Is there a future for ovulation induction in the current era of assisted reproduction?

E.J.P. van Santbrink1 and B.C.J.M. Fauser

Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus Medical Center, Rotterdam, The Netherlands

1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Division of Reproductive Medicine, Erasmus Medical Center, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. e-mail: e.vansantbrink{at}erasmusmc.nl


    Abstract
 Top
 Abstract

 References
 
The clinical use of medical induction of ovulation in normogonadotrophic anovulatory women (WHO II), including polycystic ovary syndrome, is increasingly questioned. However, we believe that this treatment modality still represents a highly effective means of fertility treatment in women with low pregnancy chances without intervention. A conventional treatment algorithm involving clomiphene citrate (CC) followed by FSH induction of ovulation may result in a 71% cumulative singleton live birth rate. In attempts to improve treatment outcome further and reduce complication rates, new compounds such as insulin-sensitizing agents or aromatase inhibitors are currently used increasingly. Approaches such as patient selection for different treatment modalities on the basis of initial screening characteristics and alternative protocols for FSH ovulation induction may also be proposed to render treatment algorithms more patient tailored and therefore improve overall outcomes. More research is needed in this area, rather than referring these patients to assisted reproduction prematurely. This may lead to a more individually tailored approach for ovulation induction in a given patient, resulting in a further improvement of the balance between chances for success versus complications.

Key words: anovulation/FSH/ovulation induction/prediction model/step-down


   
 Top
 Abstract

 References
 
Classic induction of ovulation strategies [clomiphene citrate (CC) followed by FSH injections] in patients with normogonadotrophic anovulation (World Health Organization, 1993Go; ESHRE Capri Workshop Group, 2003Go) can be experienced as a time-consuming and ineffective treatment modality with high complication rates. To deal with this, patients are increasingly offered ‘controlled’ ovarian stimulation combined with intrauterine insemination or IVF as first-line treatment, regardless of the type of infertility (Homburg and Insler, 2002Go). This alteration in treatment strategy is not based on sound scientific evidence and is likely to result in substantially higher multiple pregnancy rates and a major increase in overall treatment costs. The objective of this debate is, in response to treatment strategy alterations as mentioned above, to discuss the efficacy and efficiency of current ovulation induction strategies and point out possibilities for improvement.

In a prospective follow-up study, starting in 1993, of 240 WHO II patients in our fertility clinic, effectiveness of the approach of classical ovulation induction (CC as first-line, exogenous FSH as second-line treatment) was evaluated (Imani et al., 2002aGo; Eijkemans et al., 2003Go). Initial treatment with CC (highest daily dose of 150 mg for a maximum of six cycles) resulted in ovulation in 77% of all patients. A pregnancy occurred in 47% of all patients and in 61% of ovulatory patients (cumulative singleton live birth rate 41% and multiple live birth rate 2%). Both chances for ovulation (Imani et al., 1998Go, 2000Go) and pregnancy (Imani et al., 1999Go) may be predicted on the basis of initial screening characteristics such as age, body mass index (BMI = weight/height2), free androgen index [(FAI = testosterone x 100/sex hormone-binding globulin (SHBG)], cycle history and polycystic ovaries.

Subsequently, second-line FSH induction of ovulation in our study population failing to ovulate or conceive after CC resulted after a mean of 3.5 stimulation cycles in an ovulation rate of 82%, a cumulative pregnancy rate of 56%, a singleton live birth rate of 43% and a multiple live birth rate of 5% (Mulders et al., 2003aGo). Overall, treatment outcome in our study population resulted in a cumulative singleton live birth rate of 71% after ‘classical’ ovulation induction using CC followed by exogenous FSH (Eijkemans et al., 2003Go). The remaining group was exposed to IVF, resulting in a live birth rate of 40% after a maximum of three cycles (Mulders et al., 2003bGo).

