What is Endometriosis?

A Disease of Unknown Origin

Endometriosis is a disease of unknown origin, which causes pain and infertility. The disease, inflammatory in nature, generally affects the lower part of the abdominal cavity, the ovaries and the lining of the uterus known as the endometrium. In the pelvic cavity, endometriosis is characterized by inflammatory lesions that are constituted of tissue similar to what is normally present in the uterine cavity – or endometrium-like. This tissue originates from the uterus (back flow through the Fallopian tubes) or develops by itself in the pelvic cavity. As it is the case for the normal lining of the uterus – the endometrium – the endometriotic lesions tend to bleed at the time of menses due to the fall in hormone that takes place. The blood released – minute amounts – causes inflammation within the pelvic cavity. This often leads to adhesion formation between the lesion and nearby structures such as loops of bowel, the ovaries or uterine ligaments. These lesions generally involve nerve endings and are painful. Pain is exacerbated at the time of the minimal bleeding that takes place during menses.

Pain Caused By Inflammatory Lesions

Pain caused by endometriosis typically peaks during menses – causing painful cramping or dysmenorrhea – and in the days preceding menses. Moreover, endometriosis is often associated with deep pain during intercourse that often persist after intercourse is over. The bleeding caused by the lesion self-perpetuates an inflammatory process that leads to more adhesion formation and causes abdominal cramping and pelvic pain. Moreover, the state of inflammation existing in the pelvic cavity generates an immunological reaction whereby immune cells – macrophages – accumulate in increased amounts. The macrophages activated by inflammation exert negative effects on sperm present in the vicinity of the ovary – at the end of the Fallopian tube. This interaction between macrophages and toxic substances produced by macrophages – cytoxins – interfere with the sperm-oocyte interactions and thereby reduce the chances of natural conception.

Pain due to endometriosis is variable in nature and intensity. In certain cases, women can control it by simple pain killers taken at the time of menses. In other cases, menstrual cramping can be excruciating and truly invalidating. For unknown reasons, certain women on the contrary can have extensive endometriotic lesion covering the whole lower abdomen and feel practically no pain. In the latter cases, endometriosis is a fortuitous discovery at time of surgery.

Finally, in certain circumstances endometriosis can even extend beyond its primary territory – the gynecological organs – and also affect the walls of the bowel and bladder. The signs – the symptoms – are digestive cramping and pain as for example while moving bowel particularly, during the premenstrual and menstrual period.

Endometriotic Cysts In The Ovary: The Endometriomas

Endometriotic lesions developing in the ovary cause cyst formation, generating the infamous ‘chocolate cyst’ or endometrioma. The term cyst is actually improper as ovarian cysts normally have well-defined walls whereas, endometriomas do not. Rather than cysts, endometriomas result from in-folding of the ovarian surface that fills itself with old blood, giving the dark brown ‘chocolate’ appearance. This distinction between endometriomas and true ovarian cysts has practical consequences. Because endometriomas are not true cysts but rather in-folding of the ovarian surface, there is no proper cleavage plan – clear-cut division – with nearby ovarian tissue when attempting to remove them surgically. This explains that the excision of endometriomas is traumatic for the ovarian reserve because healthy tissue – containing oocytes – is also removed when operating on endometriomas.

Endometriomas can be of different size, sometimes pretty large up to 5-7 cm in diameter, at other times smaller. They can be isolated or multiple, uni- or bilateral. In principle, endometriomas are easily and clearly identifiable on ultrasound where they appear as grey-looking cystic structure. This aspect is drastically different from the classical appearance of fluid-filled cysts that have a ‘black’ appearance on ultrasounds.

Do I Have Endometriosis?

Endometriosis is found in approximately 10% of women of reproductive age and 35-40% of infertile women. If my attempt to conceive has remained unfruitful – I suffer from infertility – I should ask myself whether I might have endometriosis. The question is also pertinent for young women doubling up in pain at each menses.

