Download POF

“POF”
Premature Ovarian Failure
“New Fronteries”
N.Cem FIÇICIOĞLU, M.D., Ph.D.
Professor and Director
Department of Gynecology & Obstetrics and IVF Center
Yeditepe University, School of Medicine
Istanbul
Ovarian failure is
a natural consequence of the aging
process
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The life history of ovarian follicles
Atresia
initial recruitment
ovulation
cyclic recruitment
After puberty
Atretic
maturation
Depletion of
follicles
Antral
Seconder
primer
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Primordial
(initial recruitment)
(depletion)
Recruitment
Initial Recruitment
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Growth of significant
number of small follicles
Long time
Slow developement
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Cyclic Recruitment
Begins with puberty
FSH
A limited count of
follicles
Every mounth
Hirshfield 1989
Before menopause
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The last 10-15 years
before menopause
The rapid depletion of
follicle when the total
count reduced to 25.000
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Unfortunately, many women experience
premature ovarian failure while still in
reproductive age
Clinical Criteria for Diagnosing Premature Ovarian Failure
 4 months of amenorrhea
Two serum FSH values  40 mIU/mL
1 month apart in a woman aged  40
7
Anasti JN. Fertil Steril 1998;70:1-15
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POF
Incidence
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By age 30’s%0.1
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By age 40’s%1
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FSH≥40 IU/lthere is no follicle in
the ovaries
Goldenberg RL
Am J Obstet Gynecol 1973;116:1003-9

There are some intermittent
ovarian functions in karyotypically
normal ovarian failure
Rebar RW
J Reprod Med 1982;27:179-186
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Functional Classification of
Premature ovarian failure
Ovarian follicle depletion
Ovarian follicle dysfunction
Decreased reserve Accelerated atresia
Steroidogenic enzyme defects
- Pure gonadal dysgenesis - X-related (Turner synd)
- Thymic hypo/aplasia
- FMR-1 gene mutation
- Idiopathic
- Galactosemia
- Toxins
- Iatrogenic
- Viral oophoritis
- Ataxia telangiectasia
- Idiopathic
Autoimmunity
- Lymphocytic oophoritis
- 17  hydroxylase deficiency
- 17-20 desmolase deficiency
- Aromatase deficiency
- Gonadotropin receptor antibodies?
Signal defects
- Abnormal gonadotropin receptor
- Abnormal G protein signaling
Specific genetic defects
- Blepharophimosis-epicantus-ptosis syndrome
Idiopathic
- Resistant ovary syndrome
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Nelson et al. Endocrinol Metab Clin North Am. 2003;32(3):613-37
Increasing Number of POF-Related Genes are
Identified on X-Chromosome
Zfx (X-linked zinc finger protein)
- located on Xp 22.1 and 21.3
- Zfx knock out mouse is infertile
and has dimished number of germ cells
DIA gene(Diaphanous gene)
-located on Xq21
-contain 7 different regions
for ovarian development in
drosophilia
USP9X gene (ubiquitin-specific protease 9 gene)
- located on Xp11.4
- required for eye and gonad development
in drosophila
- function unknown in mammals
XIST locus (X inactivation site)
- located on Xq13
- required for the reactivation of the silenced X
chromosome during oocyte maturation
- 2 X chromosomes with 2 intact XIST loci
are necessary for a normal meiosis to occur in the
oocyte
- mutation causes meiotic arrest and oocyte
depletion
FMR1 gene (Fragile X) “ %6”
-located on Xq27.3
-extreme expansion of CGG
repeats is associated with mental
retardation without POF
-modest repeats cause POF
without mental retardation
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8 Nelson
et al. Endocrinol Metab Clin North Am. 2003;32(3):613-37
Fragil X mental retardation 1
“FMR1” %6
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Triple CGG repeats
41-55 intermediate… increase risk of POF?
