Endometriosis: The mystery prevails

Management of endometriosisEndometriosis is a relatively common condition in which cells that normally grow within the uterus are found affecting other structures in the abdominal-pelvic cavity.

 The ectopic foci of endometrial deposits respond to cyclic hormonal fluctuations in much the same way as the intrauterine endometrium, with proliferation, secretory activity, and cyclic sloughing of the menstrual lining.

These endometrial deposits may result in the formation of lesions and cysts that cause scarring to organs such as the ovaries, fallopian tubes, bladder and rectum. These lesions also lead to inflammation, abnormal nerve growth and fibrosis causing persistent abdominal–pelvic pain.

Clinical manifestation and management

Endometriosis is therefore viewed as a chronic disease requiring life long management. The clinical manifestations classically are pelvic pain, infertility and the presence of a pelvic mass.

Management strategies incorporate a definite diagnosis, optimising medical management and using minimally invasive surgical techniques. Surgically removing lesions or cysts can temporarily relieve pain until the deposits recur.

A better solution is to reduce levels of the hormone estrogen throughout the body as healthy endometrial tissue in the uterus relies heavily on estrogen to grow and survive.

Reducing the hormone throughout the body has unfortunate side effects, such as menopausal symptoms and infertility.  Although there is no true clear treatment of endometriosis, laparoscopic diagnosis remains the gold standard and provides an opportunity for histological diagnosis and conservative surgical treatment.

 Treatment

Therefore, treatment decisions are individualised, taking into account the severity of the symptoms, the extent and location of disease, the desire for pregnancy, the age of the patient, medication and its side effects, surgical complications and overall costs.

Treatment options include:

  • Expectant management.
  • Analgesia.
  • Hormonal medical therapy.
    • Estrogen-progestin oral contraceptives, cyclic or continuous.
    • Gonadotropin-releasing hormone (GnRH) agonists.
    • Progestins, given by an oral, parenteral, or intrauterine route.
    • Danazol
    • Aromatase inhibitors.
  • Surgical intervention, which may be conservative (retain uterus and ovarian tissue) or definitive (removal of the uterus and possibly the ovaries).
  • Combination therapy in which medical therapy is given before and/or after surgery.

Pelvic pain

Should endometriosis be highly suggestive after a detailed history and clinical examination empiric medical treatment may be initiated before a definitive diagnosis by laparoscopy. A general guide is to determine the severity of pain and then adjust the treatment as needed.

For mild pain it is suggested that non-steroidal anti-inflammatories are used in combination with the oral combined contraceptive pill. A GnRH agonist will benefit those patients with moderate to severe pelvic pain.

Progestins, more recently dienogest, have shown a significant improvement in symptom relief. Other classes of progestins, injectables and intrauterine contraceptive devices have also shown to reduce symptoms and slightly decrease severity of endometrial lesions.

With medical treatment the majority of patients, almost 90%, will have some improvement with symptoms but no improvement with infertility nor experience a significant decrease with regards to lesions and fibrosis.

These individuals will often need further surgical intervention. In some studies acupuncture has shown to reduce the need of analgesics. Cognitive behavior therapy has shown to reduce symptoms. The use of transcutaneous nerve stimulation (TENS) and heat application, from hot water bottles has also provided symptom relief for some patients.

Nerve ablation of the superior hypogastric plexus, which provides sympathetic innervation to the uterus, can be used in patients with debilitating disease whilst preserving fertility.

Surgical management

Gold standard laparoscopy offers the benefits of a definitive diagnosis, mapping/staging of the severity of the disease and obliteration of disease where possible by ablation or excision. Pelvic masses are also excisable.

This modality should be performed in experienced hands as the obliteration of endometrial lesions can pose hostile to surrounding organs and tissues. Latrogenic perforation and further scarring can worsen the initial diagnosis.

Ultimately the procedure with the greatest success rate to reduce the severity of symptoms as well as recurrence remains a hysterectomy with bilateral salpingo-oophorectomy.

In young patients, who have completed their families and have had a hysterectomy and bilateral salpingo-oophorectomy for definitive symptom control, care should be taken to use hormone replacement therapy, as there is a 3.5% disease recurrence.

Infertility

Despite having experienced severe symptoms, most women will be driven to present by a desire for fertility. The American Society of Reproductive Medicine has quoted studies that suggest that 25% to 50% of infertile women have endometriosis and that 30% to 50% of women who have endometriosis are infertile.

