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GENERAL MANAGEMENT

This section covers aspects of the management of couples with male infertility not amenable to specific treatment (Table 6). A number will conceive during investigation. Others will decide not to continue with medical intervention. Some patients with treatable conditions may choose ICSI instead of treatment or after a treatment has been unsuccessful. However, most couples with male infertility have conditions for which there is no clearly defined and certainly effective treatment. In these cases, it is important to discuss the prognosis for a natural pregnancy occurring, the ineffectiveness of treatments, and the availability of IVF and ICSI, donor insemination, and adoption. The investigation of the female partner should be reviewed and abnormalities treated when possible. Patients should be acquainted with the physiology of the menstrual cycle and symptoms of ovulation to help time sexual intercourse over the fertile phase of the cycle.¹²¹ Good health practices should be promoted, particularly cessation of smoking because it reduces fertility in women. The psychological upheaval experienced by the couple should be discussed and additional help offered if necessary. Specialist infertility counselors and patient support groups are particularly valuable in this area.

PROGNOSIS FOR NATURAL PREGNANCY

A number of factors in addition to semen quality affect the likelihood of natural pregnancies occurring. ^{1, 2, 4, 10, 122, 123} Some are obvious, such as female disorders and coital dysfunction. Female age is important because fertility declines after approximately 35 years of age. Duration of infertility is a major factor in most studies: The longer the infertility, the worse the outlook. The prognostic factors found in a study to determine the effect of varicocele surgery were duration of infertility (negative), mean sperm concentration (positive), untreated sperm autoimmunity (negative), ovulatory disorders (negative), occupational group (farmers doing better than other occupations), female age (negative), and previous fertility in the couple (positive).⁸ Interestingly, varicocele presence and size were positive prognostic factors even though varicocele surgery was not significant. The pregnancy rate curves for different sperm concentration groups are shown in Figure 9. Subfertile patients seen in the late 1990s had similar natural conception rates.¹⁰ Such factors can be used to advise patients about their chances of producing a natural pregnancy over time. The accuracy of prediction is low because the statistically significant factors only explain a small part of the variability of the pregnancy rates. New studies using automated methods for semen analysis reveal the percentage of sperm with characteristics conforming to morphometrics preferred for binding to the ZP, and the straight line velocity, may have better predictive value.¹⁰ However, other factors currently not assessable, such as gamete transport, may have an important bearing on conception and may explain the occurrence of pregnancies in some couples despite severely abnormal semen analysis results. Patients should not be told natural conception is impossible unless there is an absolute barrier to fertility.

PSYCHOLOGICAL ASPECTS

Infertility causes major trauma to the ego of most patients, but few suffer serious psychological disorders. Many undergo a grief reaction with initial denial of the problem followed by a tendency to blame others and a period of depression before final acceptance of the infertility. The reaction may take years to resolve, and it can threaten the stability of the partnership, interfere with investigation and management of infertility, and lead to futile involvement in expensive "cures" offered by the unscrupulous. Participation in unsuccessful treatments during this phase is often particularly difficult emotionally for the patients. Stresses of ordinary existence are unlikely to influence semen quality.¹²⁴ An empathetic approach and involvement of independent counselors or self-help infertility groups may assist some couples. In most, the unpleasantness of the psychological reaction subsides with time.

TIMING OF COITUS

A practical approach is to advise intercourse each day when ovulation might occur. Ovulation can be predicted to occur approximately 14±2 days before a period is due. Knowing the range of menstrual cycle length allows calculation of the days when ovulation is most likely to occur. Symptoms of ovulation including mittelschmerz and mid-cycle mucus changes also help identify the fertile time.¹²¹ Temperature charts may be used to indicate the end of the fertile time as the basal body temperature rises after ovulation. Ovulation timing by measurement of estrogen and progesterone metabolites in urine, urine or serum LH levels, or ovarian ultrasonography may also be used.

GENERAL HEALTH ASPECTS

Although correction of adverse lifestyle factors in the most men seen for infertility is unlikely to produce normal fertility, healthy living has positive long-term benefits. The following are advised: weight reduction for the obese, reduced alcohol intake for the moderate to heavy drinker, avoidance of social drugs including tobacco, avoidance of heat from frequent sauna and spa baths, and management of stress in the workplace, in marriage, and that engendered by the infertility.

