Lec 4: Hormones and typical and atypical sexual development

Question 1

What are the levels of sex determination?

Answer 1

• There are several different ways to define sex determination - many different levels.
• It occurs in many steps, each step is a different layer of sex determination.
• Each step influences the next level of sex determination.
• dotted arrow: exception of this cascade of event.

Question 2

Why sex differences exist?

Answer 2

Sexual reproduction provides genetic variability that enhances evolutionary flexibility
* There are several cases where the species reproduction happens without the need of 2 different sex. ie: bamboo shark. This is called asexual reproduction.
* Most vertabrates display sexual reproduction rather than asexual.
* Asexual reproduction: very efficient, do not need anyone else. However, there is very little genetic variation. This means it is quite easy for this species to be extinct.
* Sexual reproduction: Seperation of chromosome pairs into haploid gametes provides genetic variability that enhances evolutionary flexibility (genetic material of this individual will be more diverse).
* We prob would not be here today if animals reproduced asexually.
* Evolution of sex remains an unsolved issue that is from from being settled among evolutionary biologists.

Question 3

Why sex dimorphic behaviours exist?
Mating system: Monogamous species

Answer 3

• because we have sexual reproduction, there are a lot of behaviors that differs between males and females. These differences between sex are mainly attributed to the mating systems.
• monogomous = single mating partner
• Monogomous species show less sexual dimorphism than polygamous species.
• monogomous leads to the 2 sexes of the species displaying less different characteristics, they are more equal.
• Prairie voles are monogamous. Almost impossible to distinguish which is the male and female without looking at genitals. Look very similar due to their mating system - lack of sexual dimorphism.
• Elk are polygamous: males have antlers that are much larger than females.
• We need this to have sexual reproduction to have a diverse genetic background.

Question 4

Why sex dimorphic behaviours exist?
Mating system: Polygamous species

Answer 4

• Polygamous members of one sex compete with another sex to mate.
• Males compete and females choose (is the main rule).
• Bowerbirds males have a lot of female partners. Females must chose their males wisely based on characteristics (he decorates his bower).
• Sexual selection favors sexual dimorphism and amplifies it over time.
• Female does not pay much attention to the resources the male can offer because there is already a lot of resources in the environment, instead they pay attention to the beauty of the bower.

Question 5

Sex dimorphic behaviours are a product of nature and nurture

Answer 5

• Pattern of play displayed by boys and girls differs from an ealry age. Boys = rough and tumble. Female =
• These patterns of play reflect patterns of biological aspects but also environment and culture play a role in secually dimorphic behavioir –> seen in their social behaviour.
• To identify if this is hormonal, we would need to manipulate hormones in developping humans (ethical concers).
• Interaction between nature and nurture.

Question 6

Recap

Answer 6

• Sex determination occurs in various steps.
• Sexual reproduction favors evolutionary flexibility by providing genetic variability.
• Possibly because of the matting system related to the sexual reproduction, several behaviours are sex dimorphic.
• Sex dimorphic behaviours are a product of nature and nurture.

Question 7

Mammalian sexual differentiation: Chromosome Sex

Answer 7

• Chromosomal sex is the primary step in the process of mammalian sexual differentiation.
• Defined during fertilization.
• Female gamates is X chromosome and the sex of chilfren is determined whether it interacts with an X or Y chromosome from sperm.
• The sex of the child is determined by whether the sperm contributes with an X or Y chromosome
• Chromosomal sex will contribute to the gonadal sex.

Question 8

Mammalian sexual differentiation:
Gonadal sex

Answer 8

• Each embryonic individual, regardless of chromosomal sex, develops a thickening called the germinal ridge on the ventromedial surface of each protokidney. Everybody has this thickening (no matter the sex).
• THis germinal ridge is Bipotential primordial gonad, meaning it can become either an ovary or a testes (potential to go both way either female or male path). This depends (whether it will follow the female or male pathway) on the expression of SRY gene found on the Y chromossome produces testis determination factor (TDF).
• Male path, you need the expression od the SRY gene which produces the TDF. If this is the case, the medulla is going to form the testis.
• If no SRY gene is expressed, then the ridge will form ovaries. Embryo will follow a female path.

