Reproductive endocrinology Flashcards
1
Q
what are the 2 sequential steps involved in sexual differentiation
A
- establishment of genetic sex (XX or XY)
- translation of genetic sex into gonadal sex (ovaries or testis)
- translation of gonadal sex into phenotypic sex (secondary characteristics + reproductive organs)
2
Q
About the X chromosome
A
- 160 megabases
- 5% of haploid genome
- encodes 850 proteins of which several regulate gametogenesis and hypothalamus-pituitary functions BUT most result non-reproductive functions
3
Q
About the Y chromosome
A
- 60 megabaess long (2% of genome)
- encodes 57 proteins of which most genes regulate reproductive functions
4
Q
most genes found on the X chromosome regulate reproductive functions. true or false
A
false, most genes regulate non-reproductive functions
5
Q
what is Klinefelter syndrome
A
47 chromosomes with XXY
6
Q
what is Turner’s syndrome
A
45 chromosomes with XO
7
Q
which genotype of sex chromosomes is nonviable
A
45 chromosomes OY
8
Q
what causes sex chromosome aneuploidy
A
nondisjunction of sister chromatids during meiosis
9
Q
what causes sex chromosome mosaicism
A
nondisjunction of sister chromatids in zygote
10
Q
if there is a Y chromosome with the ____ gene, there will always be a ____ phenotype
A
Y chromosome with functional SRY -> male
11
Q
what does the non-viability of OY confirm?
A
Confirms that X chromosome is important for development of female reproductive tract but also for non-reproductive functions such as development of embryo
12
Q
the Wolffian duct develops in _____
A
male reproductive tract
13
Q
the Mullerian duct develops in ______
A
female reproductive tract
14
Q
the ______ will differentiate into external genitalia depending on ______
A
urogenital sinus
depending reproductive tract
15
Q
_____ are essential for male sexual differentiation, but the _____ are not necessary for female differentiation
A
testes are necessary for male sexual differentiation
ovaries are not necessary for female differentiation
16
Q
germ cells are not _____ in origin
A
gonadal
17
Q
pathway to go from primordial germ cells to testis or ovaries
A
- primordial germ cells differentiate in allantoic ectoderm
- they migrate into endoderm
- migration along endoderm and hindgut to the genital ridges
- genital ridges develop in ovaries or testis depending on the sex chromosomes brought by primordial germ cells
18
Q
how do the primordial germ cells migrate
A
HORMONAL guiding with secretion of local factors
- they put be polar during migration
- migration involves cell protrusion and adhesion in the leading edge and retraction of the lagging edge
- guiding cells biochemically direct the migration
19
Q
what is the typical male development events during gestation
A
- germ cell migration until genital ridges -> differentiation into testis (week 5-6)
- Sertoli cells -> Mullerian duct regression
- Leydig cell -> Wolffian duct stabilization
- Male external genital differentiation
- external genital growth (week 20)
20
Q
____ cells are involved in regression of the Mullerian duct and _____ cells stabilize the Wolffian duct
A
Sertoli cells -> regression of M duct
Leydig cells -> stabilization of W duct
21
Q
what are the 3 pre-requisites for normal sex differentiation
A
- normal intact chromosome complement
- fully functioning sex determination genes
- intact steroidogenic pathway and receptors
22
Q
genital ridges are considered to be _____ as they can differentiation either into testis or ovaries
A
bipotential
23
Q
_____ are the regions on the X and Y chromosome s that can undergo recombination
A
Pseudoautosomal region PAR
24
Q
the _____ region of the Y chromosome contains the ______ gene that allows for development of the testis
A
Male specific region of Y (MSY) contains the Sex determining region of Y (SRY)
25
how can fertilization by sperm produces an XX male?
