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Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Section 1
Anatomy and Physiology of the Male Reproductive System
Anatomy and physiology of the male
The male reproductive hormonal axis
known as the adenohypophysis, in contrast communicates via blood­borne factors secreted by the hypothalamus. These neu­ Maintenance of normal reproductive function is depend­ ropeptides are transported by the portal blood system to the ent on the coordinated release of hormones in the hyp o­ anterior lobe where they stimulate synthesis and secretion of thalamic−pituitary−testis cascade. Gonadotropin­releasing adenohypophyseal hormones. Including the gonadotropes, LH
hormone (GnRH) is released in a pulsatile pattern into the pitu­ and FSH, the anterior pituitary also secretes other glycoprotein
itary portal blood system from neuroendocrine cel s in the basal hormones, corticotropin-related peptides, and somatomam-
hypothalamus and acts to stimulate gonadotropes in the anter­ motropin hormones. Prolactin and growth hormone have a sig­
ior pituitary to synthesize and release two peptide hormones, nificant contribution to male reproductive function.
follicle­stimulating hormone (FSH) and luteinizing hormone (LH) into the circulation. Once in the bloodstream these hor­ mones reach the testis, where LH stimulates testosterone pro-
Steroid feedback loop
duction by the Leydig cells in the interstitium while FSH
Testosterone provides negative feedback suppression of the supports spermatogenesis in the seminiferous epithelium by
release of GnRH through androgen receptors in the pituitary stimulation of the Sertoli cells. A focused network of negative
and hypothalamic neurons. Testosterone is also readily metab­ feedback relationships finesse testosterone secretion and sperm olized to dihydrotestosterone and estradiol by 5α­reductase production. This cascade is maintained by steroid and peptide and aromatase, respectively, in the testis and peripheral tissues. feedback within the testis as well as the hypothalamic and pitu­ Both testosterone and estrogen play important roles in the
itary gland (see Figure 1.1).
regulation of reproductive function at the cellular and tis-
sue levels. This can be demonstrated clinical y by individuals
with genetic mutations resulting in partial or complete loss of The hypothalamus is located in the lower aspect of the third function in androgen and estrogen receptors with increased ventricle of the brain. It is a complex region in the brain, which pituitary release of LH [1]. Stimulation of the Sertoli cell by responds to different signals generated external y and intern­ FSH results in production of inhibin, a glycoprotein hormone, al y as it is richly connected by neural projections to other which suppresses FSH secretion by gonadotropes. Regulation parts of the brain including the amygdala as well as the olfac­ of gonadotropin secretion exists for different steroids. While tory bulbs. The output of GnRH is influenced by three different the negative effect of testosterone on LH secretion is primarily rhythms including seasonal, circadian, and pulsatile, leading to mediated by the androgen itself, the effect of testosterone on peak levels during the spring, the early morning hours as well FSH secretion is mediated by estradiol [2].
as every 90 to 120 minutes. The precursors of GnRH neurons migrate to their position in the hypothalamus from the olfac­ Development of the male reproductive axis
tory placode during embryonic development.
Testosterone, dihydrotestosterone, and müllerian inhibiting substance from the fetal testes are important determinants of sexual phenotype. Sertoli cell precursors secrete müllerian The pituitary body is found in the hypophyseal fossa inferior to inhibiting substance (also known as anti­müllerian hormone) the hypothalamus. It is divided into two distinct lobes: anterior which prevents the development of the female reproductive and posterior. The posterior lobe is known as the neurohypo­ tract structures leading to a male phenotype [3]. Secretion of physis and is stimulated by neurons from the hypothalamus to testosterone by the fetal Leydig cel s stimulates differentiation secrete both oxytocin and vasopressin. The anterior lobe, also of the wolffian duct system, which later develops into the vas Surgical and Medical Management of Male Infertility, Marc Goldstein and Peter N. Schlegel. Published by Cambridge University Press. Cambridge University Press 2013.
in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Section 1: Anatomy and Physiology
Tunica albuginea Figure 1.2 Schematical drawing of the human testis showing seminiferous
tubules, epididymis, and vas deferens.
made up of three distinct layers surrounds the parenchyma of Figure 1.1 Diagram of the hypothalamic−pituitary−testis axis.
the testis: the tunica vaginalis, tunica albuginea, and the tunica vasculosa. The testes receive their blood supply from the tes­ ticular arteries, the cremasteric arteries, and the deferential deferens, epididymis, and sex accessory glands. Events of early
arteries. The testicular artery arises from the abdominal aorta testis differentiation are controlled by the sex-determining
just below the renal artery and becomes a component of the region on the Y chromosome (SRY) gene. The SRY gene acts
spermatic cord above the internal inguinal ring as well as being synergistical y with other transcription factors to initiate male intimately associated with a network of anastomotic veins, sex differentiation [4].
