Multiple Sclerosis: A Theory

In late April / early May, 2007, it was reported that MS in women has increased. The following is my explanation of this phenomenon and it may put my explanation of 1997 in some question. However, I will say that my interest in the connection of testosterone with MS in women was involved in my new explanation.

An Explanation of the Current Increase in Multiple Sclerosis in Women

I wish to suggest an explanation for the increase in multiple sclerosis currently demonstrated in the population. When treated with testosterone, male and female rats, 5alpha-reductase type 2 mRNA while decreasing type 1 mRNA (Neurochem Int 2006; 49: 626-30). Earlier work has suggested that 5alpha-reductase type 1 isoform is the "most relevant 5alpha-R present in myelin" (Mol Cell Endocrinol 1997; 129: 181-90).

It is my hypothesis that the "secular trend," the increase in size and earlier puberty of children, is caused by an increase in the percentage of women of higher testosterone with time within the population. This means that women of higher testosterone may be increasing and myelination may be adversely affected by an increase in the ratio of 5alpha-reductase type 2 to type 1.

I suggest the current rise in multiple sclerosis may be occurring as the numbers of women of higher testosterone increase. Multiple sclerosis is lower in males and blacks, compared to whites. I suggest increased testosterone in males, and the findings that blacks produce more testosterone than whites, may result in reduced births of these individuals due to negative pregnancy outcomes. That is, individuals of higher testosterone are negatively affected prior to birth and do not survive to be counted as cases of multiple sclerosis. This may also explain why more females are born compared to males and why blacks exhibit more problems with negative pregnancy outcomes. This may explain why women are increasing in multiple sclerosis at this time.

(..........Also, in humans testosterone increases in the autumn and winter so the effects of autumn / winter conceptions should show an increase in MS, according to my explanation. I believe it has been reported that a significant increase in MS occurs in May births as opposed to November births.)

This is a new theory of the cause of multiple sclerosis (MS).

My explanation is based on my theory of the interaction of the hormones, melatonin (MLT) and dehydroepiandrosterone (DHEA), which I call the "melatonin - DHEA cycle," and testosterone, and the effects these have on the nervous and immune systems. I suggest all tissues are dependent on the MLT - DHEA cycle, principally the nervous and immune systems, and the gonadal (sexual) hormones evolved as a means of manipulating this cycle. MS is a disease characterized by demyelination of nerves. At its most basic, my work suggests MS results from an "attack" of the immune system on myelin, as a result of over-stimulation of the MLT - DHEA cycle in the immune system, triggered by lack of normal growth of myelin, as a result of deficient effects of testosterone. (The following treatise explains this in detail, it will take some length to do this. Please bear with me. Since this is written for internet posting, I am not including diagrams here; they may be accessed in the articles I specify on the internet.)

In 1985, I developed a theory of sleep that explains the connection of MLT with DHEA. The importance of my sleep mechanism to MS is that it explains that when MLT levels are high, DHEA is low, and when DHEA is high, MLT levels are low. My work further says that DHEA levels will rebound to the suppression of DHEA caused by MLT. It is a "cycle." A direct connection of MLT and MS has been reported by two investigators, Sandyk and Awerbuch. Since no work has been done on MS and DHEA, I will show how their work to date supports the connection of the MLT - DHEA cycle to MS. MS cannot be explained by melatonin alone.

In an abstract of International Journal of Neuroscience 1993; 68: 209, Sandyk explains the connection of MLT and MS:

"Epidemiological studies demonstrate that the incidence of multiple sclerosis (MS) is age-dependent being rare prior to age 10, unusual prior to age 15, with a peak in the mid 20s. It has been suggested that the manifestation of MS is dependent upon having passed through the pubertal period. In the present communication, I propose that critical changes in pineal melatonin secretion, which occur in temporal relationship to the onset of puberty, are intimately related to the timing of onset of the clinical manifestations of MS. Specifically, it is suggested that the fall in melatonin secretion during the prepubertal period, which may disrupt pineal-mediated immunomodulation, may stimulate either the reactivation of the infective agent or increase the susceptibility to infection during the pubertal period. Similarly, the rapid fall in melatonin secretion just prior to delivery may account for the frequent occurrence of relapse in MS patients during the postpartum period. In contrast, pregnancy, which is associated with high melatonin concentrations, is often accompanied by remission of symptoms. Thus, the presence of high melatonin levels may provide a protective effect, while a decline in melatonin secretion may increase the risk for the development and exacerbation of the disease. The melatonin hypothesis of MS may explain other epidemiological and clinical phenomena associated with the disease such as the low incidence of MS in black African and American populations, ..."

Melatonin is produced in the pineal gland. It is known that calcification of the pineal gland occurs with age and the reduction of MLT. Sandyk and Awerbuch address this in MS.