The SRY gene is located very closely to the PAR1 region that undergoes recombination. Therefore, if there is recombination beyond PAR1, the SRY gene will be transferred to X chromosome leading to a sperm with X + SRY => fertilization by sperm produce an XX male
26
how can XY genotype result in an female phenotype
the Y chromosome may have a deletes/muted SRY gene therefore the primordial gonad will develop into an ovary -> XY female
27
what is the role of the HMG box found on the SRY gene
HMG box is the DNA binding domain which can regulate transcription of target genes
28
what are the consequences of mutations in the DNA binding domain of SRY gene
non-functional SRY -> female phenotype development although XY chromosomes
29
gonadial differentiation is based on the presence or absence of _____
SRY
30
development of testes depend on _____ and _____ factors
transcription and paracrine factors
31
which transcription factor gene is expressed by SRY
SOX9
32
SOX9 drives the expression of _____ and ____ which are paracrine factors
FGF9, Amh, PGD2
33
If there is no SRY, there is no SOX9 thus the biopotential gonad develops into ovary due to _____, _____, and ____
WNT4, RSPO1, FOXL2
34
if there is an ovary, the ____ duct continues to grow and _____ duct undergoes regression
mullerian duct
| wolffian duct
35
if there is testis, the _____ duct undergoes regression
mullerian duct
36
How does the presence of testes results in male reproductive tract development?
if there are testes, Sertoli cells produce anti-mullerian hormones which bind to TGF-beta receptor 2 causing heterodimerization with TGF-beta receptor 1
-> phosphorylation of TGF-bR1 drives phosphorylate of transcription factors Smad: heterodimerization of Smad2 and 3 followed by trimerization with Smad4
Trimer complex translocates from cytoplasm to nucleus and binds to promoter region of genes expressing pro-apoptotic genes causing regression of mullerian duct
37
which genes cause regression of mullerian duct
pro-apoptotic genes
38
which nuclear receptor signals regression of wolffian duct, resulting in female reproductive tract and phenotype
NR2F2
39
what is the mechanism of action of NR2F2
NR2F2 inhibits FGF paracrine factor allowing for Wolffian duct regression
40
which are the survival factors for Wolffian duct
FGF
41
what are the various errors that can occur during sex differentiation
1. defects in testosterone synthesis or actions
| 2. congenital adrenal hyperplasia
42
what are the consequences of defects in testosterone synthesis or actions
androgen insensitivity syndrome -> there is testicular feminization
- phenotypic female with XY genotype
- no ovaries
- gonads develop into testes but cryptorchidism (undescended testicle)
- infertile (spermatogenesis is disrupted)
- blind ending vagina
43
in androgen insensitivity disorders, where can the error come from?
there is either disruption/problem with any of the enzymes involved in steroidogenesis converting cholesterol into androgen (steroidogenesisi stops at previous step) OR all the enzymes are functional and androgen metabolites are produced in sufficient amounts BUT problem is at the receptor level
44
what is congenital adrenal hyperplasia CAH
masculinization of external genitalia at birth due to hyperplasia of adrenal glands before birth -> excessive androgen production -> masculinization of genitalia
45
which enzyme is mission in CAH that causes reduced synthesis of aldosterone and cortisol but excessive androgen production
CYP21A2
46
what is the normal development of females external genitalia
- primordial gonad develops into ovary as there is not Y chromosome with SRY gene
- no testosterone -> no development of wolffian duct or male reproductive tract and no DHT (dihydrotestosterone)
- no anti-mullerian hormone AMH therefore mullein duct is maintained -> uterus
=> female external genitalia
47
what happens in CAH females in terms of phenotype development
- primordial gonad develops into ovary as there is not Y chromosome with SRY gene
- no anti-mullerian hormone AMH therefore mullein duct is maintained -> uterus
- HOWEVER there is more androgen synthesis from bona reticular due to lack of CYP21A2 therefore DHT (dihydrotestosterone) concentration Is high -> masculinization of external genitalia
48
what is responsible for masculinization of external genitalia in CAH female
high dihydrotestosterone DHT concentration due to increased androgen synthesis
49
when does sexual differentiation in brain (marked differences between the sexes - structural and behavioural) occur in primates
3-6 months prenatal
50
there is ______ in terms of brain structure
sexual dimorphism
