PROSPECTS FOR FERTILITY IN PATIENTS BORN WITH GENITOURINARY ANOMALIES

0022-5347/01/1656-2354/0 THE JOURNAL OF UROLOGY® Copyright © 2001 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 165, 2354 –2360, June 2001 Printed in U.S.A.

John W. Duckett, Jr. Lecture PROSPECTS FOR FERTILITY IN PATIENTS BORN WITH GENITOURINARY ANOMALIES C. R. J. WOODHOUSE From the Institute of Urology and Nephrology, University College London, London, England

ABSTRACT

Purpose: The effect of congenital genitourinary anomalies on fertility and the impact of current therapies are reviewed. Materials and Methods: The literature of each of the 2 components was used to define the present status and to make proposals for future management. Results: Infertility may be caused by gonadal failure (intersex states), failure of sperm transport (exstrophy) or both (bilateral undescended testes). In some conditions it is uncertain whether there are any fertility problems despite an identifiable genital problem. In cases of unilateral undescended testis the fertility rate may be unaffected by surgery and be no different from that in the normal population. Techniques of in vitro fertilization, particularly intracytoplasmic sperm injection, have allowed previously untreatable patients to become parents. Successful pregnancies in patients who had the prune belly syndrome and Klinefelter’s syndrome have been reported in the last year. Conclusions: Prospects for fertility with current techniques and those that might be discovered in the next 20 years should strongly influence decisions about the treatment of infants and children. KEY WORDS: fertility, urogenital system, abnormalities

It has been known for many years that some of the major congenital anomalies of the genitourinary tract cause infertility. In some cases, for example the prune belly syndrome, complete sterility was thought to be inevitable, while in others, such as undescended testes, there was debate about the degree of infertility. This has not changed. However, that which has changed are the prospects for the treatment of infertility, the unattractively named “reproductive technology.” For children born as recently as 10 years ago there was a tacit acceptance that infertility was likely. Although steps were taken to facilitate sexual intercourse, there seemed little that could be done to improve the chances of fertility. For boys born with undescended testes early surgery was encouraged but proof that fertility was improved was lacking. It has now become apparent that children born with even the most gross anomalies can have children. In the future decisions on early management will be influenced not only by the technology currently available, but by the thought that 20 years hence even more remarkable discoveries will have been made. Very broadly, the congenital causes of infertility may be classified as failures of germ cell production and/or transport or storage mechanisms (see Appendix). In boys there may be failure to make sperm or deliver the sperm to the cervix with intercourse. In females the problems range from ovarian failure to inadequacy of the uterus or even the vagina. Obviously, in many cases several factors may be present. UNDESCENDED TESTES

The influence of undescended testes on fertility has been the subject of extensive literature but with incomplete conclusions. The difficulties are obvious. Boys are found to have

a missing testis (or 2) which may or may not be due to true maldescent. An operation may be performed in infancy which may or may not have been appropriate. The operation itself may damage the testis and/or the vas. A man who has had an orchiopexy may find himself infertile 20 or more years later. By this stage the cohort of boys operated on is difficult to trace, and so the incidence of infertility attributable to the original maldescent cannot accurately be determined. To compound matters, many of the reports on long-term followup of undescended testes rely on a single semen analysis to determine fertility, which is a completely unreliable method of confirming or refuting an ability to father a child. Even if there are abnormalities of sperm count, they may not be sufficient to impair fertility, especially in those with unilateral undescended testis. There is no series that reports the rate of fertility in all operated boys with proof of paternity. Paternity rates from the current literature are shown in table 1. Although it might be that poor fertility with undescended testes is a function of germinal failure, there is a compounding factor. Up to 43% of undescended testes have abnormalities of the epididymis and its testicular attachment. The

TABLE 1. Fertility rates judged by paternity in cohabiting men operated on for undescended testes in childhood References Atkinson66 Lipshultz et al67 Kumar et al68 Cendron et al70 Lee et al8 * The percentage of the

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No. Pts. (%)*

% Bilat.

112 (not available) 102 (54) 113 (59) 40 (82) 363 (not available) original cohort available for

44 60 33 53 followup.

