Reproduction 3

Question 1

What is the fundamental reproductive unit in the female?

Answer 1

follicle

Question 2

What is the female gonad?

Answer 2

ovary

Question 3

Describe the anatomy of the female reproductive tract.

Answer 3

Reproductive tract =
oviducts, uterus, cervix, vagina, external genitalia

upper 1/3 of vagina, through uterus and oviducts is considered internal genitalia- these are structures derived from Mull. ducts

Question 4

How is it that someone could lack female internal genitalia but have external female genitalia?

Answer 4

lower 2/3 of vagina, all external genitalia. those developmental processes controlled diff. this is why we see vagina could end in blind pouch w no internal genitalia (external structures go along default pathway)

male Pseudohermaprhoditism (46 XY loss of X linked AR gene 
Y chromosome – induces mullerian duct regression, testes (undescended); lack of androgen effects (no Wolffian duct development, no external genitalia)

Question 5

Describe the female pubertal activation of HPG axis.

(focus on GnRH)

childhood
puberty
reproductive years
menopause

Answer 5

Slide 8

GnRH activated at puberty by Kisspeptin in the hypothalamus

Increased GnRH pulsatility during REM sleep promotes secondary sex characteristics

GnRH stimulates pulsatile release of gonadotropins

in childhood GnRH turned off (no activity, no pulsatility, quiescent state) Kisspeptin will activate GnRH at puberty.

reprod. years its consistent. day and night no pulsatile change. only during puberty

metapause its elevated levels of GnRH across board (lack of neg. feedback occurring)

gonadotropins … lots of gonadotropin surges in fetus before birth, driving development

Question 6

What is the difference between the menstrual rhythm and menstrual cycle?

Answer 6

HPG axis feedback mechanisms generate a cyclical monthly pattern of hormone secretion called the “Menstrual Rhythm”

The menstrual cycle consists of physiological changes in 2 organs: ovary and uterus.
Ovary = ovarian cycle
Uterus = endometrial cycle

Question 7

How do ratios of LH: FSH change across female lifespan?

gestation, childhood, reproductive period, menopause/senescence

Answer 7

childhood- FSH more than LH

reprod. LH more than FSH

senescence FSH more than LH

FSH- early FSH imp. for initial development of follicles that happens in gestation.

Question 8

What are the two cell types in ovary? What receptors are present? Describe their action.

Answer 8

OVARY:

THECA CELLS –
Produce androgens and progestins
Have LH receptors

GRANULOSA CELLS –
Produce estrogens, progestings, inhibins, activins
Have both LH and FSH receptors

Question 9

There is negative AND positive feedback actions of estrogens. When does positive feedback occur?

Answer 9

positive feedback ONLY happens at time of ovulation.

Positive feedback important for ovulation

Question 10

When is day 1 of the cycle?

Answer 10

DAY 1 = FIRST DAY OF MENSES

Question 11

Describe the menstrual cycle. Ovarian and Endometrial. Describe the phases. Include approx time length.

What drives these physiological changes? What structure is signaled by these changes?

Answer 11

OVARIAN CYCLE – 3 PHASES (OVARY)
Follicular phase = growth of dominant follicle (10-14 days)
Ovulatory phase = follicle rupture and release of oocyte (1-3 days)
Luteal phase = formation of corpus luteum (14 days)

ENDOMETRIAL CYCLE – 3 PHASES (UTERUS)
Menstrual phase
Proliferative phase
Secretory phase

HPG AXIS HORMONES DRIVE COORDINATED PHYSIOLOGICAL CHANGES DURING THE MENSTRUAL CYCLE. PHYSIOLOGICAL CHANGES SIGNAL HYPOTHALAMUS

Question 12

What is a Graafian follicle?

Answer 12

this is the mature/dominant follicle.

Question 13

When do primordial follicles reach their peak?

How many are left at puberty?

Answer 13

Primordial follicles reach peak at 20 weeks gestation. Only 10% remaining at puberty.

primary oocyte, that has been arrested in diplotine stage of meiosis, surrounded by follicular cells. at time of birth (peak follicle at 20 weeks) have lost lots of primordial follicles, and by puberty only have 300,000 primordial follicles left (from starting w 7 mill. follicles), most die and undergo atresia before go any further maturation beyond primordial follicle …have about a tenth remaining that will grow and become primary, secondary, tertiary … 30, 000 will maybe grow, and 30,000 won’t go further
only 450 become dominant follicles during female reprod. lifetime

slide 17

Question 14

Describe primordial and primary follicles. What stimulates primordial to primary stage?

