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Male Infertility

Author: Stephen W. Leslie Author: Taylor L. Soon-Sutton Editor: Moien AB Khan Updated: 6/19/2026 5:19:50 AM

Introduction

Infertility is usually defined as the inability of a couple to conceive even after 1 year of unprotected, frequent sexual intercourse.[1] Infertility affects about 15% of couples in the US and at least 180 million couples worldwide.[2] Male infertility is defined by the World Health Organization (WHO) as the inability of a man to impregnate a fertile woman after at least 1 year of regular unprotected intercourse. The male partner is solely responsible for about 20% of cases and is a contributing factor in another 30% to 40% of infertility cases.[3][4]

Because male and female causes often coexist, both partners should be evaluated for infertility and treated together. Overall, the male factor substantially contributes to about 50% of infertility cases.[5] Causes of male infertility include reversible and irreversible conditions. Additional factors may affect either partner, including age, medications, surgical history, exposure to environmental toxins, genetic problems, and systemic diseases. The primary goals of evaluating a man for infertility are to identify contributing factors, offer treatment for reversible causes, determine if he is a candidate for assisted reproductive techniques, and provide counseling for irreversible and untreatable conditions.[6] Up to 6% of men evaluated for male infertility will be found to have more serious underlying pathology, such as cancer.[5][7][8][9][10][11][12] The possibility of serious underlying disease provides an additional reason to perform a comprehensive evaluation of the male partners of couples with infertility so that clinically significant underlying medical conditions can be identified and treated.[5][7][8][9][10][11][12]

Etiology

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Etiology

Male infertility has multiple causes, which can be broadly classified by underlying etiology. Categories include endocrine disorders (usually due to hypogonadism), estimated to account for 2% to 5% of cases; sperm transport disorders (such as vasectomy), estimated at 5%; primary testicular defects (which include abnormal sperm parameters without any identifiable cause), estimated at 65% to 80%; and idiopathic infertility, in which a man with infertility has normal sperm and semen parameters, estimated at 10% to 20%.[13] These estimates are broad because accurate statistics are unavailable due to general underreporting, cultural factors, and regional variations. Patients referred to a tertiary referral center are more likely to have their condition reported, whereas patients evaluated in private settings may never have their data collected.[13] A partial summary of specific etiologies is listed below as follows:

  • Acquired urogenital abnormalities: bilateral obstruction or ligation of the vas deferens, bilateral orchiectomy, epididymitis, transurethral resection of the prostate, varicoceles, and retrograde ejaculation
  • Congenital urogenital abnormalities: absent, dysfunctional, or obstructed epididymis; congenital abnormalities of the vas deferens; undescended testes; and ejaculatory duct disorders (cysts)
  • Endocrinological causes: congenital gonadotropin-releasing hormone deficiency (Kallmann syndrome), Prader-Willi syndrome, Laurence-Moon-Biedl syndrome, iron overload syndrome, familial cerebellar ataxia, head trauma, intracranial radiation, testosterone supplementation, and hyperthyroidism
  • Environmental toxins: insecticides, fungicides, pesticides, smoking, excessive alcohol consumption, Agent Orange, and other chemical exposures
  • Genetic causes: mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR), primary ciliary dyskinesia, Kallmann syndrome, Klinefelter syndrome, Young syndrome, Sertoli cell-only syndrome, KAL1, KAL2, follicle-stimulating hormone, luteinizing hormone, FGFS, GNRH1, GNRHR, PROK2, and PROK2R gene deficiencies; chromosomal anomalies; Y chromosome microdeletion; androgen receptor gene mutations; and gr/gr deletion
  • Idiopathic causes: idiopathic male infertility, which accounts for 10% to 20% of cases and occurs when semen parameters are normal but the man remains infertileImmunological causes: lymphocytic hypophysitis, hemosiderosis, hemochromatosis, sarcoidosis, histiocytosis, tuberculosis, and fungal infectionsMalignant neoplasms: sellar masses, pituitary macroadenomas, craniopharyngiomas, and surgical or radiation treatment for these conditions; testicular tumors; and adrenal tumors leading to androgen excessMedications or drugs: cannabinoids; opioids; psychotropic drugs that can inhibit gonadotropin-releasing hormone; exogenous testosterone or androgenic corticosteroid supplementation; gonadotropin-releasing hormone analogs and antagonists used in prostatic carcinoma; chronic glucocorticoid therapy; alkylating agents; antiandrogens; ketoconazole; cimetidine; and α-blocker medications for benign prostatic hyperplasia. A complete list of potentially toxic drugs can be found at https://reprotox.orgSexual dysfunction: premature ejaculation, anejaculation, infrequent sexual intercourse, and erectile dysfunctionUrogenital tract infections: gonococcal infection, chlamydia, syphilis, tuberculosis, recurrent urogenital infections, prostatitis, and recurrent prostatovesiculitis [5]

Male infertility can also be classified based on the medical interventions that can potentially assist conception as follows: 

  • Treatable causes of male infertility are found in 18% of cases and include obstructive azoospermia, ejaculatory duct and prostatic midline cysts, gonadotropin deficiency, sexual function disorders, sperm autoimmunity, varicoceles, and reversible effects of toxins.
  • Uncorrectable male infertility or subfertility is found in 70% of cases and includes oligozoospermia, asthenozoospermia, teratozoospermia, and normospermia with functional defects. Assisted reproductive technology is generally be necessary for reproduction in these patients.
  • Untreatable male sterility is seen in 12% of cases and includes primary seminiferous tubular failure, Sertoli cell–only syndrome, and bilateral orchiectomy.[14]

Epidemiology

The prevalence of infertility is variable, and epidemiologically, male infertility has been documented less frequently in resource-limited countries.[15] The burden of infertility is generally worse in resource-limited regions due to constrained medical resources, the high cost of treatment, and cultural fears, taboos, and stigmas. Infertility is much more challenging to identify and treat in areas where medical resources for basic health care are already strained.

Globally, infertility affects approximately 13% to 15% of all couples, and 1 in 5 couples are unable to achieve pregnancy in the first year of trying.[16] About 50% of young, healthy couples in the US who could not conceive during their first year of unprotected sexual intercourse will successfully conceive during the subsequent 12 months, even without any specific treatment.[17] With the first child, 1 in 6 couples encounter some fertility problems, and with a subsequent child, 1 in 6 couples still have issues.[18] In 20% to 30% of infertility cases, men can be solely responsible, with an overall contribution to infertility in couples of about 50%.[3][19]

Regarding male infertility, the exact prevalence remains uncertain because male infertility is not a reportable disease. Furthermore, payment for male infertility treatment is usually private, and therefore, treatments are not reflected in medical insurance statistics. Male infertility is also often treated in outpatient settings, and such data are not typically added to large clinical databases.[13] 

Agarwal et al estimated that the overall pure male factor infertility could range between 2.5% and 12%.[19] In North America, the estimated male infertility rate is between 4.5% and 6%, whereas the rate is 9% in Australia and could be as high as 8% to 12% in Eastern Europe.[19] Results from a study by Bayasgalan et al estimated the cause of infertility due exclusively to a male factor at 25.6%.[20] Results from a similar study conducted by Thonneau et al found that among the French population, 20% of all infertility cases were due exclusively to a male factor.[2] Similarly, Philippov et al. used a WHO questionnaire in Western Siberia and reported a rate of 6.4%, whereas in Nigeria, Ikechebelu and associates reported a male infertility prevalence of 42.4%.[21][22] For most practical purposes, clinicians assume that about one-sixth of all couples worldwide have an infertility issue and that male factor infertility is significant in about half of cases and is the only cause in about 20% to 30% of cases.

Widespread reports of a global trend toward declining sperm counts in recent decades are concerning.[23][24] The average sperm count in 1940 was 113 million/mL but dropped to 66 million/mL in the 1990s.[25] This trend has continued worldwide, with the mean sperm count declining by 51.6% between 1973 and 2018.[24] More concerningly, the rate of decline increased after 2000, from 1.16% per year to 2.64% per year.[24] Although the exact causes are not known, contributing factors are thought to include increasing long-term exposure to environmental toxins and improved global medical care, which paradoxically allows more men with marginal health to participate in reproductive activities. However, the reported decrease in sperm counts might merely reflect differences in laboratory techniques, inconsistent laboratory criteria, and varying counting methods.

Men with infertility issues tend to have more health-related comorbidities than men with normal fertility.[9][26][27][28] Men with infertility and abnormal semen parameters have an increased risk of testicular cancer, with the highest risk in men with azoospermia.[10][11][12][29][30][31] Men with azoospermia also have a greater overall cancer risk and higher mortality rate compared to men with normal sperm counts.[29][32] First- and second-degree relatives of men with infertility may also have an increased cancer risk.[32][33] Conversely, reports indicated that 5% to 8% of patients with testicular cancer have azoospermia.[34]

COVID-19 appears to cause somewhat reduced fertility and even infertility in some recovered men, especially if the infection is severe. The virus appears to affect the testes by direct cellular infection, cytokine storm–mediated injury, and adverse effects of the various antiviral and immunological therapies used in its treatment.[35] Further investigations are needed to better elucidate the mechanisms of injury and possible treatments specific to COVID-19 infection–related infertility.[35]

Pathophysiology

Male infertility can also be classified by the site of dysfunction as follows:

Pretesticular causes include hypogonadotropic hypogonadism, erectile dysfunction, and coital disorders such as retrograde ejaculation or anejaculation, as well as genetic factors and chromosomal abnormalities.

Testicular disorders include testicular tumors, orchiectomy, primitive testicular dysfunction, cryptorchidism, and atrophic testes. Varicoceles are associated with male infertility, most likely through impairment of testicular thermoregulation due to disruption of the pampiniform venous plexus heat regulation mechanism. Epididymal dysfunction can be caused by fetal intrauterine exposure to estrogens, various drugs and chemical toxins, epididymal cysts, spermatoceles with or without a prior surgical procedure, or epididymitis, or it may be idiopathic.[36][37]

Posttesticular etiologies include lesions of the seminal tract, inflammatory diseases, congenital absence of the vas deferens, postvasectomy status, erectile dysfunction, premature ejaculation, and the use of a condom or diaphragm. Posttesticular causes also include bladder neck surgical procedures, transurethral resection of the prostate, retroperitoneal lymph node dissection, rectal surgical procedures, multiple sclerosis, and α-antagonist medications such as tamsulosin.

Any medication, tumor, disease, or disorder that affects the pituitary gland or hypothalamus can potentially cause male infertility by altering gonadotropin-releasing hormone or causing gonadotropin deficiency, such as idiopathic hypogonadotropic hypogonadism, Kallmann syndrome (idiopathic hypogonadotropic hypogonadism with anosmia), and combined pituitary hormone deficiency. Pituitary neoplasms, such as sellar tumors, macroadenomas, and prolactinomas, will also result in male infertility due to alterations in gonadotropin production, as will various genetic causes, such as Prader-Willi, Young, and Laurence-Moon-Biedl syndromes. Various acquired disorders, such as primary androgen overproduction and exogenous testosterone supplementation, will also directly decrease gonadotropic secretion, causing reduced sperm counts and infertility. A few special cases are discussed below.

Cryptorchidism

Men with a history of undescended testicles tend to have lower fertility than men without that history, even if the cryptorchid testicle was surgically repaired at an early age. This lower fertility is thought to be due to an inherent testicular defect. Men with cryptorchid testicles typically have poorer-quality sperm (lower motility and increased abnormal morphology) and lower sperm counts. Interestingly, testosterone levels and Leydig cell function are usually unaffected despite disruptions in sperm counts and Sertoli cell function.

The longer the testicle remains undescended, the greater the risk to future fertility. For this reason, surgical repair of an undescended testicle is now recommended before age 1. Starting even before 1 year of age, the germ cell density of the cryptorchid testicle decreases. Spermatogenesis is generally absent in untreated abdominal testes after puberty. The risk of infertility increases as the distance from the normal anatomical testicular location increases.[38][39][40]

The disruption of spermatogenesis in undescended testes is linked to the underlying hormonal, developmental, and genetic abnormalities of cryptorchidism. Some of these abnormalities may be reversible with early surgical intervention. Adult sperm counts appear to be related to the number of existing, functional germ cells at the time of orchidopexy. The risk of infertility is increased in cases of bilateral cryptorchidism, abdominal testicles, and delayed orchidopexy.[41][42] Please see StatPearls' companion reference, "Cryptorchidism," for further information.

