Sudden Infant Death Syndrome, Melatonin, DHEA, and Testosterone


Copyright 1996 James Michael Howard.


 

The following is a compilation of three postings to newsgroups at different times regarding my idea about Sudden Infant Death Syndrome (SIDS).

Part I (August 11, 1996)


My work suggests that sudden infant death syndrome (SIDS) results from a time during sleep when melatonin is too high and this reduces DHEA so low that there is insufficient DHEA to maintain function in the brainstem. (If this interests you, you should read my theory of sleep. Part of my theory suggests melatonin increases at night, which decreases DHEA, and that increases in DHEA during sleep cause REM sleep. I think that melatonin and DHEA reciprocate during the night so that sufficient DHEA is always present to maintain function of the brainstem. As DHEA increases to maintain brainstem function at night, the increase in DHEA also activates areas other than the brainstem and this causes REM sleep.

My idea that DHEA causes REM sleep was supported in 1995. "DHEA administration induced a significant increase in rapid eye movement (REM) sleep, whereas all other sleep variables remained unchanged compared with placebo condition." (American Journal of Physiology 1995; 268: E107)

With the connection of DHEA and REM sleep in mind, consider the following quotation concerning the reduction in REM sleep that occurs as melatonin increases. Keep in mind that the time of maximum SIDS is from 2 months to six months; this is the time when melatonin starts to really increase and reduce REM sleep. Note that at 4 months, the adult pattern of significant increases in non-REM sleep begins to precede the first REM sleep. My work suggests that this is time when melatonin is exerting its most profound depression of DHEA, therefore, this should be the most deadly time for infants. (You can see my chart of DHEA and melatonin during the human life-span in my sleep article at my website.) The following will make more sense if you look at my chart and read my theory.

"Electroencephalographic studies have shown that the amount of REM sleep changes with age. While newborns spend almost 50% of their sleep time in REM, the percentage of REM sleep decreases to 30% by the age of 3 months and to 20% by the age of 6 months. In addition, newborns enter REM sleep soon after the initiation of sleep, but by the age of 4 month entry into sleep assumes the adult pattern in which a significant period of non-REM sleep precedes the onset of REM sleep. Since reduction in the amount of REM sleep is associated with cerebral maturation and since the pineal gland has been implicated both in cerebral development and in the organization of REM sleep, the pineal gland may be involved in the maturation of the adult REM sleep pattern. Prior to the age of 3 months melatonin plasma levels are low and the characteristic circadian rhythms of melatonin are absent. Thereafter, melatonin secretion increases and circadian rhythmicity of melatonin becomes apparent. Thus, the decline in the percentage of REM sleep coincides with the emergence of melatonin secretion coincident with the maturation of the pineal gland." (International Journal of Neuroscience 1992; 63: 1)

If I am correct, REM sleep should exhibit a higher activity than slow wave sleep (SWS or non-REM sleep); I think this is due to the possibility that DHEA is an activator of nervous function. "During REM sleep, brain reactivity and brain excitability thus seem to be higher than during SWS; the reactivity thresholds are lower during REM and a stimulation more readily evokes a cortical response during this stage than during SWS." (Physiology & Behavior 1990; 47: 1272.) What this means is that if melatonin rises too high and DHEA is too low, the activity caused by DHEA during sleep in the brainstem may falter and cause death. I think this is the explanation of SIDS.

Part II (September 5, 1996)


Earlier, I posted my hypothesis that SIDS occurs during a time when melatonin is high and DHEA is low. I suggested that DHEA is a stimulator of the nervous system, that melatonin reduces DHEA during sleep, and levels of DHEA that are too low will result in loss of DHEA stimulation of the brainstem. Hence, when DHEA is too low, death occurs. I want to extend this with further supporting evidence that involves epidemiological findings in SIDS.

