ASHEVILLE, North Carolina — What makes a woman and what makes a man; what is male and what is female? What was once a very taboo subject in our culture, only seriously (and quietly) contemplated by doctors and researchers, is becoming dinner-table talk with the new, greater visibility of transgender and intersex people. Perhaps a little thought experiment can add to this conversation?
Say that Sarah is an ordinary woman inside and out. When would she stop being a woman, a female, and what would it take to make her a male, a man? Consider:
DNA: Let’s exchange one of Sarah’s X chromosomes for a Y. Would this make her a male, a man? Not necessarily. Androgen Insensitivity Syndrome is an intersex condition in which a person’s body is unable to respond to testosterone. So their body does not masculinize from the default female form of all mammals, including humans. With Complete Androgen Insensitivity Syndrome (CAIS), Sarah is a girl to all outward appearances: she is assigned female, usually knows herself to be a girl, and is raised as a girl. Then as she approaches womanhood, it is discovered that she cannot menstruate and is sterile; further investigation reveals her to be a female with XY DNA. 
There are also instances where the SRY gene (the short arm of the Y gene) malfunctions  and does not stimulate the production of male internal genitalia, so this XY girl will never have testes, for example. And because she will not produce testosterone, her body will never take on male form, like the CAIS child she may discover she is an XY female when she reaches adulthood.
The Y chromosome has surprisingly little influence in humans and other mammals. We all start out life in female form. The first (and main) purpose of the Y chromosome is to “trigger” the creation of an initial burst of testosterone in a developing child (who will later pass on that gene in reproduction). The window for this is probably very small  and sometimes it doesn’t happen. With this “spark,” the body is changed so it can create more testosterone to do the rest of the work, much like the proverbial farmer pulling himself up by his own bootstraps.
Gonads: Okay, let’s give Sarah some testes. Various combinations of X and Y genes can do this, as can faulty XX genes. Another way Sarah could develop testes is because she might have the DNA of two (or more) people in her: chimerism,  which is quite rare, but happens. Yet another possibility is that her gonads might be a blend of ovaries and testes known as ovotestes , and as their owner she would be hermaphrodite (an outdated term). Like virtually all of our sexual anatomy, male “bits” develop from existing female structures. Testes and ovaries develop from the same fetal tissue, for example.
Hormones: the two main groups of sex hormones in the animal kingdom are estrogens and androgens. These are amazingly similar chemically and like other hormones, their job is to “signal” various tissues in the body – they act as a catalyst, as switching agents. It is interesting to note that humans (and other mammals) produce both hormones, and our tissues are selectively sensitive to these hormones. For example, human breasts are very sensitive to estrogen, while our facial hair is very sensitive to testosterone (hormones cause permanent changes in both of these). Depending on when the exposure to one or the other happens, the path of internal and external development may be altered, and it matters not whether the hormones come from inside the body or from outside. For example, between weeks 9 and 11, testosterone will change the default female genitalia into male form. In the next week after this, the female brain exposed to testosterone is rewired into male pattern.  It is because these changes are ordered in stages that a person can have the genitalia of one sex and the brain wiring of another. These things comprise our primary sex characteristics.
Puberty is the next big hormonal event, and during this period the body develops secondary sex characteristics: bone structure changes in male and female typical ways, testosterone enlarges the voice box, hair develops in male or female pattern and texture, and soft tissues like musculature and fat distribution make a child into the recognizable form of an adult woman or man. Again, if testosterone is absent, blocked or replaced, the child’s form (regardless of their primary sex characteristics) will develop along female lines in response to the estrogen normally produced by all humans. In puberty, some of these changes are essentially permanent: one’s skeletal structure is finalized, which determines things like one’s overall size, the width of hips, the lengths of arms and legs. Breasts normally develop under the influence of estrogen (or don’t when testosterone “swamps” the estrogen). Genitalia mature in size and shape; fertility begins. Puberty has an additional influence on the brain’s basic wiring, further pushing in the male direction or leaving it to further mature as female.
Hormones are the chief agent for making us female or male in our phenotype — they make us look and function like men or women. They also deeply influence our initial brain structure, which lays the biological foundation for how we think and feel as gendered humans.
Even after development, the loss or cross-replacement of hormones can change one’s secondary sex characteristics to the extent of changing soft tissues and developing undeveloped structures. Thus an XY person can re-shape into a female form with breasts, generally residing on the “boyish” end of appearances, and hormones can influence some of the plastic/pliable parts of the person’s brain.
Internal genitalia: What if Sarah did not develop a uterus or fallopian tubes? This can happen with various intersex conditions like Congenital Adrenal Hyperplasia (CAH). In this condition, an XX person masculinizes, which can mean missing or undeveloped internal genitalia. And there are other, far more common, non-intersex reasons why women may be missing their inner “bits.” Does this make them a male, a man? 
External genitalia: Few people realize that our genitalia (both internal and external) develop from the same tissue. So, for example, the scrotum forms from tissue that would otherwise be a labia majora. The penis and clitoris are likewise related. Much of sex distinctive male and female anatomy is homologous.
Sarah might be a one of the approximately 1 in 100 children born with ambiguous genitalia. It might be hard to tell if she is a girl or a boy at birth, and it may require further testing to get an idea of where Sarah resides on the spectrum of male and female sex characteristics. Regardless, early in childhood, Sarah will naturally begin to manifest an innate gender identity — the brain wiring will begin to be revealed with Sarah’s self expression as it blossoms in its social environment.
Social rearing: What if Sarah is raised as a boy? What if her genitalia were ambiguous enough that she was “marked” as a boy and everyone treated her that way? The social pressures involved are as insidious and pervasive as they are powerful, and anyone who deviates from these expectations (in many cultures) can expect generally harsh, even lethal treatment. Does Sarah’s rearing determine whether she is a girl or boy, and whether she will grow to be a woman or man?
