Sperm DNA damage in male infertility: etiologies,assays, and outcomes

Male factor infertility is the sole cause of infertility in approximately 20% of infertile couples, with an additional 30% to 40% secondary to both male and female factors. Current means of evaluation of male factor infertility remains routine semen analysis including seminal volume, pH, sperm concentration, motility, and morphology. However, approximately 15% of patients with male factor infertility have a normal semen analysis and a definitive diagnosis of male infertility often cannot be made as a result of routine semen analysis. Attention has focused on the role of sperm nuclear DNA integrity in male factor infertility. Here we review the structure of human sperm chromatin, the etiology and mechanisms of sperm DNA damage, current tests available to assess sperm DNA integrity, and effect of sperm DNA integrity on reproductive outcomes.     

Male infertility and microdeletions of the Y chromosome

It is estimated that about 10% of men suffer from male infertility. Male infertility is associated with a reduction in the quantity, reduced mobility or abnormal morphology of sperm. In about 50-60% of cases the etiology can be identified. When the cause is unknown, it is referred to as idiopathic infertility. A genetic cause is suspected in some of the latter cases since chromosome anomalies and familial forms of male infertility have been reported. Three different regions of the Y chromosome, termed AZFa, AZFb and AZFc are recurrently deleted in about 15% of cases of idiopathic azoospermia or severe oilgozoospermia. AZFc deletions form the majority of these deletions. The presence of a Y microdeletion does not seem to alter the fertilisation of the oocyte or the development of the embryo. However, if the child is a boy, he will inherit the deletion from his father and will most likely be infertile when he is an adult. In the absence of any other information concerning an association between Y chromosome microdeletions and other development anomalies of the child, in genetic counselling the principal risk for male offspring appears to be infertility.     

Empirical therapy of the male with clomiphene in couples with unexplained infertility

Unexplained infertility may be secondary to a cryptic male or female factor. Although most often empirical therapy of the female partner may be attempted, clomiphene has been claimed, after uncontrolled studies, to improve fertility in men with subnormal spermograms. We chose to determine if clomiphene therapy of the male would improve fertility in couples with unexplained infertility despite normal-appearing semen parameters. One hundred husbands were randomized to treatment with clomiphene citrate, 25 mg daily for 25 days with 5 days' rest each month, if their social security numbers ended in an even number or ascorbic acid, 500 mg daily, if ending in an odd number. All female infertility factors had to be meticulously corrected for at least eight cycles for inclusion in the study, along with a minimum of 1 1/2 years' duration of infertility. Within 8 months, 29 of 50 couples (58%) with clomiphene therapy of the male achieved a pregnancy, but only 8 of 50 (16%) with ascorbic acid treatment of the male. There were no appreciable changes in sperm counts, motility, or morphology after either treatment, nor were there any significant differences in semen parameters in those conceiving versus those who did not. Further, improved fertility could not be accounted for by improvement in the hamster ova penetration test. Possibly, clomiphene improves some quality of the sperm that is defective but not measurable by standard androgenologic methods, or it improves some aspect of the seminal plasma. Perhaps, though, the results might be better explained on a psychogenic basis, i.e., clomiphene is a "better" placebo than ascorbic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

常规IVF-ET中完全体外受精失败发生的相关因素的探讨

目的:探讨IVF-ET完全体外受精失败发生的相关危险因素。方法:回顾性分析行常规体外受精-胚胎移植(IVF-ET)的2 429个周期。应用单因素及多因素Logistic回归分析夫妇之间受孕史、精子正常形态率、精液量、精液浓度、精液活力、男方生育史、女方年龄、女方原发/继发不孕、是否有输卵管性因素、不孕年限、获卵数、月经第3日的FSH、T、PRL、LH、E2、hCG注射前LH、E2、P对完全受精失败发生的影响。结果:IVF完全不受精发生率为5.7%。完全受精失败组的精子正常形态率(11.1±5.8%)、a+b级百分比(47.4±10.5%)显著低于受精组(13.4±5.3%、50.1±8.6%)(P<0.05);完全受精失败组的女方原发不孕构成比(69.1%)、男方原发不孕构成比(74.8%)、无管性因素构成比(30.2%)、夫妇间无受孕史构成比(79.1%)显著高于受精组(36.3%、41.7%、13.6%、44.3%)(P<0.05)。此外,畸精组的完全不受精发生率(15.0%)显著高于精子形态正常组(5.2%)。Logistic回归分析亦显示精子正常形态率、精液浓度、夫妇间受孕史、不孕年限与完全受精失败有显著相关性(P<0.05)。结论:对治疗周期中畸形精子症患者、精液浓度、活力偏低、男方原发不育、女方原发不孕、无输卵管性因素、不孕年限长、夫妇之间无孕史的患者应纳入受精失败的高危人群,考虑行部分ICSI,以保障受精,对防止完全不受精的发生具有积极意义。     

