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Even with the most aggressive of therapy, success rates in treatment of severe forms of male infertility have remained low. For some, the only options have been either donor sperm or adoption. Often the major block to male fertility is at the point of fertilization (the physical union of the sperm and egg). Now, through a procedure where a single sperm is directly injected into the oocyte (egg), (Intracytoplasmic Sperm Injection (ICSI)), pregnancies are possible when all other options have been exhausted. Candidates for ICSI include couples where fertilization in conventional IVF has failed without explanation, individuals with known severe reduction in sperm numbers, antisperm antibodies ("allergic", or protective proteins which attack and destroy cells), and where there is a perceived disorder in sperm binding or penetration into the oocyte.
ICSI is also used in cases where low numbers and/or immature sperm are expected as a part of the procedure of direct Testicular/Epidydimal Sperm Aspiration (TESA). TESA is a procedure used in men who produce sperm but have a block preventing the release or transport of sperm. The most common indications for TESA is failed vasectomy reversal and other cases of obstructive disorders.
ICSI is generally unsuccessful when used to treat fertilization failures that are primarily due to poor egg quality.
The human oocyte (egg) is surrounded by a variety of barriers that are important in its maintenance and survival, but may also form a formidable block to normal fertilization. While a single sperm is all that is necessary for pregnancy, the chance of a pregnancy is reduced when there are fewer than 20 million total motile sperm in the semen sample. With conventional IVF, the success rate is low when sperm numbers drop below one million. With intercourse, the large numbers are necessary to provide a sufficient number of sperm to arrive at the site of fertilization in the distal part of the Fallopian tube. With IVF usually several thousand sperm are placed with each oocyte to ensure fertilization. Sperm must have special adaptions to transverse the barriers that arise between ejaculation and fertilization. In some cases of male infertility, it may be a simple matter of numbers of sperm. By the recent successes with ICSI, it would seem that major blocks to fertilization are in the modifications that the sperm undergoes to penetrate the barriers around the oocyte rather than in the quality of the genetic material carried by the sperm. "There may be a good message but, the mechanisms to communicate this message are defective."
The specific processes that sperm must perform as a part of fertilization start with the dispersion (separation) of the supportive cells (cumulus mass) surrounding the oocyte. Here, many sperm working together loosen these cells "clearing the path" to the oocyte. Once through the cumulus the sperm attach (bind) to the zona pellucida, a "clear" protein halo surrounding the oocyte. A specialized cap (acrosome) over the head of the sperm contains enzymes that are released on binding of the sperm to the zona pellucida. This partially dissolves the zona pellucida and facilitates sperm penetration into the oocyte.
In the past, popular techniques to improve fertilization were either to partially dissolve/penetrate this layer (zona drilling or partial zona dissection PZD), or to insert sperm directly underneath the zona (subzona sperm insertion - SUZI). These techniques have been abandoned in favor of ICSI.
Like all cells, the oocyte has a thin envelop surrounding it called the oocyte membrane. Also like all other cells, the oocyte has a nucleus and cytoplasm. The nucleus is where the genetic material, which simplistically might be thought of as the brain of the cell, is stored. The cytoplasm, in many ways, analogous to the body of the cell, supports and takes commands from the nucleus. The cytoplasm of the egg is much more abundant than in most cells. The sperm membrane must fuse with the oocyte membrane and the sperm head along with associated parts must be drawn into the the egg. Once a single sperm enters, the oocyte responds by a physical/chemical change (cortical reaction), that blocks the entry of more than one sperm. Still, other changes occur in the egg that are necessary to prepare the genetic material (DNA) for joining with that of the sperm. These changes are collectively known as oocyte activation and are directed by changes in the oocyte cytoplasm and probably sperm factors.
Subsequently, the nuclear membranes surrounding the sperm and egg "pro"nucleus break-down and there is a union of the female and male genetic material (syngamy). It is at this point that the genetic identity of the conception is determined. Syngamy is often mistakenly confused with the process, or at least the term, fertilization.
Many fertilization failures are thought to occur at either the penetration of the zona pellucida or fusion of the cell membranes. While more often fertilization failure is of sperm origin, it can also occur due to abnormalities of the zona pellucida or oocyte membrane. ICSI bypasses both of these potential blocks. Still, ICSI cannot correct the genetically abnormal sperm.
