HB Lecture 2

GnRH (gonadotrophin-releasing hormone) is synthesised in hypothalamic neurones and released as [1] into the [2], causing release of [3] from the pituitary.

1) pulses; 2) portal system; 3) LH and FSH

Gonadal feedback regulates pituitary activity via sex steroids and the gonadal peptide […].

inhibin

In females, GnRH injected directly into the brain facilitates [1], so the peptide controls both pituitary gonadotrophins and [2].

1) lordosis; 2) sexual behaviour

Lordosis (the reflexive receptive posture of a female rodent in oestrus that allows the male to mate) involves [1] and [2].

1) arching the back; 2) elevating the head

Natural hormonal sequence leading to rodent mating: low oestrogen, then growth of the [1], then high oestrogen, then [2], then mating.

1) follicle; 2) progesterone

In an ovariectomised (ovaries removed) female rodent, lordosis is restored by oestrogen for [1] followed by one injection of [2], with receptivity appearing about [3] later.

1) 2 days; 2) progesterone; 3) 6 hours

A female rodent made receptive by oestrogen then progesterone is said to have been […] by her hormonal history.

primed

Castrated male rats or guinea pigs given the same oestrogen plus progesterone regimen [1] show lordosis, indicating that male and female brains are [2].

1) do not; 2) organised differently

Phoenix et al. (1959) injected testosterone into pregnant guinea pig mothers; as adults, their genetically female offspring showed [1] lordosis but [2] male-like mounting.

1) greatly reduced; 2) very frequent

Phoenix's prenatal experiments concluded that early androgens […] the developing brain.

permanently alter

Organisational hypothesis (Phoenix): [1] early in life organises the brain's "hardware" for [2].

1) testosterone; 2) a male behavioural pattern

The window of sensitivity to organising sex steroids in rats lasts up to […] post-natal.

10 days

Compared with the window for organising the genitalia, the brain's window of sensitivity to sex steroids closes […].

later

Booth (1977): in male rats castrated from postnatal day 1, a single injection of [1] was as effective as testosterone at organising male-like behaviour, and oestrogen is about [2] more potent.

1) oestrogen; 2) 100-1000 times

Conversion of testosterone to oestrogen is [1], whereas the reverse conversion is [2].

1) energetically favourable; 2) virtually impossible

5α-reductase converts testosterone to [1], which drives development of the [2].

1) 5α-dihydrotestosterone (DHT); 2) external genitalia

Aromatase converts testosterone to [1], which drives sexual differentiation of the [2].

1) oestradiol-17β; 2) brain

Aromatase is encoded by the gene […], and the hypothalamus is rich in cells that express it (Naftolin, 1975).

Cyp19a1

In steroid chemistry, a ring in which electrons circulate in a stable, cyclic, planar, conjugated structure (like [1]) is called [2].

1) benzene; 2) aromatic

Radiolabelled [1] can be recovered from the hypothalamus as radiolabelled [2], some of it bound to [3].

1) testosterone; 2) oestrogen; 3) oestrogen receptors

Aromatisation hypothesis: […] masculinise the brain.

aromatised oestrogen metabolites of testosterone

In the rat brain, most oestrogen receptors are in the […], which is also a rich site of aromatisation.

hypothalamus

Oestrogen receptors in the rat brain cluster mainly in the [1] and the bed nucleus of the [2].

1) medial preoptic area; 2) stria terminalis

Few oestrogen receptors are found in the [1] and [2] of adult rats.

1) cerebellum; 2) cortex

The placenta produces high levels of maternal oestrogen, and sex steroids cross the placental barrier readily; α-fetoprotein (AFP), a fetal plasma globulin, binds oestrogens with […].

high affinity

Two competing hypotheses for AFP in female differentiation: AFP [1], or AFP [2] to promote feminisation.

1) keeps oestrogen out of the brain; 2) delivers oestrogen to specific brain regions

The male fetus produces testosterone, which […] the AFP system and is converted to oestradiol inside neurones by aromatase.

bypasses

Brain sex is determined less by the presence or absence of oestrogen than by […].

the amount of oestrogen reaching neurones

In primates, AFP has a different structure and […]; other globulins may fill the protective role.

does not bind oestrogen

Male aromatase-knockout mice supplied with exogenous oestrogens can copulate normally but lack [1] and [2].