"Twenty-one age and sex-matched neurological patients served as controls. PC [pineal calcification] was seen in 100% of MS patients, while 72.4% patients had CPC [choroid plexus calcification]. In the control sample, PC was found in 42.8% and CPC in 28.5%. Thus, the strikingly high prevalence between MS and abnormalities of the pineal gland. Moreover, since pineal melatonin is involved in neuroimmunomodulation, we propose, for the first time, that abnormalities of pineal melatonin functions are implicated in the pathophysiology of the disease [MS]." (International Journal of Neuroscience 1991; 61: 61)

Melatonin is produced in the highest levels during nighttime, lowest in daytime. In a study of nocturnal melatonin levels, Sandyk and Awebuch, reported that: "Abnormal melatonin levels were found in 13 patients (52.0%), 11 of whom had nocturnal levels which were below the daytime values." (International Journal of Neuroscience 1992; 67: 173) Calcification of the pineal increases with age. Now, this fits my theory. If MS represents a state in which the MLT - DHEA cycle is increased, then the MLT - DHEA cycle will increase. This will literally increase aging, part of which would show as increased calcification of the pineal gland.

I suggest it is the connection of MLT with DHEA that is the real connection of MLT with MS. In Sandyk’s summary (1993), he describes the age-dependence of MS. These ages are very important to my explanation of MS, but I want to postpone them momentarily and directly consider the times and levels of melatonin he lists. My work in other parts of my work at my page explains why, and shows actual measurements, of MLT and DHEA during the human life-span. When MLT starts its steep decline just prior to puberty, DHEA starts a strong increase, known as "adrenarche." My work suggests this rise occurs, because the brain is finishing its use of DHEA for growth and development in infants and children. What is really happening is that the "measurable" levels of DHEA are rapidly increasing as less and less DHEA is absorbed by the brain for growth and development.

The importance of this rise in DHEA for MS is that this "free" DHEA can then be used by the immune system. (My work suggests all tissues compete for DHEA; the brain is simply the best at absorbing it. I will explain how DHEA affects the immune system below.) Sandyk suggests that "the fall in melatonin secretion during the prepubertal period, which may disrupt pineal-mediated immunomodulation, may stimulate either the reactivation of the infective agent or increase the susceptibility to infection during the pubertal period." (A number of citations suggest that an infective agent is involved in MS; this is why he mentions an infective agent. My explanation suggests these potential infections merely stimulate increased DHEA; they are not the actual cause of MS. This will be explained.) Further, Sandyk says: "Similarly, the rapid fall in melatonin secretion just prior to delivery may account for the frequent occurrence of relapse in MS patients during the postpartum period. In contrast, pregnancy, which is associated with high melatonin concentrations, is often accompanied by remission of symptoms." The protective effect Sandyk suggests for melatonin here is, I suggest, simply due to another use of DHEA, similar to that of the brain in infants and children, which I described above.

My work suggests that tissues use DHEA, therefore, the mother makes DHEA for herself and her fetus. This stimulates the MLT - DHEA cycle in the mother; her melatonin increases to stimulate DHEA in large amounts for the growing fetus. This DHEA is absorbed by the rapid growth of the fetus, so the DHEA levels actually stay low in the pregnant woman. Her immune system is not activated enough to start the MS cycle. Since DHEA may be involved in starting delivery: "labor is associated with a significant increase in umbilical artery levels of DHEA" (Journal of Clinical Endocrinology and Metabolism 1976; 42: 744), available DHEA rises at birth. That is, the fetus stops using DHEA, which then becomes available to stimulate tissues in the mother. It is this rise in DHEA at birth that starts contractions and also stimulates the immune system, and increases MS. So, I am saying that the "protective" effects of high melatonin result from the fact that melatonin is high when a very large amount of DHEA is needed for growth and development. These two times of high melatonin are times of high DHEA and high DHEA use; melatonin does not protect against MS. The connection of MLT is DHEA.

My work suggests that DHEA directly stimulates the immune system. This can be seen quite well in a number of studies of HIV infection and AIDS. What is found is that DHEA increases dramatically upon infection by the HIV. I think DHEA increases whenever infection, bacterial or viral, occurs. MS appears to be associated with viruses; the hypothesis depends on the findings that MS often appears in a cluster.

"Geographic and temporal variation and migration studies point to an exogenous agent in the etiology of multiple sclerosis. If infectious etiology is involved, space-time clustering would also be expected. The authors analyzed 381 patients with a clinical onset of multiple sclerosis between 1953 and 1987 in the county of Hordaland, Norway. Patients [MS] within the same birth cohort had lived significantly closer to each other than would be expected during ages 13-20 years, with peak clustering at age 18 years (p = 0.002). Clustering was also shown between patients in pairs comprised of one individual with initial remittent disease and the other with chronic progressive course of disease, suggesting a similar etiology for both clinical patterns. Clustering between cases with widely divergent dates of clinical onset provides evidence of marked variation in latency. No similar clustering was observed in age-, sex-, and area-matched hospital controls without multiple sclerosis, and no clustering was found among the cases when using fixed number of years before onset. These results are compatible with a common infectious agent, such as the Epstein-Barr virus, acquired in adolescence in genetically vulnerable persons who are also not protected by an infection acquired before this age of susceptibility." (American Journal of Epidemiology 1991; 133: 932)

There are other studies that suggest viral infections may be part of the mechanism of MS. However, I suggest that viral infections are merely activating the MLT - DHEA cycle. The increased DHEA activates "monitoring" by the immune system. The increased monitoring of the immune system picks up a "lesion" that causes an "autoimmune response" that causes the MS. Now, I suggest that this mechanism, which will be described below, can manifest itself without the influence of an infection. An infection simply increases the probability; infections are not the actual cause of MS.

