Week 3: Ovarian and Menstrual Cycle Flashcards
Identify
When does oogenesis begin?
~week 4 of embryo
When does follicle formulation begin?
~week 18
How many oogonia do you have at birth
somewhere between 400,000 and 600,000 for your entire reproductive life
Describe the meitotic arrest of oocytes
All eggs are arrested at an early stage (prophase I) of the first meiotic division as a primary oocyte (primordial follicle). Following purberty, during each menstrual cycle, pituitary gonadotrophin stimulates completion of meiosis 1 the day before ovulation
Meiosis I proceeds until birth and then picks up again after puberty
Describe the process of the menstrual cycle
Portion of the ovary where the vasculature comes in
What is the final fate of corpus luteum
Corpora albicans (scars throughout every menstrual period of lifetime)
of Primordial follicles
about 400,000 - 600,000
What are the possible fates of primordial follicles?
Each primordial follicle has four possible fates:
- remain quiescent
- die by attrition
- begin development but later be lost by atresia
- or begin development and ultimately release an oocyte followed by formation of a short-lived corpus luteum
Describe the process of growth of Primordial follicles
they undergo cycles of growth and atresia
For the beggining growth after puberty, they grow independent of hormonal stimulation
If they are not rescued by gonadotropins they go into a cycle of atresia (85 days)
Growth is promoted by FSH
Follicle activation reversibility
follicle activation is irreversible
Describe the process of recruitment of primordial follciles
- Early growth is independent of hormonal stimulation and eventually cells reach a stage where they need to be rescued by FSH or will become atretic (atresia)
- follicles continue over several cycles of growth and rescued by gonadotropins (FSH) to grow each time
- The follicle destined to ovulate is recruited (along with a cohort of other follicles which managed to achieve adequate hormonal stimulation
Identify the features of primordial follicles
Describe the signalling pathway for primordial follicles
Endocrine cycle of hypothalamus ant pit amd ovary
hypothalamus -GnRH-> Ant. Pit -FSH & LH-> Ovary primordial follicle growth by FSH
What is the effect of FSH on primordial follicles
FSH induces aromatization of androgen and results in the production of estrogen in granulosa cells
Estrogen synthesis in granulosa cells
FSH -> granulosa cell FSH receptor activates aromatase
Androstendione/testosterone -Aromatase-> Estrone/Estradiol
How is a primordial follicle chosen for ovulation?
The follicle which produces the most estrogen from:
FSH stimulation and the conversion of Androstendione/Testosterone -aromatase-> Estrone/Estradiol
The production of E2 actually further stimulates the granulosa cell to convert more androstendione to Estradiol by increasing the number of FSH receptors on the surface of the granulosa cell
E2 AKA
Estradiol
What is Estradiol?
A very potent form of estrogen produced by granulosa cells in response to FSH activation of aromatase
Estradiold is also the most common estrogen component of birth control pills
Most common estrogen component of birth control pills
Estradiol
FSH receptor signals for upregulation
FSH and E2
Where are FSH receptors first detected on primordial follicles?
FSH receptors are first detected on the pre-antral follicle
Primordial follicle Estrogen production is limited by?
The number of FSH receptors
Ways to upregulate FSH receptors
- FSH raises the concentration of its own receptor on granulosa cells
- Estrogen increases the concentration as well
The success of pre-antral folicles to ovulate depends upon?
its ability to convert an androgen-dominated microenvironment to an estrogen-dominated microenvironment
What happens to a follicle/granulosa cells that are dominated by androgens?
wont become the dominant follicle
Identify features of secondary (pre-antral) follicles
Where are LH receptors in respect to the mestrual cycle during the secondary follicle stage
- LH receptors are present only on the Theca cells
- FSH receptors are only on the granulosa cells
What receptors do Theca cells have
During the secondary follicle stage Theca cells have LH receptors
*FSH receptors are only on the granulosa cells*
What receptors do granulosa cells have during the secondary follicle stage?
During the secondary follicle stage Granulosa cells have FSH receptors
*LH receptors are only on Theca cells*
Aromatase activity in Granulosa cells and Theca cells
The aromatase activity of granulosa cells far exceeds
Theca cells and granulosa cells function in making estrogen
LH receptor on theca cells causes conversion of cholesterol to androstendione
Granulosa cells also convert cholesterol to androstendione but not as much as theca cells
the androstendione then is converted by aromatase which is activated by FSH receptors
Theca cells produce more substrate (androstendione) for the aromatase in granulosa cells to produce more E2
Features of a tertiary follicle
Antrum which is filled with an estrogen rich fluid
How many follicles are still in the race in the tertiary follicle stage?
still a bunch
So how is a dominant follicle chosen?
