FERTILITY AND STERILITY
Vol. 55, No.3, March 1991
Copyright 1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility
William C. Dodson, M.D. A. F. Haney, M.D. The Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, and Duke University Medical Center, Durham, North Carolina
The effectiveness of treatment of disorders of sterility is easily assessed by the pregnancy rates (PRs) that result from that therapy. Cycle fecundity after in vitro fertilization and embryo transfer (IVF-ET) in women who have had their oviducts surgically removed indicates the degree of success, or efficacy, ofiVF for that condition. Similarly, cycle fecundity after artificial insemination with donor semen in wives of azoospermic men reflects the suitability of that treatment. The underlying assumption in the analysis of efficacy for any treatment of sterility is that the likelihood of pregnancy without treatment is negligible. Most couples seeking infertility care do not have problems rendering them completely unable to conceive. Rather, the couples have conditions associated with a relative decrease in the monthly likelihood of conception (or, subfertility) in which pregnancy can occur without treatment. 1 Examples of subfertile conditions include endometriosis, oligoasthenospermia, idiopathic infertility, minimal adnexal adhesions, luteal phase defect, and cervical factor infertility. In contrast to the treatment of sterility, one cannot assume that pregnancies occurring after treatment of subfertility are due to the treatment or would not have occurred without treatment. 2 To evaluate the efficacy of treatment of subfertility, it is necessary to perform controlled, randomized trials comparing PRs of treated and untreated subjects. Unfortunately, few such trials exist. In this review, we will evaluate the results of controlled ovarian hyperstimulation with intrauterine insemination (lUI) in the management of subfertility. It is important to remember that the evaluaVol. 55, No.3, March 1991
tion of the efficacy of this technique is limited because most of the reports are uncontrolled studies, describing heterogeneous groups of patients with dissimilar diagnostic entities, duration of infertility, prior therapy, age, and experience of the physician. Unfortunately, this problem is not unique to this infertility therapy and is frequently a fault of reports of other treatments of subfertility, such as IVF, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), and medical management of endometriosis and oligoasthenospermia.
INTRAUTERINE INSEMINATION
Intrauterine insemination, alone or in combination with ovarian stimulation, has been used for treatment of infertility for many years, 3•4 but its use remains controversial. 5 Initially, this treatment was abandoned because of the occasionally intense reaction of the uterus to insemination of raw semen and the risk of pelvic infection. 4 The use of split ejaculates,&-8 small amounts of semen,9 •10 or dilution and freezing of semen with egg yolk buffer11 reduced the incidence of adverse reactions; however, it was only with the advent of sperm separation techniques 12 that relatively painless lUI was feasible. 13 The rationale for lUI as treatment of subfertility focuses on the filtration effect of cervical mucus. Studies of normal women by Settlage et al./ 4 indicate that only approximately 0.1% of sperm placed in the upper vagina are present in the cervical canal in the 1st hour after insemination. In this study, it was estimated that within 1 hour of vaginal insemi-
Dodson and Haney
Controlled ovarian hyperstimulation and lUI
457
nation at midcycle, 1 of every 14 million motile sperm deposited in the vagina reached the oviduct. Furthermore, the number of sperm in the oviduct was proportional to the number of motile sperm inseminated. Similarly, Mortimer and Templeton 15 showed that there is a reduction in sperm number of five to six orders of magnitude along the length of the female reproductive tract. If infertility is associated with low numbers of motile sperm per ejaculate, poor quality cervical mucus, or toxic substances in the peritoneal environment, and if the probability of fertilization is density-dependent, then increasing the number of sperm reaching the uterine