Endo 2: 9 Komar Female Reproductive

Front 1

Describe the Hypothalamic-Pituitary-Gonadal axis.

Back 1

- GnRH from the nasal placode migrates to the hypothalamus and into the anterior pituitary.
- the anterior pituitary releases LH and FSH which acts upon the testis and ovary.
- the testis produce inhibin (which inhibits release from the anterior pituitary) and testerone (which inhibits GABA)
- the ovary produces inhibin (inhibits ant. pit.), Estradiol (inhibits anterior pit. and GALP), and progesterone (which inhibits as well)

Front 2

What stimulates the release of LH and FSH?

Back 2

GnRH or LHRH (luteinizing hormone releasing hormone), released in pulsatile pattern and originate outside of the CNS

Front 3

How does the pulsatility of GnRH effect Gonadotropin secretion?

Back 3

LH - is released rapidly
FSH - is released more slowly

Front 4

What hormones are associated with what stage?

Back 4

Estradiol = follicular stage
Progesterone = luteal phase

Front 5

What is the menstrual cycle?

Back 5

- a 28 (21-35) day cycle divided between a follicular phase and a luteal phase. The follicular phase marks the beginning of the cycle, and starts during menses.
- (While the length of the follicular phase can vary, the luteal phase always precedes the onset of menses by 14 days)

Front 6

What are the histological stages of the follicular phase? 4

Back 6

Primordial follicle → Primary follicle → Secondary follicle → Graafian follicle, with atresia of neighboring follicles.

Front 7

Describe folliculogenesis: the primordial follicle.

Back 7

-Primordial follicle - oocyte development has been arrested in meiosis I (prophase I).
- It is surrounded by squamous cells. As the follicle is stimulated to grow, the oocyte becomes larger and the flat squamous cells begin to become cuboidal.

Front 8

Describe folliculogenesis: the primary follicle.

Back 8

- the flat squamous cells have became cuboidal cells that have differentiated into granulosa cells.
- the granulosa cells begin to grow and divide to eventually create a basement mem.
- the zona pellucida forms
- oocyte is fully grown

STAGE DETERMINED WHEN GRANULOSA CELLS SURROUND THE OOCYTE.

Front 9

Describe folliculogenesis: the secondary follicle.

Back 9

- the basement laminae grows and separates the stromal layer and the developing thecal layer
- granulosa grows surrounding the oocyte and divides it from the thecal layer

Front 10

Describe folliculogenesis: the tertiary follicle/graafian. (antral).

Back 10

- the theca externa develop and secrete hormones
- antrums develop - fluid filled cavities w/ waste and nutrients b/c the thecal cells are vascular but the rest of the follicle is not.

Front 11

What is a Graafian cell?

Back 11

A large antral follicle

Front 12

What is the timeline for follicular development?
1. Primordial to primary?
2. Primary to secondary?
3. Secondary to early antral?
4. Early Antral to Graafian?

Back 12

1. Primordial to primary = 150 days
2. Primary to secondary = 120 days
3. Secondary through early antral = 71 days
4. Small Antral follicles to Graafian = 14 days


If women are on replacement hormones and stop them, they might still have an effect for months afterwards.

Front 13

What are the 2 gonadotropins and 2 cells involved follicular steroidogenesis?

Back 13

2 cell: 1) theca
2) granulosa

2 gonadotropins:
1) LH
2) FSH

Front 14

What cell produces Estradiol? And which receptor does it have? What is the other cell?

Back 14

1. Granulosa produces Estradiol and has the FSH receptor
2. Theca cells produce Androstenedione and have a LH receptor

Front 15

What is the relationship between the Theca and granulosa cell?

Back 15

Granulosa cell is dependent on the theca cell for androgen b/c it doesn’t have 17 alpha OH. Theca don’t have aromatase so they cant produce estrogen, theca only produce androgens. Both cell types are needed.

Granulosa develop LH receptors and can pump out even more estradiol.

Front 16

What is Inhibins? Action?

Back 16

- peptide hormones produced by granulosa cells and luteal cells
- inhibits FSH

Front 17

What the hell is AMH? Action? Why do we measure it?

Back 17

1. produced by granulosa cells from 2º stage to small antral stage of development
2. restraining influence on growth of primordial / primary follicles
3. used to assess follicular reserve; hyper-/hyposecretory states

Front 18

Explain the roles of hormones during the follicular stage.

Back 18

1. Follicles will begin to grow and inc their numbers. They then produce estradiol and inhibin.
2. These feedback at hypothalamus and dec LH and FSH.
3. Even though they might be in the same stage, follicles are at different times in that stage. Some may "die" when FSH is dec but others may keep going.
4. Even higher levels of estradiol, select out for only 1 cell that has reached the pt in development w/ LH and FSH receptors. This final cell continues to produce Estradiol to inhibit other antral cells.
5. At this stage, a final surge of LH will release the oocyte, triggers luteinization of both granulosa and theca cells.