Answer 14

Primordial follicles: outer layer of pregranulosa cells + small oocyte
*oocytes are arrested in diplotene stage of prophase (meiosis I); no thecal cells

Primary follicles: larger oocyte surrounded by cuboidal granulosa cells

Require FSH stimulation to develop from primordial to primary stage… has to happen at time of puberty (when start getting increased levels of gonadotropins). Can happen in utero bc of spikes you see of FSH during infancy. some primary follicles at birth as well

Question 15

Describe secondary follicles. (How differ from primary? )

Answer 15

Secondary follicles:
Differentiation of stromal cells to Theca cells

Increased numbers of granulosa cells that become multilayered

Enlargement of oocyte

Question 16

What are pre-antral follicles?

Answer 16

Note: primary and secondary follicles are also called “pre-antral” follicles

if does not have antrum- call pre-antral…and can be primary and secondary state

Question 17

Describe the tertiary follicle.

Answer 17

Early antral follicle = tertiary follicle

Granulosa cells secrete fluid and create antrum

Granulosa cells closest to oocyte secrete mucopolysaccharides – forms zona pellucida
protective coating around oocyte that the sperm will have to penetrate through and this is why sperm needs hydrolytic enzymes in cap to penetrate through z. pellu. to get to oocyte.

*several antral follicles are “recruited” at the end of each ovarian cycle to become the next dominant follicle.

14 days to get to this point.

Question 18

How long does maturation from primary to Graafian follicle take?

How is it determined which becomes the dominant follicle?

Answer 18

10-14 days maturation from primary to dominant

The initial cohort of follicles that started maturing will all undergo atresia except 1 (usually).

Dominant follicle is based on sensitivity to FSH and local paracrine actions of AMH (produced by granulosa cells) AMH prod. by gran. cells. secrete in paracrine way to cause other follicles nearby to undergo atresia.

which becomes dominant dep. on FSH receptors and how sensitive a follicle is to FSH. the more FSH receptors a follicle has, the more sensitive to FSH and that will become the dominant follicle and the rest will die.

Question 19

Granulosa cells stratify to 3 types:

Which type will form luteal cells after ovulation? Which are most metabolically active? Which are shed at ovulation? Which are farthest from oocyte? nearest to ooycte?

Answer 19

Mural = farthest from oocyte. Lots of LH receptors; most metabolically active

Cumulus = near oocyte; shed at ovulation

Antral = face antrum; forms luteal cells after ovulation

gran. cells have both LH and FSH receptors.
Mural has most LH receptors ( all 3 types have lots of FSH receptors)

once oocyte released- cumulus cells go w the oocyte but Ant. remain behind and help to form the corpus lut.

Question 20

What type of oocyte do you have with a tertiary follicle?

Answer 20

NOTE: Oocyte is arrested until LH surge (day 13-14)
still a primary oocyte

oocyte here still primary. all way to end of follicular phase when get dominant follicle. still a primary. still in meiosis I.

at time of ovulation there is LH surge and that LH surge signals oocyte to enter into meiosis II

Question 21

Describe ovarian histology.

Where are follicles located? Where does follicular development occur?
What innervates?
Classical/non-classical endocrine gland? Why?

Answer 21

Cortex: follicles located in cortex (developing follicles all in slightly diff stages of development. )

Medulla: neurovascular innervation

follicular deve. happens in cortex of ovary… medulla is for vascular and NS innervation

Classical endocrine gland – no ducts to convey gametes to uterus
highly vascularized.

no ducts to convey oocyte into tubular system. oocyte is released into space- into peritoneal cavity
fimbrae of oviducts try to capture that oocyte as it is released and bring it into duct system.

Question 22

Describe the follicular phase of the ovarian cycle. At the beginning and end of follicular phase, describe the levels of FSH and LH relative to e/o and the significance.

Answer 22

NOTICE ratio of LH to FSH. slightly higher FSH at beginning of follicular phase and at end see FSH higher… imp. for recruiting new cohort of follicles that start to develop. as follicles start to develop, will start to make inhibin.
inhibin B will inhibit and shut of FSH. now LH higher… flip. that is an important switch.

