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Abstract

Gender-specific medicine is a new discipline. It has made significant progress over the last couple of decades, which has the potential to transform not only medicine but also the pharmaceutical industry and global healthcare. This article explores some of the most important ethical and legal aspects associated with implementing the principles of gender-specific medicine. This will require that the biopharmaceutical industry focuses on biological sex differences that play an important role in human disease and will mandate changes in global healthcare systems as well. Since drug discovery and development is a very complex, expensive, and time-consuming process that involves not only the biopharmaceutical industry but also entrepreneurs, regulatory bodies, federal funding agencies, private investors, advocacy groups, and nongovernmental/philanthropic organizations, this commentary analyzes how gender-specific research can move from the laboratory bench to the patient's bedside. We will also explore the disease areas most suitable for investigation to begin this translational process. We will discuss the ethical considerations involved in the genetic manipulation of human embryos. Finally, we summarize the driving forces for the full incorporation of gender-specific medicine into clinical practice.

Gender-Specific Medicine's Imminent Coming of Age

Gender-specific medicine, despite being a fairly new discipline, is an area of medicine that has made significant progress in the last couple of decades. It continues to amass a great deal of evidence about the abundant and in many cases unexpected biological differences between men and women. Thanks to great advances in genomics, molecular and cellular biology, biochemistry, physiology, immunology, neurobiology, and pharmacology—to mention just a few adjuvant disciplines—we can say with all certainty, that these biological sex differences, which start at the level of the genome, play a fundamental role in normal human function and the unique ways in which males and females experience the same diseases. They also explain the sex-specific response to treatment.

The dimorphism that we observe in the morphology, the physiology, and even sometimes the behavior of humans is not only due to the differential action of sex hormones but is also encoded in our genes. At least 6500 genes are expressed differently between men and women, and this differential expression may be crucial in evolution as well as in health.¹ During development, at least 15–23% of the genes in the silenced X chromosome escape inactivation, which may explain some of the phenotypic differences observed between the sexes that cannot be explained by the action of sex hormones alone.^2,3 We have also learned that some autosomal chromosomes can be directly and indirectly controlled by sex chromosomes^4,5 and this phenomenon is crucially relevant to human sexual dimorphism. Furthermore, we know that there are epigenetic events, such as methylation among many others, that play a role in the transcriptional pattern of genes and these epigenetic events lead to phenotypic differences between sexes.⁶ Hormonal factors also play a crucial role in determining both the physical sexual characteristics of individuals as well as their psychological identification with their biological sex and/or with their sexual behavior.⁷ These new findings have taught us that every single organ in the human body, including the reproductive organs, functions differently in men and women. There are some disorders that are sex specific or sex biased. Others affect males and females with equal frequency, but their mechanisms of action and manifestations differ between the sexes (Table 1). Importantly, there is a large body of evidence that demonstrates that humans metabolize and respond to drugs differently, according to sex.^8,9

Table 1.

List of Selected Diseases That Are Either Gender Specific or Gender Biased

	Men	Women
Diseases affecting only one sex	• Prostate cancer and other diseases of the male reproductive system. • X-linked recessive disorders, including the following: - Red-green color blindness - Hemophilia A (factor VIII) - Hemophilia B (factor IX) - Duchenne muscular dystrophy - X-linked agammaglobulinemia - X-linked ichthyosis - Becker muscular dystrophy - Nonspecific X-linked mental retardation • X-linked dominant disorders include the following: - Fragile X syndrome • Others - Male pattern baldness - Type II mucopolysaccharidosis - Klinefelter's syndrome - X-linked adrenoleukodystrophy (Lorenzo's oil) - Micropenis - Diseases that are caused by a defective Y chromosome or by a defective number of them (such as 47, XYY syndrome; 48, XYYY syndrome; and 48, XXYY syndrome).	• 99% of breast cancer occurs in women. • Ovarian cancer and other diseases of the female reproductive system occur only in women. • Endometriosis, another female reproductive disorder, occurs almost exclusively in women, but has rarely been found in men undergoing estrogen treatment for prostate cancer. • X-linked dominant disorders include the following: - Rett's syndrome
Sex-biased diseases	• Abdominal aortic aneurysms are six times more common in men, and thus some countries have introduced screening for males at risk of suffering the condition. • Autism is approximately four times more prevalent in males than females. • Psychologists are more likely to diagnose men than women with antisocial personality disorder and substance-abuse disorders. • More males are diagnosed with Parkinson's Disease	• More women than men suffer from osteoporosis. • Autoimmune diseases, such as Sjögren's syndrome, scleroderma, multiple sclerosis, and many others, are more prevalent in women. An estimated 75% of those living with autoimmune diseases are female • In Western cultures, more women than men suffer from eating disorders such as anorexia nervosa and bulimia. • Alzheimer's disease has a higher rate in women than in men. • Women are more likely to suffer from unipolar clinical depression (although bipolar disorder appears to affect both sexes equally) • Psychologists are more likely to diagnose women than men with borderline or histrionic personality disorder. There is no current agreement on whether this is because of a real underlying difference between the sexes or simply because of deeply ingrained social attitudes.