EMPIRCAL TREATMENTS: EVIDENCE-BASED VERSUS UNCONFIRMED TREATMENTS

Treatments of some causes of male infertility are available as discussed previously, but for the majority of patients with abnormal semen analyses, there are no methods of proved effectiveness.^{13, 125} A medical or surgical treatment may become established because it is logical and obviously effective, for example, gonadotropin treatment for Kallmann syndrome or vasoepididymostomies for postinflammatory obstructions of the tails of the epididymides. However, in other situations in which semen quality is reduced and there is subfertility rather than absolute sterility, it is necessary to demonstrate that the treatment increases semen analysis results and pregnancy rates by a clinically meaningful amount. This evidence-based medicine approach generally requires controlled clinical trials of promising methods. These trials are usually designed to detect a certain magnitude of difference in the primary responses and thus a positive result supports the use of the method. However, if the trial is negative, it merely does not confirm the magnitude of benefit tested; it does not prove the method is of no value. In time, the results of several trials can be combined by meta-analysis to get better estimates of the overall effects of the method.

In the past, many treatments were used in an uncontrolled fashion for defects of sperm production.^{13, 125} Androgens have been given to suppress spermatogenesis in the hope that there would be "rebound" improvement after the treatment is stopped. Low-dose testosterone or weak androgens, such as mesterolone, have been given in the hope of improving epididymal maturation of sperm. Human chorionic gonadotropin has been given for similar reasons. Antiestrogens have been used to increase gonadotropin secretion or gonadotropins (FSH and human chorionic gonadotropin) given to "stimulate" spermatogenesis. Antibiotics and anti-inflammatory drugs have been given for subtle infections or inflammations in the accessory sex organs. Antioxidants, amino acids, vitamins, herbs, and minerals such as zinc, cold baths, and testicular coolers have been used. There are difficulties with the interpretation of the results of these treatments.¹³ Marked improvements in semen quality can occur spontaneously (Fig. 10). Semen analysis results also display the phenomenon of regression to the mean. That is, on average, repeated semen analyses improve in men with initially abnormal results.¹¹⁸ Pregnancy rate data were not analyzed effectively in many early studies. Floating numerator pregnancy rates, in which a percentage of patients pregnant is given without regard for time of exposure, have caused confusion in the infertility literature. Statistical methods for life table analysis and regression analysis with censored data are especially useful for assessing the impact of groups of variables on pregnancy rates, for analysis of prognostic factors, and for testing results of therapeutic trials.¹³

The empirical treatments either have not been submitted to adequately controlled clinical trials, or when they have, the trials have not shown consistently positive results. Meta-analyses have also produced conflicting results, probably because of the variable quality of the trials included in the analyses. Until there is sound evidence of the value of a drug or procedure from controlled therapeutic trials, patients should be advised that none of the empirical methods meet the requirements of evidence-based medicine.

AIH is widely practiced with dubious evidence of efficacy in patients who do not have coital difficulties. Ovulation induction with intrauterine artificial insemination probably does increase the pregnancy rates by increasing the number of oocytes exposed to the sperm.¹²⁶ Results are lower with timed intercourse and multiple ovulation induction. Generally, the results are poor when the semen analysis is abnormal. Although this may be acceptable in countries where ART is expensive, the risk of multiple pregnancy is substantial. IVF or ICSI would be preferable because the number of embryos placed in the uterus can be controlled and high multiple pregnancies avoided.¹²⁶

IN VITRO FERTILIZATION/INTRACYTOPLASMIC SPERM INJECTION FOR MALE INFERTILIT

ICSI has revolutionized the management of male infertility. It involves the injection of a single sperm into the ooplasm (Fig. 11).^{127, 128} ICSI can be used with almost any live sperm with an expectation of results similar to those obtained with standard IVF using normal sperm. ICSI may not be needed with mild semen disorders. Provided that more than approximately 2 million motile sperm can be harvested from an ejaculate, IVF can be attempted with an expectation of success close to that of IVF for other indications. The outcome depends particularly on sperm morphology and the ability of the sperm to bind to and penetrate the ZP. ICSI should be offered if there is a chance of failure of fertilization with IVF: less than 2 million motile sperm per ejaculate, less than 5% of sperm with normal morphology, less than 5% of sperm with progressive motility, sperm autoimmunity, and defects of sperm-oocyte interaction.

