eMedicine Specialties > Urology > Male Infertility

Infertility, Male

Author: Jonathan Rubenstein, MD, Staff Physician, Department of Urology, University of California, San Francisco
Coauthor(s): Robert E Brannigan, MD, Associate Professor, Department of Urology, Northwestern Memorial Hospital
Contributor Information and Disclosures

Updated: Mar 26, 2008

Introduction

Background

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, 30% due to male factors alone, 20% due to a combination of female and male factors, and 15% unexplained. Conditions of the male that affect fertility are still generally underdiagnosed and undertreated.

Causes of infertility in men can be explained by deficiencies in sperm formation, concentration (eg, oligospermia [too few sperm], azoospermia [no sperm in the ejaculate]), or transportation. This general division allows an appropriate workup of potential underlying causes of infertility and helps define a course of action for treatment.

The initial evaluation of the male patient should be rapid, noninvasive, and cost-effective, as nearly 70% of conditions that cause infertility in men can be diagnosed with history, physical examination, and hormonal and semen analysis alone. More detailed, expensive, and invasive studies can then be ordered if necessary.

Pathophysiology

Gonadal and sexual functions are mediated by the hypothalamic-pituitary-gonadal axis, a closed-loop system with feedback control from the testicles (see Image 1). The hypothalamus, the primary integration center, responds to various signals from the CNS, pituitary gland, and testicles to secrete gonadotropin-releasing hormone (GnRH) in a pulsatile pattern approximately every 70-90 minutes. The half-life of GnRH is 2-5 minutes. Release of GnRH is stimulated by melatonin from the pineal gland and inhibited by testosterone, inhibin, corticotropin-releasing hormone, opiates, illness, and stress. GnRH travels down the portal system to the anterior pituitary, located on a stalk in the sella turcica, to stimulate the release of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).

FSH and LH, glycopeptides with a molecular weight of 10,000 daltons, are each composed of an alpha chain that is identical to that of human chorionic gonadotropin (HCG) and thyroid-stimulating hormone (TSH), but with a beta chain that is unique for each. FSH has a lower plasma concentration and longer half-life than LH, and it has less obvious pulsatile changes. The pulsatile nature of GnRH is essential to normal gonadotropin release; a continuous stimulation inhibits their secretion.

The hypothalamus also produces thyrotropin-releasing hormone (TRH) and vasoactive intestinal peptide (VIP), both of which stimulate prolactin release from the anterior pituitary, and dopamine, which inhibits prolactin release. Men with elevated prolactin levels present with gynecomastia, diminished libido, erectile dysfunction, and occasionally galactorrhea. Prolactin inhibits the production of GnRH from the hypothalamus and LH and FSH from the pituitary. Gonadotropin release is modulated by various other signals, such as estradiol (a potent inhibitor of both LH and FSH release), and inhibin from the Sertoli cell, which causes a selective decrease in FSH release.

FSH and LH are released into system circulation and exert their effect by binding to plasma membrane receptors of the target cells. LH mainly functions to stimulate testosterone secretion from the Leydig cells of the testicle, while FSH stimulates Sertoli cells to facilitate germ cell differentiation.

Testosterone is secreted in a diurnal pattern, peaking early in the morning. In the body, testosterone circulates 2% in the free form, 44% bound to sex hormone–binding globulin (SHBG), and 54% bound to albumin. Testosterone is converted to dihydrotestosterone (DHT) by the action of 5-alpha reductase, both locally and in the periphery, and to estrogen in the periphery. Testosterone and estradiol function as feedback inhibitors of gonadotropin release.

The testicle (Image 2), contains the Leydig cells and the Sertoli cells and is covered by the tunica albuginea, which also provides septae that divide it into approximately 200-350 pyramids. These pyramids are filled with the seminiferous tubules. A normal testicle contains 600-1200 seminiferous tubules with a total length of approximately 250 meters. The interstitium between the seminiferous tubules contains the Leydig cells, fibroblasts, lymphatics, blood vessels, and macrophages. Histologically, Leydig cells are polygonal with eosinophilic cytoplasm. Occasionally, the cytoplasm contains crystalloids of Reinke after puberty.

Seminiferous tubules are made up of Sertoli cells and germ cells and are surrounded by peritubular and myoid cells.

Sertoli cells are columnar, with irregular basal nuclei that have prominent nucleoli and fine chromatin. They 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. Sertoli cells also secrete inhibin, which provides negative feedback on the hypothalamus, and androgen-binding protein, which helps modulate androgen activity in the seminiferous tubules. In addition to FSH, Sertoli cell function is modulated by intratesticular testosterone and signals from peritubular myoid cells.

Germ cells (precursors to spermatozoa) are derived from the gonadal ridge and migrate as gonadocytes to the testicle before testicular descent. In response to FSH stimulation at puberty, germ cells become spermatogonia and undergo an ordered maturation to become spermatozoa. The entire process of development from spermatogonium to spermatid takes 74 days and is described in 14 steps; as they mature, the developing spermatids progress closer to the lumen of the seminiferous tubule.

