Abstract
Reproductive problems in the male contribute significantly to subfertility in heterosexual couples but can also impact on the ability of single or homosexual men to take part in donation or surrogacy. The main causes of reproductive problems in males can be classified as either (1) pre-testicular (those affecting the regulatory hormonal pathway); (2) testicular (those which relate to impaired testicular function); and (c) post-testicular, where there is a blockage of the male genital tract or other problems with associated ejaculation or sperm delivery; however, it is possible that there can be more than one cause. The main diagnostic procedures include physical examination, followed by semen analysis and, in some instances, endocrine tests (follicle-stimulating hormone and testosterone), genetic tests (karotyping, Y chromosome microdeletion testing and cystic fibrosis testing) and radiological investigations. In the case of secondary hypogonadism, medical treatment with human chorionic gonadotropin can improve sperm quality but in the majority of azoospermic men only various surgical interventions to recover sufficient sperm for intracytoplasmic sperm injection are of proven value.
5.1 Introduction
Reproductive problems in the male are a significant cause of infertility in heterosexual couples. For the general gynaecologist, or specialist in reproductive medicine, this is an important part of their infertility practice, but one in which they may feel less confident or have had little or no formal training. Moreover, in addition to the infertility of heterosexual couples, an understanding of male fertility is important in its own right given that increasing number of single men or homosexual couples may present in the clinic either for their own reproductive needs, or to take part as donors in the family building for single women or same-sex (female) couples. It is, therefore, important that the gynaecologist or reproductive medicine specialist has a good understanding of issues in clinical and laboratory andrology as outlined in this chapter.
5.2 The Male Reproductive Tract and Physiology
A schematic diagram of the male reproductive tract is shown in Figure 5.1 with an overview of the main endocrine mechanisms controlling testicular function in Figure 5.2.
In most boys, sperm production begins early in puberty at around age 13.5 years and in most individuals continues relatively unhindered throughout life (but see Section 5.3). The starting point of spermatogenesis is a population of testicular stem cells in the germinal epithelium which begin to proliferate and self-renew, sending copies of themselves down a pathway of differentiation to make sperm. Most of the stages of spermatogenesis take place in a close connection with Sertoli cells over around 74 days (95% confidence interval [CI]: 69–80 days). Since each Sertoli cell can only support a finite number of developing sperm at any one time, the number of Sertoli cells (as evidenced by testicular volume) is the factor limiting how many sperm a testis can produce per unit time. Spermatogenesis typically takes place in a ‘wave-like’ manner along the seminiferous tubule, suggesting some element of paracrine or autocrine coordination. The developing stages of sperm undergo meiotic divisions to generate sperm with half the number of chromosomes while at the same time, the sperm differentiate into the familiar plan of head, midpiece and tail (see Figure 5.3) as they pass through Sertoli cells and are released into the lumen.
Figure 5.3 The ultrastructure of human spermatozoa.
Fully differentiated sperm released into the lumen of seminiferous tubules are not motile and are therefore moved gently by cilia, muscular contractions and back-pressure along to the efferent ducts and into the epididymis. Their passage along the epididymis typically takes about 7 to 10 days and it is during this time that sperm develop the capacity to become motile and also acquire the ability to bind to the egg. These functions are probably obtained through a series of modifications to surface proteins by epididymal secretions, although the exact details are not clear.
Compared to other mammals, there is limited sperm storage capacity within the human male reproductive tract to store sperm once they have finished epididymal maturation and before they are ejaculated. However, some sperm are probably stored in the cauda epididymis and testicular portion of the vas deferens. When ejaculation occurs, there is a ‘pinching’ of the muscular walls of the vas deferens and a bolus of sperm forced along it by peristaltic contractions towards the penile urethra. The process of ejaculation is highly coordinated and is normally associated with the release of a series of fluid ‘fractions’ in which sperm and fluid from the prostate tend to be in the first and second fractions and secretions from the seminal vesicles the later ones. This has implications for semen collection in diagnostic laboratories (where if the first fraction is not collected this can have an impact on the results of semen analysis) and for those couples practising ‘coitus interruptus’ as a form of contraception.
5.3 Causes of Male Subfertility
To determine the likely cause of male factor infertility, it is helpful for the clinician to place the patient into a mechanistic category. One approach is to divide the causes of male subfertility into (1) pre-testicular (those affecting the regulatory hormonal pathway); (2) testicular (those which relate to impaired testicular function); or (3) post-testicular (where there is a blockage of the male genital tract or other problems with associated ejaculation or sperm delivery). However, it is important to consider that there can be more than one cause.
