Clomiphene citrate + gonadotropins · Dose‐finding study Prospective randomized trial Pre‐treatment with oral contraceptives Clomiphene 100 mg/d (days 1‐5) Various combinations

Clomiphene citrate + gonadotropins

Antoni J. Duleba

Department of Reproductive Medicine

University of California, San Diego

Disclosure

No conflicts of interests

Antoni J. Duleba, M.D.

Department of Reproductive Medicine

University of California, San Diego

Outline

Rationale

Actions of clomiphene citrate

Review of studies

Rationale

Maximize success

◦ Maximize embryo quality

◦ Search for ideal protocol for poor responders

Maximize safety

◦ Reduce risk of OHSS

Minimize interventions

Minimize cost

Poor responder protocols

High dose approaches

◦ Typically gonadotropins at 300‐600 IU/day◦ ± Flare‐up protocols

Mixed results when compared to standard protocols

◦ Retrospective study: comparison of outcomes of cycles at 225 IU/day followed by cycles at 450 IU/day: Greater stimulation resulted in more oocytes but no difference in embryos (Land et al.)

◦ Retrospective study: comparable outcomes with 150 IU/day vs. 200‐300 IU/day ( Lekamge et al.)

Land et al. Fertil Steril 1996, 65:961Lekamge et al. J Assist Reprod Genet 2008, 25:515

Less is more? Retrospective study (n=806)

Fewer cancelations, no improvement of outcomes

Dose of gonadotropin predictive for reduced success after adjustment for age, FSH, E2, duration of infertility

Pal et al. Fertil Steril 2008, 89:1694


Stimulation of gonadotropin release

Effects on granulosa cells

◦ Increase of aromatase activity and estradiol production in granulosa cells; potentiation of effects of FSH and LH (Zuang et al.; Bussenot et al.)

◦ Inhibition of estradiol production by luteinized granulosa cells (Olsson and Granberg)

◦ Inhibition of progesterone production by granulosa cells (Yuen et al.)

Adverse effects on endometrium

Zhuang et al. Endocrinology 1982, 110:2219Bussenot et al. Hum Reprod 1990, 5:533Olsson and Granberg Hum Reprod 1990, 5:928Yuen et al. Fertil Steril 1988; 49:626


Teramoto and Cato Reprod BioMed Online 2007, 2:124

Short administration of clomiphene citrate

Early studies:

◦ Regimens tested: clomiphene 50 mg/d (CD5‐9), hMG 75‐225 IU/d (CD5‐retrieval) (Quigley et al.)

◦ No benefit of higher doses of hMG vs. clomiphene alone

◦ Risk of premature LH surge (20‐25%)

Clomiphene + hMG + GnRH antagonist

◦ Clomiphene 100 mg/d (CD3‐7), HMG 150 IU/d (CD4, 6, 8‐retrieval) + cetrorelix with lead follicle of 14 mm

◦ Effective suppression of LH surge

◦ Sixteen pregnancies (40%)

Quigley et al. Fertil Steril 1984, 42:25Quigley et al. J IVF and ET 1985, 2:11Eibschitz et al. Fertil Steril 1985, 45:231Hwang et al. Hum Reprod 2003, 18:45

Short administration of clomiphene citrate Prospective study

◦ Not a randomized trial: patients were offered an option to lower the cost of IVF by participation in the study (n=55)

Control group◦ Long protocol with luteal‐phase GnRH‐a

Minimal stimulation group◦ Clomiphene citrate (100 mg/d CD3‐7) + FSH (150 IU/d) starting CD9

Williams et al. Fertil Steril 2002, 78:1068


Dose‐finding study

◦ Prospective randomized trial

◦ Pre‐treatment with oral contraceptives

◦ Clomiphene 100 mg/d (days 1‐5)

◦ Various combinations of gonadotropins on alternate days 1, 3, 5,…

Weigert et al. Fertil Steril 2002, 78:34


Comparison with standard protocol

◦ Prospective randomized trial (n=294)


◦ Group A: clomiphene 100 mg/d (days 1‐5) + on alternate days gonadotropins (FSH 225 IU + LH 75 IU)

◦ Group B: buserelin (luteal suppression) FSH (150 IU) daily

Weigart et al. Fertil Steril 2002, 78:34

Group A (CC+FSH/LH) Group B (FSH)

Age 32.9±4.1 32.7±4.1

Cancelled cycles 16.9% 15.7%

Oocytes retrieved 7.7±3.6 8.7±5*

Embryo score 33±25 36.5±26.6

OHSS 3% 10%*

Pregnancy rate/ET 42.9% 36.6%

Implantation rate 21.3% 17.4%

* P<0.05


Comparison with standard protocol

◦ Prospective randomized trial (n=294)


◦ Group A: clomiphene 100 mg/d (days 1‐5) + on alternate days gonadotropins (FSH 225 IU + LH 75 IU)

◦ Group B: buserelin (luteal suppression) FSH (150 IU) daily

Weigart et al. Fertil Steril 2002, 78:34

Group A (CC+FSH/LH) Group B (FSH)

