Endometriosis

Endometriosis

1 Overview

Summary and Quick Facts

  • In the United States, chronic pelvic pain accounts for 10% of all outpatient gynecologic appointments and 66% of women with pain or tenderness on a pelvic examination have endometriosis. Endometriosis describes a condition in which tissue that normally resides in the inner lining of the uterus, the endometrium, emerges elsewhere in the body, usually in the pelvic area.
  • This protocol will discuss endometriosis and how it can cause pain, infertility and other complications. It will also outline the conventional treatments for endometriosis and their associated risks, as well as some emerging therapies.
  • Incorporating natural compounds that may modulate the underlying pathophysiology of endometriosis alongside conventional therapies represents an encouraging option for women afflicted by this condition, especially given the relative safety of these natural approaches.

In the United States, chronic pelvic pain accounts for 10% of all outpatient gynecologic appointments and 66% of women with pain or tenderness on a pelvic examination have endometriosis. Endometriosis describes a condition in which tissue that normally resides in the inner lining of the uterus, the endometrium, emerges elsewhere in the body, usually in the pelvic area.

Mounting evidence suggests natural interventions such as omega-3 fatty acids from fish oil and N-acetyl cysteine may play a role in the management of endometriosis.

Symptoms

  • Pelvic pain
  • Infertility

Risk Factors

  • A family history of endometriosis is one of the most important risk factors
  • Early menarche and never having been pregnant
  • Exposure to certain pesticides (eg, organochlorine)

Diagnosis

  • The gold standard for diagnosing endometriosis is visual inspection via laparoscopy. Laparoscopy also helps classify the severity of endometriosis into four stages: minimal, mild, moderate, and severe.

Conventional Treatment

  • Pain-relieving medications such as non-steroidal anti-inflammatory drugs (NSAIDs) can help reduce pain. However, NSAIDs can lead to gastric ulcers and may inhibit ovulation.
  • Suppressing the activity of the ovaries via the use of oral contraceptives is one of the most commonly used medical treatments.
  • For women who cannot obtain satisfactory relief with NSAIDs and oral contraceptives after six months of therapy, other medications may be tried. These medications include progestins, which are synthetic progesterones.
    • Note: Progestins are meant to function like natural progesterone, but a huge body of data indicates potential for adverse side effects.

Novel and Emerging Therapies

  • Clinical trials using pentoxifylline have shown significant increases in fertility and pain relief as compared to placebo.
  • Clinical trials have found that adding aromatase inhibitors to conventional treatments reduces endometriosis pain and may improve quality of life.
  • Studies have found that acupuncture is effective at relieving chronic pelvic pain in women with endometriosis.

Dietary and Lifestyle Considerations

  • Consuming red meat increases the risk of endometriosis, while increased consumption of long-chain omega-3 fatty acids (prevalent in fatty, cold-water fish) is associated with a decreased risk.
  • Women consuming a diet rich in trans fats are at higher risk of being diagnosed with endometriosis.
  • Eating more fruits and vegetables may play a protective role.
  • Support groups can be invaluable as they can provide a connection to other women suffering from similar symptoms.

Integrative Interventions

  • Omega-3 fatty acids. A large study found that women who ate greater amounts of long-chain omega-3 fatty acids were also less likely to develop endometriosis.
  • Vitamins C and E. In a randomized placebo-controlled trial, 59 women between 19 and 41 years of age were allocated to receive a combination of vitamins E and C or placebo daily for eight weeks. Following the treatment period, 43% of women who received vitamins E and C experienced reduction in chronic pain, 37% experienced reduction in pain associated with menstruation, and 24% experienced reduction in pain during intercourse compared with the placebo group.
  • N-acetyl cysteine (NAC). After the 3-month study period, endometriotic cysts were slightly reduced in size among women who took NAC, while a significant increase in cyst size was observed in the women who received no treatment. The researchers noted their findings for the efficacy of NAC were better than those reported after hormonal treatment of endometriosis.
  • Epigallocatechin gallate (EGCG) from green tea. In preclinical research of endometriosis, EGCG decreased the growth of endometrial implants and reduced the formation of new blood vessels to endometrial tissue.
  • Resveratrol. In preclinical research of endometriosis, resveratrol reduced endometrial implants by 60% and total volume of lesions by 80%.

2 Introduction

Endometriosis describes a condition in which tissue that normally resides in the inner lining of the uterus, the endometrium, emerges elsewhere in the body, usually in the pelvic area. The growth of this misplaced (ectopic) endometrial tissue can cause significant pelvic pain, pain during menstruation or sexual intercourse, fertility problems, and in some cases gastrointestinal or urinary problems and abnormal vaginal bleeding (Connolly 2009; Schenken 2013; Giudice 2010; Cox 2003). Endometriosis is estrogen-dependent and often progressive, resulting in worsening pain and other symptoms over time (Simoens 2007; Bulun 2009; Schenken 2013; Laufer 2003). Endometriosis should not be confused with endometrial cancer (Connolly 2009).

In the United States, chronic pelvic pain accounts for 10% of all outpatient gynecologic appointments and 66% of women with pain or tenderness on a pelvic examination have endometriosis (Giudice 2010). In 2002, endometriosis cost an estimated $22 billion in the United States due to treatment costs and lost productivity; this number increased to over $69 billion in 2009 (Simoens 2007; Burney 2012). It has been estimated that about 5–10% of women of reproductive age in the United States are affected by endometriosis (Bulun 2009).