 Klinefelter Syndrome

Klinefelter syndrome is a genetic condition in which a male has XXY instead of the usual XY chromosomes. Patients are typically infertile with hypogonadism. Clinical manifestations vary, but the most typical features are bilateral atrophic or hypertrophic testes, reduced muscle mass, scant body and facial hair, and gynecomastia. Often, the diagnosis is not made until adulthood, and infertility with azoospermia or severe oligozoospermia is a common presenting symptom. Klinefelter syndrome is the most commonly diagnosed cause of primary hypogonadism, even though the majority of men with Klinefelter syndrome (50% to 75%) are never diagnosed at all. The incidence is approximately 1 to 2 per 1000 live male births.

Infertility treatment usually consists of adoption, use of donor sperm, or possibly sperm harvesting with microscopic testicular sperm extraction together with in vitro fertilization and intracytoplasmic sperm injection.[43] Even in patients with Klinefelter syndrome with clinical testicular atrophy, modern assisted reproductive technology now offers a 40% to 60% rate of successful sperm recovery, with pregnancy achieved in 60% of cases.[44] Aside from fertility concerns, the usual treatment of Klinefelter syndrome in adults is full testosterone replacement therapy.[45][46][47][48] Please see StatPearls' companion reference, "Klinefelter Syndrome," for further information.

Prolactinoma

Prolactin levels in men usually are quite low. Elevated prolactin levels suggest a possible prolactin-secreting pituitary tumor. Such tumors may cause infertility, hypogonadism (low testosterone), gynecomastia, galactorrhea, and possibly a reduction of the peripheral visual fields due to compression of the optic chiasm. Prolactin levels greater than 150 µg/L suggest this condition, whereas levels greater than 300 µg/L are highly suggestive. MRI or CT of the sella should be obtained for confirmation.

Dopamine agonists, such as cabergoline and bromocriptine, are generally used as medical therapy to suppress prolactin secretion, and many men will then have normalized testosterone levels and sperm counts. Surgical treatment with a transsphenoidal resection of the prolactinoma is successful in 80% to 90% of cases, but the tumors often recur. A surgical procedure is usually reserved for patients with visual field loss and for those in whom medical therapy is unsuccessful or not well tolerated.[49] Please see StatPearls' companion reference, "Prolactinoma," for further information.

Testosterone Supplementation

Anabolic-androgenic steroid abuse and testosterone supplementation therapy are growing worldwide.[50] At least 25% or more of clinicians who prescribe testosterone to patients are unaware that it will cause significant, possibly long-term fertility and sterility problems in their patients.[51][52][53][54] Patients are often not informed of this likely complication.[55] Exogenous androgen causes infertility by suppressing follicle-stimulating hormone and luteinizing hormone production by the pituitary. The loss of follicle-stimulating hormone and luteinizing hormone shuts down endogenous intratesticular testosterone production and spermatogenesis.[51][52][56][57][58] Testosterone therapy can inhibit spermatogenesis in as few as 3.5 months.[59][60][61] 

Testosterone supplementation has no role in patients with male infertility who are trying to conceive.[62] Patients who need testosterone supplementation can preserve their fertility by taking clomiphene, which helps maintain follicle-stimulating hormone and luteinizing hormone levels.[63] Most patients who become infertile during testosterone therapy will eventually regain their sperm counts and fertility, but recovery will take time, and there are no guarantees. The best available data indicate that two-thirds of testosterone-treated men can expect the recovery of sperm production in 6 months, 90% after 1 year, and almost 100% after 2 years.[59] Please see StatPearls' companion reference, "Androgen Replacement," for further information.

Viral Mumps Orchitis

Mumps and several similar viruses constitute the most common cause of acquired testicular failure, and their incidence is increasing. This increase is probably due to reduced use of the measles, mumps, and rubella vaccine among children in the early 1990s. About one-quarter of the adults who get mumps will develop orchitis. Of these, one-third will have bilateral disease. The infection may cause damage directly to the seminiferous tubules or indirectly through compressive ischemia from severe intratesticular swelling, which is restricted by the very tough tunica albuginea.[64][65]

Testicular atrophy may occur 1 to 6 months after infection, and some shrinkage is apparent in about half of men with mumps orchitis. The degree of testicular atrophy is unrelated to the severity of the infection or the ultimate degree of possible infertility. One-quarter of adult patients with unilateral mumps orchitis will develop infertility, along with two-thirds of those with bilateral disease.[66][67] 

History and Physical

The purpose of evaluating the male partner of a couple suffering from infertility is as follows:

  1. To determine if the male factor is contributing to the couple's infertility issue
  2. To identify the small percentage of cases (about 20%) that can be normalized with treatment
  3. To determine if ART would ultimately benefit the couple 
  4. To identify significant underlying pathology or associated medical comorbidities
  5. To determine if there are age, health, lifestyle, or genetic factors that could affect the outcome or success rate if ART is required [5][68] 

Although an initial evaluation, such as a history and physical examination, can be performed by primary care clinicians with an initial semen analysis ordered, all men with infertility should generally undergo evaluation by a male reproductive specialist, especially if any abnormalities are found, because the workup and treatment are complex.[5][69] Patients who have previously received testosterone supplementation should also be referred directly to a specialist in male reproduction.

The evaluation starts with a complete and comprehensive sexual and medical history, including reproductive history; family history; history of significant trauma to the pelvis, testicles, or head; sexual performance; libido; occupation; systemic diseases; intake of alcohol; smoking; recreational drugs; medications; anabolic-androgenic corticosteroid use; previous chemotherapy or radiotherapy; pubertal development; testicular descent; surgical history involving the scrotum and inguinal regions; exposure to toxic chemicals such as pesticides; loss of body hair; shaving frequency; sexually transmitted infections; tuberculosis; mumps; scrotal infections such as epididymitis; prior biological children produced; maternal exposure to diethylstilbestrol; anosmia (associated with Kallmann syndrome); breast enlargement and galactorrhea; and precocious puberty (at age 9 years or earlier).[5]

An undescended testicle, whether unilateral or bilateral, can affect male fertility even when surgically repaired. Sickle cell disease can cause intratesticular ischemia. Chronic renal failure has been associated with hypogonadism, whereas liver failure sometimes causes gynecomastia (from increased estrogen levels), testicular atrophy, and reduced secondary sex characteristics. Tuberculosis, prostatitis, epididymitis, and sexually transmitted infections (especially gonorrhea) can cause vasal scarring and obstructive azoospermia, whereas Mycoplasma spp infections tend to reduce sperm motility.

The use of sexual lubricants that are toxic to sperm (such as water-based, water-soluble personal lubricants, saliva, and others) should be eliminated. Nontoxic options include egg whites, peanut oil, and vegetable oil. Petroleum jelly is not particularly spermatotoxic, but it is still not recommended due to its viscosity.

During the physical examination, clinicians should evaluate body habitus and assess for possible signs of endocrinopathy, gynecomastia, abnormal skin findings, abnormal hair distribution, and, in particular, secondary sexual characteristics. If the patient appears muscular and has a low sperm count, clinicians should order an endocrine screening panel (testosterone, follicle-stimulating hormone, and luteinizing hormone) because he could have a very low luteinizing hormone level, which would be suggestive of exogenous testosterone use. Please see StatPearls' companion reference, "Anabolic Steroid Use Disorder," for further information. Furthermore, obesity tends to increase the peripheral conversion of testosterone to estrogen. Higher estrogen levels decrease luteinizing hormone levels and have been associated with reduced sperm counts.[70] 

Examination of the penis should include assessment for hypospadias, phimosis, and Peyronie plaques. Testicular size should also be measured. In an average adult man, the testicular volume should be at least 15 mL, and the length of the testis should be at least 4 cm. If the testis measures less than 4 cm in its largest dimension, the testis is considered small. The presence or absence of the vas deferens on each side should be noted and documented. Bilateral absence of the vas deferens is reported in 1% to 2% of infertile men and is related to mutations of the cystic fibrosis transmembrane conductance regulator gene (CFTR), even without any clinical signs of cystic fibrosis.[71] Any clinical abnormalities of the testicles, such as epididymal lesions, spermatoceles, and large varicoceles, should be identified.[5] 

The presence of a hydrocele should be noted. If a hydrocele is present, testicular ultrasonography should be used to examine the testicle because an adequate direct physical examination is not otherwise possible.[5] Testosterone deficiency may cause various physical signs, depending on its severity and age at onset. Hypogonadism in early gestation results in atypical genitalia, whereas hypogonadism in late gestation causes micropenis. Hypogonadism in childhood causes delayed puberty, whereas adult-onset hypogonadism causes decreased libido, erectile dysfunction, decreased body hair, infertility, and loss of secondary sexual characteristics. Please see StatPearls' companion reference, "Male Hypogonadism," for further information.

A varicocele that is identifiable on physical examination might be clinically significant with regard to possible infertility. Varicoceles are the most common correctable cause of male infertility, so clinicians should carefully assess for their presence. These lesions are relatively easy to identify, even on a simple physical examination. Varicoceles are present in 15% of men, but among men with an abnormal semen analysis, the incidence increases to 40%.[72] Only clinically significant varicoceles are generally believed to impact male fertility.[5][73][74][75][76] When present, varicoceles are typically found on the left side of the scrotum due to anatomical reasons. Please see StatPearls' companion reference, "Varicoceles," for further information.

Isolated right-sided varicoceles have traditionally been thought to be suggestive of retroperitoneal pathology, such as a right-sided renal cell carcinoma with an obstructing tumor thrombus in the vena cava.[77][78][79] However, recent evidence indicates that the incidence of renal cell carcinoma in patients with right-sided varicoceles is no higher than in the general population, so routine abdominal imaging based solely on the presence of a varicocele of the right scrotum is no longer recommended.[5][80][81] However, imaging should be considered if the right-sided varicocele is nonreducible, newly acquired, or particularly large.[5][79][82][83] 

Bilateral absence of the vas deferens on physical examination accounts for about 1% to 2% of all male infertility cases and is associated with CFTR gene mutations.[84][85][86] In such cases, both partners should undergo genetic testing. If test results are positive, genetic counseling should be performed before any ART, in vitro fertilization (IVF), or intracytoplasmic sperm injection (ICSI). Furthermore, the presence of a buffalo hump (a pad of fatty tissue just below the neck and between the shoulders), along with a round (moon) face, thin skin with multiple bruises, and stretch marks, would be suggestive of Cushing disease, whereas patchy, diffuse hyperpigmentation might suggest iron overload syndrome.[5] Please see StatPearls' companion reference, "Hypercortisolism (Cushing Syndrome)," for further information. In general, if a patient has azoospermia with bilateral atrophic testes, a good outcome from treatment may be possible only with IVF and ICSI.

Evaluation

The semen analysis is the cornerstone of laboratory evaluation of male infertility. At least 2 separate samples should be collected, with a minimum interval of 1 week, ideally 1 month.[5] At least 3 days of abstinence should precede each specimen.[87] Repeat testing is recommended because semen analyses exhibit a high degree of variability.[88] The outcomes and prognosis of male infertility greatly depend on the semen analysis results as well as the female partner's fertility status, along with the categorization of whether fertility is primary or secondary.[89][90] Semen analyses greatly assist in identifying and classifying the severity of any male factors.[5][91]

The World Health Organization has published a detailed methodology for collecting semen. At-home sperm tests are now commercially available but are not recommended because their reliability is questionable, and they do not evaluate all recommended semen parameters.[91][92] Clear instructions for semen collection are essential. Semen can be collected by masturbation or using special condoms for collection, which do not contain any toxic substances.[93] The specimen is ideally collected at the laboratory but can be collected at home. If collected at home, the specimen should be kept at room temperature and delivered promptly to the laboratory, as it must be examined within 1 hour of collection.

