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Male infertility is responsible for 40–50% of human infertility. Earlier treatment options for male factor infertility included timed intercourse, intrauterine insemination, or in vitro fertilization. These techniques are not helpful in severe male factor infertility cases as either the sperm number is extremely low or sperm motility is very poor. The introduction of intracytoplasmic sperm injection has opened the door for numerous advancements as only one sperm is needed for one egg. It has enabled men with few or no sperm in their ejaculates to have their own offspring. Surgical sperm retrieval techniques, with or without the help of a microscope, have been invented to retrieve sperm from the epididymis or testicular tissue. The clinical outcomes after the utilization of these techniques are similar to those obtained after the use of ejaculated sperm. Preimplantation genetic tests are now available to detect chromosomal aneuploidies, single gene defects, or chromosomal structural rearrangements in embryos created by using normal or defective sperm or eggs. This chapter explains in a comprehensible way, the basic and the more advanced assisted reproductive technologies to treat male factor infertility.
OriginElle Fertility Clinic and Women’s Health Centre, Montreal, Canada
Seang L. Tan
OriginElle Fertility Clinic and Women’s Health Centre, Montreal, Canada
*Address all correspondence to: murid.javed@gmail.com
1. Introduction
Infertility is an inability to achieve pregnancy after one year of unprotected sex. It can be due to male factors, female factors or their combination. Male factor infertility can be treated with medicines or utilization of assisted reproductive technologies. The effects of medicines or hormones on sperm production or quality are noticeable after about 90 days as it takes this much time to observe new sperm population. The assisted reproductive technologies, on the other hand, make use of existing levels of sperm production and provide immediate solutions that could be simple washing or concentrating sperm for intra-uterine insemination (IUI), in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). After the advent of ICSI, only one sperm is needed to fertilize an egg as compared to millions of sperm required for natural conception, IUI or IVF. For ICSI, the sperm can be processed by simple wash [1], density gradient [2], swim up [3], or by using newly introduced devices like Microfluidic [4, 5] or Zymote [6]. Ejaculated, surgically collected, fresh or cryopreserved sperm have been used successfully. This chapter will explain basic and advanced assisted reproductive technologies to treat male factor infertility. The advanced scientific information is presented for easy understanding by a general reader. Those seeking in-depth knowledge are recommended to read the referenced articles.
The male reproductive organs are shown in Figure 1. The sperm are produced in the testes and stored in the epididymis. At the time of ejaculation, the sperm are transported in a small quantity of fluid through the vas deference. The seminal vesicles and the prostate glands add their secretions to increase the seminal volume. The semen is then ejaculated through the urethra which is a common passage for the urine and the semen.
Figure 1.
Diagrammatic presentation of male reproductive organs. A = testis; B = epididymis; C = penis; D = vas deferens; E = prostate gland; F = bulbourethral gland; and G = urinary bladder. (the diagram is modified from Serono educational pamphlet).
Semen evaluation is required to determine male factor infertility. The laboratories have been performing semen analysis by manual microscopy [7, 8]. The determination of semen volume, sperm concentration, motility, and morphology are minimal requirements. These parameters can be accurately determined by manual microscopy; however, variations exist between different technologists and different labs. Computerized semen analysis [9, 10] was introduced to eliminate these variations and to determine additional sperm characteristics. The computer-assisted semen analysis systems have enabled partial automation of routine semen analysis. These systems can determine some semen parameters which cannot be determined by manual microscopy like the speed of sperm progression. They lacked wider acceptance [11] due to their complicated operation, high initial cost, expensive maintenance, and inability to analyze Micro-TESE and severe male factor samples. Newer and improved computer-assisted semen analyzers are gradually improving and entering the market to overcome these difficulties by integrating artificial intelligence optical microscopic technology [12].
The semen parameters are affected by days of abstinence, temperature at which semen is kept after ejaculation, and the time of evaluation after ejaculation. To avoid any deleterious effects and to get an accurate analysis, the production of semen at the treating facility is recommended. The lower reference limits for the most commonly assessed semen parameters are given in Table 1. These are usually considered standard semen values [13].
