Female Reproductive System I

Hypothalamic components

GnRH

Pituitary gland components

Gonadotropins

Ovary components

• Oogenesis

• Steroidogenesis

Oviduct components

• Gamete transport

• Site of fertilization

• Site of segmentation

Uterus components

• Thick, muscular organ

• Maintenance of lining (endometrium), regulated by estrogen and progesterone

The ______ is the functional unit of the overy, providing a niche with the purpose of _______________

follicle, producing a healthy mature oocyte

Preantral follicle growth is __________

gonadotropin-independent

Antral follicle growth is _________

gonadotropin dependent

Corpus luteum formed in ________

luteogenesis

Primordial follicle has granulosa cells arranged in ______

one layer

Qualities of primary and secondary

• Cuboidal granulosa

• Zona pellucida surrounds oocyte

Amtral follicle

• Cumulus granulocytes

• Central cavity forms

Graaf follicle

• Preovulatory/tertiary follicle

• About to be activated

• Large central cavity

• Increased granulosa cells

Ovarian follicle structure

• Oocyte

• Zona pelucida

• Cumulus granulosa

• Mural granulosa

• Basement membrane

• Theca interna (granulosa)

• Theca externa

________ orchestrate the uterine cycle

hormones

Follicular phase

• Dominant follicle selection

• Menses

• Proliferative phase

Luteal phase

• Corpus luteum

• Secretory phase

Concentration of estrogen throughout ovarian cycle

Highest right before ovulation, then drops, rises and falls at mid-secretory stage

Concentration of progesterone through ovarian cycle

Low until mid-secretory phase

LH during ovarian cycle

Low, surges right below ovulation

FSH during ovarian cycle

Low throughout, small spike with LH surge

The mid-secretory stage of the luteal phase also corresponds to the ______

receptive state

Primordial follicles

• Contain prikmary oocyte (9-25um)

• Single layer of squamous granulosa cells

• First noted at 16 weeks of intrauterine life in humans

• Surviva LH/FSH independent

• Constitute resting pool

Primordial follicles remain ________, undergo _______, and enter a _______ ()

quiescent, apoptosis, growth phase (recruitment/initiation)

Primordial follicle quiescence is maintained by inhibiting ____ activation

AKT

Non-growing oocyte

1. TSC1/2 inhibits mTORC1 in granulosa

2. FOXO3A and LHX8 keep oocyte in meiosis I

3. Inhibits PDk1 and thus AKT activation

Growing oocyte

1. Unknown activation of mTORC1

2. Increased protein synthesis

3. KIT ligand binds KIT

4. PI3K and AKT activated

5. Stops arresting in meiosis I

Cumulus granulosa infiltrate the zona pelucida via ______, which is important for ____ of the oocyte

Transzonal projections, nutrition

Transzonal projections enable _____ to communicate with the oocyte and provide ______ to support oocyte growth

cumulus granulosa cells, essential molecules

Transzonal projections are narrow _____ extend through the ZP and contact the _______

cytoplasmic bridges, oolemma

Gap junctions in cumulus granulosa provide portals for molecules up to _______

1 kDa

Cumulus cells provide ____ (), _____, and ______

amino acids (alanine, glycine, proline), pyruvate, cholesterol

FGF8

• Fibroblast growth factor 8

• Granulosa cell proliferation

• Oocyte to cumulus cells

GDF9

• Growth differentiation factor 9

• Granulosa cell proliferation

• Increased cholesterol biosynthesis

BMP15

• Bone morphogenic protein 15

• Increased cholesterol biosynthesis

From cumulus cells

KITL; continued oocyte protein synthesis

Preantral growth occurs through life, uninterrupted until _____

menopause

Granulosa cells proliferate to _____, oocyte diameter to _____

~600, 80um

Granulosa cells express _____, _____, and ____ receptors

FSH-R, estrogen, androgen

Granulosa cells in preantral growth phase are sensitive to ____ and _____ but won’t die without

LH, FSH

In preantral growth, _____ are recruited from the stroma by ____ secreted from granulosa, and become ____, acquire ______, and express ______

Theca cells, GDF9, epithelioid, increased organelles, LH-Rs

Follicles develop _______ in preantral growth phase

Vascular wreath

Tonic growth phase (preantral)

• 600-fold increase in granulosa cells

• Increase in follicle diameter

• Gonadotropin support is required but able to thrive in low levels

• Observed in ovaries from juvenile females and pregnant women

• Growth occurs over several menstrual cycles

• Fluid-filled antrum will develop

Order of follicular development

Primordial → primary → secondary → antral → selection and dominance → graafian dominant follicle

Selection and dominance requires high levels of ______

gonadotropins

If no FSH and LSH, follicles will undergo _____ at the ___ stage

atresia, antral

Dominant follicles have ______ since they have more granulocytes

FSH receptors

Selection and dominance takes _____, the same length as the ____ phase. Therefore, primoridal follicles are recruited ~ ____ before

in 14 days, follicular, 6 months

Follicles can be classified according to their ____, and are constantly undergoing ____

size, atresia

Gonadotropin dependent stage occurs between days ____ and ____, characterized by ______

