Infertility is defined as the inability to achieve pregnancy after one year of unprotected intercourse.

An estimated 15% of couples meet this criterion and are considered infertile, with approximately 35% due to female factors alone, 3 % due to male factors alone, ! % due to a combination of female and male factors, and 15% unexplained. "onditions of the male that affect fertility are still generally underdiagnosed and undertreated. "auses of infertility in men can be explained by deficiencies in sperm formation, concentration #eg, oligospermia $too few sperm%, a&oospermia $no sperm in the e'aculate%(, or transportation. )his general division allows an appropriate wor*up of potential underlying causes of infertility and helps define a course of action for treatment. )he initial evaluation of the male patient should be rapid, noninvasive, and cost+effective, as nearly , % of conditions that cause infertility in men can be diagnosed with history, physical examination, and hormonal and semen analysis alone. -ore detailed, expensive, and invasive studies can then be ordered if necessary. )reatment options are based on the underlying etiology and range from optimi&ing semen production and transportation with medical therapy or surgical procedures to complex assisted reproduction techni.ues. )echnological advancements ma*e conceiving a child possible with as little as one viable sperm and one egg. Although the wor*up was traditionally delayed until a couple was unable to conceive for 1! months, evaluation may be initiated at the first visit in slightly older couples. An image depicting male ductal anatomy can be seen below. -ale infertility. /ormal male ductal anatomy. 0athophysiology 1onadal and sexual functions are mediated by the hypothalamic+pituitary+gonadal axis, a closed+loop system with feedbac* control from the testicles #see image below(. )he hypothalamus, the primary integration center, responds to various signals from the "/2, pituitary gland, and testicles to secrete gonadotropin+releasing hormone #1n34( in a pulsatile pattern approximately every , +5 minutes. )he half+life of 1n34 is !+5 minutes. 3elease of 1n34 is stimulated by melatonin from the pineal gland and inhibited by testosterone, inhibin, corticotropin+releasing hormone, opiates, illness, and stress. 1n34 travels down the portal system to the anterior pituitary, located on a stal* in the sella turcica, to stimulate the release of the gonadotropins, luteini&ing hormone #64(, and follicle+stimulating hormone #724(. -ale infertility. 4ypothalamic+pituitary+gonadal axis stimulatory and inhibitory signals. 1onadotropin+releasing hormone #1n34( from the hypothalamus stimulates the release of follicle+stimulating hormone #724( and luteini&ing hormone #64( from the pituitary. 724 stimulates the 2ertoli cells to facilitate sperm production, while 64 stimulates testosterone release from the 6eydig cells. 7eedbac* inhibition is from testosterone and inhibin. 724 and 64, glycopeptides with a molecular weight of 1 , daltons, are each composed of an alpha chain that is identical to that of human chorionic gonadotropin

#4"1( and thyroid+stimulating hormone #)24(, but with a beta chain that is uni.ue for each. 724 has a lower plasma concentration and longer half+life than 64, and it has less obvious pulsatile changes. )he pulsatile nature of 1n34 is essential to normal gonadotropin release8 a continuous stimulation inhibits their secretion. )he hypothalamus also produces thyrotropin+releasing hormone #)34( and vasoactive intestinal peptide #9I0(, both of which stimulate prolactin release from the anterior pituitary, and dopamine, which inhibits prolactin release. -en with elevated prolactin levels present with gynecomastia, diminished libido, erectile dysfunction, and occasionally galactorrhea. 0rolactin inhibits the production of 1n34 from the hypothalamus and 64 and 724 from the pituitary. 1onadotropin release is modulated by various other signals, such as estradiol #a potent inhibitor of both 64 and 724 release(, and inhibin from the 2ertoli cell, which causes a selective decrease in 724 release. 724 and 64 are released into system circulation and exert their effect by binding to plasma membrane receptors of the target cells. 64 mainly functions to stimulate testosterone secretion from the 6eydig cells of the testicle, while 724 stimulates 2ertoli cells to facilitate germ cell differentiation. )estosterone is secreted in a diurnal pattern, pea*ing early in the morning. In the body, testosterone circulates !% in the free form, ::% bound to sex hormone;binding globulin #24<1(, and 5:% bound to albumin. )estosterone is converted to dihydrotestosterone #=4)( by the action of 5+alpha reductase, both locally and in the periphery, and to estrogen in the periphery. )estosterone and estradiol function as feedbac* inhibitors of gonadotropin release. )he testicle contains the 6eydig cells and the 2ertoli cells and is covered by the tunica albuginea, which also provides septae that divide it into approximately ! +35 pyramids #see image below(. )hese pyramids are filled with the seminiferous tubules. A normal testicle contains > +1! seminiferous tubules with a total length of approximately !5 meters. )he interstitium between the seminiferous tubules contains the 6eydig cells, fibroblasts, lymphatics, blood vessels, and macrophages. 4istologically, 6eydig cells are polygonal with eosinophilic cytoplasm. ?ccasionally, the cytoplasm contains crystalloids of 3ein*e after puberty. -ale infertility. )esticular histology magnified 5 times. 6eydig cells reside in the interstitium. 2permatogonia and 2ertoli cells lie on the basement membrane of the seminiferous tubules. 1erm cells interdigitate with the 2ertoli cells and undergo ordered maturation, migrating toward the lumen as they mature. 2eminiferous tubules are made up of 2ertoli cells and germ cells and are surrounded by peritubular and myoid cells. 2ertoli cells are columnar, with irregular basal nuclei that have prominent nucleoli and fine chromatin. )hey rest on the basement membrane and serve mainly to support, nourish, and protect the developing germ cells and to provide a blood+testis barrier to provide a microenvironment that facilitates spermatogenesis and maintains the germ cells

