Androgen misuse and abuse

The Nobel prize-winning identification of testosterone as the mammalian male sex hormone in 1935 was the culmination of an ancient pursuit to learn how the testis was responsible for masculine virility and superior muscular strength. Within two years, testosterone was being used clinically, and within a decade much of the clinical pharmacology and many applications were recognised (1, 2). Given its weighty historical legacy as the archetypal virilizing substance, testosterone was soon being evaluated to boost pharmacologically the muscular size and strength of healthy men beyond physiological development. In the years following the Second World War, the pharmaceutical industry undertook an extensive quest to identify an ‘anabolic steroid’, an androgen without virilizing properties. Although this proved futile, with the search abandoned, the now meaningless term ‘anabolic steroid’, perpetuating a distinction without a difference, has persisted long beyond its scientific obsolescence largely as a journalistic device for sensationalism and demonization (3). Systematic androgen abuse first appears an epidemic, with an epicentre among Eastern European elite athletes, in the mid 1950s (4). This timing coincided with the golden age of steroid pharmacology in the postwar pharmaceutical industry boom years, which produced the oral contraceptive and synthetic glucocorticoids, and with the early years of the Cold War. This fortuitous intersection of industrial means, unscrupulous operators, and political goals shaped the emergence of systematic androgen abuse as a convenient tool by which sociopolitically dysfunctional Eastern bloc countries could gain short-cut ascendancy through symbolic victories over Western political rivals, a challenge quickly reciprocated by athletes and trainers from the advanced noncommunist countries. This bidding war escalated into national sports doping programs operated covertly by Eastern European communist governments. These organized programs of unscrupulous cheating mixed competitive fraudulence with callous ruination of their athletes’ welfare for national political goals. Of these, only the East German program, with its dire consequences for athletes’ health, has so far been fully disclosed (5). Over the next 4 decades, androgen abuse became endemic in countries where the population is sufficiently affluent to support this consumer variant of drug abuse. Once entrenched in the community, androgen abuse spreads beyond elite sports, where it remains as a low level endemic, to nonsporting users with recreational, cosmetic, and occupational motivations for body-building, such as seeking to promote a fearsome muscular image (6).

Transsexualism

Transsexualism is the condition in which a person with apparently normal somatic sexual differentiation is convinced that he/she is actually a member of the opposite sex. It is associated with an irresistible urge to be hormonally and surgically adapted to that sex. Traditionally transsexualism has been conceptualized as a purely psychological phenomenon, but research on the brains of male-to-female transsexuals has found that the sexual differentiation of the brain—the bed nucleus of the stria terminalis (BSTC) and the hypothalamic uncinate nucleus—had followed a female pattern (1). This finding may lead to a concept of transsexualism as a form of intersex, where the sexual differentiation of the brain (which in mammals also undergoes sexual differentiation) is not consistent with the other variables of sex, such as chromosomal pattern, nature of the gonad and nature of internal/external genitalia. Thus it can be argued that transsexualism is a sexual differentiation disorder.

Insemination, in vitro fertilization, and intracytoplasmic sperm injection

Anamnesis, physical examination, and additional tests may reveal a specific cause of reproductive failure in infertile men. Whenever this is found, a specific treatment or cure should be applied. When no such treatment is available, or when specific treatment has failed, techniques of assisted reproduction may be proposed to couples suffering from long-standing male infertility. The rationale behind these is to bring the spermatozoa closer to the oocyte in an attempt to enhance the fertilization process. In recent years the role of assisted reproduction has become more important, and it has often been stated that these techniques have made clinical work-up or specific treatment of the male partner pointless. However, this is far from true. Not only may correction of a specific dysfunction in the male avoid the use of assisted reproductive techniques, but careful work-up and treatment may also enhance the outcome of these treatments. Assisted reproductive techniques should not be viewed as a primary treatment option, but rather as a complementary treatment when other treatments have failed, or have been judged inadequate after a complete work-up.

