Is waiting for an endogenous luteinizing hormone surge and/or ...

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We could not establish any benefit in waiting for a spontaneous LH surge before administering HCG in the presence of a mature follicle(s) in this study.
Human Reproduction vol.14 no.7 pp.1765–1770, 1999

Is waiting for an endogenous luteinizing hormone surge and/or administration of human chorionic gonadotrophin of benefit in intrauterine insemination?

Awoniyi Awonuga1 and Jyoti Govindbhai Midland Fertility Services, Third Floor, Centre House, Aldridge, WS9 8LT, UK 1To

whom correspondence should be addressed at: City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH, UK

This retrospective study was undertaken to investigate the observation that the probability of pregnancy was higher with intrauterine insemination (IUI) when human chorionic gonadotrophin (HCG) was administered after the onset of the luteinizing hormone (LH) surge. A total of 219 patients who had 524 IUI cycles was included in this study. IUI cycles were divided into three groups: group 1, patients who had an endogenous LH surge but no HCG; group 2, patients given HCG after an endogenous LH surge was observed; and group 3, patients given HCG before an endogenous LH surge could be demonstrated. The overall clinical pregnancy rate was 16%. Forty-two (19.2%) patients had 91 cycles with their partner’s semen, while 177 (80.8%) used donor semen in 433 cycles; clinical pregnancy rates were 12.1% and 16.9% respectively. There was no significant difference in pregnancy rate per cycle between patients in group 1 (12.7%) compared with those in groups 2 (15.6%) or 3 (20.5%). We could not establish any benefit in waiting for a spontaneous LH surge before administering HCG in the presence of a mature follicle(s) in this study. This strategy avoids further monitoring to detect the LH surge, allowing treatment to be planned for a time convenient to the patient. Key words: clomiphene/FSH/HCG/intrauterine insemination/ LH surge/natural cycle

Introduction Intrauterine insemination (IUI) is a popular treatment for infertile women with patent uterine tubes. While IUI is a widely accepted form of treatment for women using donor semen, its clinical value in those using their partner’s spermatozoa remains controversial. Various factors are known to influence the treatment outcome in IUI. These include: use of ovulation augmentation with clomiphene citrate (Hughes and Vandekerckhove, 1996), human menopausal gonadotrophin (HMG) (Cohlen et al., 1998) or follicle stimulating hormone (FSH) (Hughes, 1997); method of sperm preparation (Berger et al., 1985); timing of ovulation and insemination (Allen et al., 1985; Martinez et al., 1991; Pearlstone and Surrey, 1994; Horne et al., 1998); number of pre-ovulatory follicles © European Society of Human Reproduction and Embryology

(Dickey et al., 1991; Tomlinson et al., 1996); motile sperm count of semen used for insemination (Burr et al., 1996; Ombelet et al., 1997; Cohlen et al., 1998); and number of inseminations per treatment cycle (Ransom et al., 1994; Khalifa et al., 1995). Of these variables, the timing of insemination is possibly the most important. Initially, timing of insemination was scheduled using past cycle length and basal body temperature charts (Curie-Cohen et al., 1979). Federman et al. (1990) later showed that using the luteinizing hormone (LH) surge to time ovulation affords substantial benefits in cost effectiveness without diminishing fecundability, and therefore recommended its use on a routine basis (Federman et al., 1990). Lately, the use of human chorionic gonadotrophin (HCG) (Pittrof et al., 1996; Manganiello et al., 1997) and gonadotrophin releasing hormone analogue (GnRHa) (Romeu et al., 1997) have been advocated, but two studies (Martinez et al., 1991; Deaton et al., 1997) in which clomiphene citrate was used for stimulation found no advantage in using HCG to time insemination. As the LH surge can last for up to 2–3 days before ovulation in some patients (Cohlen et al., 1993), a treatment plan based on the LH surge alone can result in inaccurate timing of ovulation and insemination. When HCG is given before the LH surge there can be mistiming of follicle maturity. It is therefore reasonable to expect a better pregnancy rate when an ovulatory dose of HCG is administered after the LH surge (Fuh et al., 1997). Here, we present a retrospective analysis of our treatment results compared with relevant control groups to assess whether this strategy is of benefit to women having IUI.