in an immunologically privileged location. 2ertoli cells also secrete inhibin, which provides negative feedbac* on the hypothalamus, and androgen+binding protein, which helps modulate androgen activity in the seminiferous tubules. In addition to 724, 2ertoli cell function is modulated by intratesticular testosterone and signals from peritubular myoid cells. 1erm cells #precursors to spermato&oa( are derived from the gonadal ridge and migrate as gonadocytes to the testicle before testicular descent. In response to 724 stimulation at puberty, germ cells become spermatogonia and undergo an ordered maturation to become spermato&oa. )he entire process of development from spermatogonium to spermatid ta*es ,: days and is described in 1: steps8 as they mature, the developing spermatids progress closer to the lumen of the seminiferous tubule. 2permatogonia rest on the basement membrane and contain dense nuclei and prominent nucleoli. )hree types are described@ A dar* #Ad(, A pale #Ap(, and < cells. Ad cells #stem cells( divide to create more Ad cells #stem cell renewal( or differentiate into daughter Ap cells every 1> days. Ap cells mature into < spermatogonia, which then undergo mitotic division to become primary spermatocytes, which are recogni&ed by their large centrally located nuclei and beaded chromatin. )he mitotic division does not result in complete separation8 rather, daughter cells maintain intracellular bridges, which have functional significance in cell signaling and maturation. 0rimary spermatocytes undergo meiosis as the cells successively pass through the preleptotene, leptotene, &ygotene, and pachytene stages to become secondary spermatocytes. =uring this time, the cells cross from the basal to the adluminal compartments. 2econdary spermatocytes contain smaller nuclei with fine chromatin. )he secondary spermatocytes undergo a second meiosis and become spermatids. )his reduction division #ie, meiosis( results in a haploid chromosome number. )herefore, a total of : spermatids are made from each spermatocyte. /ext, the spermatids undergo the process of spermiogenesis #through stages named 2b1, 2b!, 2c, 2d1, and 2d!(, which involves the casting of excess cytoplasm away as a residual body, the formation of the acrosome and flagella, and the migration of cytoplasmic organelles to their final cellular location. )he acrosome, a derivative of the 1olgi process, surrounds the nucleus anteriorly and contains en&ymes necessary to penetrate the ovum. )he mature spermatid is then located ad'acent to the tubule lumen and contains dar* chromatin with an oval+shaped nucleus. After their release from the 2ertoli cells into the lumen of the seminiferous tubules, the spermatids successively pass through the tubuli recti, rete testis, ductuli efferentes, and, finally, the epididymis #see image below(. )he epididymis is a 3+ to :+cm long structure with a tubular length of :+5 m. As sperm move from the head to the tail, they mature and ac.uire fertili&ation capacity. 2perm from the head move with immature wide arcs and are generally unable to penetrate the egg, while those from the tail propel forward and have better penetration capacity. )he transit time varies with age and sexual activity but

is usually from 1+1! days. )he epididymis additionally secretes substances for sperm nutrition and protection such as glycerophosphorylcholine, carnitine, and sialic acid. -ale infertility. /ormal male ductal anatomy. 2perm next enter the vas deferens, a 3 + to 35+cm muscular conduit of Aolffian duct origin. )he vas is divided into the convoluted, scrotal, inguinal, retroperitoneal, and ampullary regions and receives its blood supply from the inferior vesicle artery. In addition to functioning as a conduit, the vas also has absorptive and secretory properties. =uring emission, sperm are propelled forward by peristalsis. After reaching its ampullary portion behind the bladder, the vas 'oins with the seminal vesicles, at the e'aculatory duct, which empties next to the verumontanum of the prostate. =uring e'aculation, the e'aculate is propelled forward by the rhythmic contractions of the smooth muscle that surrounds the ducts and by the bulbourethral muscles and other pelvic muscles. <ladder nec* closure during e'aculation is vital to ensure antegrade e'aculation. /ormal e'aculate volume ranges from 1.5 to 5 m6 and has a p4 level of ,. 5+,.B. )he seminal vesicles provide : +B % of the semen volume, which includes fructose for sperm nutrition, prostaglandins and other coagulating substances, and bicarbonate to buffer the acidic vaginal vault. /ormal seminal fructose concentration is 1! +:5 mgCd6, with lower levels suggesting e'aculatory duct obstruction or absence of the seminal vesicles. )he prostate gland contributes approximately 1 +3 % # .5 m6( of the e'aculate. 0roducts include en&ymes and proteases to li.uefy the seminal coagulum. )his usually occurs within ! +!5 minutes. )he prostate also secretes &inc, phospholipids, phosphatase, and spermine. )he testicular+epididymal component includes sperm and comprises about 5% of the e'aculate volume. In addition to the components already listed, semen is also composed of secretions from the bulbourethral #"owper( glands and the #periurethral( glands of 6itre, each producing !+5% of the e'aculate volume, serving mainly to lubricate the urethra and to buffer the acidity of the residual urine. )he ordered se.uence of release is important for appropriate functioning. 7or conception, sperm must reach the cervix, penetrate the cervical mucus, migrate up the uterus to the fallopian tube, undergo capacitation and the acrosome reaction to digest the &ona pellucida of the oocyte, attach to the inner membrane, and release its genetic contents within the egg. )he cervical mucus changes consistency during the ovulatory cycle, being most hospitable and easily penetrated at mid cycle. After fertili&ation, implantation may then ta*e place in the uterus. 0roblems with any of these steps may lead to infertility. Dpidemiology 7re.uency Enited 2tates An estimated 1 +15% of couples are considered infertile, defined by the Aorld 4ealth ?rgani&ation #A4?( as the absence of conception after at least 1! months of unprotected intercourse. In American men, the ris* correlates to approximately 1 in !5. 6ow sperm