Question 9

Mammalian sexual differentiation: Gonadal Sex

Answer 9

• SRY gene expression produces testis determination factor (TDF).
• TDF + the presence of another protein called SF-1 (steroidogenic factor 1 protein), produces a transcription factor that regulates expression of SOX9 gene.
• The protein products of SRY and SOX9 lead to the development of the middle of the medulla of the germinal ridge develops and testis are formed.
• If SRY or SOX9 are not produced/present the outer part of the germinal ridge develops and an ovary is formed.
• Recent evidence suggests that Wnt4 gene (wingless-related MMTV integration site 4) is required for normal ovarian development. In the absence of Wnt4, the expression of the SOX9 is upregulated, even in the absence of the SRY gene, and the offspring (gonads of the XX mice) will exhibit partial masculination. Similarly in the male path, the repression of the Wnt4 expression is also needed for the male development.
• In the past, we thought that for the female path to occur, we didnt need any kind of gene expression. It was just absence of the SOX9 gene or absence of the SOX9 production

Question 10

Mammalian sexual differentiation: How does gonadal sex determine hormonal sex?

Answer 10

• Hormonal secretions from the developing gonads determine whether the individual develops in a male or female manner.
• The mammalian embryonic testes produce androgens (ie, testosterone) as well as peptide hormones which lead to the male direction.
• The embryonic ovaries of mammals do not secrete high concentration of hormones –> follow a female pathway. This is why the female sex is often called the default sex.
• In the presence of ovaries or in the complete absence of any gonads the development follows a female pathway.
• Gonads are differentiated by genetic differences (SRY gene, SOX9 gene) and all other differentiation reflects the hormone mediation that happens afterwards the development of the gonads and the secretion of the steroid hormones(secretion of the gonads).
• There is some evidence that suggests that chromosomes might also directly influence sexually dimorphic anatomy and function. This is represented by the dotted line linking chromosomal sex to behavioral sex in the diagram. This means that some sex differences in brain and behavior might be mediated more directly by gene expression in non gonodal tissue.
• Some of the sex differences might be mediated by gene expression in non gonodal tissue.

Question 11

Chromosomal sex can also influence sex dimorphism independently of the action in the gonads.

Answer 11

• 50 genes that were different between males and females.
• The differences in the expression of these genes are not mediated by the gonads but by the sex chromosome genes themselves.
• Cell culture from XY mice so female mice contain more cells expressing tyrosine hydroxylase then cells cultured from XX mice irrespective of the gonado sex of the embryo that the cells were taken from.
• This is important because tyrosine hydrozylase is a precursor of the dopamine synthesis.

Question 12

Mammalian sexual differentiation: How hormonal sex influences Morphological sex

Answer 12

• In contrast to the single bipotential primordial gonad, we have something called Dual Anlagen/primordia for the accessory sex organs that are present very early (especially in the embryo) –> Anlagen is the rudimentary basis of a particular organ.
• In the development of the accessory sex organs, we have the apparatus for both pathways already (male and female).
• The embryo has a dual anlagen - which means we have the apparatus for both accessary organs.
• Mullerian: connected to the female development. Develops into the female accessory organs: Fallopian tube, uterus and cervix.
• Wolffian: connected to the male development. Develops into the male accessory organs: connects testes to the penis
• Has both the mullerian and wolferian duct system. One of the two diminishes.

Question 13

Mammalian sexual differentiation: Morphological sex

Answer 13

• Male accessory sex organs require two products from the embryonic testes to develop: Testosterone (an androgen) and Müllerian inhibitory hormone (MIH).
• Testosterone stimulates Wolffian duct development and MIH causes the regression of the Müllerian duct system.
• Masculination caused by testosterone and a defeminization caused by MIH.
• In females, no hormones are necessary to their development (it is already there what is needed for the female). Happens during first trimester of pregnancy. This is why when a women is pregnant, we can only determine the sex by the 4th month (this is when we can see the morphology of the sex organs).