Materials and methods A total of 235 patients underwent 555 IUI treatment cycles between June 1996 and March 1998 at the Midland Fertility Services. Of the 555 cycles, 524 in 219 patients were analysed in this study. A total of 31 cycles in 17 patients was excluded; these were 16 cycles (12 patients) where GnRHa/HMG were used for ovulation induction, 10 (three patients) with missing data, and four (two patients, one of whom had a cycle at the age of 44 years and hence had that cycle included in the analysis) in which treatment took place when patients were aged over 44 years. Sub-fertility was primary in 128 (58.5%) couples. Forty-two (19.2%) patients with a mean (6 SD) age of 33.3 6 3.9 years (range 26–43 years) had 91 treatment cycles with their partner’s semen, while 177 (80.8%) with a mean age of 32.9 6 5.0 years (range 21–44 years) used donor semen in 433 cycles. For the purpose of this study, IUI cycles were divided into three groups, namely: group 1 [n 5 142 (27.1%)], cycles in which patients had an LH surge but had no HCG; group 2 [n 5 250 (47.7%)], cycles in which patients were given HCG after an endogenous LH surge was observed; and group 3 [n 5 132 (25.2%)], cycles in

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A.Awonuga and J.Govindbhai

Table I. Demographic characteristics and baseline serum gonadotrophins of patients in relation to the treatment groups

No. of patients Age (years) Duration of infertility (years)a Baseline FSH (IU/l) Baseline LH (IU/l) Patients with primary infertility (%)

LH surge alone (Group 1)

HCG after LH surge (Group 2)

HCG alone (Group 3)

73 33.5 4.3 6.7 5.4 40

104 32.9 4.6 7.4 5.4 60

42 32.5 4.8 7.2 5.2 28

6 4.9 (4, 1–18) 6 1.9 6 2.0 (54.8)

6 4.7 (4, 0.5–20) 6 2.4 6 2.2 (57.7)

6 4.9 (3, 1–18) 6 3.4 6 3.5 (66.7)

Data are mean 6 SD. aValues in parentheses are median, range. FSH 5 follicle stimulating hormone; LH 5 luteinizing hormone; HCG 5 human chorionic gonadotrophin.

Table II. Clinical pregnancy rate per cycle in relation to the motile sperm count of semen used for insemination Semen source Donor Partner

Motile sperm count (3106) ,0.99

1–4.99

17/83 (20.5) 1/5 (20)

43/301 (14.3) 12/36 (33.3) 1/10 (10) 0.024 6/29 (20.7) 1/20 (5) 3/37 (8.1) NS

5–9.99

.10

P

Values in parentheses are percentages. NS 5 not significant. Motile sperm count was not recorded in some cycles.

which patients had HCG before an endogenous LH surge could be demonstrated. Intrauterine insemination was performed either in natural cycles or with ovarian stimulation. In stimulated cycles, patients received clomiphene citrate (50–100 mg) (Merrel Dow, Uxbridge, UK) orally from day 1 or 2 of the menstrual cycle for 5 days, or gonadotrophins [urofollitrophin high purity (uFSH HP)/follitrophin alpha (rFSH)] (Metrodin HP or Gonal F; Serono Laboratories, Welwyn Garden City, UK), usually 150–300 IU on alternate days starting on day 3 of the menstrual cycle. Patients who had ovarian stimulation were first scanned on day 3 of their menstrual cycle. Other patients had their first scan on days 9–11. Thereafter, patients either stopped stimulation, continued on alternate days, or had a daily injection depending on the size of the recruited follicles. Serial transvaginal ultrasound scans were continued until the dominant follicle was .15 mm, whereupon patients tested their urine each morning (using the second morning sample) with a commercial urinary LH dipstick (Clear Plan One Step; Unipath Ltd, Bedford, UK) and returned for a repeat scan on the day the LH test was positive. Patients were offered HCG injection on the day of the LH surge on the understanding that its value has not yet been proven. Depending on the patient’s choice, an intramuscular injection of 5000 IU HCG (Pregnyl; Organon, Cambridge, UK) was given at the time of the visit and IUI planned for the following morning approximately 24–30 h later (Cohlen et al., 1998). Alternatively, when the dominant follicle was .17 mm and the LH test was negative, 5000 IU HCG was administered i.m. that evening, and IUI planned for 40 h later. IUI was performed when the largest follicle was .17 mm and there were no more than three follicles with mean diameter .14 mm present in total. IUI was performed once in every cycle. If ovarian response exceeded these criteria the cycle was either abandoned or, following the administration of HCG, converted to in-vitro fertilization (IVF). For IUI, either fresh semen (obtained by masturbation) or frozen donor semen was used. The cryopreserved sperm samples were thawed at room temperature. Liquefied semen was added to 1–2 ml

