Andrology: Current and Future Developments

Andrology has emerged since the 1950’s, when gynecologists started to consistently refer to this word. However, in 1891, there was already an editorial in JAMA suggesting that andrology could evolve to become an important discipline. It was proposed that, as gynecology is a discipline that is focused on the study of genitourinary female system, andrology could emerge as the discipline focused on the genitourinary system of males. For many years, this issue was disregarded and there was a long period until the first societies of andrology appeared and establish it in a definitive way. This historical affirmation of andrology as a discipline will be briefly presented, together with a critical view on some aspects that are still a matter of controversy. Reproductive science is a growing discipline that needs economic support from health care systems, institutions responsible for funding research, and training centers. There was never a greater need for trained and well-prepared scientists and physicians to study human reproductive health. Most countries, developed and developing, are witnessing unprecedented rates of people seeking for assisted reproductive technologies. Decreased sperm quality and male reproductive complications are factors that unquestionably contribute to the observed decline in nativity rates. On the other hand, even though females have various contraceptive methods available, men are still limited. This could be improved if more knowledge on sperm formation, maturation and overall testicular physiology arises. In this introductory chapter, we will discuss some challenges for the upcoming years in the field of Andrology.

In multicellular organisms, and particularly in mammals, both gonadal and germ cell development are essential for the transmission of genetic information to the next generations. The testes are paired ovoid organs located inside the scrotum but outside the abdominal cavity. They have two major functions: spermatogenesis and steroidogenesis. The former corresponds to the production of male gametes, spermatozoa; the latter, to the production of hormones that will influence spermatogenesis and consequently male reproductive function and health. The male and female reproductive organs have the same precursor tissues. Initially, the embryo has a bipotential gonad which may have a testicular or ovarian fate. Accordingly, Müllerian ducts form the uterus and fallopian tubes in females and Wolffian ducts form the epididymis, vas deferens, and ejaculatory duct in males. On the other hand, male sex determination is triggered by sex-determining region Y (SRY), which is located on the Y chromosome and works as a master regulator, initiating SOX9 expression. The latter causes urogenital development, a highly complex process, through a complex cascade of transcription factors and signaling events. These will promote testis differentiation and ultimately the production of hormones that will lead to male development and testicular function during adulthood. In this chapter, we will provide a brief overview of the testicular anatomy and functional organization, as well as its embryonic development.

Within the testes there is a considerable histological diversity, reflected in a significant variety of different circumscribed environments and cells. As is always the case regarding structures slowly forged by evolution, this translates into meaningful differences in the physiology and function for each cell type. Leydig cells are essentially known for their steroidogenic potential; Sertoli cells are known for their local support to germ cells, and peritubular myoid cells are rapidly transcending a simple structural role. They are all known to actively determine and contribute to spermatogenesis in some way. Moreover, the physiological interplay between these types of cells is known to functionally impact male fertility. However, the specific physiological mechanisms by which each cell type governs spermatozoa production are not fully accounted for, and pathways underlying the cooperative action of these cells in the process are far from being clarified. Increased knowledge regarding the function and interaction of these cells could potentially lead to important breakthroughs within the contexts of testes disease, infertility and contraception.

In what male reproduction is concerned, postnatal testis development comprises five sequencial stages: neonatal, infantile, juvenile, peripubertal and late pubertal. Each of these stages is associated with several regulation factors that may directly or indirectly affect them. After full testis differentiation, the individual is ready to commit to spermatogenesis. Spermatogenesis is a highly complex process that aims to produce spermatozoa through three consecutive steps (mitosis, meiosis and spermiogenesis) that culminate in spermiation. All these checkpoints have an intrinsic relationship with the cycle of the seminiferous epithelium, which allows their deeper understanding and integration. Given all the participants involved in spermatogenic cycle, it can be easily realized that there is a need for a controlled environment that maintains its correct development. This is achieved through the interconnected role of hormonal and paracrine/autocrine regulation factors. Each of them target a specific variety of somatic and germ cells, balancing their response in accordance with testis needs. Attention has also been given to the factors that control the genetic environment. In fact, male fertility is associated with a unique and indispensable set of genes, which are naturally influenced by several protein families with transcriptional and/or translational approaches. With this information in mind, the present chapter aims to discuss the most relevant research on the mechanisms involved in the basis of spermatogenesis.