Immunological infertility

Immunological infertility is the presence, in one or both partners, of an antisperm immune reaction capable of interfering with fertility variables. In about 8–10% of these couples the immunological phenomenon is on the male side, causing ‘male immunological infertility’ (1). Since the first demonstration that a significant number of infertile men show an autoimmunity to sperm, experiments have suggested that antisperm antibodies (ASA) can interfere with the fertilizing ability of spermatozoa (2). ASA can act negatively on the motility of spermatozoa in semen, on their ability to pass through female genital secretions, or on the penetration of the oocyte. In particular, owing to in vitro fertilization techniques, it has been possible to demonstrate the effects of antibody-bound sperm directly, at the level of in vitro gamete interaction (3). ASA can reduce the motility and concentration of spermatozoa, and can induce sperm agglutination. However, normozoospermia can be accompanied by a high percentage of antibodies bound to the sperm surface, or a high ASA titre in serum or seminal plasma. In addition, ASA can affect sperm penetration of cervical mucus. When ASA are present in cervical mucus or bound to the sperm surface, impaired sperm penetration of cervical mucus, and abnormal swimming behaviour within cervical mucus—ranging from complete immobilization of sperm, to vibratory motion with limited progression (‘shaking reaction’), to restricted tail beat frequency and loss of rotatory motion—may be observed during the post-coital test (PCT). The shaking reaction in these cases is presumably due to cross-linking of motile, antibody-coated spermatozoa to the cervical mucus gel via the Fc part of the antibody (4). ASA may also inhibit fertilization by binding specifically to membrane antigens involved in sperm–oocyte interaction. They can additionally impair the fertilization process at the levels of the acrosome reaction, of zona pellucida recognition and penetration, and of sperm–vitellus interaction (5).

Obstructions

Azoospermia, the absence of sperm, is the most challenging of clinical conditions despite recent progress in diagnosis and treatment. The prevalence of azoospermia is less than 1% among all men, and approximately 10–15% among infertile men. Its incidence in the general male population is 2–3% (1). Testicular (secretory) azoospermia is untreatable in most cases, and even when a cure can be attempted, success is usually low. Obstructive azoospermia, in contrast, is characterized by normal spermatogenesis and is therefore potentially treatable. Accordingly, this condition has always been the focus of physicians’ interest and attention.

Infections/inflammation of the genital tract

Sexually-transmitted diseases (STDs) are the primary cause of infections of the genital apparatus, and are an important cause of morbidity worldwide. These diseases diminished after the advent of antibiotics, but in the 1970s new sexual behaviour and use of non-protective contraceptive methods brought about a significant increase in genito-urinary infections, especially in young adults of fertile age. New diseases appeared alongside the classic infections syphilis, gonorrhoea, soft ulcers, venereal lymphogranuloma, and inguinal granuloma, and increased continuously in industrialised nations. Previously unknown pathogens such as Chlamydia trachomatis, genital Mycoplasma, and others came to the attention of andrologists, particularly because of often irreversible complications in the sexual and reproductive realm (1).

Testicular tumours

Testicular cancer and the problems of male hypogonadism and infertility are closely related to each other—from a clinical as well as a biological point of view. Thus, men previously treated for testicular cancer are more and more frequently seen among patients referred to infertility clinics. This is due to the fact that: ◆ the survival rate among young testicular cancer patients is very high, being close to 95%, and the quality of life—including gonadal function—plays an important role in the men who have been cured ◆ there is an increasing knowledge that testicular function—both spermatogenesis and androgen production—in men with germ cell cancer is severely impaired. Recent research indicates a common prenatal cause of these pathologies of reproductive system ◆ modern techniques of assisted reproduction, particularly intracytoplasmic sperm injection (ICSI), have made it possible to obtain fertilization even when using ejaculates of extremely poor quality. This option has improved the possibility of cancer treated men becoming fathers. However, a source of potential worry is possible sperm DNA damage related to cancer and its treatment ◆ testicular germ cell cancer is more common in men presenting with poor semen quality. Thus, when investigating a man for infertility he should be assessed as to whether he belongs to a high-risk group for which a proper screening procedure should be offered (see below) Apart from this clinical link between testicular cancer and male infertility, there are also some indications of common biological factors involved in aetiology and pathogenesis. In this chapter some basic biological aspects of testicular cancer will be described. In Chapter 9.5.1 the hypothesis linking a rise of gonadal malignancy and poor testicular function is explained in more detail.