The standards of the semen analysis quality control program are set by the Clinical Laboratory Improvement Amendments, and detailed information is available on their website. The semen is evaluated for volume, pH, leukocytes, immature germ cells, and liquefaction, while the sperm is assessed for count, concentration, vitality, motility, progression, debris, and morphology.[94] Either the WHO criteria for scoring sperm morphology or the Kruger-Tygerberg criteria should be used. The WHO lower reference limits were obtained from the fifth percentile of values among men whose partners became pregnant within 12 months.[91][95]

The Lower Reference Limits of a Semen Analysis

The following lower reference limits (with 95% confidence intervals) are adapted from WHO (2010):

  • Ejaculate volume: 1.5 mL (1.5-5 mL). If volume is low, retrograde ejaculation, anejaculation, ejaculatory duct obstruction, or hypogonadism are possible. Check postejaculation urine, transrectal ultrasonography, and hormonal analysis. If volume is high, suspect contamination.
  • pH: greater than 7.2.
  • Sperm concentration: 15 million/mL (12-16). The usual reference value is greater than 20 million/mL. If the concentration is low, check for a varicocele and consider a hormonal analysis.
  • Total sperm count: 39 million/ejaculate (33-46 million).
  • Sperm morphology: greater than 4% normal forms. The usual reference value is greater than 30%. 
  • Motility: 40% (38%-42%). The usual reference value is 60%. If motility is low, check for varicocele and consider an antisperm antibody test.
  • Vitality: 58% live (55%-63%). If vitality is low, check for varicocele and consider an antisperm antibody test.
  • Progressive motility: 32% (31%-34%).
  • Total motility: greater than 40%. The usual reference value is greater than 60%. If total motility is low, check for varicocele and consider an antisperm antibody test.
  • Forward progression: greater than 2.
  • Seminal fructose: greater than 13 µmol/ejaculate.
  • Liquefaction: 20 to 30 minutes.[91][96]

Optional investigations:

  • Immunobead test: fewer than 50% motile spermatozoa with bound beads
  • Mixed antiglobulin reaction test: fewer than 50% motile spermatozoa with bound particles
  • Seminal fructose: greater than or equal to 13 µmol/ejaculate
  • Seminal neutral glucosidase: less than or equal to 20 mU/ejaculate
  • Seminal zinc: greater than or equal to 2.4 µmol/ejaculatee [91][96][97][96] 

The Nomenclature Related to the Pathological Semen Quality

The following nomenclature is adapted from the World Health Organization Laboratory Manual for the Examination and Processing of human semen, WHO (2010): 

  • Aspermia: No semen in the ejaculate at all. May indicate the absence of seminal fluid production or blockage.
  • Asthenozoospermia: Fewer than 32% progressively motile spermatozoa. Absolute asthenozoospermia occurs when no sperm moves at all, but the sperm remain viable.
  • Azoospermia: No spermatozoa in the ejaculate.
  • Cryptozoospermia: Spermatozoa absent from fresh preparations but observed in a centrifuged pellet.
  • Leukospermia: Greater than 1 million white blood cells/mL ejaculate (also called pyospermia and leukocytospermia).
  • Necrospermia or necrozoospermia: Complete necrospermia occurs when all the sperm are dead on a fresh semen sample; necrospermia is incomplete if 5% to 45% are still viable.
  • Normospermia: All semen parameters are within the acceptable reference limits.
  • Oligozoospermia: Sperm concentration less than 15 million/mL; total sperm number less than 39 million/mL. Oligozoospermia is severe if sperm concentration is less than 5 million/mL and very severe if less than 1 million/mL.
  • Oligo-astheno-teratozoospermia: Disturbance of all 3 parameters.
  • Teratozoospermia: Fewer than 4% morphologically normal spermatozoa.[91][95][96]

Other Tests

Antisperm antibodies (ASA) should be suspected in patients with sperm agglutination or isolated asthenozoospermia with average sperm concentrations. These antibodies can form in men after testicular surgical procedures or vasectomy, in prostatitis, or anytime sperm comes into contact with blood. In women, the cause is an allergic response to sperm.

DNA integrity testing assesses the degree of sperm DNA fragmentation. The test should be done in those with recurrent miscarriages.[98]

Genetic screening and chromosomal testing may be indicated with azoospermia or severe oligozoospermia because chromosomal defects are more common in infertile men (up to 15%) than in men with normal fertility (about 0.6%).[99] The common genetic factors associated with male infertility are impaired testicular function due to chromosomal abnormalities, isolated spermatogenic impairment due to Y chromosome microdeletions, and congenital absence of the vas deferens due to a cystic fibrosis  (CFTR) mutation.[85][91] CFTR mutations have been linked to unilateral congenital absence of the vas deferens, ejaculatory duct obstruction, oligozoospermia, epididymal abnormalities, and seminal vesicle disorders, but traditionally, are most closely linked to bilateral congenital absence of the vas deferens.[85][100][101][102][103]

Klinefelter syndrome is the most common karyotype abnormality causing male infertility, but other abnormalities can also cause infertility.[104][91][105][106] Although ICSI has allowed many men with defective genes to father children, ICSI also increases the risk of transmission of various genetic defects to the progeny, and this risk should be carefully considered before proceeding. Therefore, genetic testing is typically recommended for patients with severe oligozoospermia (no more than 5 million sperm/mL with elevated follicle-stimulating hormone [FSH] levels or atrophic testes) or azoospermia, including karyotype, CFTR, and Y chromosome testing for microdeletions (sometimes called azoospermia factor [AZF] testing).[91][107] Microdeletions of the Y chromosome are present in an estimated 8% to 12% of men with nonobstructive azoospermia and about 3% to 7% of those with severe oligozoospermia.[91][107][108] In such cases where ART is used, preferential selection of female embryos may be reasonably recommended to avoid congenital infertility in future male children.[91][109]

Hormonal tests are indicated if a low sperm count and concentration are present or clinical findings are suggestive of an endocrine disorder or impaired sexual function. Many experts recommend hormonal laboratory testing for all men undergoing infertility evaluation. The endocrine laboratory test panel includes serum levels of FSH, testosterone, luteinizing hormone (LH), prolactin, and estradiol, with optional thyroid-stimulating hormone (TSH) levels. An elevated estradiol level or a testosterone to estradiol ratio less than 10 suggests a possible fertility benefit from an aromatase inhibitor to reduce the estrogen effect.

Cushing disease can be confirmed by a 24-hour urine test for free cortisol, a dexamethasone suppression test, or measurement of the midnight salivary cortisol concentration. Thyroid dysfunction can be identified by abnormal serum thyroid function test results, particularly an elevated TSH level. In general, elevated FSH levels indicate abnormalities in spermatogenesis. Although gonadotropin hormones are secreted in a pulsatile manner, a single test may be sufficient to assess the patient's endocrine status. Optional additional hormonal tests include sex hormone-binding globulin and free testosterone.

  • Low testosterone with high FSH and LH suggests primary hypergonadotropic hypogonadism, which would affect both sperm production (FSH) and testosterone levels (LH). A karyotype should be performed.
  • Low testosterone with normal or low FSH and LH indicates secondary hypogonadism. Check serum prolactin.
  • Normal testosterone and LH with a high FSH are suggestive of primary spermatogenic failure, especially if associated with azoospermia or severe oligozoospermia. (The normal LH indicates proper Leydig cell function, but the high FSH suggests damage to the seminiferous tubules.)
    • Check testicular size and consider karyotyping and Y-chromosome microdeletion testing.
    • A less severe form with mild oligozoospermia might indicate Sertoli cell dysfunction, leading to reduced inhibin production and elevated FSH levels.
  • Normal testosterone, LH, and FSH suggest the need for further evaluation depending on the semen analysis and physical findings.
    • If azoospermia is present (no sperm in the ejaculate) and normal testicle size, the pattern suggests obstructive azoospermia, which can potentially be treated surgically.
    • If associated with bilaterally absent vas deferens, this could indicate a CFTR gene mutation with or without clinical signs of cystic fibrosis. A family history of cystic fibrosis should be obtained, and both partners should be checked for CFTR gene mutations. 
  • High testosterone and LH, with normal FSH, would be consistent with partial androgen resistance.

Postcoital testing is suggested in cases of hyperviscosity of the semen, normal sperm density with increased or decreased semen volumes, and idiopathic or unexplained infertility. About 10% of all infertile couples will have an abnormal postcoital test. The test is done by examining the cervical mucus for viable sperm 8 hours after intercourse. Postcoital testing is optimally done 1 to 2 days before female ovulation when the cervical mucus is most abundant. Finding any viable sperm that are still motile suggests a normal sperm and vaginal mucus interaction and proper sexual technique for a potential pregnancy.

If the postcoital test results are normal, more specific sperm function tests can be done, such as:

  • Capacitation, acrosomal reaction, and sperm penetration assays: Used for cases where a sperm defect is suspected, such as cases where intrauterine insemination (IUI) has repeatedly been unsuccessful. In vitro fertilization with ICSI is the preferred treatment for men whose sperm show poor results on any of these tests.
  • Hypoosmotic swelling test: Live sperm tend to swell upon exposure to very dilute solutions, whereas dead sperm do not. Therefore, this test can differentiate between dead sperm and viable but nonmotile sperm for ICSI.
  • Inhibin B level: Acrosomal activity requires the presence of inhibin B. A high inhibin B level may be caused by seminiferous tubular disorders or ductal obstruction and can lead to sperm self-destruction.

Sperm vitality staining: Only live sperm can avoid staining by special dyes on a test slide. Although sperm vitality staining may be useful in discriminating between viable nonmotile sperm and dead sperm, the test is of limited clinical use because the sperm tested cannot be salvaged for ICSI. However, sperm vitality staining may help identify the presence of necrospermia.

Postejaculatory urinalysis is recommended with a semen volume less than 1.0 ml, because a postejaculatory analysis for sperm may be required to confirm retrograde ejaculation.[110] Any sperm collected during postejaculatory urinalysis can be used for IVF with ICSI.

Renal imaging is recommended when unilateral or bilateral absence of the vas deferens is present, given its association with kidney abnormalities, including agenesis.[5][103] The incidence of associated renal anomalies ranges from 10% up to 75%.[5][111][112][113][114][115] CFTR testing is also suggested, but renal imaging should be performed regardless of CFTR test results where one or both vas deferentia are absent.[5][91][103]

Scrotal ultrasonography is required to definitively identify pathologies such as spermatoceles, varicoceles, absence of the vas on physical examination, or the presence of any testicular masses. Scrotal ultrasonography may identify prostatic and ejaculatory duct cysts, but transrectal ultrasonography is usually preferred. Nonpalpable varicoceles detected only on scrotal ultrasonography are generally not considered clinically significant, and, by most experts and guidelines, subclinical cases are not usually recommended for varicocelectomy to improve fertility, though this remains somewhat controversial.[5][91]

American Urological Association guidelines do not recommend the routine use of scrotal ultrasound in male infertility; however, some experts recommend scrotal ultrasonography because the test is safe, painless, inexpensive, provides an accurate size measurement for the testes, and helps identify pathology not otherwise clinically detectable, such as small spermatoceles, subclinical varicoceles, and testicular cancers.[5][91] Although the incidence of testicular cancer in men with infertility is low at 0.5%, the incidence is still 100 times greater than the risk in the general population.[31] Results from reports showed that scrotal ultrasonography identified abnormalities in 38% of men with infertility. Of these, 30% had a varicocele, and 0.5% had testicular cancer.[116] 

Testicular biopsy may be indicated in some cases to exclude spermatogenic failure. Testicular biopsy is typically performed in men with suspected ductal obstruction who would generally present with azoospermia with normal hormonal screening test results and normal-sized testes. Vasography may be done at the same time as the biopsy. Sperm and testicular tissue may also be retrieved and frozen for ART when performing the biopsy, but care must be taken to avoid killing the sperm with preservatives. A discrepancy exists in the findings from the testicular biopsies between the 2 sides, so bilateral biopsies should be considered.