PREPARATION OF THE PATIENTS

The couple needs to be counseled carefully about the procedures, predicted chance of a live birth, and the possible complications. Special arrangements for the collection of semen, or for its preparation, may be required. Trial-run sperm preparations help to identify those patients who have difficulty collecting semen. These patients should practice collections before attending for the IVF procedure. Men with many inflammatory cells in the semen could be treated with antibiotics. Those with low motility or sperm autoimmunity may have better sperm motility with short, 1- to 2-day durations of abstinence. Cryopreserved semen can be used as backup if the fresh semen is particularly poor on the day of ICSI in patients with fluctuating semen abnormalities. This is particularly useful when sperm are present in the semen only intermittently. Those patients who produce an unexpectedly poor sample on the day of IVF should provide a second sample later to supplement the first sample. Electroejaculation or needle biopsy of the testes can be used if the man is unexpectedly unable to collect semen. Patients with genital tract obstruction can have sperm retrieved from the testis or epididymis by needle aspiration.

ICSI also allows patients with severe primary spermatogenic disorders to be treated provided some live sperm or elongated spermatids can be recovered from the semen, testes, or genital tract (Table 172-7). If no sperm can be found in the semen, the likelihood of finding elongated spermatids in the testicular tissue can be estimated by the clinical situation and testicular histology. Sperm can be found by biopsies in approximately 50% of men with Klinefelter syndrome. Results are good if any tubules with complete spermatogenesis can be seen in diagnostic biopsies. However, if there are no elongated spermatids, the success rate with open biopsies is low: approximately 25% with Sertoli-cell-only syndrome and rarely with germ cell arrest at the primary spermatocyte stage.^{91, 129} Yq microdeletions in the AZFa and b regions are also associated with a complete absence of spermatogenesis. Other factors such as hormone levels and testicular size do not seem to be predictive. The use of donor sperm should be discussed during preparation of the couple if the outlook is poor.

Testicular biopsy techniques should maximize the chance of finding sperm while minimizing damage. Microsurgery with examination of exposed testicular tissue under the operating microscope may allow selection of the larger diameter tubules, which are more likely to contain more advanced spermatogenesis.^{129, 130} Alternatively, multiple sampling through small holes in the tunica may be used.¹³¹ Large biopsies, particularly at multiple sites, have higher complication rates and will further impair testicular function. Generally, repeat open biopsies for sperm collection should be performed only after the patient and testes have recovered from the previous surgery, and this may take 4-6 months.

APPROACHES

The standard approach is to stimulate multiple ovarian follicular development with FSH and collect the oocytes by ultrasound-guided transvaginal needle puncture of the ovaries after administration of human chorionic gonadotropin to mature the oocytes. ICSI or IVF is performed, and the resulting embryos are transferred into the uterine cavity, usually at the four- (day 2) to eight-cell (day 3) or blastocyst (day 5 or 6) stage with cryopreservation of remaining embryos. Although cryopreservation reduces the implantation potential frozen embryos produce good pregnancy outcomes.¹³²

Biopsy of blastomeres for detection of chromosomal and genetic abnormalities is used to avoid transmission of serious hereditary diseases.¹³³

SPERM PREPARATION

Various procedures have been developed for sperm preparation for IVF. Most popular is centrifugation on gradients of colloidal silica because this can be performed with high reproducibility.¹³⁴ Cryopreserved samples require especially gentle handling, particularly with dilution of the semen cryoprotectant medium with culture medium. Motility, even just an occasional slight twitch of the tail, is required in selecting sperm for ICSI. The morphology of the sperm cannot be assessed in detail at the magnification used, but obviously grossly abnormal sperm are excluded. If no motile sperm can be found, motility stimulation with pentoxifylline or hypoosmotic swelling can be used to show that the sperm are alive.¹³⁴

