Agglutination of sperm is detected and graded on wet-mount examination. If extensive and associated with a history testicular trauma or vasectomy reversal, it suggests the presence of antisperm antibodies. Evidence suggesting antibodies should be substantiated with specific testing, most commonly with the immunobead test [127–129]. Antibodies may be directed at a variety of antigens on different regions of spermatozoa, with differing consequences for fertility [130, 131]. Pregnancy can occur spontaneously in the presence of antisperm antibodies, but IUI has been used successfully when it does not [132]. Rapid dilution of semen upon collection for IUI may be beneficial [133]. ART has also been used as treatment for antisperm antibodies [132]. The addition of ICSI addresses concern for interference of antibodies with fertilization, but is currently without evidence for clinical benefit [134, 135].

Absent motility occurring with normal measures of vitality indicates one of several ultrastructural defects affecting ciliary function in primary ciliary dyskinesia syndrome. With chronic respiratory infection and situs inversus, the diagnosis of Kartagener’s syndrome can be made [136–138]. These disorders are autosomal recessive gene defects affecting the several proteins critical for normal ciliary ultrastructure and movement. Chronic/recurrent respiratory function in these men is due to impaired mucociliary function. Evaluation of sperm tail ultrastructure by electron microscopy can confirm diagnosis, but the classic findings on semen analysis with a typical history of respiratory disease and clinical findings for situs inversus are sufficient for clinical diagnosis. Pregnancy is achieved with ART and ICSI [139, 140].

Absent or minimal ejaculate after orgasmic masturbation suggests retrograde ejaculation or ejaculatory duct obstruction. Distinction between the two depends upon post-ejaculation urine analysis , which will show abnormally elevated sperm numbers after retrograde ejaculation. Causes include anatomic disruptions from prostate surgery, and neurologic dysfunction related to diabetes, demyelinating disorders, or sequelae of retroperitoneal node dissection. Pharmacologic disruption of the ejaculatory signaling pathway may occur with alpha-adrenergic blockers used for urine flow with prostatic hyperplasia. Medical treatments using alpha sympathomimetic agents (ephedrine, phenylephrine) or tricyclic antidepressants may help in some instances [141, 142]. More often, harvesting of sperm from post-ejaculatory urine that has been alkalinized by bicarbonate ingestion is done so that IUI or ART may be undertaken [143–145].

Abnormalities of semen among infertile males are rarely limited to a single parameter and commonly present as subnormal values for sperm density, motility, and normal morphology. This constellation is often termed OAT, or OAT syndrome. OAT, when severe, should be evaluated for genetic, chromosomal, and endocrine origins as described below for the evaluation of azoospermia. OAT is often idiopathic [146]. Two groups of OAT have been described, one affected primarily in density and motility and the other in sperm morphology, with the latter showing higher correlation with the presence of sperm aneuploidy [147, 148]. OAT is associated with sperm aneuploidy in many studies, with the rate of aneuploidy found in normal and abnormally formed sperm from men with OAT being similar to that in abnormally formed sperm from normal semen specimens [149–152]. Elevated frequencies of aneuploidy in sperm from men with OAT likely explain the increased aneuploidy in embryos created from their sperm using ICSI [153]. Other sperm abnormalities in OAT include increased DNA fragmentation, mitochondrial abnormalities, epigenetic alterations, and disordered chromatin organization [154–156]. Management of infertility due to OAT includes consideration of donor insemination, ART with ICSI, and attempts at medical therapy (discussed below). Surgical or embolic treatment for varicocele for men with OAT may be appropriate.

Treatment of varicocele with surgery or embolization is performed for discomfort and for infertility. Additionally, when low serum testosterone levels are present, they may be corrected with surgical treatment [78, 157]. Improvement in semen varies widely after varicocelectomy, and may be more likely in younger individuals. [158] Even azoospermic individuals may show return of sperm to the ejaculate after surgery [158]. Surgical techniques have advanced in recent decades to reduce unintended vascular or lymphatic injury [159, 160].

