Unexplained infertility—the value of Pergonal* superovulation combined with intrauterine insemination

FERTILITY AND STERILITY Copyright 0 1988 The American Fertility Society

Vol. 49, No.4, April1988 Printed in U.S.A.

Unexplained infertility-the value of Pergonal* superovulation combined with intrauterine insemination

Paul F. Serhal, M.D.t Maurice Katz, M.R.C.P. Valerie Little, M.B.B.S. Helen W oronowski, B.Sc. Department of Obstetrics and Gynecology, University College and Middlesex School of Medicine, London United Kingdom

Sixty-two women with unexplained infertility were studied. Fifteen (group 1) had timed intrauterine insemination (lUI), 25 (group 2) were treated by Pergonal (Serono Laboratories, Ltd., Welwyn Garden City, England) superovulation, and 22 (group 3) underwent Pergonal superovulation combined with lUI. Where Pergonal treatment was followed by insemination, a significantly greater pregnancy rate per cycle (P < 0.05) was achieved, whether this group of patients was compared with those treated by lUI alone or with those treated with Pergonal alone. Moreover, the pregnancy rate in group 3 was comparable to that reported following gamete intrafallopian transfer (GIFT). The authors therefore suggest this form of treatment for patients with unexplained infertility prior to their referral to the more invasive procedure of GIFT. Fertil Steril49:602, 1988

Despite improved diagnostic techniques, there remains, in most fertility clinics, a residue of approximately 24% to 28% of couples in whom no cause of infertility can be found. 1 •2 Such couples are labeled as having "unexplained infertility" and are given a host of empirical treatments that achieve a pregnancy rate no better than the spontaneous pregnancy rate of untreated couples. Gamete intrafallopian transfer (GIFT) 3 has achieved a modicum of success in such patients, but this treatment is invasive, not readily available, and achieves a pregnancy rate of 27% to 30%, 4 at best. We recently documented our experience using intrauterine insemination (lUI) for the treatment of couples with a variety of infertility problems. 5 Two out of five patients with unexplained infertility conceived in

their first treatment cycle after being superovulated with gonadotropins followed by lUI. The patients had primary infertility of 6 and 11 years' duration, and had previously received various empirical treatments, including gonadotropins, without success. We hypothesized that their chances of conception had been improved by combining controlled Pergonal (Serono Laboratories Ltd., Welwyn Garden City, England) superovulation, which increased the number of oocytes available for fertilization, with lUI, which increases the concentration of motile spermatozoa and their proximity to the eggs. To evaluate this proposal, we treated an additional 62 couples with unexplained infertility. MATERIALS AND METHODS Patients

Received September 2, 1987; revised and accepted November 23, 1987. * Serono Laboratories Ltd., Welwyn Garden City, England. t Reprint requests: Paul F. Serhal M.D., Clinical Lecturer, Department of Obstetrics and Gynecology, University College and Middlesex School of Medicine, 88-96 Chenies Mews, London WC1E 6HX, United Kingdom.

Sixty-two couples with unexplained infertility were studied. Fifteen women were inseminated at midcycle without pretreatment with gonadotropins (group 1); 25 women were superovulated with gonadotropins but were not submitted for midcycle

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Table 1

Clinical Data No. of patients

Age range (years)

Duration of infertility (years)

Type of infertility

Group 1: intrauterine insemination

15

26-37 (median, 33)

2.5-7 (median, 3.5)

Primary infertility, 7 Secondary infertility, 8

Group 2: Pergonal

25

24-43 (median, 31)

3-13 (median, 6)

Primary infertility, 23 Secondary infertility, 2

22

28-42 (median, 33)

4-10 (median, 7)

Primary infertility, 21 Secondary infertility, 1

Treatment

Group 3: Pergonal

+ insemination

insemination (group 2); while an additional 22 women were superovulated with gonadotropins followed by midcycle insemination (group 3). Of the latter, 15 had lUI alone (group 3a) and the remaining had lUI plus direct intraperitoneal insemination (DIPI) (group 3b). The clinical data of these groups are recorded in Table 1. All patients had previously had routine fertility screening, which demonstrated normal semen analyses according to the World Health Organization (WHO) criteria (>12 million motile spermatozoa per milliliter), positive postcoital tests (three or more unidirectional motile sperm per high power field); and biphasic basal body temperature recordings with luteal phase lengths of ~ 12 days, luteal progesterone (P) concentrations of ~35 nmol/1, and normallaparoscopic findings. All patients had normal follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin concentrations and none had clinical, hormonal, or ultrasonic evidence of polycystic ovarian disease. Treatment Protocol