Endometriosis causes distorted anatomy, swollen, inflamed and fibrosed fallopian tubes as well as impaired ovarian function. A reduced fecundity rate due to a molecular basis has been seen in women who experience even mild symptoms.

There is a signifi­cant reduction in the oocyte quality and ciliary function in the fallopian tubes due to disruption of a number of immunological factors in the peritoneal fluid.

Continuing debates question the medical therapy of endometriosis with regards to infertility. Medical management has the risk of further delaying infertility but lessens the chance of iatrogenic complications and injury.

There appears to be some consensus of the use of GnRH analogues for six to 12 months prior to assisted reproductive techniques. Other contributors to infertility need to be established and corrected before any form of definite surgery for endometriosis is considered.

This would include modifiable patient factors/disease and evaluation of the male factor and relevant components. Ultimately consultation timeously with an endometriosis/infertility specialist will benefit the couple and diminish time of action to result without causing further anatomical damage.

Avoiding surgery all together, a possible way forward…

The University of Illinois has discovered that the oestrogen receptors in endometrial lesions are different from those found in normal reproductive tissue. In view of this two drugs have found to reduce the size of existing endometrial lesions and have stopped the growth of new lesions.

The drugs chloroindazole (CLI) and oxabicycloheptene sulfonate (OBHS), which target ERα and ERβ, respectively, interfere with inflammation pathways.

The compounds prevented the development of new nerves in the lesions and also decreased pain. Current studies are being conducted on mice. The drugs have not altered fertility nor have had an effect on the health of the rodent pups.

The drugs have had a similar effect on human endometrial tissue, specimens taken from cysts that had been removed from patients. Prominent endometriosis experts across the globe have marked this research as encouraging although it may take several years before human trials are expected to start.

ESHRE guideline for the treatment of endometriosis-associated pain

The European Society of Human Reproduction and Embryology (ESHRE) recommends the following treatment for endometriosis-associated pain.

Empirical treatment of pain

Many women suffering from pelvic pain, while there is a high suspicion of endometriosis, use analgesics and hormonal medication without a prior definitive diagnosis of the disease by laparoscopy.

This is partially due to the invasiveness of the laparoscopic procedure, but also to the ease of prescribing hormonal contraceptives, which would be prescribed for prevention of pregnancy anyway. This empirical treatment is especially common in adolescents with pelvic pain and dysmenorrhoea.

However, before starting empirical treatment other causes of pelvic pain symptoms should be considered and excluded where possible. It is common practice that if women do not react favourably to empirical treatment a laparoscopy is performed to exclude or diagnose endometriosis.

However, the response to hormonal treatment does not always predict the presence or absence of endometriosis. Finally, it has been argued that starting hormonal contraceptives in young girls because of primary dysmenorrhoea could be indicative of the diagnosis of deep endometriosis in later life.

It is clearly a paradox that by recommending empirical treatment in symptomatic (young) women one might induce the above-mentioned delay in diagnosing the disease.

ESHRE recommends that clinicians counsel women with symptoms presumed to be due to endometriosis thoroughly, and to empirically treat them with adequate analgesia, combined hormonal contraceptives or progestagens.

Are hormonal therapies effective for painful symptoms associated with endometriosis?

Currently, hormonal contraceptives, progestagens and anti-progestagens, gonadotropin-releasing hormone (GnRH) agonists and antagonists and aromatase inhibitors are in clinical use.

With no overwhelming evidence to support particular treatments over others, it is important that the decisions involved in any treatment plan are individual, and that a woman is able to make these based on an informed choice and a good understanding of what is happening to her body.

Clinicians are recommended to prescribe hormonal treatment hormonal contraceptives, progestagens, anti-progestagens, or GnRH agonists as one of the options, as it reduces endometriosis-associated pain.

ESHRE recommends that clinicians take patient preferences, side effects, efficacy, costs and availability into consideration when choosing hormonal treatment for endometriosis-associated pain.

Hormonal contraceptives: Hormonal contraceptives were shown to be effective in treating pain in women with endometriosis, as discussed in a Cochrane review, which is based on only one small study. Other studies compared different regimens and routes of administration for hormonal contraceptives.

Despite limited evidence of effectiveness, hormonal contraceptives are widely used as treatment for pain in women with endometriosis, which could be due to some practical advantages, including contraceptive protection, long-term safety and control of menstrual cycle.

Clinicians can consider prescribing a combined hormonal contraceptive, as it reduces endometriosis-associated dyspareunia, dysmenorrhea and non-menstrual pain.

