Continuing Education Activity

Infertility is usually defined as the inability of a couple to conceive even after 1 year of unprotected, frequent sexual intercourse. The male is solely responsible in about 20% of cases and is a contributing factor in another 30% to 40% of all infertility cases. As male and female causes often co-exist, it is essential that both partners are investigated for infertility and managed together. Overall, the male factor substantially contributes to about 50% of all cases of infertility.

The initial evaluation includes a detailed sexual history and physical examination, together with 2 separate semen analyses. Hormonal testing and an optional scrotal ultrasound can then be performed if abnormalities are found. This is usually sufficient to make an initial determination of the nature and severity of the underlying problem. The key purpose for evaluating a male for infertility is to identify the contributing factors, offer treatment for those that are reversible, determine if the patient is a candidate for assisted reproductive techniques, and offer counseling for irreversible and untreatable conditions.

This activity highlights the etiology and epidemiology of male infertility. The course also reviews the evaluation and management of male infertility as well as the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Differentiate between various causes of male infertility through a comprehensive understanding of reproductive anatomy, endocrinology, and genetic factors.
• Identify systemic factors contributing to male infertility, such as lifestyle factors, environmental exposures, and occupational hazards, incorporating preventive measures and health promotion strategies into patient care.
• Apply cutting-edge treatment modalities for male infertility, including assisted reproductive technologies, hormonal therapies, and surgical interventions, while considering the individualized needs and preferences of each patient.
• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients with male infertility.

Introduction

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

As male and female causes often co-exist, it is essential that both partners are investigated for infertility and managed together. Overall, the male factor substantially contributes to about 50% of all cases of infertility.[4]

There are several reasons for male fertility, including both reversible and irreversible conditions. Other factors can influence each partner, including age, medications, surgical history, exposure to environmental toxins, genetic problems, and systemic diseases. The key purpose for evaluating a male for infertility is to identify his contributing factors, offer treatment for those that are reversible, determine if he is a candidate for assisted reproductive techniques (ART), and provide counseling for irreversible and untreatable conditions.[5]

Up to 6% of men evaluated for male infertility will be found to have more serious underlying pathology, such as cancer.[4][6][7][8][9][10][11] This is an additional reason to do a comprehensive evaluation of the male partners of infertile couples so that any significant, underlying medical conditions can be identified and treated.[4][6][7][8][9][10][11]

Etiology

There are multiple causes for male infertility, which can be broadly classified due to their general underlying etiology. These include endocrine disorders (usually due to hypogonadism) estimated at 2% to 5% of cases, sperm transport disorders (such as vasectomy) at 5%, primary testicular defects (which include abnormal sperm parameters without any identifiable cause) at 65% to 80% and idiopathic (where an infertile male has normal sperm and semen parameters) at 10% to 20%.[12] These are broad estimates only, as accurate statistics are unavailable due to general underreporting, cultural factors, and regional variations. Patients sent to a tertiary referral center are more likely to have their condition reported, while private patients may never have their data collected.[12] A partial summary of specific etiologies is listed below as follows: [4]

• Acquired urogenital abnormalities - bilateral obstruction or ligation of the vas deferens, bilateral orchiectomy, epididymitis, TURP, 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 GnRH Deficiency (Kallmann syndrome), Prader-Willi syndrome, Laurence-Moon-Beidl syndrome, iron overload syndrome, familial cerebellar ataxia, head trauma, intracranial radiation, testosterone supplementation, and hyperthyroidism.
• Environmental toxins - insecticides, fungicides, pesticides, smoking, excess alcohol, Agent Orange, and other chemical exposures.
• Genetic causes - mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, primary ciliary dyskinesia, Kallmann syndrome, Klinefelter syndrome, Young syndrome, Sertoli cell-only syndrome, Kal- 1, Kal -2, FSH, LH, FGFS, GnRH1/GNRHR PROK2/PROK2R gene deficiencies, chromosomal anomalies, Y chromosome microdeletion, AR mutations, and gr/gr deletion.
• Idiopathic causes - idiopathic male infertility (10% to 20%) where semen parameters are all normal, but the male remains infertile.
• Immunological causes - lymphocytic hypophysitis, hemosiderosis, hemochromatosis, sarcoidosis, histiocytosis, tuberculosis, and fungal infections.
• Malignancies - sellar masses, pituitary macroadenomas, craniopharyngiomas, and surgical or radiation treatment for these conditions, testicular tumors, and adrenal tumors leading to an excess of androgens.
• Medications or drugs - cannabinoids, opioids, psychotropic drugs that can cause inhibition of GnRH, exogenous testosterone or androgenic steroids supplementation, GnRH analogs and antagonists used in prostatic carcinoma, chronic glucocorticoid therapy, alkylating agents, antiandrogens, ketoconazole, cimetidine, and alpha-blocker medications for BPH. A complete list of potentially toxic drugs can be found at https://reprotox.org.
• Sexual dysfunction - premature ejaculation, anejaculation, infrequent sexual intercourse, and erectile dysfunction.
• Urogenital tract infections - Gonococci, chlamydia, syphilis, tuberculosis, recurrent urogenital infections, prostatitis, and recurrent prostatovesiculitis.

Male infertility can also be classified based on the medical interventions that can potentially assist conception as follows: [13]

• Treatable causes of male infertility are found in 18% of cases - 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 - oligozoospermia, asthenozoospermia, teratozoospermia, and normospermia with functional defects. ART will generally be necessary for reproduction.
• Untreatable male sterility is seen in 12% of cases - primary seminiferous tubular failure, Sertoli cell-only syndrome, and bilateral orchiectomy.

Epidemiology

The prevalence of infertility is variable, and epidemiologically, male infertility has been documented less in developing countries.[14] The burden of infertility is generally worse in the developing world due to constrained medical resources and the high cost of treatment, as well as cultural fears, taboos, and stigmas. It is much more challenging to identify and manage infertility in areas where medical resources for basic health care are already strained.

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

With regard to male infertility, the exact prevalence is still uncertain, as male infertility is not a reportable disease. Furthermore, payment for male infertility treatment is usually private, and hence, treatments are not reflected in medical insurance statistics. Further, male infertility is often treated in outpatient settings, and such data is not typically added to large clinical databases.[12] 

Agarwal et al estimated the overall pure male factor infertility could range between 2.5% and 12%.[18] In North America, the estimated male infertility rate is between 4.5% to 6%, while it's 9% in Australia and could be as high as 8% to 12% in Eastern Europe.[18] A study by Bayasgalan et al estimated the cause of infertility due exclusively to a male factor at 25.6%.[19] A similar study conducted by Thonneau et al found that among the French population, a prevalence of 20% of all infertility was due exclusively to a male factor.[2] Similarly, Philippov et al used a WHO questionnaire in Western Siberian to show a rate of 6.4%, while in Nigeria, Ikechebelu et al found a male infertility prevalence of 42.4%.[20][21]

For most practical purposes, we assume that about one-sixth of all couples worldwide have an infertility issue and that the male factor infertility is significant in about half of cases and is the only cause in about 20% to 30% of cases.

Of great concern is the widely reported general trending, over recent decades, of reductions in sperm counts globally.[22][23] The average sperm count in 1940 was 113 million/mL but dropped to 66 million/mL in the 1990s.[24] This trend has continued worldwide as the mean sperm count declined by 51.6% between 1973 and 2018.[23] Even more concerning is that the rate of decline increased after 2000, from a decline of 1.16% per year post-1972 to 2.64% annually post-2000.[23]

While the exact causes are not known, contributing factors are thought to be increasing long-term exposure to environmental toxins as well as improved global medical care, which paradoxically allows more men with marginal health to participate in reproductive activities. There is also the possibility that the reported decrease in sperm counts might merely reflect differences in laboratory techniques, inconsistent lab criteria, and varying counting methods. 

