PHSL 570Q: Ovary
References:
Fortune, J.E. 1994. Ovarian Follicular Growth and Development in Mammals. Biol. Reprod. 50:225-232
Greenwald, G.S. and S.K. Roy. 1994. Follicular Development and Its Control. In: Knobil E, and J.D. Neill (eds.), The Physiology of Reproduction, 2nd Ed.. Raven Press, New York, NY
Espy, L.L. and H. Lipner. 1994. Ovulation. In: Knobil E, and J.D. Neill (eds.), The Physiology of Reproduction, 2nd Ed.. Raven Press, New York, NY.
Murphy, B.D. 2000. Models for Luteinization. Biol. Reprod. 63:2-11.
Niswender, G.D. et al.. 1994. Luteal Function: The Estrous Cycle and Early Pregnancy. Biol. Reprod. 50:239-247.
I. Ovarian Function
1. Topics to be covered
A. Follicle Development
B. Ovulation
C. Luteinization
D. Luteolysis
E. Maternal Recognition of Pregnancy
2. Endocrine Control
A. Systemic
a. Hypothalamic-pituitary-ovarian axis
b. Ovarian-Uterus axis
B. Local
a. Paracrine/Autocrine/Intracrine activity at the ovary
II. Follicle Development
1. Cell types of the follicle/endocrinology
A. Theca Cells (Interna)
a. Stimulated by LH
b. Steroidogenesis
i. Progesterone to Testosterone
ii. Testosterone transported to Granulosa Cells
c. Peptide hormones/Growth Factors
i. Relaxin, Renin, Oxytocin, Vasopression,
IGF-I & II, TGF-beta2, bFGF, IL-1,
IGFBP, TGF-alpha
B. Granulosa Cells
a. Stimulated by FSH
b. Steroidogenesis
i. Converts Androgens to Estrogens: Aromatization
ii. Some production of Progesterone
iii. Lack enzymes that convert progesterone
to testosterone
--weak 17-alpha-hydroxylase
--very little C-17, 20-lyase
c. Peptide hormones/Growth Factors
i. Inhibin, Activin, Follistatin, Oxytocin, GnRH,
GHRH, POMC, MIS, IGF-I & II, EGF, TGF-beta2, OMI
C. Cumulus and Corona Radiata Cells
a. Mediate Oocyte Maturation
D. Oocyte
a. Maturation Stimulated by LH
b. Inhibited by OMI, MIS, etc.
2. Stages of Follicle Development
A. Primordial Follicle
a. Resting stockpile
b. Formed during prenatal period
i. Greatest number found 90-130 d postconception
c. Frequently seen in groups called egg nests
in the parenchyma
B. Primary Follicle
a. One layer of cuboidal granulosa cells surrounding oocyte
with no antrum (cavity)
C. Secondary Follicle
a. Multilayers of granulosa cells surrounding
the oocyte with no antrum
D. Tertiary Follicle
a. Multilayers of granulosa cells
with antrum starting to form
b. Antrum fills with fluid
i. Follicular Fluid or Liquor Folliculi
ii. Rich in Reproductive Steroid Hormones
iii. Nonsteroid Hormones/Factors also present
E. Graafian Follicle
a. Preovulatory follicle
b. Fluid filled blister on surface of ovary
3. Follicular Atresia
A. Most follicles never ovulate (70-99%)
B. They grow to a certain point and become atretic
a. Basal atresia related to number of granulosa
cell generations
i. Most follicles become atretic
at 8 or 9th generation unless recruited
b. Mechanism for atresia is apoptosis (programmed cell death)
C. Follicular apoptosis is under hormonal control
a. FSH, IGF-I, and Estrogen inhibit
b. Androgens, GnRH, and Activin stimulate
4. Follicle Dynamics
A. 3 major divisions in folliculogenesis
a. Recruitment
b. Selection
c. Dominance
B. Recruitment
a. Cohort of follicles start to develop
b. High FSH + Low LH + No inhibin
c. Follicles start to produce estrogen
C. Selection
a. Emergence of dominant follicles
b. Moderate FSH + Moderate LH + Low inhibin
D. Dominance
a. Follicle(s) destined to ovulate emerge
b. Low FSH + Moderate LH + High inhibin
c. Dominant follicle(s) reach a threshold
to become ovulatory follicle
i. Doesn't rely on as much on FSH
ii. Local estrogen and IGF may act
as "survival" factors
d. Inhibin and Follistatin produced
by dominant follicle to inhibit
FSH stimulation of subordinate follicles
e. Subordinate follicles undergo apoptosis
i. Decreased FSH (Inhibin, Follistatin, Estradiol)
ii. Dominant follicle Activin stimulates
iii. Other hormonal factors
5. Follicular Waves
A. Two patterns of follicular development of large antral follicles
occur in mammals
a. Suppression of large ovulatory follicles except during
the follicular phase
--Primates, Rodents, Pigs
b. Development of large ovulatory follicles during luteal
and follicular phase.
