1 Introduzione Introduzione

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Introduzione
CLINICA VALLE GIULIA, Rome
Diverso approccio farmacologico
alla induzione della ovulazione e
superovulazione in donne con
alterazioni endocrino-metaboliche
Filippo Maria Ubaldi
M.D. M.Sc.
L’induzione dell’ovulazione o superovulazione in donne
con anovulatorieta’ e alterazioni del ciclo spesso correcorrelate a problematiche endocrino-metaboliche preprevede l’utilizzo di farmaci con diverse modalita’ di
somministrazione
Le pazienti che possono usufruire di questo tipo di trattamento rientrano principalmente in due categorie:
I Master di Medicina della Riproduzione Umana
Padova, 2009-2010
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Introduzione
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Fattori ambientali
IV compartimento
SNC
1) Amenorree ipogonadotrope (ipogonadismo
Ipotalamo
ipogonadotropo o amenorrea ipotalamica)
amenorrea di tipo I (WHO)
GnRH
2) Sindrome dell’Ovaio Policistico (amenorrea
iperandrogenica)
amenorrea di tipo II
(WHO)
III comp.
Ipofisi
FSH
LH
II comp.
Ovaio
3) Amenorrea ipergonadotropa (ipogonadismo
ipergonadotropo
(WHO)
amenorrea di tipo III
Progesterone
Estrogeni
Utero
I comp.
Mestruazioni
1
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ASRM Practice Committee (Fertil Steril 2008)
Introduzione
I compartimento
-disordini a livello vaginale o uterino
II compartimento
-disordini a livello ovarico
III compartimento
-disordini a livello ipofisario
IV compartimento
-disordini a livello ipotalamico o del SNC
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ASRM Practice Committee (Fertil Steril 2008)
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ASRM Practice Committee (Fertil Steril 2008)
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Amenorrea ipotalamica
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Amenorrea ipotalamica: GnRH pulsatile
Letteratura:
Terapie
Miller ‘83
 GnRH pulsatile
Mason ‘84
 Gonadotropine
Hurley ‘84
 Clomifene Citrato
Santoro ‘86
Filicori ‘ 87
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Amenorrea ipotalamica: GnRH pulsatile
GnRH
pulsatile
utilizzato in varie
condizioni di anovulatorieta’
20-30 % grav/ciclo
60-90 % grav/paziente
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Amenorrea ipotalamica: GnRH pulsatile
Via di somministrazione
Endovena
Sottocute
Dosaggi: 2.5 - 20 mg/pulse
Intervallo pulse: 60’ - 90’ - 120’
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Amenorrea ipotalamica: GnRH pulsatile
Hypogonadotropic hypogonadism
Results of ovulation induction using hMG or FSH-HP
in hypogonadotropic hypogonadism patients
Effetti collaterali
 Cefalea, nausea
 Orticaria, broncospasmo, ipotensione
 Tromboflebite (somministrazione e.v.)
 Ematomi (somministrazione s.c.)
 Endocardite (somministrazione e.v.)
Shoham Z et al., Fertility Sterility 56(6):1048, 1991
FSH-HP:
amps (<0,04);
leading follicle (<0,05)
serum E2 (<0,002);
endometrial thickness (<0,02);
ovulation rate (<0,05)
Conclusions: In isolated hypogonadotropic hypogonadism
patients it is consistent with the two-cell two-gonadotropin hypothesis, that both gonadotropins are required to
Drop-out
accomodate their synergistic action for appropriate stero-
 Scarsa compliance
idogenesis. The superior efficacy of hMG compared with
FSH-HP is beyond question
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Hypogonadotropic hypogonadism
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Hypogonadotropic hypogonadism
Extensive clinical testing in patient suffering from severe deficiency in LH and FSH has demonstrated that
A daily dose of 75 IU rec-LH in addition to rec-FSH
serum LH levels >0,5 IU/L are necessary to provide
is effective in the majority of women in promoting
adequate LH support to FSH-induced follicular deve-
optimal follicular development and steroidogenesis
lopment when endogenous LH secretion is absent.
in WHO I women and safe in all of them. Good preg-
O’Dea, 2002
nancy rate can be achieved.
The European Recombinant Human LH Study Group. J.Clin.