FSH is high at end of cycle.
High FSH recruits new cohort of follicles to enter follicular phase.
Recruited follicles produce inhibin B – negative feedback on FSH
Decreased FSH ensures that only the follicle most sensitive to FSH survives

Question 23

When LH becomes greater than FSH, what will happen?

Answer 23

More LH than FSH – leads to increased steroidogenesis in thecal cells

Inhibin B has positive paracrine effect in thecal cells to augment steroidogenesis

Inhibin B has paracrine effect on ovaries (like in testes but InhibinB is not inhibitory in testes, has a positive effect… and augments steroidogenesis) but in pit. gland inhibits FSH to allow for switch.

Question 24

What do follicles produce as they grow?

What will the resultant feedback favor?

Answer 24

Growing follicles produce increasing amounts of E2

E2 feedback favors LH over FSH (high frequency, low amplitude GnRH pulses)

GnRH freq. dep. on estrogen feedback on FSH inhibited by inhibins. more LH prod.

Note: this negative feedback is not a complete shutdown, it just keeps the “volume” down as capacity builds.

estrogen prod. has positive effects on ovarian system and on the growth of ovarian follicles but also inhibit. effect on GnRH and at pit. gland. doesn’t totally shut it down but keeps process from building too quickly. high amplitude but low freq? GnRH pulses and keeps volume down so capacity builds
as follicles get bigger, make more steroids, estrogen will keep going up
estrogen keeps rising and eventually you get pos. feedback switch .

Question 25

Describe the two compartment theory of E2 synthesis. Describe what is happening in each compartment

Answer 25

Thecal cells have LH receptors - synthesize androgens Granulosa cells have LH and FSH receptors: FSH stimulates LH receptor expression – required for response to “LH surge” FSH increases aromatase expression -- converts androgens to E2 Thecal cell: LDLR and HDLR mediated uptake (cholesterol) LH increases expression of steroidogenic enzymes

Question 26

Describe the ovulatory phase of the ovarian cycle. | LH surge and ovulation

Answer 26

LH SURGE (periovulatory period 32-36 hours) Switch from negative to positive feedback Follicle continues to mature Oocyte completes meiosis I and enters meiosis II – secondary oocyte arrested at metaphase II (meiosis II completes upon fertilization) threshold of estradiol function where it will stimulate GnRH instead of inhibiting it. does switch from neg. to pos. feedback. surge in GnRH immed. followed by a surge in LH. OVULATION Expulsion of oocyte-cumulus complex out of ovary (into peritoneal cavity) Increased inflammatory cytokines Breakdown of ovarian wall expelled into peritoneal cavity …rupturing body tissue so that will induce inflammatory cytokines to be expressed and get complete breakdown of ovarian wall in enclosed space.

Question 27

When does the oocyte enter meiosis II? What stimulates this? How can the oocyte be classified now?

Answer 27

LH SURGE (periovulatory period 32-36 hours) Oocyte completes meiosis I and enters meiosis II – secondary oocyte arrested at metaphase II (meiosis II completes upon fertilization) surge in GnRH immed. followed by a surge in LH. LH surge is what then causes the oocyte to complete Meiosis I and enter Meisosis II.. now have secondary oocyte… arrested at that stage unless becomes fertilized at some point.

Question 28

Increased LH leads to more E2; more E2 leads to more LH….. POSITIVE feedback. LH surge – positive feedback is unsustainable.... OVULATION What is happening with E2 now?

Answer 28

E2 increases progesterone receptors Rupture of follicle causes decrease in E2 Loss of E2 positive feedback Decrease in LH to new plateau. once follicle ruptures and oocyte gone, dominant follicle making all those hormones not there anymore, so now get drop in estrogen at end of that cycle and get loss of that positive feedback and you establish a new plateau pretty fast. 1-3 days.

Question 29

Describe follicle maturation during the ovulatory phase. What forms during this phase?

Answer 29

Cumulus cell expansion. Forms corona radiata and cumulus oophorus Detachment of cumulus-oocyte complex – free floats in antrum Follicle forms bulge against ovarian wall (stigma) Slide 33

Question 30

What are the following: corona radiata cumulus oophorus stigma?

