March is Endometriosis Awareness Month. Endometriosis is a painful condition where endometrial tissue grows outside the uterus. It is estimated that up to 10% of women have endometriosis (Ozkan 2008). Endometriosis can cause infertility and for women with subfertility the prevalence rate ranges from 25% to 40% (Ozkan 2008). Endometriosis frequently presents with the symptom of pain (Barlow 1993) including dysmenorrhoea (painful periods), dyspareunia (pain during sexual intercourse), and pelvic or abdominal pain.
We invited Edgardo Somigliana, MD-PhD (Dept Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy) to share his clinical view on endometriosis:
“Endometriosis is an enigmatic but curable disease. Significant improvements have been reached over the last two decades and most women can now be effectively cured. Indeed, when properly combined, surgery, hormonal medical therapy and assisted reproductive techniques can overcome endometriosis-related symptoms in the vast majority of cases. These results have not be obtained with revolutionary new therapies but, conversely, through a wiser use of the available tools (Vercellini 2015). Several challenges remain. Of utmost relevance is still disentangling the origin and pathogenesis of the disease. This unsolved issue is crucial and only progresses in this area could open new avenues or research that can ultimately lead to significant steps forwards, including prevention and early diagnosis.”
Cochrane Gynaecology and Fertility group has published over 20 intervention reviews and protocols investigating the effectiveness and safety of treatments for the management of endometriosis. In addition, we have published five diagnostic test accuracy reviews assessing the effectiveness of various tests in the diagnosis of endometriosis. We are joining #EndometriosisAwarenessMonth by sharing a special collection of our reviews on endometriosis that focus on pain-related outcomes and fertility outcomes. The treatments include pharmacological interventions (hormonal therapy, immune-modulators, anti‐inflammatory drugs), surgery, and alternative medicine.
Endometriosis: Special Collection
We published an overview of Cochrane reviews on Endometriosis in 2014. The objective of this overview was to summarise the evidence from Cochrane systematic reviews on treatment options for women with pain or subfertility associated with endometriosis. The overview included reviews pain relief (14 reviews) as well as review reporting fertility outcomes (8 reviews).
- Pharmacological interventions
Danazol is a hormone that produces male characteristics as well as weight gain and acne. It does, however, relieve the painful symptoms of endometriosis, although the side effects can be unacceptable (such as acne or muscle cramps). The improvement was still present six months after treatment was stopped. There was some evidence that women who took danazol were satisfied with the treatment compared with women who had inactive treatment.
GnRHas are a group of drugs often used to treat endometriosis by decreasing hormone levels. This review found evidence to suggest treatment with a GnRHa improved symptom relief compared with no treatment or placebo. There was no evidence of a statistically significant difference when compared with danazol or intra‐uterine progestagen. However, there more side effects in the GnRHa group compared with the danazol group. There is not enough evidence to make clear if higher or lower doses of GnRHa are better, or which length of treatment is best.
Possible adverse effects of GnRHas include loss of bone density, loss of sex‐drive and hot flushes. The decrease in bone density is particularly important because it increases the risk of osteoporosis. The review found that taking hormone replacement therapy with GnRHas can prevent this adverse effect. Danazol can also prevent loss of bone density, but adverse effects of danazol can include acne, weight gain and headaches.
Progestagens and anti‐progestagens are some of the hormonal drugs used for treatment. This systematic review of trials found limited evidence for the effectiveness of these drugs in the reduction of pain from endometriosis. This was due to the limited number of randomised controlled trials comparing each drug. There was no evidence of a benefit of depot or oral progestagens over other treatment. There was no evidence of a benefit of anti‐progestagens. Data should be interpreted with caution due to the limited number of trials and small sample sizes.
