A randomized study comparing IVF in the unstimulated cycle with IVF following clomiphene citrate

Hans Jakob Ingerslev1,3, Astrid Højgaard1, Johnny Hindkjær1 and Ulrik Kesmodel2

1 Fertility Clinic and 2 Perinatal Epidemiological Research Unit, Department of Obstetrics and Gynaecology, Aarhus University Hospital, Skejby Sygehus, Aarhus, Denmark


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The efficiency of IVF in unstimulated cycles was compared with that following ovarian stimulation with clomiphene citrate in a simple protocol with ultrasound monitoring only. A total of 132 couples with no previous IVF attempts, selected by female age <35 years, indication for intracytoplasmic sperm injection or infertility caused by tubal factor or unexplained infertility were randomized to the two protocols. Randomization yielded two comparable groups. The clomiphene group (68 couples) performed significantly better than the unstimulated group (64 couples) in terms of number of cycles with oocyte harvest (90/111 or 81% versus 65/114 or 57%; {chi}2 = 9.21, P < 0.002), embryo transfers per started cycle (59/111 or 53% versus 29/114 or 25%; {chi}2 = 18.14, P < 0.0001), live intrauterine pregnancy rate per started cycle (20/111 or 18% versus 4/114 or 4%; {chi}2 = 12.42, P < 0.0001), live intrauterine pregnancy rate per embryo transfer (20/59 or 34% versus 4/29 or 14%; {chi}2 = 3.96, P = 0.047), but not in terms of implantation rate (22/85 or 26% versus 4/29 or 14%; {chi}2 = 1.65). Only two twin pregnancies occurred. Modest side-effects were recorded following clomiphene. Accordingly, a simple clomiphene citrate protocol, but not IVF in unstimulated cycles, seems compatible with the concept of `friendly IVF', yielding a fair pregnancy rate both per cycle started and per embryo transfer in selected patients. The results do not substantiate any important negative anti-oestrogenic effects of clomiphene.

Key words: clinical pregnancy rate/clomiphene citrate/IVF/unstimulated cycles


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Increasing efficiency of assisted reproductive procedures, especially IVF, has been obtained by steadily more aggressive hormone stimulation protocols and improved techniques for gamete and embryo handling. This has not been without costs both for health care systems and patients in terms of increased expenses, high multiple pregnancy rates, and side-effects of stimulation regimens. The objective of stimulation in IVF is to increase oocyte and embryo numbers to compensate for a poor implantation rate per embryo. Nevertheless, with implantation rates in the order of 20–30% within reach of any modern IVF clinic in patients below 40 years of age, it seems necessary to look again for `friendly IVF' regimens, tailored to the individual patient at an intervention and stimulation level which is just necessary for her to obtain a reasonable pregnancy rate, ideally resulting in the delivery of a single, healthy child (Edwards et al., 1996Go; Fleming, 1996Go; Olivennes and Frydman, 1998Go). The ideal IVF protocol secures a high chance of embryo transfer and accordingly a low cancellation rate, a high pregnancy rate, a low intervention level, low risk and few side-effects, low costs and practical convenience both for the patient and the clinic. For the community, a low multiple pregnancy risk is important due to the increasing costs associated with multiple pregnancies and delivery, and the fetal morbidity connected with it.

IVF in the natural or unstimulated cycle fulfils some of these criteria, although most studies are associated with a rather high proportion of cancelled cycles (25–75%) and a low clinical pregnancy rate per started cycle (range 0–23%), but higher per embryo transfer (range 0–30%) (Ranoux et al., 1988Go; Foulot et al., 1989Go; Svalander et al., 1991Go; Lenton et al., 1992Go; Paulson et al., 1992Go; Taymor et al., 1992Go; Claman et al., 1993Go; MacDougall et al., 1994Go; Daya et al., 1995Go; Fahy et al., 1995Go; Seibel et al., 1995Go; Kim et al., 1996Go).

