Abstract
Endometriosis is a chronic and recurrent condition affecting 6–10% of women of a reproductive age. It results from implantation of endometrial tissue outside the uterine cavity. It is associated with pelvic pain and infertility. Treatment for endometriosis ranges from medical management, to conservative surgery, to definitive surgery with a hysterectomy and bilateral salpingo-oophorectomy, and should be based on patient's fertility desires and tolerance. Medical treatment involves hormonal manipulation to induce a hypoestrogenic or antiestrogenic state to induce regression and apoptosis of lesions. Endometriosis can have dire effects on women's lives and productivity; this article will focus on early diagnosis, treatment and prevention of recurrence of the disease.
Keywords
Endometriosis is a chronic and recurrent condition resulting from the attachment and implantation of functional endometrial tissue outside the uterine cavity. It affects 6–10% of women of a reproductive age with a and IL 20–50% in women suffering from infertility and of 71–87% in women suffering from chronic pelvic pain. Endometriosis is more common in women with: early menarche, polymenorrhea, menorrhagia, outflow genital tract obstruction, and a family history of the disease. Women who have a first degree relative affected by endometriosis are seven times more likely to suffer from the disease [1]. The prevalence of endometriosis is most common in the third and fourth decades of life but can also affect adolescents. Endometriosis is diagnosed at laparoscopy in 45% of teenagers with chronic pelvic pain, and in 70% of teenagers with pelvic pain who have not responded to oral contraceptives and NSAIDs [2].
Symptoms of endometriosis affect approximately 10 million American women, disrupting the patients' lives causing emotional and physical disabilities and decreased productivity. The annual cost of managing endometriosis is greater than US $20 billion. Unfortunately, despite the high incidence of endometriosis and the debilitating symptoms associated with this condition, most women are not properly diagnosed and treated until 7 years after becoming symptomatic and after having seen several physicians. The goals of this article will be to not only address early diagnosis and treatment of endometriosis but also to focus on prevention of recurrence of disease and symptoms.
Etiology & clinical manifestations
The etiology of endometriosis depends on the complex interaction of multiple factors: genetic, immunologic, environmental and hormonal. Sampson's theory of retrograde menstruation explains how the ectopic endometrium gets into the peritoneal cavity but does not explain why some women get endometriosis and some do not, as 90% of women with patent fallopian tubes experience retrograde menstruation every month. Other theories, including Meyer's theory of coelomic metaplasia, explains the rare occurrence of endometriosis in women with mullerian agenesis. Halban's theory of lymphatic and vascular dissemination of endometrial tissue explains the occurrence of endometriosis in the lungs and other organs distant from the pelvis [3]. However, retrograde menstruation, coelomic metaplasia and vascular dissemination occur in most women and only 10% are affected by the disease.
Genetics plays a significant role in the pathogenesis of endometriosis; it has been found that the endometrium of women with endometriosis differs from the endometrium of women who do not develop the disease in several different ways, explaining why some women and not the majority of women develop the disease. The endometrium of women with endometriosis exhibits aromatase enzyme activity, allowing the endometriosis implant to make its own estrogen to promote its proliferation and growth. In addition, both eutopic endometrium and ectopic endometriosis implants have increased expression of the adhesive molecules VEGF and matrix metalloproteinase-2, which promote attachment, vascularization and invasiveness of ectopic endometrium in affected women. Finally, endometriosis implants decrease the immunologic activity of macrophages, inducing an immunologic tolerance of the endometriosis. These changes in the endometrium of affected women are genetically determined and passed on from one generation to the next and explain why endometrial tissue in women affected by endometriosis is able to implant outside the uterus and lead to the associated pathology. Although the complexity of the pathogenesis of endometriosis may not be completely understood, the symptoms that result from this condition are classic and congruent with the disease process.
