Science Spin September 2008

Men and women: Different brains, different disease risks

Alzheimer's and Parkinson's disease are two of the most common neurodegenerative disorders which affect older people. Their incidence is ever increasing as our population ages, and they cost the Irish economy €350 million euro per year. But although the diseases were discovered over 100 years ago, their causes remain elusive. Yet several risk factors have been found to be associated with the disease. And while old age is an obvious contender, gender is actually one of the biggest risk factors for both diseases. Old men have 1.5 times the risk of developing Parkinson's disease and old women have twice the risk of developing Alzheimer's disease.

It could be argued that men are simply more physical, and women simply more thoughtful. Therefore with age older men get movement disorders and women get cognitive disorders. But gender differences are apparent across a wide variety of brain diseases. Not only are men more likely to develop Parkinson's, but boys are 3-6 times more likely to develop Autism and ADHD, and women are more likely to be hit with mental illness and depression. Yet the role of gender in brain disease is hotly disputed.

In the early 1900s studies in England by proponents of eugenics, such as Francis Galton on gender differences in the brain, claimed that women had smaller heads and ergo lower IQs. A small head circumference was used later that century to discriminate against non-white immigrants landing at Ellis Island and prevented their entry to schools and better jobs. Recently, in 2007, the celebrated scientist, James Watson, was widely criticized for his comments linking brain size, gender, race and low IQ and he was forced to resign from his position in Cold Spring Harbour in the US. However, despite the public disquiet with the remarks of Watson and others, several studies on gender differences in the brain have found physiological and functional differences in male and female brains.

A brain of two halves

Developmental neuroscientists have suggested that map reading and verbal skills are hotwired into our heads early on. In the womb male brains develop better spatial and visual processing connections, but females develop better connected temporal lobes which regulate speech. Thus as the joke would go; while a woman is more likely to stop the car to ask for directions, a man is more likely to understand them.

On a more detailed level, women have better connections between their left and right hemispheres, while men are left hemisphere dominant. Evidence for this connectivity stems from studying people's recovery after an injury. Aphasia; a loss of language, is nearly 4 times more common in males after left hemisphere damage (48 per cent in males vs 13 per cent in females), whereas right side damage produces no sex differences because men are less reliant on their right hemisphere for language processing. Thus better connectivity between the hemispheres allows women to recover from damage.

The dominance of the left hemisphere in men and use of both hemispheres would suggest it is simple to define the sex of a brain simply in terms of which hemisphere a person uses. But, in June this year researchers from the Stockholm Brain institute in Sweden suggested that gender differences in the brain are not that simple. Their imaging study found that the brains of homosexual men resembled those of heterosexual women, and that lesbians' brains showed similarities with those of straight men. This suggests differences between men and women may be more complicated.

Defining the gender of a person's brain is complicated because gender isn't simply a matter of knowing whether a person has XX or XY chromosomes. Instead you need to know how that person represents themselves and this may be shaped by their environment and experience rather than genes only. Thus gender differences may be less easy to define biologically.

Sex differences are easy to define however. Sex differences are defined simply by the presence or absence of the SRY gene which is found on the Y chromosome and is responsible for the male sex. In the absence of this gene, embryos, even those with both X and Y chromosomes will develop ovaries rather than testes.

But in the developing brain, sex differentiation is actually regulated by estrogen rather than testosterone. In the male brain testosterone is converted to estrogen by an enzyme named aromatase. Exposure to high levels of estrogen results in the masculinisation of the developing brain, while ironically lack of exposure to estrogen encourages feminisation of the brain. Thus while SRY produces gonadal differences, estrogen actually produces sex differences in the brain.

If the conversion of testosterone to estrogen masculinises the brain, this may make you wonder what a masculine brain is.

A manly brain

Physiologists define the masculine brain in terms of its ability to behave in a masculine way. In simple terms this means masculinised rats are more likely to be attracted to and attempt to mate with female rats. Interestingly last year Harvard researchers described in Nature Neuroscience how they could chemically engineer female mice to behave like males by changing the pheromone sensors in their brains. The research team led by Catherine Dulac genetically engineered female mice to lack a gene TRPC2 which allows females to sense pheremones in an organ in the nose called the vomeronasal gland.

Without the gene, the female mice behaved exactly like male mice, with the same attempted mating behaviour and calls that males use to attract their mate. Thus while the sex of your brain may be controlled early on by gonadal hormones and your X and Y chromosomes, how feminised or masculinised your brain is can be altered throughout adult life by the use of hormones, pheromones and pharmaceuticals.

Gender balance in brain studies

Gender differences in the prevalence of diseases such as Alzheimer's, Parkinson's, ADHD and Autism are well known. But these gender differences rarely translate to research practices aimed to understand why these differences exist. Technically at the bench-top cell biologists tend to work in a "gender" neutral environment. Apart from commercially available immortal cell lines such as the HeLa line, so named after a woman named Henrietta Lacks who donated her cells to research, very few cell biologists would be able to tell you the sex of their cells.