The high cancellation rate in unstimulated cycles is partly due to spontaneous LH surge and ovulation, and partly to the fertilization rates unavoidably determining a high proportion of the cancellation rate in cases of harvesting of only one oocyte.

The latter problem associated with unstimulated cycles may be overcome by a low-grade stimulation yielding a better chance of collecting more than one oocyte.

Clomiphene citrate has recently been re-evaluated (Dickey et al., 1998Go; Messinis and Milingos, 1998Go; Out and Coelingh Bennink, 1998aGo,bGo; Tarlatzis and Grimbizis, 1998Go). In favour of clomiphene is its effectiveness, cheapness, high patient compliance, and the reduced need for monitoring. This drug induces development of two or more follicles in most normally ovulating women and may impede spontaneous LH surges (Messinis and Melingos, 1998Go). On the other hand, an unwanted anti-oestrogenic effect of clomiphene citrate has been suspected at several levels of the reproductive system, suggested to explain a claimed discrepancy between ovulation rates and pregnancy rates following clomiphene treatment of anovulation, and furthermore suspected to induce LH concentrations with an adverse effect on oocyte and embryo quality (Schmidt, 1984Go; Out and Coelingh Bennink, 1998bGo; Messinis and Melingos, 1998Go). Nevertheless in a computer literature review and manual search of major journals collecting a total of 39 754 commenced assisted reproductive cycles (IVF and gamete intra-Fallopian transfer) only an insignificantly higher clinical pregnancy rate per embryo transfer was found in gonadotrophin-releasing hormone analogue (GnRHa) cycles compared with clomiphene citrate cycles (28.2 versus 20.5%) (Kenny, 1995Go).

The purpose of the present study was to evaluate the efficiency, in terms of pregnancy rates per cycle and embryo transfer, of low cost, low intervention IVF with minimal monitoring comparing IVF in the unstimulated cycle with IVF following stimulation with clomiphene citrate.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study was performed between the August 1 and December 31, 1997.

Among 564 couples waiting for IVF or intracytoplasmic sperm injection (ICSI) treatment, 196 were invited to participate in the present study, fulfilling the following criteria: age <35 years, infertility unexplained, tubal or due to severe male factor with indication for ICSI, regular menstrual cycles (± 3 days), presence of two ovaries, and no previous IVF treatment. Of these, 29 did not respond, 35 were enrolled in a pilot study and the remaining 132 participated in the present study.

All patients gave written informed consent after counselling, and the study was approved by the Regional Ethics Committee.

At entry to the study, patients were randomized (block randomization, five patients in each block) by the sealed envelope method to either clomiphene citrate (Clomivid®; Astra, Denmark) 100 mg from cycle day 3–7 or to IVF in the unstimulated cycle, but with timing of oocyte retrieval by human chorionic gonadotrophin (HCG) injection. Once randomized to one arm, the patients stayed on that treatment, but at least one `wash-out' cycle was interposed between two treatment cycles, because of the relatively long half-life of zuclomiphene.

All cycles were monitored by vaginal ultrasound on cycle day 3, and subsequently on day 9 in natural cycles and day 11 in clomiphene citrate cycles and thereafter as necessary. All cycles were followed until the dominant follicle was >=17 mm (natural cycle) or >=20 mm (clomiphene citrate cycles), and then HCG (Pregnyl®; 5000 IU) was given at 10:00 h followed by oocyte retrieval 35–36 h later. If spontaneous ovulation occurred in one cycle, these criteria were 1 mm less in the next cycle. No routine endocrinology was performed, but from cycle day 9 (unstimulated) or 11 (clomiphene citrate) the patients were instructed to test a morning urine sample for LH by a qualitative test (Clearplan®; Unipath Ltd., Bedford, UK). If positive, HCG was given the same morning and oocyte retrieval was performed the next morning. LH was tested in an afternoon urine sample and the result was recorded, but no action was taken if positive.