Answering the question of whether I have endometriosis is a two-step process:

1. Do I Have Signs – or Symptoms – Suggestive of Endometriosis?

The call signs or symptoms of endometriosis need to be carefully evaluated.

These include: Painful cramping during menses. When does the cramping start? At the time of menses? A few days before? What is the intensity of pain? Is it controlled simple pain medication? Does it require major pain killers?

Did I have painful menses at the time of adolescence? Was this bad enough to miss school? Was I put on the contraceptive pill in an effort to alleviate menstrual cramps?

If the answers to these questions – all or part of them – is yes, you may be suffering from endometriosis. It’s actually important to know, as the finding of endometriosis will orient the management of infertility and, in the case of ART, will entail specific measures. Hence if endometriosis is suspected, further specific evaluations are needed to sort out the issue.

2. Has Endometriosis Been Identified In Me?

Classically, endometriosis is said to be a surgical diagnosis. Endometriotic lesions are seen during abdominal exploration by laparotomy (full opening) or laparoscopy (button hole surgery). Formal diagnosis is made by removing a fraction of the lesion for definitive identification under the microscope, a process called a biopsy.

Today, things have changed for the following reasons:

• In days of IVF, routine surgical exploration – diagnostic laparoscopy – is generally not warranted any more in infertility management.

• Surgery is not recommended in case of infertility associated with endometriosis when age and/or ovarian reserve parameters mandate immediate access to ART (IVF).

• Imaging techniques – ultrasounds and MRI – have made tremendous progress. When performed by expert hands, endometriosis can be ruled in, or ruled out using imaging with great reliability.

As surgery is not necessarily indicated in our ART era, one cannot just count on surgery for diagnosing endometriosis. This leads us to drastically under estimate the incidence of endometriosis, as is the case in some ART database reports (Senapati S, et al. Fertil Steril 2016;106:164-71.). In this study of 400,059 ART cycles conducted in the US from 2008 to 2010, endometriosis was only reported in 39,356 of them or 11%, clearly a drastic underestimate in an infertile population. This finding underscores the fact that we also have to rely on imaging approaches for diagnosing endometriosis. Today therefore, endometriosis is a diagnosis made on either surgical, or imaging findings. This concept is important because too many cases of endometriosis are ignored simply, simply because surgery is not routinely performed anymore in infertility.

Surgery Helps Conceiving Naturally, Provided There Is Time

Remarkably, surgery enhances the chances of conceiving naturally. This beneficial effect of surgery has been observed at all stages of endometriosis. Meta-analyses – regrouping multiple studies – indicate that the chances of conceiving naturally are of approximately 50% over 18 months following surgery. Some claim that these number slightly exceed reality for 2 reasons: (i) Only the best surgeons publish their data and, (ii) certain women might not have been actively trying to conceive before surgery, but were encouraged after because of the finding of endometriosis.

The studies indicate that to fully benefit from the effects of surgery, one should allocate 18 months for natural conception to occur. This therefore implies that time and ovarian reserve allow to dedicate 18 months for conceiving naturally after surgery. Of course, it is also necessary that sperm is of a sufficient quality for natural conception and that the Fallopian tubes are permeable before programming surgery.

If Surgery, Consider Fertility Preservation

Women who undertake surgery for endometriosis – mainly for non-manageable pain – should consider fertility preservation. Indeed, as surgery may compromise ovarian reserve it makes sense to save oocytes in the event that natural conception in the future becomes problematic. This consists in undertaking ovarian stimulation – as for ART – collect the stimulated oocytes and freeze them, or more rightfully said ‘vitrify’ them. Oocytes are the person’s own property. They can be used at a later time. They are then thawed and inseminated with the partner’s sperm (or that of a donor) and transferred, as in ART. The extra embryos possibly obtained are re-vitrified and stored. The efficacy of fertility preservation is directly related to the number of oocytes obtained and vitrified. Often, one considers several ovarian stimulations and oocyte harvests. These stimulations can even be conducted back to back – one directly after the previous one – which, as we showed, allows to obtain twice as many eggs in 28 days or less.

