Endometriosis The International Week of Endometriosis is held in March each year, and this year was no exception. This article addresses this largely unknown disease only suffered by women, and analyses the main potential benefits of the therapeutic use of cannabis for its treatment.
It may be known as the silent disease, but the number of women who suffer endometriosis has now reached 176 million around the world. Their lives are bound by the disease, and the suffering and misunderstanding that stems from the ignorance and silence surrounding it. More chronic and disabling than most, the disease has devastating consequences for feminine fertility.
Rectifying the scarcity of medical knowledge and the lack of financial resources dedicated to researching the causes and treatments has not been made a priority. As a result, countless women have had to consult several specialists, or have operations, before receiving a diagnosis, even though the number of women affected grows considerably every year.
What is Endometriosis?
Endometriosis is a disorder whereby the endometrial tissue, the tissue women shed each month during menstruation, spreads to around the ovaries in the majority of cases, but sometimes also to other parts of the body, such as the peritoneum, the intestine and other parts of the abdominal cavity, forming what are called endometriomas or endometriotic cysts. In some cases, the endometrial tissue even reaches the lungs.
The disease is particularly characterized by severe pain, alongside irregular bleeding and fertility problems. The pain that occurs during periods, also known as dysmenorrhea, is normally a physiological pain caused by the inflammatory alterations suffered by women during menstruation. In the case of endometriosis, however, painful periods are also manifested at other times: abdominal pain and cramps before and during menstruation, pain during or after sexual intercourse, painful bowel movements, and pelvic or lower back pain. Besides all this unbearable pain, many of these women also experience vomiting, fainting and extreme irritability.
Many specialists believe that the normal menstrual cycle should not be painful, and that the premenstrual cycle should not occur, as the presence of both of them indicates a neuroendocrine alteration in the body.
Despite the fact that the average time taken to diagnose endometriosis is around 7-8 years, some women have had to wait almost 30. Although endometriosis usually begins to appear when regular menstruation begins – that is to say, in adolescence – patients suffer irremediably until doctors can give them the correct diagnosis. They continue suffering afterwards too, as explained by the patients themselves in this revealing and extremely interesting documentary, Endometriosis, the tip of the iceberg, filmed by RTVE in 2010.
Sometimes the average number of specialists which a patient must consult before being diagnosed is 5 to 6; sometimes even more. It is estimated that 40% of women who have difficulty getting pregnant, and between 8 and 10% of women of childbearing age, suffer from the disease. It is currently the most serious pathology in gynaecology and the number of affected women has increased enormously in recent years.
Most common treatments
The type of treatment depends on the age, the severity of the symptoms, the severity of the disease, and whether the woman wishes to have children in the future. Depending on each of these aspects, there are various treatment options.
Given that one of the main symptoms of endometriosis is pain, one of the basic treatments is soothing this symptom with analgesics, whether over-the-counter, like paracetamol and ibuprofen, or prescription drugs, if the pain is stronger. Also, patients are advised to do exercise, use relaxation techniques, and have regular medical check-ups to make sure the disease does not worsen.
If the symptoms are minor, hormone therapies are also used to prevent endometriosis from worsening, but they clearly do not cure it. Contraceptive pills usually ease most symptoms, but they do not prevent scarring nor do they heal any damage already done. Progesterone pills or injections and gonadotropin-releasing hormone agonists help to reduce the size of tumours and prevent the ovaries from producing oestrogen, respectively, but they also have serious side effects.
The most frequent treatment, when the symptoms are serious and do not remit with other treatments, is surgery. Normally, it is performed using laparoscopy, which helps to diagnose the disease once and for all, and can also eliminate tumours or cysts and scar or endometrial tissue. Other techniques used are laparotomy and hysterectomy, with the latter being the most aggressive surgery of all and normally a last-resort solution.
The problem is that during most of these surgical interventions, surgeons do not completely remove the endometrial tissue and the cells left behind reproduce immediately, forming a sheet of tissue as hard as marble. In addition, the disease usually relapses. It is thus vital that all the nodules of endometriosis are removed during a single instance of optimal surgery. It also seems evident that there should be consensus in the medical community in regard to the treatment of endometriosis, and that new less aggressive treatments must be found. The multiple benefits provided by cannabis could clearly be applied in this regard.