RESULTS

With IVF and ICSI, 60% of oocytes fertilize and cleave normally over the first 48 hours. For women younger than 35 years of age, the clinical pregnancy rate (fetal heart positive ultrasound at 6 weeks gestation) for transfer of one fresh 2-day old embryo is approximately 30% and for transfer of two 2 day old embryos 40%. Pregnancy rates are approximately 25% lower with cryopreserved embryos. The cumulative live birth rates with transfer of fresh and cryopreserved embryos from the first oocyte collection are approximately 50% and 80% by the third oocyte collection in women under 35 years of age. Approximately 25% of the births resulting from transfer of two 2-day old embryos are twins. Multiple pregnancy is more frequent if three or more cleave stage embryos or two or more blastocysts are transferred. Many clinics are transferring single embryos (elective single embryo transfer) in patients with good prognosis to minimize the multiple pregnancies. A number of other factors influence the results of ART, including embryo quality and particularly female age. Implantation and pregnancy rates decrease and pregnancy losses increase after age 35, mostly due to increasing abnormalities in the oocytes. For women aged 36-39 years the live birth rate is about 70% of that for women under 36 and for those 40 years and over using their own oocytes, about 30% that for women under 36.

EVALUATION OF FAILED FERTILIZATION

When most or all oocytes fail to fertilize in IVF, the cause is usually defective sperm. Oocytes may not fertilize because of immaturity or abnormality, but this is an unusual cause of total failure of fertilization of all the oocytes retrieved from a woman.⁶⁶ Unexpected failures of fertilization should be evaluated by examination of the number of sperm bound on the ZP and penetrating the ZP. Low numbers usually indicate sperm defects.⁶⁶ Low fertilization rates may also result from undiagnosed sperm autoimmunity, the presence of sperm antibodies in maternal serum added to culture media, infected semen, or technical problems in the IVF laboratory. Careful evaluation of the semen quality and screening patients with idiopathic infertility for defects of sperm-oocyte interaction before IVF should allow most couples likely to have low fertilization with standard IVF to be directed to ICSI.^{66, 135} ICSI of unfertilized oocytes with the man’s sperm 12 to 24 hours after standard IVF insemination may result in fertilization and pregnancy, but, overall, the results are poor and many clinics do not perform this "ICSI rescue" procedure. Re-insemination of failed fertilization oocytes with donor sperm is also possible for diagnostic or therapeutic purposes. This procedure is not permitted in some countries.

Individual oocytes may not fertilize with ICSI. In these, the sperm head is often only partially decondensed. Failure of fertilization of all oocytes with ICSI is rare. Globospermic, immotile and rarely sperm from patients with severe oligospermia may produce low or zero fertilization rates with ICSI. In these cases there may be a deficiency of an oocyte-activating factor from the sperm. Modified ICSI techniques may be successful in artificially activating the oocytes in some of these cases.⁷⁶

COMPLICATIONS OF IN VITRO FERTILIZATION/INTRACYTOPLASMIC SPERM

Potential adverse effects of ART include well-understood conditions in the woman and a variety of possible issues for the offspring. In general, the outcome and complications of ART are the same for standard IVF and ICSI.^{136, 137} The implantation rate, pregnancy wastage, pregnancy complications, perinatal mortality, and risk of congenital abnormalities are no greater for ICSI than with IVF. Recent results for ART for male infertility are compared with those for infertility of other causes in Table 7.¹³⁸ The pregnancy, miscarriage and other outcomes are if anything better not worse for male infertility.

In 2005 48% of embryo transfers were with single embryos and the multiple pregnancy rates were for fresh embryo transfers following IVF: 16.2%, ICSI 14.7% and thawed cryopreserved embryo transfers (FET) 10.9%. The perinatal mortality (stillbirth and neonatal deaths within 28 days of life) was for IVF 18.2, ICSI 15.3 and FET 11.8 per 1000 births. The perinatal mortality for ART singletons was 9.6 and for the general population in 2004: 10.2.

Risks for the Woman

The ovarian hyperstimulation syndrome is a major risk with gonadotropin stimulation of multiple follicular development.¹³⁹ Careful monitoring of the patients is necessary. If many follicles develop, embryo freezing rather than transfer avoids pregnancy and allows the ovaries to recover, reducing the risk of severe complications such as thromboembolism, renal failure, and death. Surgical complications including bleeding and infection from the oocyte collection procedure are rare. There is also a small risk of complications from anesthesia and sedation. Maternal complications of pregnancy increase in frequency with multiple pregnancy. Cesarean section is more frequent for singleton ART births than in the general community. There are also concerns about the ovarian stimulation drugs predisposing to breast or gynecologic cancers.¹⁴⁰