which eventual y form the pampiniform plexus. A counter cur­ Aging of the male reproductive system
rent heat exchange in the spermatic cord provides blood to the testis that is 2 to 4°C lower than the rectal temperature in a Epidemiologic studies have demonstrated that with age, circulat­ normal male [11]. The testicular arteries penetrate the tunica ing levels of testosterone progressively decline [5]. This decline albuginea and then travel inferiorly along the posterior surface in androgen levels is associated with modifications in body of the testicle and eventual y ascend onto the anterior surface composition, diminished energy, muscle strength and physical with several branches that course into the parenchyma. The function, reduced sexual function, and depressed and decreased location of these vessels should be considered as they may be cognitive function [6]. This age­related decline of testosterone injured during biopsy or orchidopexy. The medial and lateral levels is complex involving both intrinsic and extrinsic factors aspects of the superior pole have the lowest density of super­ to the Leydig cel . The brown Norway rat has become a well ficial vessels compared with the inferior and anterior portions established model for human reproductive aging, and studies of the testicle.
have reported that the number of Leydig cel s per testis remains The testicle is divided into compartments by septa, which unchanged compared to younger controls [7]. These findings are projections of the tunica albuginea. Each septum separates suggest that functional changes to the Leydig cel s rather than the seminiferous tubules, as well as the interstitial tissue which their loss account for the reduction in testosterone [8]. High tes­ is composed of Leydig cel s, blood vessels, lymphatics, mast ticular concentrations of testosterone are essential to maintain cel s, nerves, and macrophages. The seminiferous tubules are
spermatogenesis and men older than age 40 years have been the site of germ cell production. They are looped tubules con­
shown to have significantly lower fecundity [9]. Further studies tinuous at their ends with the rete testis, a network of collecting are likely to center on investigation of the intracel ular molecu­ tubes that eventual y coalesce to form efferent ducts that pro­ lar mechanisms leading to decreased Leydig cell steroidogen­ vide a conduit for collecting the testicular fluid and spermato­ esis. These may lead to the discovery of potential methods by zoa to the caput epididymis. The seminiferous tubule is made which to ameliorate the decline of testosterone synthesis in the up primarily of Sertoli cel s, germ cel s, and peritubular myoid aging male, which may have an impact on male infertility.
cel s (see Figure 1.2).
Macroscopic anatomy of the testis
The Leydig cell
The ovoid testis in young healthy males has a volume of 15 to Leydig cel s can be identified by their location in the intersti­ 25 mL and a longitudinal length of 4.5 to 5.1 cm [10]. A capsule tium of the testis. They are distinguished by the presence of a in this web service Cambridge University Press

Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Chapter 1: Anatomy and physiology
Figure 1.3 A diagrammatic representation of the
seminiferous tubule and the interstitium of the Tight junctionalcomplex round nucleus, prominent nucleolus, and Reinke crystals in the this provides an arrangement such that each germ cell is sup­ cytoplasm. Numerous gap junctions allow direct communica­ ported by a number of adjacent Sertoli cel s [13]. The Sertoli cell
tions between Leydig cel s. The Leydig cell is responsible for has several distinct functions that facilitate the maturation
the majority of androgen steroid production. The potency of of the germ cells. First, it provides a physical scaffold upon
the steroid hormones secreted by Leydig cel s is reflected by which the germ cells develop and migrate towards the lumen
the small percentage of the human testis occupied by Leydig of the tubule. Second, the Sertoli cell forms the blood−testis
cel s [12]. Circulating levels of testosterone in the serum dra­ barrier with specialized tight junctions that exist between
matical y fluctuate in a life cycle. The maximal concentration these cells. Third, Sertoli cells create the focused microenvir-
of testosterone is reached during the second and third decade onment essential for germ cell maturation. These distinctive
of life, reaches a plateau, and then starts to decline thereafter. functions also encompass phagocytosis, fluid secretion, and Leydig cell function is regulated by pituitary hormones, para­ production of a variety of molecules (see Figure 1.3).
crine factors secreted by cel s within the seminiferous tubules, The quest for a Sertoli cell product as a marker of Sertoli cell as well as autoregulatory factors.
