OPTIMIZATION OF STIMULATION PROTOCOLS

IN PCOS PATIENTSDr Hakan ÖZÖRNEK

OHSS

OHSS is a serious, potentially life-threatening, iatrogenic complication of “controlled” ovarian stimulation.

To optimize the ovarian response without provoking OHSS is the best compromise that should be reached by an ideal regimen of stimulation, which is unfortunately still not consistently achievable.

PCO - OHSS

PCO-like ovarian ultrasound features (more than 10 follicles) are a predictive factor for OHSS in IVF.

Increased risk for OHSS in patients with a LH/FSH ratio of more than 2.

The incidence of OHSS in PCOS patients is 6%

Tibi, 1989

Delvigne, Human Reprod 1993

Brinsden, Br J Obstet Gynecol 1995

Clomiphen citrate Nonstimulated – natural cycle Low dose gonadotropin protocols

› Agonist› Antagonist

Trigger the ovulation Luteal phase support Metformin IVM Coasting

Naturel cycle

Patients with PCOS are unlikely to benefit from this procedure since their success in development of a single follicle leading to the retrieval of a single, good quality oocyte during a spontaneous cycle remains uncertain.

CC

Ovulation is restored in 80%, but pregnancy is achieved in 35% of patients

75% of the pregnancies occur within the first three cycles of CC treatment

20-25% of PCOS patients remain resistant to CC

CC is rarely associated with severe OHSS

Imani, Fertil Steril 2002

Gysler, Fertil Steril 1982

Kistner, Obstet Gynecol Surv 1965

Which gonadotropin?

Two reviews from The Cochrane Library on clinical trials investigating gonadotropin therapy for ovulation induction in women with clomipheneresistant PCOS, concluded that no significant benefit could be demonstrated from urinary FSH versus hMG in terms of pregnancy rate, but a significant reduction in OHSS associated with FSH was observed.

Hughes 1997, Nugent 2002

Which gonadotropin?

Early reports suggested a relationship between the type of gonadotropin preparation utilized and the risk of OHSS. More recent comparisons between recombinant follicle-stimulating hormone (rFSH) and human menopausal gonadotropins (hMG) did not show significant differences among variable drug regimens.

Which gonadotropin?

The clinical pregnancy rates per cycle started were higher with rFSH than uFSH, although the magnitude of the observed difference was small, 3.7%. No significant differences were detected in the rates of miscarriage, multiple pregnancy and OHSS. European and Middle East Orgalutran Study

Group, Human Reprod 2001

Which protocol?

During cycles without GnRH-a suppression, either a significant LH surge or at least marked luteinization will limit continued gonadotropin stimulation and thus lead to a concomitantly lower risk of OHSS.

Which protocol?

FIVNAT results showed that the use of GnRH-a led to significantly higher preovulatory estradiol concentrations, and to more frequent severe hyperstimulation (4.6% vs. 0.6% for nonGnRH-a/hMG cycles).

FIVNAT, Contracept Fertil Sex 1989

How to use agonist?

The type of GnRH agonist to be used in patients at risk of OHSS has not been extensively studied. It is obvious that the short protocol should not be proposed, as the initial flare-up effect could lead to an excessive ovarian response.

In the long protocol, depot formulation versus daily injection and follicular versus luteal start have not been compared prospectively in patients at risk of OHSS.

Which protocol?

It has been proposed that a longer period of desensitization (30 instead of 15 days) is of benefit by reducing androgen levels.

The longer duration of treatment did not improve pregnancy rates but did apparently decrease the incidence of hyperstimulation. Salat-Baroux, Human Reprod 1988

Why antagonist?

Patients receiving antagonist treatment have lower estradiol serum levels at the time of hCG administration, mostly because of a lower number of follicles, which could explain the lower incidence of OHSS.

Ludwig M, Arch Gynecol Obstet 2000

Which protocol?

