Sexual Differentiation in the Brain

Question 1

Describe Lordosis behaviour in female rats

Answer 1

• Lordosis in female rodents is a stereotypic behavior induced by hormones
• During low estrogen, female will exhibit little behavioural proceptivity
• As you get follicle growth and ovulation, you get a surge of estrogen and high progesterone
• This leads to around 6-8 hours of lordosis behavior
− Arched back
− Elevated head
− Reflexive behavior to allow male to mate
• Occurs due to the priming effects of steroids

Priming effects of steroids
• Lordosis only occurs at specific phase of the estrus cycle
• If ovaries are removed – cannot exhibit lordosis
• If you ovariectomise, then give estrogen for 2 days, then 1 injection of progesterone → 6 hours later the female is receptive. She has been ‘primed’ by her hormonal history.
• Males do not show lordosis
• If you castrate a male then repeat the hormone regimen, they do not respond
• They have not been primed
• Concludes → male and female brains are organized differently.
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Question 2

Describe the ‘Organisational Hypothesis’ of the brain by Pheonix

Answer 2

• Relates to the effects of prenatal exposure to steroids
• If you treat female guinea pigs with pre-natal testosterone, and repeat the same hormonal regimen (estrogen and progesterone) – they will not respond
• Leads to the conclusion that early androgens permanently alter the developing brain
• There is a window of sensitivity to these sex steroids
• In rats, it is up to 10 days postnatal
• Sex steroids therefore organise the secondary sexual characteristcs and organise the brain

Question 3

What is the role of estrogen in masculinisation of the brain?

Answer 3

• Single injection of estrogen is just as effective as testosterone in masculinising the brain
• Estrogen is actually 100-1000 more potent
• Such treatments have no effects on genitalia
• This challenges the organizational hypothesis

• Testosterone can be converted to estrogen by aromatase

Question 4

What is the aromatisation hypothesis of brain differentiation?

Answer 4

Aromatized estrogen metabolites of testosterone masculinise the brain.

• Maleness is imposed on neural structures by high local concentrations of estrogen converted locally from testosterone.

Question 5

How is the female brain protected during development from testosterone from male siblings in utero?

Answer 5

Placenta has aromatase - converts it to estrogen

Question 6

How is the female brain protected during development from the masculinising effects of estrogen?

Answer 6

Protection from estrogen
• Alphafetoprotein (AFP) binds estrogen and prevents passage through the placenta.

From Puts et al, 2006:
• Findings soon arose that were inconsistent with the idea that AFP acts by keeping estrogen out of the brain
• Some studies suggested ovariectomising rats made their behavior less feminine (not more feminine as one would predict if estrogen masculinizes the brain)
• We know that a lot of estrogen will masculinize the brain – so the question became whether a modest dose is needed to complete feminine development.
• Perhaps the role of AFP is to bring estrogen into the brain
• May bring estrogen in specific neural circuits of the brain that favour female development

So what is true?
• In mice with AFP knockout, both hypothesis would predict that males would be normal and females would be masculinized → this is what was found
• Blocking estrogen synthesis in AFP knockout females rescues the feminine phenotype → consistent only with the hypothesis that AFP excludes estrogen from the brain.

Question 7

Summarise the model of masculinisation of the brain

Answer 7

• Males need estrogen → Testosterone reaches the fetal brain and is aromatized into estrogens. Estrogens bind to ERs, promote gene expression that masculinizes neural circuits and defeminizes others.
• Did females need small estrogen amounts? → AFP may serve to deliver estrogen to specific neural elements to promote feminization of these circuits
• Did females need protection from estrogen? → AFP may serve to completely keep estrogens out of the female brain
• This is the true one! Because blocking estrogen synthesis in females keeps feminine phenotype, so it obviously isn’t needed.
– female phenotype develops in apparent absence of hormone action.

Question 8

Examples of sexually dimorphic structures

Answer 8

Rats – Preoptic Area
• Sexually dimorphic nucleus of the preoptic area is larger in males → sensitive to testosterone early in life, then later on it has little effect
• Posterodorsal medial amygdala is large in males → retains responsiveness to testosterone

Humans – Corpus Callosum
• In females, the splenum which forms the caudal corpus calossum, is more bulbous than in males

Humans – Dimorphic nuclei
• larger in males

Humans – finger length
• Women tend to have similar length index finger to ring, or longer index
• Males have longer ring fingers compared to index
• The fact the 2D:4D ratio is smaller in men has been used as a biomarker for embryonic exposure to testosterone
• Using this, researchers have found evidence that prenatal androgens affect many sexually differentiated human behaviours, including sexual orientation in women (but not in men), attention deficit disorder, autism, eating disorders, aggression and risk taking.
• Lower 2D:4D ratio associated with more male-like behavior

Question 9

Is sexual orientation linked to differentiation of the brain?

Answer 9

• Sexual orientation is a sexually differentiated trait → many sexually differentiated characteristics are organized during early life by sex steroids. Is the same true for orientation?
• Evidence supports this:
• Multiple sexually differentiated behavioural, physiological or even morphological traits are different in homo and heterosexual people. Some of these traits are known to be organized by prenatal steroids → suggest homosexual subjects exposed to atypical endocrine conditions during development
• Clinical conditions associated with significant endocrine changes during embryonic life associated with increased incidence of homosexuality
• Therefore seems prenatal endocrine environment has significant effect
• Genetic differences that effect behavior in a direct manner or by changing embryonic hormone secretion may also be involved

eg)

1. Sexual preference of a male for a female is controlled, like the expression of male-typical sexual behavior, by the medial part of the POA. Lesions of this brain region cause a reversal in the males preference. This preference is also determined by prenatal hormones, and can be reversed by hormonal treatments during early development.
2. The SDN of the ovine POA shown to be significantly smaller in homosexual rams than heterosexual. Also contains fewer neurons and expresses reduced aromatase.

Do these mechanisms have significance in humans?
• Sexual orientation is clearly not affected by steroids in adulthood → Gonadectomy does not influence orientation nor does adult hormonal treatment
• Plasma concentrations of sex steroids are normal in gay men and lesbians
• Male embryo exposure to testosterone is greater than females, but it can vary in levels
− Male ubjects at the lower end of the distribution could acquire a female-typical orientation
− Female subjects at the higher end of the distribution could a acquire a male-typical orientation
− → Argued that is is impossible, as would imply homosexual men have feminized genital structures, and lesbians should have masculinized.
− Recall however, the genital structures and behavior structures develop at different times.
− Possible that males may have normal testosterone concentrations during gonadal development, but then experience a drop during behavior structure development.

eg)
• Multiple studies show that the 2D:4D ratio is masculinesed in lesbians → suggests lesbians have been exposed to higher androgens

Question 10

Give an example of sexual dimorphism acting outside the brain

Answer 10

• Before birth , the spinal nucleus of the bulbocavernosus (SNB) is present in both male and female rats
• Involved in stimulating muscles needed for erection
• The SNB relies on apoptosis for sexual differentiation
• Male rats have a more larger SNB than females → muscles and their neurons die shortly after birth unless exposed to testosterone
• Testosterone acts to prevent the muscles from dying – this secondarily prevents death of the motor neurons (induces muscles to produce a trophic factor that preserves the muscles and the motor neurons).
• So testosterone acts indirectly on the SNB to keep it alive
• Example of a direct action of testosterone, not testosterone aromatized to estrogen
• Acts outside the brain (muscles) and indirectly affects structures within the brain