There are many treatment options for endometriosis; however, there is no consensus that one type of therapy is superior to another (Kennedy 2005; Schenken 2012). Consequently, therapeutic regimens are determined on a case-by-case basis, dependent on a number of factors, including the extent of disease, woman’s desire for pregnancy, and cost. Conventional treatment options include pain relievers, hormones, and other pharmaceuticals. In some cases, surgery may be necessary to reduce pain and restore fertility. Unfortunately, these treatments are not always effective and can have significant side effects, including weight gain, irregular bleeding, and changes in the uterine tissue (Schenken 2012; Connolly 2009).

A fundamental problem with conventional medicine’s approach to many women’s health concerns is the reliance upon synthetic hormones. Copious evidence shows that natural bioidentical hormones may offer a safer alternative. Since unopposed or excessive estrogenic activity drives endometriosis, many women with this condition are treated with synthetic progestins, which mimic the action of progesterone but are structurally different than progesterone produced naturally in a woman’s body (Schweppe 2001). This exposes them unnecessarily to increased risk of several diseases, including breast cancer and heart disease (Zhou 2013; Chlebowski 2013; Liang 2010; Baker 1994; Vehkavaara 2001; Adams 1997; Morey 1997; Houser 2000). Topical application of a natural progesterone cream may combat endometriosis while sparing women from the ravages of synthetic hormones.

In addition to natural bioidentical hormones, several other promising interventions exist that may ease the suffering women with endometriosis experience.

An overlooked drug called pentoxifylline has been shown in both experimental and human studies to improve several endometriosis-related outcomes, including pain intensity and pregnancy rates. Moreover, laboratory studies have shown that this unique drug can counteract some of the specific mechanisms that contribute to endometriosis (Balasch 1997; Creus 2008; El Darouti 2011; Gonzalez-Espinoza 2012; Kamencic 2008; Vlahos 2010).

Mounting evidence suggests that natural interventions such as omega-3 fatty acids from fish oil and N-acetyl cysteine may play a role in the management of endometriosis. Incorporating natural compounds that may modulate the underlying pathophysiology of endometriosis alongside conventional therapies represents an encouraging option for women afflicted by this condition, especially given the relative safety of these natural approaches (Porpora 2013; Hansen 2013; Netsu 2008; Herington 2013; Missmer 2010; Ngo 2009).

This protocol will discuss the pathophysiology of endometriosis and how it can cause pain, infertility, and other complications. It will also outline the conventional treatments for endometriosis and their associated risks, as well as some emerging therapies. Several natural interventions and lifestyle considerations that may provide relief to women afflicted by endometriosis will also be discussed.

3 Biology and Pathophysiology

Endometriosis is characterized by the presence of endometrial tissue in parts of the body where it should not normally be present. The pelvic peritoneum (membrane that covers the organs within the pelvis), ovaries, and rectovaginal septum (area between the rectum and vagina) are the most susceptible (Burney 2012; Bulun 2009). As of the time of this writing, there is no single unifying theory as to the genesis of endometriosis; although several have been proposed (Burney 2012; Connolly 2009).

Retrograde Menstruation

One predominant theory is that endometriosis occurs via a process known as “retrograde menstruation” (Burney 2012; Schenken 2013). This theory suggests that endometrial tissue leaks into the peritoneal cavity during menstruation, allowing endometrial tissue to implant into other sites in the pelvis (Burney 2012). Women with congenital anatomical abnormalities that impair the flow of menses from the uterus into the vagina have an increased risk of endometriosis, further supporting this theory (Olive 1987). However, retrograde menstruation occurs in up to 90% of menstruating women and not all of these women develop endometriosis, suggesting other factors may also be important (Burney 2012; Schenken 2013; Connolly 2009).

Coelomic Metaplasia

Another theory on the development of endometriosis is called the “coelomic metaplasia” theory. This theory suggests that endometriosis occurs when cells lining the coelom, the cavity between the body wall and intestines, change their cell type to form endometrial tissue. Cells of the endometrium and coelom arise from the same cell type during embryonic development, and their differentiation is under the control of hormones, primarily estrogen (Signorile 2010; Rizner 2009; Schenken 2013; Matsuura 1999). This theory is supported by a case report of endometriosis in a woman without a uterus due to a genetic defect (ie, Mayer-Rokitansky-Küster-Hauser syndrome), suggesting retrograde menstruation could not have been the cause of her condition (Mok-Lin 2010).

Blood and Lymphatic Dissemination

Other researchers hypothesize that viable endometrial cells may travel from the endometrium through lymphatic or blood circulation. Eventually, these cells may implant at other sites and grow, giving rise to endometriosis in a manner similar to the metastasis of tumor cells. There are many aspects of this theory that still need to be conclusively studied (Tempfer 2011; Burkle 2013; Elsevier 2011).

Inflammation

Inflammation may also play an important role in endometriosis (Ziegler 2010; Reis 2013). Endometriotic tissue produces excess inflammatory mediators such as prostaglandin E2 and prostaglandin F2α (Bulun 2009; Ziegler 2010; Reis 2013). In addition to helping ectopic endometrial tissue implants grow in other parts of the body, inflammation may also play an important role in the pain caused by endometriosis (Reis 2013; Bulun 2009). Endometrial tissue in areas outside the uterus can trigger an immune response that causes the release of large amounts of inflammatory cytokines (Bruner-Tran 2013; Reis 2013). These cytokines may increase the activity of immune cells, such as mast cells, which can affect nearby nerves and contribute to pain (Anaf 2006). In addition to increased overall inflammation, women with endometriosis may have defects in their immune systems that make it easier for endometrial tissue to grow and survive (Schenken 2013; Ziegler 2010).