For the gonadotropin-treated patients, a uniform treatment protocol was used. Three ampules of Pergonal (75 IU FSH and 75 IU LH per ampule) were administered intramuscularly on alternate days, starting on day 2 or 3 of the menstrual cycle. All patients receiving Pergonal were monitored after day 8 by serial ultrasound scanning. Alternate-day Pergonal injections were adjusted according to the patient's response and continued until two to five dominant follicles ~ 17 mm in diameter were present. Ovulation then was induced by an intramuscular injection of 10,000 units human chorionic gonadotrophin (hCG; Profasi, Serono, UK). Inseminations were performed 32 to 36 hours after hCG injections. Those patients not having inseminations were advised to have coitus on the night of hCG administration and the followVol. 49, No.4, April1988

·ing night. Those patients treated by lUI without gonadotropin pretreatment had timed inseminations 12 to 24 hours after their urinary LH dipstick became positive (OvuStick Self Test, Medimar Laboratories, Buckinghamshire, England.) A single insemination procedure was performed per cycle in all groups. Sperm Preparation

The semen samples were assessed initially for sperm count, motility (linear progression), and morphology. The samples then were divided and pipetted into two sterile conical tubes. An equal volume of Ham's F-10 (Flow Laboratories Ltd., Irvine, Ayrshire, Scotland) solution, supplemented with penicillin and streptomycin, was added to each tube, which was then centrifuged at 1500 rpm for 10 minutes. The supernatants were discarded and the pellets were carefully overlayered with 0.3 ml of Ham's F-10 culture medium. The tubes were left for 30 minutes at room temperature to allow the highly active motile sperm to swim up into the medium, which then was carefully removed with a sterile pipette without disturbing the residual pellet. Samples destined for DIPI were adjusted to contain approximately 5 million sperm and made up to 2 ml with Ham's F-10 solution containing 10% albumin. Method of Insemination

All inseminations were performed in the dorsal lithotomy position. For lUI, 0.3 ml of the sperm suspension was drawn into a Kremer de la Fontaine catheter (Laboratoire CCD, Paris, France), attached to a 1-ml tuberculin syringe. The suspension then was injected slowly into the uterine cavity, after which time the catheter was withdrawn gradually. Serhal et al.

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Statistics

group 1 (X 2 = 3.27; P < 0.07) and for group 3 versus group 2 (X 2 = 3.05; P < 0.08). The pregnancy rate for group 3 patients was even more significant when calculated per cycle, group 3 versus group 1 (X 2 = 4.83; P < 0.05) and group 3 versus group 2 (X 2 = 4.9; P < 0.05). Where Pergonal treatment was followed by insemination (group 3), a significant pregnancy rate per cycle was achieved, whether this group of patients was compared with those treated with lUI alone (group 1) or with those treated by Pergonal alone (group 2). However, treatment with Pergonal plus lUI and DIPI (group 3b) achieved no better results than treatment by Pergonal plus lUI alone (group 3a) per couple (X 2 = 0.01; P = NS) and per cycle (X 2 = 0.34; P = NS). Twelve of the 13 pregnancies occurred during the first treatment cycle and 1 in the second treatment cycle.

Chi-square analysis was used to assess the significance of our results.

Pregnancy Outcome

In patients submitted for lUI and DIPI, the posterior fornix was sprayed with 10% xylocaine spray (Astra Pharmaceutical Ltd., Kings Langley, Hertfordshire, England) 10 minutes before the procedure. The sperm suspension was drawn into a 2-ml syringe, which was attached to a 22-gauge spinal needle and injected into the pouch of Douglas. After the procedure, patients remained supine for approximately 5 to 10 minutes and then were allowed to leave without restriction of their activity. All patients had luteal phase support in the form of P (Cyclogest-Cox Pharmaceuticals, Barnstaple, Devon, England) vaginal suppositories 400 mg twice daily or dydrogesterone (Duphaston, Duphar Laboratories Ltd., Southampton, England) 10 mg three times daily orally.