Birth after intracytoplasmic sperm injection with use of testicular sperm from men with Kartagener/immotile cilia syndrome

OBJECTIVE: To describe two cases of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with testicular sperm in men with immotile cilia syndromes. DESIGN: Case report. SETTING: A university-based male infertility clinic and assisted reproduction unit. PATIENT(S): Two couples with male factor infertility due to Kartagener/immotile cilia syndrome. INTERVENTION(S): IVF/ICSI with testicular sperm. MAIN OUTCOME MEASURE(S): Semen characteristics, sperm viability, fertilization rate, and pregnancy. RESULT(S): With testicular sperm, the two pronuclear fertilization rates were 63% and 60% in two cases. One case resulted in the birth of normal healthy girl. CONCLUSION(S): With testicular sperm, successful oocyte fertilization after ICSI in couples with male Kartagener/immotile cilia syndrome is possible despite the lack of sperm motility.     

Assisted reproduction and the male

Male reproductive problems are the commonest single cause of infertility and respond poorly to conventional treatment. Because of this, and because of the importance of co-existing female pathology, the techniques of assisted reproduction have acquired an important place in the management of male infertility. For many couples with a male factor, conventional in vitro fertilisation and embryo transfer will be appropriate. However, for those who fail with IVF, or whose semen is too poor (perhaps below 0.5 × 10⁶ progressive spermatozoa/ejaculate), the techniques of micro-assisted fertilisation show much promise. These include partial zona dissection (PZD), sub-zonal sperm insertion (SUZI) and intracytoplasmic sperm injection (ICSI) the latter showing much promise, with pregnancy rates in excess of 30% per cycle being reported. However, the diagnosis of ‘male-factor’ infertility remains problematic, as does the intelligent selection of couples for treatment by these techniques.     

Correlation between the zona-free hamster egg sperm penetration assay and human in vitro fertilization

The association between in vitro fertilization (IVF) and the zona-free hamster egg sperm penetration assay (SPA) was studied in 134 couples. The indications for IVF were tubal disease in 82 couples, unexplained infertility in 23, male infertility in 10, and combined mechanical and male factors in 19. In general, a positive SPA was a good predictor of subsequent IVF (91 of 107 couples). Specificity (number of couples with fertilization in vitro divided by the number of couples with a positive SPA times 100) was 94% for tubal infertility, 76% for unexplained infertility, and 46% for male infertility. A negative SPA predicted an overall fertilization failure of 78% (21 of 27 couples). Sensitivity of the test (number of couples with IVF failure divided by the number of couples with a negative SPA times 100) was 100% for tubal and unexplained infertility but only 63% for male infertility. The high predictive value of the SPA for subsequent IVF outcome in tubal infertility and unexplained infertility warrants its routine use for prescreening in IVF programs. Because of the lack of association between SPA and IVF in oligoasthenospermia, the bioassay should not be relied upon for predicting IVF outcome in male subfertility. The overall high association between the animal model and human IVF reinforces the use of the SPA for both basic research and clinical decision-making.     

