In this guide, whenever we use the medical term “vagina,” we’ll also include “front hole” as clinically recommended by researchers in the BMC Pregnancy and Childbirth journal.

The sine qua non of human sex designation in humans is chromosomal—all your cells either have two X chromosomes, making you female, or one X and one Y, making you male. End of story. But no: Instead, there’s various chromosomal disorders where individuals can be XYY, XXY, XXX, X, or XXYY. Most result in infertility; some, like Turner syndrome (in which there is solely an X) produce neurological, metabolic, endocrine, and cardiovascular abnormalities.

Much more interesting than these rare disorders is the recent finding that adult men typically have some XX (i.e., female) stem cells scattered throughout the body, which have differentiated into mature cells, including neurons. Meanwhile, women who have given birth to a son have a similar scattering of XY stem cells. Remarkably, during pregnancy, some maternal stem cells become incorporated into the fetus, some fetal stem cells into the mother. Thus, many of us are sex-chromosome mosaics (with, at present, unknown consequences).

Once sex chromosomes are determined, everything else about gender designation follows suit: XX versus XY determines whether you wind up with ovaries or testes. That determines whether it’s predominantly estrogen and progesterone, or testosterone in your bloodstream. The hormones you’re marinated in then determines which type of genitals you form as a fetus, as well as secondary sexual characteristics ranging from the chemical composition of your sweat to the workings of your brain. Chromosomal, gonadal, endocrine, genital, and phenotypic sex go hand in hand.

Except they don’t, as it turns out—there are numerous disorders where someone might be male in some of those ways, but female in others.

To begin with, chromosomal sex and gonadal/anatomical sex can disagree. In a syndrome called 46,XY DSD, people have normal male sex chromosomes, testes—genitals that are usually classified as male—plus a womb and Fallopian tubes. In ovotesticular disorder, the person has the sex chromosomes of one sex, but both ovarian and testicular tissue, producing ambiguous genitals. (...)

Hormones affect target cells by interacting with specific receptors (estrogen receptors bind estrogen, insulin receptors bind insulin). Another type of dissociation at the hormone level is seen with “testicular feminization syndrome,” where there is a mutation that inactivates the androgen receptor, which normally binds testosterone and DHT. Normal XY, normal testes, normal levels of the two hormones, but the hormones have no effects, producing a phenotype that ranges from ambiguous to female. In the latter case, the disorder is usually discovered around puberty, when the girl fails to start menstruating. She fails to start because, as it turns out, there’s no ovaries or uterus, the vagina dead ends, and way up in the stomach are testes pouring out androgens.

Thus there’s numerous ways where chromosomal sex and phenotypic sex differ, accounting for 1 percent of births. This is not rare—pick a human at random and the odds are greater that they were born with ambiguous intersex genitals than they have an IQ greater than 140.

Perhaps the most interesting dissociation occurs one step further down the line. This is where the person has the chromosomes, gonads, hormones, genitals, and secondary sexual characteristics—hair, voice, musculature, facial structure, the works—of one sex. But has always felt like the other. (...)

 
Makes sense to me and, i can think of lots of examples of the shading of gender in the general population.

EDIT: R_P, your comment was really helpful. I'll be reflecting on it

 
exactly. our understanding of the interaction of symptoms is also in it's infancy.

(...) This is the transgendered world, and some intriguing science hints at its neurobiological bases. There are a number of places in the human brain that are “sexually dimorphic” (where the size, structure, function, and/or chemical makeup of the area differ by sex). The differences aren’t big enough so that you could identify someone’s sex just by knowing the size of one of those regions. However, there are statistical differences between populations of men and women, differences with likely functional consequences.

So you have someone who by every measure discussed, from sex chromosomes to phenotype, is Sex A, but who insists that they have always felt like they are Sex B. What’s up in the sexually dimorphic brain regions? A number of studies report the brain bears a close resemblance to Sex B. And this shouldn’t seem surprising—we are determined by our brains, we are our brains, regardless of our pattern of facial hair, the thickness of our larynx, or what the landscape is like between our legs.

In other words, it’s not that transgendered individuals think they are a different gender than they actually are. It’s that they’ve had the profoundly crappy luck to be stuck with bodies that are a different gender from who they actually are.

Slowly, a word becomes pertinent—“continuum.” Gender in humans is on a continuum, coming in scads of variants, where genes, organs, hormones, external appearance, and psychosexual identification can vary independently, and where many people have categories of gender identification going on in their heads (and brains) that bear no resemblance to yours. All with a frequency that, while rare, are no rarer than various human traits we label as “normal.” (...)

Then there’s cases where a disconnect occurs at the level of hormones. One well-studied example concerns the fact that testosterone exerts some of its effects in target cells by being converted to a related hormone, DHT (dihydrotestosterone)—unless you have a mutation that inactivates the enzyme that does that conversion. This occurs in “5-alpha-reductase deficiency”; the individual is XY, has testes and normal levels of testosterone, but the person’s phenotype—their external appearance—can range from male to ambiguous to female. For those with a predominantly female phenotype at birth, there’s typically masculinization at puberty (the long-hidden testes descend, the clitoris enlarges, voice deepens). Clusters of cases of this disorder have been identified in some inbred, isolated populations (for example, in the mountains of the Dominican Republic) where, remarkably, there’s been a fair degree of cultural accommodation—“Honey, this is called puberty. Sometimes you get acne. Sometimes your clitoris becomes a penis. Whatever.”

while it's nice to find a biological basis to any presenting problem, I think that we have to be really careful about drawing too many conclusions at this point other than that "there appears to be a biological basis to this."

Our knowledge/understanding of the brain is in it's infancy.

while it's nice to find a biological basis to any presenting problem, I think that we have to be really careful about drawing too many conclusions at this point other than that "there appears to be a biological basis to this."

Our knowledge/understanding of the brain is in it's infancy.

 
this is a really good article.