The first place to look, given my hypothesis, is the adrenal glands, the site of DHEA production. Well, I did and the adrenal glands are normal in SIDS. "Our data revealed a normal maturation of the adrenal glands in SIDS cases." (Int. J. Legal Med. 1994; 106: 224.) I decided to look elsewhere, i.e., I decided to look at the influence of testosterone on the incidence of SIDS. More boys than girls are affected by SIDS. Additionally, I have already shown that testosterone has a negative effect in HIV infection and AIDS, so this is a logical thing, for me, to check. This ...is... where the answer lies. (You may find my hypothesis of AIDS on the index page.)

If you read my first posting on SIDS, you will remember the connection of REM sleep and DHEA. The idea is that REM sleep is a healthy sign for infants during the time of SIDS incidence. (Proper amounts of REM sleep mean proper amounts of DHEA during this time.) In the following quotation, note that there is a "lag in the maturation of REM sleep" in SIDS. This indicates to me that DHEA is in low amounts as melatonin increases in the first months of life.

"The data show that risk male infants fail to demonstrate an increase in wakefulness with age and reveal a lag in the maturation of REM sleep compared to controls and female risk infants during the critical age for SIDS. Significant sex differences within the first six months of life are of particular importance because of the consistently reported higher incidence of SIDS in males than females." (Neuropediatrics 1993; 24: 8)

My idea, in SIDS and in AIDS, is that the hormone, testosterone, directs DHEA to use by "testosterone target tissues." You see, my principle hypothesis is that DHEA is required for optimal transcription and replication of DNA. Therefore, testosterone increases use of DHEA for its target tissues; they grow bigger because of this, and this is why men are bigger than girls. Men produce more testosterone. However, in a situation of limited DHEA, this can be a problem, because testosterone redirects DHEA for its target tissues. (This is why men of high testosterone to DHEA become bald.) I think the same thing occurs in SIDS. One of the main causes of SIDS, then, is a high ratio of testosterone to DHEA. The idea that testosterone is involved in SIDS has been tested in an infant primate.

"In postnatal infants, there is similarity between the time course of transient gonadal steroid secretion and the age-related incidence of sudden infant death syndrome (SIDS). The cause of death in SIDS is generally thought to be a ventilatory arrest, but the mechanism responsible for such an event remains unknown. Testosterone has been demonstrated to depress ventilatory drive and increase sleep apnea in adult men. We tested the hypothesis that the gonadal steroid testosterone depresses infant ventilatory drive during sleep. Three newborn male infant primates were gonadectomized after birth. Ventilation was observed and quantified for each animal during completely natural unencumbered sleep by plethysmography for an average of 16 wk. Ventilatory patterns were recorded, and ventilatory drive was challenged with hypercapnia and hypoxia during quiet sleep on the night before and the night after testosterone administration. Hypercapnic ventilatory drive during sleep was significantly depressed by an average of 33.6% on the night after compared with the night before testosterone administration. Depression of the response to hypercapnia after testosterone was not accompanied by any change in resting minute ventilation measured during quiet sleep. Hypoxic ventilatory drive, incidence of apneic events, and length of apnea were not different after testosterone. The effects of injecting a placebo on ventilatory patterns and drive were tested by giving the placebo to all animals on several test weeks. Placebo injections produced no significant change in any measured parameters. These results support the hypothesis that testosterone depresses hypercapnic ventilatory drive during sleep in the infant primate." (J. Appl. Physiol. 1994; 76: 1786)

Does increased testosterone cause increased SIDS in humans?


Well, I think the case is supported for male vs. female SIDS victims. SIDS is higher in "preterm" infants: "Although only 9% of infants are born at less than 36 weeks' gestation, 20% of SIDS victims are former premature infants." [Clin Pediatr (Phila) 1995; 34: 410.] Testosterone is increased in preterm infants during the time when SIDS occurs at increased frequency.