Transrectal ultrasound (TRUS) can identify ejaculatory duct obstruction where dilated ejaculatory ducts and seminal vesicles are seen.[117] While rare, it should be considered, along with a postejaculatory urinalysis, when the semen volume is low (< 1.5 mL), the pH is acidic, and in azoospermia when the vas deferentia are palpable with normal serum testosterone, as this is suggestive of ejaculatory duct obstruction.[5][91] 

Other signs suggestive of ejaculatory duct obstruction include:

  • Ejaculatory duct diameter greater than 2.3 mm
  • Dilation of the ampulla of the vas greater than 6 mm
  • Seminal vesicle anteroposterior diameter greater than 15 mm
  • Visible midline or paramedian ejaculatory duct cyst [91] 

Vasography is used to evaluate vasal patency and identify the precise location of any vasal obstruction. Vasography is most useful in men with azoospermia or severe oligozoospermia with mature sperm on testicular biopsy and at least 1 identifiable vas deferens. The procedure can be done simultaneously with a testicular biopsy, as a separate open procedure, or percutaneously. Normal saline (with or without blue dye) or radiological contrast is injected into either end of the vas deferens lumen. If the blue dye is seen in the urine, no distal vasal obstruction is present. Radiologic contrast and radiography can help identify the location of any proximal obstruction.

Summary of Semen Analysis Results with Suggested Treatment

Normospermia (normal semen analysis): Men with normal semen analyses will either have idiopathic male infertility or a partner with infertility. IVF with ICSI, an advanced form of assisted reproduction, should be considered in these cases.

Low motility (asthenozoospermia): Check for antisperm antibodies for severe, isolated asthenozoospermia (low motility), especially if associated with increased agglutination. Results from a meta-analysis of published studies suggested that L-carnitine and N-acetylcysteine can significantly improve sperm motility and morphology compared to placebo.[118] Additional treatment includes the use of condoms to minimize exposure, immunosuppressive corticosteroid therapy for both partners, and special processing of sperm for direct IUI and IVF. Low motility is often due to disorders or pathology of the epididymides or a structural defect of the sperm's flagellum.[119][120]

Low morphology (teratozoospermia): Not to be confused with leukocytes, large numbers of immature germ cells in semen suggest a problem with spermatogenesis. L-carnitine and N-acetylcysteine appear to be beneficial in improving isolated sperm morphology.[118] Further treatment would be ART, possibly IVF with ICSI. 

Low motility (asthenozoospermia) or abnormal morphology (teratozoospermia) with normal sperm count: Low motility and abnormal morphology are not considered significant contributors to infertility unless severe. Isolated low sperm motility alone does not appear to affect natural pregnancy rates unless severe.[121] In such cases, ART with ICSI can be used to treat infertility.

Low sperm count or concentration (oligozoospermia or < 15 million sperm/mL): Oligozoospermia is considered severe if sperm concentration is 5 million/mL or less and very severe if sperm concentration is 1 million/mL or less. Check hormone levels (testosterone, FSH, LH, and prolactin). Consider genetic testing if the sperm count is 1 million/mL or less.

Low testosterone with high FSH and LH suggests possible Klinefelter syndrome. Karyotyping is recommended because Klinefelter syndrome is likely, especially if testes are small and firm bilaterally. If the karyotyping results are normal, consider ART, possibly IVF with ICSI. If severe oligozoospermia (less than 1 million/mL) is found, consider Y chromosomal defects and microdeletions, which typically cause extremely low sperm counts and may occur in up to 20% of men with infertility.[122] Such genetic problems can be transmitted to the offspring by ART and IVF with ICSI. Other causes include postcancer chemotherapy and radiation therapy, bilateral testicular trauma or torsions, and significant testicular infections such as mumps.[123][124]

Low testosterone with low or normal FSH and low or normal LH suggests possible pituitary issues. Check thyroid function, 8 AM cortisol, and prolactin levels to identify hormonal problems and prolactinomas.

Normal testosterone and LH levels with high FSH suggest abnormal spermatogenesis, with seminiferous tubular damage but normal Leydig cell function.

Normal testosterone, LH, and FSH with normal testicular size should prompt evaluation for genital tract obstruction (especially if poor sperm motility is also present).[125] Congenital absence of the vas deferens can be detected on physical examination. The condition may be associated with an abnormally low semen pH. Congenital absence of the vas deferens can be verified with scrotal or transrectal ultrasonography.[84][126] The condition may also be associated with cystic fibrosis mutations and a solitary kidney. Genetic testing and renal ultrasonography can be diagnostic and confirmatory.[84][126] Ejaculatory duct obstruction can also be caused by sexually transmitted infections or postvasectomy status. Scrotal ultrasonography would typically show dilated seminal vesicles secondary to infections like chlamydia, gonorrhea, tuberculosis, or surgical vasectomy. Scrotal or transrectal ultrasonography in such cases shows dilated seminal vesicles.[127]

High testosterone with a high LH and normal FSH is suspicious for partial or total androgen resistance. These patients may also have gynecomastia with a variable presentation of male genitalia.[128]

Any testosterone level with a low LH in an athletic or very muscular man should prompt consideration for possible androgen use.[129]

Low sperm count, low motility, and low morphology (oligo-astheno-teratozoospermia): This pattern is the most common abnormal semen analysis encountered in male infertility evaluations. When mild, the pattern could indicate a stress pattern that might respond well to a varicocelectomy if a varicocele is present. When severe, infertility is highly likely. Treatment would be ART, possibly IVF with ICSI.[121] 

Very low sperm count (severe oligozoospermia) or no sperm (azoospermia): Check hormone levels and consider genetic testing. If the vasa deferentia are present bilaterally on physical examination and testicular volumes are normal, consider possible obstructive azoospermia. Obstructive azoospermia can usually be treated surgically with a vasovasostomy or vasoepididymostomy. However, even if the surgical procedure is unsuccessful, the condition can always be treated with ART because viable sperm are available directly from the testicle via biopsy using sperm extraction techniques. In the case of congenital bilateral absence of the vasa deferentia, ART with testicular sperm retrieval followed by IVF with ICSI is the only viable option. The absence of sperm in semen does not necessarily indicate a lack of sperm production. Even finding a few viable sperm using enhanced techniques may make ART possible.

About 10% to 18% of men with infertility who also have severe oligozoospermia (sperm concentration of 1 million/mL or less) have microdeletions of the Y chromosome.[130] Chromosomal testing should be done in these men but not if they have a sperm concentration greater than 5 million/mL because chromosomal microdeletions would be quite rare.[131] Microdeletions of the Y chromosome are one of the genetic disorders that can be transmitted to male children via ICSI.[132]

Low semen volume: Typically, low semen volume is due to poor or incomplete collection technique; however, the finding could also indicate retrograde ejaculation or an ejaculatory duct obstruction. A postejaculatory urinalysis to look for sperm should be performed. Retrograde ejaculation may be psychogenic or result from diabetes mellitus, multiple sclerosis, retroperitoneal lymph node dissection, spinal cord injury, transurethral resection of the prostate, or transverse myelitis.[133]

Low semen volume associated with low sperm concentrations might also indicate low serum testosterone. If associated with a low sperm count, the finding is suggestive of ejaculatory duct obstruction, which can be verified with scrotal or transrectal ultrasonography. Ejaculatory duct obstruction can be treated surgically, whereas retrograde ejaculation may respond to sympathomimetic medications. Low semen volume with azoospermia or an extremely low sperm count might be due to ejaculatory duct obstruction or congenital bilateral absence of the vasa deferentia, in which seminal vesicle development fails.[111]

Prolonged semen liquefaction time: Lengthy semen liquefaction does not necessarily indicate a fertility issue. This finding is one reason a second semen analysis is recommended because the next follow-up sample has a good chance of normal results. If prolonged liquefaction (greater than 30 min) persists, a postcoital test can help determine whether this finding is clinically significant. The main enzymes responsible for semen liquefaction are prostate-specific antigen, fibrinolysin, and plasminogen, which come primarily from the prostate and seminal vesicles. Normal liquefaction time is generally less than 30 minutes.

Causes of delayed semen liquefaction include prostate infections, seminal vesicle dysfunction, disorders of the bulbourethral glands, dehydration, improper specimen collection, ejaculatory duct obstruction, decreased prostatic production of proteolytic enzymes, and congenital absence of the vas. Other possible contributors to prolonged semen liquefaction time include smoking, high alcohol intake, poor diet, age, exposure to toxic chemicals, and the use of antihistamines and antidepressants. Of these, the most common are infection and dehydration, which are both of which are correctable. High white blood cell levels in the semen suggest infection and may warrant a trial of antibiotics.

Improper specimen collection can also cause an abnormal liquefaction test result. For example, the first third of the semen sample is primarily prostatic secretions, whereas the last third is mainly seminal vesicle fluids. If part of the specimen is lost or not collected, specimen loss will affect the test results. A low ejaculate volume is suggestive of improper specimen collection.

Nutritional supplements, including antioxidants such as vitamins C and E, folic acid, and zinc, may be beneficial in this condition. However, definitive evidence of efficacy in reducing overly long semen liquefaction times is lacking.[134] The standard recommended treatment for persistent, prolonged semen liquefaction time is sperm washing combined with intrauterine insemination.

Pyospermia or leukospermia (excessive white blood cells in the semen): Leukocytes are normally found in the semen. Levels greater than 1 million/mL in the semen are considered excessive and possibly indicative of infection. Excessive numbers of leukocytes in the semen could contribute to infertility by the release of free radicals from the neutrophils, resulting in oxidative damage to the sperm. Treating pyospermia with antibiotics or nonsteroidal anti-inflammatory drugs may be tempting. However, no clear data support treatment, and drug therapy has the potential for adverse effects on general health and fertility. Although some patients may have chronic prostatitis, specific organisms are rarely identified, and no clear benefit to fertility has been demonstrated by antibiotics or other treatments in controlled trials.[18][135][136][137]

Schistosoma haematobium: Schistosoma ova can appear in the semen during an evaluation for male infertility in men who have lived in or traveled to regions where the parasite is endemic, primarily in Southeast Asia and Africa. This finding is rare in the Western world, but laboratory personnel should nevertheless be able and prepared to identify the ova if present.[138] Schistosoma haematobium can affect the male urinary tract and lead to infertility.[138] Schistosoma haematobium has also been associated with a higher risk of both prostate cancer and HIV infection.[139][140] Any semen parameter may be affected. Testicular damage from Schistosoma is reported in about 35% of affected men, and the damage becomes permanent and irreversible once granulomas form.[141][142] Please see StatPearls' companion reference, "Schistosomiasis," for further information.

Male Infertility in Severe Renal Failure

Significant renal failure, especially end-stage kidney disease, dramatically reduces male fertility. However, patients on dialysis who are interested in treating their infertility are relatively uncommon. The causes of infertility in severe renal failure include hypogonadism, erectile dysfunction, and direct impairment of spermatogenesis with spermatotoxicity and late-stage maturational arrest, causing oligospermia or azoospermia.[143] Renal transplant helps some of these abnormal semen parameters normalize.[144] Leydig cell dysfunction is common, resulting in hypergonadotropic hypogonadism in more than 50% of men on dialysis.[143][144][145] Evidence also supports decreased anti-Müllerian hormone, indicating Sertoli cell dysfunction.[146]

The typical man with end-stage renal disease demonstrates oligoasthenozoospermia and decreased semen volume.[147] The decrease in sperm viability, motility, concentration, count, and normal morphology is roughly 50% in patients with end-stage renal disease compared to controls.[148] Testicular volume tends to shrink, and pathological examination of testis tissue shows increased fibrosis with decreased germ cell proliferation.[149] A trial of clomiphene should be considered in these patients because study results have shown that clomiphene increases FSH and LH through a central mechanism.[145][150] Many, however, will require ART, such as ICSI, to achieve a pregnancy.

