Lecture 8:female Reproductive Cycle

Front 1

in menstrual cycle there is follicular phase and luteal phase describe what happens to GnRH pulses,Anterior pituitary hormones,ovarian hormones,and ovary as you go through cycle

Back 1

GnRH pulses:steady in follicular, lot more before ovulation, less pulses in luteal
Anterior pituitary Hormones: in follicular FSH little higher than LH, before ovulation LH/FSH peak (LH lot higher since its the trigger),in luteal phase low steady levels
Ovarian hormones: progesterone is low throughout follicular but after ovulation increases (due to corpus luteum and placenta if pregnant). Estradiol steady increase in folicular then peaks before ovulation and in luteal declines and steady.
Ovary: in follicular have recruitment,selection of follicle, dominance. Then ovulation and rupture of follicle into corpus luteum. Then that degrades near end of luteal phase.

Front 2

GnRH also called GNRH1 has ___forms in humans but ___most relevant to reproduction

Back 2

two,GNRH1

Front 3

GnRH is decapeptide processed from pre-proGNRH1 precursor and is secreted from nerve terminal in___into___

Back 3

ME,pituitary portal vessels

Front 4

GnRH is the_____pathway for neural control of reproduction

Back 4

final common

Front 5

need GnRH for sexual maturation in humans. People with hypogonadotropic hypogonadism (HH) have what problem and whats the mutation?

Back 5

delay/absence of puberty since gonadotropin deficient; frame shift (1 bp insertion) in the GNRH1 gene and is autosomal recessive

Front 6

theres not many GnRH neurons and they are found dispersed in the____and ____

Back 6

POA,MBH

Front 7

hypogonadal mice (hpg) cannot make___protein and therefore are ___and ___

Back 7

GnRH,infertile,sexually immature

Front 8

hpg mice reproductive tissues dont mature, the seminal vesicles are___sensitive while uterus is ____sensitive

Back 8

androgen,estrogen

Front 9

in hpg mice if give them POA graft see reproductive tract development. In female mice LH increases after ovaries taken out do to _____ but this is not seen in hpg/POA mice. _______ suppresses LH in normal females but doesn't in hpg/POA.Hpg/POA do not _____ spontaneously. But hpg/POA mice still have mating behaviour,reflex ovulation,pregnancy,give birth. All in all this shows that

Back 9

-no negative feedback
- Estradiol
-ovulate
-in hpg/POA graft the neural connection for regulating GnRH secretion not made and that GNRH neurons are NOT direct targets of steroid (-) or (+) feedback

Front 10

GNRH neurons are regulated ____synaptically

Back 10

trans

Front 11

GnRH is regulated more at level of

Back 11

release than synthesis.

Front 12

GnRH release in

Back 12

pulses,

Front 13

the pulse generator in rhesus monkeys found in ___(2)

Back 13

MBH/Arc nucleus

Front 14

main endogenous regulators of GnRH secretion

Back 14

theres neural: dynorphin A, Kisspeptin, Neurokinin B
theres endocrine: sex steroids,adipose hormones,melatonin

Front 15

during menstrual cycle have both negative and positive feedback. MOst of cycle is negative and the positive comes at the time of

Back 15

pre ovulatory gonadotropin surges

Front 16

predominant mediator of estrogen feedback

Back 16

estrogen receptor alpha

Front 17

two types of estrogen receptor alpha and beta beta is smaller. Their genes have 5 important sites

Back 17

-transcriptional activity
-DNA binding
-HInge
-Ligand binding (need ligand to activate TF)
-agonist/antagonist distinction

Front 18

If you knockout ERalpha see____

Back 18

increase estardiol and infertility (loss of neg feedback)

Front 19

In vivo the GnRH neuons do not express ERalpha true or false

Back 19

true

Front 20

estradiol does what to GnRH neuronal activity

Back 20

it inhibits it

Front 21

kisspeptins have role in

Back 21

estrogen negative feedback, its a trans synaptic effect

Front 22

progesterone also has negative feedback at __level mainly and inhibits

Back 22

hypothalamic,GnRH neuronal activity

Front 23

are there progesterone receptors on GnRH neurons

Back 23

no

Front 24

progesterone receptors in what areas (3) and are affected by feedback

Back 24

arc nucleus,VMN,POA

Front 25

both ER and PR seen in the arcuate nucleus

Back 25

true

Front 26

in female rats during LH surge the ____nucleus neurons are activated

Back 26

anteroventral periventricular

Front 27

both ______and _____ neurons project into GnRH neurons in mice

Back 27

AVPV;ERalpha

Front 28

in mice who's Er alpha has been knocked out the mice do not show surges of ____or activation of ___neurons

Back 28

LH;AVPV

Front 29

estrogen at hypothalamic level does what feedback and at pituitary?