function that is helpful in the evaluation of an infertile patient The Sertoli cell
has yet to be elucidated. Androgen­binding protein was one of the first extracel ular protein markers identified in the 1970s The Sertoli cell is a non­dividing somatic cell of epithelial ori­ and since then a myriad of other secretory products have been gin that rests on the basement membrane and forms the wall discovered as wel . Inhibin is a glycoprotein hormone secreted of the tubule. An irregularly shaped nucleus, prominent nucle­ primarily by the Sertoli cel s and suppresses FSH secretion. olus, low mitotic index, Sertoli−germ cell connections, as well Some have proposed that serum inhibin B could possibly be as unique tight junctional complexes between adjacent Sertoli an independent marker of impaired testicular function, as well cell membranes characterize this unique cel . Surface processes as a predictor of the presence of sperm in the testes of infertile from the Sertoli cel s extend outward to surround germ cel s as in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Section 1: Anatomy and Physiology
The blood−testis barrier spermatogonia and primary spermatocytes that are present at Within the testis there exists a functional blood−testis barrier. birth. There appears to be very little activity in further devel­ This barrier, made up of specialized junctions, creates a division opment until the onset of puberty. There are three types of in the seminiferous epithelium between adjacent Sertoli cel s spermatogonia: the dark type A, the pale type A, and the type that forms a basal compartment and an adluminal compart­ B spermatogonia. These cel s undergo several mitotic divisions ment [15]. The basal compartment is accessible to blood­borne to produce a large number of cel s that will either participate in substances via the extracel ular spaces; however, due to the stem cell renewal or go on to create daughter cel s, which will occluding nature of the barrier these substances are prevented later become spermatocytes.
from directly reaching the adluminal compartment. The adlu­ Primary spermatocytes are unique in that they undergo minal compartment contains mature germ cel s, while the basal two successive cell divisions that produce the spermatids. compartment contains spermatogonia and young spermato­ This process, called meiosis, comprises two cell divisions fol­ cytes. The different functional components of the blood−testis lowing replication of the chromosomes, generating haploid barrier include the tight junctional complexes between Sertoli germ cells. It is the fusion of the haploid spermatozoon with cel s, peritubular myoid cel s, as well as the endothelial cel s in an equally haploid ovum that restores the diploid number of the nearby capil aries [16]. The clinical significance of this bar­ chromosomes in the cells of the embryo. There are two meiotic rier is reflected by post­pubertal protection of the adluminal divisions involving primary and secondary spermatocytes. (inferior) compartment of the testis from post­pubertal tes­ Each meiotic division is comprised of four distinct phases ticular insults and the lack of development of antisperm anti­ including prophase, metaphase, telophase, and anaphase. bodies unless this barrier is breached.
Primary prophase I is long and subdivided into five stages: leptotene, zygotene, pachytene, diplotene, and diakinesis. Spermiogenesis refers to the dramatic metamorphosis that
a round spermatid undergoes to become an elongated fla-
Spermatogenesis is an elaborate process of cell differentiation gellar cell capable of motility. This transformation includes
concluding with development of the ful y differentiated highly the development of the acrosome, condensation of chroma­ specialized haploid motile spermatozoa. Spermatogonia, the tin, formation of the flagellum, and migration of cytoplasmic most immature germ cel s, reside along the basement mem­ organelles [18].
brane of the seminiferous tubule in the basal compartment. The sperm head consists principally of a nucleus, which The slow evolution of spermatogonia into highly special-
contains the condensed chromatin material as well as the ized spermatozoa requires approximately 64 days [17]. The
acrosome. The acrosome is a membrane­bound organelle that first mitotic divisions occur in the fetal testis generating the contains the hydrolytic enzymes necessary for penetration of Figure 1.4 Diagram of a typical mammalian
spermatozoon. Cross-sectional insets show the orientation of the internal cell structure.
Mitochondrial sheath in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Chapter 1: Anatomy and physiology
the egg before fertilization [19]. The flagellum forms at the communicate directly with the pampiniform plexus. The veins lower pole where the mitochondria coalesce and generate the arising from the cauda and distal corpus eventual y communi­ energy needed for motility. The mitochondria are arranged cate with the deferential or cremasteric veins.
in a helical pattern surrounding a set of outer fibers and the characteristic 9 + 2 microtubular structure of the axoneme Functions of the epididymis The initiation and maintenance of normal spermatogen-
The three primary functions of the epididymis are sperm mat-
esis is dependent on the synergistic effect of FSH and testos-
uration, sperm transport, and sperm storage. Maturational
changes allow sperm the capacity to become motile and fer­ [20]. While germ cel s require these hormones they do tilize as they transit from the testis, through the epididymis to not possess receptors for either FSH or testosterone. Sertoli cel s the vas deferens. It has been shown that as human spermato­ possess both these receptors and it is thought that the actions of zoa migrate through the epididymis they develop increased FSH and testosterone are mediated by the Sertoli cel .