"When preterm male and full-term male infants were compared, no difference was seen in the T [testosterone] peak in the first day of life. However, the 1-3, and 60-90 days concentrations of T were 2-fold higher in the preterm group. ...The immediate postnatal peak in plasma T levels persisted longer in the preterm than in the full-term male infants." (Acta Paediatr. Scand. 1982; 71: 425)

SIDS is increased in women who smoke. I have developed a theory that suggests that the rise in testosterone of puberty triggers smoking. (You can use my name and "smoking" to find this with Dejanews.) Since I think testosterone is rising in this society, I explain the increase in smoking in young people as a result of the increase in testosterone. Women who smoke, therefore, may be women of higher testosterone. While the following investigator gives credit to "sociological factors" in addition to testosterone in adolescent smoking in (Addict. Behav. 1992; 17: 459), his first publication concerning adolescent smoking and testosterone is more to the point for this treatise. "Social and psychological variables are used to explain why young people become cigarette smokers, whereas biological factors have been virtually ignored as possible determinants of that behavior. In this study, salivary testosterone was positively associated with cigarette smoking among 201 subjects 12-14 years of age. This finding suggests that testosterone should be included in future considerations of adolescent cigarette smoking." (J. Behav. Med. 1989; 12: 425.) I think the connection of smoking and SIDS is that women who smoke are higher in testosterone. They produce children who are higher in testosterone, which increases SIDS.

If testosterone is redirecting DHEA use, where is it going?


I think the DHEA is being redirected to brain structures that are testosterone target tissues. Consider that "The Nv [volume of hypoglossal nucleus - cells per mm3] of synapses did not differ significantly between SIDS cases and controls, although the total number of synapses was greater (61%) in SIDS." (J. Neuropathol. Exp. Neurol. 1995; 54: 627.) In some songbirds, testosterone has an effect on the hypoglossal nucleus. "We find anatomical correlates for each of these attributes in the nXIIts [hypoglossal nucleus]. This nucleus is 83% larger in males than in females." (J. Comp. Neurol. 1991; 307: 65.) Earlier, this reference says "Its [the hypoglossal nucleus] neurons concentrate androgens." This means that the hypoglossal nucleus is a "testosterone target tissue."

An increase in synaptic growth in lower brain structures may cause two phenomena. Firstly, it may make these structures more "mature" in that they grow faster. This could result in shorter gestation, i.e., preterm delivery. The neonate participates in the time of delivery. These neonates would be smaller, because less time would be available for growth. "Mothers of SIDS infants give birth to smaller babies in general. SIDS infants weighed, on average 85 g less at birth than their siblings and 164 g less compared with babies in nonaffected sibships. When birth weights were standardized for gestational age, most of the weight difference between SIDS infants and siblings was due to a shorter gestational age of SIDS infants, while the difference between surviving siblings of SIDS infants and births from nonaffected sibships remained. All births in sibships with a SIDS infant were intrauterine growth retarded. This may reflect factors that contribute to SIDS risk (such as maternal smoking)." (Am. J. Epidemiol. 1995; 142: 84.)

Structures in the brainstem that have excess synapses may require more DHEA in order to maintain sufficient activity of these structures. When melatonin reduces DHEA at night, there may be insufficient DHEA to properly activate these structures. The hypoglossal nucleus is in the brainstem.

SIDS should be more prevalent in women who are higher in testosterone.

Part III (September 12, 1996)


African women produce more testosterone than white women. This is very difficult to find in current journals. I know of one group of endocrinologists who measured testosterone in African American women and European American women and found much higher levels of testosterone in the African Americans, but did, or would not, publish. The following is the best I could find.

Dada ,O.A., et al., "17 Beta-estradiol, Protesterone and Testosterone in the Normal Menstrual Cycle of Nigerians," (Int J Gynaecol Obstet 1984; 22: 151)

"Circulating blood levels of estradiol, progesterone and testosterone are reported in 17 normally menstruating Nigerian women. The pattern of secretion and the range of levels of estradiol and progesterone are similar to those reported in other ethnic groups. Testosterone levels were, in general, higher than corresponding values in Caucasian or Asian women, but were of the same order of magnitude as previously reported in Zambian African women."