Infertility counselling – a comprehensive handbook for clinicians (second edition)

In 50% of involuntarily childless couples a male infertility associated factor is found together with abnormal semen parameters. Surgical management of male infertility has advanced significantly over the last decade. This improvement in operative intervention is due in part to advancements in assisted reproductive technologies and associated new sperm retrieval techniques, an increased awareness among vasectomised men that they may still have their own biological offspring after a vasectomy reversal, and a more scientific understanding of the effects of varicoceles on spermatogenesis as well as the introduction of innovative techniques in their surgical repair. We describe various investigations to determine the underlying aetiology for male infertility and surgical techniques to improve semen parameters and sperm delivery, including microsurgical procedures which are technically challenging and demand specialised skills and andrological expertise.     

The role of urological surgery in male infertility

In 50% of involuntarily childless couples a male infertility associated factor is found together with abnormal semen parameters. Surgical management of male infertility has advanced significantly over the last decade. This improvement in operative intervention is due in part to advancements in assisted reproductive technologies and associated new sperm retrieval techniques, an increased awareness among vasectomised men that they may still have their own biological offspring after a vasectomy reversal, and a more scientific understanding of the effects of varicoceles on spermatogenesis as well as the introduction of innovative techniques in their surgical repair. We describe various investigations to determine the underlying aetiology for male infertility and surgical techniques to improve semen parameters and sperm delivery, including microsurgical procedures which are technically challenging and demand specialised skills and andrological expertise.     

Sperm motility in the semen analysis affects the outcome of superovulation intrauterine insemination in the treatment of infertile Asian couples with male factor infertility

Objective To ascertain the relationship between the initial and unprocessed sperm parameters and pregnancy rates in SOIUI, for Asian couples with male factor infertility
Design Retrospective study.
Setting A large government tertiary-care women's hospital with 15,000 deliveries per year
Population One thousand four hundred and seventy nine couples undergoing 2846 cycles of SOIUI
Methods All couples enrolled in the SOIUI programme were analysed, comparing initial sperm parameters and the post-processed total motile sperm, against pregnancy rates per cycle
Main outcome measures Pregnancy rates in relation to initial sperm parameters and post-processed total motile sperm
Results Ninety-three percent of the couples had male factor infertility. The average normal forms for these men was 14.7%. Overall pregnancy rate was 12.1% per completed SOIUI cycle. We found a significant drop in pregnancy rates if the percentage of motile sperms in the unprocessed sperm sample fell below 30%. We also found that insemination of at least 1 million motile sperm resulted in a significant increase in pregnancy rates
Conclusions We recommend SOIUI as an effective treatment of suitable couples with male infertility, before embarking on IVF. However, if the initial percentage of motile sperm fell below 30%, or if after processing, the total motile sperm count was fewer than 1 million, these couples should consider in vitro fertilisation     

Zygote intrafallopian transfer with "donor rescue": a new option for severe male factor infertility

Clinical pregnancies have been initiated by ZIFT using zygotes produced by reinsemination of oocytes with donor sperm ("donor rescue") after an initial 15- to 20-hour exposure to husband's sperm. A total of 54 oocytes from four couples experiencing failed fertilization by husband's sperm were reinseminated with donor sperm, resulting in 38 zygotes (70.4% fertilization). Four zygotes were transferred during ZIFT in each case and resulted in two (50%) continuing pregnancies. Additional zygotes from donor reinsemination were cryopreserved for each couple. Donor rescue expands the utility of ZIFT as a treatment for male factor infertility.     

经皮睾丸精子抽吸术结合卵浆内单精子注射治疗严重男性因素不育的研究

目的 了解经皮睾丸精子抽吸术（PTSA）结合卵浆内单精子注射（ICSI）技术治疗严重男性因素不育的治疗效果。方法 于1998年10月10日至2000年12月31日,我中心采用PTSA结合ICSI技术治疗162对严重男性因素不育的夫妇,短方案超排卵,对处于细胞分裂中期（MⅡ期）的成熟卵母细胞行ICSI。结果 185个周期共注射1517个MⅡ期卵母细胞,其中990个正常受精,正常受精率为65.3%,移植胚胎周期152个,54例妊娠,临床妊娠率为35.5%。结论 PTSA结合ICST技术为严重男性不育症患者提供了一种快速、方便、无痛、有效的治疗方法。     

Pretreatment of sperm with human follicular fluid for borderline male infertility