- Estrogen acts as a negative feedback inhibitor of the hupothalamus (GnRH) which results in reduced pulsatile GnRH secretion and reduced FSH secretion
- Less FSH to the ovary leads to less help from FSH of the follicles
- The follicles that really upregulated the FSH receptors are able to continue to grow leading to a dominant follicle
- The fall of FSH leads to limited estrogen production of the less mature follicles
- The dominant follicle overcomes the decline of FSH by
- having more FSH receptors due to increased rate granulosa cell development and enhanced FSH action because of its high intrafollicular Estrogen concentration
Describe features of graffian follicle
increased vascularity brings more nutrients and FSH for more estrogen production
menstrual cycle day 9 events
On cycle day 9, the vascularity in the dominant follicle is twice that of other antral follicles allowing preferrential delivery of gonadotropins to the follicle
This is important for both the emerging dominant follicle as well as the early corpus luteum
dominat follicle and increasing negative feedback
The dominant follicle optimizes its own environment to the detriment of the lesser follicles
Graffian follicle progression
FSH focus change
- Mid-cycle, with increasing estrogen in the follicle, FSH changes its focus from up-regulating its own receptor to generation of LH receptors on the granulosa cells
- LH can also induce the formation of its own receptors in FSH-primed granulosa cells
What is the functional change of LH receptors appearing on the granulosa cells
This increase in LH receptors on the granulosa cells helps to prepare the follicle to become the corpus luteum
Describe the dual role of estrogen in the menstrual cycle
- Estrogen can have both negative and positive feedback on LH
- At low levels estrogen has a negative feedback on LH
- As estrogen levels increase it exerts a positive stimulatory feedback on LH
- This level of estrogen is generally not reached until the dominant follicle reaches ~15mm in diameter
Function of inhibin in the menstrual cycle
Important inhibitor of FSH secretion
Function of activin in the menstrual cycle
Stimulates FSH release in the pituitary and augments FSH activity in the ovary
Function of follistatin in the menstrual cycle
Suppresses FSH activity (likely by bindind activin)
Types of inhibin
Inhibin A
Inhibin B
When is inhibin A secreted and by what?
- secreted in the follicular phase by granulosa cells
When is inhibin B secreted and by what?
Secreted in the luteal phase
What stimulates the secretion of inhibin A?
Stimulated by FSH
What is the function of inhibin A?
suppresses FSH secretion
This withdrawal of FSH caused by inhibin further amplifies the effects on smaller follicles, helping to secure growth of the emerging dominant follicle
Graffian follicle and ovulation
LH helps synthesize proteases and cell membrane enzymes to cleave the follicle
bursts open releasing the oocyte
Describe corpus luteum formation
- upon ovulation, the membrane between granulosa cells and theca cells of the empty follicle breaks down and blood vessels invade
- granulosa cells hemorrhage into follicle and hypertrophy to form large yellow lutein cells
- Theca cells form the small lutein cells
- Both make progesterone due to LH stimulation
Describe the features of the luteal phase
- Progesteron produced by luteal cells
- Corpus luteum makes inhibin which inhibits FSH secretion
- Progesterone rises - negative feedback to hypothalamus and pituitary
- LH decreases from the negative feedback so progesterone decreases
Possible fates of the corpus luteum
sperm fertilizes egg process of pregnancy (corpus albicans)
or
process of menstruation
Identify hormones at specific time periods in the menstrual cycle
1 = FSH
2 = Estrogen
3 = LH
4 = Progesterone
Ovulation and meiosis
- Stimulation to ovulate (rising LH) induces the egg to continue through meisosis
- The first meiotic division is completed and the first polar body is formed prior to release of the egg from the ovary
- The second meiotic division begins immediately but stops at metaphase, where the oocyte remains arrested until fertilization
- Penetration by the sperm triggers completion of the final meiotic division and the formation of the second polar body
Abnormal menses Mnemonic
PALM-COEIN
Polyp
Adenomyosis
Leiomyoma (submucosal or other)
Malignancy & hyperplasia
Coagulopathy
Ovulatory dysfunction
Eendometrial
Iatrogenic
Not yet classified
or
POLICEMAN
menorhhaga amount of blood
~>80cc
Question 1
E. Progesterone
Histology of endometrium
What phase is this endometrium in?