Characteristic
Lower reference limit
Semen volume (ml)
1.5 (1.4–1.7)
Total sperm number (106 per ejaculate)
39 (33–46)
Sperm concentration (106 per ml)
15 (12–16)
Total motility (Progressive + non-progressive, %)
40 (38–42)
Progressive motility (%)
32 (31–34)
Sperm morphology (normal forms, %)
4 (3.0–4.0)
Table 1.
Lower reference limits (5th centiles and their 95% confidence intervals) for semen characteristics.
Determination of sperm DNA fragmentation is now becoming a routine. Abnormal expression of any functional gene in the process of spermatogenesis, maturation, and storage may affect sperm morphology, structure, or function, and induce male infertility. The sperm DNA integrity is crucial for fertilization, blastocyst formation, and the development of healthy offspring [14]. A number of tests are available for the detection of sperm DNA fragmentation [15]. Less than 30% sperm DNA fragmentation is generally acceptable and requires no medical intervention.
Sperm aneuploidy is associated with detrimental effects, particularly recurrent pregnancy loss. These sperm chromosomal abnormalities happen during meiosis or mitosis of sperm. Sperm aneuploidy is detected by fluorescent molecular probes for chromosomes 13, 18, 21, X, and Y [15]. This test is not widely available; therefore, fertility clinics rely on semen analysis, sperm DNA fragmentation test, and male karyotyping for the evaluation of male factor infertility.
Home-based semen analysis systems have also been introduced like Sperm Check Fertility and Micra Sperm Test [16, 17]. These tests only indicate whether further testing is needed or not, as many tests can only provide information on one or a few sperm parameters. Thus, these home base tests are not a replacement for semen analysis in a specialized laboratory.
The decision of a reproductive laboratory technique to treat male factor infertility is based on the results of basic semen evaluation, determination of sperm DNA fragmentation, sperm aneuploidy, semen culture and sensitivity, presence of round cells, and sperm agglutination. In the majority of men, semen evaluation on two different occasions, karyotyping and sperm DNA fragmentation test are enough. The most commonly adopted treatment pathway is given in Figure 2. The choice of treatment is determined by the specialist. The number of attempts and duration in between attempts is determined by the specialist and the couple. The success rates vary among treatment options and are described in the subsequent sections.
Figure 2.
The most commonly adapted treatment pathway based on semen analysis. In this case, there is no apparent female factor infertility. The deficiency is found in semen characteristics.
The specialist will monitor the menstrual cycle and determine the best time for the release of ova based on the ovarian follicular measurements and reproductive endocrine hormone profile to recommend the time for intercourse. The chance of achieving a clinical pregnancy after timed intercourse with ovulation prediction is about 9% [18]. The number of attempts of timed intercourse is dependent on the specialist and the couple. This procedure may be more helpful for couples with younger female ages and men with almost normal sperm parameters.
Intrauterine insemination is a relatively cheaper, less intensive treatment as compared to IVF/ICSI, for achieving pregnancy [19]. Usually, the ovaries are stimulated with a low dose of follicle-stimulating hormone (FSH) to increase the number of follicles. The ovulation is triggered with human chorionic gonadotropin (hCG) for maturation and release of oocytes. On the day of IUI, semen produced from the male partner is washed, concentrated, and deposited in the uterine cavity for in vivo fertilization (Figure 3). Many variables may influence success rates after IUI. On average, pregnancy rates of 7.9–23% per IUI cycle have been reported [20]. Usually, more than three IUI attempts are not recommended as the cost of treatment exceeds than one attempt of IVF/ICSI, and the latter provides higher success rates.
Figure 3.
Diagrammatic presentation of intrauterine insemination procedure. Semen from the male partner is washed, concentrated, and injected into the uterine cavity for in vivo fertilization. A = ovary; B = fallopian tube; C = uterine cavity; and D = a syringe attached to a catheter containing processed semen. (the diagram is modified from Serono educational pamphlet).