counts, poor semen .uality, or both account for 5 % of cases8 however, studies of infertile couples without treatment reveal that !3% of these couples conceive within ! years, and 1 % more conceive within : years. Dven patients with severe oligospermia #F ! million spermCm6( have a ,.>% chance of conception within ! years.$1% International 0atterns of male infertility vary greatly among regions and even within regions. )he highest reported fertility rates are in 7inland, while 1reat <ritain has a low fertility rate. A combination of social habits, environmental conditions, and genetics is suspected to contribute to this variation. 3ecent debate has occurred in the literature regarding a poorer semen .uality, decreased sperm counts #113 millionCm6 in 15: compared with >> millionCm6 in the 155 s(, and decreased fertility in men today compared with fertility 5 years ago.$!% Investigators hypothesi&e that environmental conditions and toxins have led to this decline8 however, others argue that this is solely because of differences in counting methods, laboratory techni.ues, and geographic variation. -ortalityC-orbidity -any patients who present with infertility as their primary symptom have a serious underlying medical disease, such as pituitary adenomas, hormonally active tumors, testicular cancer, liver and renal failure, and cystic fibrosis #"7(. Dvaluating patients for life+threatening or life+altering conditions during the wor*up is important. 2ex Isolated conditions of the female are responsible for infertility in 35% of cases, isolated conditions of the male in 3 %, conditions of both the male and female in ! %, and unexplained causes in 15%. Dven if one partner has an obvious cause for the infertility, a thorough evaluation of both partners for completeness is prudent. In addition, both partners may be aided by evaluation of their sexual practices. Age )he effect of aging on fertility is unclear. As men age, their testosterone levels decrease, while estradiol and estrone levels increase. 2tudies have shown that, as men age, their sperm density decreases. Goung men have spermatids present in 5 % of seminiferous tubules, which decreases to 5 % by age 5 +, years and to 1 % by age B years. Additionally, 5 % of 2ertoli cells are lost by age 5 years, 5 % of 6eydig cells are lost by age > years. =espite this, aging men may achieve fertility rates similar to those in younger men, although conception often ta*es longer. 4istory )he initial step in the evaluation of an infertile male is to obtain a thorough medical and urologic history. Important considerations include the duration of infertility, previous fertility in the patient and the partner, and prior evaluations. )he couple should be as*ed

specifically about their sexual habits, including their level of *nowledge of the optimal timing of intercourse and the use of potentially spermatocytic drugs and lubricants. 0atients should be as*ed about a history of childhood illnesses such as testicular torsion, postpubertal mumps, developmental delay, and precocious puberty, as well as urinary tract infections, sexually transmitted diseases, and bladder nec* surgery. A history of neurological diseases, diabetes, and pulmonary infections should be elicited. Anosmia #lac* of smell(, galactorrhea, visual+field defects, and sudden loss of libido could be signs of a pituitary tumor. )he status of the partnerHs wor*up should also be *nown. )iming of puberty #early, normal, or delayed( 0recocious puberty, defined as the onset of puberty before age 5 years in males, may be the sign of a serious underlying endocrinologic disorder. 4ormonally active tumors from the testicle, adrenal gland, or pituitary, along with adrenal hyperplasia, may result in early puberty. In contrast, a delay in puberty may be caused by problems with testosterone secretion due to hypothalamic, pituitary, or testicular insufficiency or to end+organ androgen insensitivity. "hildhood urological disorders or surgery <oth unilateral and bilateral cryptorchidism are associated with a decrease in sperm production and semen .uality, regardless of the timing of orchidopexy. 0atients with hypospadias may not place the semen at the cervical os. 0renatal exposure to diethylstilbestrol #=D2( may cause epididymal cysts and cryptorchidism. 0rior bladder nec* procedure, such as a 9+G plasty performed at the time of ureteral reimplantation, may lead to retrograde e'aculation. )he vas deferens or the testicular blood supply may be in'ured or ligated at the time of inguinal surgery, hernia repair, hydrocelectomy, or varicocelectomy. )esticular torsion and trauma may result in testicular atrophy and the production of antisperm antibodies. -edical history =iabetes may cause autonomic neuropathy, neurogenic impotence, and retrograde e'aculation. ?besity alters hormonal metabolism, leading to increased peripheral conversion of testosterone to estrogen and decreased 64 pulse amplitude.

2ic*le cell disease may lead to sic*ling and, therefore, direct testicular ischemia and damage. 0atients with sic*le cell disease or thalassemia may have infertility due to hemosiderosis from multiple blood transfusions. "hronic renal failure leads to hypogonadism and femini&ation. 6iver disease may result in decreased male secondary sexual characteristics, testicular atrophy, and gynecomastia due to increased estrogen levels. 4emochromatosis leads to hypogonadism and signs of androgen deficiency without gynecomastia and is associated with decreased estradiol levels. 0ostpubertal mumps may lead to testicular atrophy. 2exually transmitted diseases and tuberculosis can cause obstruction of the vas deferens or epididymis. -ycoplasma fastens itself to sperm, decreasing sperm motility. 2mallpox, prostatitis, orchitis, seminal vesiculitis, and urethritis may lead to obstructive a&oospermia. Acute and chronic medical illnesses 0atients should be as*ed about recent acute febrile illnesses, which may temporarily suppress gonadotropin release. )he decrease in sperm production may not be reali&ed until 1+3 months later. Anesthesia, surgery, starvation, myocardial infarction, hepatic coma, head in'ury, stro*e, respiratory failure, congestive heart failure, sepsis, and burns are associated with a suppression of gonadotropin release, possibly through an increase in dopamine and opiate levels. "hronic medical illnesses may directly suppress sex hormone production and sperm production, leading to end+organ failure. 2exual history )he fre.uency, timing, and methods of coitus and *nowledge of the ovulatory cycle should be elicited. 2tudies show that the optimal timing for intercourse is every :B hours at mid cycle. 6ubricants such as 2urgilube, Ieri lotion, IG Jelly, and saliva are spermatotoxic, whereas egg whites, peanut oil, vegetable oil, and petroleum 'elly are not *nown to be

