Section 7- Reproductive endocrinology Flashcards
Sequential process of sexual differentiation
- Establishment of genetic sex
- Translation of genetic sex into gonadal sex
- Translation of gonadal sex into phenotypic sex
Which duct is typical for males and which is for females?
which organs does each of those ducts give rise to?
Females: mullerian duct-> Female tract (oviduct, uterus, upper vagina)
Males: Wolffian duct-> Male tract (Epididymis, vas deferens, seminal vesicle)
What is urogenital sinus?
common primordium for external genitalia
Will develop in either Clitoris and vulva in females, or penis and scrotum in males
What happens if we remove testes from embryos? What happens to female embryos that had their gonads removed?
What does that mean?
embryos developed a female reproductive tract and female genitalia.
But, gonadectomised female embryos also developed into female features
it means that The TESTES are essential for male sexual differentiation, but the ovaries are NOT necessary for female differentiation
-> embryos develop in females by default and a switch is requried for an embryo to start developign in a male
Which of the developmnet pathways (male or female) are dependent on hormones? Why
Male development pwathway is hormonal dependent as hormones act as a switch to swith from default female pathway into male pathway
Pre-requisites for normal sex differentiation
Normal intact chromosome complement
Fully functioning sex determination genes
Intact steroidogenic pathway and receptors
Is female fomration abolutelty default?
No, it stil requires some signalling but less than in males
Allozome vs isozome
allozome= sex chromosomes isozome= all chromosomes
What are the functions of sexes that result form sexual differentiation
Males: provision of sprem, provision of different set of chromosomes
Females: Provision of eggs, Fertilization, Pregnancy, Lactation
Classification of sexual differences: Chromosomal, gonadal, inernal ducts, external genitalia, Phenotypic, behavioural
What are all the possible male and female phenotypes?
Presence of _ = MALE
Presence of Y = MALE
How does sexual reproduction produce new combinations of genes? Why is it beneficial?
recombination occurs between homologous chromosomes-> genetic variation-> benefit for survival
Which regions of sex chromosomes can participate in recombination
only a small portions on either ends of X and Y that can participate in recombination-> these are called pseudoautosomal regions
What is MSY region
MSY does not participate in recombination at all; it is the whole of Y chromosome, but the PAR region (Pseudoautosomal region that participates in recombination)
Does the whole X chromosome participate in recombination?
The whole X chromosome participates in recombintion only if 2 Xs are present
if X and Y are present, only the PAR regions of X participate in recombination
What is SRY? Where is it found?
Sex determining region of Y
Present in MSY (Male specific region of Y)
Proof of the role of the SRY gene
male Y chromosome was cut up in chunks
DNA pieces were injected into pronuclei in hope for integration into a sex chromosome
Some embryos contained ovaries, some contained testis
They were interested in those, that contained tesits as they had male phenotype, but had female chromosomal pattern XX
some fetuses had XX but yet had testes due to SRY gene DNA- Thus SRY is required for testis development and male phenotype
What is the effect of SRY on Bipotential Genital ridge
Converts Bipotential Genital ridge into testis
Why is the location of SRY in MSY a bit problematic
SRY is oacted close to the region that participates in recombination
1) Can lead to XX male
2) Y chromosome can have abnormal SRY-> Deleted/mutant SRY gene-> XY female
What is the role of HMG proteins
bend the DNA after they bind to it
SRY has DNA __ capability
SRY has DNA binding capability
in which region of DNA are SRY genes found?
In DNA binding domain
SRY protein binds to DNA to __ because it is a __
SRY protein binds to DNA to induce trancription of other genes because it is a transcription factor
What is the consequence of SRY absence in sex determination?