Cytogenetics and molecular genetics

Genetic aberrations are important causes of spermatogenic and endocrine testicular failure. Often, clinical skills are insufficient to demonstrate the primary genetic nature of a gonadal disorder, and cytogenetic and molecular tests should be considered for the diagnostic process (Table 9.5.3.1) (1–7). They are helpful, not only for establishing the basic aetiology of certain types of male endocrine disturbances, but also in that karyotyping and some DNA tests have attained a pivotal role in genetic risk counselling for severely infertile couples. Also, the diagnosis of a chromosomal abnormality or single gene mutation in an infertile man can have repercussions for other members of his family. They may carry the same type of genetic aberration, and thus be at increased risk for inadvertent reproductive outcomes. The most time-honoured method in male endocrinology is the analysis of banded metaphase chromosome preparations from blood lymphocytes, which remains of undiminished practical importance (8, 9). This technique allows for the direct visualization of the complete set of chromosomes in a somatic cell lineage and provides information on both chromosome number and structure. However, a regular karyotype in somatic cells, such as lymphocytes, does not necessarily translate into normal meiotic pairing and segregation of the chromosomes in the germ cell lineage. Meiotic cell preparations and ejaculated spermatozoa may thus be included in the diagnostic work-up of an infertile man. The place of these techniques is more in the realm of research than of daily clinical practice, as discussed below. In contrast, several molecular genetic tests are firmly established as valuable diagnostic tools. Details concerning the two most important tests, mutation analysis of the CFTR gene and screening for Y-chromosomal microdeletions, are given below.

Semen analysis

Semen analysis remains the most important diagnostic tool for the study of male infertility to date. For this reason, and because of the ease of carrying out this analysis, examination of seminal fluid should be among the first diagnostic steps in cases of suspected infertility, prior to subjecting the man’s partner to long and complex diagnostic tests. The efficacy of an examination of seminal fluid depends on the experience and ability of the seminologist, who must first undertake a subjective analysis of fundamental parameters such as motility and morphology. Moreover, laboratories specialized in such analyses may apply different criteria to the evaluation of sperm parameters, making it extremely difficult to compare tests carried out in different laboratories (1). In an attempt to resolve these problems of inconsistency, and in order to standardize laboratory techniques, a committee of experts from the WHO established guidelines for semen analysis in 1980 (an updated version was published in 1999) (2). In recent years, numerous other methods of semen analysis capable of providing in-depth diagnostic information on the fertilising capacity of spermatozoa have become available. The computer-aided sperm analysis (CASA) system is a technique for sperm analysis designed to provide objective data on sperm motility (3). Because of persisting difficulties in software set-up (4), it should not be used for routine analysis, but rather as a research tool. At the same time, significant advances have been made in the study of sperm morphology through the use of scanning and transmission electron microscopes (5). Finally, within the past decade several tests capable of evaluating the integrity of sperm components, such as the membrane, acrosome, DNA, and nuclear protein, have been developed and put into use. These more complex and costly analytical tools should be considered of secondary or tertiary importance, and are to be carried out in specific cases only after standard semen analysis. Standard semen analysis remains the first and fundamental diagnostic tool.

Endocrine evaluation

The main constituent of endocrine laboratory diagnosis of testicular dysfunction is the determination of the gonadotropins, luteinizing hormone and follicle-stimulating hormone (FSH) secreted from the pituitary gland, of testosterone secreted from the Leydig cells, and of inhibin-B secreted from the Sertoli cells. Where hypothalamic or pituitary disorders are suspected as causes of testicular dysfunction, a gonadotropin-releasing hormone (GnRH) stimulation test can be performed for further differentiation. A human chorionic gonadotropin (hCG) stimulation test is done for evaluation of the endocrine reserve capacity of the testis. Additional hormone measurements are performed for special diagnostic questions, e.g. of oestradiol in cases of gynaecomastia, or hCG and oestradiol upon suspicion of a testicular tumour. Various steroid hormones, including dihydrotestosterone, androgen receptors, or androgen metabolizing enzymes (e.g. 5α‎-reductase) in the target organs are analysed in patients with disturbances of sexual differentiation.