What determines biological sex?

Biological Sex Determination

Biological sex is primarily determined by the complement of sex chromosomes (X and Y), with females typically having two X chromosomes and males having one X and one Y chromosome, though this interacts with multiple genetic, hormonal, and environmental factors that influence physical and physiological characteristics. 1

Chromosomal Sex Determination

• Chromosomal sex is defined by the X and Y chromosome complement, with females typically having two X chromosomes (XX) and males having one X and one Y chromosome (XY) 1
• The Y chromosome contains the SRY gene (Sex-determining Region Y), which triggers testicular development in embryonic development 2
• Variations in sex chromosome complement are not uncommon, occurring in approximately 1 in 400 to 1 in 1,000 individuals 1
• These variations contribute to phenotypic sex differences but are often overlooked in research 1

Beyond Chromosomes: Multiple Determinants

• Biological sex encompasses multiple dimensions beyond chromosomes, including:
  • Gonadal development (testes or ovaries) 2
  • Hormonal influences throughout development and life 1
  • External and internal genitalia 1
  • Secondary sex characteristics 1
• No single variable or trait completely defines biological sex; it encompasses many dimensions 1

Genetic Mechanisms in Sex Determination

• The SRY gene on the Y chromosome initiates a complex genetic cascade leading to testicular differentiation 2
• Other genes play crucial roles in male differentiation, including SOX9 and FGF9, which contribute to testicular cord formation 2
• In females, certain genes influence ovarian development, though this pathway is less well understood than the testicular pathway 2
• Only a minority of sex-reversed cases can be explained by mutations in known genes, suggesting many genes influencing sex determination remain undiscovered 2, 3

Differences of Sex Development (DSD)

• Individuals with differences of sex development (DSD) or intersex individuals may be born with varying presentations of male and female genitalia 1
• These conditions challenge the binary notion of biological sex 1
• Genitalia and gonad development occur as the result of genetics, hormones, and environmental factors 1

Clinical Implications

• Understanding sex determination is crucial for:
  • Diagnosing and managing differences of sex development 1
  • Developing sex-specific medical treatments 1
  • Recognizing sex differences in drug pharmacokinetics and adverse events 1
• Females are nearly twice as likely to develop adverse drug events, some requiring hospitalization, likely due to sex differences in drug metabolism 1

Important Distinctions

• Sex and gender are different but related concepts that are frequently incorrectly used interchangeably in research 1
• Sex refers to biological attributes while gender refers to socially constructed roles, behaviors, expressions, and identities 1
• Neither sex nor gender is strictly binary, and both can be defined in multiple ways 1
• Understanding both biological sex differences and gendered environmental differences is key for developing efficacious and safe therapies for all 1