In vitro fertilization is a process in which ovaries are stimulated to produce more follicles. Each ovarian follicle is expected to have one egg. The eggs are retrieved and fertilized in vitro (outside the body) by the addition of the appropriate number of sperm. Figure 4 outlines the timeline for the IVF procedure. The period from point A to B takes several days depending on the protocol for ovarian stimulation. The eggs are usually collected 36 hours after administration of an injection that further grows and matures the eggs. The collected oocytes from ovarian follicles are given to the Embryology laboratory for their maintenance in appropriate culture conditions of temperature, humidity, gas, and nutrition. Usually, 3–4 eggs are placed in a petri dish and the appropriate number of processed sperm is added for IVF (Figure 5). The egg collection day is considered day-0. The fertilization is checked 16–19 hours after egg insemination and the culture is continued for up to 7 days. If the couple is undergoing fresh embryo transfer, one embryo at the blastocyst stage (day-5 to day-7) is transferred into the uterus for further growth inside the body. Extra embryos are cryopreserved for future use. The pregnancy test is performed 14 days after egg collection and the fetal heartbeat is checked from 42 to 56 days. If the embryo transfer is not successful, another attempt at frozen embryo transfer is performed after proper preparation of endometrium.
Figure 4.
Timeline for IVF or ICSI procedure starting from ovarian stimulation to the detection of fetal heartbeat.
Figure 5.
In vitro fertilization in a petri dish. Usually, 3–4 eggs are placed in a petri dish and an appropriate number of sperm is added. The fertilization is checked 16–19 hours later.
With advancements in the technology, more options are available. These include; (1) performing embryo biopsy for genetic testing at the blastocyst stage (day-5 to day-7) and cryopreserving biopsied embryos, and (2) cryopreserving all embryos without biopsy for future use.
Depending on the quality of oocytes, sperm, or cause of infertility, about 50% of eggs fertilize. The chances of complete failed fertilization after IVF are 5–10% [21]. Couples who cannot take the risk of complete failed fertilization or want a higher number of eggs fertilized, prefer ICSI. The fertilization rate after ICSI among injected oocytes is significantly higher (72.3% ± 24.3%) than for IVF (59.2% ± 25.9%). However, complete failed fertilization still occurs after ICSI and the incidence is 1–3% [22, 23]. The good-quality embryo rate and clinical outcomes are not different between embryos from conventional IVF (16.6% ± 23.2%) and embryos from ICSI (16.6% ± 26.6%). Split fertilization (fertilizing some eggs with IVF and some with ICSI) decreases the risk of total fertilization failure. The assurance of fertilization with ICSI has gradually increased the use of ICSI [24] to the extent that many Embryology labs are performing 100% ICSI for all infertility cases.
The success after IVF varies significantly depending on the underlying infertility cause and the type of IVF treatment. The age of the female partner remains the most influential factor. During the initial years of IVF, most embryo transfers were performed on day-3 with multiple embryos, resulting in multiple pregnancies. The multiple pregnancies posed great risks to the mother and the developing fetuses. There has been a gradual transition from day-3 embryo transfer to day-5 embryo transfer with a single embryo to reduce the multiple births and to improve the pregnancy rate. Presently, almost all embryo transfers are performed at the blastocyst stage (day-5 to day-7) with a single embryo at each transfer.
The cumulative live-birth rate from up to six cycles of IVF in a study of more than 6000 patients undergoing 14,248 cycles was 51% with the conservative analysis and 72% with the optimistic analysis. The conservative analysis assumed that no live births happened among patients who did not return for subsequent IVF cycles and the optimistic analysis assumed that patients who did not return would have the same chance of a pregnancy resulting in a live birth as patients who continued treatment [25]. In another study, using freeze all strategy, the overall live birth rate of 50.74% in the first complete cycle among 20,687 women was achieved through IVF [26]. The complete cycle was defined as all the frozen-thawed embryo transfer attempts resulting from one round of ovarian stimulation. In this study, the live birth rate declined from 63.81% for women under 31 years of age to 4.71% for women over 40 years of age. The main cause of infertility in this study was tubal occlusion. The IVF was performed in 66.38%, ICSI in 27.38%, and both IVF and ICSI in 6.24% of cycles. The IVF not only increases the success rate as compared to the IUI procedure but overcomes problems in female partners like blocked fallopian tubes. The IVF treatment often overcomes infertility in younger women; however, it does not reverse the age-dependent decline in fertility [25].
