Exam 2 - Female Repro Endo Flashcards
Describe the anatomy of the female reproductive system and the basic functions
vagina - site of sperm deposition/birth canal
cervix - selective barrier
uterus:
(myometrium) - expulsion of fetus at birth / muscular layer
(endometrium) - site of embryo implantation / glandular layer
ovary - site of ooctye, estradiol, and progesterone production
fimbria - pick up oocyte from ovary
ampulla - site of fertilization
isthmus - involved in embryo transport to the uterus
What are the two basic functions of the ovary? What are the two endocrine glands contained in the ovary?
functions:
- produce oocytes
- secretes hormones (estradiol and progesterone)
endocrine glands:
- follicle (contains developing oocytes)
- corpus luteum (derived from the follicle after ovulation)
How are the timings of sperm production and oocyte/hormone production different?
sperm production is continuous, while oocyte release and hormone secretion is periodic
Describe the basic structure of a follicle - what cells types are there?
follicle contains germ and somatic cells
germ cells: oocytes
somatic cells: granulosa and theca cells
Describe the process of oogenesis, including the phases, names of the developing oocyte in each phase, and chromosome/chromatid count.
oogonium (46/46) undergo mitosis and become primary oocytes (46/92) prior to birth (females are born with primary oocytes)
primary oocytes (46/92) start meiosis 1 but arrest in prophase 1 until puberty
after puberty, every month a single primary oocyte will complete meiosis 1 just before ovulation becoming a secondary oocyte and a first polar body (23/46).
The secondary oocyte is ovulated and starts meiosis 2 before arresting in metaphase 2.
If the secondary oocyte is fertilized, it will complete meiosis 2 and become a mature ovum and a second polar body (23/23).
What is the basic event that happens in meiosis 1 and meiosis 2?
meiosis 1: separation of homologous chromosomes, 46/92 –> 23/46
meiosis 2: separation of sister chromatids, 23/46 –> 23/23
When do the two arrests in oogenesis occur? What causes the development to resume in each case?
primary oocytes arrest in prophase 1 of meiosis 1, and complete it just before ovulation of that individual oocyte (1each month from puberty to menopause)
an ovulated econdary oocyte arrests in metaphase 2 of meiosis 2, and complete it if the oocyte is fertilized
Describe the follicular structures and what each structure looks like
primordial follicle - oocyte with one layer of granulosa precursors and an outer basal lamina
primary follicle - oocyte with one layer of true granulosa cells and an outer basal lamina
pre-antral follicle (secondary) - oocyte with multiple layers of granulosa cells, a basal lamina, and a layer of theca cells on the outside
antral/Graafian follicle - oocyte with many granulosa cells, a basal lamina, and many theca cells but the outermost layer called theca external cells
What types of follicles do not have theca cells? What does this mean?
primordial and primary do not have theca cells, so they do not produce very much hormone
What is the basic function of granulosa and theca cells?
granulosa - surround and nourish developing germ cells, role in hormone production
theca cells - role in hormone production
Describe the location/function of the basal lamina vs the zona pellucia.
basal lamina - Between the theca and granulosa cells, not touching the oocyte itself. Extracellular matrix that is secreted by the basement membrane, only role is separating these cells.
zona pellucida - First layer outside of the oocyte, before any granulosa cells. The mucopolysaccharide layer that surrounds the plasma membrane of the oocyte.
Granulosa cells that directly surround the oocyte inside the antrum of a Graafian follicle are called…
cumulus cells
The outermost layer of granulosa cells before the basal lamina/theca cells are called the…
mural granulosa cells
Just prior to ovulation, there is —– mature follicle(s) in the ovary.
1 - the dominant follicle
Describe the pathway of estrogen biosynthesis
cholesterol uses LH and cholesterol side-chain cleavage to become pregnenolone
Pregnenolone either:
becomes progesterone and uses 17a-hydroxylase to become 17 OH progesterone
or uses 17a-hydroxylase to become 17 OH Pregnenolone
17 OH Progesterone —> Androstenedione
17 OH Pregnenolone —> DHEA —> Androstenediol or Androstenedione
Androstenedione can:
- use FSH to become estrogens
- become testosterone and use FSH to become estrogens
What are the three estrogens and where do they mostly come from? What is the relative potency?
most potent = E2: estradiol, produced by granulosa cells
intermediate potency = E1: estrone, produced by peripheral conversion of adrenal androgens
least potent = E3: estriol, produced by the placenta
What is important about estrone compared to estradiol?
it is produced in small amounts, but it is the only estrogen produced after menopause
How do LH and FSH stimulate hormone production? What types of cells are involved, and how do they each work?
