It’s a boy! Or is it? Variability in human gender development. Cynthia J. Gill, Ph.D. University of Texas

Androgen-receptor deficient male (TFM)

Sex determination and differentiation Objectives Distinguish gender as defined by various criteria. State the critical factors for reproductive system differentiation. Predict the result of variations during development.

Chromosomal sex (genetic sex) XX or XY, Y has SRY gene Gonadal sex (gametic sex) ovary or testis (eggs or sperm) Hormonal sex estrogen or testosterone Morphological sex Behavioral sex (internal and external genitalia, 2° sex characteristics) (brain morphology, behavior) Gender identity “I am male” or “I am female”

Gonad and internal genitalia differentiation

Cascade of events in development of male

Synthesis pathway for steroid hormones 5  reductase

Sex differentiation: cascade event rules SRY gene determines testes development Testes make testosterone and MIS Testosterone differentiates Wolffian ducts MIS inhibits Müllerian duct differentiation Testosterone masculinizes external genitalia but full differentiation is by DHT

Identify the sex determination and/or differentiation: XY XX XY with absent SRY gene XX with SRY gene XY with no functional androgen (T & DHT) receptor XX with hypersecretion of testosterone XY with no 5  reductase enzyme Gonads: testes or ovaries? Internal genitalia: Wolffian or Müllerian duct development? External genitalia: male-like or female-like?

How would you decide who is ‘male’ and who is ‘female’ for gender-separate sports events in the Olympics?

Pathways of adrenal hormone synthesis.

Sexual Differentiation: gonads Every embryo initially has two undifferentiated primordial gonads The Y chromosome directs development into male gonads, testes The absence of the Y chromosome causes development into the female gonad, or ovary Sexual differentiation: Internal Genitalia Each embryos has two sets of internal organs, the Wolffian and the Mullerian ducts The Wolffian ducts are the precursors of the male internal genitalia, and develop under the influence of testosterone The Mullerian ducts are the precursors of the female genitalia and develop unless Mullerian inhibiting substance is present

Sexual differentiation: External Genitalia Both male and female embryos have protruding tufts of flesh called the genital tubercle, urethrogenital folds, and labioscrotal swellings In the male body, testosterone is converted to dihydrotestosterone, the androgen that converts the embryonic external genitalia into the penis and scrotum In the absence of dihydrotestosterone, the external genitalia become female