cavity may improve the likelihood of pregnancy. Weathersbee et al. 16 showed that lUI increases the proportion of women with intraperitoneal sperm isolated at laparoscopy within 2 hours after insemination. Using lUI may increase the number of sperm reaching the distal oviduct/ 7 assuming that the sperm separation procedure recovers a high proportion of motile sperm from the ejaculate. Unfortunately, bypassing the cervical mucus, which acts as a reservoir for sperm at midcycle, requires timing coincident with ovulation for insemination. The precision of timing required for this technique is unknown. Many different methods have been used to determine the time for insemination. Basal body temperature (BBT), urinary luteinizing hormone (LH) concentration measurements, and ultrasound (US) monitoring have all been used in an attempt to time inseminations coincident with ovulation. Alternatively, multiple inseminations per cycle have been used to circumvent imprecise timing. There is no consensus for what should be used to schedule lUI in spontaneous or stimulated cycles. This lack of agreement may be reflected in the variation of reported results. The treatment of male factor infertility with lUI has been frequently studied; however, results reported for lUI during spontaneous cycles have not been consistent (Table 1). In one of the few trials of lUI having a control treatment group, Kerin et al. 18 showed a high degree of success achieved with lUI in oligospermic couples when timed with LH surges, compared with intercourse scheduled by BBT charts or LH surges. However, a controlled, prospective, crossover study by te Velde et al., 19 comparing lUI with intercourse showed no advantage of lUI. Another randomized, prospective trial comparing lUI with intercourse showed very poor results in both treatment arms. 20 With one excep458
Table 1 Literature Summary of lUI for Male Factor Infertility
Unstimulated cycles Byrd et al. 21 Contino et al. 13 Dmowski et al. 27 Glass et al. 51 Harris et al. 28 Hughes et al. 25 Hull et al. 23 KerinetaU 8 Marrs et al. 12 te Velde et al. 19 Thomas et al. 26 CCcycles Blumenfeld et al. 38 Bolton et al. 40 Hewitt et al. 41 HMGcycles Blumenfeld et al. 38 Cruz et al. 37 Horvath et al. 54 Sher et al. 45 Sunde et al. 76 Current summary
Patients
Pregnancies/ cycle
Fecundity
21 27 27 19 20 20 8 34 4 30 8
9/58 0/108 4/90 0/67 3/120 0/32 0/20 8/39 0/12 3/112 0/24
0.16 0 0.04 0 0.03 0 0 0.21 0 0.03 0
13 29 36
5/43 5/158 3/64
0.12 0.03 0.05
8 48 39 4 40 39
4/32 7/96 6/175 1/4 8/56 13/85
0.13 0.07 0.03 0.25 0.14 0.15
tion, 21 others have reported similarly poor results.12·13·22-28 There is no consensus for the role of lUI in oligoasthenospermic couples.5 Measures of male fertility potential other than the semenalysis may provide prognostic information for management of infertility with lUI. Wiltbank et al. 29 evaluated the results of lUI in 35 infertile couples. In this study, sperm from 19 of the men showed poor results with the zona-free hamster egg penetration test, and sperm from 16 men showed normal results. Cycle fecundity for couples in whom the male had normal results was 0.13, and for couples with abnormal egg penetration test results, 0.02. Intrauterine insemination for treatment of cervical factor infertility is also controversial. Although some report cycle fecundity approximating 20%, 13 others show intermediate 10·21 ·30 or poor results. 23 ·31 ·32 te Velde et al., 19 using a randomized, crossover comparison of lUI with intercourse for couples with cervical factor infertility, showed a cycle fecundity of 0.16 after lUI and no pregnancies after intercourse. Again, differences in patient selection, diagnostic criteria, method of sperm separation, method of ovulation prediction, and timing of inseminations may account for differences in results.31 The efficacy of lUI for treatment of unexplained infertility has been evaluated by Serhal et al. 33
Dodson and Haney Controlled ovarian hyperstimulation and lUI
Fertility and Sterility
Table2
Literature Survey of lUI for Idiopathic Infertility Patients
Pregnancies/ cycle
Fecundity
14 14 15
6/48 1/42 1/30
0.13 0.02 0.03
5 9
4/10 1/12
0.40 0.08
3 15 5 11 57
2/7 6/19 2/5 1/15 17/116
0.29 0.32 0.40
