mayo Clinic 2014a; Khan 2014).

Uterine Fibroid  

Fibroids can vary in size, number, and location. There are multiple types of uterine fibroids, each characterized based on their location (Mayo Clinic 2014a):

  • intramural fibroids grow within the muscular wall of the uterus
  • submucosal fibroids grow toward and into the uterine cavity from the uterine wall
  • subserosal fibroids grow toward the outside of the uterus
  • cervical fibroids are located in the cervix of the uterus (Mitwally 2013)

Treatment of uterine fibroids is often dependent on a woman’s symptoms and desire to maintain fertility. Conventional treatment options include gonadotropin-releasing hormone agonists, which temporarily stop the menstrual cycle and help decrease fibroid size; estrogen/progestin hormone therapy when control of excessive bleeding is a primary concern; minimally invasive surgical treatment such as myomectomy to remove fibroids; uterine artery embolization to disrupt blood supply to the fibroid; and surgical procedures such as hysterectomy (removal of the uterus) (Evans 2007). Uterine fibroids are a common indication for hysterectomy, and approximately one-third of hysterectomies in the United States are performed because of symptomatic fibroids (Elsevier BV 2011).  

Uterine power morcellation, which can be performed as part of a laparoscopic hysterectomy, is a procedure in which a woman’s uterus is shredded into small pieces using an electrically powered device and then removed through a small incision in her abdomen. Although this approach is less surgically invasive than the traditional abdominal hysterectomy, little-appreciated until recently is the risk for distribution of occult, cancerous uterine tissue throughout the abdominal cavity as a direct result of the procedure. During the surgical shredding process, small pieces of uterine tissue can be dispersed into the abdominal cavity. While this does not cause problems in most cases, one in 350 women with fibroids has a fibroid tumor that harbors undetected malignant tissue (ie, leiomyosarcoma) at the time of the operation. The surgical shredding can spread leiomyosarcoma cells in the abdominal cavity, which can result in the dissemination of this aggressive form of cancer (Park 2011). In light of these revelations, in mid-2014 the US Food and Drug Administration (FDA) warned against the use of uterine power morcellation procedures (FDA 2014a), and some insurers stopped covering the cost of these operations (Reuters 2014b). The July 2014 issue of Life Extension magazine contains a detailed exposé of the dangers of these potentially deadly procedures along with an account of the diligent work of Dr. Hooman Noorchashm of Harvard Medical School and Brigham and Women’s Hospital and his wife, Dr. Amy Reed, who developed a rare form of uterine cancer after undergoing uterine power morcellation. Drs. Noorchashm and Reed relentlessly campaigned to bring the shortcomings of power morcellation to light, and as a result some medical centers have modified their positions on uterine power morcellation.

In this protocol you will learn about causes of uterine fibroids, how they develop, and how they are conventionally treated. You will discover several novel and emerging treatment approaches that may improve outcomes for women with fibroids. Also, we will review a number of dietary and lifestyle considerations that may help prevent uterine fibroids. Additionally, we will explore integrative and natural approaches to fibroids, such as the ability of green tea extract to significantly reduce the size of fibroids as well as the severity of fibroid symptoms.

3 Background

Uterine fibroids are derived from smooth muscle within the uterine wall (Mitwally 2013). Fibroids may also be located in the cervix; the broad ligament, which connects the uterus to the pelvic wall; or can be attached to the interior or exterior of the uterus by a stalk, in which case they are called pedunculated leiomyomas. In some cases, fibroids may develop in other abdominal structures; these are called parasitic leiomyomas (Ferri 2014; Phupong 2003; Jebunnaher 2013). Women can have a single fibroid or multiple fibroids of different sizes and in different locations (Elsevier BV 2011).

The exact cause of uterine fibroids is not completely understood. However, the sex hormones estrogen and progesterone play an important role in fibroid growth (Mitwally 2013). Estrogen and progesterone control the growth of the uterine lining (endometrium) during a woman’s reproductive cycle and help prepare the uterus for pregnancy (Goldsmith 2009). The incidence of fibroids fluctuates throughout different hormonal phases of a woman’s life, with the majority occurring during reproductive years (Ciavattini 2013). Some, but not all, studies have found that high estrogen levels and increased blood flow during pregnancy can cause existing fibroids to enlarge (Ferri 2014; UMMC 2014). This effect may depend on the trimester of pregnancy and size of the fibroids, though one study found no change in fibroid size for most women during pregnancy. In that study, the fibroids that did enlarge grew less than 25% (Lev-Toaff 1987; Aharoni 1988). After menopause, when hormone levels decline, existing fibroids often decrease in size (Elsevier BV 2011).

Compared with surrounding normal tissue, fibroids contain higher levels of receptors for progesterone and estrogen and are more responsive to hormonal stimulation. Estradiol, a type of estrogen, promotes fibroid cell replication, while progesterone blocks fibroid cell death. These combined effects can result in growth of fibroid tissue (Elsevier BV 2011). Moreover, fibroid tissue has higher levels of the enzyme aromatase, which converts testosterone into estrogen, compared with healthy uterine tissue. This may lead to higher levels of estrogen in the fibroid tissue, which may further stimulate fibroid growth (Ishikawa 2006; Bulun 2013; Ishikawa 2009).

4 Risk Factors

Body Weight

Women who weigh more than 154 pounds have three times the risk of developing fibroids than women weighing less than 110 pounds (Elsevier BV 2011). In one study, women with fibroids were significantly more likely to have a higher body mass index compared to women without uterine fibroids (He 2013). Fat tissue converts testosterone into estrogen, and obesity can lead to decreased levels of a protein called sex hormone binding globulin that binds to estrogen and progesterone, resulting in more unbound (active) hormones. These combined effects result in more estrogen and progesterone within the uterus, which may lead to fibroid development (Wise 2005; Sam 2007; Ciavattini 2013).