Like normal endometrium, endometriosis implants respond to cyclic ovarian hormone fluctuations proliferating with estrogen stimulation and bleeding at the end of each menstrual cycle. This leads to a chronic inflammatory milieu with increased numbers of inflammatory cytokines (TNF-α, and IL-1, −6 and −8) and macrophages within the peritoneal cavity. The cytokines induce prostaglandin production, leading to pain. There is also an increase in nerve fibers and NGF found in deep endometriosis lesions, increasing symptoms of pain [1]. This inflammatory response also leads to adhesion formation, which immobilizes structures and alters the normal anatomy leading to infertility and additional pain from nongenital organs such as the bowel or bladder.
Besides the classic triad of endometriosis symptoms, dysmenorrhea, infertility and dyspareunia, endometriosis may also cause symptoms from other organs, such as dyschezia and tenesmus when it involves the bowel or dysuria and/or hematuria when it invades the bladder. When endometriosis affects distant sites like the lungs, chest wall or diaphragm, patients may complain of catamenial hemoptysis, pneumothorax or shoulder pain. Clinical signs of endometriosis include: fibrosis and tenderness of the anterior/posterior cul-de-sacs and uterosacral ligaments, fixed tender uterus, and adnexal tenderness or masses. Transvaginal ultrasound can be an adjunct to the pelvic examination, aiding in the diagnosis of endometriomas and deep infiltrating endometriosis of the rectovaginal septum, but it is not diagnostic of the disease. Although these symptoms and clinical signs are common in women with endometriosis they may also occur with other conditions, such as chronic pelvic inflammatory disease, adhesive disease or neoplasm, thus, the diagnosis of endometriosis can only be confirmed by laparoscopy with histologic confirmation of resected lesions that show evidence of endometrial stroma and glands.
Treatment
Medical
Since endometriosis is a hormonally responsive disease, proliferating with estrogen and regressing with progesterone/progestins and androgens, the medical treatments for endometriosis have concentrated on establishing either a hypoestrogenic milieu with gonadotropin-releasing hormone analogs (GnRH-a) or an antiestrogenic environment with progestins or danazol to improve symptoms, induce apoptosis and regression of existing lesions, and prevent growth of new lesions. Although definitive diagnosis of endometriosis requires a laparoscopy, empiric medical treatment has been advocated to not only treat symptoms but also to make a presumptive diagnosis of endometriosis. A randomized study treated 100 symptomatic women with clinically suspected endometriosis with empiric leuprolide (GnRH-a) for 3 months and found that nearly 90% of the subjects experienced significant improvement in their symptoms. Subsequent laparoscopy in these patients, confirmed the diagnosis of endometriosis in 80%, suggesting that a good response to empiric medical treatment correlates well with the diagnosis of endometriosis [4]. Not everyone agrees with this conclusion and feel that the 20% of subjects who were not found to have endometriosis at laparoscopy would be wrongly diagnosed with endometriosis based on empiric response alone. This may be important since a diagnosis of endometriosis has implications not only for the subject but also for her siblings and offspring. Medical treatment for endometriosis is first line in patients whose chief complaint is pelvic pain but not infertility, for which medical treatment has been consistently found to be ineffective. Besides GnRH-a, other medical treatment options include progestins, as well as impeded androgens, and they are all equally effective in the management of symptomatic endometriosis, so decisions regarding use should focus on patient tolerability and, finally, cost.
First-line treatment for endometriosis-related pelvic pain is hormonal contraceptives taken continuously to effect amenorrhea, along with NSAIDs. When taken together this regimen is associated with significant pain reduction. For severe recalcitrant symptoms more aggressive medical therapy could be considered. Another option, if no improvement is seen, is to consider a laparoscopy to definitively diagnose endometriosis and rule out any other pelvic pathology.