5.3.1 Pre-testicular Causes
The development of the male urogenital system during neonatal life is under the primary control of the SRY gene. From about week 7 of gestation, this leads to the development of the indifferent gonad to the male phenotype which can be clearly seen by about week 12. This is largely driven by a rise in fetal testosterone which triggers the regression of the mullerian duct system and the subsequent differentiation of the Wolffian ducts. A key part of the process is the transabdominal migration of the testis from the abdominal wall to the inner inguinal ring which occurs from weeks 10 to 23 of gestation. The failure to migrate correctly leads to cryptorchidism, with lifelong consequences for fertility. Also, during this time, fetal testosterone is thought to contribute to the proliferation of Sertoli cell numbers that directly influences the maximum sperm production in adulthood, as outlined earlier. It is suggested that the anogenital distance (the distance between the midpoint of the anus to the underside of the scrotum) in adults is a readout of androgen exposure in utero. However, while it broadly correlates with testis size, sperm production and fertility it is not sufficient to be diagnostic.
Less common are gene defects that affect the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, leading to congenital hypogonadotropic hypogonadism. The most common condition is Kallmann syndrome (affecting about 1 in 10,000 males) but there are many gene mutations which are thought to underpin this.
Finally, there are a number (acquired) of endocrine disorders that may lead to pre-testicular causes of male subfertility, including pituitary tumours (e.g. Cushing syndrome) or traumatic brain injury. Exogenous testosterone administered either medically as replacement therapy or by individuals in order to build muscle mass as part of sporting activity will cause a negative feedback on the hypothalamic–pituitary axis which in turn will reduce the secretion of luteinising hormone (LH) and follicle-stimulating hormone (FSH) which will lower (or abolish) sperm production (see Figure 5.2). While these effects can be reversed if the testosterone use is discontinued, this may take many months [1].
5.3.2 Testicular Causes
A number of genetic issues can trigger developmental problems which are associated with poor testicular development. These include Klinefelter’s syndrome (typically 47 XXY but other variants are possible) which occurs in about 1 in 1,000 males. The testes in these men are typically small (<3.5 mL in volume) and histologically show degeneration of the seminiferous tubules, hyalinisation and fibrosis. Since the majority of genes which control spermatogenesis are located on the long arm of the Y chromosome, there are several key areas which are important for fertility. For example, men with (1) the AZFa microdeletion have Sertoli cell only syndrome; (2) the AZFb pattern have maturation arrest; and (3) AZFc have hypospermatogenesis.
One of the most common iatrogenic causes of testicular damage is as a consequence of chemotherapy or radiotherapy treatments delivered as part of cancer treatment. In each case, this can cause a depletion in the population of testicular stem cells which are the starting material for spermatogenesis (see Section 5.2). The extent of damage is difficult to predict in advance and seems to depend on the specific agents used as well as their dose and duration. Other prescription medicines can have similar effects although these are often poorly documented in the literature and so the clinician needs to be very thoughtful when taking a medical history.
Other testicular damage may be caused by varicoceles (an abnormal enlargement of the pampiniform venous plexus in the scrotum) and are more commonly seen in subfertile men. It is believed that they impair spermatogenesis through a heating effect, although the link between varicoceles and fertility is controversial. They can be observed during physical examination (see Section 5.4.1) and can be successfully treated by surgery (see Section 5.5.2).
Sexually transmitted infections (such as Chlamydia trachomatis) have the potential to influence male fertility as a consequence of the inflammatory reaction which may lead to tissue damage, the generation of free radicals from leucocytes or by direct damage on sperm by triggering apoptotic pathways [2]. The impact of other micro-organisms (e.g. Neisseria gonorrhoea/human papillomavirus) are less well understood, although have been implicated in poor reproductive outcome.
Some adult and post-pubertal infections such as mumps orchitis can dramatically influence testicular function, although historically has seen a decline in incidence due to childhood vaccination programmes. However, the controversy surrounding such vaccines in some parts of the world has led to a resurgence of cases. Damage is thought to occur because of direct damage to the germinal epithelium as well as by triggering an immunological reaction leading to the formation of sperm antibodies.
Lifestyle habits are a common concern for doctors and patients alike, often fuelled by media reports. Although there is some evidence that excessive alcohol intake, smoking of tobacco products (or cannabis), increases in testicular temperature due to occupation or choice of underwear [3] or some occupational chemical exposures (e.g. lead or glycol ether) can reduce semen quality, there is little evidence to date that lifestyle changes can improve matters and increase sperm quality or enhance fertility.
