Season 1: Sexual Differentiation 101
NB: Editor's Note
This series was conceived as a series of lectures to interested undergraduates. The course would be open to all, from freshman to graduate students and its class size limited only by the fact that no grades would be assigned, and no credit toward graduation. It is what educators call, "An enrichment course." Which is to say, it's likely to have little appeal to the ordinary student because there is no payoff in terms of GPA, professional school admissions or academic prizes. "Lectures" are planned to be interrupted by questions, but students who stand must ask a question, as opposed to making a speech.
Season 1: Sex and Sexuality--The Hook
When I was 24 years old, in 1971, and still a student, the faculty presented for consideration a case of a 16 year old patient who had not had a menstrual period. In medical terms, her problem was that of "primary amenorrhea."
She was lucky because she had been brought to The New York Hospital in Manhattan, which did not have much of an endocrine department, but it was home to a stellar biochemist, named Ralph Peterson, and the pediatric endocrine department had Maria New. In a very real sense, this patient had come to the perfect place to make her diagnosis.
This was before CT scans or ultrasounds, so her internal organs could only be examined by physical exam, and exploratory surgery, and she was found to have normal labia, a vagina which ended "blindly," which is to say, which had no cervix at the north end, and her clitoris was described as "a small phallus." She was sent to surgery where no uterus or fallopian tubes were found but gonads were located in the inguinal canals and on microscopic examination, "early spermatogenesis" was noted. Her breasts were normal pubertal female.
A karyotype, which is a picture (in those days, literally a photograph) of the patient's chromosomes, revealed the normal complement of 23 autosomes and an X and a Y chromosome.
The 2 main questions our faculty presented the students were:
A/ What is this patient's sex and its corollary: is there a difference between "biologic sex" and gender?
B/ What gender should this patient be "assigned?"
As students, we had learned enough to understand two things even before this riddle was presented us:
1/ We knew that during fetal life the collection of cells which start to form tissues, and ultimately recognizable organs, are something like Playdough, or wet clay, which start out as nubbins of primordial structures and gradually take shape into forms which we can see form, as gestation progresses into a heart, brain, gut and sexual structures and organs.
2/ With respect to sexual differentiation of primordial genitalia, in the absence of the effect of male hormones on developing tissues, the tissues "develop along female lines," which is to say, female is the default mode for our homo sapiens species. This is an important concept: without the action of male hormone on the nubbin of tissue which can become either clitoris or penis, the wet clay goes clitoris.
3/ The production of male hormones occurs as the downstream products of at least three separate assembly lines which occur in the ovaries, testes and adrenal glands. At the beginning of the line is cholesterol, sort like a base frame for an automobile, with protuberances where wheels, then tires can be added, and the rest of the product can be assembled at each station along the way, and what moves the thing along the line, at each step are workers called "enzymes." At certain points in the lines, the assembled structure can be diverted toward an SUV or a sedan or a sports car: working machines with very different functions, but the origins for all of these different end products has a common origin, cholesterol.
The key concept here is that if you throw a block anywhere along these assembly lines, or you may think of them as roadways, there is spill over into the other pathways, like cars bailing out of Rte 95 when an accident slows down traffic, or going back to the assembly line analogy, if the process runs into a slowdown at one point, the thing on the line gets diverted from the sedan route down another line to the SUV route, so a lot more SUV's get made in this factory than is normal.
What Ralph Peterson discovered, running this patient's blood through his lab, was that there was a block along the road to Testosterone because there was a deficit of a specific enzyme, and as a result precious little testosterone got made during the patient's gestation, and if not enough testosterone is not made, normal quantities of dihydrotestosterone, which is the next step beyond testosterone, are not made.) The entire androgen pathway was at least partially blocked.
The patient's parents told Dr. New their daughter had been a normal little girl, although, her mother added, "a classic tomboy." She had preferred playing with boys, chasing them around and shouting "Bang! Bang!" shooting them with her finger gun, and climbing trees and she liked her hair cut short and did not like dresses much. "I just never felt much like a girl," the patient said.
That, I thought, was perhaps a bit more than "classic tomboy" and her remark would come back to haunt me years later as the "gender dysphoria" discussion arose, where patients began to say they felt like a man trapped in a woman's body (or vice versa) but for this patient, there was no real note of desperation, just simple observation.
What had happened to the patient's genitalia was easy enough to appreciate: No androgen (male hormone) , no penis, no scrotum.
But what about her mind? Why did she not feel "much like a boy." This feeling stuff goes beyond structure to behavior, from anatomy you can see with your eyes to electrical activity in the brain.
The faculty had a hypothesis for that, but only a guess, really. They could measure hormone levels in the blood, but the brain is a black box.
The hypothesis was this: During life we all remember going through puberty, around age 12, or thereabouts, and we remember what that felt like. But actually, there are "three puberties" in a way, or at least three times when a surge in male hormones occur: Once around 6 weeks gestation, once shortly after birth to about 6 months and then the one we all know 12 years later.
The faculty guessed this girl had enough testosterone during fetal life to "condition" her brain in a male direction, and that was enough to cause "tomboy" behavior. They emphasized that this did not explain tomboy behavior in patients who had normal biochemistry, which is to say "normal tomboys" may be tomboys for any number of reasons, and often embrace their female roles enthusiastically, later on, but maybe this patient had just enough of a surge of male hormone at a critical time during fetal life to play a role in this particular patient.
So the answer to question A was clear enough. The patient's "phenotype" i.e., what she looked like, what her genitalia looked like, was different from her "chromosomal sex." When the phenotype does not match the chromosomes, or the internal glands, this is called "pseudohermaphrodism." When both female and male organs are found in one patient, that is called "hermaphrodism."
But what about question "B," her "gender"?
What should the doctors tell the patient, and her parents, about her gender? Is she a girl or a boy, will she grow into a woman or a man? What should she grow into? Or, in short, is she a "she" or a "he?"
In those days, there was no option for calling her a "they" or talking to the patient or her parents about "gender fluidity."
The students (90% male) voted for "male." She was "chromosomally male" we argued, so her "biology" was male and she should be raised a male and live her life as a male.
But the faculty had a different point of view: What do we mean when we say a person is "biologically" or "chromosomally" a male? We know the Y chromosome plays a role in sexual differentiation, but it does that by directing the production of certain hormones, and if the hormones that chromosome affects cannot be made, is the biology not altered? If the Y chromosome, for whatever reason, fails to do its job in directing the timely production of the right amount of the right male hormones, who is to say the patient is "biologically" a male?
And then there was the practical consideration, beyond any theory about what nature defines as a male: As one of the faculty members said, holding up her pinky, "If this patient's penis is never going to be any bigger than the tip of my finger, she is never going to function as a male."
The faculty had, in fact, done one more set of tests on the patient: they infused testosterone into her and she did respond to it by growing hair in male places, on her chin and face. So she could respond to testosterone; she just couldn't make much on her own, so she had "developed along female lines."
Defining her as "male" because she had a Y chromosome in every cell was narrow minded, the faculty argued. The Y worked through hormones and this patient could not make those hormones. The fact she had testes rather than ovaries meant she'd never be able to have a child, but she could have sex with the vagina she had.
Of course, in those days, the doctors felt they had to "assign" her a gender, but, even in 1971, ultimately, accepting that advice was up to the patient and her parents.
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