Abstract
The past 15 years have produced enormous advances in our understanding of the unique features of biological sex. Nevertheless, important and different tasks remain. One of these is to address the difficulties inherent in including premenopausal women in prospective, randomized trials characterizing the impact of new drugs and interventions. A second compelling mandate is to expand our knowledge of men using the same concentration on the unique features of male biology as we have used in studying women. The inclusion of men in our scientific investigations is a natural evolution of our development of the discipline of gender-specific medicine and will yield the same rich harvest as has our work in women's health.
Keywords
Over the past 20 years we have seen an unprecedented interest in the unique properties and characteristics of the biology of the human female. This lazer-like focus on women's health is a new and compelling phenomenon. Traditionally, clinical studies of humans were restricted to men: males were considered a more stable and homogeneous study population because they were relatively immune from hormonal shifts, and there was no obvious danger to an unborn fetus conceived during the course of a clinical trial. The idea that sperm might be affected adversely by an untested drug or intervention was never really an issue or concern, and the fact that the reproductive competence of these men was as likely – or not – to be impaired as that of women was generally ignored. Like much of what we do – and what we think about it – the way we plan clinical trials is determined by our culture: in most societies (ours is no exception) a man's worth is assessed by what he accomplishes. “Money”, said one of my more worldly male friends, “is the report card of life”. Most women, on the other hand, no matter what their accomplishments, view their ability to conceive and bear children as one of the most fundamentally important characteristics by which they define their worth. They were – and remain – concerned that joining a trial to test the safety and efficacy of a new drug might damage their reproductive competence. It is also true that we ask men to take greater risks and to volunteer for more dangerous tasks than we do women; men accept these challenges without complaint and, indeed, often with enthusiasm, considering it their duty to do so. However, as the Belmont Report pointed out, justice is an important consideration in planning who will be the subjects of clinical trials: “Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of ‘fairness in distribution’ or ‘what is deserved’” [1]. Although the primary thrust of the Belmont Report was to establish guidelines for the protection of research subjects, it is important to point out that women have benefited from the risks men have accepted in the course of clinical investigation and, as a matter of fairness, should also be incorporated into study populations.
Studying women: an (imperfect) work in progress
Since the US Public Health Service published its landmark assessment of what was known about women in 1985, [2] the lay public, policy-makers and scientists alike have made an effort to expand the ‘bikini view’ of women, which assumed that breast and reproductive health were the only unique features of the female patient. The direct study of women was not accomplished without a struggle: investigators feared that the cost of expanding study populations to power investigation for a gender effect would limit the number of research projects too severely. Moreover, there were moral, ethical and economic consequences to including premenopausal woman in clinical trials: the dilemma of what to do if a child conceived during the course of a clinical trial were born with developmental defects is still not solved. What we have done, in essence, is to largely limit our investigation of women to the postmenopausal subject: the Women's Health Initiative, for example, was devoted to subjects well beyond the age of menopause at the time the study was begun. The ensuing information regarding the impact of starting hormone therapy in this elderly population produced unprecedented confusion in the minds of patients and physicians alike. In fact, the same authorities who conducted the study are working on a reinterpretation of the data it yielded for the lay public and physicians to use in caring for perimenopausal or even younger individuals [3].
Caveats and concerns notwithstanding, it was the emergence and growing power of the feminist movement that made a focus on women's biology inevitable. That movement was the direct result of women's experiences in the two great wars that dominated the first half of the twentieth century. This powerful impact of feminism has been a double-edged sword: there is, and always has been, a deeply entrenched resistance to paying ‘special attention’ to women's health which has, and continues to be, a powerful deterrent to progress in expanding and correcting our male models of human function and the pathophysiology of illness. Many professional men in a medical audience simply leave the room when a topic that incorporates the term ‘women’ or ‘women's health’ is announced. Conferences dedicated to women's health are attended exclusively by women; if there are three men in an audience of 150 attendees, it is unusual. Some of the resistance and resentment is justified: much of what has been advanced as ‘women's health’ is laced with feminist polemic and anger. Others view the interest in women with some skepticism, knowing that, in fact, much of the impetus to open ‘women's health centers’ in hospitals and academic institutions has been commercial. Marketers know that a family's initial contact with hospitals is often during its first pregnancy. Women shepherd their children and husbands to physicians and centers that they choose and create their family's healthcare systems. To bring a woman into a medical facility and offer her a good experience is to ensure that the rest of her relatives will follow. It is also regrettable that the directives that come from institutions as prestigious as the US National Institutes of Health are obviously impacted by political concerns: the incorporation of women into clinical studies wherever appropriate was mandated in 1990, but there has not been any universal demand for the inclusion of both sexes in animal studies financed by federal funding, much less a requirement that cells in tissue culture be analyzed for whether they contain an XX or an XY complement of chromosomes.