Treatment / Management

No Treatment

When left untreated, some couples still achieve pregnancy. Results from studies showed that 23% of untreated couples conceive after 2 years, increasing to 33% after 4 years. Even among men with severe oligozoospermia (less than 2 million sperm/mL), 7.6% of untreated patients with male infertility are able to achieve pregnancy within 2 years.[151] 

Lifestyle Changes

Reasonable healthy lifestyle changes should be recommended or at least discussed with all patients with male infertility. Recommended changes include stopping smoking; limiting or eliminating alcohol intake; adopting a more nutritious diet; pursuing weight loss if the patient has obesity; increasing exercise; avoiding potentially toxic artificial lubricants during sexual activity; reducing stress; eliminating illegal and recreational drug use, such as marijuana; minimizing prescription drugs; avoiding exposure to pesticides and heavy metals, such as lead, mercury, boron, and cadmium; and eliminating any unnecessary chemical exposures.[152][153][154][155] Low body weight and obesity are also possible risk factors for male infertility.[156][157] Fish oil supplements have also been suggested to be helpful for male fertility, but evidence is insufficient to make a recommendation.[156](B2)

Clothing selection, such as boxers versus briefs, might play a role in male infertility due to possible alterations in scrotal temperature, with boxers being preferred, although the evidence is not compelling or definitive.[158] Although avoiding hot baths, saunas, and tight-fitting underwear has not been conclusively demonstrated to improve male fertility significantly, discussing these suggestions with patients is reasonable. The degree of influence from these factors remains unclear, but avoiding potentially spermatotoxic activities and adopting a healthier lifestyle may improve overall male fertility.[153](A1)

Oral Therapies: Antioxidants, Aromatase Inhibitors, Clomiphene, L-Carnitine, N-Acetylcysteine, Nutritional Supplements, and Tamoxifen

Clinicians often have difficulty recommending or discussing nontraditional or alternative treatments because the medical literature contains conflicting or contradictory data and often includes only low-quality studies supporting their use. Simple treatment options for the majority of men with proven male factor infertility are essentially limited to ejaculatory duct resections, vasectomy reversals, and varicocele repairs. However, clinicians should properly inform patients and their partners about optional, alternative therapies even when the available data are inadequate, incomplete, contradictory, or inconclusive.

The following therapies have all demonstrated some limited beneficial effects on sperm quality or male infertility in the medical literature. Although their use may be controversial, patients deserve the right to make an informed decision about their personal infertility treatment. The therapies are relatively inexpensive and may provide some psychological benefits. Enough reports describe a potential benefit to justify a clinical trial in patients with male infertility who cannot afford or are not otherwise candidates for other therapies.[159][160][161][162] A trial also allows the clinician to provide treatment while giving the couple more time for natural conception. Oral therapies are considered optional and categorized as antioxidant-based, nutrition-based, and hormonal. Oral therapies are considered optional and categorized as antioxidant-based, nutrition-based, and hormonal. (A1)

Antioxidants to reduce the effects of oxidative stress on semen and sperm would seem a reasonable male infertility therapy, but data on this is somewhat conflicting.[163] Results from a 3-year, multi-institutional study from 9 fertility centers that included 174 men with infertility using antioxidant therapy alone, without L-carnitine, showed no benefit in improving semen parameters or pregnancies during the 6 months the patients were monitored.[164] However, substantial evidence supports the use of antioxidants in male infertility.[155][161][165][166][167][168][169] (A1)

For example, results from a 2020 single-blinded study involving 50 men with idiopathic infertility and abnormal semen analyses (oligozoospermia and asthenozoospermia) showed that a proprietary daily antioxidant mixture of coenzyme Q10 (30 mg), zinc (8 mg), vitamins C (100 mg) and E (400 IU), folic acid (400 µg), and selenium (200 µg) taken for 3 months resulted in statistically significant improvements in sperm count, concentration, motility, progressive motility, and morphology, as well as better semen volume and pH.[170] Please see StatPearls' companion references, "Vitamin C (Ascorbic Acid),"  and "Vitamin E," for further information. Results from a similar trial comparing daily coenzyme Q10 (200 mg) with placebo in 114 men with infertility, evaluated for 26 weeks, showed statistically significant improvements in sperm motility, count, and strict morphology. Interestingly, the improved sperm parameters returned to pretreatment levels 12 weeks after coenzyme Q10 was discontinued. Pregnancy rates were not reported.[171] (A1)

Results from a randomized trial using just zinc and folic acid supplementation failed to show any significant benefit to male semen parameters or pregnancy rates.[172] Conversely, results from several meta-analyses suggested that vitamins C and E can significantly improve multiple semen parameters, including sperm counts, motility, concentration, and morphology.[173][174][175] The most-studied vitamins, minerals, and antioxidants used to treat male infertility include coenzyme Q10, folic acid, L-carnitine, lycopene, N-acetylcysteine, vitamin C, vitamin E, selenium, and zinc.[161][176] Each of these is discussed briefly below. An extensive systematic review of antioxidant supplementation in male infertility has been published elsewhere.[161][177](A1)

Coenzyme Q10 (CoQ10) appears to have a beneficial effect on sperm quality. CoQ10 reduces organic peroxides in semen, thereby decreasing oxidative stress in sperm cells.[178][179][180][181] CoQ10 reportedly improves sperm motility, morphology, and concentration.[171][179][180][181][182][183][184] The usual recommended dose is 300 mg daily. Please see StatPearls' companion reference, "Coenzyme Q10," for further information.(A1)

Folic acid, also known as vitamin B9, is a potent antioxidant and is intimately involved in numerous cellular functions, including cell division and the synthesis and repair of DNA and RNA.[185][186][187] Folic acid improves spermatogenesis by enhancing the methylation of DNA, limiting the activity of apoptotic genes in the testes, reducing reactive oxygen species through its antioxidant activity, and treating abnormal testicular methylenetetrahydrofolate reductase (an enzyme involved in DNA methylation).[185][188][189][190] Improvements in semen parameters, especially sperm motility, have been noted in patients receiving folic acid supplementation.[185][191][192] Folic acid is often used together with zinc supplementation.[185] The recommended daily dose of folic acid is 500 to 1000 µg.[192] Higher doses are not recommended and may actually decrease sperm quality by downregulating DNA methylation.[193](A1)

L-carnitine is an amino acid and antioxidant typically found at high concentrations in the epididymis and has long been suggested as a possible, nontoxic general therapy for male infertility.[173][194][195][196] L-carnitine is known to increase fatty acid transport into sperm mitochondria, which is needed for epididymal sperm energy production. This supplement also appears to increase sperm motility, morphology, and maturation while reducing apoptosis.[118][195][196][197][198] Results from a recent study of 180 men with idiopathic oligo-astheno-teratozoospermia (low sperm counts with decreased motility and poor morphology, a stress pattern) who received an L-carnitine supplement demonstrated significant improvements in sperm count, concentration, and morphology. However, motility was unaffected, and the study was insufficiently long to determine whether pregnancy rates were affected.[199][200] A daily dose of 3 g has been suggested.(A1)

Lycopene is a carotenoid antioxidant and the organic pigment that makes fruits and vegetables yellow, orange, or red. Lycopene is naturally found in carrots, pink watermelon, grapefruit, apricots, and especially tomatoes. Lycopene is a powerful antioxidant shown to increase male fertility and significantly improve semen parameters.[201] Sperm counts can increase by up to 70% and progressive motility by up to 54%, whereas morphology improves by up to 40% in various studies.[162][202][203][204][205][206] The recommended dosage of lycopene used as a supplement for male infertility is 6 mg daily.[205](A1)

N-acetylcysteine (NAC) is a dietary supplement and mucolytic agent sometimes used to treat overdoses of acetaminophen and paracetamol.[207] NAC is a thiol-based derivative of the amino acid L-cysteine and a precursor to glutathione peroxidase, with significant anti-inflammatory, mucolytic, and antioxidant properties.[207] When used in men with infertility, NAC therapy increases sperm counts, enhances motility, reduces abnormal morphology, decreases DNA fragmentation, improves acrosomal activity, and acts as an effective antioxidant in semen.[118][165][166][208][209][210] The usual dose is 600 to 1200 mg daily; no prescription is required. However, since NAC was previously available as a prescription medication, the US Food and Drug Administration (FDA) is reviewing its status as an over-the-counter dietary supplement. Please see StatPearls' companion reference, "N-Acetylcysteine," for further information.(A1)

Selenium, especially when used with N-acetylcysteine, appears to improve sperm concentration, motility, and morphology by enhancing enzymatic antioxidant activity.[161][211][212][213] Selenium is critical for the biosynthesis of testosterone and sperm production.[214] Selenium can also reverse the negative effects of heavy metal exposure on spermatogenesis and male fertility.[215] The recommended dosage when used as a supplement is 200 µg/d and is often used together with 400 IU of vitamin E. Please see StatPearls' companion reference, "Selenium," and "Vitamin E," for further information.[212][216](A1)

Vitamin C (ascorbic acid) is a potent antioxidant normally found in large amounts in the semen, which protects against DNA damage and may improve semen viscosity.[217][218][219] Supplemental vitamin C also appears to improve the hormonal profile of men with subfertility and their semen parameters.[220] Patients given vitamin C tended to have improved progressive motility, sperm counts, concentration, morphology, and pregnancy rates.[174] Vitamin C supplementation for male infertility is often given with 400 IU of vitamin E daily.[173][174][175] The suggested dosage of supplemental vitamin C is 500 to 1000 mg daily. Please see StatPearls' companion reference, "Vitamin C," for further information.[221][218](A1)

Vitamin D supplementation may help with sperm motility.[222][223][224] Evidence also suggests that men with unexplained infertility and low vitamin D levels may have increased sperm DNA damage.[222][225] Please see StatPearls' companion reference, "Vitamin D," for further information.(A1)

Zinc is the most abundant metal in the human body after iron. According to the WHO, over 17% of the global population is zinc deficient.[226] Zinc is important for sperm maturation and testicular development, protecting spermatozoa from damage by oxidized thiols, improving sperm function, and maintaining fertilization capacity.[161][227][228][229] Zinc is often given alongside folate, which seems to improve results.[230] Seminal zinc levels appear important in maintaining sperm counts, but excessive levels can adversely affect motility.[231] The best results were found when zinc was used together with folic acid.[185] Zinc also appears able to reverse damage from heavy metal exposure.[215] The suggested daily dosage of supplemental zinc is 200 mg (25-400 mg). Zinc sulfate 220 mg contains only 50 mg of elemental zinc. Please see StatPearls' companion reference, "Zinc," for further information.(A1)

Hormonal therapies considered optional include aromatase inhibitors, clomiphene, and tamoxifen, which are discussed briefly below. Results from studies showed that aromatase inhibitors can improve semen parameters but have not been conclusively proven to improve pregnancy rates, because most of the available studies are either case reports, anecdotal, or of low quality.[232] Results from a recent review and meta-analysis of aromatase inhibitors for male infertility suggested that these drugs can statistically improve abnormal semen and hormonal parameters, and they appear to be safe.[233] Aromatase inhibitors are most useful when testosterone levels are normal, but estradiol levels are relatively high. Additionally, aromatase inhibitors can be used together with clomiphene, which is recommended.(A1)

Both the steroid-based (testolactone) and nonsteroidal (anastrozole and letrozole) drugs appear to have equivalent efficacy. However, recommending an aromatase inhibitor is difficult without adequate prospective, randomized, placebo-controlled multicenter trials to definitively determine its efficacy and optimal dosage.[232][233][234] Anastrozole and letrozole are inexpensive and have minimal adverse effects. The recommended dose of anastrozole for male infertility is 1 mg 3 times weekly, whereas the dose for letrozole is 2.5 mg 3 times weekly. The most common adverse effects of these medications are joint pain and stiffness. Only 1 of these medications is required. Please see StatPearls' companion reference, "Aromatase Inhibitors" for further information.(A1)

Clomiphene is an antiestrogen and, in small doses (25 mg every other day up to 50 mg daily, with 25 mg daily most commonly recommended), can increase gonadotropin levels (FSH and LH) and stimulate spermatogenesis, making clomiphene potentially useful in idiopathic male infertility. Clomiphene works by inhibiting the negative feedback of estradiol on the hypothalamus, which results in greater LH release, leading to higher testosterone levels but also higher estradiol levels. Most patients will notice an improvement in semen analyses in 3 months, but some will need 6 months or longer.[150][235] This benefit can be increased by adding tamoxifen (10 mg twice daily), which also acts as an estrogen receptor antagonist.[159][236][237] Clomiphene is also possibly helpful in hypogonadotropic hypogonadism, although there is limited data showing any significant improvement in pregnancy rates.[160][238] See the companion StatPearls reference article on "Clomiphene," for further information.(A1)

Tamoxifen is a selective estrogen receptor modulator (SERM) that competes with the hormone for binding sites, acting as a competitive inhibitor, and is most often used in estrogen-receptor-positive breast cancer. Please see StatPearls' companion reference, "Tamoxifen," for further information. By selectively blocking hypothalamic estrogen receptors, tamoxifen stimulates gonadotropin-releasing hormone secretion, greatly increasing FSH and LH levels and ultimately promoting spermatogenesis.[236][239][240] Tamoxifen is best used for idiopathic oligospermia because this medication tends to be most effective in boosting sperm count and concentration.[159][236][237][240] Motility, viability, and morphology may also improve, but generally not to the same degree.[236][237][240] (A1)