Unstimulated cycles Byrdetal.21 Quagliarello et al. 30 Serhal et al. 33 CCcycles Blumenfeld et al. 38 Hewitt et al. 41 HMGcycles Blumenfeld et al. 38 Serhal et al.33 Sher et al.45 Sunde et al. 76 Current summary
O.o7 0.15
(Table 2). Poor cycle fecundity has resulted from this treatment. 30•32 In: contrast, Yovich and Matson24 showed a cycle fecundity of 0.08 in their series of 183 cycles of lUI for treatment of unexplained infertility, and in a series of 14 couples, Byrd et al. 21 reported a cycle fecundity of 0.13. OVARIAN STIMULATION
Ovarian stimulation has been used for specific as well as empiric therapy for subfertility. Correction of subtle, unpredictable ovulatory dysfunction has been the rationale for the use of agents such as clomiphene citrate (CC), human menopausal gonadotropins (hMG), or both in combination. Furthermore, with the use of hMG alone, there is the opportunity for superovulation, providing enhanced opportunity for oocyte capture, fertilization, and implantation, without the adverse effects of CC on estrogen sensitive tissues. Theoretically, subfertility disorders in which the normal interaction of the oviduct and ovary is altered or in which a postulated unfavorable peritoneal environment is present, would benefit from an increased number of oocytes produced each month. Few studies have reported the results of empiric treatment of subfertility with controlled ovarian hyperstimulation. W elner et al. 34 showed that approximately 11% of women with unexplained infertility of long duration conceived after up to four cycles of controlled ovarian hyperstimulation. Information allowing calculation of cycle fecundity in this study is lacking. Serhal et al. 33 also treated women with unexplained infertility with controlled ovarian hyperstimulation using hMG, reporting a cycle fecundity of0.06. Aboulghar et al. 35 superovulated 42 women with peritubal and periovarian Vol. 55, No.3, March 1991
adhesions, resulting in a cycle fecundity of 0.21. Unfortunately, in the latter study, there was an ectopic PR of 18% and severe ovarian hyperstimulation occurred in 23%. It is not clear why superovulation did not improve cycle fecundity in women with subfertility in two of the three studies cited above. Perhaps the probability of pregnancy is not oocyte density dependent. Perhaps there are deleterious effects of ovarian stimulation. Evans and Armstron~6 showed that ewes, superovulated with follicle-stimulating hormone (FSH) or pregnant mare serum gonadotropin, had a lower density of motile sperm reaching the upper reproductive tract after intravaginal insemination, compared with inseminations during unstimulated estrus cycles. Of particular interest is that sperm density was restored to normal with lUI in this animal model. Human data supporting this phenomenon were presented by Cruz et al., 37 who found that lUI in superovulated women with oligoasthenospermic husbands was more successful than intracervical inseminations. In this prospective, randomized, crossover study of 49 couples, superovulation with lUI resulted in a cycle fecundity of 0.07, compared with 0.01 in cycles with intracervical inseminations. Furthermore, Serhal et al., 33 comparing superovulation with controlled ovarian hyperstimulation and lUI in couples with unexplained infertility, found that the addition ofiUI was associated with an increase of cycle fecundity from 0.06 with superovulation alone to 0.26 with controlled ovarian hyperstimulation and lUI. CONTROLLED OVARIAN HYPERSTIMULATION WITH lUI
In an attempt to circumvent postulated subtle problems of ovulation and to enhance the accuracy of ovulation prediction, ovarian stimulation with CC in conjunction with lUI has been evaluated (Tables 1 and 2).38-41 As with lUI alone, results have been variable, with some studies reporting relatively good cycle fecundity 38 and others showing poor results. 40-43 Deaton et al., 39 in a randomized prospective trial, compared CC and lUI with well-timed intercourse in couples with unexplained infertility or surgically corrected endometriosis. They found that the cycle fecundity in couples treated with CC and lUI was 0.08, compared with 0.03 for couples with well-timed intercourse; how~ ever, in this preliminary report, the difference was not statistically significant.