Men with infertility issues tend to have more health-related comorbidities than normally fertile males.[8][25][26][27] Infertile men with abnormal semen parameters have an increased risk of testicular cancer, with the highest risk in azoospermic individuals.[9][10][11][28][29][30] Azoospermic men also have a greater overall cancer risk and higher mortality rate compared to males with normal sperm counts.[28][31] There may also be an increased cancer risk in first and second-degree relatives of infertile men.[31][32] Conversely, it has been reported that 5% to 8% of patients with testicular cancer have azoospermia.[33]

COVID-19 appears to cause somewhat reduced fertility and even infertility in some recovered males, especially if the infection is severe. The virus appears to affect the testis by direct cellular infection via a cytokine storm and through the side effects of the various antiviral and immunological therapies used in its treatment.[34] Further investigations are needed to better elucidate both the mechanisms of damage and possible remedies specific to COVID-19 infection-related infertility.[34]

Pathophysiology

Male infertility can also be classified as follows: 

Pre-testicular causes include hypogonadotropic hypogonadism, erectile dysfunction, or coital disorders such as retrograde ejaculation, anejaculation, 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 surgery, epididymitis, or may be idiopathic.[35][36]

Post-testicular etiologies include lesions of the seminal tract, inflammatory diseases, congenital absence of the vas deferens, post-vasectomy, erectile dysfunction, premature ejaculation, and the use of a condom or diaphragm. This category would also include bladder neck surgery, post-TURP surgery, retroperitoneal lymph node dissection, rectal surgery, multiple sclerosis, and alpha 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 gonadotropic releasing hormone or causing gonadotropin deficiency such as idiopathic hypogonadotropic hypogonadism (IHH), Kallmann syndrome (IHH 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 well as 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 will be 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 is thought to be due to an inherent testicular defect. Men with cryptorchid testicles will typically have poorer quality sperm (lower motility, high abnormal morphology) and lower sperm counts. Interestingly, testosterone levels and Leydig cell performance are usually not affected despite the disruption 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 starts to decrease. There is generally no spermatogenesis at all in untreated abdominal testes after puberty. The risk of infertility increases as the distance from the normal anatomical testicular location lengthens.[37][38][39]

The disruption of spermatogenesis in undescended testes is related to the underlying hormonal, developmental, and genetic abnormalities associated with cryptorchidism. Some of these may be reversible with early surgical intervention. Adult sperm counts seem to be related to the existing and functioning germ cells at the time of orchidopexy. The risk of infertility is increased in cases of bilateral cryptorchidism, abdominal testicles, and delayed orchidopexy.[40][41]

Klinefelter Syndrome

This is a genetic mutation where the male has XXY instead of the usual XY chromosomes. Patients are typically infertile with hypogonadism. There is a spectrum of symptoms, but the most typical 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 IVF and ICSI.[42] Even in Klinefelter patients with clinical testicular atrophy, modern ART now offers a 40% to 60% rate of successful sperm recovery, with 60% resulting in a pregnancy.[43] Aside from fertility concerns, the usual treatment of Klinefelter syndrome in adults is full testosterone replacement therapy.[44][45][46][47]

Prolactinoma

Prolactin levels in men usually are quite low. When elevated, they 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 >150 mcg/L suggest this condition, while a level >300 mcg/L is pretty much diagnostic. An MRI or CT scan of the sella should be done for confirmation.

Dopamine agonists, such as cabergoline and bromocriptine, are generally used as medical therapy to suppress prolactin secretion, and many men will then normalize their testosterone levels and sperm counts. Surgical treatment with a trans-sphenoidal resection of the prolactinoma is successful in 80% to 90% of cases, but the tumors often recur. Surgery is usually reserved for patients with visual field loss and for those where medical therapy is unsuccessful or not well tolerated.[48]

Testosterone Supplementation

Anabolic steroid abuse and testosterone supplementation therapy are growing worldwide.[49] At least 25% or more of physicians who prescribe testosterone to patients are unaware that it will cause significant, possibly long-term fertility and sterility problems in their patients.[50][51][52][53] Patients are often not informed of this likely complication.[54] Exogenous androgen causes infertility by suppressing FSH and LH production by the pituitary. The loss of FSH and LH shuts down endogenous intratesticular testosterone production and spermatogenesis.[50][51][55][56][57] It only takes about 3.5 months for testosterone therapy to inhibit spermatogenesis.[58][59][60] 

Testosterone supplementation has no role in male infertility patients trying to conceive.[61] Patients who need testosterone supplementation can preserve their fertility by taking clomiphene, which helps maintain FSH and LH levels.[62] Most patients who become infertile on testosterone therapy will eventually regain their sperm counts and fertility, but it 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.[58]

Viral Mumps Orchitis

Mumps and several similar viruses constitute the most common cause of acquired testicular failure, and their incidence is increasing. This is probably due to a reduction in the usage of the MMR vaccine in children during 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 from compressive ischemia caused by severe intratesticular swelling while being restricted by the very tough tunica albuginea.[63][64]

Testicular atrophy may occur from 1 to 6 months after the infection, and some shrinkage will be apparent in about half of all 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 the adult patients with unilateral mumps orchitis will develop infertility, as well as two-thirds with bilateral disease.[65][66] 

History and Physical

The purpose of evaluating the male partner of a couple suffering from infertility is as follows: [4][67] 

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

While an initial evaluation such as a history and physical can be performed by primary care clinicians and an initial semen analysis ordered, it is generally recommended that all infertile men have an evaluation performed by a male reproductive specialist, especially if any abnormalities are found, as the workup and treatment are complex.[4][68] Patients who have previously been on 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, steroid abuse, previous chemo/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 (STIs), tuberculosis, mumps, scrotal infections such as epididymitis, prior biological children produced, maternal exposure to DES, anosmia (associated with Kallman syndrome), breast enlargement and galactorrhea, and precocious puberty (at 9 years of age or earlier).[4]

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, while liver failure sometimes causes gynecomastia (from increased estrogen levels), testicular atrophy, and reduced secondary sex characteristics. Tuberculosis, prostatitis, epididymitis, and STIs (especially gonorrhea) can cause vasal scarring and obstructive azoospermia, while mycoplasma 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 lubricants would include egg whites, peanuts, and vegetable oil. Petroleum jelly is not particularly spermatotoxic but is still not recommended due to viscosity.

During the physical examination, it is important to look at the body form as well as to check for possible signs of endocrinopathy, gynecomastia, skin, hair distribution, and particularly secondary sexual characteristics. If the patient appears muscular and has a low sperm count, do an endocrine screening panel (testosterone, FSH, and LH), as he could have a very low LH, which would be suggestive of testosterone abuse.[69] Obesity tends to increase the peripheral conversion of testosterone to estrogen. This decreases LH levels and has been associated with reduced sperm counts.[70] 

Examination of the penis would include a check for hypospadias, phimosis, and Peyronie plaques. 

Testicular size should be measured. In an average adult male, 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 <4 cm in its largest dimension, it is considered "small." The presence or absence of the vas deferens should be noted and documented. Bilateral absence of the vas is reported in 1% to 2% of infertile men and is related to mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, 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.[4] 

The presence of a hydrocele should be noted. If a hydrocele is present, a testicular ultrasound should be used to examine the testicle since an adequate direct physical examination is not otherwise possible.[4] 

Testosterone deficiency might cause various physical signs depending on its severity and age of onset. Hypogonadism in early gestation results in atypical genitalia, but in late gestation, it causes micropenis. Hypogonadism in childhood causes delayed puberty, while in adults, it causes decreased libido, erectile dysfunction, decreased body hair, infertility, and loss of secondary sexual characteristics. 

A varicocele that is identifiable on the physical examination might be clinically significant with regard to possible infertility. Varicoceles are the most common correctable cause of male infertility, so a careful check for their presence should be undertaken. They are relatively easy to identify, even on a simple physical examination. Varicoceles are present in 15% of men, but in those with an abnormal semen analysis, the incidence increases to 40%.[72] Only clinically significant varicoceles are generally believed to impact male fertility.[4][73][74][75][76] When present, varicoceles are typically found on the left side of the scrotum due to anatomical reasons.[77]

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.[78][79][80] However, recent evidence indicates that the incidence of renal cell cancer 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.[4][81][82] However, imaging should be considered if the right-sided varicocele is not reducible, is newly acquired, or is particularly large.[4]

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.[83][84][85] In such cases, both partners should be genetically checked. If a positive result is found, genetic counseling should be done before any ART, IVF, or ICSI. 

