Disorders of sex development expose transcriptional autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes. by Holterhus PM, Bebermeier JH, Werner R, Demeter J, Richter-Unruh A, Cario G, Appari M, Siebert R, Riepe F, Brooks JD, Hiort O. BMC Genomics. 2009 Jul 1;10:292.
BACKGROUND: Gender appears to be determined by independent programs controlled by the sex-chromosomes and by androgen-dependent programming during embryonic development. To enable experimental dissection of these components in the human, we performed genome-wide profiling of the transcriptomes of peripheral blood mononuclear cells (PBMC) in patients with rare defined "disorders of sex development" (DSD, e.g., 46, XY-females due to defective androgen biosynthesis) compared to normal 46, XY-males and 46, XX-females.Nothing terribly novel, except a way of testing something we already thought to be true. But every piece of the puzzle helps us become just a bit more confident in what we think we know. To say that this kind of thing is still "unproven" or "controversial" is, I think, inaccurate now. There's too much evidence, from too many independent sources, in too many different disciplines. I think we have a good handle on sexual development now.
RESULTS: A discrete set of transcripts was directly correlated with XY or XX genotypes in all individuals independent of male or female phenotype of the external genitalia. However, a significantly larger gene set in the PBMC only reflected the degree of external genital masculinization independent of the sex chromosomes and independent of concurrent post-natal sex steroid hormone levels. Consequently, the architecture of the transcriptional PBMC-"sexes" was either male, female or even "intersex" with a discordant alignment of the DSD individuals' genetic and hormonal sex signatures.
CONCLUSION: A significant fraction of gene expression differences between males and females in the human appears to have its roots in early embryogenesis and is not only caused by sex chromosomes but also by long-term sex-specific hormonal programming due to presence or absence of androgen during the time of external genital masculinization. Genetic sex and the androgen milieu during embryonic development might therefore independently modulate functional traits, phenotype and diseases associated with male or female gender as well as with DSD conditions.
How neurological anatomy leads to sex identity, that we're less sure of. That trans people have cross-sexed neuro-anatomy, we know. But exactly what areas are affected, and by how much, that's less well understood. We know some areas quite well, others not. And it's not a simple "male or female", there's degrees, and trans people appear to have some neuro-anatomy that matches neither sexual stereotype. This basic research, not concentrated purely on neuro-anatomy, but anatomy generally, may help us understand why, and how this anomaly occurs.
I think that some further work on what happens during puberty is going to be our next challenge: the extent to which hormones can affect anatomy long after foetal development is complete. The externals are obvious, but the BSTc layer of the hypothalamus, a "touchstone" for sex identity, only differentiates during puberty. And it does so regardless of whether in a masculine or feminine hormonal bath. In trans people, a masculine hormone bath still produces a feminine outcome, (or the reverse for FtoMs). If we understood why that is so, what causes the pre-destined outcome, I think we'd have a good grasp of the whole picture. We know it's pre-destined, because the signs of transsexuality are visible long before puberty, in general. What we don't know is why, what is the mechanism.