Risks for the Child

Multiple Pregnancy

The risks of multiple pregnancy for the child, prematurity, low birth weight, increased perinatal mortality and morbidity, less parental attention during childhood, are well known and can be controlled by reducing the numbers of embryos transferred together.^{136, 139, 141, 142}

Transmission of Genetic and Chromosomal Disorders

The known genetic risks were covered previously (see Table 4). For conditions such as cystic fibrosis and myotonic dystrophy, pre-implantation genetic diagnosis can be used so that only unaffected embryos are transferred. Balanced chromosomal translocations may become unbalanced in embryos and result in miscarriage or rarely in the birth of an abnormal child. Pre-implantation genetic diagnosis may also be used to detect unbalanced chromosomal constitution in the pre-implantation embryo.¹³³

Defects Possibly Associated with Abnormal Spermatogenesis

There is a correlation between the production of abnormal sperm with poor morphology and motility and abnormal sperm DNA measured by a variety of techniques including acridine orange fluorescence, sperm chromatin structure assay, chromomycin staining, and comet assays. ¹⁵ Abnormal sperm produce reactive oxygen species that could damage sperm DNA and result in defects of implantation or pregnancy loss. ¹⁵ However, the results of ART do not reveal such problems (see Table 7).¹⁷ A number of mechanisms reduce the likelihood such abnormal sperm would be involved in natural or assisted fertilization such as sperm aggregation caused by heavy coating with clusterin, poor motility, and limited ability to bind to the zona pellucida.^{143, 144}

A two- to sixfold increase in de novo sex chromosomal aneuploidy and structural autosomal defects has been reported with ICSI, probably related to increased rates of chromosomal nondisjunction as a general association with abnormal spermatogenesis.^{87, 145, 146} Bonduelle and colleagues showed that the rate of de novo chromosomal defects in prenatal tests was higher after ICSI with sperm from oligospermic men (2.1%) than from normospermic men (0.24%).¹⁴⁵

Embryo Defects Possibly Caused by Laboratory Conditions

Laboratory conditions or procedures on gametes could affect embryo development and health of the child. In domestic animal IVF, there is a syndrome of large offspring that results from stress-induced changes in gene expression that may involve changes in DNA methylation and gene imprinting in embryos cultured to blastocysts.¹⁴⁷ Increased frequencies of rare conditions caused by disorders of imprinting such as Beckwith-Weidemann syndrome and Angelman’s syndrome have been reported in children born from ART procedures.¹⁴⁸ Increased frequencies of tumors in children born after ART have also been claimed, for example, retinoblastoma, but other studies do not support a general increase in childhood cancer rates.¹⁴⁹

Surveillance Studies

The fertilization, implantation, and pregnancy failure rates and congenital malformation rates are no greater with ICSI than with standard IVF.^{136, 137} However, overall results are different from those in the general population: preterm birth (6%), low birth weight (5%), major congenital malformations (2%), and perinatal mortality (1%)(see Table 7). The differences are partly explained by the high multiple pregnancy rate with IVF and ICSI, and perhaps female age and infertility factors. Closer surveillance and more accurate reporting may also contribute. The lower birth weight also affects singletons and there is a difference between the results of fresh and cryopreserved embryo transfers the low birthweight being more frequent in babies born after fresh embryo transfers.¹³²

Studies of children born as a result of ART have not revealed any consistently associated congenital malformations, but there are data suggesting generally increased congenital malformation rates.^{150, 151} However, these studies may be biased. For example, if IVF and ICSI babies are examined more thoroughly and reporting to health registers is more complete, the malformation rates may appear higher than for naturally conceived children who are less carefully examined and reported. A higher uptake of prenatal screening for Down syndrome and other triploidies in ART patients may also influence the reported rates of birth defects. Even with perfect reporting, differences in malformation rates could be caused by other factors, such as age, parity or health of the mothers, which have not been adequately allowed for in the statistical analysis.