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, while patchy, diffuse hyperpigmentation might suggest iron overload syndrome.[4]

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, separated by at least 1 week but optimally by a month.[4] At least 3 days of abstinence should precede each specimen.[86] This is recommended due to the extremely high degree of variability in semen analyses.[87] The outcomes and prognosis of male infertility greatly depend upon the semen analysis results as well as the female partner's fertility status, along with the categorization of whether fertility is primary or secondary.[88][89] Semen analyses greatly assist in identifying and classifying the severity of any male factors.[4]

The WHO has published a detailed methodology for collecting semen. At-home sperm tests are now commercially available but are not recommended as their reliability is questionable, and they do not check all of the recommended semen parameters. 

It is essential to give clear instructions for the semen collection. Semen can be collected by masturbating or using special condoms for collection, which do not contain any toxic substances.[90] The specimen is ideally collected at the laboratory but can be collected at home. If collected at home, it should be kept at room temperature and rushed to the laboratory, as it is critical that the sample is examined within 1 hour of collection.

The standards of the semen analysis quality control program are set by the Clinical Laboratory Improvement Amendments (CLIA), 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.[91]

Either the WHO criteria for scoring sperm morphology or the Kruger-Tygerberg criteria should be used. 

The Lower Reference Limits of a Semen Analysis (with 95% confidence intervals) Adapted from WHO (2010)

• Ejaculate volume: 1.5 mL (1.5–5 ml) (If low volume, possible retrograde ejaculation, anejaculation, ejaculatory duct obstruction, or hypogonadism. Check post-ejaculation urine, TRUS, and hormonal analysis. If high volume, suspect contamination)
• pH > 7.2
• Sperm concentration: 15 million/mL (12–16) (Usual normal value is >20 million/mL). If low, check for varicocele and consider a hormonal analysis.
• Total sperm count: 39 million/ejaculate (33–46 million)
• Sperm Morphology: > 4% normal forms (Usual normal value >30%)
• Motility: 40% (38%–42%) (Usual normal value is 60%). If low, check for varicocele and consider an anti-sperm antibodies test.
• Vitality: 58% live (55%–63%). If low, check for varicocele and consider an antisperm antibodies test.
• Progressive motility: 32% (31%–34%)
• Total motility: >40% (Usual normal value is >60%). If low, check for varicocele and consider an anti-sperm antibodies test.
• Forward progression: >2 
• Seminal fructose: >13 micromol/ejaculate
• Liquefaction: 20 to 30 minutes
• Optional investigations 

  • Immunobead test with <50% motile spermatozoa with bound beads
  • Mixed antiglobulin reaction test with <50% motile spermatozoa with bound particles 
  • Seminal fructose≥13 micromol/ejaculate
  • Seminal neutral glucosidase ≤20 milliunits/ejaculate
  • Seminal zinc ≥2.4 micromol/ejaculate [92] 

The Nomenclature Related to the Pathological Semen Quality as Adapted from the World Health Organization Laboratory Manual for the Examination and Processing of Human Semen, WHO (2010)  [93]

• Aspermia: No ejaculate at all.
• Asthenozoospermia: <32% progressively motile spermatozoa. Absolute asthenozoospermia is when no sperm moves at all, but they are still viable and not dead.
• Azoospermia: No spermatozoa in the ejaculate.
• Cryptozoospermia: Spermatozoa absent from fresh preparation but observed in a centrifuged pellet.
• Leukospermia:  >1 million white blood cells/mL ejaculate (also called pyospermia and leukocytospermia).
• Necrospermia or Necrozoospermia: Complete when all the sperm are dead on a fresh semen sample; incomplete if 5%-45% are still viable.
• Normospermia: All semen parameters within the acceptable reference limits.
• Oligozoospermia: Sperm concentration <15 million/mL; total sperm number <39 million/mL. Severe if <5 million/mL. 
• Oligo-astheno-teratozoospermia: Disturbance of all 3 parameters.
• Teratozoospermia: <4% morphologically normal spermatozoa. [93]

Other Tests

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

DNA integrity test: assesses the degree of sperm DNA fragmentation. The test should be done in those with recurrent miscarriages.[94]

Genetic Screening: chromosomal testing may be indicated with azoospermia or severe oligozoospermia, as chromosomal defects are more common in infertile men (up to 15%) than in normally fertile males (about 0.6%).[95] The common genetic factors which are associated with infertility in males 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 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation.

While ICSI has allowed many men with defective genes to father children, there is also the increased risk of transmission of various genetic defects to the progeny, and this should be carefully considered before proceeding. Therefore, genetic testing would typically be recommended for patients with severe oligozoospermia (<5 million sperm/mL) or azoospermia and consist of karyotype, CFTR, and Y chromosome testing for microdeletions (sometimes called AZF testing). 

Hormonal tests: are indicated if there is a low sperm count and concentration or clinical findings are suggestive of an endocrine disorder or impaired sexual function. Many experts recommend hormonal laboratory testing on all men undergoing infertility evaluation. The endocrine (hormonal) lab test panel would include serum follicle-stimulating hormone (FSH), testosterone, luteinizing hormone (LH), prolactin, estradiol, and optional thyroid-stimulating hormone (TSH) levels. (An elevated estradiol level and/or a testosterone/estradiol (T/E) ratio <10 suggests a possible fertility benefit from an aromatase inhibitor to reduce the estrogen effect.)

In general, a raised FSH level is indicative of spermatogenesis abnormalities. Though gonadotropin hormone is secreted in a pulsatile manner, a single test may be deemed sufficient to assess the endocrinological status of the patient. Optionally, some additional hormonal tests might 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 testicle size and consider karyotyping as well as Y chromosome microdeletion testing. A less severe form with mild oligozoospermia might indicate Sertoli cell dysfunction, causing reduced production of inhibin, which increases FSH.
• Normal testosterone, LH, and FSH: Further evaluation depends on the semen analysis and physical findings. If there is azoospermia (no sperm in the ejaculate) and normal testicle size, this would indicate obstructive azoospermia, which can potentially be treated surgically. If associated with bilaterally absent vas, 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 but normal FSH: This would be consistent with partial androgen resistance.
• Cushing's disease can be confirmed by a 24-hour urine test for free cortisol, a dexamethasone suppression test, or by checking the midnight salivary cortisol concentration.
• Thyroid dysfunction can be identified by abnormal serum thyroid function tests and is suggested by an abnormal TSH level.

Postcoital test is suggested in cases of hyperviscosity of the semen, normal sperm density with increased or decreased semen volumes, and in cases of 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. It is optimally done 1-2 days before female ovulation when the cervical mucus is most abundant. Finding any viable sperm that are still motile suggests a normal sperm/vaginal mucus interaction and proper sexual technique for a potential pregnancy. 

If the postcoital exam is 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, as in cases where intrauterine insemination (IUI) has repeatedly failed. IVF with ICSI is the preferred treatment for men whose sperm show poor results on any of these tests.
• Hypoosmotic Swelling Test: Live sperm will tend to swell with exposure to very dilute solutions, but dead sperm will not. Therefore, this can differentiate between dead sperm and viable but non-motile 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. While it may be useful in discriminating between viable non-motile sperm and dead sperm, it is of limited clinical use since the sperm tested cannot be salvaged for ICSI but may be helpful by identifying necrospermia. 

Post-ejaculatory urinalysis is recommended with a semen volume <1.0 ml, as a post-ejaculatory analysis for sperm may be required to confirm retrograde ejaculation.[96] Note: any such sperm collected can be used for IVF with ICSI.