Spermatogonia rest on the basement membrane and contain dense nuclei and prominent nucleoli. Three types are described: A dark (Ad), A pale (Ap), and B cells. Ad cells (stem cells) divide to create more Ad cells (stem cell renewal) or differentiate into daughter Ap cells every 16 days. Ap cells mature into B spermatogonia, which then undergo mitotic division to become primary spermatocytes, which are recognized by their large centrally located nuclei and beaded chromatin. The mitotic division does not result in complete separation; rather, daughter cells maintain intracellular bridges, which have functional significance in cell signaling and maturation.

Primary spermatocytes undergo meiosis as the cells successively pass through the preleptotene, leptotene, zygotene, and pachytene stages to become secondary spermatocytes. During this time, the cells cross from the basal to the adluminal compartments. Secondary spermatocytes contain smaller nuclei with fine chromatin. The secondary spermatocytes undergo a second meiosis and become spermatids. This reduction division (ie, meiosis) results in a haploid chromosome number. Therefore, a total of 4 spermatids are made from each spermatocyte.

Next, the spermatids undergo the process of spermiogenesis (through stages named Sb1, Sb2, Sc, Sd1, and Sd2), 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. The acrosome, a derivative of the Golgi process, surrounds the nucleus anteriorly and contains enzymes necessary to penetrate the ovum. The mature spermatid is then located adjacent to the tubule lumen and contains dark chromatin with an oval-shaped nucleus.

After their release from the Sertoli 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 3). The epididymis is a 3- to 4-cm long structure with a tubular length of 4-5 m. As sperm move from the head to the tail, they mature and acquire fertilization capacity. Sperm 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. The transit time varies with age and sexual activity but is usually from 1-12 days. The epididymis additionally secretes substances for sperm nutrition and protection such as glycerophosphorylcholine, carnitine, and sialic acid.

Sperm next enter the vas deferens, a 30- to 35-cm muscular conduit of Wolffian duct origin. The 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. During emission, sperm are propelled forward by peristalsis. After reaching its ampullary portion behind the bladder, the vas joins with the seminal vesicles, at the ejaculatory duct, which empties next to the verumontanum of the prostate. During ejaculation, the ejaculate is propelled forward by the rhythmic contractions of the smooth muscle that surrounds the ducts and by the bulbourethral muscles and other pelvic muscles. Bladder neck closure during ejaculation is vital to ensure antegrade ejaculation.

Normal ejaculate volume ranges from 1.5 to 5 mL and has a pH level of 7.05-7.8. The seminal vesicles provide 40-80% of the semen volume, which includes fructose for sperm nutrition, prostaglandins and other coagulating substances, and bicarbonate to buffer the acidic vaginal vault. Normal seminal fructose concentration is 120-450 mg/dL, with lower levels suggesting ejaculatory duct obstruction or absence of the seminal vesicles. The prostate gland contributes approximately 10-30% (0.5 mL) of the ejaculate. Products include enzymes and proteases to liquefy the seminal coagulum. This usually occurs within 20-25 minutes. The prostate also secretes zinc, phospholipids, phosphatase, and spermine. The testicular-epididymal component includes sperm and comprises about 5% of the ejaculate volume.

In addition to the components already listed, semen is also composed of secretions from the bulbourethral (Cowper) glands and the (periurethral) glands of Litre, each producing 2-5% of the ejaculate volume, serving mainly to lubricate the urethra and to buffer the acidity of the residual urine. The ordered sequence of release is important for appropriate functioning.

Frequency

United States

An estimated 10-15% of couples are considered infertile, defined by the World Health Organization (WHO) as the absence of conception after at least 12 months of unprotected intercourse. In American men, the risk correlates to approximately 1 in 25. Low sperm counts, poor semen quality, or both account for 90% of cases; however, studies of infertile couples without treatment reveal that 23% of these couples conceive within 2 years, and 10% more conceive within 4 years. Even patients with severe oligospermia (<2 million sperm/mL) have a 7.6% chance of conception within 2 years.¹

International

Patterns of male infertility vary greatly among regions and even within regions. The highest reported fertility rates are in Finland, while Great Britain has a low fertility rate. A combination of social habits, environmental conditions, and genetics is suspected to contribute to this variation.

Recent debate has occurred in the literature regarding a poorer semen quality, decreased sperm counts (113 million/mL in 1940 compared with 66 million/mL in the 1990s), and decreased fertility in men today compared with fertility 50 years ago.²  Investigators hypothesize that environmental conditions and toxins have led to this decline; however, others argue that this is solely because of differences in counting methods, laboratory techniques, and geographic variation.

Mortality/Morbidity

Many 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 (CF). Evaluating patients for life-threatening or life-altering conditions during the workup is important.