% Unilat. 77 66 84 87 75

FERTILITY IN PATIENTS WITH GENITOURINARY ANOMALIES

most common finding is flimsy attachment of the epididymis to the testis (50%) but 20% are atretic or completely separated from the testis.1, 2 Therefore, the infertility may be due in part to obstruction. Sperm quality is difficult to assess. It would seem that the man with undescended testis and oligozoospermia has a similar prognosis for paternity as a man with the same poor sperm count from other causes. There is no excess of antisperm antibodies.3 Infertility with bilateral undescended testes. Men with untreated bilateral undescended testes, with a few poorly documented exceptions, are infertile. A group of 17 men from an infertility clinic investigated by biopsy or semen analysis were “totally sterile.”4 There is a disproportionate number of men with a history of unilateral and bilateral undescended testes attending fertility clinics. For example, in a French series 6.5% of males had undescended testis, which was bilateral in 60%, and 80% of the bilateral group were azoospermic.5 Bearing these observations in mind, the fact that some men operated on for bilateral undescended testes can produce children indicates that surgery does some good. The question then is at what age should it be performed. The basic idea that early surgery was better than late surgery has been well established. Surgery after puberty has a limited effect with an estimated fertility of only 13.5% compared to 30% in boys operated on before puberty.6 In boys operated on before puberty it seems possible that the age at surgery is irrelevant. Semen analyses may be better in boys operated on early in life, particularly before the age of 2 years.7 However, in a study comparing boys with bilateral undescended testes, unilateral undescended testis and controls age at surgery (range 1 month to 13 years in the bilateral cases) was not a factor in subsequent paternity.8 The current pressure for early surgery comes from the knowledge of the early development of germinal function, assessments of fertility as judged by semen analysis and hormone profiles. The data are conflicting. The traditional view that the infantile testis is quiescent is supported by some studies. Until the age of 4 years histology shows that the seminiferous tubules are small and there is no cellular differentiation.9 McAleer et al found no differences between an undescended testis, its normally descended pair and controls up to the age of 1 year.10 However, a large body of work shows that there are differences. In a comparison of semithin sections of biopsies from 459 cases of unilateral undescended testis and 356 normal partners important abnormalities were found. In year 1 of life there were reduced numbers of Leydig cells and delayed maturation towards the mature histological appearance. Adult dark spermatogonia should appear in year 1 of life and meiosis by the end of year 3.11 Therefore, it is suggested that surgery should be performed in the first year before the developmental phase of the germinal cells. Whether this will translate into an improvement in fertility remains to be seen. Infertility with unilateral undescended testis. Untreated unilateral undescended testis is compatible with normal fertility although there is again a disproportionate number of such men attending infertility clinics. In the series of Scott 60% of men with untreated unilateral undescended testis had infertile sperm counts and his literature review gave similar figures.4 Levin and Sherman, although having an excess of cryptorchid cases, found that 75% had a normal sperm count.12 For men with surgically treated unilateral undescended testis fertility is probably fairly close to normal. The figures in table 1 are for men in partnerships who wished to have children. Lee et al reported no difference in paternity between men with treated unilateral undescended testis and controls.8 It has even been suggested that surgery makes no difference in fertility in boys with unilateral undescended testis. In a review of the world literature Chilvers et al found that the