spermatotoxic but still should be used in only the smallest amounts possible if needed for lubrication during intercourse. )esticular cancer )esticular cancer is associated with impaired spermatogenic function, even before orchiectomy, with a degree of dysfunction higher than that explained by local tumor effect. ?ligospermia is observed in more than > % of patients at the time of diagnosis of testicular cancer. 1erm cell tumors may to share common etiological factors with testicular dysfunction, such as testicular dysgenesis, androgen insensitivity, and cryptorchidism. "ontralateral abnormalities of spermatogenesis are more common in patients with testicular cancer. 2perm function often remains impaired, even after orchiectomy. )reatment for testicular cancer "hemotherapy has a dose+dependent effect on germ cells. Al*ylating agents, such as cyclophosphamide, mustine, and chlorambucil, severely alter the seminiferous tubules and destroy spermatogonia. #/ote that chemotherapy is also mutagenic, so sperm should be donated before treatment, or attempts at conception should be postponed until K1 year after treatment.( 3etroperitoneal lymph node dissection #306/=( may impair emission #of semen into the urethra( andCor cause retrograde e'aculation.$3% 3adiation therapy affects mainly type < spermatogonia and, possibly, spermatocytes. A dose of as little as .15 1y may cause irreversible damage, although complete recovery may be possible if stem cell numbers are not depleted. After exposure of less than 1 1y, sperm production may return in 5+1B months, while :+> years may be necessary to recover sperm production after a dose of up to 5 1y. =espite radiation therapy and chemotherapy, nearly two thirds of patients retain the ability to father a child if the e'aculatory function is retained. )o potentially decrease the morbidity of ad'unct therapy, select patients with grade I germ cell tumors are now undergoing unilateral orchiectomy with surveillance. 4owever, 306/= performed for salvage therapy is associated with a higher ris* of retrograde e'aculation than that performed initially. 0atients with reference range 724 levels at baseline usually observe an improvement in semen parameters and sperm density after orchiectomy. )his is thought to be unrelated to the orchiectomy, stress factors, and release of substances by the tumor because decreased sperm counts are observed even before surgery and they do not return to baseline after surgery. )herefore, the disturbance that leads to testicular cancer is thought to be inherent and present in the primordial cell.

0atients with a testicular tumor in a solitary testicle may be offered a partial orchiectomy in an attempt to retain fertility. Additionally, healthy testicular tissue away from the tumor can be dissected free and cryopreserved at the time of orchiectomy for future use in in vitro fertili&ation #I97( with intracytoplasmic sperm in'ection #I"2I(. 2ocial history "igarette and mari'uana smo*ing lead to a decrease in sperm density, motility, and morphology. Alcohol produces both an acute and a chronic decrease in testosterone secretion. Dmotional stress blunts 1n34 release, leading to hypogonadism. Dxcessive heat exposure from saunas, hot tubs, or the wor* environment may cause a temporary decrease in sperm production. "ontrary to widely held beliefs, no evidence supports that wearing constrictive underwear, or Lbriefs,L decreases fertility. Dven with an elevation in temperature of .B+ 1M caused by wearing constrictive underwear, no changes in sperm parameters, no decrease in spermatogenesis, and no changes in sperm function are observed.$:% -edicines 2pironolactone, cyproterone, *etocona&ole, and cimetidine have antiandrogenic properties. )etracycline lowers testosterone levels ! %. /itrofurantoin depresses spermatogenesis. 2ulfasala&ine leads to a reversible decrease in sperm motility and density. "olchicine, methadone, methotrexate, phenytoin, thiorida&ine, and calcium channel bloc*ers have all be associated with infertility. 7amily history "ongenital midline defects, cryptorchidism, hypogonadotropism, and testicular atrophy in family members may be a sign of a congenital disease. A history of "7 or hypogonadism should be elicited. 3espiratory disease Infertility and recurrent respiratory infections may be due to immotile cilia syndrome, which may be isolated or part of Iartagener syndrome #with situs inversus(.

"7 is associated with congenital bilateral absence of the vas deferens #"<A9=(, leading to obstructive a&oospermia. Ahile both copies of this recessive gene are necessary for clinical disease, the presence of only one copy may lead to "<A9=. Goung syndrome results in recurrent pulmonary infections and a&oospermia due to inspissated material in the epididymis causing obstruction. Dnvironmental andCor occupational exposure -any pesticides have estrogen+li*e effects. =ibromochloropropane #=<"0( is a nematocide widely used in agriculture that causes a&oospermia without recovery by an un*nown mechanism. 6ead exposure depresses the hypothalamic+pituitary axis. "arbon disulfide exposure from the rayon industry leads to semen, pituitary, and hypothalamic changes. 4eat exposure, as seen in wor*ers in the steel and ceramic fields, decreases spermatocyte maturation. 2pinal cord in'ury 2evere spinal cord in'ury may lead to ane'aculation. )hese men may be treated with electroe'aculation or sperm retrieval techni.ues.$5% Dpididymal and testicular factors appear to play a role, although the most severe dysfunction seems to come from prostatic and seminal vesicle dysfunction. In addition, the semen .uality in patients with a spinal cord in'ury may gradually decline owing to un*nown causes. Aithin a year after in'ury, many have semen with dead sperm with signs of neutrophil infiltration on semen analysis. )his is hypothesi&ed to be due to accessory gland dysfunction rather than lac* of e'aculation and atrophy. In patients with spinal cord in'ury, sperm parameters from the vas deferens show 5:% motility and ,:% viability, while only 1:% motility and !>% viability is observed in e'aculated sperm. )hese are both much lower than that in control sub'ects.$>% 0hysical )he physical examination should include a thorough inspection of the testicles, penis, secondary sexual characteristics, and body habitus. It should include a detailed examination of other body functions based on the history. )esticles )he testicular examination should occur in a warm room with the patient relaxed. )he testicles should be palpated individually between the thumb and first ! fingers. )he