There is a third category of diseases, such as cardiovascular disease, type 2 diabetes, and cystic fibrosis, which occur in equal number in men and women, but the manifestation or severity of the symptoms varies between them. Adapted from Sánchez-Serrano in Legato's Principles of Gender Specific Medicine (Academic Press, 2017).

This new view of biology completely transforms our traditional views of the homogeneity of the human body, particularly those concerning the way in which men and women adapt to the environment and how diseases affect them. Accordingly, one would expect that gender-specific medicine is considered a central area of research in the life sciences—especially in the pharmaceutical industry drug discovery and development arena—and that it is a comprehensive part of the global healthcare system programs. In reality, this is not the case, even though nowadays, at least in the United States, pharmaceutical companies are required to include women in their clinical trials and submit to the regulators information regarding sex-related differences/reactions observed during clinical trials,¹⁰ and even when the World Health Organization includes gender and genetics as part of their programs.¹¹ Although I have discussed elsewhere the reasons for this current state of affairs,¹² I would like to mention here four important points that might account for this apparent lack of interest in gender-specific biomedical research: first, this may be due to insufficient knowledge and understanding of the discipline by academics, medical practitioners, scientists, drug developers, investors, and the general public at large; second, this may be due to lack of information about many of the biological mechanisms underlying sexual dimorphism in normal or diseased phenotypes; third, the assumption that gender-specific medicine is only about the male and female reproductive organs or endocrine systems; and, fourth, the pharmaceutical industry's misconception or fear that developing drugs based on biological sex differences may not only be more costly, time-consuming, and complex but also represent fewer profits if efficacy is different for one sex compared to the other. Yet, there is plenty of scientific evidence supporting the fact that biological sex plays an important direct and indirect role in human disease,^8,13–16 even if at times the molecular mechanisms involved in pathogenesis in either sex have not been elucidated or fully understood. In fact, the role of biological sex-specific differences in human disease is particularly relevant to the pharmaceutical industry's current efforts and interest in precision and personalized medicine. If anything, gender-specific medicine actually opens up a new, broad field of opportunity.

However, besides potential commercial and financial advantages, gender-specific research highlights some important ethical, legal, and socioeconomic concerns associated with access to and the delivery of healthcare. Ethical concerns, because in our current healthcare and biopharmaceutical systems, some drugs are probably being administered without adequate testing for sex-specific efficacy and safety. Past examples of this situation include thalidomide (Thalomid), which in the early 1960s had been licensed as a tranquilizer in Europe, though not in the United States, but was responsible for serious birth defects in the children of women who had taken the drug during pregnancy. More recent examples are illustrated by the results of the 2001 Government Accountability Office study, which found that 8 of 10 drugs removed from the market from 1997 through 2000 posed greater health risks to women.¹⁷ For instance, the antihistaminic terfenadine (Seldane, Hoetchst Marion Russell; now Sanofi) and the gastrointestinal drug cisapride (Propulsid, Janssen-Ortho), both triggered a potentially fatal heart arrhythmia more often in women than in men and for that reason were withdrawn from the market. The drug, troglitazone (Rezulin, Daiichi Sankyo), an antidiabetic and anti-inflammatory, increased the risk of liver failure in women.