In Principle, No Surgery Before ART

Surgery, which is effective for treating pain and favoring natural conception – during the 12-18 months following surgery – does not help ART outcome, and may actually worsen it. It has been known for several years that ART outcome is not improved by surgery in case of endometriosis (Garcia-Velasco). On the contrary, surgery for endometriosis – particularly, when the disease affects the ovary in the form cysts – is prone to reduce the response to ovarian stimulation needed in ART. After surgery for endometriosis, the ovarian response can be markedly diminished and at times so profoundly affected that it is insufficient for proceeding to an oocyte retrieval.

Surgery is particularly harmful for ovarian function – altering ovarian reserve – in the following three circumstances and should be therefore avoided if at all possible.

• Bilateral development of endometriotic cyst or endometriomas.
• Already compromised ovarian reserve.
• Past history of surgery for endometriosis

Recently it has been demonstrated that the rate of normal embryos – euploidy rate – in endometriosis is not different from findings made in normal disease-free patients of the same age (Juneau et al. Fertil Steril 2017;108:284-88.). All therefore indicates that endometriosis does not affect oocyte quality. The disease however affects oocyte quantity and is often the cause of poor ovarian response. It is however worth struggling for even meager oocyte yields as quality is in principle preserved.

In certain circumstances, surgery is necessary for removing a cystic enlargement of the Fallopian tube or hyrdrosalpynx, as this decreases ART outcome. In these cases however, conservative surgery is often preferred today. This implies that the diseased tubes are removed while deliberately not touching endometriosis lesions that might be present for the fear of harming ovarian reserve and compromising ART outcome.

Medications Available For Endometriosis

Several types of medication have been developed for endometriosis. All share the common property of blocking ovulation, and are therefore all contraceptive. These medications are generally similarly effective on pain caused by endometriosis, but differ by their side effects.

Historically, the first medication offered for endometriosis was danazol (Dnacrin®). Danazol is a male hormone derivative that is effective on pain but carries severe side effects related to masculinization (increased hair growth, possible deepening of the voice, etc.). Danazol has since been replaced by the family of GnRH agonists – medications such as Lupron® or Zoladex® – which block ovarian function and create an artificial menopause. While different from danazol, Lupron and Zoladex have their side effects too. These are the symptoms of menopause – hot flushes, vaginal dryness, mood changes, etc. – but of course are fully reversible upon stopping. Because of the side effects of artificial menopause – Lupron and Zoladex – attempts have been made to co-administer hormones in order to alleviate the symptoms of menopause. This approach combining Lupron or Zoladex and hormones is called ‘addback therapy’. The remarkable finding is that the addback therapy – including adding back the contraceptive pill – does not decrease the efficacy of Lupron or Zoladex. Finally, it has been shown in large trials by the Italian endometriosis specialist, Paolo Vercellini, that the contraceptive pill taken alone – continuously (without posing) – is as effective as Lupron or Zoladex for the average patient. Individually, it is obviously possible that certain women respond better to Zoladex or Lupron than the contraceptive pill.

Natural blockage of ovulation as it occurs during pregnancy or breast feeding is equally effective at blocking the symptoms of endometriosis.

Medication Treats Pain, Not Infertility

As said above, all medications are equally effective at treating pain due to endometriosis. This effect however important is unfortunately not complete. Certain women will continue to suffer despite taking their medication. Certain may even break through with acute relapses of pain while on medication. It is impossible to predict the response to medication nor the risk of disease flaring while on medication.

Medication – all equally well – generally prevent relapse of symptoms and lesion recurrence after surgical removal. It is generally believed that women operated for endometriosis – because of pain – who do not directly intend to conceive should be put on medication until they decide to conceive. One would generally prefer the contraceptive pill as first choice therapy. The pill is taken continuously, making 3-4 one-week pauses a year to prevent disturbing intermittent – breakthrough – bleeding.

