Possibilities and limitations of techniques of assisted reproduction for the treatment of male infertility

Since relatively few spermatozoa are needed for oocyte fertilization during gamete intra-Fallopian transfer (GIFT) or in-vitro fertilization (IVF), these methods have been applied in couples with infertility due to male causes. Forty-six couples with male factor infertility were enrolled in this study and results were compared with those attained in 48 couples treated with the same techniques for other than male causes. Overall, GIFT resulted in 26% ongoing pregnancies. GIFT seems to be particularly successful when the sperm concentration is 20 x 10(6)/ml or more, but sperm motility and/or morphology are poor. Nine pregnancies occurred out of 26 GIFT cycles in 18 cases selected on this basis. The ongoing pregnancy rate after IVF was 16% per patient. The latter treatment should be attempted in male immune infertility and in cases with a low sperm concentration, with or without abnormal sperm motility and/or morphology. In these circumstances, five pregnancies were attained out of 28 cycles in 14 cases. For similar sperm concentrations, the conception rate per cycle attained with techniques of assisted reproduction was more than twice that attained with conventional treatment of male infertility.     

Pure human follicle stimulating hormone has a role in the treatment of severe male infertility by assisted reproduction: Norfolk's total experience.

Fifty patients [79 in-vitro fertilization (IVF) cycles] with severe male factor infertility were included in an experimental clinical trial running from October 1987 to March 1991 to assess the potential of systemic follicle stimulating hormone (FSH) treatment to improve sperm fertilizing ability in IVF. Two groups were defined: a secondary group (24 patients, 33 IVF cycles) with a history of failed fertilization in previous IVF attempts and a primary group (26 patients, 46 IVF cycles) with poor sperm parameters which suggested that fertilization would not occur according to previously established criteria. Basic semen analysis and a battery of endocrine radioimmunoassays [serum FSH, luteinizing hormone (LH), oestradiol, prolactin and testosterone] were performed in these patients. Bioactive-FSH and LH were also determined in some patients. For this study, pure FSH was administered (150 IU i.m. three times per week) for at least 3 months, after which the semen analysis and endocrine tests were repeated. Although no significant changes were observed after FSH therapy, either in the endocrine profile or in the basic semen parameters, except for FSH radioimmunoassay levels, the fertilization rate of pre-ovulatory oocytes was significantly improved from 2 to 54.4% in the secondary group; the primary group showed a 52.3% fertilization rate. Eighteen clinical pregnancies were achieved, 11 in the primary group and seven in the secondary group, giving 30 and 26% term pregnancy rates per transfer respectively. These results, which are in complete agreement with our preliminary study, re-emphasized the benefits of systemic FSH administration as an adjunct to assisted reproduction in selected cases of severe male factor infertility.(ABSTRACT TRUNCATED AT 250 WORDS)     

Infertility, infertility treatment and twinning: the Danish National Birth Cohort

BACKGROUND: We have previously observed that an increasing time to pregnancy (TTP) is associated with a reduced frequency of twin deliveries in couples not receiving infertility treatment. By using updated information, we assessed the frequencies of dizygotic (DZ) and monozygotic (MZ) twin deliveries as a function of infertility (TTP > 12 months), as well as infertility treatment. METHODS: From the Danish National Birth Cohort (1997-2003), we identified 51 730 fertile couples with TTP 12 months and 5163 infertile couples who conceived after treatment. Information on zygosity, available for part of the cohort (1997-2000), was based on standardized questions on the similarities between the twins at the age of 3-5 years. RESULTS: Compared with fertile couples, the frequency of DZ twin deliveries was lower for infertile couples conceiving naturally (odds ratio 0.4, 95% confidence interval 0.2-0.7) and was much higher for infertile couples conceiving after treatment (17.3, 14.4-20.7). The frequency of DZ twin deliveries decreased with TTP in untreated couples, whereas the frequency of MZ twin deliveries remained constant. CONCLUSIONS: The frequency of DZ twin deliveries decreased with TTP and substantially increased with infertility treatment, whereas MZ twin deliveries remained substantially unchanged.     

Cancer incidence following treatment for infertility at a clinic in the UK

BACKGROUND: There is concern about the long-term health impact of ovarian stimulation treatment for infertility, in particular the effect on cancer risk. The aim of this study was to investigate the incidence of cancer in a cohort of women attending a large infertility clinic in the UK. METHODS: Women who were UK residents attending the clinic between January 1, 1975 and December 31, 1989 were identified for the study. The cohort was followed-up and cancer incidence rates calculated. RESULTS: The study cohort was made up of 5556 women of whom 75% had received ovarian stimulation drug treatment at the clinic. A total of 118 cancers (including 55 breast, four corpus uteri and six ovarian) were incident in the cohort from the beginning of 1990 to the end of 1997. The incidence rates of cancer of the breast, corpus uteri and ovary were not significantly different from expectation based on national cancer rates, and were similar for women who had received hormonal treatment to stimulate their ovaries and those who had not. CONCLUSIONS: These data do not support a hypothesis linking infertility treatment involving ovarian stimulation with increased breast, uterine and ovarian cancer over the follow-up period studied.     