Hormonal Imbalance

Hormonal imbalance may contribute to endometriosis as well. During a woman’s menstrual cycle, endometrial tissue grows and then regresses (Reis 2013; Krikun 2012). Estrogen is responsible for the proliferation of the endometrial lining (Bulun 2006; Burney 2007). The growth and progression of endometriosis is also dependent on estrogen and can be treated by suppressing estrogen levels (Kitawaki 2002; Bulun 2006). Conversely, progesterone can help stop the growth of normal and ectopic endometrial tissue. However, tissue from endometriosis is notably more resistant to progesterone’s anti-growth effects (Zeitoun 1998; Reis 2013; Bulun 2006). This idea is supported by genetic studies of endometriotic tissue samples that have shown reduced activity of an enzyme called 17β-hydroxysteroid dehydrogenase type-2 (17β-HSD2), which is needed to metabolize (and inactivate) estrogen (Zeitoun 1998). Normally, this enzyme is expressed in response to the hormone progesterone. However, in “resistant” endometriotic tissue, progesterone does not trigger the expression of 17β-HSD2 and subsequent metabolism of estrogen (Reis 2013; Zeitoun 1998; Bulun 2006).

Genetics

Genetic mutations that cause abnormal cell growth also promote endometriosis (Burney 2012; Reis 2013). Inherited genetic alterations may account for the increased risk of endometriosis in women with a first-degree relative (mother or sibling) with endometriosis (Burney 2012; Simpson 1980; Schenken 2013).

Endometriosis vs. Endometrial Cancer

Endometriosis should not be confused with endometrial cancer; although endometrial tissue appears in inappropriate locations in endometriosis, the tissue is not malignant (Connolly 2009). Endometriosis and endometrial cancer are distinctly different diseases. The abnormal endometrial tissue in endometriosis does not display the cellular changes that cancer does, including the ability to invade normal tissue and spread to different parts of the body. The abnormal tissue implants seen in endometriosis are essentially “normal” endometrial glands, as seen even at the microscopic level (Schenken 2013), and endometriosis is not considered a precancerous condition (Elsevier 2011). Although endometriosis and some forms of endometrial cancer are both influenced by hormone levels, they are different diseases (Schenken 2013; Zeitoun 1998). It is important to note, however, that in a small percentage (ie, up to 1%) of endometriosis cases, endometriotic tissue may undergo malignant transformation (Higashiura 2012).

4 Symptoms

Pain

One of the most common symptoms of endometriosis is pelvic pain. This pain can occur during menstruation (dysmenorrhea), sex (dyspareunia), and/or be present chronically (Sinaii 2008; Schenken 2013; Porpora 1999). Approximately 75% of all women with symptomatic endometriosis will experience pain (Schenken 2013; Sinaii 2008). Interestingly, no clear correlation has been consistently observed between the extent of endometriosis and pain perception. In fact, some women with extensive endometriosis may only have minimal symptoms and vice-versa (Sinaii 2008). Other symptoms include low back pain, constipation, diarrhea, bloating, fatigue, and abnormal menstrual bleeding (Schenken 2013; Sinaii 2008). Bladder and bowel symptoms are typically cyclical, meaning they are usually worse around the time of menstruation (Giudice 2010).

The process by which endometriosis causes pelvic pain is complex and not entirely clear. Some of the hormonal and chemical changes caused by endometriosis could influence the growth of nerves into the ectopic endometrial tissue, leading to increased sensations of pain in the uterus (Triolo 2013; Burney 2012). The production of excess amounts of inflammatory mediators by endometriotic tissue contributes to increased pelvic pain as well (Triolo 2013; Bulun 2009). This is one of the reasons anti-inflammatory therapies, such as naproxen sodium and ibuprofen, offer effective pain relief for many endometriosis patients. These drugs are non-selective inhibitors of the COX-2 enzyme, which produces inflammatory mediators by metabolizing arachidonic acid (Bulun 2009). Interestingly, evidence suggests that progesterone can counter some of the molecular inflammatory actions that play a role in the development of endometriosis (Reis 2013).

Infertility

Another manifestation of endometriosis is impaired fertility (Sinaii 2008). Healthy couples trying to become pregnant have a 15–20% chance each month of achieving a pregnancy. By comparison, women with endometriosis have a 2–10% chance of becoming pregnant each month. Between 25% and 50% of infertile women have endometriosis, and 30–50% of women with endometriosis have fertility problems (Bulletti 2010). Women with endometriosis are also less likely to have a live birth. In addition, endometriosis is associated with a higher rate of complications during pregnancy, including preeclampsia, preterm birth, abnormal vaginal bleeding, and an increased rate of a Caesarean-section delivery (Bulletti 2010; Falconer 2013; Sinaii 2008).

There are many theories as to how endometriosis causes infertility. The abnormal endometrial tissue could disrupt the anatomy of the pelvis, thus making ovulation, fertilization, and transport of the fertilized egg to the uterus more difficult (Bulletti 2010). Endometriosis can cause bands of scar tissue, called adhesions, to form between the female reproductive tract (uterus, ovaries, and fallopian tubes) and other organs in the pelvis and abdomen. This can also distort gynecological anatomy (Schenken 2012; Schenken 2013; Elsevier 2011). Endometriosis could also impair the function of the ovaries. Inflammation caused by endometriosis impairs sperm migration or the fertilization and implantation of the embryo into the uterus as well (Ziegler 2010). Other biochemicals, such as prostaglandins produced by abnormal endometrial tissue, could result in uterine contractions that make implantation difficult (Bulletti 2010). Also, resistance to progesterone and amplified estrogen production may also render the uterus unsuitable for supporting a pregnancy (Ziegler 2010).

