6 Sexual Development and Puberty
Recap: the HPG axis
The lecture opened with a memory test on the hypothalamus–pituitary–gonadal (HPG) axis from the previous lecture (the questions are in Check yourself at the end). The slide that followed showed the axis as a reminder.
The hypothalamus releases GnRH, which acts on the pituitary. The pituitary releases LH and FSH, which act on the gonads (testis or ovary) to produce testosterone. The enzyme aromatase converts testosterone into estrogen. Testosterone and estrogen act back on the pituitary and the hypothalamus; as the previous lecture showed, when too much of them binds to receptors in the hypothalamus, GnRH release drops (negative feedback).
The objectives for this lecture were to:
- describe both the typical and the non-typical pathways of sexual development;
- understand why the term “biological sex” is limiting and misleading in its scope;
- describe common exceptions to typical sexual development, and what they tell us about the distinction between sex and gender identity in humans.
Dimensions of sexuality in humans
Genetic sex, chromosomal sex, gonadal sex, gender identity and sexual orientation are related but separable concepts. Sexual orientation and gender identity have complex potential biological and genetic underpinnings. The reason to study these questions is to increase our understanding of the human brain, behaviour and psychological processes. It is not to “fix” something that has gone “wrong” developmentally.
Chromosomal and genetic sex
Parents pass on 23 chromosome pairs to their offspring: 22 autosome pairs and 1 sex chromosome pair. The slide pictures the two usual sex-chromosome pairs: an X with a much smaller Y (XY), and two X chromosomes (XX).
Definition 6.1 (Chromosomal and genetic sex). Chromosomal sex is which sex chromosomes a person carries (typically XY or XX). Genetic sex depends on the SRY gene (“Sex-determining Region on the Y chromosome”), which the Y chromosome typically carries. SRY gives the body the instruction “make testis”. In the absence of SRY, ovaries develop.
Sexual development can then be followed down four levels: chromosomes, the SRY gene, the gonads, and the external genitalia. The slide’s drawing of the external genitalia at 15 weeks of gestation labels the epididymis, seminal vesicle, prostate, penis and scrotal swelling on the male side, and the clitoris, labia minora, labia majora and vagina on the female side.
Exceptions in the sex chromosomes
There are many exceptions to traditional genetic and chromosomal sex. Four common ones:
| Condition | Chromosomes | Appearance | Prevalence | Other features | Gonads | Fertility |
|---|---|---|---|---|---|---|
| Klinefelter syndrome | XXY | masculine | 1 in 500 | less body hair; wide hips, long arms and legs; feminine pubic hair pattern | small testes | infertility common |
| XYY syndrome | XYY | masculine | 1 in 1000 | cognitive difficulties | testes present | often normal |
| Turner syndrome | X (a single X) | feminine | 1 in 2000 | short stature | variable ovary function | infertile |
| XXX syndrome | XXX | feminine | 1 in 1000 | deficits in verbal skills | ovaries present | often normal |
Gonadal sex: how the reproductive tract differentiates
Gonadal sex is differentiated by genetic sex. At 6 weeks of gestation the fetus is still undifferentiated: every fetus has the same set of structures, labelled on the slide as the gonad, the Wolffian duct, the Müllerian duct, the kidney, the urogenital sinus, the genital tubercle and the genital fold.
What happens next depends on SRY.
- In the presence of SRY, the gonads develop into testes. The testes release anti-Müllerian hormone, so the Müllerian duct regresses. Testosterone makes the Wolffian duct develop into the male internal reproductive tract and makes the penis and scrotum develop. The slide’s drawing at 8 weeks labels the testis, vas deferens, bladder and glans penis; at 15 weeks, the epididymis, seminal vesicle, prostate, penis and scrotal swelling.