Question 14

Mammalian sexual differentiation: Morphological sex

Answer 14

• Androgens are responsible for the differentiation of the external genitalia.
• When it is forming we have the genital ridge that has 2 flaps on the side called genital folds.
• Urogenital sinus is surrounded both sides by thickened urogenital ridge that are flanked by two flaps called the genital folds.
• In the front/anteroventral of the urogenital opening, the two regions meet to form a medium of growth called the genital turbercal.
• The genital tubercle and the genital folds are common to both sexes and developed into the external genitalia.
• In the presence of androgens, the urethral groove fuses, the genital tubercle develops into a penis, and the genital folds fuse into the scrotum (eventually contains the testes).
• In the absence of hormones, a clitoris develops from the genital tubercle and vaginal labia develop from the genital folds.

Question 15

Mammalian sexual differentiation (Recap)

Answer 15

Question 16

Mammalian sexual differentiation:behavioral sex

Answer 16

Mating behavior in both sexes is under the control of gonadal steroid hormones.
* For example, castration of males stops mounting behavior, and testosterone replacement therapy restores mounting behavior to its original levels.
- Females arch their backs (lordosis posture)
- Were able to causally link testosterone with the behaviour of coppulation.
* Injection of adult females with testosterone does not increase their mounting behavior to male-typical levels. Therefore, testosterone does not cause the mounting behavior. Females are not able to demonstrate this male mounting behaviour. Similarly, males injected with female hormings do not show female typical behaviours (such as lordosis).

Question 17

The organizational/activational hypothesis of hormonal sexual differentiation: Experiment by Young

Answer 17

Experiment to better understand the different effects of hormonal exposure during development and their differential effected depending on time of exposure.
* They studied the effects of prenatal and early postnatal androgen treatment (testosterone) on female reproductive behavior by observing and manipulating mating behavior.
* if testosterone dictates the mounting behaviour but when injected in females it does not show the same level of mounting behaviour, then what is happening?? Same goes for when we inject estrogen to males and they dont show the same level of lordosis. It there a special time where this differentiation occurs and then it is no longer replacable?
* Published a classical study of androgen treatment on female reproductive behavior.
* Hypothesis: hormonal events early in development must be responsible for the induction od feminine and masculine behavioral patterns.
* To test this, they looked at behavioral measures (mounting and lordosis –> mating postures).
* interested in the sex differences in reproduction behaviour due to hormonal action. Looked at an observable behaviour that is known to be different between males and females –> licking and grooming.

Question 18

The organizational/activational hypothesis of hormonal sexual differentiation: 1st phase of the study

Answer 18

• Injected testosterone to pregnant guiney pigs throughout the pregnancy
• Larger dose of testosterone-> Female offspring possessed external genitalia that were indistinguishable from those of their brothers or of typical males
• Smaller dose of testosterone -> Female offspring had no visible changes to the external genitalia and were referred to as “unmodified females”
• All offspring, female and male, were kept to mature and later
  had their behaviour examined (in the 2nd phase of the study)
• First phase = they analyzed the morphology.

Question 19

The organizational/activational hypothesis of hormonal sexual differentiation: 2nd phase of the study

Answer 19

• The three groups (small dose, large dose and control group) All were gonadectomized, then injected with estrogen and progesterone to stimulate female sexual behavior and paired with a male guinea pig.
• Need control group or else cannot infer causation.
• Some time later, all animals were injected with androgens to stimulate male sexual behavior and paired with a standard conspecific female that was in mating condition.

Question 20

The organizational/activational hypothesis of hormonal sexual differentiation: Conclusion of the study

Answer 20

Androgens given to guinea pigs prenatally:
(1) Decreased the tendency of both experimental groups (smaller or larger dose of testosterone) of females to display lordosis in adulthood.
(2) enhanced the tendency of both experimental groups of females to display mounting behavior in response to testosterone therapy (increased their tendency to display male sexual behaviour = mounting).
(3) caused no deleterious effect on mounting behavior or other masculine behavioral patterns in males similarly treated.
!!review study

• A clear distinction can be made between the prenatal actions of hormones in causing differentiation, or organization, of neural substrates for behavior and the actions of hormones in adulthood in causing activation of these substrates.