70-90 days, exponential growth

Theca cells responsive to ___ and granulosa responsive to___

LH, FSH

Lh helps convert ____ into _____ and ___ helps convert ____ into ____

cholesterol, progestins, androgens, estrogens

Steroidogenesis in theca cells

Cholesterol → Pregnenolone → 17-OH-pregnenalone → DHEA → androstenedione

LH/FSH mediated steroidogenesis leads to increased ___ and _____

cAMP, PKA

Steroidogenesis in theca cells

Androstenedione (theca) → estrone → estradiol-17B

Androstenedione converted to estrone via _____

Aromatase

_____ has positive feedback on FSH when at a high enough amount, and has negative feed back at extremely____- and ____ amounts

Estradiol, high, low

Estradiol increases at ovulation dramatically because the ______ has increased ____ and therefore express more FSH receptors

dominant follicle, granulocytes

Estrogen _______ GnRH and LH/FSH but ______ at high levels

inhibits, activates

______ inactivates FSH/LH

inhibin

Progesterone inhibits _______ but also activates ____ at high levels

GnRH, LH/FSH

Estrogens and progestrones stimulate

• Somatic tissue growth

• Development and maintenancy of mammary gland

• Cyclic changes in reproductive organs

Hormonal contraceptives modify ______

feedback

Why does estrogen and inhibin exert negative feedback?

• Energy resources

• Only want the best oocyte

Corpus luteum regression leads to a drop in ___, ____, and ____ removing _________ on pituitary, allowing ____ to rise

progesterone, estrogen, inhibin, negative feedback, FSH

Transient ______ initiates ________ tonic growth the next cycle, as rising ____ from developing follicles gradually suppresses _____ again

FSH increase, pre-antral follicle, estradiol, FSH

In the early follicular phase, increased ____ stimulates ____- to increase ___ production/secretion

FSH, aromatase, estrogen

In the mid-follicular phase, the follicle producing the most ____ has an advantage

estrogen

Traits of dominant follicle in mid follicular phase

• Enhanced follicular fluid generation

• Increased LH/FSH receptor content

• Increased number of granulosa cells

• Increased inhibin production

• 2X vascularity than subordinate follicles by day 9

From day 1 to day 14, ______ amount decreases as ______ amount increases

activin, inhibin

a-subunit + Ba subunit comprise inhibin ___

A

a-subunit + Bb subunit comprise inhibin __

B

_____ secreted by the ovary inhibit pituitary _____

Inhibin A and B, FSH secretion

Ba subunit + Bb subunit = _______ , which when secreted by the pituitary, can stimulate pituitary _____ (via _____)

activin A, FSH secretion, activin B

Inhibin A or B prevents ____ from binding its receptor

activin

Activin-mediated FSH production

1. Activin binds activin type I/type II receptor

2. Smad phosphorylated

3. Promotes FSHB production

In primordial follicles activin __ regulates _____ and ______

A, germ cell proliferation, primordial follicle formation

In primary and secondary follicles, activin stimulates _____________, ____, and ___ growth

Granulosa cell proliferation, follicle, oocyte growth

In the antral follicle, activin accelerates ______ and stimulates ______

oocyte maturation, aromatase

In the pre-ovulatory follicle, the ____ has activin receptors

oocyte

In corpus luteum, activin delays ______ inhibiting ______

luteinization, progesterone production

In corpus albicans, activin _____ promotes regression of the ______ during luteal regression

A, corpus luteum

In early follicular phase ____>____

activin, inhibin

The early follicular phase favours a less ____ environment due to high ____

androgenic environment, activin

Inhibin and activin are released from ______

granulosa cells

IN late follicular phase, _____ >_____

inhibin, activin

By mid-follicular phase, one follicle is producing more ____ than the others

estrogen

In late follicular phase, granulosa also stimulates ___ and _____/__ to act on theca cells

insulin, IGF-I, II

Role of estrogens

• Proliferation of granulosa cells

• Survival of the follicle

• Increase ERa, LH-R, FSH-R, aromatase

• Increased gap junction formation

• Era-KO mice are infertile, no antrum formed

• BERKO mice subfertile; ovaries small and folliculogenesis minorly impaired

• Aromatase KO mice infertile, antral follicles but do not ovulate; cystic follicles

Role of FSH

• Receptors only on granulosa cells

• Granulosa cell proliferation and differentiation

• Increases aromatase

• Synergizes with E to increase FSH-R

• Gap junctions in granulosa cells

Role of LH

• Acts upon thecal cells to stimulate androgen production

• Induces 17a-hydroxylase to convert pregnenolone into DHEA

• Ovulation and luteinization

(In follicular phase) Granulosa cells express enzymes necessary to make _______ and to make ______ from androgens but lack ____ to make androgens

progesterone, estrogen, 17a-hydroxylase

Why is progesterone not made during the follicular phase?

• Enzyme dependent

• Activity of HSD3B2 which converts pregnenolone to progesterone is more prominent in luteal phase

Granulosa cells are regulated by signals from the _____ and _____ during folluculogenesis

theca, oocyte

BMP-4 secreted from the ______ and enhances _____ action

Theca, FSH

BMP-7 is released from the _____ and inhibits ______ via ______

theca, progesterone synthesis, HSD3B2

_____ and _____ are released from the ______ to inhibit progesterone synthesis via HSD3B2 and are no longer present after ______

BMP-15, BMP-6, oocyte, ovulation

Menopause is defined as a _______ of menses that results from the depletion of the ________

Permanent cessation of menses, ovarian reserve

Average age of menopause transition is ___

51 yo

Menopause is preceded by a period of _______ caused by____ and _____

subfertility, less follicles, environmental toxins