Sex as a Biological Variable: Who, What, When, Why, and How

Abstract

The inclusion of sex as a biological variable in research is absolutely essential for improving our understanding of disease mechanisms contributing to risk and resilience. Studies focusing on examining sex differences have demonstrated across many levels of analyses and stages of brain development and maturation that males and females can differ significantly. This review will discuss examples of animal models and clinical studies to provide guidance and reference for the inclusion of sex as an important biological variable relevant to a Neuropsychopharmacology audience.

Figure 1

How to examine menstrual cycle impact in human studies. Depicted is an idealized 28-day cycle, although studies for which menstrual cycle length is considered frequently include women with regular cycles from 25 to 34 days in length from day 1 (first day of menstrual flow) to day 1 (first day of menstrual flow) of the next cycle. If necessary, varying cycle lengths can be modified statistically to conform to a standardized 28-day cycle. However, the most straightforward way to assess changes in outcomes across the cycle or between phases is to target when a given women is likely to be in the hormonal and/or behavioral state of interest (Epperson et al, 2007; Comasco et al, 2014; Timby et al, 2016). Many women will have several days of spotting before experiencing a full flow. Whether investigators choose to consider any spotting as day 1 or onset of full flow as day 1 varies, but should remain consistent within a given study.

Figure 2

Sex differences in gonadal and pituitary hormones in middle- and late-aged adults. Data depicting general fluctuations in reproductive hormones across the life span from the typical age of late pre-menopause to the late post-menopause in women and age-matched men (Moroz and Verkhratsky, 1985; Liu et al, 2015). A rapid effect is indicated by two arrows. A slow or moderate effect on gonadal and pituitary hormones is indicated by one arrow.

Figure 3

Sex and gender differences across the life span. Based on preclinical and clinical research: (a) maternal and paternal life experience can impact fetal programming and offspring behavior in a sex-specific manner (Bale and Epperson, 2015; Rodgers and Bale, 2015). (b) Postpartum depression is associated with behavioral differences in female and male infants and young children (Azak, 2012; Kingston et al, 2012). (c) Neuropsychiatric conditions are more common among prepubertal males than prepubertal females. Limited early life stress may lead to resilience to depression among women (Zahn-Waxler et al, 2008). (d) Onset of sex differences in affective disorders and female-specific mood disorders at puberty. Ovarian hormones modulate brain neurochemistry, structure, and function (Shanmugan and Epperson, 2014; Hantsoo and Epperson, 2015). (e) Prenatal stress contributes to risk for diseases that exhibit sex differences across the life span (Goldstein et al, 2014). (f) Mid-life is associated with marked hormonal shifts for women, but not men. Estradiol effects on stress responses varies in pre- vs post-menopausal women (Dumas et al, 2012; Albert et al, 2015). (g) Females are at greater risk of dementia and adverse effects of many pharmacologic agents used in the treatment of adult disorders (Parekh et al, 2011; Franconi et al, 2012; Spoletini et al, 2012).

Figure 4

Masculinization of the male brain. In most mammalian species, testosterone is produced by the testes during testes development in late gestation. The presence of testes results from the testis-determining factor, Sry, on the Y chromosome that determines the direction the bipotential gonad develops. Circulating testosterone enters the brain and is aromatized to estradiol during this critical organizational window. Estradiol produces hosts of cellular effects to then ‘masculinize' the male brain.