Endometriosis, Major Depressive Disorder, and Restless Leg Syndrome share common pro-inflammatory-cytokine markers.

Endometriosis

[1]Endometriosis is a disease in which the endometrium (the tissue that lines the inside of the uterus or womb) is present outside of the uterus. Endometriosis most commonly occurs in the lower abdomen or pelvis, but it can appear anywhere in the body. Symptoms of endometriosis include lower abdominal pain, pain with menstrual periods, pain with sexual intercourse, and difficulty getting pregnant. On the other hand, some women with endometriosis may not have any symptoms at all.

Approximately 10% of reproductive-aged women have endometriosis. However, the true prevalence is unknown since the diagnosis requires laparoscopy (a surgery where a doctor looks in the abdomen with a camera through the belly button) to visualize and biopsy endometriosis lesions. Endometriosis is seen in 12-32% of women having surgery for pelvic pain, and in up to 50% of women having surgery for infertility. Endometriosis is rarely found in girls before they start their period, but it is seen in up to half of young girls and teens with pelvic pain and painful periods.

Women with endometriosis have elevated levels of pro-inflammatory cytokines, IL-1β, IL-6, and TNF-α.

Major Depressive Disorder

A mental disorder characterized by a persistently depressed mood and long-term loss of pleasure or interest in life, often with other symptoms such as disturbed sleep, feelings of guilt or inadequacy, and suicidal thoughts.

When compared to healthy controls, the patients with MDD had significantly higher levels of IL-1β, IL-10, and TNF-α. IL-6 is also implicated in MDD.

[2]The epigenetic effects IL-6 have been implicated in the pathology of depression. The effects of IL-6 on depression are mediated through the repression of brain-derived neurotrophic factor (BDNF) expression in the brain.

BDNF is a neurotrophic factor implicated in spine formation, density, and morphology on neurons. Downregulation of BDNF, therefore, may cause decreased connectivity in the brain.

Depression is marked by altered connectivity, in particular between the anterior cingulate cortex and several other limbic areas, such as the hippocampus. The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience. Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions. This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF.

A meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations,

These and many other reports suggest that a clinical study of a neutralizing IL-6 biological or drug- based antagonist is likely warranted in patients with major depressive disorder, with or without co-morbid chronic inflammatory based illnesses; IL6 blockers may represent a new, potentially biomarkable approach to major depression.

The IL-6 antibody Sirukumab is now undergoing clinical trials against major depressive disorder.

[3]The TNF-α SNP, rs1799724 (TNF-850 or 857 C/T), has a notable effect on the brain structure in both patients with MDD and healthy controls, with disease-related effects localizable to the occipital cortex. Our observations raise questions regarding the disruptions in the trophic role played by pro-

inflammatory cytokine system in depression. Our results are highly relevant to

understanding the brain-basis of anti-inflammatory treatments in depression, as well as isolating sub-groups of depressed subjects who may differ in cortical anatomy, genotype as well as response to novel therapeutics.

Tumour Necrosis Factor alpha (TNF alpha), is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation.

Restless Leg Syndrome

[4]Restless legs syndrome (RLS), also called Willis-Ekbom Disease, causes unpleasant or uncomfortable sensations in the legs and an irresistible urge to move them. Symptoms commonly occur in the late afternoon or evening hours and are often most severe at night when a person is resting, such as sitting or lying in bed. They also may occur when someone is inactive and sitting for extended periods (for example, when taking a trip by plane or watching a movie). Since symptoms can increase in severity during the night, it could become difficult to fall asleep or return to sleep after waking up. Moving the legs or walking typically relieves the discomfort but the sensations often recur once the movement stops. RLS is classified as a sleep disorder since the symptoms are triggered by resting and attempting to sleep, and as a movement disorder, since people are forced to move their legs in order to relieve symptoms. It is, however, best characterized as a neurological sensory disorder with symptoms that are produced from within the brain itself.

RLS is one of several disorders that can cause exhaustion and daytime sleepiness, which can strongly affect mood, concentration, job and school performance, and personal relationships. Many people with RLS report they are often unable to concentrate, have impaired memory, or fail to accomplish daily tasks. Untreated moderate to severe RLS can lead to about a 20 percent decrease in work productivity and can contribute to depression and anxiety.

