Sex Cells: The Forgotten Biological Variable

Bethany T. Samuelson Bannow, MD
Assistant Professor of Medicine at Oregon Health & Science University in Portland, Oregon

The preponderance of the recently discovered COVID-19 vaccine–induced thrombotic thrombocytopenia (VITT) in women prompted several colleagues to reach out to me, a self-proclaimed “women’s hematologist,” to ask, “Why is this complication so much more common in women than men?” Truthfully, I had no answer except to point out that this is far from the first disease to present with such apparent inequity. Autoimmune and connective tissue diseases, in particular, are much more common in women than men, with lupus affecting up to 15 times more women than men.

Before delving further into this topic, it is important to address the difference between “sex” and “gender.” Gender is defined as “socially constructed and enacted roles and behaviors that occur in a historical and cultural context and vary across societies and over time.” Sex refers to biological differences between males and females, including chromosomes, sex organs, and hormones.1 All human cell lines have a sex and the biology and behavior of cells are demonstrably different between male and female cells, even cells from nonreproductive tissues.2 The National Institutes of Health (NIH) considers these differences so important that, in order to receive funding from the agency for research studies of vertebrate animals and humans, sex as a biological variable must be considered in the design, analysis, and reporting of those studies.

As hematologists, we are all aware of sex-determined differences in the presentation and management of diseases, particularly in the field of hemostasis and thrombosis. While von Willebrand disease is equally common in men and women, symptoms are more common and potentially more severe in women who experience bleeding challenges related to menstruation and childbirth.

Hemophilia, once thought to cause bleeding only in men, has proven to affect women as well, often severely. Individuals previously referred to as “carriers” may have factor levels in the same range as men with “mild” hemophilia due to differences in x-inactivation. Even those with factor levels in the “normal” range are frequently symptomatic, with excessive menstrual bleeding and postpartum and procedure-related bleeding that could not be predicted based on factor levels alone.

MRIs performed in older “carriers” have demonstrated evidence of chronic joint changes despite a lack of clinical evidence of acute joint bleeding. Such differences are also found with thrombotic disorders, and, importantly, change throughout a patient’s life. Young women are at higher risk of venous thromboembolism (VTE) compared with men of the same age, due largely to estrogen-related factors, while postmenopausal women have a lower risk compared with men. Women enjoy a lower risk of recurrence than men, especially for estrogen-provoked clots.

Lest we imply this is only true in “classical” hematologic diseases, sex is also an important biological variable in hematologic malignancy. Acute leukemia is more common in males, while non-Hodgkin lymphoma is less common, presents in different locations, and responds differently to treatments in women. Hematopoietic cell transplant (HCT) outcomes, including relapse, non-relapse mortality, and graft-versus-host disease, vary based on the sex of both donor and recipient. Symptoms, cytopenias, transfusion requirements, and disease duration differ between men and women suffering from myeloproliferative neoplasms.

While most of us can freely quote, or at least are aware of, data regarding these sex differences in our area of specialty, how many of us deeply consider the importance of sex when discussing these diseases with our patients? Likely only a few, reflecting that sex is, unfortunately, often an afterthought in the research studies upon which we base our diagnoses and management strategies. An analysis of studies in the American Journal of Physiology-Cell Physiology over a one-year period demonstrated that 75% failed to specify the sex of cells from human lines.2

While sex is almost always collected as a variable in clinical studies, it is seldom considered beyond inclusion in logistic regression models. Rarely, if ever, are results reported independently for men and women, and studies are almost never powered to detect differences in outcomes between sexes. As discussed in my Editor’s Corner in the February 2021 issue, “A Period Piece,” outcomes and functions unique to women, such as changes in menstruation, are rarely included in trial designs, even in the studies for which such data would be most relevant, as in those of anticoagulants.

So, how can we address this important issue if we lack the necessary data and if, as we all know, increasing study enrollment to power for differences between men and women is likely to be cost- and resource-prohibitive? We can start by being open with our patients, each other, and funding agencies about what we know and what we don’t know about the influence of sex as a biological variable on the diseases we treat.

We can also make a concerted effort to report outcomes by sex in both observational and interventional studies. In the future, meta-analyses of larger data sets may better inform the care we provide. We can call on our scientific and institutional review boards (IRBs) to suggest sex-specific reporting in their reviews. Finding data relevant only to one sex, when individuals of both sexes have been included, is, indeed, an ethical and scientific issue. We also can advocate for other funding agencies to follow in NIH’s steps and require consideration of sex as a biological variable in study design and reporting.

To improve reporting, the European Association of Science Editors (EASE) developed and published the Sex and Gender Equity in Research (SAGER) guidelines.3 These guidelines provide important suggestions for authors to address the role of sex and gender in every section of their papers and further suggest that editors of journals incorporate such guidelines into the peer review process. Few journals incorporate the SAGER guidelines into author instructions, but this does not prohibit individual authors, or even peer reviewers, from addressing these important issues.

Properly addressing the importance of sex as a biological variable in the care of patients with hematologic disorders will require everyone’s involvement, from those on the frontlines of patient care, in clinical and basic research, sitting on IRBs, reviewing grant applications, heading funding agencies, and editing journals. However, imagine if addressing such a simple variable could improve care and outcomes in patients suffering from conditions across the range of hematologic disease, from simple VTE to the most complex HCT. That’s a return on investment we could all appreciate.

Bethany Samuelson Bannow, MD
Associate Editor

References

  1. NIH Office of Research on Women’s Health. Accessed July 20, 2021. https://orwh.od.nih.gov/sex-gender.
  2. Shah K, McCormack CE, Bradbury NA. Do you know the sex of your cells? Am J Physiol Cell Physiol. Jan 1 2014;306(1):C3-18.
  3. Heidari S, Babor TF, De Castro P, et al. Sex and gender equity in research: rationale for the SAGER guidelines and recommended use. Res Integr Peer Rev. 2016;1:2.