Dodson and Haney Controlled ovarian hyperstimulation and lUI
459
Controlled ovarian hyperstimulation similar to that used for IVF and G1FT cycles has been used with lUI to treat subfertility. The purpose of this technique is identical to the empiric use ofiVF and GIFT to treat subfertility, that is, to increase the number of male and female gametes at the site of fertilization. The experience reported by Serhal et al. 33 indicates that the combined use of controlled ovarian hyperstimulation and lUI may show a potentiation of effects. In this study, the cycle fecundity achieved with the combination of controlled ovarian hyperstimulation and lUI was greater than the sum of the cycle fecundity for lUI or controlled ovarian hyperstimulation alone. Kemmann et al. 43 showed that couples with male factor or cervical factor infertility had a cycle fecundity of 0.14 for controlled ovarian hyperstimulation (using hMG) and lUI, compared with a cycle fecundity of 0.02 for lUI alone. Corson et al. 22 retrospectively reviewed the course of 302 couples receiving 991 cycles of lUI. They determined that the use of controlled ovarian hyperstimulation and lUI improved the cycle fecundity for women with infertility associated with minimal and mild endometriosis and for women with tubal abnormalities, compared with treatment with lUI alone. Our experience, accumulated since 1985, initially reported in 198744 and expanded here, is presented for the purpose of illustrating the technique of controlled ovarian hyperstimulation and lUI. Because there is no untreated control group, our data do not prove efficacy. Couples with infertility were evaluated with at least one semenalysis, a hysterosalpingogram, or hysteroscopy to detect uterine anomalies, a laparoscopy for detection of potential peritoneal factors of infertility, and a midluteal serum progesterone assay and/or endometrial biopsy. Couples with infertility of at least 1-year duration, who were ovulatory with a regular menstrual interval of
Vol. 55, No.3, March 1991
Copyright 1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility
William C. Dodson, M.D. A. F. Haney, M.D. The Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania, and Duke University Medical Center, Durham, North Carolina
The effectiveness of treatment of disorders of sterility is easily assessed by the pregnancy rates (PRs) that result from that therapy. Cycle fecundity after in vitro fertilization and embryo transfer (IVF-ET) in women who have had their oviducts surgically removed indicates the degree of success, or efficacy, ofiVF for that condition. Similarly, cycle fecundity after artificial insemination with donor semen in wives of azoospermic men reflects the suitability of that treatment. The underlying assumption in the analysis of efficacy for any treatment of sterility is that the likelihood of pregnancy without treatment is negligible. Most couples seeking infertility care do not have problems rendering them completely unable to conceive. Rather, the couples have conditions associated with a relative decrease in the monthly likelihood of conception (or, subfertility) in which pregnancy can occur without treatment. 1 Examples of subfertile conditions include endometriosis, oligoasthenospermia, idiopathic infertility, minimal adnexal adhesions, luteal phase defect, and cervical factor infertility. In contrast to the treatment of sterility, one cannot assume that pregnancies occurring after treatment of subfertility are due to the treatment or would not have occurred without treatment. 2 To evaluate the efficacy of treatment of subfertility, it is necessary to perform controlled, randomized trials comparing PRs of treated and untreated subjects. Unfortunately, few such trials exist. In this review, we will evaluate the results of controlled ovarian hyperstimulation with intrauterine insemination (lUI) in the management of subfertility. It is important to remember that the evaluaVol. 55, No.3, March 1991
tion of the efficacy of this technique is limited because most of the reports are uncontrolled studies, describing heterogeneous groups of patients with dissimilar diagnostic entities, duration of infertility, prior therapy, age, and experience of the physician. Unfortunately, this problem is not unique to this infertility therapy and is frequently a fault of reports of other treatments of subfertility, such as IVF, gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), and medical management of endometriosis and oligoasthenospermia.