Question 21

What did the conclusions of the study lead to

Answer 21

These conclusions lead to the basis for the organizational/activational hypothesis of sexually dimorphic behaviors.
* This hypothesis postulates that sex hormones act during prenatal stage to permanently (irreversibly) organize the nervous system in a sex-specific manner
* During adult life, the same hormones have activation effects.
* Today we know that hormones have a broader timing effect. Depends on the timing of exposure.

Question 22

Mammalian sexual differentiation: Behavioral sex

Answer 22

Hormonal control of ovulation:
* Female mammals display cyclic gonadal function, whereas males have more or less tonic reproductive function. Expulsion of the mature egg from ovaries occurs constantly, whereas sperm production is constant.
* The reproductive behavior of the sexes follows these fundamentally different patterns of gamete production, with females displaying cycles of mating behavior and males displaying more or less continuous willingness to mate
* What causes these different patterns of gonadal function?
- Gonadal function is driven by gonadotropins secreted from the anterior pituitary.
- The gonadotropins are driven by the gonadotropin releasing hormone (secreted by the hypothalamus). This terminates the pattern of the release of the Luiteinizing hormone (LH - this is a gonadotropin from the anterior pituitary). So, GnRH determines the pattern of release of the LH from the anterior pituitary that then drives the function of the gonads.
* Females have negative feedback control of GnRH secretion -> this changes on a cyclical basis. As LH hormone concentration rises, they feedback to suppress further GnRH secretion.
* LH is released in a pulsatile fashion in both sexes. This means the hypothalamus provides a pulsatile delivery of GnRH in both males and females which subsequently drives the anterior pituitary which eventually drives gonadal function in females.
* Increase of pulsitile release of luienizing hormone and an increase of LH release around ovulation in females.

Question 23

Mammalian sexual differentiation: behavioral sex

Answer 23

In females the negative feedback control of GnRH secretion is altered on a cyclical basis.
* As concentration of LH and sex steroid hormones rise, they feedback to suppress further GnRH secretion to maintain a steady pulsatile release of LH.
* As the steroid homrones and LH level rises, information is sent to the hypothalamus to tell it to stop producing more GnRH.
* In females, this negative feedback control of GnRH secretion is altered in a cyclical basis.

Question 24

Positive feedback and the control of ovulation

Answer 24

• On a cyclical basis in females, there is a steady increase of estrogen produced by the ovaries against the backdrop of continuous pulses of GnRH and the negative feedback endocrone regulation.
• The amount of estrogen produced by ovaries significantly rises and then the females break free from the negative feedback of the GnRH secretion.
• As these pulses increase in both frequency and amplitude, the female escape from rigid negative feedback control.
• So estrogen accumulates in the blood, a signal from a putative surge center in the anteroventral periventrical nucleus of the hypothalamus drives gonodotropin release hormone. A surge of GnRH causes a surge of LH and FSH which in turn stimulates ovulation via a positive feedback mechanism.

SUMMARY: females escape the rigig negative feedback control of GnRH which then leads to a surge of secrition of LH and FSH whihc in turn stimulates ovulation. The break of this negative feedback occurs because of the accumulation of estrogen in the blood.

Question 25

Atypical sexual development

Answer 25

Chromosomal sex --> determined at conception. Gonodal sex --> type of gonade = having ovaries or testies Homronal sex --> most females have high estrogen to androgen ratio. Morphological sex --> these morphological differences lead to behavioral differences. * A lot can happen in this process of sexual differentiation because it’s a complicated process it has a high potential for atypical development * Sex determination is far from binary.

Question 26

Chromosomal to gonadal sex

Answer 26

* Some situations where the sexual development can be atypical. * Partial exppresion of SRY or SOX9 gene can lead to incomplete gonal differentiation which can lead to a ovotestes (has aspects of both). * Without SRY gene = develop ovaries * Inserted SRY into XX transgenic mice = develop testes.