5 Risk Factors

Family History

A family history of endometriosis is one of the most important risk factors for this condition; women who have a first-degree relative with endometriosis have a 6- to 7-fold increased risk of developing the condition (Burney 2012).

Early Menarche and Never Having Been Pregnant

For women who have not had a child, experiencing menarche at an early age and having shorter menstrual periods are associated with an increased risk of endometriosis. Alternatively, for mothers, number of children and length of lactation are associated with a decreased risk of endometriosis (Missmer 2004). Also, menarche after age 14 appears to greatly reduce risk of endometriosis (Treloar 2010). Women who have never had children (nulliparity) are also at an increased risk (Schenken 2013). However, because endometriosis can cause infertility, nulliparity may in part be a sign rather than a risk factor for endometriosis.

Lifestyle, Dietary, and Environmental Risk Factors

Exposure to certain pesticides (eg, organochlorine) may also increase the risk of endometriosis (Cooney 2010; Buck Louis 2012). Women with endometriosis tend to have a lower body mass index (BMI) (Hediger 2005); however, women who get more physical activity may be at a slightly reduced risk of developing endometriosis (Vitonis 2010). Diet may also play a role, as some research has suggested that a diet low in vegetables and omega-3 fatty acids and high in red meat and trans fats may increase the risk of endometriosis (Parazzini 2013; Missmer 2010). 

6 Diagnosis

Diagnosing endometriosis can be difficult, and there is often a significant delay between the onset of symptoms and diagnosis (Husby 2003; Kennedy 2005). Endometriosis may be initially suspected based on signs and symptoms and medical history (Ballard 2008; Laufer 2003), but a physical examination should also be performed (Laufer 2003). Pelvic tenderness and enlarged ovaries are suggestive of endometriosis (Kennedy 2005). In many cases, endometriosis is a diagnosis of exclusion, meaning doctors may come to the diagnosis once other causes of pelvic pain or infertility have been ruled out (Elsevier 2011).

The gold standard for diagnosing endometriosis is visual inspection via laparoscopy (Kennedy 2005; Schenken 2013; Winkel 2003). Laparoscopy is a surgical procedure that allows surgeons to look for ectopic endometrial tissue, which typically appear as black, dark-brown, or blue lesions that may resemble a powder burn (lesion sometimes seen after the skin is near the ignition of gunpowder). These lesions can be visually seen on the ovaries, peritoneum, and/or other structures within the pelvis. Laparoscopy can also help determine the extent of endometriosis (Schenken 2013; Kennedy 2005). Accuracy of this procedure depends heavily on the location of the lesions, extent of endometriosis, and experience of the person performing the procedure. There can be error when relying on laparoscopy findings alone to diagnose endometriosis (Wykes 2004; Schenken 2013; Winkel 2003). Ideally, suspicious lesions seen on laparoscopy should be sampled by performing a biopsy, thus allowing for microscopic confirmation of ectopic endometrial tissue (Schenken 2013; Kennedy 2005; Mounsey 2006). Although laparoscopy is the gold-standard technique for diagnosis, it is an invasive procedure. As a result, many doctors will first treat a woman suspected of having endometriosis with hormonal therapy before resorting to laparoscopy (Hsu 2010). Imaging studies, such as transvaginal ultrasound, can also help detect severe disease and may be useful as a test before laparoscopy (Holland 2010; Abrao 2007).

Staging

Laparoscopy also helps classify the severity of endometriosis into four stages: minimal, mild, moderate, and severe. Minimal endometriosis causes only isolated implants of ectopic endometrial tissue with no adhesions. Mild endometriosis is characterized by the presence of endometriotic implants on the peritoneum and ovaries cumulatively totaling less than 5 cm in size; no significant adhesions are present at this stage. In moderate endometriosis, multiple implants are present, including some that deeply penetrate the pelvic tissue and can cause significant adhesions (Schenken 2013; ASRM 2012). Women with severe disease have many deep implants and may have large masses called endometriomas (Schenken 2013).

7 Conventional Treatment

Pain Management

Pain-relieving medications such as non-steroidal anti-inflammatory drugs (NSAIDs) can help reduce pain (Kennedy 2005; Laufer 2003). However, NSAIDs can lead to gastric ulcers and may inhibit ovulation (Kennedy 2005).

Hormonal Treatments

Oral contraceptives. Endometriosis symptoms often resolve during menopause and pregnancy and hormonal therapies are used to produce similar states to treat this condition (Winkel 2003). Suppressing the activity of the ovaries via the use of oral contraceptives is one of the most commonly used medical treatments (Laufer 2003; Kennedy 2005), though this also prevents pregnancy and may be associated with other side effects (CDC 2013; Winkel 2003). In addition, oral contraceptives fail to control endometriosis pain in approximately 20–25% of patients (Giudice 2010).

GnRH agonists. For women who cannot obtain satisfactory relief with NSAIDs and oral contraceptives after 6 months of therapy, other medications may be tried (Schenken 2012). These medications include gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide (Lupron®) (Laufer 2003; Schenkin 2012; Kennedy 2005; Giudice 2010). One effect of GnRH agonists is lowered estrogen levels, which may be of benefit for women with endometriosis since estrogen stimulates the growth of endometriotic tissue (Giudice 2010). GnRH agonists can cause significant bone loss after a few months of therapy, which is only partially reversible. However, adding small amounts of estrogens to the treatment to maintain a low, stable estrogen level can help retain bone density (Giudice 2010; Hornstein 1998; Kennedy 2005).

