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The menstrual Cycle
François Pralong
Services d’Endocrinologie, Diabétologie et Métabolisme, HôpitauxUniversitaires de Genève et Lausanne
Centre des Maladies CardioVasculaires et Métaboliques, Lausanne
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Two functions of the ovary
GametogenesisGametogenesis
SteroidogenesisSteroidogenesis
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Functional anatomy of the ovary
Carr and Wilson, 1987
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Gonadotropin-independant Gonadotropin-dependent
Simpson et al, Am J Med Genet 1999
Primordial follicles:ovum + unicellular layer of granulosacells
Primary follicles:ovum growing + additional layers ofgranulosa cells
Primary follicles:ovum growing + granulosa + theca cells(originating from ovarian stroma)
Accelerated growth of theca andgranulosa cells, stimulated bygonadotrophins
Secretion of follicular fluid (richin E2) by theca and granulosacells : apparition of antrum
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Gonadotropin-dependentHighly gonadotropin-dependent
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Follicular growth, gonadotropin dependent
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cholesterol
pregnenolone
estradiol
DHEA
progesterone
17-OH progesterone
androstenedione testosterone
estrone
P-450scc
P-450arom P-450arom
17β-HSOR
3β-HSD
P-450c17
17-OH progesterone
P-450c17
P-450c17
3β-HSDP-450c17
THEC
A
GR
NU
LOSA
CO
RPU
S LU
TEU
M
LH
FSH FSH
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The two cell hypothesis in a pre-ovulatory follicle
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The two cell hypothesis in the corpus luteum
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Effects of oestrogens
On uterus : growth at puberty; increase in size of fallopian tubes
On vagina: increase in size; transformation of epithelium, fromcuboid to stratified.
On endometrium: prolifération of endometrium; apparition ofendometrial glands, useful to implantation and nutrition offecondated ovum.
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Effects of oestrogens
On bone : increase of osteoblastic activity; closure of epiphyses.
On adipose tissue: female-like repartition of fat (mammary gland,thighs)
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The menstrual cycle
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The menstrual cycle
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Primary or secondary
Differential diagnosis
• Physiological processes :Pregnancy, menopause
• Congenital or acquired anomalies
• Hypothalamic pathologies: hypogonadotropeamenorrhea (low LH and FSH)
• Ovarian pathologies: hypergonadotrope amenorrhea(high LH and FSH)
Amenorrhea
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Genetic anomalies(Turner syndrome, FSH inactivating mutations)
Precocious ovarian insufficiencyAcceleration of follicular atresia in women of childbearingage
Chronic anovulationOften secondary to other endocrine dysfunctions, obesity,or of toxic origin (drugs...)
Polycystic ovarian syndromeMost frequent endocrine pathology
Ovarian insufficiency
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Consequences of amenorrhea
· Increased risk of osteoporosis
· Increased incidence of diabetes mellitus
· Increased cardio-vascular risk
· Possible increased risk of breast cancer
· Increased risk of endometrial cancer
· Hirsutism/acne (androgene excess)
· Infertility
· Menstrual dysfunction
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Consequences of amenorrhea
All occurences of amenorrheamust be worked up, and then
taken care of.
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Four cases described
• Phenotype:– delayed puberty– primary amenorrhea– normal response to FSH
with achivement offertility
FSH Deficiency - FemalesFSH−R
FSHβ
FSHβ FSH-R
• Phenotype:– primary amenorrhea– ovarian dysgenesis
with normal karyotype
Finnish study
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FSH Deficiency - Males
Three cases described
• Phenotype:1) delayed puberty, low
testosterone and absentspermatogenesis
2) normal puberty andvirilization,spermatogenic arrest
Finnish study
• normal virilization• decreased testicular
volume• variable suppression of
spermatogenesis
FSHβ FSH-RFSH−R
FSHβ
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Role of the FSH/FSH-R System
• Important for estrogen production, follicularmaturation and fertility
• Role of FSH in spermatogenesis remainsunclear:– variable spermatogenesis in FSH-R mutations– absent spermatogenesis in FSHβ mutations
FSH−R
FSHβ
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• normal external genitalia• normal pubertal
development• primary amenorrhea• no pre-ovulatory
follicles
LH-R
LH Deficiency - Females LHβ
LH-R
One case described
• Phenotype:1) Secondary amenorrhea and
infertility
LHβ
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LH Deficiency - Males
Four cases describedBio-inactive LH
Impaired heterodimer
• Phenotype:– normal male– delayed puberty– response to hCG:
LHβ
LHβ
LH-R
Broad spectrum ofphenotypic expression of
inactivating mutations
– pseudohermaphroditismand completeazoospermia
– micropenis, delayedpuberty and arrest ofspermatogenesis
LH-R
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Role of the LH/LH-R System
• Important for normal male development
• LH-R plays a role in spermatogenesis as well asovulation
LH-R is a candidate gene for male as well as femaleinfertility
LHβ
LH-R
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Mean 50 yrs– precocious <40 yrs– late >55 yrs
Factors influencing the age at menopause:Heredity, smoking, ethnical background, climate (?)
Female life expectancy (1997): 82.3 yrs32.3 yrs in menopause
Age at menopause in Switzerland
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Physiopathology of menopause:the apoptose phenomenon
Landmarks in ovocyte count in the human
– Fœtus: 7 millions– Birth: 1-2 millions– Puberty: 400 000
Follicular depletion accelerates at around 37 yrs:imbalance beetween pro-apoptotic (Bax) and anti-apoptotic (Bcl2) transcription factors
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Evaluation of ovocyte depletion The Faddy-Gosden equation
Faddy et al. Hum Reprod 1996,7, 1342-1346
Dy/dx=-y[0.0595+3716(11780+y)]X=ageY=number of primordial follicles
A=701 000 folliclesB=25 000 folliclesC=1000 follicles
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Production of germinal stem cells by the ovary
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Nature, Mars 2004
•Germline stem cells present inthe ovary, outside follicles
•These stem cells are dividing
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Nature, Mars 2004
•Germline stem cellstransplanted intorecipient ovariesproduce new follicles