The endocrine aspects of folliculogenesis
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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

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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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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)


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

“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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

ATRESIARESCUE

Androgenic

milieu

Estrogenic

milieu

LH

FSH

aromatase

5α-reductase

FOLLICLE GROWTH


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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)


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

NORMAL CYCLE

LH SURGE

LUTEAL

PHASE

FOLLICULAR PHASE

EarlyMid- 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. 


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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

714 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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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


The endocrine aspects of folliculogenesis

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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