In a trial, 68 men with infertility were treated with either a placebo, folate, tamoxifen, or a combination of folate and tamoxifen for 3 months. Sperm concentrations and counts were improved by tamoxifen therapy, whereas adding folate 5 mg daily increased motility, suggesting the 2 supplements are complementary when used together.[192] The recommended dose of tamoxifen is 10 to 20 mg twice a day. See the companion StatPearls reference article on "Tamoxifen" for further information. (B2)

Overview of Oral Therapies for Male Infertility 

Overall, high-quality data are insufficient to definitively support the recommendation of any of these nutritional or antioxidant therapies. Most studies are low-quality, small, short-term, do not assess actual pregnancy rates, lack an adequate control group, and few show consistent benefits.[241] Even when semen parameters and sperm quality improve, the pregnancy rate may not change.[242] Further, too many nutraceuticals and antioxidants or the wrong combination may actually impede essential oxidative mechanisms or increase reductive stress, resulting in poor sperm function with reduced fertility.[243][244](B3)

Findings fro conflicting studies also show little to no benefit, although the majority generally support the use of supplements for idiopathic male infertility.[161] The optimal composition and dosages of the supplements have not been determined, and environmental factors have largely been excluded, making definitive conclusions difficult.[161] For all of these reasons, the European and American guidelines do not currently recommend supplements to treat male infertility.[161][245]  A large variety of male fertility supplements are commercially available and marketed directly to the consumer (patient), even though the majority have never undergone a clinical trial.[245] Where studies have been done, they are generally of poor quality.[245] (A1)

Although data are insufficient to formally recommend antioxidant and nutritional therapy for mild to moderate male factor infertility, a trial may not be unreasonable in selected couples. The approach is inexpensive, and adverse events are minimal to nonexistent. A trial also buys the couple time to consider more costly options and provides psychological reassurance that their problem is being treated rather than ignored. A pregnancy may develop naturally in the interim. Every clinician must decide individually whether to offer any of these tempting yet largely unproven remedies. Few clinicians can deny a simple, harmless, inexpensive potential therapy to a desperate couple, even if its actual clinical efficacy is currently unclear.[164][194][246][247][248][249] (A1)

Couples should be informed that published guidelines do not recommend the use of supplements, nutraceuticals, or vitamins for male infertility, as existing studies are generally inadequate to definitively prove efficacy.[245][250] Further randomized controlled studies with larger sample sizes are needed to definitively determine the value of antioxidant and nutraceutical therapy in male infertility, as well as the optimal ingredients and dosages, because most reported trials are of low quality, are conflicting, or otherwise inadequate.[161][162][163][245][251][252] Researchers should collaborate to increase the sample size to minimize uncontrollable variation, select the most promising agents and dosages, use strict randomization protocols, and follow patients long enough to evaluate outcomes and endpoints, including live births.[253] An additional benefit would be identifying patient subsets that would benefit from a particular nutraceutical or antioxidant therapy.[245][253](A1)

Gonadotropic Therapy

The use of gonadotropin therapy in most men with idiopathic infertility is controversial. Results from a meta-analysis of 6 randomized trials of gonadotropic therapy in patients with male infertility reported higher pregnancy rates than the placebo group. However, the overall quality of these studies was low, with highly variable treatment protocols and follow-up periods.[254] (B3)

FSH stimulates Sertoli cell activity and sperm production, but when used alone as a therapy for male factor infertility, it appears to have only a limited benefit on sperm production.[255] Results are better when gonadotropins are used to correct specific pituitary and hypothalamic disorders. Successful gonadotropin therapy typically consists of some combination of human chorionic gonadotropin (hCG), LH, FSH, gonadotropin-releasing hormone, and human menopausal gonadotropin. Human chorionic gonadotropin acts similarly to LH but is cheaper and has a longer half-life. Human menopausal gonadotropin contains both FSH and LH and works similarly to gonadotropin-releasing hormone (GnRH).(A1)

For men with infertility and idiopathic hypogonadotropic hypogonadism, the first step is usually to stop any exogenous testosterone supplementation. Although exogenous testosterone supplementation is often used in symptomatic hypogonadal men, this therapy only worsens semen parameters and exacerbates their infertility by reducing FSH and LH.[256][257][258][259] Various combinations of hCG, FSH, GnRH, and hMG have been successfully used to treat male infertility in men with idiopathic hypogonadotropic hypogonadism. Spermatogenesis has been stimulated in only about 20% of cases treated with hCG and pulsatile GnRH, but adding human FSH appears effective in normalizing fertility.[260] Results from one study showed that combination therapy with hCG and FSH for 1 to 2 years increased testicular size in almost every patient, improved spermatogenesis in about 80% of men, and increased pregnancy rates to about 50%.[259][261][262] Referral to a reproductive endocrinologist is suggested for such patients.

Patients who previously used testosterone supplementation can benefit from gonadotropic therapy.[91][263] Testosterone therapy, even when used correctly for verified medical disorders, will suppress spermatogenesis.[91][264] This effect can be minimized by the simultaneous use of clomiphene, hCG alone, or a combination of hCG with selective estrogen receptor modulators (SERMs, such as tamoxifen) or FSH.[91][265][266][267] In some men with hypogonadism, testosterone therapy can be eliminated entirely, and clomiphene can be used alone to boost natural testosterone production without limiting spermatogenesis.[268](A1)

Normal spermatogenesis and fertility will eventually recover in most patients with hypogonadism who have previously used testosterone supplementation therapy, but it can take up to 2 years.[59] The average recovery of motile sperm count is about 85% of the level before testosterone supplementation.[269] Older patients, those who used testosterone therapy longer, and men with lower sperm counts before androgen replacement will not recover their fertility as quickly or to the same degree.[263][270] Medications to promote more rapid recovery of spermatogenesis are suggested in cases where recovery is prolonged or delayed, in older patients, in patients with azoospermia, and in patients with prolonged testosterone use (longer than 1 year).[271][272] (A1)

Medications used include hCG, which acts as an analog of LH to stimulate natural endogenous testosterone production from the testes, plus either FSH or a SERM to increase FSH production. No standardized dosage or schedule exists. Optimal dosing of hCG has not been definitively determined. However, hCG has been administered by intramuscular injection at doses of 3000 to 10,000 IU 2 to 3 times weekly, along with anastrozole, clomiphene, tamoxifen, or FSH, which is typically administered concomitantly.[263][273][274][275][276][277][278] (A1)

SERMs work by inhibiting negative feedback by estrogen, which then raises GnRH and gonadotropin levels, increasing testicular production of testosterone and spermatogenesis.[56][263][273] Although definitive comparative studies are not available, some findings suggest that clomiphene may be more effective than tamoxifen in promoting sperm recovery (70% vs 30%).[56] The dosage of clomiphene ranges from 25 mg every other day up to 50 mg daily. Please see StatPearls' companion reference, "Clomifene," for further information.

Sexual Disorders

Sexual intercourse during the most fertile period should occur at least twice weekly. Erectile dysfunction should be treated appropriately, and retrograde ejaculation generally responds to oral sympathomimetic drugs, although few data describe its ultimate effectiveness in producing pregnancy in couples with infertility.[279][280] Please see StatPearls' companion reference, "Erectile Dysfunction," for further information. Premature ejaculation is highly treatable with a combination of behavioral, psychological (sex therapy), and pharmacological interventions. Please see StatPearls' companion reference, "Premature Ejaculation," for further information.(A1)

Ejaculatory Duct Cyst Puncture or Resection

Midline prostatic and ejaculatory duct cysts are present in about 5% of all men with infertility.[281][282] The presence of such cysts should be suspected in men with low ejaculate volume, azoospermia or severe oligozoospermia, normal hormonal screening, normal secondary sexual characteristics, and dilated seminal vesicles or vas deferens on TRUS examinations.[283][284] To be clinically significant, cysts are typically identified as having a size greater than 0.017 mL and are typically identified with TRUS.(B3)

The cysts can be treated either with transurethral resection or with cyst puncture and aspiration under TRUS guidance.[285] Transurethral resection is considered the most definitive therapy for this condition. Improvement in semen analysis is generally seen in about 50% of treated men with infertility, and about half of these will eventually produce a pregnancy.[283][284][286](B3)

Varicocelectomy

Varicocele repairs are generally only recommended in men with infertility and abnormal semen parameters who have large, clinical grade 3 varicoceles.[250] Clinical grade 3 varicoceles are clinically apparent on physical examination. Varicocele repair is also reasonable if the varicocele is causing symptoms with or without infertility. According to most experts and published guidelines, men with infertility and small varicoceles that are not palpable on physical examination (typically with varicose vein diameters less than 3 mm) are not likely to benefit from varicocelectomy, but this issue is somewhat controversial.[76][250][287][288] (A1)

Overall, varicocelectomy is expected to ultimately improve semen parameters in at least 60% to 70% of patients with clinically significant varicoceles. Results from a recent, comprehensive meta-analysis demonstrated that all significant standard sperm characteristics in men with infertility and significant varicoceles improved after varicocele repair.[289] Although data support an improved pregnancy rate in men after varicocele repair, the evidence is somewhat conflicting.[73][290][291] (A1)

Varicocele repair is not recommended in men with extremely low sperm counts (severe oligozoospermia or azoospermia) or high FSH concentrations with bilateral small testes because these features suggest extensive testicular germ cell damage, making fertility potential unlikely to improve.[250] Varicocelectomy may reduce the need for more aggressive procedures later, even if the repair is unsuccessful, such as use of intrauterine insemination instead of in vitro fertilization.[250] 

In appropriately selected men, varicocelectomy surgery is far more cost-effective than assisted reproductive procedures.[292] Varicocelectomy may reduce the need for more aggressive surgeries later, even if they fail, such as being able to use intrauterine insemination instead of in vitro fertilization.[91][292][293][294] Results from recent studies suggest that subclinical varicoceles may affect semen characteristics, depending on testicular size and intratesticular hemodynamics rather than on varicocele size, palpability, or vein diameter.[199][287][295][296] Among men with subclinical varicoceles, those with infertility were more likely to have bilateral disease, lower average testicular volumes, and higher resistive and pulsatility indices, as well as increased peak retrograde flow rates, higher average scrotal temperatures, and lower end-diastolic and peak systolic velocities.[199][287][295][296](A1)

A high resistive index and lower end-diastolic and peak systolic velocities would suggest decreased intratesticular vascular flow, which may be more significant than clinical varicocele size alone. If these findings are confirmed, testicular volume measurements and ultrasonographic assessments of intratesticular hemodynamics may ultimately be better predictors of improved sperm parameters and fertility following varicocele repair in men with infertility than the simple identification of a clinically significant varicocele on physical examination. Surgical decisions regarding subclinical varicoceles become far more complex when the patient is still an adolescent. A careful review of the latest data and an honest, comprehensive discussion of the pros and cons of the surgical procedure with the patient and family remain the best way to help men and their families make these difficult decisions.

Transurethral Resection of the Ejaculatory Ducts

Patients with ejaculatory duct obstructions, usually found on transrectal ultrasonography, are likely to benefit from transurethral resection of the ejaculatory ducts. Transurethral resection is done by resection of the verumontanum but must be done carefully to avoid injury to the external sphincter. Elevation of the distal prostatic urethra with a digit, using an O'Connor drape, may help ensure a safe procedure. Afterward, patients may develop epididymitis from reflux.

Vasovasostomy and Vasoepididymostomy

Vasovasostomy and vasoepididymostomy are advanced microsurgical procedures performed on men with obstructive azoospermia due to bilateral epididymal or vasal obstruction. Obstruction may be obvious in a patient who had a bilateral vasectomy procedure, but in others, obstructive azoospermia is suggested by the finding of no sperm in the semen, together with normal testicular size and hormone levels. The use of surgical microscopes has dramatically increased the success rates of these procedures. Improved fertility rates occur with vasovasostomy compared to vasoepididymostomy, with a shorter interval from the original obstructive procedure or injury, sperm present at the time of vasovasostomy (especially bilaterally), and a surgical rather than infectious cause of the original obstruction.