Oocyte retrieval was performed ultrasound-guided transvaginally half an hour after the patient had taken paracetamol 1 g and diazepam 10 mg orally. No other analgesia was offered routinely. Oocytes were collected with a single-lumen needle (Cook®, Brisbane, Australia, 16G) in oocyte collection media (Medicult®, Jyllinge, Denmark) with careful flushing of each follicle. Oocytes were subsequently moved to harvest medium (Medicult®) in Nunc® 4-well chambers and incubated at 37°C in a humid atmosphere containing 5% CO2. The oocyte from the largest follicle was recorded specifically so that the fate of this particular oocyte (embryo quality, pregnancy) could be traced. Two hours later 150 000 spermatozoa were added to each oocyte. Sperm samples were prepared by gradient centrifugation (Percoll®; Pharmacia, Sweden). ICSI was performed according to standard procedures (Van Steirteghem et al., 1993Go) using pipettes from Swemed Lab International AB and micromanipulators from Narishige Co. The oocytes were moved to another well containing clean medium 24 h later and inspected for fertilization. Embryo transfer was performed 2 days after the oocyte retrieval using a Cook® embryo transfer catheter. Fertilization rates were calculated on the basis of the number of oocytes with two pronuclei and/or cleavage. No luteal phase support was given.

Measurement of serum HCG concentration was performed 2 weeks later following the embryo transfer and a concentration >=20 IU/l was considered a positive test. Pregnant patients were routinely scanned 5 weeks after embryo transfer. Clinical pregnancy was defined as a live intrauterine pregnancy.

Endometrial thickness was measured as the maximum width of the two endometrial layers in a sagittal plane between the inner margins of the underlying sonolucent layers.

Statistical analysis
Primary endpoints were chance of live intrauterine pregnancy per cycle and per embryo transfer. All data were analysed by Statistics Package for Social Sciences. Comparisons of frequencies were made by {chi}2-test, means by t-test if data followed normal distribution, otherwise by Mann-Whitney U-test. Means are given ±SD. No pre-study power calculation was possible because of economic limitations and availability of patients.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Randomization
Randomization gave two groups, which were comparable with respect to relevant characteristics (Table IGo). The distribution of patients and cycles in each diagnostic category between clomiphene and unstimulated cycles indicated that the randomization of patients in the ICSI group (24/68 clomiphene citrate patients versus 13/64 unstimulated patients ({chi}2 = 3.67) and the unexplained group (13/68 versus 21/64; {chi}2 = 3.23) was not ideal. However, there were significantly more clomiphene citrate (38) than unstimulated ICSI cycles (22) ({chi}2 = 6.42, P < 0.001) and fewer clomiphene citrate (20) than unstimulated unexplained cycles (37) ({chi}2 = 6.198, P < 0.001). A surprisingly high proportion of the patients were smokers.


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Table I. Characteristics of the two groups
 
Follicular development
All of the 132 patients started their first cycle, 90 received two cycles and only three a third cycle. Cycle day for HCG injection was similar in the two groups [12.39 ± 1.99 versus 12.3 ± 2.61, not significant (n.s.)]. The mean number of follicles developed on the day of HCG injection was 2.5 ± 1.26 and 1.2 ± 0.47 in the clomiphene citrate and unstimulated groups respectively (Mann-Whitney U-test, P <= 0.0001). A few cycles were cancelled due to lack of normal follicular development [2/111 (1.8%) in the clomiphene citrate group compared with 6/114 (5.3%) in unstimulated cycles (n.s.)].

A premature spontaneous LH surge was detected in a morning urine sample on the day of HCG injection in 12/109 (11.1%) clomiphene citrate cycles compared with 11/106 (10.4%) of the unstimulated cycles. According to the protocol, oocyte collection was planned for the next day and performed with retrieval of at least one oocyte in 15 cases. None of these became pregnant. In the afternoon urine samples LH surges were detected in 18/91 (19.8%) in clomiphene citrate cycles compared with 10/90 (11.1%) in unstimulated cycles (n.s.).