1) motivation; 2) sexual preference

Human aromatase deficiency is rare; affected females are diagnosed early because of [1], and later show high testosterone, low oestrogen, cystic ovaries, amenorrhoea and [2].

1) pseudohermaphroditism (ambiguous genitalia) at birth; 2) delayed bone maturation

Human aromatase deficiency in males is usually diagnosed much later because puberty is normal, but [1] and [2] become apparent.

1) infertility; 2) persistent bone growth

Artificial oestrogens that bypass the body's protective mechanisms (e.g. AFP) can be […].

potent and dangerous

Feminisation of the brain is the [1] process occurring in the absence of high levels of [2] during a perinatal sensitive period (McCarthy and Arnold, 2011).

1) default; 2) gonadal steroids

Masculinisation is the hormonally driven process that [1]; defeminisation is the separate process that [2].

1) promotes male-typical behaviours; 2) suppresses female-typical behaviours

Under the organisational/activational model, the organised neural substrate is […] by adult gonadal steroids, which is required for sex-typical behaviours to be expressed.

activated

In the classic organisation hypothesis, "tonic" GnRH release in males refers to the [1], whereas females show [2] GnRH release.

1) lack of ovulatory LH surges; 2) phasic

Harris's pituitary transplantation work showed that a male pituitary in a female host can still support [1], so the sexual dimorphism resides in the [2].

1) ovulation; 2) hypothalamus

Pfeiffer transplanted ovaries to the eye capsule of rats and observed ovulation only in […].

females

The sexually dimorphic nucleus of the preoptic area (SDN-POA) is larger in [1] rats, and testosterone has little effect on it [2].

1) male; 2) after development

The SDN-POA is also sexually dimorphic in humans, being larger in [1] (Swaab and Fliers, [2]).

1) men; 2) 1985

The rat posterodorsal medial amygdala (MePD) is about [1] larger in males and remains responsive to testosterone manipulation in [2].

1) 1.5 times; 2) adults

In the human corpus callosum, the splenium (caudal part) is more [1]; the sex difference is due to [2] rather than total cross-sectional area.

1) bulbous in females; 2) shape

In male rats, testes secrete testosterone, which is aromatised to oestrogen in the brain; oestrogen binds oestrogen receptors (ER) and alters gene expression so the SDN-POA […], leaving more surviving neurones in males.

reduces naturally occurring cell death

Mouse hypothalamic explant cultures grown with oestrogen show […] than those grown without it.

more extensive neurite outgrowth

2D:4D is the length of the second digit divided by the fourth digit. Men tend to have a [1] than index finger; women tend to have similar-length digits or a [2].

1) longer ring finger (4D); 2) longer index finger (2D)

A lower 2D:4D ratio reflects […] prenatal exposure to testosterone.

greater

2D:4D is feminised in XY [1] and masculinised in [2]; in men it also correlates with polymorphism in the [3] gene.

1) androgen insensitivity syndrome; 2) congenital adrenal hyperplasia; 3) androgen receptor

In humans, retrospective markers of prenatal androgens (e.g. 2D:4D) have been associated with […] among women, but not with androphilia among men.

gynephilia (attraction to females)

The spinal nucleus of the bulbocavernosus (SNB) system and its functional neuromuscular junction are present before birth in [1] of rats; after birth the muscle and motor neurones die unless exposed to [2].

1) both sexes; 2) testosterone

In males, testosterone acts primarily to prevent [1] death, which secondarily prevents death of the [2]; one hypothesis is that muscle produces a [3].

1) muscle; 2) motor neurones; 3) trophic factor

In both sexes, the bulbocavernosus muscle contributes to erection of the penis and clitoris and to the […].

contractions of orgasm

Androstenone, a […], is the first mammalian pheromone identified.

steroid

Freemartinism: opposite-sex bovine twin fetuses share a circulation through [1], so the female's ovaries become transformed into [2] and her tract is partially masculinised.