It is estimated that up to 7-10 percent of the U.S. population may have RLS. RLS occurs in both men and women, although women are more likely to have it than men. It may begin at any age. Many individuals who are severely affected are middle-aged or older, and the symptoms typically become more frequent and last longer with age.

More than 80 percent of people with RLS also experience periodic limb movement of sleep (PLMS). PLMS is characterized by involuntary leg (and sometimes arm) twitching or jerking movements during sleep that typically occur every 15 to 40 seconds, sometimes throughout the night. Although many individuals with RLS also develop PLMS, most people with PLMS do not experience RLS.

Results: Serum IL-1β, IL-6, and TNF-α levels of the patient group were statistically significantly higher in RLS patients. There were 8 patients with mild RLS [28%], 13 patients with moderate RLS [45%], and 8 patients with severe RLS [28%]. Only IL-6 values were significantly different between the groups. In the severe group, the value of IL-6 was significantly higher than in the other groups.

Conclusion: Patients with endometriosis, restless leg syndrome, and major depressive disorder, share elevations in IL-1β, IL-6, and TNF-α.

[5]More than any other cytokine family, the IL-1 family is primarily associated with innate immunity. More than 95% of living organisms use innate immune mechanisms for survival whereas less than 5% depend on T-and B-cell functions.

3 Immunol Rev. Author manuscript; available in PMC 2018 Jan 7.

Published in final edited form as:

Immunol Rev. 2018 Jan; 281(1): 8–27.

doi: 10.1111/imr.12621

Innate immunity is manifested by inflammation, which can function as a mechanism of host defense but when uncontrolled is detrimental to survival.

IL-1β is the most studied member of the IL-1 family due to its role in mediating autoinflammatory diseases. Unquestionably, IL-1β evolved to assist host defense against infection and this landmark study established how a low dose of recombinant IL-1β protects mice against lethal bacterial infection in the absence of neutrophils. Although we now accept the concept that cytokines like IL-1β served millions of years of evolution to protect the host, in the antibiotic and antiviral therapies era of today, we view cytokines also as the cause of disease due to acute or chronic inflammation.

Traditional Chinese Medicine

Endometriosis This is primarily an issue which pertains to the liver, as the liver is responsible for the movement of qi and blood, and also, the storage of blood. When qi rebels, blood follows. Without ‘rebellious’ qi, there could not be endometrial implants outside of the uterine cavity. When qi is stuck, it transforms into heat. The etiology of endometriosis is rebellious qi and blood with hidden heat trapped in the interior. Even if your patient has a pulse of 60bpm, and a swollen tongue, with a thick white coating: there is still heat. We know this because we know that endometriosis is a pro inflammatory cytokine disorder. Endometrial implants are stuck qi and blood which, over time, generate heat.

RLS – From the perspective of a ‘pattern-of-disharmony’, RLS can be referred to as wind stirring internally due to blood vacuity.

The liver stores the blood and the heart governs the blood. If the liver or the heart present with blood vacuity, wind invades and tremors present.

The liver is the organ associated with wind disorders. Blood vacuity will engender wind which is etiologic of RLS. Additionally, blood vacuity will, over time, create stagnation of qi, engendering heat. This won’t be seen in the legs, but rather the pelvis, manifesting further inflammation of endometriosis.

Why the pelvis? Because the three yin channels of the legs, the foot meridian of spleen taiyin, the foot meridian of liver jueyin and the foot meridian of kidney shaoyin are all related to the uterus.

The spleen meets the chong mai at spleen 4, the kidney meridian meets with the chong mai from kidney 11 through and including kidney 21, and the liver meridian encircles the reproductive organs and connects with the du mai. According to the Su Wen, chapter 60, ”the du mai goes to the uterus and the pubic bone. In women it flows around the vagina and passes through the perineum, and the buttocks to meet the kidney and bladder channels in the thighs.” According the classical text Yi Zong Jin jian, “in women it is the uterus, in men it is room of sperm.”

The liver channel ‘crosses’ with ren 2, 3, and 4, thereby gaining access to the liver, kidney and spleen. The kidney channel enters the kidney and connects with the bladder, passes through the liver and diaphragm and enters the lung. Endometriosis is found in the diaphragm, amongst other locations.

The spleen is related to, and connects with, the stomach. The stomach is related to the chongmai which enters the uterus. You can see, via these organ and channel relationships how RLS may exacerbate endometriosis.