What causes endometriosis?
There are different theories on the cause of endometriosis. Specialists point to intrinsic genetic and personal factors, although they do not rule out possible environmental factors as triggers of this aggressive ailment.
According to Dr Carme Valls Llobet, endocrinology doctor and director of the Women and Health Program (CAPS), it would seem that the endometrium of affected patients has some molecular immunohistochemical characteristics that give these molecules the ability to adhere to the surface of the peritoneum, multiply, and increase the vascularization around the implants. These immunological alterations may also be due to environmental factors. In endometriosis, the tissue that enters the abdominal cavity generates new tissue through angiogenesis. The reason for this major inner proliferation is the presence of a hormone which greatly stimulates it: oestrogen. Oestrogens are, however, also found in the environment, where there are over 15,000 substances of this type: in water (bisphenols), in the air (hydrocarbons which are released in car exhaust during combustion), and in foods (dioxins in animal feed).
Research carried out by the Endometriosis Association at the beginning of the 1990s, discovered an initial link between exposure to dioxin (TCCD) and the development of endometriosis. Dioxin is a toxic chemical substance derived from the manufacture of pesticides, pulp and paper bleaching, and medical and municipal waste incineration. A study conducted by the EA discovered that a colony of chimpanzees had developed endometriosis after being exposed to dioxin. Of the chimpanzees exposed, 79% developed endometriosis, and furthermore, the higher the exposure to dioxin, the more severe the endometriosis.
How do cannabis and cannabinoids help in the treatment of endometriosis?
As we have explained, endometriosis is a chronic disease and there is still no cure. We have extensive medical and scientific evidence that demonstrates that the cannabinoids contained in the cannabis plant (phytocannabinoids) can ease the majority of the symptoms caused by endometriosis, such as pain, depression, headache, hypoglycemia, anxiety, fatigue, inflammation, and many others.
Anti-inflammatory and immunoregulatory properties
Many patients say they have benefited from consuming cannabis during the crises of certain inflammatory diseases, especially if they have an autoimmune component. In these cases, it seems that cannabis not only acts as an analgesic, but also has an anti-inflammatory action. This has been demonstrated in several studies with experiments on animals.
It is believed that antagonists, like CBD, and agonists, such as THC and the endogenous agonist 2-AG, reduce inflammation by inhibiting the function of macrophages, which are large, specialized white blood cells that are essential for various immune responses.
Research indicates that cannabidiol (CBD), the non-psychoactive component of cannabis, is responsible for the reduction of inflammation associated with chronic inflammatory states, as demonstrated in a 2004 study by Italian researchers from the University of Milano-Bicocca. In the case of endometriosis, the cells that line the uterus (the endometrium) are present outside of it and can bleed, releasing inflammatory mediators and causing localised pain. The administration of cannabidiol greatly improves the patients’ quality of life because they can control the pain, and even completely stop taking any other medicine.
Cannabis is widely used in the treatment of chronic pain resulting from a large number of different diseases. Perhaps it is the therapeutic application of marijuana that has been referred to most throughout the centuries, from its appearance in the first pharmacopeia of the emperor Shen Nung (3750 B.C.) to Queen Victoria’s reference to its use in the nineteenth century. A tincture of cannabis was prescribed by her personal physician for the menstrual pain and cramps (dysmenorrhea) that she experienced. In that century and before the commercialisation of opium, it was considered one of the most valuable medicines.
Researchers from Florida State University in Tallahassee (U.S.A.) have studied the role of the endocannabinoid system in endometriosis-associated pain. Using a rat model, they discovered that the agonists of the CB1 receptors reduce endometriosis-associated hyperalgesia, whereas the antagonists of these receptors increase it. Blocking the CB1 receptors increased the sensitivity to pain, while stimulating them reduced it. The authors of this study concluded that the endocannabinoid system plays an important role in the development of abnormal growths and pain associated with endometriosis, which suggests that cannabinoids could provide “a novel approach for the development of badly-needed new treatments for endometriosis pain.”
