Folliculogenesis

Primordial Germ Cells

Mesonephro

Dorsal mesentry of the

hindgut
GERM CELL NUMBER IN RELATION TO AGE
Duration of follicle recruitment and selection in
human and rat ovaries.
LANDMARKS OF FOLLICULAR DEVELOPMENT DURING FETAL
AND NEONATAL LIFE
IN HUMANS AND RODENTS
Initial Recruitment
• Initial recruitment is a continuous process that
starts just after follicle formation, long before
pubertal onset.
• Initiation of growth of primordial follicles occurs
continuously and in a random fashion.
• Takes three months .
• For those follicles not recruited, the default
pathway is to remain dormant.
Initial recruitment
 FSH and LH are unlikely to exert direct actions on
primordial follicles because functional
gonadotropin receptors have not yet developed
in them
• During initial recruitment, intraovarian and/or
other unknown factors stimulate some
primordial follicles to initiate growth
• Alternately, initial recruitment may be due
to a release from inhibitory stimuli that maintain
the resting follicles in stasis.
PRIMORDIAL CELL TO PRIMARY CELL

stimulators inhibitors
Kit ligand FGF-2 PTEN tumor suppressor gene

KGF(keratinocyte growth factor) Tsc1/mTORC1

LIF(leukemia inhibiting factor) FoXo 3a

BMP-4/7/15(Bone morphogenetic P27

factor)
Foxl 2
Growth differentiation factor-9)
GDF-9( AMH
PRIMORDIAL CELL ACTIVATION
PRIMORDIAL FOLLICLE ACTIVATION
Genes involved in early stages of
folliculogenesis
Cyclic Recruitment

• In contrast, cyclic recruitment starts after pubertal

onset and is the result of the increase in circulating
FSH during each reproductive cycle that rescues a
cohort of antral follicles from atresia.

• The selective rise in serum FSH beyond a critical

‘threshold’ level during the luteal follicular
transition is a potent stimulus for cyclic
recruitment
INTER CYCLE RISE OF FSH
‘‘CYCLIC RECRUITMENT’’
Cyclic Recruitment
Oocytes in these follicles have already completed
their growth, acquired a zona pellucida, and are
competent to resume meiosis
• Out of this cohort one becomes dominant follicle
and rest undergo apoptosis
 Initial Recruitment Cyclic Recruitment

Initiation of growth. Escape from atresia

Continuous and random
fashion. Takes 3
months.

STAGE Primordial Antral

HORMONES Intraovarian factors FSH

INVOLVED like TGF beta, BMP,
activin.

DEFAULT PATHWAY To remain dormant Apoptosis

TIMING Continues throughout Cyclical starts after

life puberty

OOCYTE STATUS Starting to grow, not Completed growth

capable of undergoing Competent to undergo
FACTORS INVOLVED IN
Important concepts in
Folliculogenesis.
• FSH threshold.
• The concentration of FSH required to initiate secondary
recruitment.
• FSH window/gate
• The time frame for which this level of FSH needs to be
maintained for follicular recruitment and growth.
• LH window/ ceiling.
• The concentration of LH essential for follicular growth and
selection of dominant follicle.
• LH surge.
• Rise in LH that triggers the cascade of events leading to
ovulation.
 FSH Threshold & window Concept
 Follicular development at the beginning
of each cycle occurs only if serum FSH
concentration exceeds a certain threshold
 The number of follicles to ovulate is
determined by length of time that the level
of FSH remains above the threshold value
FSH threshold and window
• (left panel) -Monofollicular
selection –narrow FSH window

 (right panel) - represents the

concept of extending the FSH
window by administering
exogenous FSH in the early-
midfollicular phase to maintain
FSH levels above the
threshold
allowing multifollicular
development

• Each arrow represents a

developing follicle.
The LH ‘ceiling’
hypothesis
• Ovarian follicles have development-related
requirements for stimulation by LH
• LH, beyond a certain ‘ceiling’ level, suppresses
granulosa proliferation, and initiates atresia
(immature follicles) or premature luteinization
(preovulatory follicles)
• Mature follicles are more resistant (higher
‘ceiling’) to LH than immature ones
• During ovulation induction, LH dose should not
exceed the ‘ceiling’ of the most mature follicles
LH THESHOLD AND CEILING
Selection
• Selection of the dominant follicle is explained by development-
related changes occuring in granulosa and theca cells in
responsiveness to FSH and LH, modulated by ovarian para
(auto)crine mechanisms.