Efforts to enhance efficiency and safety of FSH ovulation induction treatment include the use of new gonadotrophin preparations, alternative treatment dose regimens and prediction models (ESHRE Capri Workshop Group, 2003Go). Initial patient characteristics may be able to predict chances of treatment response and outcome of both CC and FSH ovulation induction. In this way, it may also be possible to identify women who would benefit from alternative treatment algorithms, including first-line treatment with insulin-sensitizing drugs (Lord et al., 2003Go), aromatase inhibitors (Mitwally and Casper, 2003Go) or ovarian drilling (Farquhar et al., 2001Go; Pirwany and Tulandi, 2003Go). For these new treatment modalities, it can be concluded that, although initial studies are promising, their role in everyday clinical practice remains uncertain until data from prospective follow-up studies become available regarding large series of well defined patient groups.

A major difficulty associated with FSH ovulation induction is the individual variability in ovarian response to a given dose. Treatment regimens which involve a stepwise increase in low dosages of gonadotrophin during follicular development (‘step-up’ regimens) are now in common clinical use. The conventional step-up regimen employed relatively high initial doses of gonadotrophins. While ovulation rates of 70% were achieved, multiple pregnancy rates were observed to occur in 36% of pregnancies, and the potentially life-threatening ovarian hyperstimulation syndrome (OHSS) in 14% (Dor et al., 1980Go). The subsequently introduced ‘low-dose, step-up’ regimen is associated with considerably lower complication rates (White et al., 1996Go), and this regimen is now employed in most European centres. Studies of the endocrine physiology of normal follicular development have highlighted the essential unphysiological nature of step-up regimens (van Santbrink et al., 1995aGo). In an attempt to mimic physiology more closely in anovulatory women, a stimulation regimen has been developed which involves reducing (instead of increasing) the dose of gonadotrophins administered during the period of follicular development (van Santbrink and Fauser, 1997Go). This ‘low-dose, step-down’ regimen has proven itself as a reliable clinical tool for the induction of ovulation in our tertiary referral centre, although monitoring of a step-down cylcle may need more experiece and skills compared with a low-dose, step-up regimen (van Santbrink et al., 1995bGo). In a small prospective randomized trial, the low-dose, step-down and the low-dose, step-up regimen gave comparable clinical outcomes. However, in the step-down group, a substantially reduced stimulation period was required with a more physiological late-follicular FSH serum profile. This resulted in more monofollicular stimulation cycles, coinciding with more cycles in which estradiol (E2) serum levels were within the physiological range (van Santbrink and Fauser, 1997Go). As we know, multi-follicular growth and high late follicular phase E2 serum levels are associated with increased multiple gestation rates and higher chances for ovarian hyperstimulation (Haning et al., 1983Go; Blankstein et al., 1987Go)

In a recently published randomized multi-centre study reported in this journal, comparing a low-dose, step-up versus a step-down gonadotrophin protocol in polycystic ovary syndrome (PCOS) (Christin-Maitre et al., 2003Go), 83 patients were included over an extended period of time in 11 centres. This, again emphasizes how difficult it currently is to execute these kind of studies with sufficient patient numbers. It strongly suggests that many PCOS patients are indeed treated differently. Patients included in the study presented with oligo-amenorrhea, normal BMI (23.5 ± 4.4 kg/m2), no signs of hyperandrogenism (testosterone < 1 ng/ml) and sonographic mild polycystic ovary (PCO) criteria. Hence, this seems like a group with potentially favourable ovulation induction outcome, since overweight and hyperandrogenaemia are clearly associated with poor ovulation induction results, as discussed earlier. Treatment results showed a relatively high cancellation rate (38% versus 15%) in the step-down compared with the step-up group, but a similar overall ovulation rate (62% versus 70%). Pregnancy rates were comparable, but there was a clear tendency for hyperstimulation in the step-down group (multi-follicular growth and high serum E2 concentrations). These findings are not surprising considering that a step-down protocol with a starting dose of 100 IU was applied to an unselected, mild (or non) PCOS population. Most of these patients can be expected to be good responders to FSH stimulation, i.e. low FSH response dose (Imani et al., 2002bGo). Chances for multiple follicle development during FSH induction of ovulation may be predicted by a model in which initial serum androstenedione (AD), ovarian response during preceding CC treatment and number of antral follicles upon initial screening are represented (van der Meer et al., 1998Go; van Santbrink et al., 2002Go; Jonard et al., 2003Go; Mulders et al., 2003cGo). As multiple follicle growth is associated with chances for OHSS and multiple pregnancy (Blankstein et al., 1987Go), patients at risk may be identified using this prediction model. Study data (Christin-Maitre et al., 2003Go) confirm this contention since at least 55–73% of the patients randomized for the step-up protocol did not need a dose increase to develop a pre-ovulatory follicle.

