My pleasure. Please see below:
ENDOMETRIOSIS AND INFERTILITY: A RATIONAL BASIS FOR TREATMENT.
Women who have endometriosis are much more likely to be infertile. There are several reasons for this:
· First,endometriosis is associated with the presence of toxins in peritoneal secretions. As sperm and egg(s) travel towards the fallopian tubes they are exposed to these toxins which compromise the fertilization process
· Second, in about 25 - 30% of cases, endometriosis is associated with ovulation dysfunction.
· Third, in its most severe form, the condition is associated with scarring and adhesions in the pelvis, resulting in damage to, or blockage of the fallopian tubes, thereby preventing the union of sperm and eggs.
· Fourth, endometriosis is associated with abnormalities of the woman's immune system which interfere with the ability of the fertilized egg to attach (implant) to the uterine wall.
Until quite recently, we really had no clue as to how reproductive problems associated with endometriosis, evolve. Recent medical research has helped shed light on the subject and offers promise with regard to the future treatment of infertility/ reproductive failure associated with this condition. A few examples of recent breakthroughs include the following:
Endometriosis appears to have a genetic (familial) component .In the future, the development of genetic markers might provide an important diagnostic tool.
Patients with endometriosis have immunologic abnormalities. The most significant of these involve the presence of harmful antibodies known as antiphospholipid antibodies (APA) are in the bloodstream of about 66 percent of women with endometriosis. In about half such cases (i.e. about 1/3 of all cases of endometriosis…regardless of severity) the immunologic implantation is profoundly aggravated by the presence of activated (i.e. “toxic”) Natural Killer cells (Nka) in the uterine lining (endometrium). These NKa attack the invading trophoblast cells (developing "root system" of the embryo/early conceptus) as soon as it tries to gain attachment to the uterine wall. In most cases, this results in death of the embryo even before the pregnancy is diagnosed and sometimes, in a chemical pregnancy or even an early miscarriage. . As such, many women with endometriosis, rather than being infertile, in the strict sense of the word, often actually experience repeated undetected “mini-miscarriages”.
Endometriosis often goes unnoticed for many years. Such patients are frequently, erroneously labeled as having "unexplained infertility", until the diagnosis is finally clinched through direct visualization of the lesions at the time of laparoscopy or laparoscopy. Not surprisingly, many patients with so called "unexplained" infertility, if followed for a number of years, will ultimately reveal endometriosis.
Advanced Endometriosis: In its most advanced stage, anatomical disfiguration is causally linked to the infertility. In such cases, inspection at laparoscopy or laparoscopy will usually reveal severe pelvic adhesions, scarring and “chocolate cysts". However, the quality of life of patients with advanced endometriosis is usually so severely compromised by pain and discomfort, that having a baby is often low on the priority list. Accordingly, such patients are usually often more interested in relatively radical medical and surgical treatment options (might preclude a subsequent pregnancy), such as removal of ovaries, fallopian pubis and even the uterus, as a means of alleviating suffering.
Moderately Severe Endometriosis. These patients have a modest amount of scarring/ adhesions and endometriotic deposits which are usually detected on the ovaries, fallopian tubes, bladder surface and low in the pelvis, behind the uterus. In such cases, the fallopian tubes are usually opened and functional.
Mild Endometriosis: These patients who at laparoscopy or laparotomy are found to have no significant distortion of pelvic anatomy are often erroneously labeled as having "unexplained" infertility. To hold that the there can only infertility can only be attributed to endometriosis if significant anatomical disease can be identified, is to ignore the fact that, biochemical, hormonal and immunological factors profoundly impact fertility. Failure to recognize this salient fact continues to play havoc with the hopes and dreams of many infertile endometriosis patients.
Endometriotic implants produce a toxic “peritoneal factor”
As mentioned above, toxins that impair fertilization are present in the peritoneal secretions of most patients with endometriosis. Impaired fertilization is a feature of endometriosis regardless of its severity. This explains why women with endometriosis are three times less likely to conceive per month of trying and why procedures such as intrauterine insemination do not increase the chances of pregnancy over no treatment at all. It also explains why in vitro fertilization (which relies upon removing eggs through aspiration of the ovarian follicles before they can be affected by peritoneal toxins), by bypassing this handicap improves pregnancy rates dramatically and accordingly is the treatment of choice for most endometriosis patients with infertility.