• The follicle whose granulosa cells are most responsive to FSH

(lowest FSH ‘threshold’) becomes first in the cohort to secrete
estrogen

• Induction of more LH receptors

• Increasing E2 feeds back through the HPA and begins to suppress

pituitary FSH secretion.

• Only one of the selected follicle grows and becomes the dominant
one.
• Blood FSH, therefore, declines to a concentration insufficient to
sustain the development of other follicles that have higher FSH
thresholds. These latter become nonovulatory and undergo atresia .
Dominance
• Mid-follicular phase(D7) – The pre-ovulatory follicle becomes
recognizable as the largest healthy follicle in either ovary

• Maturing follicle reduces its dependence on FSH by acquiring

LH receptors

• It contains granulosa cells that express LH receptors coupled

to aromatase and inhibin synthesis

• Since this follicle is uniquely responsive to both FSH and LH, it

continues to grow and secrete estrogen despite decreasing
plasma concentrations of FSH

• Development-dependent paracrine signals maintain the

dominance of this follicle, amplifying its responsiveness to
FSH and LH
 Rise of FSH beyond certain threshhold during luteal follicular
transition

Follicular recruitment

Selection of dominant follicle – Follicle with GC most responsive to

FSH (lowest FSH thresh hold), secrete Estrogens

-ve feed back to hypothalamo-pituitary axis

Suppress FSH secretion

FSH insufficient to sustain development of other follicles with higher

FSH thresh hold

Non-ovulatory

Undergo atresia while dominant follicle continues to grow, secrete E2

 Dominant follicle

Increased synthesis of E2 with increased expression of LH

receptors on GC which are adequately stimulated by FSH as well
as well as LH
LH sustains preovulatory follicular endocrine activity induced by
FSH

LH plays primary role in complete maturation of follicle &

development of oocyte competence

Mid cycle LH surge

Disrupts GC contacts in cumulus oophorus & induces oocyte

maturation

Follicle rupture followed by induction of GC lutenization

Follicle divergence
Role of androgens

Aromatization Estrogens

Low
Inhibito
Androgens ry

Hig
5α reduction
h 5 α androgens
Role of androgens
1.Aromatise to estrogens – success of follicle
2.Local role in ovary to enhance atresia of non dominant follicle
Role of androgens
ROLE OF AMH IN FOLLICULOGENESIS

AMH inhibits the recruitment of primordial follicles

Thus in the absence of AMH there is increased increased recruitment
Of primordial follicles leading to follicular depletion from the ovaries
Also AMH reduces the responsiveness of follicle to FSH and act
as a negative of regulator of follicular selection
Theories of Follicular Recruitment

a)Continuos Recruitment theory

a)Single Recruitment theory

a)Follicular wave theory

Continuos Recruitment Theory

Small antral follicles (<4-6cm) are recruited

to grow continuosly at all stages of
reproductive life independent of
gonadotropins.
Follicles destined to ovulate is said to be
selected by chance from the continuos
supply of antral follicles by virtue of being
at right stage of maturity to respond to the
rise in FSH that occurs following Luteal
regression
Single recruitment theory

Cohort of 2-5mm antral follicles are

recruited from continous Supply of antral
follicles once during each menstrual phase.
The single raise in the number of 2-5mm
follicles detected after Corpus Luteum
regression in late luteal phase or early
follicular phase is referred as “previleged
phase” of follicular development
Follicular Wave Theory

The wave theory of follicle recruitment

suggests that two or more cohorts(i.e.waves) of
antral follicles are recruited during the ovarian
cycle.
The dominant follicle that develops in the final
wave ovulates while preceding waves are
anovulatory, dominant follicles develop in a
minority of anovulatory waves
2 WAVE CYCLE
Anovulatory wave emerged at the time of
ovulation (day 0) followed by emergence
of the ovulatory wave during the early-
follicular phase in women with two
follicular waves.

The final wave of the cycle was

ovulatory and the preceding waves
were anovulatory.
3 WAVE CYCLE
While in women with three waves, the first
anovulatory waves emerged at day 0 and the
second anovulatory wave emerged during the
mid-to late- luteal phase followed by the third
wave (the ovulatory wave) emerged in the early-
to mid-follicular phase.