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incidence of azoospermia or oligozoospermia was 43% whether or not patients had undergone surgery.13 This view is supported by 2 intriguing studies on men with proved fertility.14, 15 There were 16 men who had undergone surgery for unilateral undescended testis and were requesting vasectomy for contraception. Each was persuaded to have the operation staged so that a semen analysis could be performed after the vasectomy on the normally descended side. In only 1 of the 16 men was the semen analysis of the undescended testis normal. The difficulty, as ever, with these data is that surgery was performed late by current standards and the patients were selected. It seems likely that fertility with unilateral undescended testis is close to normal, regardless of treatment and that the apparent high incidence of infertile men is due to some selection bias. If unilateral undescended testis does cause a lowered rate of fertility, it remains to be seen whether earlier surgery improves the outcome. Infertility with retractile testes. Many babies and young boys presenting with undescended testes do not have an anatomical problem but have a normal testis that is located for some or all of the time in the lower inguinal canal. Such testes can be manipulated into the scrotum. In many the testis may be found in the scrotum when examined in a warm room or with the boy in a warm bath. These so-called retractile testes descend with growth and at the latest by puberty. In adult life the men have normal testicular volumes and fertility.16 Management of infertility in patients with undescended testes. Until the advent of reproductive technology and, particularly intracytoplasmic sperm injection (ICSI), there was no effective treatment for this type of male factor infertility. The management now is along standard lines of collecting sperm from ejaculate, epididymis or testis for in vitro fertilization. The advent of this technology does not alter the surgical management in infancy. If early surgery does improve fertility, it should obviously be performed as natural paternity is more desirable and much cheaper than that created in a laboratory. Nonetheless, it is important to establish that early surgery as currently practiced is not actually harmful. This is a possibility and continued followup is essential as it has yet to be shown that orchiopexy in infancy improves the prospects for fertility. For example, violation of the tunica albuginea of the infantile testis may be harmful to the germinal epithelium. This possibility was first raised in 1956 when it was common practice to suture the operated testis to the inside of the thigh to maintain its position during healing. Gross et al stated that this technique might cause avascular necrosis, thus accounting for the high rate of infertility.17 In their own patients the thigh stitch was not used and 6 of their 16 patients with bilateral undescended testes fathered 14 children. There are 2 reports that also raise the possibility that the infantile testis is vulnerable to permanent damage. Coughlin et al showed that fertility may be impaired in men who had even a simple suture fixation of the testis to the dartos at orchiopexy.18 In their series in which they analyzed the significance of a number of factors that influenced infertility, a testicular suture was more important even than bilateral maldescent (relative risks 7.56 and 5.51, respectively). Their study was retrospective and, although the number of operated boys was large, the results cannot be taken as conclusive. Nonetheless, as suture fixation is not an essential part of orchiopexy, it seems reasonable to avoid its use. There is the suggestion that testicular biopsy at the time of orchiopexy increases the risk of later testicular neoplasia. It has been recognized for many years that undescended testis is an etiological factor in germ cell neoplasia. In a careful but retrospective study of boys undergoing orchiopexy at Great Ormond Street the overall risk of neoplasia was 6.7 times

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FERTILITY IN PATIENTS WITH GENITOURINARY ANOMALIES

that of the normal population.19 However, in boys who had a biopsy at the time of orchiopexy the risk was increased by 66.7-fold. All of the biopsies were normal and there seemed to be no reason for them to have been done other than the whim of the surgeon. EXSTROPHY

Exstrophy in males. The sexual and reproductive consequences of exstrophy in males have been well documented. It is likely that the gonads are normal at birth unless some other problem is present. Even in boys born with cloacal exstrophy the testes of 6 that were removed at gender reassignment were found to be normal on microscopy.20 The problem lies in the delivery of sperm to the vagina. Erectile deformities may prevent vaginal penetration altogether.21 Once correction has been made, intercourse should be possible but the shortness of the penis may prevent the delivery of semen to a point close enough to the cervix for insemination. Unfortunately, many boys with exstrophy do not ejaculate because of the absence of a circular prostate and a bulbospongiosus muscle. Repeated operations to reconstruct the bladder neck may cause damage to the vasa or seminal vesicles. Incidence rates of infertility in males with exstrophy are unreliable as most series report the number of patients who were found to be infertile but not the population from which the cohort was drawn. Ejaculation cannot, by definition, be normal. It is a process that depends on forceful expulsion of a bolus of semen from the prostatic urethra augmented by contraction of the bulbospongiosus muscle. As patients with exstrophy do not have an encircling prostate or a bulbospongiosus muscle they cannot achieve forceful ejaculation. Most men report that some semen dribbles out with orgasm but others say that there is a regular discharge of semen from the meatus unrelated to sexual activity. If men are asked for a semen sample for analysis, few can produce more than 1 ml., although volumes up to 5 ml. have been reported.22 In a review of the current literature ejaculation was reported in 101 of 134 men (75%).23 In isolated epispadias ejaculation appears to be more normal, although I still doubt if it can have the same force as from a normal man unless the abnormality is distal. Of 29 adults 17 were said to have normal ejaculation, 3 had fathered about 6 children (details incomplete) but 3 had required some form of artificial insemination, in 1 case using sperm retrieved from the bladder.24 It has been suggested that men who underwent early diversion are better able to ejaculate than those who underwent reconstruction. Most authors who have specifically addressed this problem give results that appear to support this conclusion. For example, in a German series all 5 unreconstructed cases had normal ejaculation, while 83% of 23 reconstructed cases had only post orgasmic dribble and the rest had no ejaculate.25 In an updated review of the same series, it was even stated that no patient who had undergone genital (as opposed to bladder) reconstruction could ejaculate properly and none was fertile.26 However, the opposite view is taken by Ben-Chaim et al.27 Of 16 patients 12 had satisfactory ejaculation. Previous surgery was not given but it was implied that they had undergone reconstruction and, furthermore, that cystectomy was a cause of infertility. In reviewing the literature I have found that neither view is supported. About 75% of both groups have some form of ejaculation. Several reports do not indicate what surgery was done or the power of ejaculation. It is hard to believe that any man with exstrophy ejaculates with normal force. In my review of the literature from 1974 to 1998 I found that about half of the men who wished to have children were successful. Whatever may be said about ejaculatory function, fertility was definitely better in boys who had had an early diversion rather than reconstruction.28

