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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Induction of ovulation with MRL/41. Preliminary report.JAMA. 1961, 178:101-4.

Greenblatt RB, Barfield WE, Jungck EC, Ray AW

HYPOTHALAMUS

HYPOTHALAMUS

PITUITARY

OVARY

PITUITARY

OVARY

NORMAL CLOMIPHENE

(-) (-)

GnRH GnRH

FSHLH

FSHLH

E2 E2

ER

ER ER

ER

Clomid LHFSH

Estradiol-17β

Progesterone

1 5 14 28Day of cycle

EFFECT ON GONADOTROPHINS

Adashi, 1984Fertil. Steril. 42, 331-44

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)

CC ADMINISTRATION

• For 5 days• Onset on days 2-5• No difference between different days

of onset• Starting dose 50 mg/day per os

CC: MONΙTORING OF TREATMENT

• No consensus• Progesterone assay • Ultrasound• Estradiol assay• Basal body temperature chart

2 6 21 28

CC50 mg/day

P4 P4

CYCLE DAYS

PROTOCOL OF CLOMIPHENE CITRATE USE

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

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%

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

(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%

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

RECOMMENDATION

• In properly selected PCOS patients with no other causes of infertility, treatment with CC can be extended beyond the 6 cycles.

OVULATION INDUCTION WITH CLOMIPHENE

• Response (ovulation – conception)• Response (ovulation – no

conception) CLOMIPHENE FAILURE

• No response (no ovulation) CLOMIPHENE RESISTANCE

CLOMIPHENE FAILURE (Ovulation but no conception)

• Anti-estrogenic effects on: - cervical mucus - endometrium - oocytes

• High LH

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

• 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.)

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.

CC FAILURECan we improve?

• Patients selection • Combinations of clomiphene with

other drugs• Second line treatment

- 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)

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

(%)

• Higher doses (up to 250 mg)• Extended treatment (~ 20 days)• Combinations with other drugs

CC RESISTANCE Is it possible to sensitize?

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

• Is clomiphene still the first line of infertility treatment in PCOS?

Alternatives as first line?

• Insulin sensitizers (Metformin)• Aromatase inhibitors (Letrozole)• Laparoscopic ovarian drilling (LOD)• Low-dose FSH

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

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

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

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

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)

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

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

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.

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

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%

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

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%)

CC: ADVANTAGES

• Low cost• Oral administration• Reasonably efficacious• Few side effects• Safe for offspring

• 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

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

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

• 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

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