Needless to say, the legal consequences of providing a drug that may create serious adverse events and complications, including death, which could have been avoided if the biological sex element had been better understood, could be disastrous for any biopharmaceutical company. The economic outcome is no less serious, because limited healthcare resources are being wasted treating a patient who either will not benefit from a given drug or will actually endure significant harm from its use. The resultant increased consumption of healthcare resources and the societal impact of disability add to the socioeconomic burden of drug misuse.

From a global healthcare perspective, we need to take into consideration Article 25 of the United Nations' Universal Declaration of Human Rights of 1948, which states that “Everyone has the right to a standard of living, adequate for the health, and well-being of himself (herself) and of his (her) family, including food, clothing, housing and medical care, and necessary social services.”¹⁸ The World Health Organization's Constitution states that “the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being.”¹⁹ Fundamental human rights include the principle of nondiscrimination, which seeks “to guarantee that human rights are exercised without discrimination of any kind based on race, color, sex, language, religion, political or other opinion, national or social origin, property, birth or other status such as disability, age, marital and family status, sexual orientation, and gender identity, health status, place of residence, and economic and social situation.”¹⁹ Therefore, access to gender-specific medical care is an inalienable human right.

All of these pose the question of how to address the principle that the consideration of biological sex differences in medicine is a human right. And based on this, how do we steer the life sciences, the biopharmaceutical industry, and global healthcare toward a more profound consideration of biological sex differences in human disease? To begin to develop answers to this conundrum, let us briefly review what it takes to develop a novel drug.

Research and Development

The fundamental driving force toward a greater focus on gender-specific medicine is research: basic, applied, and translational. Also, the way to integrate the results of such research into the operation of the pharmaceutical industry (and, by implication, global healthcare) is through advocacy founded on solid scientific data. We also need to educate and convince the biopharmaceutical industry that more investment in gender-specific medicine will eventually represent financial and political/propaganda benefits for them, while increasing our knowledge and treatment of human disease. This will lead to a permanent and positive change in world health because of the quintessentially important role that the pharmaceutical industry plays in the global healthcare systems and in the world's healthcare crisis.²⁰ Thus, given the life-death implications associated with how well we recognize and improve our information of biological sex differences and their impact on the political–economic interests at stake, the real changes will start at the pharmaceutical industry level.

According to the Tufts Center for the Study of Drug Development, in general, it takes, on average, between 10 and 15 years and over 2.558 billion U.S. dollars to develop a new drug.²¹ However, these figures are controversial given that they take into account the complexity and size of clinical trials, including the significant attrition of subjects and the expected returns that investors forego while a drug is in development. These and other factors, such as whether the drug is developed by a pharmaceutical or a biotechnology company, impact the actual expenditure. In any event, drug discovery and development is much more than pouring money, time, and effort into applied research. It is actually an ecosystem that requires (1) an academic/innovative base, made up of universities and research centers; (2) an industrial base, constituted by drug companies (“big pharma” and “biotech”); (3) a regulatory infrastructure, embodied principally by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA); (4) a financial/investment platform, represented by private investors (such as venture capitalists and institutional investors); and (5) a public base such as government-sponsored research agencies (i.e., the National Institutes of Health [NIH] and the U.K. Medical Research Council), philanthropic organizations, and advocacy groups. Contrary to what is usually assumed, that is, that drug development is the sole role of the pharmaceutical industry, each one of the five sectors mentioned in this study performs a vital role in drug discovery and development, and without one of them, the drug creation machinery would not function.²⁰

Following this pharmaceuticals development framework, let us examine the current state and challenges of gender-specific medicine, observing that for some of the agents involved in drug development, gender-specific data have already been integrated into the process.

On the academic front, we have a significant number of scientists all over the world, working on all facets of gender-specific medicine, from genetics to behavioral sciences, trying to develop an understanding of the biological mechanisms/environmental factors that explain the dimorphism that we observe. More funding for basic academic research and the legitimization of gender medicine as a solid academic activity, which will interest tenure-track researchers into this field, are still needed, as well as more academia–industry/private–public sector interaction.