Danocrine. Danocrine (Danazol®) is another effective treatment option. It is a synthetic hormone that works by creating a lower estrogen, higher androgen environment resulting in a reduction of endometriosis lesions (Selak 2007; Cottreau 2003; Laufer 2003). Although effective, it can cause weight gain, depression, reduced breast size, deepening of the voice, skin rash, and increased body hair (Laufer 2003). In addition, research suggests Danazol may increase the risk of ovarian cancer (Cottreau 2003).

Progestins (synthetic, unnatural progesterone-like drugs). A fourth possible therapy is a synthetic progestin, such as Provera® (medroxyprogesterone acetate) (Laufer 2003; Schenken 2012). Progestins are synthetic versions of the hormone progesterone (Spark 2009). These medications can cause weight gain, depression, bloating, and irregular bleeding, as well as increase cardiovascular risk (Laufer 2003).

  • The flaws of synthetic progestins. A major problem with progestins is that they are not natural to the human body. In other words, their chemical structure differs from that of the progesterone humans produce naturally. Progestins are patented, synthetic drugs that protect against estrogen-induced endometrial cancer (UMMC 2013a). Progestins are meant to function like natural progesterone, but a huge body of data indicates potential for adverse side effects. For example, some data suggests natural progesterone may confer a protective effect against breast cancer (Holtorf 2009; Wood 2007; Zhou 2013; Chlebowski 2013), whereas progestins have been linked with increased risk (Zhou 2013; Chlebowski 2013; Liang 2010; Baker 1994; Vehkavaara 2001).

    Compared to synthetic progestin that stimulates breast cell proliferation, natural progesterone has demonstrated a protective effect. There are at least 17 studies showing that progestins significantly increase breast cell replication and growth (Chlebowski 2013; Vehkavaara 2001; Jeng 1992; Kalkhoven 1994; Papa 1990; Jordan 1993; Catherino 1993; Cline 1998; Cline 1996; Menendez 2005; Seeger 2005; Murkes 2011; Wood 2009; Neubauer 2013; Murkes 2012; Chang 1995; Foidart 1998). In stark contrast, at least 11 studies have shown that natural progesterone does not induce estrogen-stimulated breast cell proliferation (Neubauer 2013; Murkes 2012; Chang 1995; Foidart 1998; Mueck 2003; Inoh 1985; Barrat 1990; Malet 2000; Laidlaw 1995; van Leeuwen 1991; Fournier 2005).

    Numerous studies have demonstrated an increased risk of breast cancer with the use of synthetic progestins (Rossouw 2002; Vehkavaara 2001; Porch 2002; Fournier 2008; Plu-Bureau 1999). However, the use of natural (bioidentical) progesterone has not been associated with an increased risk of breast cancer (Holtorf 2009; Wood 2007; Zhou 2013; Chlebowski 2013; Fournier 2008; Micheli 2004). Quite to the contrary, research has revealed that natural progesterone decreases the risk of breast cancer. In a study published in the journal Breast Cancer Research and Treatment, 80,000 postmenopausal women using various forms of hormone replacement therapy (HRT) were followed for more than 8 years. Women who used estrogen in combination with synthetic progestin had a 69% increased risk of breast cancer compared to women who had never used HRT. However, for women who used natural progesterone in combination with estrogen, the increased risk of breast cancer was completely eliminated with a significant reduction in breast cancer risk compared with synthetic progestin use (Micheli 2004). In another investigation, these same researchers found a 40% increased risk of breast cancer for women who used estrogen with synthetic progestin (Fournier 2008). Interestingly, in women who used estrogen combined with natural progesterone, there was a promising trend toward a reduced risk of breast cancer compared to women who never used HRT (Fournier 2008). In essence, natural progesterone appeared to protect women against the development of breast cancer. These findings confirm work done six years earlier that found a trend toward a reduced risk of breast cancer in 1150 women using natural progesterone compared to non-users of progesterone (Cowan 1981).

    Compelling research offers further insight into natural progesterone’s ability to defend against breast cancer. In a fascinating study, scientists administered estrogen alone, natural progesterone alone, estrogen plus natural progesterone, or placebo to 40 women prior to surgery to remove a breast lump. The hormones were applied topically to the breast for about 12 days before surgery. As expected, when given alone, estrogen caused a 62% increase in breast cell proliferation rates compared to placebo. Conversely, the addition of natural progesterone to estrogen resulted in a significant decrease in the estrogen-induced increase in breast cell proliferation rates. Even more impressive was the finding that the group receiving natural progesterone alone had a nearly 76% lower breast cell proliferation rate compared to the placebo group (Mueck 2003).

Bioidentical Hormone Replacement Therapy

Since a relative excess of estrogenic activity is a major driving force in endometriosis, maintaining hormonal balance may help ensure that endometrial tissue, either normal or ectopic, does not grow in unchecked fashion (Bulun 2006; Brosens 2011). The combination of regular blood testing and bioidentical hormone replacement therapy may help women achieve such a hormonal balance. Bioidentical hormones are designed to be identical to the hormones that the body makes (Holtorf 2009; Moskowitz 2006). Doctors can check for hormonal imbalances and design a natural bioidentical hormone regimen to maintain hormone levels in the right proportions (Holtorf 2009; Moskowitz 2006). In the context of discussions about bioidentical hormones, the term “natural” when appearing before the name of a hormone, for example “natural estrogen,” should be interpreted to mean that the molecular structure of the compound in question is identical to that which occurs naturally in the human body.

Bioidentical progesterone is especially intriguing in the context of endometriosis. Progesterone is a key hormone in endometriosis, as it counters the effects of estrogen by inhibiting harmful inflammatory mediators (eg, interleukin-8) and inducing apoptosis (programmed cell death) (Reis 2013). Using bioidentical progesterone may be an effective approach to the treatment of endometriosis (Jain 2012). Bioidentical progesterone may cause fewer side effects than the synthetic progestins used in conventional hormone replacement therapy (Jain 2012; Holtorf 2009; Moskowitz 2006).