Accordingly, in our selected (tertiairy referral) study population, 31% of the patients developed a pre-ovulatory follicle without a dose increase in the low-dose, step-up protocol (E.J.P.van Santbrink, unpublished) (see also Table I). These patients were shown to be good responders to the initial starting dose of gonadotrophins. Evaluation of late follicular phase characteristics of similar patients demonstrated a decremental FSH serum profile close to physiology, probably due to the negative feedback of the growing follicle on pituitary FSH release (Schoot et al., 1992Go; van Santbrink and Fauser, 1997Go). It may be proposed, as reported earlier, that these women would hyper-respond in cases where a step-down regimen was offered with a relatively high starting dose, resulting in increased chances for treatment complications. In an attempt to avoid this, new patients for induction of ovulation with gonadotrophins are currently offered first a ‘dose-finding’ low-dose, step-up induction cycle in our centre, in which the FSH response dose is determined (Imani et al., 2002bGo). After that, step-down induction cycles are applied with a starting dose 37.5 IU above the effective response dose in the initial low-dose, step-up cycle. A fixed dose is applied in the following cycle if the patient responded with sufficient follicle growth in response to the starting dose during the dose-finding first low-dose, step-up induction cycle. Treatment results of the dose-finding low-dose step-up cycle and following step-down induction cycle are shown (Table I). Comparing the results of ovulation induction of the multi-centre trial (Christin-Maitre et al., 2003Go) with the results in our sequential low-dose step-up followed by step-down treatment group (E.J.P.van Santbrink, unpublished observations), it can be concluded that the low-dose step-up results show comparable monofollicular development rates, ovulation rates and (ongoing) pregnancy rates (see Table I). In addition, the step-down results are also comparable except for the monofollicular development rates (32% versus 50%). It should be noticed that patient characteristics in both step-down populations are very different. Substantially more severe PCOS characteristics (obesity, hyperandrogenism and more frequent PCO ovaries) are found in the low responder group (Mulders et al., 2003aGo) compared with good responders. A recent systemic review regarding patient characteristics predicting ovulation induction outcome could confirm these findings (Mulders et al., 2003aGo).


View this table:
[in this window]
[in a new window]
 
Table I. Treatment results of 83 normogonadotrophic anovulatory patients in three consecutive FSH ovulation induction cycles randomized for a low-dose step-up or step-down protocol (Christin-Maitre et al., 2003) and 91 normogonadotropic anovulatory patients during FSH ovulation induction treated according to a first dose-finding low-dose step-up cycle followed by a step-down cycle in women in which the FSH starting dose was determined by the response-dose in the first treatment (E.J.P.van Santbrink, unpublished)
 
A new approach to prevent hyperstimulation in gonadotrophin ovulation induction due to a starting dose far above the FSH threshold may be to determine the individual effective FSH starting dose using a prediction model. Time-consuming low-dose increments may be overcome by starting with a higher dose in women with an augmented FSH threshold. It may also reduce chances for hyper-response in women with a low FSH threshold. Initial patient and treatment characteristics (BMI, ovarian response during preceding CC therapy, insulin-like growth factor 1 and basal FSH) may be able to predict the individual response to FSH (Imani et al., 2002bGo). Obviously, more widespread clinical use of these predictors awaits external validation of the developed model.