Endocrinol. Metab. 1998
Sufficient LH supply can be delivered by
a daily injection of 75 IU r-LH
The Spanish Collaborative Group on Female Hypogonadotrophic Hypogonadism. Hum. Reprod. 2001
4
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Amenorrea ipogonadotropica: GnRH pulsatile vs hMG
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Amenorrea ipogonadotropica: GnRH pulsatile vs hMG
Gravidanze multiple
Martin, JCEM 1993
Martin, JCEM 1993
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Amenorree ipergonadotropiche
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PCO syndrome
When amenorrea is associated with evidence of androgen
excess the most common disorder is PCOS and less com-
Fallimento ovarico primitivo (POF)
mon the hyperandrogenism is from adrenal disease or
from androgen-producing tumors (Moran, 2000)
PCOS patients are more likely to present with oligomenor-
Ovodonazione
rhea (76%) than with amenorrhea (24%) (Imani, 2002;
Bili, 2001) and 75% of North American PCOS women are
obese (Legro, 2001) and most of them hyperinsulinemic
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PCOS
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PCO/PCOS classification
(The Rotterdam ESHRE/ASRM-sponsored PCOS consensus)
PCOS is one of the most common endocrinopathies affecting 5-10% of women of reproductive age with a lot
Diagnostic criteria of polycistic ovaries (PCO)
of controversies regarding both its diagnosis and treat-
1) Presence of >12 follicles (2-9 mm in diameter)
ment
2) and/or increased ovarian volume (>10 ml)
(ESHRE/ASRM-Sponsored PCOS Consensus Whorkshop 2008)
 A woman having PCO in the absence of an ovulatory
Revised 2003 diagnostic criteria of PCOS
disorder or hyperandrogenism (“asymptomatic” PCO)
should not be considered as having PCOS
1) Oligo- and/or anovulation
2) Clinical or biochemical signs of hyperandrogenism
3) Policistic ovaries
 “Asymptomatic” PCO ovaries if stimulated for IVF
behave like the ovaries of PCOS women at increased
(2 out of 3 criteria)
risk for hyperstimulation and OHSS (McDougall 1992)
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PCO syndrome
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PCOS: suggested treatment
Hyperinsulinemia due to insuline resistance occurs in 80%
of women with PCOS and central obesity but also in 40%
Various interventions have been proposed:
of lean women with PCOS (Dunaif, 1997) due to a post-re-
o Lifestyle modification (diet, exercise)
ceptor defect affecting glucose transport, unique to PCOS
o Insulin-sensitizing agents
PCOS
HYPERINSULINEMIA
+
Central obesity
Ovarian
androgen
production
SHBG
Free
testosterone
5 alpha
reductase
ANOVULATION
FSH for
ovulation
induction
Multifollicular
response
pregnancy
miscarriage
o Laparoscopic ovarian drilling
o Clomiphene Citrate (and aromatase inhibitors)
o Gonadotropins with or without GnRH analogues
 Ovulation induction
 Controlled ovarian hyperstimulation for IUI or IVF
Hirsutism/Acne
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PCOS obese: lifestyle modification
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PCOS obese: lifestyle modification
Perdita di peso e outcome clinico
PERDITA DI PESO
La diminuzione del 5-10% del peso corporeo
COMPLETED
(N = 67)
la severita’
dell’irsutismo e dell’acne, ripristina la regolarita’ del ciclo
CHANGE IN BMI (Kg/m2)
e l’ovulazione nel 60-70% delle pazienti soprattutto con
RESUMED OVULATION
- 3,7 ± 1,6
“DROP-OUT”
(N = 20)
- 0,4 ± 1,4 a
90 %
0,0 %
SPONTANEOUS
27
0,0
TREATMENT
53
0,0
MISCARRIAGES (%)
18
0,0
DA SEGNALARE: miglioramento della efficacia di tutte le
WOMEN PREGNANT (%)
77,6
0,0
terapie farmacologiche per la induzione ovulazione
WOMEN WITH LIVE BIRTH (%)
67
0,0
WRH (obesita visceale) (Pasquali 1989) e protegge per il
diabete tipo 2, migliorando la dislipidemia.