Renal imaging is recommended when there is unilateral or bilateral absence of the vas deferens due to its association with kidney abnormalities, including agenesis.[4] The incidence of associated renal anomalies ranges from 10% up to 75%.[4][97][98][99][100][101] CFTR testing is also suggested, but renal imaging should be performed regardless of CFTR test results where 1 or both vas deferens are absent.[4]

Scrotal ultrasound is required to definitively identify pathologies such as spermatoceles, varicoceles, absence of the vas on physical examination, or the presence of any testicular masses. It may be able to identify prostatic and ejaculatory duct cysts, but transrectal ultrasound is usually preferred. Nonpalpable varicoceles found only on scrotal ultrasound are generally not considered clinically significant, and varicocelectomy is not usually recommended to improve fertility by most experts or guidelines, but this is somewhat controversial.[4]

Scrotal ultrasound has been reported to identify abnormalities in 38% of infertile men. Of these, 30% had a varicocele, and 0.5% had testicular cancer.[102] American Urological Association (AUA) guidelines do not recommend the routine use of scrotal ultrasound in male infertility. Still, some experts recommend it because it 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.[4] While the incidence of testicular cancer in infertile men is low at 0.5%, this is still 100 times greater than the risk in the general population.[30]

Testicular biopsy may be indicated in some cases to exclude spermatogenic failure. Testicular biopsy is typically performed in men suspected of ductal obstruction who would generally present as azoospermic with normal hormonal screening tests 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. There is a reported discrepancy in findings on testicular biopsy between the 2 sides, so consider bilateral biopsies.

Transrectal ultrasound (TRUS) can identify ejaculatory duct obstruction where dilated ejaculatory ducts and seminal vesicles are seen.[103]  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 are palpable, and the serum testosterone is normal, as this is suggestive of ejaculatory duct obstruction.[4] 

Vasography is used to evaluate the patency of the vas and identify the precise location of any vasal obstruction. It is most useful in azoospermic or severely oligozoospermic men with mature sperm on testicular biopsy and at least 1 identifiable vas. It 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 lumen of the vas. If the blue dye is seen in the urine, no distal vasal obstruction is present. Radiologic contrast and x-rays 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 an infertile partner. 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. A meta-analysis of published studies suggests that L-carnitine and N-acetyl cysteine can significantly improve sperm motility and morphology compared to placebo.[104] Additional treatment includes the use of condoms to minimize exposure, immunosuppressive steroid 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.[105][106]

Low morphology (teratozoospermia): Not to be confused with leukocytes, large numbers of immature germ cells in the semen suggest an issue with spermatogenesis. L-carnitine and N-acetyl cysteine appear to be beneficial in improving isolated sperm morphology.[104] Further treatment would be ART, possibly IVF with ICSI. 

Low motility (asthenozoospermia) and/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.[107] In such cases, ART, like ICSI, can be used to treat infertility.

Low sperm count or concentration (oligozoospermia or <15 million sperm/mL): Considered "severe" if <5 million/mL. Check hormone levels (testosterone, FSH, LH, and prolactin). 

Low testosterone with high FSH and LH suggests possible Klinefelter syndrome. Karyotyping is recommended as Klinefelter syndrome is likely, especially if testes are small and firm bilaterally. If the karyotyping is normal, consider ART, possibly IVF with ICSI. If severe oligozoospermia (<5 million/mL), consider Y chromosomal defects and microdeletions, which typically cause extremely low sperm counts and may occur in up to 20% of infertile men.[108] Such genetic problems can be transmitted to the offspring by ART and IVF with ICSI. Other causes include postcancer chemo and radiation therapy, bilateral testicular trauma or torsions, and significant testicular infections such as mumps.[109][110]

Low testosterone with low or normal FSH and low or normal LH: possible pituitary issues. Check thyroid function, 8 AM cortisol, and a prolactin level to identify hormone problems and prolactinomas.

Normal testosterone and normal LH with high FSH: suspect abnormal spermatogenesis with seminiferous tubular damage but with normal Leydig cell function.

Normal testosterone, normal LH, and normal FSH with normal testes size: evaluate for genital tract obstruction  (especially if poor sperm motility is also present)[111]

• Congenital absence of the vas deferens can be detected on physical examination. It may be associated with an abnormally low semen pH. It can be verified with scrotal or transrectal ultrasound.[83][112]
• It may also be associated with cystic fibrosis mutations and a solitary kidney. Genetic testing and renal ultrasonography can be diagnostic and confirmatory.[83][112]
• Ejaculatory duct obstruction can also be caused by STD infections or postvasectomy. A scrotal ultrasound would typically show dilated seminal vesicles secondary to infections like chlamydia, gonorrhea, tuberculosis, or surgical vasectomy. Scrotal or transrectal ultrasound in such cases shows dilated seminal vesicles.[113]

High testosterone with a high LH and normal FSH: suspicious for partial or total androgen resistance. These patients may also have gynecomastia with a variable presentation of male genitalia.[114]

Any testosterone level with a low LH in an athletic or very muscular male: consider possible androgen abuse.[115]

Low sperm count, low motility, and low morphology (oligo-astheno-teratozoospermia): This is the most common abnormal semen analysis encountered in male infertility evaluations. When mild, this could indicate a "stress pattern" that might respond well to a varicocelectomy if 1 is present. When severe, infertility is highly likely. Treatment would be ART, possibly IVF with ICSI.[107] 

Very low sperm count (severe oligozoospermia) or no sperm (azoospermia): Check hormone levels and consider genetic testing. If the vas 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 vasoepididyostomy. Still, even if the surgery fails, the condition can always be treated with ART as viable sperm are available directly from the testicle via biopsy using sperm extraction techniques. In the case of congenital, bilateral absence of the vas, ART with testicular sperm retrieval followed by IVF with ICSI is the only viable option. The lack of sperm in the semen does not necessarily mean a lack of sperm production. Even finding a few viable sperm using enhanced techniques may make ART possible. 

About 10%-18% of infertile men who also have severe oligozoospermia (sperm concentration of 5 million/mL or less) will be found to have microdeletions of the Y chromosome.[116] Chromosomal testing should be done in these men, but NOT if they have a sperm concentration >5 million/ml, as chromosomal microdeletions would be quite rare.[117] Microdeletions of the Y chromosome are 1 of the genetic disorders that can be transmitted to male children via ICSI.[118]

Low semen volume: Typically, this is due to poor or incomplete collection technique; however, it could also indicate retrograde ejaculation or an ejaculatory duct obstruction. A postejaculation urinalysis looking for sperm should be done. Retrograde ejaculation may be psychogenic or result from diabetes, multiple sclerosis, retroperitoneal lymph node dissection, spinal cord injury, transurethral resection of the prostate, or transverse myelitis.[119]

Low semen volume associated with low sperm concentrations might indicate low serum testosterone. If associated with a low sperm count, this is suggestive of ejaculatory duct obstruction, which can be verified with a scrotal or transrectal ultrasound. Ejaculatory duct obstruction can be treated surgically, while 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 from the congenital bilateral absence of the vas deferens where there is a failure of seminal vesicle development.[97]

Prolonged semen liquefaction time: Lengthy semen liquefaction does not necessarily indicate a fertility issue. This is 1 reason a second semen analysis is recommended, as there is a good chance the next follow-up sample will be normal. If prolonged liquefaction (>30 min) is persistent, a postcoital test can help determine if 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 <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, or 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 correctable. High white blood cells (WBCs) 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, while the last third is mainly seminal vesicle fluids. If part of the specimen is lost or not collected, it will affect the test results. A low ejaculate volume is suggestive of improper specimen collection.

Nutritional supplements such as antioxidants like vitamins C and E, folic acid, and zinc have been suggested. Still, there is no definitive evidence or proof of efficacy in reducing overly long semen liquefaction times.[120] The standard recommended treatment for persistent, prolonged semen liquefaction time is sperm washing combined with IUI.

Pyospermia or leukospermia (excessive WBCs in the semen): Leukocytes are normally found in the semen. Levels >1 million/mL in the semen are considered excessive and possibly indicative of infection. It has been suggested that 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. It is very tempting to attempt to treat pyospermia with antibiotics or nonsteroidal anti-inflammatory drugs (NSAIDs). Still, no clear data exists supporting treatment, and there is the potential for adverse effects on general health and fertility from drug therapy.