INTRAUTERINE INSEMINATION
Intrauterine insemination, alone or in combination with ovarian stimulation, has been used for treatment of infertility for many years, 3•4 but its use remains controversial. 5 Initially, this treatment was abandoned because of the occasionally intense reaction of the uterus to insemination of raw semen and the risk of pelvic infection. 4 The use of split ejaculates,&-8 small amounts of semen,9 •10 or dilution and freezing of semen with egg yolk buffer11 reduced the incidence of adverse reactions; however, it was only with the advent of sperm separation techniques 12 that relatively painless lUI was feasible. 13 The rationale for lUI as treatment of subfertility focuses on the filtration effect of cervical mucus. Studies of normal women by Settlage et al./ 4 indicate that only approximately 0.1% of sperm placed in the upper vagina are present in the cervical canal in the 1st hour after insemination. In this study, it was estimated that within 1 hour of vaginal insemi-
Dodson and Haney
Controlled ovarian hyperstimulation and lUI
457
nation at midcycle, 1 of every 14 million motile sperm deposited in the vagina reached the oviduct. Furthermore, the number of sperm in the oviduct was proportional to the number of motile sperm inseminated. Similarly, Mortimer and Templeton 15 showed that there is a reduction in sperm number of five to six orders of magnitude along the length of the female reproductive tract. If infertility is associated with low numbers of motile sperm per ejaculate, poor quality cervical mucus, or toxic substances in the peritoneal environment, and if the probability of fertilization is density-dependent, then increasing the number of sperm reaching the uterine cavity may improve the likelihood of pregnancy. Weathersbee et al. 16 showed that lUI increases the proportion of women with intraperitoneal sperm isolated at laparoscopy within 2 hours after insemination. Using lUI may increase the number of sperm reaching the distal oviduct/ 7 assuming that the sperm separation procedure recovers a high proportion of motile sperm from the ejaculate. Unfortunately, bypassing the cervical mucus, which acts as a reservoir for sperm at midcycle, requires timing coincident with ovulation for insemination. The precision of timing required for this technique is unknown. Many different methods have been used to determine the time for insemination. Basal body temperature (BBT), urinary luteinizing hormone (LH) concentration measurements, and ultrasound (US) monitoring have all been used in an attempt to time inseminations coincident with ovulation. Alternatively, multiple inseminations per cycle have been used to circumvent imprecise timing. There is no consensus for what should be used to schedule lUI in spontaneous or stimulated cycles. This lack of agreement may be reflected in the variation of reported results. The treatment of male factor infertility with lUI has been frequently studied; however, results reported for lUI during spontaneous cycles have not been consistent (Table 1). In one of the few trials of lUI having a control treatment group, Kerin et al. 18 showed a high degree of success achieved with lUI in oligospermic couples when timed with LH surges, compared with intercourse scheduled by BBT charts or LH surges. However, a controlled, prospective, crossover study by te Velde et al., 19 comparing lUI with intercourse showed no advantage of lUI. Another randomized, prospective trial comparing lUI with intercourse showed very poor results in both treatment arms. 20 With one excep458
Table 1 Literature Summary of lUI for Male Factor Infertility
Unstimulated cycles Byrd et al. 21 Contino et al. 13 Dmowski et al. 27 Glass et al. 51 Harris et al. 28 Hughes et al. 25 Hull et al. 23 KerinetaU 8 Marrs et al. 12 te Velde et al. 19 Thomas et al. 26 CCcycles Blumenfeld et al. 38 Bolton et al. 40 Hewitt et al. 41 HMGcycles Blumenfeld et al. 38 Cruz et al. 37 Horvath et al. 54 Sher et al. 45 Sunde et al. 76 Current summary
Patients
Pregnancies/ cycle
Fecundity
21 27 27 19 20 20 8 34 4 30 8
