Infertility: Higher pregnancy rates with a simple method for Fallopian tube sperm perfusion, using the cervical clamp double nut bivalve speculum in the treatment of unexplained infertility: a prospective randomized study

The object of this study was to evaluate the efficacy of thenewly developed cervical clamp double nut bivalve (DNB) speculumused for Fallopian tube sperm perfusion (FSP) with 4 ml of theinseminate, in comparison with standard intrauterine insemination(IUI) using a volume of 0.5 ml of the inseminate. Couples withunexplained infertility (n = 104), undergoing 202 cycles, wereenrolled in this study. Cycles were assigned randomly to eitherIUI (group A, n = 92) or FSP + DNB speculum^® (group B, n= 110). Ovarian stimulation was achieved using three differentovarian stimulation protocols in both groups. The age and folliculardevelopment of the patients were similar in both groups. Theserum hormonal measurements and the endometrial thickness wasalso similar on the day of human chorionic gonadotrophin (HCG)administration. The mean (± SD) number of motile spermatozoainseminated was 44.83 ± 16.57 x 10⁶ in group A and 42.68± 13.44 x 10⁶ in group B. In group A (IUI), 11 clinicalpregnancies (presence of gestational sac with heart beats) occurred(11.95% per cycle). In group B (FSP + DNB speculum^®) 29clinical pregnancies occurred (26.36% per cycle). These differenceswere statistically significant (P <0.001). The results ofthis study for the treatment of unexplained infertility indicatethat this simple, well tolerated, inexpensive method of usingthe DNB speculum for FSP is more successful than standard IUI.     

Fallopian tube sperm perfusion used in a donor insemination programme.

Ninety-six couples were enrolled in a programme of Fallopian tube sperm perfusion (FSP). FSP is a method combining ovarian stimulation, ovulation induction and intra-uterine insemination with a 4 ml volume of sperm suspension. Frozen/thawed donor semen was used in all cycles. A total of 196 treatment cycles were started and of these 172 were completed. Twenty cycles were cancelled because of maturation of too many follicles, a low ovarian response, or formation of ovarian cysts. Five of the women enrolled in the programme did not have any inseminations. Forty-eight pregnancies occurred (27.9% per cycle) among 45 women (49.5%). There were five spontaneous abortions and one ectopic pregnancy. Sixteen pregnancies are on-going (greater than 12 weeks) and 26 women have delivered (including two sets of triplets and one set of twins). The pregnancy rate declined from the first attempt (34.1%) to the fourth attempt (14.3%). The pregnancy rate was significantly higher in women with three to five mature follicles compared to women with two or fewer mature follicles (P less than 0.05). Cycles in which human chorionic gonadotrophin (HCG) was administered on day 11 or later had a higher pregnancy rate than cycles where HCG was administered on day 10 (P less than 0.01). There was no difference in pregnancy rates between insemination with 8-10 x 10(6) motile spermatozoa and insemination with greater than 30 x 10(6) motile spermatozoa. FSP used in a programme of artificial insemination by donor using frozen/thawed donor semen is relatively simple to perform and gives a high pregnancy rate per cycle.     

Infertility: A simple, non-invasive method of Fallopian tube sperm perfusion

This case report describes a simple non-invasive method of Fallopiantube sperm perfusion using a paediatric Foley catheter, whichdoes not require cannulation of the Fallopian tube and can beperformed on an outpatient basis. The patient achieved an intra-uterinepregnancy with demonstrable fetal heart beats. Subsequently,use of this method in 29 treatment cycles in 14 women with unexplainedinfertility has resulted in six singleton and one twin ongoingclinical pregnancies.     

Intrauterine insemination versus Fallopian tube sperm perfusion in non-tubal subfertility: a systematic review based on a Cochrane review

BACKGROUND: The objective of this review was to compare the efficacy of Fallopian tube sperm perfusion (FSP) with intrauterine insemination (IUI) in the treatment of non-tubal subfertility. METHODS: The principles of the Cochrane Menstrual Disorders and Subfertility Group were employed. Only randomized controlled studies comparing FSP with IUI were included in this review. The main outcome measures included live birth rates and pregnancy rates per couple. RESULTS: Twenty-eight studies were found performing the comparison of interest. Overall six studies involving 474 couples were included in the meta-analysis. One study only assessed live birth rates, which resulted in no difference in outcome between FSP and IUI [odds ratio (OR) 1.17, 95% confidence interval (CI) 0.39-3.53]. The results in pregnancy rate per couple revealed no statistically significant difference between FSP and IUI (OR 1.76, 95% CI 0.77-4.05). Subgroup analysis revealed that couples suffering from unexplained subfertility clearly benefit from FSP over IUI (OR 2.88, 95% CI 1.73-4.78). Excluding studies which used the Foley catheter for tubal perfusion resulted in a significant difference favouring FSP for all indications (OR 2.42, 95% CI 1.54-3.80). CONCLUSIONS: There is firm evidence that FSP gives rise to higher pregnancy rates in couples with unexplained subfertility and should therefore be advised in these couples. For other indications FSP has not been proven more effective compared with IUI. Results showed that the Foley catheter might not be effective for FSP. Future research should focus on comparing different types of catheters.     

