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Endometriosis & Infertility

Infertility

Endometriosis & Infertility

August 2019

By Dr. Vandana Bhatia

OVERVIEW

Endometriosis derives its name from the word endometrium i.e. lining of the uterus. Endometriosis is a condition in which tissue resembling lining of the uterus (called “the endometrium”) is found outside the uterus and develop into lesions, implants, nodules or growths. These growths are generally benign. Being an estrogen-dependent condition,  these implants bleed internally during the menstrual cycle resulting in the chronic inflammatory reaction, scar formation and adhesion of the surrounding tissues distorting a woman’s pelvic anatomy. 

Endometriosis is a very common debilitating disease that occurs in 6 to 10% of the general female population. About 25 to 50% of infertile women have endometriosis and 30 to 50% of women with endometriosis are infertile. In women with pain, infertility or both, the frequency is 35–50%.

The symptoms of endometriosis include painful periods, painful ovulation, pain during or after sexual intercourse, heavy bleeding, chronic pelvic pain, fatigue, and infertility, and can impact on general physical, mental, and social well being. Pain can be cyclic or non-cyclic. However, 20–25% of patients remain asymptomatic. A general lack of awareness by both women and health care providers, due to a “normalisation” of symptoms, results in a significant delay from when a woman first experiences symptoms until she eventually is diagnosed and treated.

There is no known cause of endometriosis. Though endometriosis is associated with inflammation and immunological dysfunctions, it has not been proven itself to be an autoimmune disease. Certain genes may predispose women to develop the disease. Thus, women have a higher risk of developing the disease if their mother and/or sister(s) are also affected. Factors influencing endometriosis are -- the age when the menstrual period starts, other gynecologic factors, and environmental exposures to agents like dioxin.

Transvaginal ultrasonography accurately diagnoses endometriotic ovarian cysts. Laparoscopy remains the gold standard for diagnosing the disease especially for minimal to mild superficial lesions. Laparoscopy helps in the staging of the disease and enabling effective treatment at the same time. The symptoms of endometriosis may not always correlate with the laparoscopic findings.

There is no known cure of endometriosis and though it can be treated effectively with drugs, most treatments are not suitable for long-term use due to side-effects.

ENDOMETRIOSIS AND INFERTILITY

Endometriosis impairs infertility and it is due to the progression of the disease. The mechanisms responsible seem to be different in different stages of the disease. Factors causing infertility in patients with mild or minimal endometriosis, where ovaries and fallopian tubes are normal are ---  ovulatory dysfunction, impaired folliculogenesis and an inflammatory state. These have a toxic effect on gametes, embryos and is also associated with impairment of tubal motility. Endometrial receptivity is deranged in such patients leading to implantation failure. In moderate to severe disease, along with the above factors, there is a reduced quantity of functional ovarian tissue,  pelvic anatomy becomes distorted which impair tubal transport, oocyte release, sperm migration and uterine contractility. Thus endometriosis appears to be multifactorial involving mechanical, molecular, genetics and environmental causes.

TREATMENT OF ENDOMETRIOSIS ASSOCIATED INFERTILITY

The treatment plan is individualized and the aim is to maximize the benefits of medical therapy and avoid repeat surgeries. The clinical management of an infertile couple should take into account the age of the female, duration of infertility, male factor, pelvic pain, stage of endometriosis, and family history.

The current treatments include medical, surgical, assisted reproductive technologies or a combination of these approaches.

EXPECTANT MANAGEMENT

Expectant management may be considered for patients with minimal –mild endometriosis despite the significantly lower pregnancy rate when compared to normal women.

MEDICAL MANAGEMENT                                                            

Medical therapy is effective for relieving pain associated with endometriosis though there is no evidence that it improves fertility. Since endometriosis is an estrogen-dependent disorder,  medical therapies are aimed at treating ovarian estrogen production. These therapies include hormonal medications as combined oral contraceptive pills, progestins, aromatase inhibitors, danazol and GnRH analogues. These delay the patient from achieving conception. Newer medical therapies like selective estrogen receptor modulators, selective progesterone receptor modulators and others tending to reduce inflammation and improve angiogenesis like VEGF receptor antagonist, statins, immunoconjugates ( ICON ) are still in the experimental stage. As a general rule, for patients who desire pregnancy, medical therapy should be discouraged. Hormonal agents have been shown to suppress disease or to prevent recurrence since surgery may not remove the microscopic disease. Studies comparing surgery plus hormonal treatment versus surgery plus no treatment has shown no difference in the pregnancy rates. In infertile women with endometriosis through the clinicians are recommended not to prescribe adjunctive hormonal treatment before surgery to improve spontaneous pregnancy rates, however, clinicians mustn't withhold hormonal treatment for symptomatic women in the waiting period before undergoing surgery or assisted reproduction.

