My name is Emma, I am 14 years old. Every month, I have terrible periods; the pain is so bad that I have to stay in bed for 2 or 3 days with a hot water bottle on my tummy. I take Mercyndol. I don’t want to go to school, anyway, because I bleed so much, with these horrible clots, that I am terrified of having an accident. So, I end up missing one week of school every month. I have been put on the pill, but it’s not helping much, and I don’t like it.

Emma has endometriosis. Her symptoms started when she was 12; her young life has been so severely affected that she is taking anti-depressants. Although severe, her symptoms are, unfortunately, not particularly unusual.

Endometriosis is a relatively common disease, affecting mostly women or reproductive age. It is characterised clinically by the presence of ectopic endometrium, that is endometrium (the lining of the uterus) attached to and growing in abnormal locations. In the vast majority of cases, endometriosis affects the pelvic organs, although it has been found in remote locations, such as the lungs and the brain. If endometriosis is extensive, it can cause organs to adhere together. Both the endometrial deposits themselves and the adhesions cause a vast array of symptoms, the most constant being pelvic pain: dysmenorrhea (period pain), low pelvic pain, pain on intercourse (dyspareunia), painful defecation or urination. Irritable Bowel Syndrome (IBS) is also common; a survey of 3020 American women (1) puts the incidence of IBS in woman with endometriosis at 85%. Endometriosis is currently thought to be responsible for up to 80% of women complaining of Chronic Pelvic Pain (CPP).

One must distinguish between the condition of endometriosis, that is the clinical finding of endometrial deposits, and the disease itself. With the progress of endoscopic techniques of investigation, endometriosis is now increasingly found in women. Indeed, some gynaecologists believe that every woman will have it at some time. Only 5% to 20% of women develop the symptoms of the disease itself. Despite a growing body of research worldwide, its causes remain largely unknown. What is becoming obvious is that endometriosis is the multifactorial disorder par excellence (2).

Whether endometriosis causes infertility is by no means certain. IVF studies show that the embryos of women with the condition do not implant as readily as those of “normal” women. (3). However, it is not known whether this is because of poor egg quality or whether the endometrium, in which the embryo implants, is at fault. In any case, a causal relationship with endometriosis has not been proven.

Conventional treatments
They aim at reducing pain and improving fertility.
They fall into two categories: hormonotherapy and surgery.

Hormonal treatments
Ovarian secretion of oestrogens and progesterone is controlled by pituitary hormones, the gonadotropins LH (luteinising hormone) and FSH (follicle stimulating hormone), themselves dependant upon the release of GnRH, or Gonadotropin Releasing Hormone by the hypothalamus. Like many hormones, GnRH needs to bind to a specific receptor to exert its action. GnRH agonists, like Synarel or Zoladex, are synthetic molecules with a much greater binding affinity for the GnRH receptors than the natural hormone. In effect, they saturate the receptors, with the result that, after an initial period of super-stimulation, within 2 to 3 weeks the pituitary gland is totally desensitized to GnRH, a process known as “down-regulation” The ovaries are no longer stimulated and oestrogen levels fall, which causes endometrial lesions to shrink.

Side-effects include menopausal-type symptoms, such as hot flushes, headaches and nausea. More importantly, these synthetic hormones induce significant and irreversible bone loss after 6 months of continuous therapy. In recent years, low doses of oestrogens and progesterone have been added to the GnRH treatment to try and mitigate the risk of osteoporosis, a method known as “add-back”.

Since the relatively recent advent of GnRH analogues, previous treatments with Danazol, a testosterone analogue or Provera, a progesterone analogue have been almost discontinued.

Surgery
Endometriosis is now usually removed by laparoscopy, or key-hole surgery. It is a minor procedure during which small lesions, cysts and adhesions are either burned (cauterised) or lasered. Extensive lesions might require the much more invasive laparotomy, a major operation which involves incision of the abdominal wall. Intractable symptoms might necessitate hysterectomy, the removal of the uterus. Radical hysterectomy involves the removal of all the reproductive organs.