There was a statistically significant reduction in incidence of severe OHSS with antagonist protocol. The relative risk ratio was 0.61 (P=0.01; 95% CI 0.42 - 0.89).

In addition, interventions to prevent OHSS (e.g. coasting, cycle cancellation) were administered more frequently in the agonist group (P=0.03; OR 0.44, 95% CI 0.21 - 0.93).

Al-Inany, Cochrane Database 2006

Which protocol?

The GnRH-antagonist protocol involved starting gonadotropins on day 3 of the menstrual cycle. Transvaginal ultrasound monitoring was commenced on day 5 of ovarian stimulation and repeated every 2-3 days.

Antagonist protocol

150 IU225 IU

3th day 7th day

USG

300 IU

USG

12th day

HCG

Antagonist (start at 6th day)

Which dose?

The starting dose for gonadotropin is based on › age, › body mass index (BMI)› existence of PCOS, › previous history of OHSS or high response.

Which protocol?

Two comparative prospective studies of the conventional regimen, with the chronic low-dose step-up protocol using urinary FSH or rhFSH for ovulation induction in PCOS patients, showed that the low-dose approach eliminated complications of OHSS and multiple pregnancies without jeopardizing the incidence of pregnancy.Homburg, Fertil Steril 1995

Hedon, Human Reprod 1998

Classic step up protocol

150 IU225 IU

3th day 7th day

USG

300 IU

USG

12th day

HCG

Agonist

Midluteal

Low dose step up protocol

75 IU150 IU

3th day 7th day

USG HCG

Agonist

Midluteal

Chronic low dose step up protocol

75 IU

3th day 14th day

USG

112.5 IU150 IU

21st day

USG

Which protocol?

The step-down protocol applies decremental doses of gonadotropins once ovarian response is established, but the starting dose is higher than in the step-up approach.

Monitoring of follicular growth is, however, more stringent than with the step-up approach. In addition, the long half-life of currently available FSH preparations makes it difficult to judge the correct reduction of dose.

Clinical results are similar to those obtained with the step-up approach.van Santbrink, Human Reprod 1995

Step down protocol

Agonist

3th day 6th day

USG

150 IU300 IU

HCG

Midluteal

Which protocol?

Unlike a step-up protocol, which continuously rescues follicles from atresia, a step-down protocol will allow more follicles to undergo atresia, thus reducing the overall number of follicles capable of secretory activity by the time hCG is administered.

Which protocol?

An alternative method for ovulation induction with FSH in PCOS patients is the so-called sequential protocol, which combines an initial step-up gonadotropin administration followed by a step-down regimen after follicular selection (leading follicle > 14 mm). In a comparative study with the standard low-dose step-up regimen, both approaches were shown to be safe and effective.

Hugues, Human Reprod 1996

Low dose HCG

More recently, Filicori et al. proposed conducting the end of stimulation using a treatment composed of low-dose hCG. Low-dose hCG as a source of LH activity was associated with FSH or was used alone in the second part of the follicular phase.

Filicori, Human Reprod Update 2002

Low dose HCG

Ovarian stimulation with daily late follicular phase administration oflow-dose human chorionic gonadotropin for in vitro fertilization:

a prospective, randomised trial Serafini, et al, Fertil Steril 2006

Low dose HCG

Ovarian stimulation with daily late follicular phase administration oflow-dose human chorionic gonadotropin for in vitro fertilization:

a prospective, randomised trial Serafini, et al, Fertil Steril 2006

Monitoring

Use a combination of frequent serum estradiol measurements and ultrasonographic assessments of follicular growth.

How to trigger the ovulation?

Decrease in hCG dose› 10.000 IU vs. 5.000 IU or 3.000 IU no difference

The use of GnRH antagonists could further decrease the incidence of OHSS in high-risk patients when replacing hCG by a GnRH agonist to trigger ovulation.

  A recent prospective study found a lower

pregnancy rate in patients in whom GnRH agonists were used to trigger ovulation.

How to trigger the ovulation?