motility. In comparison to the caput epididymis the more dis­ Genetic factors critical for spermatogenesis are being tal portions of the epididymis house a higher percentage of rapidly elucidated. Investigations in men with severely
impaired spermatogenesis led to the discovery of submicro-
spermatozoa capable of efficient motility [25]. While the exact scopic deletions of a region of the Y chromosome
mechanisms that detail sperm maturation are not ful y under­ stood, the consensus is that these processes are potentiated These regions are referred to as the azoospermic factor (AZF)
through the interaction with the epididymis during migration a, b, and c with distinct genes that have been deleted in azoo­ into more distal regions of the duct.
spermic men such as the DAZ (deleted in azoospermia) gene The transit time of the sperm in the human epididy-
found in the AZFc region. Localization of specific genes that mis averages 12 days but is highly variable, with some
are critical for spermatogenesis remains the subject of active sperm moving ahead through the epididymis in as little as
2 days [26–28]. Transport through the proximal epididymal
duct is principal y due to spontaneous, peristaltic contrac­ tions of the smooth muscle that surrounds the epididymal Spermatozoa acquire the capacity to become ful y motile as duct. Other contributing factors that aid in the transport of well as the ability to recognize and fertilize an egg within the sperm include motile cilia as wel as the flow of the secreted epididymis. These transformations of spermatozoa are called testicular fluid. Sperm transport time through the epididymis sperm maturation. Sperm motility and fertilization capacity has also been shown to vary with age and sexual activity with are both androgen­dependent processes. The loss of androgens a direct correlation to the differences in daily rate of sperm results in the loss of epididymal weight, as well as changes in production [29].
the components of the epididymal fluid secretions [22]. The In humans the major storage site of spermatozoa is the epididymis, derived from the wolffian (mesonephric) duct, is cauda epididymis where approximately half of the total num­ an organ consisting of a single highly convoluted duct, which ber of spermatozoa are stored [26]. It has been suggested that the testicular sperm must pass through. It is attached to the preservation of sperm viability and motility in humans is not as superior and inferior pole of the testis and is closely applied efficient as it is in other species [30]. While there are numerous to the posterior aspect. The epididymis is divided into three studies using experimental animals, the fate of unejaculated major regions: caput, corpus, and cauda. The caput epididymis sperm is still unknown.
overlies the superior pole of the testis and the cauda overlies the inferior pole of the testis. The intervening region is referred Ductus vas deferens
to as the corpus.
The vas deferens is a thick muscular tube that measures The epididymis is surrounded by the visceral layer of the approximately 30 to 40 cm from the cauda epididymis to the tunica vaginalis, except over the posterior aspect, which is point of fusion with the seminal vesicle and ejaculatory ducts. attached to the scrotum and spermatic cord by a fibrofatty Five portions have been previously described: epididymal, connective tissue. Approximately 10 ductuli efferentes arise
scrotal, inguinal, pelvic, and ampul a. The vas deferens, like the from the rete testis that eventually come together to form a
epididymis and seminal vesicle, is derived from the mesone­ single epididymal duct. In humans, the epididymal tubule is
phric duct. The ability to propel sperm forceful y is depend­ approximately 3 to 4 m in length [23]. The vascular supply to
ent on a three­layered muscular coat, with an inner and outer the epididymis is from two sources. The caput and corpus are longitudinal layer and a middle circular layer. While the vas supplied from the superior and inferior epididymal branches of deferens receives nerve fibers from both the sympathetic and the testicular artery. The cauda is supplied from the branches of parasympathetic nervous system, the rich supply of adrenergic the deferential artery. This blood supply is characterized by tor­ fibers contributes to the efficiency of sperm transport. The vas tuosity of the vessels as well as a large number of anastomotic deferens receives its blood supply from the deferential artery communications [24]. While the venous drainage of the epi­ via the inferior vesical artery, and the deferential vein accom­ didymis may vary, the veins of the caput and proximal corpus in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Section 1: Anatomy and Physiology
• Approximately 10 ductuli efferentes arise from the rete testis that eventual y come together to form a single • LH stimulates testosterone production by the Leydig cel s epididymal duct. In humans, the epididymal tubule is in the interstitium while FSH supports spermatogenesis in approximately 3 to 4 m in length [23].
the seminiferous epithelium by stimulation of the Sertoli • The three primary functions of the epididymis are sperm maturation, sperm transport, and sperm storage.