In conclusion, it can be proposed that: (i) it is more difficult to induce ovulation in patients with more severe PCOS criteria (overweight, hyperandrogenaemia and with polycystic ovaries); (ii) an FSH starting dose >50–75 IU may result in ovarian hyperstimulation in at least 30% of an unselected PCOS population; (iii) it remains questionable if IVF with or without in-vitro maturation of oocytes provides improved efficacy and safety compared with ovulation induction strategies; and (iv) classical induction of ovulation is a highly effective treatment modality and there is still room for improvement applying new compounds and prediction models, resulting in a more individually tailored approach


    References
 Top
 Abstract

 References
 
Blankstein, J., Shalev, J., Saadon, T., Kukia, E.E., Rabinovici, J., Pariente, C., Lunenfeld, B., Serr, D.M. and Mashiach, S. (1987) Ovarian hyperstimulation syndrome: prediction by number and size of preovulatory ovarian follicles. Fertil. Steril., 47, 597–602.[ISI][Medline]

Christin-Maitre, S., Hugues, J.N. on behalf of the recombinant FSH study group (2003) A comparative randomized multicentric study comparing the step-up versus step-down protocol in polycystic ovary syndrome. Hum. Reprod., 18, 1626–1631.[Abstract/Free Full Text]

Dor, J., Itzkowic, D.J., Mashiach, S., Lunenfeld, B. and Serr, D.M. (1980) Cumulative conception rates following gonadotropin therapy. Am. J. Obstet. Gynecol., 136, 102–105.[ISI][Medline]

Eijkemans, M.J., Imani, B., Mulders, A.G., Habbema, J.D. and Fauser, B.C. (2003) High singleton live birth rate following classical ovulation induction in normogonadotropic anovulatory infertility. Hum. Reprod., 18, in press.

ESHRE Capri Workshop Group (2003) Mono-ovulatory cycles: a key goal in profertility programmes. Hum. Reprod. Update, 9, 263–274.[Abstract/Free Full Text]

Farquhar, C., Vandekerckhove, P. and Lilford, L. (2001) Laparascopic ‘drilling’by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst. Rev., 4.

Haning, R.V., Austin, C.W., Carlston, I.H., Kuzma, D.L., Shapiro, S.S. and Zweibel, W.J. (1983) Plasma estradiol is superior to ultrasound and urinary estradiol glucuronide as a predictor of ovarian hyperstimulation during induction of ovulation with menotropins. Fertil. Steril., 40, 31–36.[ISI][Medline]

Homburg, R. and Insler, V. (2002) Ovulation induction in perspective. Hum. Reprod. Update, 8, 449–462[Abstract/Free Full Text]

Imani, B., Eijkemans, M.J., te Velde, E.R., Habbema, J.D. and Fauser, B.C. (1998) Predictors of patients remaining anovulatory during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J. Clin. Endocrinol. Metab., 83, 2361–2365.[Abstract/Free Full Text]

Imani, B., Eijkemans, M.J., te Velde, E.R., Habbema, J.D. and Fauser, B.C. (1999) Predictors of chances to conceive in ovulatory patients during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J. Clin. Endocrinol. Metab., 84, 1617–1622.[Abstract/Free Full Text]

Imani, B., Eijkemans, M.J., de Jong, F., Payne, N.N., Bouchard, P., Giudice, L.C. and Fauser, B.C. (2000) Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. J. Clin. Endocrinol. Metab., 85, 676–682.[Abstract/Free Full Text]

Imani, B., Eijkemans, M.J., te Velde, E.R., Habbema, J.D. and Fauser, B.C. (2002a) A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility. Fertil. Steril., 77, 91–97.[CrossRef][ISI][Medline]

Imani, B., Eijkemans, M.J., Faessen, G.H., Bouchard, P., Giudice, L.C. and Fauser, B.C. (2002b) Prediction of the individual follicle-stimulating hormone threshold for gonadotropin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency. Fertil. Steril., 77, 83–90.[CrossRef][ISI][Medline]

Jonard, S., Robert, Y., Cortet-Rudelli, C., Pigny, P., Decanter, C. and Dewailly, D. (2003) Ultrasound examination of polycystic ovaries: is it worth counting the follicles? Hum. Reprod., 18, 598–603.[Abstract/Free Full Text]

Lord, J.M., Flight, I.H.K. and Norman, R.J. (2003) Insulin-sensitizing drugs for polycystic ovary syndrome (Cochrane review). In: The Cochrane Library, Issue 3. Update Software, Oxford.