SURGICAL MANAGEMENT

The surgical approach in endometriosis aims to normalize pelvic anatomy, do adhesiolysis and remove macroscopic deposits as these have deleterious effects on oocyte quality, embryo development or implantation,  though it may not stop the inflammatory process. Surgery can be both diagnostic or therapeutic. Laparoscopy is preferred to laparotomy as it is more cost-effective,  causes minimal tissue damage, has a faster recovery and a shorter hospital stay. In minimal–mild endometriosis: ablation of endometriotic lesions plus adhesiolysis to improve fertility is effective compared to diagnostic laparoscopy alone. In moderate-severe endometriosis: It is difficult to answer whether surgical excision enhances pregnancy rates. Also, the woman should be counselled regarding the risks of reduced ovarian function after surgery and the loss of the ovary.

COMBINED MEDICAL AND SURGICAL THERAPY

Medical treatment can be combined with laparoscopic procedures either pre-operatively or postoperatively.

Pre-operative medical therapy

The advantages of preoperative therapy are that it aims to reduce inflammation, reduce vascularity and shrink the endometriotic lesions making the surgery easy and less traumatic.

The disadvantages are that small lesions may regress further and escape recognition during surgery, side effects of the drugs and the cost of the treatment increases.

Although theoretically advantageous, preoperative medical therapy does not suggest any benefit in enhancing fertility and may, in fact, delay further treatment.

Postoperative medical therapy:

Aims to eradicate the residual disease where complete resection was not possible or prevent a recurrence. However, the evidence does not suggest any favourable effect on the pregnancy rate. It may lead to inhibition of ovulation for a few months. Hence adjuvant medical therapy is not recommended.

Medical therapy may be of limited benefit in patients with endometriosis. Combination of medical and surgical therapy may theoretically improve fertility but it may delay further fertility therapy. The treatment of choice in such cases include surgery or straight away IVF followed by embryo transfer. Repeat surgery is unlikely to be beneficial in patients if initial surgery does not result in a pregnancy.IVF is a therapeutic option for such patients. Also, IVF particularly is an appropriate treatment if the tubal function is compromised or if there is associated male factor infertility or if other treatments have failed. It is suggested that, when the objective is to treat infertility, IVF-ET without prior surgery would probably be the best option. Thus, patients with a diagnosis of advanced endometriosis may be encouraged to undergo IVF-ET as the first-line treatment, before any attempt at surgical treatment.

ROLE OF CONTROLLED OVARIAN STIMULATION AND INTRAUTERINE INSEMINATION

The outcome of COH with or without IUI depends on patients age, duration of infertility and the stage of the disease.COH with IUI is recommended in surgically corrected patients with minimal – mild endometriosis rather than leaving the patient untreated. However, there is no role of IUI in moderate to severe endometriosis and it is better to proceed to IVF in these patients.

IMPACT OF ENDOMETRIOSIS ON IVF OUTCOME

Data regarding the impact of endometriosis on the IVF outcome is still controversial. Factors influencing the IVF outcome are the presence of ovarian endometrioma any past therapy, ovarian reserve, untreated hydrosalpinges, uterine evaluation, sperm function testing and ovulatory factors. Furthermore, the severity of the disease also affects the outcome --- stage III-IV disease has lower fertilization, implantation and pregnancy rates as compared with stages I and II. Nowadays preservation of ovarian tissues, oocytes or embryos should be discussed as an option as there may be a reduction in ovarian reserve after resection of endometriomas.

Though it is uncertain as to how much endometriosis affects IVF success rates, IVF is still currently the most effective treatment for patients all stages of endometriosis.

MEDICAL THERAPY BEFORE  IVF

Hormonal therapy such as oral contraceptive agents, GnRH agonists has not been proven to increase the chances of conception either in natural or stimulated cycles in patients undergoing IVF. GnRH before IVF stimulation may act by decreasing inflammatory factors or by having direct effects on the endometrium.

Apart from GnRH agonists, pretreatment with oral contraceptives for 6-8 weeks before IVF have also shown to have beneficial effects on pregnancy rates as compared to controls but without endometriosis.

SURGERY BEFORE IVF

The role of operative laparoscopy before IVF is controversial and it is not sure whether surgery adds anything of value or whether it is undertaken just because it is so-called gold standard. Surgery before IVF  may lead to ovarian failure in a few cases, may decrease ovarian responsiveness to stimulation and hence may increase the total FSH requirement. Also, resection does not improve pregnancy rates. Further IVF doesn’t increase the chance of recurrence. Treating hydrosalpinx secondary to endometriosis is controversial.  Laparoscopic salpingectomy or proximal tubal occlusion in patients with hydrosalpinges have better conception rates as compared to untreated hydrosalpinx or similar pregnancy rates as compared to patients without hydrosalpinges.  Good results have even been shown after hysteroscopic tubal occlusion.

CONCLUSIONS

Patients with stage I/II disease :

  • Though laparoscopy in asymptomatic women is of limited benefit,  it must be considered before treating the patient with ovulation-inducing agents and if undertaken then ablation or excision of visible lesions should be considered.
  • For young women < 35 years expectant management or COH with IUI after surgery may be offered but for women > 35 years more aggressive approach with COH with IUI or IVF-ET should be planned.

Patients with stage III/IV disease :

  • There is no role of expectant management
  • With no other infertility factor, conservative surgery with laparoscopy or laparotomy before IVF or straight away IVF-ET  is recommended.
  • In recurrent endometriosis, IVF ET is a better option than a repeat surgery