1) fused placental blood vessels; 2) sterile testes

Opposite-sex twin marmoset fetuses almost invariably share a circulation, yet the female's development is [1], attributed to different placental structure and different timing of [2].

1) completely unimpaired; 2) hormonal sensitivity

Bakker and Brock: female-typical neural differentiation in mice probably occurs [1], driven by oestradiol from the [2], once AFP no longer plays a neuroprotective role.

1) postnatally; 2) ovaries

Individual brain regions vary in how masculinised or feminised they are, producing a […] of relative maleness or femaleness that increases variance between individuals of the same sex.

mosaic

In the twenty-first-century view, sex-specific [1] variables act to [2] sex differences rather than induce them.

1) compensatory; 2) reduce

In the twenty-first-century view, [1], [2] and [3] have independent, parallel differentiating effects that can interact, often synergistically.

1) hormones; 2) sex chromosome genes; 3) sex-specific environments

[APPLICATION] A pregnant rat is given repeated oestrogen injections. Her genetically female pups grow up with a masculinised brain because the injections [1], so [2].

1) swamped the α-fetoprotein (AFP) system; 2) excess oestrogen reached developing neurones

[APPLICATION] A male rat castrated on postnatal day 1 receives one oestrogen injection and still develops male-like behaviour, seeming to contradict the organisational hypothesis. The resolution is that testosterone normally acts in the brain after being [1], making [2] the active masculinising agent.

1) aromatised to oestrogen; 2) oestrogen

[APPLICATION] An aromatase inhibitor is given to a male rat pup during the neonatal critical period. Its adult SDN-POA is expected to be [1], because [2] without local oestrogen signalling.

1) smaller; 2) more neurones die

[APPLICATION] A girl has an enlarged clitoris, elevated testosterone, low oestrogen, cystic ovaries, no menstrual periods at puberty and delayed bone maturation. The most likely diagnosis is […].

aromatase deficiency

[APPLICATION] A boy has normal pubertal development but is later found to be infertile with persistent bone growth. A rare enzyme defect to consider is […].

aromatase deficiency

[APPLICATION] Testosterone is injected into a pregnant guinea pig. Her adult genetically female offspring, given oestrogen then progesterone, would show [1] and [2].

1) reduced lordosis; 2) frequent male-like mounting

[APPLICATION] A cow is born as the co-twin of a bull calf and is infertile with a partially masculinised reproductive tract and testis-like gonads. This condition is called [1], caused by [2].

1) freemartinism; 2) a shared circulation through fused placental vessels

[APPLICATION] A man has a 2D:4D ratio that is high and typical of women. This suggests his prenatal testosterone exposure was […] than is typical for males.

lower

[APPLICATION] A female rat pup is given testosterone shortly after birth. Her SNB muscle and motor neurones are expected to […], whereas untreated females lose them.

survive

[APPLICATION] A genetically female fetal rodent has no functional α-fetoprotein (AFP). Her brain is at risk of [1] because [2].

1) masculinisation; 2) more oestrogen reaches her neurones

[APPLICATION] An LH recording from an adult rat shows regular pulses with no large surge. This profile indicates a [1]; a profile with pulses plus a large surge indicates a [2].

1) male; 2) female

[APPLICATION] Radiolabelled testosterone is injected into a rat and radiolabelled oestrogen is recovered from the hypothalamus. This is evidence that testosterone was […].

converted locally in the brain

[APPLICATION] An adult male rat is castrated and then given testosterone manipulations. Of SDN-POA and MePD, the structure whose volume would still change is the [1], because the [2] is largely unresponsive to testosterone after development.

1) MePD; 2) SDN-POA

[APPLICATION] An XY individual with androgen insensitivity syndrome would be expected to have a […] 2D:4D ratio.

feminised (higher)

[APPLICATION] A girl with congenital adrenal hyperplasia would be expected to have a [1] 2D:4D ratio, reflecting excess [2] exposure.

1) masculinised (lower); 2) prenatal androgen