Comparison of different gonadotrophin preparations in intrauterine insemination cycles for the treatment of unexplained infertility: a prospective, randomized study

BACKGROUND: A comparison of the effectiveness of different gonadotrophin preparations in intrauterine insemination (IUI) cycles for patients with unexplained infertility was performed. METHODS: Two hundred and forty-one patients were prospectively randomized using computer-generated random numbers into three groups: 81 in the Follitropin alpha (Group I), 80 in the urinary FSH (uFSH) (Group II) and 80 in the hMG (Group III). The primary outcome was clinical pregnancy rate with duration of stimulation, total gonadotrophin dose, number of dominant follicles, clinical pregnancy rate, multiple pregnancy, miscarriage rate and ovarian hyperstimulation syndrome (OHSS) rate being secondary outcomes. RESULTS: Clinical pregnancy rate was significantly higher in the rFSH group (25.9% in Follitropin alpha, 13.8% in uFSH and 12.5% in HMG groups; P = 0.04). There was no significant difference in terms of duration of stimulation, but mean FSH dose consumed per cycle was significantly lower in the recombinant FSH (rFSH) group compared with others (825 IU in Follitropin alpha, 1107 IU in uFSH and 1197 IU in HMG groups; P = 0.001). The number of follicles > or =16 mm diameter was significantly higher in the rFSH group compared with the uFSH and HMG groups (2.6 in Follitropin alpha, 1.3 in uFSH and 1.4 in HMG groups; P = 0.001). CONCLUSION: rFSH may result in a better outcome in IUI cycles for unexplained infertility.     

Immunology: Formation of antisperm antibodies in women treated with Fallopian tube sperm perfusion

Fallopian tube sperm perfusion (FSP) is a combination of ovarianstimulation and intra-uterine insemination using a large volume(4 ml) of inseminate containing 10⁷–10⁸ spermatozoa. Theinseminate will flush the Fallopian tubes and some of it willend up in the pouch of Douglas. In the present study, we haveinvestigated whether the FSP method will result in the formationof serum antisperm antibodies in the female. A total of 184treatment cycles were given to 128 women. The indications fortreatment were: unexplained infertility (n = 35), various infertilitydiagnoses (n = 28) and donor insemination (n = 65). Prior totreatment, 11 (8.6%) women had a positive tray-agglutinationtest (Friberg) and/or a positive immunobead test. After completingone to four treatment cycles, another six (4.7%) women had developedserum antisperm antibodies. The antibodies induced by the treatmentwere of isotype IgM and directed against the tailtip of thespermatozoa. Two of the women, who prior to the treatment hadantisperm antibodies, showed an increase in antibody titre duringtreatment. There was no statistically significant differencein the pregnancy rate between the women with antisperm antibodiesand the women without. In our opinion, the small risk of developingantisperm antibodies is no contra-indication for treating infertilecouples with FSP.     

Homologous intra-uterine insemination has no advantage over timed natural intercourse when used in combination with ovulation induction for the treatment of unexplained infertility

The objective was to evaluate the role of homologous intra-uterineinsemination compared with timed natural intercourse, both combinedwith ovulation induction, in the management of unexplained infertility.A total of 48 couples presenting at a large teaching hospitalinfertility clinic with unexplained infertility of at least3 years duration comprised the main study group, and 36 coupleswith identical entry criteria but under the care of anotherclinician made up a parallel control group. A randomized designof treatment cycles with within-group and between-group controlswas used. Couples in the main study group were treated witheither homologous intra-uterine insemination or timed naturalintercourse in gonadotrophin-releasing hormone analogue down-regulatedcycles, in which ovulation was induced with human menopausalgonadotrophin and human chorionic gonadotrophin. Alternate cycleswere monitored to enable optimum timing of natural intercourseprovided within-group controls. Couples in the control groupunderwent timed homologous intravaginal artificial insemination.Cycle fecundity and pregnancy outcome in treated and controlgroups were monitored. Cycle fecundity of 0.11 in 85 ovulation-inducedcycles was significantly higher than 0.02 in 62 within-groupand 0.01 in 103 between-group control cycles. There was no differencein conception rates between homologous intra-uterine inseminationand timed natural intercourse cycles with ovulation induction.Of the 11 established pregnancies in the ovulation induced group,nine delivered healthy babies (five singleton, three twin, onetriplet) and two were ectopic. Results confirmed the value ofactive management for couples with long-standing unexplainedinfertility but failed to demonstrate any advantage of homologousintra-uterine insemination over ovulation induction alone.     