Even after successful surgical procedures, some men will remain infertile due to their development of an exaggerated immune response to the sperm granulomas that form on the proximal side of a vasectomy.[297] Men with increased FSH levels may require additional ART to achieve a pregnancy even after successful surgical procedures.[298] Varicocele repairs and vasovasostomies should never be performed simultaneously due to the risk of testicular vascular compromise, which can cause atrophy. Robotic-assisted vasovasostomy can be done in selected cases with similar overall pregnancy rates of about 60%.[299][300](B2)

Intrauterine Insemination 

Intrauterine insemination (IUI) is a form of assisted reproduction where semen and sperm are collected from the male partner or a donor and artificially instilled into the fertile female uterus. IUI is most useful when the postcoital test shows no sperm but may also be used in cases of idiopathic infertility or when significant abnormal sperm parameters are present, but some normal spermatozoa remain. IUI avoids potential vaginal allergic responses and toxic cervical mucus. The overall pregnancy success rate is only 4% if used alone. However, when combined with female superovulation (produced by aromatase inhibitors, clomiphene, and gonadotropins), the success rate increases up to 17% per attempt. The overall success rate is about 12% per attempt, which decreases with additional attempts. Pregnancy rates increase about 40% to 50% after 9 attempts.

In most cases of unexplained or mild male factor infertility, 3 to 4 attempts are often recommended before resorting to IVF.[301] Reasonable pregnancy rates can be expected in women up to age 40 with this technique if their male partner has a total viable sperm count of at least 5 million. Women aged 38 and 39 years of age respond well only if their partner's total sperm counts are over 5 million. In contrast, after age 40, even higher total sperm counts of up to 10 million do not appear to substantially improve the pregnancy rate, and IVF should be performed.[302]

Intrauterine insemination techniques should not be used when the sperm are dead, as determined by hypoosmotic swelling test or sperm vitality staining results. Abnormal functional sperm tests, such as capacitation, acrosomal reaction, and sperm penetration assays, would suggest that IVF with ICSI should be used instead. Semen can be processed in various ways to isolate only high-motility sperm with normal morphology. The semen is washed to remove dead cells, leaving healthy sperm, which are concentrated for the insemination. If the man has a low semen volume, several specimens can be combined and then injected into the female partner's uterus at the optimal time.

A total motile sperm count of at least 1 million is needed for successful intrauterine insemination. The formula is:

Total Motile Sperm Count = Sperm Concentration (million/mL) × Sperm Motility (%) × Semen Volume (mL),

Although IUI is less reliable than ICSI, IUI is far less expensive, so the procedure can be easily repeated and may be optimal where no female factor is present, and the male's semen and sperm count and quality are acceptable.[303][304][305](B2)

In Vitro Fertilization and Intracytoplasmic Sperm Injection

In vitro fertilization can be used in couples when IUI with ovarian stimulation has failed, in women over 40 years of age, or when there are known conditions precluding the use of simpler techniques, such as bilateral tubal disorders.[301] In vitro fertilization involves fertilizing an egg outside the woman's body. About 100,000 sperm are added to each egg in a special medium. The source of sperm used for ICSI does not appear to affect outcomes, whether sperm are obtained from ejaculated semen or direct microdissection testicular sperm extraction (TESE), because no significant variation has been reported in miscarriages or live birth rates.[306] A minimum of 50,000 to 500,000 motile sperm are generally required for IVF; otherwise, ICSI will be necessary.

Direct microdissection TESE is the preferred method of sperm retrieval for ICSI.[91][250][307][308] Microdissection TESE is 50% more successful in retrieving sperm than other sperm extraction procedures that do not use microsurgical techniques.[91][307] Both fresh and cryopreserved sperm may be used as they produce equivalent results.[91][250][309] A small risk exists of testosterone deficiency after microsurgical TESE, but the risk is less than with conventional TESE.[91][310](A1)

In men with nonobstructive azoospermia, spermatozoa extraction may be performed in advance of IVF or simultaneously.[91] The advantage of having sperm retrieval performed earlier is that it spares the female partner from unnecessary IVF procedures if no viable sperm are found. Simultaneous sperm retrieval permits immediate use of whatever viable sperm are found and avoids any possible sperm damage from freezing and subsequent thawing. Patients with retrograde ejaculation may require sympathomimetic medications, urinary alkalinization, urethral catheterization, induced ejaculation techniques, or TESE for sperm acquisition.[250] Sperm retrieval techniques for men with aspermia include induced ejaculation (sympathomimetic stimulation, vibratory effects, or electroejaculation), and surgical sperm extraction with TESE.[250]

Usually, about 12 eggs are retrieved per cycle. After 2 days, the embryos from successfully fertilized eggs are at the 3- to 8-cell stage. Two to 4 embryos are implanted into the female partner, and the remaining embryos are frozen. Pregnancy rates are reported at 10% to 45% but average about a 37% live birth rate per IVF cycle.[91] The ultimate ART currently available, ICSI, is similar to the IVF described above but involves the use of a microscope and micropipette to inject a single sperm taken from the male partner directly into an egg from the female partner that has been surgically extracted. The fertilized eggs are implanted in the female partner's uterus. The overall fertilization rate of ICSI is about 60%, with an initial pregnancy rate of about 20% to 30% per cycle.[311] The pregnancy rate increases by up to 45% for multiple cycles.[311] Multiple fetuses occur in about 30% to 40% of all pregnancies produced by IVF with ICSI.[312] Please see StatPearls' companion reference, "Assisted Reproductive Technology (ART) Techniques," for further information.(A1)

Overall, IVF with ICSI is preferred when there are very significant male factors that cannot be overcome by other means, but at least a few viable sperm can still be retrieved, or when all other treatments have failed. The only contraindications to the procedure in men are the absence of retrievable, viable sperm and necrospermia, which, fortunately, is quite rare. Where ART has consistently failed, further evaluation of male sperm (karyotype, zeta potential [sperm cell surface charge], and sperm DNA fragmentation) may be helpful.[91][313][314][315][316][317][318][319][320][321][322][323] Please see StatPearls' companion references, "Assisted Reproduction Technology," and "In-Vitro Fertilization," for further information.(A1)

Artificial intelligence applications that use neural networks, deep learning techniques, and advanced machine learning capabilities are beginning to be used in male reproductive medicine, where these tools can provide consistency in diagnosis and treatment. Artificial intelligence applications have already been used for clinical decision-making assistance and infertility research, as well as to support clinical treatment, improve the selection of individual spermatozoa, oocytes, and embryos, and predict outcomes.[324][325] The integration and implementation of improved artificial intelligence systems are expected to reshape the entire field of male reproductive medicine.[324]

Differential Diagnosis

Multiple conditions and disorders can cause or contribute to male infertility. The differential diagnosis of male infertility includes the following:

  • Adult growth hormone deficiency 
  • 5α-reductase deficiency
  • Androgen receptor gene polymorphisms
  • Bilateral testicular torsion
  • Bilateral vasectomy
  • Brain damage from tumors or trauma
  • Celiac disease (associated with androgen resistance)
  • Chemotherapy (especially alkylating agents such as cyclophosphamide)
  • Chromosomal abnormalities (Y chromosome microdeletions in azoospermic regions AZFa, AZFb, and AZFc)
  • Congenital adrenal hyperplasia (21-hydroxylase deficiency)
  • Cryptorchidism
  • Cushing disease
  • Cystic fibrosis
  • Down syndrome
  • Drug use (even commonly prescribed medications such as cimetidine, spironolactone, tetracycline, nitrofurantoin, sulfasalazine, and calcium channel blockers)
  • Ejaculatory duct obstruction
  • Estrogen excess
  • FSH abnormalities 
  • FSH receptor gene mutation
  • Hemochromatosis 
  • HIV infection (causes low sperm motility) 
  • Hodgkin lymphoma (due to the need for extensive chemotherapy)
  • Human β-defensin abnormalities
  • Hypogonadism
  • Hypogonadotropic hypogonadism
  • Hypopituitarism 
  • Immotile cilia syndrome
  • Kallmann syndrome
  • Kartagener syndrome
  • Klinefelter syndrome
  • Lead exposure
  • Leprosy
  • Liver failure
  • Luteinizing hormone deficiency 
  • Marijuana-associated disorders
  • Mixed gonadal dysgenesis
  • Mumps
  • Myotonic dystrophy
  • Noonan syndrome (male Turner syndrome) 
  • Obesity
  • Opioid use disorder
  • Pesticide, fungicide, and chemical exposure
  • Pituitary adenomas, prolactinomas
  • Primary hypogonadism 
  • Prostate and pelvic surgical procedures
  • Radiation exposure (Sertoli and sperm cells are much more sensitive than Leydig cells)
  • Recurrent urinary tract infections  
  • Reifenstein syndrome (partial androgen insensitivity)
  • Renal failure
  • Sarcoidosis
  • Seminomatous and nonseminomatous germ cell testicular tumors 
  • Sertoli cell-only syndrome (azoospermia with high FSH levels. Testis biopsy needed for diagnosis.)
  • Sickle cell anemia (due to intratesticular ischemia)
  • Smoking
  • Spinal cord injury
  • Sex reversal syndrome
  • Sexually transmitted infections
  • Testicular cancers 
  • Testicular torsion
  • Testicular trauma
  • Testosterone supplementation
  • Thalassemia
  • Thyroid disorders
  • Tuberculosis 
  • Urethral infection, stricture, or trauma 
  • Varicoceles
  • Young syndrome

Prognosis

The prognosis of male infertility is individualized and depends on the cause. An appropriate workup should be done based on clinical need. Clinicians should pursue such investigations after a frank discussion with the patient, as the evaluation carries financial and psychological implications. Following an appropriate workup, reasonably selected treatments, counseling, surgical procedures, or assisted reproductive technology can be offered to the couple. As the male partner ages, the incidence of sperm aneuploidy, chromosomal structural abnormalities, fragmentation of spermatic DNA, and congenital disabilities in the resultant offspring increases, independent of other factors.[5]

Complications

Complications are typically due to psychological distress, stress, and issues with the marital relationship. Financial concerns may also occur. Evaluation and treatment of infertility can be expensive in the US and frustrating because success is not guaranteed, and insurance does not typically cover this condition. Complications related to any required surgical procedures may also occur.

Consultations

Clinicians treating infertile couples should be prepared to refer patients for genetic counseling, reproductive endocrinology, and assisted reproductive services such as IUI, IVF, and ICSI, as needed. Couples with infertility will need support and reassurance. Infertility can be a stressful and challenging time for them, especially if family pressure to conceive is present, which can be quite intense in some cultures. Counseling may be needed because infertility is frequently associated with psychological distress, sometimes severe. Counseling is particularly important if genetic abnormalities are found.

Deterrence and Patient Education

Deterrence and patient education play crucial roles in addressing male infertility. Educating patients about modifiable risk factors, such as lifestyle choices and environmental exposures, serves as a preventive measure to deter the development of fertility issues. Healthy lifestyle changes and practices are generally helpful in optimizing fertility. Patients are encouraged to stop smoking, eliminate cannabis use, reduce weight, and stop drinking excess alcohol. According to the Centers for Disease Control and Prevention, no evidence indicates that any vaccines cause or contribute to infertility in either men or women, including COVID-19 vaccines.

Promoting awareness of the significance of timely fertility evaluations encourages men to seek early medical intervention. Additionally, patient education aids in dispelling misconceptions and reducing the stigma associated with male infertility, fostering a proactive approach to seeking medical assistance. By empowering individuals with knowledge, clinicians help deter avoidable causes while promoting proactive healthcare-seeking behaviors, ultimately enhancing reproductive health outcomes for men and couples.

