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Does your next patient have a Y chromosome? The answer could impact the diagnosis more than you realize

As you walk to the parking lot with your mind still buzzing after a busy shift, you consciously sort through your last few patients: the coughing febrile preemie, the senior with new onset atrial fibrillation, the concussed soccer player and the stressed out law student looking for a sleeping pill before finals. As your weary brain flips through random snippets about CRPs and Canadian Head Injury Rules, it may skip over one of the more salient clinical features of each of these patients: their gender.

Most of us honestly think about gender as an important co-variable to disease presentation only in its most extreme examples. For example, most of our patients who were “minding their own business” right before they got shot, stabbed and rolled are likely guys. And a woman with a mangled hand from her first tangle with a snowblower is probably a JAMA case report. Similarly, when we think about diseases associated with women, our brains quickly default to what some experts refer to as “bikini medicine” or pathology associated with reproductive organs like ectopic pregnancy or PID. Realistically, how often do we or should we consider gender in other disease presentations such as stroke, infection or toxicology? Spotlight stage left and enter Dr. Marianne Legato, a pioneer in the world of Gender Specific Medicine (GSM).

Dr. Legato’s “Aha!” GSM moment came in the early 1990s when she was researching cardiac physiology at Columbia and the American Heart Association approached her to study gender differences in heart disease. At the time she, like most of her cardiology colleagues, believed that a vessel was a vessel and scoffed at the idea that it might behave differently simply because it resided in an XX or XY zip code. But as she began to appreciate significant gender differences in the molecular biology and cellular anatomy of cardiovascular disease her skepticism quickly faded. The clinical relevance was obvious: heart disease presented differently in women and they were being both under diagnosed and undertreated.

After finding gender differences in cardiovascular disease, Dr. Legato began to wonder what other gender based differences had snuck under the medical radar; she ultimately redirected her own career to focus on this search. Fast forward 20 years and Legato has become the world’s foremost expert in the rapidly expanding field of GSM. Her definitive textbook Principles of Gender Specific Medicine is in its second edition, she’s the founder of the journal Gender Specific Medicine, runs a partnership with Columbia on GSM and is author of several award winning and popular lay-public books including Eve’s Rib, and Why Men Never Remember and Women Never Forget. I recently had a chance to catch up with her between her clinical responsibilities (in her mid 70’s she still runs a private NYC internal medicine practice) and her duties as director of her Foundation for GSM.

Before proceeding, it is important to clarify the terminology sex and gender. While the public uses these terms interchangably, the Institute of Medicine, in its 2001 Report: “Exploring the Biological Contributions to Human Health: Does Sex Matter?” defined sex as a classification according to reproductive organs and functions assigned by chromosomal complement. Gender, on the other hand, refers to a person’s self-representation as male or female, or how that person is responded to by social institutions based on the individuals’s gender presentation.” While GSM incorporates the impact of both “sex” and “gender” on overall physical and mental health of an individual, most of the research referred to in this article pertains to the differences sex plays in health.

First off, Dr. Legato is very clear to state that GSM is distinct from Women’s Health. “Gender Specific Medicine is not some feminist push and is not just about women but about women and men equally based on the very fundamental knowledge that men and women are different in every system of the body in ways that we never anticipated.” Dr. Legato wants to focus on the science: “If we assume that men and women are interchangeable we are going to make gross errors as we did with our approach to CAD and it will essentially cause loss of human life.” But she does worry that sometimes the science gets lost in the details. For example, she recently traveled to Norway to review research grant applications. She found it odd that the Norwegians – who are incredibly progressive (Norway mandates that its companies have 40% women on their boards) – and who likely track the gender of the researcher in their grant approvals, had failed to consider the importance of sex in data outcome in the more than 150 grants that she reviewed.

Dr. Legato stresses that GSM-based studies lead to medical advancements that benefit both sexes. For example, by identifying and then studying disease processes in which women appear to have a distinct advantage like infectious disease, where women are better suited to battle off 7 out of the 10 most common illnesses, researchers can develop new innovative treatments geared towards men. Her book, Why Men Die First, focuses on GSM areas in which there is an increased male vulnerability. For example, birth ratios suggest that for every 105 males born there are about 100 females. (This falls outside of the totally skewed ratios found in countries where sex selective abortions are believed to have accounted for 100 million “missing” females.) But let’s rewind to conception ratios; Dr. Legato states that these may be as high as 240:100 male to females respectively! XY sperm may be less discriminative in egg choice and XY embryos may have an early advantage in uterine implantation. But male embryos also have a higher metabolic rate and are more prone to DNA mutations and miscarriage. In addition, they are more susceptible to the stress and nutritional status of the mother. Supporting this is an interesting little study by Catalano (Human Reproduction 2006) that examined NYC birth ratios in the months after 911 and showed them briefly dipping to 1. Women carrying boys are also more likely to get gestational diabetes, have nuchal cords and require C sections. Developmentally, boys are weeks behind their female peers at birth (mostly in lung development) and this “male vulnerability” continues across the human lifespan with men having higher mortality across all ages.

