September 24, 2021

I, Science

The science magazine of Imperial College

Liger and male handler

The battle of the sexes is as old as time itself. George Gilder commented that “differences between sexes are one of the most single important facts of human society”. These differences are also one of the most important foundations for human existence. Evolution has gradually crafted us from the humblest of beginnings, essentially through a series of genetic mishaps that have altered form and physiology to produce patchwork, sometimes plagiarised, genomes of astonishing complexity.

Without variation in the genetic code, we simply wouldn’t be here.

Sexual reproduction results in a manifest increase in offspring variation. This enhanced variation occurs within the safe confines of a genome that has already proved itself successful – the parents are alive and capable of out-competing other organisms. Sexual selection also tends to drive evolution faster than natural selection. Sexually selected traits take just a few generations to appear whilst chronic pressures deliver changes more slowly.

So sexual reproduction means greater variation and swifter evolution. But what does gender mean for the organism itself? Is it better to be male or female?

XX or XY?

In its basic form, human gender is conferred by the inheritance of X and Y chromosomes. One X chromosome is sufficient for life and women essentially turn off one X in every cell – allowing them to pick the superior version. Meanwhile men upregulate expression of genes from their single X to compensate. Unfortunately they have all their eggs in one basket; if they inherit a faulty X then they are stuck with it. This means that sex-linked disease is strikingly common in men.

Colour blindness is a common example, affecting 10% of males. Since the receptor for red light is carried on the X-chromosome, men inheriting this receptor mutation will be unable to differentiate red or green. Women will be fine since they have an alternative copy. Furthermore some women possess two functional but distinct red receptors– possibly seeing the world in a different way. It’s been suggested that women are better at differentiating red shades, which may have helped in berry collection, or psychosocial reasons aside, why girls like pink.

There are myriad other X-linked diseases, from clotting disorders to muscular dystrophy. Thus in terms of sex-linked disease men have definitely drawn the short straw.

However there are also imminent disadvantages to possessing two X chromosomes; the double dose effect. In medicine we often rely on using lethally toxic drugs to correct disease; however they’re managed in doses that are beneficial to the patient. For example gentamycin is a very useful and commonly-administered antibiotic. But too much and renal failure and deafness ensue.

Women face a similar problem when it comes to the X chromosome. While they do inactivate one X, the process is incomplete and also degrades with time. The immune system is poised on the brink of chaos; much like a standing army, aggressive towards invaders but ready to aggravate and pillage the locals. Multiple genes regulating the immune system are present on X chromosomes. Thus women are ten times more likely to experience auto-immune disorders where white blood cells turn on self cells. Common conditions are multiple sclerosis, lupus and rheumatoid arthritis.

A recent study has found one of the genetic culprits, TLR7. This gene is responsible for activating a small subset of white blood cells with a tendency to become self-reactive. The gene is essential for a functional immune system, but a double dose precipitates disease; it is found in young women who present with auto-immune conditions and also in the age group where auto-immune disease appears later in life, as X inactivation gradually fails. The introduction of a second copy into male mice causes auto-immune syndromes that rarely occur naturally. Meanwhile the suppression of one copy in the affected females substantially reduces the incidence and severity of illness.

Direct Competition

X and Y chromosomes compete directly via parental imprinting – some gene expression is solely dependent on instruction from one parent or the other. Paternally imprinted genes like Mest in mice tend to encourage the growth and development of the offspring at the expense of the mother and any co-developing half-siblings.

Male imprinting and copulation encourage changes in the mother’s digestive tract (storing and absorbing more nutrients reduces her desire to mate again), alters the female reproductive system to make it hostile for foreign sperm, prompts excessive nest-building and nurturing behaviour, and also encourages the growth of a large foetus. Thus his genes are responsible for the implantation of the placenta and the sac in which a foetus develops, sucking the most available nutrients from the maternal environment.

A poignant illustration is made by hydatidiform moles – pregnancies where only paternal alleles are expressed. The placenta and extraembryonic membranes develop as normal, but with no embryo inside. Most spontaneously ‘abort’ or are removed as they can become malignant.

Another striking example of parental competition is shown by the differences between lion-tiger hybrids dependent on paternal species.

A lion father / tiger mother produces the most enormous big cat (a liger), almost 25% as big again as its parents and some weighing over 400 kgs. A tiger father / lion mother, on the other hand, produces equivalently sized progeny (tigons). Female tigers are ill-equipped to defend against male imprinting since they mate with one male at a time. Consequently male tigers have not developed the need to ensure profligate growth of their offspring since any womb roomates are related. Lionesses are more promiscuous however, and males wish to drive the development of their own individual cubs.