51
how is sexual differentiation of the hypothalamus in male carried out
- the fetal testis secretes testosterone which freely enters the brain and is converted to estradiol/estrogen
- estrogen defeminizes the surge centre in males (does not develop)
- male has tonic cents to control LH/FSH post-puberty
52
unlike males, females have both _____ and _____ that are active
females have both tonic and surge centers
53
what is the difference between male and females in regards to sexual differentiation of the hypothalamus
- males have fetal testes that secrete testosterone which can cross the blood Brian barrier and be converted into estradiol which eventually inactivates the surge centre (defeminization) and keeps only tonic centre active to control LH/FSH post-puberty
- in females, estradiol produced by fetal ovary cannot cross the blood brain barrier as it binds to alpha-FetalProtein (a-FP) thus, the female restainssurge centre + tonic centre to control LH/FSH after puberty
54
the lack of estrogen inside the CNS allows for development of ______
surge center
55
what are the functions of alpha-fetal protein
a-FP is produced very early in embryonic development, it is also produced by fetal liver and functions as albumin, binding to fat soluble molecules
it can also bind to estrogen in females which allows for the development of the surge centre since estrogen won't be able to cross the BBB
56
describe the hypothalamo-pituiary-gonadal axis
- environmental factors + physiological factors act on brain/hypothalamus -> secrete GnRH -> acts on pituitary -> LH and FSH are secreted and acts on gonads -> gametogenesis, gonadal growth, steroidogenesis (testosterone or estrogen)
Steroidogenesis has a negative feedback on hypothalamus and pituitary
57
what are the functions of the gonads (testis and ovaries)
gonads -> gametogenesis and steroidogenesis
| Steroidogenesis -> electrolyte homeostasis, fuel and protein metabolism, adiposity ad muscle mass
58
describe the plasma testosterone levels at various ages in human males
- increase during fetal development
- increase during Neo-natal period
- gonads quiescent pre-pubertal period (super low levels)
- exponential increase in levels during puberty
- slow decrease during adulthood and onwards
59
what are the signs of female puberty? male puberty
- females: first cycle - menarche in women
- males: first ejaculation - semenarche/spermache
=> both events do not signify fertility (fertility reaches its maximum later than puberty)
60
GnRH is released in a ____ fashion. It controls _____
pulsatile fashion
| controls puberty/sexual development
61
tonic enters are extremely sensitive to ________
steroid negative feedback
62
what happens before puberty and after puberty in regards to changes in hypothalamic secretion of GnRH
Before puberty: in female and male, GnRH neurons in both the tonic centre and the surge centre of the hypothalamus release low amplitude and low frequency pulses of GnRH
After puberty: in female, the tonic centre controls basal levels of GnRH but they are higher than in prepubertal female because the pulse frequency increases. The surge centre control the preovulatory surge of GnRH. the male does not develop the surge centre
63
what controls the preovulatory increases of GnRH
the surge centre -> controls preovulatory surge in GnRH
64
what causes the increase in GnRH pulses (amplitude and frequency)
decreased sensitivity of TONIC centre to negative feedback from gonadal steroids
65
which neurons regulate pulsatile secretion of GnRH
Kisspeptin KISS1 neurons
66
where are Kisspeptin neurons located
located in anteroventral periventricular and arcuate nuclei of the hypothalamus
=> AVPV and ARC nuclei
67
the KISS1 enrols in ARC are initiated by _____ and regulate ______
inhibited by steroid feedback and regulate tonic centre => negative feedback
68
the KISS1 neurons in AVPC are activated by _____ and regulate _____
activated by estradiol and regulate tonic centre
69
GnRH neurons don't express _____ thus their regulation is done by other neurons _____
GnRH neurons don't express steroid hormone receptors (androgen receptors) thus are regulated by KISS1 neurons
70
GnRH stimulate gonadtraophs in ______
anterior pituitary
71
GnRH is only synthesized in the hypothalamus. true or false
false, it is also synthesized din the placenta, gonads, breast, lymphocytes and pituitary but the function is unknown
72
FSH and LH have a common ____ sub and different ____ subunit
common alpha subunit
| different beta subunit
73
the alpha chain of FSH and LH is also common to ____
TSH
74
LH stimulates GPCR receptors and activate which pathways?