- In the absence of SRY, the gonads develop into ovaries. With no anti-Müllerian hormone, the Müllerian duct develops into the female internal reproductive tract; with no testosterone, the Wolffian duct regresses and the clitoris and labia develop. The drawing at 8 weeks labels the ovary, fallopian tube, uterus, bladder and glans clitoris; at 15 weeks, the clitoris, labia minora, labia majora and vagina.
The SRY gene isn’t so simple
What if an XY individual lacks a functional SRY gene (for instance, the SRY gene doesn’t develop on the Y chromosome)? The person is XY, so chromosomally male. With no SRY there is no testis, so the person is genetically and gonadally female. With no testis, the phenotype (the body’s observable traits) is feminine.
What if the SRY gene is translocated (moved) onto an X chromosome in a person with XX? The person is XX, so chromosomally female. SRY makes testes develop, so the person is genetically and gonadally male. The testes produce a masculine phenotype.
So chromosomal sex and genetic sex can come apart: what sends the gonads down one path or the other is whether a working SRY gene is present, wherever it sits.
Gender and sexuality
Definition 6.2 (Gender identity, sexual orientation, sexual identity). Gender identity is a person’s internal sense of who they are, with identity terms shaped by social and cultural understandings of gender and sex (for example gender non-conforming, agender, trans- or cis-woman, trans- or cis-man).
Sexual orientation is a person’s attractions or desires (bisexual, homosexual, asexual, heterosexual, and so on).
Sexual identity is the sociopolitical label or community that a person adopts or associates with (queer, femme, gay, heterosexual, asexual, and so on).
Example 6.3 (The sex assignment of David (Brenda) Reimer: a case of mistaken identity). An accident during circumcision left one of a pair of twin boys with little penile tissue. The psychologist John Money recommended sex reassignment in childhood, and the child was raised as a girl, Brenda. At puberty Brenda took estrogen and progesterone supplements. Throughout, he always “felt” like a boy, not a girl. When his parents finally told him what had happened, he stopped taking the hormones and lived his life as a man, David. Being assigned and raised as a girl, with female hormones at puberty, did not change his gender identity.
The slide shows a photograph of David Reimer as an adult and the cover of John Colapinto’s book about him, As Nature Made Him: The Boy Who Was Raised as a Girl.
Intersex conditions
Definition 6.4 (Intersex). A person is intersex if they are born with a reproductive or sexual anatomy that doesn’t seem to fit the typical definitions of female or male.
Intersex has a prevalence of about 1.7%, which makes it more common than being red-haired in the USA. The lecture looked at three intersex conditions: congenital adrenal hyperplasia (CAH), androgen insensitivity syndrome (AIS), and 5α-reductase type 2 deficiency (the guevedoces).
Congenital adrenal hyperplasia (CAH)
In congenital adrenal hyperplasia, the adrenal gland releases too much testosterone (and related androgens) before birth, because of a deficiency of the enzyme 21-hydroxylase.
- In XY individuals it has minimal effect on sexual development.
- In XX individuals it causes ambiguous genitals, irregular or absent periods, and infertility.
- Other effects are early puberty, problems with blood pressure and with the response to stress, and relatively short stature.
Females with CAH typically identify as girls or women, and they are significantly more likely to prefer women as sexual partners.
Androgen insensitivity syndrome (AIS)
Recall that, typically, when testes are present the Wolffian ducts develop, the Müllerian ducts regress (anti-Müllerian hormone), and the penis and scrotum develop (testosterone).
The main feature of androgen insensitivity syndrome is a dysfunctional androgen (testosterone) receptor. In an XY individual the SRY gene is present, so testes develop and the Müllerian ducts regress as usual. But because testosterone binds poorly to its receptors, it produces less masculinization of the internal reproductive tracts and of the external genitalia. The result is a feminine phenotype, and the person is infertile.
People with AIS often identify as women, and often prefer men as sexual partners.
