Neurobiology of gender identity and sexual orientation

Phenotypic sex

The observable physical and physiological characteristics of an individual, primarily defined by internal and external genitalia, gonads (testes or ovaries), and secondary sex characteristics

DNA and chromosomes for sex

23 pairs of chromosomes = 46 total chromosomes, and 1 pair of sex chromosomes

female = XX

male = XY

The female in her ovaries only gives an X chromosome to her offspring. Men have an XY genome in their bodily cells, so one-half of sperm are X, and the other half are Y chromosomes.

the Y chromosome

on the Y chromosome there is a gene with a transcription factor, called testis determining factor (TDF) or the SRY (sex determining region of the Y chromosome).

This gene (‘TDF/SRY) is the sole determinant for developmental male gonadal tissues.

SRY (sex determining region of the Y chromosome)

the SRY is on top of a genetic network that mediates the differentiation of male primary and secondary sex characteristics

• They are a transcription gene that transforms gonads into testes. by telling the genital ridges to develop into testes, which create testosterone, continuing the masculine development.

  • SRY > genital ridges > testis > testis secrete testosterone > early surge of testorsterone = masculination of body and brain

androgens

group of male sex hromone, testosterone is one

default pathway and male pathway

default = female: genital ridges> ovaries > other female sex organs (uterus vagian, oviducts)

male = SRY > genital ridges > testis > testis secrete testosterone > early surge of testorsterone = masculination of body and brain

Transcription factor

a protein that enables gene expression, helps with transcription from DNA to RNA level and helps with protein translation

The development of internal sex oragns

1. Early in embryonic development, internal sex organs are bisexual; all embryos contain a double set of precursors for both male and female sex organs.

2. Third month: The presence of the Y-chromosome's SRY gene drives testis development and androgen production. This causing only one system to develop

   1. allowing the Wolffian system to develop while Anti-Müllerian Hormone (AMH) inhibits the Müllerian system, leading to masculinization.

   2. in the absence of SRY and testosterone, the Müllerian system develops by default into female structures while the Wolffian system degrades.

Mullerian system

embryonic precursors of the female internal sex organs

 Does not need hormonal stimulation and will develop by default

Wolffian system

embryonic precursors of the male internal sex organs, do not develop  unless androgens from the testis are present

Anti-mullerian hormone

a hormone secreted by the fetal testes to inhibit the development of the Müllerian system by binding to the receptors on the tubes of the Müllerian system and shutting down development. Thus shutting down natural system to become internal female sex organs

detemrining effect

the antimullarian hormone

masculizing effect

testosterone stimulate development of Wolffian system

androgen insensitivity syndrome

androgen insensitivty syndrome, not hypothesis definition

• With an XY chromosome, the male body normally develops. But have developed a female body, and have a female gender identity.

The XY embryo develops as a female body because it is insensitive to testosterone due to a mutation in the testosterone receptor. But no female, as there is an anti-Mullerian hormone from the XY chromosome. Thus, they have no womb. 

• No reports of bisexuality or homosexuality,

  • no effect of androgens on the brain associated with heterosexual orientation in AIS women

Persistent Mullerian duct syndrome 

A condition caused by a congenital lack of anti-Mullerian hormone or receptors for this hormone: in a male, causes development of both male and female internal sex organs, a small uterus in the abdomen/ can become tumorous.

Sexual orientation and heritibility

the direction of an individual’s sexual attractions, biolgically detemrined

men:

• genes 40%

• unique uterine environment 60%

• social factors 0%

female:

• genes 20%

• unique uterine environment 65%

• social factors 15%

Gender identity

person’s subjective sense of gender

Prenatal hormone exposure is critical for development gender identity

Schedule

1st trimester maturation of internal-external sex organs. diferetation of goands and (internal and external) sex organs

3rd trimester, early sexual development of the brain.