Front 19

What ruptures a follicle, releases an oocyte into ovulation, and causes lutinization?

Back 19

LH surge.

Front 20

What occurs w/ oocyte maturation? 2

Back 20

resumption of meiosis
cytoplasmic maturation

Front 21

What occurs w/ luteinization? 4

Back 21

increased StAR
increased P450scc, 3βHSD
increase in LH receptors
increase ER and mitochondria

Front 22

What occurs w/ ovulation? 2

Back 22

1. progesterone receptor - COX-2 (PGF2α and PGE2)
2. proteolytic enzymes - plasminogen activator

Front 23

What is the MOA behind the ovulatory process? The role of FSH?

Back 23

FSH stimulates Cumulus expansion.

Front 24

What is the MOA behind the ovulatory process? The role of LH?

Back 24

1. LH stimulates:
- resumption of meiosis
- progesterone receptor =>stimulates COX-2 receptor =>prostaglandin => inflammation/lysosomal enzymes => presumptive stigma
- luteinization => stimulates Granulosa lutein cells and theca lutein cells

THIS ALLOWS FOR THE OOCYTE TO RUPTURE FROM THE FOLLICLE FROM THE STIGMA.

Front 25

When is meiosis fully completed?

Back 25

arrested in meiosis I then continues to grow until meiosis II then completes development when fertilized

Front 26

What is the cumulus expansion? Why is it important?

Back 26

The granulosa cells after the LH surge begin to spread out, allowing for sperm to penetrate the egg.

Front 27

After the developing egg is ovulated, what happens to the remaining follicle?

Back 27

it regresses to form a corpus luteum which synthesizes and secretes progesterone that causes proliferation of arteries and glandular secretions from the endometrial lining (helps prepare the endometrium for receipt of a fertilized egg).

Front 28

When does ovulation occur?

Back 28

regardless of length of cycle, always 14 days before menses

Front 29

What happens if fertilization does not occur?

Back 29

If fertilization does not occur, the corpus luteum regresses at the end of the luteal phase, and estradiol and progesterone levels decrease abruptly. This sudden decrease in hormones causes shedding of the endometrial lining and the onset of menses.

Front 30

What does the corpus luteum produce?

Back 30

progesterone and lots of it

Front 31

Might want to look at Komar's nifty lil drawing...

Back 31

I think it helps somewhat.

Front 32

I love pictures...let's put it alllll together now.

Back 32

Front 33

Histo for the hell of it...

Ep=epithelium
Gl=glands
SF=stratum functionale
SB=stratum basale
M=myometrium

Back 33

and why not a lil more

Front 34

When does full boobie development occur?

Back 34

preggo and lactation

Front 35

What role does estradiol play in the development of breast tissue? 2

Back 35

proliferation of epithelium; developmet of ducts

Front 36

What role does progesterone play in the development of breast tissue? 3

Back 36

branching of ducts and proliferation of alveoli; synergizes w/ estradiol to maximize epithelial development

Front 37

What role does oxytocin play in the development of breast tissue?

Back 37

promotes milk secretion by (+) contraction of smooth muscle cells to move milk from glands into ducts

Front 38

A review chart...

Back 38

Front 39

What effects female repro system? 4

Back 39

Age
Menopause
Polycystic Ovary Syndrome (PCOS)
Obesity

Front 40

How does age effect female fertility? 3

Back 40

1. Late 30s: effects of age on fertility become significant

2. Pool of primordial follicles decreases
- Reduced inhibin production, eventually, reduced estradiol production
- Decrease in (-) feedback to hypothalamus/pituitary
( Increased FSH nd LH)

Oocyte is a 1° factor contributing to sub-/infertility as females age => Meiotic nondisjunction
- Reduced formation of chiasmata during fetal oogenesis
- Accumulation of reactive oxygen damage during prolonged interval until ovulation

Front 41

What are the consequences of vitro fertilization?

Back 41

maternal Ovarian hyperstimulation syndrome
affects up to 10% of women who go through IVF
- cause ?
- ↑ permeability of capillaries in ovary which leads to loss of protein
rich fluid from intravascular compartment to interstitial space
- hCG treatment associated with risk


mild: abdominal discomfort; elevated E2 and P4
moderate: abdominal distension; diarrhea; vomiting
severe: electrolyte imbalances; ascites; shock; acute respiratory distress syndrome

Front 42

What are the consequences of vitro fertilization? maternal mortality.