5α-reductase type 2 deficiency: the guevedoces
The name guevedoces means “eggs (testes) at twelve”. The condition occurs in genetically isolated populations, for example a remote village in the Dominican Republic. Affected individuals are XY males with a deficiency in the gene for the enzyme 5α-reductase type 2, which converts testosterone into dihydrotestosterone (DHT). So they have low levels of DHT, the hormone that normally masculinizes the genitals. At puberty, though, the testes secrete enough testosterone to masculinize the external genitalia.
The enzyme labels in the pathway are gene names: SRD5A1 and SRD5A2 are the genes for 5α-reductase types 1 and 2, and the deficiency blocks the step from testosterone to DHT.
In the studied populations, many affected individuals were raised as girls, and many adopted a male gender role and identity after their bodies masculinized (virilized) at puberty. Outcomes vary. The slide shows a photograph of an affected young man after puberty.
Gender and neurobiology
The BNST (bed nucleus of the stria terminalis) contains a sexually dimorphic nucleus, one that differs between the sexes: it has a large population of cells in men and a very small one in women. Among transgender individuals, the size of this nucleus matches the gender they identify as, not the one they were assigned at birth, and this is independent of hormonal treatments.
The slide shows four stained brain sections through this nucleus (the dense patch labelled BSTc, beside the lateral ventricle, LV). It is large and dense in the cisgender man and small in the cisgender woman. In the transgender woman it is small, matching her gender identity. The fourth panel, labelled “transgender man” on the slide, shows a large BSTc.
A related observation concerns phantom sensations, the feeling that a body part is still there after it has been removed. After genital surgery, transgender women report phantom penile sensations far less often than men who lose the penis for other reasons.
Atrazine feminizes frogs
Atrazine is an endocrine-disrupting pesticide (one that interferes with the hormone system) that is widely used in agriculture. This is the work of Dr. Tyrone Hayes. Atrazine chemically castrates and feminizes genetically male frogs:
- 10% of genetically male frogs develop into sexually functional female frogs.
- The remaining males are castrated, with suppressed mating and decreased testosterone.
The slide’s graphs compare control males (Con) with atrazine-exposed males (Atr). Body weight did not differ between the groups across four trials. Successful amplexus (the mating clasp of frogs) dropped sharply, from 11 in controls to 2 in atrazine-exposed males, a significant difference. Testosterone levels in most atrazine-exposed males fell below the dashed line at about 7.5 ng/ml, many of them at zero, while most controls were above it. Photographs from the study show the frogs’ reproductive anatomy and mating pairs.
Check yourself
Question 6.5 (The HPG axis (memory test)). Draw out and label, or at least describe, the HPG axis, labelling the anatomical structures, the key hormones secreted from each part, and how those hormones stimulate or inhibit other regions.
Show solution
The hypothalamus releases GnRH, which stimulates the pituitary to release LH and FSH; these stimulate the testes or ovaries to make testosterone, which aromatase converts into estrogen. Testosterone and estrogen feed back on the hypothalamus and pituitary and inhibit GnRH release (negative feedback).
Question 6.6 (Broken receptors (memory test)). What may happen if GnRH receptors aren’t working properly? What about if estrogen receptors aren’t working?
Show solution
Without working GnRH receptors the pituitary can’t respond to GnRH, so little LH and FSH are released and the gonads make little testosterone and estrogen. Without working estrogen receptors in the hypothalamus the negative feedback signal is lost, so GnRH release (and with it LH, FSH and the sex hormones) stays high, while estrogen’s own effects on the body are lost.
Question 6.7 (Aromatase (exit discussion)). What happens anatomically if the enzyme that converts testosterone to estrogen (aromatase) is overactive? Underactive? Think about both XY and XX individuals.
Show solution
One way to reason it out: overactive aromatase turns more testosterone into estrogen, leaving less testosterone, so XY development would be less masculinized (a little like AIS) and XX individuals would have extra estrogen. Underactive aromatase leaves testosterone unconverted, so it builds up: XX individuals could be masculinized, as in CAH (ambiguous genitals), and XY individuals would make little estrogen.