Management of infertility in males with exstrophy. The collection of semen for analysis is difficult because of the eccentricities of ejaculation. Once the extent of ejaculation has been established, some semen may be collected. The presence of even a few sperm indicates that production is occurring and some technique of assisted conception may be possible. At the simplest level, men may be taught to collect some semen in a syringe and to use it themselves for artificial insemination. Most will have to be taught about the identification of the fertile period of their partners and the necessity for her to remain lying down, preferably with the buttocks supported on several pillows for 4 hours to ensure close contact of the cervix with the limited volume of semen. If this fails, sperm collected by masturbation may be used for ICSI. If no semen can be collected for analysis, a measure of serum follicle-stimulating hormone (FSH) gives a reasonable indication of testicular germ cell function, and a normal level suggests that some sperm are probably being made. A testicular biopsy will be the final test but should only be performed in conjunction with a procedure to collect sperm from the epididymis or, in countries where it is legal, from the testis. It is unethical to perform a testicular biopsy other than as part of a planned strategy to produce a pregnancy. Fertility in females with exstrophy. The problem in females is entirely anatomical. The introitus is narrow and almost always requires surgical enlargement. Thereafter, the girls appear to have normal fertility. There is at least a 50% incidence of uterine prolapse, in many cases amounting to procedentia. Few women with exstrophy are able to have more than 2 children before repair of the prolapse. As the repair involves a sling around the cervix, further pregnancy may be impossible.29 MYELOMENINGOCOELE

The prospects for fertility in patients with myelomeningocoele are particularly intriguing. In females fertility is thought to be normal. In males potency is closely linked to the neurological defect and any infertility might be due to failure of transport rather than to testicular failure. In both sexes research has concentrated on the prevention of neural tube defects in the offspring and the prospects for marriage. Fertility in females. Although sexual function, as defined by sexual sensation and orgasm, is dependent on neurological level, females with spina bifida are thought to have normal fertility. Indeed, a difficult area of community policy is how to prevent unwanted pregnancies and sexual abuse in affected girls of low intelligence. For females in general and girls with spina bifida in particular one of the great success stories of the last 20 years has been the discovery of the prophylactic role of folic acid. The Kennedy Foundation International Award for Scientific Achievement was recently given to the 3 doctors who made the discovery. The incidence of all neural tube defects in babies in the western world diminished even before this discovery. In a recent study from the United Kingdom it was shown that the incidence of neural tube defects started to decrease about 18 years before the use of folic acid began to increase.30 However, the main protection against conception of a baby with a neural tube defect is to give the mother folic acid supplements in the 3 months before conception and for the first trimester.31, 32 The Public Health Service of the United States recommends 400 ␮g. folic acid daily for prophylaxis. The Department of Health in the United Kingdom now recommends that women who are at high risk for conceiving a baby with a neural tube defect should take 5 mg. daily. This therapy would include all women who are affected and normal women married to an affected male.33 Despite this prophylaxis, there remains a small risk of an affected pregnancy. At least 1 cause appears to be an inborn error of folic

