The first apocalypse: the human male has lower life expectancy before birth. − Rakyat Biologi

Detailed analysis of spontaneous abortions reveals that these affect male embryos and fetuses more often. There are at least five killers which disfavor the male embryo or fetus: infections, errors of mitosis (of cell division), vascular anomalies and diseases, chromosomal aberrations, and disorders of cell migration.

The human male is inherently at greater risk than the female for infections throughout the life span. I say "inherently" because some cultures place such low value on the life of girls that neglect can lead to high rates of infections for the female child. Of course, some infections are severe enough to cause death, and reduce life expectancy. Why is the human male inherently more at risk ? The reason for this phenomenon is rather straightforward. The immune system of the human male is less aggressive against “hosts”, especially the truly dangerous ones that can infect and kill us, but also many of those that can cause developmental malformations. One exception is the class of antigens which make us allergic: boys are more often allergic than girls because of an over-enthusiastic response of their immune system to things like pollen, dust mites, dog and cat dandruff, etc. Note though that this sex difference is only temporary. After puberty, women become three times more at risk than men for developing allergies. But allergy is not the immune process of greatest interest for our purposes here. So let’s return to those immune processes which protect us from infection. Most types of immune processes including the proliferation and voraciousness of B and T lymphocytes in reaction to deadly intruders are weaker in human males. Lymphocytes are circulating cells which attack and disintegrate undesirable foreign bodies (particularly viruses and bacteria). Some of these mature from the bone marrow (B cells) or from the thymus (T cells). A third category of lymphocyte is the natural killer (NK) cell circulating in the body (white blood cells are natural killers responsible for the color of pus), and which literally envelop and devour foreign bodies. The weaker immune system of the male human begins to put him at a disadvantage even before he is born, which is why male fetuses succumb more frequently to infections transmitted from the mother during gestation such as toxoplasmosis, rubella, etc. The infectious agents more likely to kill men in adulthood have historically included agents such as tuberculosis and pneumonia. It has long been believed that steroid hormone differences between the sexes suffice to create the cascade of developmental events leading to the basic sex difference in the immune system. After all, it is well documented that estrogen fans auto immune inflammation, and is prophylactic against infection. However, to preclude an overly simplistic interpretation of the relation between estrogen and immune function, I have to say this: estrogen reaches its highest concentration in women as pregnancy advances toward parturition. However, at this same point most immune responses are actually weaker than in women who are not pregnant. Why ? So that the mother will not reject the foreign body (parasite) which is her own baby ! In short, hormonal-immune relations are very complex. There is increasing evidence, though still tentative, to the effect that X-linked genes also play a modulatory role in immunoregulation -even though the most important gene complex in immunoregulation is located on the sixth chromosome, an autosomal chromosome supposed to be identical in the two sexes.

The mechanism, or mechanisms responsible for the greater risk of the human male of mitotic error is less understood. Mitosis is nothing other than cell division. Cancer is an error of cell division. In fact, it consists of unbridled mitosis. The young male of the human species is at greater risk for most cancers (but not all kinds) than his female counterpart. A recent study conducted in Italy reviewed 90,431 cases of cancer in humans. Women had a better prognosis for most cancer sites (overall 5-year relative survival in women 48% vs 32% in men). Of course, it would be very difficult for men to have higher rates of breast or ovarian cancer since men do not have these organs. Actually, things are not quite that simple. Men have rudimentary vestigial mammary glands, and the odd few can get breast cancer (and Klinefelter patients, who have gynecomastia or female-like breasts, are more at risk than normal men). However, in the cases of those organs which are similar in both sexes (viscera, bone, muscle, brain, etc.), the human male is slightly more at risk for cancer, at all ages. Though this is an overriding general tendency, there are some exceptions. For example, the incidence of gastric cancer is much higher in men than in women, and a similar sex difference is also seen in a rat experimental model of gastric cancer. One line of investigation which could explain the generally greater male risk for cancer is biomolecular research into X-linked mechanisms. The catalytic polypeptide of DNA-polymerase-alpha, which seems to play a basic role in cell division in the entire body, has been mapped to the X chromosome, thus offering a tentative mechanism for female resistance to cancer. Finally, at least one cancer has been linked to concentrations of a male steroid hormone. Indeed, cancer of the prostate (a male organ) has recently been found to be curable with a treatment involving, among other things, administration of Zoladex, a testosterone antagonist.

Excessive proliferation of cells in the brain is one problem which affects male fetuses more than female. However, insufficient cell division can be another major problem. One of the severest such problems, anencephaly, consists of a failure of development of the last layers of brain tissue. Anencephaly is the failure of development of the most anterior part of the brain. It occurs very early in prenatal development at the moment when the brain consists of a mere tube (the neural tube). This problem is very rare, but it affects females more often than the male fetuses. The female to male ratio is 1.49: 1. Female newborns are also at greater risk for an abnormally small head and brain (microcephaly). This is also a failure of growth which usually occurs very early on in fetal brain development. Later occurring disorders of fetal brain development are more common in the male sex. For example, the corpus callosum is a large bundle of neurons which develops relatively late in fetal development. Male fetuses are more at risk for all callosal abnormalities including holoprosencephaly (fusion of the two brain hemispheres) and callosal agenesis (failure of development of the corpus callosum). Spina bifida, a failure of encasement of the spinal cord into the vertebrae (or spinal cord hernia), is also preponderant in male over female newborns. Hydrocephaly is also more common in the male sex (2.2: 1). Some authors call these disorders defects of “canalization” of the nervous system.