Up to 80% of women experience partial or total symptom remission with either approach. Unfortunately, none of the treatments, with the exception of radical hysterectomy represents a permanent cure, and symptoms recur, sometimes within 6 months. It is estimated that 50% of women will have a recurrence within 5 years. As one of the researchers said at the London Congress in 2000, “new approaches to this disease are urgently needed”. In a recent review of current treatments (4), the authors express the conservative opinion that “ all major therapies appear to be superior to placebo” and that “none seems to be drastically better than the other”.

Aetiology : what causes endometriosis Physiology of menstruation
With the exception of a few primates, elephants and bats, women are the only menstruating mammals. Every month, the endometrium undergoes elaborate cyclical changes in anticipation of pregnancy: first it thickens, or proliferates, with rising oestrogen levels; after ovulation, during the luteal phase, rising progesterone levels stop its proliferation and prepare it for pregnancy (diagram 1). When this fails to occur, complex mechanisms intervene, and the endometrium breaks down; aided by uterine contractions, it is washed out of the body in a flow of blood a process known as menstruation or menses.

Pathological events: what goes wrong?
The medical and scientific community generally agrees that endometriosis starts with a process called retrograde menstruation. During menstruation, some of the endometrium and accompanying blood frequently refluxes into the Fallopian tubes, a process known as retrograde menstruation. Some endometrial cells can then shower into the pelvic cavity from the fimbrial end of the tubes. This process was first observed in 1927, during an operation performed on a menstruating woman (5). General consensus ends at this point; whether these cells then directly implant in the pelvis (metastatic theory of endometriosis) or whether they trigger a local tissue reaction (metaplastic theory) is still intensely debated.

The question of real importance though, particularly for endometriosis sufferers is: why do some women then go on developing the disease while others remain unaffected by retrograde flow?
What are the crucial, determining factors for the evolution of an apparently benign condition into a debilitating disease?

Despite intense international scientific activity, no one knows the answer to this question yet. The medical literature on this disease is enormous. Every two years, a World Congress on endometriosis gathers for several days. (Melbourne will be host to the 2008 Congress). There is no doubt that the basic scientific understanding of its causes is increasing; unfortunately, the clinical applications are lagging behind and no new treatment has appeared for a few years.

It is becoming clear that the answer to this question lies in a combination of endocrine, immune, inflammatory, genetic and environmental factors. In other words, endometriosis appears as a systemic disorder. For a good review of the recent literature, see Gazvani (6). Let’s examine these factors one by one.

Endocrine (hormonal) causes.
The ovarian steroids, oestrogen and progesterone, play a crucial part in the development of endometriosis; this much has been acknowledged for a long time. Like the endometrium (eutopic endometrium) itself, endometriotic (ectopic) lesions are receptive (contain receptors) to ovarian hormones, oestrogen and progesterone, and they grow and bleed cyclically; however, unlike for the endometrium, blood and debris having no outlet, they accumulate in the tissues and form cysts.

In the past, endometriosis has been viewed as a disease of the endometrium (more exactly of his sub-unit, the archimetra). According to this model, the endometrium produces abnormal levels of oestrogens which indirectly induce uterine spasms, not only causing pain but also increasing the shedding of endometrial tissues into the Fallopian tubes. From a clinical perspective, it is certain that suppressing ovarian oestrogens, either with the contraceptive pill or with GnRH agonists, is generally effective. Another facet of the hormonal paradigm is that, unlike the normal endometrium, ectopic endometrium actually secretes oestrogen, thereby increasing the overall oestrogen load. This secretion is under the control of the hormone aromatase. Aromatase inhibitors have been developed and are now in clinical use.

In more recent years, some research teams, in particular Kevin Osteen’s at Vanderbilt University (7), have investigated the progesterone connection: could it be that endometriosis is controlled not so much by too much oestrogen but by too little progesterone? In other words, is endometriosis the result of an ovulation disorder? According to the metastatic theory, establishment and early implant of endometrial cells require the breakdown of the interstitial tissue known as the extra-cellular matrix (ECM). The ECM acts as a kind of cement to cells. For the ECM to breakdown requires special enzymes, the metalloproteinases, or MMPs. MMP’s function is regulated by a number of factors, one of them being progesterone. When progesterone is high (during the luteal phase of the menstrual cycle) MMP activity, or expression, is low, and the ECM does not breakdown easily; conversely, as progesterone drops, at the end of the cycle, MMP’s expression increases, and tissue breakdown is easier. Interest in progesterone and the progesterone receptors continues to grow and connections are starting to emerge with other fields of research.