While 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.[17][121][122][123]

Schistosoma haematobium: Schistosoma ova can appear in the semen during an evaluation for male infertility in men who have lived or traveled to where the parasite is endemic, primarily in Southeast Asia and Africa. This is a rare finding in the Western world, but laboratory personnel should nevertheless be able and prepared to identify the ova if present.[124] Schistosoma haematobium can affect the male urinary tract and lead to infertility.[124] It has also been associated with a higher risk of both prostate cancer and HIV infection.[125][126] Any semen parameter may be affected. Testicular damage from Schistosoma is reported in about 35% of affected men, which becomes permanent and irreversible once granulomas form.[127][128]

Male Infertility in Severe Renal Failure

It is well known that significant renal failure, and especially end-stage kidney disease (ESKD), will dramatically reduce male fertility. Still, it is relatively uncommon to see male dialysis patients who are interested in treating their infertility. The causes of infertility in severe renal failure include hypogonadism, erectile dysfunction (ED), and direct impairment of spermatogenesis with spermatotoxicity and late-stage maturational arrest, causing oligospermia or azoospermia.[129] Renal transplantation helps some of these abnormal semen parameters normalize.[130]

Leydig cell dysfunction is common, resulting in hypergonadotropic hypogonadism in over 50% of male dialysis patients.[129][130][131] There is also evidence of decreased anti-Mullerian hormone, indicating Sertoli cell dysfunction.[132]

The typical male patient with ESKD will demonstrate oligoasthenozoospermia and decreased semen volume.[133] The decrease in sperm viability, motility, concentration, count, and normal morphology is roughly 50% in ESRD patients compared to controls.[134] Testicular volume tends to shrink, and pathological examination of testis tissue shows increased fibrosis with decreased germ cell proliferation.[135]

A trial of clomiphene should be considered in these patients as it has been shown to increase FSH and LH through a central mechanism.[131][136] Many, however, will require ART, such as ICSI, to achieve a pregnancy.

Treatment / Management

No Treatment

When left untreated, some infertile couples still manage to achieve a pregnancy. Studies have shown that 23% of untreated infertile couples conceive after 2 years, which goes up to 33% after 4 years. Even in men with severe oligozoospermia (<2 million sperm/mL), 7.6% of these untreated male infertility patients are able to produce a pregnancy within 2 years.[137] 

Lifestyle Changes

Reasonable healthy lifestyle changes should be recommended or at least discussed with all male infertility patients. These changes include stopping smoking, limiting or eliminating alcohol intake, adopting a more nutritious diet, weight loss measures if obese, increased 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.[138][139][140][141] Low body weight and obesity are also possible risk factors for male infertility.[142][143] Fish oil supplements have also been suggested as helpful in male fertility, but there is insufficient evidence to make a recommendation.[142]

Clothing selection, "boxers or 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.[144] While avoiding hot baths, saunas, and tight-fitting underwear has not been conclusively demonstrated to improve male fertility significantly, it is not unreasonable to discuss these suggestions with patients. 

While it remains unclear exactly how much influence these factors have in male infertility, it is reasonable to expect that avoiding potentially spermatotoxic activities and adopting a healthier lifestyle will improve overall male fertility.[139]

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

It is often difficult for physicians to suggest or even discuss nontraditional, alternative treatments to patients when the medical literature shows so much conflicting and contradictory data or only poorly done 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. 

Although it may be difficult, it is still important to properly inform patients and their partners about optional, alternative therapies even when the available data is 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. While 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. There are enough reports of a potential benefit to justify a clinical trial in male infertility patients who cannot afford or are not otherwise candidates for other therapies.[145][146][147][148] It also gives the physician a way to provide a "treatment" while just giving the couple more time for natural conception. 

Oral therapies are considered optional and categorized as antioxidant-based, nutrition-based, and hormonal. 

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.[149] A 3-year, multi-institutional study from 9 fertility centers that included 174 infertile male patients using antioxidant therapy alone, without L-carnitine, showed no benefit in improving semen parameters or pregnancies for the 6 months the patients were followed.[150] However, significant other data supports antioxidant use for male infertility.[141][147][151][152][153][154][155] 

For example, a 2020 single-blinded study involving 50 idiopathic infertile men with 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 mcg) and selenium (200 mcg) 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.[156] See the companion StatPearls reference article on "Vitamin C" and "Vitamin E."[157][158]

A similar trial using just daily coenzyme Q10 (200 mg) compared to placebo in 114 infertile men followed for 26 weeks found statistically significant improvements in sperm motility, count, and strict morphology. Interestingly, these improved sperm parameters returned to pretreatment levels 12 weeks after coenzyme Q10 was discontinued. Pregnancy rates were not reported.[159] 

A randomized trial using just zinc and folic acid supplementation failed to show any significant benefit to male semen parameters or pregnancy rates.[160] This is contradicted by several meta-analyses suggesting that vitamins C and E can significantly improve multiple semen parameters, including sperm counts, motility, concentration, and morphology.[161][162][163] 

The most studied vitamins, minerals, and antioxidants used for male infertility include coenzyme Q10, folic acid, L-carnitine, lycopene, N-acetyl cysteine, vitamin C, vitamin E, folic acid, selenium, and zinc.[147][164] Each of these is discussed briefly below. An extensive systematic review of antioxidant supplementation in male infertility has been published elsewhere.[147][165]

Coenzyme Q10 or CoQ10 appears to have a beneficial effect on sperm quality. It reduces organic peroxides in the semen, which decreases sperm cell oxidative stress.[166][167][168][169] It reportedly improves sperm motility, morphology, and concentration.[159][167][168][169][170][171][172] The usual recommended dose is 300 mg daily. See the companion StatPearls reference article on "CoQ10."[173]

Folic acid, also known as vitamin B-9, is a very effective antioxidant intimately involved in numerous cellular functions, including cell division and the synthesizing and repairing of DNA and RNA.[174][175][176] 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 managing abnormal testicular methylenetetrahydrofolate reductase (an enzyme involved in DNA methylation).[174][177][178][179] Improvements in semen parameters, especially sperm motility, have been noted in patients on folic acid supplementation.[174][180][181] Folic acid is often used together with zinc supplementation.[174] The recommended daily dose of folic acid is 500 to 1000 mcg.[181] Higher doses are not recommended and may actually decrease sperm quality by downregulating DNA methylation.[182]

L-carnitine is an amino acid and antioxidant that is typically found in high concentrations in the epididymis and has long been suggested as a possible, nontoxic general therapy for male infertility.[161][183][184][185] It is known to increase fatty acid transport into sperm mitochondria, which is needed for epididymal sperm energy production. It also appears to increase sperm motility, morphology, and maturation while reducing apoptosis.[104][184][185][186][187] Recently, 180 infertile male patients with idiopathic oligo-astheno-teratozoospermia (low sperm counts with decreased motility and poor morphology, a "stress pattern") were given an L-carnitine supplement and demonstrated significant improvements in sperm count, concentration, and morphology. However, motility was not affected, and the study was of insufficient duration to determine if pregnancy rates were affected.[188][189] A daily dose of 3 gm per day has been suggested.

Lycopene  is a carotenoid antioxidant and the organic pigment that makes fruits and vegetables yellow, orange, or red. It is naturally found in carrots, pink watermelon, grapefruit, apricots, and especially tomatoes. It is a powerful antioxidant shown to increase male fertility and significantly improve semen parameters.[190] Sperm counts can increase up to 70% and progressive motility up to 54%, while morphology improves by up to 40% in various studies.[148][191][192][193][194][195] The recommended dosage of lycopene used as a supplement for male infertility is 6 mg daily.[194]

N-acetyl cysteine (NAC) is a dietary supplement and mucolytic agent sometimes used to treat overdoses of acetaminophen and paracetamol.[196] A thiol-based derivative of the amino acid L-cysteine and a precursor to glutathione peroxidase, it possesses significant anti-inflammatory, mucolytic, and antioxidant properties.[196] When used in infertile men, NAC therapy increases sperm counts, enhances motility, reduces abnormal morphology, decreases DNA fragmentation, improves acrosomal activity, and acts as an effective semen antioxidant.[104][151][152][197][198][199] The usual dose is 600 mg to 1200 mg daily; no prescription is required. However, since it was previously available as a prescription medication, the FDA is reviewing its status as an OTC dietary supplement. See the companion StatPearls reference article on "N-Acetyl Cysteine."[173]

Selenium, especially when used together with N-acetyl cysteine, appears to help improve sperm concentration, motility, and morphology by acting to enhance enzymatic antioxidant activity.[147][200][201][202] It is critical for the biosynthesis of testosterone and sperm production.[203] Selenium can also reverse the negative effects of heavy metal exposure on spermatogenesis and male fertility.[204] The recommended dosage when used as a supplement is 200 mcg per day and is often used together with 400 IU of vitamin E. See the companion StatPearls reference articles on "Selenium" and "Vitamin E."[158][201][205]