examiner should note the presence, si&e, and consistency of the testicles, and the testicles should be compared with each other. A 0rader orchidometer or ultrasonography may be used to estimate the testicular volume, with normal considered to be greater than ! m6. "alipers may be used to measure testicular length, which is usually greater than : cm, although the lower limits of normal length #mean minus ! standard deviations( is 31 mm in white men and 3: mm in blac* men. )he testes of Japanese men are typically smaller than the testes of white men. )esticular atrophy may be observed in primary testicular failure, Ilinefelter syndrome, endocrinopathies, postpubertal mumps, liver disease, and myotonic dystrophy. 2welling with pain indicates orchitis, whereas nontender enlargement may be observed in testicular neoplasms, tuberculosis, and tertiary syphilis. Dpididymis )he head, body, and tail of the epididymis should be palpated and assessed for their presence bilaterally. /ote induration and cystic changes. An enlarged indurated epididymis with a cystic component should alert the examiner to the possibility of ductal obstruction. )enderness may be due to epididymitis. 9as deferens Dvaluate the vas for its presence bilaterally and palpate along its entire length to chec* for defects, segmental dysplasia, induration, nodularity, or swelling. )he complete absence bilaterally is observed almost exclusively in patients with either one or two copies of the gene for "7, although even a small defect or gap indicates the possibility of a "7 gene mutation. A thic*ened nodular vas deferens may be observed in patients with a history of tuberculosis. If a prior vasectomy has been performed, the presence of a nodular sperm granuloma at the proximal vasal end should be assessed. 2permatic cord "hec* patients for the presence of a varicocele, which is the most common surgically correctable cause of infertility #see image below(. )o elicit this, the patient should perform a 9alsalva maneuver in the sitting and standing positions in a warm room. 1rade 1 varicocele is defined as palpable only with 9alsalva, while grade ! is palpable at

standing, and grade 3 is visible at rest. )he presence of asymmetry or an impulse with 9alsalva may best help the examiner find a varicocele. -ale infertility. 9aricocele. A + 0hysical examination revealing the characteristic Lbag of worms.L < + Anatomy of the dilated pampiniform plexus of veins. )he sudden onset of a varicocele, a solitary right+sided varicocele, or a varicocele that does not change with 9alsalva indicates the possibility of a retroperitoneal neoplastic process or vein thrombosis. 0enis )he examination should focus on the location and patency of the urethral meatus and the presence of meatal strictures. 0atients with hypospadias or epispadias may not deposit semen appropriately at the cervix. 0enile curvature and the presence of penile pla.ues should be noted. 3ectal examination )he prostate should be of normal si&e and without cysts, induration, or masses. )he seminal vesicles are usually not palpable. A midline prostatic cyst or palpable seminal vesicles may be due to obstruction of the e'aculatory ducts. <ody habitus A eunuchoid body habitus, consisting of infantile hair distribution, poor muscle development, and a long lower body due to a delayed closure of the epiphyseal plates, may be observed in patients with endocrinological disorders. )runcal obesity, striae, and moon facies may be due to "ushing syndrome. 1ynecomastia, galactorrhea, headaches, and a loss of visual fields may be observed in patients with pituitary adenomas. 7ocus the nec* examination on thyromegaly and bruits. 0alpate the liver for hepatomegaly and examine the lymph nodes to rule out lymphoma. "auses "auses generally can be divided into pretesticular, testicular, and posttesticular. 0retesticular causes of infertility 0retesticular causes of infertility include congenital or ac.uired diseases of the hypothalamus, pituitary, or peripheral organs that alter the hypothalamic+pituitary axis.

=isorders of the hypothalamus lead to hypogonadotropic hypogonadism. If 1n34 is not secreted, the pituitary does not release 64 and 724. Ideally, patients respond to replacement with exogenous 1n34 or 4"1, an 64 analogue, although this does not always occur. Idiopathic hypogonadotropic hypogonadism A failure of 1n34 secretion without any discernible underlying cause may be observed alone #isolated( or as part of Iallmann syndrome, which is associated with midline defects such as anosmia, cleft lip and cleft palate, deafness, cryptorchidism, and color blindness. Iallmann syndrome has been described in both familial #N+lin*ed and autosomal( and sporadic forms, and its incidence is estimated as 1 case per 1 , +> , births. A failure of 1n34 neurons to migrate to the proper location in the hypothalamus has been implicated. 0atients generally have long arms and legs due to a delayed closure of the epiphyseal plates, delayed puberty, and atrophic testis. )estosterone therapy may allow patients to achieve normal height but does not improve spermatogenesis. Dxogenous testosterone should never be administered in an attempt to boost sperm production because it actually decreases intratesticular testosterone levels owing to feedbac* inhibition of 1n34 release. 0ulsatile 1n34 and 4"1 have been used but result in only ! % achieving complete spermatogenesis. Adding recombinant human 724 to 4"1 has been shown to be effective in achieving spermatogenesis in most patients.$,% 2elect patients with adult+onset idiopathic hypogonadotropic hypogonadism may respond to clomiphene citrate therapy.$B% 0rader+Ailli syndrome 0atients have characteristic obesity, mental retardation, small hands and feet, and hypogonadotropic hypogonadism due to a 1n34 deficiency. 0rader+Ailli syndrome is caused by a disorder of genomic imprinting with deletions of paternally derived chromosome arm 15.11+13. 6aurence+-oon+<iedl syndrome 0atients with this syndrome have retinitis pigmentosa and polydactyly. Infertility is due to hypogonadotropic hypogonadism. ?ther conditions

