Male-to-female transgenderism is defined as identification as female, given one’s natal or biological sex as male [1]. Recent studies have shown that there is an increase in the number of people who identify as transgender [2]. As both the prevalence and insurance coverage have increased, more patients are having gender-affirming surgery (GAS). Both hormonal therapy and surgery can significantly impact future fertility. Medical providers should be aware of treatment impact, fertility preservation (FP) options, and barriers that may prevent infertility.

The definition of male infertility is the inability of a male to impregnate a fertile female. Infertility is a worldwide problem and, according to Sharlip et al., affects around 15 percent of couples [1]. Based on different studies, approximately 20–30 percent of infertility cases are due to male problems, 20–35 percent due to female problems, and 25–40 percent due to combined problems in both parts, while in 10–20 percent of cases, no causes are found (hence idiopathic infertility). Furthermore, nearly half of human infertility cases can be attributed to abnormal spermatogenesis [2]. Genetic causes for male infertility are related to a limited number of cases in which altered seminal parameters (motility, morphology, and concentration) are directly associated with a genetic mutation such as chromosome aberration or microdeletions at the Y chromosome [3]. The complexities to define the origin of this infertility have led researchers to suspect that both genetic and environmental factors contribute. The complex pathology and difficulty in identifying molecular abnormalities make it challenging to determine the etiology of male infertility. The molecular mechanisms and chromosomal variations associated with the infertility phenotype, consecutive pregnancy losses, or recurrent miscarriage, and idiopathic infertility cases remain to be elucidated [4, 5]. However, recent research indicates the presence of epigenetic alterations may provide further insights into the pathogenesis of male infertility [6]. The increased use of human assisted reproductive technology (ART) has created an enormous interest in identifying, diagnosing, and potentially treating male infertility. In recent years, advancements in the field of ART have provided indirect evidence for the role of epigenetic mechanisms in male infertility [2].

Medical treatment of male infertility can be divided into two categories – targeted therapy to a known cause of infertility and empirical treatment. The most common reason to use targeted therapy is to treat hypoandrogenism. Primary hypoandrogenism (steroidogenic dysfunction) is defined as a low serum testosterone level with compensatory elevated luteinizing hormone (LH) level. Secondary hypoandrogenism (pituitary dysfunction) can be categorized further into congenital forms, such as idiopathic hypogonadotropic hypoandrogenism, or acquired forms and is characterized by low serum testosterone level associated with a low LH level relative to serum testosterone level. Other medical indications for targeted therapy are infections, inflammation, antisperm antibodies, and retrograde ejaculation, all of which are discussed elsewhere in this book. Empirical treatment is defined as treatment that relies on experience or observation alone, without due regard for system and theory, and it is routinely used in the treatment of males with idiopathic infertility or with an uncorrectable cause of their infertility.

While we have no way to know exactly, Homo sapiens have probably had fertility problems for many thousands of years, though the causes ascribed to infertility have changed, as have the treatments. What has certainly changed over the millennia are the causes of male infertility and our understanding of these etiologies and, of course, the treatments for male infertility.

The last and fourth edition of Infertility in the Male was published in 2009, and significant advances were realized in reproductive medicine and surgery in the intervening decade. In this edition, we have covered the more recent advances in the field while maintaining the core foundation of information needed for practitioners in diagnosing and treating the man seeking care for fertility. We have also endeavored to make the book more structured, and hopefully easier to use, for the student and specialist alike.

The evolutionary branch from early primates to human beings dates back about 400 000 years (personal communication, Dr Lee Silver, Princeton University), and in that time, man has endured an “ice age.” In more recent history, man’s interest in cellular responses to freezing temperatures has been primarily concerned with his defense against it. The first cells discovered for the microscopic assessment of changes were sperm by van Leeuwenhoek in 1677, and in 1827, Karl Ernst von Baer later discovered the egg [1]. However, it was a very different and difficult concept for the public to grasp that human life can start with two microscopic gametes and that these cells can be frozen and survive thawing [2].