Gonadotropin-releasing hormone analogs are an effective treatment for endometriosis as they induce a hypogonadotropin–hypoestrogenic environment with low follicle-stimulating hormone and luteinizing hormone. GnRH-a have been shown to be as effective as other medical therapies in treating endometriosis-associated pain with a different side-effect profile. Side effects from GnRH-a include hot flashes, night sweats, vaginal dryness, decreased libido, emotional lability and muscle soreness, and therapy for greater than 6 months has been associated with a significant reduction (5%) in bone mineral density. Two studies evaluated the effectiveness of add-back therapy in the form of low-dose norethindrone acetate or low-dose combination estradiol and norethindrone acetate therapy on women treated with GnRH-a and found a reduction of vasomotor symptoms and bone mineral density loss in these women with no change in relief of endometriosis symptoms [5,6]. This has led to the recommendation that any prolonged use of GnRH-a should be accompanied by add-back therapy and some authors suggest all patients on GnRH-a should be treated with add-back.
Progestins have been used for treating endometriosis-related pain by inducing regression and apoptosis of endometriosis lesions. Progestins come in many forms including pills, injections and intrauterine devices. Medroxy-progesterone acetate was the first progestin used to treat endometriosis and was found in one placebo-controlled prospective trial to be effective at a dose of 100 mg/day in treating endometriosis when compared with placebo. Side effects include acne, muscle cramps, weight gain, edema and spotting [7]. Medroxy-progesterone acetate is also available as a trimonthly depot shot either 104 mg subcutaneously or 150 mg intramuscularly. Side effects are similar to oral medroxy-progesterone acetate but also include reversible bone loss after long-term use.
In addition, noethindrone acetate (NETA) has been given in oral dosages of 2.5–10 mg/day to effect amenorrhea and relieve symptoms associated with endometriosis. NETA is associated with acne and irregular bleeding. Dienogest, a similar progestin to NETA, is approved in Europe at doses of 2 mg/day to treat endometriosis pain and was found to be very effective with minimal side effects, including break through bleeding, nausea and breast tenderness [8]. This medication is currently only used in the USA in combination oral contraceptives. The levonorgestrel intrauterine device (LNG-IUS) has been used to treat endometriosis-associated pain and has been found to be very effective with minimal side effects. In one recent study comparing LNG-IUS to GnRH-a, the LNG-IUS was found to be equally effective to GnRH-a in reducing pelvic pain in women surgically diagnosed with endometriosis [9].
Danazol, an attenuated androgen, has been used in the past to treat endometriosis-related pain. Side effects from this medication include hirsutism, deepening voice, acne, changes in liver enzymes, decreased high-density lipoprotein and increased low-density lipoprotein levels. Owing to poor tolerability, this medication is used very rarely now but was found to be equally effective to GnRH-a in relieving symptoms of endometriosis [10].
Aromatase inhibitors are being studied for use in treating symptomatic endometriosis. Initial studies were performed on women who had a hysterectomy and bilateral salpingo-oophorectomy with residual pain from endometriosis. These studies revealed that aromatase inhibitors were very successful in treating these refractory cases. Aromatase inhibitors are associated with hot flashes, mild headache, nausea, myalgia, arthralgia, and in premenopausal women, ovarian cyst formation. Most studies evaluating the use of aromatase inhibitors combine them with oral contraceptives or NETA to avoid the follicular recruitment and ovarian stimulation associated with the elevated follicle-stimulating hormone levels induced by aromatase inhibitor activity. Initial studies have shown significant relief of pain similar to GnRH-a with less side effects [11]. A review of aromatase inhibitors to treat endometriosis-related pain looked at four prospective nonrandomized trials and four randomized placebo-controlled trials and concluded that aromatase inhibitors are effective in treating endometriosis-related pain but should be used in combination with progestin or oral contraceptives in premenopausal women [12].