Progesterone receptor modulators have been advocated as one of the hormonal treatments for endometriosis. Moderate‐quality evidence shows that mifepristone relieves dysmenorrhoea (painful periods) in women with endometriosis. Evidence suggests that if 40% of women taking placebo experience dysmenorrhoea, then between 3% and 10% of women taking mifepristone will do so. Low‐quality evidence suggests that mifepristone also relieves dyspareunia (pain during sexual intercourse). However, amenorrhoea (absence of menstrual periods) and hot flushes were common side effects of mifepristone. Nearly 90% of the mifepristone group had amenorrhoea, and 24% had hot flushes, although researchers reported only one event of each (1%) among women taking placebo. Evidence was insufficient to show differences in rates of nausea, vomiting, or fatigue, if present. Comparisons of different doses of mifepristone were inconclusive, although evidence suggests that the 2.5 mg dose may be less effective than higher doses. Other studies assessed other progesterone receptor modulators. Researchers compared gestrinone versus other treatments (danazol or leuprolin), ulipristal versus leuprolide acetate, and asoprisnil verus placebo. However, evidence was insufficient to allow firm conclusions regarding the safety and effectiveness of these interventions.
The combined oral contraceptive pill (COCP) is commonly used to treat pain associated with endometriosis but how well it works is unclear. This review looked at two main comparisons. The quality of the evidence was very low. This means that we cannot be confident about the results.
Combined oral contraceptive pill versus placebo
Authors found two trials including 354 women that compared the COCP with a placebo (pretend treatment). The evidence was at high risk of bias. There was very low quality evidence that treatment with the COCP was associated with an improvement in self‐reported dysmenorrhoea (period pain) at the end of treatment measure on a verbal rating scale (where the woman rates her pain as (for example) "no pain," "slight pain," "moderate pain," "severe pain" and "unbearable pain") and low quality evidence for an improvement in self‐reported dysmenorrhoea pain at the end of treatment using a visual rating scale (where the woman marks her pain visually on a line) compared with placebo. There was very low quality evidence that there was a reduction in menstrual pain from the beginning to the end of treatment in the COCP group compared with women having a placebo.
Combined oral contraceptive pill versus other medical treatment
Authors found one trial of 50 women that compared the COCP with another medical treatment (goserelin). The study was at high risk of bias. At the end of treatment, the women in the goserelin group were not having a period and therefore the authors could not compare the groups. Six months after the end of treatment, there was very low quality evidence that there was no clear difference between women treated with the COCP and women treated with goserelin for self‐reported dysmenorrhoea, using a visual rating scale or a verbal rating scale. Six months after the end of treatment, there was very low quality evidence that there was no clear evidence of a difference between the COCP and goserelin groups for reporting complete absence of pain, as measured by a visual rating scale and low quality evidence using a verbal rating scale.
Hormone replacement therapy for women with endometriosis and post‐surgical menopause could result in pain and disease recurrence. However, the evidence in the literature is not strong enough to suggest depriving severely symptomatic patients from this treatment in order to relieve their menopausal symptoms.There is a need for double‐blinded randomised controlled studies to investigate further the effects of hormone replacement therapy on disease and pain recurrence.
Some studies support the contributing role of inflammation in endometriosis‐related pain. Since anti‐TNF‐α drugs can inhibit the inflammation process, they may relieve the symptoms of the disease without inhibiting ovulation. However, this systematic review included one randomised controlled trial and found that there was not enough evidence from which to draw conclusions about the effectiveness and safety of anti‐TNF‐α drugs in relieving pain in women with endometriosis. There was no evidence of an increase in adverse events in the anti‐TNF‐α drugs group compared with the placebo group.