55-200 premutations… FXTAS…FXPOF
>200 Full mutation… Fragile X syndrome
Fertil Steril March 2007, Wittenberger, et all
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Autoimmune Lymphocytic
Oophoritis “%4”
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Markedly enlarged ovaries with luteinized
cysts (like PCOS but androgen deficiency)
Intense lymphocytic infiltration of theca
Primordial follicles spared
Typically with subsequent Addison’s, rarely
isolated
Adrenal cortex autoantibodies
Part of autoimmune polyendocrinopathy (MIM)
FSH, LH, Androgens, Inhibin b
Fertil Steril 2005 Bakolov et all
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Laboratory Evaluation of POF
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Karyotype for all (incidence not affected by
age if not primary amenorrhea)
thyroid& adrenal antibodies
Ovarian antibodies of no proven benefit
Fragile X testing if family history of POF, MMR,
Ataxia, Tremor etc.
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Antimüllerian Hormon “AMH”, ‘MIF’
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This marker shows Primordial follicles pool
Ovarian aging / oocyte morfology
The relations with Antral follicles and age
Fıçıcıoğlu C., Fertil.Steril. 2006
Silberstein T., Human Reproduction, 2005
De Vet A et al., Human Reproduction, 2002, NL
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Early foll. AMH as an indicator of ovarian reserve.
Fıçıcıoğlu C., et all. Fertil.Steril. 2006
AMH >0.25 ng/ml %96,
<0.25ng/ml only %23
good responders
5<
5>
p
Age
32.63 ± 3.58
30.75 ± 4.10
NS
BMI
26.68 ±5.14
24.69 ±2.94
NS
D3 FSH
7.35 ± 3.49
7.53 ± 2.23
NS
D3 E2
36.40 ±22.86
33.16 ± 9.83
NS
D3 AMH
0.15 ±0.11
0.67 ±0.41
<0.001
Antral
6.90 ±3.41
10.63 ±3.89
<0.001
E2 on HCG day
1252.54
±605.29
2584.81
±927.02
<0.001
Mature oocyt
2.6 ±1.2
9.21 ±3.68
<0.001
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A fertility profile,
consistent of
autoimmune testing and assessment
of triple CGG repeats on the FMR1
gene, could thus become a universal
screening test for the fertility
potential of young women.
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The prediction of ovarian function
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FSH
Inhibin b
AMH
E2
Antral follicle count
Over 30 triple count CGG repats on
the FMR1 gene denote incresed risk
toward premature ovarian senescence
Autoimmune testing
Fertil Steril 2008, Gleicher N et all
HumReprod 2008,Rohr J et all
J Clin endocrino Metob 2008,Tsigkou A et all
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Treatment and Follow Up
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Prednisone for auotimmune ovarian failure
unproven
Gonadotropin treatment is unproven and can
exacerbate unrecognized autoimmune
ovarian failure
ERT does not prevent pregnancies
Annual follow up for thyroid/diabetes
screening; others if clinically indicated
Addison screening if antibody- positive
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POF & Fertility Restoration

CC
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Oestrogens
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Ishizuka B, 1992
Corticosteriods
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Johnson TR, 1979
GnRH Analogs
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Anasti JN, 1994
Gonadotrophins
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Check JH, 1990
Danazol
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Chen FP, Chang SY, 1997
OCP
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
Mehta AE, 1992
Cowchock FS, 1988
Van Kasteren YM, 1999
Effects of pretreatment with estrogens on ovarian stimulation with
gonadotropins in women withpremature ovarian failure: a randomized,
placebo - controlled trial
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Tartagni, M.
Fertil Steril 2007;87:858 – 61.
The combination of corticosteroids with pituitary suppression followed by ovarian
stimulation with gonadotrophin appeared to be beneficial in restoring ovarian
function in patients with idiopathic POF and normal karyotype.
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Corticosteroids do not influence ovarian responsiveness to gonadotropins in
patients with premature ovarian failure: a randomized, placebo-controlled trial
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Facts about cancer
Chemotherapy
Not all cancer drugs
have the same
gonadotoxic
potential
Radiotherapy
Gonadotoxicity.