As all medications block ovulation, they are all contraceptive. Hence, for such medication to be effective on fertility there would need a rebound of fertility upon stopping the medication. While this has been a lingering diehard wishful thinking, adequately conducted studies have clearly indicated that such rebound of fertility upon stopping meds does not exist. The time spent on medication is simply time lost for conceiving. After surgery, if a woman wishes to conceive she should be encouraged to try right of way, as this gives her the best chances. If her plans are not for an immediate conception, then she should go on medication for preventing relapse.

ART Is Effective In Endometriosis

ART is an effective treatment of infertility associated with endometriosis. Despite poorer response to ovarian stimulation often encountered in case of endometriosis, oocyte quality is basically normal and concordant with age. We realize today that surgery for endometriosis often has more deleterious effects on ovarian reserve than the disease itself. Indeed, surgery for endometriosis has been shown to hamper ovarian response to stimulation used in ART particularly, if it includes the removal of endometriomas. This is due the important amount of ovarian tissue lost during surgery, even when performed by the most expert hands. Evidently in case of endometriosis, ovarian stimulation for ART should be adjusted to the parameters of ovarian reserve, often opting for high doses of gonadotropins. Yet despite the high doses used, ovarian stimulation often results in oocyte yields that are below par. There are regimens proposed to enhance the ovarian response to the drugs used for ovarian stimulation – gonadotropin (Gonal-F®, Puregon®, Menopur®, etc.). These revolve in attempting to benefit from the fact that male hormone (testosterone, androstenedione, DHEA) enhance the sensitivity of the FSH receptor in the ovary. Testosterone can be administered by transdermal skin patches. DHEA can be administered orally at the dose of 75mg/day. A fraction of DHEA administered – approximately 2% – is converted into testosterone. The net amount produced – approximately 0.5mg/day – is equivalent to the normal production of testosterone by the ovary, so that there are no risks of overdosing.

The quality of endometrial receptivity to embryo implantation is a source of debate. Numerous publications describe alterations of the endometrium in case of endometriosis. These alterations by and large consist of an impaired response to the effects of progesterone. Extensive descriptions made by Giudice’s group revealed that both the anti-proliferative and differentiating genic pathways of progesterone are altered in case of endometriosis (Aghajanova L. et al. Biol Reprod. 2011;84:801-15.). Indeed, progesterone exerts two type of effects on the endometrium: 1. Progesterone antagonizes the growth promoting effects of estrogen. During the first half of the cycle – follicular phase – estrogens induce the proliferation of the endometrium, which translates in increased thickness on ultrasound and mitosis – cellular division – in the tissue itself. All these effects are blocked by progesterone through series of genic actions. 2. Progesterone also induces the differentiation of the endometrium, generating glandular secretion and other changes that will facilitate the attachment and implantation of the embryo. The differentiation effects of progesterone are mediated by other sets of genes. Both genic actions of progesterone – anti-proliferative and differentiation – are partially inhibited through inflammation-mediated mechanisms in case of endometriosis.

Numerous studies indicated that ovarian blockage using either the GnRH agonist – Lupron® or Zoladex® – or the contraceptive pill restored normal endometrial response to progesterone. Altered endometrial response to progesterone results in overexpression of endometrial BCL6, as shown by Lessey’s group (Evans-Hoeker E. Reprod Sci. 2016;23:1234-41). This property has given rise to an endometrial marker of endometrial receptivity commercialized under the name of Receptiva®. On the contrary, an alternate marker of endometrial receptivity also commercialized – ERA® test – is not altered in case of endometriosis (Garcia Velasco et al. Reprod Biomed Online. 2015;31:647-54.). It is thus fair to say today that the jury is still out regarding the effects of endometriosis on endometrial receptivity.

Certain groups – including ours – reported diminished implantation rates in cases of endometriosis unless pretreatment by Lupron or the oral contraceptive pill is applied. Other groups reported identical implantation rates in cases of endometriosis. We reported this dilemma in a review article in the English journal The Lancet (de Ziegler et al. Lancet  2010;376(9742):730-8.). In general endometriosis is not seen as a source of repeated implantation failure provided that appropriate measures are followed with either prolonged ovarian suppression or freeze all and deferred embryo transfer.