Control cell growth
Cannabinoids also have properties that can be used to control another main aspect of severe endometriosis: hyperproliferation. Due to their effect on proliferation, apoptosis and angiogenesis, cannabinoids control cell growth and regulate cell migration. Its anti-proliferative effects are the result of the inhibition of growth factors and the deregulation of signalling pathways. These mechanisms have suggested new goals in the treatment of endometriosis, as endometrial cells have a hyperproliferative phenotype and pro-angiogenic properties.
Researchers of various institutions in Paris conducted a study in 2010 in which they demonstrated that cannabinoids reduce the growth of human endometrial tissue implanted in mice, and came to the conclusion that cannabinoid agonists exert anti-proliferative effects on stromal endometriotic cells.
Endometriosis and the endocannabinoid system (ECS)
Endocannabinoids are natural endogenous cannabinoids produced by the human body that enable various biological functions and activate cannabinoid receptors (CB1 and CB2). Due to the importance of the endocannabinoid system, drugs that can interfere in the activity of endocannabinoids are currently considered candidates for the treatment of various diseases, including endometriosis.
Many of the components of the endocannabinoid system are found in the endometrial tissue and their levels are regulated by the menstrual cycle, as has been proven in rodent models with the disease. Among these components are type 1 and type 2 cannabinoid receptors (CB1 and CB2), N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), an enzyme which synthesizes endocannabinoids, and fatty acid amide hydrolase (FAAH), an enzyme that breaks down endocannabinoids. The highest concentration of anandamide endocannabinoid (AEA) in the reproductive system is found in the uterus.
A recent study, which we have not mentioned previously and which used a rat model, discovered that CB1 cannabinoid receptors are expressed in the somata as well as in the fibres of sensory and sympathetic neurons which innervate the abnormal growth of endometriosis. It was determined that CB1 receptor agonists reduce hyperalgesia associated with endometriosis, whereas CB1 receptor antagonists increase it. Together these discoveries suggest that the endocannabinoid system contributes to the mechanisms which underlie the peripheral innervation of abnormal growths and endometriosis-associated pain, thus providing a novel approach for the development of badly needed new treatments.
It is thus clear that endometriosis is associated with clinical endocannabinoid deficiency (CECD). Women with endometriosis have lower levels of CB1 receptors in the endometrial tissue. The reduction of the ECS function leads to the growth of the endometriosis throughout the body and to feeling more pain. Endometriotic pain is mediated with the CB1 receptor.
It has been demonstrated that human endometrial cells proliferated (divided and grew) less when they were stimulated with a synthetic cannabinoid called WIN 55212-2. Studies on endometriosis conducted on rodents have discovered that animals had more pain when they were treated with AM251, a drug which inhibits the cannabinoid receptors, and less pain when they were treated with WIN 55212-2.
Likewise, environmental toxins like dioxin have been linked to endocannabinoid deficiency and endometriosis. Dioxin reduces the levels of CB1 in the endometrial tissue. As we are subjected to contamination in the air, in water, and in food, it is not surprising that so many women in developed countries now have severe endometriosis. It is very probable that in the future more toxins will be associated with the risk of endometriosis, as well as with endocannabinoid deficiency.
Continued research is necessary
It is essential to research in greater depth the levels of endocannabinoids in women in order to determine whether they are lower in the plasma or in the endometrial cells of women with endometriosis, or whether the levels of endocannabinoids change throughout the menstrual cycle in human beings, as occurs in rodents. We can thus precisely determine if women who use therapies with cannabinoids experience less pain and a reduction in endometrial growth, or if women who consume cannabis are less likely to develop endometriosis, as indicated by many of the studies conducted up until now.
As we explained before, it is currently very complicated to diagnose this disease, which is why a simple biomarker (biological marker) of endometriosis, such as a reduced level of endocannabinoids in the blood or in the endometrial tissue, could save millions for health systems around the world, and years of unnecessary pain for the 176 million women who suffer from this disease.