Ethnicity

African-American women have an approximately 3-fold greater risk of developing fibroids than Caucasian women (Elsevier BV 2011). Although the precise reasons for this are unclear, increased levels of the aromatase enzyme in fibroid tissue itself may contribute; fibroid tissue from African-American women has been shown to contain higher aromatase levels than fibroid tissue from Caucasian and Japanese women (Ciavattini 2013; Bulun 2013; Ishikawa 2009).

Family History and Genetics

There is considerable evidence that heredity may be involved in some cases of uterine fibroids (Ligon 2001). Women who have a first-degree relative with uterine fibroids have a 2.5-fold increased chance of developing fibroids (Elsevier BV 2011). Also, identical twins are more likely to have fibroids than non-identical twins (Mayo Clinic 2014a).

Dietary Habits and Alcohol

There is some evidence suggesting a correlation between uterine fibroid development and dietary habits. Women who eat more red meat, drink more alcohol, and eat fewer vegetables and fruits have a significantly higher chance of developing fibroids (Mayo Clinic 2014a; Chiaffarino 1999; He 2013; Nagata 2001). Among African-American women, long-term alcohol consumption has been associated with an increased risk of fibroids (Wise 2004).

High Blood Pressure

A study of over 104 000 women reported that for every 10 mm Hg increase in diastolic blood pressure, the risk of fibroid development increased an average of 8-10%. It is hypothesized that this increase may be caused by the release of cytokines in the smooth muscle of the uterus (Boynton-Jarrett 2005; Elsevier BV 2011).

Other Risk Factors

Other factors associated with an increased risk of fibroid growth include first menstruation before 10 years of age, not having children, polycystic ovary syndrome, diabetes, and being over 40 years of age (Ciavattini 2013; Elsevier BV 2011; Islam 2013). Fibroids are associated with a group of conditions – diabetes, obesity, hypertension, and polycystic ovary syndrome – that are also associated with metabolic syndrome. Metabolic syndrome and the aforementioned conditions are often associated with insulin resistance and abnormal glucose metabolism. This connection is also suggested by evidence presented elsewhere in this protocol, as fibroids appear to respond to the antidiabetic, insulin-sensitizing drug metformin; are associated with excessive carbohydrate consumption; and respond to exercise. Many, but not all, researchers investigating this association have confirmed a relationship between abnormal glucose metabolism and uterine fibroids (Wise 2007; Kong 2014; Takeda 2008; Sadlonova 2008; Ekpo 2013).

5 Signs and Symptoms

Uterine fibroids oftentimes do not cause noticeable signs or symptoms (Mitwally 2013). However, fibroids can cause pain, pressure, and a significant reduction in quality of life (Bulun 2013; Zimmermann 2012). Symptoms are generally dependent on the number, location, and size of fibroids (Mayo Clinic 2014a). On rare occasions, extremely large fibroids have been known to cause the uterus to expand to a size similar to that of the sixth or seventh month of pregnancy (Bulun 2013).

The most frequently reported symptom of uterine fibroids is increased and prolonged menstruation, that is, heavy bleeding and bleeding outside of the normal menstrual cycle (Gonsalves 2008; Mayo Clinic 2014a; Ferri 2014; Zimmermann 2012). Other possible fibroid symptoms include pelvic pain or pressure, leg or back pain, painful intercourse, increased urinary frequency or incontinence, and constipation. Infertility or pregnancy complications, including miscarriage, are also possible (Zimmermann 2012; Gonsalves 2008; Mitwally 2013).

Symptoms can also vary according to the location of the fibroid. Submucosal fibroids grow toward and into the inner uterine cavity from the uterine wall and often cause heavy menstrual bleeding or fertility problems. Subserosal fibroids grow toward the outside of the uterus and may cause urinary problems, rectal pressure, or backache as a result of pressure on related structures. Intramural fibroids grow within the muscular wall of the uterus, potentially leading to heavy, prolonged periods; pain; and pressure (Mayo Clinic 2014a). 

Less common complications of uterine fibroids include fluid accumulation in the abdominal cavity (ascites), slow blood flow in the veins of the legs, or rarely, transformation to a cancerous uterine sarcoma (Ferri 2014; Khan 2014; ACS 2014a).

6 Diagnosis

A physician may suspect the presence of uterine fibroids if a patient has sensations of pelvic fullness, increased or extended menstrual bleeding, or is experiencing infertility. Sometimes fibroids are diagnosed during routine pelvic examinations (Elsevier BV 2011). In order to confirm the presence of uterine fibroids, physicians generally use one or more diagnostic procedures.

Ultrasonography

Ultrasonography (ultrasound) is the most frequently used diagnostic tool for fibroids because of its availability and relative low cost. However, the accuracy and diagnostic capability of ultrasonography is highly dependent on the technician performing the scan, and the images that ultrasonography provides are not as consistently reproducible as those of magnetic resonance imaging (MRI). Ultrasonography can be performed transabdominally or transvaginally; accuracy is improved when both are performed. Transvaginal ultrasound is able to detect smaller fibroids than transabdominal scans. A skilled technician can detect fibroids as small as 5 mm with transvaginal ultrasonography (Khan 2014).

Magnetic Resonance Imaging

MRI is often used as a second diagnostic option if the physician is uncertain about the type of pelvic mass a patient has. MRI is a more costly procedure than ultrasonography; however, it is more sensitive, with the ability to detect fibroids in 88-93% of patients. Also, the scan is better able to distinguish between submucosal, intramural, and subserosal fibroids, which is important for making future treatment decisions (Khan 2014; Mitwally 2013). 

Saline Infusion Sonohysterography

Saline infusion sonohysterography is occasionally used for diagnostic purposes to supplement either ultrasonography or MRI. In this procedure, sterile saline is injected into the uterus to expand it, allowing clearer images of uterine growths, which are obtained by ultrasonography (ACOG 2004). The quality of the images is dependent on the amount of uterine expansion and therefore, the amount of associated discomfort the patient can tolerate (Khan 2014). This test may be used if a woman has excessive menstrual bleeding or if ultrasonography tests are normal (Mayo Clinic 2014a).