Answer 30

Cumulus cell expansion. Forms corona radiata and cumulus oophorus Follicle forms bulge against ovarian wall (stigma) corona radiata are the cumulus cells immediately around it (oocyte)

Question 31

In ovulation, after rupture of ovarian wall and extrusion of cumulus-oocyte complex? What happens to the rest of the follicle?

Answer 31

Increased vascularization Differentiation of mural granulosa cells into large luteal cells; thecal cells into small luteal cells- they will secrete lots of progesterone. end up w large amount of progesterone made from this structure.

Question 32

What is the corpus luteum? Major hormone product? What are levels of E2 like? Inhibin?

Answer 32

Corpus Luteum = remnant follicle Major hormone product = progesterone (imp. w preparing endometrium for implantation of a fertilized oocyte. still get estradiol made but not as high quant. still made from corpus lut.) Lower levels of E2 Follicle no longer producing inhibin B – less negative feedback on FSH Corpus luteum produces inhibin A LH and FSH will drop. reason you have LH dropping below the levels here, where you end up getting switch; bc you lose neg. feedback from inhibin- that the follicle was making so now FSH not as inhibited as LH…thats where you get that switch which is important for next cycle to begin.

Question 33

Summarize whole menstrual cycle.

Answer 33

FSH is stimul. growth of follicle and is up regulating the LH receptors on that follicle so it can respond to upcoming LH surge at ovulation. increases prod. of inhibin-which augments steroid prod. in Theca cells. despite fact that inhibin levels are increasing, cells most sensitive to FSH. setting up follicle to respond to LH surge. surge causes oocyte to complete meiosis I and enter meiosis II ..then after ovulation happens, LH causes formation of corpus luteum. (follicle stimulating hormone stimulates follicle during follicular stage to prepare for surge) then get surge and its called Leutizing hormone bc it creates the corpus luteum once follicle is remaining, oocyte has been released from this follicle - going to be captured by oviducts and sent down oviduct toward uterus. what remains behind is corpus luteum. (remnant of follicle) now gran cells make large cells. Theca make small ones. prod. lots of progesterone. progesterone HIGH in luteal phase. this imp. for what happens w endometrial lining and preparing it for implantation. progesterone is high, estradiol high but not as high as when follicle growing. pos. feedback turned off, neg. feedback again. FSH starts increasing again as inhibinB not prod. and this is imp. for setting up next cycle.

Question 34

Describe the luteal phase of ovarian cycle. What hormones are high? What will loss of LH lead to? What hormone would interfere with this process?

Answer 34

Negative feedback dominates High progesterone, E2 decrease GnRH, LH, and FSH Loss of LH will cause the corpus luteum to degrade unless it is “rescued” by the equivalent hormone secreted by implantation of a fertilized embryo- HCG. Absent HCG and LH, E2 and progesterone decrease, endometrium degrades, “withdrawal” bleeding (menses) indicates beginning of the next phase.

Question 35

What is the one thing that could prevent the corpus luteum from degrading?

Answer 35

Loss of LH will cause the corpus luteum to degrade unless it is “rescued” by the equivalent hormone secreted by implantation of a fertilized embryo- HCG. HcG can bind LH receptors and if fertilization embryo will make HcG and that will rescue corpus lut. so it can keep making high levels of estrogen and progesterone which are absolutely required for maintenance of endometrial lining. embryo makes that

Question 36

What will happen in the absence of HCG?

Answer 36

Absent HCG and LH, E2 and progesterone decrease, endometrium degrades, “withdrawal” bleeding (menses) indicates beginning of the next phase. in absence of fertilization corpus lut. dies and you cycle starts over. get withdrawal of endometrial lining and withdrawal bleeding.

Question 37

Draw out how progesterone, estradiol 17B, FSH and LH change throughout cycle.

Answer 37

Slide 41

Question 38

Given endometrial cycle, which phase is coincident with luteal phase, early follicular phase, or follicular phase?

Answer 38

Menstrual phase (early follicular phase) ``` Proliferative phase (coincident with follicular phase for ovary) ``` Secretory phase (coincident with luteal phase for ovary)

Question 39

Describe the uterine anatomy. Layers, parts. Which part is shed during mensturation?