Vascular disease of blood vessels can lead to two types of conditions which kill people: bleeding (hemorrhage) and obstruction (thrombosis or embolus). Heart disease is another vascular condition. All three forms affect the human male more than the human female. Because it is rightly known that an unhealthy life style (alcohol, smoking, heart disease, fatty diet, sedentarism, stress) can increase risk for heart (especially the strongly male prevalent coronary atherosclerosis) and other vascular diseases, it has been argued that women will catch up with men -as they seem to be doing as a direct function of the decreasing sex difference in prevalence of smoking. This well founded observation does not however explain the whole story. The male fetus and child are particularly at greater risk for vascular disease, a sex difference difficult to attribute to life style. In other words, there is a biologically inherent weakness in the male vascular system in the human species.

Of course, it is easy to explain why there would be more gonosomal aberrations in the male sex. The male is not protected by lyonization (see chapter 3 if you have forgotten the explanation of this mechanism). However, the human male is slightly more at risk for autosomal aberrations as well ! This is truly a remarkable sex difference. Why in heaven's name would there be significantly more boys with Down's syndrome (trisomy 21) than girls ? It has now been found in several investigations that whereas female humans are more susceptible to errors occurring at the moment where the future mother's egg (ovum) is dividing up its chromosomes into half the full set (meiosis), human males are also in addition to that, more at risk for such an error occurring in the future father's sperm. This sex difference seems to be most true of one of the most common chromosomal aberrations, trisomy-21 or Down's syndrome. It is still not known why this paternal legacy is handed down so much more often to the male offspring, nor what is special in this respect about the 21st chromosome. Curiously, I have come across many reports of an exception to the overall trend disfavoring males: the female sex has been reported to be at greater risk for Edward's syndrome (trisomy 18). I have not been able to find much scientific explanation of this phenomenon, but it seems that more female zygotes with major chromosomal abnormalities (trisomy 13 or Patau's syndrome, trisomy 18 or Edward's syndrome) actually survive to term. So in fact, the male sex is probably truly more at risk for all the autosomal trisomies. Overall, the most extensive investigations of chromosomal aberrations (trisomies, monosomies, structural abnormalities such as partial deletions) of very large cohorts have found that the male sex is somewhere between 1.2 and 1.3 times more at risk.

Neuronal migration in the brain, like neuronal proliferation (cell division or mitosis), is a phenomenon of prenatal development. Neurons are most often born in a central area of the brain called the periventricular area. That is where the mother neurons divide and multiply (mitosis), a process reaching near-completion around the fourteenth week after conception. I cannot resist mentioning that this process of mitosis becomes so intense that at the high point of the process, the fetus's neurons are multiplying by a factor of 5,000 a second ! Shortly after they are born, many things happen to the daughter neurons. They migrate, differentiate, interconnect, form systems, etc. Given the rapid rate at which all of these processes occur in fetal development, is it any wonder that errors may sometimes occur ? One of the errors that does occur is in the migration of the daughter neurons to the gray area of the brain, the intelligent part, called the cortex. Neuronal migration is guided by complex chemical processes diffusely (and not so diffusely) occurring in the brain. Newborn neurons are attracted to specific mature neurons (targets) with which they are destined to make contact and form synapses. A diversity of molecules located on the targets (cell adhesion molecules) and around the targets (hormones, immune processes, etc.) also play a role. Most of the process of neuronal migration is complete by the time of birth. Sometimes, cell migration is off by a whole cortical layer. One such syndrome is called double cortex, and is characterized by extra layers of cells in the cortex, beyond the usual six. Incidentally, the double cortex syndrome is very rare, and the few cases reported in the medical literature that I have consulted were all of the female sex, for reasons that remain, I think, completely unknown. However, several more common syndromes due to errors of neuron migration are more prevalent in the male sex. One disorder of neuronal migration, which is less dramatic than double cortex, causes dyslexia. During fetal development, pockets of neurons get installed here and there in inappropriate layers of cortex, and these can be accompanied by micro-vascular anomalies as well. These migrational anomalies are called ectopias. They are characteristic of all developmental dyslexics which have been studied post mortem. Dyslexia is a male-prevalent disorder. It is not clear to which extent the male sex is at risk for errors of cell migration in the brain in other developmental disorders. Many developmental disorders have not been systematically explored with autopsy material. More severe disorders of neuronal organization may involve multiple errors of cell division as well as migration. Trigonocephaly is a deformation of the cranium and brain characterized by a triangular forehead. This condition was studied in a pedigree and was found in six relatives through three generations of one family. In addition to the trigonocephaly, the carriers had minor ear, vertebral, and genital abnormalities, mild microcephaly, and minor eye abnormalities. In this family, trigonocephaly was an autosomal dominant trait. The ratio of affected males to affected females was 5 to 1. Porencephaly is a major aplasia (localized failure of development of the brain). One study investigated porencephaly in 2793 consecutive autopsies of children aged up to 18 years. There were 12 cases of porencephaly, accounting for 0.43% of the autopsy material, and 5.2% of all anomalies of the central nervous system in this age group. The anomaly was twice as frequent in boys than girls.

An intact brain requires not only proper emplacement of neurons, but also of all the other tissues forming the head, including bone. It is easy to detect errors of bone development because the cranium can be assessed directly in a living newborn. One of the disorders of development of the cranium is craniostosis, inappropriate timing of the fusion of the bone plates forming the head. This results in deformities of the head and of the underlying brain. And indeed, boys are slightly more frequently victims of this developmental disorder than are girls.