Natural progesterone has numerous other benefits over progestins as well. The Women’s Health Initiative, a large randomized clinical trial, demonstrated that the addition of synthetic progestins to estrogen therapy resulted in a substantial increase in the risk of heart attack and stroke (Rossouw 2002). In one trial published in the Journal of the American College of Cardiology, researchers studied postmenopausal women with a history of heart attack or coronary artery disease. The women were given estrogen in combination with either natural progesterone or synthetic progestin. After 10 days of treatment the women underwent exercise treadmill tests. Compared to the synthetic progestin group, the amount of time it took to produce myocardial ischemia (reduced blood flow to the heart) on the exercise treadmill was substantially improved in the natural progesterone group (Register 1998).

Atherosclerosis (hardening of the arteries) is a leading cause of heart disease. Several studies have determined that synthetic progestin promotes the formation of atherosclerosis (Adams 1997; Morey 1997; Houser 2000). The story is quite different for natural progesterone, where multiple animal studies have shown that natural progesterone inhibits the process of atherosclerosis (Houser 2000; Adams 1990; Tall 2008). To illustrate, scientists fed monkeys with surgically induced menopause a diet known to cause atherosclerosis for a total of 34 months. The scientists then divided the monkeys into groups that received estrogen alone, estrogen plus synthetic progestin, or a control group that did not receive hormones. The control group developed substantial atherosclerotic plaque. The administration of estrogen resulted in a 72% decrease in atherosclerotic plaque compared to the control group (Houser 2000). Treatment with synthetic progestin yielded disturbing results. The group of postmenopausal monkeys that received estrogen combined with synthetic progestin had a similar amount of atherosclerotic plaque as the control group. This showed that synthetic progestin completely reversed estrogen’s inhibitory effects on the formation of atherosclerosis (Houser 2000). In contrast, when the same investigators administered natural progesterone along with estrogen, no such inhibition of estrogen’s cardiovascular benefit was seen (Fåhraeus 1983).

Readers interested in learning more about bioidentical hormone restoration are encouraged to review Life Extension’s Female Hormone Restoration protocol.

Surgery

Surgical treatment of endometriosis can either be a first-line therapy or an option when medical therapy fails (Giudice 2010; Laufer 2003; UMMC 2013b; NYT 2013). Laparoscopic ablation of implanted endometrial tissue reduces pain in about 65% of cases (Giudice 2010). However, recurrence of pain requiring additional therapy occurs within 12 months for up to 60% of women (Giudice 2010; Laufer 2003). A more invasive surgical option is a hysterectomy with removal of both ovaries (bilateral salpingo-oophorectomy). This treatment more effectively treats pain from endometriosis, as shown by a study in which 10 years after undergoing this type of surgery, only 10% of women had recurrent symptoms (Mounsey 2006).

Maintaining Fertility

Improving fertility is an important consideration for women with endometriosis who want to become pregnant (Schenken 2012; Giudice 2010). Laparoscopic destruction of ectopic endometrial tissue along with removal of any adhesions has been found to improve fertility in women with minimal or mild endometriosis. Women receiving hormonal treatments for endometriosis show no significant effects on rates of pregnancy or live birth when compared to women receiving no treatment or a placebo (Giudice 2010). In-vitro fertilization, artificial insemination, and other fertility-promoting techniques may help women with endometriosis become pregnant (Giudice 2010).

8 Novel and Emerging Therapies

Pentoxifylline

One of the most intriguing aspects of endometriosis is the role of inflammation in the development of endometriotic lesions and the propagation of pain. A major inflammatory mediator, tumor necrosis factor-alpha (TNF-α), has been implicated as a driving force behind this inflammation (Guerra-Infante 1999; Kim 2009). Pentoxifylline is a novel drug typically used to improve blood flow in conditions such as intermittent claudication. However, it is also a robust modulator of TNF-α (Gonzalez-Espinoza 2012; El Darouti 2011; Guerra-Infante 1999; Kim 2009). This has led some researchers to investigate the efficacy of pentoxifylline in treating endometriosis in both experimental and clinical settings.

In an animal model, 20 rats with induced endometriosis were allocated to receive pentoxifylline or control for 3 weeks. After the 3-week period, the extent of the animals’ endometriosis was evaluated. In the group that received the pentoxifylline, the average volume of endometriotic lesions was reduced significantly compared to control animals. Moreover, not only was lesion size reduced, but the overall number of lesions in the group that received pentoxifylline was lower than in the control group. The researchers also found that treatment with pentoxifylline reduced expression of a protein called vascular endothelial growth factor (VEGF), which plays a role in the development of endometriotic lesions. The scientists remarked “Pentoxifylline may cause suppression of endometriotic lesions…” (Vlahos 2010).

A clinical trial investigated the effects of pentoxifylline in women who underwent laparoscopic surgery in attempt to alleviate endometriosis-associated infertility. Ninety-eight subjects were randomized to receive either pentoxifylline 800 mg daily or placebo for 6 months. By the end of the study period, only 14% of the women in the placebo group had achieved pregnancy, whereas 28%–fully twice as many women–in the pentoxifylline group became pregnant (Creus 2008). In a separate, similarly designed study of 12-month duration, a trend toward higher pregnancy rates was observed among 30 women who received pentoxifylline compared to 30 who received a placebo (Balasch 1997).