Age 32.9±4.1 32.7±4.1

Cancelled cycles 16.9% 15.7%

Oocytes retrieved 7.7±3.6 8.7±5*

Embryo score 33±25 36.5±26.6

OHSS 3% 10%*

Pregnancy rate/ET 42.9% 36.6%

Implantation rate 21.3% 17.4%

* P<0.05


Prospective trial (D’Amato et al.):◦ Poor responders (e.g. hx of ≤ 3 mature oocytes in past IVFs)

◦ Quasi‐randomization (based on the day of the week)

◦ Group 1 (n=60): mid‐luteal leuprolide acetate suppression, hFSH

◦ Group 2 (n=85): clomiphene 100 mg/d (CD2‐6) + hFSH 300 IU b.i.d. (CD2‐6, then adjusted to response) + cetrorelix (when lead follicle 16mm)

D’Amato et al. Fertil Steril 2004, 81:1572

Group 1 (FSH) Group 2 (CC+FSH)

Age 33.02±3.09 34.01±2.89

FSH day 3 (IU/ml) 11.8±2.9 13.7±3.3*

No of ampules FSH 53.3±16.6 83.5±7.1***

No of MII oocytes 2.65±1.12 4.29±0.95***

Cancellation rate (%) 34 4.8***

Pregnancy rate (%) 15.3 22.2

Implantation rate (%) 7.6 13.5

* P<0.05; ** P<0.01; *** P<0.0001


Prospective trial (D’Amato et al.):◦ Poor responders (e.g. hx of ≤ 3 mature oocytes in past IVFs)

◦ Quasi‐randomization (based on the day of the week)

◦ Group 1 (n=60): mid‐luteal leuprolide acetate suppression, hFSH

◦ Group 2 (n=85): clomiphene 100 mg/d (CD2‐6) + hFSH 300 IU b.i.d. (CD2‐6, then adjusted to response) + cetrorelix (when lead follicle 16mm)

D’Amato et al. Fertil Steril 2004, 81:1572


Age 33.02±3.09 34.01±2.89

FSH day 3 (IU/ml) 11.8±2.9 13.7±3.3*

No of ampules FSH 53.3±16.6 83.5±7.1***

No of MII oocytes 2.65±1.12 4.29±0.95***

Cancellation rate (%) 34 4.8***


Implantation rate (%) 7.6 13.5

* P<0.05; ** P<0.01; *** P<0.0001


Prospective randomized trial

◦ Male factor only, ages 20‐38 y.

◦ Block randomization

◦ Group 1 (n=60): buserelin suppression, hMG (Pergonal, 150‐300 IU) daily

◦ Group 2 (n=60): clomiphene 100 mg/d (CD3‐7) + hMG (Pergonal, 150‐300 IU) CD4, 5, 8, then daily from CD9 + cetrorelix (when lead follicle 14mm)

Lin et al. Gynecol Endocrinol 2006, 22:297

Group 1 (hMG) Group 2 (CC+hMG)

Age 30.7±4.4 31.3±4.4

No of gonadotropin injections

15.7±3.1 6.8±1.1*

No of MII oocytes 14.1±5.6 9.6±3.6*

Pregnancy rate (%) 40 41.7

Implantation rate (%) 35 36.7

* P<0.001



◦ Male factor only, ages 20‐38 y.

◦ Block randomization

◦ Group 1 (n=60): buserelin suppression, hMG (Pergonal, 150‐300 IU) daily

◦ Group 2 (n=60): clomiphene 100 mg/d (CD3‐7) + hMG (Pergonal, 150‐300 IU) CD4, 5, 8, then daily from CD9 + cetrorelix (when lead follicle 14mm)

Lin et al. Gynecol Endocrinol 2006, 22:297

Group 1 (hMG) Group 2 (CC+hMG)

Age 30.7±4.4 31.3±4.4

No of gonadotropin injections

15.7±3.1 6.8±1.1*


Pregnancy rate (%) 40 41.7

Implantation rate (%) 35 36.7

* P<0.001



◦ First IVF cycle, ages 18‐35 y.

◦ Computer generated randomization

◦ Group 1 (n=100): buserelin suppression, rFSH (150‐225 IU) daily

◦ Group 2 (n=100): clomiphene 100 mg/d (CD3‐7) + rFSH daily from CD5(75IU) + cetrorelix (when lead follicle 12mm)

Karimzadeh et al. Arch Gynecol Obstet 2010, 281:741


Age 30.0±2.3 29.4±2.4

No of ampules FSH 22±3.6 12.1±4.3*


OHSS (%) 6 0*


* P<0.05

Mild stimulation: short administration of clomiphene citrate

Women with low ovarian reserve and poor response to COS

Randomized trial (n=695) “Mild” protocol◦ Clomiphene citrate (100 mg/day) on days 2‐6 followed by gonadotropin (150 IU/day)◦ GnRH antagonist from day 8

“Long” protocol◦ GnRH agonist (Buserelin), urinary hMG (Meropur; 300 IU, after 7 days increase to 450 IU)

Revelli et al. J Assist Reprod Gent 2014, 31:809






Ferraretti et al. Fertil Steril 2015, 104:333

Prospective cohort (n=163)