GSM got off to a late start in human subject research due to several ethically questionable well-publicized research trials that put women at risk. The federal government acted to “protect” vulnerable populations including pregnant women and women in general restricting their participations in most federally funded research. This was reversed in 1993 by the NIH Revitalization Act but prior research had assumed that men and women, outside their reproductive organs, shared similar pathophysiology. But this myth was quickly disproved as researchers actually began to analyze sex-based outcomes. The military, prompted by the large number of women who enlisted during the first Gulf War and a 40 million dollar congressional grant, was a big contributor to the early science of GSM. Ultimately military researchers published over 240 studies from this grant. Findings included dispelling the misconception that extremely fit women would suffer amenorrhea and bone loss; identification of gender specific incidence and location of stress fractures during basic training; and the demonstration that men and women could perform equally well in extreme weather conditions. A series of studies even highlighted the need for sex-specific equipment adjustment such as: backpack adjustment based on hip and shoulder disparities, helmet adjustment based on neck strength and cockpit instrumentation modification based on handgrip strength. This last item may resonate with female surgeons who suffer joint pain that developed over years of using laparoscopic equipment designed for men.

In the past 15 years, GSM has exploded and important differences have been discovered in literally every medical field. Notably absent from the GSM bandwagon, however, is the pharmaceutical industry. This seems somewhat odd because there are clear sex-based differences in drug pharmacokinetics and dynamics. For example, women secrete less stomach acid, have decreased GI motility, larger fats stores and slower glomerular filtration rates. Benzos, opioids, neuromuscular blockers, digoxin and warfarin are just a sprinkle of drugs that affect men and women differently.

What is likely to be the next big thing in GSM? Dr. Legato points to genomic medicine. Men and women share 99% of the 36,000 genes in the human genome (the Y chromosome contributes only 500 genes). However, it is becoming clearer that how those genes are expressed is dependent on their sex. “I think as people go forward and do not pay attention to the maleness and femaleness on the impact of genomic behavior, we are going to make the same ridiculous errors that we did before,” states Legato. A recent review by Morgan and Bale (Biology of Sex Differences) underscores her point and suggests that important differences occur at the cellular level based on whether you are genetically male or female.

So how is emergency medicine doing in the recognition of and contribution to GSM? In a review of almost 2500 EM articles, Safdar and company found less than 2% statistically analyzed for valid sex specific outcomes. Other fields like cardiology are way ahead with similar reviews showing sex-specific outcome analysis occurring in 24% and 50% of their articles respectively. Fortunately there is a core group of emergency medicine researchers dedicated to closing this gap. Dr Basmah Safdar and Dr Marna Greenberg have helped set up a GSM research network within Society of Academic Emergency Medicine (SAEM) and have spearheaded a 2014 GSM SAEM consensus conference. In addition, the Academy of Women in Academic Emergency Medicine (AWAEM) sponsors yearly GSM didactic lectures at the annual SAEM meeting. Finally, the Warren Alpert Medical School at Brown is the first ED to have its own dedicated GSM two year fellowship.

Returning to our original patients: If that coughing and wheezing febrile premee is a boy he is at greater risk for a bad outcome due to his prenatal testosterone causing a delay in his lung maturity. If the patient with afib is a woman, she is at higher risk to stroke out and her stroke is more likely to be hemorrhagic. In addition, she is at a greater risk for developing both a prolonged Qtc from certain anti-arrhythmics, and for digoxin toxicity. Not to mention that she will require smaller amounts of warfarin. What about that soccer player? Although there is conflicting evidence, several studies suggest that women are more susceptible to concussions and perform more poorly on post-concussive neurocognitive testing. Some of this may be related to anatomical differences in neck structure and the smaller size of a female’s shock absorbing lateral ventricle. And finally if you are going to write out an Ambien prescription for that stressed out law student remember to ½ the dose if the patient is female to prevent excessive residual AM drowsiness that may impair her ability to drive.

The National Academy of Medicine said it best, “Sex does matter. It matters in ways that we did not expect. Undoubtedly, it also matters in ways that we have not begun to imagine.”

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Answers: 1-Male; 2-True; 3-True; 4-False; 5-True; 6-Female; 7-False

 

 

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