Despite beneficial effects of varicocelectomy on semen quality, endocrine function, and pain, its role as a fertility treatment is controversial; analyses of literature using live birth as the outcome of interest yields conflicting conclusions [159, 161–163]. The advent of ART and ICSI for male factor infertility adds complexity to knowing varicocelectomy’s role [163, 164]. Pregnancy as a result of varicocelectomy may occur over an extended window of time (as is true for pregnancy among normally fertile couples) and, therefore, youth of a couple, and lack of urgency would favor an attempt at correcting infertility with varicocelectomy, prior to advancement of care to ART. The presence of pain or hypoandrogenism would favor surgery, as would religious or other barriers to ART. Alternatively, progression to ART, without varicocele correction, may be preferred for couples not comfortable accepting its uncertain benefit and for couples for whom time to pregnancy is a concern, especially where female age is a factor.

Azoospermia requires examination of centrifuged semen for confirmation. It may be due to obstruction, inadequate gonadotropins, or defective germinal epithelium. The latter two comprise the two causes for nonobstructive azoospermia (NOA ), and the laboratory plays an important role in differentiating between them. The nature of the semen is helpful in distinguishing the causes of azoospermia [165]. Smaller semen volumes and greater acidity without fructose suggest absent seminal vesicles (CBAVD), which can be confirmed on scrotal examination. Smaller semen volumes will also be seen in severe hypogonadism. Normal semen volumes with normal pH suggest primary testicular (germinal) defects or ductal obstruction at the level of the vas or epididymis. Surgery for cryptorchidism in childhood is a risk factor for NOA and these occurring together may implicate the putative “testicular dysgenesis syndrome ,” warranting careful testicular examination for mass [21, 24, 166]. Surgery for cryptorchidism or for torsion that harms the contralateral ducts or history of prior epididymitis may account for proximal ductal obstruction. Exogenous androgen use may profoundly suppress spermatogenesis [53, 54]. Examination of the scrotal contents helps differentiation of ductal disorders (the presence of normal testicular volume and turgor, palpable ductal abnormalities) from primary testicular and endocrine control disorders (small testes of reduced turgor). Congenital bilateral absence of the vas is evident from palpation and has implications for CFTR mutation screening in the event of ART.

The principal value of endocrine testing in evaluation of azoospermia lies in distinguishing testicular from central causes of NOA. It is rarely helpful in the evaluation of OAT or sexual dysfunction. Some degree of elevation of follicle-stimulating hormone (FSH) levels is expected with primary testicular disorders, and though cutoff values for this are elusive, such findings usefully contrast with the very low FSH, luteinizing hormone (LH), and testosterone levels seen in hypogonadotropic disorders [167].

Principal hypogonadotropic disorders are either congenital (frequently as classic Kallman’s syndrome, which includes anosmia), in which impaired pubertal development may have led to androgen replacement, or acquired disorders, in which the principal concern is pituitary or juxtapituitary neoplasm [168–170]. Therefore, when adult-onset hypogonadotropic hypogonadism is diagnosed, the serum prolactin levels should be determined; CNS and pituitary imaging should be performed if it is elevated, or if there is evidence for global pituitary insufficiency (central hypothyroidism, hypoadrenalism, or diabetes insipidus) or symptoms of intracranial mass. Treatment of endocrine disorders for fertility restoration is discussed below.

NOA of testicular origin and severe OAT warrant genetic and chromosomal evaluation, especially prior to ART. Identifiable chromosomal and genetic abnormalities are common among men requiring ICSI [171–174]. Five percent of ICSI patients exhibit chromosome errors, and these involve the sex chromosomes in approximately two-thirds of instances. Frequency of chromosomal errors increases with the severity of semen impairment, reaching 10% or greater among men with the most profound deficits in sperm density [171, 175]. Y-chromosomal microdeletion is roughly as common as chromosomal error in this population and also most prevalent among men with the greatest depression of spermatogenesis [171, 172].

Sex chromosome aberrations are the most frequent of the few chromosome abnormalities compatible with adult life in men. Klinefelter syndrome (XXY and mosaics) and XYY syndrome both include infertility and each occurs in one to two per 1000 births [173, 174, 176]. Non-mosaic Klinefelter’s syndrome is common among azoospermic individuals, and men mosaic for the disorder frequently present with abnormal semen [175]. Klinefelter’s patients have harvestable sperm with TESE, more often than not. Testicular volume and hormone levels are of limited utility in predicting TESE success [167, 177, 178]. Because spermatogenesis may be focal, microdissection may provide the best TESE success rate [177, 179]. Fluorescence in situ hybridization (FISH ) to exclude embryonic aneuploidy should be considered if ART/ICSI is undertaken for Klinefelter’s syndrome [180]. Autosomal-balanced translocations (and the Robertsonian translocation form of these) are associated with infertility, recurrent abortion, and rarely, offspring with deficits owed to unbalanced chromosomes [173–175]. Effects of autosomal translocations and inversions arise through disruption of normal meiotic bivalents such that azoospermia, due to meiotic arrest, or oligospermia occurs. Interchromosomal effects, whereby other, normal chromosomes are collaterally damaged during meiotic errors, add to the reproductive morbidity of autosomal chromosomal rearrangements [181]. Frequencies of sperm aneuploidy, likelihood of embryonic aneuploidy, and successful reproduction vary widely according to the defect present [173, 182].