Infertility occurs in 10–15 percent of couples of reproductive age [1]. Male factor contributes to approximately 50 percent of couples with infertility, with the male being the sole contributor in 20 percent of the time and a combination between male and female in 30–40 percent of the time [1, 2]. Infertility in the male can result from several factors, which may be congenital or acquired. Historically, infertility workup and treatment have overemphasized the female factor. Fortunately, there is increased awareness of the factors that can affect fertility in the male. Evaluation of the infertile male should achieve certain goals. These include: (1) identifying reversible causes that can improve fertility status; (2) identifying irreversible causes which may lead to treatment by assisted reproductive technology (ART); (3) identifying irreversible causes not amenable to ART; (4) identifying medically significant pathologies underlying infertility; and (5) identifying genetic causes that may have implications for the patient and their offspring.

Physicians caring for male reproductive patients should be aware of potential legal issues that may arise, particularly when dealing with sperm donation, cryopreserved embryos, and postmortem use of sperm. The laws in this area continue to evolve, and in many places remain unsettled or are based on strict compliance with a relevant statute or court practice. Laws vary, depending on the type of fertility treatment provided, as well as by country, province, state, and even counties or districts within a state. Prior to engaging in medical treatment, the physician should, at a minimum, require the patient to consult with an attorney specializing in assisted reproductive technology (ART) to ensure the patient is aware of any and all legal consequences which may arise. Moreover, unlike other areas of medicine where treatment only affects the physician’s patient, physicians who practice ART should also consider the rights of the children and families they are helping to create. This article will explore legal issues that may arise when providing medical treatment in the area of male reproduction.

Sperm retrieval is most commonly performed for azoospermic men. Azoospermia may be the result of severely impaired sperm production (azoospermia due to spermatogenic dysfunction) or normal sperm production in the setting of physical blockage of sperm transport (obstructive azoospermia). Although microsurgical reconstruction is possible for many men with obstructive azoospermia, some couples will still elect sperm retrieval with use of assisted reproductive technology (ART), including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). ART allows men who have surgically retrieved sperm to contribute to pregnancies, even when limited numbers of viable sperm are available and even if sperm have not matured by proceeding through the entire male reproductive system. The management of men with obstructive azoospermia and of those with azoospermia due to spermatogenic dysfunction is markedly different. Not only does the genetic/diagnostic testing vary for these two conditions, but also the management and outcomes take different directions.

The male reproductive endocrine system function is strictly dependent on the dynamic interplay between neural and hormonal signals originating from the hypothalamus where specific neurons secrete gonadotropin-releasing hormone (GnRH) in an episodic pattern of pulses under the control of excitatory and inhibitory signals from neuromodulators, the anterior pituitary where GnRH binds to its own receptors on a specific pituitary cell type to stimulate pituitary gonadotropin secretion, and the testes where the trophic actions of gonadotropins result in the promotion of spermatogenesis and secretion of testicular steroids and peptides, which, in turn, modulate hypothalamic and pituitary function in both positive and negative feedback loops.

Infection and inflammation of the male reproductive tract are complex clinical conditions that can impact reproductive potential through a variety of pathophysiologic mechanisms. In this chapter, we discuss sites of genitourinary (GU) tract infections, infectious organisms, and the numerous ways in which leukocytes may impair male reproduction. Clinically, these processes most likely manifest as leukocytospermia and bacteriospermia.

Becoming a parent is the logical progression for individuals who have found a life mate or have decided they wish to become solo parents. Most heterosexual couples assume that pregnancy will happen when they stop using birth control. With the advent of assisted reproductive technology (ART), same-sex couples are now able to assume they too can create families. There is also a societal value to create family [1]. When the expected does not happen, there can be a variety of psychological reactions.

Sperm are critical for fertility. Thus, a properly collected semen analysis is the keystone of the laboratory evaluation of the infertile male. Combined with the history and physical examination, semen analysis can suggest an etiology for infertility and direct the clinician towards further evaluation and treatment options. This chapter will discuss the components of the standard semen analysis and their interpretation, as well as commonly ordered adjunct semen, hormonal, and genetic testing.