The greatest challenges for those of us who have shaped this field is to base what we teach and do on science, to purge it of polemic and to resist the highjacking of science by politics. It has not been an easy task, but as a community of scholars we have been able to establish what is now abundantly clear: not only are men and women vastly different in important respects in every system of the body, but the new information has forced us to formulate entirely new questions which we would never otherwise have even considered and which, if answered, will make our prevention and treatment of disease tremendously more effective for both sexes. In spite of all the opposition to focusing on women as more than reproductive machines and possessed of other body parts than breasts, ovaries and a uterus, which differ from those of men in unique ways, we have now amassed an impressive and stunningly interesting body of information that affirms that indeed, sex does matter [4,5]. As the Institute of Medicine observed in its 2001 landmark monograph: “Sex…matters in ways that we did not expect. Undoubtedly, it also matters in ways that we have not begun to imagine” [6]. To put it succinctly, the power of the new science of gender-specific medicine is compelling and extraordinarily valuable for both men and women. It has already transformed the way we care for patients with a powerful positive impact on the quality and length of human lives.
How focusing on women is impacting how we think about the unique biology of men
One of the most unexpected and valuable benefits of thinking so deeply and meticulously regarding the nature of women's biology, surprisingly, has been a new view of how to investigate the unique biology of men. Instead of simply assembling male cells, animals or humans for scientific investigation to answer questions and test hypotheses that we assumed would be identical for both sexes, we are asking very different questions about men than we have ever asked before. What are the particular problems of males? How can the information we've learned about women be applied to the prevention and amelioration of illness in men? Even the willingness to consider men unique, to look at their issues with the same exclusionary concentration that we have used in our exploration of women is shaping a whole new field of scientific investigation. Here are some of the more fascinating facts about men that are unique to their sex – facts that should prompt us to formulate and address proposals, and in doing so, improve the quality and, importantly, the length of men's lives.
Men have only one X chromosome. Women enjoy the luxury of two, in spite of the phenomenon of lyonization, in which one of the two is randomly chosen for inactivation and the genes carried on it extensively silenced. Some, however, remain active. These ‘surviving’ genes may have profound effects on structure and function, either directly or through their governance and modulation of other genes. Moreover, lyonization is incomplete until the time of implantation, and this double complement of the genes that are responsible for virtually every aspect of tissue organization and function may give the female not only a different early physiology compared with the male, but a distinct survival advantage. Lyonization also produces what might be viewed as a heterogeneous reserve of genetic material in the female, since the silencing of one of the pairs of X chromosomes is random and not the same for all cells. An equally fascinating difference between the two sexes is the result of the phenomenon of imprinting, in which some genes transmitted to the fetus are expressed only from the maternal allele and others only from the paternal allele. Since the female has an X chromosome from each parent, she can transmit both paternal and maternal X-linked genes; males can only transmit their X-linked genes to females and not to males. These are only a few of the profoundly important sex-specific aspects of mammalian biology that may have a far-reaching effects on function and length of life. It is clear that the male fetus is more fragile than the female and, for poorly understood reasons, becoming more so: even though there are more males conceived than females, the ratio of surviving males to females is decreasing throughout the industrialized world [7]. In Japan, for example, the male female ratio of miscarriage has increased steadily from 1.34 in 1972 to 1.72 in 1996 [8]. Certainly the molecular biology of fertilization and implantation would prove a fascinating and important area of future gender-specific investigation.
Even after his exit from the womb, the baby boy is at a developmental and survival disadvantage: developmental disorders are 3–4-times more frequent in boys [9,10]. Brain tumors in infancy [11,12] and some neurodevelopmental malformations are more frequent in males [13]. In a fascinating paper, Nagy and colleagues pointed out that male newborns had larger brains but that they were slower to mature than those of female neonates [14]. The boys in their study had a significantly lower resting heart rate than girls and lower body temperatures; and the authors suggested that the greater metabolic demands of boys' larger brains were not adequately met by their slower metabolism at this stage of development. Again, the comparison of simultaneously acquired data from both sexes in a single research protocol poses not only new information, but suggests new approaches to attacking such phenomena as developmental disabilities in boys – even to test the impact of amplifying the metabolic rate of newborn males on brain development might prove fruitful.