5.3.3 Post-testicular Causes
Post-testicular causes of male infertility relate to issues of sexual function, and male genital tract obstruction. The most common reason for azoospermia is vasectomy, but unintended vasal injury resulting in obstruction can occur as a consequence of groin surgery, such as hernia repair or orchidopexy. Non-iatrogenic causes include congenital absence of the vasa deferens, which is commonly linked to mutations in the cystic fibrosis (CF) genes. Obstruction can also be a consequence of genital tract infection. Whilst some of these causes may be suitable for genital tract reconstruction, many men will end up requiring surgical sperm retrieval for intra-cytoplasmic sperm injection (ICSI) (see Section 5.5.3).
Perhaps the most obvious reason for ejaculatory failure is in those men with spinal cord injury (SCI). In these men natural conception is rare because their ability to obtain a penile erection is usually impaired and as a consequence penile–vaginal intercourse is extremely difficult for them. Moreover, very few can achieve a normal (anterograde) ejaculation. Although sperm production is normally unaffected by their injury, because they ejaculate so infrequently, they often have samples with poor motility and an increased number of dead spermatozoa.
In some of men, anejaculation can be the reason for fertility problems and is usually due to peripheral nerve damage caused by generalised neuropathy (e.g. diabetes, or by damage to the pelvic plexi by surgery or trauma). Ejaculation requires intact sympathetic nerves (erections require parasympathetic pathways) and damage at any point from the relevant spinal cord segments to the genital tract can cause this problem.
In other men retrograde ejaculation can occur where at orgasm, sperm passes into the bladder due to bladder neck incompetence caused by surgery or drugs. Less commonly, ejaculatory duct obstruction caused by infection, cysts or calculi can result in anejaculation, often associated with pain at orgasm. In these men, semen follows the path of least resistance and sperm are deposited in the bladder (an obvious hindrance to fertility).
In men without any underlying physical or pharmacological cause, ejaculatory failure can still occur during intercourse and may have a psychosexual basis. It is important in such men therefore to enquire about libido and in their ability to reach orgasm. Anorgasmia and hypoactive sexual desire can have an endocrinological cause and those affected should be screened by checking their testosterone, prolactin and thyroid function (some clinicians also advocate checking oestrogen levels). Other causes can include medication, particularly drugs used to treat psychological disorders. However, disorders of libido and ejaculation are more commonly psychosexual in origin and may require referral for psychosexual counselling. Premature ejaculation is a common condition, but only rarely has an impact on fertility.
Erectile dysfunction (ED) becomes increasingly more common as men age, occurring in approximately 50% of men older than 50 years. Most ED is physical in origin and is related to the impact of the aging process on penile arteries and the corpora cavernosa. Problems are more commonly seen in men with diabetes, hypertension, cardiovascular disease and dyslipidaemia, so it is important that these parameters are checked when the patient reports an issue. Lifestyle factors such as obesity, cigarette smoking and excessive alcohol consumption are also relevant and should be enquired about. Hormonal factors such as a low testosterone or an elevated prolactin can be relevant also. ED is more common in subfertile men and may reflect an increased frequency or adverse health factors and psychological stress. The latter is more commonly seen in younger men, where it presents often suddenly with intermittent erections and the preservation of morning erections. ED of physical origins conversely is progressive, consistent and the patient will only rarely experience morning erections.
5.4 Investigation and Diagnosis of the Infertile Male
5.4.1 History and Physical Examination
A lot of useful information can be obtained by taking a detailed history from the male partner and by performing a genital examination, although the latter may require some specific training. It is not unusual to pick up associated medical issues that may require further management and, increasingly, men are expecting that this be performed. In heterosexual couples, it is important to remember that there are two patients and female factors might determine what the ultimate management strategy might be.
Table 5.1 summarises some key questions for a simple medical history of the male that the gynaecologist or reproductive medicine specialist may find useful. The responses to each will alert the clinician to a possible problem that may require further evaluation. Importantly, however, it should be noted that many men may not remember (or even be aware) of some procedures (e.g. orchidopexy) that may have been performed in infancy. While partners can be an invaluable source of information, they can also be a hindrance to the taking of an accurate medical history, particularly if the male is too embarrassed to answer some questions honestly. The clinician should be mindful of this. Many men have reported the feeling of being ‘side-lined’ in a fertility consultation and therefore it is important to make them feel ‘welcome’ and ‘involved’.
Table 5.1 A suggested questionnaire for undertaking a simple medical history of the male
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