controlled ovarian hyperstimulation in combination

Reprinted From : The Journal of the Egyptian Society of Obstetrics and .Gynecology Vol. 23 No. 7, 8 & 9, July, August, September 1997

CONTROLLED OVARIAN HYPERSTIMULATION IN COMBINATION WITH INTRAUTERINE INSEMINATION FOR TREATMENT OF UNEXPLAINED INFERTILITY HISHAM A. SALEM* and KHALED A. SALEM** * Department of Obstetrics and Gynecology, Faculty of Medicine, Tanta University ** Department of Urology, Faculty of Medicine, Tanta University

CONTROLLED OVARIAN HYPERSTIMULATION IN COMBINATION WITH INTRAUTERINE INSEMINATION FOR TREATMENT OF UNEXPLAINED INFERTILITY

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HISHAM A. SALEM* and KHALED A. SALEM** * Department of Obstetrics and Gynecology, Faculty of Medicine, Tanta University ** Department of Urology, Faculty of Medicine, Tanta University ABSTRACT Many therapeutic modalities have been suggested for treatment of couples with unexplained infertility. Treatment options range from an expectant manage ment to the various methods of assisted procreation such as GIFT and IVF. In the present study unex plained infertility was defined as infertility for 3 years or more in spite of normal findings of standard diagnostic work-up of infertility including history taking, clinical examination, semen analysis, postcoital test, ultrasound pelvic examination including serial ovarian folliculometry, hormonal assay for serum prolactin, luteal phase serum progesterone, and thyroid function, hysterosalpingography, pre menstrual endometrial biopsy, laparoscopy and hysteroscopy. The aim of the present study was to eval uate the clinical efficacy of controlled ovarian hyperstimulation using a long protocol of gonadotro pin releasing hormone agonist (buserelin nasal spray), urofollitropin (Metrodin) and human chori onic gonadotropin (Profasi), in combination with in trauterine insemination for treatment of couples with unexplained infertility. Vaginal ultrasound scan was used for monitoring of the treatment cycles. A total of 84 couples were included in the study. Couples were treated for up to three cycles, with a total of 126 treatment cycles. 21 clinical pregnancies were Vol. 23 No. 7, 8 & 9, JULY, AUGUST, SEP. 1997

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achieved (19 term and ongoing pregnancies, and 2 , sppntaneous abortions) the total pregnancy rate was 25% per patient, and 16.66% per treatment cycle while the successful pregnancy rate was 22.61% per patient, and 15.08% per treatment cyple. These re sults showed that controlled ovarian hyperstimula tion in combination with intrauterine insemination achieves a reasonable success rate in the treatment of couples with unexplained infertility, and should be offered prior to considering the more sophisticat ed assisted procreation techniques.

Introduction The term unexplained infertility may be applied to a couple that has failed to achieve pregnancy for a minimum of 3 years with no obvi ous reason could be discovered through the complete work-up of in fertility performed according to the current diagnostic standards. The average incidence of unex plained infertility among infertile couples has been estimated as ap proximately 15% (1). Several organs and many pro cesses are essential for conception, and pathologic interference with any of these oragans or processes may lead to infertility. So, the complete diagnostic work-up of infertility should aim to evaluate all these or gans and processes. However, many of the essential steps required for re production occur within the repro ductive tract of male and female be yond the reach for evaluation. Even the current advanced state of diag nostic sophistication is limited in the extent to which each process in

volved in. human reproduction can be reliably evaluated. However, the infertility evaluation must be ex haustive, trying to evaluate as much as possible of the essential steps necessary for reproduction. The more exhaustive the evalua tion of the infertile couple the great er the probability of discovering the aetiologic factor(s) responsible for the couple's infertility. This concept emphasizes one of the major diffi culties in identifying couples who truly qualify as having unexplained infertility. Complete diagnostic works-up of infertility must include investigation of the male factor, evaluation of cer vical, uterine, tubal, peritoneal, ovarian and immunologic factors and assessment of the couple's sexu al relationship (2). Several modal ities of treatment have been de scribed for management of couples with unexplained infertility. These treatment modalities include ovula tion induction alone, ovulation in duction in combination with intrau terine or intraperitoreal

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Aim of the work : This study aimed to evaluate the clinical efficacy of controlled ovari an hyperstimulation using a long protocol of gonadotropin releasing hormone agonist, urofollitropin, hu man chronic gonadotropin, and sim plified cycle monitoring with vagi nal ultrasound scan, in combination with intrauterine insemination for treatment of couples with unex plained infertility.