9/58 0/108 4/90 0/67 3/120 0/32 0/20 8/39 0/12 3/112 0/24
0.16 0 0.04 0 0.03 0 0 0.21 0 0.03 0
13 29 36
5/43 5/158 3/64
0.12 0.03 0.05
8 48 39 4 40 39
4/32 7/96 6/175 1/4 8/56 13/85
0.13 0.07 0.03 0.25 0.14 0.15
tion, 21 others have reported similarly poor results.12·13·22-28 There is no consensus for the role of lUI in oligoasthenospermic couples.5 Measures of male fertility potential other than the semenalysis may provide prognostic information for management of infertility with lUI. Wiltbank et al. 29 evaluated the results of lUI in 35 infertile couples. In this study, sperm from 19 of the men showed poor results with the zona-free hamster egg penetration test, and sperm from 16 men showed normal results. Cycle fecundity for couples in whom the male had normal results was 0.13, and for couples with abnormal egg penetration test results, 0.02. Intrauterine insemination for treatment of cervical factor infertility is also controversial. Although some report cycle fecundity approximating 20%, 13 others show intermediate 10·21 ·30 or poor results. 23 ·31 ·32 te Velde et al., 19 using a randomized, crossover comparison of lUI with intercourse for couples with cervical factor infertility, showed a cycle fecundity of 0.16 after lUI and no pregnancies after intercourse. Again, differences in patient selection, diagnostic criteria, method of sperm separation, method of ovulation prediction, and timing of inseminations may account for differences in results.31 The efficacy of lUI for treatment of unexplained infertility has been evaluated by Serhal et al. 33
Dodson and Haney Controlled ovarian hyperstimulation and lUI
Fertility and Sterility
Table2
Literature Survey of lUI for Idiopathic Infertility Patients
Pregnancies/ cycle
Fecundity
14 14 15
6/48 1/42 1/30
0.13 0.02 0.03
5 9
4/10 1/12
0.40 0.08
3 15 5 11 57
2/7 6/19 2/5 1/15 17/116
0.29 0.32 0.40
Unstimulated cycles Byrdetal.21 Quagliarello et al. 30 Serhal et al. 33 CCcycles Blumenfeld et al. 38 Hewitt et al. 41 HMGcycles Blumenfeld et al. 38 Serhal et al.33 Sher et al.45 Sunde et al. 76 Current summary
O.o7 0.15
(Table 2). Poor cycle fecundity has resulted from this treatment. 30•32 In: contrast, Yovich and Matson24 showed a cycle fecundity of 0.08 in their series of 183 cycles of lUI for treatment of unexplained infertility, and in a series of 14 couples, Byrd et al. 21 reported a cycle fecundity of 0.13. OVARIAN STIMULATION
Ovarian stimulation has been used for specific as well as empiric therapy for subfertility. Correction of subtle, unpredictable ovulatory dysfunction has been the rationale for the use of agents such as clomiphene citrate (CC), human menopausal gonadotropins (hMG), or both in combination. Furthermore, with the use of hMG alone, there is the opportunity for superovulation, providing enhanced opportunity for oocyte capture, fertilization, and implantation, without the adverse effects of CC on estrogen sensitive tissues. Theoretically, subfertility disorders in which the normal interaction of the oviduct and ovary is altered or in which a postulated unfavorable peritoneal environment is present, would benefit from an increased number of oocytes produced each month. Few studies have reported the results of empiric treatment of subfertility with controlled ovarian hyperstimulation. W elner et al. 34 showed that approximately 11% of women with unexplained infertility of long duration conceived after up to four cycles of controlled ovarian hyperstimulation. Information allowing calculation of cycle fecundity in this study is lacking. Serhal et al. 33 also treated women with unexplained infertility with controlled ovarian hyperstimulation using hMG, reporting a cycle fecundity of0.06. Aboulghar et al. 35 superovulated 42 women with peritubal and periovarian Vol. 55, No.3, March 1991