The incidence of spontaneous ovulation in terms of follicular rupture before oocyte retrieval was significantly higher in unstimulated cycles [34/105 (32.4%)] than following clomiphene citrate [17/108 (15.7%); {chi}2 = 8.10, P = 0.004]. A positive morning LH test was predictive for later ovulation. In the total series, a negative morning LH test was associated with a relatively low risk of ovulation before oocyte retrieval [36/190 (18.9%)] compared with a positive test [13/21 (61.9%); {chi}2 = 19.57, P < 0.0001]. A similar trend was found in the case of a positive LH test in the afternoon, which was associated with a high risk of spontaneous ovulation [13/27 (48.1%)] compared with a negative test [22/151 (14.6%); {chi}2 = 16.35, P < 0.0001].

Oocyte collection
The cycle outcome in terms of oocyte aspiration, harvest and fertilization is shown in Table IIGo. Cancellation due to lack of follicular development and to spontaneous ovulation meant that oocyte collection was performed in 95/111 (85.6%) (clomiphene citrate) and 74/114 (64.9%) (unstimulated) of the initiated cycles ({chi}2 = 9.93, P = 0.02). At least one oocyte was collected in 90 (clomiphene citrate) and 65 (unstimulated) cycles respectively. The mean day of oocyte aspiration was 14.23 (clomiphene citrate) and 14.25 (unstimulated) (n.s.) respectively.


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Table II. Cycle outcomes in clomiphene citrate and in unstimulated cycles
 
In the total series, the diameter of the largest follicle was significantly larger in clomiphene citrate cycles (22.0 mm ± 3.15, n = 98) than in unstimulated cycles (19.1 mm ± 2.20, n = 73; t = 6.618, P < 0.0001) and so was follicular volume of the largest follicle (5.17 ml ± 2.31, n = 95 in clomiphene citrate cycles compared with 3.01 ml ± 2.18, n = 71 in unstimulated cycles; P < 0.0001).

In cycles with only one dominant follicle and where the aspirated oocyte came from that follicle, the mean follicular volume was significantly greater in cycles ending with a clinical pregnancy (4.86 ml ± 2.03, n = 13) compared with those without (3.57 ml ± 1.88, n = 37; t = 2.031, P = 0.042).

Despite spontaneous ovulation, it was possible to rescue the cycle in three cases by aspirating an oocyte from a secondary follicle. Aspiration of follicular fluid was performed from the peritoneum in the case of spontaneous ovulation in 14 cases without oocyte harvest.

A total number of 242 oocytes was collected at the 169 oocyte retrievals (1.43 per aspiration). In ICSI cycles 61 out of 69 (88.4%) collected were metaphase II, indicating a proper timing of oocyte retrieval. There was no significant difference in the rate of metaphase II oocytes in clomiphene citrate and unstimulated cycles respectively (data not shown).

Fertilization and embryo transfer
In non-ICSI cycles, there was no difference between the two treatment groups in terms of sperm concentration, percentage motile sperm or progressive motility in untreated semen samples or after swim-up. Due to lack of fertilization, 27 clomiphene citrate cycles and 33 unstimulated cycles were cancelled.

Fertilization was recorded in 137/242 oocytes (56.6%) in the total series, in 105/174 oocytes (60.3%) from clomiphene citrate cycles and in 32/68 oocytes (47.1%) from unstimulated cycles ({chi}2 = 3.51, n.s.). The fertilization rate was significantly higher in patients receiving clomiphene citrate-IVF on the indication of ICSI or tubal factor compared with couples with unexplained infertility (Table IIIGo).


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Table III. Fertilization rates indicated by number of fertilized oocytes/total number of oocytes harvested (%) according to treatment group and indication for IVF
 
A total of 114 embryos were transferred (Table IIGo). In the clomiphene citrate group 33 transfers with one embryo and 26 with two embryos were performed, and 29 with one embryo in the unstimulated group. There were significantly more cycles with embryo transfer in the clomiphene citrate than in the unstimulated group (Table IVGo). The maximum number of embryos obtained in one cycle was six. Supernumerary embryos were frozen in one case.