FERTILITY IN PATIENTS WITH GENITOURINARY ANOMALIES

acid metabolism which was found in 16 women who gave birth to 2 successive babies with myelomeningocele despite prophylaxis.34 There also appears to be better absorption of synthetic folic acid (from folic acid pills or fortified food) than natural folic acid in food.35 Women relying on increased folate in their diet may get suboptimal prophylaxis. A common consequence of severe spina bifida is obesity. Unfortunately, the incidence of neural tube defect pregnancies is nearly double in women who are obese at the time of conception (body mass index greater than 29 kg./m.2).36 The use of selective termination of pregnancy in cases of neural tube defect is as much a social as a medical issue. In a series in South Australia between 1966 and 1991 the prevalence of affected pregnancies did not change but the number of affected live births decreased by 84% from 2.29 to 0.35/1,000, with a liberal termination program.37 There have been few reports of pregnancies in females with spina bifida. Richmond et al summarized their experiences with difficult pregnancies in difficult (medically) patients from difficult (socially deprived) families.38 Although good outcomes have been reported, especially with liberal use of cesarean section,39 several specific problems have been identified. Urinary tract infections are almost invariable, bladder function often deteriorates, and the small deformed pelvis makes accommodation of the fetus difficult leading to premature labor and increased need for cesarean section.38, 40 In a series of 20 pregnancies 35% were delivered before 37 weeks of gestation, and 8 required a cesarean section, all for obstetric indications, most commonly disproportion.40 Fertility in males. Erection and ejaculation in males are largely under neurological control. In men with spina bifida and intact sacral reflexes and about two-thirds of those with absent reflexes but a neurological level below L3 are likely to have normal sexual function. A few men with levels up to T10 may have erections but many are not associated with sexual stimulus. Although there has been no formal study, it is probable that men with low lesions have normal fertility. In men with higher lesions it might be thought that infertility would be a transport problem due to the impotence. Although this is undoubtedly true in part, preliminary results of a continuing study have identified another problem.41 All 10 impotent males with spina bifida were found to be azoospermic on semen analysis obtained by electroejaculation. On testicular biopsy all 10 men had Sertoli cells only. Poor semen quality has been reported in men with acquired spinal lesions using electroejaculation.42 For all babies born with open spina bifida the prognosis is poor and only 60% survive into adulthood.43 Despite the many problems, men with spina bifida have a good outlook for establishing long-term sexual relationships. Surprisingly, the degree of continence is not relevant. In 1 series 16 of 28 men were married or living with a steady partner.44 Only 5 men believed they had no prospects of dating or marriage, and 9 had fathered 23 children. Management of infertility in males with spina bifida. Impotence responds to conventional management such as intracorporeal injection.45 Sildenafil may be used with appropriate dose reduction. In the only trial to date in this group dose escalation was used with patients as their own controls, and 80% responded to a 50 mg. dose.46, 47 Although 1 patient subsequently responded to 100 mg., it was recommended that such a high dose should not be used in cases of spina bifida. Of the 11 responders in the series 5 were wheelchair bound. In view of the possibility that impotence is associated with azoospermia, the prospects for fertility may not be improved. Further study is needed in these patients to determine if the present methods for treating azoospermia will work.

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PRUNE BELLY SYNDROME

One of the few certainties in pediatric urology used to be that all patients with the prune belly syndrome were infertile. All men who had been investigated in my own practice were azoospermic and testicular biopsies showed Sertoli cells only.48 Subsequently, in infants younger than age 1 year it was found that germ cells were present but were abnormal.49 Therefore, it is not surprising that there have been occasional cases of germ cell neoplasia in patients with the prune belly syndrome, which obviously implies that there must have been some germ cells present. Even now, there has been no report of a patient with the prune belly syndrome becoming a father naturally. In 3 recent patients sperm were found in the testis and retrieved from the epididymis in 2.50 In 1 case a twin pregnancy produced a normal female newborn and the other twin had multiple congenital anomalies but a normal urinary tract. Unfortunately, 1 of these men had spontaneous descent of the solitary testis which casts some doubt on the diagnosis of the prune belly syndrome. Although these data are conflicting and incomplete, it seems that some boys with the prune belly syndrome have testicular germ cells. The fact that even one has fathered a child shows that there may be a potential for fertility, just as there is for germ cell neoplasia. In the future it is important that the undescended testes are managed like any others. If there is a case for early surgery to preserve fertility, boys with the prune belly syndrome should have the same opportunity as others. POSTERIOR URETHRAL VALVES