In this technique, a sperm is injected directly into the cytoplasm of an egg. The processes of ovarian stimulation, egg collection, and culture are similar to the IVF procedure. The only difference is the fertilization process. For ICSI, after collection, the eggs are stripped of all cells surrounding the zona pellucida so that the egg maturity can be determined and sperm can be deposited accurately. Both sperm and eggs are microscopic structures, therefore very precisely made microscopic tools and a high-power inverted microscope are required (Figure 6).
Figure 6.
Inverted microscope equipped with micro-tools for handling the egg and sperm and performing the ICSI procedure. A vibration free table is required to prevent damage to the egg during injection procedure.
For injection, the sperm is immobilized by an injection pipette (Figure 7 A) and aspirated into it (Figure 7 B). The egg is held in a desired position by a holding pipette and the injection pipette containing the sperm is inserted from the opposite end (Figure 7 C). The injection pipette is advanced further close to the opposite end of the egg (Figure 7 D). A small amount of cytoplasm is aspirated into the injection pipette to ensure egg membrane breakage. If the cytoplasm moves freely, the sperm is deposited there (Figure 7 E), and the injection needle is drawn out of the egg slowly (Figure 7 F).
Figure 7.
ICSI steps. (A) the sperm is immobilized and its membrane broken by the injection pipette; (B) the sperm is aspirated into the injection pipette; (C) the egg is held by a holding pipette and the injection pipette is inserted through the zona pellucida into the egg cytoplasm from the opposite end; (D) the injection pipette is advanced further close to the opposite end of the egg; (E) a small amount of cytoplasm is aspirated into the injection pipette to ensure egg membrane breakage. If the cytoplasm moves freely, the sperm is deposited there; and (F) the injection needle is drawn out of egg slowly.
There are many situations, like severe male factor, globozoospermia, and azoospermia, for which fertilization by IVF cannot happen, therefore, the sperm has to be injected directly into the egg. For ICSI, only one sperm is needed for an egg, whereas, for IVF about 100, 000 motile sperm per 1 mL, and the IUI 5 million sperm per insemination are generally recommended. Because of this requirement of one sperm for one egg, many men with rare sperm in their ejaculate have been able to father their children. In men suffering from azoospermia (who have no sperm in their ejaculate), sperm can be retrieved from the epididymis or directly from the testis by different techniques.
Figure 8 explains different sites and techniques for obtaining sperm from male reproductive organs. The preferred, simple, and economical method for sperm availability is to have a male partner ejaculate a semen sample even in severe male factor infertility cases (Figure 8, H). The semen is diluted and mixed with appropriate media, centrifuged, supernatant removed, and only the 50 micro-liter pellet is examined to find enough sperm for the expected number of retrieved eggs. This procedure should be repeated multiple times before egg collection to obtain and freeze enough sperm for subsequent use on the day of egg collection.
Figure 8.
Diagrammatic presentation of different sources of sperm for ICSI from male reproductive organs. The complexity of sperm retrieval depends on the site of collection and the type of retrieval procedure. The sperm are made in the seminiferous tubules of the testicles, stored in the epididymis, and transported by various ducts. Based on the source of sperm, appropriate assisted reproductive technique is applied. A = testicle, the site of spermatogenesis; B = epididymis, a place for sperm maturation and storage; C = penis, D = vas deference, a tube to transport sperm at ejaculation; E = prostate glands, adds their secretion to sperm; F = seminal vesicles, adds their secretion to sperm; G = urinary bladder; H = ejaculated sperm source; I = site for surgical sperm retrieval from testicular tissue; J = epididymis for sperm collection; K = microscopic structure of a tubule where the sperm are formed; L = a section of the tubule showing different cell types and progression from round cells to a flagellar cell (sperm); and M = a fully formed sperm. (the diagram is extracted from Serono educational pamphlet).