Early proliferative
What phase is this endometrium in?
Late proliferative
What phase is this endometrium in?
Secretory
What phase is this endometrium in?
Menstrual
Day 1 of the menstrual cycle is?
Menses
When is progesterone in the menstrual cycle
only in the second half of the menstrual cycle
What does estrogen do to the endometrium
growth and proliferation
What does progesterone do to the estrogen
causes a little bit of growth but to create a 1:1 gland to stroma ratio and caps the growth for a stable structure for the possibility of implantation
Describe an endometrial biopsy
Simplified menstrual cycle for clinical purposes
What is the most common cause of irregular menstruation
anovulation
Endometrial cycle
estrogen first
progesterone after arrow (ovulation)
Question 2
A. Adenomyosis
nonfocal thickening and myometrium and pelvic pain are the clues
what kind of Symptoms from endometrial polyps
abnormal bleeding
what kind of Symptoms from endometritis
signs of infection
what kind of Symptoms from Leiomyoma
Heavy bleeding
what kind of Symptoms from Mittelschmerz?
pain of ovulation (middle cycle pain)
Adenomyosis vs Leiomyomata
Adenomyosis - endometrial glands and stroma in the myometrium (a form of endometriosus)
Leimyomata - polyp or fibroids
Question 3
C. Elevated LH
PCOS AKA
Polycystic Ovarian Syndrome
Polycystic Ovarian Syndrome clinical presentation
- Hyperandrogenism
- Anovulation
- Obesity/infertility
Polycystic Ovarian Syndrome epidemiology
5-10% of women
Polycystic Ovarian Syndrome diagnostic criteria
- Irregular menses caused by anovulation or irregular ovulation
- Evidence of elevated androgen levels
- signs (excess hair growth, acne or male-pattern balding)
- Blood tests (high androgen levels)
- Polycystic ovaries on pelvic ultrasound
Etiology of PCOS
- Insulin resistance
- leads to increased insulin
- high levels of insulin lead to increased production of ovarian androgens
- Interferes with ovulation, leading to infertility
- 50% risk of Type 2 diabetes by age 40
- High levels of LH and androgens interfere with menstrual cycle
- Classically, LH/FSH ratio is high
Question 4
B. Complex hyperplasia
Anovulation and the endometrium
unopposed estrogen
Pathophysiology of complex hyperplasia
Unopposed estrogen
Histology of complex hyperplasia
Endometrial cancer pathophysiology
More unopposed estrogen
Histology of Endometrial cancer
Question 5
D. 21 days
because 35 - 14 = 21 days
the luteal phase of the menstrual cycle is very regular while the follicular phase can be highly variable in length
Menstrual cycle length
majority of women 28 days
What determines the menstrual cycle length?
The duration of the follicular phase determines the menstrual cycle length (12-16 days)
The luteal phase is constant at 14 days
Length of the menstrual period closer to menopause
The follicular phase shortens the closer to menopause resulting in a shorter mentrual cycle length
Question 6
C. Granulosa cells begin to express LH Receptors
Describe the 2-cell gonadotropin model
occurs around mid-cycle
before mid-cycle the granulosa cells only have FSH receptors
Wrong answers to question 6
Important concepts of the 2-cell gonadotropin model
Question 7
A. Anovulatory cycles
clues:
- *proliferative*
- disorganized endometrial glands
- on day 20 she should be in the secretory phase
- since shes not must be anovulatory
- straight glands (progesterone causes 1:1 gland to stroma and they tend to be more tortuous)
Question 8
B. Complex hyperplasia
clues:
- 4 months of continuous bleeding throughout her cycle (think anovulation)
- anovulation is a risk factor for hyperplasia
- small crowded glands with atypia (atypia is concerning for endometrial cancer)
Question 9
E. Low progesterone
luteal phase defect should be debunked but the idea is that there is not a long-enough luteal phase, however, the luteal phase is thought to be constant so it doesn’t make a lot of sense
but the thought is that;
not enough LH receptors leading to insufficient progesterone leading to inadequate luteal phase
Describe the Luteal phase defect
luteal phase defect should be debunked but the idea is that there is not a long-enough luteal phase, however, the luteal phase is thought to be constant so it doesn’t make a lot of sense
but the thought is that;
not enough LH receptors leading to insufficient progesterone leading to inadequate luteal phase
Question 10
E. Progesterone
Question 11
E. Ovarian follicle
Question 12
Whats likely and whats bad?
Describe anovulation
Additional considerations
Endometrium on COCs
