Endometriosis was a puzzling disease when first described by pathologist Rokitansky in 1860. Though we now have a clearer understanding of some aspects of the biology of this disease, it still remains largely a mystery 150 years later.

Endometriosis affects about 5 million women in the U.S. Of women with infertility, approximately 25% are diagnosed with endometriosis. The symptoms fall into two categories: 1) pelvic pain, most significantly with menses, and 2) infertility. The definitive method to diagnose this disease is surgery. A laparoscopy is performed to obtain tissue biopsies of typical peritoneal lesions (peritoneum is the internal layer overlaying pelvic organs including the uterus, fallopian tubes and ovaries); and confirm the presence of endometrial glands in those biopsies. The American Fertility Society has created a classification scheme which grades the disease (Grade I-IV). It is important to understand that there is not necessarily a correlation between pelvic pain and the severity (or grade) of the disease. Another method for presumptively diagnosing endometriosis is with ultrasound, if the patient has endometriosis ovarian cysts (endometriomas), or with MRI if one there is endometriosis growth in the
uterine muscle layer (adenomyosis).

A diagnosis of even minimal to mild endometriosis (stage I and II) can have significant consequences on fertility success rates. A fertile 30 year old woman has about a 25% chance of pregnancy per month (fecundity rate). A patient diagnosed with minimal to mild endometriosis has about a 3% monthly fecundity rate (1, 2, 3). If surgery is performed to dissect and remove the visible endometriosis lesions, the fecundity rate improves to 6%; but this is still much lower than the 25% afforded a fertile 30 year old. If that same patient undergoes ovarian stimulation and insemination cycles, her monthly fecundity rate increases to 11% (4). If the combination of ovarian stimulation/IUI treatment is going to increase chances of pregnancy, results are usually seen within the first 3-4 treatment cycles. Undergoing additional IUI cycles is not typically beneficial, and proceeding to in-vitro fertilization (IVF) treatment would be the next step. For patients with severe endometriosis, gonadotropin/IUI therapy is of minimal assistance. Most patients with moderate to severe endometriosis (stage III and IV) will need to pursue IVF therapy (5).

IVF studies from the 80s and 90s indicate that patients with endometriosis have a slightly lower chance of achieving a pregnancy than patients with other infertility diagnoses (6). With current IVF laboratory techniques and current ovarian stimulation strategies, this difference will probably disappear—but up-to-date studies are needed as proof. When assessing if the lower pregnancy rate is because of a uterine or ovarian issue, it appears that the uterus of endometriosis patients is effective in providing a supportive environment for the embryo to attach (7). However, the oocytes (eggs) from endometriosis patients, particularly those with endometriomas, seem to have some compromised quality (8). This lower egg quality seems to lead to less healthy and effective embryos, and therefore overall lower pregnancy rates.

We clearly understand that strategies of suppressing endometriosis growth by using medications such as birth control pills, Danazol, Lupron or others, does not lead to improved pregnancy rates (9). The concept of a fertility “rebound” post-medical suppression has been proven false over-and-over again. These strategies only lose potentially precious time for the patient. Similar strategies of using medical suppression post surgical removal of endometriosis also fail to improve fecundity rates. The best approach is to move forward with an appropriate form of fertility treatment as soon as the patient desires fertility.

How to treat endometriomas has been debated, but we now have some studies to guide us. Collectively these studies indicate that patients who have undergone surgery for their endmetrioma(s) have the same IVF outcomes as those where the endometrioma(s) was left alone (10). We feel that the patient’s current clinical situation should be scrutinized carefully before recommending ovarian surgery for a patient who is seeking fertility. With surgical removal of an endometioma (ovarian cystectomy), we know that the ovary where surgery is performed will have fewer eggs and less normal ovarian tissue post surgery (11). This implies that we will have a lower chance of gathering eggs in an IVF cycle. Additionally, the patient will have a greater chance of having an elevated FSH after a cystectomy procedure, especially if she undergoes cystectomies of both ovaries (11). The risk of premature ovarian failure (POF or premature menopause) for a patient undergoing cystectomies of both ovaries for endometriomas is about 2% (12).

Historically the strategy for treating endometriosis has been to surgically remove or hormonally suppress its growth with various medications. As we better understand the biology of this disease, we can use more targeted therapies which interrupt the biochemical pathways that promote the growth of endometriosis lesions: aromatase inhibitors, estrogen and progesterone receptor blockers, angiogenesis inhibitors, etc. All of these types of medications are being studied in endometriosis patients. The future may hold some promising new medical options.

In summary, endometriosis clearly affects fecundity rates, even with minimal and mild disease. Using hormonal medications to suppress endometriosis provides no improvement in pregnancy rates, and surgical intervention provides minimal improvement. Most patients will need to pursue fertility treatment. For patients with moderate to severe disease, they most often will need to pursue IVF. For patients with endometriomas, careful consideration has to be given to all factors (age, assessment of egg quality, prior fertility treatment, etc.). The patient needs to be fully counseled prior to surgery, including risk of diminished ovarian quality (DOR) and premature menopause (POF). Patients with adenomyosis seem to have impaired implantation rates, and those with severe adenomyosis may need to consider a gestational carrier. Having a clear understanding of endometriosis as it impacts fertility, and having realistic expectations with each treatment type is most important when choosing fertility treatment options.

– Isabelle Ryan, M.D.