The “immunologic connection”
More than two third of patients with endometriosis, have APA's in their blood and that these antibodies, given certain conditions, are capable of attacking the embryo and preventing implantation. There are at least 18 varieties of APA. Treatment requires prior and specific identification of all 18 sub-types and their gammaglobulin isotypes. Unfortunately, only a handful of Laboratories in the United States are capable of adequately testing for APAs. But it probably not APAs that cause infertility in endometriosis patients. Rather it is the co-existence of toxic or activated NK cells (Nka) that attack the early embryo’s root system as soon as it tries to attach to the uterine wall that causes the problem. The presence of APAs probably represents a marker which identifies those endometriosis patients who have immunologic problems requiring immunotherapy (approximately 30% of women with endometriosis (regardless of its severity) test positive for Nka cells). Optimal treatment is predicated upon an accurate diagnosis (see below).
How should infertility associated with endometriosis be managed?
The following basic concepts apply to management of endometriosis-related infertility:
v Ovulation induction with/without intrauterine insemination: Toxins in the peritoneal secretions of women with endometriosis exert a negative effect on fertilization potential regardless of how sperm reaches the fallopian tubes. It follows that intrauterine insemination will not improve the chances of pregnancy (over no treatment at all) in women with endometriosis.
v Surgery aimed at restoring the anatomical integrity of the fallopian tubes does not counter the negative influence of toxic peritoneal factors that inherently reduce the chances of conception in women with endometriosis approximately three fold. Nor does it address the immunologic dysfunction commonly associated with this condition.
Pelvic surgery is relatively contraindicated for the treatment of infertility associated with endometriosis, when the woman is more than 35 years of age. With the pre-menopause approaching, such women do not have the time to waste on such less efficacious alternatives. In contrast, younger women who have time on their side might consider surgery as a viable option. Approximately 30 -40 percent of women under 35 years of age with endometriosis will conceive with in two to three years following corrective pelvic surgery.
v In vitro fertilization is the treatment of choice for women with endometriosis. This is especially true for women more than 35 years of age or where surgery and treatment with fertility agents has proven to be unsuccessful. We anticipate that approximately 75 percent of such women will achieve the birth of one or more babies within three IVF attempts performed at SIRM.
v The role of selective immunotherapy
Women with APA's experience improved IVF birth rates when mini-dose heparin is administered from the onset of ovarian stimulation with gonadootropins (Repronex, Gonal F or Follistim) until the 8th week of pregnancy.
Recently we discovered that heparin therapy only benefits APA+ women who do not have positive blood tests Nka. Women who test positive for Nka require intravenous immunoglobulin (IVIG) therapy.
About IVIG:Since IVIG is a blood product, any suggestion that it be administered usually evokes a fear that it could transmit the HIV virus to recipients. In this regard, it is important to point out that not a single case of HIV, attributable to IVIG administration has been reported in the United States. This, in spite of the fact that more than two million individuals have received such treatment in this country, to date. Furthermore, IVIG administration has not been found to be associated with serious long term complications Side effects are usually mild and transient in nature. The occurrence of serious allergic reactions to IVIG can almost always be avoided by recognizing individuals at risk and pre-medicating them appropriately before initiating treatment. Accordingly IVIG preparations can be considered to be safe when administered by trained personnel.
While the exact cause of endometriosis remains an enigma, it is now apparent that immunologic dysfunction is a significant feature of this disease. Whether immunopathology is causally linked to this condition or whether it occurs in response to endometriosis is unknown. Regardless, the underlying immunologic disorder adversely impacts on implantation of the embryo/early conceptus. It is possible, through thorough and meticulous evaluation, to quantify, typify and thereupon, selectively treat the underlying immunopathology. In so doing, IVF pregnancy rates can be significantly improved.