Se
SRY absence: Ovary is formed-> female
SRY presence: SOX9-> testis-> male
At what day is SRY expressed in bipotential gonad?
day 10-12
SOX9 expression is __ throughout embryonic development in the gonad
SOX9 expression is continuous throughout embryonic development in the gonad
SOX9 and SRY relationship
SOX9 is the target gene of SRY
As pregnancy progesssess:
SOCS9 takes over the role of SRY
SOCS9 inhibits the expression of SRY
How does SOX prevent the embryo from becoming a female
other factors + SOX9 lead to amh expression
- anti mullerian hormone (or MIS Mullerian inhibiting substance)-> responsible for destruction of mullerian duct (which transforms into female reproductive organs)
Wolffian duct takes over-> male is formed
Female phenotype requires other hormones and proteins (WNT4 and RSPO1) along with TF FOXL2 determines ovary formation and thus female phenotype - these have to be present to form fa female (thus it is not formed by default)
What is the site of GnRH production?
hypothalamus is the site of GnRH production as there ar GnRH neurones
WHat are the 2 centers of the hypothalamus that release GnRH?
It is synthesized in two different centres of the hypothalamus, the tonic (male) and the ovulatory or surge centre (female).
Estradiol entrance to the brain: male vs female fetus
What is the consequent effect
In male fetus, testosterone freely enters brain and converted to estradiol by aromatase
- as testosterone is not bound to a protein that is produced only during fetal period
- this protein is called alpha-fetal protein; produced by fetal liver
In female, estradiol cannot cross the blood-brain barrier (binds to alpha-Fetoprotein)
- this is why estradiol doesn’t end up in the brain and de-feminize the surge center
absence of estrogen causes the surge center to mature and become functional post-puberty - Female retains surge center + tonic center to control LH/FSH after puberty
this estrogen presence in the brain is responsible for de-feminization, lack of maturation of another center called surge center
what is the imortance of the surge center in females?
surge center is important for females in the post puberty period where there’s a surge release of GnRH, leading to a surge release of gonadotropins that are responsible for ovulation and reproductive cycle
The hypothalamo-pituitary-gonadal axis
hypothalamus produces GnRH
which stimulates the production of FSH and LH from the pituitary
They act upon gonads to produce gonadal hormones that can have negative impact on hypothalamus and pituitary
The function of the gonads
- Gametogenesis
- Hormonogenesis (mostly steroids)
- Electrolyte homeostasis
- Fuel and protein metabolism
- Adiposity and muscle mass
Effect of plasma testosterone levels at various ages in human males
testosterone levels at fetal stage are responsible for Sexual differentiation (maturation of testis and their descent, formation of reproductive organs, formation of tonic center and inhibition of surge center)
testosterone levels at neonatals stage are a tiny bit hihger than at fetal, but the function is unknown; some infants show pimple development because of this increase
Pre-puberty: Gonads quiescent in both sexes
Surge in pubertal perdiod and remains high durign adulthood (same increases are seen in estradiol in females )
What are the chnages that occur in puberty
Includes all physiological, morphological & behavioral changes
v Gonads/brain/phenotype change from adolescent to adult
v In females, first menstrual cycle – menarche
v In males, first ejaculation - semenarche
GnRH, FSH and Lh levels: Prepubertal period vs Puberty
Prepubertal period
- minimal GnRH release; low amplitude and low frequency
- FSH and LH low
- minimal to no folliculargenesis or spermatogenesis
Puberty
- increase in the pulse frequency and amplitude of GnRH release
- once the puberty occurs, the tonic center produces more frequent GnRH pulses; in case of adult females only, the surge center becomes active and results in massive release of GnRH
- increase in FSH and LH pulses
- folliculargenesis and spermatogenesis occur
What are the changes in that occur in hypothalamic senstitivity to estradiol and negative feedback that allow puberty to occur
Gonadotrophin Releasing hormone- structure
vSmall peptide of 10 a.a. cleaved from a larger precursor
vSynthesized by about 1000-3000 neurons in the hypothalamus
Where do axons of neruones that release Gonadotrophin Releasing hormone terminate? What is their consequent role?
Where else is GnRh made and what is the role?
vMost axons terminate in the hypophyseal portal capillaries and release GnRH → Stimulation of gonadotrophs in the anterior pituitary
vSome axons terminate in other brain areas and may affect sexual behavior
GnRH is also synthesized in the placenta, gonads, breast, lymphocytes and the pituitary, but function unknown
Structure of Gonadotropins LH and FSH
Glycoprotein
What are the subunits of Gonadotropins LH and FSH
Common α-subunit and different β-subunit that provides specificity (there’s LH-beta and FSH-beta gene).
the alpha-gene is not only common for gonadotropins, but also for TSH
What are the consequences of changes in glycosylation of Gonadotropins LH and FSH that may occur in circulation
different isoforms with slightly different biological properties
What is the receptor and pathways used by LH and FSH
G-linked: Activation of adenylate cyclase and also phospholipase C (PKA and PKC pathways)
What is the release pattern of LH and FSH
Pulsatile release (in response to GnRH)
Which cells have LH receptors? What is the pathways tiggered by LH binding in these cells?