Pearls and Other Issues

Key facts to keep in mind regarding male infertility include the following:

  • Clinicians should examine men for suspected urogenital abnormalities when the couple is diagnosed with fertility problems, particularly when semen analysis results are abnormal.A hormonal screening panel (testosterone, FSH, TSH, LH, estradiol, and prolactin) is necessary whenever abnormal semen analysis results are present in a patient with male infertility.
  • A minimum of 2 semen analyses, optimally 1 month apart, is recommended before making any conclusions regarding male infertility or semen or sperm quality.
  • Both partners must be examined to correctly identify all the causes and contributing factors of their infertility.
  • Men with normal hormonal levels (or isolated FSH elevation) together with very low sperm concentrations (less than 5 million/mL) should be checked for Y chromosomal defects.Infertile men with low testosterone levels may be treated with hCG, estrogen receptor modulators (tamoxifen, clomiphene, or raloxifene), aromatase inhibitors, or a combination of these.
  • Nasal testosterone gel is a testosterone replacement supplement that appears to uniquely have minimal effect on semen parameters, unlike virtually all other forms of testosterone replacement therapy.[326][327] 
  • The nasal testosterone gel is applied at a very low dose, 2 or 3 times daily. Unlike clomiphene, estradiol levels remain normal, and there may be increased libido compared to hypogonadal men taking clomiphene to boost their testosterone levels.[326]
  • Men interested in preserving their future fertility should generally not be treated with testosterone supplementation alone. Clomiphene can help preserve sperm production when used alone or together with testosterone therapy. Cryopreservation of semen should be considered when appropriate before starting testosterone supplementation therapy.
  • Bilateral absence of the vas deferens on clinical examination suggests a CFTR gene mutation, especially if associated with a positive family history. Renal imaging is recommended.
  • Normal-sized testicles with low semen volumes suggest retrograde ejaculation or ejaculatory duct obstruction. Obtain a transrectal ultrasound and check a postejaculatory urinalysis.
  • Suspect testosterone abuse in muscular men with small testes bilaterally.
  • An elevated estradiol level or a testosterone to estradiol ratio less than 10 suggests a possible fertility benefit from an aromatase inhibitor to reduce the estrogen effect.
  • Azoospermia with bilateral atrophic testes is exceedingly difficult to treat without ART. Please see StatPearls' companion reference, "Azoospermia," for further information.
  • Suspect possible Klinefelter syndrome, especially if associated with hypogonadism.[104]

Men who are anticipating either chemotherapy or radiation treatment should discuss fertility issues with their clinicians before starting therapy and consider sperm cryopreservation. Sperm banking is encouraged in such situations. Attempting pregnancy should be avoided for at least 1 year (optimally 2 years) after completing such gonadotoxic therapy.[250] A genetic analysis of almost 2000 men with infertility and azoospermia and significant oligozoospermia showed that 9% had chromosomal abnormalities and about 10.5% had an AZF microdeletion.[328] This evidence suggests that genetic analysis may play a significant role in the evaluation and treatment.[328]

A couple with a male infertility factor may reasonably consider a trial of treatment with one of the unproven therapies if no better treatment alternative is immediately available. A trial may buy time, and little harm is done even if unsuccessful. A pregnancy may develop just from waiting. Some of the treatments to consider include clomiphene (with or without tamoxifen), aromatase inhibitors, vitamin supplements (vitamins C, D, and E), and antioxidants (including coenzyme Q10 and L-carnitine).[245][251] Such treatments should be presented as possible fertility aids for which there may be some limited evidence or expectation of efficacy but no proof.[245] The couple should be informed of the available data and allowed to make their own decisions. Clinicians should avoid giving unrealistic expectations about the proven efficacy of any of these remedies.[251]

Clinicians should know where to refer couples with infertility in the community for reproductive endocrinology assistance, ART, IVF, and ICSI. Informing patients of the expected estimated cost of these services is helpful. Clinicians should not hesitate to discuss adoption as a reasonable alternative to expensive and potentially futile fertility treatments.

Summary of the Recommended Initial Evaluation of a Patient with Male Factor Infertility

  • A comprehensive history and physical examination with particular attention to the sexual history and examination of the body habitus, hair distribution, and male genitalia. Consider the following:
    • Varicoceles can be surgically corrected with an expected improvement in sperm counts and other semen parameters.
    • Bilateral small, firm testes would suggest Klinefelter syndrome or possible testosterone supplementation.
    • Bilateral absence of the vas deferens is associated with cystic fibrosis.
  • At least 2 separate semen analyses are required, optimally 1 month apart.Hormonal screening should include testosterone, FSH, LH, estradiol, and prolactin. A TSH level can be added.
  • Consider scrotal ultrasonography selectively.
  • Genetic screening is recommended for patients with severe oligozoospermia (less than 5 million sperm/mL). Genetic screening would include karyotype, CFTR, and Y-chromosome testing for microdeletions (sometimes called AZF testing), as appropriate.

If the workup shows mild or moderate sperm abnormalities without an apparent cause, consider discussing the optional treatments noted earlier and summarized below. The example patient handout below can help couples determine whether they wish to pursue optional treatments and therapies.

A Couple's Guide to Optional Treatments for Male Infertility

Few patients are as anxious or desperate as the couple who has not conceived a child. A couple must have at least 1 year of adequate, unprotected sexual intercourse before being considered medically infertile. A contributing male factor is present in about 50% of all infertility cases. Some men will have an obvious or easily correctable problem, such as a history of a vasectomy, an undescended testicle, or a varicocele that can be surgically corrected. Unfortunately, the vast majority of patients with male infertility cannot be successfully treated by simple remedies and will ultimately require some degree of assisted reproduction, which can be quite costly.

Some couples can conceive a child without treatment. About 23% of such couples will conceive after 2 years, even without receiving any medically assisted therapy. Couples should be informed about some of the somewhat less orthodox or unofficial oral treatments available for male infertility for which data are incomplete, anecdotal, inadequate, or conflicting, making these treatments difficult for clinicians to recommend or prescribe. The following therapies have all demonstrated some beneficial effects on sperm quality or male infertility in the medical literature.

Patients should always check with their clinician before starting any new treatment. Standard lifestyle improvements, such as a healthy diet, losing weight and exercising, eliminating prescription medications if possible, and avoiding all illegal drugs, smoking, marijuana, alcohol, and testosterone, should be implemented. Men should avoid taking any testosterone supplements, even if prescribed, because this therapy will significantly decrease sperm counts and worsen their infertility. Patients should discuss this thoroughly with their clinician before discontinuing any prescribed medication. Patients should already have had at least 2 semen analyses showing mild to moderate problems with sperm count, concentration, maturity, motility (activity), or morphology (normal or abnormal sperm). Men with severe defects in any of these parameters are unlikely to benefit from the optional remedies discussed here. These patients should speak with their clinicians about assisted reproduction techniques and other treatment options.

Patients with relatively mild sperm defects might benefit from trying one or more of the treatments mentioned. None are specifically recommended or officially approved for male infertility, but some evidence of benefit exists in the medical literature to warrant consideration. Most remedies will require at least 3 months of continuous treatment to show any benefit, and several will need at least 6 months.

Antioxidants, Vitamins, and Minerals

The most studied vitamins, minerals, and antioxidants for male infertility include L-carnitine, lycopene, coenzyme Q10, vitamins C, D, and E, folic acid, selenium, and zinc. No consensus or recommendation exists on which of these, if any, is most effective or on what dosage is optimal. Given their low cost and lack of adverse effects, they should be considered by every patient with male infertility, and their use is an individual decision. The monthly cost varies but is generally nominal. Some combination products promoted specifically for male infertility are generally more costly and, therefore, are not recommended. No prescriptions are needed.

Aromatase Inhibitors and Antiestrogens (Anastrozole and Letrozole)

Aromatase inhibitors are medications that block the conversion of various hormones, including testosterone, to estrogen compounds. These medications are usually used to reduce the estrogen effect in women but have shown beneficial activity in male infertility as well. Aromatase inhibitors are considered the treatment of choice for men with infertility with normal testosterone but relatively high estrogen levels and can be used together with clomiphene. The recommended dose of anastrozole is 1 mg 3 times weekly, whereas the dose of letrozole is 2.5 mg 3 times weekly. Only 1 of these medications is needed. The most common adverse effects reported with these medications are joint pain and stiffness. The estimated monthly cost for either of these drugs is about US $10, and a prescription is required.

Clomiphene

Clomiphene is an antiestrogen medication that is primarily used as a fertility-enhancing drug for women because men typically produce only a minimal amount of estrogen. Evidence indicates that, in low doses, clomiphene can increase male fertility hormones (FSH and LH) and stimulate sperm production by lowering estrogen levels. Clomiphene may also be useful in some men with hypogonadism and infertility with low testosterone levels. The recommended dose is 25 mg daily. Possible adverse effects include headache, nausea, vomiting, diarrhea, flushing, and visual disturbances such as blurred vision. The estimated cost is only about $20 monthly, but a prescription will be required.

L-Carnitine

L-carnitine is an amino acid and antioxidant typically found in high concentrations in the epididymis and has long been suggested as a possible, nontoxic general therapy for male infertility. L-carnitine increases sperm motility, morphology, and maturity. A 6-month trial is suggested using a daily dose of 3 g/d. Since L-carnitine is an amino acid, the supplement is extremely safe. The estimated monthly cost is about US $30; no prescription is required.

N-Acetylcysteine

N-acetylcysteine is an amino acid derivative with significant antioxidant properties. N-acetylcysteine has improved sperm counts, motility, maturity, and morphology. The usual dose is 600 to 1200 mg daily, and no prescription is currently required, although this may change as N-acetylcysteine undergoes FDA review, since the supplement was once a prescription medication. The estimated monthly cost is US$ 10-$15.

Tamoxifen

Tamoxifen is an estrogen receptor blocker that has been shown to improve semen parameters, especially when used together with clomiphene, so these medications are often taken together. Like many of the therapies listed here, evidence indicates that tamoxifen can improve sperm counts and other semen parameters in infertile men, but data are insufficient on outcomes or pregnancies to recommend tamoxifen officially. The usual dose is 10 mg twice daily. Possible adverse effects include weight gain, edema, leg swelling, nausea, skin rash, and erectile dysfunction. The estimated cost is US $20-$30 per month, and a prescription will be required.

Suggested Dosages for Vitamins, Minerals, Nutraceuticals, and Antioxidants for Empiric Oral Therapy in Male Infertility

  • Coenzyme Q10: 300 mg daily
  • Folic acid: 500 µg-1000 µg daily
  • L-Carnitine: 3 grams (1000 mg three times daily or 1500 mg twice daily) 
  • N-acetylcysteine: 600 mg-1200 mg daily
  • Selenium: 200 mcg daily
  • Vitamin C: 500 mg twice daily
  • Vitamin D: 5000 units daily
  • Vitamin E: 400 units daily
  • Zinc: 200 mg daily

Antiestrogen Medications

Clomiphene: 25 to 50 mg 3 times a week, plus either:

  • Anastrozole: 1 mg 3 times a week, or
  • Letrozole: 2.5 mg 3 times a week, or
  • Tamoxifen: 10 mg twice daily

Enhancing Healthcare Team Outcomes

Effective care for male infertility necessitates an interdisciplinary approach involving various healthcare professionals. Clinicians, advanced care practitioners, nurses, pharmacists, and others must possess comprehensive skills in reproductive medicine, endocrinology, andrology, and psychological support to address diverse aspects of male infertility. Primary care clinicians should initiate the evaluation of infertility by identifying the problem early, obtaining 2 complete semen analyses, drawing basic laboratory studies, and making the appropriate referrals. Providing genetic counseling to couples with an abnormality in the clinical or genetic investigation or those who carry a potentially inheritable disease is also prudent.

Although many of the causes of male infertility are due to spermatogenesis failure, some are medically treatable. Male infertility has significant psychological, social, emotional, and health effects on the couple and their families. The barriers from stigma associated with infertility arising from religious and cultural beliefs should be considered and reduced where possible. Strategic collaboration is essential, with each professional contributing specialized knowledge to formulate personalized treatment plans. For example, close collaboration and communication among urology, reproductive endocrinology, obstetrics and gynecology, and other specialists on the healthcare team are optimal for advising patients on the most appropriate therapeutic options based on each case's presentation, severity, and clinical characteristics.

Responsibilities involve clear communication and ensuring patients are well informed and involved in decision-making. Interprofessional communication is key to fostering seamless collaboration and holistic patient care. Care coordination ensures that interventions are timely, reducing delays in diagnosis and treatment. This collaborative, patient-centered approach enhances outcomes, patient safety, and overall team performance in the treatment of male infertility.

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