Endometriosis and Infertility
Ervin E. Jones, MD, FACOG, PhD, HCLD
Enigmatic, capricious, and complex are all terms that have been used to describe endometriosis. Enigmatic because it is poorly understood, capricious because it is unpredictable and complex because it is. Endometriosis is defined as growth of endometrial tissue outside the uterine cavity. Women with endometriosis generally have pelvic pain or are infertile. In many cases, they are diagnosed at the time of surgery for unrelated causes.
Presentation and Prevalence
Although estimates of prevalence vary greatly, as many as 10% of all reproductive age women have endometriosis and it has been estimated that as many as 40% of all infertile women have endometriosis. The usual age range of women diagnosed with endometriosis is 20 to 45 years. Endometriosis affects 5.5 million women and girls in the United States and Canada and millions more worldwide. It has been estimated that the annual costs of endometriosis reached $22 billion in 2002, assuming a 10% prevalence rate among women of reproductive age. Women with endometriosis incur total medical costs that are, on average, 63% higher than medical costs for the average woman.
Although the causes of endometriosis have been debated and several plausible theories have been proffered, the cause of a woman's endometriosis generally cannot be determined. The most accepted theory of how endometriosis develops is Sampson's retrograde transplant theory. Sampson's theory proposes that endometrial cells contained in the menstrual flow pass backwards through the fallopian tubes at the time of menstruation and implant on pelvic organs such as the ovaries, uterus, fallopian tubes, suspensory ligaments of the uterus, bowel and peritoneum (lining of the body cavity). Other theories include bloodborne transport and transport of endometrial cells via lymphatics to sites beyond the confines of the uterine cavity. More contemporary evidence indicates that endometriosis may arise from adult stem cells located in the endometrium supporting the concept of a stem cell origin of endometriosis. Linkage and association analyses have shown that endometriosis tends to cluster in families. although there is no clear pattern of inheritance. Regardless of how endometriosis begins, it is stimulated by high levels of estrogen and goes through cyclic changes in synchrony with the menstrual cycle, as does the normal uterine lining.
Mechanisms of the Disease
Over the last three decades the medical community has devoted remarkable resources to the understanding of endometriosis. Endometriosis was once questioned as a legitimate cause of infertility. The prevailing opinion of the putative "most learned." bolstered by a modicum of scientific evidence, is that endometriosis definitely causes infertility. D'Hooghe and colleagues make a cogent argument that all stages of endometriosis cause infertility. A meta analysis of 22 published reports found that patients with endometriosis-associated infertility undergoing IVF have significantly decreased levels of all markers of the reproductive process, resulting in a pregnancy rate that is almost one half that of women with other indications for IVF. These data suggest that the effect of endometriosis is not exclusively on the receptivity of the endometrium but also on the development of the oocyte and embryo.
No one mechanism explains how endometriosis decreases fertility. Several studies have concluded that endometriotic tissue releases substances into the pelvic cavity that are toxic to eggs and embryos. Other studies revealed that a high concentration of peritoneal fluid from patients with minimal or mild endometriosis suppresses progesterone production in vitro and that the degree of suppression is correlated with the severity of the disease. Progesterone is necessary for development of the uterine lining during the latter half of the menstrual cycle and for normal implantation. Not only is pregnancy potential compromised in patients with endometriosis, the rate of spontaneous miscarriage in these patients is reportedly increased.
Kissler and collaborators have drawn attention to the coexistence of endometriosis with adenomyosis. Adenomyosis is endometrial tissue embedded in the muscle wall of the uterus. Adenomyosis, not unlike endometriosis, responds to cyclic changes in estrogen levels during the menstrual cycle. Although endometriosis and adenomyosis are viewed as different diseases, often overlooked is the high prevalence of coexistence between the two disorders--and they may be regarded as different symptoms of the same unique disease. Patients with endometriosis often have significant impairment of sperm transport from the uterus to the fallopian tubes, which is increased in proportion to the adenomyotic component of the disease. Interestingly, a recent study found that pregnancy rates are markedly decreased in egg donor recipients with documented adenomyosis, suggesting compromised implantation in women with adenomyosis (the source is an unpublished communication).
The presence of ovarian endometriomas (chocolate cysts of the ovary) is associated with a marked reduction in responsiveness to hormones used to stimulate the ovaries. The deleterious effect of endometriomas is more evident in women with larger cysts and in those with more than one cyst. Surgery for resection of endometriomas may also compromise ovarian response to hormonal stimulation and diminish pregnancy rates after in vitro fertilization.
Although removal or suppression of endometriosis by medical or surgical means constitutes contemporary management of endometriosis, the optimal choice of management for endometriosis-associated infertility remains obscure. Surgery is probably effective for all stages of the disease. Controlled ovarian stimulation with intrauterine insemination is recommended in early-stage and surgically corrected endometriosis when pelvic anatomy is normal. The need for in vitro fertilization instead of other assisted reproductive technologies is correlated with the severity of the woman's endometriosis and associated tubal pathology. In vitro fertilization is also appropriate treatment, especially if there are coexisting causes of infertility and/or other treatments have failed. Oocyte donation also is a viable option for women whose ovarian reserve has been compromised or lost because of the destructive effects of endometriosis or as a result of ovarian surgery.
Despite the complexity involved in the diagnosis and management of endometriosis, there are some promising new horizons. Through unraveling the mechanisms by which endometriosis leads to infertility, researchers are sure to find a non-surgical means to diagnose endometriosis, most likely through serum and peritoneal markers. Similarly, after analyzing the pathogenic mechanisms of endometriosis, it seems that future treatment of this entity may include chemical inhibitors, modulators of the immune system, or hormonal suppressive therapy to eliminate the need for surgical treatment. For example, Pentoxiphylline--a substance that changes the immune system, has shown promise in the treatment of endometriosis, particularly when used as follow up treatment to surgery.
It has been suggested that ovarian hyperstimulation in women with endometriosis might increase the severity of the lesions and the risk of complications. Mild in vitro fertilization (low stimulation) offers a potential solution to the problem in young women with normal ovarian reserve. In vitro maturation (IVM) of eggs in natural (unstimulated) cycles offers another alternative for patients with endometriosis who wish to preserve their fertility and for those whose future ovarian function may be compromised by severe endometriosis. It has been shown that large endometriomas and the surgery used to treat them may result in diminished ovarian reserve or, in certain cases, removal of all ovarian tissue. Fertility preservation in the form of egg and/or ovarian tissue freezing will become another viable option for young women with severe endometriosis.
Although it is clear that no single mechanism can be used to explain how endometriosis decreases fertility, some common themes have emerged. Decreased ovarian reserve, poor quality of oocytes and embryos and inadequate implantation are the primary reasons for decreased pregnancy rates in women with endometriosis. Mechanical factors caused by advanced stage endometriosis interfere with the action of the fallopian tube. Surgical removal of endometriosis, ovarian stimulation and intrauterine insemination, in vitro fertilization, and egg donation are the most effective options for treatment of infertile women with endometriosis. In the future, immune system modulators, minimal or natural cycle in vitro fertilization combined with in vitro maturation of eggs, and egg freezing will be treatment options for some women with severe endometriosis.
Editor's Note: This article, with a complete list of references, is available on http://www.givf.com/library/