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American College of Embryology

Miracle Babies: Chapter 17 Endometriosis: Conquering the Silent Invader                      Send Link
Endometriosis
Conquering the Silent Invader


"When we had sex on our wedding night, instead of having an ultimate experience with my husband, sex was so painful I ended up in tears," Marilyn P. wrote to her Witsendo friends. "I thought something was wrong with me . . .that I was frigid or something.

"When I went to the doctor, I told him I'd always had some pain with my periods but that my cramps were getting worse.

"He did a pelvic exam and I screamed when he touched my left ovary. After doing an ultrasound examination, he told me that my left ovary was swollen to twice its normal size. He also felt small bumps behind my uterus. He recommended doing a laparoscopy to find out what was going on.

"That's when I got the news: endometriosis at the ripe old age of twenty-three, and that I had probably had endometriosis as a teenager! What a way to start married life."

What is it?

Endometriosis is described as the presence of endometrial tissue in locations outside the endometrial (uterine) cavity. Endometriosis is commonly found in the cul-de-sac (behind the uterus), the rectovaginal septum (the tissue between the rectum and vagina), on the surface of the rectum, the fallopian tubes and ovaries, the uterosacral ligaments, the bladder, and the pelvic side wall. Generally endometriosis in the rectovaginal septum is more likely to deeply invade the underlying structures.

Is endometriosis a genetic disease?
Studies have shown that sisters have a six times increased risk compared to their husband's sisters. Other studies show up to an eight times increased risk when compared to other women. Affected sisters are more likely to have severe disease than other. Although these studies suggest a genetic basis, presently, the mode of inheritance is unknown. The OXEGENE Study is enrolling family members with endometriosis to try and identify the genetic basis of this disease.

How common is it?
At the time of tubal ligation 2-5% of women will have endometriosis, while between 25-50% of infertile women have been reported to have endometriosis. Endometriosis affects 5 million U.S. women, approximately 6-7% of all females, 30-40% of whom are infertile.

What are the causes?
No one theory seems to explain all cases. Several theories, however, have been postulated:

  • The endometrial tissue migrates from the uterus through the tubes into the pelvis. (This doesn't explain how women with their tubes tied develop the disease or why it remains after hysterectomy.)
  • An abnormality in the immune system allows normally shed endometrial cells to attach and grow.
  • The disease is caused by a genetic birth defect as evidenced by the tendency for it to run in families. Patients with an affected mother or siblings are more likely (61 percent) to have severe endometriosis than those without affected relatives (23 percent).
  • Tissue in the abdominal cavity changes into endometrial tissue as a result of repeated inflammation (sheer speculation at this point).
  • The endometrial tissue spreads from the uterus to the abdominal cavity through the lymphatic system or bloodstream.

Commonly during the menstrual period, cells can be found in the fluid behind the uterus. The most widely held theory, retrograde menstruation, states that endometriosis occurs when endometrial fragments attach to nearby pelvic structures and grow. Other theories include tissue transplantation, induction of changes in peritoneal lining cells, spread through uterine veins, and direct extension through the lymphatic system.

As endometrial cells are frequently seen in peritoneal fluid in all women at the time of menses, one would expect endometriosis to develop in everyone. Obviously this is not appear the case. Unfortunately, we don't really know why. Is the immune system the cause? Immunological changes have been demonstrated in women with endometriosis, however, it is uncertain whether these immunologic findings are responsible for the endometriosis or are a result of the inflammation caused by endometriosis.

How Does Endometriosis Cause Fertility Problems?
In cases where there is obvious disruption of the normal anatomy, endometriosis is a known cause of fertility problems. In fact 30-40% of patients with endometriosis are infertile. This is two to three times the rate of infertility in the general population.

In patients with endometriosis, the monthly fecundity (chance of getting pregnant) decreases by 12-36%. However, the long term cumulative pregnancy rates are normal in patients with minimal endometriosis and normal anatomy. Studies provide contradicting information, but the bulk of research at this time indicates that pregnancy rates are not improved by treating minimal endometriosis.

Under the influence of cycling female hormones, each month the displaced endometrial tissue grows and sheds blood at the time of menses. Instead of flowing harmlessly outside the body, however, the excrement wreaks havoc in the abdominal cavity.

The resulting chronic tissue inflammation leads to the formation of adhesions and scars, which surround and entrap delicate reproductive organs. The adhesions can be so extensive that they literally freeze the tubes, ovaries, and uterus into place (stages III and IV). The eggs themselves are trapped in the heavy shrouds of scar tissue surrounding the ovaries, and infertility results. As the disease spreads, the older endometrial cells burn out, leaving dead scar tissue in their wake.