cAMP/PKAabd PLC-> IP3 and DAG
75
FSH stimulates GPCR receptors and activate which pathway
Granulosa cells and sertoli (male) cells -> cAM/PKA
76
what are the actions of LH and FSH
similar to ACTH on adrenal cortex cells
- increase of intracellular cholesterol
- trnasport of cholesterol to the inner mitochondrial membrane by StAR (rate limiting step)
- conversion to pregnennolone by side chain cleavage (CYP11A1)
77
what are the target cells of LH and FSH in tetsis
LH acts on Leydig cells (testosterone) and FSH on Seertoli cells (estradiol)
78
what are the target cells of LH and FSH in ovaries
LH acts on theca interna (testosterone), granulosa cells (estradiol) and luteal cells (progesterone) and FSH acts on granulosa cells (estradiol)
79
what are the three difference cell types of importance in spermatogenesis
- spermatogonia
- sertoli cells
- leydig cells
80
which are the most important androgens secreted by testes
DHEA and testosterone
81
adrenal and testes contribution to DHEA and testosterone secretion is equivalents. true or false
false, testes have a greater contribution to androgen secretion -> adrenal secretion contribution is less than 5%
82
98% of testosterone and DHEA secretion is in bound form. what do they bind to
albumin and sex-hormone binding globulin SHBG
83
testosterone can be converted into ____ (its active form) or _____
DHT or estradiol
84
what is the action of androgens
powerful anabolic hormones
- production of steroid hormones -> secondary sex characteristics at puberty
- spermatogenesis, skeletal muscle growth, larynx development, hard growth, behavioral changes, changes in excretion of sebaceous gland (acne)
85
the oocyte is surrounded by single cell layer of granulosa to form ______
primordial follicles
86
there is a _____ in number of primordial follicles before brith and a _____ of primordial follicles after birth
an increase in number until 5th month of gestation
| after that -> continuous loss
87
which follicles en up ovulating
mature follicles
88
the remnant of ovulated follicle forms ______
corpus luteum
89
what is the relationship between theca/LH and granulosa/FSH cells
the cells of the theca interna contain receptors for LH. Theca cells produce testosterone from cholesterol that diffuses into the granulosa cells that contain FSH receptors. Binding of FSH to the granulosa cell receptors causes the synthesis of enzymes that are responsible for the conversion of testosterone to estradiol
90
which enzyme is responsible for the conversion of cholesterol into testosterone in theca cells
CYP17A1
91
which enzyme is responsible for the conversion of testosterone to estradiol E2 in granulosal cell
CYP19A1
92
ovarian follicles have 2 somatic cells which are
granulosa cells and theca cells
93
what are the 2 conditions for estradiol to have a positive feedback on surge centre
1. high estradiol
| 2. low progesterone
94
inhibit produced by granulosa cells of ovary specifically inhibits ____- secretion
FSH
95
what is he difference between tonic vs surge centre
- tonic center relates small episodes of GnRH in a pulsatile fashion similar to a dripping faucet -> episodic release is continuous throughout reproductive cycle
- surge centre is sensitive to positive feedback and releases high amplitude, high frequency pulses of GnRH (gushing, wide-opened faucet) in a relatively short period after estrogen reaches a threshold level
96
ovulation occurring at the middle of menstrual cycle is preceded by a dramatic increase in LH. why?