MECCANISMI: riduzione insulina, riduzione androgeni
PREGNANCY (%)
a = P<0.01
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PCOS obese: lifestyle modification
Perdita di peso e modifiche sull’assetto ormonale, sul
metabolismo e caratteristiche cliniche in PCOS obese
Effetti
Parametri
Ridotta
grasso totale e viscerale
Migliorata
Hirsutism score
Cicli mestruali (n°)
Ovulation and pregnancy rate
Acanthosis nigricans
Ridotta
Testosterone
Androstenedione
Insulina
Migliorata
Insulino sensibilità
Uguale / aumentato
SHBG
Uguale / ridotto
LH
Clark, 1998
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PCOS obese: ipoglicemizzanti orali
FARMACI IPOGLICEMIZZANTI (Metformina)
MECCANISMI: riduzione della concentrazione plasmatica di insulina e androgeni; ripristino dell’ovulazione
METFORMINA: da 500mg x 3 a 850mg x 3/die
EFFETTI COLLATERALI: diarrea, disturbi neurovegetativi
La metformina non induce ipoglicemia nelle pazienti
normoglicemiche
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PCOS obese: metformina
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Change in frequency of menstruation (cycle/month)
1.25
1.00
E’ stato dimostrato che questo farmaco, da solo
0.75
o in combinazione con farmaci induttori della
0.50
ovulazione, è utile per il ripristino dell’ovula-
0.25
zione e per l’ottenimento di una gravidanza in
0.00
pazienti affette da PCOS
-0.25
Nestler et al., New Engl J Med. 1998; Fertil Steril 2002
-0.50
Metformina
Placebo
Moghetti, J Clin Endo Metab 2000
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Metformina e fertilita’ in PCOS
PCOS: ovulation induction
CC is the treatment of first choice in anovulatory women
Migliori risultati ovulatori su cicli spontanei o indotti da
clomifene citrato (Nestler, 1998-2002; Moghetti, 2000; Ibanez,
2001; Vandermolen, 2001; Kelly, 2002; Kocak, 2002;
Fleming, 2002; Yarali, 2002)
Incremento della fecondazione ovocitaria con ICSI
(Stadtmauer et al 2001)
Ridotto rischio di OHSS in seguito a trattamenti farmacologici di induzione dell’ovulazione (De Leo et al 1999)
Aumento della pregnancy rates dopo cicli di induzione
dell’ovulazione (Stadtmauer et al 2001, Vandermolen, 2001;
Batukan et al 2002, Kocak et al 2002, Heard et al 2002)
-low cost
-oral route is patient friendly
-few adverse effects
-little ovarian response monitoring
-aboundant data regarding the safety of the drug
Efficacy
70-85% of patients with PCOS will ovulate after CC
(Homburg 2005; Messinis 2005)
Life-table analysis indicates a conception rate of up to
22% per cycle in those ovulating on CC (Hammond 1983;
Kousta 1997; Heijkemans 2003; Messinis 2005)
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PCOS: CC e induzione della ovulazione
Risposta inversamente correlata a BMI, FAI, volume
ovarico e gravità del disturbo del ciclo
PCOS: ovulation induction
Combination therapy
There is clear evidence that the addition of metformin
E’ da valutare la opportunità di aggiungere piccole dosi
(Moll 2006; Legro 2007) or dexamethasone (Daly 1984) to
di EE nei giorni successivi per contrastare l’azione anti-
CC as primary therapy for OI has no beneficial effect
estrogica del CC sul muco cervicale ed endometrio
50 mg/die x 5 gg
100 mg/die x 5 gg 200 mg/die x 5 gg
dal 3° o dal 5° gg
dal 3° o dal 5° gg
Se no ovulazione
Se no ovulazione
dal 3° o dal 5° gg
Alternative therapies
Anti-estrogenes other than CC: Tamoxifen, comparable
efficacy (Messinis 1982; Steiner 2005) (not licensed for this
porpouse), alternative in women with intolerable side
effects to CC
Se no ovulazione
IA / gonadotropine
Aromatase inhibitors (Bayar 2006; Begun 2008; Badawy 2008)
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PCOS: aromatase inhibitors and OI
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PCOS CC resistant: aromatase inhibitors
Mechanism of action
AIs block E2 production by inhibiting aromatization in
Authors
Dose mg
Letrozole
Follicles
number
Ovulation Endometrial
rate (%) thickness mm
the ovary (conversion of A and T to E2) releasing the
Mitwally
2001
2,5
2,1
75
8,1
development of ovarian follicles (Lidor 2000; Mitwally 2001)
Al-Omari
2001
5
1,9
87,5
9,4
Androgens augment follicular FSH receptor expression
Elnashar
2006
2,5
1,2
54,6
10,2
hypothalamic/pituitary axis from E2 negative feedback
As a result, FSH secretion increases stimulating the
in primates and promote follicular growth indirectly by
amplifying FSH effects (Fisher 2002; Kilic 2003; Mitwally 2005)
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AI vs CC in PCOS (RCTs): clinical results
Authors
Dose mg