Sex

Isolated conditions of the female are responsible for infertility in 35% of cases, isolated conditions of the male in 30%, conditions of both the male and female in 20%, and unexplained causes in 15%. Even 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

The effect of aging on fertility is unclear. As men age, their testosterone levels decrease, while estradiol and estrone levels increase. Studies have shown that, as men age, their sperm density decreases. Young men have spermatids present in 90% of seminiferous tubules, which decreases to 50% by age 50-70 years and to 10% by age 80 years. Additionally, 50% of Sertoli cells are lost by age 50 years, 50% of Leydig cells are lost by age 60 years. Despite this, aging men may achieve fertility rates similar to those in younger men, although conception often takes longer.

Clinical

History

The 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. The couple should be asked specifically about their sexual habits, including their level of knowledge of the optimal timing of intercourse and the use of potentially spermatocytic drugs and lubricants.

Patients should be asked 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 neck surgery. A history of neurological diseases, diabetes, and pulmonary infections should be elicited. Anosmia (lack of smell), galactorrhea, visual-field defects, and sudden loss of libido could be signs of a pituitary tumor. The status of the partner's workup should also be known.

• Timing of puberty (early, normal, or delayed)
  • Precocious puberty, defined as the onset of puberty before age 9 years in males, may be the sign of a serious underlying endocrinologic disorder. Hormonally 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.
• Childhood urological disorders or surgery
  • Both unilateral and bilateral cryptorchidism are associated with a decrease in sperm production and semen quality, regardless of the timing of orchidopexy.
  • Patients with hypospadias may not place the semen at the cervical os.
  • Prenatal exposure to diethylstilbestrol (DES) may cause epididymal cysts and cryptorchidism.
  • Prior bladder neck procedure, such as a V-Y plasty performed at the time of ureteral reimplantation, may lead to retrograde ejaculation.
  • The vas deferens or the testicular blood supply may be injured or ligated at the time of inguinal surgery, hernia repair, hydrocelectomy, or varicocelectomy.
  • Testicular torsion and trauma may result in testicular atrophy and the production of antisperm antibodies.
• Medical history
  • Diabetes may cause autonomic neuropathy, neurogenic impotence, and retrograde ejaculation.
  • Obesity alters hormonal metabolism, leading to increased peripheral conversion of testosterone to estrogen and decreased LH pulse amplitude.
  • Sickle cell disease may lead to sickling and, therefore, direct testicular ischemia and damage.
  • Patients with sickle cell disease or thalassemia may have infertility due to hemosiderosis from multiple blood transfusions.
  • Chronic renal failure leads to hypogonadism and feminization.
  • Liver disease may result in decreased male secondary sexual characteristics, testicular atrophy, and gynecomastia due to increased estrogen levels.
  • Hemochromatosis leads to hypogonadism and signs of androgen deficiency without gynecomastia and is associated with decreased estradiol levels.
  • Postpubertal mumps may lead to testicular atrophy.
  • Sexually transmitted diseases and tuberculosis can cause obstruction of the vas deferens or epididymis.
  • Mycoplasma fastens itself to sperm, decreasing sperm motility.
  • Smallpox, prostatitis, orchitis, seminal vesiculitis, and urethritis may lead to obstructive azoospermia.
• Acute and chronic medical illnesses
  • Patients should be asked about recent acute febrile illnesses, which may temporarily suppress gonadotropin release. The decrease in sperm production may not be realized until 1-3 months later.
  • Anesthesia, surgery, starvation, myocardial infarction, hepatic coma, head injury, stroke, 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.
  • Chronic medical illnesses may directly suppress sex hormone production and sperm production, leading to end-organ failure.
• Sexual history
  • The frequency, timing, and methods of coitus and knowledge of the ovulatory cycle should be elicited.
  • Studies show that the optimal timing for intercourse is every 48 hours at mid cycle.
  • Lubricants such as Surgilube, Keri lotion, KY Jelly, and saliva are spermatotoxic, whereas egg whites, peanut oil, vegetable oil, and petroleum jelly are not known to be spermatotoxic but still should be used in only the smallest amounts possible if needed for lubrication during intercourse.
• Testicular cancer
  • Testicular cancer is associated with impaired spermatogenic function, even before orchiectomy, with a degree of dysfunction higher than that explained by local tumor effect.
  • Oligospermia is observed in more than 60% of patients at the time of diagnosis of testicular cancer.
  • Germ cell tumors may to share common etiological factors with testicular dysfunction, such as testicular dysgenesis, androgen insensitivity, and cryptorchidism. Contralateral abnormalities of spermatogenesis are more common in patients with testicular cancer. Sperm function often remains impaired, even after orchiectomy.