Question 27

Swyer syndrome

Answer 27

* Rare disorder characterized by the failure of the sex glands (i.e., testicles or ovaries) to develop in XY individual that lack SRY gene. * Classified as a disorder of sex development (DSD), which encompasses any disorder in which chromosomal, gonadal or anatomic sex development is atypical. * Gonadal streaks are developed. These are typically surgically removed because they have a high risk of developping cancer. The gonads are functionless!!. * During puberty, menstruation fails to occur and this is when they find out that they have this disorder. Treatment is hormone replacement therapy.

Question 28

Hormonal to morphological sex

Answer 28

* mallerian duct system develops even if the individual is XY - because the male needs both the mallerian inhibiting hormone and the testosterone to develop.

Question 29

Intersex

Answer 29

* Intersex is a general term used for a variety ofconditions in which a person is born with a reproductive or sexual anatomy that doesn’t seem to fit the typical definitions of female or male. * Individual has both ovaries and testicle tissue. Considered an intersex individual - there is discrepency between the external genitals of the individual and the internal reproductive organs. * This does not fit typical binary - this is considered a disorder but is not well accepted anymore. Should it be considered a disorder (meaning it is something to fix)?

Question 30

Shifting the paradigm of intersex treatment

Answer 30

* Focus more on being an individual instead of fixing it. * Based the decision of being a female or male (surgical intervention) on whether they looked more female or male. * Little genital development being made then they would decide to intevene to make it a female. * Fostered the change of treatment guidance - following consultation a gender should be decided by the individual - what gender would they want? * The society suggests that no surgery that cemments the gender shoild be done until the individual is old enough to make their own decision.

Question 31

Hormonal to morphological sex

Answer 31

* Typical development is seen along 2 dimensions: females must be demasculanized and feminized. * There are 2 continuums: female to defiminization and male to demasculinization. Many things can haopen during this process, some extremes.

Question 32

Prader scale for scoring degrees of genital virilization

Answer 32

* This is a scale used in clinical medicine to grade the degrees of genital masculinization. * It represents the continuum - androgens are responsible for the differentiation of the external genitalia, if there is no androgens acting, the individual follows the female path.

Question 33

Hormonal to morphological sex

Answer 33

* Androgens are responsible for the differentiation of the external genitalia. When androgen is acting they follow the male pathway. Absence of androgen = follows female pathway. * One of the androgenic metabolites of testosterone, 5αdihydrotestosterone (DHT), is critical for this process of genital fusing. Testosterone is converted to DHT by the 5αdihydrotestosterone which is locally abundant in the embryonic genital skin of both males and females. * If unsually high concentrations of androgen are available to female fetus then DHT conversion in the genital skin occurs and the development of typical external male genitalia occurs in an XX individual

Question 34

5α-reductase deficiency

Answer 34

* Genetic males (XY) with 5α-reductase deficiency are born with ambiguous genitalia and small, undescended testes (incomplete development). They are usually considered females at birth and reared as females. At puberty, testosterone masculinizes the body, which develops male-typical musculature and axillary hair growth, and the genitalia develop to resemble a maletypical penis and scrotum.

Question 35

Turner syndrome

Answer 35

* A congenital condition in which individuals lack an X chromosome (XO) or damage to the second X (or Y) chromosome. * These individuals have a female external appearance (at birth), but ovarian development is usually limited, and they do not attain puberty without medical attention. * Girls with turner syndrome must be treated with sex steroid hormones because they lack to produce these (treated at puberty). * However, in some cells they may have both XX chromosomes even though they dont have the overall two XX chromosomes. * Hallmark: short statured

Question 36

Congenital adrenal hyperplasia

Answer 36

* These individuals lack enzyme called 21-hydroxylase which results in an over prodiction of adrenal androgens. * In the absence of this enzyme, it does not cause sexual development problems in genetic males, but results in moderate to severe masculinization of the genitalia in affected females. This lack of enzyme leads to the overproduction of androgen - this doesnt effect males because they already have high levels of androgen but it affects females because they do not have high androgen levels. * Exposure to prenatal exogenous or endogenous androgens (often causes issues in female development). * Congenital adrenal hyperplasia: condition is characterized by the lack of 21-hydroxylase enzyme. This leads to the overproduction of adrenal androgens.