There was no statistically significant difference between rhCG vs uhCG regarding the incidence of OHSS.

A multicenter double-blind study

revealed that new recombinant human LH can be as effective as hCG in inducing the final follicular maturation in IVF treatment with a lower incidence of OHSS. European Recombinant LH Study Group 2001

Al-Inany, Cochrane Database 2005

Luteal phase support

The odds of OHSS were more than 2-fold higher with treatments involving hCG than with progesterone alone (OR 3.06, 95% CI 1.59 to 5.86).

Comparing routes of progesterone administration, reductions in clinical pregnancy rate with the oral route, compared to the intramuscular or vaginal routes, did not reach statistical significance, but there was evidence of benefit of the intramuscular over the vaginal route for the outcomes of ongoing pregnancy and live birth. Daya, Gunby, Cochrane Database 2004

IVM

Due to the abundance of follicles in the ovary, PCOS patients present an excellent clinical opportunity for the retrieval of unstimulated immature eggs and do In Vitro Maturation.

IVM

The immature oocytes are retrieved from antral follicles of unstimulated (or minimally stimulated) ovaries via the transvaginal approach.

The oocytes are subsequently matured in vitro in a special formulated culture medium for 24-48 h. The mature oocytes are fertilized, usually by intracytoplasmic sperm injection (ICSI), and the selected embryos are transferred to the uterus 2-3 days later.

IVM

Because no expensive gonadotropin stimulation and no extensive monitoring scans are required, the cost of IVM treatment is lower than that of IVF.

The IVM treatment schedule is shorter, causing less stress, and it is not necessary to wait for 2 to 3 months between treatment cycles because no stimulation is involved. The risk of OHSS can be avoided by IVM treatment, especially in women with PCO/PCOS.

Child, Obstet Gynecol 2002

IVM

ART Service Paris Montreal Taipei Helsinki Seoul Seoul

Cycles (n) 138 254 68 239 203 419

Oocytes retrieved

12.1 11.9 22.5 8.0 15.5 16.4

Maturation rate (%)

61.7 78.8 74.2 58.6 55.3 73.2

Fertilization rate (%)

62 69.2 72.8 51.3 75.1 79.0

Transferred embryo

2.4 3.4 3.8 5.0 4.3

Clinical Pregnancy rate(%)

24.5 24.0 33.8 26.6 21.9 32.7

Tan SL, et al. In vitro Maturation of Human Oocytes, 2007

IVM

Clinical pregnancy rate 35% per cycle Implantation rate 15% per embryo

Al-Sunaidi, Fertil Steril 2007

Metformin

Metformin has been studied and mostly shown to restore menstrual cycles and confirm ovulation in anywhere between 25 - 90% of cases.

A recent analysis of 13 randomized controlled trials showed that metformin increased the ovulation rate almost four times compared to placebo when it was administered in combination with clomiphene citrate.

Metformin

No metformin (n=159)

Metformin (n=128)

Age 34.8 33

BMI 27.2 27.8

HMG ampoules 37.1 41.1

Oocytes retrieved 23.8 18.8

Embryos tranferred 2.8 3

Clinical pregnancies 37.6 30.5

Moderate and severe OHSS*

20 1

Khattab, Reprod Biomed Online, 2006

Metformin

Metformin (n=52) Placebo (n=49)

Cancellation % 9.6 4.1

Nr of eggs 17.3 16.2

Nr of embryos transferred

2 2

Clinical preg rate % 38.5 16.3*

Live birth rate % 32.7 12.2*

Severe OHSS % 3.8 20.4*

Tang, Human Reprod, 2006

* p< 0.05

Coasting

First described and applied by Sher et al in 1993

hCG administration postponed until the patients serum E2 level decreases to a safer zone.

E2 levels usually rise rapidly in the 48 h following initiation of the coasting period, then plateaued and began to fall 96-168 h after the gonadotropins were stopped.

Coasting

Cochrane review identified 13 studies of which only one trial met the inclusion criteria.

