ovulation induction with clomiphene citrate in pcos professor ioannis e. messinis md, phd (aberdeen,...
DESCRIPTION
HYPOTHA LAMUS HYPOTHA LAMUS PITU ITA RY OVARY PITU ITA RY OVARY NORMALCLOMIPHENE (-) GnRH FSH LH FSH LH E2 ERTRANSCRIPT
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OVULATION INDUCTION WITH CLOMIPHENE CITRATE IN PCOS
Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen, UK)
Head of Department of Obs/GynaeUniversity of Thessalia
Larissa, Greece
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. Link
s
Induction of ovulation with MRL/41. Preliminary report.JAMA. 1961, 178:101-4.
Greenblatt RB, Barfield WE, Jungck EC, Ray AW
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HYPOTHALAMUS
HYPOTHALAMUS
PITUITARY
OVARY
PITUITARY
OVARY
NORMAL CLOMIPHENE
(-) (-)
GnRH GnRH
FSHLH
FSHLH
E2 E2
ER
ER ER
ER
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Clomid LHFSH
Estradiol-17β
Progesterone
1 5 14 28Day of cycle
EFFECT ON GONADOTROPHINS
Adashi, 1984Fertil. Steril. 42, 331-44
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CC VS PLACEBO4 studies (cross-over)- CC increased ovulation (OR: 6.8) (3 studies) and pregnancy rate (OR: 3.41) (2 studies) (Hughes et al., 2000 Cochrane Database Syst. Rev. (2): CD000056)
3 RCTs- CC increased pregnancy rate (OR 5.8, 95% CI 1.6 to 21.5)
(Beck et al., 2005 Cochrane Database Syst. Rev. (1): CD002249)
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CC ADMINISTRATION
• For 5 days• Onset on days 2-5• No difference between different days
of onset• Starting dose 50 mg/day per os
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CC: MONΙTORING OF TREATMENT
• No consensus• Progesterone assay • Ultrasound• Estradiol assay• Basal body temperature chart
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2 6 21 28
CC50 mg/day
P4 P4
CYCLE DAYS
PROTOCOL OF CLOMIPHENE CITRATE USE
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RESULTS OF TREATMENT WITH CC
5 STUDIES (1968-1983): A total of 5878 cases
- Ovulation rate: 70-86%- Pregnancy rate: 34-43%- Miscarriage rate: 13-25%
Messinis, 2002; Clomiphene citrateIn: Ovulation induction, Elsevier, pp. 87-97
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100
50
0 2 4 6 8 10Number of cycles
Hammond et al., 1983; Obstet. Gynecol. 62, 196-202 (modified)
OVULATION INDUCTION WITH CLOMIPHENE
Diaphragm
Clomiphene
Cumulativepregnancyrate (%)
97%
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100
80
60
40
20
01 2 3 4 5 6 >6
23.232.6
39.042.5
51.561.3
67.3
17.726.6
32.736.0
45.251.4 56.6
%conceived
CYCLE NUMBER
CUMULATIVE CONCEPTION AFTER CCKousta et al., 1997Hum. Reprod. Update 3, 359-65(n=128 women)
All patientswho responded
Excluding other infertility factors
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(n=55 women) 284 cycles
Messinis & Milingos, 1997Hum. Reprod. Update, 3, 235-253
1 2 3 4 5 6 7 8 9 10 11 12Treatment cycle
Clomiphene Low dose HMG100
80
60
40
20
0
Cumulativepregnancyrate (%)
OVULATION INDUCTION IN PCOS
63%
91%
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A CONSECUTIVE SERIES OF 240 NORMOGONADOTROPHICANOVULATORY WOMEN (CC first, followed by FSH)
0 3 6 9 12 15 18 21 24Follow-up (months)
1
0.8
0.6
0.4
0.2
0
50%
71%
Eijkemans et al., 2003; Hum. Reprod. 18, 2357-2362
Ong
oing
Sin
glet
on P
regn
ancy
Rat
eR
esul
ting
in L
ive
Birt
hA
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RECOMMENDATION
• In properly selected PCOS patients with no other causes of infertility, treatment with CC can be extended beyond the 6 cycles.