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of Medicult IVF medium (Medicult, Copenhagen, Denmark) and then layered onto the top of Pure Sperm gradient (NidaCon International AB, Gothenburg, Sweden) which consisted of 0.5 ml each at a lower layer of 100%, a middle layer of 80%, and an upper layer of 50%. Samples were centrifuged at 300 g for 35 min. The pellet was removed, resuspended in 2 ml of Medicult IVF medium, and centrifuged for 10 min. The supernatant was removed down to 0.2 ml and used for insemination. This final sample contained motile spermatozoa and was resuspended by drawing it up and down the pipette. One drop of this sample was placed on a Horwell Counting Chamber for an estimation of sperm concentration and motility, and the motile sperm count (sperm concentration3percentage motile spermatozoa) was calculated. Patients were routinely scanned (not included in the number of scans performed per treatment cycle in the analysis) before IUI, and evidence of ovulation recorded: an irregularly shaped follicle with marked reduction in size, with or without fluid in the periovulatory area; disappearance of the previously seen follicle; or the presence of a corpus luteum. The cervix was exposed with a bivalve speculum and cleaned with a dry sterile swab or a swab soaked in phosphatebuffered saline. The loaded catheter was passed gently through the cervix and 0.2 ml sperm sample injected high into the uterine cavity. The luteal phase was not routinely supported pharmacologically in our IUI programme, even in stimulated cycles. A pregnancy test was performed 2 weeks after IUI and, if positive, patients underwent ultrasound scanning 2 weeks later to establish the number of gestation sacs and embryonic viability, and to exclude ectopic pregnancy. Clinical pregnancy was defined as the presence of an intrauterine gestation sac with yolk sac, fetal pole and fetal heart pulsations. Statistical analysis was performed on an IBM-compatible computer, using the statistical package SPSS for Windows 6.1 program. Betweengroup differences were analysed with chi-square test and Fisher’s exact test for categorical data, and analysis of variance (ANOVA) for continuous variables. When ANOVA revealed a difference within the three treatment groups, the Bonferroni multiple comparisons procedure was done as a post-hoc comparison to determine which means were significantly different from each other. Statistical significance was set at P , 0.05.

Results Overall, there were no statistically significant differences in the three groups in relation to mean age, mean duration of infertility, mean baseline FSH, mean baseline LH and the proportion with primary infertility (Table I). This remained true when these demographic variables were analysed in relation to the stimulation protocol.

Spontaneous LH surge, HCG and IUI

Table III. Clinical pregnancy rate per cycle in relation to the use of partner’s or donor semen in natural, clomiphene citrate and ovarian stimulation cycles Partner’s semen

Natural Clomiphene citrate u/rFSH Total

Donor semen

Total (n 5 191)

LH surge alone HCG after LH surge (Group 1) (Group 2)

HCG alone (Group 3)

Total (n 5 433)

LH surge alone (Group 1)

HCG after LH surge (Group 2)

HCG alone (Group 3)

5/58 (8.6) 2/9 (22.2) 4/24 (16.7) 11/91 (12.1)

0/12 (0) 0/1 (0) 0/1 (0) 0/14 (0)

2/10 (20) 1/2 (50) 4/23 (17.4) 7/35 (20)

55/342 (16.1) 7/28 (25) 11/63 (17.5) 73/433 (16.9)

17/114 (14.9) 1/7 (14.3) 0/7 (0) 18/128 (14.1)

31/186 (16.7) 2/11 (18) 2/11 (18.2) 35/208 (16.8)

7/42 (16.7) 4/10 (40) 9/45 (20) 20/97 (20.6)

3/36 (8.3) 1/6 (16.7) 0/0 (0) 4/42 (9.5)

Values in parentheses are percentages. FSH 5 follicle stimulating hormone.