Women with three follicular waves per cycle

have 2-days longer IOI (29 days), which was
significantly different from that in the women
with two waves (27 days).
Major waves were defined as those in which one follicle
grew to no less than 10 mm and exceeded all other
follicles by 2 mm at least.

Minor waves were defined as those in which follicles

developed to a diameter of no more than 10 mm and
follicle dominance was not manifest.

However, both in 2-wave and 3- wave women, it seems

that the preceding anovulatory waves can be either
major or minor waves.
Indeed, whether in anovulatory waves or
ovulatory waves, the loss of dominant follicle is
accompanied by decreased levels of hormones
synthesized by the follicle, such as oestrogen and
inhibin.

Hormones dropping then result in a temporary

increase of FSH secretion by the pituitary gland
through a negative feedback mechanism.

In consequence, the rise of FSH level is thought

to be responsible for preventing atresia of next
cohort of 2–5 mm antral follicles .
 Puzzles and Unanswered Questions

Does early onset of menarche lead to a

corresponding younger age at menopause?

No.
As discussed, initial follicle recruitment and follicle loss
from the resting pool begins long before pubertal onset.
Changes in the age of menarche as the result of
environmental, nutritional, or pathophysiological
factors (such as in women with central precocious
puberty) allow an earlier onset of cyclic follicle
recruitment but should not affect the timing of follicle
pool depletion.
Do women of reproductive age who have undergone unilateral
ovariectomy or chemotherapy have an earlier onset of
menopause?
Yes

but it is dependent on the timing of the procedure. Unilateral

oophorectomy or chemotherapy, which reduces the pool of resting
follicles, shortens the reproductive life span. If unilateral oo-
phorectomy is performed in the later part of the human reproductive
years when the resting pool is smaller, substantial advancement in
menopausal age occurs . However, when the same procedure is
performed early in life, the menopausal age is less affected, suggesting
that a compensatory mechanism in initial follicle recruitment might
allow a lower number of follicles to initiate growth
Do women who have used steroidal
contraceptives have delayed menopause?

Probably no.

Prolonged exposure to steroidal contraceptive pills

mainly affects the ovulatory surges of circulating
gonadotropins during the fertile period. Thus,
ovulation is suppressed, but follicles continue to grow
to the antral stage . It would seem likely that neither
initial nor cyclic recruitment of follicles would be
affected. However, since the advent of the oral
contraceptive pill in the 1950s, the first generation of
pill takers have reached menopause, and ep-
idemiological studies have suggested that menopausal
age may be slightly delayed.Further studies of sub-
sequent generations of pill takers are needed to rule
out compounding variables in the population of “pill
pioneers”.
Do women with increased parity have delayed menopause?

Yes.

Epidemiological studies indicate that women with increased parity show

a delay in menopausal onset. Prolonged elevation of circulating
progesterone during pregnancy may suppress initial follicle
recruitment, thus maintaining a larger follicle pool size.

One is unable to distinguish, however, between a direct action of

progesterone on resting follicles and an indirect effect of progesterone
mediated by changes in gonadotropin secretion. Additional pregnancy-
related factors may also override the facilitatory effect of hCG on
follicle exhaustion and could result in the protection of the follicle pool..
Do women with dizygotic twins have an earlier onset of
menopause?

Maybe not.

The exact mechanism of dizygotic twining is still uncertain, although

increased numbers of large antral
follicles have been found in mothers of dizygotic twins during the
follicular phase of their cycle . Assuming the increases in
preovulatory follicles found in these individuals are due to elevated
gonadotropins during the early follicular phase of their menstrual
cycle , this condition is likely due to enhanced cyclic recruitment of
follicles and should not alter initial recruitment and menopausal age.
However, some epidemiological studies have suggested that mothers
of twins have an earlier menopause although this may be related to
other variables such as cigarette smoking which was not evaluated.
Do women who have undergone repeated cycles of controlled
ovarian hyperstimulation with gonadotropins have an earlier
onset of menopause?

A qualified no

because exogenous gonadotropins are believed to act mainly on

antral follicles to start cyclic recruitment
Thank
You