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.[206][207][208] Supplemental vitamin C also appears to improve the hormonal profile of subfertile men and their semen parameters.[209] Patients given vitamin C tended to have improved progressive motility, sperm counts, concentration, morphology, and pregnancy rates.[162] Vitamin C supplementation for male infertility is often given with 400 IU of vitamin E daily.[161][162][163] The suggested dosage of supplemental vitamin C is 500 mg to 1000 mg daily. See the StatPearls reference article "Vitamin C (Ascorbic Acid)."[157][207]

Vitamin D supplementation may help with sperm motility.[210][211][212] There is also evidence that men with unexplained infertility and low vitamin D levels may suffer increased sperm DNA damage.[210][213] See the StatPearls reference article on "Vitamin D."[214]

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.[215] Zinc is important for sperm maturation and testicular development, protecting spermatozoa from damage by oxidized thiols, improving sperm function, and maintaining fertilization capacity.[147][216][217][218] Zinc is often given together with folate, which seems to improve the results.[219] Seminal zinc levels appear important in maintaining sperm counts, but excessive levels can adversely affect motility.[220] The best results were found when used together with folic acid.[174] Zinc also appears able to reverse damage from heavy metal exposure.[204] The suggested daily dosage of supplemental zinc is 200 mg (25-400 mg). (Note that zinc sulfate 220 mg has only 50 mg of elemental zinc.) See the companion StatPearls reference article on "Zinc."[221]

Hormonal therapies considered optional include aromatase inhibitors, clomiphene, and tamoxifen. 

Aromatase inhibitors have shown an ability to improve semen parameters but have not been conclusively proven to improve pregnancy rates, as most of the available studies are either case reports, anecdotal, or of low quality.[222] A recent review and meta-analysis of aromatase inhibitors for male infertility have suggested that these drugs can statistically improve abnormal semen and hormonal parameters, plus they appear to be safe.[223] They are most useful when testosterone levels are normal but estradiols (estrogens) are relatively high. Also, they can be used together with clomiphene, which is recommended.

Both the steroid-based (testolactone) and nonsteroidal (anastrozole and letrozole) drugs appear to have equivalent efficacy. Still, it is difficult to recommend an aromatase inhibitor without adequate, prospective, randomized, placebo-controlled multicenter trials to determine their efficacy and optimal dosage definitively.[222][223][224] Anastrozole and letrozole are inexpensive, with minimal adverse effects. The recommended dose of anastrozole for male infertility is 1 mg 3 times a week, while the dose for letrozole is 2.5 mg also 3 times weekly. The most common adverse effects of these medications are joint pain and stiffness. Only 1 of these is required. See the companion StatPearls reference article on "Aromatase Inhibitors."[225]

Clomiphene is an antiestrogen and, in small doses (25 mg every other day up to 50 mg daily, with 25 mg daily being recommended most often), can increase gonadotropins (FSH and LH) and stimulate spermatogenesis, making it potentially useful in idiopathic cases of male infertility. It works by inhibiting the estradiol negative feedback response to the hypothalamus, which results in a higher release of LH, causing higher testosterone levels but also resulting in higher estradiol levels.[136] Most patients will notice an improvement in semen analyses in 3 months, but some will need 6 months or longer.[226] This benefit can be increased by adding tamoxifen (10 mg twice daily), which also acts as an estrogen receptor antagonist.[145][227][228] Clomiphene is also possibly helpful in hypogonadotropic hypogonadism, although there is limited data showing any significant improvement in pregnancy rates.[146][229] See the companion StatPearls reference article on "Clomiphene."[230]

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.[231] By selectively blocking hypothalamic estrogen receptors, tamoxifen stimulates GnRH secretion, greatly increasing FSH and LH levels and ultimately promoting spermatogenesis.[227][232][233] It is best used for idiopathic oligospermia as it tends to be most effective in boosting sperm count and concentration.[145][227][228][233] Motility, viability, and morphology may also improve, but generally not to the same degree.[227][228][233] In a trial, 68 infertile men 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, while adding folate increased motility, suggesting the 2 supplements are complementary when used together.[181] The recommended dose is 10 mg twice a day. See the companion StatPearls reference article on "Tamoxifen."[231]

Overview of Oral Therapies for Male Infertility 

Overall, there is a paucity of high-quality data to support definitively recommending any of these nutritional or antioxidant therapies. Most studies are low quality, small, short-term, fail to follow through to actual pregnancy rates, or lack an adequate control group, and few show consistent benefits.[234] Even where improved semen parameters and sperm quality can be documented, the pregnancy rate may not necessarily change.[235] 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.[236][237]

There are also some conflicting studies showing little to no benefit, although the majority generally support the use of supplements for idiopathic male infertility.[147] The optimal composition and dosages of the supplements have not been determined, and environmental factors have largely been excluded, making definitive conclusions difficult.[147] For all of these reasons, the European and American guidelines do not currently recommend supplements to treat male infertility.[147][238] 

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.[238] Where studies have actually been done, they are generally of poor quality.[238] 

While there is insufficient data to formally recommend antioxidant and nutritional therapy for mild to moderate male factor infertility, a clinical trial may not be unreasonable in selected couples. It is inexpensive, and adverse events are minimal to nonexistent. A trial also buys time for the couple to consider more costly options and provides psychological reassurance that their problem is being treated and not ignored. A pregnancy may develop naturally in the interim. Every clinician must decide individually whether or not to offer any of these tempting but still mostly unproven remedies. It is the rare physician who can deny a simple, harmless, inexpensive potential therapy to a desperate infertile couple, even if its actual clinical efficacy is currently unclear.[150][183][239][240][241][242] 

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.[238][243]

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, as most reported trials are of low quality, conflicting, or otherwise inadequate.[147][148][149][238][244][245] Researchers should collaborate to enlarge the sample size to minimize variations that are not controllable, select the most promising agents and dosages, utilize strict randomization protocols, and follow patients long enough to evaluate outcomes and endpoints that include live births.[246] An additional benefit would be the identification of patient subsets who would benefit from a particular nutraceutical or antioxidant therapy.[246][238]

Gonadotropic Therapy

The use of gonadotropin therapy in most men with idiopathic infertility is controversial. A meta-analysis of 6 randomized trials of gonadotropic therapy in male infertility patients reported higher pregnancy rates than the placebo group. Still, the overall quality of these studies was low, with highly variable treatment protocols and follow-up periods.[247] 

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.[248] 

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, GnRH, and human menopausal gonadotropin (HMG). HCG acts similarly to LH but is cheaper and has a longer half-life. HMG contains both FSH and LH and works similarly to GnRH.

For infertile men with idiopathic hypogonadotropic hypogonadism (IHH), the first step is usually to stop any exogenous testosterone supplementation. (While often used in symptomatic hypogonadal men, exogenous testosterone supplementation only worsens semen parameters and exacerbates their infertility by reducing FSH and LH.)[249][250][251][252]

Various combinations of HCG, FSH, GnRH, and HMG have been successfully used to treat male infertility in men with IHH. 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.[253] In 1 study, 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%.[252][254][255] It is suggested that such patients be referred to a reproductive endocrinologist.