To test the usefulness of human follicular fluid (FF) in treating male infertility, we incubated washed sperm specimens from 31 couples undergoing intrauterine insemination (IUI), for male and/or unexplained infertility, with either FF or Ham's F-10 medium (Gibco, Grand Island, NY), in alternating cycles in a randomized manner. Semen specimens from 28 men were incubated with either medium or FF. Incubations with FF have increased sperm penetration assay (SPA) scores from 24.8 +/- 17.3 to 34.3 +/- 13.6 (P less than 0.01). Incubation with heat-inactivized FF also has increased SPA scores, although to a lesser extent than noninactivized FF. Seventeen pregnancies occurred in the 31 couples treated by IUI (54.8%), 16 of them in FF-treated cycles (51.6%) and one in "control" IUI cycles (3.2%, P less than 0.01). All pregnancies occurred within four treatment cycles. Thus, IUI after sperm wash and preincubation with FF may be suggested for four to six cycles to couples with male factor and/or unexplained infertility who are reluctant to resort to artificial insemination by donor or adoption, before attempting the more costly and complex in vitro fertilization-embryo transfer procedure.     

Intrauterine Insemination with Husband's Sperm: Comparison of Pregnancy Rates in Couples with Cervical Factor, Male Factor, Immunological Factor and Idiopathic Infertility

Summary: Intrauterine insemination with husband's sperm (IUI) is offered to couples with infertility due to various causes although there is no general agreement on which of these causes should be so treated. In this report 77 couples were diagnosed as having either cervical factor, male factor, immunological factor or unexplained infertility, insemination was performed 24–32 hours after a rapid rise in the serum LH level. Two of 16 pregnancies which resulted miscarried, 1 was ectopic and the remainder were full term. Eleven occurred in the cervical factor group, 3 in the immunological factor and only 1 in each of the male factor and unexplained infertility groups. The differences in the number of pregnancies between the cervical factor and male and unexplained infertility groups are significant but not between the groups with cervical and immunological factors. The majority of pregnancies (81%) were achieved in the first 4 cycles.
Patients with the cervical factor as the cause of their subfertility are likely to benefit from the IUI with their husband's sperm. The small number of patients with the immunological factor in this study does not allow for a conclusion. In our experience the male factor and unexplained infertility patients are unlikely to benefit from intrauterine insemination with husband's sperm.     

Sexual,Marital, and Social Impact of a Man's Perceived Infertility Diagnosis

IntroductionMale factor infertility is a relatively common problem. This diagnosis may increase sexual, marital, and relationship strain in male partners of infertile couples.AimTo measure the personal, social, sexual, and marital impacts of a male factor infertility diagnosis among men in couples evaluated for infertility.MethodsCross-sectional analysis of 357 men in infertile couples from eight academic and community-based fertility clinics. Participants completed written surveys and face-to-face and telephone interviews at study enrollment. This interview queried each participant's perception of their infertility etiology to determine the primary study exposure (i.e., male factor only, male and female factors, female factor only, unknown).Main Outcome MeasuresPersonal Impact, Social Impact, Marital Impact, and Sexual Impact scales.ResultsAmong the 357 men, no male factor was reported in 47%, isolated male factor was present in 12%, combined male and female factors were present in 16%, and unexplained infertility was present in 25% of couples. Male factor infertility was independently associated with worse Sexual (mean 39 vs. 30, standard deviation [SD] 2.7, P = 0.004) and Personal (mean 37 vs. 29, SD 3.8, P = 0.04) Impact scores relative to men in couples without male factor infertility. These differences remained statistically significant after controlling for male age, partner age, race, religion, educational level, employment status, prior pregnancy, duration of infertility, and prior paternity.ConclusionsMale partners in couples who perceive isolated male factor infertility have a lower sexual and personal quality of life compared with male partners of couples without perceived male factor infertility. Social strain is highest among couples without a clear etiology for infertility. These findings highlight the clinically significant negative sexual, personal, and social strains of a perceived infertility diagnosis for men. Smith JF, Walsh TJ, Shindel AW, Turek PJ, Wing H, Pasch L, Katz PP, and The Infertility Outcomes Program Project Group. Sexual, marital, and social impact of a man's perceived infertility diagnosis. J Sex Med 2009;6:2505–2515.     