Back 42

maternal mortality rates are rising in the US and elsewhere
rationale?: today more pregnant women have health problems – diabetes, obesity, and many are older
: the reasons why a woman undergoes IVF may account for the increases risk of death

Front 43

Consequences of ART: offspring. 6

Back 43

1. increased risk of Angelman syndrome: a genetic disorder characterized by severe mental retardation, seizures, ataxic gait, jerky movements, lack of speech, microencephaly, and frequent smiling and laughter
2. increased risk of Beckwith-Wiedemann syndrome: a congenital (present from birth) growth disorder that causes large body size, large organs, and other problems.
3. increased risk of cerebral palsy
4. higher systolic and diastolic bp, and fasting glucose compared with age matched naturally conceived controls
5. altered body fat composition in children conceived by IVF compared with age matched naturally conceived controls
6. altered pattern of DNA methylation between children conceived in vitro versus in vivo

Front 44

Menopause reflects changes where?

Back 44

reflects changes at the level of the ovary AND hypothalamus / pituitary

Front 45

What is Menopause?

Back 45

1. decrease in number of ovarian follicles below threshold necessary to maintain ovulatory cycles

2. changes in the neuroendocrine axis that are independent of altered ovarian steroidogenesis
- age related changes in responsiveness to GnRH
- hypothesized change(s) in effects of E2 (+) feedback

Front 46

What is Polycystic Ovary Syndrome (PCOS)? sx? 3 biochem features? 5 KNOW.

Back 46

1. obesity, hirsutism, and amenorrhea frequently associated
2. Biochemical features (compared to normal early follicular phase)
↑ LH
↓ or ↔ FSH
↑ androgens
↔ inhibins
↑ or ↔ estradiol

Front 47

What is the number 1 cause of infertility n premenopausal women? KNOW.

Back 47

Polycystic Ovary Syndrome (PCOS)

Front 48

NIH criteria for diagnosis: Polycystic Ovary Syndrome?

Back 48

1) clinical evidence of hyperandrogenism and/or hyperandrogenemia
- hirsutism; acne; alopecia…
2) oligoovulation
3) exclusion of other disorders
- hyperprolactinemia; thryoid dysfunction; CAH; tumor…

Front 49

Rotterdam criteria for diagnosis (2003): 2 of the following 3: Polycystic Ovary Syndrome?

Back 49

1) oligo- or anovulation
2) clinical and/or biochemical evidence of hyperandrogenism
3) polycystic ovaries

Front 50

What is the principle abnormality of polycystic ovary syndrome?

Back 50

- (may also involve adrenal androgen production but minor)
- hyperandrogenemia
- may facilitate visceral fat deposition
- visceral fat ↑ lipolytic activity - - - ↑ FFA
- increase in FFA may lead to insulin resistance in muscle
- (-) SHBG syn. - - - more androgens free in circulation

Front 51

Polycystic Ovary Syndrome: abnormal insulin resistance.

Back 51

- hyperinsulinemia ? due to post-receptor signaling lesion - ↑ ovarian androgen production
- ↑ basal cell growth of skin (acanthosis nigricans)
- affects on vascular and endothelial cells (hypertension…)
- affects liver and peripheral lipid metab (dyslipidemia…)
: (-) SHBG production by liver

Front 52

What are the insulin signaling defects in polycystic ovary syndrome?

Back 52

- The signaling defect is due to serine phosphorylation of the insulin receptor and IRS-1 secondary to intracellular serine kinases. This results in decreased insulin-mediated activation of PI3-K and resistance to the metabolic actions of insulin. There is constitutive activation of kinases in the ERK/MAPK mitogenic pathway in PCOS, and these kinases contribute to inhibitory serine phosphorylation of IRS-1 in PCOS skeletal muscle. Serine phosphorylation of P450c17 increases its activity, and it has been postulated that the same kinase may inhibit insulin signaling and increase androgen production in PCOS.

Front 53

What is Hyperthecosis in polycystic ovary syndrome?

Back 53

- inc thecal androgen production
↑ LH (+) theca cell androgen production
Insulin (+) theca cell androgen production
Elevated androgens enhance number of small, healthy follicles

Front 54

Do Androgens ↑ sensitivity to GnRH ?

Back 54

Anovulation due to too many small, antral follicles changing endocrine environment - - inhibin and estradiol keep FSH in check

Anovulation - - No CL - - No progesterone - - lack of (-) on GnRH secretion

Front 55

What are the clinical problems associated with PCOS? 3

Back 55

Women with PCOS at increased risk for
: hyperovarian stimulation syndrome
: developing gestational diabetes
: developing preeclampsia

Front 56

What is the proposed pathophysiology of PCOS?

Back 56

Front 57

Prepregnancy maternal obesity increases risk of: 3.