Assessing the gender of cells may be a bit over the top, but animal studies should offer better opportunity to examine gender differences in diseases. Yet, animal studies rarely take gender into the equation. For the most part, researchers tend to only use male animals in their experiments. Most researchers suggest that the female menstrual cycle "complicates things", therefore they prefer to work with male rodents.

The National Institute for Health (NIH) is one of the largest funding bodies in the US. In order to address gender imbalance in research they advocate that gender differences in study populations both in clinical and laboratory experiments need to be considered. However the NIH guidelines are a suggestion rather than requirement in grant funding applications. Until gender balance is required to meet the bottom line of funding applications it is unlikely to become a routine part of research protocols.

In Ireland, neither Science Foundation Ireland, nor the Health Education Authority require that gender differences be addressed in study designs or funding applications. This may mean we generate drugs that have only been tested as safe for use for half of the population.Attempts to address gender imbalance in medical studies have been made with the Women's Health Initiative in the US. Advocates for the involvement of women in research pushed in 1991 for the studies specifically focussed on promoting women's health.

One such trial involved 27,347 women and was designed to measure the health benefits of hormone replacement therapy (HRT). Unfortunately the trial had to be suspended in July 2002 due to unexpected side effects of the HRT. The treatment actually increased the risk of strokes and heart attacks in some women, although it was also associated with decreased risk of hip fracture and colorectal cancer in others.Perhaps not surprisingly, the original studies on the safety and side-effects of the female contraceptive pill were conducted using only male animals.

Risky business of gender

Not only do brain diseases affect men and women disproportionately, there are also differences in the types of risk factors associated with these diseases in men and women. Drinking coffee decreases the risk of Parkinson's disease in men. But in women the story is slightly more complicated. One study on 77,000 nurses found while coffee made the women 65 per cent less likely to get Parkinson's disease, if the women were also on hormone replacement therapy they were actually 1.5 times more likely to develop Parkinson's.

There are also sex differences in the risk factors for Alzheimer's disease. Obesity at middle age is a risk factor for the disease in men, but for women depression is a greater risk factor. Men and women also differ in terms of their brain's immune responses to diseases. Women have a greater incidence of auto-immune diseases such as Lupus and arthritis than men, but men have a greater incidence of asthma prior to puberty. Both testosterone and estrogen are involved in the immune system and may be associated with autoimmune diseases that affect men and women.

For women estrogen is particularly important and has key anti-inflammatory properties. Older women have greater inflammation than older men and younger women. And this is thought to be associated with a lack of estrogen production after the menopause. Interestingly heightened immune response in women led to controversial speculation in the US in the 1990s that the AIDs epidemic particularly affected homosexual men because they had "feminised" immune systems.

This speculation led to outcry that the researchers were attempting to link homosexuality with a dysfunctional immune system. People felt that suggesting homosexual men had a dysfunctional immune system that made them more likely to develop AIDs was the same as suggesting homosexuality caused by a dysfunctional immune responses.

Gender specific treatments

In general it is well known that men and women have different immune systems. And immunosuppressant drugs work differently in men and women. Tumour Necrosis Factor alpha blockers are immunosuppressant drugs which decrease the risk of arthritis in older men but not in older women. And the use of Aspirin is reported to decrease the risk of developing Parkinson's disease in women but not men.

Yet when it comes to prescribing drugs to treat neurodegenerative diseases, gender specific drugs are rarely prescribed.The advent of gender specific drugs may seem like a pharmaceutical goldmine. Drugs may be repackaged into male and female varieties, and adverse effects for one gender may turn out to be opportunities for another. But it is not all about rebranding diseases.

Dr Marianne Legato is an advocate of Gender Specific Medicine and based at Columbia University in New York. But she writes that studying gender is "an intellectual imperative, that women's health is more than a political or feminist issue or a marketing tool for hospitals."

Dr Legato has also written a book "Why men die faster" and suggests that all kinds of differences between men and women, including speed of their digestive system which alters how well drugs enter the bloodstream, differences in the ability of the liver to detoxify compounds and faster heart rates which alter how effectively blood is pumped around the body necessitate gender specific drugs.So while we know there are differences in the prevalence of risk factors and efficacy of drugs associated with brain diseases, the jury is still out as to why these gender differences exist.

And most likely the jury will remain out, until brain researchers focus not only on grey and white matter but also the differences in the blue and pink bits in between.

Dr Veronica Miller, a researcher and science writer, is currently working at the New York Wadsworth Centre . Veronica Miller's book, All about the brain, is due for publication soon as the third in Science Spin's Discovery Series.