Table IV. Clinical pregnancy rate and ovulatory status on the day of IUI in the three treatment groups

Ovulated Not ovulated Total

LH surge alone (Group 1)

HCG after LH surge (Group 2)

HCG alone (Group 3)

18/130 (13.8) 0/12 (0) 18/142 (12.7)

37/231 (16) 1/16 (6.3) 38/247 (15.4)

26/123 (21.1) 1/9 (11.1) 27/132 (20.5)

Values in parentheses are percentages.

The overall clinical pregnancy rate was 16% (84/524). There was no significant difference in pregnancy rate between patients in group 1 [12.7% (18/142)] compared with those in group 2 [(15.6% (39/250)] or group 3 [(20.5%) 27/132)]. Forty-two (19.2%) patients had 91 treatment cycles with their partner’s semen, while 177 (80.8%) used donor semen in 433 cycles with clinical pregnancy rates of 12.1% and 16.9% respectively. Table II shows the results of the motile sperm count of semen used for insemination, and the associated pregnancy rate in couples using partners’ and donor semen. With increasing motile sperm count, the pregnancy rate per cycle increased up to a motile sperm count of ,53106 when homologous semen was used and ,103106 when donor semen was used. Thereafter, the pregnancy rate decreased with increasing motile sperm count used for insemination. With donor semen, performing IUI in a natural cycle gave a good pregnancy rate whether the timing of treatment was by the LH surge alone or by the administration of HCG before or after the LH surge (Table III). Although this was also true for cycles in which partner’s semen and stimulation with clomiphene citrate and gonadotrophins were used, the numbers of treatment cycles involved were too small for meaningful statistical comparison. Data on the ovulatory status at the time of IUI was recorded in 521 treatment cycles. The proportion of ovulatory cycles was similar in the three treatment groups: group 1, 130/142 (91.5%); group 2, 231/247 (93.5%); group 3, 123/132 (93.2%). Although no significant difference could be demonstrated, the clinical pregnancy rate was higher in cycles with evidence of ovulation [16.7% (81/484)] than those without [5.4% (2/37)] (Table IV). The clinical pregnancy rate was lower in patients with unexplained infertility. This remains true irrespective of whether the data are pooled or analysed in the three different treatment groups (Table V). However, these differences were not statistically significant. The mean (6 SD) cycle day of treatment was significantly

shorter in group 3 than in groups 1 or 2: group 3, 14.3 6 3.4; group 2, 15.2 6 2.4; group 1, 15.1 6 2.5; P 5 0.004. In addition, the mean (6 SD) diameter of the leading follicle on the day of the LH surge or on the day that HCG was given was significantly smaller in group 3 compared with that in groups 1 or 2: group 3, 18.6 6 1.8 mm; group 1, 19.5 6 2.2 mm; group 2, 19.6 6 2.4 mm; P 5 0.0004. This however, remained true for only those cycles in which no stimulation was used and even then a significant difference in follicle size could only be demonstrated between groups 3 and 2: group 3, 18.6 6 1.6 mm; group 2, 19.6 6 2.3 mm; group 1, 19.4 6 2.2 mm; P 5 0.01. Data on the number of recruited follicles were available in 521 treatment cycles. The mean (6 SD) number of follicles .14 mm present on the day of the LH surge or when HCG was given was significantly higher in group 3 compared with groups 1 and 2: group 3, 1.6 6 0.9 mm; group 1, 1.1 6 0.5 mm; group 2, 1.2 6 0.5 mm; P 5 , 0.001. However, these differences were no longer apparent when the number of follicles recruited in the three groups were analysed in relation to whether treatment took place in natural, clomiphene or gonadotrophin cycles. Significantly more transvaginal scans were performed in patients in group 3 compared with groups 2 and 1. Also more scans were performed in group 2 compared with group 1: group 3, 2.4 6 1.2; group 2, 2.2 6 0.9; group 1, 1.6 6 1.1; P ,0.001. However, only in the data from the subset of those who had treatment in the natural cycles did the between group differences in the number of scans performed per cycle remain strong for those cycles in groups 3 and 2 compared with group 1: group 3, 2.2 6 1.2; group 2, 2.1 6 0.9; group 1, 1.5 6 1.1; P , 0.001.