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OVULATION INDUCTION WITH CLOMIPHENE
• Response (ovulation – conception)• Response (ovulation – no
conception) CLOMIPHENE FAILURE
• No response (no ovulation) CLOMIPHENE RESISTANCE
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CLOMIPHENE FAILURE (Ovulation but no conception)
• Anti-estrogenic effects on: - cervical mucus - endometrium - oocytes
• High LH
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CC: EFFECTS ON CERVICAL MUCUS
Meta-analysis
6 RCTs (1980-1996)Unfavorable effect:CC (100 mg/d)
(OR 7.90, 95% CI 4.15 to 15.0)CC (150 mg/d)
(OR 7.50, 95% CI 1.97 to 28.6)CC 50 mg: No adverse effect
Roumen, 1997, Ned.Tijdschr. Geneeskd 141, 2401-5
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• Thickness • Number and diameter of glands • Number of vacuolated cells • β3 integrin expression (out-of-phase) • Failure in the down-regulation of PR• Affected endometrial receptivity?
CC: EFFECTS ON CC: EFFECTS ON ENDOMETRIUMENDOMETRIUM
Nakamura et al., 1997 (Fertil. Steril.); Sereepapong et al., 2000 (Fertil. Steril.); Palomino et al., 2005 (Fertil. Steril.)
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CC: EFFECTS ON THE OOCYTE
• CC in vivo did not affect cleavage in vitro• CC adversely affects oocyte in vivo
maturation• Increased rate of immaturity with CC vs
GnRH-a• CC induces aneuploidy in mouse oocytes
Messinis & Templeton, 1986; BJOGSeibel & Smith 1989; J. In Vitro Fert. Embryo TransferPieters et al., 1991; Fertil Steril.London et al., 2000; Fertil. Steril.
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CC FAILURECan we improve?
• Patients selection • Combinations of clomiphene with
other drugs• Second line treatment
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- Increase in:• FAI• BMI• Mean ovarian volume• Insulin, LH• Age
- Amenorrhea
Imani et al., 1998 (JCEM), 1999 (JCEM), 2002a (Fertil. Steril.), 2002b (Fertil. Steril.),Van Santbrink et al., 2002 (Fertil. Steril.)
CLOMIPHENE RESISTANCE (No ovulation)
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FAI BMI Age
Chance ofovulation
(%)
Chance of alive birth (%)
(95% CI)O
ligo- Am
eno-
Olig
o-A
men
o-
A NOMOGRAM PREDICTING LIVE BIRTH (CC)
Imani et al., 2002; Fertil. Steril. 77, 91-97
740
36
36
3511
Chance ofovulation
(%)
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• Higher doses (up to 250 mg)• Extended treatment (~ 20 days)• Combinations with other drugs
CC RESISTANCE Is it possible to sensitize?
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CC DOSE – PREGNANCY(PCOS)
Treatmentdose (mg)
Womenconceiving (n=35)
%
50
100
150
18
11
6
51
32
17
Based on: Messinis & Milingos, 1997 Hum. Reprod. Update, 3, 235-253
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• Is clomiphene still the first line of infertility treatment in PCOS?
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Alternatives as first line?
• Insulin sensitizers (Metformin)• Aromatase inhibitors (Letrozole)• Laparoscopic ovarian drilling (LOD)• Low-dose FSH
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METFORMIN vs CCFirst line
626 women with PCOSLive-birth rate
CC 39.5% 47/209 (22.5%)CC + M 46.0% 56/209 (26.8%)M 21.7% 5/208 (7.2%)
P<0.001P=0.002
Conception rate
Legro et al., 2007N. Engl. J. Med. 356, 551-66
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METFORMIN+CCFirst-line (Dutch study)
• CC+M vs CC+P (228 PCOS women) No difference in:
• Ovulations (64% vs 72%)• Ongoing pregnancies (40% vs 46%)• Miscarriages (12% vs 11%)
Moll et al., 2006BMJ 332, 1485
PRT
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CC+M IN PCOSSystematic review
• CC is still first choice therapy• In CC-resistant women, CC+M is the
preferred treatment before moving to LOD or FSH
Moll et al., 2007Hum. Reprod. Update 13, 527-537
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CC+M IN PCOSMeta-analysis
• 17 studies, 1639 women with PCOS
CC+M vs CC (in CC resistance) (12 studies)– Ovulation (OR 4.39, 95% CI 1.94 to 9.96)– Pregnancy (OR 2.67, CI 1.45 to 4.94)
Creanga et al., 2008Obstet. Gynecol. 111, 959-68
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Probability ofBaselineestimate Range
Live birth on CC 0.21 0.15-0.22Live birth on M 0.15 0.07-0.52Live birth on M+CC 0.23 0.18-0.27
FERTILITY TREATMENT IN WOMEN WITH PCOS
Jungheim and Obido, 2010Fertil. Steril. May 6 (Epub)
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CC vs METFORMIN
Clinicalpregnancy
rate
Livebirthrate
CC 39% (14/36) 36% (13/36)M 40% (14/35) 29% (10/35)CC+M 54% (19/35) 43% (15/35)
Johnson et al., 2010Hum. Reprod. Apr 30 (Epub)
BMI32 Kg/m2
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METFORMIN vs CC
• Metformin improves clinical pregnancy and ovulation rates.