Even mild forms of the disease (stages I and II) may interfere with fertility. It is hypothesized that the prostaglandins (hormones) secreted by the active, young endometrial implants or other chemicals secreted by white blood cells may interfere with the reproductive organs by causing muscular contractions or spasms. The tube may be unable to pick up the egg, and the stimulated uterus may reject implantation. In addition, sperm motility may be adversely affected along with the ability of the sperm to penetrate into the egg. Although the mechanisms are not fully understood, endometriosis may also result in anovulation (17 percent), cause a luteal phase defect interfering with implantation, or cause a luteinized unruptured follicle.

Some researchers suggest that the woman's body may form antibodies against the misplaced endometrial tissue. The same antibodies may attack the uterine lining and cause the high spontaneous-abortion rate: up to three times the normal rate. (Fortunately, removing the endometriosis with medication or with surgery will reduce this risk to normal.)

The normal tissue surrounding the endometriosis implant becomes puckered and ischemic (suffering from lack of oxygen), causing pain similar to that from a heart attack. Attacked over a prolonged period, the fallopian tubes may become inflamed and swell shut. Blocked by adhesions, the tubes can no longer provide safe passage for egg, sperm, and embryo. Ectopic pregnancies become a real danger: up to sixteen times more likely than the normal population (16 percent vs. 1 percent). Let's evaluate the specific factors that may contribute to infertility in patients with endometriosis.

Hormonal parameters:
Compared to a normal cycle, the follicular phase may be shorter in patients with endometriosis, the estradiol may be lower, and a blunted LH surge may be seen. Progesterone levels and luteal phase endometrial biopsies, however, are normal. There is a tendency towards greater number of follicles which are smaller at the time of the LH surge in patients with endometriosis. However, this data does not prove that endometriosis is the cause of infertility. Women with subtle ovulatory dysfunction are more likely to have infertility and it may be that infertility or an abnormal hormone profile increases the likelihood of endometriosis.

Luteinized unruptured follicle syndrome:
In women with severe pelvic adhesions where the ovary is encased, luteinized unruptured follicle (LUF) may be noted. This is believed to occur when, despite normal hormonal parameters (LH surge), the egg is not released from the ovary. Endometriosis is found in 63% of those patients reported to have LUF. LUF is seen in 35% of patients with endometriosis versus 11% of patients without endometriosis. However, the detection of follicular rupture by ultrasound and laparoscopy is very subjective and the diagnosis of this condition is complicated. Therefore, studies that look at endometriosis and LUF must be held suspect.

IVF and experimental models:
Studies in rabbits have shown that surgical induction of endometriosis leads to a decrease in fertility from 75% to 25%. This may be due to anovulation associated with endometrial implants. Studies have evaluated immune modification in the rabbit model to attempt to restore fertility.

We know that during in vitro fertilization endometriosis patients have normal hormonal profiles. There is a tendency towards fewer oocytes and it appears that oocytes derived from ovaries with endometriomas may have a lower fertilization rate and implantation rate.

In order to understand whether this effect is due to the embryo or the uterine environment we can look at donor embryo studies. Dr. Simon found decreased donor oocyte implantation rates when the oocytes were from women with endometriosis. In his study, endometriosis in the recipient had no effect on implantation while other studies have found conflicting results.

On the other hand, Dr. Bruce Lessey performed endometrial biopsy surface at the time of implantation and found lower levels of vitronectin (an adhesion molecule on the endometrial surface) in women with unexplained and endometriosis related infertility. Treatment with Lupron and ovulation induction appeared to restore this implantation marker and fertility.

Peritoneal Effects:
The effect of endometriosis on the peritoneal environment may adversely affect fertility. There is an increased volume of peritoneal fluid, and peritoneal macrophages (scavenger white blood cells), are increased both in number and activity. Cytokines (white blood cell chemical messengers) such as IL-1, IL-2, IL-6, TNF-alpha, Interferon, C3, C4 are all increased. These may adversely affect sperm oocyte interaction, sperm mobility and survival, and oocye pick up. In addition, serum samples obtained from women with endometriosis were found to be embryotoxic in mouse embryo cultures 78% of the time versus 20% in women without endometriosis.

Immune System:
The immune system is affected by endometriosis and may adversely affect fertility. Patients with endometriosis may show decreased nature killer cell function, and decreased reactivity to transplanted endometrial tissue. In addition, complement, an immune component that breaks apart abnormal cells, is elevated in patients with endometriosis.

What Are the Symptoms of Endometriosis?