Discussion In assisted reproductive technology, as in any other field of medicine, there is always the quest to improve treatment outcome. Innovations are always welcomed provided that they are neither associated with added inconvenience nor increase the cost of treatment. With artificial insemination, a recent beneficial innovation was the substitution of IUI for intracervical insemination (Patton et al., 1992). Another potential beneficial innovation was the suggestion by Fuh et al., that the pregnancy rate could be improved when HCG was administered after the LH surge in IUI (Fuh et al., 1997). We also recognized the potential benefit of such a strategy and, from June 1996, 1767

A.Awonuga and J.Govindbhai

Table V. Clinical pregnancy rate per cycle in relation to the aetiology of infertility Treatment group/aetiology

LH surge alone (Group 1) (n 5 142)

HCG after LH surge (Group 2) (n 5 250)

HCG alone (Group 3) (n 5 132)

Total (n 5 524)

Unexplained Male factora Single women Othersb

0/5 (0) 12/87 (13.8) 6/44 (13.6) 0/6 (0)

1/24 (4.2) 20/138 (14.5) 15/71 (21.1) 3/17 (17.6)

0/11 (0) 19/87 (21.8) 5/18 (27.8) 3/16 (18.8)

1/40 (2.5) 51/312 (16.3) 26/133 (19.5) 6/39 (15.4)

Values in parentheses are percentages. aIncludes cycles in which donor semen was used. bOthers included predisposition to genetic disorders having four cycles (n 5 2); psychosexual disorders having 13 cycles (n 5 3); mild endometriosis having seven treatment cycles (n 5 4); ovulatory dysfunction having 15 treatment cycles (n 5 6).

offered 5000 IU HCG i.m. to our patients on the day of the LH surge, on the understanding that this was as yet of no proven value. The overall clinical pregnancy rate in this study was 16% per cycle. The rates of 12.1% and 16.9% achieved with the use of homologous and donor semen respectively were consistent with those cited in earlier reports (Dickey et al., 1991; Hurd et al., 1993; Fuh et al., 1997), but lower than that of another (Pittrof et al., 1996). That poor result was achieved when IUI was performed with homologous semen in natural cycles irrespective of the indication for treatment (Irianni et al., 1990; DiMarzo et al., 1992), was borne out by the results of our study. In addition, our results were in agreement with a previous report (Cohlen et al., 1998) that cycles in which .103106 motile spermatozoa were inseminated resulted in a lower pregnancy rate. This would suggest that subtle female factors may also be contributing to the sub-fertility in such cases. It is perhaps not surprising that the mean cycle day of treatment was less, and the mean diameter of the leading follicle smaller, in cycles where HCG injection was administered before the LH surge (Martinez et al., 1991). In contrast to the findings by Fuh et al. (1997), these variables did not affect the treatment outcome in this group (Fuh et al. 1997). The mean number of follicles .14 mm present on the day of the LH surge (or HCG administration) was significantly higher in group 3 compared with that in groups 1 and 2. However, this difference was no longer apparent when the number of follicles recruited in the three groups was analysed in relation to the type of stimulation used. Therefore, this variable is unlikely to account for the higher (but not significantly better) pregnancy rate seen in group 3 in the different stimulation protocols. It was a disadvantage that significantly more transvaginal scans were performed in patients in group 3. This was true only for the data from the subset of those who had treatment without stimulation, but it did not influence the pregnancy rate when donor semen was used. Only few patients used their partner’s semen for treatment in a natural cycle for meaningful statistical comparison. In artificial insemination, it has always been known that some form of timing is necessary to achieve an optimal pregnancy rate (Allen et al., 1985). In IUI, unlike timed intercourse, most authorities agree that the timing of insemination needs to be more precise and closer to the actual time of 1768