9arious other lesions and diseases, such as "/2 tumors, temporal lobe sei&ures, and many drugs #eg, dopamine antagonists( may interrupt the hypothalamic+pituitary axis at the hypothalamus. <oth pituitary insufficiency and pituitary excess cause infertility. 0ituitary failure may be congenital or ac.uired. Ac.uired causes include tumor, infarction, radiation, infection, or granulomatous disease. /onfunctional pituitary tumors may compress the pituitary stal* or the gonadotropic cells, interrupting the proper chain of signals leading to pituitary failure. In contrast, functional pituitary tumors may lead to unregulated gonadotropin release or prolactin excess, interrupting the proper signaling. 0rolactinoma A prolactin+secreting adenoma is the most common functional pituitary tumor. 0rolactin stimulates breast development and lactation8 therefore, patients with infertility due to a prolactinoma may have gynecomastia and galactorrhea. In addition, loss of peripheral visual fields bilaterally may be due to compression of the optic chiasm by the growing pituitary tumor. A prolactin level of more than 15 mcgC6 suggests a pituitary adenoma, while levels greater than 3 mcgC6 are nearly diagnostic. 0atients should undergo an -3I or ") scan of the sella turcica for diagnostic purposes to determine whether a microprolactinoma or a macroprolactinoma is present. <romocriptine and cabergoline are dopamine agonists used to suppress prolactin levels. )hese are both treatment options for microprolactinoma. 2ome men respond with an increase in testosterone levels8 many also recover normal sperm counts. )ranssphenoidal resection of a microprolactinoma is B +5 % successful, but as many as 1,% recur. 2urgical therapy of a macroprolactinoma is rarely curative, although this should be considered in patients with visual+field defects or those who do not tolerate bromocriptine. Isolated 64 deficiency #fertile eunuch( In these patients, 64 levels are decreased while 724 levels are within the reference range. 0atients have eunuchoidal body habitus, large testis, and a low e'aculatory volume. )he treatment of choice is exogenous 4"1. Isolated 724 deficiency )his is a very rare cause of infertility. 0atients present with oligospermia but have 64 levels within the reference range. )reatment is with human menopausal gonadotropin #4-1( or exogenous 724. )halassemia

0atients with thalassemia have ineffective erythropoiesis and undergo multiple blood transfusions. Dxcess iron from multiple transfusions may get deposited in the pituitary gland and the testis, causing parenchymal damage and both pituitary and testicular insufficiency. )reatment is with exogenous gonadotropins and iron+chelating therapy. "ushing disease Increased cortisol levels cause a negative feedbac* on the hypothalamus, decreasing 1n34 release. 0eripheral organ )he hypothalamus+pituitary axis may be interrupted by hormonally active peripheral tumors or other exogenous factors, due to cortical excess, cortical deficiency, or estrogen excess. Dxcess cortisol may be produced by adrenal hyperplasia, adenomas, carcinoma, or lung tumors. 4igh cortisol levels may also be seen with exogenous steroid use, such as that administered to patients with ulcerative colitis, asthma, arthritis, or organ transplant. 7or example, high cortisol levels are seen in patients with "ushing syndrome, which causes negative feedbac* on the pituitary to decrease 64 release. "ortical deficiency may be seen in patients with adrenal failure due to infection, infarction, or congenital adrenal hyperplasia #"A4(. "A4 may be due to the congenital deficiency of one of several adrenal en&ymes, the most common of which is !1+ hydroxylase deficiency. <ecause cortisol is not secreted, a lac* of feedbac* inhibition on the pituitary gland occurs, leading to adrenocorticotropic hormone #A")4( hypersecretion. )his leads to increased androgen secretion from the adrenal gland, causing feedbac* inhibition of 1n34 release from the hypothalamus. 0atients present with short stature, precocious puberty, small testis, and occasional bilateral testicular rests. 2creening tests include increased plasma 1,+hydroxylase and urine 1,+*etosteroids. Dstrogen excess may be seen in patients with 2ertoli cell tumors, 6eydig tumors, liver failure, or severe obesity. Dstrogen causes negative feedbac* on the pituitary gland, inhibiting 64 and 724 release. 0rimary testicular causes of infertility 0rimary testicular problems may be chromosomal or nonchromosomal in nature. Ahile chromosomal failure is usually caused by abnormalities of the sex chromosomes, autosomal disorders are also observed. "hromosomal abnormalities An estimated >+13% of infertile men have chromosomal abnormalities #compared with .>% of the general population(. 0atients with a&oospermia or severe oligospermia are more li*ely to have a chromosomal abnormality #1 +15%( than infertile men with sperm

density within the reference range #1%(. A *aryotype test and a G chromosome test for microdeletions are indicated in patients with nonobstructive a&oospermia or severe oligospermia #F 5 million spermCm6(, although indications are expanding.$5% Ilinefelter syndrome Ilinefelter syndrome is the most common chromosomal cause of male infertility, estimated to be present in 1 per 5 +1 male births. "lassic Ilinefelter syndrome has a :,, NNG *aryotype and is caused by a nondis'unction during the first meiotic division, more commonly of maternal origin8 mosaic forms are due to nondis'unction following fertili&ation. )he only *nown ris* factor for Ilinefelter syndrome is advanced maternal age. Infertility is caused by primary testicular failure, and most patients are a&oospermic. 4ormonal analysis reveals increased gonadotropin levels, while > % have decreased testosterone levels. 2urprisingly, most patients have normal libido, erections, and orgasms, so testosterone therapy has only a limited role8 exogenous testosterone may also suppress any underlying sperm production. 0hysical examination reveals gynecomastia, small testis, and eunuchoid body habitus due to delayed puberty. In some patients, secondary sex characteristics develop normally, but they are usually completed late. )hese men are at a higher ris* for breast cancer, leu*emia, diabetes, empty sella syndrome, and pituitary tumors. )esticular histology reveals hyalini&ation of seminiferous tubules. 2ome men with Ilinefelter syndrome may be able to conceive with the help of assisted reproductive techni.ues. ?f a&oospermic patients with Ilinefelter syndrome, ! % show the presence of residual foci of spermatogenesis. Although the NNG pattern is observed in the spermatogonia and primary spermatocytes, many of the secondary spermatocytes and spermatids have normal patterns. )he chromosomal pattern of the resultant embryos can be assessed with preimplantation genetic diagnosis. NN male #sex reversal syndrome( An NN *aryotype is due to a crossover of the sex+determining region #23G( of the G chromosome #with the testis determining factor( to either the N chromosome or an autosome. 0atients are often short, with small firm testis and gynecomastia, but they have a normal+si&ed penis. 2eminiferous tubules show sclerosis. NGG male An NGG *aryotype is observed in .1+ .:% of newborn males. )hese patients are often tall and severely oligospermic or a&oospermic. )his pattern has been lin*ed with aggressive behavior. <iopsy reveals maturation arrest or germ cell aplasia. 7unctional sperm that are present may have a normal *aryotype. /oonan syndrome #:>, NG(