Back 57

- fetal growth abnormalities
- stillbirth (by 2-5 fold)
- Risk of having a child born with congential heart defect(s) increases dramatically with BMI in obese women (BMI ≥ 30 kg/m2)

Front 58

Obese women risk factors 4

Back 58

Reduction in fertility
lower success rate with ART
increase maternal mortality
greater risk of miscarriage

Front 59

Can maternal under- OR over-nutrition can predispose offspring to develop metabolic syndrome (obesity; type II diabetes)?

Back 59

Yes, maternal under-nutrition during pregnancy can lead to a premature leptin surge and a lack of leptin.
- overnutrition can lead to maternal hyperleptinemia and leptin resistance.

Front 60

Where do GnRH neurons originate? What problem can this lead to?

Back 60

GnRH neurons originate OUTSIDE of CNS
- originate from nasal placode
- migrate into hypothalamus during development

Kallman syndrome occurs (hypogonadism) when this development is improper...pt will not be able to smell either

Front 61

as follicles grow in size in the female, what do they release? what is the effect of this? how does it change? what does this lead to?

Back 61

Estradiol---inhibitory of GnRH

when it reaches a critical threshold it becomes stimulatory of the GnRH

this leads to LH/FSH surge causing ovulation and formation of corpus luteum

Front 62

Theca cells have what type of receptor? What does this lead to the production of? where is this brought to?

Back 62

LH receptor

produces Androstenedione

brought to granulosa cells

Front 63

Granulosa cells have what receptor? what does this lead to the production of? What else can they produce (and where did they receive the starting product)?

Back 63

FSH receptor

produces progesterone

also produces Estradiol from conversion of androgens made in the Theca cells

Front 64

17 alpha OH is in what type of cell? Leads to the production of?

Back 64

Theca

Androgens

Front 65

aromatase is in what type of cell? Leads to the production of?

Back 65

Granulosa

estradiol

(GnRH-->FSH-->Granulosa-->aromatase-->estrodiol)

Front 66

starting with cholesterol, go through production of estrogens

Back 66

cholesterol-->progestins-->androgens-->estrogens

Front 67

as a follicle matures, why is it able to produce large amounts of estradiol?

Back 67

the granulosa cell gains an LH receptor (it already had an FSH receptor)

this helps produce more estradiol (not really sure how...)

remember you convert androstenedione to estradiol in these granulosa cells

Front 68

what properties will a follicle have that is able to continue to grow and develop into the dominant follicle in the menstrual cycle?

Back 68

one that has both FSH and LH receptors on the granulosa cell, and can produce large amounts of estrodiol

Front 69

increased StAR is associated with what process? Leading to?

Back 69

Leteinization

increased progesterone

Front 70

Please run through the menstrual cycle.

Back 70

LH/FSH hits the follicles--> increases estradiol and inhibin

One follicle is able to grow a bit more than the others (more mature) and continues to produce estrodiol and inhibin (maintaintaing an inhibitory affect on LH/FSH)

maturing follicle then gains LH/FSH granulosa site leading to an even bigger release of estrodiol causing the threshold to be reached when Estrodiol stops being inhibitory and instead causes the LH/FSH surge

ovulation occurs and the corpus luteum produces a whole bunch of Progesterone

if the egg is not fertilized you have menses and the process starts over

Front 71

in the oviduct, what happens due to the follicular phase (estradiol) and luteal phase (progesterone)

Back 71

follicular: increase ciliogenesis

luteal: increase secretions

Front 72

in the cervix what happens due to the follicular phase (estradiol) and luteal phase (progesterone)

Back 72

follicular: increase watery mucous production

luteal: decrease viscous mucus

Front 73

in the vagina, what happens due to the follicular phase (estradiol) and luteal phase (progesterone)

Back 73

follicular: increase glycogen deposits in epitheial cells

luteal: increased desquamation

Front 74

in the breast, what happens due to the follicular phase (estradiol) and luteal phase (progesterone)

Back 74

follicular: fat deposition, duct development

luteal: alveolar development, duct branching

Front 75

String of pearls on ovary =

Back 75

Polycystic Ovary Syndrome (PCOS)

Front 76

an obese woman presents to your office saying that she is having issues getting pregnant. She has notable hirsutism and ultrasound of her ovaries shows string of pearls....what she got? 2 possible mechanisms cause this problem?

******

Back 76

Polycystic Ovary Syndrome (PCOS)

Insulin resistance
or
Theca cell androgen production

Front 77

what is cumulus expansion? 2 things this allows for?

Back 77

egg has ovulated

cumulus become more diffuse in their surrounding of the egg

this allows the fibrae to easily pull the egg into the ovaduct

secondly it allows for sperm to enter the egg more easily