ovulation. The ability to determine the most opportune time of insemination would make performing a single insemination more cost-effective (Martinez et al., 1991). This is supported by the findings in this study, where 17% compared with a 5% clinical pregnancy rate was achieved in cycles where there was evidence of ovulation at the time of IUI (Table IV). The results of this study confirm the previous report by Pittrof et al. (1996) that when HCG is used to time IUI, the prior detection of a spontaneous LH surge does not affect the pregnancy rate (Pittrof et al., 1996). Whereas it is routine in our unit for patients to test their urine daily for an LH surge once a dominant follicle is identified, this was done in less than half of the treatment cycles presented (Pittrof et al., 1996). Our result is at variance with the findings by Fuh et al. (1997), who concluded that a significantly higher pregnancy rate was achieved if a spontaneous LH surge occurred before HCG administration, especially where administration of HCG was delayed for 8–20 h after an observed LH surge (Fuh et al., 1997). It is reasonable to expect a better pregnancy rate in IUI if imminent ovulation, as ascertained by the detection of an LH surge, occurs before injecting HCG to ensure and time ovulation more precisely. Several reasons could be put forward to explain why this strategy should improve the treatment outcome in IUI: an improvement in the accuracy of timing because of the known oocyte release after HCG injection; the presence of an LH surge is an indication that the final process of natural follicular maturation has commenced and that ovulation is imminent; the likelihood that ovulation could be triggered in the presence of an immature follicle(s) is avoided; luteinized unruptured follicle—which occurs in up to 9% of cycles in women with unexplained infertility (Daly et al., 1985)—as a cause of treatment failure is avoided; occult ovulatory dysfunction (Tummon et al., 1988; Daly, 1989) may be corrected; urinary LH assays may not correlate completely with ultrasound findings in the identification of ovulation (Shoupe et al., 1989); and wide variance in the temporal identification of the LH surge has been found using several commercial LH kits (Vermeah et al., 1987). Despite these, we could not establish any benefit in waiting for a spontaneous LH surge before administering HCG in the presence of a mature follicle(s) in this study. Although this was true for cycles in which homologous semen and stimulation with clomiphene citrate and gonadotrophins were used, the number of cycles involved did not allow for proper statistical com-

Spontaneous LH surge, HCG and IUI

parison. With donor semen, performing IUI in a natural cycle gives a good pregnancy rate, whether the timing of treatment is by LH surge alone or by administration of HCG before or after the LH surge. We could not evaluate the time interval between the LH surge and HCG administration because there were too many missing data for meaningful statistical comparison. It is therefore not possible to comment on the impact of this variable on the treatment outcome. Following a demonstration of the LH surge, all patients had their IUI treatment within 30 h. Fuh et al. (1997) in their study concluded that the longer the time interval (up to 20 h) between the LH surge and subsequent HCG administration, the better the pregnancy rate (up to 30–38%) (Fuh et al., 1997). Although in this study—unlike our own—gonadotrophins were used in virtually every treatment cycle, this assertion needs to be investigated further. However, our result is in agreement with their findings that the timing of IUI based on the LH surge is not critical to the achievement of pregnancy. In conclusion, our results show that there is no benefit in waiting for the LH surge in the presence of a mature follicle when donor semen is used for IUI in a natural cycle. Similar clinical pregnancy rates per cycle could be achieved in this group of patients, irrespective of whether HCG, the LH surge, or both are used to time IUI. With this strategy, further monitoring to detect the LH surge is avoided and treatment planned for a time convenient to the patient. Two sources of bias in our study are worth mentioning. Firstly, the design of our study is retrospective; hence it does not represent the best evidence. Secondly, patients were allowed to choose their treatment but the reasons for their choice have not been analysed; hence the possible effect on the outcome is uncertain. Nevertheless, this report adds to the debate concerning the effectiveness of the administration of HCG before or after an LH surge versus LH surge alone in IUI. What is now needed is a prospective randomized study—that takes into consideration the confounding variables mentioned in this study—to determine whether in the presence of a mature follicle there is any benefit in waiting for the LH surge before administering HCG in patients having IUI. Acknowledgements The authors would like to acknowledge the contributions of the embryologists (Susan Barlow and Bert Stewart) and fertility nurse specialists (Beverley Adkins, Vicki Robinson, Heidi Birch). We are grateful to Anna Kavanagh, Andy Walker, Nigel Bickerton, Kevin Artley, Mat Tomlinson and Peter Bromwich for revising the manuscript.

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