The

François Pralong Service of Endocrinology GnRH GnRH

Pituitary

LH LH, FSH FSH E2, T Inhibin Facilitation Inhibition

GnRH neurons

Gonadotrophs LH Childhood years Facilitation Inhibition

GnRH neurons

Gonadotrophs LH

Post-pubertal Period Belchetz et al, Science 1978; Functional anatomy of the

Carr and Wilson, 1987 The Two Functions of the Ovary

GametogenesisGametogenesis

SteroidogenesisSteroidogenesis cholesterol

P-450scc

pregnenolone

LH P-450c17 3β-HSD 17-OH progesterone progesterone

P-450c17 P-450c17 THECA CORPUS LUTEUM DHEA 17-OH progesterone P-450 3β-HSD c17

androstenedione 17β-HSOR

P-450 P-450 FSH arom FSH arom

estrone GRNULOSA Two-cell hypothesis in pre-ovulatory follicles Two-cell hypothesis in the corpus luteum Gonadotropin-independent Gonadotropin-dependent

Simpson et al, Am J Med Genet 1999 Heavily gonadotropin- Gonadotropin-dependent dependent The different types of follicles

Pre-antral follicles

Primordial follicles: single ovum + uni-cellular layer of granulosa cells

Primary follicles : ovum grows + additional layer of granulosa cells

Primary follicles : ovum grows + granulosa + thecal cells (origin: ovarian stroma) The different types of follicles

Antral follicles

Accelerated growth of theca and granulosa cells, stimulated by gonadotophins

Secretion of follicualr fluid (E2 rich) by theca and granulosa cells: antrum formation How does this all end up together? How does this all end up together? How does this all end up together? FSH Deficiency - FSHβ FSH−R

FSHβ FSH-R

Three cases described Finnish study

• Phenotype: • Phenotype: – delayed – primary amenorrhea – primary amenorrhea – ovarian dysgenesis – normal response to FSH with normal karyotype with achivement of FSH Deficiency - Males FSHβ FSH−R FSHβ FSH-R

Two cases described Finnish study

• Phenotype: 1) , low • normal testosterone and absent • decreased testicular volume • variable suppression of 2) normal puberty and spermatogenesis virilization, spermatogenic arrest Role of the FSH/FSH-R System

• Important for production, follicular maturation and fertility

• Role of FSH in spermatogenesis remains unclear: – variable spermatogenesis in FSH-R mutations – absent spermatogenesis in FSHβ mutations

FSHβ FSH−R LH Deficiency - Females LHβ LH-R

LH-R

No LH-β mutation yet • normal external genitalia described in a • normal pubertal patient development • primary amenorrhea • no pre-ovulatory follicles LH Deficiency - Males LHβ LH-R LH-R LHβ

Two cases described Broad spectrum of Bio-inactive LH phenotypic expression of Impaired heterodimer inactivating mutations

– pseudohermaphroditism • Phenotype: and complete – normal male – delayed puberty – , delayed – response to hCG: puberty and arrest of spermatogenesis Role of the LH/LH-R System

• Important for normal male development

• LH-R plays a role in spermatogenesis as well as

LH-R is a candidate gene for male as well as female infertility

LHβ

LH-R Production de cellules souches germinales par l’ovaire •Cellules souches germinales présentes dans les ovaires, à l’extérieur des follicules

•Ces cellules souches germinales se divisent

Nature, Mars 2004 •Des cellules souches germinales transplantées dans des ovaires receveuses produisent de nouveaux follicules

Nature, Mars 2004