Physiology: Human tubal fluid: formation and composition during vascular perfusion of the Fallopian tube

A vascularly perfused preparation of the Fallopian tube hasbeen developed as a model to study the formation and compositionof human tubal fluid. An artery serving the tube was cannulatedand perfused at a rate of 0.7 ml/min for 1 h with Medium 199supplemented with bovine serum albumin, heparin and antibiotics.A cannula was also inserted into the lumen. Light and scanningelectron micrographs of control and perfused tubes showed thatthe epithelial lining was intact after perfusion. Tubal fluidwas collected in 13 out of 19 experiments. Fluid could alwaysbe collected from patients who were in the follicular phaseof their ovarian cycle. The mean rate of appearance was 48 µl/h.The glucose, lactate and pyruvate concentrations in the tubalfluid, as assessed by fluorescence microanalysis, were 0.53,8.58 and 0.17 mM respectively. There were no correlations betweenmetabolite concentration and the length of perfusion, cannulationtime, patient's age or condition. This technique provides acontrolled method with which to access and examine human tubalfluid and will allow the physiology of both healthy and diseasedtubes to be studied.     

Endocrinology: A randomized prospective study of gonadotrophin with or without gonadotrophin-releasing hormone agonist for treatment of unexplained infertility

The use of gonadotrophin-releasing hormone agonist (GnRHa) incombination with human menopausal gonadotrophin (HMG) for ovulationinduction has been advocated for the treatment, particularlyby in-vitro fertilization (IVF) of various types of infertility.The present study was designed to compare the clinical efficacyof HMG alone with a short protocol of GnRHa/HMG for treatmentof unexplained infertility. A total of 91 couples with unexplainedinfertility were randomly assigned to one of two treatments;either HMG with intra-uterine insemination (IUI) (45 patients,62 cycles) or GnRHa/HMG with IUI (46 patients, 69 cycles) treatments.Progesterone concentrations on the day of human chorionic gonadotrophin(HCG) administration were significantly higher in HMG (1.5 ±0.9 ng/ml) versus GnRHa/HMG (0.8 ± 0.6 ng/ml; P <0.05)cycles. Furthermore, GnRHa suppressed the occurrences ofpremature luteinization (GnRHa/HMG 5.8% and HMG 24.2% respectively).However, there were no significant differences in HMG dose requirements,plasma oestradiol concentrations or follicular development onthe day of HCG administration between the two groups. Nor wereany significant differences found in the pregnancy rates betweenthe two treatment protocols (GnRHa/HMG 13.0% and HMG 11.3% respectively).Our results suggest no beneficial effect of GnRHa/HMG comparedto HMG alone for the treatment of unexplained infertility, basedon pregnancy rates.     

A randomized trial between GIFT and ovarian stimulation for the treatment of unexplained infertility and failed artificial insemination by donor.

This study was designed to investigate the surplus effect of gamete intra-Fallopian transfer (GIFT) over ovarian stimulation alone, in patients with unexplained infertility. A total of 50 patients with unexplained infertility of at least 3 years duration, or unexplained failure of artificial insemination by donor (AID) for at least 12 cycles, meeting strict inclusion criteria, were randomly selected for either two GIFT cycles or two ovarian stimulation cycles. Ovarian stimulation was combined with timed intercourse, or timed cervical donor insemination. In 38 completed GIFT cycles, five clinical pregnancies (13.2% per cycle) occurred and in 44 ovarian stimulation cycles four clinical pregnancies occurred (9.1% per cycle). Five remaining GIFT cycles were converted into in-vitro fertilization leading to two pregnancies. Of the 50 patients suffering from unexplained infertility, the 23 who did not have AID gave rise to four pregnancies out of 39 cycles (10.3%); from the remaining 27 patients who underwent AID, seven pregnancies were achieved out of 48 cycles (14.6%). No statistical differences between GIFT and ovarian stimulation treatment were found. Therefore, the GIFT success rates can be explained at least in part, if not fully, by the effect of ovarian stimulation alone. Consequently, ovarian stimulation should be considered in unexplained infertility before more elaborate forms of assisted reproduction are used.     