Let
CC
Pregnancy (%)
Let
CC
P
ASRM 2005: Higher risks of congenital cardiac and bone
malformations in the newborns (Biljan, Fertil Steril, 2005)
Atay
2006
2,5 100
21%
9%
ns
Bayar
2006
2,5 100
22%
17%
ns
Babies born after CC or AI treatments in Canada: 2001-2005
Treatment
No. of newborns
Sohrabvand 2,5 100
2006
Begun
2008
Total
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Aromatase Inhibitors: safety considerations
7,5 150
33%
16%
ns
18%
<0,05
43/152 (28%) 23/157 (14%) 0,005
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Ovulation induction with gonadotropins
252
Birth weight (gr.) 3287,3
Age of mother
40%
Letrozole
33,1
Letrozole+FSH
CC
CC+FSH
262
293
104
3248,4
3158,8
3322,5
32,9
33,9
32,4
Major malformation 6/514 (1,2%)
P=0,07
12/397 (3%)
Minor malformation 9/514 (1,6%)
P=0,8
7/397 (1,8%)
Tulandi, 2006
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Ovulation induction: type of gonadotropins
In PCOS with high LH, u-FSH or rec-FSH have theore-

13-44% of PCOS will not ovulate with CC or AI
(Guzick, 1998; Kovacs, 2001; Slowey 2001; Mitwally 2001; Al-Omari 2001
Homburg 2005; Messinis 2005; Elnashar 2006; Atay 2006; Begun 2008)
thical advantages over HMG, but whether this claimed
advantage extends into clinical practice is uncertain
Gonadotropins
1) Type of gonadotropins
2) Stimulation protocols
Issue 2, 2008
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FSH vs HMG: ovulation rate
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FSH vs HMG: multiple pregnancy rate
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FSH vs HMG: pregnancy rate
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FSH vs HMG: miscarriage rate
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FSH vs HMG: OHSS
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Ovulation induction: stimulation protocols
The aim of OI in anovulatory PCOS is to restore fertility
and achieve a singleton live birth
hCG
FSH threshold
FSH dose
FSH dose
FSH window
FSH window
Follicular growth
Low dose step-up
Follicular growth
Step-down
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Low dose step-up regimens
hCG
FSH threshold
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Step-down regimens
The original gonadotropin administration in PCOS ano-
Achieve the FSH threshold through a loding dose of
vulatory women used 150 IU/day
FSH with a subsequent stepwise reduction when as soon
unacceptable rate
of multiple follicle development (risk of multiple pregnancies)
and of OHSS (Dor 1980; Wang 1980)
Chronic low doses of gonadotropins (Kamrava 1982)
o 75 IU/day for 7-14 days starting any time
if no
follicle >10 mm
37,5 IU/day at weekly intervals
up to maximum dose of 225 IU/day.
o HCG when the leading follicle >18 mm with no other
follicles >14 mm (Polson 1987; Messinis 1997; Sagle 1991)
as follicular development is observed on US (Schoot 1992)
Step-down regimens (Schoot 1992)
o 150 IU/day untill a follicle >10mm is seen by US
37,5 IU/day for 3 days and
to 75 IU/day untill
the day of HCG (Macklon & Fauser 2002)
o 300 IU/day followed by 3 days with no treatment
75 IU/day individually adjusted with a step-up
protocol (Balasch 2001)
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Step-down regimens
Combination with GnRH analogues
LH serum levels may interfere with fertility (?):
To optimize treatment with the stepdown regimen:
- premature oocyte maturation (Jacobs 1990)
o First cycle with a dose finding low-dose step-up
- deleterius effect on granulosa cell steroidogenesis
(Willi 1996; Willi 1998)
protocol to determine the FSH threshold (Imani 2002)
- increased pregnancy loss (Regan 1990; Balen 1993)
o Starting daily dose is the effective response dose of
the first cycle increased by 37,5 IU. Comparing the
first step-up and the second step down cycle no differences in terms of monofollicular development and
pregnancy rates (van Santbrink & Fauser 2003)
(not confirmed by more recent data Rai 2000; Oliveira 2007)
No
o
o
o
in pregnancy rates (Dodson 1987; Fleming 1988)
Risk of OHSS (Homburg 1990; Scheele 1993; van der Meer 1996)
Risk of multiple pregnancy (Homburg 1993; Clifford 1996)
Costs and disconfort
The use of GnRH agonists is not justified
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Combination with GnRH analogues
(Hughes 2004)
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Combination with GnRH analogue:ovulation rate
Issue 2, 2004
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Combination with GnRH analogue:ovulation rate
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Ultrasound monitoring