LH binds to the theca cell -
- activate cAMP to turn cholesterol to pregnenolone
- pregnenolone uses 17a-hydroxylase to become androstenedione
-androstenedione diffuses across the basal lamina to the granulosa cells
- in the granulosa cell, androstenedione becomes testosterone
- FSH binds to granulosa cells, activates cAMP production of aromatase to turn testosterone into estradiol
- cAMP also makes inhibin
In regards to theca and granulosa cells, what stimulates them, what do they produce, and what cells do they mimic in the male reproductive system?
theca - stim. by LH, produce androgens, analogous to Leydig cells
granulosa - stim. by FSH, produce estradiol, analogous to Sertoli cells
Late in the follicular phase, the granulosa cells experience elevated estradiol and FSH that stimulate…
development of LH receptors in preparation for ovulation
What are the three phases of the ovarian cycle?
follicular phase, ovulation, and luteal phase
After oogonia undergo mitosis, what happens next in the fetal ovary (during gestation)?
- by 20 weeks gestation, some oogonia are surrounded by a single layer of granulosa cells to form primordial follicles
- any that do not become a primordial follicle degenerate before birth
- primordial follicles form the reservoir from which all oocytes in adult females arise
- the oogonia within primordial follicles begin and arrest in meiosis 1 (firing primary oocytes) prior to birth and remain in this state until the individual follicle is recruited for ovulation (anywhere from 13-50 years)
Starting at birth and ending at puberty, what generally occurs in the ovary?
- the pool of primordial follicles gives rise to a continuous trickle of developing follicles
- prior to puberty, all developing follicles and oocytes within them undergo atresia
- after puberty, one follicle will reach maturity and be ovulated while all others undergo atresia
What is the average cohort of follicles per cycle for a 20 year old female vs a 40 year old female?
20Y: 10-20 follicles
40Y: 4-5 follicles
Is the signal to recruit follicles gonadotropin dependent?
No - independent of gonadotropin
What happens as a follicle develops into the small antral stage? Are the changes gonadotropin dependent?
gonadotropin dependent changes
form a zona pellucida, granulosa cells proliferate, and theca cells start to differentiate outside the basal lamina
What happens as a follicle develops into the antral stage? Are the changes gonadotropin dependent?
gonadotropin dependent changes
theca and granulosa cells become capable of estradiol synthesis and secretion, theca cells express LH receptors and granulosa express FSH receptors, estradiol is secreted into the antrum which then enters the systemic circulation and can affect other tissues
What happens during the selection phase of follicle development?
- the mature/Graafian follicle (generally only 1) bulges from the ovary
- follicle may be 15-20 mm in diameter
- elevated estradiol induces expression of LH receptors on granulosa cells in preparation for ovulation
What final change takes place to prepare for ovulation? How is this change/ovulation timed?
prostaglandins, collagenases, and proteases break down the wall of the ovary
timing is coordinated with oocyte development
What signal triggers ovulation? What 3 major changes take place as a result?
LH surge triggers ovulation
- stimulates follicular prostaglandin production
- stimulates differentiation of theca and granulosa cells into luteal cells
- reinitiates meiosis of the oocyte (complete M1 and start M2, produce first polar body)
After the follicle ruptures and releases the oocyte, the ovulated oocyte is surrounded by what?
cumulus cells (derived from granulosa cells)
At what point do follicles become dependent on gonadotropin stimulation for their growth and development?
Once they become antral
At what point does selection start occurring and some follicles undergo atresia?
starting on cycle day 1 (menses), when follicles are considered large antral follicles
What produces AMH in the female reproductive system?
primary (pre-antral) follicles, secondary (pre-antral) follicles, and small antral follicles
What types of follicles do NOT produce AMH?
primordial and large antral
What happens to AMH production with age? What do high and low levels of AMH indicate?
AMH decreases with age because follicular reserve/recruitment decreases and runs out
Low AMH - low follicle recruitment, low fertility or infertile
High AMH - PCOS, follicles get stuck in pre-antral stages and do not develop, instead they build up and produce more AMH
What is the approximate number of eggs at various life stages?
mid-gestation: 6-7 million oogonia
birth: 2 million primary oocytes
puberty: 400,000 primary oocytes
menopause: 0
What causes the decline in the number of eggs from mid-gestation to birth?
they undergo atresia if they don’t get covered in a layer of granulosa cells to become primordial
What is the average number of oocytes ovulated in a lifetime?
These are the only oocytes to undergo….
Only —– oocytes undergo meiosis 2.
450, these are the only ones to undergo all of meiosis 1.
Only fertilized oocytes undergo meiosis 2.
If a 20 year old woman is taking birth control pills or does not ovulate for some other reason, how many follicles are recruited each month?