The vulnerability of the adult female to depression is well established and it is generally accepted that the incidence of depression in women is twice that of men. Nevertheless, successful suicide and violent death is much more common in the adolescent male than in his female counterpart; some of the violent ‘accidental’ deaths may, in fact, be the result of reckless risk-taking that is actually the consequence of depression. We have observed this lethal behavior in adolescent males for decades, but the conditions that produce it, whether societal or biological (or a combination of the two), require careful investigation. There is an inherent contradiction in our observation that the incidence of depression in adult females is double that of adult men, while adolescent boys kill themselves more frequently than adolescent girls [15,16]. Whether the tendency to violence and danger in teenage boys is a reaction to a much higher incidence of depression than we realize requires investigation. Alternatively, what Sebastian Kraemer has termed “a pattern of poor motor and cognitive regulation in the developing male leading to misjudgment of risk” might be at least part of the issue [17]. The biology that produces the superior judgment and better coordination of adolescent girls, if better understood, might lead to more effective therapies and/or interventions to preserve the lives of adolescent boys.
The constitutional fragility of adult men compared with adult women is sobering; we need to give more careful attention to the fact that men live shorter lives than women. By 1970 in the USA women's life expectancy was 8 years longer than men's [18]. However, the gap is narrowing: by the 1990s the gap for healthy life expectancy had narrowed to 4 years [19]. Nevertheless, men suffer in greater numbers than women from seven out of the ten most common infections that affect Americans (e.g., tuberculosis, Lyme disease and hepatitis A and B [20]), die twice as frequently from cardiovascular disease and die 1.7-times more frequently than women as a result of cancer [21]. The relatively weaker immune system of men and their propensity for developing coronary artery disease a decade sooner than is the case for women undoubtedly plays a role in this sex-specific vulnerability of the adult male. What protects the premenopausal woman from coronary artery disease is probably far more complex than hormones. If we could unravel the physiology that produces women's age-specific immunity from this illness (which kills twice as many men as women, and 75% of those men die before they are 65-years-old), we might find therapies that extend such protection to men.
Future perspective
Gender-specific medicine is not only about women. It is the systematic study of the differences in the normal function of men and women and in their experience of the same diseases. Its mission is to promote research that uses biological sex as an important variable in constructing scientific study protocols. The work we are doing now uncovers new information every day that is not just unexpected – it is astonishing. The differences between men and women are far more widespread than we had ever imagined. The potential significance of these differences makes it imperative to consider changing the way we care for patients in fundamentally important ways. It is essential to test whether or not the new science, if applied thoughtfully to the prevention, amelioration and/or cure of disease will improve the quality and length of human life. To that end, we are urging the systematic development of evidence-based recommendations in all the subspecialties of medicine, which will provide guidelines for optimal gender-specific care to patients. We have finished developing the first of such recommendations for the diabetic patient [22]. But as important as it will be to put those guidelines into practice, that is only half the task: we must also develop effective instruments for documenting patient outcome so that we can test whether or not such care actually improves or prolongs the sick patient's life. While it seems self evident that this new, fascinating and provocative information will certainly result in more effective therapies for disease, it requires solid outcome data to prove that this will be the case.
Persuading the world of healthcare professionals that studying women's unique biology would improve their lives has not been an easy task; many scientists and physicians are still not convinced that women are significantly different from men in any area except that of their reproductive biology. We expect no less difficulty in persuading the medical profession that the best way to care for both women and men will take into account their sex-specific, diverse, striking and, in almost every case, completely unexpected attributes. It will require convincing science, massive educational efforts of the professional and lay communities, and thoughtful assessment of what we achieve with each of the modifications we make.
Executive summary
The conviction that biological sex and gender are important determinants of human health is only 15 years old.
Our study of women has been imperfect and important gaps in our information remain; for example, the difficulties we have faced in the direct investigation of the premenopausal patient continue and have not been adequately addressed or remedied.
The effort to expand the discipline of women's health has been hampered by a commercialization and politicization of our efforts. For example, the mandate to include both sexes in human studies should logically be applied with the same rigor to research at other levels from work on populations of single cells to animal studies.
We have done a credible, if imperfect, job on developing a broader concept of the features of human biology that are unique to women. The same approach should now be extended to men and the wider concept of gender-specific medicine embraced at all levels from research to clinical care.