The fine structure of the human endometrial glandular epithelium in cases of unexplained infertility: a morphometric study

In the present study attempts have been made to express in quantitativeterms the fine structure of the endometrial glandular epitheliumin well-timed biopsies from fertile women during the early lutealphase. Biopsies from women with unexplained infertility havealso been examined. Certain abnormalities of glandular maturationwere found in these women. The nuclear channel system was notpresent at day luteinizing hormone (LH) + 4 in the infertilegroup while at LH + 6 there were more cells containing thisfeature than seen in the fertile group. There also seem to beabnormalities associated with intracellular deposits of glycogen-richmaterial and mitochondrial elaboration in the infertile women.Changes in the secretory apparatus and rough endoplasmic reticulumwere observed. The evidence from the present study suggeststhat the endometria in the examined group of infertile womenis responsive to steroidal stimulation. This response however,may be delayed or inadequate.     

'Blind' transcervical transfer of gametes in the fallopian tube: a preliminary study

The aim of the study was to assess, in a small number of volunteers, the feasibility of transferring gametes by blind transcervical tubal catheterization. Forty patients underwent ovarian stimulation with a combination of a luteinizing hormone-releasing hormone analogue and exogenous gonadotrophin. Twenty-six patients were submitted to echographical oocyte retrieval and subsequent blind transcervical tubal transfer of the gametes. Successful cannulation of the tube was achieved in 18 subjects, at the first attempt and in four subjects at the second attempt; in the remaining four subjects, three or more attempts were needed. No complications were recorded during the tubal transfer. Seven clinical pregnancies (27% of all transfers) were obtained: three ended in abortion (11%), one was ectopic (4%) and three were ongoing (11%). These preliminary results encourage larger studies using this approach.     

Lipiodol fertility enhancement: two-year follow-up of a randomized trial suggests a transient benefit in endometriosis, but a sustained benefit in unexplained infertility

BACKGROUND: A New Zealand randomized trial has shown that lipiodol treatment enhances fertility with high short-term effectiveness for women with endometriosis. METHODS: An open randomized trial in a single-centre secondary- and tertiary-level infertility service assessing lipiodol flushing versus no intervention. A total of 158 women with unexplained infertility (62 women with mild endometriosis and 96 women with pure unexplained infertility) were evaluated at 24 months after trial entry. The main outcome measure was clinical pregnancy, assessed using a Cox proportional hazards regression model. RESULTS: There was a significant benefit in overall pregnancy rate following lipiodol [hazard ratio 2.0, 95% confidence interval (CI) 1.3-3.2]. Among women with endometriosis, the benefit in pregnancy rate seen in the first 6 months following lipiodol (hazard ratio 5.4, 95% CI 2.1-14.2) was not present at 6-24 months (hazard ratio 0.6, 95% CI 0.2-2.1). There was a more consistent effect of lipiodol on fertility throughout the 24-month follow-up among women with unexplained infertility (hazard ratio 2.0, 95% CI 1.1-3.5). CONCLUSIONS: Lipiodol flushing is effective at enhancing fertility not only for women with endometriosis, but also for those with pure unexplained infertility.     

Studies on direct intraperitoneal insemination in the management of male factor, cervical factor, unexplained and immunological infertility.

One-hundred-and-twenty couples with male factor, cervical factor, unexplained or immunological infertility underwent direct intraperitoneal insemination (DIPI) of capacitated spermatozoa, combined with ovarian stimulation for a total of 254 cycles. Pregnancy occurred in 47 cycles, resulting in an overall pregnancy rate of 40.5% per patient (two pregnancies occurred in two patients) and a cycle fecundity of 18.5%. Of the patients, 23 have delivered live infants (one twins, 22 singletons), 15 (32%) miscarried and 9 have ongoing pregnancies. The cycle fecundity rates increased with increasing sperm concentration and total progressive motile count, both before and after sperm preparation (r = 0.8161, r = 0.8717 and r = 0.759, r = 0.795, respectively). However, there were two pregnancies where the inseminates had a count of 0.1 x 10(6) total motile spermatozoa. DIPI as an outpatient, in-vivo conception procedure offers encouraging results and is recommended before attempting more costly and invasive assisted reproduction techniques.     