Materials and Methods: This was a prospective study ex tending from January 1994 to June 1996 and including all couples diag nosed as suffering from unexplained infertility for at least 3 years, in whom the female partner was below the age of 40 years with no contrain dication to application of the plane of management. The diagnosis of unexplained in fertility was based on the normal findings of a standard diaignostic work-up of infertility consisting of a detailed history taking with special attention to full inquiry about the menstrual histroy and the couple's sexual relationship and habits, full systemic and gynecologic clinical examination, and the standard basic infertility investigations including semen analysis, documentation of ovulation and evaluation of the lu teal phase through serial ultrasonic ovarian folliculometry, luteal phase

serum progesterone and premenstru al endometrial biopsy, timed postcoital test, ultrasound pelvic exami nation, hysterosalpingography, laparoscopic pelvic examination, hysteroscopy, serum prolactin as say, and thyroid function tests. A total of 84 couples were en rolled in this study . Couples were treated for one , two , or a maximum of three cycles, with a total of 126 treatment cycles. For pituitary down-regulation a long course of the GnRH agonist buserelin nasal spray was used at a dose of 300 ug three times a day (900 ug per day) starting from the day 21 of the prestimulation cycle to the day of HCG injection in the stimulation cycle. Ovarian follicular growth was in duced with i.m. injections of urofol litropin (Metrodin) at a dose of 225 IU per day, starting with the onset of menses. An initial vaginal ultra sound scan was performed before starting ovarian stimulation to ex clude ovarin cysts, then another vaginal ultrasound scan were per formed on the fifth and ninth days of ovarian stimulation with FSH to evaluate the ovarin follicular growth and to modify the FSH dose accord ing to the response. If there were 3 or more follicles with a mean diameter of 18 mm or more, an i.m. injection of 10,000 IU of HCG (Profasi) was given. If the follicle on the day of the scan did

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HISHAM A. SALEM and KHALED A. SALEM f

not meet this ultrasound criterion, FSH injections were continued, and a calculated follicular growth rate of 2 mm per 24 hours was used to pre dict the time for HCG injection when a vaginal ultrasound folliculometry was performed before giv ing the HCG injection. When 10 fol licles or more with a size of 15 mm or more were present in each ovary, this was regarded as a potential risk for ovarian hyperstimulation syn drome, and these cycles were can celled. Luteal support was given as micronized progesterone capsules (Uterogestan) 300 mg daily starting from the next day after IUI. Intrauterine insemination with prepared semen specimen was per formed 36-40 hours after the HCG injection. Couples were requested not to have intercourse for 3 days befor the days of semen collection. Semen specimens were prepared by the direct swin-up technique. The semen sample was allowed to lique fy for approximately 30 minutes. Once liquifaction was complete, the semen sample was analysed before the washing procedure, according to the WHO guidelines. Ham's F-10 medium was used for washing and swin-up of the spermatozoa. The se men sample was mixed with an equal volume of Ham’s F-10 medi um at 37 °C and centrifuged at 320 g for 10 minutes.

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The Supernatant was discarded and the remaining pellet was resus pended in 1 ml. of Ham's F-10 me dium. This mixture was centrifuged for an additional 10 minutes. Again the supernatant was carefully dis carded, then 1 ml of Ham's F-10 medium was layered over the semen pellet. This mixture was incubated at 37 °C in 5% C 0 2 for 45 minutes to allow the motile spermatozoa to swin-up into the medium. After the appropriate incubation the superna tant was examined for sperm count and motility, then the supernatant sperm suspension was placed high in the uterine cavity using a syringe attached to an IUI catheter.

Results : For the 84 treated couples, the mean age of the female partners was 28.8 ± 3.5 years ( range 23-39 ) and the means duration of infertility was 5.4 ± 2.1 years ( range 3-11 years ). Out of the 126 treatment cycles, 8 cycles (6.35% ) were cancelled because of the potential risk for ovarian hyperstimulation syndrome (OHSS). However, 6 cases (4.76%) of OHSS occurred. All of them were mild to moderate and no severe cas es. The mean number of Metrodin ampules used per cycles was 25.6± 5.9, the mean day for HCG injection was 11.8±3, and the mean day for


CONTROLLED OVARIAN HYPERSTIMULATION IUI was 13.1+1. Out of the 84 treated couples, 54 couples were treated for one cycle only, 18 couples were treated for two cycles, and 12 couples were treated for three cycles. Out of the 126 treatment cycles, 84 cycles were done for the first time, 30 cy cles were repeated cycles done for the second time, and 12 cycles were repeated cycles done for the third time. The total number of achieved pregnancies was 21 clinical preg nancies, out of them 2 cases (9.52% of achieved pregnancies) spontane ously aborted in the first trimester,

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and 2 cases (9.52% of achieved pregnancies) carried twin pregnan cies. The overall pregnancy rate per treatment cycle was 16.66%,while the overall pregnancy rate per treat ed couple was 25%. The pregnancy rate per treatment cycle for those cases treated for the first time was 19.05% for those cas es treated for the second time was 13.33% and for those cases treated for the third time was 8.33 %. The cumulative pregnancy rate per treated couple after three cycles of treatment was 40.71 %.