Question 37

Androgen insensitivity syndrome

Answer 37

* Functional androgen receptors are absent caused by genetic mutation on the X chromosome. * Syndrome effects XY males. Genetic XX females with this mutation have a second X chromosome that contains the normal gene for androgen receptors, so they suffer no real effects. * XY individuals born with androgen insensitivity syndrome have normal appearing female external genitalia and are sexed and reared as girls. * However, because the Y chromosome is present, the SRY gene is activated and testicular development proceeds followed by significant prenatal androgen secretion. The testes produce MIH which causes suppresion of the malerian duct system. However, the Wolfirian duct system is underdeveloped even in the presence of androgen because there is a lack of receptor for that molecule. * Condition is noticed at adolescense when menstruation fails to occir. Vagina is reduced in length * Infertile, no ovaries or fallopian tube due to the failure of Mullerian ducts development. * Estrogen treatment is provided.

Question 38

Trisomic anomalies

Answer 38

* Klinefelter syndrome (XXY) - extra X chromosome * The presence of the Y chromosome is sufficient for the SRY gene to be activated and masculinization to occur, and these individuals are sexed as males at birth (altough the testes develop normally, they are sterile because of less sperm production), higher risk of learning dissabilities. * This disorder seems to mainly reflect variation in the androgen receptor * XYY --> considered male at birth, but may be considered sterile, taller than average and increased risk for learning disabilities. Possess traits that increase the likelyhood of criminilization (tend to be identified more randomly as potential danger). * XXX --> many girls and women do not experience symptoms or only mild ones. Possible symptoms: developmental delays or learning disabiliteies

Question 39

The modern organizational/activational hypothesis of hormonal sexual differentiation

Answer 39

* the organizational effects of hormones are considered relatively permanent changes evoked in response to hormones early in life and that these were permanent changes and that nothing much could be done. * organizational hypothesis continues to be accepted with some minor adjustments. ie, it is now clear that gene products encoded by sex chromones participates in sexual differentiation of brain and consequently behavior (independent of the gonads). * because of substantial programming of adult behavior during puberty, it has been suggested that the organizational temporary window should be extended to the peripheral period just before puberty. * The 21st century model of sexual differentiation of the brain gives importance to genetics and environment, together with the effects of hormones to provide a portrayal of other types of variables that can cayse sex differences. * Included in this view are the principles that hormones, sex chromosome genes and sex specific environments have independent parallel differentiation effects that can interact with each other to cause differences in the brain. There are also compensatory sex specific variables that act to reduce sex diffences rather than induce them. * Main difference is that this theory is much less fixed, it has potential for variation and changes that go beyond the prenatal period. It is more comprehensive and considers phenotopic development.

Question 40

Why sex matters for neuroscience

Answer 40

* With a sufficiently large sample size, relatively small differences in the performance or frequency of given behavior can be statistically signifiant. * Average differences between the sexes is about half the size of the standard deviation of the scores within each sex. * So, when we talk about sex differences in humans, we will typically be discussing only its behavioural sex differences. * Consequences of differences in treatment are only starting to be explored (ie, females are at greater risk for developing depression --> need to consider this in their studies on depression).

Question 41

Conclusion

Answer 41

* Sexual developments occur on a continuum rather than a dichotomy * Continuum leads to differences in gender identity beyong binary identities (boy and girl). * These differences have both biological components as well as cultural differences as gender roles are culturally constructed. Gender Role * What roles society expects genders to perform. Gender Identity * The internal and personal process by which individuals come to perceive themselves and what they understand their own gender to be. Binary, nonbinary and plural. Sexual Orientation * enduring pattern of emotional, romantic, and/or sexual attractions that individuals feel toward people of the same and/or opposite sex.