Surgical
All medical treatments for endometriosis-related pelvic pain are equally effective in suppressing symptoms, however, none are curative. Often these patients require surgical management as well. Excision and ablation of endometriosis lesions has been shown to improve pain in patients with endometriosis, however, postsurgical recurrence of symptoms and disease approaches 50% unless definitive surgery with hysterectomy and bilateral salpingo-oophorectomy is performed. In a recent study, Shakiba
Recurrence of symptoms may be due to residual endometriosis that was not removed at initial surgery or recurrence of the disease itself with reseeding of implants from recurrent menstruations. Indeed, when menses are suppressed with continuous use of oral contraceptives or with Mirena® (LNG-IUS, Bayer HealthCare Pharmaceuticals, Pittsburgh, PA, USA) or with endometrial ablation following conservative surgery for endometriosis, recurrence of symptoms and disease is decreased by as much as 75% [8,14]. In women with endometriomas seen on pelvic ultrasound and treated by excision of cyst wall at laparoscopy, two studies have shown that the use of combined oral contraceptives postoperatively reduces recurrence of endometriomas. A statistically significant difference in endometrioma recurrence was seen in combined oral contraceptive users versus patients who had no postoperative treatment [15,16].
A recent comprehensive review of literature regarding laparoscopic treatment of endometriosis answers important questions regarding surgical management and made four important conclusions:
Laparoscopic treatment of endometriosis is beneficial for reducing pain and improving fertility;
Presacral neurectomy, not uterosacral nerve ablation, is a useful adjunct to conservative surgery especially in patients with ‘central pain‘;
Postoperative hormonal suppression with GnRH-a, progestins, or LNG-IUS is effective in reducing pain and increasing time to recurrence;
Excision of the cyst wall is the preferred method of treating endometriomas for both pain and fertility [17].
Medical management is not effective in treating endometriosis-related infertility as their mechanism of action prevents pregnancy. Patients with endometriosis have decreased fecundity rates compared with women not affected by endometriosis and surgical management improves pregnancy rates but the magnitude is unknown. Excision of endometrioma cyst walls has been shown to improve pregnancy rates over ablation of the cyst wall, however, removal of deep infiltrating endometriosis has not been clearly shown to improve fertility [18]. If initial surgery is not successful, repetitive surgeries have not been shown to be beneficial in improving fertility and may have a negative effect on ovarian reserve if multiple ovarian surgeries are performed. Assisted reproductive technologies may be more effective in these patients [19].
Prevention or suppression of recurrence
Early diagnosis and suspicion of endometriosis is the key in preventing symptoms. Patients with daughters who have dysmenorrhea and pelvic pain should be alerted to these symptoms and have their daughters evaluated by experts who can diagnose and treat them if necessary. Although the exact cause of endometriosis is unknown, factors that can increase the risk of developing endometriosis are known. Decreasing the duration and amount of menstrual bleeding is key in improving symptoms and in reducing the progression and recurrence of endometriosis. This can be accomplished with the continuous use of oral contraceptives, postoperative GnRH-a and LNG-IUS, all of which have been shown to increase the disease-free interval and reduce recurrences.
Women who have endometriosis-related infertility often require surgery. Actively trying to conceive after surgery with or without the use of controlled ovarian stimulation, or assisted reproductive technologies should be recommended to minimize recurrence of disease. The high progesterone state of pregnancy often relieves patients of symptoms of endometriosis.
In women who have completed child bearing and have persistent and debilitating symptoms from endometriosis should be counseled regarding definitive treatment with a hysterectomy and bilateral adnexectomy. This surgery is associated with the least recurrence of symptoms.
Endometriosis is a chronic and often debilitating condition that requires vigilance in diagnosis and treatment. Although its cause and mechanism of action is not fully understood, aggressive medical and surgical management can treat many symptoms and minimize recurrence.
Future perspective
Endometriosis is a chronic condition that affects reproductive aged women and recurs without treatment. Focus over the next 5–10 years will continue to be on preventing disease or recurrence of disease so these women can lead productive lives. Current research is looking at selective estrogen receptor modulators and selective progesterone receptor modulators to target endometriosis implants. Current therapies are not as specific and have associated hypoestrogenic or antiestrogenic side effects, which are not always well tolerated. More targeted therapies have the potential to improve our patients' symptoms without adversely affecting their quality of life.