0atients with /oonan syndrome, also *nown as male )urner syndrome, have physical characteristics similar to that of women with )urner syndrome #:5, N(. 7eatures include a webbed nec*, short stature, low+set ears, ptosis, shield+li*e chest, lymphedema of hands and feet, cardiovascular abnormalities, and cubitus valgus. 6eydig cell function is impaired, and most patients are infertile due to primary testicular failure. -ixed gonadal dysgenesis #:5, NC:>, NG( 0atients have ambiguous genitalia, a testis on one side, and a strea*ed gonad on the other. G chromosome microdeletion syndrome )he long arm of the G chromosome #G.( is considered critical for fertility, especially G.11.!3 #interval >(. -acroscopic deletions of G.11 are often observed in patients with a&oospermia, although many new microdeletions have been implicated as a significant cause of infertility. )hese microdeletions are not observed on regular *aryotype8 rather, their identification re.uires polymerase chain reaction #0"3(;based se.uence+tagged site mapping or 2outhern blot analysis. )hree regions have been described, called a&oospermic factors a, b, and c #AO7a, AO7b, AO7c(. )hese deletions are observed in 3+ 15% of patients with idiopathic infertility and >+1:% of patients with oligospermia, although up to ,% of patients with other *nown causes of infertility may also be found to have a deletion. 0atients with a&oospermia or severe oligospermia see*ing assisted reproductive techni.ues should be screened. <ilateral anorchia #vanishing testis syndrome( 0atients have a normal male *aryotype #:>, NG( but are born without testis bilaterally. )he male phenotype proves that androgen was present in utero. 0otential causes are un*nown, but it may be related to infection, vascular disease, or bilateral testicular torsion. Iaryotype shows a normal 23G gene. 0atients may achieve normal virili&ation and adult phenotype by the administration of exogenous testosterone, but they are infertile. =own syndrome )hese patients have mild testicular dysfunction with varying degrees of reduction in germ cell number. 64 and 724 levels are usually elevated. -yotonic dystrophy )his is an autosomal dominant defect in the dystrophin gene that causes a delay in muscle relaxation after contraction. 2eventy+five percent of patients have testicular atrophy and primary testicular failure due to degeneration of the seminiferous tubules. 6eydig cells are normal. 4istology reveals severe tubular sclerosis. /o effective therapy exists. /onchromosomal testicular failure

)esticular failure that is nonchromosomal in origin may be idiopathic or ac.uired by gonadotoxic drugs, radiation, orchitis, trauma, or torsion. 9aricocele A varicocele is a dilation of the veins of the pampiniform plexus of the scrotum. Although varicoceles are present in 15% of the male population, a varicocele is considered the most common correctable cause of infertility #3 +35%( and the most common cause of secondary #ac.uired( infertility #,5+B5%(. 9aricoceles are observed more commonly on the left side than the right. )hose with isolated right+sided varicoceles should be evaluated for retroperitoneal pathology. 9aricoceles are generally asymptomatic, and most men with varicoceles do not have infertility or testicular atrophy. 4owever, varicoceles may lead to impaired testicular spermatogenesis and steroidogenesis, potentially due to an increased intratesticular temperature, reflux of toxic metabolites, andCor germ cell hypoxia as potential causes of these changes, and this appears to be progressive over time. 9aricoceles lead to an increased incidence of sperm immaturity, apoptosis, and necrosis with severe disturbances in meiotic segregation compared to fertile men without varicoceles, and these parameters generally improve after repair. 0atients with a grade 1+3 varicocele #visible or palpable( associated with infertility should consider having the varicocele repaired. After repair, : +, % of patients have improved semen parameters, while : % are able to achieve a pregnancy without other interventions. )hose with a varicocele diagnosable only on scrotal ultrasonography have subclinical varicoceles and will li*ely not benefit from repair. Adolescents with a varicocele and testicular atrophy or lac* of growth should similarly consider repair. "ontroversy exists regarding whether to routinely repair an adolescent varicocele not associated with testicular atrophy. In those with a&oospermia and a varicocele, sperm may appear after repair in up to one third, but most of these men return to an a&oospermic state within a few months. If sperm appears, these men should be offered cryopreservation. "ryptorchidism An estimated 3% of full+term males are born with an undescended testicle, but fewer than 1% remain undescended by age 1 year. Endescended testicle may be isolated or may be observed as part of a syndrome such as prune belly syndrome. 0atients are at increased ris* of infertility, even if the testicle is brought down into the scrotum, as the testicle itself may be inherently abnormal. )he farther from the scrotum, and the longer duration that the testicle resides outside the scrotum, the greater the li*elihood of infertility. )esticular histology typically reveals a decreased number of 6eydig cells and decreased