• There is no evidence that metformin improves live birth rates whether it is used alone or in combination with CC, or when compared with CC.
Tang et al., 2010Cochrane Database Syst. Rev. Jan 20; (1): CD 003053
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Letrozole5 mg/d (n=218)
Clomiphene100 mg/d (n=220) P
No. of follicles 4.40.4 6.80.3 0.042Endom. Thick. (mm) 8.1±0.2 9.2±0.7 0.021Serum E2 (pg/ml) 255.1±64.2 384.0±91.3 0.022Serum P4 (ng/ml) 7.1±0.9 11.1±1.2 0.024Days of stimulation 12.1±1.38 8.0±2.9 0.036Preg./cycle 82/540 (15.1%) 94/523 (17.9%)Miscarriage/patient 4 (12.1%) 4 (9.7%)
LETROZOLE vs CLOMIPHENE(First-line)
Badawy et al., 2007Fertil. Steril. doi:10.1016/j.fertnstert.2007.02.062.
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LETROZOLE IN PCOSMeta-analysis
• 4 RCTs
Letrozole vs CC– Ovulation (OR 1.17, 95% CI 0.66 to 2.09)– Pregnancy/cycle (OR 1.47, CI 0.73 to
2.96)– Pregnancy/patient (OR 1.37, CI 0.70 to
2.71) Requena et al., 2008Hum. Reprod. Update 14, 571-82
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1 2 3 4 5 6 7 8 9 10 11 12
70
60
50
40
30
20
10
0
CC LOD
OVULATION INDUCTION IN PCOS CC vs LOD as first line
Amer et al., 2009; Hum. Reprod. 24, 219-225Time (months)
Cumulative pregnancy rate%
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OI IN PCOSCC vs rFSH (first line)
CC rFSH
Women/cycles 38/104 38/91Ovulation 53% 74%Preg./cycle 9% 18%Preg./ov. Cycle 16% 29%Preg./woman 24% 42%Live births/woman 16% 29%Twins 0 19%
Lopez et al., 2004RBMOnline 9, 382-390
3 months treatment
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CC: SIDE EFFECTS
• Hot flushes (10%)• Nausea, vomiting, breast tenderness,
dizzines, mild skin reactions (2%)• Visual disturbanses (blurred vision)
(1.6%)• Multiple follicles – OHSS (rare)• Multiple pregnancies (2-17%)
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CC: ADVANTAGES
• Low cost• Oral administration• Reasonably efficacious• Few side effects• Safe for offspring
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• Consensus on infertility treatment related to polycystic ovary syndrome.
The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group et al. Hum. Reprod. 23, 462-77, 2008 Fertil. Steril. 89, 505-22, 2008
WHO GROUP IIPCOS
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Obese
Diet-Life style No compliance changes
Ov (+) Ov (-)
Pregnancy (-)
Lean
CC (6 m)
Ov (-) Ov (+)
M+CC (?) (6 m)
Ov (-) Ov (+) Pregnancy (-)
FSH (6 m) (LOD?)
Ov (-) Ov (+) Pregnancy (-)
IVF
OVULATION INDUCTION ALGORITHM IN WHO GROUP II (PCOS)
?
M: MetforminCC: Clomiphene citrateOv: OvulationLOD:Laparoscopic ovarian drilling
1st line
2nd line
3rd line
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SUMMARY I
• A high ovulation rate is achieved with CC
• Conception rate can be also high in properly selected patients
• Consecutive treatments with CC and low-dose FSH result in high cumulative conception and singleton live birth rates
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• In CC failure, it is recommended to proceed with the next step, i.e. low-dose FSH
• In CC resistance, combinations of CC with metformin may be efficacious before the use of second line therapeutic regimens
SUMMARY II
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CONCLUSIONS• CC effectively induces ovulation in
PCOS patients• Conception and singleton live birth
rates are reasonable• Side effects and complications are
rare• CC remains the first choice for
infertility treatment in PCOS