In 2007, with many more teams investigating the progesterone connection than when this article was first published, the consensus concerning the impact of progesterone (P) seems to be as follows: Oestradiol (E2) is highly “mitogenic”; it induces abnormal endometrial growth and inflammation, causing pain. In a normal endometrium, P stimulates the production of unknown endocrine factors which in turn induce the expression of the enzyme 17-beta-hydroxysteroid dehydrogenase type 2 (HSD-2); this enzyme is responsible for the transformation of active oestradiol (E2) into much less active oestrone (E1). This process fails in endometriosis, with the accumulation of E2, which causes endometrial growth and inflammation. (30) It seems that some patients develop resistance to P, that is, they no longer respond to the beneficial impact of P. Authors speculate that it could be because of down-regulation, that is reduction in the populations, of the progesterone receptors (PRs). Less receptors to P imply less P action and more E2 impact. Resistance to P can also increase expression of the MMPs, which, as seen above, increases the chances of implantation of ectopic endometrium. (31) It is probable that progesterone resistance will be shown to have even more repercussions on the aetiology of endometriosis.

However, hormonal factors alone cannot fully account for the disease.

Immune dysregulation hypothesis
In healthy women, it is assumed that the endometrial cells which shower into the pelvic cavity are efficiently removed by the immune system. Why is this not the case in women who develop the disease? In recent years, endometriosis, even in its milder forms, has been associated with a large number of immune abnormalities. Macrophages, for instance, our “first line of defense”, are scavenging immune cells which appear quickly on the site of either infection or abnormal cell growth. They are found in abnormally high levels in the peritoneal fluid of women suffering of endometriosis (8). What factors render them ineffective? Some authors believe that the culprits might be high levels of oxidants (”toxins”) in the peritoneal fluid (9, 10). Immune parameters might also be a determining factor on what is known as angiogenesis. In order to grow, endometrial deposits, like tumours, need a regular supply of nutrients and oxygen via the blood stream. Angiogenesis is the name given to the formation de novo of the network of capillaries necessary for this development. It is a process controlled by a cascade of events in which progesterone plays an active role and which researchers are only beginning to elucidate (11).

Recently, some research groups have observed that endometriosis shares some of the characteristics of auto-immune diseases such as Crohn’s disease, rheumatoid arthritis or psoriasis. For a review of the recent literature on this subject, see Nothnick (12). Whether this immune dysfunction is genetic or due to environmental influences is not established.

The inflammation hypothesis
Endometriosis shares several of the clinical characteristics of inflammatory disorders, notably pain and increased secretion of fluid in the pelvic tissues, hence the symptoms of abdominal swelling and discomfort. It is well-known that high levels of inflammatory mediators, notably prostaglandins (PGs) are found in the endometrial tissue and menstrual fluid of women with endometriosis. One of them, PGE2, causes constriction of blood vessels and pain.

The interest in prostaglandins has been revived by the discovery of the enzyme aromatase, mentioned earlier: PGE2 is one of the most potent activators of aromatase, which results in local synthesis of oestrogen, which, in turn, stimulates PGE2 production! This type of vicious circle is known in scientific circles as a positive feed-back cycle (13).

Genetic influences
That endometriosis “runs in families” has been known for decades. Icelandic studies (14) have shown that a woman’s risk of developing the disease is multiplied by 5 if her sister is affected. It is possible that environmental factors are responsible for triggering specific genes.

Environmental factors
Certain environmental contaminants are known to disrupt steroids production and action. Most of the research on contaminants and endometriosis seems to revolve around the impact of dioxin, a chlorinated benzene derivative. A commonly used pesticide, Dioxin, appears to up-regulate the function of metalloproteinases (MMPs) by interfering with the suppressive action of progesterone (15, 16).