High percentages of embryos from men with structural rearrangements have aneuploidy, and preimplantation genetic diagnosis (PGD ) can increase the likelihood of transferring normal embryos [183]. It is most clearly of use in cases of recurrent abortion, in which ART/PGD may shorten the time to implantation of a normal embryo, or in the uncommon cases in which abnormal offspring with unbalanced chromosomal complement have been born [184]. PGD technologies will be transformed by the advent of emerging array technologies [173].

It is likely that genetic lesions often explain severe male infertility, but only a few are described [185, 186]. Microdeletions in the AZF region of the Y-chromosome long arm have been extensively studied. A prevalence of 7.4% among infertile men is estimated, and their likelihood is proportional to the severity of spermatogenic abnormality. Deletions in the various AZF subregions (“a,” “b,” or “c”) or combinations of them occur with differing frequencies and with differing implications for the degree of impairment of spermatogenesis, and the likelihood of retrievable sperm if there is NOA. Large areas of deletion and deletions involving the a and b subregions are associated with failure to retrieve sperm on TESE [180, 185, 187]. Because of this, testing for AZF deletion is advisable before attempting TESE for NOA. Mutations with severe functional consequence for the androgen receptor lead to infertility and intersex conditions and lesser lesions to infertility alone [188–190]. Such mutations were found in 1% of a large series of men with severe oligospermia undergoing ICSI [172].

Identification of chromosomal or genetic causes for male infertility thus has implications for health of embryos and offspring, and can predict TESE success for NOA. Using results of genetic and chromosomal evaluation of the male to provide counseling about pregnancy likelihood and outcomes is an important element of care for couples treated for severe male factor infertility [171–173, 187, 191].

Treatments available for azoospermic disorders include donor insemination in all cases, surgical repair for some ductal obstructions, and ART with TESE and ICSI in selected instances [192–194]. Genetic and chromosome evaluation should be encouraged prior to ART for non-ductal azoospermia (see above). CBAVD signals a high likelihood of CFTR mutation, and ART care should always include screening for these in the female partner prior to ART. When azoospermia is associated with varicocele, treatment may restore sperm to the ejaculate of some patients [158, 195, 196]. Administration of gonadotropins can be effective as sole therapy for hypogonadotropic disorders or to provide ejaculated sperm for ICSI. Fertility can be restored with dopamine agonists for most men with pituitary tumors; when treated surgically, gonadotropins are usually required (see below).

Medical therapy for male infertility falls into three categories: replacement of deficient gonadotropins for men with hypogonadism of central origin, empiric direct or indirect augmentation of gonadotropins for men with unexplained infertility, and use of nutritionals and supplements.

Induction of spermatogenesis in constitutional hypogonadotropic hypogonadism, including patients with anosmia (Kallman’s syndrome), can be accomplished with administration of pulsatile gonadotropin-releasing hormone (GnRH), which precisely targets the pathophysiology, but is cumbersome [197]. Fertility in Kallman’s syndrome and idiopathic or postsurgical hypogonadotropic states is often achievable with administration of human chorionic gonadotropin (hCG) alone, typically in doses of 1500–2000 IU twice weekly, but many patients will require co-administration of FSH [198, 199]. When required, FSH doses as low as 150–225 IU weekly may be sufficient [200]. Pregnancies often occur once there are sperm densities that are usually considered oligospermic [199].

Surgical management of prolactinomas in men is complicated by a high rate of persistent hypogonadotropic hypogonadism and recurrent hyperprolactinemia such that replacement gonadotropins are still necessary for fertility [201]. Medical therapy has emerged as a preferable course for most cases. Treatment with the dopamine agonist Cabergoline allows for regression of lesion size, normalization of the hypothalamic–pituitary–testicular axis, normalization of androgens, and restoration of spermatogenesis in a majority of instances, including cases of large prolactinomas [169, 170, 202].