In the public domain, two important policies have taken place, one at the FDA, which in 1993 published guidelines requiring that women regardless of their premenopausal or postmenopausal stage be included in clinical trials. It also called for studies of sex differences at the earliest stages of drug development, as well as for analysis of clinical trial data by sex.²² The second policy is the NIH's 1999 “Agenda for Research on Women's Health for the 21st Century,”²³ which called for further assessment of sex-related differences in pharmacokinetics and pharmacodynamics. At present, the FDA has a division focused on women's health named the Office of Women's Health.²⁴ So, both the FDA and the NIH mandates cover two very important and critical bases that pave the way for further research in basic and translational science, which is paramount for drug discovery and development. Equal interest in male-specific issues is still needed, since men have shorter life spans than women, are more vulnerable to some diseases, and face enormous challenges even at the early stages of development and before birth.⁷

On the other hand, the biotech and pharmaceutical industries have not entirely neglected gender-specific medicine. They have developed a number of drugs in the areas of reproductive medicine, diseases associated to the male and female reproductive organs (including various types of gender-specific cancers and sexual erectile dysfunction), and treatment for some genetic diseases that happen to be gender-specific (Table 2). Also, at least in the United States, the industry's compliance with the FDA and NIH mandates on biological sex differences is an important step in data collection. However, the biopharmaceutical industry (and by extension, the diagnostic and medical device industries) has not totally embraced gender-specific medicine, which should be part of a systematic and comprehensive approach to studying disease. For instance, some studies have recently demonstrated that major cellular pathways involved in the pathogenesis of Parkinson's Disease present different patterns of deregulation between males and females, with more prominent downregulation of genes related to oxidative phosphorylation, apoptosis, synaptic transmission, and transmission of nerve impulse in the male population,²⁵ all of which are in accordance with some clinical observations that Parkinson's Disease progression and presentation are biased toward the male sex. This type of observation is extremely valuable in obtaining a better understanding of the molecular basis of this disease and may have important implications in the development of pharmaceutical products used for its treatment.

Table 2.

Selected List of Gender-Specific Pharmaceutical Drugs

Drug name	Developer	Indication	Sex
Mestranol/norethynodrel (Enovid^®, “The pill”)	G.D. Searle & Company	Oral contraceptive	Women
Trastuzumab (Herceptin^®)	Genentech	HER2/neu-positive breast cancer	Women
Abiraterone acetate (Zytiga^®)	Cougar Biotechnology/Janssen Biotech	Prostate cancer	Men
Alosetron (Lotronex^®)	Prometheus Laboratory	Irritable bowel syndrome	Women
Sildenafil (Viagra^®)	Pfizer	Erectile dysfunction	Men
Idursulfase (Elaprase^®)	Shire	Mucopolysaccharidosis type II (Hunter syndrome)	Men

Multiple Internet sources.

Other illnesses, such as Alzheimer's disease,²⁶ cardiovascular disease,^14,27 and some autoimmune disorders²⁸ develop and evolve through very complex, but different biological pathways in males and females. For example, in some cases, such as in autoimmune diseases, environmental factors (such diet, contact with some infectious agents and chemicals, life-style, etc.) interact with the genotype to influence the prevalence, expression, and severity of disease. Disorders of sexual development (DSD) and the health issues associated with the hormonal treatment of transgender individuals are also important subjects of interest. DSD and transgender patients have the same rights to adequate healthcare as any other individual—something that is often ignored. All these areas represent novel and exciting frontiers for the biopharmaceutical industry.

It is important to keep several other factors in mind: further progress in gender-specific medicine will significantly depend on the selection or development of adequate animal models in which gender-specific hypotheses might be effectively tested. The way in which clinical trials are, in general, conducted will have to become highly modulated and more “adaptive” based on known biological sex differences identified prior or during the clinical trials. Again, this will require close collaboration between academia and industry and effective translational research.