• Treatment for testicular cancer
  • Chemotherapy has a dose-dependent effect on germ cells. Alkylating agents, such as cyclophosphamide, mustine, and chlorambucil, severely alter the seminiferous tubules and destroy spermatogonia. (Note that chemotherapy is also mutagenic, so sperm should be donated before treatment, or attempts at conception should be postponed until >1 year after treatment.)
  • Retroperitoneal lymph node dissection (RPLND) may impair emission (of semen into the urethra) and/or cause retrograde ejaculation.³
  • Radiation therapy affects mainly type B spermatogonia and, possibly, spermatocytes. A dose of as little as 0.15 Gy may cause irreversible damage, although complete recovery may be possible if stem cell numbers are not depleted. After exposure of less than 1 Gy, sperm production may return in 9-18 months, while 4-6 years may be necessary to recover sperm production after a dose of up to 5 Gy. Despite radiation therapy and chemotherapy, nearly two thirds of patients retain the ability to father a child if the ejaculatory function is retained.
  • To potentially decrease the morbidity of adjunct therapy, select patients with grade I germ cell tumors are now undergoing unilateral orchiectomy with surveillance. However, RPLND performed for salvage therapy is associated with a higher risk of retrograde ejaculation than that performed initially.
  • Patients with reference range FSH levels at baseline usually observe an improvement in semen parameters and sperm density after orchiectomy. This 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. Therefore, the disturbance that leads to testicular cancer is thought to be inherent and present in the primordial cell.
  • Patients 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 fertilization (IVF) with intracytoplasmic sperm injection (ICSI).
• Social history
  • Cigarette and marijuana smoking lead to a decrease in sperm density, motility, and morphology.
  • Alcohol produces both an acute and a chronic decrease in testosterone secretion.
  • Emotional stress blunts GnRH release, leading to hypogonadism.
  • Excessive heat exposure from saunas, hot tubs, or the work environment may cause a temporary decrease in sperm production.
  • Contrary to widely held beliefs, no evidence supports that wearing constrictive underwear, or "briefs," decreases fertility. Even with an elevation in temperature of 0.8-1° caused by wearing constrictive underwear, no changes in sperm parameters, no decrease in spermatogenesis, and no changes in sperm function are observed.⁴
• Medicines
  • Spironolactone, cyproterone, ketoconazole, and cimetidine have antiandrogenic properties.
  • Tetracycline lowers testosterone levels 20%.
  • Nitrofurantoin depresses spermatogenesis.
  • Sulfasalazine leads to a reversible decrease in sperm motility and density.
  • Colchicine, methadone, methotrexate, phenytoin, thioridazine, and calcium channel blockers have all be associated with infertility.
• Family history
  • Congenital midline defects, cryptorchidism, hypogonadotropism, and testicular atrophy in family members may be a sign of a congenital disease.
  • A history of CF or hypogonadism should be elicited.
• Respiratory disease
  • Infertility and recurrent respiratory infections may be due to immotile cilia syndrome, which may be isolated or part of Kartagener syndrome (with situs inversus).
  • CF is associated with congenital bilateral absence of the vas deferens (CBAVD), leading to obstructive azoospermia. While both copies of this recessive gene are necessary for clinical disease, the presence of only one copy may lead to CBAVD.
  • Young syndrome results in recurrent pulmonary infections and azoospermia due to inspissated material in the epididymis causing obstruction.
• Environmental and/or occupational exposure
  • Many pesticides have estrogen-like effects.
  • Dibromochloropropane (DBCP) is a nematocide widely used in agriculture that causes azoospermia without recovery by an unknown mechanism.
  • Lead exposure depresses the hypothalamic-pituitary axis.
  • Carbon disulfide exposure from the rayon industry leads to semen, pituitary, and hypothalamic changes.
  • Heat exposure, as seen in workers in the steel and ceramic fields, decreases spermatocyte maturation.
• Spinal cord injury
  • Severe spinal cord injury may lead to anejaculation. These men may be treated with electroejaculation or sperm retrieval techniques.⁵
  • Epididymal 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 quality in patients with a spinal cord injury may gradually decline owing to unknown causes. Within a year after injury, many have semen with dead sperm with signs of neutrophil infiltration on semen analysis. This is hypothesized to be due to accessory gland dysfunction rather than lack of ejaculation and atrophy.
  • In patients with spinal cord injury, sperm parameters from the vas deferens show 54% motility and 74% viability, while only 14% motility and 26% viability is observed in ejaculated sperm. These are both much lower than that in control subjects.⁶