USE OF DONOR SPERM

Donor insemination is a common method of managing male sterility.^152-155 Donor sperm may be involved in approximately 1 in 200 births in countries where it is permitted. The main indications for donor insemination are untreatable sterility in the man or when treatments and ICSI for severe or chronic subfertility have failed. The couple may choose donor insemination as the primary method of managing their infertility. Donor insemination is also used to avoid transmission of a severe genetic or infectious disease in the man. Women without a male partner may use donor insemination to have children. Donor sperm may also be used in IVF when there is a combination of female infertility and male sterility. Because of the higher pregnancy rates, IVF with donor sperm may be used if donor insemination fails.¹⁵⁴ Donor sperm may also be used in IVF procedures as a backup, for example, when there is a high risk of failure with of sperm extraction with a severe spermatogenic defect.

CRYOPRESERVATION OF SEMEN

Donor insemination can be performed in the setting of a specialist infertility clinic with all donor and patient management available. Alternatively, the sperm bank may only supply semen for the patient and be separate from the clinics or physicians performing the artificial insemination. Because of the risk of transmission of infectious diseases, particularly HIV, and also for convenience, donor insemination services now use only cryopreserved semen.^{152, 154} Semen cryopreservation with glycerol–egg yolk cryoprotectant and either vapor freezing or controlled-rate freezing in plastic straws or vials produces pregnancy rates equal to those with fresh semen. Importantly, cryopreservation allows the semen to be quarantined for 6 months for donors to be recalled and retested for infectious diseases before it is used.

SELECTION OF DONORS

Prospective donors have their medical and family histories evaluated and a physical examination to exclude the possibility of transmitting serious genetic diseases such as hemoglobinopathies or sexually transmissible infections. Donors sign a lifestyle declaration to indicate that they are not involved in any practices that might expose them to serious infections, such as HIV. There usually is an upper age limit of 40 to 45 years because of the increasing frequency of genetic abnormalities in sperm with age. Semen quality is selected to be in the upper part of the normal range, particularly for concentration and motility.^{152, 153} The semen is cultured for bacteria and blood is tested for hepatitis and HIV antibodies. Genetic screening for hemoglobinopathies and cystic fibrosis or other conditions may be included depending on their prevalence in the community. The freezing of semen does not appear to cause any increase in the frequency of congenital abnormalities.^{152, 154, 156}

It is usual to match the physical characteristics of the recipient’s husband and the donor including race, complexion, build, height, and hair and eye color. In addition, blood groups may be matched. In some programs, the recipient couple may be able to choose the donor on other information such as occupation and education. Known donors may also be used; these may be friends or relatives of the infertile couple. In this situation, special counseling of the donors and recipients is necessary. Also, there should be a full workup of the known donor as for an anonymous donor, including cryopreservation and quarantining of the semen.

Donor factors relevant to the success of donor insemination are mainly to do with the quality of the semen. Post-thaw motility has the strongest predictive value for high fertilization rates, but sperm morphology, motility, and concentration are also significant.^{152, 154} Despite selection of high-quality semen, there remains considerable variability in the pregnancy rates between donors. A policy to discard semen from a donor who produces no pregnancy after a certain number (e.g., 20–40) of inseminations is necessary.¹⁵³

COUNSELING

The special nature of the use of donor sperm is discussed in detail with the couple so that they are fully aware of the implications for the child and their family. Donor insemination is forbidden in some religions. There may be local legislation or regulations to control the use of donated gametes. In some countries, special laws have been enacted that may either allow or prevent the child from obtaining identifying information about the donor. The legal status of the child may also be specified in various ways. The couple needs to decide how and when to disclose the child’s donor sperm origin. What and how much they should tell their friends and relatives about their infertility treatment should also be discussed, as should their reaction to acquaintances questioning the paternity of the child. The possibility that in the future half-siblings may unwittingly find each other and attempt to have children is of concern to some prospective parents and donors. This needs to be discussed carefully and the risks explained in view of the number of pregnancies permitted per donor by the clinic. Studies of donor families in which there has been expert pretreatment counseling indicate no physical or emotional problems with the children, and greater marital stability than average.¹⁵⁶