In terms of advocacy groups, we have a number of foundations all over the world focused specifically on men's or women's health, gender-specific sports medicine, genetic and orphan/neglected disease disorders, and even a foundation for gender-specific medicine. However, except for the Foundation for Gender-Specific Medicine,²⁹ all the others work, understandably, in silos. It is very important that advocacy groups, private foundations/philanthropic institutions, and the World Health Organization establish communication with the goal of securing collaboration and to come up with a list of the haves/haves not in the field, and identify ways of meeting unmet gender-specific medical needs. In fact, patient groups (as well as health systems that are partners with the pharmaceutical industry in clinical trials) are now playing an active role beyond advocacy, including actual financing of drug development, especially in rare diseases. This was the case, for instance, with the Cystic Fibrosis Foundation financing Kalydeco³⁰ with Vertex, and thus bypassing big pharma. Patient opinion leaders and online communities are now collaborating in clinical trials and conducting their own observational studies, as in the case of PatientsLikeMe³¹ and its 600,000 members. The importance of patient-reported outcomes in collecting real-world evidence is covered in several policy journals, such as Health Affairs and Value in Health.^32,33 These initiatives are becoming a novel and important model for improving drug development.

The areas where funding and interest are crucially needed for the full realization of gender-specific medicine are in the field of private equity investment and entrepreneurship to take basic academic science in gender-specific medicine from the laboratory bench to bedside, in a so-called “pure play” manner. However, here again, we need a clear understanding of the biological sex mechanisms that affect human disease, not only to incentivize entrepreneurs and private investors but also to justify the inherent risks associated to the undertaking of investment in drug discovery and development in this field. So, it is very important that universities establish ways for scientists working in gender-specific medicine to communicate their findings to technology transfer officers of their respective universities and to the venture capital community. We also need consortia dedicated to biomarker development in gender-specific medicine or their inclusion in the agenda/portfolio of the consortia that already exist, of which there are several. In fact, the creation of a human biological sex differences map ought to become a priority in the life sciences. In these areas, advocacy groups and philanthropic organizations can provide the necessary driving force.

Now, assuming that there is genuine interest by all the players mentioned above to take gender-specific medicine to the next level, what areas within gender-specific medicine should we focus on at this stage?

Gender-Specific Biopharmaceutical Development

Since we have three different scenarios in gender-specific medicine (sex-specific disorders; disorders that are biased toward one sex; and diseases that affect people of opposite sex in similar quantity, but with different characteristics), one might start by picking the “low-hanging fruits,” that is, diseases that are better characterized as evidently sex specific or sex biased, those for which clinical trials would have clearly defined endpoints, and those on which the pharmaceutical industry is already working, but without any consideration of sex differences. We also need to find a match between particular disease areas, unmet medical needs, and commercial opportunities. The field of genetic disorders is a case in point. Many genetic diseases are not only gender specific, but orphan and pediatric disorders, which could provide developers with great advantages such as access to public and private funding, easy collaboration with academia, orphan-disease status application, accelerated FDA review and approval, market exclusivity for seven years, and so on. This area has important implications for healthcare, for it means, in general, saving the life or immensely improving the child's living conditions.

Another potential area could be the field of male-specific or biased disorders, which overall have received significantly less attention to women's disorders (Table 3), even if up until recently (and even now), pharmaceutical drug discovery and development has been focused on males as experimental models.

Table 3.

Male-Biased Diseases

1. Abdominal aortic aneurysm, 2. Actinic keratosis, 3. Acute myeloid leukemia, 4. Alcohol abuse, 5. Alopecia, 6. Amyotrophic lateral sclerosis, 7. Anaplastic thyroid cancer, 8. Ankylosing spondylitis, 9. Antisocial personality disorder, 10. Aortic aneurysm, 11. Attention deficit hyperactivity disorder, 12. Autism, 13. Barrett's esophagus, 14. Benign prostatic hyperplasia, 15. Bladder cancer, 16. Burn, 17. Club foot, 18. Corneal abrasion, 19. Dupuytren's contracture, 20. Ectodermal dysplasia, 21. Emphysema, 22. Epilepsy, 23. Esophageal cancer, 24. Gastritis, 25. Golfer's elbow, 26. Gout, 27. Cardiovascular disease, 28. Hirschsprung's disease, 29. Hodgkin's lymphoma, 30. Hypospadias, 31. Inguinal hernia, 32. Kaposi's sarcoma, 33. Kawasaki disease, 34. Kidney cancer, 35. Kidney Stone, 36. Kyphosis, 37. Leprosy, 38. Liver tumor, 39. Meningococcal disease, 40. Multiple myeloma, 41. Myocardial infarction, 42. Myocardial Ischemia, 43. Nephrotic syndrome, 44. Nongonococcal urethritis, 45. Non-Hodgkin lymphoma, 46. Obstructive sleep apnea, 47. Paget's disease of bone, 48. Pancreatic cancer, 49. Parkinson's disease, 50. Pectus excavatum, 51. Prostate cancer, 52. Pyloric stenosis, 53. Retroperitoneal fibrosis, 54. Sebaceous cyst, 55. Seborrheic dermatitis, 56. Stroke, 57. Syphilis, 58. Tetralogy of Fallot, 59. Tinea pedis, 60. Transient Ischemic attack, 61. Urethritis, 62. Urolithiasis, 63. Ventricular tachycardia.