There is a limited literature supporting a variety of empiric therapies for unexplained male infertility [203]. These treatments presume etiologies such as minimally defective gonadotropin secretion, oxidative insult, or nutritional deficiency. Administration of gonadotropins for men with apparently intact hypothalamic–pituitary–gonadal axes and poor semen quality is supported by limited trial data [204, 205]. Indirect enhancement of gonadotropin secretion with antiestrogens (tamoxifen citrate and clomiphene citrate) is less cumbersome and costlier than gonadotropin administration and is also supported by limited evidence [204, 206–209]. Use of aromatase inhibitors has also shown some promise, especially for men with low ratios of circulating testosterone to estradiol [210, 211]. Among supplements, zinc and folate may improve semen parameters [212]. Studies of carnitines and of antioxidants suggest possible benefits [209, 213–215]. Evidence for these several putative therapies for unexplained male infertility is hampered by high intra-individual variation in semen values, limited expression of results in terms of pregnancies, and the likely heterogeneous nature of underlying causes. None of these is adequately supported by high-quality evidence [216]. Large and carefully conducted clinical trials for the treatment of idiopathic OAT that utilize pregnancy as the outcome are needed [146].

IUI is widely employed for infertility due to mild or moderate male factor or unknown cause. Often the latter, may have undiagnosed mild male factor. The rationale for IUI is based on several conjectures, including the bypass a hostile vaginal and or cervical environment, reducing the distance for sperm transport, selection of the most fertile sperm, concentrating fertile sperm at the site competition for fertilization, reducing the concentration of spermatotoxic molecules in the seminal fluid (capacitation inhibitors, free radical, etc.), and improved timing of the ovum–sperm exposure. IUI require that the female has spontaneous or inducible ovulation, and has normal anatomy, including normal uterine cavity and patent fallopian tubes. Timing IUI is determined by home kits for detection of the LH surge, or by a triggering injection of hCG given when follicle diameters reach at least 18–20 mm. If hCG is used, artificial insemination is timed 32–36 h after the injection. Success rates are not affected by whether the endogenous LH surge or hCG administration is used for timing [217]. Frequent intercourse through midcycle appears preferable to prescribed abstinence prior to collection of the specimen for IUI [1, 2, 4]. Semen is prepared for insemination using one of several aimed at selecting the most fertile pool of sperm and, importantly, to separate sperm from seminal prostaglandins which can cause painful contractions. Density gradient preparation is commonly used, although there is no evidence of the superiority of any of the sperm preparation techniques [218].

The prepared sperm is typically concentrated to a volume of ½ to 1 cc and injected into the uterine cavity gently, using a sterile catheter passed through the cervical canal after wiping the cervix free of secretions or excess mucus. Triggering of upper reproductive tract infection with IUI is a rare complication. IUI shows a higher pregnancy rate when compared to intracervical insemination in couples with unexplained infertility but may not be superior to timed intercourse when done without superovulation [219, 220]. Although superovulation adds efficacy to IUI, and pregnancy rates show some proportionality to numbers of maturing follicles, this must be balanced against significant risks for high-order multiple pregnancy [219, 221–223]. Double inseminations have been proposed to increase success. However, most studies show little evidence of the benefit of this maneuver, which increases the cost and complexity of IUI considerably [224–227]. IUI success depends on female age and quality of semen. Older women fare poorly, and pregnancies are uncommon if they are older than 40 [228]. Pregnancy success is a function of total motile sperm in the insemination; a preparation that contains 5 million motile sperm appears to be the threshold for benefit of IUI, although preparations with fewer sperm may rarely yield pregnancy [223, 229, 230]. Artificial insemination is typically attempted for 3–4 cycles; series do not show a significant increase in cumulative pregnancies beyond that [223]. A recent critical review found a limited number of adequately conducted trials, few subjects overall for evaluation, and thus limited evidence for a benefit for IUI vs. timed intercourse [220]. It is likely that couples vary in the degree to which IUI might benefit them, and that substantial benefit for some couples, and little benefit for others, underlies the generally low statistics for IUI outcomes. A trial of IUI is often selected in hopes that success will obviate the need to progress to the more invasive and costly undertaking of ART.