Thecal cells in females; Leydig cells in males
1) Adenylel cyclase-> cAMP-> PKA
2) Phospholipase C-> DAG-> PKC
2) Phospholipase C-> IP3-> Ca2+
Which cells have FSH receptors? Which pathways are triggered in these cells by FSH binding?
Granulosa cells; sertoli cells
Adenylel cyclase-> cAMP-> PKA
What is the overall effect of gonadotropins on gonads
Oogenesis, spermatogenesis, steroidogenesis
Target cells and actions differ in male and female
- Testis: Only LH is steroidogenic (acts on Leydig cells)-> produce testosterone
- Ovaries: Both LH and FSH are steroidogenic act on two cell types (theca and granulosa cells)
What are the actions of LH and FSH in non-gonadal tissues?
v Increase of intracellular cholesterol.
v Transport of cholesterol to the inner mitochondrial membrane by StAR
v Conversion to pregnenolone; effect and mechanism similar to ACTH action in adrenal cortex
What is the role of sertoli cells?
sertoli cells main role is to support spermatogenesis, but they can also produce some estrogen when stimulated by FSH; thus sertoli cells also have some steroidogenic role
What are the 2 stages of follicules
- primordial
- primary
- secondary
What are the types of somatic cells in follicles
1) Theca cells are the endocrine cells associated with ovarian follicles that play an essential role in fertility by producing the androgen substrate required for ovarian estrogen biosynthesis.
2) A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete
What is a follicular antrum?
The follicular antrum is the portion of an ovarian follicle filled with follicular
What is the role of corpus luteum?
it is the main producer of progesterone which is essential for the establishment of pregnancy and maintenance
Positive and netative feedback of estrogen
low estrogen can have a negative effect at the level of pituitary and tonic center as a negative feedback loop. It will inhinbit LH and FSH release
but higher levels of estrogen can act upon the surge centre as a positive feedback which results in GnRH surge release-> pre-ovulatory FHS and LH surge-> ovulation
Do we have just 1 follicule growing at one particular time?
group of follicles grow together at a certain period of time, but there is one follicle that will continue to grow; other follicles will undergo attrition (death)
this one follicle becomes large- dominate follicle
When would dominant follicule ovulate?
dominant follicle doesn’t ovulate unless there’s and LH surge; will die if it doesn’t occur
Hormonal profile changes during estrous cycle
LH peak in the beginning- responsible for ovulation of the dominant follicle from the previous cycle
One at the end- initiation of the next cycle
LH has one peak per cycle, and then remains at a lower concentration for the rest of the cycle
Progesterone concentrations starts to increase after the begging of the cycle
This is because there’s a corpus luteum that is formed in the beginning of the cycle after ovulation
Remains functional for some time; then undergoes luteolysis and progesterone levels decrease
When progesterone levels are high: luteal phase
Low levels of progesterone: follicular phase as there’s only the follicle that is present (releases estrogen); responsible for LH surge
Estrogen there are periodic increases and decreases
Estrogen surge preseeds LH surge; this is the postive feedback that results in LH release
FSH surge along with LH surge
Smaller periodic increases in FHS
Peak estrogen levels is associated with low levels of FSH; low estrogen levels are associated with peak FSH levels- reverse relationship between FHS and estrogen- negative feedback regulation
how does the level of estrogen change as follicule growth?
as follicle growth, estradiol levels increase as dominant follicle is the main source of estrogen in females
What happens when a dominant follicule dies>
As dominant follicle dies, estrogen levels go down -> no negative feedback-> increase in FSH-> next wave
Surge in which hormone leads to ovulaion
FSH
What are the hormonal levels durign the Follicular phase
low progesterone levels, increased levels of estrogen-> stimulation of pre-ovulation gonadotropin surge-> ovulation
