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Male Reproductive
Male Reproductive
1 reproductive system
Ray Costabile
The male reproductive hormonal axis known as the adenohypophysis, in contrast communicates via
blood-borne 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 hypo
anterior lobe where they stimulate synthesis and secretion of
thalamic−pituitary−testis cascade. Gonadotropin-releasing
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 cells 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.
follicle-stimulating 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 5α-reductase
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 clinically by individuals
Hypothalamus 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 externally and intern FSH results in production of inhibin, a glycoprotein hormone,
ally 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
Pituitary of sexual phenotype. Sertoli cell precursors secrete müllerian
The pituitary body is found in the hypophyseal fossa inferior to inhibiting substance (also known as anti-müllerian 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 cells 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.
Epididymal duct
Hypothalamus Efferent
ducts
– GnRH
Vas deferens
– Pituitary +
Tunica albuginea
Testosterone
Inhibin
Dihydrotestosterone
Activin
Estradiol Figure 1.2 Schematical drawing of the human testis showing seminiferous
tubules, epididymis, and vas deferens.
Target organs
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
synergistically with other transcription factors to initiate male intimately associated with a network of anastomotic veins,
sex differentiation [4]. which eventually form the pampiniform plexus. A counter cur
rent heat exchange in the spermatic cord provides blood to the
Aging of the male reproductive system 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 eventually 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 age-related 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 cell. 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 cells 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 cells 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 cells, blood vessels, lymphatics, mast
ticular concentrations of testosterone are essential to maintain cells, 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 intracellular molecu tubes that eventually 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 cells, germ cells, and peritubular myoid
aging male, which may have an impact on male infertility. cells (see Figure 1.2).
Late
spermatid
testis
Adluminal
compartment Early
spermatid
Sertoli cell
Spermatocyte
Basal
compartment Tight junctional
complex
Spermatogonia
Arteriole
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 cells [13]. The Sertoli cell
tions between Leydig cells. 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 cells 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
cells [12]. Circulating levels of testosterone in the serum dra barrier with specialized tight junctions that exist between
matically 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 cells 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
has yet to be elucidated. Androgen-binding protein was one of
The Sertoli cell the first extracellular protein markers identified in the 1970s
The Sertoli cell is a non-dividing 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 well. Inhibin is a glycoprotein hormone secreted
of the tubule. An irregularly shaped nucleus, prominent nucle primarily by the Sertoli cells 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 cell. Surface processes as a predictor of the presence of sperm in the testes of infertile
from the Sertoli cells extend outward to surround germ cells as men [14].
The blood−testis barrier spermatogonia and primary spermatocytes that are present at
birth. There appears to be very little activity in further devel
Within the testis there exists a functional blood−testis barrier.
opment until the onset of puberty. There are three types of
This barrier, made up of specialized junctions, creates a division
spermatogonia: the dark type A, the pale type A, and the type
in the seminiferous epithelium between adjacent Sertoli cells
B spermatogonia. These cells undergo several mitotic divisions
that forms a basal compartment and an adluminal compart
to produce a large number of cells that will either participate in
ment [15]. The basal compartment is accessible to blood-borne
stem cell renewal or go on to create daughter cells, which will
substances via the extracellular spaces; however, due to the
later become spermatocytes.
occluding nature of the barrier these substances are prevented
Primary spermatocytes are unique in that they undergo
from directly reaching the adluminal compartment. The adlu
two successive cell divisions that produce the spermatids.
minal compartment contains mature germ cells, while the basal
This process, called meiosis, comprises two cell divisions fol
compartment contains spermatogonia and young spermato
lowing replication of the chromosomes, generating haploid
cytes. The different functional components of the blood−testis
germ cells. It is the fusion of the haploid spermatozoon with
barrier include the tight junctional complexes between Sertoli
an equally haploid ovum that restores the diploid number of
cells, peritubular myoid cells, as well as the endothelial cells in
chromosomes in the cells of the embryo. There are two meiotic
the nearby capillaries [16]. The clinical significance of this bar
divisions involving primary and secondary spermatocytes.
rier is reflected by post-pubertal protection of the adluminal
Each meiotic division is comprised of four distinct phases
(inferior) compartment of the testis from post-pubertal tes
including prophase, metaphase, telophase, and anaphase.
ticular insults and the lack of development of antisperm anti
Primary prophase I is long and subdivided into five stages:
bodies unless this barrier is breached.
leptotene, zygotene, pachytene, diplotene, and diakinesis.
Spermiogenesis refers to the dramatic metamorphosis that
Spermatogenesis 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 fully 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 cells, 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 membrane-bound organelle that
first mitotic divisions occur in the fetal testis generating the contains the hydrolytic enzymes necessary for penetration of
Nucleus
Plasma
membrane
Middle piece
Mitochondrial sheath
End piece
Fibrous sheath
Principal piece
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 eventually 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
(see Figure 1.4)
The three primary functions of the epididymis are sperm mat-
The initiation and maintenance of normal spermatogen-
uration, sperm transport, and sperm storage. Maturational
esis is dependent on the synergistic effect of FSH and testos-
changes allow sperm the capacity to become motile and fer
terone [20]. While germ cells 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 cells
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 cell.
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
spermatozoa capable of efficient motility [25]. While the exact
impaired spermatogenesis led to the discovery of submicro-
mechanisms that detail sperm maturation are not fully under
scopic deletions of a region of the Y chromosome [21].
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
investigation.