Nonsteroidal anti‐inflammatory drugs (NSAIDs ) are readily available without prescription for pain relief. They work by preventing or slowing down the production of prostaglandins, which helps to relieve the painful cramps associated with endometriosis. However, a Cochrane review on the use of NSAIDs for painful periods found greater risk of stomach upset (e.g. nausea, diarrhoea) or other side effects (e.g. headache, drowsiness, dizziness, dryness of the mouth). Authors conducted this review to compare all NSAIDs used to treat women with painful symptoms caused by endometriosis versus placebo, other pain management drugs or no treatment, to evaluate their effectiveness and safety. The review found limited evidence on the effectiveness of NSAIDs (specifically naproxen) for management of pain caused by endometriosis. This review is also limited in that it includes only one study with data suitable for analysis, and this study involved only 20 women. Available evidence is of very low quality, mainly owing to poor reporting of methods, lack of precision in findings for overall pain relief, unintended side effects of treatment and the need for extra pain relief. The included trial did not report on quality of life, effects on daily activities, absence from work or school or participant satisfaction with treatment. Available evidence does not allow us to conclude whether NSAIDs are effective for managing pain caused by endometriosis, or whether any individual NSAID is more effective than another. As has been shown in other Cochrane reviews, women who use NSAIDs must be aware that NSAIDs may cause adverse effects such as nausea, vomiting, headache and drowsiness. Unless we identify new evidence in the future, the authors will not update this review again.
- Post-operative medical treatments
- Levonorgestrel‐releasing intrauterine device (LNG‐IUD) for symptomatic endometriosis following surgery
The progestogen levonorgestrel is a hormonal medication. The aim of this review was to assess whether the use of a hormone‐releasing intrauterine device was beneficial for managing associated painful symptoms and for preventing recurrence of endometriosis following surgery. Although preliminary findings are encouraging, at this stage there is only limited evidence from three randomised trials of a beneficial role with the use of the LNG‐IUD in reducing the recurrence of painful periods following surgery for endometriosis. The strength of the evidence was graded as moderate reflecting our belief that future evidence will most likely not change these findings.
- Alternative treatments
Acupuncture is frequently used to treat both pain and various gynaecological conditions. This review examined the effectiveness of acupuncture for reducing pain in endometriosis; however only one study met our inclusion criteria. The data from the included study, involving 67 women, indicated that ear acupuncture is more effective compared to Chinese herbal medicine for reducing menstrual pain. The study did not report whether participants suffered any side effects from their treatments. Larger, well‐designed studies comparing acupuncture with conventional therapies are necessary to confirm these results.
The two small studies in this review suggest that Chinese herbal medicine (CHM) may be as effective as gestrinone and may be more effective than danazol in relieving endometriosis‐related pain, with fewer side effects than experienced with conventional treatment. However, the two trials included in this review were small and of limited quality so these findings must be interpreted cautiously. Better quality randomised controlled trials are needed to investigate a possible role for CHM in the treatment of endometriosis.
Reviews reporting fertility outcomes
- Pharmacological interventions
Recent studies support the influence of the immune system on endometriosis. Pentoxifylline is an immunomodulator drug (used for effects on the immune system) which may relieve the symptoms of the disease without inhibiting ovulation. It may improve blood flow through blood vessels and, therefore, help with blood circulation because of its anti‐inflammatory activity. However, this systematic review of four trials found there was not enough evidence upon which to draw conclusions about the effectiveness and safety of pentoxifylline in terms of fertility and pain relief outcomes in women with endometriosis. At the update in 2011, there was still no evidence of an increase in pregnancy events in the pentoxifylline group compared with placebo.
This review of 23 trials involving 3043 women with endometriosis has shown that there is no evidence of benefit with the use of ovulation suppression for women with endometriosis and infertility. Endometriosis is caused by the lining of the uterus (endometrium) spreading to a site outside the uterus. It is associated with subfertility and can cause pain during both sexual intercourse and menstruation. The hormone oestrogen stimulates the growth of endometriosis. For many years, the use of drugs such as danazol to stop ovulation and the production of oestrogen has been standard practice in the treatment of pain and subfertility caused by endometriosis. This works well for pain, but does not appear to improve fertility. In fact, as ovulation and periods are stopped for the time of treatment, fertility may be reduced by this approach.
- Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis
Infertile women with endometriosis are often treated with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) but have a lower chance of becoming pregnant compared to women who are infertile with blocked tubes. It has been suggested that giving gonadotrophin releasing hormone (GnRH) agonists before IVF or ICSI could increase the chances of pregnancy. We have reviewed the literature and found that treating women for three to six months with GnRH agonists before IVF or ICSI increases the odds of clinical pregnancy four‐fold. However, at present there is no information on the effect of this treatment on the incidence of ectopic pregnancy, multiple pregnancies or complications arising for the women or their offspring. This will review will be superseded by a new review currently in preparation: Long-term GnRH agonist therapy before in vitro fertilization (IVF) for improving fertility outcomes in women with endometriosis.
- Surgical interventions
Different treatments for endometriosis are available, one of which is laparoscopic ('key hole') surgery, performed to remove visible areas of endometriosis. In 2014 Cochrane review authors assessed the evidence on the use of laparoscopic surgery to treat pain and fertility problems in women with endometriosis. Laparoscopic surgical techniques include ablation, which means destruction of a lesion (for example by burning), and excision, which means cutting a lesion out. The authors found that laparoscopic surgery may be of benefit in treating overall pain and subfertility associated with mild to moderate endometriosis. Laparoscopic excision and ablation were similarly effective in relieving pain, although this result came from a single study. There was insufficient evidence on adverse events to allow any conclusions to be drawn regarding safety. The quality of the evidence was moderate with regard to the effectiveness of laparoscopic surgery. Additional studies are needed in this field, and these should report adverse events as an outcome.
Endometriomata are benign growths of the ovary. Evidence suggests that surgery to remove the endometrioma provides better results than draining and destroying the lining of the cyst with regard to the recurrence of the cyst, pain symptoms and also the chance of a spontaneous pregnancy in women who were previously subfertile. Surgery to excise the cyst should be the favoured surgical approach. Evidence that one technique is favoured in women who desire to conceive and who seek in vitro fertilization (IVF) treatment is however lacking. An additional randomised trial demonstrated that in women trying to conceive the ovarian response to stimulation, as part of fertility treatment, is better in women who have undergone surgery to remove the cyst rather than draining and destroying the endometrioma. The subsequent likelihood of pregnancy was not affected. Further research is required in this field to assess quality of life after surgery, clarify the effect of surgery on fertility with IVF treatment and to study the effect of surgery on ovarian function.
Common treatments of endometriosis are hormonal suppression with medical therapy to reduce the size of endometrial implants or laparoscopic surgery (where small incisions are made in the abdomen) to remove visible areas of endometriosis. There is no evidence that hormonal suppression either before or after surgery is associated with a benefit compared with surgery alone with regard to the outcomes evaluated (including pregnancy).
Diagnostic test accuracy (DTA) reviews
Currently, the only reliable way of diagnosing endometriosis is to perform laparoscopic surgery and visualise the endometrial deposits inside the abdomen. Because surgery is risky and expensive, imaging tests have been assessed for their ability to detect endometriosis non‐invasively. None of the imaging methods was accurate enough to provide this information on overall pelvic endometriosis. Transvaginal ultrasound identified ovarian endometriosis with enough accuracy to help surgeons determine whether surgery was needed, and magnetic resonance imaging (MRI) was sufficiently accurate to replace surgery in diagnosing endometrioma but was evaluated in only a small number of studies. Other imaging tests were assessed in small individual studies and could not be evaluated in a meaningful way. Transvaginal ultrasound could be used to locate more anatomical sites of deep endometriosis when compared with MRI, helping surgeons better plan an operative procedure. Endometriosis in the lower bowel appears to be relatively accurately identified by both transvaginal and transrectal ultrasound, by MRI and by multi‐detector computerised tomography enema. New types of ultrasound and MRI show a lot of promise in detecting endometriosis but studies are too few to clearly show their diagnostic value. Additional high‐quality research is needed to accurately evaluate the diagnostic potential of non‐invasive imaging tests for endometriosis.