Depression – There are, in TCM, various ‘patterns of disharmony’ which may be contributing factors leading to depression. One may be a gui pi tang pattern, another may be stagnation of liver qi, and yet another can present due to phlegm misting the mind. There are, of course, other patterns-of-disharmony which are etiologic of depression.

For purposes of this discussion, I’ll focus on liver qi stagnation. The liver-qi-stagnation depression-patient consists mostly in persons who are highly stressed, or, chronically stressed. This includes the ‘type A personality’ patient. When qi is stuck, the emotions are stuck; when the emotions are unexplored and not- understood, qi can stagnate; all leading to depressive disorders.

When the liver is stuck for a long period of time it will inevitably attack the spleen causing a degradation in the source of post heaven qi and blood. This is why, in certain cases, you will find a patient with depression and RLS. When blood is empty, wind will invade contributing to RLS.

As blood is the mother of qi, if blood is vacuous, the qi will stagnate. If left untreated, or treated improperly, this will progress to heat as a result of stuck qi, and vacuity of blood. This heat then may manifest in the uterus via the relationship between the liver and the uterus leading to an explanation of inflammation found in endometriosis.

Liver Blood is supplied to the Chong Mai, then the Chong Mai separately sends blood to the uterus. Hopefully this will elucidate on the pathomechanism of RLS and endometriosis found in the same patient.

Western scientific data proves that an inflammatory mileu exists in all three: endometriosis, major depressive disorder, and RLS. It may behoove us, as practitioners of TCM, to dig deeper into our diagnostic tool-kits and see if we too can find any inflammatory processes going on, i.e. ‘Heat’ which may manifest from qi stagnation or, blood vacuity. We don’t, generally speaking, think of ‘heat’ when we talk about depression or RLS. But why wouldn’t we? If there is extended blood vacuity, leading to wind and stuck qi, wouldn’t heat present?

One may not find heat signs via the tongue and pulse but that irrelevant. One of my teachers, Dr. Yan Wu, a practitioner of TCM for fifty-years once told me that “if the signs and symptoms don’t coincide with the tongue and pulse findings, disregard the tongue and pulse findings and focus on the signs and symptoms.” In the case of RLS and depression there may not be signs or symptoms of heat. This is where some knowledge of Western medical science is helpful. We know FOR A FACT that these three disorders ALL have inflammatory markers; therefor, heat is prevalent in each and every one of these pathologies in the context of Western medicine and TCM. We can refer to it as ‘hidden heat’

The one thing the TCM practitioner should remember is that the TCM knowledge and experience base continues to develop, grow, and to reveal secrets. Perhaps this article may contribute to understanding a new perspective.

Below are some examples of herbal formulas that may be utilized for the pathologies indicated. The modifications are my own.

Modified Shao Fu Zhu Yu Tang for endometriosis

The above formula invigorates qi and blood, softens hardness, calms the spirit, clears heat, and reduces pain. This formula is only to be used status-post laparoscopy.

Modified Si Wu Tang for RLS

The above formula generates and nourishes blood, dispels wind and stops tremors.

Modified Xiao Yao San for Depression

The above formula clears heat from the liver, invigorates qi, softens the liver, calms the shen, and alleviates depression

We have three pathologies which share the same or similar cytokines and different herbal formulas for each.

This serves to show the complexity of pathology and, moreover, the difficulty in treating this constellation of pathologies. Most antidepressants exacerbate RLS; most RLS medicine exacerbate depression. Endometriosis can contribute to depression.

Hopefully Western medical scientific researchers can arrive at treatment option for people who present with the above three disorders.

It is my opinion that even after laparoscopy, for the endometriosis patient, herbal-medicine should be continued for the patient trying-to-conceive, as in most cases, even after laparoscopy, endometriosis still exists as many endometriotic implants look like normal tissue.

The above herbal medicine formula for endometriosis is a good option for women who are trying-to-conceive after a laparoscopy to help reduce the inflammatory effects of remaining endometriotic tissue.

It is my hope that Western medicine doctors would consider using an antidepressant for their depressed patient while simultaneously having the patient take herbal medicine for the other two pathologies as there is no Western medicine extant which can treat all three pathologies simultaneously; the same is true of herbal medicine therapeutics. An integrative-medical-approach seems reasonable for this type of presentation.

Mike Berkley, L.Ac., FABORM

berkleycenter.com

Keywords: endometriosis, restless leg syndrome, major depressive disorder, traditional Chinese medicine, herbal medicine