2 days [26–28]. Transport through the proximal epididymal
duct is principally due to spontaneous, peristaltic contrac
Epididymis tions of the smooth muscle that surrounds the epididymal
duct. Other contributing factors that aid in the transport of
Spermatozoa acquire the capacity to become fully motile as
sperm include motile cilia as well as the flow of the secreted
well as the ability to recognize and fertilize an egg within the
testicular fluid. Sperm transport time through the epididymis
epididymis. These transformations of spermatozoa are called
has also been shown to vary with age and sexual activity with
sperm maturation. Sperm motility and fertilization capacity
a direct correlation to the differences in daily rate of sperm
are both androgen-dependent processes. The loss of androgens
production [29].
results in the loss of epididymal weight, as well as changes in
In humans the major storage site of spermatozoa is the
the components of the epididymal fluid secretions [22]. The
cauda epididymis where approximately half of the total num
epididymis, derived from the wolffian (mesonephric) duct, is
ber of spermatozoa are stored [26]. It has been suggested that
an organ consisting of a single highly convoluted duct, which
preservation of sperm viability and motility in humans is not as
the testicular sperm must pass through. It is attached to the
efficient as it is in other species [30]. While there are numerous
superior and inferior pole of the testis and is closely applied
studies using experimental animals, the fate of unejaculated
to the posterior aspect. The epididymis is divided into three
sperm is still unknown.
major regions: caput, corpus, and cauda. The caput epididymis
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 ampulla. 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 forcefully is depend
approximately 3 to 4 m in length [23]. The vascular supply to ent on a three-layered 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 panies it.
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 follicle-stimulating hormone (FSH) deletions in the Y chromosome of infertile men. Hum Reprod
is a more sensitive marker than serum FSH alone for impaired 1997;12:1635–41.
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 alpha-steroid reductase
1999;84:2496–501. inhibitors. Experientia 1981;37:1031–2.
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. Macmillan 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
1980;124:211–5.
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
1978;19:212–6. Steril 1970;21:390–6.
29. Curtis SK, Amann RP. Testicular development and
20. Simoni M, Gromoll J, Hoppner W, et al. Mutational analysis
establishment of spermatogenesis in Holstein bulls. J Anim Sci
of the follicle-stimulating hormone (FSH) receptor in normal
1981;53:1645–57.
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.
1999;84:751–5. Hum Reprod 1994;9:2187–99.
Section 2
1 Evaluation
Introduction 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 fallopian 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-
Jelly® (McNeil-PPC, Inc., Skillman, NJ), Surgilube® (Fougera,
ferent laboratory tests is determined by the history and phys-
Melville, 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 well 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.
Surgical and Medical Management of Male Infertility, Marc Goldstein and Peter N. Schlegel. Published by Cambridge University Press. © Cambridge
University Press 2013.
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].
Prolactinoma or other pituitary tumors should be suspected
Various surgical procedures could potentially disrupt the
with a history of severe headaches, galactorrhea, or impaired
physiologic regulation of different functions of the male repro-
visual fields. Anosmia associated with male infertility should
ductive tract, as well as damage the anatomic integrity of this
raise the possibility of Kallmann syndrome, a congenital form
system at different sites along its course. Surgery or trauma of
of hypogonadotropic hypogonadism.
the brain or pituitary could impair the hormonal regulation of
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 exposure
for testis cancer may involve sympathetic nerve injury, resulting
Certain medications, including nitrofurantoin, cimetidine,
in failure of emission or retrograde ejaculation. Bladder neck
and sulfasalazine, have been reported to impair spermato
surgery may also result in retrograde ejaculation. Inguinal her-
genesis [2]. A similar effect has been attributed to certain rec-
nia repair may be associated with damage to the vas deferens,
reational drugs, including cocaine [22,23] and marijuana [24],
by inadvertent direct injury or compromising its blood supply.
as well as to anabolic steroid and chronic alcohol abuse [25].
Additionally, the vas deferens may be entrapped in dense fibro-
Additionally, the androgenic effect of steroids may cause
sis associated with hernia repair using mesh, leading to vasal
hypogonadotropic hypogonadism, which is usually but not
obstruction. Finally, scrotal surgery such as hydrocelectomy,
always reversible after the discontinuation of these agents
spermatocelectomy or orchidopexy for torsion may result
[26]. While the effect of cigarette smoking on spermatogenesis
in injury and obstruction of the vas deferens and/or the epi-
is unclear, it has been suggested that smoking could possibly be
didymis. Testicular trauma or torsion may result in testicular
a cofactor in male patients with other causes of infertility [27].
atrophy or scarring. Furthermore, these events may lead to the
Occupational or environmental exposure to pesticides or
formation of antisperm antibodies, possibly due to the disrup-
other toxic chemicals should be noted, as these substances
tion of the blood−testis barrier.
may have a deleterious effect on sperm production or func-
tion. Additionally, a history of excessive heat exposure, either
Systemic medical illnesses 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 Family history
involve the genitourinary tract, could cause spermatogenesis
The family history of the infertile male should focus on the
impairment for up to 3 months [12]. End-stage renal disease
phenotype of the maternal uncles, as the androgen receptor
has been reported to be associated with male infertility [2].
gene, as well as multiple other genes affecting male reproduc-
Men with testicular cancer or lymphoma may have fertility
tion, is located on the X chromosome.
difficulties even before initiation of treatment, as low sperm
concentrations have been reported in 60% or more of patients
at the time of diagnosis [13,14,15]. Obviously, chemotherapy Physical examination
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
Section 2: Evaluation
hypogonadotropic hypogonadism. Additionally, 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-
ive without overheating the examiner or the patient. The testi
Genital examination 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 bilaterally calipers (Figure 2.1) for determination of the long and short
absent vasa deferentia or clinically 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 carefully, 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 normally
ings concerning for sexually transmitted diseases, such as have smaller testicles but higher sperm production per cubic
10