adhesions, resulting in a cycle fecundity of 0.21. Unfortunately, in the latter study, there was an ectopic PR of 18% and severe ovarian hyperstimulation occurred in 23%. It is not clear why superovulation did not improve cycle fecundity in women with subfertility in two of the three studies cited above. Perhaps the probability of pregnancy is not oocyte density dependent. Perhaps there are deleterious effects of ovarian stimulation. Evans and Armstron~6 showed that ewes, superovulated with follicle-stimulating hormone (FSH) or pregnant mare serum gonadotropin, had a lower density of motile sperm reaching the upper reproductive tract after intravaginal insemination, compared with inseminations during unstimulated estrus cycles. Of particular interest is that sperm density was restored to normal with lUI in this animal model. Human data supporting this phenomenon were presented by Cruz et al., 37 who found that lUI in superovulated women with oligoasthenospermic husbands was more successful than intracervical inseminations. In this prospective, randomized, crossover study of 49 couples, superovulation with lUI resulted in a cycle fecundity of 0.07, compared with 0.01 in cycles with intracervical inseminations. Furthermore, Serhal et al., 33 comparing superovulation with controlled ovarian hyperstimulation and lUI in couples with unexplained infertility, found that the addition ofiUI was associated with an increase of cycle fecundity from 0.06 with superovulation alone to 0.26 with controlled ovarian hyperstimulation and lUI. CONTROLLED OVARIAN HYPERSTIMULATION WITH lUI
In an attempt to circumvent postulated subtle problems of ovulation and to enhance the accuracy of ovulation prediction, ovarian stimulation with CC in conjunction with lUI has been evaluated (Tables 1 and 2).38-41 As with lUI alone, results have been variable, with some studies reporting relatively good cycle fecundity 38 and others showing poor results. 40-43 Deaton et al., 39 in a randomized prospective trial, compared CC and lUI with well-timed intercourse in couples with unexplained infertility or surgically corrected endometriosis. They found that the cycle fecundity in couples treated with CC and lUI was 0.08, compared with 0.03 for couples with well-timed intercourse; how~ ever, in this preliminary report, the difference was not statistically significant.
Dodson and Haney Controlled ovarian hyperstimulation and lUI
459
Controlled ovarian hyperstimulation similar to that used for IVF and G1FT cycles has been used with lUI to treat subfertility. The purpose of this technique is identical to the empiric use ofiVF and GIFT to treat subfertility, that is, to increase the number of male and female gametes at the site of fertilization. The experience reported by Serhal et al. 33 indicates that the combined use of controlled ovarian hyperstimulation and lUI may show a potentiation of effects. In this study, the cycle fecundity achieved with the combination of controlled ovarian hyperstimulation and lUI was greater than the sum of the cycle fecundity for lUI or controlled ovarian hyperstimulation alone. Kemmann et al. 43 showed that couples with male factor or cervical factor infertility had a cycle fecundity of 0.14 for controlled ovarian hyperstimulation (using hMG) and lUI, compared with a cycle fecundity of 0.02 for lUI alone. Corson et al. 22 retrospectively reviewed the course of 302 couples receiving 991 cycles of lUI. They determined that the use of controlled ovarian hyperstimulation and lUI improved the cycle fecundity for women with infertility associated with minimal and mild endometriosis and for women with tubal abnormalities, compared with treatment with lUI alone. Our experience, accumulated since 1985, initially reported in 198744 and expanded here, is presented for the purpose of illustrating the technique of controlled ovarian hyperstimulation and lUI. Because there is no untreated control group, our data do not prove efficacy. Couples with infertility were evaluated with at least one semenalysis, a hysterosalpingogram, or hysteroscopy to detect uterine anomalies, a laparoscopy for detection of potential peritoneal factors of infertility, and a midluteal serum progesterone assay and/or endometrial biopsy. Couples with infertility of at least 1-year duration, who were ovulatory with a regular menstrual interval of