Physical

The 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.

• Testicles
  • The testicular examination should occur in a warm room with the patient relaxed. The testicles should be palpated individually between the thumb and first 2 fingers. The examiner should note the presence, size, and consistency of the testicles, and the testicles should be compared with each other.
  • A Prader orchidometer or ultrasonography may be used to estimate the testicular volume, with normal considered to be greater than 20 mL.
  • Calipers may be used to measure testicular length, which is usually greater than 4 cm, although the lower limits of normal length (mean minus 2 standard deviations) is 31 mm in white men and 34 mm in black men. The testes of Japanese men are typically smaller than the testes of white men.
  • Testicular atrophy may be observed in primary testicular failure, Klinefelter syndrome, endocrinopathies, postpubertal mumps, liver disease, and myotonic dystrophy.
  • Swelling with pain indicates orchitis, whereas nontender enlargement may be observed in testicular neoplasms, tuberculosis, and tertiary syphilis.
• Epididymis
  • The head, body, and tail of the epididymis should be palpated and assessed for their presence bilaterally.
  • Note induration and cystic changes. An enlarged indurated epididymis with a cystic component should alert the examiner to the possibility of ductal obstruction.
  • Tenderness may be due to epididymitis.
• Vas deferens
  • Evaluate the vas for its presence bilaterally and palpate along its entire length to check for defects, segmental dysplasia, induration, nodularity, or swelling.
  • The complete absence bilaterally is observed almost exclusively in patients with either one or two copies of the gene for CF, although even a small defect or gap indicates the possibility of a CF gene mutation.
  • A thickened 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.
• Spermatic cord
  • Check patients for the presence of a varicocele, which is the most common surgically correctable cause of infertility (see Image 4). To elicit this, the patient should perform a Valsalva maneuver in the sitting and standing positions in a warm room. Grade 1 varicocele is defined as palpable only with Valsalva, while grade 2 is palpable at standing, and grade 3 is visible at rest. The presence of asymmetry or an impulse with Valsalva may best help the examiner find a varicocele.
  • The sudden onset of a varicocele, a solitary right-sided varicocele, or a varicocele that does not change with Valsalva indicates the possibility of a retroperitoneal neoplastic process or vein thrombosis.
• Penis
  • The examination should focus on the location and patency of the urethral meatus and the presence of meatal strictures.
  • Patients with hypospadias or epispadias may not deposit semen appropriately at the cervix.
  • Penile curvature and the presence of penile plaques should be noted.
• Rectal examination
  • The prostate should be of normal size and without cysts, induration, or masses.
  • The seminal vesicles are usually not palpable.
  • A midline prostatic cyst or palpable seminal vesicles may be due to obstruction of the ejaculatory ducts.
• Body 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.
  • Truncal obesity, striae, and moon facies may be due to Cushing syndrome.
  • Gynecomastia, galactorrhea, headaches, and a loss of visual fields may be observed in patients with pituitary adenomas.
  • Focus the neck examination on thyromegaly and bruits.
  • Palpate the liver for hepatomegaly and examine the lymph nodes to rule out lymphoma.

Causes

Causes generally can be divided into pretesticular, testicular, and posttesticular.

Pretesticular Causes of Infertility

Pretesticular causes of infertility include congenital or acquired diseases of the hypothalamus, pituitary, or peripheral organs that alter the hypothalamic-pituitary axis.

Hypothalamus

Disorders of the hypothalamus lead to hypogonadotropic hypogonadism. If GnRH is not secreted, the pituitary does not release LH and FSH. Ideally, patients respond to replacement with exogenous GnRH or HCG, an LH analogue, although this does not always occur.

• Idiopathic hypogonadotropic hypogonadism
  • A failure of GnRH secretion without any discernible underlying cause may be observed alone (isolated) or as part of Kallmann syndrome, which is associated with midline defects such as anosmia, cleft lip and cleft palate, deafness, cryptorchidism, and color blindness. Kallmann syndrome has been described in both familial (X-linked and autosomal) and sporadic forms, and its incidence is estimated as 1 case per 10,000-60,000 births.
  • A failure of GnRH neurons to migrate to the proper location in the hypothalamus has been implicated. Patients generally have long arms and legs due to a delayed closure of the epiphyseal plates, delayed puberty, and atrophic testis. Testosterone therapy may allow patients to achieve normal height but does not improve spermatogenesis. Exogenous testosterone should never be administered in an attempt to boost sperm production because it actually decreases intratesticular testosterone levels owing to feedback inhibition of GnRH release.
  • Pulsatile GnRH and HCG have been used but result in only 20% achieving complete spermatogenesis.
  • Adding recombinant human FSH to HCG has been shown to be effective in achieving spermatogenesis in most patients.⁷
  • Select patients with adult-onset idiopathic hypogonadotropic hypogonadism may respond to clomiphene citrate therapy.⁸
• Prader-Willi syndrome: Patients have characteristic obesity, mental retardation, small hands and feet, and hypogonadotropic hypogonadism due to a GnRH deficiency. Prader-Willi syndrome is caused by a disorder of genomic imprinting with deletions of paternally derived chromosome arm 15q11-13.
• Laurence-Moon-Biedl syndrome: Patients with this syndrome have retinitis pigmentosa and polydactyly. Infertility is due to hypogonadotropic hypogonadism.
• Other conditions: Various other lesions and diseases, such as CNS tumors, temporal lobe seizures, and many drugs (eg, dopamine antagonists) may interrupt the hypothalamic-pituitary axis at the hypothalamus.

Both pituitary insufficiency and pituitary excess cause infertility. Pituitary failure may be congenital or acquired. Acquired causes include tumor, infarction, radiation, infection, or granulomatous disease. Nonfunctional pituitary tumors may compress the pituitary stalk 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.