RESULTS

One pregnancy occurred in the 15 couples with unexplained infertility in whom lUI alone was performed. Of the 25 women who received gonadotropins alone, 3 conceived, whereas 9 of the 22 women who were treated with Pergonal and insemination (lUI ± DIPI) achieved pregnancy (Table 2). Where pregnancy rate per couple was calculated, there was no difference between groups 1 and 2, and the pregnancy rate was significant at the 10% level, but not at the 5% level, for group 3 versus

The only patient who conceived after lUI alone had a twin pregnancy. All 3 women who became pregnant after Pergonal superovulation as their sole form of treatment have ongoing singleton pregnancies. Six of the 9 women achieving pregnancy following Pergonal and lUI± DIPI had singleton pregnancies. Two patients had multiple pregnancies: one had a set of twins and one had triplets. There was one clinical abortion. Both multiple pregnancies and the abortion occurred in the group of patients having Pergonal and lUI without DIP I.

Table 2 Comparison of Pregnancy Rates Achieved Following lUI, Pergonal Superovulation, and Combined Pergonal Superovulation Plus Insemination Pregnancy rate

No. of couples

No. of treatment cycles

No. of pregnancies

Per couple %

%

Group 1: intrauterine insemination

15

30

1

6.7

2.7

Group 2: Pergonal superovulation

25

49

3

12.0

6.1

Group 3: Pergonal + insemination

22

34

9

40.9

26.4

15/22

19

6

40.0

31.5

7/22

15

3

42.8

20.0

Treatment

lUI" lUI+ DIPib

a Pregnancy rate per couple: group 1 versus 2, NS; group 1 versus 3, X2 = 3.27; P < 0.07; group 2 versus 3, X2 = 3.05; P < 0.08; group 3 (a) versus 3 (b) NS.

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Per cycle

b Pregnancy rate per cycle: group 1 versus 2, NS; group 1 versus 3, X2 = 4.83; P < 0.05; group 2 versus 3, X2 = 4.90; P < 0.05; group 3 (a) versus 3 (b) NS.

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DISCUSSION

Historically, the main indication for homologous artificial insemination (AIH) by the intravaginal or the intracervical method was the inability of the male to ejaculate into the vagina (e.g., impotence or retrograde ejaculation). In the early days of lUI, a small portion of the ejaculated semen was injected transcervically into the uterine cavity. This technique had the disadvantage of causing uterine cramps due to the prostaglandin content of the semen. Although some centers still perform lUI with untreated semen, there is now general concensus that semen should be washed in a culture medium before use. The improved techniques in sperm washing and preparation have led to renewed interest in lUI as a form of treatment for a variety of fertility problems. Where the sole cause of infertility is poor or absent cervical mucus, lUI would seem a logical form of treatment. Indeed, various investigators have claimed success rates ranging from 50% to 70% in this situation. 6- 10 By contrast, the biologic role of the cervix in sperm selection and transport is presumably operative in patients with unexplained infertility. Hence, in such couples, lUI whereby sperm are deposited into the uterine cavity should offer no advantage over properly timed intercourse. It comes as no surprise, therefore, that we recorded only a single pregnancy following timed lUI in our group 1 couples, giving an insignificant pregnancy rate of 6. 7% per couple treated and an even smaller rate of 2. 7% per cycle. Similarly, Irvine et al.U achieved no pregnancy in 21 couples with unexplained infertility treated by timed lUI. They performed 63 cycles of lUI and 39 control cycles of intracervical insemination. No pregnancy occurred in any of the 102 treatment cycles. In our group 2 patients, i.e., those who received gonadotropin stimulation without insemination, 3 out of 25 conceived, giving a pregnancy rate of 12%. An identical pregnancy rate was achieved by Weiner and et alP who administered Pergonal empirically in patients with unexplained infertility enrolled in their in vitro fertilization (IVF) program. Ninety-five women received three to six cycles of Pergonal during an 8- to 10-month waiting period for IVF; 12.7% achieved pregnancy on gonadotropins prior to IVF. Our results using a combination of Pergonal superovulation and insemination (group 3), whether intrauterine alone or lUI combined with direct intraperitoneal insemination, are more encouraging. Vol. 49, No.4, April1988