Good prognosis, no past IVF

Fixed protocol

◦ CC 100 mg/d CD3‐7

◦ FSH 150 IU CD 5, 7, 9, ◦ GnRH agonist◦ Cumulative delivery after 3 fresh and/or frozen transfers


Ferraretti et al. Fertil Steril 2015, 104:333


Oride et al. J Obstet Gynaecol 2015, 35:163

Retrospective review◦ (n=66 cycles, 13 patients)

History of poor response; at least 2 of:

◦ Age ≥ 40 y◦ ≤ 3 oocytes in past conventional cycle◦ AFC<7 or AMH <1.1

Stimulation

◦ hMG 150‐300 IU every other day (20 cycles)

◦ CC 100‐150 mg + hMG (46 cycles)

Mild stimulation: long administration of clomiphene citrate

Oride et al. J Obstet Gynaecol 2015, 35:163

Less hMG (p=0.03)

Four pregnancies in CC + hMG group

Long administration of clomiphene citrate

Retrospective study (Teramoto and Kato):

◦ 44,345 IVF cycles (from 2001 to 2005)

Teramoto and Kato Reprod BioMed Online 2007, 2:124


Teramoto and Kato Reprod BioMed Online 2007, 2:124


Highest success from vitrified blastocysts

Kato et al. Reprod Biol Endocrinol 2012, 10:35


Retrospective review

Single center: 7,244 patients undergoing 20,244 cycles in 2008

Use of clomiphene citrate in 82% of cycles, natural cycles (16.2%) and letrozole cycles (1.8%)

Cato et al. Reprod Biol Endocrinol 2012, 10:35

Clomiphene citrate: fresh vs. vitrification

Retrospective review: 2,516 patients in 2,957 cycles

Clomiphene 50 mg CD3‐7, hMG 150 IU (Menopur) every other day starting on CD5 or 8

Comparison of outcomes for fresh vs. frozen (vitrified) cycles and according to FSH on CD3

Zhang et al. Reprod BioMedicine Online 2010, 21:485

FreshFSH≤15

FreshFSH>15

VitrifiedFSH≤15

VitrifiedFSH>15

Clinical pregnancy per ET (%)

21.4 18.2 40.1 41.7

Implantation rate (%) 19.4 13.9 35.5 38

Live birth per ET (%) 8.9 6.3 18 14.2


Retrospective cohort evaluation.

Patients with history of poor embryo quality

Two protocols of ovarian stimulation in IVF were compared:

Low stimulation (LS, n=38 cycles): clomiphene citrate (100 mg) and 150 IU of hMG

Standard stimulation (SS, n=38 cycles): FSH/hMG protocol dosed according to the assessment of ovarian reserve

Median age of 38.5, cycle day 3 FSH of 7.9 IU/L and AMH 1.1 ng/mL.

Each subject underwent at least one cycle of LS and one cycle of SS.

The outcomes included:

Day 3 embryo quality: scale from 1 (poor)‐3 (good),

Day 5 blastocyst quality: scale 0 (arrested)‐7 (expanded, good).

Garzo et al. ASRM 2013


Garzo et al. ASRM 2013

Low Stimulation(N=38)

Standard Stimulation (N=38)

P-value

Number of oocytes retrieved

8.9±1.0 10.0±1.2 0.44

Number of oocytes inseminated

6.9±0.7 6.8±0.7 0.93

Number of 2PN embryos

5.0±0.6 4.6±0.6 0.66

Quality of the best embryo on day 3

2.91±0.05 2.67±0.11 0.047

Average embryo quality on day 3

2.46±0.08 2.04±0.10 0.002

Quality of the best blastocyst

6.1±0.16 4.5±0.5 0.01

Average blastocyst quality

3.73±0.34 1.79±0.26 0.0004

Meta‐analysis: Live birth rate

Gibreel et al. Cochrane Database Syst Rev 2012,

Meta‐analysis: OHSS


Meta‐analysis: Clomiphene + gonadotropins vs. long or short GnRHa protocols


◦ Increased cycle cancellation rate:(OR 1.83, 95% CI 1.39 to 2.42)◦ Decrease of ampoules of gonadotropin:

(MD‐16.2, 95% CI ‐15.6 to ‐16.8)◦ Decrease of number of oocytes:

(MD ‐2.7, 95% CI ‐2.4 to ‐2.95)◦ No difference in miscarriage rate:

(OR 1.26, 95% CI 0.53 to 1.72)

Meta‐analysis: Clinical pregnancy

Figueiredo et al. Arch Gynecol Obstet 2013, 287:779

Meta‐analysis: Live birth


Meta‐analysis: OHSS


Conclusions

Use of clomiphene citrate + gonadotropins leads to comparable success as standard protocols

Lower risk of OHSS

Lower cost

Fewer oocytes

Improved embryo quality?

Questions

Dose and duration of clomiphene treatment?

Use in fresh or frozen cycles?

Effects in individual subgroups of patients?

Need for randomized trials

Thank you

Documents

Clomiphene citrate + gonadotropins · Dose‐finding study Prospective randomized trial Pre‐treatment with oral contraceptives Clomiphene 100 mg/d (days 1‐5) Various combinations