• The hypothalamus is a complex region in the brain that • The transit time of the sperm in the human epididymis responds to different signals generated external y and averages 12 days but is highly variable, with some sperm internal y as it is richly connected by neural projections to moving ahead through the epididymis in as little as 2 days other parts of the brain including the amygdala as well as the olfactory bulbs.
• The vas deferens is a thick muscular tube that measures • Apart from the gonadotropes, LH and FSH, the anterior approximately 30 to 40 cm from the cauda epididymis to pituitary also secretes other glycoprotein hormones, the point of fusion with the seminal vesicle and ejaculatory corticotropin­related peptides, and somatomammotropin • Both testosterone and estrogen play important roles in the regulation of reproductive function at the cel ular and tissue levels.
• Events of early testis differentiation are controlled by the 1. Shupnik MA, Schreihofer DA. Molecular aspects of steroid sex­determining region on the Y chromosome (SRY) gene.
hormone action in the male reproductive axis. J Androl • The ovoid testis in young healthy males measures 15 to 25 mL in volume and has a longitudinal length of 4.5 to 2. Hayes FJ, Pitteloud N, DeCruz S, Crowley WF Jr, Boepple PA. 5.1 cm [10].
Importance of inhibin B in the regulation of FSH secretion in the human male. J Clin Endocrinol Metab 2001;86:5541–6.
• A counter current heat exchange in the spermatic cord provides blood to the testis that is 2 to 4°C lower than 3. Lee MM, Donahoe PK. Mullerian inhibiting substance: a gonadal hormone with multiple functions. Endocr Rev 1993;14:152–64.
rectal temperature in a normal male.
• The medial and lateral aspects of the superior pole have 4. Sekido R, Lovel ­Badge R. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature the lowest density of superficial vessels compared with the inferior and anterior portions of the testicle.
5. Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. • The seminiferous tubules are the site of germ cell Longitudinal effects of aging on serum total and free testosterone levels in healthy men: Baltimore Longitudinal Study of Aging. • The Sertoli cell has several distinct functions that facilitate J Clin Endocrinol Metab 2001;86:724–31.
the maturation of the germ cel s. First, it provides a 6. Matsumoto AM. Andropause: clinical implications of the decline physical scaffold upon which the germ cel s develop and in serum testosterone levels with aging in men. J Gerontol A Biol migrate towards the lumen of the tubule. Second, the Sci Med Sci 2002;57:M76–99.
Sertoli cell forms the blood−testis barrier with specialized 7. Wang C, Leung A, Sinha­Hikim AP. Reproductive aging in the tight junctions that exist between these cel s. Third, Sertoli male brown­Norway rat: a model for the human. Endocrinology cel s create the focused microenvironment essential for germ cell maturation.
8. Midzak AS, Chen H, Papadopoulos V, Zirkin BR. Leydig cell • The slow evolution of spermatogonia into highly aging and the mechanisms of reduced testosterone synthesis. Mol specialized spermatozoa requires approximately 64 days 9. Ford WC, North K, Taylor H, et al. Increasing paternal age is • Spermiogenesis refers to the dramatic metamorphosis associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. The that a round spermatid undergoes to become an elongated ALSPAC Study Team (Avon Longitudinal Study of Pregnancy flagel ar cell capable of motility.
and Childhood). Hum Reprod 2000;15:1703–8.
• The initiation and maintenance of normal spermatogenesis 10. Winter JS, Faiman C. Pituitary­gonadal relations in male children is dependent on the synergistic effect of FSH and and adolescents. Pediatr Res 1972;6:126–35.
testosterone [20].
11. Agger P. Scrotal and testicular temperature: its relation to sperm • Investigations in men with severely impaired count before and after operation for varicocele. Fertil Steril spermatogenesis led to the discovery of submicroscopic deletions of a region of the Y chromosome [21].
12. Kaler LW, Neaves WB. Attrition of the human Leydig cell • Spermatozoa acquire the capacity to become ful y motile population with advancing age. Anat Rec 1978;192:513–8.
as well as the ability to recognize and fertilize an egg 13. Nagano T. Some observations on the fine structure of the Sertoli within the epididymis.
cell in the human testis. Z Zellforsch Mikrosk Anat 1966;73:89–106.
in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Chapter 1: Anatomy and physiology
14. von Eckardstein S, Simoni M, Bergmann M, et al. Serum inhibin 21. Girardi SK, Mielnik A, Schlegel PN. Submicroscopic B in combination with serum follicle­stimulating hormone (FSH) deletions in the Y chromosome of infertile men. Hum Reprod is a more sensitive marker than serum FSH alone for impaired spermatogenesis in men, but cannot predict the presence of 22. Cohen J, Ooms MP, Vreeburg JT. Reduction of fertilizing sperm in testicular tissue samples. J Clin Endocrinol Metab capacity of epididymal spermatozoa by 5 alpha­steroid reductase 15. Fawcett DW. Observations on the organization of the interstitial 23. Turner TT, D'Addario D, Howards SS. Further observations on tissue of the testis and on the occluding cell junctions in the the initiation of sperm motility. Biol Reprod 1978;19:1095–101.
seminiferous epithelium. Adv Biosci 1973;10:83–99.