The experiences of couples who have had infertility treatment in the United Kingdom: results of a survey performed in 1997

A questionnaire was sent to 2000 members of two of the largest national infertility support organizations as part of the National Infertility Awareness Campaign (NIAC), 1997. A total of 980 questionnaires was completed and returned to the market research company, Ballington Hall. Some 69% of the respondents were aged between 30 and 39 years. One-third of the couples had been trying for a baby for more than 3 years, including one-tenth who had been trying to conceive for more than 10 years. Some 40% of respondents were successful in conceiving, although a significant proportion of these took more than 6 years. About 75% of those surveyed had been forced to pay for some or all of their infertility treatments and investigations, whereas 18% had their treatments funded fully by the National Health Service (NHS). Funding sources for the remaining 7% were unknown. Just over one-third of respondents felt that their GP provided sufficient information about the causes of infertility investigations and treatment, while the majority said that their specialists had been helpful. One in three said that they did not fully understand the medical nature of their own or their partner's infertility. A wide range of negative emotions was experienced by respondents. One in five said they experienced suicidal feelings; one in three said that infertility had strained their relationship; and just over one-quarter found that their relationship improved as a result of the treatment. Some 71% said that they would request counselling if it were offered free, but only 12% had been provided with free counselling on the NHS.     

Pregnancy outcome after IVF and ICSI in unexplained, endometriosis-associated and tubal factor infertility

BACKGROUND: This study was undertaken in order to compare pregnancy outcome after IVF and ICSI in unexplained and endometriosis-associated infertility using tubal factor infertility as controls. METHODS: This was a retrospective cohort study of early IVF/ICSI pregnancies verified by serum hCG measurement, comparing the subsequent outcome in unexplained (n = 274) and minimal endometriosis-associated (n = 212) with tubal factor (n = 540) infertility as controls. From January 1990 to December 2002, 1026 conception cycles after treatment with IVF or ICSI complied with the inclusion criteria. RESULTS: Live birth rate, twin birth rate after transfer of two embryos and abortion rate prior to 6 weeks of gestation were superior for the unexplained (78.8, 23.5 and 11.7%) compared to endometriosis-associated (66.0, 15.0 and 19.3%) and tubal factor (66.7, 18.1 and 18.0%) infertility groups (P < 0.05). Compared to the endometriosis-associated, the unexplained infertility group attained a higher pregnancy rate after the first treatment cycle (P < 0.05). CONCLUSIONS: The overall better outcome for the unexplained infertility group with respect to live birth rate, twin birth rate and early abortion rate compared to the minimal peritoneal endometriosis-associated and tubal factor infertility groups might be a guide to select diagnostic groups for single embryo transfer and be useful in patient counselling.     

Definition and prevalence of subfertility and infertility

A common definition of sub- and infertility is very important for the appropriate management of infertility. Subfertility generally describes any form of reduced fertility with prolonged time of unwanted non-conception. Infertility may be used synonymously with sterility with only sporadically occurring spontaneous pregnancies. The major factor affecting the individual spontaneous pregnancy prospect is the time of unwanted non-conception which determines the grading of subfertility. Most of the pregnancies occur in the first six cycles with intercourse in the fertile phase (80%). After that, serious subfertility must be assumed in every second couple (10%) although--after 12 unsuccessful cycles--untreated live birth rates among them will reach nearly 55% in the next 36 months. Thereafter (48 months), approximately 5% of the couples are definitive infertile with a nearly zero chance of becoming spontaneously pregnant in the future. With age, cumulative probabilities of conception decline because heterogeneity in fecundity increases due to a higher proportion of infertile couples. In truly fertile couples cumulative probabilities of conception are probably age independent. Under appropriate circumstances a basic infertility work-up after six unsuccessful cycles with fertility-focused intercourse will identify couples with significant infertility problems to avoid both infertility under- and over-treatment, regardless of age: Couples with a reasonably good prognosis (e.g. unexplained infertility) may be encouraged to wait because even with treatment they do not have a better chance of conceiving. The others may benefit from an early resort to assisted reproduction treatment.     