The prospective recipients are screened for HIV, hepatitis B and C, rubella immunity, blood group, and genetic conditions if necessary. Tests of tubal patency are performed if the history suggests pelvic pathology. The inseminations are timed to coincide with natural ovulation. Careful monitoring of ovulation and timing of intrauterine insemination of prepared motile sperm suspensions (as for IVF) appear to increase the pregnancy rate. Pregnancy rates are approximately 10% to 25% per month for the first 4 to 6 months and then 5% to 10% thereafter, so that approximately 50% of women are pregnant by 4 to 6 months.^{152, 154, 155} Female age affects the pregnancy rates.^{152, 155} Women with subfertile male partners have on average lower pregnancy rates than those with sterile male partners, indicating the presence of female factors contributing to the infertility when the male partner is subfertile.^{152, 155} Cumulative pregnancy rates for women who have had more than one pregnancy by donor insemination indicate higher conception rates over the first few months for the second pregnancy, approximately 33% pregnant in the first cycle and 55% by the second cycle.¹⁵²

Multiple ovulation induction and intrauterine insemination may increase the pregnancy rates but at the risk of multiple pregnancy.^{152, 155} IVF may be used if no pregnancy has occurred after a reasonable number of inseminations (e.g., 4–6).¹⁵⁴ Live birth pregnancy rates with IVF in such patients are high, and women in good health can be advised that they have an 80% chance of having a child within 2 years.

PREVENTION OF INFERTILITY

Prevention is difficult because of the lack of understanding of the causes of most types of male infertility. Mumps orchitis was an uncommon cause of infertility, and childhood immunization for this disease should make it very rare. It is important to recognize that subfertility often is a couple problem, with both partners contributing. Therefore, general factors that would change a society’s attitude to child bearing could have an important impact on the frequency of infertility, for example, a trend toward having children at earlier ages. On the other hand, toxins and environmental factors known to cause defects of sperm production, such as heat, dibromochlorobenzine, lead, benzene, ionizing radiation, and microwaves, are probably well controlled by environmental health measures.

PREVENTABLE DISEASES AND CONDITIONS

Sexually Transmissible Infections

Post-gonococcal epididymal obstructions appear to be the most important cause of infertility from sexually transmitted diseases. In countries where gonorrhea is treated promptly, post-gonococcal epididymal obstruction is rare. On the other hand, it remains a common preventable cause of infertility in other countries.

Undescended Testes

Although undescended testes have been sought and treated aggressively over the past 50 years, previously undescended testes remain a common association of male infertility, affecting approximately 7% of the men seen. It is therefore uncertain whether early surgery for undescended testes has any impact on subsequent fertility. It is possible that the failure of normal descent is a feature of testicular dystrophy and that the sperm production will be poor whether or not the testes are placed in the scrotum.

Varicocele

The effectiveness of varicocelectomy for sperm defects is controversial. Varicoceles are common and usually appear about the time of puberty. Although some groups believe that varicoceles should be sought actively and treated in adolescence to prevent infertility, this approach could pose a major burden on the health resources because at least 15% of men have varicoceles. Long-term prospective trials are needed.

Vasectomy

Vasectomy reversal and treatment for continuing infertility after attempted vasectomy reversal are now common. Better counseling about the limited effectiveness of vasectomy reversal is needed and cryopreservation of semen before vasectomy in men who are uncertain about their need for future fertility should be promoted.

SEMEN CRYOPRESERVATION BEFORE LOSS OF FERTILITY

Men about to have treatment for malignant conditions may have sperm cryopreserved before commencing chemotherapy or radiotherapy.¹⁵⁷ Although pretreatment semen quality may be too poor for AIH, ICSI now has improved the outlook for successful pregnancies. Semen collected during chemotherapy or radiotherapy must not be used because of the likelihood of induced mutations.¹⁵⁸ Other illnesses that require treatment that might cause sterility include nephritis, prostatic disease, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases. Semen cryopreservation can also be offered to adolescents. Sperm may be obtainable from the semen or testis after mid puberty. Some groups are offering to cryopreserve prepubertal testicular tissue before potentially sterilizing treatments in the expectation that effective techniques for transplantation or in vitro production of sperm will be developed in the future.¹⁵⁷

Infertile men with conditions such as orchitis or severe primary spermatogenic disorders that might involve progressively declining semen quality should also store any live sperm that can be obtained as insurance for the future. A similar approach could be extended to adolescents with risk factors for infertility such as undescended testes in childhood, testicular torsion, and possibly a family history of infertility or a father with a Yq microdeletion. Semen may also be stored after treatment of gonadotropin deficiency or surgery for genital tract obstruction in case of re-stenosis. Although only a small proportion of men who store semen may use the frozen sperm, the service continues to provide insurance for future fertility.