Hysteroscopy

Hysteroscopy is performed by inserting a small, lighted instrument called a laparoscope into the uterus for direct visualization. The physician then injects saline or carbon dioxide gas into the uterus to allow expansion and examination through the laparoscope (Mayo Clinic 2014a). Hysteroscopy can be diagnostic and/or surgical, as a biopsy can be performed, and some fibroids can be surgically removed during the procedure (Ferri 2014; UMMC 2014; ASRM 2012a; A.D.A.M. 2012; ACOG 2011). 

Additional Tests

Excessive bleeding caused by fibroids may result in iron-deficiency anemia (Elsevier BV 2011). Symptoms of iron-deficiency anemia include fatigue, pale skin, weakness, shortness of breath, chest pain, headache, and dizziness (Mayo Clinic 2014b). A physician may request a complete blood count (CBC) to analyze the number of red blood cells (Elsevier BV 2011). 

If uterine fibroids are causing significant urinary symptoms, doctors may also perform tests to examine a patient’s urinary system. Other tests may include a pregnancy test, cervical Pap smear, erythrocyte sedimentation rate, and fecal occult blood test (Ferri 2014).

7 Conventional Treatment

Many women do not need treatment for uterine fibroids because their fibroids do not cause any noticeable symptoms. For fibroids that require intervention, treatment can be approached medically or surgically (Mitwally 2013).

Medical Treatments

Gonadotropin-releasing hormone agonists. Gonadotropin-releasing hormone (GnRH) agonists such as leuprolide (Lupron) and nafarelin (Synarel) are non-surgical options to treat uterine fibroids (Doherty 2014). They inhibit the production of estrogen and progesterone, resulting in a decrease in fibroid size (Mayo Clinic 2014a). GnRH agonists may be prescribed to shrink fibroids before a hysterectomy or myomectomy, as they appear to improve outcomes and may allow more patients to undergo a less invasive vaginal hysterectomy instead of an abdominal procedure (Lethaby 2001).

Side effects of GnRH agonists are similar to symptoms and complications that can accompany menopause: hot flashes, vaginal dryness, and bone loss (Islam 2013; Magon 2011). Because of this effect on bone, the FDA recommends that GnRH agonists should only be used for the short-term treatment of fibroids – less than six months (Doherty 2014; Gargiulo 1997). The effects of GnRH agonists are reversible, and fibroids tend to return to their pretreatment size approximately six months after drug discontinuation (Golan 1996; Mayo Clinic 2014a). 

Estrogen and progestin therapy. Estrogens and progestins (synthetic, progesterone-like drugs) are commonly combined in oral contraceptive pills. They are often a first-line therapy for patients with excessive bleeding symptoms associated with uterine fibroids; however, they do not reduce fibroid size. In fact, estrogens and progestins may stimulate fibroid growth. Therefore, oral contraceptives should be used with caution in patients with symptoms caused by large fibroids (Doherty 2014).

Tranexamic acid. Tranexamic acid (Lysteda) stabilizes blood clots and is frequently prescribed to prevent excessive menstrual bleeding in women with uterine fibroids who want to maintain fertility and are unable to take oral contraceptives (Doherty 2014; Kumsar 2011; Sweet 2012). It is a well-tolerated drug that works by causing blood clots to form in fibroids, which results in fibroid cell death and eventual fibroid regression. This can cause symptoms of pelvic pain, nausea, fatigue, and low-grade fever (Doherty 2014). 

Non-steroidal anti-inflammatory drugs. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Advil) or naproxen (Aleve), are commonly prescribed to reduce pain associated with fibroids (UMMC 2014). NSAIDs are also able to reduce menstrual bleeding by approximately 30-40% (Livshits 2010). Women who have heavy menstrual bleeding may have abnormal levels of prostaglandin in their endometrial tissue, and NSAIDs may mitigate uterine bleeding by modulating these prostaglandin levels (Smith 2007; Livshits 2010).

A review of 17 randomized, controlled trials found that NSAIDs were more effective than placebo but less effective than tranexamic acid at reducing excessive menstrual bleeding (Lethaby 2007). NSAIDs reported to be effective for heavy menstrual bleeding include ibuprofen, mefenamic acid (Ponstel), and naproxen (ARHP 2008).

Surgical Procedures

Hysterectomy. Hysterectomy is the surgical removal of the uterus, which can be performed abdominally, vaginally, or laparoscopically (Elsevier BV 2011). Approximately 15% of women who have uterine fibroids undergo hysterectomies (Ferri 2014). One study found that women who underwent hysterectomy reported greater improvements in subjective measures compared to women treated pharmacologically (Kuppermann 2004). 

In abdominal hysterectomy, the uterus is removed through a large incision in the abdomen (Mitwally 2013). In a vaginal hysterectomy, an incision is made in the vagina in order to access and remove the uterus. Compared with abdominal hysterectomy, women report less pain and better physical capability after vaginal hysterectomy (Silva-Filho 2006).

In laparoscopic hysterectomy, small incisions are made in the abdomen, and the uterus can be shredded using a process called power morcellation to allow extraction through the incisions (Nevarez Bernal 2012; Serur 2011). However, the use of power morcellation increases the risk of disseminating undetected (occult) cancer (Mitwally 2013; FDA 2014a; FDA 2014b; Nappi 2014; Della Badia 2010). Given the risks associated with power morcellation, women should discuss other options with their healthcare providers.

Surgical procedures that are less invasive than traditional abdominal hysterectomy and that do not involve power morcellation include minilaparotomy, laparoendoscopic single-site manual morcellation, and vaginal manual morcellation via culdotomy or colpotomy. In these procedures, physicians gain access to the uterus through relatively small incisions in the vagina or abdominal wall. If the target tissue needs to be cut into smaller pieces to be extracted, this can be accomplished manually with a scalpel. However, there is no strong evidence that clearly indicates so-called manual morcellation confers less risk for disseminating hidden cancer than power morcellation, yet the current FDA position only advises against power morcellation (AAGL 2014; FDA 2014b).