The impact of treatment experiences on the course of infertility distress in male patients

BACKGROUND: Previous research on infertile males has delivered equivocal findings on the course of infertility distress in males. The present longitudinal study examines whether there are differentials associated with specific treatment experiences (i.e. duration of treatment, the diagnosis received, and treatment failure of assisted reproductive technologies). METHODS: The sample consisted of 118 patients who twice visited an andrology clinic on their own initiative for fertility work-ups. Baseline and follow-up examinations were > or = 6 months apart. Prior to each fertility work-up, patients completed a questionnaire assessing distress due to infertility. RESULTS: No uniform course of distress could be detected. A significant interaction between treatment experiences indicated that distress rises significantly only in those patients who were in treatment > or = 17 months and experienced treatment failure between the first and the second psychological evaluation. For the diagnosis of male infertility, however, neither a direct nor an indirect impact was identified. CONCLUSION: The present study indicates that the interaction of specific treatment experiences is associated with changes in distress of infertile males.     

The 2004 Italian legislation regulating assisted reproduction technology: a multicentre survey on the results of IVF cycles

BACKGROUND: The new Italian law, passed in 2004, regulating assisted reproduction technology imposes that no more than three oocytes can be fertilized at one time and that all embryos obtained must be transferred simultaneously. Oocyte cryopreservation is allowed while embryo cryostorage is banned. The aim of this study was to evaluate the clinical impact of these limitations. METHODS: Seven Italian infertility centres were invited to collect data on IVF cycles performed over the first 4 months of application of the new legislation. As a control, all centres provided data on cycles performed in the same solar period, 1 year before. RESULTS: Data from 1861 cycles were obtained, 961 in the pre-law period and 900 in the post-law period. Pregnancy rate per oocyte retrieval and rate of multiple pregnancies in the pre- and post-law periods were 27.0 and 24.2% (P=0.18) and 25.8 and 20.9% (P=0.11) respectively. However, the prohibition to freeze embryos does appear to have markedly reduced the cumulative rate of success. CONCLUSIONS: The rate of success of IVF-ICSI cycles using fresh embryos is not significantly influenced by the new legislation while the prohibition to freeze embryos seems to result in a more relevant impact.     

Immunological testing and treatment in reproduction: frequency assessment of practice patterns at assisted reproduction clinics in the USA and Australia

BACKGROUND: The roles that alloimmunity and autoimmunity may play in reproductive failure, including recurrent pregnancy loss and failed IVF, have not been clearly established. To help define practice patterns, we investigated what tests clinicians in the USA and Australia were offering, to which patients (diagnostic groups) the tests were recommended, and in what situations immunological/anticoagulation treatment was advised. METHODS: A five section survey was completed by senior physicians attending the annual national fertility society meetings in the USA and Australia. Results were tabulated and analysed. RESULTS: Antiphospholipid antibody testing was offered to patients with recurrent pregnancy loss by almost all physicians surveyed. Patients with previous failure of IVF were tested much less often. Other immune tests (embryotoxic assay, natural killer cells and leukocyte antibodies) were ordered by none of the Australian participants and approximately 25% of the American participants. The use of immunotherapy and anticoagulation therapy for patients who tested positive for various immunological tests was also evaluated for frequency of use and reported secondary complications. CONCLUSIONS: Large, well-structured studies examining the benefits of immunological evaluation and treatment are necessary before definite recommendations can be made.     

The OVEIA assay, a simultaneous measurement of oestrone and pregnanediol glucuronides, for studying the treatment of infertility patients

A new simple assay developed for establishing the limits ofthe fertile period was evaluated in infertility patients. Thisassay is a colorimetric method for measuring the oestrone glucuronide/pregnanediolglucuronide ratio. Steroid levels were assayed simultaneouslyand an index of their ratio was obtained in this dual analyteassay (DAA). Twenty subfertile women, receiving domiphene citratefor ovulation induction, were monitored for the DAA index usingearly morning urine samples. Ten of these women were also monitoredin a pre-treatment cycle. A further 10 patients on an in-vitrofertilization (IVF) programme were assessed with the same assay.DAA ratios were found to correlate with foUkular phase serumoestradiol levels. Peak DAA ratios dropped dramatically whensignificant rises in urinary luteinizing hormone concentrationsoccurred prior to ovulation. An association between high DAAratios and adequate luteal phase activity was also established.In addition, the total volume of the three largest ovarian follicles,as measured by ultrasound, in IVF patients was found to correlatewith DAA measurements.     