The value of intrauterine insemination with washed husband's sperm in the treatment of infertility

Twenty-nine infertile couples were treated by intrauterine insemination(IUI)of washed sperm from a sub-fertile husband (n = 16), incases of gynaecological (n = 3), combined (n = 4) or idiopathic(n = 6) infertility; 116 treatment cycles redted in 11 ongoingpregnancies. Between 0.25 and 0.45 ml of capacitation medium,containing at least 500 000 pretreated spermatozoa, were inseminated.Pretreatment of first split fractions was performed by centrifugationand swimming up of motile spermatozoa. The pregnancy per cycleindex (P/C) for IUI was 9.5% for a total of 37.9% of all couplestreated achieving pregnancy. These results suggest a substantialbenefit compared with a calculated six months' cumulative pregnancyrate of 4.2% independent of treatment, for this infertile population.The value of IUI in selected cam of infertility seems obviousbut needs further investigation.     

The FLUSH trial--flushing with lipiodol for unexplained (and endometriosis-related) subfertility by hysterosalpingography: a randomized trial

BACKGROUND: To assess the effectiveness of flushing with the oil-soluble contrast medium lipiodol in women with unexplained infertility. METHODS: An open randomized controlled trial design in a single centre secondary and tertiary level infertility service setting. A total of 158 women with unexplained infertility were stratified into two populations: 96 women without confirmed endometriosis and 62 women with endometriosis who had normal Fallopian tubes and ovaries. Randomization was computer-generated, with allocation concealment by opaque sequentially numbered envelopes. Lipiodol flushing was tested versus no intervention. The main outcome measures were clinical pregnancy (assessed at 6 months following randomization) and live birth. RESULTS: Lipiodol flushing resulted in a significant increase in pregnancy [48.0 versus 10.8%, relative risk (RR) 4.44, 95% confidence interval (CI) 1.61-12.21] and live birth (40.0 versus 10.8%, RR 3.70, 95% CI 1.30-10.50) rates versus no intervention for women with endometriosis, although there was no significant difference in pregnancy (33.3 versus 20.8%, RR 1.60, 95% CI 0.81-3.16) or live birth (27.1 versus 14.6%, RR 1.86, 95% CI 0.81-4.25) rates for women with unexplained infertility without confirmed endometriosis. CONCLUSIONS: Lipiodol flushing is an effective treatment for couples with unexplained infertility (based on meta-analysis data), but is particularly effective for women with endometriosis who have normal Fallopian tubes and ovaries.     

Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility

The aim of this prospective randomized controlled study wasto determine the possible role of ovulation induction with intrauterineinsemination (IUI) in the treatment of unexplained infertility.A total of 100 patients were randomized to receive ovulationinduction with or without IUI. All patients were treated withlong-course gonadotrophinreleasing hormone analogue (GnRHa),starting in the luteal phase, and exogenous follicle stimulatinghormone (FSH) to induce follicular growth. Ovulation was inducedusing human chorionic gonadotrophin and timed intercourse (TI)was advised 24–48 h later or IUI was effected 36—48h later. Both the cycle fecundities (21.8 and 8.5%) and thecumulative ongoing pregnancy rates after three cycles (42 and20%) were significantly higher (P < 0.03) in the IUI groupthan in the TI group respectively. This is a clear indicationthat ovulation induction with IUI is an effective treatmentmethod for unexplained infertility, but ovulation inductionwith TI has a negligible impact in this large group of patients.     

The effectiveness of IVF in unexplained infertility: a systematic Cochrane review. 2002,

BACKGROUND: IVF is an accepted treatment for unexplained infertility. The objective of this review was to determine whether, for unexplained infertility, IVF improves the probability of live birth compared with: (i) expectant management; (ii) clomiphene citrate (CC); (iii) intrauterine insemination (IUI); (iv) IUI with controlled ovarian stimulation; and (v) gamete intra-Fallopian transfer (GIFT). METHODS: This was based on a Cochrane review. Randomized controlled trials (RCTs) which compared the effectiveness of IVF with expectant management, CC, IUI with or without controlled ovarian stimulation and GIFT were included. Patients included couples with unexplained infertility. Live birth rate per woman/couple was the main outcome measure. RESULTS: Nine RCT were identified. Five RCTs were included in the final meta-analysis. There were no comparative data for CC and live birth rates for expectant management or GIFT. There was no significant difference in clinical pregnancy rates between IVF and expectant management. There was no evidence of a difference in live birth rates between IVF and IUI either without (OR 1.96, 95% CI 0.88 to 4.36) or with (OR 1.15, 95% CI 0.55 to 2.42) ovarian stimulation. Clinical pregnancy rates with IVF were significantly higher compared with GIFT (OR 2.14, 95% CI 1.08 to 4.22) as were the multiple pregnancy rates (OR 6.25, 95% CI 1.70 to 23.00). Clinical heterogeneity was present among the studies. There was no evidence of statistical heterogeneity. CONCLUSIONS: The effectiveness of IVF in unexplained infertility remains unproven. Larger trials with adequate power are warranted.