10-20
Recruitment happens no matter what, can’t be controlled and is not FSH/LH dependent, they will just all undergo atresia
What happens to the remaining follicle after it ruptures during ovulation?
luteinization to form the corpus luteum:
- theca and granulosa cells differentiate into luteal cells that express LH receptors
- LH stimulates progesterone synthesis and secretion
- progesterone secretion increases as the size of the corpus luteum increases
Luteinized cells (theca lutein and granulosa lutein cells) have what changes to enzyme activity? What effect does this have on hormone production?
increases SCC enzyme activity
decreased 17a-hydroxylase activity
decreased aromatase activity
20x more progesterone than estradiol
How do the cells in the corpus luteum work together to produce progesterone (and some estradiol)?
In both the theca lutein and granulosa lutein cells:
LH stimulates cAMP to produce elevated SCC, converting more cholesterol to pregnenolone, which then converts to PROGESTERONE
In the theca lutein cells…
Less 17a-hydroxylase converts only some progesterone to androstenedione - diffuses over to granulosa lutein cells, becomes testosterone
lower FSH triggers less cAMP to produce less aromatase - converts only some testosterone to estradiol
How can you tell the difference between a follicle and the corpus luteum on ultrasound?
corpus luteum is less fluid, so it shows up as a solid structure/lighter color
the follicle has lots of fluid in the antrum so it appears dark
How does the endometrium change in response to elevated progesterone from the corpus luteum? How does this change the ultrasound image?
increased vascularization, glycogen content, epithelial cell endoplasmic reticulum, and mitochondria content
creates a hazy endometrium on ultrasound
What happens to the corpus luteum if a woman is not pregnant?
LH (a luteotropin) stimulates CL growth and biosynthesis in nonpregnant women
the CL functions for 14 days and then undergoes luteolysis (programmed degeneration of the luteal cells)
What happens to the corpus luteum if a woman is pregnant?
hCG is released after implantation, which stimulates CL growth and steroid biosynthesis until the placenta takes over
If a female patient has a 17a-hydroxylase deficiency, they may…
have decrease synthesis of androgens and estrogen (not progesterone, 17a-hydroxylase is not needed for that)
What are the two patterns of regulation of ovarian function, and what are their basic components?
Tonic (basal) LH secretion: regulates ovarian steroidogenesis via negative feedback, including follicular estradiol secretion and luteal progesterone/estradiol
LH surge: regulates ovulation via positive feedback that is triggered by a sustained, elevated estradiol
Describe the process of tonic (basal) LH secretion
GnRH release is pulsatile
In the follicular phase estradiol > progesterone
In the luteal phase progesterone > estradiol
Both have negative feedback on the hypothalamus via ARCKiss1 neurons
How does kisspeptin stimulate the adult reproductive axis in tonic (basal) regulation?
high levels of estrogens are sensed, suppressing the Kiss1 neurons, which suppresses the GnRH neurons, and causes less release of GnRH/LH/FSH
Why does estrogen’s negative feedback have to use the Kisspeptin route instead of directly contacting the GnRH neurons?
GnRH neurons don’t have classic estrogen receptors, but Kiss1 neurons do, and GnRH neurons have kisspeptin receptors called GPR54
When a female is menopausal, what happens to LH and FSH levels?
they increase (no ovarian estrogen production, no negative feedback, increase kiss stimulation, increase GnRH, increase LH/FSH)
Describe the LH surge/how Kisspeptin functions in the reproductive axis for this process.
When estradiol levels are elevated for a sustained amount of time, they have positive feedback on the hypothalamus via APVP Kiss1 neurons
really high estradoil will stimulate the AVPV Kiss1 neurons to stimulate more GnRH neurons, releasing more GnRH and more FSH/LH
Do the AVPV and ARC Kiss1 neurons function at the same time or separate times? Explain.
they can both be functioning at the same time, but when estradiol gets really high the AVPV neurons (the gas pedal) override the ARC neurons (the brake) and there is a net increase in stimulation
Why is the AVPV vs. ARC pathway unique between females and males?
AVPV is sexually dimorphic, meaning females have a 25 greater Kiss1 neurons than males, so they in turn have more AVPV neurons. This produces the sex-specific ability to have an LH surge (that males do not have)
When estradiol gets really high, what TWO changes happen that contribute to increase FSH and LH?
the anterior pituitary gonadotropes increase in sensitivity to GnRH (same amounts of GnRH will produce more FSH and LH)
the hypothalamus increases the pulses of GnRH secretion (more GnRH released overall)
GnRH must be —– for the maintenance of gonadotropin secretion. In what circumstance is LH or FSH favored?
must be pulsatile
fast: favors LH
slow: favors FSH
Describe the study by Wildt on monkeys.
ovariectomized female rhesus monkeys with hypothalamic lesions delivered 1 pulse of GnRH per hour
Each GnRH pulse was followed by an LH and FSH peak
Increasing the frequency increased LH but decreased FSH, while lowering the frequency increased FSH and decreased LH
What changes does the LH surge cause?