24. Macmil an EW. The blood supply of the epididymis in man. 16. Dym M, Fawcett DW. The blood–testis barrier in the rat and the Br J Urol 1954;26:60–71.
physiological compartmentation of the seminiferous epithelium. Biol Reprod 1970;3:308–26.
25. Bedford JM, Calvin H, Cooper GW. The maturation of spermatozoa in the human epididymis. J Reprod Fertil Suppl 1973;18:199–213.
17. Clermont Y. Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and spermatogonial renewal. 26. Amann RP, Howards SS. Daily spermatozoal production and Physiol Rev 1972;52:198–236.
epididymal spermatozoal reserves of the human male. J Urol 18. de Kretser DM, Kerr JB, Paulsen CA. Evaluation of the ultrastructural changes in the human Sertoli cell in testicular 27. Johnson L, Varner DD. Effect of daily spermatozoan production disorders and the relationship of the changes to the levels of but not age on transit time of spermatozoa through the human serum FSH. Int J Androl 1981;4:129–44.
epididymis. Biol Reprod 1988;39:812–7.
19. McMaster R, Yanagimachi R, Lopata A. Penetration of 28. Rowley MJ, Teshima F, Heller CG. Duration of transit of human eggs by human spermatozoa in vitro. Biol Reprod spermatozoa through the human male ductular system. Fertil 20. Simoni M, Gromoll J, Hoppner W, et al. Mutational analysis 29. Curtis SK, Amann RP. Testicular development and of the follicle­stimulating hormone (FSH) receptor in normal establishment of spermatogenesis in Holstein bul s. J Anim Sci and infertile men: identification and characterization of two discrete FSH receptor isoforms. J Clin Endocrinol Metab 30. Bedford JM. The status and the state of the human epididymis. Hum Reprod 1994;9:2187–99.
in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Section 1
Section 2
History and physical examination
of the infertile male
2 Moshe Wald
days near the time of ovulation, ensuring the presence of viable sperm in the female reproductive tract during the critical 12- to The evaluation of the infertile male consists of a variety of com- 24-hour period in which the oocyte is within the fal opian tube ponents, which include a detailed medical, surgical, develop- and is capable of being fertilized [2]. While exceedingly frequent mental, and reproductive history, as well as a careful physical intercourse may result in inadequate numbers of sperm being examination, semen analyses and possibly other laboratory deposited in the vagina, conversely, ovulation could be missed tests, all performed in concert with the evaluation of the female with infrequent sexual activity. The use of vaginal lubricants partner. The history and physical examination, along with during intercourse should also be determined, as some of these appropriately obtained semen analyses, represent the core of substances, such as Astroglide® (BioFilm, Inc., Vista, CA), K-Y the evaluation of the infertile male. In fact, the need for dif- Jel y® (McNeil-PPC, Inc., Skillman, NJ), Surgilube® (Fougera, ferent laboratory tests is determined by the history and phys- Melvil e, NY), and saliva, have been reported to negatively affect ical examination findings. For example, a cystic fibrosis screen, sperm motility [3,4,5]. Decreased libido, as wel as erectile or which is not part of the routine male infertility evaluation, ejaculatory dysfunction should be noted, as these could be asso- should be ordered when a vas deferens can not be palpated ciated with hypogonadism or other systemic disorders. While a on physical examination, a finding concerning for congenital history of absent or noticeably low ejaculate volume could also absence of the vas deferens (CBAVD). This chapter will provide be part of the clinical picture of hypogonadism, it also suggests a comprehensive review of the history and physical examin- the possibility of other conditions, including retrograde ejacula- ation of the infertile male as well as the indications and recom- tion, ejaculatory duct obstruction, or congenital absence of the mended timing for the performance of each component.
vas deferens.
