endometrium within the womb is a dynamic tissue that secretes a wide variety of nutrients and hormones required for normal conception. The endometriotic implants also secrete these same substances, but instead of depositing them into the lumen (centre) of the womb as normal, the implants release their chemical secretions into the abdominal cavity. Some of these substances, which are in effect strong hormones, could interfere with fertility. Recent studies suggest that endometriotic implants also produce cytokines.4 These inflammatory immune cells are in the peritoneal fluid and, in patients with endometriosis, this fluid has been shown to be toxic to the preimplantation embryo. It also contains macrophages and growth factors.
PROSTAGLANDINS
One major group of hormones secreted by the normal endometrium is the prostaglandins. These are oil-based hormones found in nearly all the tissues of the body and are required for many bodily processes, including several stages of the menstrual cycle and pregnancy. Prostaglandins are required for ovulation, regression of the corpus luteum (ending the monthly menstrual cycle), sperm motility, immune interactions, contraction of the uterus at birth and menstrual cramps. Endometriotic implants and the endometrium of the uterus are the richest source of prostaglandin production in the body.
However, the problem with endometriotic implants is two-fold:
1 Prostaglandins are released into the abdomen instead of inside the womb.
2 Prostaglandin release by the implants seems to be out of phase with their release by the uterus. Prostaglandins are produced at the wrong time sending the wrong message.
For instance, there is a natural surge in prostaglandin F production at the end of the menstrual cycle, causing the effects of the corpus luteum of the ovary to die down and signalling the start of a new menstrual cycle. The endometriotic implants produce their prostaglandin surge several days after that of the womb lining. This may be one of the main causes of very early miscarriage. Approximately 31 per cent of biochemically detected pregnancies fail to atain viability; of these, 50 per cent are lost prior to the first missed period due to defective implantation. The majority (60 per cent) of lost pregnancies are due to chromosomal aberrations.5 If a woman is a few days pregnant then the implant-produced prostaglandin F would wrongly tell the ovary to start a new menstrual cycle, causing the womb lining with the implanted egg to be sloughed off – an early miscarriage. Prostaglandins are messengers and like all messengers they sometimes get it wrong.6
Prostaglandins also play an important role in the contractions of the womb and Fallopian tubes. During the normal menstrual cycle the gentle contractions of the womb and Fallopian tubes aid the movement of egg and sperm to the outer third of the Fallopian tube where fertilization occurs. High concentrations of endometriotic implant prostaglandins at the wrong time could interfere with this and may prevent fertilization. An excess of PGF2 and PGE2 could cause contractions that are too strong and expel the egg too quickly. Series 2 prostaglandins are produced from the fats in dairy and meat products, and it is recommended that intake of these foods be kept to a minimum.
Series 2 prostaglandins are also responsible for the contractions of the uterus at the end of pregnancy, stimulating the powerful uterine muscle contractions required for the birthing process. Inappropriate concentrations of implant-produced prostaglandins could stimulate forceful uterine contractions (cramps) at the time of embryo implantation and lead to early expulsion of the embryo.7 Indeed, in both humans and domestic animals, prostaglandin F is used clinically to induce abortion or to hasten the birthing process.
Series 1 and 3 prostaglandins, enhance the immune response and, as we will discuss in chapter 9, they may even modify normal immune interactions that could prevent conception. Prostaglandins also stimulate sperm motility, and high levels of proinflammatory series 2 prostaglandins could lead to early ‘burn-out’ of the sperm, preventing fertilization.8
Although prostaglandin secretion into the peritoneal cavity is required for the reproductive process, it is clear that too much of the wrong type of prostaglandin in the wrong place, or prostaglandin production at the wrong time, could easily interfere with fertility. Exactly how or even whether prostaglandins play a role in the infertility associated with endometriosis is not known, but they do seem to be involved.
PROTEIN PRODUCTION
The endometrium of the uterus and endometriotic implants have ‘a prolific ability to produce hundreds of different types of proteins’.9 Although the roles of all these proteins are not known, some of them are used by the body as nutrition for the developing embryo, and some function as hormones or trigger hormone release.
Various laboratory studies have shown that most of these proteins are produced by both implants and womb endometrium. However, two proteins have been discovered that are produced only by the endometriotic implants10 – Endo I and Endo II. These two unique proteins may interfere with fertility. It is also possible that proteins that are common to both the uterus and implants, like prostaglandins, may be inappropriately produced by endometriotic implants, and have a bad effect on the reproductive system. These proteins may interfere with immune system surveillance so that implants are not removed by normal macrophages and natural killer cells. Isolated endometriosis stroma cells secrete more sICAM-1 than normal endometrium.11
ABNORMAL OVULATION
The monthly maturation of eggs and the process of ovulation may be altered in the patient with endometriosis: ‘Women with endometriosis have been shown to have smaller, but many more, follicles maturing at the time of ovulation than controls’.12 This suggests that the chemical secretions from endometriotic implants hamper the ability of the ovary to respond correctly to the message from the pituitary hormones, or that hormones secreted by the ovary do not give the correct message to the pituitary gland. Indeed, high prolactin levels are known to inhibit ovulation.
Under the influence of the pituitary luteinizing hormone, the follicular wall of the ovary close to the Fallopian tube thins and ruptures, releasing the ova. Endometriosis may prevent the completion of this ovulatory process. This inability to ovulate is called ‘luteinized unruptured follicle syndrome’ (LUF). In LUF syndrome, women have the normal sequence of endocrine events and a normal menstrual period, but their ovaries do not release any eggs at the time of ovulation.
This syndrome is difficult to diagnose since, from all external measurements (hormone concentrations and menstrual flow), nothing appears to be wrong. As the egg is but a single cell and the ovary wall repairs itself almost immediately after ovulation, the absence of ovulation usually goes unnoticed. However, some researchers have tried meticulously to check for ovulation with laparoscopic examination of the ovary at the presumed time of ovulation.13 They found that the incidence of signs of ovulation was lower in endometriosis patients than in fertile control patients.
The precise means by which endometriotic implants adversely affect the development of the egg within the ovary is not yet known, but it is suggested that implant secretions, such as prostaglandins and excess natural oestrogens, or even oestrogens from outside the body (xeno-oestrogens), are damaging to conception. Non-steroidal anti-inflammatory drugs give rise to LUF, research has shown. In women with LUF syndrome, steroid hormone concentrations in the peritoneal fluid are much lower after the ovulatory cycle. It is felt that this may facilitate the development of endometriosis.14
IMPAIRED FERTILIZATION
In addition to an alteration in follicular development and ovulation, the actual quality of the eggs in women with endometriosis may be different. Various in vitro fertilization (IVF) programmes have observed that the presence of endometriosis in the abdomen, and especially in the ovary, adversely affects the appearance of the egg and decreases its ability to fertilize.
Normally the eggs have a yellowish appearance with a smooth oatmeal texture. The eggs of the endometriosis patient are sometimes dark brown in colour and have a granular texture. In 1985 Wardle noted that the fertilization rate of eggs from endometriosis patients was significantly lower than in patients who had unexplained infertility or blocked Fallopian tubes.15 Again, this could be explained by the chemical secretions from the endometriotic