Oophorectomy – removal of the ovaries – is sometimes performed at the time of hysterectomy, though controversy exists over whether or not this relatively aggressive treatment is warranted in this context. This procedure may be indicated when there is a high risk of ovarian cancer or of certain types of breast cancer, but bilateral oophorectomy is performed in over 55% of women who undergo hysterectomy for uterine fibroids; a growing concern is the appropriateness of such aggressive treatment in the context of uterine fibroids. Fewer than 5% of women undergoing oophorectomy and hysterectomy actually meet the high-risk criteria for ovarian or breast cancer (Larson 2011; Hickey 2010; Shoupe 2007).

Hysterectomy prevents future menstruation and any chance of recurrent uterine fibroids. However, it also poses potentially serious risks, including damage to the bowel, bladder, or ureter; hemorrhage; infection; wound rupture; blood clots; and pulmonary embolism, a blockage of lung arteries (Khan 2014).

Removal of the ovaries causes an abrupt decline in sex hormones and disrupts the hypothalamic-pituitary-ovarian axis (Rocca 2009). This results in premature menopause, potentially causing symptoms of hot flashes, vaginal dryness, depression, anxiety, and decreased sex drive, and increased risk of heart disease, osteoporosis, and memory loss. These complications are usually treated with hormone replacement therapy (Mayo Clinic 2014c). Some evidence suggests that oophorectomy may do more harm than good (Parker 2014; Parker 2010; Shuster 2008; Rivera 2009). A 24-year follow-up study of over 29 000 women compared the outcomes of women who had either hysterectomies that preserved their ovaries or complete hysterectomies with oophorectomy. While oophorectomy decreased the risk of developing cancer of any kind, including breast cancer and of course ovarian cancer, an increased risk of myocardial infarction (heart attack), stroke, lung cancer, and death from cancer or any cause was noted (Parker 2009). Other studies have confirmed these risks, with one analysis showing that obesity may mediate some of the negative risks of oophorectomy (Duan 2012; Orozco 2014; McCarthy 2012; Parker 2013).

The Dangers of Uterine Power Morcellation

About 500 000 women undergo hysterectomy each year in the United States, making it one of the most common gynecological surgical procedures (CDC 2002; Gaba 2014).

Historically, removal of the uterus through an incision in the abdomen was the standard method of performing a hysterectomy (Baggish 2005; Fram 2013). In recent decades, however, laparoscopic hysterectomy has become increasingly popular (Salama 2013). A laparoscopic operation involves making only a few small holes in the patient’s abdominal wall through which fine surgical instruments are inserted to perform the operation. This approach is more appealing from a cosmetic perspective because it causes considerably less scarring than a traditional abdominal hysterectomy (Reich 1994). However, laparoscopic hysterectomy poses an important obstacle: how to remove the excised uterus from the patient’s abdominal cavity (Kho 2014).

The medical community overcame this barrier by developing a procedure called uterine power morcellation. Power morcellation involves shaving or shredding uterine tissue into smaller pieces that can be extracted with laparoscopic instruments. This procedure uses an electrically powered device to shred the tissue. Although power morcellation offers an effective means of removing the uterus without leaving a large scar, there is a risk of spreading occult/undetected cancerous tissue throughout the abdominal cavity.

During the uterine power morcellation procedure, small pieces of tissue and cellular debris can be spread through the abdominal cavity. If any malignant cells are present in the morcellated uterine tissue, deposition of tissue debris in the abdominal cavity during power morcellation can give rise to disseminated cancer, which has a very poor prognosis (Kho 2014; Park 2011).

Uterine fibroids are benign, but unsuspected uterine sarcoma is present in about one in 350 women undergoing surgery for fibroids (FDA 2014a). In these cases, cancer that was contained within the uterus, and which could have been removed completely via a vaginal or abdominal hysterectomy, may be spread to other parts of the body during power morcellation (Kho 2014; FDA 2014a; Mitwally 2013; Mayo Clinic 2014a; Song 2013).

In light of these findings, on April 17th, 2014 the FDA issued a statement discouraging the use of power morcellation procedures for the removal of uterine fibroids and hysterectomy (FDA 2014a).

Power morcellation runs the risk of other complications as well, including injury to nearby organs and dissemination of fragments of uterine fibroid tissue, which, even if not malignant, can deposit elsewhere in the body and cause problems. For example, if noncancerous fibroid cells are dispersed into the abdominal cavity during power morcellation, they may attach to another abdominal structure, acquire a blood supply, and form a parasitic leiomyoma (Milad 2014; Kho 2014; Takeda 2007; Jebunnaher 2013; Yoshida 2014).

Myomectomy. Myomectomy is the surgical removal of fibroids without removal of the uterus. This procedure may preserve fertility and improve pregnancy outcomes (Mayo Clinic 2013). It can be performed with an abdominal incision; laparoscopically, often with the use of power morcellation; and hysteroscopically, in which the surgical instruments are introduced through the vagina and cervix. The success of myomectomy in treating symptoms associated with fibroids depends on the number and extent of the fibroids. Women who undergo myomectomy have a 10-30% chance of recurrent fibroids within 5 years (Evans 2007; Fauconnier 2000; Rossetti 2001; Desai 2011; Mayo Clinic 2013). 

In rare circumstances, surgical blood loss cannot be controlled or other uterine problems are discovered during a myomectomy procedure, and the surgeon must perform a hysterectomy. Cesarean section deliveries are often performed on women who have had a myomectomy due to risk of complications during vaginal birth (Mayo Clinic 2013).

In abdominal myomectomy, fibroids are removed by making a large incision in the abdomen. Compared with abdominal hysterectomy, abdominal myomectomy is a longer procedure; however, patients typically have significantly less blood loss and, on average, shorter hospital stays (Khan 2014).