Pregnancy: Cumulative pregnancy rates and pregnancy outcome after in-vitro fertilization: >5000 cycles at one centre

Cumulative pregnancy rates and pregnancy outcome analysis areuseful methods for advising an infertile couple of the probabilityof in-vitro fertilization (IVF) success. All 5209 IVF cyclesin 2391 couples at University Hospital, London, Ontario, Canada,over 10 years were studied. Cumulative pregnancy rates wereestimated using life table analysis. The Cox proportional hazardsmodel was used to estimate the influence of covariates. Oocyteretrieval and embryo transfer were achieved in 84 and 64% ofcycles initiated respectively. There were 644 intra-uterineand 24 ectopic pregnancies (13%/cycle initiated, 15%/oocyteretrieval and 20%/embryo transfer). Cumulative pregnancy ratesfollowing six cycles were: tubal 55%, idiopathic 65%, endometriosis60%, multifactorial 63% and male 40%. There were 68 spontaneousabortions (10.6%) and three induced abortions for congenitalanomalies. The multiple gestation rate was 22%. Caesarean sectionand preterm delivery rates were 35 and 20% respectively, duein part to the high proportion of multiple gestations. Of 15deliveries which resulted in stillbirths and/or neonatal deaths,12 were multiple gestations; 18 pregnancies (3.3%) were complicatedby congenital malformations. No increases in congenital malformationsor spontaneous abortions were identified. Cumulative pregnancyrates were lower in cases of male infertility. Success ratesdid not decline with successive IVF cycles. IVF is an evolvinginfertility treatment.     

Comparison of in-vitro fertilization in male and tubal infertility: a 3 year survey.

The in-vitro fertilization and embryo transfer (IVF-ET) procedure was compared in 175 couples with male infertility and 480 couples with tubal infertility. In cases of male infertility, more oocytes were recovered but fewer oocytes were fertilized. Although the cleavage rate was decreased, no difference in embryo quality was found. In male infertility, fewer transfers were performed and the average number of embryos per transfer was lower. The total pregnancy rate was also lower per cycle (12.8 versus 22.9%), but not per transfer (25.4 versus 25.7%). The further obstetrical outcome was similar in both groups. We conclude that male infertility can be treated by IVF-ET but results are still disappointing when compared to a control group with normal spermatozoa.     

Development of embryos from natural cycle in-vitro fertilization: impact of medium type and female infertility factors

Single embryos derived from natural cycle in-vitro fertilization(IVF) were graded during the pre-transfer culture period usingmorphological criteria. Most embryos developed well in culturewith 96% showing continuing division and 68% showing good morphologicalappearance, although embryo quality tended to decline with anincreased incidence of fragmentation and uneven cleavage asdivision proceeded. Both the pregnancy rate and the distributionof embryo grades were similar among four different culture mediaused, suggesting that choice of medium had little impact onoutcome. In contrast, there were marked differences in pregnancyrate according to the type of infertility, which was not reflectedin a decrease in embryo quality. However, although embryos frompatients with tubal infertility implanted and formed viablepregnancies irrespective of morphological appearance, only ‘good’quality embryos from patients with non-tubal (or ‘unexplained’)infertility were able to implant. Thus the appearance of theembryo derived from natural cycle IVF in women with unexplainedinfertility may be of clinical relevance.     

Sperm treatment with extracellular ATP increases fertilization rates in in-vitro fertilization for male factor infertility

Previous work from our laboratory has revealed that extracellular ATP is a rapid and potent activator of human sperm acrosome reaction and fertilizing ability. In the present study, we assessed the effects of in-vitro sperm incubation with ATP on fertilization and embryo development in couples undergoing in-vitro fertilization (IVF) for male factor infertility. Oocytes from 22 women undergoing ovulation induction were divided in two groups and inseminated in vitro either with selected spermatozoa from the corresponding partner suffering from male factor infertility pre-incubated with ATP (2.5 mM) for 1 h, or with spermatozoa incubated with 0.9% NaCl solution (control group). After insemination, fertilization was assessed by the presence of pronuclei and then by embryo cleavage. The fertilization rate in the group of oocytes inseminated with ATP-treated spermatozoa improved significantly with respect to the control group (65.7 versus 42.5%, P < 0.01). No significant differences were observed in embryo cleavage and embryo quality. Embryos from both treated and control groups were transferred together in 20 transfer procedures, and in two couples fertilization was not obtained. Nine pregnancies occurred: one biochemical, one miscarriage, and seven patients delivered 9 healthy babies. Two pregnancies were twin with an overall pregnancy rate of 40.9% per cycle and of 45% per transfer. In conclusion, the results of the present study demonstrate that, in humans, extracellular ATP induces a significant increase of sperm fertilizing potential, as these findings are a rationale for the use of ATP for in-vitro treatment of human spermatozoa during IVF.     

