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THE ENDOCRINE ASPECTS OF FOLLICULOGENESIS. Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen, UK) Head of Department of Obs/Gynae University of Thessalia Larissa, GREECE. STAGES OF FOLLICULOGENESIS. CLASS 5. CLASS 6. CLASS 4. 3-5 mm. 6-10 mm. 1-2 mm. CLASS 3. CLASS 7. 12-16 mm.

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The endocrine aspects of folliculogenesis

THE ENDOCRINE ASPECTS OF FOLLICULOGENESIS

Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen, UK)

Head of Department of Obs/Gynae

University of Thessalia

Larissa, GREECE


STAGES OF FOLLICULOGENESIS

CLASS 5

CLASS 6

CLASS 4

3-5

mm

6-10

mm

1-2

mm

CLASS 3

CLASS 7

12-16

mm

0.9

HUMAN

OVARY

Early

antral

0.2

18-20

mm

CLASS 2

Pre-antral

0.1

CLASS 8

CLASS 1

Based on:

Gougeon, 1986


FACTORS INVOLVED IN HUMAN FOLLICULAR GROWTH

INITIATION

OF GROWTH

(Not FSH)

GONADOTROPHIN

DEPENDENT

(FSH, LH)

TONIC GROWTH

PHASE

(FSH possibly important)

70 days

15 days

15 days

CLASS 1

CLASS 5

CLASS 8

Primor-

dial

Cyclic

recruitment

selection

Initial

recruitment

Based on: Gougeon, 1986; Hum. Reprod. 1, 81-87


Initial recruitment
INITIAL RECRUITMENT

  • IGF-1, EGF, TGF-α, TGF-β, GDNF, KGF, KITL, HGF, PDGF, LIF, BMP-4

  • Anti-mullerian hormone (AMH or MIS)

  • Others (WT1, pRb, myc etc)


ANTI-MULLERIAN HORMONE (AMH)

AND FOLLICULOGENESIS IN MICE

FSH

FSH

(-)

(-)

AMH

AMH

(+)

(+)

(-)

Primordial Primary Pre-antral Antral

Visser & Themmen, 2005

Mol. Cell. Endocrinol. 234, 81-86


FOLLICULOGENESIS

(TGF-β family)

BMP-2,-5,-6 (+)

AMH (-)

Inhibin

Activin

BMP-4 (+)

BMP-7 (+)

TGF-β

Oocyte

Granulosa

Theca

GDF-9 (+)

BMP-15 (+)

BMP-6 (+)

ΑΜΗ (-)

Inhibin

Activin

BMP-2,-5,-6 (+)

Knight & Glister, 2006

Reproduction, 132, 191-206


FACTORS FROM THE OOCYTE

PREANTRAL

FOLLICLES

ANTRAL

FOLLICLES

GDF-9

(+)

BMP-15

(GDF-9B)

BMP-6

FGF-8

TGF-β2

(-)

Granulosa

cells

Theca

cells

Reviews:

Erickson & Shimasaki,

2000; Erickson & Shimasaki, 2001; Moore & Shimasaki, 2005

OOCYTE


DIFFERENTIATION OF GRANULOSA CELLS

Oocyte

morphogens

FSH receptor

High mitotic index

IGF-1

HAS2

Cox-2

FSH receptor

Cumulus

oophorus

Periantral

FSH receptor

LH receptor

P450arom

Kit ligand

u-PA

Membrana

Erickson & Shimasaki, 2000, TEM, 11, 193-198


FACTORS INVOLVED IN HUMAN FOLLICULAR GROWTH

INITIATION

OF GROWTH

(Not FSH)

GONADOTROPHIN

DEPENDENT

(FSH, LH)

TONIC GROWTH

PHASE

(FSH possibly important)

70 days

15 days

15 days

CLASS 1

CLASS 5

CLASS 8

Primor-

dial

Cyclic

recruitment

selection

Initial

recruitment

Based on: Gougeon, 1986; Hum. Reprod. 1, 81-87


INTERCYCLE RISE OF FSH

FOLLICULAR

LUTEAL

6

LH

IU/l

FSH

IU/l

4

2

8

6

4

2

-8 -6 -4 -2 1 3 5 7

DAYS

Messinis et al., 1993; Clin. Endocrinol. 38, 159-163


CYCLIC RECRUITMENT’’

SELECTION

Intercycle rise

of FSH

FSH

Follicles

8 mm

10-12 mm

16 mm

CLASS 5 CLASS 6 CLASS 7

DOMINANCE

RECRUITMENT

SELECTION


FSH

FSH

R

R

Induction of

FSHR

cAMP

cAMP

aromatase

R

A

E1

Chole-

sterole

LH

A

T

T

E2

(-)

5α-reductase

5α-reduced A

Theca

cell

Granulosa

cell

TWO-CELL TWO-GONADOTROPHIN THEORY

(Early follicular phase)


Paracrine autocrine factors
PARACRINE/AUTOCRINE FACTORS

  • Inhibin, activin

  • Insulin-like growth factors (IGFs) and IGFBPs

  • Androgens

  • Estrogens

  • Others


ROLE OF INHIBIN/ACTIVIN

INHIBIN

FSH

LH

(+)