DHEA and cortisol are the major hormones produced by the adrenal glands. DHEA and cortisol secretions may be separated, but often these occur simultaneously. While no one has measured DHEA in MS, and it might actually be "low" during active MS because of use by the immune system, two studies have found cortisol to be "significantly higher" in MS (Experimental and Clinic Endocrinology and Diabetes 1996; 104: 31; Journal of Clinical Endocrinology and Metabolism 1994; 79: 848). While this does not prove that DHEA is involved, it does show that the adrenal glands are very active in MS.

To summarize to this point, I suggest MS is a state of activated DHEA production that stimulates the immune system to attack a "lesion." I suggest the lesion that provides the "initial antigenic material to the immune system" results from immature myelin in people with MS.

"In a correlative study involving protein chemical, mass spectrometric, and electron microscopic techniques we have determined that myelin obtained from victims of MS is arrested at the level of the first growth spurt (within the first 6 yr of life) and is therefore developmentally immature. ...We postulate that this developmentally immature myelin is more susceptible to degradation by one or a combination of factors mentioned above, providing the initial antigenic material to the immune system." (Journal of Clinical Investigation 1994; 94: 146)

The "factors" suggested by these investigators are "genetic, environmental, infective, and immunological factors..."

What causes the immature myelin in MS that stimulates the immune system? A number of factors caused me to look at the connection of testosterone in MS. These include: "A review of population studies demonstrates that the preponderance of women in MS is almost a constant." (Canadian Journal of Neurological Sciences 1992; 19: 466); "Mortality rates from MS show a well-known north-south gradient, both within the United States and internationally." (Neuroendocrinology 1992; 11: 244); "The data suggest that onset of pathogenesis of MS is dependent on passing or having passed through the puberty period." (American Journal of Epidemiology 1981; 114: 24); "MS is rare among the indigenous black people of Africa." (Journal of Neurology, Neurosurgery and Psychiatry 1994; 57: 1064).

Testosterone is lower in women. My theory, from which this work is derived, suggests that the hominids that migrated out of Africa, into the north, were hominids of lower testosterone. Therefore, in general, I expect lower testosterone in Europeans (Whites) than Africans (Blacks.) European and whites represent lower testosterone. DHEA increases, starting at adrenarche, to a high point in the mid-twenties. This fits the findings listed by Sandyk, early in the paper, that is, that MS peaks in the mid 20s. DHEA would be highest at this time and, therefore, the immune attack would be greatest at this time. Earlier this month, I developed an explanation for migraine headaches that suggested migraines are caused by increased DHEA. As part of my support of my explanation of migraines, I pointed out that blacks produce significantly more testosterone than whites (Journal of the National Cancer Institute 1986; 76: 45). My work suggested testosterone causes DHEA to be reduced in the blood, because testosterone causes DHEA to be used more by "testosterone target tissues;" Blacks have fewer migraines than whites. This fit very nicely with this work, too, i.e., MS is rare in blacks. The increased testosterone in blacks would reduce the immune response of MS. However, I found out that women MS patients had "significantly higher concentrations of total and free testosterone" (Journal of Internal Medicine 1989; 226: 241).

This contradiction caused me to find and propose a reason for the "lesion" of MS, the immature myelin. I suggest the immature myelin of MS results from lack of testosterone’s effect on growth. I am saying that myelin growth occurs because of two different hormones. The early large production of DHEA following birth causes the early growth of myelin of the "first growth spurt." Subsequent to this, the nervous system becomes a "testosterone target tissue." That is, testosterone stimulates growth of the nervous system too. Men produce more testosterone than women; the brains of men are bigger than the brains of women. Based on the following quotation, I am saying that the "white matter" of the brain is a testosterone target tissue. The "metabolic activity" of white matter is mainly due to myelin. Myelin is sensitive to the levels of testosterone.

"Previous results obtained in this laboratory indicate that in the rat brain the 5 alpha-reductase, the enzymatic activity involved in metabolizing testosterone into 5 alpha-androstan-17 beta-ol-3-one (dihydrotestosterone), particularly concentrated in the white matter. ...The high metabolic activity associated with the white matter structures appears to be linked to the presence of myelin, since the specific activity of the enzyme is particularly elevated in purified preparations of myelin sheaths." (Journal of Steroid Biochemistry 1988; 31: 173)

I suggest that the low testosterone of women, and people whose ancestors developed in the north, is interacting with a genetic predisposition toward weak, or malfunctioning, 5 alpha-reductase in the nervous system. This could result in the "immature myelin" found in MS and the significantly increased testosterone in female MS patients. That is, these women are not absorbing and converting their testosterone. Therefore, I suggest multiple sclerosis is the result of increased DHEA, causing the immune system to attack the immature myelin. This explains the chronic demyelination of multiple sclerosis.