Table (1): Clinical Characteristics of the Infertile Couples and Treatment Cycles Item

Data

No. of patients Mean age of patients Mean duration of infertility No. of started cycles No. of cancelled cycles Mean No. of Metrodin ampoules per cycles Mean day for HCG injection Mean day for IUI Mean No. of follicles > 1 8 m m in diam eter •

48 28.8 ± 4.5 (23-39) years 5.4 ± 2.1 (3-9) years 126 8 25.6 ±2.3 11.1+0.8 13.1+0.5 5.4 ±2.1

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HISHAM A. SALEM and KHALED A. SALEM Table (2) : The Clinical outcome of the Treatmant Cycles •

.

•

The Clinical outcome Clinical pregnancies Spontanous abortions Continued pregnancies Twin pregnancies Ovarian hyperstimulation syndrome (OHSS) Cancelled cycles

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Number

Percentage

21 2 19 2 6

25% per patient 6.5% per achieved pregnancy . 22.62% patient 9.5% per achieved pregnancy 4.76% per cycle

8

6.35% per cycle

Continued pregnancy means pregnancy progressed beyond 16 weeks.

Table (3) : The Pregnancy Outcome of the Treatment Cycles The Pregnancy outcome

Number

Percentage

Pregnancy rate/cycle Continued pregnancy* rate/cycle Abortion rate/achieved pregnancy Pregnancy rate/patient Continued pregnancy rate/patient Twin pregnancies/achieved pregnancy

21/126 19/126 2/21 21/84 19/84 2/21

16.66% 15.08% 9.52% 25% 22.6% 9.52%

* Continued pregnancy means pregnancy progressed beyond 16 weeks.

Table (4): Distribution of patients according to the number of treatment cycles Distribution of Patients

Number of Patients

Percentage

Patients treated for one cycle Patients treated for two cycles Patients treated for three cycles

54 18 12

64.29% 21.42% 14.29%

The total

84

100%


CONTROLLED OVARIAN HYPERSTIMULATION

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Table (5): The pregnancy outcome related to the repetition of the treatment cycles

Cycle order

Number of cycles

Number Pregnancy rate per of pregnancies cycle

Treatment cycles done for 1st time Treatment cycles done for 2nd time Treatment cycles done for 3rd time

84 30 12

16 4 1

19.5% 13.33% 8.33%

The total

126

21

16.66%

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pregnancy rate per patient

Cumulative Pregnancy Rate


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HISHAM A. SALEM and KHALED A. SALEM

Discussion : Intrauterine insemination has been used to treat infertility for over 100 years (4) . Treatment regimens, Insemination methods, and indica tions have all undergone significant changes during this time . One re cent innovation is the combination of IUI with controlled ovarian hy perstimulation. This regimen is reported to be su perior to either controlled ovarian hyperstimulation or IUI alone (5,6), and it is now used for treatment of infertility because of male factor, cervical factor, and ovulatory dys function ( 4,7,8). Controlled ovarian hyperstimula tion in combination with IUI has also been advocated for treatment of unexplained infertility and for wom en who have been treated for endo metriosis (5,6). As it can be understood from the term " unexplained infertility ", the cause of infertility in such cases can not be determined, and for this rea son it has not been possible in such patients to select scientifically the specific and most appropriate treat ment. It is only possible to use a nonspecific assessing therapeutic method to improve the possibility of conception. Among the different methods proposed for treatment of unexplained infertility are the ex pectant management, controlled ovarian hyperstimulation alone, or in combination with intrauterine or

intraperitoneal insemination, GIFT, PROST, and IVF-ET(3). So, it is important to be known how these nonspecefic methods proposed for treatment of unexplained infertility compare. However , not only the efficacy of each method of treatment is im portant, but equally important also is the cost effectiveness of each method, considering that some methods of treatment e.g GIFT, PROST, and IVF-ET, are expen sive, invasive, sophisticated, and in stitute lot of physical and psycho logic burden to the treated couple. Interfering with the proper com parison of the results of the different methods of treatment are the widely varible definitions of "unexplained infertility" in the different studies (9), and the wide variations between the different studies in the extent of the diagnostic work-up which should be applied before assigning the case as unexplained infertility ( 10). However availability of the data about the results of the different methods of treatment may allow a more confident treatment choice. In the current study, for con trolled ovarian hyperstimulation it has been preferred to use a long pro tocol of GnRH analogue (superfact) together with urofollitropin (Metrodin) to obtain an optimal follicular maturation and to avoid ovarian hy perstimulation syndrome (11,12)


