Transcript Document

The use of hCG in microdose to
support ovarian folliculgenesis
Michel Abou Abdallah, M.D.
FSH is currently considered the only
stimulatory factor needed for ovulation
induction which acts through specific
receptors present on the granulosa cells
of ovarian follicles
LH is another critical hormone involved in
the control of the human menstrual cycle,
its roles are traditionally believed to be
limited to stimulating theca cells androgen
production, triggering ovulation and
supporting the corpus luteum
Nevertheless, granulosa cell LH receptors
are expressed in more mature ovarian
follicles (>10 mm in diameter) and that
explains the efficacy of gonadotropin
preparations containing LH
The addition of Rec-hLH to stimulation
regimen of Rec-hFSH enhanced steroid
and follicle development in patients with HH or
patients undergoing stimulation with GnRH-A
for ART.
(Filicori et al Fertil Steril 1999 vol 72, No 6)
(Sullivan et al, J Clin Endo Metab 1999, Vol.84, No.1)
(Abou Abdallah et al, Fertil Steril 2000, Vol74 No 3S)
Menstrual cycle
recruitment
FSH
maturation
LH
COH
LH
FSH
recruitment
FSH
FSH
maturation
?
LH
FSH
FSH
E2
E2
E2
E2
E2
E2
E2
E2
E2
COH
LH
FSH
recruitment
FSH
FSH
maturation
?
LH
FSH
E2
FSH
A4, T
A4, T
A4, T
A4, T
E2
E2
E2
A4, T
A4, T
E2
A4, T
E2
A4, T
E2
A4, T
E2
A4, T
E2
A4, T
Detrimental
effects of E2?
Simon C. et al.
Fertil Steril 1998;70:234-9
86 High responders
previous failed IVF
>3 good quality embryos
•24 Step down
•62 Regular protocol
Step down
4
3 2
2
1.5
hCG
Age
Amps
E2
Oocytes
E.Trans.
E. frozen
PR
Impl R
OHSS
Step-dn
31.6
22.4
1919
18.1
3.3
2.5
64.2
29.3
0
Std
P
33.9 NS
31.6 NS
5271 0.001
23.1 0.001
3.4
NS
3.1
NS
24.2 <0.001
8.5
0.02
12.9 0.04
The absolute concentration of LH present
during the mid-through late follicular phase
of the spontaneous cycle may play an
important role in maintaining preovulatory
folliculogenesis, and even in protecting the
maturing follicle as FSH concentrations
decline.
FSH operates in a threshold manner ( Brown
J. 1978.Aust NZ J Obstet Gynecol.18:47-54) once
adequate FSH concentrations in blood are
achieved, follicles advance from antral
stages until maturity, acquire LH receptors
on granulosa cells and respond to either
FSH or LH stimulation (Zeleznik and Hiller,
1984.Clin Obstet Gynecol.27:927-940)
Sullivan et al.1999 confirmed the hypothesis
that a key mechanism by which the dominant
follicle continues to develop in the face of
decreasing concentration of FSH is by
acquiring LH responsiveness.
24 women down regulated with GnRH
agonist received r-hFSH until a 14mm
follicle appeared on ultrasound. They were
randomized to 1 of 4 groups for a 2 day
period: continued r-hFSH, saline only;
r-hLH 150 IU bid, or r-hLH 375 IU bid.
Demographic characteristics of the treatment groups
Group
Age (yr)
BMI (kg/m2)
Cycle length
(days)
Duration of
infertility (yr)
Saline
(group A)
30.17 ± 3.2
25.52± 4.5
28.2 ± 3.3
3.5 ± 2.2
r-hFSH
(group B)
31.00 ± 2.1 24.44 ± 2.4 28.5 ± 2.4
3.5 ± 2.4
r-hLH high
(group C)
29.33 ± 1.2
22.20 ± 2.5
28.8 ± 0.8
4.0 ± 2.9
r-hLH low
(group D)
31.33 ± 3.0
23.48 ± 4.4
28.5 ± 2.7
3.8 ± 1.7
Baseline parameters in the four treatment groups.
