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Immune Pathology Evaluation of the Endometrium
Introduction 
Immune pathology studies of a biopsy of the endometrium (uterine lining) in women with recurrent pregnancy losses, IVF failures and implantation failures show that lymphocytes can damage the lining as well as the embryo. These lymphocytes are not seen in the uterus of fertile women. To find if a woman has this problem an endometrial biopsy is done by a gynecologist on cycle day 26 or a few days before menstruation.
These unwanted immigrant cells that take up house-keeping in the uterus are:
- Activated macrophages that secrete IL-1 (toxic to the lining and to the embryos);
- CD 57+ cells that secrete tumor necrosis factor alpha (toxic to the embryos and uterine tissue). These cells can cause stromal hemorrhages, subchorionic hemorrhages and early premenstrual spotting;
- Mast cells (associated with hives and rashes in the skin of allergic individuals), when present in the uterus, cause stabbing pains, bad premenstrual syndrome, severe cramping and ill feelings after intrauterine insemination or embryo transfer.
Most individuals with category 5 immune problems have increased numbers of CD 57+ cells in the blood, and increased cytotoxicity (killing power) of these cells when tested in the NK assay. Some women, who have had category 5 immune problems for a long time, have natural killer cells that have migrated to the uterus and are living there as "tissue residents."
Background
At the time of ovulation the uterus and the endometrial lining are prepared for implantation. The glands and the endometrium are thickened to 10-14 mm, have formed three zones, blood vessels and blood flow have entered zone three and the glands are producing rich sugar-like secretions to nourish the embryo until it implants. New molecules are forming on the lining to make it receptive and sticky (integrins) for the embryo. Heparin molecules are arriving into the uterus to help cross link the embryo with the lining. Lymphocytes are arriving (TH-2) that will secrete cytokines (growth molecules) that help with implantation and growth of the embryo. All of this can be seen by immune pathology and can be seen as in good order. Immune pathology can also find the TH-1 natural killer cells that do not put the uterus and the lining in good order.
Many of the women that I see have a chaotic situation in the uterus. The lining development is disordered because of CD57+ cells that have taken up residence there. CD57+ cells live in the uterine glands, lining and in the stroma (soon to become decidua). This stroma is the tissue that nourishes the glands and the lining. It will soon nourish the placenta and we call this tissue decidua. When the embryo arrives, these CD57+ cells are activated and secrete Tumor Necrosis Factor alpha, which causes a breakdown in the lining of the uterus, the glands and the stroma. When the stroma breaks down, hemorrhages and blood cysts appear. This can cause severe cramping and some bleeding. This results in the uterus becoming a hostile environment for the embryo. Pregnancies fail very early or do not occur at all.
Women at Risk for Elevated CD57+ cells in Uterine Tissue
Women who are at risk for having elevated CD57+ cells in the uterine tissue are:
- Women with a known autoimmune disorder such as fibromyalgia, lupus, rheumatoid arthritis, Crohn's Disease, thyroiditis, chronic fatigue syndrome, Raynaud's disease, mixed connective tissue disorder and ulcerative colitis;
- Women with a history of dysplasia of the cervix, carcinoma in situ of the cervix or papilloma virus infections (HPV);
- Infertile women with endometriosis prior to their first assisted reproductive technology (ART) or IVF cycle;
- Women with recurrent spontaneous abortions who lose their pregnancies earlier and earlier or who have secondary infertility;
- Women with two IVF failures;
- Women with repeated implantation failures;
- Women who experience flu like symptoms with implantation, transfer or implantation failure;
- Women who experience stabbing pelvic pains or intense cramping with inseminations or embryo transfers.
In many women, all of these situations and complaints are discounted and minimized by most reproductive endocrinology or OB/GYN doctors. These symptoms are not in your head as figments of your imagination. They are real and demand attention and workup.
What can Diagnose this Problem?
- An endometrial biopsy done two or three days before expected menses or, at the latest, on the first day of menstruation of a normal non-conception cycle.
- An endometrial biopsy done 10-14 days post transfer when the pregnancy test is negative and before menstruation begins.
How is the Biopsy Done?
The information on how the biopsy is done is intended for registered patients of our program.
- The instruments used by the doctor is a disposable Endometrial Suction Curette or a Novak curette. The biopsy is done in the doctor's office or at the hospital.
- The doctor places the tissue in 10% formalin. He/she can send the tissue directly to my laboratory, or it can be sent to his/her pathologist to be embedded in paraffin blocks and the paraffin blocks can be sent. The tissue should be sent by overnight mail to
Alan E. Beer Laboratory for Reproductive Medicine
7013 Realm Dr.
Suite A
San Jose, CA 95119
Prior to shipping a pathology specimen, you should contact us and register your information. If a specimen arrives without a completed patient registration packet, then the specimen will not be submitted for a pathology evaluation.
- When the test results are available, someone from our office will contact you. However, it is a good practice to contact us at (408) 356-9500 if you do not hear from us more than three weeks from your specimen ship date.
- A consultation will be set up with one of our physicians to discuss the results (please note, there will be a charge for both phone and e-mail consultations).
Costs
If you are a registered patient with our program
- Please contact info@repro-med.net for the most current price.
- There is an additional fee for reviewing the registration packet and medical records. This review allows the physician to make recommendations for testing that will need to be
completed prior to initiation of treatment.
References
1. Kwak JY, Beer AE, Kim SH, Mantouvalos HP. Immunopathology of the implantation site utilizing monoclonal antibodies to natural killer cells in women with recurrent pregnancy losses. Am J Reprod Immunol. 1999 Jan;41(1):91-8.
2. Vassiliadou N, Bulmer JN 1996. Immunohistochemical evidence for increased numbers of 'classic' CD57+ natural killer cells in the endometrium of women suffering spontaneous early pregnancy loss. Hum Reprod 1996 Jul;11(7);1569-74.
3. Van den Hove L E, Van Gool S W, Vandenberghe P, Boogaerts M A and Ceuppens. CD57+/CD28- T cells in untreated hematooncological patients are expanded and display a Th1-type cytokine secretion profile, ex vivo cytolytic activity and enhanced tendency to apoptosis. Leukemia 1998 12(10):1573-1582.
The information contained in this article is not intended to be a medical diagnosis, treatment or medical advice in any way, as it is general information and cannot be relied on without consultation with your physician. It is not intended nor is it implied to be a substitute for profession medical advice. As medical information can change rapidly, we strongly encourage you to discuss all health matters and concerns with your physician before embarking on new diagnostic or treatment strategies.
Alan E. Beer Center for Reproductive Immunology & Genetics
15151 National Ave. #2; Los Gatos, CA 95032; Phone: (408) 356-9500; Fax: (408) 356-9509; E-mail: info@repro-med.net.
Date: 7-24-08, Time: 9:53 am.
General Question? E-mail: info@repro-med.net.
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