--Cattle, Ewes, Horses
B. Two to three waves of follicular development to large
antral follicles occur each estrous cycle in sheep, cattle,
and horses
a. Two waves are more common, especially in ewes
i. Start day 2 and 11 of estrous cycle
ii. 1/3 of mares have two waves
b. Three waves occur more often in cattle
i. Start day 2, 9, and 16 of estrous cycle
c. During each wave a group of follicles are recruited
and start to grow
i. At least one follicle is always dominant
d. The first wave or two are anovulatory
i. No LH surge for ovulation
ii. All follicles become atretic
C. In other species cohorts of follicles develop but undergo atresia
before the large antral follicle stage.
III. Ovulation
1. Site of Ovulation
A. In most animals, ovulation can occur at any point
of ovary except hilus
B. Mares ovulate at only one place on the ovary
a. Ovulation Fossa
C. In farm animals, ovary that ovulates is independent
of which ovary has a C.L.
a. 50/50 over time
D. Some mammals do alternate ovaries
a. Primates
b. C.L. inhibits follicular growth
E. In some mammals, most ovulations are from one side
a. Whales
2. Graafian follicle
A. Undergoes three major changes as ovulation approaches
a. Maturation of oocyte
i. Resumption of meiosis
ii. Primary to Secondary oocyte
b. Dissociation of cumulus from granulosa layer
c. Thinning and rupture of external follicular wall
i. Stigma (bulge) forms at site of ovulation
ii. Caused by proteolytic enzymes, edema,
and follicular contraction
3. Endocrinology of Ovulation
A. LH spike
a. Initiates sequence of events that lead to ovulation
i. Increase blood flow
ii. Dissociation of cumulus
iii. Resumption of Meiosis
iv. Increase and shift in steroid secretion
v. Increase prostaglandin secretion
b. Ovulation occurs 24 to 45 hours after LH spike
B. Steroid hormones
a. Progesterone increases first, followed by estradiol
i. P4:E2 ratio increas
b. The steroid hormones increase follicle edema
i. Swelling that contributes to stigma formation
c. Progesterone increases theca collagenases
i. Help to thin follicle wall
C. Prostaglandins
a. Both PGE2 and PGF2alpha
b. Produced by Granulosa
c. PGE2 increase plasminogen activator
i. Breaks down basement membrane
d. PGF2alpha cause lysosome rupture and release
of proteolytic enzymes
i. Breakdown of tunica albuginea and theca
e. PGF2alpha also cause follicular contractions
i. Cause follicular rupture and oocyte expulsion
f. Prostaglandins have also been proposed to cause
theca apoptosis.
