Assisted Reproductive Techniques (ART)

Introduction

Male factor infertility may be described as any condition in which the man adversely affects the chances of a couple achieving a pregnancy. Most commonly, male factor infertility is described in terms of abnormal sperm concentration (oligospermia), impaired sperm motility (asthenospermia) or teratospermia (abnormal sperm morphology.) Oligospermia is the presence of less than 20 million sperm per cc. in a semen specimen, and it may reflect an impairment of fertility for the man with this finding. In addition, impaired sperm motility (sperm motility <50%), and impaired sperm morphology (normal forms < 30% [World Health Organization Criteria], or < 14% [Kruger strict criteria]) are associated with impaired fertility'. In addition to men with abnormal sperm production, male factor infertility describes men with normal sperm production but mechanical problems with sperm transport to the vagina during intercourse. When a male factor is found during evaluation of a couple for infertility, a complete evaluation of the man is warranted. If treatable conditions causing the male factor are found, they should be corrected. If treatment is unsuccessful, or if the couple still does not conceive, then assisted reproduction is indicated. Assisted reproductive techniques (ART) include intrauterine insemination (IUI), in vitro fertilization (IVF), and IVF with micromanipulation. In this review we will emphasize recent advances in IVF, including IVF with micromanipulation, as a tool for treatment of the infertile couple with male factor infertility.

Evaluation of Male Factor Infertility Before ART

The cornerstones of evaluation of a subfertile man include a comprehensive history, physical examination, multiple semen analyses and an endocrine evaluation. In specific circumstances, additional testing is indicated. For men with severe male factor infertility (sperm concentration < 10 x 106/cc), karyotype evaluation and testing for microdeletions of the Y chromosome are appropriate, especially prior to micromanipulation-assisted reproduction . In the case of any other genetic condition, including treatment of men with Klinefelter's syndrome, and in the case of couples with a female partner over age 40, genetic counselling is recommended prior to assisted reproduction treatments.

Treatment Of Male Factor Infertility Before ART

Up to 75 % of men with a male factor will have identifiable or treatable conditions found that affect their fertility. Nearly all men with male factor infertility are treatable with assisted reproductive techniques (ARTs). Prior to applying more invasive techniques, however, specific intervention should be instituted to avoid gonadotoxic factors such as exogenous heat, chemical gonadotoxins (e.g., sulfasalazine and Tagamet), or medications that adversely affect fertilization (including calcium channel blockers). Treatment of varicoceles, antisperm antibodies, infections, and obstructive azoospermia have all been demonstrated using randomized or other appropriately designed studies to have a worthwhile role in the management of male infertility. Since specific treatment is usually less invasive and of lower risk than IVF, and may have similar benefits, evaluation of the couple with a male factor remains important. In addition, it is worthwhile to remember that up to 1 % of men with subfertility have a potentially life threatening condition associated with their fertility problem, (e.g. testis tumor). Suffice it to say that evaluation of a man with male factor is worthwhile, despite the recent advances in assisted reproduction.

Background: In Vitro Fertilization (IVF)

Male factor infertility was initially considered a contraindication to IVF because abnormal sperm are less likely to fertilize eggs than normal sperm. Subsequent experience starting just a decade ago, however, indicated that fertilizations and subsequent live births were possible despite impaired sperm quality . IVF has had some success in the treatment of these men, however it has been recognized that even normal concentrations of sperm from oligozoospemic men, placed directly with oocytes in culture, do not fertilize at the same rates as sperm from otherwise normal men. In addition, adequate numbers of sperm cannot be obtained from all men to allow insemination of oocytes with the usual numbers of gametes (100,000 sperm/oocyte). Initial concerns that assisted fertilization with apparently defective sperm may lead to the development of abnormal embryos and an increase in the number of birth defects, have not been founded. In fact, once fertilization has been achieved for male factor couples, implantation and subsequent pregnancy appear to be just as likely, if not more likely, to occur than in other cases of IVF. The technique of IVF is described in greater detail elsewhere. Briefly, it involves down-regulation of the woman's pituitary function with GnRH agonists given during the preceding luteal phase. This is followed by controlled ovarian hyperstimulation using a combination of FSH-stimulating agents, to increase the number of oocytes produced. Follicle development in the ovary is evaluated directly with transvaginal ultrasound imaging of follicular growth and by measurement of serial serum estrogen and progesterone levels. A dose of hCG (5-10,000 units) is given when optimal follicular development is achieved. Retrieval of oocytes is performed by transvaginal follicular aspiration using ultrasound guidance. The transvaginal approach has obviated the need for general anesthesia and laparoscopy to perform IVF. Many oocytes (up to 30 or more) can be obtained from otherwise normal women with ovarian hyperstimulation. Morphologically mature, metaphase II eggs may then be inseminated with sperm. Human eggs survive freezing poorly since they are in metaphase, therefore, all retrieved and mature eggs are inseminated. Immature eggs may mature in vitro and subsequently be inseminated. A semen specimen is then obtained and processed to remove dead or dysfunctional sperm as well as to remove seminal fluid which may adversely affect the fertilization process. Processing is performed using either swim-up, gravity sedimentation, Percoll gradient sedimentation, or simple washing. Insemination of oocytes is performed in simulated human (fallopian) tubal fluid medium, and the oocytes that fertilize (embryos) are usually allowed to divide up to the 8-cell stage prior to embryo transfer. Embryo transfer back to the uterus is usually performed after 2-3 days of incubation in vitro. Up to 4 embryos may be transferred to the uterus, and excess embryos may be frozen. The implantation rate per embryo ranges from 15-25% in most IVF programs.

Micromanipulation

Gamete micromanipulation technology has enabled the reproductive biologist to circumvent inefficient steps in the fertilization process. Instead of simply facilitating sperm-egg interaction in vivo, sperm-egg interaction is enhanced by manipulation of the egg in vitro. This means that oocytes (eggs) are manipulated and subsequently inseminated with spermatozoa in glassware, outside the body. The first category involves the creation of an opening in the zona pellucida, an acellular layer surrounding the egg which serves as a major barrier to sperm penetration. Subsequently, the micromanipulated oocyte is inseminated according to standard IVF guidelines. These procedures have been broadly termed " zona drilling." Specifically, one variant of zona drilling involving mechanical piercing of the zona pellucida has been successful in male factor patients". This method has been called partial zona dissection (PZD). A second category of micromanipulation techniques directed at facilitating sperm-egg interaction is the subzonal insertion of sperm (SuZI). SUZI involves direct placement of sperm into the perivitelline space between the zona pellucida and egg completely bypassing the zona pellucida". The third and most invasive form of microsurgical fertilization is the microinjection of a single sperm into the cytoplasm of the oocyte, referred to as intracytoplasmic sperm injection (ICSI). This technique for manipulation has a higher risk of oocyte injury than SUZI or PZD, but overall higher fertilization and pregnancy rates . Most importantly, relatively few sperm are necessary for ICSI. The tremendous superiority of results after application of ICSI when compared to PZD and SUZI have relegated both PZD and SUZI to techniques of historical importance only. With micromanipulation, fertilization and pregnancy rates appear to be independent of sperm quality, which is the opposite of what has been demonstrated for both IUI and IVF.