The sexual and fertility problems in adults born with posterior urethral valves are interesting and incompletely researched. In about 40% of patients ejaculation is slow or absent. There is no proved reason for this phenomenon but marked dilatation of the prostatic urethra seems a likely cause. The first part of ejaculation requires establishment of a bolus of semen that is forcefully expelled by the prostate and if the prostatic urethra is dilated adequate pressure cannot be generated. Despite the open bladder neck, retrograde ejaculation is rare.51 In about half the men who have been evaluated the semen is grossly abnormal. The pH is high, (range 8.4 to 9.2), and the semen is viscous and fails to liquefy after ejaculation. To perform a sperm count it is often necessary to slice the specimen in a way that a section is made for histology. Motility is hampered by the high viscosity. Unfortunately, there is no solid information on fertility in this group of patients. In my own series reviewed in 1989, 6 of 21 men were married and 2 of their wives had produced children.51 Another wife had had a miscarriage after many years of trying to become pregnant. It seems likely that some men born with posterior urethral valves are infertile, and a simple head count in a large pediatric urology unit should, at least, quantify the problem. UTERINE ANOMALIES

Most uterine anomalies, such as didelphic, bicornuate or septate uterus, are symptomless and menstruation is normal. During pregnancy there is an increased incidence of spontaneous abortion, especially if the pregnancy is in a rudimentary portion. At present there is no easy solution to the problem. If the uterus fails to develop, there is nothing that can be done to enlarge it. If 1 side is larger than the other, it may be possible to establish an embryo in vitro and implant it into the larger side. There is a small group of patients who are severely affected and infertile. In some the problem is implantation of the embryo. In the past it was untreatable but recently there has been some success in

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FERTILITY IN PATIENTS WITH GENITOURINARY ANOMALIES

implanting an embryo. Overall, half of the women achieved a successful delivery. However, the pregnancy rate per embryo transfer is low (19% for unicornuate and septate uteri, and 11% for didelphic uterus).52

about double normal. The most common major anomaly was hypospadias with a relative risk of 3.0.

KLINEFELTER’S SYNDROME

If developments continue at the present rate, one might imagine that infertility will be abolished altogether. It would seem prudent to treat children on the basis that fertility will be possible so that gonadal tissue and the reproductive organs should be preserved. When there is a conflict between treatment of a major disease and preservation of fertility, the debate will be intense. The recent advances in reproductive technology have altered the balance of the debate such that future fertility has become a critical issue rather than an improbable dream. In men with untreated bilateral intra-abdominal undescended testes, the general recommendation in the United Kingdom now is to remove the gonads because of the risk of neoplasia. It has been suggested that they should be left in the abdomen because the risk of death from testicular neoplasia in early disease is so low.59 This policy begs the question that early diagnosis of neoplasia will be made, which is an unlikely proposition with intra-abdominal testes. In the future greater consideration may be given to orchiopexy, either with the Fowler-Stephens operation or microvascular technique to at least get 1 testis into the scrotum.60, 61 Both methods have been used successfully (at least in children), with an apparent advantage for auto-transplantation when there has been a direct comparison.60 The former may be refined by the use of laparoscopy and the latter by enlisting the help of a specialist microvascular surgeon. Similarly, in cases of the prune belly syndrome orchiopexy should assume major importance rather than being left until other reconstructions have been completed. In girls with poor development of the uterus or absent fallopian tubes the uterus should be preserved. There have even been anecdotal cases of term pregnancy running outside a uterus.62, 63 In the future a uterus may not be a prerequisite for pregnancy. Gender assignment for infants with ambiguous genitalia remains a controversial issue. In some countries male are economically more valuable than female children and in others the prospects for sexual intercourse are influential. Gender assignment may be governed by factors that impress the parents and physicians but might be rejected by the child when an adult. With such rapid advances in reproductive technology, it is now reasonable to consider in which gender the child is most likely to become a parent. The patient pressure group, Intersex Society of North America, advocates at the very least withholding genital surgery until children are old enough to identify their own sexuality. Such a view seems even more correct when the possibilities for fertility are considered. In children with cancer in whom treatment is likely to produce sterility, it is now possible to store germinal tissue. The practicalities are experimental and the ethical aspects are unresolved. In some European countries but not in the United States there is government legislation on the issue. In the United Kingdom the HFEA controls that which can be stored but tissue from prepubertal children is not covered. The Royal College of Obstetricians and Gynaecologists has produced useful guidelines.64 It is emphasized that the ideal conditions for collection, storage and unfreezing of germinal tissue are not known, and all techniques should be considered experimental. Nonetheless, if storage is not undertaken, the present generation of patients will lose any possibility of parenthood. For both sexes gonadal tissue may be preserved with the consent of the parents (or child if competent) when treatment is given that will destroy fertility. There is a theoretical risk that malignant cells may be preserved with the gonad and produce a recurrence if reimplanted back into