The potential for chemicals and toxicants to adversely impact health and reproduction is not a new concern; it dates back to biblical times, ancient Egypt, Greece, and the Roman Empire [1, 2]. However, it was not until the middle of the twentieth century that concerns about the effects of chemicals on reproduction were raised. In 1962, Rachel Carlson published her landmark book The Silent Spring, in which she described the harmful effects of pesticides on wildlife reproduction [3]. She is credited with starting the environmental movement, leading to the establishment of the National Institute of Environmental Health Sciences (NIEHS) in 1966 [4] and the National Institute for Occupational Safety and Health (NIOSH) in 1970 [5]. The mission of the NIEHS is to “discover how the environment affects people, in order to promote healthier lives and to provide global leadership for innovative research that improves public health by preventing disease and disability.” The mission of NIOSH is to “generate new knowledge in the field of occupational safety and health and to transfer that knowledge into practice for the betterment of workers.” Through the stewardship of these agencies, as well as those in Europe and the World Health Organization (WHO), research in the fields of occupational and environmental effects on reproduction has dramatically increased [6–8]. Nonetheless, relatively few of the thousands of chemicals used in the workplace or as ingredients in commonly used products, or identified in the environment (air, water, earth, and food), have been examined for their effects on reproductive function. Of those chemicals that have been studied, few have been definitively shown to induce reproductive toxicity.

Medically assisted reproduction (MAR) procedures require the processing of semen and sperm samples. There are several variables which can affect the quality of spermatozoa during the processing of sperm cells, which can, in turn, influence the outcomes of embryo development, pregnancy, and live births [1]. The objective of this chapter is to describe the various techniques utilized for processing human sperm in order to enrich for the best and most competent sperm used for MAR, including intrauterine insemination (IUI), in vitro fertilization (IVF), and intracytoplasmic sperm insemination (ICSI) [2, 3].

Infertility is common, affecting up to 15 percent of couples [1]. One-third of infertility is attributed to a female factor, whereas 20 percent of infertility is attributed to a male factor. In up to 20–40 percent of cases, there are both a female and a male factor contributing to infertility [1, 2]. The evaluation of infertility is warranted after 12 months of unprotected intercourse in couples when the female partner is aged 35 or younger. The natural decline in fertility begins to increase more rapidly after age 35. Thus, in women aged 35 years or older, evaluation should be initiated after 6 months of unprotected intercourse. In women with known risk factors for infertility, such as irregular menstrual cycles or endometriosis, a complete evaluation should be performed sooner. Since infertility may be the result of both female and male factors, couples already diagnosed with male factor infertility should also undergo a complete workup [1]. In this chapter, we will focus on the evaluation of the female partner.

Infertility is generally defined as the inability to achieve conception after 12 months of regular unprotected sexual intercourse (World Health Organization (WHO)) [1]. It is estimated that approximately one-third of infertility cases are due to male factor infertility, another one-third due to female factor infertility, and the remainder due to combined male and female factors or unexplained cause(s). A recent large cross-sectional study suggests that about 10.1 percent of men experience infertility [2], and in a birth cohort study, in men aged 38 years, male infertility ranged from 14.4 to 21.8 percent [3]. Endocrine causes of male infertility are surprisingly infrequent, given that fertility is dependent on an intact hypothalamic–pituitary–testicular (HPT) axis (see Chapter 4) for adequate spermatogenesis. Systemic endocrine diseases and disturbances of the HPT axis comprise approximately 2 to 5 percent of causes of male infertility [4, 5]. Though uncommon, endocrine causes of infertility are important to diagnose, as specific treatment is available in most cases to ameliorate the clinical symptoms of hypogonadism and, in some instances, for treatment of infertility. Understanding the underlying endocrine etiology of infertility allows for shared decision-making in the management of a couple with infertility; furthermore, certain conditions may have serious health consequences if left untreated. Evaluation of endocrine causes is essential when investigating male factor infertility.