Gr

Th

E

A

(+)

(-)

ACTIVIN

ACTIVIN

Th: Theca cell

Gr: Granulosa cell

Based on a review by: Hillier, 2001


FSH ΚΑΙ IGFs

IGFs

IGFs

IGFBP-4

(-)

IGFBP-4

PROTEASE

(PAPP-A)

Granulosa

cell

(+)

E2, P4 and/or

LH receptor

R

(+)

(+)

R

FSH

Based on reviews by:

Εrickson & Shimasaki 2001; Spicer, 2004


ROLE OF IGF-1

HDL/LDL

THECA CELL

R

_

+

R

C

EGF/TGFα

+

R

IGF-1

P450ssc

+

Pr

+

+

+

3β-HSD

R

ΤGFβ

cAMP

PKA

_

P

P45017α

R

LH

AC

GS

A

+

ATP

+

A

cAMP

PKA

P450arom

R

E1

FSH

AC

GS

17βHSD

+

E2

ATP

E2

IGF-1

+

GRANULOSA CELL


ROLE OF IGF-2

Androstenedione

Testosterone

IGF-2

THECA

CELL

R

LH

R

IGF-2

R

FSH

GRANULOSA

CELL

E1, E2

R

IGF-2

IGF-2


EFFECT OF ANDROGENS

(small antral follicles)

GRANULOSA

CELL

GRANULOSA

CELL

A

A

R

FSH

R

FSH

(+)

(+)

T

DHT

(+)

R

E

E

Harlow et al., 1986; Endocrinology 119, 1403-05

Weil et al., 1999; JCEM 84, 2951-56


EFFECT OF ANDROGENS VIA OOCYTE

FACTORS

14000

**

DO+IGF1

*

3H-thymidine

Incorporation

(cpm)

GDF9+IGF1

7000

**

*

*

IGF1

0

C

0

5

50

500

IGF1

DHT (nM)

14000

**

DO+IGF1

3H-thymidine

Incorporation

(cpm)

**

GDF9+IGF1

**

7000

**

**

IGF1

*

0

Hickey et al., 2005

Biol. Reprod.

73, 825-32

C

0

10

100

1000

IGF1

T (nM)

Porcine GC


EFFECT OF ESTROGENS

(rat antral follicles)

GRANULOSA

CELL

GRANULOSA

CELL

R

FSH

arom

R

arom

FSH

(+)

R

E

Adashi and Hsueh 1982

J. Biol. Chem. 257, 6077-83


LEPTIN AND REPRODUCTION

HYPOTHALAMUS

GnRH

+

FAT

TISSUE

PITUITARY

+

LEPTIN

FSH

LH

?

+

OVARY

?

Leptin

Based on:

Messinis & Milingos, 1999 Hum. Reprod. Update 5, 52-63

E2

P4


EFFECT OF LEPTIN

(human luteinized granulosa cells)

360000

270000

E2

pmol/l

180000

90000

0

GH

IGF-1

GH+L1ng

GH+L10ng

IGF-1+L1ng

GH+L100ng

IGF-1+L10ng

IGF-1+L100ng

Karamouti et al., 2008

Fertil. Steril. 90, 1444-50


GHRELIN AND REPRODUCTION

HYPOTHALAMUS

GnRH

- ?

STOMACH

PITUITARY

-?

GHRELIN

FSH

LH

-

?

Based on:

Messini et al., 2009;

Hum. Reprod.

Martini et al., 2006;

Endocrinology

Viani et al., 2008

JCEM

OVARY

E2

P4


ATRESIARESCUE

Androgenic

milieu

Estrogenic

milieu

LH

FSH

aromatase

5α-reductase

FOLLICLE GROWTH


SINGLE FOLLICLE SELECTION

15

FSH

IU/L

E2

pg/ml

Intercycle

rise

10

5

0

400

300

200

van Santbrink et al.,

1995, Fertil. Steril.

100

0

M: menses

D: Dominance

M D LH

peak


FOLLICLE GROWTH IN THE

NORMAL CYCLE (Ultrasound)

20

Follicle

diameter

(mm)

15

10

0

-5 -4 -3 -2 -1 0 +1

DAYS FROM LH SURGE ONSET

Mean values

(n=11)

Templeton, Messinis & Baird, 1986;

Fertil. Steril. 46, 1113-1117


GROWTH OF THE DOMINANT FOLLICLE

MIDCYCLE

INTERCYCLE

FSH

LH

dependence

Intrafollicular

regulators

10-12 16 18-20 mm

CLASS 5 CLASS 6 CLASS 7 CLASS 8

Messinis 2008; In: Infertility and Assisted Reproduction; Rizk et al., (eds), Cambridge UP


Intrafollicular regulators

GRANULOSA

CELLS

IGFs

Inhibin/activin

Estrogens

TGF-β

FGF

TNF-α

IL-1β

THECA

CELLS

BMP-4

BMP-7

TGFα

HGF

FGF

CRH

KGF (FGF-7)