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Combination with GnRH analogues: OHSS rate
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Low dose step-up vs step-down: efficacy
o Baseline assessment of the ovary before starting OI
o Accurate assessment of follicles >10mm
o Cycle cancellation when >3 follicles >16mm (Calaf 2003)
-
>4 follicles >14mm (Hughes 2006)
>2 follicles >14mm (Fahri 1996)
>3-4 follicles >10mm (Tur 2001; Dickei 2005)
>1 follicle >16mm >1 foll. >12mm (Leader 2006)
It is prudent to withhold HCG administration with >2
follicles of >16mm or with one 1 follicle >16mm and 2
follicles of >14mm under the age of 38
(ESHRE/ASRM-Sponsored PCOS Consensus Whorkshop 2008)
(ESHRE/ASRM-Sponsored PCOS Consensus Whorkshop 2008)
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Ovulation induction and IUI
Because subfertility is mainly due to anovulation in PCOS
OI is the main treatment
No RCTs in women with PCOS comparing OI and spontaneous intercourses vs OI and IUI
In PCOS associated to mild male factor or after having
failed OI and spontaneous intercourses, OI and IUI may
be considered (Cohlen, 2000)
Careful monitoring is essential to reduce the risk of
OHSS and multiple pregnancies (ESHRE Capri Workshop, 2003)
and in case TV ultrasound-guided aspiration of the supernumerary follicles (De Geyter, 1996)
Ovarian superovulation and IVF
o Anovulation is not an indication for IVF
o After failure of weight reduction, CC, or ovarian drilling
OI with gonadotropins
o It may be argued to replace OI with IVF(Eijkemans 2005)
in order to make single embryo transfer with
of multiple pregnancies
Data from IVF cycles irrespective for indication for IVF
are not in concordance
Meta-analysis
(Daya, 2002)
- rec-FSH significantly higher pregnancy rate
- total dose of rec-FSH significantly lower
- spontaneous abortion, multiple pregnancy and
OHSS rates comparable
 For every 19 patients treated 1 additional patient
would conceive when treated with rec-FSH
risks
(Papanikolau, 2006; Heijnen, 2007)
o PCOS with associated pathologies (tubal damage, severe endometriosis, PGD, severe male factor)
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COH and IVF: gonadotropins of choice?
risks of multiple
pregnancies.
IVF
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COH and IVF: gonadotropins of choice?
Meta-analysis
(Al-Inany, 2002)
- comparable pregnancy rate between
u-FSH vs rec-FSH
Meta-analysis
(van Weley, 2003)
- significantly increased pregnancy rate
with HMG in GnRH-a cycles
Prospective study
(Goldfarb, 2003)
- significantly increased implantation rate
with rec-FSH
No firm conclusions can be reached regarding
the superiority of one gonadotropin in IVF-PCOS
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Conclusions
COH and IVF: combination with GnRH-analogue
Suppression of LH with GnRH-agonist may reduce the
incidence of spontaneous abortion
(Homburg 1993)
Spontaneous abortion was not affected by using HMG
vs u-FSH
CC is the treatment of first choice in anovulatory women. AIs are effective in OI in PCOS women and may
have better clinical results than CC. Some concerns
are risen on their safety and actually are off-labelled
(Balen 1993; Homburg 1993)
No differences in term of ovulation, clinical pregnancy
GnRH-antagonists: no controlled study that compare
multiple pregnancy and miscarriage rates between FSH
agonists and antagonists in IVF PCOS patients
and HMG. Significantly increased OHSS with HMG

Theoretical advantage to reduce the incidence of
Low-dose step-up and step down protocols are compa-
OHSS by GnRH agonist induced LH surge to trig-
rable in term of ovulation rate and clinical outcome in
ger ovulation
OI. Combination with GnRH-analogs
(Engmann 2008; Kol 2008)
risk of OHSS
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Conclusions
CLINICA VALLE GIULIA, Rome
US monitoring must be very accurate. During OI it is
prudent to withhold HCG administration with >2 foll.
of >16mm or with one 1 foll. >16mm and 2 foll. of
>14mm under the age of 38
Centre for Reproductive Medicine
Gynaecology:
Embriology:
No firm conclusions can be reached regarding the su-
Filippo Ubaldi
Laura Rienzi
periority of one gonadotropin in IVF-PCOS
Elena Baroni
Stefania Romano
Silvia Colamaria
Roberta Maggiulli
Fabio Sapienza
Laura Albricci
Maddalena Giuliani
Antonio Capalbo
The combination of GnRH-agonists might
the risk
of miscarriage
The combination of GnRH-antagonists might the risk
of OHSS by GnRH agonist induced LH surge to trigger ovulation
16