GIVF Fertility eNews
December 2008


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Endometriosis and Infertility

Ervin E. Jones, MD, FACOG, PhD, HCLD 
Dr. JonesIntroduction
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

What's New at GIVF

EGG BANK The Genetics & IVF Institute soon will be offering vitrified (frozen) donor egg cycles using eggs from our pilot GIVF Egg Bank. The eggs come from GIVF's large selection of fully-screened egg donors. This opportunity to cycle with frozen eggs may particularly appeal to those who are looking for a more cost-effective alternative to a fresh donor egg IVF cycle and those who may not wish to create large numbers of embryos. Please contact Jenn Machovina, RN, BSN, Director of the Donor Egg IVF Program at 1-800-442-4363 or 703-698-7355, or click here for additional information.
GIVF EGG DONOR POOL TOPS 190 GIVF continues to offer the largest selection of fully screened, immediately available egg donors in the country. For more information, visit our website at
MICROSORT® TO OFFER IUIs IN FAIRFAX BEGINNING JANUARY 1 GIVF will resume offering IUIs for MicroSort® in Fairfax, Virginia as of January 1.  MicroSort® just recently received approval from the FDA to enroll new patients for at least another six months and is now accepting new patient enrollments. Couples interested in enrolling in the trial may now begin the enrollment process. Couples who are already enrolled may proceed with scheduling treatment. For more information, visit the MicroSort® website at
SHANGHAI CLINIC HOLDS INTERNATIONAL SCIENTIFIC CONFERENCE Over 250 guests participated in a two-day scientific conference sponsored by GIVF in China for the celebration of the tenth anniversary of GIVF's infertility clinic in Shanghai. The conference included speakers from China, the United States and Europe and dealt with the the latest technology and techniques used in the fields of infertility and genetic testing. For more information, visit our website at or clicking here.
GIVF NURSE VOLUNTEERS TIME TO PROVIDE MEDICAL CARE IN HONDURAS  The Virginia Hospital Center Medical Brigade made its annual trip to Honduras in early November. GIVF's Head Nurse, Maureen Hanton, participated in this mission for the second consecutive year. This year's brigade provided free medical services to over 8,000 patients. 
Ask a Question  
I have seen on television some programs calling for more disclosure about sperm donors. What has been the effect of removing anonymity for donors where that has been tried?
A severe shortage of sperm donors has resulted from changes in donor anonymity laws overseas. The most pronounced example is in Britain, where a 2005 law has resulted in a shortage of sperm donors and long waits at clinics. Some clinics have even stopped offering donor sperm services entirely. Fertility specialists are now calling for nationwide changes to increase the availability of donor services. In 2005 donor anonymity in Britain was revoked. Those conceived after the law took effect have the right to seek out their donor when they turn 18. Yet the effect on donor recruitment is dramatic. Each year, Britain needs at least 500 donors to provide sperm for approximately 4,000 women. But in 2006, only 307 donors registered, according to a report published by the British Fertility Society in September. Furthermore, of those 307 registered donors many had unique arrangements only to donate to one couple (directed or known donors are people who agree to donate as a favor for loved ones) and hence were unavailable for other couples. The law also forbids donors to be paid for their donations, further deterring their participation. The waiting lists have ballooned and many couples wait years with no hope of ever being offered a donor. Physicians suspect many travel to other countries to receive care. Some British clinics have resorted to 'sperm sharing' in which men involved in an IVF cycle agree to share their sperm with other women they don't know in return for reduced fees for their fertility treatments. Ultimately hundreds of British women and couples will not be able to have children because the sperm donor shortage has taken that opportunity to have a family away.
Frontiers in Preimplantation Genetic Diagnosis and Screening (PGD/S)
Gary L. Harton, BS, TS(ABB) and Shelby Duffer, MS, CGC
Preimplantation genetic diagnosis (PGD) was first developed in 1990. Dr. Alan Handyside's lab in London was the first to be able to take a single cell from a three-day old embryo and use the genetic material inside that cell to run a genetic test. This allowed him to choose embryos that would not have the specific genetic disease carried by the biological parents. Since the embryos were screened before implantation, there were fewer worries about the health of an ongoing pregnancy and increased chances that any required prenatal testing would be normal. PGD was a revolution in genetic testing and was quickly adopted by a number of assisted reproductive technology (ART) centers around the world. Today, PGD is available for a large variety of genetic diseases.
In recent years, it has been proposed that preimplantation information about embryos might be helpful for many couples experiencing infertility. Abnormalities in the chromosomes (the genetic material inside the cell) are responsible for a large percentage of pregnancy losses. Preimplantation genetic screening (PGS) is the testing of a single cell from an embryo for these common chromosomal anomalies. Our expectation is that finding and eliminating chromosomally abnormal embryos during an IVF cycle will increase pregnancy rates and help patients deliver more healthy children.
Currently PGD only examines a few of the 24 human chromosomes. This detects common abnormalities, but leaves many untested. New technologies are emerging that will allow testing of all 24 chromosomes for errors as well as the ability to combine general chromosome screening with specific genetic disease diagnosis.
Genetics & IVF Institute (GIVF) is collaborating with the father of PGD, Dr. Alan Handyside (The London Bridge Fertility, Gynecology and Genetics Centre, London) on a new PGD technology called Karyomapping. Our collaboration presented data this year describing this technique at the prestigious American Society for Reproductive Medicine (ASRM) meeting. It allows the simultaneous detection of anomalies in all 24 chromosomes and virtually any genetic disease in embryos. The ASRM meeting also included presentations on another new PGD technique called comparative genomic hybridization (CGH). An American/English partnership showed initial information confirming very good pregnancy rates into the third trimester following testing of all 24 chromosomes.
GIVF continues to be a leader in the development of new technologies and new applications of science to assisted reproduction and infertility treatment. These new techniques may be the next step in allowing doctors and scientists to choose the best embryos for transfer in IVF cycles.

Copyright © 2008 Genetics & IVF Institute