The considerable emotional, physical and financial burden associated with infertility treatment in general and with IVF in specific, demand that factors known to affect outcome be identified and regulated prior to initiating treatment. In this post, I’ll address the influence of factors that affect uterine/endometrial receptivity to embryo implantation and discuss approaches to treatment.

1. Contour of the uterine cavity
It has long been suspected that anatomical defects of the uterus might result in infertility.
While the presence of myomas (fibroids) in the uterine wall are unlikely to cause infertility, an association between their presence and infertility has been observed in cases where they distort the uterine cavity, or protrude as submucous polyps through the endometrial lining. It would appear that even small submucous myomas have the potential to prejudice implantation.

It is likely that any surface lesion in the uterine cavity, whether an endometrial, placental or fibroid polyp (no matter how small), or intrauterine adhesions, has the potential to interfere with implantation by producing a local inflammatory response, not too dissimilar in nature from that which is caused by a foreign body such as a intrauterine contraceptive device. Unfortunately, a dye X-Ray test (hysterosalpingogram or HSG) will miss the diagnosis in approximately 20% of cases. The only reliable methods for diagnosing even the smallest of such lesions is through the performance of a sonohysterogram (SHG), or by hysteroscopy.

Sonohysterography (SHG): A sonohysterogram (also known as a Fluid Ultrasound [FUS]) is a procedure whereby a sterile solution of saline is injected via a catheter through the cervix and into the uterine cavity. The fluid-distended cavity is then examined by vaginal ultrasound for any irregularities that might point to surface lesions such as polyps, fibroid tumors, scarring, or a uterine septum. If performed by an expert, SHG is highly effective in recognizing even the smallest surface lesions that protrude into the uterine cavity. SHG is less expensive, less traumatic, and equally diagnostically reliable as hysteroscopy. The only disadvantage lies in the fact that if a lesion is detected, it may require the subsequent performance of hysteroscopy to treat the problem anyway.

Hysteroscopy: Diagnostic hysteroscopy is an office procedure that is performed under intravenous sedation, general or local anesthesia, with minimal discomfort to the patient. The procedure involves the insertion of a thin, lighted, telescope‑like instrument known as a hysteroscope through the vagina and cervix into the uterus in order to fully examine the uterine cavity. The uterus is first distended with carbon dioxide gas, which is passed through a sleeve adjacent to the hysteroscope. As is the case with FUS, diagnostic hysteroscopy facilitates examination of the inside of the uterus under direct vision for defects that might interfere with implantation.

We have observed that approximately one in eight candidates for IVF have intrauterine lesions that require attention prior to undergoing IVF in order to optimize the chances of a successful outcome. We strongly recommend that all patients who have such lesions undergo therapeutic surgery (usually via hysteroscopic resection) to correct the pathology prior to undergoing IVF. Depending on the severity and nature of the pathology, therapeutic hysteroscopy may require general anesthesia. If so, it should be performed in an outpatient surgical facility or in a conventional operating room.

2. Endometrial Thickness
In 1989, we were first to show that in both normal and “stimulated” cycles, preovulatory endometrial thickness as assessed by ultrasound examination, is predictive of embryo implantation (pregnancy) potential following IVF. Ideally, the endometrium should measure at least 9.0mm in thickness. However, although much less likely, healthy pregnancies can occur with linings that measure between 7.5 and 9.0mm

A “poor” endometrial lining is most commonly due to: 1) inflammation of the uterine lining (endometritis) that usually occurs as a result of a septic delivery, abortion or miscarriage, 2) severe adenomyosis (gross invasion of the uterine muscle by endometrial glandular tissue), 3) multiple fibroid tumors of the uterine wall) 4) prenatal exposure to the synthetic hormone, diethylstilbestrol (DES) and, 5) following back to back cycles of clomiphene citrate ovulation induction.

Treatment with vaginal Viagra: Hitherto, attempts to augment endometrial growth in women with poor endometrial linings by bolstering circulating estrogen blood levels (through the administration of increased doses of fertility drugs, aspirin administration and by supplementary estrogen therapy) have yielded disappointing results.

We recently demonstrated that the vaginal administration of sildenafil (Viagra) for several days prior to the “hCG trigger “ or progesterone administration enhances uterine blood flow and estrogen delivery to the uterine lining, and so improves endometrial thickening.

In October 2002, we reported on the administration of vaginal Viagra to 105 women with repeated IVF failure due to persistently thin endometrial linings. All of the women had experienced at least two (2) prior IVF failures attributed to intractably thin uterine linings. About 70% of these women responded to treatment with Viagra suppositories with a marked improvement in endometrial thickness and 45% of these achieved live IVF- births following a single cycle of treatment with Viagra. 9% miscarried. None of the women who had failed to achieve an improvement in endometrial thickness following Viagra and who subsequently underwent embryo transfers achieved viable pregnancies.

Since the introduction of this form of treatment, more than 500 women have been reported treated and many have gone on to have babies after repeated prior IVF failure.

3. Immunologic Factors
The implantation process of the embryo in the uterus begins six or seven days after fertilization of the egg. At this time, specialized embryonic cells (i.e., the trophoblast), which later becomes the placenta, begin growing into the uterine lining. When the trophoblast and the uterine lining meet, they, along with Immune cells in the lining, become involved in a “cross talk” through mutual exchange of hormone-like substances called cytokines. Because of this complex immunologic interplay, the uterus is able to foster the embryo’s successful growth. Thus, from the very earliest stage of implantation the trophoblast establishes a foundation for the future nutritional, hormonal and respiratory interchange between mother and baby. In this manner, the interactive process of implantation is not only central to survival in early pregnancy but also to the quality of life after birth.

Considering its importance, it is not surprising that problems with this immunologic interaction during implantation have been implicated as a cause of recurrent miscarriage, late pregnancy fetal loss, IVF failure, and infertility. A partial list of immunologic factors that may be involved in these situations includes anti-phospholipid antibodies (APA), antithyroid antibodies (ATA), and, perhaps most importantly, activated natural killer cells (NKa). Presently, these immunologic markers in the blood can be adequately measured by only a few (less than a half dozen) highly specialized reproductive immunology laboratories in the United States.

The Central Role of Natural Killer Cells: After ovulation and during early pregnancy, NK cells comprise more than 70% of the immune cell population of the uterine lining. NK cells produce a variety of local hormones known as TH-1 cytokines. Uncontrolled, excessive release of TH-1 cytokines is highly toxic to the trophoblast and endometrial cells, leading to their programmed death (apoptosis) and, subsequently to failed implantation. In the following situations, NK cells become activated and start to produce an excess of TH-1 cytokines: 1) Aloimmune implantation dysfunction where the male and female partners share specific genetic (DQ-alpha and/or HLA) similarities and 2) in Autoimmune conditions such as Rheumatoid arthritis, hypothyroidism endometriosis and Lupus Erythematosis.

Activated NK cells (NKa) can be detected in peripheral blood where their toxicity can be measured. Intralipid (IL) therapy, initiated more than 1week prior to embryo transfer, can subdue activated NK cells, thereby reducing the risk of implantation failure.