Ranker. Available at www.ranker.com/list/male-diseases-with-this-risk-factor/reference. Last accessed on September 29, 2017.

Autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, among many others in the same category, and neuropsychiatric disorders, such as depression—all of which are female sex biased—are so debilitating and take such a huge toll on human health and the quality and length of life that we really require a global effort to address them on multiple fronts. Though the clinical trial endpoints for cardiovascular disease and central nervous system disorders are sometimes difficult to define, we know as a fact, as mentioned already, that cardiovascular diseases, Parkinson's disease, and Alzheimer's affect men and women differently, and so do metabolic syndrome-associated conditions such as Type 2 diabetes, hypertension, and hypercholesterolemia.^14,34,35 Even the relationship between cardiovascular disease and diabetes differs between men and women.^14,36,37

Although some understanding of the basic mechanisms responsible for these differences has already been achieved,³⁸ we still need to develop new tools, including biomarkers and novel diagnostics, to determine in more specific ways how these diseases affect men and women. This will help to incorporate the knowledge at multiple levels within clinical trials, especially in Phase I and Phase II, in which safety and efficacy are tested for, respectively. However, we also need the same strategy for Phase III clinical trials and postmarketing surveillance. Some types of cancers other than the ones affecting the reproductive organs, such as bladder and kidney cancers,³⁹ are gender biased and affect more men than women. One wonders how many other cancers actually present in a sex-biased way. More research will reveal many more differences in the pathogenesis of disease between men and women; this will represent a boom for the diagnostics and medical devices industries as well, while representing important commercial opportunities for the pharmaceutical industry and significant progress in global healthcare. Gender-specific medicine will even become part of relevant preventive and public health programs.

Finally, important research on the genomic editing of early-stage human embryos⁴⁰ and on embryonic stem cells, such as the “synthetic human entities with embryo-like features” (SHEEFS) or human-like “embryoids,”⁴¹ has been recently reported in different parts of the world. This research employs significant and novel genetic engineering tools and opens ups new ways to study what happens at the molecular and cellular levels during the early stages of human development. The fact is that a large amount of our missing knowledge on how biological sex affects normal and abnormal human development, health and disease, and bodily function is due to prohibitions against experiments on early-stage human embryos. These novel technological advances will facilitate, in an unprecedented manner, the study of many sex-determining and sex-related events that take place early on in the development of humans (as opposed to the currently used rodent models), and they should help develop treatment strategies for important health problems such as genetic disorders, infertility, or miscarriage. Although very strict ethical guidelines about the manipulation of human embryos are already in place in most developed countries, the specter of eugenics is always present in such experimentation, and the potential of these new techniques raises new ethical concerns. The dangers and bioethical implications of this kind of research deserve special consideration and dialogue. Without question, it will provide a very fertile battlefield for litigation and debate in the years to come before international consensus is reached.

In summary, it is clear that gender-specific medicine is at an inflexion point and that its coming of age is imminent, as are the ethical, legal, and socioeconomic issues associated with it. These issues cannot be hidden and need to be urgently discussed and addressed. The way to move forward is through education (including the patient, the researcher, and the healthcare provider) with more investment allocated to research at the basic, applied, and translational levels. In this process, communication and collaboration between academia, the biopharmaceutical industry, private investors, and government, and of advocacy/philanthropic groups are crucial.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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