In a trial on 34 women who underwent conservative surgery for endometriosis, pentoxifylline was shown to be superior to placebo for relieving pain during follow up. In this study, women received either pentoxifylline or a placebo for 3 months following conservative surgery for endometriosis. The women’s pain was measured using a standardized assessment each month following surgery. Pain scores were lower in the pentoxifylline group than in the placebo group at 2 and 3 months. The researchers concluded “The longer-term use of pentoxifylline after conservative surgery may improve long-term outcomes after surgical treatment for endometriosis” (Kamencic 2008).

Aromatase Inhibitors

Many of the conventional treatments for endometriosis, such as oral contraceptives and GnRH agonists, work by suppressing estrogen production by the ovaries (Ferrero 2011). Aromatase inhibitors are a class of compounds that may suppress estrogen production by ectopic endometrial tissue (Schenken 2012). Aromatase is an enzyme that converts other hormones, such as androstenedione and testosterone, into estrogen (Verma 2009; Schenken 2012). Some studies have found that the ectopic endometrial tissue found in endometriosis contains high levels of aromatase, which would allow this abnormal tissue to cause elevations in estrogen levels and may render ovary-focused treatments less effective for treating endometriosis-related pain (Verma 2009; Ferrero 2011). Excess fat tissue can also secrete large amounts of estrogen via aromatase (Verma 2009). Clinical trials have found that adding aromatase inhibitors to conventional treatments, such as oral contraceptives or GnRH agonists, reduces endometriosis pain and may improve quality of life. Randomized clinical trials have also suggested the use of aromatase inhibitors after surgery results in a reduced risk of disease recurrence (Ferrero 2011). Animal studies suggest these drugs may inhibit the growth of endometriosis lesions (Langoi 2013).

Angiogenesis Inhibitors

In order to survive, ectopic endometrial tissue must be able to generate blood vessels to supply it with oxygen and other nutrients, a process known as angiogenesis (Taylor 2011; Krikun 2012). An emerging treatment for endometriosis involves preventing this process. Preclinical studies have shown that blocking the effects of VEGF, an important protein for angiogenesis produced by ectopic endometrial tissue, helped inhibit the growth of endometriosis lesions (Ricci 2013; Taylor 2011; Imesch 2011). Researchers have also identified another protein, called tissue factor, which may promote the growth of new blood vessels in ectopic endometrial tissue (Krikun 2012). One laboratory has developed a special modified antibody (known as an immunoconjugate) called “Icon” which, at least in animal models, is able to bind to the tissue factor produced by ectopic endometrial tissue and inhibit pathologic blood vessels, thus causing the ectopic tissue to recede (Krikun 2010; Taylor 2011). Although this has yet to be tried on humans, it represents an intriguing new potential treatment for endometriosis.

Acupuncture

Acupuncture may be a viable intervention for women suffering from endometriosis. Acupuncture is increasingly used in the United States and other countries for chronic pain and gynecologic conditions (Wayne 2008). Studies have found that acupuncture is effective at relieving chronic pelvic pain in women with endometriosis (Kemper 2000; Zhu 2011; Rubi-Klein 2010; Rubi-Klein 2011; Wayne 2008; Schenken 2012). Acupuncture may be especially helpful for adolescents with endometriosis as their treatment options are often more limited (Highfield 2006).

9 Dietary and Lifestyle Considerations

Diet

There are many dietary factors that may influence endometriosis risk. Consuming red meat increases the risk of endometriosis, while increased consumption of long-chain omega-3 fatty acids (prevalent in fatty, cold-water fish) is associated with a decreased risk of endometriosis (Hansen 2013; Missmer 2010; Smith 2010; Parazzini 2004; Schenken 2012). Women consuming a diet rich in trans fats are also at higher risk of being diagnosed with endometriosis (Smith 2010). Indeed, one study found that women in the upper quintile (upper 20%) of trans-fat consumption had a 48% greater chance of being diagnosed with endometriosis (Missmer 2010). Other foods may also play a role. Increased dairy consumption was associated with a reduced risk of endometriosis in one study. Dairy may also provide vitamin D, and higher predicted vitamin D levels were associated with further reductions in endometriosis risk (Harris 2013). Eating more fruits and vegetables may also play a protective role (Parazzini 2004; Fjerbaek 2007; Schenken 2012).

Support Groups

Endometriosis is a complex disease that can cause debilitating pain and is often difficult to treat. Compounding this problem is that the diagnosis of endometriosis is often slow despite women making multiple trips to their physicians (Huntington 2005). Support groups can be invaluable as they can provide a connection to other women suffering from similar symptoms and provide an opportunity to learn more about the disease and strategies for coping with and treating the symptoms (Kennedy 2005; Whitney 1998; Huntington 2005).

10 Targeted Natural Interventions

Omega-3 Fatty Acids

The pain and infertility associated with endometriosis are likely due to increased levels of inflammation (Sekhon 2013; Bulun 2009). Omega-3 fatty acids have generated interest because of their anti-inflammatory abilities (Zhang 2012). These anti-inflammatory capabilities are likely one mechanism by which omega-3 fatty acids help prevent the development of endometriosis (Missmer 2010). Animal studies have helped validate the importance of omega-3 fatty acids for treating endometriosis. One study using an animal model of endometriosis found that supplementation with eicosapentaenoic acid (EPA), an important omega-3 fatty acid found in fish, reduced inflammation of the endometrium and also reduced levels of other molecules associated with endometriosis (eg, prostaglandin E synthase, an enzyme related to the chronic inflammation in endometriosis) (Netsu 2008). Another study examined the effects of fish oil supplementation on an animal model of endometriosis and found that fish oil was able to reduce the incidence of endometriosis-associated adhesions (Herington 2013). A large study found that women who ate greater amounts of long-chain omega-3 fatty acids were also less likely to develop endometriosis (Hansen 2013).