From the moment of birth, social and cultural aspects of gender roles start to interact

Puberty, sexual maturation of the brain and maturation of primary and secondary sex organs

Sexual orientation is largely biologically determined in the third trimester

Evidence is all around trimester 3 during the early sexual development of the brain

1. Prenatal exposure to androgens they have increased probability of having a sexual or homosexual orientation 

2. Genetic factors that underlie gene variants that make you more prone to homo and sexual behaviour

3. Birth order effect, hypotheses for male bodies,

hypothesis 1, prenatal exposure to andorgens

Evidence suggests that prenatal exposure to androgens can affect social behavior and sexual orientation

• CAH (congenital androgen hyperplasia) = an abnormal secretion of androgens by adrenals

• Seen through a hyperactive set of adrenals that creates a lot of hormones, such as testosterone. In female fetuses, there is more testosterone than normal. The development of the outer sex organs goes more to the male body type

  • enlraged clitoris, partly fused labia

  • increased liklihood homo/ bi

  • CAH girls mor elikely to have male toy preferences

CAH monkey experiment

Males have a preference for “active toys” like cars that propel, and females have no preference and want to try everything. There is a societal influence that increases the small biological effects.

hypothesis 2, Genetic factors

androgen insensitivty syndrome

• With an XY chromosome, the male body normally develops. But have developed a female body, and have a female gender identity.

The XY embryo develops as a female body because it is insensitive to testosterone due to a mutation in the testosterone receptor. But no female, as there is an anti-Mullerian hormone from the XY chromosome. Thus, they have no womb. 

• No reports of bisexuality or homosexuality,

  • no effect of androgens on the brain associated with heterosexual orientation in AIS women

Markers for prenatal androgen exposure

• otoacoustic emissions (sounds that are generated from within the inner ear

• finger length pattenrs

• patterns of eye blinks

• skeletal fuetures

all show that women with a homosexual orientation were on average

exposed to slightly more foetal androgen than were heterosexual

women

New evidence in genetic influences on sexual orientation.

They analysed same sex sexual behaviour: more closely related family members are more likely to be concordant in the same-sex behaviour 

5 significant spots (SNPs) identified in DNA that link to the biological pathways that involve sex hormone orientation and olfaction.

hypothesis 3, birth order effect

If you have more older brothers with the same biological mother, the boys that are born later are more likely to have a homosexual or bisexual orientation 

Have to do with the maternal immune response to neurologin 4 -linked protein:

• During birth, there could be a small moment where bloodstreams mix from mother and son, usually completely separate. Where this protein (NLGN4Y) is developed, which is important in male brain development, the maternal immune reaction to the uterus, in the form of anti-NLGN4Y antibodies, is thought to alter the brain structures underlying sexual orientation in the male fetus. 

Differences in Male vs. Female and Homo vs. Heterosexual brains

• Sexual dimorphic nuclei in the human brain, a specific part in the hypothalamus, are 2x bigger in males with more cells than in females.

• homo and heterosexual men: the nucleus number 3 is 2x as large in heterosexual men as in homosexual men.

• Transexual men and women decrease in density for the nucleus in the hypothalamus, more towards the female shape.

• Males have larger total brain volumes, while females tend to have a higher proportion of grey matter and thicker cortices in certain regions.

• Males have larger overall volume, larger amygdala, and larger hippocampus (when not controlling for total brain size).

gender dysphoria

distress caused by a mismatch between an individual's gender identity and their sex assigned at birth

• in first 2 months of pregenacy, sxual diferentation of genitals

• on 2nd half of pregnancy, sexual differentation of brain

these two processes can be infleunces independletlyu leading to gender disphoria

The mosaic hypothesis of brain volumes

posits that human brains are not dimorphic (simply "male" or "female") but are unique mosaics of features, some more common in females and others in males. While average sex differences exist—such as larger total volume in males and thicker cortex in females—most individuals possess a mix of these characteristics rather than a consistently "male" or "female" brain.

Hypothalamic response

Response to a molecule that is abundant in male bodily sweat and urine. If you like male bodies, you like this molecule, a sensitisation in the hypothalamus towards the smell.

Differential hypothalamic responses to the molecule, androsradienone. Heterosexual males or homosexual women show a small decrease (dampening) in hypothalamic response, which is seen in prepubertal children; the response is created in the last phase of pregnancy.

VUmc treatment of young transexuals

they used puberty suprression for young transexuals between 12 and 16 years (it is revesible)

goal:

• to relieve suffering caused by the development of secondary characteristics

• Provide time to make a balanced decision regarding actual gender

  reassignment

• Prevent appearance of difficult-to-reverse traits such as beard, breasts, low male voice, body shape

Results were much better, because no differentiation into opposite sex in puberty