• Prolactinoma
  • A prolactin-secreting adenoma is the most common functional pituitary tumor. Prolactin stimulates breast development and lactation; 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 150 mcg/L suggests a pituitary adenoma, while levels greater than 300 mcg/L are nearly diagnostic. Patients should undergo an MRI or CT scan of the sella turcica for diagnostic purposes to determine whether a microprolactinoma or a macroprolactinoma is present.
  • Bromocriptine, a dopamine agonist, is used to suppress prolactin levels and is the therapy of choice for microprolactinomas. Cabergoline is also a treatment option. Some men respond with an increase in testosterone levels; many also recover normal sperm counts. Transsphenoidal resection of a microprolactinoma is 80-90% successful, but as many as 17% recur. Surgical 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 LH deficiency (fertile eunuch): In these patients, LH levels are decreased while FSH levels are within the reference range. Patients have eunuchoidal body habitus, large testis, and a low ejaculatory volume. The treatment of choice is exogenous HCG.
• Isolated FSH deficiency: This is a very rare cause of infertility. Patients present with oligospermia but have LH levels within the reference range. Treatment is with human menopausal gonadotropin (HMG) or exogenous FSH.
• Thalassemia: Patients with thalassemia have ineffective erythropoiesis and undergo multiple blood transfusions. Excess iron from multiple transfusions may get deposited in the pituitary gland and the testis, causing parenchymal damage and both pituitary and testicular insufficiency. Treatment is with exogenous gonadotropins and iron-chelating therapy.
• Cushing disease: Increased cortisol levels cause a negative feedback on the hypothalamus, decreasing GnRH release.

The hypothalamus-pituitary axis may be interrupted by hormonally active peripheral tumors or other exogenous factors, due to cortical excess, cortical deficiency, or estrogen excess.

• Excess cortisol may be produced by adrenal hyperplasia, adenomas, carcinoma, or lung tumors. High cortisol levels may also be seen with exogenous steroid use, such as that administered to patients with ulcerative colitis, asthma, arthritis, or organ transplant. For example, high cortisol levels are seen in patients with Cushing syndrome, which causes negative feedback on the pituitary to decrease LH release.
• Cortical deficiency may be seen in patients with adrenal failure due to infection, infarction, or congenital adrenal hyperplasia (CAH). CAH may be due to the congenital deficiency of one of several adrenal enzymes, the most common of which is 21-hydroxylase deficiency. Because cortisol is not secreted, a lack of feedback inhibition on the pituitary gland occurs, leading to adrenocorticotropic hormone (ACTH) hypersecretion. This leads to increased androgen secretion from the adrenal gland, causing feedback inhibition of GnRH release from the hypothalamus. Patients present with short stature, precocious puberty, small testis, and occasional bilateral testicular rests. Screening tests include increased plasma 17-hydroxylase and urine 17-ketosteroids.
• Estrogen excess may be seen in patients with Sertoli cell tumors, Leydig tumors, liver failure, or severe obesity. Estrogen causes negative feedback on the pituitary gland, inhibiting LH and FSH release.

Primary Testicular Causes of Infertility

Primary testicular problems may be chromosomal or nonchromosomal in nature. While chromosomal failure is usually caused by abnormalities of the sex chromosomes, autosomal disorders are also observed.

Chromosomal abnormalities

An estimated 6-13% of infertile men have chromosomal abnormalities (compared with 0.6% of the general population). Patients with azoospermia or severe oligospermia are more likely to have a chromosomal abnormality (10-15%) than infertile men with sperm density within the reference range (1%). A karyotype test and a Y chromosome test for microdeletions are indicated in patients with nonobstructive azoospermia or severe oligospermia (<5 million sperm/mL), although indications are expanding.⁹