This corresponds with the findings that testosterone is higher in black men, medium in Asian men, and lowest in white men. See Table II, page 888 in Lancet 1992; 339: 887-889. In a group of college men in the U.S., black men produce significantly more testosterone than white men (Journal of the National Cancer Institute 1986; 76: 45).

If I am correct that SIDS, and premature delivery, occur more in women with high testosterone, we should find this in black women. The following three quotations support this. (I could not find an author for the first, but it was found in PubMed.)

. . . "Variations in the Incidence of Sudden Infant Death Syndrome (SIDS), United States, 1980-1988," (Stat Bull Metrop Insur Co 1993; 74: 10)

"Sudden infant death syndrome (SIDS) continues to be the second leading cause of infant mortality in the United States. In 1989, 5,634 SIDS cases were recorded, resulting in a rate of 139.4 per 100,000 live births. As with total infant mortality rates, SIDS rates have been slowly declining over the years but remain disproportionately higher among black infants than white. Unlike the total infant death rates, however, the gap between the races is narrowing--SIDS death rates among black infants decreased 19 percent between 1980 and 1988, in contrast to the 4 percent drop among white infants during the same period. The black-to-white ratio dropped from 2.18:1 in 1980 to 1.83:1 in 1988. Geographic differences in SIDS rates persist, with rates being the highest in the West and Midwest regions and lowest in the Northeast. While many SIDS risk factors have been and continue to be identified, the diagnosis remains one of exclusion. The etiology continues to elude definition, and increasingly more diagnoses are being made based on autopsy reports and death scene investigations. As these diagnostic practices become more standardized, SIDS prevalence is expected to change. Whether new insights will ultimately lead to eradication, remains unknown at this time."

Denmead, D.T., et al., "Placental Pathology is Not Predictive for Sudden Infant Death Syndrome (SIDS,)" (Am J Perinatol 1987; 4: 308)

"...There were more premature and black infants found in the SIDS group compared with the general birth population, and also lower five-minute Apgar scores (P less than 0.02) compared to matched controls. Analysis of the second control group match, including infant Apgar scores, maternal hematocrit, maternal age, and complications of pregnancy and delivery, did not influence any of our conclusions. The data suggests that matching for prematurity may be important in identifying the strength of additional risk factors for SIDS, since the risk factors for SIDS and premature delivery are similar.

Shiono, P.H. and M.A. Klebanoff, "Ethnic Differences in Preterm and Very Preterm Delivery," (Am J Public Health 1986; 76: 1317)

"Ethnic differences in preterm (less than 37 weeks) and very preterm (less than 33 weeks) delivery were evaluated in a prospective cohort of 28,330 women. Blacks had the highest rate of preterm and very preterm delivery, followed by Mexican-Americans, Asians, and Whites. Adjustment for maternal age, education, marital status, employment, parity, number of previous spontaneous or induced abortions, smoking and drinking during pregnancy, infant sex, and gestational age at initiation of prenatal care resulted in the following odds ratios for preterm delivery: 1.79 (1.55-2.08) for Blacks, 1.40 (1.19-1.63) for Mexican-Americans, 1.40 (1.16-1.69) for Asians, and 1.00 for Whites. The corresponding odds ratios for very preterm delivery were 2.35 (1.72-3.22) for Blacks, 1.31 (0.88-1.94) for Mexican-Americans, 1.10 (0.67-1.83) for Asians, and 1.00 for Whites. Exclusion of cases of premature rupture of membranes, placenta previa, and abruptio placenta did not explain the large ethnic differences. Although Whites and Mexican-Americans had similar birthweight distributions, Mexican-Americans had an increased risk for preterm delivery."