Forty-one percent of couples treated by this method achieved pregnancy, and the pregnancy rate per cycle was 26.4%. These results are all the more significant, considering the longstanding duration of our patients' infertility, all 22 patients having failed to achieve pregnancy for a minimum of 4 years, despite an accepted spontaneous pregnancy rate of 20% per year in this group. 13 These patients represent a "difficult to treat" group who would have justifiably required more invasive procedures, such as GIFT/IVF. Of those achieving pregnancy, the minimum duration of infertility was 4 years, while four couples had been trying for pregnancy for 8 to 10 years. Eight of 9 women who conceived after combined therapy became pregnant during their first treatment cycle, and 1 conceived after two treatment cycles. Our results are comparable to those reported in patients with unexplained infertility who, after hMG stimulation, were treated by GIFT. We doubt whether GIFT would have achieved such favorable results without pretreatment with hMG. In fact, we suspect that Pergonal superovulation improves the chances of pregnancy during a host of procedures aimed at bringing concentrated numbers of motile sperm into close proximity with a greater number of eggs. Such procedures include lUI, DIPI, and GIFT (Fig. 1). The greater the number of gametes (sperm and eggs) and the closer they are brought together, the better would appear to be the chances of achieving pregnancy, hence the high pregnancy rates reported with GIFT. To determine whether additional benefit could be achieved by performing DIPP 4 at the same time as lUI, a subset of seven

GIFT

Figure 1 + DIPI.

SUPEROVULATION COMBINED WITH lUI ± DIPI

Diagrammatic comparison of GIFT versus lUI

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patients were submitted to the combined insemination procedure. Similar pregnancy rates were achieved following lUI, regardless of whether DIPI was performed concurrently, suggesting that DIPI offers no advantage in this situation. There will be a group of patients with unexplained infertility who will consistently fail to conceive following gonadotropin superovulation combined with lUI. Such patients may have defective fimbrial ovum pickup, 15 the luteinized unruptured follicle syndrome, 16 or oocyte entrapment, despite follicular ruptureP In all of these conditions, GIFT is likely to prove to be the most effective treatment. Most fertility clinics have a dilemma in managing patients with unexplained infertility. In this situation, patients are either discharged after various empirical treatments or referred for GIFT or IVF. The latter facility is difficult to obtain because the number of hospitals providing IVF /GIFT services is limited and their waiting lists are long. The pregnancy rate achieved in our study is significant because it lends credibility to Pergonal superovulation followed by artificial insemination as one form of treatment for unexplained infertility. We propose that this treatment be offered definitively to such patients prior to their referral for the more invasive procedures of GIFT or IVF.

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nancy following translaparoscopic intrafallopian transfer: GIFT. Lancet 2:1034, 1984 4. Molloy D, Speirs A, duPlessis Y, McBain J, Johnston 1: A laparascopic approach to a program of gamete intrafallopian transfer. Fertil Steril 47:289, 1987 5. Serhal PF, Katz M: Intrauterine insemination. Lancet 1:52, 1987 6. Barwin BN: Intrauterine insemination of husband's semen. J Reprod Fertil 36:101, 1984 7. Glezerman M, Bernstein D, Insler V: The cervical factor of infertility and intrauterine insemination. Int J Fertil 29:16, 1984 8. Sher G, Knutzen VK, Stratton CJ, Montakhab MM, Allenson SG: In vitro sperm capacitation and transcervical intrauterine insemination for the treatment of refractory infertility: phase I. Fertil Steril 41:260, 1984 9. White RM, Glass RH: Intrauterine insemination with husband's semen. Obstet Gynecol47:119, 1976 10. Wiltbank MC, Kosasa TS, Rogers BJ: Treatment of infertile patients by intrauterine insemination of washed spermatozoa. Andrologia 17:22, 1985 11. Irvine DS, Aitken RJ, Lees MM, Reid C: Failure of high intrauterine insemination of husband's semen. Lancet 2:972, 1986 12. Weiner SL, Polan ML, Graebe RA, Barnes E, DeCherney AH: The use of empiric Pergonal therapy in patients with infertility of unknown origin (Abstr). Presented at the forty-first annual meeting of The American Fertility Society, Chicago, Illinois, September 28 to October 2, 1985 13. McBain JC, Pepperrell RJ: Unexplained Infertility in the Infertile Couple. In The Infertile Couple, Edited by RJ Pepperell, B Hudson, C Wood. Edingburgh, Churchill Livingstone, 1980, p 164 14. Forrler A, Dellenbach P, Nisand I, Moreau L: Direct intraperitoneal insemination in the unexplained and cervical infertility. Lancet 1:916, 1986 15. Croxatto HB, Ortiz ME, Diez S, Hess R, Bolmaceda J, Crozetto HD: Studies on the duration of egg transport by the human oviduct. II. Ovum location at various intervals following luteinizing hormone peak. Am J Obstet Gynecol 132:629, 1978 16. Marik J, Hulka J: Luteinized unruptured follicle syndrome a subtle cause of infertility. Fertil Steril 29:270, 1978 17. Stanger JD, Yovich JL: Failure of human oocyte release at ovulation. Fertil Steril41:827, 1984

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