These environmental studies are interesting from two points of view: firstly, they appear to vindicate the exponents of “toxins” as the source of many degenerative diseases (see below); secondly, they establish yet another link between two very different research orientations. If we are ever to solve the endometriosis puzzle, many such links will have to be unearthed.

Alternative treatments

Traditional medicines

With its multifaceted presentation, endometriosis lends itself particularly well to the wholistic treatments characteristic of the traditional systems of medicine. It is difficult to think of these therapeutic systems as “alternative” since they are hardly new. In the West, the medical literature of past centuries abounds with treatments, largely herbal, of gynaecological conditions, even if the label “endometriosis” never appears. Oriental countries, as well as the non-industrialised world, continue to use herbal medicine and other traditional therapies, sometimes alongside modern medicine.

For the traditional systems, a modern medical diagnosis such as endometriosis, although useful, is too restrictive; it does not recognise that although the disease appears to be circumscribed, the whole physiology is in fact affected. Labels such as “endometriosis” hide variable symptoms, which form recognisable patterns of imbalance, sometimes called “patterns of disharmony”. And different patterns require different treatments.

Let’s take period pain and bleeding as examples. The nature of the pain, as well as its location, is an essential diagnostic criterion. Is it stabbing, cramp-like or dragging and pulling “as though everything would fall out”? Does the pain start before the flow or during maximum flow? Is the pain relieved by hot or by cold applications? Is the flow of blood bright red and heavy, or is it scant and brownish? Does the period start suddenly or is there some pre-menstrual spotting? Is the blood clotted?

The emerging pattern is enriched by seemingly irrelevant considerations, such as whether the patient is cold or hot, suffers from digestive, respiratory, circulatory, or other dysfunctions, and whether emotional stress is high.

Although all major traditional systems of medicine practice this wholistic approach, they differ in its application. Not surprisingly, eastern and western philosophies have expressed concepts of health and disease differently. Eastern philosophies for instance strongly emphasize the concept of energy, its flow and blockages, while the West, with its more materialistic evolution has developed a superior knowledge of anatomy and physiology. And of course, the plants themselves, the “materia medica”, have varied across cultures, but international trade is changing this.

Western Herbal Medicine
Modern Australian herbal medicine is at an interesting junction. Its materia medica, European in origin with later imports from North America, now incorporates medicinal plants from the world over. As to its philosophy, although it is solidly grounded in traditional principles, it has assimilated many of the characteristics of what is known as Naturopathy, a health movement which started in Europe in the 19th century and which emphasises the importance of diet, exercise and lifestyle factors. Inevitably, its language has also evolved alongside, and been influenced by, scientific medicine.

The label “endometriosis” does not appear in the traditional literature, since the condition was only identified approximately 50 years ago. Endometriosis may be a “new “ disease but its most common symptoms- period pains, menstrual abnormalities, clotted blood, painful intercourse, sub-fertility, the various pre-menstrual symptoms, the presence of abnormal masses- are described in the old texts, and their treatments are well documented. In Australia, many herbalists who treat this condition use a dual approach: within the traditional paradigm of disease, they incorporate recent medical and scientific findings; it is very exciting that these findings appear to corroborate some of the traditional elements.

Since the wholistic approach to endometriosis is highly individualised, there can be no blanket-treatment. However, certain key-elements are likely to recur, with variable emphasis, regardless of the symptomatology. What follows is an outline of some of these elements. “Detoxification”
In the traditional perspective, all types of abnormal growths, uterine fibroids, polyps, cysts, certain cancers and, presumably, what are now identified as endometrial lesions, manifest, in part, a failure of the body to effectively eliminate toxins. These toxins can be endogenous- we would now call them metabolic wastes- or exogenous, external. In the past, the latter were mainly caused by snake or insect bites and infectious organisms; nowadays, we must add contamination by toxic substances- heavy metals, chemical or pharmacological pollutants. The treatment of these conditions always involves some level of detoxification, the more so if other inflammatory conditions- allergies, hypersensitivities, rheumatic pains etc.- are present. The concept of toxicosis and accompanying detoxification has already been treated in a previous Diversity (17 bis) article. Many herbalists consider that it is essential to identify and eliminate allergies- in particular dietary allergies or sensitivities- and to create an environment as clean of potentially harmful chemicals as possible. The recently observed connection between endometriosis and dioxin appears to vindicate this approach.