Hysteroscopic myomectomy of submucosal fibroids significantly improves the chance of becoming pregnant and decreases the risk of miscarriage. Possible complications include hemorrhage, uterine perforation, cervical laceration, uterine scars, and infertility (Khan 2014; Pritts 2009). 

Laparoscopic myomectomy removes fibroids that deform the uterine cavity, fibroids larger than 3 cm, and multiple fibroids (Desai 2011). While some authors suggest that laparoscopic myomectomy improves a woman’s chance of conceiving and having a successful delivery (Tinelli 2012), it carries risks including blood loss, problems with childbirth, and complications from tissue power morcellation (if the procedure is used) (Mayo Clinic 2013; Buckley 2014).

All three types of myomectomy may cause adhesions (bands of scar tissue), which could block the digestive system, cause abdominal or pelvic pain, or fertility problems. A survey of 414 gynecological surgeons reported that, of surgeries performed for benign conditions, myomectomy posed the second highest risk of adhesion formation behind surgery to treat endometriosis (Wallwiener 2014).

Minimally-Invasive Procedures

Uterine artery embolization. During uterine artery embolization (UAE), a catheter is inserted through the large femoral arteries in the groin and guided into the arteries that supply blood to the fibroid tissue. Chemicals that block blood flow, called embolic agents, are injected into the catheter. The embolic agents cut off the blood supply to the fibroids, causing cells to die and the fibroids to shrink in size (Evans 2007).

Compared to hysterectomy or myomectomy, UAE involves a shorter procedure time, hospital stay, and quicker return to normal activities (Mara 2006; Mara 2008). Complications from UAE can include blood collection outside of vessels (hematoma), bleeding, and infection; further surgeries are required after UAE in approximately 30% of cases (Doherty 2014; Gupta 2012). Post-embolization syndrome, which is characterized by pelvic pain, cramping, nausea, vomiting, fatigue, and mild fever affects most UAE patients, but usually resolves within 48 hours (Mitwally 2013; Doherty 2014). Many authorities do not recommend UAE for women who want to maintain fertility (Doherty 2014; Pron 2005; Cook 2010).

Endometrial ablation and resection of submucosal fibroids. In endometrial ablation, instruments are inserted into the uterus through the vagina to destroy the uterine lining (endometrium). This procedure can remove submucosal fibroids, but not intramural or subserosal fibroids. It reduces menstruation and excessive bleeding, and may cause the complete cessation of menstruation in some women. However, it may contribute to high-risk pregnancies due to injury to the uterine lining, and may increase risk of perforation of the uterine wall, pain, bleeding, infection, or neighboring organ damage (Mayo Clinic 2012). 

Magnetic resonance-guided focused ultrasound surgery. Magnetic resonance-guided focused ultrasound surgery (MRgFUS) (ExAblate 2000 system) is a non-invasive procedure that was approved by the FDA in 2004 for the treatment of uterine fibroids (Khan 2014). During the procedure, a patient is placed into an MRI machine to visualize fibroids and surrounding organs, while high-energy ultrasound waves are directed at the fibroid, causing an increase in temperature and tissue damage. Clinical studies show that 70-80% of women have improvements in clinical symptoms after MRgFUS (Roberts 2008; Abdullah 2010). However, these improvements may be temporary as one study found 71% of women experienced symptom reduction at six months, but the proportion declined to 51% at 12 months (Stewart 2006).

MRgFUS is an outpatient treatment that does not require general anesthesia, allowing patients to return to their normal routine in one or two days, compared to six weeks recovery or more for hysterectomy and 2-4 weeks for myomectomy. Side effects appear to be minimal, though damage to neighboring organs is possible but rare (Abdullah 2010). Only patients whose fibroids are located immediately beneath the frontal abdominal wall, and who have no bowel interference or prior scarring around the target area, are eligible for MRgFUS (Khan 2014). As of 2012, MRgFUS was not recommended for women who want to maintain their fertility (ASRM 2012b), though successful pregnancies have occurred following treatment (Rabinovici 2010).

8 Novel and Emerging Strategies

Selective Progesterone Receptor Modulators

The hormone progesterone is an important contributor to uterine fibroid development. Fibroids have higher levels of the progesterone receptor than the surrounding normal tissue, and inhibition of the progesterone receptor decreases fibroid growth in animal models. Drugs that are selective progesterone receptor modulators (SPRMs) include ulipristal acetate (Ella) and mifepristone (Mifeprex). They interfere with the progesterone receptor and are entering clinical practice for the treatment of uterine fibroids (Chwalisz 2005; Whitaker 2014; Donnez, Donnez 2014; Islam 2013).

Ulipristal acetate was approved by the FDA in 2010 as an emergency contraceptive (Kim 2011; Watson Pharma Inc. 2010). It has been approved in Europe (Esmya) and Canada (Fibristal) for pre-surgical medical treatment of uterine fibroids, to be used for no more than three months (Delev 2013; Health Canada 2014; Actavis 2013). In a trial comparing ulipristal acetate to placebo, the drug effectively controlled bleeding, shrank fibroids, and had a similar side effect profile to placebo (Donnez, Tatarchuk 2012). Another trial compared ulipristal acetate to the GnRH agonist leuprolide and found them similarly effective, though ulipristal acetate had a lower incidence of moderate-to-severe hot flashes (Donnez, Tomaszewski 2012). While it has not been approved for the treatment of fibroids in the United States, ulipristal acetate 5 mg is considered a new standard of medical treatment for uterine fibroids in regions where it is approved (Donnez, Donnez 2014; Whitaker 2014; Biglia 2014).