• Klinefelter syndrome
  • Klinefelter syndrome is the most common chromosomal cause of male infertility, estimated to be present in 1 per 500-1000 male births. Classic Klinefelter syndrome has a 47, XXY karyotype and is caused by a nondisjunction during the first meiotic division, more commonly of maternal origin; mosaic forms are due to nondisjunction following fertilization. The only known risk factor for Klinefelter syndrome is advanced maternal age. Infertility is caused by primary testicular failure, and most patients are azoospermic. Hormonal analysis reveals increased gonadotropin levels, while 60% have decreased testosterone levels. Surprisingly, most patients have normal libido, erections, and orgasms, so testosterone therapy has only a limited role; exogenous testosterone may also suppress any underlying sperm production.
  • Physical 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. These men are at a higher risk for breast cancer, leukemia, diabetes, empty sella syndrome, and pituitary tumors. Testicular histology reveals hyalinization of seminiferous tubules. Some men with Klinefelter syndrome may be able to conceive with the help of assisted reproductive techniques. Of azoospermic patients with Klinefelter syndrome, 20% show the presence of residual foci of spermatogenesis. Although the XXY pattern is observed in the spermatogonia and primary spermatocytes, many of the secondary spermatocytes and spermatids have normal patterns. The chromosomal pattern of the resultant embryos can be assessed with preimplantation genetic diagnosis.
• XX male (sex reversal syndrome): An XX karyotype is due to a crossover of the sex-determining region (SRY) of the Y chromosome (with the testis determining factor) to either the X chromosome or an autosome. Patients are often short, with small firm testis and gynecomastia, but they have a normal-sized penis. Seminiferous tubules show sclerosis.
• XYY male: An XYY karyotype is observed in 0.1-0.4% of newborn males. These patients are often tall and severely oligospermic or azoospermic. This pattern has been linked with aggressive behavior. Biopsy reveals maturation arrest or germ cell aplasia. Functional sperm that are present may have a normal karyotype.
• Noonan syndrome (46, XY): Patients with Noonan syndrome, also known as male Turner syndrome, have physical characteristics similar to that of women with Turner syndrome (45, X). Features include a webbed neck, short stature, low-set ears, ptosis, shield-like chest, lymphedema of hands and feet, cardiovascular abnormalities, and cubitus valgus. Leydig cell function is impaired, and most patients are infertile due to primary testicular failure.
• Mixed gonadal dysgenesis (45, X/46, XY): Patients have ambiguous genitalia, a testis on one side, and a streaked gonad on the other.
• Y chromosome microdeletion syndrome: The long arm of the Y chromosome (Yq) is considered critical for fertility, especially Yq11.23 (interval 6). Macroscopic deletions of Yq11 are often observed in patients with azoospermia, although many new microdeletions have been implicated as a significant cause of infertility. These microdeletions are not observed on regular karyotype; rather, their identification requires polymerase chain reaction (PCR)–based sequence-tagged site mapping or Southern blot analysis. Three regions have been described, called azoospermic factors a, b, and c (AZFa, AZFb, AZFc). These deletions are observed in 3-19% of patients with idiopathic infertility and 6-14% of patients with oligospermia, although up to 7% of patients with other known causes of infertility may also be found to have a deletion. Patients with azoospermia or severe oligospermia seeking assisted reproductive techniques should be screened.
• Bilateral anorchia (vanishing testis syndrome): Patients have a normal male karyotype (46, XY) but are born without testis bilaterally. The male phenotype proves that androgen was present in utero. Potential causes are unknown, but it may be related to infection, vascular disease, or bilateral testicular torsion. Karyotype shows a normal SRY gene. Patients may achieve normal virilization and adult phenotype by the administration of exogenous testosterone, but they are infertile.
• Down syndrome: These patients have mild testicular dysfunction with varying degrees of reduction in germ cell number. LH and FSH levels are usually elevated.
• Myotonic dystrophy: This is an autosomal dominant defect in the dystrophin gene that causes a delay in muscle relaxation after contraction. Seventy-five percent of patients have testicular atrophy and primary testicular failure due to degeneration of the seminiferous tubules. Leydig cells are normal. Histology reveals severe tubular sclerosis. No effective therapy exists.

Testicular failure that is nonchromosomal in origin may be idiopathic or acquired by gonadotoxic drugs, radiation, orchitis, trauma, or torsion.