Karyotype abnormalities are 8 times more common in men with nonobstructive azoospermia than in the normal population. Of these men 83% have Klinefelter’s syndrome.53 Klinefelter’s syndrome is surprisingly common, occurring in 1/500 male live births. It is seldom diagnosed until adolescence because the genitalia are normal. At puberty some secondary sexual characteristics develop but the testes remain small and soft. Characteristically the boys grow tall (with particularly long legs), have gynecomastia and appear eunuchoid. The karyotype is 47XXY. All are azoospermic, and testicular biopsy shows the presence of hyalinized seminiferous tubules and Leydig cell hyperplasia. Until recently patients were considered to be infertile. It has now been found that some men do have sperm in the ejaculate. There has been 1 successful pregnancy using testicular sperm for ICSI. The baby did not have Klinefelter’s syndrome (table 2). CURRENT RESULTS OF ICSI

The techniques that have been developed to allow direct injection of a single sperm into an ovum have revolutionized the prognosis of difficult male factor infertility. In most countries the procedure is regulated either by a government body or ethical guidelines of the profession. In the United Kingdom the controlling body is the Human Fertilisation and Embryology Authority (HFEA) which licenses procedures and storage, and the premises on which they are conducted. In the United States storage and use of genetic material (even spermatids) are legal but ethical guidelines are generally applied within the medical profession. Most countries allow use of sperm retrieved from the ejaculate, epididymis or testis. Sperm can be stored for many years and retain their viability for use in ICSI. The use of sperm precursors is more controversial because of poor results and ethical considerations. The storage of mature ova is not possible at present. In experimental animals it is possible to re-create fertility using grafted, cryopreserved ovarian tissue. There is some evidence that this will be possible in humans in the future but so far no woman has become pregnant using implanted frozen ovarian tissue.54 Embryos created in vitro by ICSI may be implanted fresh or after cryopreservation. The results of pregnancy, miscarriage, delivery and multiple births are the same for fresh or frozen sperm embryos and for ejaculated or epididymal sperm. Nearly 80% of women achieve delivery and about 20% have multiple births.55 Even when sperm have been collected from the testis of azoospermic men fertilization is achieved in more than 80% of cases and pregnancy develops in more than 40%.56, 57 It has been widely but unscientifically predicted that technology of this type will produce a large number of abnormal newborns but such fears are unfounded. In a review of 1,139 pregnancies from ICSI there were 47 major and 40 minor anomalies (7.6%).58 The risk in singleton pregnancies was no different from that in conventional pregnancies. In multiple pregnancies from ICSI the risk of a malformed newborn was TABLE 2. Findings of sperm in the ejaculate of 52 men with nonmosaic 47XXY Klinefelter’s syndrome69 No. Ejaculate Sperm ICSI Pregnancy Normal newborn

4 3 2 0

FUTURE PROSPECTS

FERTILITY IN PATIENTS WITH GENITOURINARY ANOMALIES

the child at a later date.65 The guidelines recommend preservation of ovarian tissue for appropriately selected girls. Testicular tissue can be preserved from prepubertal boys but should only be done as part of an approved research project at present. Spermarche is at a mean age of 13.4 years. The HFEA regulations would apply to any gonadal tissue or sperm from an adolescent at Tanner stage 2 or beyond. Parents cannot give consent on behalf of an adolescent. Tissue or semen would have to be stored on licensed premises. The subsequent use of stored tissue would require further consent, which could only be given by the patient as an adult. In the United Kingdom the rules of the HFEA would apply. At present it is not known what the tissues could be used for, and there are considerable ethical dilemmas in raising expectations, which may not be fulfilled, and in predicting the outcome of research yet to be done. APPENDIX: CAUSES OF INFERTILITY IN PATIENTS WITH CONGENITAL GENITOURINARY ANOMALIES

a. Males Gonadal failure Prune belly syndrome High spina bifida Chronic renal failure Bilateral undescended testes Klinefelter’s syndrome Intersex Kallman’s syndrome b. Females Gonadal failure Chronic renal failure Intersex

Transport failure (including erectile dysfunction) Exstrophy High spina bifida Chronic renal failure Posterior urethral valves Severe hypospadias Absence of vasa (congenital bilateral absence of vas deferens) Genital tract failure High spina bifida Vaginal atresia Uterine malformation Exstrophy

REFERENCES

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