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Table IV. Proportion of embryo transfers (transfers per started cycle; %) in the two treatment groups according to indication of treatment
 
In the total series the proportion of cycles with embryo transfer was significantly higher in the ICSI group compared both with the tubal group ({chi}2 = 4.13, P = 0.04), and the unexplained group ({chi}2 = 11.27, P < 0.0001) (Table IVGo). The embryo transfer rate was lower in the clomiphene citrate-unexplained group compared with both the clomiphene citrate-ICSI group ({chi}2 = 7.63, P = 0.006) and the clomiphene citrate-tubal group [{chi}2 = 5.81, P = 0.016)]. Differences in the proportion of embryo transfers between diagnostic groups in the unstimulated cycles were not significant.

Pregnancies
A total of 26 positive pregnancy tests were recorded (11.6% per started cycle), significantly more in the clomiphene citrate compared with the unstimulated group. Except for two (one biochemical and one ectopic) all were clinical pregnancies defined as live intrauterine pregnancies 5 weeks after embryo transfer. The clinical pregnancy rate in clomiphene citrate cycles was significantly higher than in unstimulated cycles both estimated per cycle started and per embryo transfer (P < 0.0001 and P = 0.047 respectively). Although the implantation rate seemed higher in clomiphene citrate cycles than in unstimulated, this difference did not reach significance (Table IIGo). There were two twin pregnancies in the clomiphene citrate group. Overall, ICSI treatments were associated with a significantly higher clinical pregnancy rate per cycle (14/60) compared with the tubal group (8/106, {chi}2 = 8.31, P < 0.01) and the unexplained group (2/57, {chi}2 = 9.73, P < 0.01). Estimated per embryo transfer, the pregnancy rate following ICSI (14/33) compared with the tubal indication group (8/40) showed the same trend ({chi}2 = 4.32, P < 0.02), but not compared with the unexplained group alone.

Differences in pregnancy rates per embryo transfer in the clomiphene citrate group within the three indication groups were not statistically significant. The numbers in the unstimulated group were too small for statistical evaluation.

Neither female nor male smoking was associated with a decreased clinical pregnancy rate per cycle or per embryo transfer compared with non-smokers.

Side-effects
In 51 (45.9%) of the 111 clomiphene citrate cycles, some type of side-effect was registered, whereas this happened in two cases in the unstimulated cycle group (one case of hot flushes and mammary tenderness) ({chi}2 = 51.96, P <= 0.0001). Of the clomiphene citrate cycles, 14 (12.6%) were associated with nausea, 35 (31.5%) with hot flushes, six (5.4%) with mammary tenderness, and four (3.6%) with visual disturbances.

Endometrial thickness
Measurements of endometrial thickness on cycle day 3, day of HCG injection and day 7 following embryo transfer (embryo transfer + 7) are shown in Table VGo. On cycle day 3 and, unexpectedly, on the day of HCG injection there was no significant difference in endometrial thickness in clomiphene citrate and unstimulated cycles respectively. In the midluteal phase (embryo transfer + 7), however, the endometrium was significantly thicker in clomiphene citrate cycles than in unstimulated cycles (t = 2.067, P = 0.04).


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Table V. Endometrial thickness (± SD) on cycle day 3, day of human chorionic gonadotrophin (HCG) injection and 7 days after embryo transfer (embryo transfer + 7)
 
Considering the two groups together and breaking measurements of endometrial thickness on day 7 following embryo transfer into intervals of 3 mm (4–6.9, 7–9.9, 10–12.9, 13–15.9, >16), significantly more embryo transfers ended in a clinical pregnancy when the endometrium was 10–12.9 mm (16/35 transfers, clinical pregnancy rate per transfer of 46%), compared with those outside this interval of endometrial thickness [6/42 (14.3%); {chi}2 = 9.24, P = 0.002]. A similar relationship was not found for the day of HCG injection.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The present study has demonstrated that it is possible to obtain reasonable results using an IVF protocol with very little monitoring with clomiphene citrate for ovarian stimulation, but not in the unstimulated cycle.