Nearly one-third of the women having endometriosis have no symptoms other than infertility. The others have varying degrees of symptoms, depending on the stage of the disease. Oddly enough, the early stages or milder forms are frequently more painful than the later stages. We believe this is because the young endometrial tissue liberates spasm-causing prostaglandins, whereas the older endometrial tissue simply burns out and turns into inactive scar tissue. The most common symptoms associated with endometriosis are pain and infertility, however, premenstrual spotting, urinary urgency, rectal bleeding, painful urination, bloody cough, and skin nodules may also be noted. Endometriosis may frequently mimic other disorders such as pelvic adhesions, dysmenorrhea (menstrual cramps), irritable bowel syndrome, colitis, and ulcer disease. Careful evaluation is necessary to ensure accurate diagnosis. Diarrhea or rectal bleeding and tenesmus (sense of rectal fullness) at the time of menses are particularly telling symptoms.

Table 17-l gives a profile of the endometriosis patient and tells where the implants, which can be found anywhere in the body, are most frequently located.

Profile of the Endometriosis Patient
(Most common age: 20-35)

Table 17

Profile of Endometriosis Incidence (%)
No symptoms 33
Infertility 70
Dyspareunia (painful menses) 28-66
Hypermenorrhea (heavy periods) 12-74
Spontaneous abortion Up to 50
Weight lower than normal Up to 50
Weight higher than normal 13
Deep dyspareunia (pain during intercourse) 12-33
Sacral backache (accentuated during menses) 25-31
Pelvic adhesions 24-50
Tender or nodular uterosacral ligaments 34
Uterus tipped anteriorly 20
Anovulation 17
Irregular periods 12
Rectal pain 4
Pregnancy rate (without treatment)
Mild cases 31-75
Moderate and severe Very low
Other symptoms
Inguinal/thigh pain; leg cramps
Intermenstrual bleeding
Spontaneous abortion (habitual)
Premenstrual spotting

Location of Endometrial Implants

Site Incidence (%)
Ovaries 61-78
Posterior cul-de-sac (behind uterus) 14-34
Uterine surface 17-55
Intramural sigmoid and rectum 3-4
Cervix, vagina, vulva Very low

Emotional Side Effects May Be Experienced

Depression
Decreased sex drive because of association with painful sex
Doubts about sexuality
Heightened guilt about sex
Poor self-image


Diagnosing Endometriosis
Any complaint related to menses suggests endometriosis. Endometriosis associated with the classic symptoms of painful menstrual periods and/or painful sexual intercourse is relatively easy to diagnose. However, when the symptoms are less suggestive-unexplained infertility, irregular periods, or spotting, for example-identifying the disease may be more difficult. Occasionally while doing the pelvic examination I can feel the telltale beading on the outside of the reproductive organs. The only definitive diagnostic procedure for endometriosis, however, is a direct look inside the abdominal cavity and a biopsy of the tissue.

Diagnostic Laparoscopy
Since laparoscopy requires general anesthesia, I try to rule out all other male and female fertility factors before performing it. Depending on the woman's age, history, and findings from the workup, however, I may choose a more aggressive diagnostic approach for a particular couple. If the woman is in her thirties and if she complains of pelvic pain or has unexplained infertility, I'm likely to perform a laparoscopy sooner.

Viewed through the laparoscope, the endometrial lesions look like raised shaggy brown or blue-black areas ranging from 2 to 10 cm (1 to 4 inches) in diameter. If the disease has been present for a prolonged period of time, the tissue adjacent to the implants will pucker and burned-out areas will show fibrotic scars. Advanced endometriosis (stage III or IV) may invade, pucker, and erode the walls of affected organs, and adhesions may be so dense that they "freeze" the pelvic organs into distorted positions.

Dr. Redwine has described the progressive nature of endometriosis lesions. They are first seen as clear vesicles, then become red, and then progress to black lesions over a period of 7-10 years. Dr. Karnaky described water blister lesions becoming blue dome cysts over a period of 4-10 years. The clear lesions are seen are at an average age of 21.5 while black scarred lesions are seen at a mean age of 31.9. This progression from clear to red to black lesions with age confirms the progressive nature of this disease if left untreated. Disease will progress in 47-64% of women without therapy and approximately 20% of women with therapy.

While performing the laparoscopy, I'll force a colored dye through the cervix, uterus, and tubes to demonstrate tubal patency. Many times, the dye will flow through only one tube (preferential flow) because that tube provides the least resistance to the colored liquid. Although this does not mean that the other tube is blocked, it does not rule out that possibility, either.

There is poor correlation between the degree of pain or infertility and the severity of disease. Early lesions which are clear or red are metabolically more active than older, dark, fibrotic lesions. This metabolic activity may be responsible for the associated infertility, immune abnormalities, urinary urgency, pelvic pain or diarrhea.

Continued