OVULATION INDUCTION WITH CLOMIPHENE CITRATE IN PCOS

1
OVULATION INDUCTION WITH CLOMIPHENE CITRATE IN
PCOS

• Professor IOANNIS E. MESSINIS MD, PhD (Aberdeen,
  UK)
• Head of Department of Obs/Gynae
• University of Thessalia
• Larissa, Greece

2
Greenblatt RB, Barfield WE, Jungck EC, Ray AW
3
NORMAL
CLOMIPHENE
HYPOTHA LAMUS
HYPOTHA LAMUS
ER
ER
GnRH
GnRH
PITU ITA RY
PITU ITA RY
ER
ER
E2
E2
FSH LH
FSH LH
(-)
(-)
OVARY
OVARY
4
EFFECT ON GONADOTROPHINS
Clomid
LH
FSH
Estradiol-17ß
Progesterone

• 5 14 28
• Day of cycle

Adashi, 1984 Fertil. Steril. 42,
331-44
5
CC VS PLACEBO
4 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

7
CC MON?TORING OF TREATMENT

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

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PROTOCOL OF CLOMIPHENE CITRATE USE
50 mg/day
CC
P4
P4
2 6
21 28
CYCLE DAYS
9
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 citrate In Ovulation
induction, Elsevier, pp. 87-97
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OVULATION INDUCTION WITH CLOMIPHENE
100
97
Diaphragm
Cumulative pregnancy rate ()
Clomiphene
50
0

• 4 6 8 10
• Number of cycles

Hammond et al., 1983 Obstet. Gynecol. 62,
196-202 (modified)
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CUMULATIVE CONCEPTION AFTER CC
Kousta et al., 1997 Hum. Reprod. Update 3,
359-65 (n128 women)
100
80
conceived
67.3
Excluding other infertility factors
61.3
60
51.5
42.5
56.6
39.0
51.4
40
32.6
45.2
36.0
23.2
32.7
20
26.6
All patients who responded
17.7
0
1
2
3
4
5
6
gt6
CYCLE NUMBER
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OVULATION INDUCTION IN PCOS
Clomiphene
Low dose HMG
100
91
Cumulative pregnancy rate ()
80
63
(n55 women) 284 cycles
60
40
20
Messinis Milingos, 1997 Hum. Reprod. Update, 3,
235-253
0

• 2 3 4 5 6 7 8 9 10 11 12
• Treatment cycle

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A CONSECUTIVE SERIES OF 240 NORMOGONADOTROPHIC ANO
VULATORY WOMEN (CC first, followed by FSH)
A
1
71
0.8
50
0.6
Ongoing Singleton Pregnancy Rate Resulting in
Live Birth
0.4
0.2
0
0 3 6 9 12 15
18 21 24
Follow-up (months)
Eijkemans et al., 2003 Hum. Reprod. 18, 2357-2362
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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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CC EFFECTS ON ENDOMETRIUM

• Thickness ?
• Number and diameter of glands ?
• Number of vacuolated cells ?
• ß3 integrin expression (out-of-phase) ?
• Failure in the down-regulation of PR
• Affected endometrial receptivity?

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 BJOG
Seibel Smith 1989 J. In Vitro Fert. Embryo
Transfer
Pieters 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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CLOMIPHENE RESISTANCE (No ovulation)

• - 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.)
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A NOMOGRAM PREDICTING LIVE BIRTH (CC)
Chance of a live birth () (95 CI)
Chance of ovulation ()
Chance of ovulation ()
Ameno-
Ameno-
36
Oligo-
Oligo-
36
40
7
35
11
FAI
BMI
Age
Imani et al., 2002 Fertil. Steril. 77, 91-97
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CC RESISTANCE Is it possible to sensitize?

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

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CC DOSE PREGNANCY(PCOS)
Treatment dose (mg)
Women conceiving (n35)

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 PCOS
Live-birth rate
Conception rate
CC 39.5 47/209 (22.5) CC M 46.0 56/209
(26.8) M 21.7?? 5/208
(7.2)? ?Plt0.001 ??P0.002
Legro et al., 2007 N. Engl. J. Med. 356, 551-66
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METFORMINCCFirst-line (Dutch study)

• CCM vs CCP (228 PCOS women) No difference in
• Ovulations (64 vs 72)
• Ongoing pregnancies (40 vs 46)
• Miscarriages (12 vs 11)

PRT
Moll et al., 2006 BMJ 332, 1485
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CCM IN PCOSSystematic review

• CC is still first choice therapy
• In CC-resistant women, CCM is the preferred
  treatment before moving to LOD or FSH

Moll et al., 2007 Hum. Reprod. Update 13, 527-537
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CCM IN PCOSMeta-analysis

• 17 studies, 1639 women with PCOS
• CCM 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., 2008 Obstet. Gynecol. 111, 959-68
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FERTILITY TREATMENT IN WOMEN WITH PCOS
Baseline estimate
Probability of
Range
Live birth on CC 0.21 0.15-0.22 Live birth on
M 0.15 0.07-0.52 Live birth on
MCC 0.23 0.18-0.27
Jungheim and Obido, 2010 Fertil. Steril. May 6
(Epub)
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CC vs METFORMIN
Clinical pregnancy rate
Live birth rate
CC 39 (14/36) 36 (13/36) M 40
(14/35) 29 (10/35) CCM 54 (19/35) 43
(15/35)
Johnson et al., 2010 Hum. Reprod. Apr 30 (Epub)
BMI?32 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., 2010 Cochrane Database Syst. Rev.
Jan 20 (1) CD 003053
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LETROZOLE vs CLOMIPHENE (First-line)
Clomiphene 100 mg/d (n220)
Letrozole 5 mg/d (n218)

P
No. of follicles 4.4?0.4 6.8?0.3
0.042 Endom. Thick. (mm) 8.10.2
9.20.7 0.021 Serum E2 (pg/ml)
255.164.2 384.091.3 0.022 Serum P4
(ng/ml) 7.10.9 11.11.2
0.024 Days of stimulation 12.11.38
8.02.9 0.036 Preg./cycle 82/540
(15.1) 94/523 (17.9) Miscarriage/patient
4 (12.1) 4 (9.7)
Badawy et al., 2007 Fertil. Steril.
doi10.1016/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., 2008 Hum. Reprod. Update 14,
571-82
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OVULATION INDUCTION IN PCOS CC vs LOD as first
line
70
Cumulative pregnancy rate
60

50
40
30
20
CC
LOD
10
0
1
2
3
4
5
6
7
8
9
10
11
12
Time (months)
Amer et al., 2009 Hum. Reprod. 24, 219-225
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OI IN PCOSCC vs rFSH (first line)
CC
rFSH
Women/cycles 38/104 38/91 Ovulation 53 74 Pr
eg./cycle 9 18 Preg./ov.
Cycle 16 29 Preg./woman 24 42 Live
births/woman 16 29 Twins 0 19
Lopez et al., 2004 RBMOnline 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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WHO GROUP IIPCOS

• 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

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OVULATION INDUCTION ALGORITHM IN WHO GROUP II
(PCOS)
Obese Diet-Life style No compliance
changes Ov () Ov (-)
Pregnancy (-)
Lean CC (6
m) Ov (-) Ov ()
MCC (?) (6 m) Ov (-) Ov ()
Pregnancy (-) FSH (6 m) (LOD?) Ov (-)
Ov () Pregnancy (-) IVF
1st line
?
M Metformin CC Clomiphene
citrate Ov Ovulation LODLaparoscopic
ovarian drilling
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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SUMMARY II

• 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

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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