Mitwally, M.F. and Casper R.F. (2003) Aromatase inhibitors for the treatment of infertility. Expert Opin. Invest. Drugs, 12, 353–371.[ISI]

Mulders, A.G., Eijkemans, M.J., Imani, B. and Fauser, B.C.J.M. (2003a) Prediction of chances for success or complications in gonadotrophin ovulation induction in normogonadotrophic anovulatory infertility. Reprod. Biomed. Online, 7, 48–56.

Mulders, A.G., Laven, S.J.L., Imani, B., Eijkemans, M.J. and Fauser, B.C.J.M. (2003b) IVF outcome in anovulatory infertility (WHO group 2)—including polycystic ovary syndrome—following previous unsuccessful ovulation induction. Reprod. Biomed. Online, 7, 50–58.[Medline]

Mulders, A.G., Laven, S.J.L., Eijkemans, M.J., Hughes, E.G. and Fauser, B.C.J.M (2003c) Patient predictors for outcome of gonadotrophin ovulation induction in women with normogonadotrophic anovulatory infertility: a meta-analysis. Hum. Reprod. Update, in press.

Pirwany, I. and Tulandi, T. (2003) Laparoscopic treatment of polycystic ovaries: is it time to relinquish the procedure. Fertil. Steril., 80, 241–251.[ISI][Medline]

Schoot, D.C., Pache, T.D., Hop, W.C., deJong, F.H. and Fauser, B.C. (1992) Growth patterns of ovarian follicles during induction of ovulation with decreasing doses of human menopausal gonadoropin following presumed selection in polycystic ovary syndrome. Fertil. Steril., 57, 1117–1120.[ISI][Medline]

van der Meer, M.M., Hompes, P.G., de Boer, J.A., Schats, R. and Schoemaker, J. (1998) Cohort size rather than follicle-stimulating hormone threshold level determines ovarian sensitivity in polycystic ovary syndrome. J. Clin. Endocrinol. Metab., 83, 423–426.[Abstract/Free Full Text]

van Santbrink, E.J. and Fauser, B.C. (1997) Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens. J. Clin. Endocrinol. Metab., 82, 3597–3602.[Abstract/Free Full Text]

van Santbrink, E.J., Hop, W.C., van Dessel, T.J. and Fauser, B.C.J.M. (1995a) Decremental follicle-stimulating hormone and dominant follicle development during the normal menstrual cycle. Fertil. Steril., 64, 37–43.[ISI][Medline]

van Santbrink, E.J., Donderwinkel, F.J., van Dessel, T.J. and Fauser, B.C.J.M. (1995b) Gonadotrophin induction of ovulation using a step-down dose regimen: single-center clinical experience in 82 patients. Hum. Reprod., 10, 37–43.

van Santbrink, Eijkemans, M.J., Macklon, N.S., Fauser, B.C.J.M. (2002) FSH response-dose can be predicted in ovulation induction for normogonadotropic anovulatory infertility. Eur. J. Endocrinol., 147, 223–226.[ISI][Medline]

White, D.M., Polson, D.W., Kiddy, D. (1996) Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analyisof 109 pregnancies in 225 women. J. Clin. Endocrinol. Metab., 81, 3821–3824.[ISI][Medline]

World Health Organization (1993) WHO Manual for the Standardized Investigation and Diagnosis of the Infertile Couple. Cambridge University Press, Cambridge, UK.