CONTROLLED OVARIAN HYPERSTIMULATION keeping in mind also that minor ovulatory dysfunctions can be the hidden cause of the unexplained in fertility (10), and optimizing the conditions for controlled ovarian hyperstimulation in this way may overcome that problem. The results of this study compare well with the results obtained by Chung C. et al. (9), Calhaz-Jorge et al (13), and the European Society for Human Reproduction and Em bryology (ESHRE) multicenter trial on the treatment of unexplained in fertility (3). In the current study, the overall pregnancy rate / treatment cycle was 16.66% and the overall pregnancy rate / treated couple was 25%, while the cumulative pregnancy rate after three cycles of treatment was 40.71%. Chung C. et al have report ed a pregnancy rate / treatment cy cle 19.2% and a pregnancy rate treatment couple 36.2% (9). CalhazJorge C. et al have reported for the cases of unexplained infertility a pregnancy rate of 18.6% (13).The ESHRE multicenter trial on the treatment of unexplained infertility has reported a pregnancy rate of 27.4% for the cases treated by con trolled superovulation with IUI (3). In the current study the best re sults were obtained after the first treatment cycle (19.05%), while the pregnancy rate after the second treatment cycle was 13.33%, and af ter the third treatment cycle was 8.33%. More or less, the same ob

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servations have been reported in other studies (13,14). However, it can be noticed that , still a reason able success rate can be obtained with the second and third treatment cycles. So, it may be worthwhile to repeate this type of treatment for up to 3 times. In the current study it has been observed that the prolongation of the duration of infertility for more than 5 years had a negative in fluence upon the pregnancy out come. This observation has been also reported in another study (13). The results of treatment of unex plained infertility with controlled ovarian hyperstimulation in combi nation with IUI as seen in the cur rent study compare well also \yith the results of controlled ovarian hy perstimulation in combination with IPI, GIFT, and IVF used for treat ment of unexplained infertility as seen in the studies done by Pattuelli M et al (15), and Leeton J et al (16), and in the ESHRE multicenter trial on the treatment of unexplained in fertility (3). Pattuelli M et al have used controlled ovarian hyperstimu lation in combination with IPI and achieved a pregnancy rate of 27.7% (15). Leeton J et al compared the pregnancy outcome after GIFT and IVF used for treatment of couples with unexplained infertility and they achieved a pregnancy outcome of 19% and 20% after GIFT andlVF respectively (16). The ESHRE mul ticenter trial on the treatment of un explained infertility achieved a pregnancy outcome of 15.2% after sur -ovulation alone and 27.4% af


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HISHAM A. SALEM and KHALED A. SALEM

ter superovulation/IUI, 27% after superovulation/IPI, 28% after GIFT and 25.7 % after IVF (3).

invasive, end less expensive then the other assisted procreation tech niques.

*

Looking to the results of the cur rent study and the results of the oth er previously mentioned studies demonstrates that controlled ovarian hyperstimulation in combination with IUI when used in treatment of couples with unexplained infertility it achieves a reasonable success rate which is much better than expectant management and superovulation alone while being well comparable to IPI, GIFT and IVF. In addition, controlled ovarian hyperstimulation/IUI has the defi nite advantage of being simple, non

Conclusion : In conclusion, controlled ovarian hyperstimulation in combination with IUI used for treatment of unex plained infertility is reasonably effi cient, simple non invasive, less so phisticated, less expensive and reasonably cost-effective. So this line of treatment can be used up to 3 cycles of treatment with reasonable expectations of suc cess, before considering the more sophisticated, expensive, and inva sive assisted procreation techniques.

REFERENCES >

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1. Templeton AA, Penny GC. The incidence, characteristics and prognosis of the patients whose infertility is unexplained. Fertil Steril 1982; 37 : 175. 2. Jaffe SB, Jewelewicz R. The basic infertility investigation. Fertil Steril 1991; 56: 599. m

}

3. Crosignani PG, Walters DE, Soliani A. ESHRE multicentre trial on the treatment of unexplained infertility : a preliminary report. Hum Reprod 1991: 6 : 953. 4. DodsonWC, Whitesides DB, Hughes CL Jr, et al. Superovulation with intrauterine insemination in the treatment of infertility : a possible alternitive to gamete intrafullopian transfer and in vitro fertilization. Fertil Steril 1987; 48 : 441. 5. Serhal PF, Katz M, Little V, Woronowski H. Unexplained infertility-the 'Value of Pergonal superovulation combined with intrauterine insemina: tion. Fertil Steril 1988; 49 : 602. 6. Corson SL, Batzer FR, Gocial B, Maislin G. Intrauterine insemination Egyptian Society of Obstetrics & Gynecology