Show Notes for Podcast Eleven, Part 2 of seX & whY

Host: Jeannette Wolfe

This is a continuation of my interview with Dr. Cara Tannenbaum, Professor in the Faculties of Medicine and Pharmacy at the Université de Montréal in Canada, and Scientific Director of the Institute of Gender and Health of the Canadian Institutes of Health Research

Our discussion and the following table is centered around this recent review article by Dr. Tannenbaum found in Pharmacology Research 2017

Type of experiment

Traditional way

Better way

Stem cells

-Male cells

-Unknown sex of stem cells

-Problems: in immortal cell lines the integrity of in vivo sex chromosomes diminishes over time and can complicate the identification of sex- based differences.

Similarly, although normal female cells have two X chromosomes- one from the mother and one from the father- one of those chromosomes is usually turned “off”. With Stem cells however, after multiple reproductive cycles there can get something called “X skewing” in which instead of some cells turning off the maternal chromosome and others the paternal one, there is overrepresentation of one line.

Conversely in “X escape”, the second X chromosome is no longer getting inactivated and this can cause trouble because too much X gene is getting expressed (for example this could lead to significant autoimmune problems)

Use and record results of both male and female cell lines

Know sex & of donor

- Include cell lines with finite life spans

- Add sex hormones to XX and XY cell

- X chromosomes house genes that influence: cellular growth, metabolism and immunity

- Y chromosomes contain genes beyond SRY (which makes testosterone), and if loss Y chromosome increased risk of Alzheimers and certain cancers

Gendered Innovations group in Korea has actually labeled sex of commercial cell lines

Lab animal

Standard use of male animals

-80% of traditional research done on males

-Females felt to be too variable due to estrous cycle* (average of 4 days)

Inclusion of female animals**

-analyze data by sex

-include factorial designs that allow for the identification of age or hormonal influence in outcome

-Consideration of housing conditions that can lead to hormonal fluctuations

Phase trials

Change began with The NIH Revitalization

Phase 1 and 2

Currently it is believed that women still make up less than 25% of Phase 1

Include sex and age as independent variables

Further query if discovered sex differences are due to sex-based differences in pharmacokinetics (how our body’s characteristics like our weight or liver function influence the drug) or pharmacodynamics (how the drug influences our body)

Phase 3 trials

As it was believed that outside the reproductive organs that males and females were physiologically the same, most studies focused on males and thus side effects in females were often missed or underappreciated

Report and analyze data by sex and age

Use updated statistical models to calculate appropriate sample sizes prior to starting study so that any identified differences are likely to represent valid findings

Further explore hormonal states of study participants. For example, if they are pre or post menopausal, pregnant, or if they are taking hormones such as estrogen or testosterone.

56% of participants in drug trials submitted to FDA in 2018 were women

Phase 4

As this is further analysis of a drug after it hits the market, it can take a long time to pick up sex-based differences.

Poster child of this is Ambien in which dosing adjustment for women took 20 years

Analyze results from “real world” use of drug and its side effects by sex and age

Go back to lab to identify etiology of discovered sex or age differences

Adjust dosing when important differences are discovered

Click here for a paper that nicely summarizes the reasons behind why females were underrepresented in scientific research during the 20th century.

Other points

Important variables to consider when talking about biological sex
- Sex chromosomes
  - X chromosome contains 1669 genes
  - Y chromosome contains 426 genes
- Sex hormones
  - We all have testosterone, progesterone and estrogen it is the ratios that differ between men and women
  - Hormones influence us in two ways
    - The cocktail of hormones our brain is exposed to during prenatal and pubertal development leads to permanent wiring changes in the brain.
    - The fluctuating blips of hormones caused by multiple different triggers (like the estrous cycle or dominance posing) can lead to transient wiring changes.
    - Depending upon specific context organizational and activational hormones can potentially influence outcome data
    - There are new study designs that can help identify potential hormonal based differences that do not require an excessive sample size or budget
  - Age
  - Gender

What we do (and what society allows us to do) influences our epigenetics and future gene expression.

For example, our gendered professions- men work more in coal mines and women in nail salons- can influence stuff we are exposed to which in turn can influence are future gene expression. This is further complicated by males and females having potentially different DNA modifications after exposure to the same insult. Ultimately this can make it tricky to sometimes distinguish what is a sex- based difference versus a gender one.

The X chromosome has 1669 known genes on it and the Y chromosome 426 genes

Miscellaneous

2017 Tetris study on decreasing PTSD intrusive thoughts after C-section.

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