If the sperm are not found from at least two ejaculates two weeks apart, the urologist’s help is needed to obtain sperm from the epididymis. The procedure is called percutaneous epididymal sperm aspiration (PESA; Figure 8, J). If this procedure does not provide sperm, the testicular biopsy/testicular sperm aspiration (TESA; Figure 8, I) has to be performed by the urologist. The advanced options are testicular sperm extraction (TESE) without a microscope or Micro-TESE in which the testicular tissue is dissected under a microscope. In Figure 8, K and L are showing the testicular tubules where the sperm are formed.
Live births have been reported from fresh or frozen-thawed sperm retrieved by any of the above-mentioned techniques [27, 28, 29]. Pregnancy and delivery have been reported after the collection of only one egg, its ICSI, and the transfer of only one embryo [30].
Globozoospermia is a condition in which all or most of the sperm are round-headed. These sperm lack PLC zeta (PLCζ) which is required for oocyte activation and fertilization [31]. The round-headed sperm are unable to fertilize eggs. Fertilization of eggs with ICSI and artificial oocyte activation with calcium ionophore or other substances have solved this problem and many births have been reported [32, 33].
Another challenge in severe male factor infertility is the presence of all immotile sperm in the semen sample. Such sperm may be alive but not moving or could be dead. The sperm motility is due to its tail which is not required for fertilization by ICSI, however, injection of a viable sperm is desired. Also, frozen-thawed testicular sperm often lack motility. For such cases, techniques have been developed to differentiate between viable and non-viable sperm. Usually, the hypoosmotic swelling technique or addition of pentoxifylline/theophylline to the sperm preparation successfully differentiates between alive and dead sperm [34, 35].
9. IVF/ICSI with preimplantation genetic testing (PGT)
The difference between IVF/ICSI and IVF/ICSI with PGT is that at the blastocyst stage (day-5 to day-7), a few cells from the outer layer (trophectoderm) of each embryo are taken and sent to the genetic testing lab. The biopsied blastocysts are frozen and transferred a few months later based on genetic test results (Figure 9).
Figure 9.
Steps to perform embryo biopsy at the blastocyst stage. It is preferred that the biopsy is performed after the embryo has become a blastocyst but has not yet fully hatched. In this figure, the blastocyst is hatched (A). The trophectoderm is stretched out by a holding pipette on the left side and by a biopsy pipette on the right side (B and C). The stretched cells are cut by laser shots (C). A few (3–5) trophectodermal cells are sent to the genetic lab for genetic testing. The biopsied blastocyst is frozen.
The blastocyst PGT is defined as a test that analyses the DNA from the trophectoderm of a blastocyst for HLA typing or for determining genetic abnormalities. There are 3 types of blastocyst PGT: PGT-A, is for the detection of chromosomal aneuploidies; PGT-M, is for the detection of monogenic/single gene defects and PGT-SR, is for the detection of chromosomal structural rearrangements [36].
Due to the new and safer embryo biopsy techniques and advancements in genetic testing, PGT-A has been widely practiced, with some clinics performing PGT-A for all infertile couples. The liberal use of this very expensive technology for all infertile couples is controversial [37, 38]. Several studies reported higher birth rates after PGT-A and elective single-euploid embryo transfer, though these studies have important limitations [39].
Assisted reproductive technologies have rapidly evolved over the past few decades and are providing significantly higher birth outcomes in all categories of infertile men. These techniques are safe and offer hope to many men wishing for a healthy child. The introduction of ICSI opened a new era and revolutionized the treatment of male factor infertility. The addition of surgical sperm retrieval techniques (PESA, TESA, TESE, and Micro-TESE) has further improved outcomes for male infertility. The newer genetic technologies (PGT-A, PGT-M, and PGT-SR provide assurance for the birth of a genetically normal child.
Acknowledgments
We acknowledge the graphic material provided by Serono Canada based on which some figures were designed.
Conflict of interest
The authors declare no conflict of interest.
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Written By
Murid Javed and Seang L. Tan
Submitted: 16 June 2023Reviewed: 14 July 2023Published: 18 August 2023
Open access peer-reviewed chapter