Mifepristone was approved by the FDA in 2000 for early termination of pregnancy up to day 49 after conception (Danco Laboratories 2009; Allen 2009). An open-label trial in 33 women with fibroids assessed the effects of a 3-month treatment with mifepristone, delivered as a vaginal suppository. Treatment was well tolerated, with no serious side effects, and resulted in a significant decrease in fibroid volume and bleeding as well as a significant increase in quality of life score (Yerushalmi 2014). However, an earlier review of three randomized controlled trials concluded that oral mifepristone did not decrease fibroid or uterine volume, but did decrease heavy menstrual bleeding and improve quality of life (Tristan 2012). Side effects of mifepristone may include hot flashes and changes in liver enzyme activity. Additional long-term, randomized trials are required to determine if oral or vaginally delivered mifepristone effectively treats uterine fibroids (Doherty 2014). 

SPRM-Induced Endometrial Changes

The endometrium – the inner lining of the uterus – plays an important role in preparation for pregnancy.  During a menstrual cycle, increased levels of estrogen cause the endometrium to thicken to allow a fertilized egg to become implanted. After ovulation, progesterone levels increase to further prepare the endometrium to receive the fertilized egg. If the egg does not become fertilized, estrogen and progesterone levels decrease, causing the endometrial lining to shed, which causes menstruation (ACOG 2012). 

If estrogen levels increase or progesterone levels decrease, the endometrial lining may thicken without being shed. This is known as endometrial hyperplasia. Endometrial hyperplasia often occurs after menopause when progesterone levels decrease, or in situations that lead to increased estrogen levels, such as the use of medication that mimics estrogen or the administration of high-dose estrogen without progesterone after menopause (Figueroa-Casas 2001; Carlson 2012; ACOG 2012). If endometrial hyperplasia is not treated, endometrial cancer may develop in 8-29% of cases (ACS 2014b).

Early studies of SPRMs, particularly mifepristone, found they cause endometrial hyperplasia. However, additional studies determined this response is dose-dependent. Higher doses of mifepristone can induce hyperplasia, whereas lower doses cause endometrial changes that are reversible. Pathologists should be aware of endometrial changes that can occur with SPRM treatment and not misdiagnose these alterations as hyperplasia (Doherty 2014).

Aromatase Inhibitors

Fibroid tissue contains high levels of aromatase, the enzyme that converts testosterone into estrogen. Thus, blocking aromatase to reduce estrogen levels may be an effective treatment for uterine fibroids (Ishikawa 2009). The aromatase inhibitors letrozole (Femara) and anastrozole (Arimidex) are approved for the treatment of hormone receptor-positive breast cancer (Sanford 2008; Knoche 1999; Cohen 2002) and are currently being studied for the treatment of uterine fibroids (Khan 2014).  

In a small study of 16 premenopausal women, letrozole decreased fibroid volume and improved heavy menstrual bleeding (Gurates 2008). Another study in 20 women showed similar effects (Hilario 2009). In a randomized study in 70 women, letrozole reduced fibroid volume by 45.6%, while the GnRH agonist triptorelin (Trelstar) decreased fibroid volume by 33.2% (Parsanezhad 2010). Anastrozole treatment in 20 women reduced fibroid volume by an average of 9.3% and reduced the amount of menstrual bleeding (Hilario 2009).

Aromatase inhibitors may promote the formation of ovarian cysts. One study on 16 patients reported that 56% of women developed ovarian cysts after letrozole treatment (Gurates 2008), though cyst formation can be prevented by co-treatment with estrogen, progesterone, or a GnRH agonist (Doherty 2014). An alternative method of aromatase inhibitor treatment may be low-dose letrozole; reductions in fibroid volume without hot flashes or ovarian cysts have been reported (Parsanezhad 2010; Doherty 2014). Additional studies are needed to determine if long-term, low-dose letrozole is safe for women with uterine fibroids (Islam 2013; Doherty 2014).

Growth Factor Inhibitors

Certain growth factors, which are a type of molecular cell messenger, promote the development of fibroids. Several inhibitors of growth factor signaling pathways have shown potential efficacy for the treatment of uterine fibroids in laboratory and case studies. However, these agents have not yet been adequately studied in clinical trials (Doherty 2014).

Insulin-like growth factor (IGF) signaling contributes to the initiation and progression of fibroid growth, and uterine fibroids have higher levels, compared to normal uterine tissue, of the receptors for IGF-1 and IGF-2. Lanreotide (Somatuline Depot) is a medication that blocks the release of growth factors such as IGF (Chanson 2008). A small study in seven women with fibroids reported that lanreotide reduced fibroid volume by an average of 42% over a 3-month period (Khan 2014). In December 2014 lanreotide was approved by the FDA for the treatment of certain gastroenteropancreatic neuroendocrine tumors; it had previously been approved for long-term treatment of acromegaly in patients who did not respond to, or were not candidates for, other types of treatment (FDA 2014c).

VizAblate and Acessa

The VizAblate and Acessa systems are new, noninvasive instruments that remove fibroids via ablation. The VizAblate device (Gynesonics, Inc.) combines real-time sonography to visualize the endometrial cavity with radiofrequencies to treat uterine fibroids in a single device. The instrument is inserted through the cervix, into the uterus, and allows the patient to be treated without incision or general anesthesia (Waltman 2011; Garza-Leal 2011). While the VizAblate device is not currently available as a treatment option in the United States, the results of an international multi-center 12-month study were published in late 2014. This study examined the use of VizAblate as a treatment for 50 women with symptomatic uterine fibroids: a total of 92 fibroids were treated. Three months after treatment, perfused fibroid volume decreased significantly, by an average of 68.8%; after six months, subjective symptom scores decreased by roughly 60%, while quality of life scores increased more than 2.5-fold compared to before treatment. Further results from this study showed that after 12 months there was a median 76% reduction in fibroid volume and a 73% median reduction in menstrual blood loss. The authors reported a good safety profile for the procedure (Gynesonics 2014a; Gynesonics 2014b; Reuters 2014a; Bongers 2014).