Hormones are key regulators of the reproductive system. These signaling molecules are transported in the blood stream to reach target organs in order to regulate physiologic processes and their function. The most relevant hormones for male reproductive system are those involved in the hypothalamus-pituitary-gonads axis. Through several stimuli, anterior pituitary produces luteinizing hormone and folliclestimulating hormone that act on testicular cells modulating both steroidogenesis and spermatogenesis. In fact, steroidogenesis, namely the production of testosterone, is crucial for the normal occurrence of spermatogenesis and for feedback actions to the pituitary and hypothalamus. However, spermatogenesis and Sertoli cells are also important to the regulation of this axis through the production of activin and inhibin B that, along with testosterone, also transmit feedback to the brain. Interestingly, in the last years, new intervenient have appeared in the regulation of male reproductive function with the discovery that adipose tissue is an endocrine organ and thus also produces hormones that may be important for this process. Along with the latter, gut hormones, which are related with the nutrient homeostasis, also modulate the function of testicular cells. In some cases, this interaction was only found due to metabolic disorders, like hyper- or hypothyroidism, obesity or diabetes mellitus. Herein, we propose to discuss the action and function of these hormones that interact with male reproductive system.

The finding of a concise definition for puberty has proved to be a difficult task for the scientific community and it remains an intense matter of discussion. Nowadays, there is consensus that puberty is a dynamic process influenced by many factors. In this chapter, we will discuss some of the most relevant biochemical markers of puberty and briefly emphasize their relevance in the development and onset of puberty. We will expose the neuroendocrine control that lies behind this very complex hormonally-dependent process. In addition, since puberty is definitely not experienced in the same way by all individuals, we will also discuss genetic, metabolic and nutritional factors as key modulators for the control of puberty onset. The final section of this chapter is dedicated to a brief overview on puberty-associated disorders, pinpointing the clinical features that should be taken into consideration and the deleterious signals that may occur until sexual maturation is achieved.

The epididymis is a long convoluted organ of the male reproductive tract. Its functionality has been overlooked for many years, but it is currently accepted that it has a preponderant role in spermatozoa post-testicular maturation. The epididymis presents a high secretory activity. Several proteins can be released in bulk through apical blebs or can be associated with epididymosomes, which fuse with sperm plasma membrane becoming integral proteins. The interaction of epididymal proteins with spermatozoa is a very important factor in the regulation of spermatozoa maturation along their passage through the different epididymal regions. A mature sperm cell recovered from the epididymal caudal region should present the ability to move (activated motility) and to fertilize the oocyte. The atmosphere created within the epididymal lumen is very dynamic, since the epididymal fluid composition is relatively different between the tubule compartments. The blood-epididymal barrier (BEB) created by junctions between principal cells of the epididymal epithelium is not only responsible for the control of epididymal luminal fluid composition, but also acts as a defense mechanism to protect spermatozoa from the immune system, harmful xenobiotics and oxidative stress. While the caput and corpus of epididymis are mainly involved in sperm maturation, the caudal region is the site of mature sperm storage in a quiescent and protected state. In this chapter, we discuss the biochemical events occurring during the transit of spermatozoa through the epididymis. We will focus on the involvement and structural organization of epididymal epithelial cells and secretory proteins on spermatozoa modifications during their maturational process.

An appropriate microenvironment in each segment of the male reproductive tract is crucial for the successful maturation and motility of sperm and thereby for male fertility. Spermatozoa are produced in the testes and transported to the epididymis along with the seminiferous tubular fluid. The epididymis contains an epididymal milieu that maintains the optimal conditions necessary for sperm maturation and storage. The composition of the luminal fluid is gradually changed along the epididymal duct due to absorption and secretion processes. The main changes in epididymal fluid and other fluids produced by accessory glands will be reflected in the ionic content, osmolality, pH and spermatocrit. Sperm motility is a good predictor of human male fertility that is controlled by some parameters such as bicarbonate and calcium concentrations, which constantly fluctuate throughout the reproductive ducts. The spermatozoa leaving the epididymis along with the epididymal fluid will join the secretions from the prostate and seminal vesicles, thus forming the seminal plasma. More attention should be paid to male reproductive tract fluids, namely its ionic composition and pH in order to unravel the causes of idiopathic infertility, which represents an elevated percentage of infertile men.