the dramatic release is due to preovulatory LH surge from surge centre positively regulated by high estradiol and low progesterone
97
what are the changes occurring during the menstrual cycle
- in the early part of the menstrual cycle, there is an increase in FSH (follicle stimulating hormone) which stimulates follicle growth and maturation
- the maturing follicle will release estradiol
- high estradiol concentration in combination with low progesterone will have a positive feedback on the surge centre and stimulate GnRH release
- GnRH release will cause a dramatic increase in LH right before ovulation happening mid-cycle => pre-ovulatory LH surge
> all of this describes the FOLLICULAR PHASE
- once ovulation occurred, the remnants of the follicle will develop into corpus luteum
- the corpus luteum produces a lot of progesterone -> surge in progesterone concentration + increase in estradiol
- decrease in progesterone and estradiol + increase in FSH -> luteolysis
> LUTEAL PHASE
98
what are the 2 phases involved in the menstrual cycle
- follicular phase
| - luteal phase
99
women have ____ cycles where are bovine have _____ cycles
```
menstrual cycle (mess at the beginning and end of cycle, ovulation in the middle)
estrous cycle (ovulation occurs at the beginning and end of cycle)
```
100
what is the hormonal profile during estrous cycle
- Luteal phase: increase in FSH which stimulates follicular wave development increase in progesterone and estradiol for follicular development -> no LH surge -> no ovulation + FSH peak with low estradiol -> negative feedback on pituitary (GnRH)
- Follicular phase: low progesterone, high estradiol -> positive feedback on surge centre -> pre-ovulatory LH surge -> ovulation
after ovulation, corpus luteum development > progesterone increases -> goes back to luteal phase
101
the dominant follicle is the one to secrete ____. if at this time there is high progesterone due to _____, there will be no _____.
dominant/mature follicle secretes estradiol. if at this time there is high progesterone due to corpus luteum, there will be no LH surge and in turn no ovulation
102
reduction fo estradiol allows for _____ to increase causing a second follicular wave
FSH concentration
103
pre puberty there are waves of _______ but due to insufficient ______ there is no _____ and atresia occurs
follicular growth but due to insufficient FSH/LH there is no maturation and atresia occurs
104
how does the resumption of the first meiosis occur
the pre-ovulatory LH surge causes the breakdown of the gap junctions between the granulosa cells and oocytes therefore the molecules inhibitory of meiosis will no longer be provided by granulosa cell -> resumption of meiosis
105
how does the preovulatory LH surge allow for fertilization
preovulatory LH surge breaks-down the gab unction between granulosa cell and oocyte -> removal of meiotic inhibition -> first polar body (small daughter cell) -> haploid oocyte, 2nd polar body (big daughter cell ) -> can undergo fertilization
106
fertilization can only occur if _____ occurs
ovulation (haploid oocyte has to get out of follicle)
107
what are the ovarian events caused by the preovulatory LH surge leading to ovulation
- increase in blood flow to ovary and dominant follicle -> increase in follicular pressure
- increase in PGF2alpha -> increase in contraction of ovarian smooth muscle and release of lysosomal enzyme -> increase in follicular pressure and follicle wall weakens, respectively
- shift from estradiol to progesterone by dominant follicle -> follicle wall weakens
=> increase in follicular pressure + follicle wall weakens => ovulation
108
what are the 3 factors allowing for ovulation
- follicular rupture
- luteinization
- resumption of meiosis
109
LH stimulates the corpus luteum to secrete ____
progesterone
110
the formation of corpus sputum is also known as ____
luteinization
111
what are the effects of the progesterone secreted by CL
- P4 has negative feedback on GnRH neurons of hypothalamus -> GnRH, LH/FSH suppressed -> little sterogen produced
- P4 exerts positive influence of endometrium of uterus -> embryo development
- P4 has negative effect on contractility of myometrium
- involved in development of mammary gland if fertilization occurs
112
if there is no fertilization, what happens to CL
luteolysis
113
what is the proposed mechanism of luteolysis in primates
increased concentration of oxytocin within ovary that contain CL which increases protaglandin F2 alpha -> luteolysis -> reduction of progesterone and estradiol -> menses
