the use of hcg in microdose to support ovarian folliculgenesis michel abou abdallah, m.d
TRANSCRIPT
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)
recruitment maturation
FSH LH
Menstrual cycle
E2
E2
E2
E2
COH
FSHLH
E2
E2
E2
E2
FSH LH
recruitment maturation
FSH ?
E2
FSH FSH
FSH LH
recruitment maturation
FSH ?COH
FSHLH
E2
E2
E2
E2
E2
E2
E2
E2
A4, TA4, T
A4, T
A4, T
A4, T
A4, TA4, T
A4, TA4, T
A4, T
E2A4, T
FSH FSH
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
Detrimental effects of E2?
4 3 2 2 1.5 hCG
Step down
Step-dn Std PAge 31.6 33.9 NS
Amps 22.4 31.6 NSE2 1919 5271 0.001
Oocytes 18.1 23.1 0.001E.Trans. 3.3 3.4 NSE. frozen 2.5 3.1 NS
PR 64.2 24.2 <0.001Impl R 29.3 8.5 0.02OHSS 0 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.
Fertil Steril 1999.
Amps=ampules;
HP= highly purified.
(B), supplementation of highly purified FSH with low dose hCG therapy (50 IU/d).
(A) dministration of highly purifies FSH alone.
The low dose hCG (50 IU/d) was highly effective at enhancing ovarian stimulation with highly purified FSH in GnRH agonist-suppresed 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)
Ovarian follicles detected at transvaginal pelvic ultrasound and daily hormone serum levels during gonadotropin administration for ovulation induction in patient MC.
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.
Filicori. ICSI pregnancy after low dose hCG. Fertliti Steril 2002
No. of days of treatment
hMG 225 IU/day hCG 200 IU/day
Ova
rian
fol
licl
es (
n)
T (
ng/m
l)P
(ng
/ml)
E2 (
pg/m
l)hC
G (
IU/L
)FSH
(IU
/L)
LH
(IU
/L)
<10
mm
10-1
4mm
>14
mm
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.
mid-lutealDT 3.75 mg
2 weeks
rFSH (150IU)
hCG10’000IU
IUI
2 weeks
Luteal sup.Vag P
Experimental protocol
40 women suffering from unexplained or male related infertility w/ reg cycles.Study population
No hormone therapy for 3 mo before study.
> 8 dsB
A
C
D
hFSH 150 IU
hFSH 50 IU
hCG 100 IU
hFSH 25 IU
hCG 50 IU
hCG 200 IU
Foll. >14mmE2 800-1’500rFSH: Puregon
Clinical & hormonal results of gonadotropin stimulation in the four treatment groupsGroup 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
Results of gonadotropin administration
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
Follicular phase hormone levels
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
aP<0.05 group A vs. groups C & D, group B vs. group D. bP< 0.05 group D vs. group B & C.cP< 0.05 group A vs. group B & C. dP< 0.05 group A vs. group B.
Filicori et al. Follicular Support by LH.
Gonadotropin concentrations. Daily gonadotropin serum levels mean ±SEM) in the 4 groups of patients participating in the study.
Days of treatment
hC
G (
IU/L
)F
SH
(IU
/L)
LH
(IU
/L)
J Clin Endocrinol Metab, March 2002, 87 (3):1156-1161
Steroid concentrations. Daily gonadal setroid serum levels (mean ±SEM) in the 4 groups of patients participating in the study.
Days of treatment
T (
ng/
ml)
P (
ng/
ml
E2 (
pg/
ml)
Filicori M et al. JCEM 2002;87:1156-61.Stimulation and growth of antral ovarian follicles by selective LH activity administration in women.
D
hCG 200 IU
CBA
>14
>10-14
<10
day of hCGDays of treatment
<10
>10-14
>14
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;2:153-61)
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
FSHLH
E2
E2
E2
E2
E2
E2
E2
E2
A4, TA4, T
A4, T
A4, T
A4, T
A4, TA4, T
A4, TA4, T
A4, T
mini hCG
75 IU, when foll. >13mm
FSH LH
recruitment maturation
FSH ?
mini hCG
E2A4, T
FSH
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
October 15-18, 2008
The Royal hotel Hammamet, Tunisia
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