Evaluation of antisperm antibodies in infertile couples with immunobead test: prevalence and prognostic value

We know that antisperm antibodies can cause infertility. We studied the prevalence of the immune response against spermatozoa in infertile couples using immunobead test. 16.2% of the men were autoimmune and 7.3% of the women isoimmune. Both partners were immune in 1.6% of the couples. We also studied the degree of impairment of sperm penetration into cervical mucus in couples in which one of the partners exhibited immunity and we found that generally it correlates with the proportion of sperm exhibiting surface-bound immunoglobulins. In some cases the sperm penetration into cervical mucus was normal in spite of immunization. So other mechanisms of interference should be explored. We found a significant difference (p less than 0.02) in the conception rate between immune and non immune couples (19.3% vs 42%). The pregnancy outcome of immune couples was favorable only in 50% of the cases.     

Contemporary approach to the male infertility evaluation

Evaluation of infertile couples has revealed that male factor infertility contributes to the problem in up to 50% of cases. Evaluation of the male infertility patient may include endocrine studies, sophisticated semen testing, and select radiographic studies. Reversible and life-threatening causes of male infertility should be identified before proceeding directly to assisted reproductive technology. For cases with irreversible causes, a proper evaluation can identify patients who may be treated with the breakthrough method of intracytoplasmic sperm injection. Many men who were previously thought to be infertile may now initiate their own biologic pregnancies. This article emphasizes the essentials of the contemporary approach to evaluating the male factor in an infertile couple.     

Classic pages in obstetrics and gynecology. Operation in cases of complete prolapse. Archibald Donald. Journal of Obstetrics and Gynaecology of the British Empire, vol. 13, pp. 195-196, 1908.

Homologous artificial insemination (AIH), with the use of a split-ejaculate technique, was performed in 62 couples following a complete infertility investigation. Fiffy per cent of all men had a sperm count less than 50 million per milliliter and 80 per cent had sperm motility less than 50 per cent. More important, 85 per cent of the initial semen samples had greater than 40 per cent abnormal forms and liquefaction was delayed beyond 20 minutes in 67 per cent of specimen. The pregnancy rate for the 28 women who underwent the prescribed course of six or more inseminations was 46.4 per cent; for the group of 60 who received split-ejaculate AIH, 21.6 per cent; and for the entire group of 62 couples, 24.2 per cent. In the split-ejaculate group 50 per cent of the pregnancies resulted in first-trimester abortions. It is suggested that the pregnancy wastage in these couples might be due to male factors.     

Intracytoplasmic sperm injection: what are the risks?

Intracytoplasmic sperm injection, a relatively new technique used at the time of in vitro fertilization to fertilize human oocytes, has provided couples with very severe male factor infertility the ability to conceive their own biologic children. Many men with severe oligospermia or azoospermia can now pass their genes on to their progeny, an event that might not have been possible for them just a few years ago. Recent studies now suggest that there may be genetic and developmental differences in some children conceived through intracytoplasmic sperm injection. It is likely that genetic testing and counseling will be recommended for all couples with male factor infertility in the near future. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this article, the reader will be able to describe the various indications for the use of ICSI in the treatment of infertility, to identify the potential long-term risks associated with the use of ICSI, and to estimate the rate of chromosomal abnormalities in this population of infertile patients.     

Successful management of infertility due to polyzoospermia.

Polyzoospermia is a rare cause of male infertility. In our clinical practice, patients with exceedingly high sperm counts (ranging from 650 million/ml to 1.75 billion/ml) have invariably been found to have associated poor sperm motility and poor sperm migration in postcoital tests, although the sperm appear morphologically normal. Cases of two infertile couples are presented in which each husband had sperm counts greater than 1 billion/ml. Two methods are reported for the successful management of their infertility problems: (1) precoital dilutional douching and (2) in vitro seminal fluid dilution with 5% dextrose-Ringer's lactate solution and artificial insemination homologous. Each method resulted in improved sperm motility, postcoital tests, and pregnancy.