How Does Endometriosis Compromise Fertility, How Should it be Treated and What is the Role of IVF?
Endometriosis, regardless of its severity, is almost always associated with a Reproductive Dysfunction that manifests as infertility or early pregnancy loss. The condition (even in its mildest, earliest stage of development) reduces the ability to conceive (diminished fecundity). In fact, even in early endometriosis, the natural conception rate per month of trying as well as the rate following the use of fertility drugs with or without IUI in such cases will inevitably be about 4-6 times lower than for women without endometriosis.
The effects of endometriosis on women trying to conceive can be summarized as follows:
- Endometriosis establishes a toxic pelvic environment that compromises fertilization: It has been estimated that even in cases of early (Stage-1) endometriosis, where there is no overt evidence of tubal damage, obstruction or tubal adhesions that might restrict egg pick-up at ovulation, and even when laparoscopy has been performed to remove all visible endometriotic deposits, the chance of pregnancy occurring following natural or fertility drug-induced superovulation is about 5 times lower than normal. The reason is believed to be that both visible and occult (non-pigmented/ non-visible) endometriotic lesions produce toxins that mix in with pelvic secretions. When following ovulation, eggs pass through such secretions to reach sperm in a Fallopian tube they become exposed to such “toxins” which markedly compromises fertilization potential. This also explains why the use of IUI, ovarian stimulation with fertility drugs, or the performance of surgery to ablate endometriotic deposits is highly unlikely to improve pregnancy potential in women with endometriosis.
- Endometriosis is a “work in progress” that is constantly evolving: The fact that endometriotic deposits can take years to become pigmented and visible at laparoscopy/laparotomy and that such non-visible lesions probably also produce “toxins” might explain why some women with endometriosis have “unexplained infertility” and only later, when bleeding into such lesions causes iron pigment (hemosiderin) to form will the diagnosis of endometriosis emerge. Up to this point, such women are routinely labeled as having “unexplained infertility”. Remember, endometriosis is a “work in progress” and for every pigmented lesion seen at laparoscopy, there are probably scores of others in the process of developing and becoming pigmented. That is why surgery which only permits removal (ablation) of identifiable, pigmented endometriosis does not enhance overall fertility potential.
- Progressive endometriosis causes pelvic adhesions and tubal obstruction: These lesions bind the Fallopian tubes and ovaries to adjacent pelvic structures, compromising egg pick up. In more advanced cases, it can cause damage to or fusion of the finger like projections (fimbria) at the ends of the tubes and so, compromise egg pick-up and transportation to the awaiting sperm lower down in the tube.
- The presence of ovarian endometriotic cysts (endometriomas) can compromise egg quality: Ovarian endometriomas, like other space-occupying lesions in the ovary, can activate connective tissue in the ovary, causing excessive male hormone (predominantly testosterone) production which can compromise egg/embryo development and quality.
- Immunologic Implantation Dysfunction (IID): About one third of women whom have endometriosis (regardless of its severity) will have activated uterine natural killer cells (NKa), the presence of which can prevent normal implantation leading to “infertility” or miscarriage.
How does Reproductive Dysfunction Manifest in Patients with Endometriosis?
a. Primary infertility readily diagnosed clinically, by ultrasound (endometriomas), or at Laparoscopy.
b. Secondary infertility: Endometriosis is one of the main causes of “secondary infertility”
c. “Unexplained Infertility”: Endometriosis is one of the leading causes of “unexplained infertility”.
d. Unexplained IVF failure with good quality embryos: Because of IID
e. Poor quality eggs/embryos: Because of, 1) compromised ovarian blood flow as a result of scar tissue, 2) ovarian endometriomas causing increased ovarian testosterone production.
f. Repeated failure to conceive in spite of induced ovulation and/or IUI: Because of a toxic pelvic environment and/or undiagnosed IID.
- Early Pregnancy Loss: This is usually due to IID resulting from antiphospholipid antibodies and/or NKa.
How to Manage Infertility in Women with Endometriosis:
- Young women (<35Y) with early endometriosis who ovulate normally: IVF is, in my opinion, the only way to enhance fertility potential in any woman with endometriosis. However, I do not advocate immediately resorting to IVF in women with early stage (Stage 1) disease who are ovulating normally on their own, unless they have (DOR) or have IID associated with NKa/APA. In my opinion, such women are advised to try on their own (using timed intercourse) for an arbitrary period of time before resorting to IVF. However, I always make a point of informing such women that in my opinion, the use of fertility hormone therapy, surgery or IUI will in my opinion is not likely to be of any additional benefit to them.
- Young women (<35Y) with early endometriosis who ovulate abnormally: Some women with endometriosis have irregular, absent or dysfunctional ovulation. In such cases, the use of fertility drugs such as clomiphene citrate and gonadotropins (Follistim, Gonal-F, Menopur) with/without intrauterine insemination is often recommended with justification. However, it is important to always remind such patients that while the use of fertility drugs might re-establish functional ovulation, it cannot and will not address the adverse effects of a “toxic pelvic environment” on egg fertilization potential. Thus, such ovulation induction will not circumvent the markedly reduced pregnancy rate per cycle of treatment (Fecundity) that such women will inevitably experience.
- Older women and those with DOR: On the other hand, women over 35Y of age, and those who have Diminished Ovarian Reserve (and accordingly are facing a rapidly “ticking biological clock”), should, regardless of age, go directly to IVF because they do not have the luxury of time.
- Women with advanced Endometriosis: Women with more advanced endometriosis (stage 3, 4), should, regardless of age and/or whether or not they are ovulating normally, likewise consider IVF as their first choice. Those women, who in addition, have one or more sizeable (>2cm) ovarian endometriomas, should have these aspirated at the start of the stimulation for IVF, or preferably (by far) have them removed surgically or by sclerotherapy, prior to undergoing ovarian stimulation for IVF.
- Women with Immunologic Implantation Dysfunction (IID): In my opinion given the added physical, financial and emotional burden associated with selective immunotherapy for IID, women who have NKa-related endometriosis (regardless of its severity) should do IVF preferentially.
When it comes to reproductive performance, all women with endometriosis are disadvantaged to some degree or other. This is because of one or more of the following: 1) reduced fertilization potential, 2) compromised egg/embryo quality; 3) tubal and ovarian adhesions; 4) ovarian endometriotic cysts (endometriomas), 5) and immunologic implantation dysfunction (in about one third of cases). To make matters worse, endometriosis, being a progressive disorder, is often accompanied by debilitation which will drive some women to seek surgery aimed at relieving symptoms. Such surgeries will often involve removal of tissue/organs that are needed to propagate fertility (tubal removal, removal of ovarian tissue, even hysterectomy) or will result in additional post-surgical scarring that damages reproductive function. So clearly, for such women, the race to achieve pregnancy before they are driven to palliative surgery and before they run out of time on the biological clock begins as soon as the condition is diagnosed. That, in my opinion, is why all women often who have endometriosis need to be proactive and why IVF is often recommended early on.
Finally, IUI/Fertility drugs and surgery (with the exception of endometriomas or treatment of debilitating symptoms), will not improve pregnancy generating potential. Only IVF will and then only if IID is ruled out or properly treated with selective immunotherapy and provided that optimal and individualized protocols for ovarian stimulation are used, especially in older women and those who have DOR.