Patients previously using testosterone supplementation can benefit from gonadotropic therapy as it appears to be beneficial.[256] While in the majority of such patients, spermatogenesis and fertility will eventually recover, it can take up to 2 years.[58] The average motile sperm count recovery is about 85% of previous levels before testosterone supplementation.[257] Older patients, those on testosterone therapy longer, and men with lower sperm counts before androgen replacement will not recover their fertility as quickly or to the same degree.[256][258] 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 where testosterone use has been prolonged (longer than 1 year.)[259][260] 

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. There is no standardized dosage or schedule. Optimal dosing of HCG has not been definitively determined. Still, it has been given by IM injections in doses of 3000 to 10,000 IU 2 to 3 times a week, along with either anastrozole, clomiphene, tamoxifen, or FSH, which is typically administered concomitantly.[256][261][262][263][264][265][266] 

SERMs work by inhibiting negative feedback by estrogen, which then raises GnRH and gonadotropin levels, increasing testicular production of testosterone and spermatogenesis.[55][230][256][261] While definitive comparative studies are not available, there are indications that clomiphene may be more effective than tamoxifen in promoting sperm recovery (70% vs 30%).[55] The dosage of clomiphene is 25mg every other day up to 50 mg daily.[230]

Sexual Disorders

Sexual intercourse during the most fertile period should be at least twice a week. Erectile dysfunction should be treated appropriately, and retrograde ejaculation generally responds to oral sympathomimetic drugs, although there is little data on its ultimate effectiveness in producing pregnancy in infertile couples.[267][268] See the companion StatPearls reference article on "Erectile Dysfunction."[214]

Premature ejaculation is highly treatable with a combination of behavioral, psychological (sex therapy), and pharmacological interventions.[269] See the companion StatPearls reference article on "Premature Ejaculation."[269]

Ejaculatory Duct Cyst Puncture or Resection

Midline prostatic and ejaculatory duct cysts are present in about 5% of all infertile men.[270][271] 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 and/or vas deferens on TRUS examinations.[272][273] To be clinically significant, it's been suggested that the cysts need to be >0.017 mL in size and are typically identified from a TRUS.

The cysts can be treated either with transurethral resection or by cyst puncture with aspiration using TRUS.[274] Transurethral resection is considered the most definitive therapy for this condition. Improvement in semen analysis is generally seen in about 50% of treated infertile men, and about half of these will eventually produce a pregnancy.[272][273][275]

Varicocelectomy

Varicocele repairs are generally only recommended in infertile men with abnormal semen parameters who have large, clinical grade 3 varicoceles.[243]  Essentially, these are the varicoceles that 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 <3 mm) are not likely to benefit from varicocelectomy, but this is somewhat controversial.[76][243][276][277] 

Overall, varicocelectomy is expected to ultimately improve semen parameters in at least 60% to 70% of patients with clinically significant varicoceles. A recent, comprehensive meta-analysis demonstrated that all significant standard sperm characteristics in infertile men with significant varicoceles improved after varicocele surgery.[278] While there is data to support an improved pregnancy rate in men after varicocele surgery, the evidence is somewhat conflicting.[73][279][280] 

Varicocele surgery is not recommended in men with extremely low sperm counts (severe oligozoospermia or azoospermia) or high FSH concentrations with bilateral small testes as these features suggest extensive testicular germ cell damage, making it unlikely they will see any improvement in their fertility potential.[243] It remains unclear if men with a clinically significant varicocele who have nonobstructive azoospermia would benefit from a surgical varicocele repair before ART.[243] 

Recent studies have suggested that subclinical varicoceles may sometimes impact semen characteristics based on testicular size and intratesticular hemodynamics rather than varicocele size, palpability, or vein diameter.[188][276][281][282] 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.[188][276][281][282]

A high resistive index and lower end-diastolic and peak systolic velocities would suggest decreased intratesticular vascular flow, which could prove to be more significant than clinical varicocele size alone. If these findings are confirmed, testicular volume determinations and ultrasonic measurements of intratesticular hemodynamics may ultimately be a better predictor of improved sperm parameters and fertility from varicocele surgery in infertile men than the simple determination of finding 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 and comprehensive discussion of the pros and cons of surgery with the patient and family is still the best advice for helping 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. This 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 finger using an O'Connor drape may help perform the procedure safely. Afterward, there is a potential for epididymitis from reflux.

Vasovasostomy and Vasoepididymostomy

These are advanced microsurgical procedures performed on men with obstructive azoospermia due to bilateral epididymal or vasal obstruction. This may be obvious in a patient who had a bilateral vasectomy surgery, but in others, obstructive azoospermia is suggested by the finding of no sperm in the semen, together with the 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, a shorter time period from the original obstructive surgery or injury, finding sperm at the time of vasovasostomy (especially if found bilaterally), and if the nature of the original obstructive event was surgical rather than infectious.

Even after successful surgery, 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.[283] Men with increased FSH levels may require additional ART to achieve a pregnancy even after successful surgery.[284]

Varicocele repairs and vasovasostomies should never be done simultaneously due to the potential risk of vascular compromise to the testicle, causing atrophy. Robotic-assisted vasovasostomy can be done in selected cases with similar overall pregnancy rates of about 60%.[285][286]

Intrauterine Insemination 

This 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. It is most useful when the postcoital test shows no sperm but may also be used in cases of idiopathic infertility or when there are significant abnormal sperm parameters but still some normal spermatozoa. It avoids potential vaginal allergic responses and toxic cervical mucus. The overall pregnancy success rate is only 4% if used alone. Still, when combined with female superovulation (produced by the use of 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 as more attempts are made. 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.[287] 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 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 done.[288]

IUI techniques should not be used when the sperm are dead (as determined by a positive hypoosmotic swelling test or sperm vitality staining). Abnormal functional sperm tests (such as capacitation, acrosomal reaction, and sperm penetration assays) would suggest that IVF with ICSI should be used instead.

The semen can be processed in various ways to collect only the high motility, normal morphology sperm. The semen is washed to remove dead cells, leaving healthy sperm, which are concentrated for the insemination. If the male 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) x Sperm Motility (%) x Semen Volume (mL).[289][290][291]

While less reliable than ICSI outlined below, IUI is far less expensive, so it can be easily repeated and may be optimal where there is no female factor present and the male's semen and sperm count/quality are acceptable. 

In Vitro Fertilization and Intracytoplasmic Sperm Injection

IVF 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.[287] IVF involves the fertilization of the female egg outside of her body. About 100,000 sperm are added to each egg in a special medium. (It does not appear to make any difference if the sperm used for ICSI is from ejaculated semen or direct microdissection testicular sperm extraction [TESE], as there is no significant variation in either miscarriages or live birth rates.)[292] 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.[243][293][294] Both fresh and cryopreserved sperm may be used.[243][295]

Patients with retrograde ejaculation may require sympathomimetic medications, urinary alkalinization, urethral catheterization, induced ejaculation techniques, or TESE for sperm acquisition.[243] Sperm retrieval techniques for men with aspermia include induced ejaculation (sympathomimetic stimulation, vibratory effects, or electroejaculation), as well as surgical sperm extraction with TESE.[243]

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%.

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 into the uterus of the female partner. The overall fertilization rate of ICSI is about 60%, with an initial pregnancy rate of about 20% to 30% per cycle.[296] This rate increases by up to 45% for multiple cycles.[296] Multiple fetuses occur in about 30% to 40% of all pregnancies produced by IVF with ICSI.[297][298] See the companion StatPearls reference article on "Assisted Reproductive Technology (ART) Techniques" and "In-Vitro Fertilization."[298][299]

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. It is also reasonable when all other treatments have failed. The only male contraindications to the procedure are the absence of retrievable, viable sperm and necrospermia, which, fortunately, is quite rare.

Differential Diagnosis

There are multiple conditions and disorders that can cause or contribute to male infertility. The differential diagnosis of male infertility includes the following:

• Adult growth hormone deficiency 
• 5-Alpha 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 (32-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
• Follicle-stimulating hormonal (FSH) abnormalities 
• FSH receptor gene mutation
• Hemochromatosis 
• HIV infections (causes low sperm motility) 
• Hodgkin lymphoma (due to the need for extensive chemotherapy)
• Human beta-defensin abnormalities
• Hypogonadism
• Hypogonadotropic hypogonadism
• Hypopituitarism 
• Immotile cilia syndrome
• Kallmann syndrome
• Kartagener syndrome
• Klinefelter syndrome
• Lead exposure
• Leprosy
• Liver failure
• Luteinizing hormone (LH) deficiency 
• Marijuana associated disorders
• Mixed gonadal dysgenesis
• Mumps
• Myotonic dystrophy
• Noonan syndrome (male Turner syndrome) 
• Obesity
• Opioid abuse
• Pesticide, fungicide, and chemical exposure
• Pituitary adenomas, prolactinomas
• Primary hypogonadism 
• Prostate and pelvic surgery
• Radiation exposure (Sertoli and sperm cells are much more sensitive than Leydig cells)
• Recurrent urinary tract infections  
• Reifenstien syndrome (partial androgen insensitivity)
• Renal failure
• Sarcoidosis
• Seminomatous and non-seminomatous 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 diseases (STDs)
• 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 upon the cause. An appropriate workup should be done based on need and necessity. Such investigations must happen after a frank discussion with the patient, as it has financial and psychological implications. Following an appropriate workup, reasonably selected treatments, counseling, surgery, 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.[4]

Complications

Complications are typically due to psychological distress, stress, and issues with the marital relationship. There may also be financial issues. Evaluation and treatment of infertility can be expensive in the U.S. and frustrating since there are no guarantees of success, and insurance does not typically cover this condition. There is also the chance for complications related to any surgical procedures required.