References

1. Jansen RP, Fertil Steril 1986; 46:141-3
2. Marcoux et al, NEJM 1997; Jul 24; 337(4):269-70
3. Parazzini, Hum Reprod 1999; 14(5):1332-4
4. Tummon et al, Fertil Streil 1997; 68(1):8-12
5. Dmowsky et al, Fertil Steril 78:750 2002
6. Barnhart et al, Fertil Steril 2002; 77:1148-1155
7. Diaz et al, Fertil Steril 2000; 74:31-34
8. Simon et al, Hum Reprod 1994; 9, 725-9
9. Hughes et al, Cochrane Database Syst Rev 2007; 3:CD000155
10. Tsoumpou et al, Fertil Steril 2009; 92, 75-87
11. Li et al, Fertil Steril 2009; 92(4):1428-35
12. Busacca et al, Obstet Gynecol 2006; (195), 4

One of the mysteries that confound reproductive biologists is the issue of why human embryos implant into the uterus at relatively low rates as compared to other animal species. This is evident when looking at implantation rates at the time of In Vitro Fertilization treatment. The chance that any one embryo will implant in the uterus varies with female age such that at age 40, only about 5-10% of transferred embryos will successfully take hold and create a viable pregnancy. Even when looking at donor egg-derived embryos from 21-28 year-old donors, the rates of implantation are about 30-45% per embryo. One mechanism to explain the failure of some embryos in implanting – perhaps the primary mechanism – is chromosomal abnormality. If an embryo does not carry a perfect set of 23 pairs of chromosomes, the embryo will likely stop developing, often before implantation can occur.

Implantation of embryos is a complex process. Initially, the embryo has to attach its placental cells to the surface cells of the uterine lining (the endometrium). This is a process that is mediated by a complex of proteins expressed both on the surface of the embryo and on the surface of the endometrium. Expression of the uterine proteins is under the influence of the ovarian hormone progesterone. There are estimated to be over 300 genes that are either turned off or turned on in the endometrium during the “implantation window,” the 3-4 days during which the endometrium is receptive to an embryo attaching. Most of the products of these genes and their role in implantation remain to be identified. In a small percentage of cases, failure to properly secrete one or more of these proteins may be a cause for implantation failure of normal embryos.

One protein produced by the endometrium during the implantation window that has some evidence for a scientific basis for a role in implantation is the cell-to-cell adhesion molecule known as beta-3 integrin. Integrins are a class of cell surface proteins that appear to act in all types of cell-to-cell recognition and adhesion processes. The beta-3 class of these proteins has been shown to be produced in response to progesterone in the endometrium and are purported to be one of the key proteins for adhesion of embryos to the endometrium. Failure to express this protein appropriately has been theorized to be a cause of unexplained implantation failure. Why some women do not produce beta-3 integrins is usually unknown. However, some proposed causes include presence of blocked fallopian tubes filled with inflammatory fluids (hydrosalpinx), endometriosis, and poor progesterone production.

In order to diagnose whether or not a patient is producing beta-3 integrins, an endometrial biopsy must be performed 8-10 days after ovulation, as determined by LH surge testing. The biopsied endometrial sample is then sent to a laboratory that performs immuno-histochemical analysis on the tissue. The tissue is fixed to a slide and treated with antibodies to beta-3 integrins. These antibodies then are further treated with a second color marker antibody, so that endometrium-secreting beta-3 integrins will light up under the microscope. The tissue is scored by manual analysis by a medical technologist specifically trained to analyze beta-3 integrin expression.

In June of this year, I had the opportunity to visit Adeza Biomedical, a Cupertino-based laboratory that offers beta-3 integrin testing. I was impressed with the facility and the scientific integrity of the staff. I was also impressed with the labor-intensiveness of the analysis process. They receive specimens every day from infertility clinics across the country and are usually processing 6-12 specimens daily. They also send a portion of the biopsied tissue to a local pathologist to determine if the configuration (histology) of the endometrial tissue indicates it has been obtained within the implantation window or whether it is “out-of-phase.” As it turns out, a high percentage of tissue samples (40-45%) at Adeza are reported as negative for beta-3 integrins. A smaller percentage of these negative specimens are “out-of-phase”. So most of the specimens failing to show beta-3 integrins production are “in-phase”. It is unclear why this lab finds such a high rate of their test samples showing negative results for beta-3 integrins when the true incidence of lack of beta-3 integrins in most patients should be low. It may be that either the lab is setting the scoring level for a positive result too high or it may be that the patient samples really reflect a selected population of women who truly have low expression of beta-3 integrins. Unfortunately, there is no clear answer to this.

Previously, we had been less inclined to perform endometrial biopsies. Even if we found out there was a lack of beta-3 integrins, we wouldn’t know what to do to induce their expression. However, we are beginning to find that we can often induce the expression by treating beta-3 integrin-negative patients with the aromatase enzyme inhibitor, letrozole (see A Closer Look at Letrozole; May 2006). Many women, especially if the histology on the original biopsy is “in-phase,” will have a positive biopsy result after treatment with letrozole.

Biopsies are typically performed 8-10 days after an LH surge in a natural cycle. Repeat biopsies on letrozole (taken days 3-7 of the cycle) are also performed at this time. We usually will use some local anesthetic in the cervix prior to passing a small plastic tube through the cervix to scrape out some endometrial tissue. Mild cramping may occur. The cost of the biopsy is $125.00 and the cost of the tissue analysis by Adeza is $400.00. It takes about 4-5 working days for the results to be received.

If you would like more information about this test, visit www.adeza.com and select the E-tegrity logo. You can download a patient brochure from this website. If you would like to know if this testing is appropriate for you, please ask your PFC physician.

– Carolyn Givens, M.D.