We believe that in today’s age of highly effective embryo vitrification, it reasonable to propose the following management in cases of endometriosis:

• Antagonist protocol
• Agonist trigger
• Systematic embryo vitrification
• Deferred embryo transfer

This strategy is recommended for the following two reasons:

1. The agonist trigger has much milder consequences on the ovary than the classical hCG trigger in terms of ovarian response and cyst formation. This is clearly an advantage when cysts are already present because of endometriosis.

2. The deferred embryo transfer takes place when ovarian function is suppressed by hormonal treatment for priming endometrial receptivity. This lessens the risk of alteration of endometrial receptivity (Bourdon M et al. Reprod Biomed Online 2017;34:248-57.).

Infertility and Endometriosis: Practical Management

A proper infertility workup should determine whether I suffer from endometriosis or not. This is based on both carefully analyzed symptoms and confirmatory examinations. If this is the case, the first question to answer is whether I might qualify for surgery. Aside of beneficial effects on pain, surgery enhances the chances of conceiving naturally during the 12-18 months following surgery. Hence, surgery – for infertility – is only indicated if the following criteria are met:

1. There is time and/or sufficient ovarian reserve for dedicating 12-18 month to conceive naturally. This should be done without seriously compromising ART chances if ART has to be undertaken in the event that natural conception fails.

2. Sperm is of quality compatible with natural conception

3. The Fallopian tubes are patent, so that natural conception can occur
   

If all these criteria are met and the patient agrees with the plan of attempting to conceive naturally for 12-18 months, surgery can be undertaken. Arguments against surgery aside from the 3 points mentioned above is a bilateral extension of endometriomas, as surgery in this case is more prone to harm ovarian reserve. Likewise, a past history of surgery for endometriosis is an indication for not re-intervening.

If surgery is chosen, no post-operative medication – Lupron®, Zoladex® – is warranted, as this only takes time away for natural conception and does not provided added chances of pregnancy upon stopping. Moreover, if surgery is performed, we recommend skipping any post-operative ovarian stimulation and intra uterine insemination (IUI). Indeed, these measures are not superior to natural conception and carry the risk of flaring the disease. Ultimately, if pregnancy does not occur after the time interval agreed upon with the patient – 12 or 18 months – one should directly undertake ART.

On the contrary if ovarian reserve is compromised and/or age does not permit dedicating 12-18 months for attempting to conceive naturally, one should go straight to ART in a so-called ‘emergency IVF’. Likewise, ART should be decided and thus, surgery avoided if sperm parameters do not offer reasonable chances of conceiving naturally and/or the Fallopian tubes are obstructed. This flow chart respects the dual principle of: (i) surgery is only indicated for favoring natural conception and, (ii) no surgery is performed before ART.

As it is the case for all rules, the general principle of ‘no-surgery-before-ART’ carries exceptions. Indeed, surgery is indicated for removing pathologic dilatation of the Fallopian tubes – hyrdrosalpynx –, as this is known to alter ART outcome. In such cases however, we strongly recommend considering conservative surgery. Hence, the diseased tube(s) can be removed or clipped, while endometriomas can be deliberately left untouched for the fear of harming ovarian reserve and further compromising ART outcome.

In certain cases, surgery has been proposed in case of repeated embryo implantation failure without – in our eyes – true proof of an actual benefit.

Finally, women reverting to donor-egg ART because of failed ovarian response in regular ART should consider curative therapy of their endometriosis, as they don’t count on their ovarian function anymore. In donor-egg ART there are in principle no negative effect of endometriosis on receptivity, as – like for frozen embryo transfer – the ovarian function is suppressed by the hormonal treatment – estrogen and progesterone – given for priming transfers.

When facing a dual picture of infertility and severe pelvic pain, one should have an explicit discussion with the patient. After thoroughly explaining the pros and cons of surgery of future ART outcome, the patient should be allowed to express what is more important for her: Treating pain or infertility first, while postponing a surgical cure of endometrio