The Acessa system, which is available in the United States, also combines ultrasound visualization and radiofrequency ablation (Brucker 2014). Two ports are inserted surgically through the abdomen and into the uterus to locate and target fibroids (Guido 2013; Halt Medical Inc. 2014). A study compared Acessa to standard laparoscopic myomectomy in 51 women with fibroids. Acessa treatment resulted in a significant reduction in hospitalization time and blood loss, and a significant increase in the number of fibroids imaged and excised. Complications following the Acessa procedure were minimal. A 2014 paper presented the results of two phase II and one phase III multi-center trial of the Acessa system for the treatment of symptomatic uterine fibroids. Combined symptom severity scores decreased by nearly 84%, quality of life scores nearly doubled, and mean uterine volume decreased by 24%, all significant outcomes. The rate of side effects and complications was low, and four women became pregnant in the year following the procedure (Brucker 2014; Galen 2014).

Uterine Artery Embolization via Transradial Access

The standard uterine artery embolization (UAE) procedure uses arteries in the groin for treatment access, which can result in significant postsurgical pain (Resnick 2014). A 2014 publication reported a novel procedure using access sites in the wrist (“transradial”), similar to treatment procedures for heart conditions (Resnick 2014; Interventional News 2014). The new UAE technique was performed on 29 women, and the procedure was technically successful in all patients with no major or minor complications reported (Resnick 2014). UAE via transradial access reduces the incidence of pain and complications related to blood loss compared to conventional UAE technique. Patients are able to walk immediately after treatment. Additional studies are needed to validate the efficacy and safety of this procedure before it becomes widely available (Interventional News 2014).

Metformin Inhibits Uterine Fibroid Cell Growth

Due to its proven ability to regulate blood glucose levels, metformin is the most frequently used antidiabetic drug in the world (Li, Takeda 2013). Metformin also possesses other properties that may be beneficial for the treatment of uterine fibroids (Beck 2013; Luo 2010; Hawley 2002). In a laboratory study, scientists measured the rate of proliferation of uterine fibroid cells following exposure to metformin. They found that “Metformin potently inhibited [uterine fibroid cell] proliferation in a dose-dependent manner.” The researchers then analyzed the molecular mechanisms by which metformin exerted this powerful effect. Their investigation revealed that metformin’s mediation of cellular pathways involved in cell proliferation may account for the beneficial effect upon uterine fibroid cells (Li, Takeda 2013). ​Metformin is thought to retard the growth of various cancers by inhibiting a molecular pathway involved in cell survival, as well as through its ability to modulate insulin signaling (Beck 2013; Hawley 2002).

9 Dietary and Lifestyle Considerations

Diet

Several epidemiological studies have analyzed associations between dietary factors and fibroid development. Women who consume greater quantities of vegetables, fruits, and dairy products appear to have a decreased risk of developing fibroids (He 2013; Wise 2011; Wise 2010) whereas women who consume more beef, ham, or other red meats may have an increased risk of developing fibroids (Trivedi 2009; Chiaffarino 1999).

Glycemic index is a measure of a food’s ability to increase blood glucose levels compared to a carbohydrate such as glucose or white bread. Glycemic load is a measure arrived at by multiplying the glycemic index of a serving of food by the grams of carbohydrates it contains. An analysis of over 21 000 African-American women reported that those with a higher dietary glycemic index or glycemic load may have a slightly increased risk of developing fibroids. Additional analysis found that African-American women under the age of 35 years with a high glycemic load diet also had an increased risk of uterine fibroids (Radin 2010).

Exercise

Women who exercise appear to have a reduced risk of developing fibroids (Elsevier BV 2011). A dose-response pattern is apparent, such that women who exercise seven hours or more per week reduce their risk more than women who exercise two hours or less per week (Baird 2007). The effects of exercise on fibroid growth may be due to loss of body fat. Studies have shown that women who exercise and reduce their body fat by more than 2% have reduced levels of the sex hormones testosterone, estrone, and estradiol (Brown 2012). Exercise also reduces levels of insulin and IGFs (Aarnio 2001). These combined effects may decrease a woman’s risk of developing uterine fibroids (Elsevier BV 2011).

10 Integrative Interventions

Green Tea and Epigallocatechin Gallate

Epigallocatechin gallate (EGCG), a polyphenol found in green tea, has antioxidant, anti-inflammatory, and anti-tumorigenic properties, and shows significant promise for the treatment of uterine fibroids (Islam 2013; Chatterjee 2012). A randomized, placebo-controlled trial studied the effect of 800 mg green tea extract, containing 45% EGCG (360 mg EGCG per day), in 39 women with symptomatic fibroids. The 22 women who took green tea extract daily for four months had a significant 32.6% reduction in fibroid volume and a significant 32.4% reduction in severity of fibroid symptoms. The green tea extract also led to significant improvements in anemia, blood loss, and quality of life. There were no reported adverse events following treatment (Roshdy 2013). EGCG also inhibited the growth of new blood vessels that supply malignant tumors with nutrients in laboratory and animal models of cancer (Carlson 2007; Khan 2010), inhibited the growth of uterine fibroid cells, and induced uterine fibroid cell death in a laboratory study (Zhang 2010). Additionally, EGCG significantly reduced the size and number of fibroids in an animal model (Ozercan 2008).