Genitourinary infections Obtaining a thorough medical and reproductive history that Information regarding any previous urinary tract infections or explores all aspects potential y related to fertility is a key com- sexually transmitted diseases should be obtained. A history of ponent of the evaluation of the infertile male [1]. While the prostatitis may lead to ejaculatory duct obstruction, and previ- detailed history focuses on the male partner, pertinent infor- ous pyospermia may represent an inflammatory process with an mation regarding the reproductive status of the female partner adverse effect on sperm production. However, the direct causa- and the couple's fertility efforts should also be gathered.
tive relationship of these conditions to infertility has not been confirmed [2,6]. A history of previous epididymitis should also Sexual and reproductive history be noted, given its possible sequelae of epididymal obstruction.
Duration of infertility and previous fertility should be determined, Mumps orchitis and other forms of viral orchitis may including details of any prior pregnancies achieved. Frequency develop in post-pubertal patients. In cases of previous mumps of sexual intercourse and masturbation should be recorded, as infection, it is important to confirm that the disease involved wel as the timing of coitus. It is important to determine whether the testicles, as only 10–30% of pubertal patients who acquire the couple attempts to time intercourse with ovulation, and mumps develop mumps orchitis [7]. Bilateral involvement has whether this is done in an effective manner that could optimize been reported in 20% to 60% of cases [2].
the chances of conception. As sperm remain viable within the cervical mucus and crypts for 48 hours or longer, the timing of Childhood illnesses and developmental history sexual intercourse does not have to coincide exactly with ovula- Delayed or absent puberty may indicate an endocrine dis­
tion, but most experts recommend vaginal intercourse every 2 order or an androgen receptor abnormality [8]. A history
Surgical and Medical Management of Male Infertility, Marc Goldstein and Peter N. Schlegel. Published by Cambridge University Press. Cambridge University Press 2013.
in this web service Cambridge University Press Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Chapter 2: History and physical examination
of gynecomastia may be associated with testis cancer, hyper- syndrome, which also includes situs inversus [18]. Frequent prolactinemia, or estrogen abnormalities [9]. While unilateral respiratory infections associated with azoospermia suggests the cryptorchidism has been reported to only slightly decrease fer- possibility of Young's syndrome, in which epididymal obstruc- tility, bilateral cryptorchidism results in a significant reduction tion is caused by inspissation of secretions [19]. A personal in fertility [10,11].
or familial history of cystic fibrosis (CF) is of importance, as almost all male patients with clinical CF have bilateral congeni- Past surgical history tal absence of the vas deferens [20,21].
Various surgical procedures could potential y disrupt the Prolactinoma or other pituitary tumors should be suspected physiologic regulation of different functions of the male repro- with a history of severe headaches, galactorrhea, or impaired ductive tract, as well as damage the anatomic integrity of this visual fields. Anosmia associated with male infertility should system at different sites along its course. Surgery or trauma of raise the possibility of Kallmann syndrome, a congenital form the brain or pituitary could impair the hormonal regulation of of hypogonadotropic hypogonadism.
spermatogenesis and testicular testosterone production. Pelvic or retroperitoneal surgery may affect erectile and ejaculatory Medications, recreational drugs, and gonadotoxin function. For example, retroperitoneal lymph node dissection for testis cancer may involve sympathetic nerve injury, resulting in failure of emission or retrograde ejaculation. Bladder neck Certain medications, including nitrofurantoin, cimetidine,
surgery may also result in retrograde ejaculation. Inguinal her- and sulfasalazine, have been reported to impair spermat o­
nia repair may be associated with damage to the vas deferens, genesis [2]. A similar effect has been attributed to certain rec-
by inadvertent direct injury or compromising its blood supply. reational drugs, including cocaine [22,23] and marijuana [24], Additional y, the vas deferens may be entrapped in dense fibro- as well as to anabolic steroid and chronic alcohol abuse [25]. sis associated with hernia repair using mesh, leading to vasal Additionally, the androgenic effect of steroids may cause
obstruction. Final y, scrotal surgery such as hydrocelectomy, hypogonadotropic hypogonadism, which is usually but not
spermatocelectomy or orchidopexy for torsion may result always reversible after the discontinuation of these agents
in injury and obstruction of the vas deferens and/or the epi- [26]. While the effect of cigarette smoking on spermatogenesis
didymis. Testicular trauma or torsion may result in testicular is unclear, it has been suggested that smoking could possibly be atrophy or scarring. Furthermore, these events may lead to the a cofactor in male patients with other causes of infertility [27].
formation of antisperm antibodies, possibly due to the disrup- Occupational or environmental exposure to pesticides or tion of the blood−testis barrier.
other toxic chemicals should be noted, as these substances may have a deleterious effect on sperm production or func- Systemic medical illnesses tion. Additional y, a history of excessive heat exposure, either occupational or secondary to the frequent use of saunas and Erectile dysfunction, retrograde ejaculation, and other ejacu- hot tubs is of relevance, as experimental hyperthermia and the latory abnormalities may develop in patients with diabetes frequent use of hot tubs have been shown to cause impaired mellitus or multiple sclerosis. Many other systemic disorders semen quality and spermatogenesis [2].