Baseline Parameters
Group A
Group B
Group C
Group D
P
Age (yr)
33.1 ± 0.9
33.1 ± 1.0
32.6 ± 1.1
30.4 ± 1.2
NS
Height (cm)
165 ± 1
170 ± 2
165 ± 2
165 ± 2
NS
Weight (kg)
58 ± 1
61 ± 1
57 ± 2
58 ± 2
NS
BMI (kg/m2)
21.1 ± 0.3
21.2 ± 0.2
20.9 ± 0.2
21.3 ± 0.3
NS
Menstrual cycle duration (d)
27.9 ± 0.5
28.0 ± 0.5
27.9 ± 0.3
27.3 ± 0.5
NS
Mean ovarian volume (ml)
6.7 ± 0.4
64 ± 0.4
6.5 ± 0.3
6.4 ± 0.3
NS
LH (IU/liter)
4.7 ± 0.4
5.0 ± 0.6
4.4 ± 0.4
4.7 ± 0.5
NS
FSH (IU/liter)
6.5 ± 0.4
6.1 ± 0.6
5.8 ± 0.5
5.8 ± 0.5
NS
PRL (ng/ml)
16 ± 1
13 ± 2
14 ± 1
16 ± 3
NS
E2(pg/ml)
79 ± 7
61 ± 8
67 ± 8
74 ± 9
NS
P(ng/ml)
0.56 ± 0.04 0.49 ± 0.07 0.52 ± 0.04 0.58 ± 0.06
NS
T(ng/ml)
0.48 ± 0.05 0.42 ± 0.07 0.39 ± 0.04 0.40 ± 0.06
NS
Serum FSH concentrations
Results show that the mean serum FSH concentration (International units per
L) ± SEM of the four treatment groups (A-D) on the day of randomization (day
0; black bars) and the day hCG administration (day 2; gray bars). The mean
concentration of FSH was maintained in the group receiving r-rFSH (group B)
as the mean concentration of FSH fell in groups A,C and D (p<0.05)
Serum LH concentrations
Results show that the mean serum LH concentration (international units per L)
± SEM of the four treatment groups (A-D) on the day of randomization (day 0;
black bars) and the day hCG administration (day 2; gray bars). Note that the
mean LH concentration of the groups receiving r-hLH (group C and D) were
greater than those of the groups not receiving r-hLH ( groups A and B; P<0.05)
Serum E2 concentrations
Results show that the mean serum E2 concentration (international units per L)
± SEM of the four treatment groups (A-D) through the study period (day 0,1,
and 2). Note that the serum E2 concentrations increased throughout the study
period in the groups receiving gonadotropin (groups B, C and D), whereas
serum E2 concentrations decreased toward the baseline in the baseline in the
saline-treated group ( group A).
HCG is usually used as a surrogate
to LH to stimulate ovulation
The effect of supplementing FSH treatment
with LH activity in the form of low dose hCG
therapy was reported by Filicori et al in
1999 (Fertility and Sterility vol. 72,No 6,
Dec 1999) the time where Rec-hLH was not
clinically available
The dosage of menotropins and levels of estrogen during treatment in a
hypogonadal patient.
Filicori.
Human chronic gonadotropin.
(A) dministration
of highly purifies
FSH alone.
Fertil Steril 1999.
(B), supplementation
of highly purified
FSH with low dose
hCG therapy (50
IU/d).
Amps=ampules;
HP= highly purified.
The low dose hCG (50 IU/d) was highly
effective at enhancing ovarian stimulation
with highly purified FSH in GnRH agonistsuppresed women undergoing COH for
ART, without causing follicle luteinization
or excessive theca cell stimulation ( Filicori
et al, J Clin Endocrinol Metab 1999;84:2659-63.)
Several days of low-dose hCG (200 IU/d)
alone can be used to stimulate
folliculogenesis, complete FSH initiated
follicle/oocyte maturation, and achieve
pregnancy in assisted reproduction
technology. (Filicori et al. Fertil Steril2002;
78:414-6)
>14mm
LH (IU/L)
<10mm
10-14mm
Ovarian follicles (n)
FSH (IU/L)
hCG (IU/L)
Filicori. ICSI pregnancy after low
dose hCG. Fertliti Steril 2002
T (ng/ml)
P (ng/ml)
The vertical arrow in the upper
right corner of the figure
indicates high dose (10,000 IU)
hCG administration to trigger
final follicle and oocyte
maturation.
hCG 200 IU/day
E2 (pg/ml)
Ovarian follicles detected at
transvaginal pelvic ultrasound
and daily hormone serum levels
during gonadotropin
administration for ovulation
induction in patient MC.
hMG 225 IU/day
No. of days of treatment
In the same year 2002, Filicori et al, tested
on 40 studied women the hypothesis that in
the late stages of ovulation induction, LH
activity can stimulate and selectively
modulate ovarian follicle function and
growth, independently of FSH
administration. (Filicori et al. J Clin Endocrinol
Metab 87:1156-1161, 2002)
Filicori M et al. JCEM 2002;87:1156-61.
Stimulation and growth of antral ovarian follicles by selective LH activity
administration in women.
Study population
40 women suffering from unexplained or male related infertility w/ reg cycles.
No hormone therapy for 3 mo before study.
Experimental protocol
2 weeks
mid-luteal
DT 3.75 mg
rFSH
(150IU)
rFSH: Puregon
A
hFSH 150 IU
B
hFSH 50 IU
hCG 50 IU
C
hFSH 25 IU
hCG 100 IU
D
hCG 200 IU
> 8 ds
Foll. >14mm
E2 800-1’500
Luteal sup.