Consultations

Physicians dealing with 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. It can be a stressful and challenging time for them, especially if there is family pressure to conceive, which can be quite intense in some cultures. Counseling may be needed, given infertility is frequently associated with psychological distress, sometimes severe. This 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 (CDC), no evidence exists 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 toward seeking medical assistance. By empowering individuals with knowledge, clinicians contribute to the deterrence of 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:

• It is important to examine men for suspected urogenital abnormalities when the couple is diagnosed with fertility problems and particularly when there is an abnormal semen analysis.

• A hormonal screening (testosterone, FSH, TSH LH, estradiol, and prolactin) is necessary whenever an abnormal semen analysis is present in a male infertility patient.

• A minimum of 2 semen analyses, optimally 1 month apart, is recommended before making any conclusions regarding male infertility or semen/sperm quality.

• It is imperative that both partners 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 (<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, 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.[300][301] 

• 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.[300]

• Men interested in preserving their future fertility should generally not be treated with testosterone supplementation alone. Clomiphene can help preserve sperm production when used together with testosterone therapy.

• Bilateral absence of the vas on clinical examination suggests a cystic fibrosis transmembrane conductance regulator (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 post-ejaculatory urinalysis.

• Suspect testosterone abuse in muscular men with small testes bilaterally.

• An elevated estradiol level and/or a testosterone/estradiol (T/E) ratio <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.[302] Suspect possible Klinefelter syndrome, especially if associated with hypogonadism.[303]

Men who are anticipating either chemotherapy or radiation treatment should discuss fertility issues with their physicians before starting therapy. Sperm banking is encouraged in such situations. Attempting a pregnancy should be avoided for at least 1 year (optimally 2 years) after completing such gonadotoxic therapy.[243]

A genetic analysis of almost 2000 infertile men with azoospermia and significant oligozoospermia showed that 9% had chromosomal abnormalities and about 10.5% had an AZF microdeletion.[304] This evidence suggests that genetic analysis may play a significant role in the evaluation and treatment of infertile men.[304]

It may not be unreasonable to suggest that a couple with a male infertility factor consider a trial of treatment with 1 of the "unproven" therapies if no better treatment alternative is immediately available. This will 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).[238][244] Such treatments should be presented as possible fertility aides for which there may be some limited evidence or expectation of efficacy but no proof.[238] The couple should be informed of the available data and allowed to decide for themselves. They should not be given unrealistic expectations about the proven efficacy of any of these remedies.[244]

It is essential to know where to refer infertile couples in the community for reproductive endocrinology assistance, as well as ART and IVF with ICSI. It is helpful to inform patients of the expected estimated cost of these services. 

Do not be afraid 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 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 be performed, which should include testosterone, FSH, LH, estradiol, and prolactin. A TSH level can be added.
• Consider a scrotal ultrasound.
• Genetic screening is recommended for patients with severe oligozoospermia (<5 million sperm/mL). This 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 any apparent cause, consider discussing some of the optional treatments as noted earlier and summarized below. 
• An example of a patient handout (below) can help couples determine if 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 failed to conceive a child. It takes at least 1 year of adequate, unprotected sexual intercourse before a couple is considered medically infertile. We know that a contributing male factor will be 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 male infertility patients cannot be successfully treated by simple remedies and will ultimately require some degree of assisted reproduction, which can be quite costly.

It should be pointed out that some infertile couples will be able to conceive a child even without treatment. About 23% of such couples will conceive after 2 years without getting any treatment.

Couples should be informed about some of the somewhat less orthodox or unofficial oral treatments available for male infertility for which there is only incomplete, anecdotal, inadequate, or conflicting data supporting their use, making it difficult for physicians 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 doctor 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, as this will significantly decrease sperm counts and worsen their infertility. Discuss this thoroughly with your physician before discontinuing any prescribed medication.

Patients should already have had at least 2 semen analyses showing some mild to moderate problems with sperm count, concentration, maturity, motility (activity), or morphology (normal vs abnormal sperm). Men with severe defects in any of these parameters will not likely benefit from the optional remedies discussed here. They should speak with their physicians about assisted reproduction techniques and other treatment options.

Those with relatively mild sperm defects might benefit from trying 1 or more of the treatments mentioned. None are specifically recommended or officially approved for male infertility, but there is at least some evidence of a benefit 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. As of yet, there is no consensus or recommendation as to which of these is the most effective or the optimal dosage. Given their low cost and lack of any adverse effects, they should probably be considered part of the treatment regimen for every male infertility patient. 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/Anti-Estrogens (Anastrozole and Letrozole)

Aromatase inhibitors are medications that block the conversion of various hormones, including testosterone, to estrogen compounds. They are usually used to reduce the estrogen effect in women but have shown beneficial activity in male infertility as well. They are considered the treatment of choice for infertile males 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 a week, while the dose of letrozole is 2.5 mg 3 times a week. Only 1 of these is needed. The most common side effects reported with these medications are joint pain and stiffness. The estimated monthly cost for either of these drugs is about $10, and a prescription is required. 

Clomiphene

Clomiphene is an anti-estrogen drug that is primarily used as a fertility-enhancing drug for women, as men typically produce only a minimal amount of estrogen. There is evidence that, in low doses, clomiphene can increase male fertility hormones (FSH and LH) and stimulate sperm production by lowering estrogen levels. It may also be useful in some hypogonadal, infertile men with low testosterone levels. The recommended dose for infertile men is 25 mg daily. Possible side 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, non-toxic general therapy for male infertility. It increases sperm motility, morphology, and maturity. A 6-month trial is suggested using a daily dose of 3 grams daily. Since it is an amino acid, its use is extremely safe. The estimated monthly cost is about $30; no prescription is required.

N-Acetyl Cysteine

N-acetyl cysteine is an amino acid derivative with significant antioxidant properties. It 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 it is undergoing an FDA review since it was once a prescription medication. The estimated monthly cost is $10-$15.

Tamoxifen

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

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

• Coenzyme Q10: 300 mg daily
• Folic acid: 500 mcg-1000 mcg daily
• L-Carnitine: 3 grams (1000 mg TID or 1500 mg BID) daily
• N-acetyl cysteine: 600 mg-1200 mg daily
• Selenium: 200 mcg daily
• Vitamin C: 500 mg BID
• Vitamin D: 5000 units daily
• Vitamin E: 400 units daily
• Zinc: 200 mg daily

Anti-Estrogen 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 BID

Enhancing Healthcare Team Outcomes

Effective care for male infertility necessitates a multidisciplinary approach involving various healthcare professionals. Physicians, 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.

It is recommended that primary care clinicians initiate the evaluation of infertility by identifying the problem early and making the appropriate referrals. It is also prudent to provide genetic counseling to couples with an abnormality in the clinical or genetic investigation or those who carry a potentially inheritable disease.

Though many of the causes of male infertility are due to spermatogenesis failure, some are medically treatable. This problem has significant psychological, social, emotional, and health effects on the couple and their families. The barriers from stigmas associated with infertility arising due to religious and cultural beliefs should be considered and reduced where possible.

A strategic collaboration is essential, with each professional contributing their specialized knowledge to formulate personalized treatment plans. 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 and patient-centered approach enhances outcomes, patient safety, and overall team performance in the management of male infertility.

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Disclosure: Stephen Leslie declares no relevant financial relationships with ineligible companies.

Disclosure: Taylor Soon-Sutton declares no relevant financial relationships with ineligible companies.

Disclosure: Moien AB Khan declares no relevant financial relationships with ineligible companies.