The spermatozoon is a highly specialized cell that is formed through a complex cellular program of differentiation during spermatogenesis. It has a unique structure and chromatin that reflects its vital function. Morphologically it comprises a head, a midpiece and a tail. The sperm DNA is confined to the nucleus of the head and it has a characteristic protamine-based chromatin that makes it the most condensed eukaryotic DNA. This super compaction of sperm chromatin enhances the protection of DNA from damage since this cell type do not possess robust repair mechanisms. The midpiece is considered the “source of power” of spermatozoa, since it contains many mitochondria, which are responsible for the energy production required for motility. The tail, also known as flagellum, is crucial for spermatozoa movement and transit until they reach the female gamete. The morphological integrity of spermatozoa is of extreme importance for their responsiveness to testicular and epididymal factors involved in maturation. One of the main features that spermatozoa acquire during the maturational process is their motility capacity. This characteristic is not only dependent on the communication of spermatozoa with their surroundings, but also on sperm intrinsic factors, such as adenosine triphosphate (ATP) and specific membrane and secretory proteins. In recent years, sperm epigenome has been a matter of debate among researchers. Its importance is related to its impact on the embryo fate and offspring development. This chapter will discuss the significance of spermatozoa exclusive structure and function for human reproduction and the preservation of generations.

Sperm released in the lumen of seminiferous tubules are functionally immature. These cells acquire maturation during their passage through the epididymis. The epididymis exhibits an extraordinary structure showing different segments with distinct luminal composition, which act as a whole for the gradual differentiation of sperm. This organ is permanently targeted by neuronal and hormonal factors, in particular by androgens. The study of the biochemical mechanisms that mediate sperm maturation has been a matter of intense debate. The current advances on the knowledge of sperm physiology was possible due to studies conducted in laboratory and domestic species, whereas in humans these processes remain to be fully explored. This is a subject with high relevance in the field of reproductive biology since defects in these events may end-up in infertility. Maturation of sperm begins in the epididymis, but does not end in this organ, since after ejaculation sperms are still unable to fertilize the oocyte. After being deposited in the reproductive female tract, sperm undergo a number of structural and biochemical changes to become “capacitated”. Non-capacitated sperm cannot interact with eggs In vivo as their failure to hyperactivate motility precludes ascent to the site of fertilization. Sperm and egg must interact so that gamete fusion and the introduction of paternal information into the egg occurs, and the program of development must be activated. Male gametes are the “vehicle” by which the genetic information is passed from fathers to the offspring. In this context, there is increasing evidence that parental lifestyle and the environment influence phenotypes of the next generation. Sperm epigenome has huge implications for the success of male fertility, fertilization, pregnancy and in the transmission of undesirable information to the next generations. In this chapter we will discuss these topics from a biochemical point of view by exploring the mechanisms that govern the most relevant processes.

In recent years, there has been growing awareness that male reproductive performance has declined. Numerous studies have focused on various aspects of adverse trends in male reproductive health. There is a wealth of data that congenital disorders, such as hypospadias, undescended testis, testicular atrophy and testicular cancer have increased among young males. Testicular cancer, in particular germ cells tumors, are the most common malignancy among young males accounting more than 10 cases per 100000 men per year in Europe. Both genetic predisposition and environmental contaminants probably contribute for its etiology. Testicular germ cell tumors arise from malignant transformation of testicular germ cells in a multistep process where several aberrant modifications occur in genes involved in proliferation/survival and differentiation. Individuals with testicular germ cell tumors present a high survival rate but during treatments they are exposed to radio- and/or chemotherapy that may induce permanent damages in male fertility. In this context, it is essential to decipher the molecular mechanisms underlying testicular-related cancers. However, other pathologies have also contributed to the decline of male reproductive health, and particularly affect male sexual behavior. Inadequate penile erection, commonly termed as erectile dysfunction (ED) mostly occurs in men older than 40 years. It is quite common in developed countries and compelling evidences have linked the development of ED to diabetes mellitus, hypertension, hyperlipidemia, metabolic syndrome and depression. In fact, it has been shown that certain environmental and factors related to daily life, such as smoking, obesity, and limited or an absence of physical exercise may also be key predictors of ED. Physicians have looked with particular concern to these issues, but also for the sexually transmitted diseases (STDs). Some STDs are resolved without treatment, but others have chronic lifelong infections. In this chapter those topics will be discussed from a biochemical point of view and the pathways that regulate the most relevant processes.