Additionally, detoxification usually involves the stimulation or support of the main eliminatory organs- intestines, kidneys, liver, lymphatic system or lungs- using dietary changes and herbs. Which organ is not performing well is generally indicated during the initial interview by “peripheral” symptoms, such as constipation, intolerance to fats or alcohol, skin or respiratory problems, etc. and the treatment may include laxatives, liver tonics, expectorants or diuretics. Poor peripheral circulation, arterial of venous, may also be instrumental in improper elimination. In fact, endometriosis is often associated with pelvic congestion, which itself may be related to hormonal factors (see below).

“Hormonal regulating” plants Most herbalists agree that endometriosis is linked to an excess of oestrogen relative to progesterone, which is likely to be caused by ovulatory dysfunction, with symptoms such as pre-menstrual breast tenderness and swelling, ovarian cysts or pelvic congestion. This last syndrome, which has long been recognised in continental Europe, is characterised by a feeling of abdominal fullness, excessive menstruation, heavy legs (with or without varicose veins), pain with intercourse and a tendency to haemorrhoids. These symptoms may be caused by ineffective return of venous return, with pooling of blood in the pelvic cavity. The causative factor could be over-dilatation of the veins and capillaries under the influence of oestrogen (17, 18).

“Hormonal regulating” plants appear to normalise ovarian function, with a resulting increase in luteal progesterone. Some may also act as phytoestrogens, effectively decreasing high oestrogen levels. These plants are the corner stone of the treatment of most gynaecological disorders, from the very benign, such as irregular menstruation, to the most severe like endometriosis. They include (Chaste tree), False Unicorn (an endangered plant) and Black Cohosh. With the exception of Chaste tree (Vitex agnus castus), which is the object of some research interest, most of the evidence concerning these plants comes from centuries of traditional use rather than from modern studies (19, 20). In clinical studies, Vitex has shown that it can increase low luteal progesterone levels. In this perspective, Kevin Osteen’s findings linking low progesterone and endometriosis (7) are particularly exciting, as they appear to vindicate the traditional use of this plant. This group of plants should never be taken in conjunction with GnRH agonists, which block ovulation.

Dietary modification may also reduce oestrogen load, through the use of phytoestrogens such as soy and linseed, and the reduction of saturated animal fats. Increasing fibre, (found in complex carbohydrates, fruit, vegetables and legumes) may also increase levels of Sex Hormone Binding Globulin, the protein which binds to and transports steroidal hormones, rendering them unavailable. The improvement of liver function with bitter foods and medicinal plants can also enhance oestrogen breakdown by the liver, thereby reducing the amount of circulating oestrogens.

Immune regulating plants are also frequently used. In this group, we find Echinacea, which in recent years has been shown to stimulate the macrophage system (24, 25). It is interesting to note that in traditional American medicine, Echinacea was one of the “blood cleansers”, a group of plants routinely used for all manners of growths, tumours and cysts, conditions which were thought to result from inadequate elimination of metabolic “toxins”. In addition to plants, many herbalists emphasise the need to deal with allergies or sensitivities, in particular to food. A food elimination programme is sometimes recommended to improve immune function and reduce inflammation.

Anti-inflammatory plants like Ginger or Feverfew are also often indicated in the treatment of endometriosis. The anti-prostaglandin action of Ginger is well-known (26). Although its action on the uterus has never been tested clinically, this plant has a long history of use in gynaecological conditions. Ginger is also a stimulant of peripheral circulation, a “warming” plant, and it is useful in “cold” conditions, for instance for cramping pains relieved by warm applications. Other “cold” conditions include cold hands and feet and slow digestion with a tendency to abdominal bloating. In my experience, the vast majority of women suffering from endometriosis present “cold” symptoms.