Back 29

negative/positive,positve

Front 30

in global ER knock out mice LH levels are___?in specific gonadotrope ER alpha knockouts LH levels____

Back 30

high, normal both due to negative feedback

Front 31

ER knockout in specific neurons lack____. Gonadotrope specific ER knock out are acyclic and infertile. At pituitary level estrogens modulate____

Back 31

estrogen induced LH surges;GnRH induced LH release

Front 32

GPR 54 what is it and where expressed (5)

Back 32

-kisspeptin receptor
-g protein coupled receptor
-in brain (hypothalamus GnRH neurons), pituitary,placenta,pancreas,spinal cord

Front 33

why are GRP54 knockout mice reproductively immature and infertile (2)

Back 33

-impaired gonadatropin secretion
-impaired GnRH secretion

Front 34

Kisseptin-54 is major peptide product cleaved and is called metastin since it

Back 34

inhibits metastasis

Front 35

kisspeptin-54 cleaced into smaller pieces and they have ___affinity for GPR54

Back 35

equivalent

Front 36

Kisspeptins expressed in

Back 36

placenta,testis,small intestine, brain (Arc, AVPV)

Front 37

kisseptins stimulate_____ by regulating ______and is released in

Back 37

pulsatile LH release;GnRH neurons; pulses in association with GnRH

Front 38

kisseptin stimulated LH release is ___dependent

Back 38

GnRH

Front 39

estradiol ___Kiss1 in the ___of mice (negative feedback) via DNA binding_______ activity ERalpha

Back 39

inhibit,arcuate nucleus,independent

Front 40

estradiol ___Kiss1 in the ___of mice (positive feedback) via DNA binding-______ activity of ERalpha

Back 40

stimulate,AVPV,dependent

Front 41

loss of estrogens leads to ____in KISS1 mRNA expression in Arc nucleus

Back 41

increase

Front 42

summary: kisspeptins role in steroid feedback to regulate GnRH secretion (7)

Back 42

-potent GnRH secretagogues
-kisspeptins neurons from AVPV/Arc project to GnRH neurons
-GnRH neurons have GPR54
-kisspeptin cells in brain regions important for steroid feedback (Arc,AVPV)
-kisseptin neurons have estrogen/progesteron receptors
-estrogens regulate kisspeptin expression such that inhibited in Arc(neg feedback on pulse generator) and stimulated in AVPV (positive)
-kisspeptins provide mechanism for trans synaptic regulation of GnRH neurons by steroids

Front 43

during GnRH/LH surge estrogens

Back 43

at the same time stimulate kisspeptin expression in AVPV and inhibit kisspeptin expression in Arc.

Front 44

in rodents they have both AVPV and arc containing Kisspeptin neurons with estrogen receptors on them. But in all other mammals

Back 44

they lack the neurons in AVPV. So just have Arc with kiss neurons still responding to either positive/negative feedback. Also in non-rodents the kisseptin neurons have Progesterone and estrogen receptors

Front 45

in rodents there's positive feedback by high estrogen levels stimulating GnRH release via increased kisseptin by AVPV neurons. Also see effects at pituitary level

Back 45

true

Front 46

arc kisspeptin neurons co express (2)

Back 46

neurokinin B and dynorphin

Front 47

KNDy neurons=

Back 47

kisspeptin+ neurokinin B + dynorphin

Front 48

neurokinin B stimulates

Back 48

GnRH/LH via kisspeptin

Front 49

if you mutates the NKB gene (TAC3) or its receptor's gene (TAC3R) it causes

Back 49

HH

Front 50

Dynorphin

Back 50

inhibits GnRH/LH release

Front 51

so KNDy may be the

Back 51

GnRH pulse generator