Pelvic irradiation
Craniospinal irradiation
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Abdominal irradiation
Total body irradiation
Different Classes of Agents Affect
Different Stages of Follicular Growth
Size of
human follicles
Small oocyte
>3 Months
Preovulatory or
Graafian follicle
500 mm
1000-6000 mm
>6000 mm
Antral Phase
Expanding antrum
Alkylating
Agents
Platinum
200 mm
Developing
antral cavity
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50 mm
Preantral Phase
Primordial follicle
Follicle initiation
Antimetabolites
FSH-dependent
Cytotoxic Agents According to the Risk of
Amenorrhea
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High Risk
 Cyclophosphamide
 Chlorambucil
 Melphalan
 Busulfan
 Nitrogen Mustard
 Procarbazine
Intermediate Risk
 Cisplatin
 Adriamycin
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Low Risk
 Methotraxate
 5-Fluorouracil
 Vincristine
 Bleomycin
 Actinomycin D
Indeterminate Risk
 Taxanes
Modified from Sonmezer & Oktay, Hum Reprod Update, 2004
Radiotherapy and the ovary
Ovarian damage
depends on
Radiation dose
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Patient’s age
Radiation field
Ovarian Tissue Freezing
Ovarian cryopreservation maybe the only option for
fertility preservation, especially in prepubertal children
and those who do not have time to undergo ovarian
stimulation for oocyte or embryo cryopreservation.
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Conclusions
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46XX POF is reversible in up to 10% of patients
Cancer treatment: most common cause of POF?
Recent research shows that OSE stem cell may produce new
egg in vitro……
Donation
There is currently no efficient treatment for POF but
fertility preservation may be considered
The prediction of ovarian function is the most
important part of preservation of female infertility
Management to symptom resolution and bone protection and
psychosocial support
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Thank you for your attention!
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Reserve
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PRENATAL 6-7 MİLYON OOSİT
YENİDOĞANDA 2 MİLYON OOSİT
PUBERTEDE 300-400 BİN OOSİT
VARDIR.
400 TANESİ SEKONDER OOSİT
OLUR OVULASYONLA ATILIR.
“Antral folikül sayısı, over rezervini değerlendirmede ilk
seçenek olarak önerilmektedir (Hendriks ve ark. 2005a).
FSH/LH,
GH,IGF1,
EGF,IL1,
NO
preovulatuar
antral
Gonadotropine
bağımlı
FSH
pre antral
sekonder
FSH,GDF-9
Aktivin,
primer
primordia
GonadotropinecGMP
cevap
?
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FOLLICLE MOUNTAIN
Yale University Fertility Center, Yale University, New Haven, CT;
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Weill Medical College of Cornell University, Center for Reproductive Medicine and Infertility, New York, NY.
Foliküllerin dinlenme havuzundan
recruitment’ı

Reprodüktif hayatta
primordial ve primer foliküller
sekonder ve daha büyük foliküller
orijinal folikül havuzunda sürekli azalma
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Recruitment terimi, folikül gelişimi sırasındaki iki önemli fakat
farklı noktayı açıklamak için kullanılmıştır.
(Meijs 1990, Gosden 1983, Rombauts 1998)
İnisiyal recruitment, önemli sayıda küçük folikülün , uzun bir
zaman içinde yavaşca büyümesini ifade eder. (Hirshfield 1989 )
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Siklik recruitment
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Puberteden sonra başlar
Birçok antral folikülü, atreziden koruyan dolaşımdaki FSH
artışı sonucu meydana gelir.
Siklik recruitment sırasında sınırlı sayıda folikül gonadotropinler sayesinde kurtularak büyümeye devam eder
Bu foliküllerde oositler büyümelerini tamamlamıştır, zona
pellucida ile mayoza devam etmeye hazırdırlar.
Her ay bir Graf folikülü ovulasyon için hazırlanır.
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Gonadotropin Receptor Defects Involved in
POF
FSHR gene
-located on 2p21-16
-mutation in the ligand binding domain of
FSHR causes dramatic reduction in FSHR
binding capacity and signal transduction
-Finnish type: auto-recessive inheritance
-spontaneous 46XX POF
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LHCGR gene
-located on 2p21
-inactivating mutation causes
follicle dysfunction:
Low E2, low/nl FSH, high LH
Multicystic Ovaries