INTRAFOLLICULAR REGULATORS

  • GDF-9

  • BMP-15

  • BMP-6

  • ΤΝF-α

OOCYTE


ROLE OF THECA-DERIVED

BMPs

FSH

LH

18-20

mm

Follicles

FSH

LH

P4

-

StAR

BMP-4,

-7

Th

Gr

Based on:

Tajima, 2007

RBMOnline

15, 591-609

P450

+

arom

A

A

E2


LH DEPENDENCE

LH

FSH

R

R

Induction of

LHR

cAMP

cAMP

aromatase

R

A

E1

Chole-

sterole

LH

A

T

T

(-)

E2

5α-reductase

5α-reduced A

Theca

cell

Granulosa

cell

MID- TO LATE FOLLICULAR PHASE

(Dominant follicle)


EXPRESSION LEVEL OF FSHR

AND LHR IN IVM-GCs

6

5

FSHR

4

LHR

Relative

expression

3

2

1

0

C

A

A+HCG

A+FSH

A+HCG

+

FSH

Human unluteinized

granulosa cells

Lindeberg et al., 2007

Hum. Reprod. 22, 401-6


DOMINANT FOLLICLE

Gonadotrophin dependence

2

FSHR

R²=69.5

P<0.01

DF gene

expression

relative to

reference

(log2

transformed)

ESR2

1

R²=57.5

P<0.01

0

-1

R²=63.7, P<0.01

-2

LHCGR

-3

1

2

3

4

5

6

Days after wave emergence

Mihm et al., 2006

Biol. Reprod. 74, 1051-9

(modified)

In cattle


NORMAL CYCLE

LH SURGE

LUTEAL

PHASE

FOLLICULAR PHASE

Early Mid- Late

LUTEAL

PHASE

FSH

  • FSH

  • Aromatase 

  • E2 

  • FSHR 

  • LHR 

  • GC prolif. 

  • LH

  • A 

  • FSH

  • Aromatase

  • E2

  • FSHR

  • LHR

  • GC prolif. 

  • LH

  • A 

  • E2 

  • GC prolif. 


FSH OR LH?

Cetrorelix 3 mg sc

E2

LH

FSH

Follicle

diameter

17 mm

0 24 hours

Based on: Leroy et al., 1994; Fertil. Steril. 62, 461-7


FSH OR LH?

(Follicle growth rate)

20

FD

mm

18

16

14

12

10

Spontaneous cycles

8

GnRH antagonist + FSH

(from FD 14 mm)

6

4

Spontaneous cycles

2

0

-6 -5 -4 -3 -2 -1 0

DAYS RELATIVE TO HCG


HYPOGONADOTROPHIC HYPOGONADISM

FSH (IU/L)

Follicle

diameter (mm)

E2 (pmol/L)

20

Follicle

15

FSH

E2

10

5

200

100

0 6 10 15 20 25 30 35 Days

recFSH

75 IU

Shoham et al., 1993

Fertil. Steril. 59, 738-42

7 14 21


Hypogonadotrophic hypogonadism use of rfsh with rlh
HYPOGONADOTROPHIC HYPOGONADISM (Use of rFSH with rLH)

FSH LH E2

IU IU (pmol/l)

Couzinet et al., 1988 225 225 2753

(HMG) (HMG)

Kousta et al.,1996 150 225 780

El-Shawarby et al., 2004 50-75 75 3155

Based on a review by: Messinis, 2005

Hum. Reprod. 20, 2688-97


LH IN FOLLICULAR MATURATION

15

FSH

IU/L

DAY 0

(FD: 14 mm)

10

5

DAY 1

0

DAY 2

(day of HCG)

4

LH

IU/L

2

0

2000

E2

pg/ml

1000

Sullivan et al.,

1999

JCEM 84, 228-232

FSH up to

14 mm

GnRH agonist

0

S

FSH

LH-H

LH-L


FSH CYCLE

LUTEAL

PHASE

FOLLICULAR

PHASE

LUTEAL

PHASE

FSH

LH

  • FSH leads the follicles to the pre-ovulatory stage

  • LH is required for the production of steroids


Lh receptors
LH RECEPTORS

  • FSH is unable to stimulate development of mice early antral follicles to the preovulatory stage in the absence of LHR

Pakarainen et al., 2005

Mol. Endocrinol. 19, 2591-2602


DUAL ACTION OF LH

ON THECA CELLS

AND ‘LH ceiling’

concept

LH

FSH

Luteinization

of theca and

granulosa cells

Steroidogenesis

(androstendione)

Based on a review by:

Tajima, 2007

RBMOnline 15, 591-07


Conclusions 1
CONCLUSIONS - 1

  • Both FSH and LH are important for the final stages of follicle maturation

  • The action of FSH predominates in the first half and that of LH in the second half of the follicular phase


Conclusions 2
CONCLUSIONS - 2

  • Different intrafollicular regulators are important for the selection and the growth of the dominant follicle

  • Under pharmacological interventions, FSH is capable to initiate and sustain the growth of the dominant follicle, while LH is required for steroids production


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