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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

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

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

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

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

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

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

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

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

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

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

mental retardation. 0atients generally have long arms and legs due to a delayed closure of the epiphyseal plates. and its incidence is estimated as 1 case per 1 . and atrophic testis. births. and hypogonadotropic hypogonadism due to a 1n34 deficiency.% 2elect patients with adult+onset idiopathic hypogonadotropic hypogonadism may respond to clomiphene citrate therapy. cleft lip and cleft palate. Adding recombinant human 724 to 4"1 has been shown to be effective in achieving spermatogenesis in most patients. 0rader+Ailli syndrome is caused by a disorder of genomic imprinting with deletions of paternally derived chromosome arm 15. 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. the pituitary does not release 64 and 724. Infertility is due to hypogonadotropic hypogonadism. an 64 analogue.=isorders of the hypothalamus lead to hypogonadotropic hypogonadism. ?ther conditions . Ideally. which is associated with midline defects such as anosmia. small hands and feet. 0ulsatile 1n34 and 4"1 have been used but result in only ! % achieving complete spermatogenesis. )estosterone therapy may allow patients to achieve normal height but does not improve spermatogenesis. patients respond to replacement with exogenous 1n34 or 4"1. and color blindness. Iallmann syndrome has been described in both familial #N+lin*ed and autosomal( and sporadic forms. +> .11+13. A failure of 1n34 neurons to migrate to the proper location in the hypothalamus has been implicated. If 1n34 is not secreted. 6aurence+-oon+<iedl syndrome 0atients with this syndrome have retinitis pigmentosa and polydactyly. delayed puberty. deafness.$B% 0rader+Ailli syndrome 0atients have characteristic obesity. Idiopathic hypogonadotropic hypogonadism A failure of 1n34 secretion without any discernible underlying cause may be observed alone #isolated( or as part of Iallmann syndrome. although this does not always occur. cryptorchidism.$.

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

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

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

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

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

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

previous attempts at sperm aspiration. 0osttesticular causes of infertility 0osttesticular causes of infertility include problems with sperm transportation through the ductal system.uent bloc*age of the epididymis. and smallpox. Additionally. Idiopathic causes =espite a thorough wor*up. nearly !5% of men have no discernible cause for their infertility.% of infertile patients. Dxcessive use of alcohol. 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. 0atients may be candidates for assisted reproduction techni. gonorrhea. cigarettes.uired. and mari'uana may lead to testicular failure. 2ic*le cell disease 2ic*ling of cells within the testis leads to microinfarcts and secondary testicular failure.uired bloc*age of the ductal system 1enital ducts may become obstructed secondary to infections. tuberculosis. 2egmental dysplasia is defined as a vas deferens with at least ! distinct sites of vasal obstruction. Ac. "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. . Goung syndrome is a condition that leads to inspissation of material and subse.ues after appropriate genetic screening in the partner. 1enital duct obstruction is a potentially curable cause of infertility and is observed in . caffeine. and inguinal surgery may also result in ductal bloc*age. )rauma. such as chlamydia. the sperm may be unable to cross the cervical mucus or may have ultrastructural abnormalities. "ystic fibrosis "7 is the most common genetic disorder in whites. either congenital or ac.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. so these patients may also have urinary tract abnormalities.

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