Metabolic disorders represent a major public health burden nowadays. From these metabolic disorders, obesity and diabetes mellitus (DM) may be considered the most significant ones. Obesity is characterized by an excess of body fat, where body mass index (BMI) is used for its classification. When an individual has a BMI between 25 and 30 kg/m2 is considered overweight, while a BMI over 30 kg/m2 classifies an individual as obese. This excessive fat is very harmful and may even reduce life expectancy. On the other hand, DM encompasses a cluster of disorders characterized by chronic hyperglycemia that are a result of defects in insulin action, insulin secretion, or both. The exponential increase of these metabolic disorders is, in part, due to erroneous dietary habits that lead to an inadequate intake of essential nutrients. Moreover, while the prevalence of metabolic diseases increases, the fertility trends decrease, illustrating an association that may, or may not, be direct. In fact, there is an increasing number of children, adolescent and men in reproductive age suffering from metabolic disorders. It is well known that the occurrence of a normal spermatogenesis is dependent on the metabolic cooperation established between testicular cells, particularly concerning glucose metabolism and insulin signaling. Therefore, it is crucial to unveil these mechanisms in individuals with metabolic disorders, how they are affected by the disease and how they change the fertility of males. In recent years, several studies have provided new information concerning alterations induced by metabolic disorders in male reproductive health. In addition, it was highlighted that testicular cells possess several mechanisms that react to hormonal fluctuations to counteract hyper- and hypoglycemic events. In this chapter, we will discuss the effects of DM and obesity in the regulation of testicular insulin signaling and glucose metabolism as well as the importance of an adequate diet and how these events are implicated in the reproductive health of males.

The increase in the occurrence of defective spermatogenesis and other important fertility issues in males evidenced over the past few decades have prompted the research on the possible contribution of environmental factors to this adverse trend. Environmental contaminants may act through different molecular targets in male reproductive system, being able to disrupt the functioning of reproductive axis and, consequently, testicular physiology and metabolism. In addition, endocrine disruptors and environmental compounds that favor adipogenesis, namely obesogens, are also related to the imbalance of tightly regulated metabolic processes and to a host of other adverse reproductive outcomes. Such effects may result from an exposure during gestation, prepubertal age or adulthood, emphasizing the importance of different environmental impacts throughout the life course. Environmental contaminants may also promote disturbances in the metabolic performance of the following generations, through epigenetic modifications passed by male gametes. As society increasingly introduces new potentially toxic substances into daily life, unveiling the molecular pathways by which environmental contaminants induce toxicity that may end-up in epigenetic modifications is imperative. Otherwise, a transgenerational susceptibility to metabolic diseases may be favored. Herein, we discuss the suggested molecular targets and potential mechanisms for environmental contaminants action and the subsequent effects of exposure during different life stages of the male. We also present an up-todate overview about the impact of endocrine disruptors and obesogens on male reproductive health, as well as the epigenetic modifications induced by these environmental cues.

Late-onset hypogonadism (LOH) is a situation where a middle-aged or older man has low serum testosterone in conjunction with diffuse symptoms resembling those of genuine male hypogonadism. Testosterone replacement therapy has become a popular choice for the treatment of LOH. Aging is a process that includes irreversible changes because of a large variety of endogenous and environmental factors. Paternal aging also causes genetic and epigenetic changes in spermatozoa that damage male reproductive functions through adverse effects on sperm quality and count, as well as on sexual organs and also on the hypothalamic-pituitary testicular axis. If on one hand, hormone production, spermatogenesis, and testes undergo changes as a man ages, on the other hand, the offspring of older fathers show high prevalence of genetic abnormalities, childhood cancers, and several disorders. Information on the impact of age on male fertility is of growing importance, therefore, further studies should investigate the onset of changes in the reproductive function and its effects on aging men. The aim of this chapter is to briefly discuss the effects of aging on the male reproductive system and function.