spermatogenesis. "ryptorchidism may be due to inherent defects in both testes because even men with unilateral cryptorchidism have lower than expected sperm counts. )rauma )esticular trauma is the second most common ac.uired cause of infertility. )he testes are at ris* for both thermal and physical trauma because of their exposed position. 2ertoli+cell+only syndrome#germinal cell aplasia( 0atients with germinal cell aplasia have 64 and testosterone levels within the reference range but have an increased 724 level. )he etiology is un*nown but is probably multifactorial. 0atients have with small+ to normal+si&ed testes and a&oospermia, but normal secondary sex characteristics. 4istology reveals seminiferous tubules lined by 2ertoli cells and a normal interstitium, although no germ cells are present. "hemotherapy "hemotherapy is toxic to actively dividing cells. In the testicle, germ cells #especially up to the preleptotene stage( are especially at ris*. )he agents most often associated with infertility are the al*ylating agents such as cyclophosphamide. 7or example, treatment for 4odg*in disease has been estimated to lead to infertility in as many as B +1 % of patients. 3adiation therapy Ahile 6eydig cells are relatively radioresistant because of their low rate of cell division, the 2ertoli and germ cells are extremely radiosensitive. If stem cells remain viable after radiation therapy, patients may regain fertility within several years. 4owever, some have suggested that patients should avoid conception for > months to ! years after completion of radiation therapy because of the possibility of chromosomal aberrations in their sperm caused by the mutagenic properties of radiation therapy. Dven with the testis shielded, radiation therapy below the diaphragm may lead to infertility due to the release of reactive oxygen free radicals. ?rchitis )he most common cause of ac.uired testicular failure in adults is viral orchitis, such as that caused by the mumps virus, echovirus, or group < arbovirus. ?f adults with who are infected with mumps, !5% develop orchitis8 two thirds of cases are unilateral, and one third are bilateral. Ahile orchitis develops a few days after the onset of parotid gland inflammation, it may also precede it. )he virus may either directly damage the seminiferous tubules or indirectly cause ischemic damage as the intense swelling leads to compression against the tough tunica albuginea. After recovery, the testicle may return to normal or may atrophy. Atrophy is observed within 1+> months, and the degree of atrophy does not correlate with the severity of orchitis or infertility. /ormal fertility is

observed in three fourths of patients with unilateral mumps orchitis and in one third of patients in bilateral orchitis. 1ranulomatous disease 6eprosy and sarcoidosis may infiltrate the testicle and lead to testicular failure. 2ic*le cell disease 2ic*ling of cells within the testis leads to microinfarcts and secondary testicular failure. Dxcessive use of alcohol, cigarettes, caffeine, and mari'uana may lead to testicular failure. Idiopathic causes =espite a thorough wor*up, nearly !5% of men have no discernible cause for their infertility. 0osttesticular causes of infertility 0osttesticular causes of infertility include problems with sperm transportation through the ductal system, either congenital or ac.uired. 1enital duct obstruction is a potentially curable cause of infertility and is observed in ,% of infertile patients. Additionally, the sperm may be unable to cross the cervical mucus or may have ultrastructural abnormalities. "ongenital bloc*age of the ductal system An increased rate of duct obstruction is observed in children of mothers who were exposed to =D2 during pregnancy. 2egmental dysplasia is defined as a vas deferens with at least ! distinct sites of vasal obstruction. "ystic fibrosis "7 is the most common genetic disorder in whites. 0atients with "7 nearly uniformly have "<A9=. )he cystic fibrosis transmembrane regulator #"7)3( protein plays a role in mesonephric duct development during early fetal life, so these patients may also have urinary tract abnormalities. 0atients may be candidates for assisted reproduction techni.ues after appropriate genetic screening in the partner. Ac.uired bloc*age of the ductal system 1enital ducts may become obstructed secondary to infections, such as chlamydia, gonorrhea, tuberculosis, and smallpox. Goung syndrome is a condition that leads to inspissation of material and subse.uent bloc*age of the epididymis. )rauma, previous attempts at sperm aspiration, and inguinal surgery may also result in ductal bloc*age.

2mall calculi may bloc* the e'aculatory ducts, or prostatic cysts may extrinsically bloc* the ducts. 2crotal surgery, including vasectomy, hydrocelectomy #5+>%(, and spermatocelectomy #up to 1,%(, may lead to epididymal in'ury and subse.uent obstruction.$1 % Antisperm antibodies Antisperm antibodies bind to sperm, impair motility, and lead to clumping, impairing movement through the female reproductive tract and interaction with the oocyte. Immotile cilia syndrome may be isolated or part of Iartagener syndrome with situs inversus. <ecause of a defect in the dynein arms, spo*es, or microtubule doublet, cilia in the respiratory tract and in sperm do not function properly. In addition to sperm immobility, patients experience sinusitis, bronchiectasis, and respiratory infections. D'aculatory duct obstruction "omplete and partial e'aculatory duct obstruction has been implicated as a cause of 1+5% of patients with male infertility. 0atients may have a normal palpable vas deferens bilaterally but show decreased e'aculate volume and hemospermia and may experience pain upon e'aculation. Dtiologies include cysts #midline and eccentric(, ductal calcification and stones, postinfectious, and postoperative. )ransrectal ultrasonography #)3E2( may reveal enlarged seminal vesicles, but this is not universal. 2eminal vesicle aspiration revealing numerous sperm or a dynamic test such as in'ection of indigo carmine into the seminal vesicle or e'aculatory duct may be necessary for diagnosis.$11% Ane'aculationCretrograde e'aculation may be due to an open bladder nec* or a lac* of rhythmic contractions during e'aculation. Dtiologies include diabetic neuropathy, bladder nec* surgery, 306/=, transurethral prostatectomy, colon or rectal surgery, multiple sclerosis, spinal cord in'ury, or the use of medicines such as alpha+antagonists. =iagnosis is suggested by history, a low e'aculate volume, and the observance of 1 +15 sperm per high+power field #407( in the poste'aculatory urine