Prior to 1992, the majority of cases of severe male infertility were virtually untreatable, and failure of fertilization was observed in up to 30% of IVF treatments for male infertility. The introduction of essential micromanipulation techniques raised the hopes of a better prognosis for these cases, but did not overall provide a substantial improvement in success rates. Subsequent introduction and successful use of intracytoplasmic sperm injection (ICSI) have led to a significant improvement in the treatment of severe male infertility by ART.
The establishment of intracytoplasmic sperm injection (ICSI) as a routine technique was quickly followed by the introduction of techniques for collecting sperm samples from the epididymis and directly from the testis, so that the whole spectrum of male infertility can now be treated, from suboptimal ejaculate samples or ejaculatory failure, to obstructive and non-obstructive causes of azoospermia.
However, an increasing number of genetic defects have been found to be associated with male infertility: a higher incidence of numerical and structural chromosomal aberrations is found in infertile and subfertile men than in the general population, in particular karyotypes 47XXY, 47XYY, 46XX, 46X, derY, Robertsonian translocations, reciprocal translocations, inversions and additional marker chromosomes. Between 12% and 18% of men with azoospermia or severe oligospermia (less than 300,000 sperm in the ejaculate) have deletions in intervals 5 and 6 on the long arm of the Y chromosome.
Microdeletions of the q11 region of the Y chromosome are related to the dysfunction of Deleted in Azoospermia (DAZ) and RNA-binding motif (RBM) genes, and androgen receptor (AR) gene mutations have also been reported in infertile men. In a population of approximately 3,000 infertile men, the pathological microdeletions rate, in at least one of four critical regions on the Y chromosome, was found to be as high as 22%, with an additional percentage being attributed to cryptic mosaicism. Furthermore, it appears that microdeletions will be transmitted in at least 10% of unselected father/son pairs.
It’s known, three to ten percent of infertile men present with congenital bilateral absence of the vas deferens (CBAVD), and approximately 65% of these individuals carry the gene for cystic fibrosis (CF), with defects in the cystic fibrosis conductance regulator (CFTR) gene. Many are compound heterozygous for the CFTR mutation, with an increased risk of having children with CF or CBVAD.
Although the genetic risk for couples who require intracytoplasmic sperm injection (ICSI) treatment has yet to be fully defined, karyotyping, and preferably also Y-microdeletion analysis, is recommended as part of the pretreatment screening process for men with severe male factor infertility referred for intracytoplasmic sperm injection (ICSI). The couple should also have access to professional genetic counseling to discuss potential risks, and appropriate informed consent must be obtained before treatment.
Surgical Sperm Retrieval
In cases of obstructive azoospermia, samples can be aspirated from the epididymis. The original “open” micro-surgical technique of micro-epididymal sperm aspiration (MESA) was superseded by the simpler procedure of percutaneous epididymal sperm aspiration (PESA), which can be carried out by fertility specialists without micro-surgical skills, and can be performed under local anesthetic or mild sedation as an outpatient procedure. Aspiration is carried out using a 25-gauge butterfly needle connected to a syringe.
If sperm cannot be aspirated from the epididymis, a modification of the technique using wide-bore needle aspiration of the testis, testicular sperm aspiration (TESA) or testicular fine needle aspiration (TEFNA) often harvests sufficient testicular spermatozoa to carry out the procedure of intracytoplasmic sperm injection (ICSI). With non-obstructive azoospermia, spermatogenesis is impaired.
The epididymis is devoid of sperm, but the testis usually contains focal areas of spermatogenesis: this focal spermatogenesis makes diagnosis based upon a single biopsy unrealistic, and multiple biopsy may be required. Prepared testicular samples can also be cryopreserved for a future intracytoplasmic sperm injection (ICSI) procedure at the time of diagnostic testicular biopsy. The biopsy is carried out either by multiple needle aspirations (TEFNA or TESA) or by open biopsy (testicular sperm extraction: TESE), and both procedures may be safely carried out with local anesthetic or mild sedation.
Indications for ICSI
The intracytoplasmic sperm injection (ICSI) procedure involves injecting a single immobilized spermatozoon directly into an oocyte, and therefore it can be used not only for cases in which there are extremely low numbers of sperm, but in bypassing gamete interaction at the level of the zona pellucida and the vitelline membrane it can also be used in the treatment of qualitative or functional sperm disorders.
Couples who have undergone fertilization recurrence after IVF-ET may have one or more gamete dysfunction disorders in which there is a barrier to fertilization at the level of acrosomal reaction, zona pellucida binding, or interaction, zona penetration, or fusion with the oolemma. Intracytoplasmic sperm injection (ICSI) should be offered to patients who have unexplained failure of fertilization in a previous IVF-ET cycle.
Severe oligospermia can be treated with intracytoplasmic sperm injection (ICSI). In patients whereas many normal vital sperm can be recovered as there are oocytes to be inseminated, fertilization can be achieved in approximately 90% of cases. In extreme cases of cryptozoospermia, where no sperm cells can be seen by standard microscopy, centrifugation of the neat sample at higher than usual centrifugal force may result in the recovery of an adequate amount of sperm cells.
Severe asthenozoospermia, including patients with sperm ultra-structural abnormalities such as Kartagener’s syndrome, or “9 + 0” axoneme disorders can be treated by intracytoplasmic sperm injection (ICSI).
Teratozoospermia, including absolute teratozoospermia or globozoospermia.
In cases of CBAVD, vasectomy or post-inflammatory obstruction of the vas, sperm samples can be retrieved by PESA, TESA or TESE.
Samples can be recovered by needle or open biopsy of the testis in cases of non-obstructive azoospermia.
In cases of ejaculatory dysfunction, such as retrograde ejaculation, a sufficient number of sperm cells can usually be recovered from the urine.
Paraplegic males have been given the chance of biological fatherhood using electro ejaculation and IVF; they may also be successfully treated using a combination of PESA/TESA/TESE and intracytoplasmic sperm injection (ICSI).
Immunological factors—couples in whom there may be antisperm antibodies in female sera/follicular fluid or antisperm antibodies in seminal plasma following vasectomy reversal or genital tract infection can be successfully treated by intracytoplasmic sperm injection (ICSI).
Oncology—in male patients starting chemotherapy or radiation therapy, sperm samples should be frozen for future use. Intracytoplasmic sperm injection (ICSI) offers the patient an excellent chance of achieving fertilization following recovery from their disease and treatment. Testicular biopsy specimens may also be cryopreserved for these patients as a further back-up when the quality of the ejaculate is inadequate for freezing.
For preimplantation genetic diagnosis (PGD) involving DNA amplification by PCR, intracytoplasmic sperm injection (ICSI) should be used as the means of fertilization to prevent sperm contamination of the sample.
Although the main indication for intracytoplasmic sperm injection (ICSI) was originally for the treatment of male factor infertility, its use has become far more widespread, with an increasing trend for its routine use in treating indications that include moderate male subfertility, advanced maternal age, low responder patients, and donor oocytes or sperm. Indeed, some clinics now use intracytoplasmic sperm injection (ICSI) as a routine for all indications.
The European Society for Human Reproduction and Embryology (ESHRE) concluded: “ICSI should be considered in the presence of severe sperm abnormalities or a history of fertilization failure in conventional IVF attempts. It must be emphasized that ICSI does not represent the most suitable treatment for female pathologies such as poor ovarian response or previous implantation failure.”