could have a negative effect on spermatogenesis. A febrile ill- ness, even if associated with a disease that does not directly involve the genitourinary tract, could cause spermatogenesis impairment for up to 3 months [12]. End-stage renal disease The family history of the infertile male should focus on the has been reported to be associated with male infertility [2]. phenotype of the maternal uncles, as the androgen receptor Men with testicular cancer or lymphoma may have fertility gene, as well as multiple other genes affecting male reproduc- difficulties even before initiation of treatment, as low sperm tion, is located on the X chromosome.
concentrations have been reported in 60% or more of patients at the time of diagnosis [13,14,15]. Obviously, chemotherapy or radiotherapy administered for these conditions or other cancers may impair spermatogenesis. While these treatments General examination may result in permanent azoospermia, return of spermatogen- The physical examination of the infertile male should not be esis is possible under certain circumstances, although it may limited to a genital examination, and should include a detailed take up to 4 to 5 years to occur after completion of treatment general examination, which can reveal identifiable abnormal- [15,16,17]. Spermatogenesis recovery following radiation ther- ities that may be associated with infertility and its underlying apy or chemotherapy varies, depending on the specific agents causes. The patient's habitus should be noted, as alterations of used, doses, and duration of treatment [17].
the normal male appearance may be associated with chromo- A history of frequent or chronic respiratory tract infections somal or endocrine disorders that have an impact on fertility in the setting of male infertility and lack of sperm motility as well as on other health issues. For example, a eunuchoid should raise the suspicion for immotile cilia (or Kartagener's) appearance could be associated with Klinefelter syndrome or in this web service Cambridge University Press

Cambridge University Press978-0-521-88109-8 - Surgical and Medical Management of Male InfertilityMarc Goldstein and Peter N. SchlegelExcerptMore information Section 2: Evaluation
Figure 2.1 Calipers used for measuring long and
short testicular axis.
Figure 2.2 Orchometer used for measuring
testicular volume. Image reproduced with kind permission from Prader.
hypogonadotropic hypogonadism. Additional y, abnormalities warts, sores, herpetic-like lesions, and any urethral discharge. of the secondary sex characteristics and changes in the pattern The penis should be examined for any curvature or plaques, of virilization, such as lack of temporal pattern balding, may which could suggest Peyronie's disease. The possible presence also indicate a congenital endocrine disorder. Other pertinent of severe chordee should also be noted. The location of the findings on the general physical examination include gyne- urethral meatus should be determined, since significant hypo- comastia, which is suggestive of either an imbalance between spadias, as well as severe penile curvatures and chordee could estrogen and androgen levels or increased prolactin levels, as interfere with proper deposition of semen in the vagina.
well as situs inversus, which may be part of Kartagener's syn- The examination of the scrotum should be performed drome, a congenital disorder associated with immotile cilia with the patient both supine and standing in a warm room to leading to absent sperm motility.
allow for relaxation of the cremaster muscle. Use of a heating pad to relax the scrotum prior to examination is very effect- Genital examination ive without overheating the examiner or the patient. The testi­
cles should be carefully palpated to assess their consistency
A careful genital examination is a critical part of the evaluation and to rule out the presence of an intratesticular mass. The
of the infertile male. This examination can allow for identifi- dimensions of the testicles should be measured, using either
cation of the cause of infertility, such as in cases of bilateral y calipers (Figure 2.1) for determination of the long and short
absent vasa deferentia or clinical y evident varicoceles, and may testicular axis, or an orchidometer for assessment of testicu­
also direct the clinician toward the next steps of the evaluation lar volume (Figure 2.2) [28]. Testicular measurement by cali-
that are required for a given scenario. For example, the absence pers should be done careful y, to avoid painful squeezing of the of any palpable vas deferens on both sides suggests the diagno- testicles. Interestingly, variations in the normal range for tes- sis of congenital bilateral absence of the vas deferens (CBAVD), ticular dimensions between different ethnic groups have been a condition closely associated with cystic fibrosis, and should reported. While the normal adult testis is greater than 4 × 3 cm prompt genetic testing for cystic fibrosis.
in its greatest dimensions or greater than 20 mL in volume for The entire genital area should be inspected for any find- Caucasians and African-Americans [29], Asian men normal y ings concerning for sexual y transmitted diseases, such as have smaller testicles but higher sperm production per cubic in this web service Cambridge University Press

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