Answer 39

3 LAYERS: Endometrium – mucosal layer (innermost) Myometrium – thick muscular layer Perimetrium – outer connective tissue and serosa (also called serosal layer) CERVIX – distinct from endometrium cervix is inferior extension of the uterus. has slightly diff. char. compared to rest of uterus. FUNCTIONAL ZONE – shed during menstruation (endometrium)

Question 40

Describe the functional zone of the uterus. Describe crucial components for embryo survival.

Answer 40

FUNCTIONAL ZONE – shed during menstruation Uterine glands – secrete substances for embryo survival Spiral arteries – reduced blood flow to spiral arteries results in ischemia >> necrosis of endometrial layer

Question 41

Describe vascular supply of functional zone and how this changes in menstruation.

Answer 41

uterine artery comes in (basal zone) and forms spiral arteries (high resistance arteries w low volume, so they will penetrate functional zone as endometrial lining grows. makes more and more vascular branches through this zone during cycle. menstruation = spiral arteries become ischemic… when uterine lining stops proliferating and they undergo necrosis and this is how lining starts to shed.

Question 42

Describe the ENDOMETRIAL CYCLE – PROLIFERATIVE PHASE. What hormone is dominant? Describe its action.

Answer 42

ESTRADIOL DOMINANT Increased E2 during follicular phase stimulates uterine cell growth *used to be used as a biological assay for “estrogenic” compounds E2 increases expression of progesterone receptors Increased vascularization

Question 43

Describe ENDOMETRIAL CYCLE – SECRETORY PHASE What hormone is dominant?

Answer 43

PROGESTERONE DOMINANT Uterine glands begin secreting large amounts of carbohydrate-rich mucus – becomes engorged High progesterone (from corpus luteum) has anti-estrogenic effects – stops further uterine growth Stroma becomes edematous Stromal cells undergo predecidualization (turning into diff kind of cell that have diff functions if embryo implants) Vascularization continues to increase

Question 44

Progesterone stops estrogen proliferation, so why must women who are taking estrogen also take progesterone with it if they still have a uterus present?

Answer 44

otherwise would have uncontrolled growth of uterus w nothing to stop proliferation from occurring but progesterone will antagonize this proliferation from continuing and you’ll build up to maximal level.

Question 45

Describe ENDOMETRIAL CYCLE – MENSTRUAL PHASE Describe hormones present.

Answer 45

LOW E2 AND P Low P4 and E2 due to demise of corpus luteum Reduced blood flow to spiral arteries results in ischemia and necrosis Proteolytic enzymes increase – digest tissue Blood does not clot due to fibrolysins – released from necrotic tissue Total volume loss ~ 30 ml

Question 46

Describe CYCLIC CHANGES THAT OCCUR IN THE FEMALE REPRODUCTIVE TRACT. Describe vaginal changes. What hormone dominates in mid to late follicular phase? How are epithelial cells affected? What hormone dominates in the luteal phase? When do you see cornified cells? When do you see basophilic cells?

Answer 46

Dominated by estrogens in mid- to late follicular phase Vaginal epithelial cells become large, squamous, cornified with small or absent nuclei Dominated by progesterone in luteal phase – small basophilic cells with many leukocytes. whole vaginal mucus becomes more acidic in this phase

Question 47

CHANGES IN CERVICAL MUCUS: Follicular phase? Ovulatory? In progesterone phase will mucus be acidic or alkaline?

Answer 47

Follicular phase: cervical mucus increases, becomes more alkaline and less viscous (sperm can survive longer and swim easier through vaginal canal) Ovulatory: Characterized by Spinnbarkeit (stretchable mucus); Ferning – pattern when dried on glass slide Changes promote survival and transport of sperm Primitive test for ovulation progesterone phase dominates then mucus is acidic and not hospitable to any additional sperm coming in

Question 48

How does body temp change during the menstrual cycle?

Answer 48

body temp increases at time of ovulation by about half a degree Slide 52

Question 49

Describe/summarize the actions of estradiol (E2).

Answer 49

Dominant follicle will secrete estrogen which will: - prime GnRH action on LH secretion to evoke ovulatory surge of LH - prepare uterine endometrium for progesterone to evoke secretory response - affect fallopian tube to favor transport of ovum and zygote - alter cervical mucus to enhance sperm transport - inhibit growth of cohort follicles