ICSI is one of a group of assisted reproductive laboratory procedures referred to as micromanipulation. Here, procedures are performed on sperm and eggs under very controlled environmental conditions using specialized equipment under high power magnification. The equipment is specially designed to allow the embryologist to perform very small intricate movements. One glass tool (holding pipet) is used to stabilize the egg while a second microscopic glass tube containing sperm (injection pipet) is used to penetrate the zona pellucida and egg membrane. Thus, a single sperm is deposited into the egg cytoplasm. An enzyme (hyaluronidase) is used to aid in removing the cumulus mass cells and to better visualize the oocyte. Sperm are suspended in a second chemical (polyvinylpyrrolidone, PVP) which improves the handling of sperm with the injection pipet. After injection of the sperm, the oocyte is released from the holding pipet and washed in a drop of fresh culture medium.
The oocyte will be checked for evidence of fertilization the morning following the ICSI procedure. Fertilized eggs will be cultured for one or two additional days, allowing the conceptus (embryo) to develop from one to two, two to four, or more cells (cleave). At the end of the culture period, normally developing embryos will be transferred to the uterus, or cryopreserved, taking into account the recommendations of the laboratory and clinical staff and the patient's wishes.
In many ways ICSI represents a calculated "gamble." Each couple individually must consider the decision carefully. The reward is obvious. A pregnancy may be established when it is not possible by any other means. The greatest risk of the ICSI, or for that matter fertility therapy in general, is failure to establish that pregnancy. With ICSI, there is no guarantee of a pregnancy, or for that matter, even fertilization. Pregnancy rate depends on many factors that are beyond physician, laboratory, and patient control. Worldwide, success rates vary and have been quoted between 0 and 30% per cycle. A reasonable estimate may be a 50% fertilization rate, and an overall pregnancy rate of 10-40%, depending on fertility of the female partner. Generally pregnancy rates approach the "center-specific rates." A problem in reporting success rates stems from the indication various centers use to perform the ICSI procedure. The success rates will be lower if ICSI is restricted to only the most severe cases of male infertility. Some Centers perform ICSI on a high percentage of patients and a few centers apply this technique to all patients. To date and especially in the United States, ICSI is usually reserved for couples with the clear indications listed in the introduction. Couples should be aware of the "to-date" "center-specific" procedure number and success rates. Rates after TESA are lower than ICSI and depend on the success of the testicular aspiration as well as the ICSI procedure.
In addition to the standard risks of conventional IVF, ICSI presents the possibility of mechanical and/or enzymatic damage to the oocyte. Damage occurs in approximately 10-15% of the oocytes subjected to ICSI. The damage is usually extensive and will destroy the oocyte.
While ICSI represents a relatively new procedure, it is not considered experimental and several thousands of babies have been born worldwide. Overall, pregnancy outcome, the risk of genetic disorders and/or birth defects after ICSI appears no different from that of IVF, or the general population. Overall pregnancy precautions should be that of other IVF pregnancies.
However, there appears to be a special consideration that has arisen in several reports describing transmission of a chromosomal alteration from men with very low sperm counts. It is possible that the offspring from these men could also be sub-fertile. As many as 15% of the men with severely compromised semen may have major, or minor sperm chromosome abnormalities. These abnormalities may include, but may not be limited to, one or more extra chromosomes(s) than normal in the sperm, one or more fewer chromosome(s) than normal in the sperm, part(s) of a chromosome may be missing (deletion), a chromosome may have extra DNA added (insertion), or a gene on a chromosome may be mutated. Particular study is being directed toward a group of men with "microdeletions" of the Y-chromosome (small portions of the chromosome are missing). Chromosomal testing (karyotype) may be used to discover some, but not all, of these abnormalities. Genetic testing is offered to all males with severe and otherwise unexplained very low sperm counts. Men with congenital absence of one or both ductus (vas) deferens and men with unexplained obstruction of the epididymis may have as much as a 50% chance of transmission (passing on to the baby) a genetic abnormality associated with cystic fibrosis (cystic fibrosis transmembrane conductance regulator, CFTR). Testing may also be important for the female partner in these cases. This highlights the need for a thorough evaluation of the male partner and establishment of a diagnoses, if possible, in couples contemplating TESA and/or ICSI.