Oestrogen or testosterone?

Hormones are responsible for the main phenotypic differences in sex, from behaviour to germ cells to genitalia. They also have a large impact on health.

Oestrogen is very protective against heart disease, since women in the menopause see a large leap in their risk of cardiovascular illness, however it also increases the risk of blood clots – this may be a mechanism to help reduce bleeding in childbirth. Oestrogen gives very clear skin, primes the immune system and has a protective effect on brain cells. Hormonal differences also mean women distribute their fat less centrally, reducing risk of diabetes and once again, heart disease.

However, oestrogen can prompt cellular proliferation, with direct implications for breast cancer, and also precipitates auto-immune disorders by activating the enzyme RAG-2. This protein churns out variant immune receptors, increasing probability of trapping a pathogen but also increasing the likelihood of developing receptors that are self reactive.

Female sex hormones are a component of being female that makes women better at coping with haemorrhagic shock, organ failure and avoiding hospital infections. In a critical care study, women were 40% less likely to die from organ failure and 23% less likely to acquire infection than men of the same age, controlled for other variables like care pathway and co-morbidities. This may be for reasons already discussed; women are designed to cope with haemorrhage as a result of labour and also monthly blood loss. Furthermore there are multitudinous reasons the female immune system is more effective under pressure.

Meanwhile testosterone primes muscular metabolism, making it easier for men to increase their strength and fitness. Men tend to have a more productive stress response and fare better after traumatic head injury, with a reduction in mortality and persistent disability rates. A 2000 study found that women were almost twice as likely to die and be permanently affected by head injuries.

High levels of testosterone in men are linked to longevity and better cognitive maintenance in senescence. However the possession of testosterone is married with the possession of a prostate gland. As Clemenceau expressed “there are only two wholly useless organs; the French presidency and the prostate”. Whilst it does actually contribute to seminal fluid and overall fertility, both are possible without it. Yet the gland autonomously continues growing to the extent where the majority of men over forty will have some sort of enlargement, 75% of which are symptomatic.

Enlargement is followed by urinary retention/urgency, cancer, and often an operation pleasantly called ‘coring’. With the operation comes a large risk of erectile dysfunction. Erectile dysfunction also occurs naturally in aging, as valves controlling the relevant hydraulics begin to calcify, weaken, and ultimately fail. In the course of a male lifetime, testosterone hangs around long enough to destroy hair follicles, producing baldness. Later in life testosterone fades as the enzymes needed to produce it disappear. Then the elderly male reverts back to the feminine. He may grow breast tissue and his voice loses its deep pitch.

Meanwhile the aging female becomes more male, growing hair, developing central obesity and less flawless skin. The loss of oestrogen causes bone weakness, a humped back, a loss of height and an excessive penchant for fracture.

Life events

Men however, do not have to undergo childbirth. That is probably why they were given the prostate. Carol Burnett described it “like taking your lower lip and forcing it over your head”. 1000 women die each day as a result of labour. The average birth leads to half a litre blood loss and 20% require stitches.

Women are also more likely to experience depression. Social causes include earning less, housewives feeling devalued and professional women feeling unequal. Women are also more likely to undergo stressful life-events, with fluctuations in social networks and romantic distress. Psychological reasons include a tendency to ruminate over complex problems while men simply seek a solution or move on. Biological reasons include increased levels of oestrogen and neurotransmitters, a more extensive/influential limbic system, and hyped immune activity with relevant cytokines. Numerous studies have linked depression to immune activation in a molecular fashion, though it is difficult to exclude this from the complex psychosocial effects of experiencing illness. Depression is twice as common in women but suicide is vastly more common in men.

Overall there’s no clear distinction between genders, but the real winner of the battle of the sexes is the human race itself. And women, because they live longer!

Immunomodulation by the Female Sex Hormones [DOI: 10.2174/1874279300903010061]
F.M. Menzies and F.L. Henriquez

TLR7-driven accumulation of a novel CD11c+ B-cell population is important for the development of auto-immunity
Rubtsov et al 2011
Blood, 4 May 2011

Characterization of the gender dimorphism after injury and hemorrhagic shock: are hormonal differences responsible?
Sperry et al 2008
Critical Care Medicine 36(6)

The independent effect of gender on outcomes following traumatic brain injury: a preliminary investigation
Kraus et al 2000
Neurosurgical Focus 8(1)

Cytokines and major depression
Schiepers et al 2005
Progress in neuro-pyschopharmacology & biological psychiatry 29(2)

Image: flickr | TechSavi