Active research is also being conducted with noninvasive blood tests examining specific proteins and genes in women affected by endometriosis with the ultimate goal of identifying women at risk for endometriosis before they even develop the disease. Perhaps once these women have been identified, treatments targeting the differences between those women affected by endometriosis versus those who are not, will allow us to treat these women more effectively. We know that endometrium in women affected by endometriosis differs from those who are not affected, perhaps molecular differences in these patients' endometrial cells can be targeted and ‘turned off’ so the disease does not progress.
Repeated surgery, especially on the ovaries, has been associated with decreasing ovarian reserve; further confirming our need to look for preventative measures as opposed to treatment exclusively. As women continue to postpone childbearing until the fourth decade of life the need to identify women at risk for endometriosis and control and prevent endometriosis from adversely affecting our patients becomes that much more relevant.
Executive summary
Endometriosis is a chronic condition that affects 6–10% of women of a reproductive age with a prevalence of 20–50% in women suffering from infertility and of 71–87% in women suffering from chronic pelvic pain.
Genetics plays a significant role in the pathogenesis of endometriosis; it has been found that the endometrium of women with endometriosis differs from the endometrium of women who do not develop the disease. The endometrium of women with endometriosis exhibits aromatase activity, has increased expression of the adhesive molecules VEGF and matrix metalloproteinase-2, and induces an immunologic tolerance of the endometriosis.
As well as the classic triad of endometriosis symptoms, dysmenorrhea, infertility and dyspareunia, endometriosis may also cause symptoms from other organs, such as dyschezia and tenesmus when it involves the bowel or dysuria and/or hematuria when it invades the bladder.
Clinical signs of endometriosis include fibrosis and tenderness of the anterior/posterior cul-de-sacs and uterosacral ligaments, fixed tender uterus, and adnexal tenderness or masses.
Transvaginal ultrasound can be an adjunct to the pelvic exam aiding in the diagnosis of endometriomas and deep infiltrating endometriosis of the rectovaginal septum.
Since endometriosis is a hormonally responsive disease, proliferating with estrogen and regressing with progesterone/progestins and androgens, the medical treatments for endometriosis have concentrated on establishing either a hypoestrogenic milieu with gonadotropin-releasing hormone analogs, or an antiestrogenic environment with progestins.
First-line treatment for endometriosis-related pelvic pain is hormonal contraceptives taken continuously to effect amenorrhea, along with NSAIDs.
Side effects from gonadotropin-releasing hormone analogs include hot flashes, night sweats, vaginal dryness, decreased libido, emotional lability and muscle soreness; and therapy for greater than 6 months has been associated with a significant reduction (5%) in bone mineral density. Prolonged use of gonadotropin-releasing hormone analogs should be accompanied by add-back therapy.
Progestins have been used for treating endometriosis-related pain as progestins induce regression and apoptosis of endometriosis lesions, and progestins come in many forms including pills, injections and intrauterine devices.
Laparoscopic treatment of endometriosis is beneficial for reducing pain and improving fertility; presacral neurectomy is a useful adjunct; postoperative hormonal suppression is effective in reducing pain and increasing time to recurrence; and excision of the cyst wall is the preferred method of treating endometriomas for both pain and fertility.
Surgical treatment in the form of a hysterectomy and bilateral salpingo-oophorectomy is often curative in patients who no longer desire child bearing.
Early diagnosis and suspicion of endometriosis is the key in preventing symptoms. Decreasing the duration and amount of menstrual bleeding with continuous oral contraceptives or the levonorgestrel intrauterine device is key in improving symptoms and in reducing the progression and recurrence of endometriosis.
Footnotes