Exploring how biological sex and gender influence our brain, body and behavior.

Dr. Jeannette Wolfe, MD

Body Pod

This “pod” is dedicated to the field of Sex and Gender Based Medicine (SGBM). This area will explore how biological sex influences our physiology and pathophysiology (how our bodies function when they are healthy and sick) and how gender influences our overall health. Historically, those of us in medicine were taught that outside our reproductive organs that men and women were essentially the same and that any results gained from studying males, who were considered better research subjects due to their lack of monthly hormonal fluctuations and inability to become pregnant, were simply equally applicable to females.

Of course we now know that science was wrong. Not only do male subjects – whether lab rats or humans – have their own hormonal fluctuations but many times when men and women are exposed to the same infection or same treatment plan their bodies simply react differently. Although we are just at the beginning of truly understanding the extent of some of these differences, now that we have actually started looking for them we are finding- from stem cell research in the lab to clinical care at the hospital- some totally unanticipated and often important results.

A great example of this is the story behind the sleeping pill zolpidem (brand name Ambien). In 2013, more than twenty years after its initial FDA approval, the makers of zolpidem decreased its suggested starting dose for women from 10mg to 5mg. To understand why,  we need to take a crash course in the science of pharmacokinetics and pharmacodynamics.

In simplified terms, pharmacokinetics is the study of how bodies impact a drug.  Our size, age, genetics and confounding illnesses can affect how certain drugs are absorbed, distributed and broken down. For example, we would never consider giving the same dose of Tylenol to a baby as to a 50 year-old. Our biological sex can also affect pharmacokinetics and in zolpidem studies in which men and women took the same dose, women had up to 40-70% more drug in their blood stream compared to men.

One of the major currently believed causes behind this sex based pharmacokinetic difference is that zolpidem appears to get broken down by an enzyme called alcohol dehydrogenase (yes the same one that breaks down alcohol) in our stomach and livers. This enzyme appears to be revved up by testosterone and it is theorized that younger men most likely break down more zolpidem (and alcohol) before it gets into their blood stream. This correlates with FDA data showing that 8 hours after ingestion of a 10mg tablet, approximately 1 in 6 women versus 1 in 33 men had blood levels of zolpidem above 50ng/ml, a level associated with driving skills on par with those of a drunk driver.

Besides absorption differences, zolpidem also appears to have a pharmacodynamics difference. Pharmacodynamics is the study of what a drug does to our body and when men and women have the same amount of zolpidem in their blood stream, it appears to do different things to women than it does to men. Specifically, women appear to have more cognitive impairment with decreased reaction time and decreased ability to concentrate.

The result is a perfect storm in that, dose for dose, women compared to men, appear to get higher blood levels and greater impairment from zolpidem. Ok, so why did these differences not get picked up during zolpidem’s original drug development trials over 20 years ago? Well, because nobody really looked.

In the 1970s – in response to the horrific congenital malformations caused by thalidomide and to the public outrage associated with the discovery of a bunch of nationally funded research projects (think Tuskegee syphilis trial)- the government enacted a series of laws geared to  protect certain “vulnerable” populations (women of child bearing age, children and prisoners) from being involved in potentially abusive or dangerous human research studies. Although well intended (remember, we truly believed that study results in men should equally apply to women) this essentially removed most women from early stage drug development trials which are where initial dosing and side effect profiles are commonly identified.

Although the FDA eliminated these restrictions in the 1990s, we still have a lot of catching up to do in identifying potential sex based differences in medications. For example, a 2001  study revealed that the majority of drugs taken off the market had unanticipated and significant side effects that were more likely to occur in women and a 2011 study revealed that >75% of participants in early drug trials were still men and that even when women were included results were often not analyzed for potential sex based differences. An important note here, although including some women in trials and seeing if there is an obvious sex based difference in results is an important first step, it is far better science to statistically design trials upfront to ensure that enough women and enough men are actually studied so that results likely reflect a real difference and not a random fluke.

So the above discussion focused on biological sex based differences. If we dig a little deeper however, there is also a gender difference associated with zolpidem.  This is because women are more likely to go see a doctor for sleeping problems; women are more likely to be given a prescription for a sleeping pill; and women are more likely to be taking other sedating medications that could dangerously enhance the effect of a sleeping pill.
The bottom line is that both biological sex and gender can affect our health and it’s time that their potential influence is consistently considered in medical research and drug development.

To explore other ways in which biological sex and gender influence our medical care, I invite you to play the below jeopardy-like game that our Sex and Gender in Emergency Medicine Interest group developed for our national academic conference to help engage our colleagues in this work.

The SAEM Jeopardy game was created by the Sex & Gender in Emergency Medicine Interest Group, the Academy of Women in Academic Emergency Medicine, and Academy of Diversity and Inclusion in Emergency Medicine. It was played during the 2018 Society of Academic Emergency Medicine’s national meeting.

How to play

  •  Download and click open

  • Click on “slide show” tab and then “play from start” in top left hand corner

  • Main game board starts on slide 9 

  • Click on any money amount to go to question

  • After you read the question put your cursor over the “go to answer” area in bottom right hand corner of screen and click 

  • Some answers cover several slides, if you see the word “next” in the right lower corner of the screen click on it to go to an additional answer slide. When the question is fully answered you will see a house signal in the bottom middle of the screen, clicking it will take you back to the main board  

  • To reset the board, press escape (to get out of slide show mode) and close the presentation (press red bottom above “home” on left upper corner of screen) and then reopen

Enjoy and share!