London Gynaecology & Fertility Centre, Cozens House, 112a Harley Street, London W1N 1AF, UK
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Abstract |
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Key words: GnRH antagonist/ovarian hyperstimulation syndrome/polycystic ovary/protocols/difficult responders
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Introduction |
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Time has proven the validity of this approach from its ubiquitous use worldwide with the long protocol becoming the preferred option over the short, or ultrashort, alternatives. However, as with most advances, there has been a `trade off' with some adverse aspects, including the cost of the increased amount of gonadotrophin required, the risk of the ovarian hyperstimulation syndrome (OHSS) and its sequelae, especially in polycystic ovary (PCO) patients, and the speculative unproven reports of an association with ovarian tumours.
Not all patients respond well and some may be categorized as `difficult responders' either because of adverse consequences of an exaggerated response leading to OHSS, or because of a failure to respond to increasing doses of gonadotrophins, sometimes administered to very high levels, when used in conjunction with the analogue given on the long, or short, protocol basis. Whilst the latter response may be more frequent in those of older age, some younger women who have quite normal day 3 follicle-stimulating hormone (FSH) values may also be difficult to stimulate.
We have considered that the failure to respond may in certain instances be due to the LHRH analogue having a direct effect on the ovary, with the assumption that the ovary, like the pituitary, also has receptors to LHRH, whose expression are not normally manifested to a degree to prevent an adequate ovulatory response. The recent finding of LHRH receptors in the human ovary lends support to our philosophy (Leung, 1999).
We came to this conclusion over a decade ago when an in-vitro fertilization (IVF) birth resulted following withdrawal of nasal Buserelin® (a GnRH agonist) in a 37 year old woman whose response to serial increases in gonadotrophin dosage was profoundly poor. Continuation of ultrasound monitoring, after this cycle had been interrupted and the nasal spray stopped, indicated a subsequent marked increase in follicle growth with later oocyte recovery, fertilization, embryo transfer and establishment of a clinical pregnancy. This effect would not normally be apparent with depot analogue use, and, in any event, follicle monitoring is usually discontinued once a decision has been made to cancel a cycle. However, we have observed this response after discontinuing nasal Buserelin, and more recently, Nafarelin.
The concept that the human ovary may have its response to gonadotrophins suppressed to a variable degree by the direct effect of LHRH analogues on the ovary in certain patients prompted an interest in Gary Hodgen's early work on LHRH antagonists aimed at developing clinical protocols using the normal follicle recruiting system and augmentation by gonadotrophins with gonadotrophin releasing hormone (GnRH) antagonists suppressing LH surges, once recruitment is promoted (Kenigsberg et al., 1984a, b
).
We have recently assessed the use of cetrorelix (GnRH antagonist; Asta Medica, Frankfurt, Germany) used in conjunction with clomiphene citrate and gonadotrophin for ovarian stimulation in a group of patients considered to be `difficult responders' to conventional GnRH analogue and gonadotrophin protocols. Two categories of patients were assessed. The majority was patients who did not respond adequately to increasing doses of gonadotrophins and a minority had been overstimulated.
The concept behind using this clinical protocol has been to establish whether a better-controlled response could be achieved with the normal pituitaryovarian axis in operation in those in whom a sub-optimal response occurred with a LHRH analogue. Before starting this clinical study we were aware that some patients would not benefit because of a decreasing ovarian reserve due to increasing age, but that a positive response would indicate an alternative stimulation regime and the potential value of this protocol for use in normal responders. This would raise the prospect of reducing the dose and cost of gonadotrophins per cycle, reducing the risk of OHSS (especially in PCO patients), and increasing patient acceptability, with particular relevance to healthy young women, including those acting as egg donors.
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Materials and methods |
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Patients
The difficult responders were divided into two groups. Group I included 18 patients (24 cycles); 16 patients (22 cycles) were known poor responders from their previous treatment on a GnRH analogue protocol. The remaining two patients had not had previous IVF or gamete intra-Fallopian transfer (GIFT), but were included as their day 23 serum FSH levels were 18 and 34 IU/l respectively. The poor responders were patients who had cancelled cycles with less than five progressing follicles following 9 days of FSH therapy given at an appropriate dosage for age and weight or those who have previously required a total dose of more than 600 IU of gonadotrophins per oocyte retrieved. Twelve patients (16 cycles) of the poor responders group were more than 37 years old. In eight patients (10 cycles) serum FSH level was more than 9 IU/l. In 23 previous IVF attempts (16 patients), 13 cycles had been abandoned because of a poor response following a mean dose of 3170 IU of FSH per cycle. Five of these 13 abandoned cycles had been converted to intrauterine insemination (IUI) or timed sexual intercourse (TSI) while the remaining eight had been totally cancelled. The remaining 10 of the previous 23 assisted conception cycles with a GnRH analogue had been completed using a mean dose of 5468 IU of FSH/cycle. A total of 47 oocytes had been retrieved with an average of 4.7 oocytes/cycle and an average total dose of 1163 IU of FSH was required per oocyte retrieved. One clinical pregnancy had been achieved and ended in a miscarriage. Group II included seven patients (seven cycles) who had PCO. One patient had not previously had IVF and the other six underwent 13 previous attempts at IVF/GIFT with a GnRH agonist. One of these 13 cycles had been converted to IUI due to a suboptimal response with cautious low FSH dosage (1200 IU). The other 12 cycles had been completed using an average dose of 2733 IU of FSH/cycle. A total number of 174 oocytes were retrieved with a mean of 14.5 oocytes/cycle. A total of 189 IU of gonadotrophins had been required per each retrieved oocyte. Following these 13 previous treatment cycles, three patients developed ovarian hyperstimulation syndrome requiring hospital admission and two patients became pregnant. One patient later miscarried and the other one had a live birth.