• Varicocele
  • 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 (30-35%) and the most common cause of secondary (acquired) infertility (75-85%). Varicoceles are observed more commonly on the left side than the right. Those with isolated right-sided varicoceles should be evaluated for retroperitoneal pathology.
  • Varicoceles are generally asymptomatic, and most men with varicoceles do not have infertility or testicular atrophy. However, varicoceles may lead to impaired testicular spermatogenesis and steroidogenesis, potentially due to an increased intratesticular temperature, reflux of toxic metabolites, and/or germ cell hypoxia as potential causes of these changes, and this appears to be progressive over time.
  • Varicoceles 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.
  • Patients with a grade 2-3 varicocele (visible or palpable) associated with infertility should have the varicocele repaired. After repair, 40-70% of patients have improved semen parameters, while 40% are able to achieve a pregnancy without other interventions. Those with a varicocele diagnosable only on scrotal ultrasonography will likely not benefit from repair. Adolescents with a varicocele and testicular atrophy or lack of growth should similarly undergo repair. Controversy exists regarding whether to routinely repair an adolescent varicocele not associated with testicular atrophy.
  • In those with azoospermia and a varicocele, sperm may appear after repair in up to one third, but most of these men return to an azoospermic state within a few months. If sperm appears, these men should be offered cryopreservation.
• Cryptorchidism: An estimated 3% of full-term males are born with an undescended testicle, but fewer than 1% remain undescended by age 1 year. Undescended testicle may be isolated or may be observed as part of a syndrome such as prune belly syndrome. Patients are at increased risk of infertility, even if the testicle is brought down into the scrotum, as the testicle itself may be inherently abnormal. The farther from the scrotum, and the longer duration that the testicle resides outside the scrotum, the greater the likelihood of infertility. Testicular histology typically reveals a decreased number of Leydig cells and decreased spermatogenesis. Cryptorchidism may be due to inherent defects in both testes because even men with unilateral cryptorchidism have lower than expected sperm counts.
• Trauma: Testicular trauma is the second most common acquired cause of infertility. The testes are at risk for both thermal and physical trauma because of their exposed position.
• Sertoli-cell-only syndrome (germinal cell aplasia): Patients with germinal cell aplasia have LH and testosterone levels within the reference range but have an increased FSH level. The etiology is unknown but is probably multifactorial. Patients have with small- to normal-sized testes and azoospermia, but normal secondary sex characteristics. Histology reveals seminiferous tubules lined by Sertoli cells and a normal interstitium, although no germ cells are present.
• Chemotherapy: Chemotherapy is toxic to actively dividing cells. In the testicle, germ cells (especially up to the preleptotene stage) are especially at risk. The agents most often associated with infertility are the alkylating agents such as cyclophosphamide. For example, treatment for Hodgkin disease has been estimated to lead to infertility in as many as 80-100% of patients.
• Radiation therapy: While Leydig cells are relatively radioresistant because of their low rate of cell division, the Sertoli and germ cells are extremely radiosensitive. If stem cells remain viable after radiation therapy, patients may regain fertility within several years. However, some have suggested that patients should avoid conception for 6 months to 2 years after completion of radiation therapy because of the possibility of chromosomal aberrations in their sperm caused by the mutagenic properties of radiation therapy. Even with the testis shielded, radiation therapy below the diaphragm may lead to infertility due to the release of reactive oxygen free radicals.
• Orchitis: The most common cause of acquired testicular failure in adults is viral orchitis, such as that caused by the mumps virus, echovirus, or group B arbovirus. Of adults with who are infected with mumps, 25% develop orchitis; two thirds of cases are unilateral, and one third are bilateral. While orchitis develops a few days after the onset of parotid gland inflammation, it may also precede it. The 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 1-6 months, and the degree of atrophy does not correlate with the severity of orchitis or infertility. Normal fertility is observed in three fourths of patients with unilateral mumps orchitis and in one third of patients in bilateral orchitis.
• Granulomatous disease: Leprosy and sarcoidosis may infiltrate the testicle and lead to testicular failure.
• Sickle cell disease: Sickling of cells within the testis leads to microinfarcts and secondary testicular failure.
• Excessive use of alcohol, cigarettes, caffeine, and marijuana may lead to testicular failure.
• Idiopathic causes: Despite a thorough workup, nearly 25% of men have no discernible cause for their infertility.

Posttesticular Causes of Infertility

Posttesticular causes of infertility include problems with sperm transportation through the ductal system, either congenital or acquired. Genital duct obstruction is a potentially curable cause of infertility and is observed in 7% of infertile patients. Additionally, the sperm may be unable to cross the cervical mucus or may have ultrastructural abnormalities.

• Congenital blockage of the ductal system: An increased rate of duct obstruction is observed in children of mothers who were exposed to DES during pregnancy. Segmental dysplasia is defined as a vas deferens with at least 2 distinct sites of vasal obstruction.
• Cystic fibrosis: CF is the most common genetic disorder in whites. Patients with CF nearly uniformly have CBAVD. The cystic fibrosis transmembrane regulator (CFTR) protein plays a role in mesonephric duct development during early fetal life, so these patients may also have urinary tract abnormalities. Patients may be candidates for assisted reproduction techniques after appropriate genetic screening in the partner.
• Acquired blockage of the ductal system: Genital ducts may become obstructed secondary to infections, such as chlamydia, gonorrhea, tuberculosis, and smallpox. Young syndrome is a condition that leads to inspissation of material and subsequent blockage of the epididymis. Trauma, previous attempts at sperm aspiration, and inguinal surgery may also result in ductal blockage. Small calculi may block the ejaculatory ducts, or prostatic cysts may extrinsically block the ducts. Scrotal surgery, including vasectomy, hydrocelectomy (5-6%), and spermatocelectomy (up to 17%), may lead to epididymal injury and subsequent obstruction.¹⁰
• 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 Kartagener syndrome with situs inversus. Because of a defect in the dynein arms, spokes, 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.
• Ejaculatory duct obstruction: Complete and partial ejaculatory duct obstruction has been implicated as a cause of 1-5% of patients with male infertility. Patients may have a normal palpable vas deferens bilaterally but show decreased ejaculate volume and hemospermia and may experience pain upon ejaculation. Etiologies include cysts (midline and eccentric), ductal calcification and stones, postinfectious, and postoperative. Transrectal ultrasonography (TRUS) may reveal enlarged seminal vesicles, but this is not universal. Seminal vesicle aspiration revealing numerous sperm or a dynamic test such as injection of indigo carmine into the seminal vesicle or ejaculatory duct may be necessary for diagnosis.¹¹
• Anejaculation/retrograde ejaculation may be due to an open bladder neck or a lack of rhythmic contractions during ejaculation. Etiologies include diabetic neuropathy, bladder neck surgery, RPLND, transurethral prostatectomy, colon or rectal surgery, multiple sclerosis, spinal cord injury, or the use of medicines such as alpha-antagonists. Diagnosis is suggested by history, a low ejaculate volume, and the observance of 10-15 sperm per high-power field (HPF) in the postejaculatory urine.

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