Inflammation is also managed with dietary modifications, typically by reducing land-animal fats (found in meat and dairy products). These fats are essentially saturated or trans-unsaturated; they tend to be pro-inflammatory. They also interfere with ovulation. By contrast, fish and vegetable oils, such as Evening Primrose or Linseed oil, which are high in omega-3 and omega-6 have an anti-inflammatory action.

Uterine anti-spasmodics, such as Wild Yam, Cramp bark or Valerian can be extremely effective at managing pain and cramping. Wild Yam’s impact on pain is likely to be complex; this plant has traditionally been used to treat various inflammatory conditions, an effect which may be due to its content in steroidal molecules, although whether these steroids can exert a hormonal action in the human body is debatable.

Likewise, anti-haemorrhagic herbs such as Beth root, Lady’s mantle or Shepherd’s purse are used for heavy menstrual flow. While their mode of action is unknown, their “astringency” may be due to their tannin or flavonoid content, and some may improve progesterone levels (27).

Uterine tonics are another group of plants with poorly understood actions. Although there is no general consensus as to the meaning of this term, some uterine tonics appear to actually regulate the contractions of the uterine muscle and to improve blood circulation to the uterus. In this category, we probably find Blue and Black Cohosh, Raspberry leaf or Dong Quai. They are useful in both spasmodic and congestive pain. It is probable that other “uterine tonics” are such via a hormonal action.

Additionally, plants like Horse Chestnut or Butcher’s broom or have been shown to improve venous tone and reduce fluid effusion (21, 22). Although their most common application is in the treatment of varicose veins and haemorrhoids, in Europe they are used extensively in cases of period pain of the congestive type (23).

Conclusion
In my experience as a practitioner, Western herbal medicine is generally highly successful at controlling the symptoms of endometriosis; improvements start quickly, within one or 2 cycles. I also believe that herbs are more effective when used in conjunction with surgery. I always recommend that such a treatment be started after all the visible lesions and adhesions have been removed. As to the effects herbal medicine may have on the disease process itself, in the absence of any controlled clinical study, it is impossible to be categorical.

Unfortunately, there is no Australian survey concerning the patterns of use of alternative therapies for endometriosis. The Victorian Endometriosis Association estimates that most women try some unorthodox therapy at some stage, whether it means self-administered vitamins and minerals, or a dedicated programme under the guidance of a therapist.

The treatment of this disorder is a challenge. It is obvious that the current medical treatments are only marginally successful and, as one of the delegates of the London World Congress admitted, new therapies are urgently needed. The ancient concept that health is overall balance and disease is imbalance might turn out to be a useful paradigm for certain grave conditions, which, like endometriosis, implicate the entire organism. I believe that the group of plants which I have called “hormonal regulators” are worth investigating; these plants exert subtle, and yet extraordinarily powerful influences on the endocrine system, influences as yet unparalleled in the pharmacological world. So far, synthetic hormones have shown the ability to block ovarian function but not optimise it.

I also believe that a treatment of endometriosis has to address nutritional issues, or it will not be deep-reaching. The medical world, which is finally starting to accept the impact of nutrition on all types of conditions, seems to be headed in this direction: recently, the prestigious Journal of Obstetrics and Gynecology reported the results of a large cohort study: women with ovulatory sub-fertility can improve their fertility by 69% by adhering to a “fertility diet”: reduced animal proteins, saturated and trans-fats; increased unsaturated oils and vegetable proteins; increased fibre; low-GI carbohydrates; multivitamins, including plant Iron. (32)

Endometriosis is a complex disorder, which requires complex, expert treatment. Self-administration of herbal or nutritional supplements is risky, as well as expensive. Inappropriate use of the hormonal regulating plants can disturb the menstrual cycle and aggravate existing symptoms, and as I have mentioned above, they should not be used in conjunction with hormonal treatments. In general, I strongly discourage self-administration of these plants. As to the endangered False Unicorn, arguably the strongest of these ovarian regulators, its used should definitely be left to the expert.

References

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