Vag P
2 weeks
hCG
10’000IU
IUI
Clinical & hormonal results of gonadotropin stimulation in the four treatment groups
Group A
Group B
Group C
Group D
p
Daily r-hFSH dose (IU),
d 8 onward
150
50
25
0
Daily hCG dose (IU),
d 8 onward
0
50
100
200
Days of gonadotropin
administration
13.7 ±1.0(11-19)
13.4 ± 0.7(10-16)
13.1 ± 0.6(11-17)
12.7 ± 0.6(10-15)
NS
Total r-hFSH dose
received(IU)
1,920 ± 146a
1,325 ± 40a
1,180 ± 15a
1,050 ± 0a
< 0.001
Total hCG dose received (IU)
0
275 ± 40b
520 ± 59b
940 ± 112b
< 0.001
Preovulatory E2 (pg/ml)
1,034 ± 51
1,274 ± 113
1,223 ± 106
1,271 ± 105
NS
LH ( IU/liter-d)
12.0 ± 3.3
12.3 ± 1.3
13.8 ± 1.0
12.4 ± 1.7
NS
FSH ( IU/liter-d)
96.6 ± 12.3
91.2 ± 3.4
79.8 ± 7.0
80.7 ± 5.5
NS
hCG ( IU/liter-d)
ND
10.2 ± 3.0b
11.8 ± 2.8b
38.5 ± 8.6b
< 0.005
E2( pg/ml-d)
3,651 ± 466
3,695 ± 662
3,929 ± 798
3,902 ± 677
NS
p (ng/ml-d)
7.4 ± 1.0c
10.7 ± 0.8c
10.7 ± 0.8c
8.1 ± 0.7
< 0.01
T (ng/ml-d)
4.2 ± 0.6d
6.8 ± 0.6d
4.9 ± 0.4
4.9 ± 0.7
< 0.05
Results of gonadotropin administration
Follicular phase hormone levels
a
P<0.05 group A vs. groups C & D, group B vs. group D.
b
c
P< 0.05 group A vs. group B & C.
d
P< 0.05 group D vs. group B & C.
P< 0.05 group A vs. group B.
hCG (IU/L)
FSH (IU/L)
LH (IU/L)
Filicori et al. Follicular Support by LH.
Days of treatment
Gonadotropin concentrations. Daily gonadotropin serum levels
mean ±SEM) in the 4 groups of patients participating in the study.
T (ng/ml)
P (ng/ml
E2 (pg/ml)
J Clin Endocrinol Metab, March 2002, 87 (3):1156-1161
Days of treatment
Steroid concentrations. Daily gonadal setroid serum levels (mean
±SEM) in the 4 groups of patients participating in the study.
Filicori M et al. JCEM 2002;87:1156-61.
Stimulation and growth of antral ovarian follicles by selective LH activity
administration in women.
>14
>14
>10-14
>10-14
<10
<10
hCG 200 IU
A
Days of treatment
B
C
day of hCG
D
Human Chorionic gonadotropin is approximately 6
times more potent than LH ( Stokman et al 1993.
Fertil Steril 60:175-178), has a longer half-life than
does LH and offers more prolonged and stable
occupancy of LH receptors between hormone
administration
(Filicori et al; Fertil Steril 2002; 76(suppl):s104-5)
(Damewood et al. Fertil Steril 52:398-400)
hCG can promote angiogenesis, a crucial
process involved in embryo implantation.
(Mannaerts et al; Hum Repod update 1996;2:15361)
Low dose hCG can hasten small follicle
development and reduce the dose and duration of
treatment with highly purified FSH without
causing follicle Luteinization or excessive theca
cell stimulation
(Filicori et al. 1999. J.Clin Endocrinol Metab
84:2659–2663 )
(Filicori et al 1999. Fertil Steril 72:1118–1120)
COH
LH
FSH
recruitment
FSH
FSH
maturation
mini
?
LH
75 IU,
when foll. >13mm
mini
hCG
FSH
E2
E2
A4, T
A4, T
hCG
A4, T
A4, T
E2
E2
A4, T
E2
A4, T
A4, T
E2
A4, T
A4, T
E2
A4, T
E2
E2
A4, T
In addition to its lower price, low dose hCG therapy can:
a. reduce the overall cost of ovulation induction by
dramatically reducing the dose of exogenous FSH
required to achieve adequate folliculogenesis and by
reducing the duration of treatment and the need for
monitoring procedures.
b. Selectively reduce the occurrence of small preovulatory
ovarian follicles and, potentially of OHSS. ( Navot D et
al 1988. Am J Obstet Gynecol 159:210–215) Thus
improving the safety of ART procedures.
Although, it cannot be excluded that low levels of
FSH activity may still be needed to optimize the
late folliculogenesis stages, novel and
unconventional protocols could be envisioned,
consisting of initial higher dose FSH
administration to boost follicle recruitment,
followed by FSH curtailment or discontinuation
along with LH activity administration until
ovulation, leading to selective promotion of larger
follicle developments.
(Filicori M, et al. 2001. J Clin Endocrinol Metab 86:1437–
1441)
Such an approach may profoundly modify
the current management of anovulation and
ART.
Additional investigations will be needed to
further assess the specific effects of r-hLH
and low dose hCG administration in
different clinical conditions and regimens.
MEFS/STGO 2008
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