Human sperm--egg interactions and their disorders: implications in the management of infertility

The present era of infertility management is characterized byan increasing interest in defects of sperm-egg interactions.When the spermatozoon meets the egg, it must first react withthe enveloping coat which controls sperm access to the cellsurface of the oocyte. Adequate sperm motility is a major conditionfor penetration through the egg investments. The ability ofspermatozoa to respond to physiological stimuli by a timelyacrosome reaction is another necessary prerequisite for thisevent, as well as for sperm fusion with the oocyte. The clinicalsignificance of current laboratory tests evaluating differentaspects of gamete function is discussed and a practical guideis given for their indication and interpretation and for theuse of their results in choosing rational therapy.     

Public perception on infertility and its treatment: an international survey. The Bertarelli Foundation Scientific Board

The first large survey on the public perception of infertility and its treatment was conducted in six European countries, the USA and Australia. A representative sample of 8194 adults was polled, using standard validated methodology. The results obtained highlighted the following major aspects: (i) infertility is perceived as a disease by less than half of the people surveyed (38%), in contrast to the accepted medical opinion; (ii) awareness about the definition and incidence of infertility is relatively low, despite the fact that half of the people polled claimed to know someone affected by infertility; (iii) close to 90% of the adults surveyed knew about in-vitro fertilization (IVF), but less than one-quarter of them knew about the chances of success of this assisted reproductive technology; and (iv) when confronted with the knowledge that the cost of three IVF cycles is roughly equivalent to the cost of a hip replacement (a commonly reimbursed procedure), a large majority (70%) of the individuals interviewed agreed that IVF should be reimbursable.     

Results of IVF from a prospective multicentre study.

Part of a cost-effectiveness study of in-vitro fertilization was the evaluation of the medical results of this fertility treatment. Data were prospectively collected from greater than 3000 IVF treatments in five Dutch hospitals during a 2-year period. The average 'take-at-least-one-healthy-baby-home-rate' per started treatment was 10% (the average clinical pregnancy rate per embryo transfer was 20%). After more IVF treatments, about one in three to four couples were successful. Differences in results were mainly caused by patient characteristics, the treatment episode and the treating hospital. These differences remained in a multivariate logistic regression analysis.     

The desire for multiple pregnancy in male and female infertility patients

BACKGROUND: It is apparent that many fertility patients consider multiple birth an ideal treatment outcome. We wished to evaluate the desire for multiple birth among patients, and the effect of patient demographics and recognition of the increased fetal risks of multiple pregnancy on this desire. METHODS: This was a prospective questionnaire study completed by 801 male and female infertility patients attending a tertiary level Canadian university fertility clinic. Two logistic regression analyses were performed with desire for multiple birth with next fertility treatment and recognition of the increased fetal risks of multiple pregnancy as the dependent variables. RESULTS: 41% of patients desired a multiple birth. Increasing duration of infertility or previous assisted reproductive treatment increased, and having previous children or recognition of the increased fetal risks decreased, this desire. Patient age or sex did not affect desire for multiple birth. Previous assisted reproductive treatment was associated with increased recognition of the fetal risks of multiple pregnancy. CONCLUSIONS: A significant proportion of fertility patients considers multiple birth an ideal treatment outcome. Recognition of the increased fetal risks of multiple pregnancy significantly reduced this desire. Patient education may play an important role in assisting physicians in the quest to reduce the contribution of assisted reproductive treatment to multiple births and their attending complications.     

The preconceptual contraception paradigm: obesity and infertility

Obesity is a major health problem across the world. Recent editorials suggest that obese patients should be denied treatment of any kind aimed to improve ovulation rates and achieve pregnancy until they have reduced their BMI. We propose that this approach is not a resolution of the problem, but indeed may amplify the maternal and perinatal complications attributed to fertility centres. Obesity independent of polycystic ovary syndrome (PCOS) is associated with anovulation, and minimal weight loss alone is an effective therapy for induction of ovulation in both obese women and obese PCOS women. Consequently, lifestyle programmes encouraging weight loss should be considered to be an ovulation induction therapy and due consideration for a potential pregnancy in an obese woman given. We propose that women with a BMI in excess of 35 kg m(2) should lose weight prior to conception-not prior to receiving infertility treatment. Therefore, clinicians undertaking the management of infertility in obese women should adopt measures to reduce their body mass prior to exposing them to the risks of pregnancy. We advocate that this approach should be aggressively managed including pharmacological strategies; intrinsic in this programme is the use of contraception and high-dose folic acid during that period of preconceptual weight reduction.