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

. Li nk s Induction of ovulation with MRL/41. Preliminary report. JAMA. 1961, 178: Greenblatt RB, Barfield WE, Jungck EC, Ray AW

HYPOTHA LAMUS HYPOTHA LAMUS PITU ITA RY OVARY PITU ITA RY OVARY NORMALCLOMIPHENE (-) GnRH FSH LH FSH LH E2 ER

ClomidLH FSH Estradiol-17β Progesterone Day of cycle EFFECT ON GONADOTROPHINS Adashi, 1984 Fertil. Steril. 42,

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)

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

CC 50 mg/day P4 CYCLE DAYS PROTOCOL OF CLOMIPHENE CITRATE USE

RESULTS OF TREATMENT WITH CC 5 STUDIES ( ): 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

Number of cycles Hammond et al., 1983; Obstet. Gynecol. 62, (modified) OVULATION INDUCTION WITH CLOMIPHENE Diaphragm Clomiphene Cumulative pregnancy rate (%) 97%

> % conceived CYCLE NUMBER CUMULATIVE CONCEPTION AFTER CC Kousta et al., 1997 Hum. Reprod. Update 3, (n=128 women) All patients who responded Excluding other infertility factors

(n=55 women) 284 cycles Messinis & Milingos, 1997 Hum. Reprod. Update, 3, Treatment cycle ClomipheneLow dose HMG Cumulative pregnancy rate (%) OVULATION INDUCTION IN PCOS 63% 91%

A CONSECUTIVE SERIES OF 240 NORMOGONADOTROPHIC ANOVULATORY WOMEN (CC first, followed by FSH) Follow-up (months) % 71% Eijkemans et al., 2003; Hum. Reprod. 18, Ongoing Singleton Pregnancy Rate Resulting in Live Birth A

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 ( ) 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,

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 ENDOMETRIUM 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; BJOG Seibel & Smith 1989; J. In Vitro Fert. Embryo Transfer Pieters et al., 1991; Fertil Steril. London et al., 2000; Fertil. Steril.

CC FAILURE Can 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)

FAIBMIAge Chance of ovulation (%) Chance of a live birth (%) (95% CI) Oligo- Ameno- Oligo- Ameno- A NOMOGRAM PREDICTING LIVE BIRTH (CC) Imani et al., 2002; Fertil. Steril. 77, Chance of ovulation (%)

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) Treatment dose (mg) Women conceiving (n=35) % Based on: Messinis & Milingos, 1997 Hum. Reprod. Update, 3,

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 CC First line 626 women with PCOS Live-birth rate CC39.5%47/209 (22.5%) CC + M46.0%56/209 (26.8%) M21.7%  5/208 (7.2%)   P<0.001  P=0.002 Conception rate Legro et al., 2007 N. Engl. J. Med. 356,

METFORMIN+CC First-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., 2006 BMJ 332, 1485 PRT

CC+M IN PCOS Systematic 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., 2007 Hum. Reprod. Update 13,

CC+M IN PCOS Meta-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., 2008 Obstet. Gynecol. 111,

Probability of Baseline estimate Range Live birth on CC Live birth on M Live birth on M+CC FERTILITY TREATMENT IN WOMEN WITH PCOS Jungheim and Obido, 2010 Fertil. Steril. May 6 (Epub)

CC vs METFORMIN Clinical pregnancy rate Live birth rate CC39% (14/36)36% (13/36) M40% (14/35)29% (10/35) CC+M54% (19/35)43% (15/35) Johnson et al., 2010 Hum. Reprod. Apr 30 (Epub) BMI  32 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., 2010 Cochrane Database Syst. Rev. Jan 20; (1): CD

Letrozole 5 mg/d (n=218) Clomiphene 100 mg/d (n=220) P No. of follicles 4.4   Endom. Thick. (mm) 8.1± ± Serum E2 (pg/ml) 255.1± ± Serum P4 (ng/ml) 7.1± ± Days of stimulation 12.1± ± Preg./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., 2007 Fertil. Steril. doi: /j.fertnstert

LETROZOLE IN PCOS Meta-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,

CCLOD OVULATION INDUCTION IN PCOS CC vs LOD as first line Amer et al., 2009; Hum. Reprod. 24, Time (months) Cumulative pregnancy rate %

OI IN PCOS CC vs rFSH (first line) CCrFSH Women/cycles38/10438/91 Ovulation53%74% Preg./cycle 9%18% Preg./ov. Cycle16%29% Preg./woman24%42% Live births/woman16%29% Twins 019% Lopez et al., 2004 RBMOnline 9, 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, , 2008 Fertil. Steril. 89, , 2008 WHO GROUP II PCOS

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: Metformin CC: Clomiphene citrate Ov: Ovulation LOD: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