A live intrauterine pregnancy rate of 34% per embryo transfer, as in the present clomiphene citrate-IVF series, is satisfactory considering the simplicity, low costs and few side-effects of the protocol. Nevertheless, a cycle cancellation rate of 46% following clomiphene citrate may seem high and may outbalance the benefits of this protocol. However, it is not known what the patients' choices would be in this respect.

The relatively young age of the population and the fact that the patients were included from their first cycle should be borne in mind when considering the relatively high pregnancy rates in the clomiphene citrate-IVF series. The rather late administration of HCG in the clomiphene citrate group (follicular size of 20 mm) did not influence oocyte maturity in terms of metaphase II oocytes. Ideally, the efficiency of the clomiphene citrate protocol should be compared with those obtainable from the present day `gold standard', the long down-regulation protocol, in a similar population. Such analyses are in progress, also in terms of economy and patients' attitudes.

An average fertilization rate of 60%, and an implantation rate of 26% obtained in the present series following clomiphene citrate stimulation, in both cases higher rates than in unstimulated cycles, does not seem to substantiate previous indications of negative anti-oestrogenic effects of clomiphene citrate on various parts of the human reproductive system as suggested by a recent literature review (Out and Bennink, 1998b), but contradicted by others (Dickey et al., (1998Go). Clomiphene citrate thus seems to be compatible with the concept of `friendly IVF', a term introduced recently (Olivennes and Frydman, 1998Go).

In comparison, unstimulated IVF did not yield satisfying results. A clinical pregnancy rate of only 3.5% per initiated cycle is unacceptable and could in part be explained by a rather high rate of spontaneous ovulation, possibly due to the intended low level of monitoring in the present protocol. Avoiding spontaneous ovulation by intense monitoring probably is not cost-effective, and timing of HCG injection at a lower follicular size increases the risk of immature oocytes. Controlling the endogenous LH surge by GnRH antagonists may increase the efficiency both in unstimulated and clomiphene citrate cycles. In a recent study, a single dose of a new gonadotrophin-releasing hormone antagonist was used to block the spontaneous LH surge for IVF in the natural cycle supplemented with human menopausal gonadotrophin support (Rongiéres-Bertrand et al., 1999Go). In that study oocyte aspiration was done in 40 out of 44 cycles commenced, but an embryo was available for transfer in only 50%, apparently due to a rather low rate of successful oocyte collection. However, due to a high implantation rate, the preliminary data were very promising with a 17.5% clinical pregnancy rate per retrieval and 32% per transfer, which is comparable with the results of the present series.

An unavoidable consequence of aspirating only one oocyte per cycle is that a high percentage of cycles will be cancelled due to lack of fertilization. The proportion of unfertilized oocytes in unstimulated cycles in the present study was 53%, possibly due to incidentally skewed randomization resulting in a disproportionately high number of patients with unexplained infertility having an overall significantly lower fertilization rate compared with the ICSI and tubal infertility group. Accordingly, IVF in unstimulated cycles seems discouraging in couples with unexplained infertility. However, ICSI seems to be an efficient tool in an unstimulated or low stimulation protocol as indicated in previous studies (Ludwig et al., 1997Go; Rongières-Bertrand et al., 1999Go).

Adding FSH to the clomiphene citrate protocol in order to increase the number of oocytes may increase the risk of spontaneous ovulation by increasing oestrogen concentrations, thereby overshooting the apparent LH surge-inhibiting the effect of clomiphene citrate. Clomiphene has been found to reduce the risk of an endogenous LH surge, perhaps by prolonged occupation of oestrogen receptors at the hypothalamic-pituitary level (Messinis and Melingos, 1998Go). In the present series the risk of LH surge was the same in clomiphene citrate as in unstimulated cycles using qualitative urinary LH monitoring, but spontaneous follicular rupture was seen significantly more often in unstimulated cycles than following clomiphene citrate stimulation. A blunting of the endogenous LH peak in response to oestradiol has been observed in many clomiphene citrate-induced cycles (Garcia et al., 1977Go; Messinis et al., 1985Go, 1986Go).