Drug protocol
All patients received clomiphene citrate and gonadotrophin injections following a baseline vaginal scan performed on day 2 of the cycle. Clomiphene citrate was given as a daily dosage of 100 mg from day 2 for 5 days. Gonadotrophin injections were either given daily, or on alternate days. The dose and the frequency of gonadotrophin injections was determined by the patient's age, body weight, FSH level and her response in previous treatment cycles, e.g., alternate days in those who have previously hyperstimulated, as opposed to daily in those who have been profoundly poor responders.
Cetrorelix was administered as a daily 0.25 mg s.c. injection. Initially the injection was started on the 5th day of gonadotrophin stimulation, i.e., on day 6 of the cycle. However, very few patients developed follicles of significant size by this stage, so we delayed the starting day of cetrorelix until day 6 of gonadotrophin injections, i.e. day 7 of the cycle, and assessed the ovarian response by ultrasound on that day. The latter has been our standard method of follicle monitoring for the past 15 years. We later modified our protocol by scanning the patients on day 8 of the cycle and starting the cetrorelix injections on the day that the leading follicle reached 14 mm in diameter irrespective of the day of the cycle, or of how many days gonadotrophins had been administered for. This observation may have particular relevance to the group considered to be `difficult responders' to previous GnRH and gonadotrophin stimulation, since we consider cetrorelix could be started unnecessarily early in such situations. Cyclogest pessaries 400 mg (Cox, Barnstaple, UK) were used twice daily for luteal phase support.
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Results |
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Discussion |
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In group II, the patients with PCO produced fewer oocytes (10.2 versus 14.5 oocytes/cycle) using a lower dose of FSH (1733 versus 2733 IU/cycle and 170 versus 189 IU/oocyte) and none developed OHSS. Although the trends were in favour of the cetrorelix protocol, the differences did not reach statistical significance. Again, this was probably due to small sample size. The use of down regulation protocols with a GnRH agonist is known to be associated with an increased risk of OHSS, particularly in patients with PCO. However, we believe that the clomiphene citrategonadotrophincetrorelix protocol reduces this risk as there is no down-regulation prior to ovarian stimulation and one is able to administer cautiously lower doses of gonadotrophins, either on an alternate day, or on a daily basis. The requirement of lower doses of gonadotrophin, with the use of GnRH antagonist, was previously suggested by Olivennes et al. (1994). Furthermore, human chorionic gonadotrophin (HCG) administration for induction of ovulation can be replaced by native GnRH or a GnRH agonist, and the luteal support might be unnecessary, both reducing the risk of ovarian hyperstimulation (Emperaire and Ruffie, 1991).
Our experience of using clomiphene citrategonadotrophincetrorelix for `difficult responders' suggests that this protocol will be of value for some patients who have not responded well to GnRH analogues and gonadotrophins. We predict that an improved response will occur in some, and the required amount of gonadotrophin injections will be reduced and hence the cost. We also believe that cetrorelix reduces the risk of OHSS, since a lower dose of gonadotrophins may be found effective in stimulating a moderate number of follicles, rather than an excessive cohort, particularly in patients with PCO because of lower stimulation. A properly controlled randomized study is required to confirm our preliminary observation which is based on a small number of cycles.
Cetrorelix therapy, we believe, will have relevance to IUI treatment cycles, and those which are converted to IVF or GIFT, for frozen embryo replacement in a natural cycle, and possibly even to IVF in natural cycles in young women with favourable features. We also consider it will have a significant place in the management of oocyte donation, both from the perspective of donors who will require less gonadotrophins, and therefore have less risk of OHSS, and also from the recipient's perspective, since donation is likely to proceed with less risk of cycle cancellation.
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Notes |
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References |
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Leung, P.C.K. (1999) GnRH receptor and potential action in human ovary. Gynaecol. Endocrinol., 13, 10.
Olivennes, F., Fanchin, R., Bouchard, P. et al. (1994) The single or dual administration of the gonadotrophin-releasing hormone antagonist Cetrorelix is an in vitro fertilizationembryo transfer programme. Fertil. Steril., 62, 468476.[ISI][Medline]
Olivennes, F., Alvarez, S., Bouchard, R. et al. (1998) The use of a GnRH antagonist (cetrorelix) in a single dose protocol in IVFembryo transfer; a dose finding study of 3 versus 2 mg. Hum. Reprod., 13, 24112414.[Abstract]
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Submitted on April 12, 1999; accepted on September 14, 1999.