Gender expression: Now let’s say that Sarah likes boy stuff, she’s “rough and tumble,” is always “hanging with the boys” and generally eschews girl things. Does this make her a male, or a boy, and if she continues into adulthood, does this make her a man?
Thinking patterns: What if Sarah likes math and science and is really good at it. What if she makes up in spatial reasoning what she lacks linguistically? What if she doesn’t seem to take interest in children and domestic life? What if her “maternal instinct” is all but missing? What if she relates to things more than people? Does this make her a boy or a man?
Sexual orientation: What if Sarah has no interest boys? What if her sexual interest is in girls, and later, women? Does this make her a boy or man?
So far we have listed many things about Sarah, and our hypothetical female is representative of millions of actual women alive today. Female people could have any or many of the aforementioned things missing and/or going on in their lives and still be women.
So when does Sarah become Sam?
Gender identity: this is our innate sense of who we are as a person. Do we sense (think/feel) ourselves to be female or male (or something else)? Our sense of who we are is core to our selves as human beings, and after decades of research and clinical experience, the consensus is that prenatal biology is the largest determiner of our sense of our gender. Parents and society can support or undermine a person’s gender identity, but cannot fundamentally change it. Like other innate parts of our personhood that we discover about ourselves, we can be forced to suppress or repress this, but we cannot change our “spots” at that deep a level — as a “computer system,” our BIOS chips are fixed. 
A few decades ago, it was all the rage in psychology and medicine to assume that one’s sense of gendered self could be changed through child rearing and cosmetic surgery. Amazingly, this ground-shaking view was based on a single study of two children, twins, and it ended in the tragic suicides of both people when one of the twins underwent a forced sex change.  This tragedy, through its failed assumptions, has hurt uncounted people to this day, no doubt contributing to many suicides.
Who gets to say what a given person’s gender identity is? Only that person can speak for themself. How often are we reminded that the brain is the body’s largest, most important sex organ?
And if Sarah identifies as Sam? What if this person, who to everyone else seems to be Sarah, the girl, the woman, knows themself to be Sam? Sam is the head of a complex being of many parts; none of those parts are able to think, feel or speak to Sam about who Sam is as a person. Neither Sam’s vagina, nor uterus, nor ovaries think, feel or speak for the rest of the human being who knows himself to be Sam. How much less can a parent, a friend, a government, a church, a society tell Sam that he is really Sarah? That Sam has probably been negatively pressured by all of these entities will be a major source of Sam’s difficulty on moving past the “Sarah presumption” to live his life as himself. Sam is a man, and so whatever else may be said about Sam’s body, it is the body of a man …
… or as pediatrician, William Reiner MD formerly of Johns Hopkins expressed:
“In the end it is only the children themselves who can and must identify who and what they are. It is for us as clinicians and researchers to listen and to learn. Clinical decisions must ultimately be based not on anatomical predictions, nor on the ‘correctness’ of sexual function, for this is neither a question of morality nor of social consequence, but on that path most appropriate to the likeliest psychosexual developmental pattern of the child. In other words, the organ that appears to be critical to psychosexual development and adaptation is not the external genitalia, but the brain.” 
And now we know when she becomes he.
Here are some places where interested readers may learn more. Caution! Many of the pictures in these articles are Not Safe For Work (NSFW).
Very first, there is a great introductory documentary to intersex conditions that may be viewed for free online called: “Me, My Sex and I” (http://topdocumentaryfilms.com/me-my-sex-and-i/)
The US Library of Medicine has general information on the topic of Intersex: (https://www.nlm.nih.gov/medlineplus/ency/article/001669.htm)
1 The Wikipedia entry on Complete Androgen Insensitivity Syndrome as a detailed summary of this condition with pictures and numerous scholarly references.
2 Embryo development: External and Internal Genital Organs
Fetal Development (http://www.baby2see.com/gender/external_genitals.html)
Developmental Disorders of the Female Reproductive Tract (https://www.nlm.nih.gov/medlineplus/ency/article/001497.htm)
Ambiguous Genitalia (https://www.nlm.nih.gov/medlineplus/ency/article/003269.htm)
3 A Critical Time Window of Sry Action in Gonadal Sex Determination in Mice, Ryuji Hiramatsu1, Shogo Matoba1, Masami Kanai-Azuma2, Naoki Tsunekawa1, Yuko Katoh-Fukui3, Masamichi Kurohmaru1, Ken-ichirou Morohashi4, Dagmar Wilhelm5, Peter Koopman5 and Yoshiakira Kanai1 (http://dev.biologists.org/content/136/1/129.short)
6 Sexual differentiation of the human brain: Relation to gender identity, sexual orientation and neuropsychiatric disorders, Bao, Ai-Min; Dick F. Swaab (18 February 2011). Frontiers in Neuroendocrinology 32 (2): 214–226.
7 In extreme AIS cases XX people become phenotypically male much as CAIS people become phenotypically female, again due to hormonal influences.
8 Sexual differentiation of the brain and behavior, D.F. Swaab (http://www.sciencedirect.com/science/article/pii/S1521690X07000334)
BIOS is the computer acronym for Basic Input Output System and it is the program upon which all other programs in a computer depend.
9 Wikipedia has a good summary of the “John/Joan” case of David Reimer (https://en.wikipedia.org/wiki/David_Reimer)
10 To Be Male or Female-That is the Question, William Reiner MD (http://web.missouri.edu/~segerti/2210/GenderIdentity.pdf)
(Photo credit: Wikipedia)