reinitiates meiotic division (finish meiosis 1 and start meiosis 2, stopping at metaphase 2)
stimulate follicular prostaglandin production
stimulate differentiation of theca and granulosa cells into theca lutein and granulosa lutein cells (all having LH receptors)
Females with PCOS have higher GnRH pulse frequency. What impact does this have?
favors LH over FSH, so estrogen secretion lowers and androgen secretion increases
What are the three phases of the ovarian cycle and how many days do they last?
follicular (1-14, variable)
ovulatory (day 14)
luteal (15-28, must be 14 days long)
Describe the follicular phase of the ovarian cycle
a cohort of follicles starts to develop
FSH stimulates the development of antral follicles and estradiol
On Day 6 - one follicle becomes dominant and others undergo atresia
Right before ovulation, granulosa cells express LH and FSH receptors
Describe the ovulatory and luteal phases of the ovarian cycle
ovulatory - LH surge stimulates ovulation of the mature follicle within 24-36 hours
luteal - corpus luteum forms and then degenerates in non-pregnant females
Describe the phases of the uterine cycle
menstrual - shedding
first day of menstruation is day 1
menses is the discharge of blood and endometrial tissue
proliferative - growth
estradiol stimulates the hyperplasia (growth) of epithelial cells
secretory - prep for possible implantation
progesterone stimulates vascularization, glycogen production, and increased epithelial endoplasmic reticulum/mitochondria
Describe the hormonal regulation of estradiol in the follicular phase
Negative feedback:
antral follicles secrete estradiol (and inhibin, both have suppress FSH)
suppression of FSH contributes to atresia of smaller follicles
low progesterone permits the rise of LH
Positive feedback:
rapid rise in estradiol, prepares body for fertilization, precedes the LH surge by 9-24 hours
What is the overall action of the LH surge? Why is the FSH surge so small?
converts follicle from estradiol to a primarily progesterone secreting tissue
inhibin diminishes the rise in FSH, so it is a smaller surge
How does an ovulation predictor kit work?
detects the LH in urine, start testing prior to expected LH surge, two lines indicate surge and the beginning of ovulation
Describe the hormonal regulation happening in the luteal phase
progesterone (and some estradiol) has negative feedback on LH and FSH
Corpus luteum secretes progesterone, which prepares the endometrium for implantation (triggers the secretion phase of the uterine cycle)
Luteolysis occurs 10-11 days after ovulation if implantation does not happen Luteolysis results in a decline in progesterone, permitting a rise in LH and FSH
Prostaglandins aid in menses
Why must the luteal phase be at least 14 days?
the embryo needs enough time to fully implant before the corpus luteum starts luteolysis and causes the endometrium to start shedding
What contributes to the thickness vs. the vascularization of the endometrium?
thickness - estrogen released during the follicular phase
vascularization - progesterone released from the corpus luteum in the luteal phase
Describe the changes in cervical mucus throughout the menstrual cycle
early cycle - sticky but minimal, low E and P
nearing ovulation - thinner, rising E and low P
at ovulation - thin and watery, high E and low P
right after ovulation - thick and sticky, low E and rising P
How does cervical mucus impact sperm movement? What are the general trends in how E and P affect cervical mucus?
thin watery secretions facilitate the movement of sperm while thick and sticky secretions don’t
high estrogen (from follicles) causes thinner mucus
high progesterone (from corpus luteum) and low estrogen cause thicker mucus
What is the name for using cervical secretions to monitor fertility?
Billings Ovulation Method
What are the general trends in basal body temp during the menstrual cycle?
rises after ovulation in parallel with progesterone from the corpus luteum, then drops when the corpus luteum degenerates and progesterone goes back down
What happens to the cervical mucus of a female who has had her ovaries removed?
there won’t be much - progesterone makes it thick (but there’s no progesterone since she isn’t ovulating or making a corpus luteum), and estrogen makes it thin (but there isn’t estrogen from follicles) so there just isn’t much at all.
Besides the ovaries, where else are estrogen and progesterone made?
small amount of estrogen from adipose tissues, no other producer of progesterone
Describe amenorrhea and anovulation
amenorrhea - failure to have menstrual cycles, primary (absence in a woman who has never menstruated, such as Turner’s syndrome XO chromosomes with no ovaries or testes) or secondary (cessation in a woman who has menstruated previously, for various reasons)
anovulation - ovulation doesn’t occur, generally associated with amenorrhea
Describe menstrual dysfunctions besides amenorrhea/anovulation
dysmenorrhea - painful menstrual cramps, overproduction of prostaglandins
menorrhagia - heavy or prolonged periods, needing to change tampon/pad less than 2 hours or clots the size of a quarter
endometriosis - cyclic growth of endometrial cells outside the uterus, can cause pain and infertility
luteal phase defect - short luteal phase, less than 14 days can cause infertility