Authors evaluated whether the results of blood tests (blood biomarkers) can help to detect endometriosis non‐invasively. Only four of the assessed biomarkers (anti‐endometrial Abs (anti‐endometrial autoantibodies), interleukin‐6 (IL‐6), CA‐19.9 and CA‐125) were evaluated by enough studies to provide a meaningful assessment of test accuracy. None of these tests was accurate enough to replace diagnostic surgery. Several studies identified biomarkers that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit. Overall, there is not enough evidence to recommend testing for any blood biomarker in clinical practice to diagnose endometriosis. More high-quality research trials are necessary to accurately assess the diagnostic potential of certain blood biomarkers, whose diagnostic value for endometriosis was suggested by a limited number of studies.
An accurate urine test could lead to the diagnosis of endometriosis without the need for surgery. Can any urine test be accurate enough to replace or reduce the need for surgery in the diagnosis of endometriosis? None of the assessed biomarkers, including cytokeratin 19 (CK 19), enolase 1 (NNE), vitamin D binding protein (VDBP) and urinary peptide profiling have been evaluated by enough studies to provide a meaningful assessment of test accuracy. None of the tests were accurate enough to replace diagnostic surgery. Several studies identified biomarkers that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit. There is not enough evidence to recommend any urinary biomarker for use in clinical practice for the diagnosis of endometriosis. More high quality research trials are needed to accurately assess the diagnostic potential of urinary biomarkers identified in small numbers of studies as having value in detecting endometriosis.
Can physicians use biomarkers (distinctive molecules, genes or other characteristics that appear in certain conditions) to reduce the need to surgically diagnose endometriosis? Only two of the assessed biomarkers, a neural fibre marker PGP 9.5 and hormonal marker CYP19, were assessed in sufficient number of studies to obtain meaningful results. PGP 9.5 identified endometriosis with enough accuracy to replace surgical diagnosis. Several additional biomarkers (endometrial proteome, 17βHSD2, IL‐1R2, caldesmon and other neural markers) show promise in detecting endometriosis, but there are too few studies to be sure of their diagnostic value. Further high quality research is necessary to accurately evaluate the diagnostic potential of the endometrial biomarkers for the diagnosis of endometriosis.
In this review, fifteen combinations of different blood, endometrial and urinary biomarkers were studied, incorporating ultrasound, clinical history and examination. Each combination of tests was assessed in small individual studies. Several studies identified the combined tests that might be of value in diagnosing endometriosis, but there are too few reports to be sure of their diagnostic benefit. The reports were of low methodological quality, which is why these results cannot be considered reliable unless confirmed in large high‐quality studies. Overall, there is not enough evidence to demonstrate benefit of any combined non‐invasive test for use in clinical practice for the diagnosis of endometriosis over the current ‘gold standard’ of diagnostic laparoscopy. More high‐quality research studies are needed to accurately assess the diagnostic potential of any type of non‐invasive tests or their combinations that were identified in only a few studies as possibly having value in the detection of endometriosis.
- Long-term GnRH agonist therapy before in vitro fertilization (IVF) for improving fertility outcomes in women with endometriosis
The objectives of the protocol are to determine the effectiveness and safety of long‐term GnRH agonist therapy versus no pretreatment or other pretreatment modalities, (such as long‐term continuous COC or surgical therapy), before standard IVF or ICSI in women with endometriosis. When published, this review will supersede Long‐term pituitary down‐regulation before in vitro fertilization (IVF) for women with endometriosis.
Objective: To determine the effectiveness and safety of GnRH antagonists in the treatment of pain associated with endometriosis.
Objective: To determine the effectiveness and safety of SERMs for the management of endometriosis.
The objective of this protocol is to determine whether surgical excision or ablation is the optimum management of peritoneal endometriosis with respect to pain and secondary outcomes on fertility, recurrence and safety or harm issues.