Vitamin D

Several studies have reported that women who have lower serum levels of vitamin D are more likely to develop uterine fibroids. In one study, there was also a significant relationship between vitamin D levels and fibroid size: women with lower vitamin D had larger fibroids, and those with higher vitamin D had smaller fibroids. This finding was especially evident among black women and present as a trend among white women. Another study found that women with sufficient vitamin D levels, defined in this study as greater than 20 ng/mL, had an estimated 32% lower odds of having fibroids compared to those with vitamin D levels below 20 ng/mL. Yet another study reported that women with vitamin D deficiency had a significant 2.4-fold greater odds of having uterine fibroids (Baird 2013; Sabry 2013; Paffoni 2013). The majority of fibroids have low levels of the vitamin D receptor compared to surrounding normal tissue. Vitamin D decreases levels of proteins known to contribute to fibroid formation and inhibits the replication of fibroid cells (Halder 2013; Sharan 2011). In a laboratory study, the active form of vitamin D, at normal concentrations, significantly inhibited growth in uterine fibroid cells by 12% compared with controls. This effect was stronger at higher concentrations; the greatest concentration of activated vitamin D significantly suppressed growth by 62% (Bläuer 2009). Furthermore, a preclinical experiment found that treatment of mice with vitamin D3, at a dosage equivalent to 124 IU/day for a 175 lb human, or paricalcitol (Zemplar), an analog of vitamin D3, resulted in a significant reduction in fibroid size (Halder 2014). These data suggest that vitamin D may potentially be an effective agent to treat fibroids (Sabry 2012). Life Extension suggests that most people maintain blood levels of 25-hydroxyvitamin D between 50 and 80 ng/mL for optimal health. 

Curcumin

Curcumin has been investigated as a potential therapeutic agent for uterine fibroids. In a laboratory setting, curcumin inhibited uterine fibroid cell growth (Tsuiji 2011). Curcumin also decreased the level of fibronectin, an important component of the extracellular matrix that contributes to fibroid progression, without significant effects on normal uterine muscle tissue (Malik 2009). Several growth factors are known to be important contributors to fibroid growth, including IGFs, fibroblast growth factors, and transforming growth factors. Curcumin has been shown to inhibit the secretion of IGF-1 in breast cancer cells; block fibroblast growth factor-2-induced blood vessel growth; and inhibit transforming growth factor-beta signaling in a variety of cells, including liver and kidney cells (Xia 2007; Mohan 2000; Li, Wang 2013; Chen, Geng 2014).

Chinese Herbal Medicine Cinnamon and Poria Formula

Traditionally referred to as Gui Zhi Fu Ling, Cinnamon and Poria Formula has been used in China to treat a range of women’s symptoms since the 3rd century AD. Cinnamon and Poria Formula is composed of a combination of 5 herbs: Ramulus Cinnamomi, Poria, Semen Persicae, Cortex Moutan, and Radix Paeoniae Rubra or Radix Paeoniae Alba (Chen, Han 2014; Liu 2013).

Cinnamon and Poria Formula is commonly administered as a capsule, tablet, or liquid herbal extract. Numerous studies have analyzed the effects of the formula on fibroids and their associated symptoms. A comprehensive review of 38 randomized controlled trials with a total of 3816 patients reported that Cinnamon and Poria Formula plus mifepristone is more effective at reducing fibroid volume than mifepristone alone (Chen, Han 2014). These results support those reached in a separate analysis that analyzed cumulative evidence from seven trials. That analysis found that Cinnamon and Poria Formula, either alone or in combination with mifepristone, also appeared to significantly improve symptoms of painful periods. Treatment with Cinnamon and Poria Formula posed minimal risks, and no serious side effects were reported in any of the trials (Liu 2013). It is important to note that 23 of 38 trials in the meta-analysis did not include safety data, and many of the studies included had a small number of participants and did not use a rigorous methodology. Therefore, definitive conclusions about the effectiveness of Cinnamon and Poria Formula cannot be reached based on currently available research (Chen, Han 2014).

Cimicifuga racemosa (Black Cohosh) Extract

Black Cohosh is an herb commonly used to treat menopausal symptoms. A 2014 trial assessed the effect of a 40 mg black cohosh extract in 34 women with menopausal symptoms and fibroids. In this trial, a different group of 28 women took the synthetic estrogen tibolone (Livial), a drug that is not approved in the United States. In 70.1% of women in the black cohosh group, fibroids decreased in size an average of 30.3% after a 12-week treatment period. In the tibolone group, fibroid size increased by 4.7% during the same time period (Xi 2014).

Tripterygium wilfordii Hook. f. Extract – Benefits and Potential Risks

Tripterygium wilfordii Hook. f., an extract from the Chinese herb Tripterygium wilfordii, is frequently used in China to treat uterine fibroids. Several clinical trials showed that Tripterygium wilfordii Hook. f. extract significantly reduced fibroid volume and heavy menstrual bleeding after 3-4 months of treatment. A 2005 paper reported on a study in 124 women, half of whom received 40 mg Tripterygium wilfordii Hook. f. extract daily for 3-6 months while the other half received mifepristone. The authors reported a significant decrease in fibroid size after 3-4 months, with a more pronounced effect detectable by 5-6 months, based on ultrasound examination (Fu 2005). In a similar 3-month trial comparing Tripterygium wilfordii Hook. f. extract to mifepristone in 62 women, the authors reported a significant reduction in fibroid size (Wen 2005). In both of these trials, results of the herbal extract were superior to those achieved by mifepristone. An earlier trial of Tripterygium wilfordii Hook f. extract found that it significantly decreased fibroid size after 3-4 months of treatment, with a somewhat higher percentage of patients responding after 5-6 months. The decrease in fibroid size with Tripterygium wilfordii Hook. f. treatment was time-dependent; the response was nearly double after 5-6 months compared to 3-4 months. It is worth noting that 38% of patients did not have a menstrual cycle during the treatment, and Tripterygium wilfordii Hook. f. treatment decreased average estradiol and progesterone levels (Gao 2000).

Despite these promising findings, several reports of severe toxicity and even death associated with the use of Tripterygium wilfordii Hook. f. are available, and it appears the dose required for clinical effectiveness is very close to the dose required to cause toxicity (Huang 2009; Wang 1989). Another report linked Tripterygium wilfordii Hook. f. use to low bone mineral density in women (Huang 2000).

Life Extension does not suggest the use of Tripterygium wilfordii outside of a clinical setting. If a healthcare practitioner decides to use this therapy with patients, only a standardized extract of the skinned root should be used, as other parts of the plant are highly toxic (NCCAM 2012).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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