The majority of previous series of IVF in unstimulated cycles have shown clinical pregnancy rates per cycle being 10% or below (Paulson et al., 1992Go; Lenton et al., 1992Go; Taymor et al., 1992Go; Claman et al., 1993Go; MacDougall et al., 1994Go; Daya et al., 1995Go; Fahy et al., 1995Go; Kim et al., 1996Go), but others have obtained better figures, up to 23%, partly by more close monitoring of cycles (Ranoux et al., 1988Go; Foulot et al., 1989Go; Svalander et al., 1991Go; Seibel et al., 1995Go). Intensive monitoring does not seem compatible with `friendly IVF'. The rather low implantation rate in unstimulated cycles in the present study is hardly due to insufficient luteal phase progesterone support. A low rate of shortened luteal phase has been found following laparoscopic oocyte retrieval (Feichtinger et al., 1982Go), and it has been estimated that of the total complement of ~50x106 granulosa cells contained in a mature Graafian follicle only ~3x106 are lost during oocyte aspiration (McNatty et al., 1979Go; Jones et al., 1981Go).

In Denmark a stable delivery rate of ~22% per started cycle has been observed during the last 3 years, accomplished mainly by the long down-regulation protocol and two-embryo transfers (Danish National Board of Health, unpublished data). Therefore, the present results do not call for a reintroduction of IVF in unstimulated cycles, despite the few side-effects, simplicity and low costs.

In the clomiphene citrate group the clinical pregnancy rate per cycle could be improved by reducing the rather high cycle cancellation rate. The frequency of cycle cancellation due to lack of fertilization could be less if more oocytes were harvested. This may be accomplished by adding FSH to the protocol. A reduction of the risk of spontaneous ovulation could be obtained by earlier administration of HCG (a follicular size of 17–18 mm) with a risk of lowering the pregnancy rate since follicular volume was found to be positively correlated to clinical pregnancy rate. Including antagonists into the protocol or closer endocrine monitoring are alternative means of reducing the risk of cycle cancellation due to spontaneous ovulation. However, these suggestions would reduce the `friendliness' of the protocol.

The clinical pregnancy rate obtained per cycle and per embryo transfer in clomiphene cycles in the present study may seem surprisingly high. This may be due to the young age of the patients being treated in their first cycle and more ICSI treatments in this group yielding a high fertilization rate.

Mean endometrial thickness was quite unexpectedly similar in unstimulated and clomiphene citrate cycles at the time of HCG injection, whereas midluteal phase measurement showed thicker endometria in patients who had received clomiphene citrate. Moreover, most pregnancies occurred in patients with a luteal phase endometrium of 10–12.9 mm indicating a prognostic value at this stage in contrast to measurements at the time of HCG administration showing doubtful or no predictive value (Coulham et al., 1994Go; Oliveira et al., 1997Go).

In conclusion, the present study suggests that a simple clomiphene citrate protocol, but not IVF in unstimulated cycles, seems compatible with the concept of `friendly IVF', yielding a reasonable pregnancy rate both per cycle started and per embryo transfer in selected patients. The present results do not substantiate any important negative anti-oestrogenic effects of clomiphene.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The authors wish to thank clinical, paramedical and laboratory staff at the Fertility Clinic at Skejby Sygehus and at The Perinatal Epidemiological Research Unit. Ingo Clausen, MD and Karl Møller Bek, MD are thanked for co-operation during the clinical phase of the study. We are very grateful to The Danish Institute for Health Technology Assessment for funding (project no. 3126-88-1997) and to Astra Denmark A/S for supplying us with Clomivid®.


    Notes
 
3 To whom correspondence should be addressed at: Fertility Clinic, Skejby Sygehus, DK-8200 Aarhus N, Denmark.E-mail: jakob.ingerslev{at}dadlnet.dk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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Submitted on September 22, 2000; accepted on January 15, 2001.