Vitamins E and C

Many lines of evidence suggest that oxidative stress, which is caused by reactive oxygen species, contributes to several aspects of endometriosis (Carvalho 2012; Augoulea 2012; Augoulea 2009; Gupta 2006; Sekhon 2013). Therefore, it is not surprising that vitamins E and C, both of which possess considerable antioxidant properties, have been studied in the context of endometriosis. In a study of 91 infertile women, those with endometriosis were shown to have lower levels of vitamin C in their follicular fluid (ie, fluid surrounding the eggs in the ovaries) compared to women who did not have endometriosis; women with endometriosis also had lower levels of the endogenous antioxidant superoxide dismutase in their plasma (Prieto 2012). In another study of 78 women aged 18–40, a modest association was observed between endometriosis and increased levels of a marker of oxidative stress called thiobarbituric acid-reactive substances (Jackson 2005).

Other evidence suggests that lower intake of antioxidants, including vitamins E and C, selenium, and zinc, in women with endometriosis correlate with more severe disease (Hernandez Guerrero 2006). These findings suggest that increasing consumption of antioxidants may benefit women with endometriosis. Accordingly, in a randomized, placebo-controlled trial, 59 women between 19 and 41 years of age were allocated to receive a combination of 1200 IU of vitamin E along with 1000 mg of vitamin C or a placebo each day for 8 weeks. Following the 8-week treatment period, 43% of women who received the vitamin E and C combination experienced reduction in chronic pain, 37% experienced reduction in pain associated with menstruation, and 24% experienced reduction in pain during intercourse compared to the placebo group. Moreover, several markers of inflammation and oxidative stress were reduced in the peritoneal fluid of women who took the antioxidants (Santanam 2013).

N-Acetyl Cysteine

N-acetyl cysteine (NAC) is a modified form of the natural amino acid cysteine (Muranaka 2013). It exerts several direct antioxidative actions and helps bolster the body’s intrinsic ability to combat oxidative stress by aiding the production of the endogenous antioxidant glutathione (Samuni 2013; Sadouska 2007). Several animal and human studies have shown that NAC may be an effective treatment option for endometriosis. In one animal model of endometriosis, 40 rats were randomized to receive one of 4 regimens: amifostine (a DNA protectant with antioxidant properties sometimes used to combat the side effects of cancer treatments), NAC, leuprolide acetate, or no treatment. Animals that received amifostine, lueprolide, and NAC exhibited a decrease in endometriotic lesion size and reduction in levels of the inflammatory marker TNF-α. When the groups were compared, the greatest reductions were noted in the animals allocated to NAC (Onalan 2013). Another study that examined the effects of NAC treatment both in human cell culture and in mice found that it reduced the oxidative stress burden and cellular proliferation in endometriosis. These findings led the researchers to conclude “Our […] model shows that antioxidant molecules could be used as safe and efficient treatments for endometriosis” (Ngo 2009). Additional positive results were noted in a study in which 92 women with endometriosis were allocated to receive NAC or no treatment for 3 months. Those who received NAC were administered 600 mg 3 times daily on 3 consecutive days per week. After the 3-month study period, endometriotic cysts were slightly reduced in size among women who took NAC, while a significant increase in cyst size was observed in the women who received no treatment. The researchers noted their findings for the efficacy of NAC were better than those reported after hormonal treatment of endometriosis. Significantly, 24 women who took NAC cancelled scheduled laparoscopy, whereas only a single non-treated subject did so. The scientists who conducted this study remarked “We can conclude that NAC actually represents a simple effective treatment for endometriosis, without side effects, and a suitable approach for women desiring a pregnancy” (Porpora 2013).

Additional Experimental Therapies

Green tea. Green tea is rich in compounds called polyphenols, which have a number of beneficial effects. In particular, green tea contains large amounts of a sub-class of polyphenols, called catechins, of which the most extensively studied is epigallocatechin gallate (EGCG). EGCG is the most abundant catechin in green tea, comprising 50–80% of the total catechins. EGCG and the other catechins have a variety of effects that may benefit women with endometriosis. They can inhibit the development of endometriotic lesions, inhibit inflammation, and exert anti-angiogenic effects (Man 2012).

The anti-angiogenic effects of green tea and EGCG have been researched in the context of endometriosis. In preclinical research of endometriosis, EGCG was able to decrease the growth of endometrial implants and reduce the formation of new blood vessels to ectopic endometrial tissue (Xu 2009; Ricci 2013).

Resveratrol. Resveratrol is a polyphenolic compound found in certain foods, including grapes, peanuts, some berries, and red wine (Higdon 2005). In preclinical research of endometriosis, resveratrol treatment reduced endometrial implants by 60% and total volume of lesions by 80%. Resveratrol inhibited angiogenesis in endometriotic lesions, a potential mechanism for resveratrol’s growth suppressing effects on this tissue (Bruner-Tran 2011; Rudzitis-Auth 2013; Ricci 2013).

Curcumin. Curcumin is a polyphenol derived from the Curcuma family of plants (Sharma 2005). Curcumin has anti-inflammatory, antioxidant, and anti-proliferative properties (Swarnakar 2009). Preclinical studies have suggested curcumin treatment would be helpful in endometriosis. Curcumin has shown anti-endometriotic effects by acting on cellular signaling pathways (eg, inhibiting NF-kB translocation and MMP-3 expression) and inducing apoptosis in endometriomas (Jana, Paul 2012; Jana, Rudra 2012; Swarnakar 2009).

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