Clinicians may consider the continuous use of a combined oral contraceptive pill in women suffering from endometriosis-associated dysmenorrhea.

Clinicians may consider the use of a vaginal contraceptive ring or a transdermal (oestrogen/progestin) patch to reduce endometriosis-associated dysmenorrhoea, dyspareunia and chronic pelvic pain.

Progestagens and anti-progestagens: Clinicians are recommended to use progestagens, dienogest, cyproterone acetate, norethisterone acetate or danazol or anti-progestagens as one of the options, to reduce endometriosis-associated pain.

ESHRE recommends that clinicians take the different side-effect profiles of progestagens and anti-progestagens into account when prescribing these drugs, especially irreversible side effects (e.g. thrombosis and androgenic side effects).

Clinicians can consider prescribing a levonorgestrel-releasing intrauterine system as one of the options to reduce endometriosis-associated pain.

GnRH agonists: GnRHagonists, with and without add-back therapy, are effective in the relief of endometriosis-associated pain, but can be associated with severe side effects, which should be discussed with the woman when offering treatment. No evidence exists on the effectiveness of GnRH antagonists for endometriosis-associated pain.

Clinicians are recommended to use GnRH agonists as one of the options for reducing endometriosis-associated pain, although evidence is limited regarding dosage or duration of treatment.

Clinicians are recommended to prescribe hormonal add-back therapy to coincide with the start of GnRH agonist therapy, to prevent bone loss and hypoestrogenic symptoms during treatment. This is not known to reduce the effect of treatment on pain relief.

The ESHRE recommends clinicians to give careful consideration to the use of GnRH agonists in young women and adolescents, since these women may not have reached maximum bone density.

Aromatase inhibitors: In women with pain from rectovaginal endometriosis, refractory to other medical or surgical treatment, clinicians can consider prescribing aromatase

inhibitors in combination with oral contraceptive pills, progestagens or GnRH analogues, as they reduce endometriosis-associated pain.

Due to the severe side effects, aromatase inhibitors should only be prescribed to women after all other options for medical or surgical treatment are exhausted.

Are analgesics effective for symptomatic relief of pain associated with endometriosis?

There is virtually no evidence on the use of non-steroidal anti-inflammatory drugs (NSAIDs) for endometriosis. NSAIDs have a favourable effect on primary dysmenorrhoea and are widely used as a first-line treatment of endometriosis-associated pain. ESHRE recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain.

When prescribing NSAIDs, clinicians should discuss the side effects associated with frequent use, including inhibition of ovulation, risk of gastric ulceration and cardiovascular disease, with the patient.

Is surgery effective for painful symptoms associated with endometriosis?

When endometriosis is identified at laparoscopy, clinicians are recommended to surgically treat endometriosis, as this is effective for reducing endometriosis-associated pain, e.g. ‘see and treat’.

Laparotomy and laparoscopy are equally effective in the treatment of endometriosis-associated pain, but laparoscopic surgery is usually associated with less pain, shorter hospital stay and quicker recovery as well as better cosmetic outcome, hence it is usually preferred to open surgery.

Clinicians may consider both ablation and excision of peritoneal endometriosis to reduce endometriosis-associated pain.

Excision of lesions could be preferential with regard to the possibility of retrieving samples for histology. Furthermore, ablative techniques are unlikely to be suitable for advanced forms of endometriosis.

When performing surgery in women with ovarian endometrioma, clinicians should perform cystectomy instead of drainage and coagulation, as cystectomy reduces endometriosis-associated pain.

Clinicians can consider performing cystectomy rather than CO2 laser vaporisation in women with ovarian endometrioma, because of a lower recurrence rate of the endometrioma.

Surgery for deep endometriosis appears possible and effective but is associated with significant complication rates, particularly when bowel surgery is required. The reported total intra-operative complication rate is 2.1% and total post-operative complication rate is 13.9% (9.5% minor, 4.6% major complications).

There is an ongoing debate about the indication for shaving nodules as opposed to segmental resection.

Clinicians can consider performing surgical removal of deep endometriosis, as it reduces endometriosis-associated pain and improves quality of life.

ESHRE recommends that clinicians refer women with suspected or diagnosed deep endometriosis to a centre of expertise that offers all available treatments in a multidisciplinary context.

References available on request.

Author: Dr Shastra Bhoora, Gynaecologist and Obstetrician, Johannesburg

 

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