IV. Luteinization
1. Transformation of theca and granulosa cells
2. Steps
A. Basement Membrane breakdown
B. Follicle collapse into many folds
C. Thecal and Granulosa cells mix
a. Theca = Small Luteal Cells
b. Granulosa = Large Luteal Cells
c. Primates form islets of cells
D. Remnants of basement membrane become C.T. network
3. Inducers
A. LH
a. Stimulates cAMP/PKA pathway
B. Serum Growth Factors
a. IGFs and unknowns
b. FGF probably involved in angiogenesis
C. Adhesion Proteins
a. Fibronectin, laminin, and collagen
D. Kip/Cip
a. Cyclin Kinase inhibitors
E. Progesterone
a. Intracrine/Autocrine effect
4. Inhibitors
A. EGF
B. ET-1
C. PKC stimulators
5. Large Luteal Cells
A. 20-40 uM in diameter
B. Contain secretory granules close to plasma membrane
a. Contain oxytocin in C.L. Spurium
b. Contain relaxin in C.L. Verum
C. Produce Progesterone
D. Undergo hypertrophy during luteinization
6. Small Luteal Cells
A. 20 uM in diameter
B. Irregular shape, with numerous lipid droplets
C. Produce Progesterone
D. Undergo hyperplasia during luteinization
7. Angiogenesis
A. Vascularization of the C.L
a. Stimulated by growth factors (angiogenic)
B. Needed for maximum function
V. Luteolysis
1. Disintegration or decomposition (lysis) of the corpus luteum
A. Occurs over 1-3 days at end of luteal phase
2. Steps
A. Cessation of progesterone production
B. Structural regression to form corpus albicans
C. Follicular development and entrance into follicular phase
3. Endocrinology
A. Oxytocin
a. Released from Large cell granules
b. Increases PGF2alpha production by uterus
B. PGF2alpha
a. Produced by uterus
i. Stimulated by Oxytocin
b. Transported to uterus to ipsilateral ovary
through vascular countercurrent exchange mechanism
i. PGF2alpha diffuses from ovarian-uterine vein
to ovarian artery
ii. Keeps PGF2alpha from getting
too dilute in systemic circulation
c. Stimulates luteolysis
4. Potential mechanisms for luteolysis
A. Ischemia
a. Reduced blood flow
b. Original hypothesis for luteolysis
i. PGF2alpha causes vasoconstriction
ii. Even after vasoconstriction blood
flow is more than adequate
c. Capillaries also breakdown during luteolysis
i. Also cause ischemia
d. Probably not total mechanism for luteolysis
B. Cellular mechanism
a. PGF2alpha binds to receptor
on large luteal cells
b. Causes cascade of events resulting
in apoptosis and cessation of steroidogenesis
i. Stimulates Protein Kinase C
--Inhibits steroidogenesis
ii. Increase Ca++ influx
--Stimulates apoptosis
C. Immune system
a. PGF2alpha stimulate macrophages and lymphocytes
migration to C.L.
i. Phagocytic cells
ii. Produce cytokines
b. Cytokines
i. Intracellular mediators
of immune response
interferons, interleukins, TNF
ii. Cause apoptosis
iii. Inhibit progesterone synthesis
by luteal cells
c. Phagocytic cells clean-up dead luteal cells
i. Form C.A.
D. Exact mechanism still unclear
a. May involve a combination of mechanisms
VI. Maternal Recognition of Pregnancy
1. Embryonic signal to maintain pregnancy
A. Prevents luteolysis (Inhibits PGF2alpha)
a. Inhibition at uterus
b. Inhibition at ovary
2. Short window of time
A. Cattle--16-17 days
Sheep--12-13 days
Swine--10-12 days
Horse--14-16 days
Humans--14-16 days
3. Sheep
A. oTP-I is the major signal (interferon tau)
a. Uterine oxytocin receptors inhibited
B. PGE2 and other factors also involved
a. PGE2 secreted from uterus, inhibits effects
of PGF2alpha on ovary
b. Platelet activating factor also reported to be involved
C. Estrogens not involved, because they cause luteolysis
by stimulating PGF2alpha.
4. Cattle
A. Similar to Sheep
B. Also produce EPSI
a. Endometrial Prostaglandin Synthetase Inhibitor
5. Pig
A. Embryonic Estrogen major player
a. Exogenous estrogen will cause pseudopregnancy
B. Interferons of TP-Family also play role
C. Embryos must be present in both horns
a. At least 2 embryos
6. Horses
A. Signal for inhibiting PGF2alpha not known
a. Estrone or Estradiol?
b. Protein factors?
B. Intrauterine migration
7. Rats
A. Cervical stimulation causes pseudopregnancy
B. Prolactin is major factor very early pregnancy
a. Until day 7
C. Chorion gonadotropin may take over after that.
8. Humans
A. hCG appears to inhibit PGF2alpha release
PHSL 570Q Webpage
~~~~~Revised 3/28/01~~~~~ TAW