There was no difference in the incidence of moderate and severe OHSS and in the clinical pregnancy rate between the groups.

D’Angelo et al., Cochrane Library, 2002

Coasting

A recent review of ten studies showed that < 2% of women developed OHSS while maintaining acceptable pregnancy rates (36.5-63%) when coasting was continued until serum estradiol levels fell below 3000 pg/ml.

Levinson-Tavor, Human Reprod 2003

Coasting studies (Garcia-Velasco, et al,Fertil Steril, 2006)

Study E2 1st day

coasting (pg/mL)No.of days coasting

E2 day Hcg (pg/Ml

No.of oocytes

Embryos transferre

dPR (%)

IR (%)

Severe OHSS(n)

Sher et al.1993 >6,000   >3,000     35.2   0/17

Sher et al.1995 >6,000   >3,000 21 5.4 41   0/51Benadiva et al 1997 3,803 2 2,206 15   58.8   1/22Tortoriello et al. 1998 4,015 3.05 2,407 15.7 4.9 44.5 16.9 3/44Dhont et al. 1998 3,834 1.9 2,341 19.7 2.3 37.5 20 1/120Lee et al.1998 5,167 2.8 3,667 17.3 3 max 40   4/20Fluker et al. 1999 5,077 2 2,832 10.8 3 36.5 14.3 1/63Egbase et al. 1999 10,055 4.9 1,410 28.3 2.7 33   3/15Waldenstrom et al. 1999 6,292 4.3 1,870 10   51 31 1/65Delvigne et al.2001 8,877 3 1,492 16 2     0/157Al-Shawaf et al. 2001 4,400 3.4 1,368 11 2.1 46.5 25.5 1/50

Grochowski et al. 2001 >3,000 3.5 >3,000     32.3 18.1 2/112

Isik et al. 2001   4 3,000 18.3 3.2 50.5    Al-Shawaf et al. 2002 4,400 3.6 2,718 13.1 2.1 35.4 24.2 1/89Ulug et al. 2002 4,563 2.9 2,613 17.5 4.2 50.7 19.0 4/207Isaza et al. 2002 6,395 4.2 2,181 19.6 2.6 52.9 22 0/15Chen et al. 2003 3,753 1.5 4,528 21 5 32.1 9.6 3/31Tozer et al. 2004 4,400 4 1,433 12 1.8 33.3 20.3 0/22Moreno et al. 2004 5,769 3.6 2,852 18.1     19 0/132Garcia-Velasco et al. 2004 5,904 3.8 3,312 19.5 2 42.4 24.8 5/159Ulug et al. 2004 5,365 2.7 3,113 19.8 3.5 56.8 28.8 4/233

34/1624

0.02%

Coasting duration

Coasting < 4 days (n=983)

Coasting >4 days (n=240)

Age 30.2 29.9

Oocytes retrieved* 16.5 14.9

Mean no of embryos trans

2.99 3.03

Clin pregnancy rate* 52.0 35.9

Implantation rate* 26.3 18.2

Mansour, et al., Fertil Steril, 2005

Coasting

Coasting is a good alternative that can avoid cycle cancellation in high responders, who have high risk of developing severe OHSS

Even if OHSS develops after coasting both its incidence and severity will be diminished

Conclusion

No one gonadotropin is superior to others for reducing the incidence of OHSS

Antagonist-low dose step up is the best protocol available

Monitoring of the E2 and USG of follicles is crucial

Luteal phase support with hCG increases the incidence of OHSS.

Progesterone intravaginally or i.m. should be used for the patients at risk of OHSS

Conclusion

IVM is a novel method and must be developed for better results

Coasting is an effective method for preventing severe OHSS

No method has been developed that will completely prevent severe OHSS after ovarian stimulation.

OHSS rate???

r FSH u FSH

Bergh, Hum Reprod 1997 5.1 1.7

Out, Hum Reprod 1995 3.2 2.0